SEMISOLID

TOPICAL DOSAGE FORM

HANDBOOK

OF

PHARMACEUTICAL

GENERIC DEVELOPMENT

S E M I
S OLIDS
VOLUME III - Part One
Generic Development Topical Dosage Forms

HANDBOOK OF PHARMACEUTICAL
GENERIC DEVELOPMENT
Handbook of Pharmaceutical
Generic Development 24 Volume Series
Handbook of Pharmaceutical

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Generic Development

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Handbook of Pharmaceutical
Generic Development Series
Compiled by :

J. D. BLOCK
BSc. MPS. D/PHARM.
Research Director Generic & Innovative Drug Development Division, Locum International Group.
Science Editor - International Journal of Generic Drugs & International Journal of Drug Development
School of Pharmacy University of the Witwatersrand and Witwatersrand Technikon
Johannesburg RSA.

Edited:
IAGIM Scientific Committee
Review Process :
Generic & Innovative Drug Development Division
Research Center
Locum International Research

Handbook of Pharmaceutical Generic Development

Vol. 1 - Tablets

Part I (Development) & Part II (Model ANDA or EU Dossier)

Handbook of Pharmaceutical Generic Development

Vol. 2 - Capsules

Part I (Development) & Part II (Model ANDA or EU Dossier)

Handbook of Pharmaceutical Generic Development

Vol. 3 - Semisolids

Part I (Development) & Part II (Model ANDA or EU Dossier)

Handbook of Pharmaceutical Generic Development

Vol. 4 - Liquids

Part I (Development) & Part II (Model ANDA or EU Dossier)

Handbook of Pharmaceutical Generic Development

Vol. 5 - SG Capsules

Part I (Development) & Part II (Model ANDA or EU Dossier)

Handbook of Pharmaceutical Generic Development

Vol. 6 - e-SOPs / SOPs.

Part I (Development) & Part II (Model ANDA or EU Dossier)

Handbook of Pharmaceutical Generic Development

Vol. 7 - Suspensions

Part I (Development) & Part II (Model ANDA or EU Dossier)

Handbook of Pharmaceutical Generic Development

Vol. 8 - Eye & Nose

Part I (Development) & Part II (Model ANDA or EU Dossier)

Handbook of Pharmaceutical Generic Development

Vol. 9 - Aerosols MDI

Part I (Development) & Part II (Model ANDA or EU Dossier)

Handbook of Pharmaceutical Generic Development

Vol. 10 -Tablets CR/MR

Part I (Development) & Part II (Model ANDA or EU Dossier)

Handbook of Pharmaceutical Generic Development

Vol. 11 -Capsules ER

Part I (Development) & Part II (Model ANDA or EU Dossier)

Handbook of Pharmaceutical Generic Development
Handbook of Pharmaceutical Generic Development
Part I (Method Validation) & Part II (Analytical Methods 1994-2003)

Handbook of Pharmaceutical Innovative Development
Handbook of Pharmaceutical Innovative Development
Handbook of Pharmaceutical Innovative Development
Handbook of Pharmaceutical Drug Development (1-5)

Vol. 12 - Tablets Oral DR
Vol. 13 - Analytical
(Top 50 Generic Assay Methods)

Vol. 14 - Tablets Oral
Vol. 15 - Capsules Oral
Vol. 16 - Suspensions Oral
Vol. 17 - MF and MMI

(Master Formula & Manufacturing Instructions Parts 1 - 5)

Handbook of Pharmaceutical Drug Development (6-10)

Vol. 18 - MF and MMI

(Master Formula & Manufacturing Instructions Parts 6 - 10)

Handbook of Pharmaceutical Innovative Development

Vol. 19 - SOPs/PAI-Checklist

Part I, Part II & Part III.(Development, Manufacturing & Engineering)

Handbook of Pharmaceutical Drug Development

Vol. 20 - Sterile Injections

Available either on Online, CD ROM or via electronic mail attachment.
Additional Drug Specific Volumes in Preparation. An on-going electronic and print series

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Electronic < Handbook Series of
Pharmaceutical Generic Development
ISSN 0793 8667 - Electronic Version
Handbook Development 24 Volume Series
ISSN Series Number 0793 761X - Electronic Version

Handbook of Pharmaceutical Generic Development

Vol. 1 - Tablets

Part I (Development) & Part II (Model ANDA or EU Dossier)

Handbook of Pharmaceutical Generic Development

Vol. 2 - Capsules

Part I (Development) & Part II (Model ANDA or EU Dossier)

Handbook of Pharmaceutical Generic Development

Vol. 3 - Semisolids

Part I (Development) & Part II (Model ANDA or EU Dossier)

Handbook of Pharmaceutical Generic Development

Vol. 4 - Liquids

Part I (Development) & Part II (Model ANDA or EU Dossier)

Handbook of Pharmaceutical Generic Development

Vol. 5 - SG Capsules

Part I (Development) & Part II (Model ANDA or EU Dossier)

Handbook of Pharmaceutical Generic Development

Vol. 6 - e-SOPs / SOPs.

Part I (Development) & Part II (Model ANDA or EU Dossier)

Handbook of Pharmaceutical Generic Development

Vol. 7 - Suspensions

Part I (Development) & Part II (Model ANDA or EU Dossier)

Handbook of Pharmaceutical Generic Development

Vol. 8 - Eye & Nose

Part I (Development) & Part II (Model ANDA or EU Dossier)

Handbook of Pharmaceutical Generic Development

Vol. 9 - Aerosols MDI

Part I (Development) & Part II (Model ANDA or EU Dossier)

Handbook of Pharmaceutical Generic Development

Vol. 10 -Tablets CR/MR

Part I (Development) & Part II (Model ANDA or EU Dossier)

Handbook of Pharmaceutical Generic Development

Vol. 11 -Capsules ER

Part I (Development) & Part II (Model ANDA or EU Dossier)

Handbook of Pharmaceutical Innovative Development

Vol. 12 - Semisolids

Handbook of Pharmaceutical Generic Development

Vol. 13 - Analytical

Part I (Method Validation) & Part II (Analytical Methods 1994-2003)

(Top 50 Generic Assay Methods)

Handbook of Pharmaceutical Innovative Development

Vol. 14 - Tablets Oral DR

Handbook of Pharmaceutical Innovative Development

Vol. 15 - Suspensions Oral

Handbook of Pharmaceutical Innovative Development
Handbook of Pharmaceutical Innovative Development
Handbook of Pharmaceutical Innovative Development
Handbook of Pharmaceutical Innovative Development

Vol. 16 - Capsules Oral
Vol. 17 - Master Formula
Vol. 18 - Master processes
Vol. 19 - SOPs/PAI-Checklist

Part I, Part II & Part III.(Development, Manufacturing & Engineering)
Available either on Online, CD ROM or via electronic mail attachment.
Additional Drug Specific Volumes in Preparation An on-going electronic and print series

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Generic Development

SEMISOLID

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HANDBOOK OF
PHARMACEUTICAL
GENERIC DEVELOPMENT

Semisolid

TOPICAL DOSAGE FORM
VOLUME III
SEMISOLID

-

Part ONE

DOSAGE

F O R M

Jeremy D. Block
B.Sc. MPS. D/Pharm.

International Euro Edition.
L O C U M
P U B L I S H I N G
H O U S E
handbooks@locumUSA.com / handbooks@locumEURO.com
Locum Publishing House - Israel Locum Pharmaceutical Publishers - USA Locum International Publishers - Cape Town

Handbook of Pharmaceutical

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Generic Development

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Handbook of
Pharmaceutical
G e n e r i c
Development

Innovative Series

Part

One

Semi

s olids

DRUG Development

Copyright © 1994-00 - Locum Publishing
House Inc.

All Rights Reserved.

Neither this book nor any part may be
reproduced or transmitted in any form or
by any means, electronic or mechanical,
including photocopying, microfilming and
recording, or by any information storage
and retrieval system,
without the
permission of the publishers.
Locum International

Publishers

Handbook of Pharmaceutical

A

L o c u m

H o u s e

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http://www.l o c u m u s a . c o m

P u b l i c a t i o n

Generic Development

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HPDD Innovative Series

- Semisolid Dosage Forms

First and Second International Edition - 01/02.
First and Second edition published and distributed in UK, US, EU, RSA, Israel and Japan in
November 1996-9: by Locum International Publishing House (Houston, Israel, South Africa).
Third International Edition - 03 (First Print).
Second printing published and distributed in UK, US, EU, Israel, Asia, and Japan in
February 2000 by Locum International Publishing House (Houston, Israel, South Africa) in
Hard Cover; Soft and Spiral Cover; Electronic Diskette; and e-mail attachment versions. All
print and electronic versions identical in content and format.
Copyright © 1995 - 2000, Handbook of Pharmaceutical Generic Development.
Text Copyright © 1995 - 2000, Handbook of Pharmaceutical Generic Development.
Illustration copyright © 1995 - 2000, Handbook of Pharmaceutical Generic Development.
Locum International Publishing House PO Box 874, 50 Gilad Street Kochav Yair 44864
Israel. - All right reserved.

ISBN 0793 873X
ISBN 0793 8748 - Electronic Version (Diskette, CD ROM, and Online version)
Handbook Development 24 volume series.
General ISSN Series number 0793 7407
General ISSN Series number 0793 7792 - Electronic Issue (Diskette, CD ROM and
Online version are identical in size and content to the printed hard or soft cover
version.)
Duplication: No part of this publication may be reproduced, stored in a retrieval
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Generic Development

SEMISOLID

TOPICAL DOSAGE FORM

EDITORIAL PREFACE

Handbook of Generic Drug Development - Semisolid Dosage Forms

T

his handbook represents the third International Edition for Europe of the ongoing
24 volume series of Generic Drug Development and appears under the
cumulative title of the Handbook series of Generic Drug Development. The ongoing
series is updated annually at the end of each year. This is an ongoing process as
new data, specifications and process techniques are added on a continual and
expanding basis. This handbook is fact, never fully complete, as each new annual
edition brings an enlarged and extended profile in the drug development process, as
well as new agency rules, guidelines and guidance to industry which continue to be
added year by year as the global product data base expands. Currently over 150
scientific publications and drug development conferences are annually referenced in
the 24 volume Handbook series of Generic Drug Development.
This mammoth task presents a continual ongoing commitment by the scientific
review committee to the improvement of the technical databases and the product
specific drug development requirements and know-how technology accessed
through the world wide IAGIM joint ventures and know-how projects currently active
in over 15 countries.
The Handbook is available in electronic format (Online and CD ROM) and the eformat is up-dated annually to association members of IAGIM.

This third international edition of the Handbook has been redesigned and updated
to meet the January 1999 Guidance for Industry - Organization of an Abbreviated
New Drug Application and an Abbreviated Antibiotic Application as well as all current
approved and draft FDA guideline requirements of the Center of Drug Evaluation
and Research (CDER) up to June 2000.
Editor-in-Chief.

ISSN 0793 873X

An on-going series
Additional Volumes in Preparation

General Series ISSN
0793 7407
Electronic Series ISSN 0793 7792

0793 7407
International Print Edition

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LOCUM

ppp

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Generic Development

SEMISOLID

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Acknowledgments
I.A.G.I.M. (R&D) Foundation.

I.A.G.I.M. Members (1994 - 2000).
Contributions - Generic & Research Firms
Associate Universities, Technicons and Consultants.
Handbook Series Coordinating Committee.
International Journal of Drug Development.
Journal of Pharmaceutical Development.
International Journal of Generic Drugs.
I.A.G.I.M. Drug Development Archives
Locum International Archives.
FDA/OGD/CDER Maryland
Guides and Guidelines
Library of Congress.
AIC Conferences.
Editorial Board.
Pharm. Eur.
USP/NF.
USPC.
BP.
°

To Doribelle
for her years of support and help
to Sean for his expert knowledge on computerization
to David and Ari for running the project's computers
and lastly to Pat for his inestimable
contribution.

Third International Edition.
2000

L O C U M

P U B L I S H I N G

Í

°Î

Í

°Î

Ï

Handbook of Pharmaceutical

H O U S E

Ð

handbooks@locumusa.com
http://www.l o c u m u s a . c o m

Generic Development

CONTENTS.

Contents
PHARMACEUTICAL

DEVELOPMENT

Table of Contents
Acronyms - Abbreviations
Introduction
Preface
Forward

Chapter

VIII
XIII
XVI
XV
XVI

1

Regulatory
- Pre-formulation checklist
Documentation
- SOP Control checklist
Development Notebooks
- Development Notebooks checklist
- SOP Control and Development Notebooks SOPs

Chapter

2

Developing the Formula -an Overview
- Formulation checklist
- Formula Development
Drug Development Checklist
Development formula SOPs
Developing the Formula
Purified Water - an ingredient
Product Development Guide

Chapter

1.1
1.2
1.3
1.4
1.5
1.6
1.7

2.1
2.2
2.3
2.4
2.5
2.7
2.12
2.19

3

Active Ingredients
-Do’s and Don’ts
-Active checklist - Approved suppliers
-Active checklist timeline
-Standard Operating Procedures, actives
-Active Ingredients - Approved suppliers SOP

Handbook of Pharmaceutical Generic Development
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3.1
3.2
3.4
3.5
3.6
3.7

24 Volume Drug Development Series
handbooks@locumeuro.com

CONTENTS.

Contents
Chapter

4

Semi active ingredients
-Validating the semi active ingredients, checklist
Non active materials (excipients)
-checklist non active ingredient
Standard Operating Procedures, Non actives
Qualifying the semiactives
Semi active Tabulations
Qualifying of the antioxidant
The Reference Listed Drug

Chapter

5

Container closure systems
-Container-liner-closure systems, Checklist
-Container-liner-closure systems, SOPs
-Container-liner-closure systems - Flowchart

Chapter

- Manufacturing Instructions; Checklist
- The Manufacturing Instructions and Controls
- The Manufacturing Process
- The Manufacturing Flow Charts
- The Manufacturing Controls
- Packaging Operation

6.1
6.2
6.5
6.9
6.16
6.21
6.25

7

In-process Quality Controls
-Manufacturing in-process controls; Checklist
-Manufacturing in-process controls; What to Validate?
-In-process Quality Controls; SOPs

Chapter

5.1
5.2
5.5
5.8

6

Manufacturing Instructions

Chapter

4.1
4.2
4.3
4.4
4.5
4.6
4.7
4.11
4.14

7.1
7.2
7.4
7.5

8

Finished Product Specifications
- Finished Product Specifications; checklist
- Glossary of Terms and Specifications
- Finished Product Specifications; SOPs
Handbook of Pharmaceutical Generic Development
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8.1
8.3
8.4
8.7
24 Volume Drug Development Series
handbooks@locumeuro.com

CONTENTS.

Contents
Chapter

9

Process Optimization
Qualification of Antioxidant and Preservatives
Qualification of finished Product Specification
Qualification of antioxidant and chelating Agent Limits
Optimization - Stability Studies

Chapter

10

Scale-up procedures
- Re-mixing & Processing Times
- Scale-up procedures; checklist
- Scale-up procedures; SOPs

Chapter

Cleaning Limits Procedures; Checklist
Cleaning Validation Requirements; SOPs

11.1
11.6
11.7

12

Analytical Validation Requirements
-Analytical Testing Out of Specification
-Analytical Testing Do's and Don'ts
-Ruggedness and Robustness
Analytical Validation Agency Guidelines

Chapter

10.1
10.3
10.4
10.5

11

Cleaning Limits

Chapter

9.1
9.2
9.3
9.5
9.8

12.1
12.21
12.23
12.27
12.31

13

Process Qualification Batch
-Process Qualification Batch; Checklist
-Process Qualification Batch; SOPs
-Process Qualification - Sampling Bias
-Process Qualification Sampling - Do's and Don'ts
-Process Qualification Protocol

Handbook of Pharmaceutical Generic Development
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13.1
13.2
13.3
13.4
13.6
13.8

24 Volume Drug Development Series
handbooks@locumeuro.com

CONTENTS.

Contents
Chapter

14

Pivotal batch
-The Pivotal Batch
-Pivotal batch Checklist
-Pivotal batch SOPs
-Sampling and Testing the Pivotal Batch
-Auditing the Pivotal batch
-Auditing the Pivotal batch Checklist

Chapter

14.1
14.2
14.3
14.5
14.10
14.11

15

Bioequivalence vs. RLD

15.1
15.2
154.
15.7
15.9

Topical Bioequivalence
Biostudy Graphs (Standard)
Diffusion Testing
SUPAC SS*

Chapter

16

Technical Transfer Documentation
-Technical Transfer Documentation; Checklist
-Technical Transfer Documentation; Pharmaceutical Part
-Technical Transfer Documentation; Analytical Part

Chapter

17

Process Validation batches
-The Process Validation Batches; Checklist
-Process Validation Requirements; SOPs
-Process Validation Master Plan
-Process Optimization Master Plan

Chapter

16.1
16.5
16.7
16.10

17.1
17.3
17.4
17.5
17.8

18

Pre--Approval Inspections
Pre--Approval Summary Audit
Pre--Approval Team Set-Up
Pre--Approval Team Audit Activities

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18.1
18.8
18.9
18.11

24 Volume Drug Development Series
handbooks@locumeuro.com

CONTENTS.

Contents
Chapter

19

Stability Testing of Drug Substance and Drug Product I
Stability Testing of Drug Substance and Drug Product II
Stability Testing of Drug Substance and Drug Product II
Stability Testing Significant Change
Storage Conditions
Setting up a functional Stability Unit
Stability SOPs Development

Chapter

19.1
19.15
19.21
19.24
19.29
19.31
19.39

20

Development SOPs
Index of Pharmaceutical Standard Operating Procedures
Index of Analytical Standard Operating Procedures
Index of Microbiological Standard Operating Procedures
Index of Stability Standard Operating Procedures

Ready-To-Go™ Drug Development Series

20.1
20.5
20.9
20.16
20.21
20.27

ISSN 0793 873X

An on-going series
Additional Volumes in Preparation

Handbook of Pharmaceutical
Generic Development Series
ISSN 0793 8748 - Electronic Versions
Handbook Development 24 Volume Series
Series ISSN Number 0793 7792 - Electronic Version

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24 Volume Drug Development Series
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CONTENTS.

DRUG DEVELOPMENT

Hand?20@&?00@Books
Drug Development & M anufacture for Pharmaceutical Technology Professions

H P G D

Handbook of Pharmaceutical Generic Development

Drug Development - Part I
ANDA™ - Part II
© Copyright 1995 -2000 Locum International Ltd.

2000 Update Program
Part I and Part II: HandBook Generic Development Series
þ Volume 1
Edition 03 - 2000
þ Volume 2
Edition 03 - 2000
þ Volume 3
Edition 03 - 2000
þ Volume 4
Edition 03 - 2000
ý Volume 5 Edition 03 - 2000
þ Volume 6 Edition 03 - 2000
þ Volume 7
Edition 03 - 2000
þ Volume 8
Edition 03 - 2000

Initiation Date :
Expiration Date :
No of Years
:
Update Period :

þ Volume 9 Edition 03 - 2000
þ Volume 10 Edition 03 - 2000
þ Volume 11 Edition 03 - 2000
þ Volume 12 Edition 03 - 2000
þ Volume 13 Edition 03 - 2000
þ Volume 14 Edition 03 - 2000
þ Volume 15 Edition 03 - 2000
þ Volume 16 Edition 03 - 2000

January 2000
January 2003
Three (3)
January 2000; to January 2003.

This ANDA Drug Registration program has been updated to January 2000 Office of Generic Drugs
requirements. Handbook clients requiring to continue this annual service need only to become
members of I.A.G.I.M. for the period of the update service required by the firm.
The ANDA Update Program is renewed in December each year as a function of the firms
requirements.
Warning: Copyright © 1985 -2000 Locum Publishing House Inc. - All Rights Reserved.
Neither this information nor any part of the data contained therein may be reproduced, copied or transmitted in
any form, modification or merged portion or by any means, electronic or mechanical, including printing
photocopying, microfilming and recording, or by any information storage and retrieval system, without the prior
written permission of the publishers. ™ Trademark - Locum Corporation, ™ Locum International Group

handbooks@locumusa.com
(See web site for IAGIM Membership Benefits / Application Forms and additional details)
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Handbook of Pharmaceutical Generic Development
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24 Volume Drug Development Series
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SEMISOLIDS

Introduction

Introduction
T

he purpose of the Handbook Series is to illustrate generic drug development from preformulation to regulatory submission. The Handbook Series on pharmaceutical dosage
forms deals with the US generic drug development process of the ANDA (Abbreviated
New Drug Application). It is equally suitable to the innovative drug development process
for the Chemistry-Manufacturing-Controls (CMC) Section of an New Drug Application (NDA).

Each book is devoted to a specific dosage form e.g. tablets, capsules, liquids, topical semi
solids, suspensions, aerosols and so forth. This is an ongoing series that is reviewed and
updated twice annually, as new agency regulations, guides, guidelines and industry
procedures are adopted or regulated.

The Handbook is a basic hands-on working approach to generic drug development and the
overall developmental process. The book ends with the requirements for manufacturing the
first three commercial product lots for distribution and marketing.
Each Handbook is presented in two volumes referred to as Part One and Part Two. These two
parts are supplementary and should be used and referenced together as they complement
each other. Electronic templates for the full registration process are available for each dosage
form. These approximate +300 templates consist of electronically completed ANDA data where
only the variable facts and figures need to be inserted into the prepared data fields.

Part One covers the development topics from pre-formulation of generic ANDAs to final FDA
filing with the Office of Generic Drugs. Each chapter details key development steps coupled
with a hands-on development checklists that dovetails with a series of SOPs on practical
generic issues that the FDA review chemists and inspectors routinely address during an ANDA
file review and during pre-approval site inspections (PAIs).
Agency site inspections routinely cover the product development unit or R&D departments,
QC and Analytical Research laboratories, as well as the manufacturing facilities and
production warehouses. During a product-specific pre-approval inspection there is a
concentration of effort by the inspectorate to thoroughly review and evaluate the drug
development process from pre-formulation to pivotal batch.

Topics covered are real life examples from A (actives) to V (validation). Procedures are kept
as simple as possible in order that the checklists and SOPs can be understood by all
departmental personnel concerned. Repetition in the checklists and SOP is routinely used to
emphasize essential procedures or requirements and to restate the aims and objective in a
tutorial manner. Thus the checklist becomes a first party audit or self-inspection format for the
Standard Operating Procedures.

Part Two is a complete real-life dosage form specific working model of a US Generic
Application or commonly known as an Abbreviated New Drug Application (ANDA).

Part THREE is a complete real-life dosage form specific working model of a EU Dossier +
Expert Report (the Electronic Handbook exhibits a unique Expert Report Compiler)

3
Handbook of Pharmaceutical

xiv

Generic Development

SEMISOLIDS

Introduction

Preface
“… getting a generic drug to the market place on time….”

G

etting a generic drug to the market place at the right time is no easy task. The
generic drug product must be approved by the FDA, close to the latest patent
and exclusivity expiration date of the innovator drug, if a firm wants to be the
first generic drug product on the retail shelves.

Furthermore the three commercial validation batches should be manufactured, filled
and packed via a full scale standard production run. The now ready-to-launch generic
drug product must meet all its product specifications and the three commercial
validation lots should be on real time stability evaluation for at least one to three
months. Should all this work have been completed on time and the manufacturing
facility is in full GMP compliance with all manufacturing and control documentation in
place - then the generic product has been developed .‘on time’.

Getting to this point is a long training and planning operation. That it can be done has
been shown by dedicated and well managed generic innovative and generic
companies. This handbook is designed to show the key highlights of the essential
training and planning along the way.

It is not a manual on how to pre-formulate or formulate a specific dosage form, more
over it is a handbook on how to plan, manage and deliver all the key ingredients of a
successful generic drug product from pre-formulation to the marketed generic drug on time and without a delay in the drug product development process.

The length and breath and importance of preparing a successful long life generic
product for the market place requires much attention to detail. Development must stop
if the product fails an essential intermediate, finished product or stability specification
and continue only after the fault has been isolated and corrected - thus the essential
use of checklists and standard operating procedures in this Handbook. The SOPs are
generic in content, they simply highlight important principles and way points and are
suitable for editing and customizing for the firms own in-house needs.

The FDA file contents and review expectations of the drug product must be well
understood and controlled early in the development process in order to avoid problems
with the approval process and later with the quality and customer acceptance of the
marketed product. This Handbook emphasizes ‘first party certification’ by in-house
auditing and self inspection programs exhibiting a past systematic QC track record that
may help streamline FDA’s enforcement of drug Good Manufacturing Practices
(GMPs).

This handbook was designed to produce a rugged generic drug product - to rapidly
facilitate FDA and pre-approval review and reach the market place on time...
Editor

Handbook of Pharmaceutical

xv

Generic Development

Forward

Clear statements, aims, objectives
conclusions and results inform the
reviewer of where you are going.
Concise - a report that is succinct and
to the point is all that's needed.
Compact, avoid any padding - period!
Controlled prospective protocols and
procedures can be written for most
studies or processes and will produce
well-controlled documents.
Certify & check - review and audit
every document your development unit
produces. Sign, date and stamp
documents that have passed a careful
and thorough audit review process.
Directive 5.
"Be innovative and creative"
Get your research department to talk to
the developers, the production people,
regulatory affairs and lab. analysts. Do
not compartmentalise your personnel.
Cross departmental communication
imparts development expertise and
builds in genuine product value.
Challenge SOPs and procedures with
the aim of producing a better product.
Documentation can always be made
more attractive and user friendly.
Writing procedures using attractive fonts
and point sizes often invite readership.
Directive 6.
"Be Open and Direct "
Never hide a bad study or cover up a
poor result. All test results are valid
unless an appropriate investigation
procedures proves otherwise. Review
your
firm's
out-of-specification
operational procedure, and check that
there are no organization omissions…
Directive 7.
"Investigate all abnormalities"
Test results that are out-of-specification
need formal written investigations based
on a Out-Of-Specification Standard
Operating Procedure. The result may
well be a simple sampling or technician
error. For example - an extraneous peak
that suddenly appeared after many
production
manufactured
lots

FORWARD
Thirteen Key Directives
on Drug Development.
Directive 1. "Write a clear SOP on drug
development".
The goal of drug
development is to present a quality
rugged drug in the overall shortest
development time. If your firm hasn't
clear, concise drug development
procedures and objectives on file,
backed-up with all the necessary
protocols, from cleaning, to process to
analytical validation - don't start the
project until this is done.
Directive 2.
"Run pilot studies - never uncontrolled
studies" - uncontrolled studies like nonvalidated assays may seem cheaper at
the time but generally give the wrong
guidance. A pilot study to evaluate a
potential bioequivalent product with a
fully
validated
analytical
assay/
metabolite/impurity procedure, prior to
the main study - often works out more
cost effective than plunging into a high
cost study without a pilot evaluation.
Never
do
uncontrolled
studies!
Directive 3.
"Write and Report Facts Faithfully"
A failed result is a positive endpoint as it
may well highlight a wrong development
route. If the result stays 'failed' after a
full investigation, then report its impact
and conclusions on the study or process
faithfully. Never average results in order
to bring an out-of-spec-result into
specification. That's a GLP violation.
Directive 4.
"Remember the 5C's of documentation”
Each documentation page of a report,
protocol, method, or submission file
should be like the 5C's of a flawless
diamond (cut, clarity, clear, carat, cost.)

Handbook of Pharmaceutical

xvi

Generic Development

Forward

in an HPLC assay spectrum, was found
on investigation to arise from a change
in an inactive dye vendor (a new
supplier) and not as was anticipated a
new product impurity or degradant.

That regulator won't forget you or your
product line up for review!
Work with regulators - or they will work
against you and your product may not
get to the market place on time.
Treat regulators with respect - as you
would like to be treated. Agency official
are
understanding,
experienced
professionals whose prime concern is
product quality and safety.
In any regulatory meeting the only
welcome outcome is a win-win scenario.
Both parties get what they want.
Remember an agency never looses an
argument - the product only suffers and
gets delayed due to incomplete data or
regulatory requirements.

Directive 8.
"Run a mock PAI against your
Application just before submitting."
The Drug Application will eventually be
judged on the acceptability of the
manufacture,
control
and
testing
facilities as documented in the agency
file and in-house supporting data. Audit
every facet of the development,
manufacture, control and stability
procedures of the drug product. Check
and cross-reference each possible
submission document against the
manufacturing / control and laboratory
files and equipment logs. Build in
routine self-inspection checks during
the development process. Formulate
this quality development routine by
SOPs and department audit checklists.

Directive 11.
"Talk to the regulators regularly."
Allow regulators to review protocols
prior to starting the work. Get their
opinion and express your concerns
openly. Regulators like openness and
honesty - and work well with polite,
respectful and professional personnel.

Directive 9.
"Make your Application really clear,
concise and user friendly "
Well prepared and assembled print or
electronic files and dossiers are a joy to
read, review, and evaluate. Use all the
desk top publishing tools to shape your
firm's reports as attractive, stimulating,
and interesting to read and review.
A document can entice or repel a reader
simply by its construction - it can also be
made a scientific work-of-art.

Directive 12.
"Take a hard look a your cGMP's "

The absence of GMP compliance simply
adulterates your drug development
pipeline. GMP compliance is targeted to
play a more dynamic role in the drug
review and PAI process.
(Establishment Evaluation System - FDA Drug Center and
Office of Regulatory Affairs electronic data sharing)

Directive 13.
"Audit everything enthusiastically".
Leave no audit stone unturned.
Establish consistent in-house audit selfinspection programs effective at each
stage of the drug development pathway.
At the end of every development report
submission stage, (refer to the Development
Checklist), audit the department and
relevant steps concerned.
End-of-study auditing is quite ineffective
as early errors or omissions can not be
corrected promptly and on-time
2

Directive 10.

"Treat regulators like
personnel treat you"

your

key

Listen to regulators - they too have their
story to tell and may know regulations
that you don't. Listen to their concerns
clearly - it's in your product's interest.
There is no greater achievement in
satisfying a PAI inspector's requests in
real-time and in producing the
documentation/data requested - before
he leaves the firms' premises.

Handbook of Pharmaceutical

xvii

Generic Development

SEMISOLIDS

D O C U M E N T A T I O N

CHAPTER 1

Regulatory
‘Sit and review with your regulatory department before you start’

D

eveloping successful generic drugs in the least possible time and without
expensive mistakes, requires significant pre-planning with the regulatory affairs
department. Successful generic project managers can visualize all the key sections
of the ANDA or EC submission file, before pre-formulation work has actually been
initiated.
The regulatory department must insure that the innovators’ drug or the reference
listed drug ( R L D ) is suitable for generic manufacture and marketing.
This purpose of this Handbook is to allow the reader to visualize the complete
generic development pathway in a concentrated rational picture.
Review the checklist titled Initial Regulatory Check Prior to Pre-formulation in order to obtain
an initial overview of the forensic regulatory elements.
An early decision on all the pack sizes is required from the marketing and sales
department in order to initiate reverse engineering of all the product specifications.

Part Two
Part Two of the Handbook of Pharmaceutical Generic Development Series provides
a full scale model of a current US abbreviated new drug application (ANDA) for the
selected dosage form chosen (e.g. tablets, capsules, semi-solids, liquids etc.)
In the model ANDA, the right hand side pages provides an example of each and
every document required to compile and assemble a complete regulatory file for
submission to the FDA’s Office of Generic Drugs (OGD).
The left hand side pages are designed for notes, summaries and explanations on the
submitted data forms and tables. These pages are designed for side-by-side
comparisons and ease of viewing. Essential tips and potential traps are explained
in the notes and summaries as well as the common do’s and don’ts regularly
addressed by the agency review chemists in a ANDA / AADA file submission.

Summary:

Review the ANDA requirements with the Regulatory Affairs Department

Know all the twenty one (21) ANDA sections in the registration file impacting on
the development, formulation, manufacturing procedures, all intermediate and
final product specifications, pivotal batch, stability requirements, as well as key
regulatory ANDA do’s and don’ts.

Complete the pre-formulation regulatory checklist and discuss and review all
the paperwork required to complete this section successfully.

Handbook of Pharmaceutical

Chapter: 1.1
1

Generic Development

SEMISOLIDS

D O C U M E N T A T I O N

CHAPTER 1

SECTION I
Section One of the ANDA file consists of three documents. A drug developer needs
to understand the information required to accurately compile these three documents
as the information impacts upon the development timeline. These three parts are:.

♦ Cover Letter and Field Letter
♦ Table of Contents
♦ Signed Application Form
Cover Letter
The cover letter should be on the letterhead of the Applicant or the Applicant's Agent
and should state the following particulars:
1.
2.

Purpose of Submission
Type of Submission
• (Original ANDA / AADA)
• (Supplement)
• (Re-submission)
• (Amendment)

3.
4.
5.
6.
7.
8.

Name of Applicant
Title of Applicant
Signature of Applicant (ink)
Proprietary name (if any)
Generic name of Drug
Number of volumes submitted.

A foreign company will have either a US agent or US subsidiary company to act as
the applicant, especially if the finished drug product is developed and manufactured
outside the US. There is nothing special about this application letter, which is
required on a standard applicant letterhead. An exact representation of the cover
and field letters are presented in Part II of the Handbook.

Table of Contents
Table of Contents laid-out to the FDA's CDER Guide to Industry Format, (April 1997
Overall ANDA Guideline Requirements) needs to provide rapid access to the twenty
one (21) sections of the ANDA submission file. A drug developer needs to
understand all 21 sections, in detail, as they contain the overall development,
manufacturing and control data that makes up the entire drug development project.
Careful review of each section and its required contents will aid significantly in the
pre-formulation to final pivotal processes. The overall development report can be
structured on each CMC section highlighting the choices made and work carried out
to fulfill each sectional requirement. The development report is a real-time ongoing
series of procedural reports that culminates in the final collated development report.
SIGNED APPLICATION FORM:
Signed Application Form (Form FDA 356h or 3439) with original ink signature
requires all DMF numbers of materials and containers used in the final product
presentation. Also no test results, analysis, or stability results may be submitted from
a QC / QA or R&D laboratory that has not received a FDA Plant DMF number (Note:
- New Revised Form FDA 356h became official from January 8, 1998).
Obtaining DMF numbers from suppliers on time requires advanced pre-planning (up
to three months or more) and scrupulous care should be taken that no Agency
deficiencies or FDA concerns of a recent or overdue nature are outstanding on the
materials or container components being used in the firm's generic formulation.

Handbook of Pharmaceutical

Chapter: 1.2
2

Generic Development

SEMISOLIDS

D O C U M E N T A T I O N

CHAPTER 1

ØCHECK LIST×
CL # HPGD-03-01YY

INITIAL REGULATORY CHECK PRIOR TO
PRE-FORMULATION
‘…model examples of each form, report and document are prepared
in Part Two of the Handbook of Generic Drug development… ‘

1. Submission Cover Letter reviewed and draft prepared?

qYes qNo

2. Revised Form FDA 356h reviewed (NB: all DMF #’s clearly noted.)

qYes qNo

3. Basis for ANDA Submission prepared and reviewed?

qYes qNo

4. Is the Patent Certification clear for a generic product development?

qYes qNo

5. Patent Certification statement prepared?

qYes qNo

6. Exclusivity period has expired and statement prepared?

qYes qNo

7. Comparison of your Generic Drug with the chosen Reference Listed qYes qNo
Drug (Select from FDA Orange Book) or original Innovator's product ?
8. Innovators package insert obtained via FOI (insure latest edition)?

qYes qNo

9. Innovators package insert has no exclusive indications?

qYes qNo

10.Labeling statement on number of strengths and package sizes?

qYes qNo

11. Proposed draft labeling for carton prepared (main & side panel)

qYes qNo

12. Innovators Insert converted to a generic package insert (remove any qYes qNo
exclusive indications)?
13. Proposed ANDA Package Insert OK (your firm's details added)?

qYes qNo

14. Side-by-Side comparison of your firm's and innovator's insert?

qYes qNo

15.Repeat check that Innovators Insert is the latest edition and date? qYes qNo
(review FDA Web Site for model insert, check immediately before
ANDA file is submitted to OGD.)
16.Obtain a full set of Jacket Covers (specific colors for file types) from qYes qNo
FDA OGD Offices and review all FDA guidelines for specific dosage
form (i.e. Topical Semisolids)
17.Review and list all DMF #'s required for early vendor implementation

qYes qNo

(Active material suppliers, special excipients, all container-closures specification)

Footnote : Bold letter in first word indicate that this work must be checked and approved before pre-formulation
work starts.

Handbook of Pharmaceutical

Chapter: 1.3
3

qYes qNo

Generic Development

SEMISOLIDS

D o c u m e n t a t i o n

CHAPTER 1

Do -

Documentation
‘If there is no documentation it’s a
rumor;
If it’s well documented - it’s a fact.’

have a SOP manual in a spiral bound
book form for all key departments e.g.
Pharmaceutical,
Analytical,
Stability,
Microbiology, Quality Assurance and
Regulatory Affairs, for ease of updating
and removing superseded (old) editions.

Do SOP CONTROL
Standard operational procedures for a
generic development unit are the first
essential documentation requirements.
Without a functional set of standard
development
procedures,
developing
generic drugs will follow a haphazard nonreproducible process. SOPs are efficient
and useful instructional and working tools.
Standard Operating Procedures should
meet six basic and functional requirements

♦ SOP Index system
♦ an intelligent numbering system
♦ standardized format
♦ approval signatures
♦ a rapid distribution procedure
♦ Annual or biannual reviews

GMP - use them frequently as operational
and training tools.
allow SOPs to become static
documents - review and amend them
regularly as procedures are optimized.

Do’s and Don’ts
- make the SOP index an actual
Standard Operating Procedure and change
the edition # for each new SOP
modification during the course of the year.

Handbook of Pharmaceutical

Don’t - write SOPs just to comply with

Don’t -

The SOP index is a list consisting of a SOP
reference numbers and the procedure titles.
The SOP number ideally has four
components, the department code (P for
pharmaceutics etc.), the SOP number e.g.
(001 to 999), the edition number (01, 02)
and the last review or the editorial date.
(e.g. P-000-01-0199).

Do

write brief and to the point SOPs so
that they can be read and understood
quickly.
Use forms or checklists for extra
information and attached to the SOP.
Don’t - have loose lying SOPs gathering
dust on the shelf.
Don’t - write a SOP that can not be
followed - routinely, by all concerned.
Don’t - write long SOPs (about 1 to 3
pages is sufficient for the average SOP).

DEVELOPMENT SOPs
A development SOP is a protocol or
summary of the overall generic drug
development process. It acts as a guideline
or road map for the development team to
follow to ensure complete product
development.
Development SOPs are not a CFR
requirement. They are designed for rapid
and complete generic drug development
and are significant aids to agency staff
during pre-approval inspections (PAIs).
DEVELOPMENT NOTEBOOKS
Similar to printed SOPs or better still
electronic SOPs, numbered and bound
printed development notebooks (no
electronic workbooks) are essential tools
for a structured generic or innovative
development program to succeed.

Chapter: 1.4
4

Generic Development

SEMISOLIDS

CHAPTER 1

D o c u m e n t a t i o n

Ø

CHECK LIST

×

CL # HPGD-02-01YY

SOP CONTROL.
‘…failure to follow your SOPs adulterates the product…’

1. Is there an Index for all the Pharmaceutical Development SOPs ?

qYes qNo

2. Is this Index a Standard Operational Procedure itself ?

qYes qNo

3. Are SOPs correctly organized according to this Index ?

qYes qNo

4. Are the SOPs available in the community language(s) ?

qYes qNo

5. Do the SOPs have a logical, intelligent SOP numbering system ?

qYes qNo

6. Are all SOPs signed and is each signature dated ?

qYes qNo

7. Check, if the circulation of SOPs is effective and on-time ?

qYes qNo

8. Check that no SOP has a date older than two (2) years ?

qYes qNo

9. Check that superseded SOP editions have all been removed ?

qYes qNo

10. Check that all department personnel have signed the ‘Agreement to
Comply with SOPs’?

qYes qNo

11. Is the effective date of the SOP about 21 days after the last signature qYes qNo
- to allow for SOP training ?
12. Has the SOP been signed by all authorizing parties within 14-21
days of the first signature?

qYes qNo

13. Are the department SOPs - brief, concise and to the point? (select
and review three examples.)

qYes qNo

14. Are the ‘responsible persons’ clearly indicated in the SOP's qYes qNo
Responsibility section?
15. Has a product specific ‘Development SOP’ been prepared for each qYes qNo
dosage form under development (i.e. SOP for Topical Semisolids etc.)?
16. Do these ‘Development SOPs’ acts as a blue print for the
development team to follow to ensure complete product development?

qYes qNo

17. Does the development team regard ‘Development SOPs’ as valuable
working tools and fail-safe procedural mechanisms?

qYes qNo

Footnote : Bold letters in checklist indicate that this work must be checked and approved before pre-formulation work starts.

Handbook of Pharmaceutical

Chapter: 1.5
5

Generic Development

SEMISOLIDS

D o c u m e n t a t i o n

Corrections to notebooks follow the

DEVELOPMENT

Correction SOP. All deletions must be
readable and no correction fluids (Tipex
Fluid™ or White-out™) are permissible.

NOTEBOOKS

All

ingredient weights and measures
require a check signature at the time of
measurement. Late signatures are invalid
and are neither GMP or professional.

‘Record every trial formula, every
method used, every result obtained
and every failure.’

DEVELOPMENT NOTEBOOKS
Pharmaceutical development notebooks are
essential tools for successful generic drug
development. The Development notebooks
are bound, numbered, 100 page, hard cover
notebooks suitable for a development
laboratory environment.
The issue and control of the development
notebooks and the signing procedures after
each work section is complete is an
important control check.
The development notebooks are used to
record all pre-formulation and product
development procedures.
All failed
procedures must be recorded. No product
was ever developed without a number of
reject lots.
Key data recorded in notebooks include :

♦ All ingredient lot # and expiry dates
♦ Active and excipient sources (supplier)
♦ all pre-formulation formula
♦ all manufacturing methods used

Development

of pre-formulation and
development lots do not require strict GMP
procedures,
however
good
GMP
development practices enhance the
scientific validity of results obtained.

Non-calibrated

equipment and poor
process techniques produce questionable
development reports and generic products.
ANDAs
derived
from
inadequate
development procedures may certainly fail
in the market place.

Development Quality Assurance
A well documented, and controlled generic
development unit permits for rapid generic
drug development at the lowest cost.

Meticulously

prepared
development
documentation aids in the timely
production of rugged generic products
within the allocated development time
frame.

Good

documentation is a cost-and-time
saver and allows for rapid data review
during pre-approval inspections (PAIs), a
blessing for agency inspectors, as well as a
proven training record for further
successful generic product development.

♦ Equipment used, speeds and times
♦ All in-process controls
♦ all results and observations
♦ all tentative specifications

The development notebook is the raw data

♦ All finished product controls
♦ proposed stability specifications
♦ all failed data, and abnormal results
♦ investigations and conclusions
Each stage and page of the notebook is
signed by a supervisor and then dated.

Handbook of Pharmaceutical

CHAPTER 1

source for the ‘Development Report’ and is
an important review document from a preapproval and regulatory viewpoint.
Up to 10% of development and research
time should be allocated to fine-tuning
development SOPs, notebooks, correct
documentation and team training in their
correct use.
3

Chapter: 1.6
6

Generic Development

SEMISOLIDS

CHAPTER 1

D o c u m e n t a t i o n

ØCHECK LIST×
CL # HPGD-02-01YY

DEVELOPMENT NOTEBOOKS.
‘…Sign every stage not every page

-

check every page and every stage….’

1. Does the Development Unit have bound & page numbered notebooks ?

qYes qNo

2. Are the printed development notebooks signed on every stage & page ?

qYes qNo

3. Has each completed section been signed with a check signature ?

qYes qNo

4. Has correcting fluid been used to cover up data ?

qYes qNo

5. Are data corrections performed according to the SOP ?

qYes qNo

6. Are all pre-formulation and development formula numerically recorded ?

qYes qNo

7. Do the notebooks record successful and failed development product formula ? qYes qNo
qYes qNo

8. Do all calculations have check signatures which are dated.

9. Has the Product Development SOP been complied with during the product qYes qNo
development phase ?
10. Is a process of formula, specifications and process optimization evident ?

qYes qNo

11. Do all specifications have an appropriate range, where absolutely needed?

qYes qNo

12. Have critical upper and lower range limits been qualified ?

qYes qNo

13. Are out-of-specification results investigated and documented ?

qYes qNo

14. Are the lot #’s, expiration dates and source of each active and non-active qYes qNo
ingredient used during routinely recorded in workbooks ?
15. Does the development notebook appear suitable as a scientific basis for the qYes qNo
generic drug product ‘Product Development Report’?
16. The Product Development Report comprises of both pharmaceutical and qYes qNo
analytical development reports.
Footnote : Bold letters in checklist indicate that this work must be checked and approved before pre-formulation work starts.

Handbook of Pharmaceutical

Chapter: 1.7
7

Generic Development

SEMISOLIDS

CHAPTER 1

D o c u m e n t a t i o n

STANDARD OPERATING
PROCEDURE

Page 1 of 1

SOP # HPGD-02-01YY

SOP CONTROL AND DEVELOPMENT

NOTEBOOKS
The

following Standard Operating Procedures are recommended for a generic
development unit and should be in place prior to initiating product development:
Electronic, computer based, SOPs are rapidly becoming a common place
phenomena in pharmaceutical environments.
Electronic updating and distribution and removal of superseded SOPs is greatly
simplified by using an internal network system (intranet) for SOP distribution and
viewing. An appropriately signed 'Master SOP' collection is held by the firms archive
or library system, while electronic copies for staff use displayed in a PDF™ format
are viewable on firms numerous internal desk computer screens.

SOP CONTROL
# HPGD-02-01YY

Indexing procedure for pharmaceutical development SOPs

# HPGD-02-01YY

Index for pharmaceutical development SOPs

# HPGD-02-01YY

Signing procedures of pharmaceutical development SOPs

# HPGD-02-01YY

Standard Operating Procedures - number and format

# HPGD-02-01YY

Circulation of pharmaceutical development SOPs

# HPGD-02-01YY

Annual review of pharmaceutical development SOPs

# HPGD-02-01YY

List of FDA guides and Guidelines impacting on product
development dosage form and type (IR)

DEVELOPMENT NOTEBOOKS
# HPGD-02-01YY

Issue and use of pharmaceutical development notebooks.

# HPGD-02-01YY

Signing procedures for development notebooks.

# HPGD-02-01YY

Development notebooks - review and audit procedures.

# HPGD-02-01YY

Standard procedures in generic product development.

# HPGD-02-01YY

Pharmaceutical development notebooks - disposition.

ED. N0: 01
Replaces NEW
Ed. Status :

Effective Date:

APPROVED:

DD / MM / YY

01

Handbook of Pharmaceutical

Department

R&D

Chapter: 1.8
8

RA

QC / QA

Generic Development

SEMISOLIDS

DEVELOPMENT

CHAPTER 2

AN OVERVIEW

Developing the Formula
‘…plan the development stages into a Development SOP
- then carefully work the plan of what you are going to do‘…

THE DEVELOPMENT SOP

THE DEVELOPMENT REPORT

development SOP is a
Thedocument
that contains each stage

The development report documents all
the results of the development process
as highlighted from pre-formulation to
the pivotal batch filing in the ANDA
The development notebooks and
reports provide the basic raw data/
results to the development report.
The development report is completed
after the pivotal batch has been
packed, tested and placed on
accelerated stability.
All
product
specifications
and
procedures and qualifications are
completed prior to the start of the
pivotal batch. Major development stops
at the conclusion of this batch.
This batch is the ANDA demonstration
batch for filing with the FDA that
demonstrates a well developed
product formula and process.
Scale-Up and Post Approval Changes
(SUPAC) are permissible after the
pivotal batch but MUST follow the
SUPAC rules for each change made.
The three validation batches, - sold as
commercial products - demonstrate
that the formula and process
consistently give the same product
specifications and are comparable to
the bioequivalency batch (i.e. pivotal).
The development process simply
establishes
the
ruggedness
or
robustness of the formula, the
manufacturing process, the product
specifications and the type of
equipment used. The pivotal and
validation batches demonstrate and
then prove the consistency of the
overall drug product and process.

of the development process of the
generic drug up to and including the
pivotal batch (submission batch).
This document brings all the
interacting
departments,
i.e.
pharmaceutical, analytical and stability
units
together
to
form
one
development program.
The overall development procedure
requires that the product formula,
manufacturing process and controls
and final product specifications
(including stability) are formulated,
optimized and qualified through a
series of upper and lower limit
specification qualifications during the
overall product development phase.
These validation qualifications are
demonstrated again for regulatory
purposes as a final single continuous
process during the manufacture of the
pivotal batch and demonstrated in the
three validation batches.
The validation process shows that all
the
ranges
and
limits
in
a
manufactured batch, produce the
desired drug product according to the
written specifications.
Optimizations and qualification of
specification limits and process
parameters are developed before the
pivotal batch manufacture in a
development batches namely the
process optimization and qualification
batch (PQ). The PQ batch is in fact the
real end point of product development.

Handbook of Pharmaceutical

Chapter: 2.1
1

Generic Development

SEMISOLIDS

DEVELOPMENT

CHAPTER 2

ØC H E C K L I S T ×
CL # HBGD-01-01YY

DEVELOPING THE FORMULA
‘…combine the development stages into an overall 'Development Report'
- what did you really do?…’

1. Is a ‘Development SOP’ for the dosage form available?

qYes qNo

2. Does a SOP specifying the contents of a Development Report?

qYes qNo

3. Are non-soluble active ingredients characterized for particle size for each qYes qNo
approved supplier (special significance in eye preparations)?
4. Are the source and supply of the excipients characterized?

qYes qNo

5. Is the source and supply of the container / closure characterized

qYes qNo

6. Does the SOP indicate that non-compendial active material assays requires a qYes qNo
validation and stability indicating assay ?
7. Does the SOP required full analysis of the reference listed drug (RLD), its qYes qNo
impurity profile and stability ?
8. Is an historical listing and summary of all experimental batches manufactured qYes qNo
required ?
9. Are the in-actives qualitatively and quantitatively compatible with the RLD for qYes qNo
topical use (same composition and strength)?
10. Do the manufacturing procedures, process parameters and in-process controls qYes qNo
require optimization and limit challenges ?
11. Is a process of tightening / qualifying the product specifications, (based on qYes qNo
batch analysis) evident as the development process undergoes optimization?
12. Does the development process identify the critical processing steps for the qYes qNo
validation protocol with the potential to affect the product?
13. Has the preservative efficacy of the RLD been evaluated to assess the qYes qNo
suitability of the RLD preservative system?
14. Does the analytical development require a final validated assay and stability qYes qNo
indicating (SI) assay well before running the pivotal batch?
15. Are stability study assays of the PO and PQ batch required to be tested by the qYes qNo
validated assay procedure and SI analysis?
Footnote : Bold numbers in checklist indicate that this work must be checked and approved before formulation work starts.

Handbook of Pharmaceutical

Chapter: 2.2
2

Generic Development

SEMISOLID

Development

CHAPTER 2

Formula Development
‘…research and evaluate the reference listed drug thoroughly…'

profiles are similar.

ANDA Topical Preparations

The

development of a semisolid
dosage requires six key decisions.
Choosing the : ♦ reference listed drug (RLD)

♦ active material (source/supply)
♦ non-active ingredients (source/supply)
♦ container-closure system (as RLD)
♦ Hanson diffusion procedure
♦ In-vitro similarity to the RLD
The RLD is chosen from the FDA
'Orange Guide' (now on the Internet).
(‘Approved Drug Products with Therapeutic
Equivalence Evaluations’ - current 18th Edition
1998).

Active substance
The active drug substance is chosen
according to standard criteria. Correct
choice of active ingredient is critical
and time consuming. Key selection
parameters include :-

♦ Analytical profile - similar to RLB
under normal and stress conditions.

♦ Impurity profile - similar to RLB
under normal and stress conditions.

♦ Approved supplier must meet all
ANDA regulatory
requirements.

documentation

♦ Active

Material
specifications
remain constant - batch-to-batch
(not a R&D lot or non-commercial
batch)

♦ Able to supply for the next 8-10
years at the similar specifications
after
ANDA
(pivotal)
batch
manufactured.
Using the RLD's Active Material
Ideally the same supplier of the active
drug substance as used by the RLD, is
the most cost-effective in the long
term, as stability, impurity, and aging
Handbook of Pharmaceutical

In-active ingredients (excipients)
The product formula of the generic
semisolid topical should contain the
same in-active ingredients at the same
quantities as the RLD (5 % variation
allowed).
The qualitative ingredients are
required to be in the OGD Inactive
Ingredient Guide (IIG).
The FDA publish the Inactive
Ingredient Guide. Inactive ingredients
found in approved semisolid drug
products in the US are listed in the IIG.
The strength (i.e. quantity) of the
inactive ingredient in the product
formula must not be greater than the
highest
concentration
previously
approved in an approved drug product
for the same route of administration
(i.e. topical route)
Semisolids development needs
specific development SOP’s to clarify
the choice of inactive ingredients for
formulation development.
The choice of a well known excipient
manufactures with an established
excipient range is very important as
long term stability, microbiological and
aging problems are minimized or
avoided. Thus source and supply of
inactive ingredients for topical semisolids are paramount

Container closure systems
The drug product container-closure
system should be a similar material
composition as the RLD containerclosure system.
The degree of product protection by
the container-liner-closure system
must prevent physical, chemical and
microbiological changes on storage
and during customer-consumer use.

Chapter: 2.3
3

Generic Development

SEMISOLID

Development

CHAPTER 2

ØC H E C K L I S T ×
CL # HBGD-01-01YY

FORMULA DEVELOPMENT
‘…Systematically compare your developing product to the chosen RLD
at all key stages…'

1. Has the Reference Listed Drug (RLD) been chosen from the Orange qYes qNo
Guide?
2. Has the RLD been purchased in all the proposed marketing sizes ?

qYes qNo

3. Have different batch numbers (3 lot #’s) of the RLD been purchased?

qYes qNo

4. Confirm if the RLD is of recent manufacture (analyze new samples)?

qYes qNo

5. Conform that at least 10-20 samples of each RLD lot # and pack sizes qYes qNo
are available for physical, chemical (assay/impurities), and stability
testing?
6. Confirm if the RLD has been placed on stability at 40o C for 3 months qYes qNo
for evaluating potential degradation and impurity levels?
7. Confirm if the impurity profile of the RLD has been evaluated?

qYes qNo

8. Has reverse engineering of the RLD formula been performed?

qYes qNo

9. Have the chosen inactive and maximum strength been crossed qYes qNo
checked in the IIG? (for unique or unusual excipients)?
10. Are the in-actives qualitatively compatible with the RLD for topical qYes qNo
use (composition and strength)?
11 Have the RLD formula been reviewed in the International Drug qYes qNo
Compendia (Italian, French, Swiss) for formula composition data?
12. Has the FOI system been used to gather data on the Innovative qYes qNo
drug?
13. Has a full analytical profile range been determined from analysis of qYes qNo
the various batch lots of the RLD (at least 3 lots #’s for Assay; Content
Uniformity)?
14. Has the chosen RLD undergone stress testing to establish the level qYes qNo
of its degradation products?
15. Has a diffusion profile of several RLD batch lots been evaluated to qYes qNo
assess the consistency of the RLD diffusion parameters?
16. Has the preservative efficacy of the RLD been evaluated to assess qYes qNo
the suitability of the RLD preservative system ?
Footnote : Bold numbers in checklist indicate that this work must be checked and approved before formulation work starts.

Handbook of Pharmaceutical

Chapter: 2.4
4

Generic Development

SEMISOLID

Development

CHAPTER 2

STANDARD OPERATING
PROCEDURES

Page 1 of 1.

SOP # HBGD-01-01YY

FORMULA DEVELOPMENT
The following selected model Standard Operating Procedures are recommended for
a generic development unit : Models of selected SOPs are provided.

DEVELOPMENT SOP
P-000-01-01YY
P-000-01-01YY
P-000-01-01YY

Setting up a General Development SOP.
Setting up a Product Specific Development SOP.
Contents of a Development SOP - Semisolids.

DEVELOPMENT FORMULA
P-000-01-01YY
P-000-01-01YY
P-000-01-01YY
P-000-01-01YY

Vendor Certification Requirements for Product Development.
Formulation of ANDA Semisolids Preparations
Formulation of ANDA to Q & Q Status (Semisolids).
Standard Procedures for Generic Product Development

DEVELOPMENT REPORT
P-000-01-01YY
P-000-01-01YY
P-000-01-01YY

SOP for Development Reports.
Contents of a Development Report - Semisolids.
Parameters for Process Optimization and Process Qualification.

NOTE ON DEVELOPMENT
The intent and purpose of the pivotal batch is as a final demonstration that the
formula, process and controls are well developed and tested during development
stages and really need no significant changes or further process qualification.
However scale-up changes can take place within the SUPAC rules after
manufacturing the pivotal batch. These SUPAC rules govern the Scale-Up from
pivotal (10% or more) to commercial (100%) and
changes after registration approval has been given.

Post-Approval Changes

i.e.

[End of Document]

Edition No. 01
Ed. Status :
New

Effective Date
:
DD/MM/YY

Handbook of Pharmaceutical

APPROVED:
APPROVED
___________
Department

____________
RD

Chapter: 2.5
5

____________
RA

_________/_________
QC /
QA

Generic Development

SEMISOLIDS

DEVELOPMENT

CHAPTER 2

Developing the Formula
‘research and evaluate the generic formula thoroughly’

Product Development Stages for a US Generic

Literature search:

P

reliminary activities in a drug
development project start with a
comprehensive
review
of
authoritative reference books on the
pharmaceutical
and
analytical
parameters and attributes of the chosen
drug. Reference works such as the US
Pharmacopoeia, (and supplements)
B.P., (and addenda) Ph. Eur.;
Pharmacopoeial Forum, Physician's
Desk Reference; Martindale; Merck;
Florey; and Vidal are thoroughly
reviewed on physical and chemicals
aspects of the active ingredient and
potential formulations. An extensive
computerized online search relating to
the specific drug substance and the
drug product is conducted.

The

USP Supplements and BP
Addenda are carefully screened for new
monographs at regular intervals during
the
ongoing
drug
development
program, as a new active monograph
may be published during the actual
product development stages.
Finally the Innovator's Summary Basis
of Approval is obtained via the Freedom
of Information Services for data review.

Patent Evaluation:
The Innovator's overall patent situation
is thoroughly evaluated with special
reference to product and use patents.
Exclusivity and Patent data is reviewed
in the FDA's Orange Book "Approved
Drug
Products
with
Therapeutic
Equivalence Evaluations " Edition 20
Handbook of Pharmaceutical

(2000) Under the section titled
'Prescription and OTC Drug Products Patent and Exclusivity Data', the patent
number and patent and exclusivity
expiration dates are obtained. The
latest cumulative index to the Orange
Book may be viewed on the FDA home
page.
Use patents (i.e. therapeutic uses) are
indicated with the symbol "U" followed
by a number representing a specific
therapeutic use. A corresponding list of
therapeutic uses are given.
Exclusivity information for a specific
category is indicated by an abbreviation
followed by the date on which the
exclusivity actually expires (NCE - Dec
30, 1999) NCE = New Chemical Entity.

Sourcing of Raw Material:
Sourcing for a potential suppliers of the
active material.
At least two approved suppliers of
active material should be qualified.
Request
samples
from
potential
suppliers. Exercised care that the active
material samples received, always
represent a production batch and are
not from an experimental batch lot
where the specifications, physical (bulk
density and particle size) and chemical
(impurity profile), may change with time.
Once a suitable active supplier has
been located sufficient material should
be ordered to allow for preliminary preformulation development to begin prior
the full analytical testing of the
suppliers sample. This is a time saving
device as a full analytical profile (with

Chapter: 2.7
7

Generic Development

SEMISOLIDS

DEVELOPMENT

[BET], polymorphism evaluation etc.)
may take one or two months to fully
appraise.

Testing
Sample:

of

Active

Material

Initiate chemical evaluation with the
analytical development laboratory as
per official pharmacopoeia monograph
(Pharmacopoeial
Forum
proposed
method, if present at time), or
alternatively by the supplier's test
method or a modified in-house
analytical method based on the
supplier's method and specifications,
where no official monograph exists.

CHAPTER 2

and microscopic tests confirming,
where possible, the identification of the
ingredients formulated.
Microscopic observation, although
mainly used for emulsion composition,
can give valuable information on nonsoluble particle size and crystal shapes
(i.e. in pastes).
Information on the presence of specific
excipients in pastes can be obtained
from microscopic observation.
Hanson P/N 57 or Franz Cell Profile
Perform a cell diffusion profile using
Reference Product with appropriate inhouse methods for soluble actives.

Marketing input requirements:

First batch of Active Material:

Based on the Innovator's product
obtained from the market place the
following
product
presentation
information is acquired;
◊ color - (possible special color)
◊ odor - Specific odor for (each)
dosage strength
◊ proposed packaging sizes (smallest;
intermediate and largest pack sizes)
◊ Specific application nozzles
◊ Custom applicators / spreaders
◊ Container - closure types. (Aluminum
epoxy coated, plastic squeeze tube.)

Active Material Release
This initial active material lot is
released by the Development (or plant
QC laboratory if the material is intended
for pivotal batches), according to
pharmacopoeia, (or in-house methods
and specifications in the absence of a
pharmacopoeia monograph).
Release of material without full
monograph testing is allowable if the
material is not intended for a Process
Qualification (PQ) and pivotal batch.

Innovator's Product Testing:
Physical Testing
Physical
tests
evaluating
the
innovator's product for odor, color, SG,
viscosity range, pH, preservative
efficacy etc. as well as an evaluation of
the delivery mechanism such as the
nozzle diameter and length (viscosity
related - nasal applicators) are now
undertaken.

Physical
Active:

Characterization

A

full analytical evaluation of the
approved supplier active material is
now undertaken that will finally end in a
comprehensive Analytical Development
Report.
Standard physical parameters for
evaluation. Where the active is
insoluble and held in suspension in the
semi solid matrix;

Inactive Ingredient Identification
Evaluation of inactive ingredients as

• Polymorphism (in pastes)

used in innovator's product are
obtained from the package insert, and /
or the PDR with supporting analytical

• Microscopic observation (in pastes)

Handbook of Pharmaceutical

of

• Particle size distribution (in pastes)

Chapter: 2.8
8

Generic Development

SEMISOLIDS

DEVELOPMENT

Chemical characterization:

- Viscosity (Rheology)

• Optical rotation
• Enantiomeric purity (if required)
• O.V.I. testing (organic volatiles)
• Impurity profile

Evaluation
supplier:

of

raw

- pH
- Emulsion Stability.

⇒ Chemical properties of semisolid:

material

• DMF availability
• Compliance with USP monograph
• Impurity profile and stability profile
• Commitment to maintain written
physical / chemical specifications
• Statement of non-patent infringement

Interim analytical and preformulation development report:
The findings of the initial development
work are summarized and tabulated
into an interim development report,
covering the analytical and preformulation findings that will eventually
form part of the overall comprehensive
product development report.

DEVELOPMENT LOTS
Developing the formula through a
series of mini experimental trials
involves evaluating the type of mixing
process and the physical properties of
the globules / emulsion formed. Steps
for the choice of a suitable process are:
♦ Evaluation of suitable excipients.
♦ Evaluation of suitable antioxidants /
preservatives.
♦ simple mixing, phase mixing, vacuum
mixing.
♦ Time, Temperature and Vacuum
requirements.
♦ Emulsifying
at
specific
phase
temperatures (low / high shear units.)
♦ Determination of target pH and target
viscosity (re: container orifice.)
♦ Physical properties of semisolid:
- Appearance / Color

Handbook of Pharmaceutical

CHAPTER 2




Assay
Uniformity of Content (three points)
Preservative Efficacy
Microbial Limit Tests.

Choosing Tube & Applicator Set:
Ordering of tubes (+applicator nozzles).
The Pivotal Batch as well as the
Process Qualification batch should be
filled on a production (or production
type) filling and capping machines.
Production supervisors are consulted
regarding the choice of the filling
machine. Avoid any manufacture with
worn-out filling heads or old tubing
(microbial hazard).
The Supervisor initiates the ordering of
the filling heads suitable for the
proposed marketed product. Nozzles
capable of extruding the semi-solid
uniformly is an important aspect. Nozzle
shape and length can affect the flow
parameters.

Analytical assay testing:
Assay, pH & viscosity tests versus
innovator's product. Uniformity of
Content and crystallization studies for
low solubility drug active concentrations
are critical development parameters.
Refer to Pharmacopoeial requirements
for Uniformity of Content testing.

Active Stability:
Ordering of raw material for Process
Qualification (PQ) and Pivotal Batches.
On accepting the stability profile data
from the active material evaluation,
coupled with the results the from the
development lots, the active supplier is
now approved. Order sufficient material
for the PQ and Pivotal Lot manufacture.

Chapter: 2.9
9

Generic Development

SEMISOLIDS

DEVELOPMENT

It

is important to use same batch of
active material for the PQ and Pivotal
batch, as these two batches are
somewhat complementary to each other
and form the culmination of the formula
and process development.
An average of 2-3 months may be
required from date of order to receipt of
approved active material, during this
period process optimization batch(es)
and scale-up work is performed.

PROCESS OPTIMIZATION
Process optimization is the process of
fine tuning the manufacturing process
and making minor adjustments to the
formula or process. It should be
performed on a larger batch size so that
the potential problems of scale-up can
be addressed, as they arise with larger
size manufacturing equipment that use
the same operating principle. Fine tune
the effects of mixing and cooling
parameters may include;
♦ mixing speeds (i.e. blade speeds (i.e.
in high speed mixers)

♦ number of mixing stages (one or two
for high shear mixing)

♦ mixing times and total overall mixing
♦ phase amounts and rate of addition
♦ In-process cooling rates.
♦ Re-mixing steps and its effect on
viscosity and flow properties (flow,
extrusion, and ability to spread).

♦ Cooling times (shortest) - the effect
on content uniformity, and product
homogeneity (any crystal growth?).

♦ Effect of pH on aging (re: assay,
content
uniformity
separation).

or

phase

♦ Qualify the preservative efficacy and
Microbial Limits (bacteria & fungi.)

♦ Final evaluation of stability profile.
Process Optimization Report:
The findings of the process optimization
work are summarized in an interim

Handbook of Pharmaceutical

CHAPTER 2

process
report,
outlining
the
optimization data for final presentation
in the product development report.

PROCESS QUALIFICATION
(The PQ Batch)
The process qualification batch is
manufactured in order to detect any
problems that may arise during the
manufacture of production size batches,
permitting a timely solution before the
manufacture of a pivotal batch.
The process qualification team and
production personnel should discuss
formula and process instructions and
decide on optimum batch size, and then
define critical processing steps and test
parameters to be evaluated.

Master Documentation:

The

project researcher finalizes the
Batch Formula and Manufacturing
Instructions documentation package for
signing by the authorizing personnel.
The process qualification team
prepares the PQ Protocol and consult
with the analytical coordinator with
respect to the analytical testing
requirements of the many PQ samples.
Production personnel are present
during the process qualification batch
run, as this process usually mimics
production conditions and acts as a
precursor to the upcoming pivotal
batch. The suitability of the process
documentation package is evaluated
during this run. Amendments are added
where necessary to effect practical
documentation for the pivotal batch.
Upon completion of the process
qualification batch testing, a Process
Qualification Report is formulated.
TEST METHODS FINALIZED
A fully validated stability indicating
assay (and impurity profile) is finalized
prior to executing the pivotal batch. The
analytical methods need to be
authorized and signed prior to the date
of the actual pivotal manufacture.

Chapter: 2.10
10

Generic Development

SEMISOLIDS

DEVELOPMENT

PIVOTAL LOTS
Based on the PQ batch results and
amended documentation, the pivotal lot is
now prepared. In the manufacture of the
Pivotal Batch, a minimum of 100 000
(net) dosage units are required. Some
firms prepare documentation for 100 000
dosage units gross, ignoring that there
may well be 3% to 5% production losses.
The net batch yield turns out to be 95 000
/ 98 000 dosage units which is below the
100 thousand net required by FDA’s
Office of Generic Drugs (OGD).
Semisolids may have a greater
manufacturing loss than solid dosage
forms - thus it is prudent to scale the
pivotal batch for at least 120 000 dosage
units.
Note: the pivotal batch may range from
10% net to 100% (i.e. full size) of the
proposed commercial batch size.
Experienced Generic firms who do not
anticipate any problems with the pivotal
documentation often target the pivotal
quantity to 70-100% of the proposed
commercial lot thus achieving appropriate
scale-up and pivotal in a single batch.

CHAPTER 2

topicals proposals. The FDA CDER home
page from time to time adds further
protocols to their established Internet list.
Where possible consult these protocols
and the FDA Topical Division prior to any
similarity evaluation or comparison.

Pivotal Sampling & Testing
The sampling and testing procedures for
the pivotal batch hold a special regulatory
significance. The pivotal batch represents
the documented batch that is filed with
the FDA's Office of Generic Drugs, as well
as being the batch representing the
therapeutic equivalence of the drug
product when compared against the
reference listed drug / the innovator's own
drug. Evaluate carefully, if such a
comparison study is actually required.
Under these circumstances, the need for
a representative sampling and testing
procedure, as required by GMP, is
achieved by a specific written 'sampling
and testing' protocol. This special batch
has both legal and regulatory aspects in
the eyes of the FDA - sampling must not
only be done but seen to be done (i.e. via
a well written protocol).

Packing the pivotal batch.

DEVELOPMENT REPORTS

The Pivotal batch needs to be fully
packed in the proposed marketing packs
(OGD rules). Frequently the pivotal batch
is packed into 2 or 3 different pack types
and several different pack sizes and
closure combinations. (combinations of,
HDPE Jars, Aluminium epoxy-coated
squeeze tubes, plastic caps, nozzles etc.)
The packaging trail documentation
identifies the exact quantity packed into
each container-closure system. The
overall packaging should total to 100% of
the net pivotal batch.
At least 15-20% of the exhibition (pivotal)
batch should be packed into each
container-closure category.

Firms should have a well structured and
assembled Product Development Report.
Although not a FDA 21 CFR regulatory
requirement, a functional Development
Report will certainly go a long way to
convince the reviewers of a fully justified
overall process that consistently produces
the desired end-product.
The Development Report is the basis on
which the validation protocol is designed
and structured, without it validation may
well be incomplete or officially queried.
Development reports are reviewed by the
site inspectors at the product specific preapproval inspection (PAI visit). The
preparation of a Product Development
Report should be based on all the
interim reports prepared during the
development work, including analytical
reports and where well prepared,
assembled, and structured - oil the official
review process - immeasurably.

IN-VITRO STUDY
Bioequivalence /Comparison evaluations
The pivotal batch samples are used to
perform a comparison study, if needed.
The FDA guidelines on topical products
are included, and highlight the agency

Handbook of Pharmaceutical

Chapter: 2.11
11

Generic Development

SEMISOLIDS

DEVELOPMENT

Purified
Water
A Key Ingredient
in the Dosage Form
Development.
‘develop all experimental
batches with Purified Water USP
or Ph. Eur. - similar or identical
to the proposed commercial
production quality.’

T

he use of appropriate water quality
as a critical non-active ingredient in
the development of pharmaceutical
dosage forms, especially topical
semisolid
presentations
is
often
realized at a late development stage occasional too late in the product’s
overall development.

Equivalent Commercial Quality
The development unit’s water quality
should be equivalent to the water
quality that is available for the
manufacture
of
the
proposed
commercial
product.
Where
development
is
separated
from
manufacture (in an overseas facility) the
problem becomes more acute.
The optimum scenario is for the R&D
department or development unit to be
connected, where possible to the same
water supply system as the commercial
production unit or alternatively install a
purified water system that mimics the
proposed production quality, scheduled
for use in the full-size commercial lots.

This implies that the experimental
batches, the scale-up lots, the process
qualification, pivotal and the initial three
validation batches will all be prepared
and manufactured with commercial
production quality water.

The

cleaning validation protocol
developed during the R&D phase
should use the same water quality.

This

section deals with the pitfalls of
failing to establishing strict criteria for
water quality both during preformulation, formula development and
designing the cleaning validation
protocol. Much of what is valid for
sensitive topical semisolid dosage
formulations, applies equally to the
development cleaning limits creams
ointments and gels forms.

Take a second look at
water as a key
non-active ingredient
for topical semisolid
development

Handbook of Pharmaceutical

CHAPTER 2

Changing the
water quality during
product development
may compromise
earlier results
Water quality for product development
should be at least purified water of
Pharmacopeial grade (USP/Pharm Eur)
and used from the very onset of the
development studies.
The research or development water
specifications should not change as the
product develops and as the awareness
grows, that microbial parameters and
pH are significant formula parameters,
to be evaluated in the development
process.

Chapter: 2.12
12

Generic Development

SEMISOLIDS

DEVELOPMENT

Purified
W a t e r
Avoid changing specifications
Changing the water quality half way
through the product development stage
when microbial parameters are being
addressed may well invalidate the early
formula development results, especially
the overall preservative package,
notable the individual preservative
concentrations chosen.

Water-soluble
preservatives,
chelating

semiactives used (i.e.
anti-oxidants
and

Using a higher than
proposed water
quality during
product development
will simply bias
test results
agents) require formulation in a stable
aqueous phase with standard and
consistent specifications. Using a lower
water quality, which will have a higher
TOC (total organic carbon) level, will
not necessary produce a more rugged
product by providing a greater
challenge vis-à-vis preservative efficacy
and microbial limit testing. To the
contrary the opposite holds true.

The test results will simply be noncomparable with future, down-the-line,
test results where the water quality has
been upgraded to a production quality,
for the manufacture of the exhibition
(pivotal)
batch(es)
required
for
government
agency
registration
purposes.

To evaluate the product’s ruggedness
in order to withstand unusual bioburden
levels that may result, when the

Handbook of Pharmaceutical

CHAPTER 2

commercial water quality increasing in
bioload at the manufacturers site,
reaches warning levels - may be
effected
by
challenging
the
development product with alert /
warning level microbial bioloads in the
formula ingredient water for PET study
evaluation- i.e. spiking the water phase.

PET testing using common organisms
found at the commercial site’s water
supply system (such as pseudomonas
cepacia - a common NY/NJ organism)
needs to be included in the PET
program, as well as a standard indicator
microbe such as, the rarely pathogenic,
gram negative, Pseudomonas statzeri.

Indicator microbes may highlight the
possible presence of pathogenic
organism that are more commonly
found - for example the gram negative,
pathogen, Pseudomonas aeruginosae
that is required to be regulated in the
production water and end-product
release specifications.

Therefore the specific organism, that is
identified as an on-site contaminant in a
drug product (liquids / suspensions),
may not be as significant as to the
actual class and type of organism, it
actually represents in the manufacturing
process or equipment configurationlayout that allows for its continual
survival, and growth.

Pharmaceutical development units, who
upgrade water quality as the product
nears final formation, may not realize
that the initial results based on a lower
water quality may have skewed the
early test results that now become
unsuitable
for
formula-to-formula
comparisons.

Development Pointers:
♦ Initiate development with plant quality
water.
♦ Preservative Efficacy Testing conducted
with specific organisms found in
commercial plant - as well.

Chapter: 2.13
13

Generic Development

SEMISOLIDS

DEVELOPMENT

Purified
W a t e r
Eventually the firm may not have a
proper basis for developing a fully
validated and optimized drug product or
for that matter, an appropriate
validation protocol without the need of
repeating
some
of
the
initial
developmental batch lots with the
applicable standardized commercial
water quality.
Similarly the use of a higher water
quality, (during the development stages
i.e. WFI) than the proposed plant
commercial quality available, will result
in a commercial product with distorted
microbial parameters, as well as a
biased stability profile. This, indeed, is
the more serious case.
These products are prone to develop
severe production problems resulting in
greater microbial bioburdens or OOS
chemical pH shifts that frequently fail
the product release specifications or
worse still, fail the annual commercial
stability tests resulting in a drug product
recall.
In such cases the Preservative Efficacy
Test results as well as the Total
Microbial Count (TMC) and the
Microbial Limit Tests (MLT) are
presented optimistically during the enddevelopment stages, which are not
actually seen in the commercially
manufactured lots.

PET study results, as the product is
refined and optimized in the end
development stages. The stability
profile will also change accordingly, and
development
batch-to-batch
comparisons will be difficult to evaluate.
Development Sites?
Remote development sites require
a water development strategy.

Generic

drug manufactures must
insure that the water quality remains
constant from pre-formulation to
commercial validation and full scale
commercial batch manufacture. Nonactive water quality specifications
should not change once the formulation
and drug product development stage is
completed.

Constant water quality
is required from
pre-formulation
to commercial
validation
Process qualification, pivotal and the
commercial validation batches must be
manufactured with the same water
quality specification.
Most important, the physical, chemical
and microbial specifications must be
constant from the pre-formulation labscale mini-batches to the commercial
batch lots.

Many firms simply wonder why there is
little correlation in the product quality,
as was so clearly demonstrated during
the development, scale-up or pivotal
batch lots. The answer lies partly in
random ad-hoc water quality changes
that took place during the development
and scale-up procedures.
These development lots will almost
certainly exhibit changes in their
microbial specifications, especially the
Handbook of Pharmaceutical

CHAPTER 2

Chapter: 2.14
14

Overseas or remote
R&D
Development Units
must harmonize
their water qualities
with commercial
production

Generic Development

SEMISOLIDS

DEVELOPMENT

Purified
W a t e r

Remote Units
Generic developers who are based in
remote affiliations or research units
(i.e. overseas development units) that
are far removed from the commercial
plant,
where
the
proposed
manufacturing will be effected, should
obtain a batch-to-batch water quality
analysis report of the previous 6-12
months
manufactured
lots
(consecutive batches) and carefully
evaluate the physical, chemical and
especially
microbial
water
specification profiles.
Worst case scenarios where water
quality has been used in commercial
production when the action and
warning limits were exceeded should
be noted and carefully evaluated in
the PET studies.

Note, the water bioburden is a
function of the purification process and
the ad-hoc addition of an added
carbon filter or on-line membrane filter
(0.2 micron) not present in the
proposed commercial unit, may
produce a higher water quality undesirable in development stages that will certainly bias PET and
stability results.
The PET profile impacts on the long
term stability and aging of the drug
product. PET should be evaluated only
under normal stability conditions
(25oC /3-6+ months). The loss of early
development stability work using a
different water quality may delay the
proposed product submission and
consequently the product launch date.

These deficiencies are your concern,
should your developmental SOPs omit
the control of the water quality during
the generic or innovative development

Handbook of Pharmaceutical

CHAPTER 2

process and its synchronization with
the water quality at the proposed
manufacturing site.

Do’s and Don’ts - during drug
development:

Choosing the wrong
water quality
during development
and pilot work
can seriously delay
your product launch
Do insure that the water quality used
during
product
development
is
equivalent to the proposed commercial
batch quality.
Do obtain the commercial water
analytical
profile
from
the
manufacturer (i.e. to be used in the
future commercial full size batches).
Do request and obtain microbial
specifications on warning and alert
TMC
parameters,
(obtain
the
commercial sites TMC lab methods
used to determine these parameters).
Do get a full analytical/microbial
batch analysis of the last 6-12 months
consecutive commercial water quality
lots produced.
Do use the same microbiological
methods for bioburden evaluation
(TMC/MLT) as used at the commercial
sites QC microbiological laboratory.
Do inquire and obtain the commercial
firms SOP / Policy, as to the use of
purified water in the commercial
product at the maximum alert limits.
Do research the proposed
commercial
site’s
water
quality
capability in the early stages of
product development.

Chapter: 2.15
15

Generic Development

SEMISOLIDS

DEVELOPMENT

Don’ts:
Don’t assume that the newly
developed generic or innovative
product will not be occasionally
manufactured for commercial use with
a water quality bioburden of 70 to 100
organisms per mL.
Don’t

formulate blind if your
development unit is remote from the
proposed commercial site and if you
are not given full and detailed water
quality specifications and satisfactory
replies to your queries.

Don’t

forget Good Manufacturing
Practices (GMP) in the development
unit are not necessary a legal
requirement in product development but promotes formulation or scientific
data validity.
Don’t start a development program
for a new drug formulation, with a
lower specification water quality than
that available at the commercial
production site.

Absent
development GMP
adulterates
the drug
development pipeline

Don’t develop

the drug formulation,
with a higher water specification
quality than that available at the
proposed commercial production site.
Don’t forget to stress your final
formula with a spiked water quality
ingredient equivalent to the maximum
warning levels acceptable for the
Standard Operating Procedure use at
the commercial production site.
Don’t forget to establish the type of
common organisms found at the
commercial site’s or in its water supply
system

Handbook of Pharmaceutical

CHAPTER 2

(such as Pseudomonas cepacia, and /
or a standard indicator microbe such
as, pseudomonas statzeri) and include
these organisms in the PET program
either as challenge organisms or in
spiked formula for evaluation.
Don’t have stagnant water pools
remaining in process equipment after
cleaning and rinsing, even if the next
non active ingredient is water.
Don’t allow residual water remaining
in process equipment after cleaning to
partially dissolve the active materials
which may re-crystallize at a later
processing stage to an altered crystal
(polymorphic) form which may result in
nucleation
and
crystal
growth
problems.
Don’t ever mix two different lots of
varying water quality (with dissimilar
microbial and pH parameters) for
either a developmental, analytical,
pivotal or validation study, due to
insufficient water.

Stagnant residual
rinse water at ambient
temperatures supports
microbial growth

Don’t

use water that has been
standing at ambient temperatures for a
lengthy period of time (weekend /
holiday / even overnight) after the
analytical, (and microbial) tests have
been
performed,
as
non
representative and non-comparative
data
(incorporating
a
higher
bioburden) will be obtained.
Don’t allow management resources
or new researchers to think water-isjust-water - water as a primary raw
material in semisolid development
needs a clear developmental strategy
by both the developers and the
manufacturers before the development
project is initiated 3

Chapter: 2.16
16

Generic Development

SEMISOLIDS

DEVELOPMENT
2

CHAPTER

ØC H E C K L I S T ×
CL # HBGD-01-029Y

Purified Water for Drug Development
‘without a full set of specifications and complete documentation
the purified water used is adulterated’

Use Pharmacopeial Water Quality (from pre-formulation to validation):
1. The minimum water quality for development is purifies water of qYes qNo
pharmacopoeial grade?
2. The latest Purified Water USP changes in the last pharmacopoeial qYes qNo
supplement has been checked for monograph changes?
3. The Purified Water used during the product development process qYes qNo
meets the requirements of the USP or Pharm Eur. Monograph?
4. Each water test result falls within the USP/Pharm Eur. limits as qYes qNo
stated in the official monograph?
5. The firms has a SOP requiring development to be performed using qYes qNo
water quality similar to the proposed commercial manufacturing site ?
6. Products being developed in R&D at the proposed commercial qYes qNo
manufacturing site use the same production water quality?
7. Process Qualification, Pivotal and Validation Batches actually use qYes qNo
purified water obtained from commercial production (where
geographically possible) and remote development sites mimic the
commercial production quality, at the same bioburden level?
8. The cleaning validation procedures and protocol is developed qYes qNo
using the same water quality?
9. No changes are permitted (SOPs) in water quality as the product qYes qNo
development procedures progress?
10. Water quality higher than the commercial available quality is qYes qNo
prohibited in the drug development process?

Handbook of Pharmaceutical

Chapter: 2.17
17

Generic Development

SEMISOLIDS

DEVELOPMENT
2

CHAPTER

ØC H E C K L I S T ×
CL # HBGD-01-029Y

Purified Water for Drug Development
‘review water quality batch lots for microbial levels - in real time’

11. Careful note is taken of the microbial alert and warning levels in qYes qNo
force at the proposed commercial site?
12. The firms water quality alert/action levels are set at NMT 30 qYes qNo
organisms /mL?
13. The firms water quality warning levels are set at NMT 70 organisms qYes qNo
/mL?
14. The firms water quality
organisms /mL?

maximum levels are set at NMT 100 qYes qNo

15. The presence of frequent found organisms at the proposed qYes qNo
manufacturing site are noted and incorporated during product
development testing
16. The indicator microbe pseudomonas statzeri is used during qYes qNo
Preservative Efficacy Studies during the product development stages.
17. 6-12 months of consecutive commercial quality water lots have qYes qNo
been evaluated for upper and lower bioburden parameters at periodic
intervals?
18. The final end-formula when spiked with water quality at the alert or qYes qNo
maximum levels adequately meets the USP Preservative Test?
19. Bulk ingredient purified water is boiled (30-45min) and cooled to the qYes qNo
required temperature immediately before use, when used in open type
manufacturing kettles for semisolid preparations?
20. Water quality when not in immediate use, is maintained at not less qYes qNo
than 80o C and continually circulated in appropriate distribution piping
that has no stagnant sections (slight downward slope)?
21. The company maintains a full batch-to-batch analysis profile (in real qYes qNo
time) of all water quality lots produced for product production use?
22. All Alert / Action and Warning level results from the batch-to-batch qYes qNo
analysis are fully investigated and proper corrective action taken ?

4
Handbook of Pharmaceutical

Chapter: 2.18
18

Generic Development

SEMISOLIDS

DEVELOPMENT

CHAPTER 2

PRODUCT DEVELOPMENT GUIDE
PRE-FORMULATION
Introduction
Guidelines for the development of a ANDA product for the US market but is equally valid for EU
general development. Note: Some tests or procedures may be unnecessary. The order of performing
the various stages may change depending on the product under development. These guidelines may
be modified for other geographic zones.

Scope of Product Development

Development Stage

Stage 1

Literature Search

Literature Research

USP; BP; Ph.Eur; USP Forum; Supplements & Addenda PDR,
Martindale, Merck, Florey, Vidal

FDA - FOI

Summary Basis of Approval

On-line
search

computerized Electronic Data Base (articles and publication on test methods,
Diffusion; synthesis procedures, drug impurities, pharmacokinetics
and dynamics)
Evaluation of topical bioequivalence parameters, Diffusion
FDA CEDER
methods (Franz and Hanson Diffusion Cells).
Patent evaluation

Stage 2

Orange Guide + FDA CDER WWW ; Patent Consultant

Active

Sourcing

Sourcing for Active
Raw Material

International Suppliers US, European Asian:- e.g. Lek (Czech)
Esteves, (Mohrs; Spain) (S.I.M Italy) Review Suppliers Catalogues

Potential Suppliers List

Request samples and C of A and Specifications
Evaluate at least two to three potential suppliers fully.

Stage

3

Evaluate
Actives

Stage

Active

Evaluation

Potential Evaluate two/three potential active suppliers for:
• DMF availability
• Compliance with USP monograph (if pharmacopoeial)
• Impurity profile and stability
• Potential Polymorphic forms (suspended semisolid formulations)
• Commitment for maintaining physical specifications
• Statement of non-patent infringement

4

Active

Purchasing

Purchase
(Potential) Evaluate at least two potential active material suppliers for
Active Material
approved supplier status

Stage

5

Active

Testing

Testing
of
Active Chemical testing by the Development analytical lab as per either:
Material sample
a. Pharmacopoeia monograph (if present)
b. Pharmacopoeia Forum (if available)
c. In-house method (based on manufacturer)
d. Supplier's test methods and specifications

Handbook of Pharmaceutical

Chapter: 2.19
19

Generic Development

SEMISOLIDS

DEVELOPMENT

CHAPTER 2

PRE-FORMULATION
Development
Stage

Stage

Scope of Product Development

6

Innovator's

DRUG PRODUCT
Innovator Samples

Stage

Product Purchasing

Purchase at least 3 different lots in smallest and largest pack size
for each product strength

7

Innovator's

Product Testing

Innovator Testing

Evaluate physical parameters:Material color, odor, visual appearance, phase separation or
bleeding, viscosity / extrudability from different pack sizes,
containers materials, closure types; caps and nozzles/applicators.
Loss of water (or other volatile components) from container system

Innovator Physical
Testing

Physical Testing:
Viscosity; SG; pH, Texture; (grittiness, greasiness, stiffness,
tackiness) Particle / globule size of dispersed phases (microscope)

Evaluation of Innovator Summary Formula in PDR; International PDRs (Italian, French,
formula ingredients
Swiss) and Innovators product's insert (obtain latest FOI -FDA)
Perform actual analytical testing on innovator's product
Microscopic
observation

Particle/crystal information on semisolid pastes:
Particle size. Phase and texture changes
Crystal shape, habit, Absence of crystal growth.
Globule size and distribution.

Evaluation of Topical Review FDA CDER Home page for listing and Bioequivalent
parameters for semisolids (e.g. topical corticosteroids).
Bioequivalent
parameters
Diffusion
profile
Active release

Stage

- FDA suggested method on Diffusion Profile (Hansen P/N 57-VC
vertical diffusion cell - evaluate where necessary).

8

Bulk

Active Testing

FIRST BATCH FROM Physical characterization of bulk batch
APPROVED SUPPLIER • Polymorphism (for insoluble active material)
Full Physical
• Particle size distribution (& method development)
characterization
• Bulk density;
• Microscopic observation
Chemical characterization where necessary:
• Assay
FULL CHEMICAL

• Stressed Analysis

CHARACTERIZATION

• Degradants (Expected)
• Impurity profile
• Optical rotation
• Enantiomeric purity
• O.V.I. Testing

Handbook of Pharmaceutical

Chapter: 2.20
20

Generic Development

SEMISOLIDS

DEVELOPMENT

CHAPTER 2

DEVELOPMENT BATCHES
Development Stage

Stage

9

Scope of Product Development
Excipients

Evaluation of formula
Excipient compatibility using FDA's Active Ingredient Guide (IIG)
with suitable excipients
and stability assessment of proposed formula

Stage

10

Evaluation of suitable
Container-Closure
System

Stage

11

EVALUATION
SUITABLE
MANUFACTURING
PROCESSES

Container Closure System
Choice of container-closure-liner system including:
• material composition
• type of thermoplastic resin and resin pigments (bulk jars)
• manufacturers and suppliers
• Al tubes, epoxy liners and closure seals
• Nozzles, spreaders and applicators
• manufacturer's DMF numbers for all component parts
• Letters of Access for regulatory authorities to view DMF dossiers

Manufacturing Process
• Determination of order of mixing
• Aqueous and non aqueous phase mixing - high/low shear mixing
• Determination of pre-mixing of separate phases (optimum ToC)
• Determination of phase addition amounts & specific
temperatures • Determination of mixing times
• Determination of torque end-point values
• Determination of viscosity parameters / Rheology1
• Time-variable rheology testing
• Determination of pH limits2
• Determination of temperature endpoints (cooling points)
1
(State machine used e.g. Brookfield™, Plate&Cone 2Mettler™).

Bulk Material
• Visual Appearance
Physical Properties of • Color Odor (pungent odor or presence of fragrance)
Semisolid bulk
• Homogeneous semisolid mixture
• Particulate contamination
Physical
Tests
on • pH
• SG / Density • Viscosity/Rheology • Color / odor
Semisolid bulk
• Homogeneity • Particle size in dispersed phases
Microbial Tests on bulk

• Preservative Efficacy Test (PET)

Final Formula

Assessment of Final Master Formula and accelerated 1-3 month
stability profile at 300 C

Established

Stage

12

Active material
Bulk purchase

Bulk Active Purchased
Ordering of Active material for Process Qualification (PQ) and
Pivotal Batch(es).
On approval of final formula, order sufficient material for the PQ
(x2) and Pivotal Lots (sufficient for all strengths and batch sizes).
NB: Never mix active material batch numbers in either the PQ and
Pivotal Lots.

Handbook of Pharmaceutical

Chapter: 2.21
21

Generic Development

SEMISOLIDS

DEVELOPMENT

CHAPTER 2

FULL LABORATORY EVALUATION
Development

Stage

13

Analytical
Semisolid

testing

Scope of Product Development
Analytical Evaluation
of • Preservative Efficacy versus Innovator's product.
• U of C - for low active concentrations. Refer to USP requirements
for uniformity of content.
• Validation of analytical package i.e. Assay; Content Uniformity
completed prior to Process Qualification

PROCESS OPTIMIZATION
Development

Stage

14

MIXING
OPTIMIZATION

Scope of Product Development
Process Optimization
◊ Effect of phase temperature parameters
◊ mixing time at set speed (rpm)
◊ Speed of mixer blades (total number of revolutions)
◊ Phase addition rate
◊ Screen size for homogenization
◊ Evaluation of optimized viscosity and spreading attributes

PROCESS
OPTIMIZATION

♦ Phase temperature and range limits and effect on semisolid
formation (viscosity, homogeneity, product appearance).
♦ Mixing times and holding temperatures
♦ The effect on Content Uniformity, and Diffusion profile.
♦ Evaluation of unit dose sampling vs. Content Uniformity.
♦ Effect of phase stability on semisolids (during aging.)
♦ Evaluation of pH and rheological range limits
♦ Evaluation of stability results of optimized mfg. process.

PROCESS
OPTIMIZATION

Prepare PO Report. This Process Optimization Report forms part
of the product Development Report

REPORT

Development
Stage

Stage

15

Scale-up

Scope of Product Development
Scale-up
Scale-up lot prepared, if larger batch size, scale up problems
anticipated.
Process Qualification batch and Scale-up batch may be evaluated
as a single batch.

Scale-up Report

The preparation of a Scale-up Report. The Scale-up report forms
part of the overall Development Report.

Handbook of Pharmaceutical

Chapter: 2.22
22

Generic Development

SEMISOLIDS

DEVELOPMENT

CHAPTER 2

PROCESS QUALIFICATION
Development
Stage

Stage

Scope of Product Development

16

Process Qualification

The process qualification batch is manufactured in order to detect any problems that may arise during
the manufacture of production size batches, allowing a solution prior the manufacture of the pivotal
demonstration batch. Scale-up to the pivotal batch size or 70% of the pivotal batch may be combined
with qualifying the manufacturing process At this stage full manufacturing documentation is prepared
alone standard procedures.

PRODUCTION
FACILITIES

Process Qualification batch should be processed in a production
(or production type with same principle and operation) machine.

BATCH SIZE

Size of pivotal and marketing batch confirmed (NLT 100 000 net/
packed at target parameters or 10% of proposed market batch).

BATCH
DOCUMENTATION

Preparation of Master Formula and Processing Instructions
Discussion of formula, manufacturing process and control
parameters with production personnel and QA Staff.

FINAL REVIEW and Review of proposed formula, manufacturing process and control
AUTHORIZATION
parameters with production personnel and QA Staff with
authorization signatures (RD; QA-QC; RA; and Production)
PROTOCOL

PQ. protocol prepared.

KEY STEPS

Critical manufacturing steps designated and sampling and testing
parameters specified.

OPERATING
CONDITIONS

Presence of production and control personnel during PQ
manufacture.

PROCESS
QUALIFICATION
REPORT

Upon completion prepare P-Q Report. This P-Q report forms part
of the overall Development Report

PIVOTAL BATCH
Development

Stage

17

Scope of Product Development
Pivotal Production

PRODUCTION
FACILITIES
BATCH
DOCUMENTATION

Pivotal batch MUST be processed in a production machine (or
production type using the same principle and operation).
Preparation of FINAL Master Formula and Processing Instructions

REVIEW and
AUTHORIZATION

Review of FINAL formula, manufacturing process and control
parameters with production personnel and QA Staff. Pivotal
authorization signatures (RD, QA, QC, RA and Production)
attached.

OPERATING
CONDITIONS

Operation of production and control personnel during Pivotal
manufacture, aided by development team.

PIVOTAL REPORT

The preparation of the Pivotal
of the overall Development Report.

Handbook of Pharmaceutical

Chapter: 2.23
23

Report

forms

part

Generic Development

SEMISOLIDS

DEVELOPMENT

CHAPTER 2

PRE-SUBMISSION AUDITING
Development
Stage

Stage

Scope of Product Development

18

ANDA Pre-Submission Auditing

Development Report

Audit all raw data supporting Development Report.

ANDA Regulatory File

Audit Plant and Laboratory Documentation as per ANDA.

SOPs

Review SOP System and Update level.

cGMP

Review cGMP of Manufacturing Processes.

Validation Protocol

Product Process Validation Protocol complete and signed.

ANDA SUBMISSION
Development
Stage

Stage

19

ANDA Submission

Scope of Product Development
ANDA Submission
Submit ANDA structured/formatted as Part Two of this Handbook
(9 Copies - as per FDA Color System)
(1 Field Copy)

VALIDATION BATCHES
Development
Stage

Stage

20

Scope of Product Development
Process Validation

Protocol

Process Validation Protocol for 3 consecutive marketing lots

Execute validation

Process Validation of the 3 consecutive marketing lots

Report

Process Validation Report

Similarity

Show intra-batch similarity

Pivotal-Validation
Similarity

Show inter-batch similarity between Pivotal Batch and the
Commercial Validation Lots.

COMMERCIAL RE-VALIDATION DUE TO SUPAC-SS CHANGE
Development
Stage

Stage

21

Formula Changes or
Process Changes.
Equipment, Process,
Formula or site change

Scope of Product Development
Process Re-validation
Revalidate procedure with new formula process or equipment with
a different manufacturing operating principle (See SUPAC-SS)
Follow SUPAC-SS Rules - Level I, II, or III

Handbook of Pharmaceutical

Chapter: 2.24
24

Generic Development

SEMISOLIDS

Development

CHAPTER 3

Active Ingredients
‘Now think about the active ingredient, its source, its supply
and how to keep its specifications constant.’

Active Ingredients
The active ingredient for your firms
generic drug must be cost-effective
and freely available (for at least 8-10
years or even more). The active drug
substance should be a commercial
product batch and not a research or
development lot (as development
specifications are still changing).
Active ingredients for innovative drugs
still on patent with 2 or 3 years to go
are the active ingredients most
interested to generic firms.

Changing specifications
Bulk pharmaceutical chemical firms
(BPCs) synthesizing
these active
substances may not have a fully
validated and optimized active product
and may supply generic firms with
developmental batch lots.
These R&D lots will most certainly
change in their drug substance
specifications, especially particle size
and bulk density as the process is
refined and optimized. The impurity
profile will also change as the active
firm optimizes the key synthesis steps
and purification process.
Generic drug manufactures must
insure
that
the
active
drug
specifications do not change once the
formulation
and
drug
product
development
stage
is
reached.
Process qualification, pivotal and the

Handbook of Pharmaceutical

commercial validation batches must be
manufactured with the fully developed
active drug substance. Most important
the
physical
and
chemical
specifications must be constant from
batch to batch.

Generic

developers should obtain a
batch-to-batch analysis report of the
last
6-10
manufacturing
lots
(consecutive batches) and carefully
evaluate the physical and impurity/
degradative analytical profiles.
Note, the impurity profile is a function
of
the
active
drug
synthesis
procedures. It should remain constant
or improve with synthesis optimization.

However

the degradative analytical
profile is a function of the stability and
aging of the active drug substance that
can be evaluated analytically either
under stress conditions (40oC/3
months) alone or in combination with
the formula excipients selected.
Certain impurities from the actual drug
synthesis may in fact increase in
percentage with drug product aging
under stressed conditions and may
then be considered degradants in this
case.

Choose established actives
Ideally the active ingredient should be
manufactured by an established and
well known pharmaceutical bulk
chemical
manufacturer
(BPC).

Chapter: 3.1
1

Generic Development

SEMISOLIDS

Development

CHAPTER 3

Active Ingredients
Remember,

BPC companies are
inspected by the FDA and the bulk
chemical manufacturer’ active drug
substance your generic firm may
require or the bulk firms GMP may be
cited for a series of regulatory or drug
master file (DMF) deficiencies.
These deficiencies are your concern,
should you choose to use their active
drug
substance
for
generic
development. Any DMF deficiencies
at the time of ANDA submission will
affect and delay the approval process
of your generic ANDA file.
It is essential for the generic developer
to communicate with the BPC firm's
regulatory affairs department and
request a summary of outstanding
DMF and GMP deficiencies specific to
the particular active drug required for
your
generic
drug
product
development. Part Two of the
Handbook contains model systems of
all
the
vendor
/
developer
documentation requirements.
Do’s and Don’ts:Do insure that the batch lots of active
drug are commercial batches.
Do obtain the drug’s active analytical
profile from the manufacture (for
commercial batches).
Do request and obtain the drug active
physical specifications on bulk density
and particle size, (obtain analytical
methods used to determine these
parameters). Check polymorphism.
Do get a analytical batch analysis of
the last 6-10 consecutive commercial
batches.
Do inquire about the regulatory status
of the firms DMF (has the DMF been
referred to previously by other ANDA
applicants and are there outstanding

Handbook of Pharmaceutical

DMF or GMP deficiencies cited by the
FDA?)
Don’t use a firms active drug
substance, if you are not given full and
detailed specifications and satisfactory
replies to your DMF and GMP queries
(Request the firms last two EIRs from
the FOI services.)
Don’t be the first to reference the
active drug in your ANDA unless a
thorough investigation has been made
and all the active drug specifications
are satisfactory.
Don’t forget to place two or more
active material drug lots (different lots
#’s) on stability (40oC/3 months) in
order to obtain a complete stressed
analytical
profile
(examine
all
extraneous HPLC peaks obtained and
cross check unidentified peak ID with
the active manufacturer.)
Don’t ever mix two lot/batch numbers
of the active drug substance for a
developmental, analytical, pivotal or
validation
study,
because
of
insufficient material available.
Don’t use active material older than
12 -18 months from date of mfg. for
analytical, stability or impurity studies,
as non-representative and noncomparative data will be obtained.
Don’t forget to obtain a statement
from the DMF holder (the active drug
manufacturer)
that
all
issues
communicated to the DMF holder by
the FDA have been fully addressed i.e.
all deficiencies in the active DMF have
been corrected and at the time of
writing there are no outstanding
deficiencies. These corrections are
also specific to the samples of
commercial batches your firm has
received for development studies.

Chapter: 3.2
2

Generic Development

SEMISOLIDS

Development

CHAPTER 3

ØC H E C K L I S T ×
CL # HBGD-01-0298

Active Ingredients Check - Approval of Supplier.
‘…without a full set of specifications and complete documentation
the active material is adulterated’…

For Pharmacopoeia Active Drug Substances - (from Approved Suppliers):

1. A full USP Certificate of Analysis has been supplied?

qYes qNo.

2. Each analytical test falls within the USP/NF limits as stated in the official
USP monograph?

qYes qNo.

3. If the USP active material monograph is in the BP as well then the active
passes the BP ‘Related Substances’ monograph test?

qYes qNo.

4. IR and UV Identification spectra (as per the USP/NF Identification test)
has been supplied by the manufacturer?

qYes qNo.

5. IR Identification Spectra of Official Reference Standards (see Forum)
have been compared with the active drug substance?

qYes qNo.

6. All spectra are fully labeled and show the active materials lot # ?

qYes qNo.

7. A letter of authorization obtained from the active supplier (DMF holder)
addressed to the ANDA applicant referencing the active DMF #, as used in
the ANDA generic product?

qYes qNo.

8. The DMF holder (active manufacturer) has included a statement that all
FDA issues / concerns communicated to the DMF holder i.e. deficiencies in
the active DMF have been fully addressed?

qYes qNo.

9. The active material safety data sheet has been provided by the approved
supplier?

qYes qNo.

10.

qYes qNo.

The latest USP supplement has been checked for monograph changes?

Footnote : Checklist applies to non compendial (non USP) active drug substances - where applicable .

Handbook of Pharmaceutical

Chapter: 3.4
4

Generic Development

SEMISOLIDS

Development

CHAPTER 3

Active Ingredients
‘…timeline for active materials from first look
to Approved Supplier…’

An Approved Supplier of an active
drug substance is the chosen vendor
that
consistently
meets
the
specifications
and
documentation
requirements of the generic drug
developer.
Step 1 - The referenced listed drug
(RLD) must be purchased immediately
the project is authorized for formula
evaluation.
Step 2 - Analytical know how :
Analytical assay and test procedures
must commence immediately in the
following key sections:Physical parameters
Bulk density and particle size are
essential QC parameters. The drug
solubility should be established in the
intended phase at the specification
pH.)
If the drug substance is a polymorph
then the type of polymorph must be
established and the active polymorph
stability evaluate with aging. Check for
crystal changes during normal aging
and stability testing.
(Remember:
the
manufacturing
parameters may affect and change the
polymorphic form and crystal habit
inadvertently.)
Chemical parameters
Assay, impurity profile and degradants
produced on forced aging (or stability
studies) are the standard stability
tests. Particle size, crystal type and
crystal
habit
are
significant
identification tests per shipment.
Microbial parameters
Evaluate the microbial purity of the
active if a bioburden is suspected
originating from the active preparation
or synthesis or if the active is derived
from a biological source.

Handbook of Pharmaceutical

Check aging parameters:
Stability studies emphasizing:- assay,
impurity profile and degradants,
crystal growth, and possible changes
in polymorphic/crystal habit forms.
Analytical methods
The assay and stability indicating
method should be well established
during this stage of the vendor
certification process.
Step 3 - Candidate vendor samples:
Once
a
potential
candidate
manufacturer (active) has been
identified - obtain a minimum of three
different batch/lots for a full analytical
profile and batch-to-batch analysis.
Step 4 - DMF and GMP issues :
Resolve any outstanding DMF and
GMP issues. (No FDA deficiencies and
no future critical changes in active
specifications.)
Step 5 - Full analytical profile :
Perform all test procedures to obtain a
full analytical profile. Analytical
procedures should be well qualified at
this time point.
Step 6 - Batch-to-batch analysis:
Perform a full batch-to-batch analysis
with in-house and vendor supplied
data.
Investigate all abnormal results and
review with vendor to a satisfactory
conclusion.
Step 7 - Stability Profile:
Conduct accelerated stability study on
active drug substance alone and in the
proposed formulation.
Step 8 - Approved Supplier:
Approval of active supplier with all
active specifications to purchasing
department.

Chapter: 3.5
5

Generic Development

SEMISOLIDS

Development

CHAPTER 3

ØC H E C K L I S T ×
CL # HBGD-01-02YY

Active Ingredients - Approved Suppliers.
‘…one approved active good - two approved suppliers better’…

1.

Three different batch lots of RLD purchased?

qYes qNo.

2.

Candidate samples of active drug obtained?

qYes qNo.

3.

Bulk density and particle size evaluated?

qYes qNo.

4.

Active solubility evaluated in proposed vehicle?

qYes qNo.

5.

Can active drug exist as a polymorph?

qYes qNo.

6.

If a potential polymorph, protocol for evaluation available?

qYes qNo.

7.

Protocol for active crystal habit studies available?

qYes qNo.

8.

Vendor EIRs reviewed and audited as satisfactory?

qYes qNo.

9.

Vendor DMF and GMP issues have been fully resolved?

qYes qNo.

10. Vendor statement on final specification obtained?

qYes qNo.

11. A full batch-to-batch analysis with three lot #’s has been tested? qYes qNo.
12. All abnormal
investigated?

results

from

the

batch-to-batch

analysis qYes qNo.

13. Are the accelerated stability results of the active drug qYes qNo.
substance alone and in the proposed product formulation
satisfactory?
14. Does the purchasing department have a full set of approved qYes qNo.
specifications for the active drug substance?
15. Has a vendor approval certificate for the approved active qYes qNo.
substance been issued (copy with purchasing department)?

Handbook of Pharmaceutical

Chapter: 3.6
6

Generic Development

SEMISOLIDS

Development

CHAPTER 3

STANDARD OPERATING

Page 1 of 1.

PROCEDURES
SOP # HBGD-01-02YY

Active Ingredients - Approved Suppliers.
The following Development Standard Operating Procedures are recommended for a
GENERIC DRUG development unit :

ACTIVE INGREDIENTS
P-000-02-01YY

Vendor Certification Requirements for Approved Actives.

P-000-02-01YY

Active Drug Substances for Generic Drugs.

P-000-02-01YY

Active Drug Substances specifications procedure prior to
purchasing.

P-000-02-01YY

Residual solvent testing and solvent specification limits prior to
approving the supplier of new active materials.

P-000-02-01YY

Developing Product Formula with Approved Actives.

P-000-02-01YY

Developing Product Formula with Approved Actives.

P-000-02-01YY

Inventory Records for the Active Drug Substance.

P-000-02-01YY

Investigating and handling abnormal batch results.

4
[End of Document]

ED. N0: 01
Replaces NEW
Ed. Status :

Effective Date:

APPROVED:

DD / MM / YY

01

Handbook of Pharmaceutical

Department

R&D

Chapter: 3.7
7

RA

QC / QA

Generic Development

SEMISOLIDS

EXCIPIENTS

CHAPTER 4

'Semi Actives'
‘…Challenge each preservative and anti-oxidant system during development
and then optimize its formula concentration…’

Semi active ingredients

S

emi
active
ingredients
are
preservative systems, antioxidants
and chelating excipients. They are
not active ingredients, nor are they
fully inactive ingredients as they
maintain the quality, inhibit impurity /
degradant growth and enhance the
stability profile of the product formula.
CHOOSING SEMIACTIVE INGREDIENTS

The evaluation of semi active
ingredients
requires
thorough
optimization qualification for:
◊ the antioxidant system
◊ the preservative system
These systems maintain an active role
by (a) minimizing the potency loss of
the active ingredient(s) (b) stabilizing
the drug's impurities (c) preserving
drug quality during aging and shelf life.
The anti-oxidant system may well
degrade significantly with time and
therefore generally does not require
any release qualification or testing of
its upper and lower operational limits.
It is important to establish and validate
drug assay and impurity profiles during
the formula development (optimization)
stage. Following this development path
the actual antioxidant loss need not be
established or even qualified during
the product development stage.

Formula Optimization:
A anti-oxidant optimization protocol
(provided in this chapter) will enable
drug developers to fully eliminate
antioxidant
release
and
check
specifications from routine product
release
and
stability
testing
requirements of the pivotal and
subsequent commercial marketed
batches
of
the
type:

Handbook of Pharmaceutical

Release specification: 90.0 - 110.0 %.
Check specification: 60.0 - 110.0 %

Semisolid

formulations can and do
consume
the
anti-oxidant
and
preservative systems during the
product’s shelf life. Heavy metals may
act a catalysts to degrade active and
semi-actives. Specifications, as above,
have a very limited value in a drug
development program. Evaluating the
total summed heavy metal content of
the combined excipients (from their
Certificate of Analyses) may provide a
starting baseline for the choice of a
suitable chelating agent.
The development formula optimization
should tabulate the loss of assay
potency and impurity / degradant
growth for the active substance over
an shelf life period of 0,1,2, 3 and 6
months at 300C/75% RH
This formula optimization procedure
simply
eliminates
any
routine
antioxidant testing in the future.
Antioxidant
and
preservative
qualification studies are needed during
the product development stage and
once performed, close the requirement
for any further testing. This is an clear
example of how careful product
development can result in reduced QC
routine finished product testing.
The first three commercial validation
lots do not require antioxidant or
preservative release or stability check
testing as their formula inclusion was
qualified during the development
optimization phase.
Product release specifications must
not become, in part, a substitute for
incomplete development validation
testing.

Chapter: 4.1
1

Generic Development

SEMISOLIDS

EXCIPIENTS

CHAPTER 4

ØC H E C K L I S T ×
CL # HBGD-03-01YY

Validating the Semi Active Ingredients
‘ …don’t test a semi-active after it has been qualified...’

1. A full development validation/qualification study of the antioxidant has qYes qNo
been performed during the development process ?
2. Has a range of antioxidant percentages been qualified by development qYes qNo
optimization studies. (e.g. lower [0.5%] middle [1.0%] and upper [1.5%])?
3. Does the of the antioxidant percent chosen represent the lowest % value qYes qNo
to minimize impurities and degradants during the inferred product shelf life?
4. Has the Preservative Efficacy been similarly evaluated at lower, and upper qYes qNo
preservative percentages to find the correct concentration
5. Has the overall excipient formula been evaluated for total heavy metal qYes qNo
content from the inactive C of As and product specification data sheets?
6. Have reducing agents, antioxidant synergists and sequestering agents not qYes qNo
appropriately validated, been excluded from the product formula?
7. Does the active ingredient remain in the check specification range (90.0 - qYes qNo
110.0 of labeled amount) at the end of accelerated stability testing?
8. Does the potency of the active ingredient decrease when the chelating qYes qNo
agent is removed from the product formulation during normal and aging
studies?
9. Have range studies been performed to evaluate the optimum amount?

qYes qNo

10. Has the product formula been evaluated at lower, middle and upper qYes qNo
antioxidant percentages and evaluated against active assay values?
11. Has it been clearly established that the inclusion of chelating or an qYes qNo
antioxidant synergist positively enhances the action of the antioxidant?
12. Does the stability testing protocol only evaluate formula specifications qYes qNo
that are directly impacted by the aging process ?
13. Has a complete product development profile of the antioxidant been qYes qNo
evaluated in order to eliminate routine release and stability testing of the
antioxidant agent during commercial manufacture ?
14. Is the stability testing protocol for the pivotal batch a logical qYes qNo
development sequence from the product development work ?
Footnote :
Bold numbers in checklist indicate this work must be qualified and or validated before
manufacturing the Process Qualification Batch, which actually marks the end of the product
development stage.

Handbook of Pharmaceutical

Chapter: 4.2
2

Generic Development

SEMISOLIDS

EXCIPIENTS

CHAPTER 4

Non-active Ingredients
‘…Each excipient must play its role - and all non active ingredients must be
necessary…’

NON ACTIVE INGREDIENTS

General Excipient Rules:

on active ingredients for topical
semisolid
preparations
are
required to meet certain minimum
agency criteria:
For ANDA submissions, the non active
must appear in the FDA’s Inactive
Ingredient Guide (IIG). This guide is a list
of inactive ingredients that have been
used in currently marketed OTC and
prescription drug products for a specific
route - in this case for oral use.

N

The non-active should ideally be
compendial (USP/NF; BP; EP; JP etc.)

The

• If the non-active is for an OTC
semisolid product only (not an ANDA)
then it should be at least in the GRAS
lists.
• It is strongly recommended that nonactives selected for ANDA formula are
subject to approved supplier procedures
- similar to Active Ingredients.

second key condition for the non
active ingredient is that the percentage
amount used in the product formula
must not exceed the maximum
percentage for the specific route (e.g.
oral use) as stated in the Inactive
Ingredient Guide.

The maximum quantity of a specific non
active ingredient is generally determined
by the FDA as the highest amount of
non active that is currently approved for
an OTC or ANDA product for that
specific dosage form or route of
administration.

ANDA

approvals may be OTCs or
prescription products. The above key
FDA rules apply only to ANDA
submissions and do not apply to OTC
non-ANDA products.

Choosing non-active ingredients.

Excipient-to-excipient interactions (color
effects and incompatibilities) must be
excluded.
Uniformity of Content for
semisolid may be impacted by the
physical specifications of the excipients.

Generic

manufacturers who evaluate
the reference listed drug (RLD) and
design a Q&Q formula may minimize
fluctuations in diffusion and topical
bioequivalent testing, where required, for
specific topical dosage forms.

Handbook of Pharmaceutical

• The non-active should ideally be in
the Handbook of Pharmaceutical
Excipients (current 2nd Edition)
• The non-active must be in the FDA’s
IIG-Inactive Ingredient Guide regarding
⇒ same dosage route only
⇒ maximum
exceeded.

percentage

Insoluble / Suspended
ingredients specifications

not

Inactive

Suspended
or
insoluble
inactive
ingredients with unspecified physical size
parameters may require quality control in
physical specifications;

particle size specifications

Uniformity of Content Studies
It
is
important
that
generic
manufacturers
correlate
excipient
specifications and evaluate the impact
on the bulk ‘uniformity of content’
assay during in-process manufacture.
Content uniformity studies evaluating
Content Uniformity of active are
recommended before (in the bulk) and
after packaging.
Specifications for suspended particles
(i.e. <50 microns) should be clearly
specified in order to prevent a nonelegant grit-free product feel .

Chapter: 4.3
3

Generic Development

SEMISOLIDS

EXCIPIENTS

ØC

CHAPTER 4

HECKLIST×

CL # HBGD-03-01YY

NON ACTIVE INGREDIENTS
‘…qualify the excipient performance at both ends of the given
specification range…’

1. Has the RLD’s non actives been qualitatively identified?

qYes qNo

2. Is the generic formulation a basic Q&Q formula of the RLD?

qYes qNo

3. Are the non actives referenced in the FDA’s IIG?

qYes qNo

4. Has the maximum percentage not been exceeded for semisolids?

qYes qNo

5. Has the particle size of insoluble or suspended non actives been qYes qNo
specified with an appropriate range, to prevent grittiness?
6. Is the in-vitro diffusion profile of the proposed generic formula qYes qNo
similar to the RLD's in-vitro diffusion profile (Hanson Diffusion Cell)?
7. Have Preservative Efficacy Testing (PET) of the Generic and RLD qYes qNo
been performed under normal room temperature testing?
8. Is the uniformity of content spread less than 4.0 - 5.0% with a RSD qYes qNo
of NMT 6.0%?
9. Does the Development Report show that the final formula was qYes qNo
derived from PET studies testing lower and upper [preservatives]
concentration levels?
10. Does the firm regularly review the Pharmacopoeial Forum for qYes qNo
proposed monographs and specifications for non-compendial
excipients ?
11. Has the firm reviewed all the suppliers for potential ‘Approved qYes qNo
Suppliers’ as listed the Handbook of Pharmaceutical Excipients ?
12. Is Purified Water USP/BP used as an approved ingredient?

qYes qNo

13. Have the excipient specifications been reviewed in USP / NF, qYes qNo
Ph. Eur / BP, and JP and the latest supplements and addenda?
14. For compendial excipients has the latest supplement been qYes qNo
checked ?
15. Does your generic firm have a current ‘ Approved Supplier SOP ' qYes qNo
for non active ingredients?
Footnote : The words non active ingredient; inactive ingredient and excipient are all the same meaning and interchangeable in use.

Handbook of Pharmaceutical

Chapter: 4.4
4

Generic Development

SEMISOLIDS

EXCIPIENTS

CHAPTER 4

ØC H E C K L I S T ×
CL # HBGD-03-01YY

Non active ingredients
‘…qualify the process performance with the chosen excipients… ’

Variables Associated with Excipients

16. Has the variability of natural, semi-synthetic, synthetic and qYes qNo
especially polymeric material as a function of source been evaluated?
17. Has the variability of natural, semi-synthetic, synthetic and qYes qNo
especially polymeric material from a single source been evaluated?

STANDARD OPERATING
PROCEDURES

Page 1 of 1.

Non active Ingredients
(excipients)
The following development Standard Operating Procedures are recommended.

NON ACTIVE INGREDIENTS (EXCIPIENTS)
P-000-01-01YY

Vendor Certification Requirements for Approved Non Actives.

P-000-01-01YY

Non Actives Ingredients for ANDA formula development

P-000-01-01YY

Use of Purified Water USP in Product Development

P-000-01-01YY

Checking Excipient in the FDA ‘Inactive Ingredient Guide'

P-000-01-01YY

Hanson cell for ‘Release Testing in Ointments & Creams'

P-000-01-01YY

Do's and Don'ts in ‘Release Testing in Ointments & Creams'

4
[End of Document]

Edition No. :
01
Ed. Status : New

Effective Date :

Handbook of Pharmaceutical

APPROVED
______________ _______________
Department
RD

Chapter: 4.5
5

_____________ _______________
RA
QC / Q A

Generic Development

CHAPTER 5

CONTAINER-CLOSURE

SEMI SOLIDS

C ontainer-closure Systems
‘…the container documentation is the key
dot every i and cross every t…’

CONTAINER CLOSURE SYSTEMS

T

he generic drug product containerclosure system should be of a
similar material composition to the
reference listed drug (RLD) containerliner-closure system.

Product protection
The degree of product protection must
be equal to the RLD’s container and the
container-closure
system
should
prevent
physical,
chemical
or
microbiological changes to the drug
product, on storage and during
customer-consumer use.
Semisolids are packed in coated
aluminum tubes, HDPE / LDPE squeeze
tubes or thermoplastic HDPE / HDPP
bulk containers or jars.
Three principal rules apply to semisolid
container-closure systems:♦ All development stability testing is
performed in the container-closure in
which the drug is to be marketed.
♦ All the manufacturer's container-linerclosure documentation must meet for
current specifications (fully audited).
♦ Container closure specifications
need to be compatible with the
commercial production filling/packaging
equipment where the lots are produced.
Container-liner-closure suppliers that
are approved must be supported by
detailed technical specifications &
testing methodology.
Special emphasis is placed on the type
of
thermoplastic
resin
utilized.
Manufacturers who change the resin
automatically compromise the generic
stability studies performed for ANDA

Handbook of Pharmaceutical

registration (pivotal and validation lots)
and post change additional stability
studies are required (SUPAC Rules).
Emphasis should be placed on the
routine QC container testing often
overlooked by development labs.

Documentation requirements

The

documentation requirements of a
suitable chosen container system
requires careful auditing and review.
Obtaining the correct documentation is
time consuming and may take several
months
before
all
supplier
documentation is complete, correct and
on file with the proposed manufacturer.
Full specifications, Letters of Access
(LOAs) for components with DMF
numbers, Certificates of Analysis and
21 CFR certification is required.
The principal components in direct
contact with the semisolid are most
critical:

Complete documentation is required:
♦ the flexible tube (Al / thermoplastic)



resin type and source for plastics
Aluminum type and resin coat
color pigment used for plastics
additives used in the resin.

♦ the closure or cap - HDPP

♦ the closure liner or laminate
♦ Nozzles and Applicators.
Documentation specifications for

each
component have been itemized in the
attached SOPs with actual model
examples of the full container-linerclosure package in Part II of this
Handbook.

Chapter: 5.1
1

Generic Development

CHAPTER 5

Containers

SEMISOLIDS

Ø CHECKLIST ×
CL # HBGD-03-0298

Container-liner-closure Systems
‘…check that the suppliers specifications - always refer to the latest USP edition…’

1.

The components of the thermoplastic tube complies with 21CFR?

qYes qNo

2.

HDPE complies with the 21 CFR 177.1520 ?

qYes qNo

3.

HDPE complies with the USP requirements for HDPE ?

qYes qNo

4.

Polypropylene complies with the 21 CFR 177.1520 ?

qYes qNo

5.

The thermoplastic colorant complies with 21 CFR 17.300 ?

qYes qNo

6.

The inner seals in the cap complies with the 21 CFR 176.180 ?

qYes qNo

(where relevant)?

21 CFR 172.280

qYes qNo

(where relevant)

21 CFR 175.300

qYes qNo

7.

The vendor’s name & address of each component is identified ?

qYes qNo

8.

The manufacturer of tubes, resin, cap and liner etc. identified ?

qYes qNo

9.

The resin type and code number is fully identified ?

qYes qNo

10. Specifications comply with the current USP requirements ?

qYes qNo

11. Each pack size (e.g. 20, 50, 100 g) has a separate set of qYes qNo
component specifications (for container, resin, liner, cap, colorant etc.)
12. Letters of authorization (LOA) from the DMF holders obtained ?

qYes qNo

13. Certificates of Compliance identifying the materials used in the qYes qNo
component manufacture conform to 21 CFR 172-177 etc.?
14. Certificate of Analysis identifying component meets specific USP qYes qNo
Test Requirements (e.g. moisture permeability test etc.)?
15. GMP Certification statement indicating GMP status of component qYes qNo
manufacturing facility?
Footnote : Bold numbers in checklist indicate that this documentation must be on file with generic drug
developer prior to process qualification or pivotal batch manufacture.

Handbook of Pharmaceutical

Chapter: 5.2
2

Generic Development

CHAPTER 5

Containers

SEMISOLIDS

Ø CHECKLIST×
CL # HBGD-03-0298

Container-Liner-Closure Systems

16.

check the suppliers documentation thoroughly
it impacts on your ANDA submission ’

GMP Certification of component manufacturing facilities indicate:

♦ All materials are manufactured in accordance with DMF # 0000

-

qYes qNo
qYes qNo

♦ Manufacturing is in compliance to Good Manufacturing Practice cGMP 21 qYes qNo
CFR Part 210-211)?

♦ No materials specification changes will be made without amendment to qYes qNo
component DMF # 000?

♦ No materials specification changes will be made without full notification to all qYes qNo
ANDA holders ?
17. Technical data sheet and component drawings supplied by manufacturer qYes qNo
for each component (container, liner composite, closure, fillers)?
18.

Separate component drawings and specifications for

- tube/container?

qYes qNo

19.

Separate component drawings and specifications for

- seal/laminate?

qYes qNo

20.

Separate component drawings and specifications for

- cap/closure?

qYes qNo

21.

Separate specifications and certificate of analysis for applicators

qYes qNo

22.

Generic Developer has a LOA for every DMF File referenced to FDA?

qYes qNo

23.

All DMF #’s referenced in ANDA are identified on ANDA cover page?

qYes qNo

24.

Documentation has been sourced on time during product design phase ?

qYes qNo

25. Documentation has been audited in-house for current pharmacopoeial qYes qNo
editions, latest Certificate of Analysis and updated component specifications?
Footnote : Insure that vendors and manufacturers have updated all their component specification and
documentation to the current year. Specifications must apply to actual batch lot supplied to developers. A
typical component description: 22mm x 100 mm blind ended metal tube with valspar 3846 (5061) lining
with HDPE cap with #16 neck

Handbook of Pharmaceutical

Chapter: 5.3
3

Generic Development

CHAPTER 5

Containers

SEMISOLIDS

STANDARD OPERATING
PROCEDURES
SOP #

Page 1 of 1.

HBGD-03-0298

Container-Liner-Closure Systems
Semisolid based topical products are marketed in single or multi-unit containers.
• Rigid bottles / jars (glass or polypropylene )
• collapsible tubes (coated metal or thermoplastic low density polyethylene (LDPE)
• Flexible pouches

Collapsible tubes are usually:
• metal (epoxy coated)
• metal-lined low density polyethylene
• laminated material (LDPP / Epoxy etc.)

The tubes are fabricated by rolling and heat-sealing flat stock into a continuous tube
of desired diameter, then trimming to length and attaching the head by injection
molding. The head insert is sometimes made of urea formaldehyde. Typically there
is no cap liner. The inner seal may be plastic or metal which is heat-sealed into
place
or molded with the tube. The former may have a lip for removal by hand. The
alternative is to incorporate a device into the construction of the cap before breaking
the inner seal. The marketed package may include a separate applicator device or
the applicator may be part of the closure.
The following selected model Standard Operating Procedures are recommended SOPs:

CONTAINER-LINER-CLOSURE SYSTEMS
# P-000-01-0298
# P-000-01-0298
# P-000-01-0298
# P-000-01-0298

- Container-liner-closure systems for generic development.
- Documentation requirements for container-liner-closure systems.
- Specific requirements for semisolid container-closure systems.
- Coating Integrity testing for flexible metal tubes (semisolid.)

21 CFR References for :Examples; HDPP (Polypropylene) 1
HDPE (Polyethylene)2
Colorant (in thermoplastic)
HDPE Resins (of thermoplastic)
Resinous and polymeric Coatings
Fluorocarbon resins
Olefin Polymers
Polyethylene phthalate polymers
Inner seals (in closures/caps)
1 High Density Polypropylene
2 High Density Polyethylene
Edition No. 03
Ed. Status : 02

Effective Date :
DD/MM/YY

Handbook of Pharmaceutical

-

177. 1520
177. 1520
175.300
177.1520
175.300
177.1380
177.1520
177.1630
176.180, 172.280, 175.300
HDPP
HDPE

APPROVED
___________
Department

___________
RD

Chapter: 5.4
4

____________ __________/___________
RA
QC
/
QA

Generic Development

CHAPTER 5

CONTAINER-CLOSURE

SEMISOLIDS

Total Number

STANDARD OPERATING

SOP # S-115-01-06YY

of Pages: 3.

PROCEDURES

CERTIFICATION OF A CONTAINER-LINER-CLOSURE SYSTEM.

PURPOSE

1.

The

purpose of this Standard Operating Procedure is to describe the vendor
documentation required in order to specify the container-closure components of a
packaging system necessary for a process qualification or pivotal batch procedure.

RESPONSIBILITY

2.

Responsibility of actions is represented by the relevant symbol in the text.
• Symbol indicates Protocol is prepared by R&D Project and Process Development
Managers. Protocols are approved by the R&D and QA.
‚ Symbol indicates performed by validation team.
ƒ Symbol indicates performed by plant QA Technicians.
„ Symbol indicates In-process testing performed by the plant QA Technicians.
… Symbol indicates Batch Release Testing performed by the plant QC Analytical
Laboratory.
† Symbol indicates testing performed by the R&D Analytical Laboratory.
‡ Symbol indicates analysis and evaluation of the test data generated, performed
by the R&D Validation Team and approved by the R&D Quality Assurance.
ˆ Symbol indicates work is performed by vendor or supplier of goods/materials.
‰ Symbol indicates work is performed by Stability Technicians.

FREQUENCY

3.

Performed with each PQ or Pivotal batch placed on stability.

PROCEDURE

4.

The following documentation is required from the original component manufacturers
for each material or part of the container-closure-system •.
The components shall be tested by the component QC laboratory …
The documentation shall be inspected and audited by ‡

Container Specifications:From the container manufacturers (including) ˆ :-

drawings / diagrams with annotated dimensions

-

USP Tests performed on container, including identification test

-

Certificate of Conformance meeting USP and 21 CFR requirements

-

Certificate of Analysis

-

DSC thermal analysis (for thermoplastic containers only)

Edition Number:
01
Ed. Status:
New

Effective Date:
DD/MM/YY

Handbook of Pharmaceutical

APPROVED
_______________ ______________
Department
R &D

Chapter: 5.5
5

C1-05-2.doc

_______________ __________/________
RA
QC / QA

Generic Development

CHAPTER 5

CONTAINER-CLOSURE

SEMISOLIDS

Total Number

STANDARD OPERATING

SOP # S-115-01-06YY

of Pages: 3.

PROCEDURES

CERTIFICATION OF A CONTAINER-LINER-CLOSURE SYSTEM.

Container Specifications (continued):From the container manufacturers (including) ˆ ;

Letters of Authorization ˆ
-

LoA from manufacturer referencing their container DMF #0000.

-

LoA from resin manufacturer referencing their resin DMF #0000 as used in the
manufacture of the container.
Obtain separate letters for each resin type used in different tubes or plastic containers.

Closure Specifications:From the closure manufacturers (including) ˆ :-

drawings / diagrams with annotated dimensions

-

Tests performed on closure

-

Certificate of Conformance meeting all USP XXIII and complies to 21 CFR
requirements

-

Certificate of Analysis

-

DSC thermal analysis (for thermoplastic closure only)

Letters of Authorization ˆ
-

LoA from closure manufacturer referencing DMF #000 of cap

-

Statement of GMP compliance of manufacturer

-

LoA from resin manufacturer referring thermoplastic resin DMF #000.

-

Statement of GMP compliance of manufacturer

Obtain separate letters for each resin type used in thermoplastic closures.

Liner Specifications (bulk jars and plastic containers):From the cap/liner manufacturers (including) ˆ:-

drawings / diagrams with annotated dimensions

-

Tests performed on seal

-

complies to 21 CFR requirements

-

Certificate of Analysis

-

Letters of Authorization ˆ
LoA from manufacturer referencing DMF #000 of seal
Statement of GMP compliance of manufacturer

Edition Number:
01
Ed. Status:
New

Effective Date:
DD/MM/YY

Handbook of Pharmaceutical

APPROVED
_______________ ______________
Department
R &D

Chapter: 5.6
6

C1-05-2.doc

_______________ __________/________
RA
QC / QA

Generic Development

CHAPTER 5

CONTAINER-CLOSURE

SEMISOLIDS

Total Number

STANDARD OPERATING

SOP # S-115-01-06YY

of Pages: 3.

PROCEDURES

CERTIFICATION OF A CONTAINER-LINER-CLOSURE SYSTEM.

Pressure sensitive, tamper resistant, adhesive seals:From the Adhesive seal manufacturers ˆ:Adhesive seal Specifications for jars and containers (including);
-

drawings / diagrams with annotated dimensions

-

Tests performed on adhesive seal

-

complies to 21 CFR requirements

-

Certificate of Analysis
Letters of Authorization ˆ

-

LoA from manufacturer referencing DMF # of adhesive seal

-

Statement of GMP compliance of manufacturer

Nozzles and Applicators:From the nozzle and applicator manufacturers ˆ;
-

drawings / diagrams with annotated dimensions

-

USP Tests performed on nozzle/applicator, including identification test

-

Certificate of Conformance meeting USP and 21 CFR requirements

-

Certificate of Analysis

-

DSC thermal analysis (for thermoplastic containers only)

Letters of Authorization ˆ
-

LoA from manufacturer referencing their nozzle/applicator DMF #0000.

-

LoA from resin manufacturer referencing their resin DMF #0000 as used in the
manufacture of the nozzle/applicator.

Obtain separate letters for each resin type used in different nozzle or plastic applicator.

3
•‚ƒ„…†‡Œ•Ž
[End of Document]

Edition Number:
01
Ed. Status:
New

Effective Date:
DD/MM/YY

Handbook of Pharmaceutical

APPROVED
_______________ ______________
Department
R &D

Chapter: 5.7
7

C1-05-2.doc

_______________ __________/________
RA
QC / QA

Generic Development

CHAPTER 5

CONTAINER-CLOSURE

SEMI SOLIDS

STANDARD OPERATING
PROCEDURES

SOP # S-115-01-03YY

Total Pages: 2

CERTIFICATION OF A CONTAINER-LINER-CLOSURE SYSTEM.
CONTAINER

CLOSURE

DRAWINGS &
SPECIFICATIONS

DRAWINGS &
SPECIFICATIONS

MATERIAL TESTS
(USP)

MATERIAL TESTS
(USP)

Certificate of
Analysis

Certificate of
Analysis

Letter of Access
(from each vendor)

Edition Number:
01
Ed. Status :
New

SEAL
DRAWINGS &
SPECIFICATIONS

MATERIAL TESTS
(USP)

Certificate of
Analysis

Letter of Access
(from each vendor)

Effective Date:

APPROVED

DD/MM/YY

_______________
Department

Handbook of Pharmaceutical

Letter of Access
(from each vendor)

C1-05-3.doc

__________________
R &D

__________________
RA

Chapter: 5.8
8

_______________
QC

________________
QA

Generic Development

SEMISOLIDS

MANUFACTURING

In order to achieve consistent batch-tobatch analysis, the manufacturing
procedure requires individual process
step
optimization
(i.e.
process
validation).

Manufacturing
Instructions
‘start with the order of addition and
the processing conditions...
End with process optimization and
process validation... ‘

The Manufacturing Instructions

THE PRODUCT FORMULA

T

he initial generic product formula
may be quantitatively based on the
EU Comparator as to the type and
grade of excipients and semi actives
present in the innovators formulation.
Ingredients
The analytical evaluation and reverse
engineering of the formula will provide
confirmation of the qualitative formula
ingredients
and
quantitative
percentages of each non active and
semi active ingredients.
Semi actives
The semi active will have been
reviewed and challenged to establish
that they perform to maintain product
quality.
The preservative systems adequately
meets
the
preservative
efficacy
requirements and the anti-oxidant
minimizes loss of active ingredient on
product aging.
Formula optimization requires that the
excipient percentage amounts have
been optimized for maximum efficacy.
Optimum formula parameters of pH,
viscosity,
preservation and stability
have been achieved from the ideal
excipient percentages evaluated and
tested.
PROCESS VALIDATION
Developing the manufacturing process
and process parameters will result in a
rugged
set
of
manufacturing
instructions and in-process controls.
The end point of the process
optimization is a consistent batch-tobatch product quality and uniform
finished product specifications.

Handbook of Pharmaceutical

CHAPTER 6

The process optimization procedure
requires
individual
process
step
evaluation during the development of
the process manufacturing instructions.
The end of the product development
phase will
result in a regulatory
demonstration of the development
optimization procedure or development
validation with the demonstration of the
pivotal generic batch and thereafter the
three consecutive validation batches.
The manufacturing process requires
certain key steps to be evaluated for
optimizing the process and producing a
rugged
end
product.
These
development steps are:
Addition of ingredients•
Screening of bulk powders
(size)

order of addition of excipients

dissolving times for solids

rinsing procedures (no
residues)
Processing of the ingredient mix•
intermediate product
temperatures

stirring / mixing speeds (rpm)

stirring times (start / stop)

heating and cooling rates

maximum processing times
From this development and optimization
procedures - key process steps can be
identified with the potential to affect the
finished drug product both in quality
and specifications. Upper and lower inprocess controls are established for
these critical processing steps and
these limits are individually challenged
and qualified.
This
process
of
developmental
validation results in a final validated
process producing a rugged drug
product
meeting the desired drug
product specifications.

Chapter: 6.1
1

Generic Development

SEMISOLIDS

MANUFACTURING

CHAPTER 6

ØC H E C K L I S T ×
CL # HBGD-01-01YY

MANUFACTURING INSTRUCTIONS
‘ write the manufacturing instructions clearly - so they can be simply followed
… one step at a time…‘

The manufacturing instructions specify the exact equipment used?.

qYes - qNo

Major equipment is identified with an ID number ?

qYes - qNo

The words “use suitable / appropriate... etc. ” are not used ?

qYes - qNo

All mixing times have a ‘start and stop’ mixing time ?

qYes - qNo

All mixing speeds are precisely stated (no ranges) ?

qYes - qNo

Instructions identify the dissolving times for solids ?

qYes - qNo

Operator and check signatures are per individual step ?

qYes - qNo

No signature is for two operations in one step ?

qYes - qNo

Manufacturing steps are broken down to one action only ?

qYes - qNo

Temperatures are recorded as T0 C ( ±20 C) - avoid ranges ?

qYes - qNo

Vacuum is recorded as P bar ( ± 0.1 bar) ?

qYes - qNo

Critical intermediate product temperatures are identified ?

qYes - qNo

The overall manufacturing time is indicated

qYes - qNo

The maximum standing time before filling is indicated ?

qYes - qNo

The sample size, number of samples and sampling location is identified ?

qYes - qNo

Sample containers for micro analysis are sterile and wrapped ?

qYes - qNo

Handbook of Pharmaceutical

Chapter: 6.2
2

Generic Development

SEMISOLIDS

MANUFACTURING

CHAPTER 6

Manufacturing Instructions

TABLE OF CONTENTS.
This section contains:
• Outlines of process and controls
• Description of Manufacturing Process
• Manufacturing Procedure Flow Chart
• Master Production Batch Records for intended production lots
• Packaging Records for intended production lots
• Formula comparison between pivotal and intended commercial lots
• Equipment Comparison pivotal and intended commercial lots
• Description of Packaging Operation
• Reprocessing Statement(s)

4

Handbook of Pharmaceutical

Chapter: 6.3
3

Generic Development

SEMISOLIDS

MANUFACTURING

CHAPTER 6

Manufacturing Instructions
OUTLINE OF STANDARD OPERATING PROCEDURES FOR :
MANUFACTURING AND PROCESSING
1.

Production Planning - Prepares a production order file for each production
batch according to the production schedule.

2.

Production Planning - Assigns batch numbers, according to the existing
code procedure, and enters these numbers in the batch numbers log.

3.

Production Planning - A photocopy of the master formula record and
manufacturing instructions is prepared with the specific manufacturing batch
number.

4.

Production Planning - Prepares all forms needed in the manufacturing
process which are placed in the product order file.
The file is then transferred to the Weighing Center/Dispensing Area.

5.

Dispensing Area - Weighs all raw material components according to the
master formula record. For each weighing, the raw material receiving
logbook number is entered on the master formula record. All materials
belonging to one manufacturing batch of the product is placed on a separate
pallet and covered with a pallet cover or clear shrink-wrap.
As per production schedule the pre-weighed raw material on pallets are
transferred to productions, by production personnel, under the responsibility
of the department head.

6.

Production Department - During manufacturing, the product test results are
recorded on the control forms which are attached to the master formula and
manufacturing instructions batch record.

7.

Production Planning - forwards a “Standard Packaging Sheet” with the
computerized order to the packaging department.

8.

Packaging Department - forwards the “Standard Packaging Sheet” and the
computer order to the packaging materials warehouse.

9.

Packaging Department - Authorizes packaging startup, in-process
compliance, on the “Packaging Work Sheet”.
After packaging, the packaged goods are transferred to the
warehouse/holding area under a quarantine status, pending QC release.
The product is tested by the QC analytical laboratory.
Production records and test results are analyzed by QA Department and on
release the product is moved to the warehouse ready for shipment.
The batch records are archived by the Quality Assurance Department.

10.
11.
12.
13.
14.

Shipping Department - maintains a complete and traceability record of the
dispatches of each product batch number and its final destination.

Handbook of Pharmaceutical

Chapter: 6.4
4

Generic Development

SEMISOLIDS

MANUFACTURING

CHAPTER 6

Manufacturing Instructions
OUTLINE OF STANDARD OPERATING PROCEDURES
FOR:

IN-PROCESS CONTROLS
1. At all stages of manufacturing, processing, time limitations and packaging
appropriate control procedures are employed in conformity with current good
manufacturing practice.
2. Appropriate in-process controls include material testing by quality control and
quality assurance personnel. These test cover:


Physical specifications of the bulk material (Uniformity of Content)
Fill Weights

3. In-process material testing is performed by Qualified Personnel.
4. The Quality Assurance Department reviews the batch test results and evaluates
the acceptance or rejection of each batch lot.

BATCH RECORDS FOR
POST-APPROVAL PRODUCTION BATCHES

E

nclosed are the production batch records (master, packaging and labeling) for
Post-Approval production batch.

Translation Policy - for Non English Speaking Areas:
Certain manufacturing and process and control documents may be written in
[English and the National Foreign language] with some information in English only.
Where information is provided in [English and a Foreign language], an authorized
English translation is provided preceding the document in [English and the Foreign
language].
Where only English is used on a page, no translation is provided.

4

Handbook of Pharmaceutical

Chapter: 6.5
5

Generic Development

SEMISOLIDS

MANUFACTURING

CHAPTER 6

Manufacturing Instructions
IN-PROCESS CONTROLS
DURING SEMISOLID FILLING
In-process testing is conducted independently by both production and
quality control trained personnel. The tests specified in the underlying
tables are performed in accord with the in-process product specifications.
When, a test is not required, according to the written specifications, it will
not be performed.
Production personnel test the physical specifications of random samples
according to the individual product specifications: A minimum sampling frequency is
tabulated for each eight hour (shift) period.

Production In-process
Testing Schedule:
TEST
PERFORMED
Bulk Description

Sample
Size

Frequency
per shift
(min)

(1)

1

At start.

Fill Weight (Active)

10

At 30 min.
intervals.

Cap Torque

6

At 30 min.
intervals.

Acceptance
Criteria (2)
Within written specifications.
NMT 2 Containers from of the 20 tested
may deviate from product spec. No
deviation permitted from Double Limits(3)
specification.
No deviation from product specifications is
permitted.

KEY:
1

The testing frequency is performed twice when the overall filling time is less than four hours.

2

Deviations from specifications and acceptance criteria, arising during the in-process
controls, shall determine the corrective action to be performed on the filling machinery
during the filling stage.

Handbook of Pharmaceutical

Chapter: 6.6
6

Generic Development

SEMISOLIDS

MANUFACTURING

CHAPTER 6

Manufacturing Instructions

Q

uality Control personnel test the physical specifications of random samples
according to the individual product specifications sheets: A minimum sampling
frequency is tabulated for each eight hour (shift) period.

Quality Control
In-process Testing Schedule:

TEST

Sample

Frequency

PERFORMED

Size

per shift
(min.)

Material Description

1 (1)

Once

(1)

at start
Individual Fill

20

(1)

6 (1)

No deviation from product specification
is allowed.

60 min

NMT 2 Containers from of the 20
tested may deviate from product spec.
No deviation permitted from Double
Limits(3) specification.

60 min

No deviation from product specification
is allowed

Weight

CAP TORQUE

Acceptance
Criteria (2)

KEY:
1

Samples are taken, independently by QC personnel for batch release purposes, at least
once per hour throughout the FILL run, producing a total representative sample quantity of 20
- 40 Containers . This representative sample lot is for QC batch release purposes .
2

Deviations from specifications and acceptance criteria, arising during the in-process controls,
shall determine the corrective action to be performed on the filling machinery during the
filling stage.
3

Double Limits for the Individual Fill Weight test are defined as the double value from the
minimum or maximum limit in relation to the nominal Fill value (i.e. target weight value).

Handbook of Pharmaceutical

Chapter: 6.7
7

Generic Development

SEMISOLIDS

MANUFACTURING

CHAPTER 6

PRODUCTION YIELDS
STANDARD OPERATION PROCEDURE - OUTLINE

C

alculation of batch yield in the overall manufacturing involves the use of three
different types of calculations.
The first yield calculation is called the
“Percentage Yield - Usable Material” [% Yield Usable].
The second term “Percentage Yield - Overall” [% Yield Overall] and the third
calculation is called the “Percentage Batch Yield. The three yield calculations are
defined as follows:
USABLE MATERIAL PERCENTAGE YIELD:

This calculation is performed at the end of each step in the manufacturing process
and is recorded on the actual Manufacturing Procedure documents. The intent of
the calculation is to define the usable amount of material available for use in the next
manufacturing step (i.e. compression, packaging, etc.). Because this value is only
determining the “available” amount of material, it does not take into consideration the
amount of material that may be lost to waste, sampling or rejection during
compression/encapsulation/coating. Logically, this value is calculated for
informational purposes and is not held to specific limits as it is partially dependent
on sampling requirements and equilibration of manufacturing equipment (i.e. tablet
presses, etc.).
PERCENTAGE YIELD OVERALL:

This calculation is performed at the end of each step in the manufacturing process
and is recorded on the attachment entitled Material Balance/Dry Production. The
intent of the calculation is to determine the overall batch yield attained at each step
in the process. Because this value determines the overall yield, it takes into account
not only the “usable” portion of the batch but also the quantity of material lost to
recoverable waste, sampling and rejection during compression/ encapsulation/
coating. Since this value incorporates all measurable and accountable quantities of
the material, it is used as a means with which to control the manufacturing process.
The limit established for this value is “Not less than 98% [in other words “not more
than 2% unexplained loss”] from the previous manufacturing stage.”
In the event that this limit is not achieved during the batch production, report of the
deviation is made in an accompanying Manufacturing Deviation Report.
PERCENTAGE BATCH YIELD:

This

calculation is performed after the completion of the entire manufacturing
process and is also recorded on the - Production Material Balance form.
The intent of this calculation is to determine the yield of the batch across the entire
manufacturing process. As this value determines the entire batch yield, it therefor
takes into account the final packaged quantity (converted to weight), as well as the
quantities of samples, rejections and recoverable waste from each processing stage.
As this yield value also incorporates all measurable and accountable quantities of
the material from an entire batch production view point, it is used as a yardstick with
which to control the manufacturing process. The limit established for this value is
“95.0% - 103.0%” [of the theoretical batch quantity]. In the event that this limit is not
achieved at the end of the manufacturing process, report of the deviation and its
resultant investigation is made in an accompanying Manufacturing Deviation Report.

4
Handbook of Pharmaceutical

Chapter: 6.8
8

Generic Development

SEMISOLIDS

MANUFACTURING

CHAPTER 6

Manufacturing Instructions
A DETAILED EXAMPLE ON DOCUMENTATION STRUCTURE
IDENTIFICATION OF BATCH PARAMETERS.

Product name:

[Generic] Cream

Strength: [000.0] - [000.0] mg/5mL

Batch Number:

AIG0000-00

Batch Size:

Department:

WET UNIT

Precautions:

Sub-lot No:

Caution:

•‚ƒ
…†

Cat./Formula No:

# AIG-[0YY001]

Cream þ ; Gel ý : Ointment ý

Based on PQ:

Batch # AIG-PQ[00-00

Semisolid þ

ý PIVOTAL

ý VALIDATION LOT

þ COMMERCIAL LOT

[000-000] units
þ1

ý2

ý3

Manufacture Date: Month DD, YY

BATCH

Change Control for this document

Original

No Change

þ

Change ý

KEY to:
Precautions:
• Wear Mask and Gloves
‚ Wear disposable overalls
ƒ Use air stream face visor with AIR filter
„ Use Mask, Gloves and Safety glasses Material causes extreme irritation to
skin and eyes Do not expose to skin or exposed areas.
Cautions:
… Avoid exposure to light / Protect form light
† Store in well closed containers and minimize or avoid exposure to
environmental air
‡ Raw material has to be stored at 5°°C - hold active material at 25o C for one
hour to reach room temperature before weighing, sampling or processing
ˆ Potential danger to pregnant women, pregnant women are prohibited in this
area
‰ Do not heat above [00]ø
øC
• Maintain Room humidity below 50%
Note:
A detailed structure for documenting the manufacturing process for emulsification
and homogenization is given as an example of how to prepare and write the
manufacturing and processing instructions.
This specific set of manufacturing instructions was chosen as it represents a
complex example and highlights numerous processing principles. The order of each
process step is critical and should follow the order that the ingredients appear in the
master formula.
As actual values and numerical parameters are not significant in the example
provided. The figures are simply reported as [00] for ease of purpose. Further
commercial examples are additionally provided annually with each new edition.

Handbook of Pharmaceutical

Chapter: 6.9
9

Generic Development

SEMISOLIDS

MANUFACTURING

CHAPTER 6

Manufacturing Instructions
MANUFACTURING INSTRUCTION
COMMERCIAL PRODUCTION
[Generic name] SEMISOLID [USP] [000.0] mg/g Lot: 000
Miconazole Cream USP [20.0] mg/gram
Batch No:

Weighing Date :
Page 1 of 2 pages

Mg
Per
gram

%
Exc
ess

Raw Material Names

#

Sign
weigh.
Dept.

per [150] kg
Kg

g

mg

L

mL

A

B

PART I - OIL PHASE
180.00
25.20
2.00
0.05
207.252

20.00
30.00
1.50
9.60
10.00

Pegoxol 7 Stearate
[Tefose 63™]
Heavy Mineral OIL NF
Benzoic Acid USP
Butylated Hydroxyanizole

27

000

3

780
300
7

500

Theoretical End Weight.
PART II

31

087

500

3
4

000
500

1
1

225
440
500

10

665

108

247

108

247

150

000

[Miconazole USP Micronized
Peglico 5 Oleate
[LABRAFIL M 1944™]
Edetate Disodium USP
st
Heavy Mineral OIL (1 Rinsing)
Heavy Mineral OIL (2nd Rinsing)
Theoretical End Weight.

SETTING OUT THE
MASTER FORMULA
IN A STANDARDIZED
FORMAT

PART III - AQUEOUS PHASE
721.650
721.650

Purified Water USP
Theoretical End Weight.

500
500

PART: IV MIXING STAGE
1000.0
1000.0
Edition Number:
01
Ed. Status:
New

Combined Phases - [1+2] + 3
Theoretical End Weight.
Effective Date:
DD/MM/YY

Handbook of Pharmaceutical

150

000

APPROVED
____________
Department

__________
R &D

Chapter: 6.10
10

_______________
RA

The ORDER
of appearance
of the ingredients
is the same
ORDER of
processing
_________/________
QC / QA

Generic Development

SEMISOLIDS

MANUFACTURING

CHAPTER 6

Manufacturing Instructions
MANUFACTURING INSTRUCTION
COMMERCIAL PRODUCTION
[Generic name] SEMISOLID [USP] [000.0] mg/g Lot: 000
Miconazole Cream USP [20.0] mg/gram
Batch No:

Weighing Date :
Page 2 of 2 pages

Mg
Per
gram

%
Exc
ess

Raw Material Names

#

Sign
weigh.
Dept.

per [300] kg
Kg

g

mg

L

mL

A

PART I - OIL PHASE
180.00
25.20
2.00
0.05
207.252

20.00
30.00
1.50
9.60
10.00

Pegoxol 7 Stearate
[Tefose 63™]
Heavy Mineral OIL NF
Benzoic Acid USP
Butylated Hydroxyanizole

54

000

7

560
600
15

Theoretical End Weight.
PART II

62

175

6
9

000
000

2
3

450
880
000

21

330

216

495

216

495

[Miconazole USP Micronized
Peglico 5 Oleate
[LABRAFIL M 1944™]
Edetate Disodium USP
Heavy Mineral OIL (1st Rinsing)
Heavy Mineral OIL (2nd Rinsing)
Theoretical End Weight.

000

PART III - AQUEOUS PHASE
721.650
721.650

Purified Water USP
Theoretical End Weight.

PART: IV MIXING STAGE
1000.0

Combined Phases - [1+2] + 3

300

000

1000.0

Theoretical End Weight.

300

000

Edition Number:
01
Ed. Status:
New

Effective Date:
DD/MM/YY

Handbook of Pharmaceutical

APPROVED
____________
Department

__________
R &D

Chapter: 6.11
11

_______________
RA

_________/________
QC / QA

Generic Development

B

SEMISOLIDS

MANUFACTURING

CHAPTER 6

Manufacturing Instructions
MANUFACTURING INSTRUCTION COMMERCIAL
PRODUCTION

[Generic name] SEMISOLID [USP] [000.0] mg/g Lot: 000
Batch No:

Weighing Date:
Page 1 of 4 pages

Machine

MANUFACTURING INSTRUCTIONS

Sign
A+B

Date

Step 1. IDENTIFY the equipment and verify the cleanliness prior
to use.

PART ONE - OIL PHASE
Step 2. LOAD into kettle No [ ] fitted with [Mixer # [ ]-Type & No)
the ingredients in the following order:
Pegoxol 7 Stearate [Tefose 63™]
Heavy Mineral OIL NF
Benzoic Acid USP
Butylated Hydroxyanizole
and mix for [20] minutes at mixer setting speed II
Step 3. HEAT while mixing to NMT [45]º C (Target: [42]º C).
Time of adding
[ ] min.
Total Mixing Time
[ ] min.

NOTE:
The ingredients are written in
the same order as they are
processed and also as they
appear in the 'Master
Formula'

PART TWO Active OILY PHASE
Step 4. LOAD into a [Small Mixer-Type & No) the ingredients in
the following order:
Miconazole USP - Micronized
Peglico 5 Oleate - [LABRAFIL M 1944™]
Edetate Disodium USP
MIX for [20] minutes at mixer speed [II] until mix is fully
micronized material is suspended and homogeneous.
Step 5. HEAT while mixing to NMT [45]º C (Target: [42]º C).
Target Temperature
[ ]º C
START of mixing
[ ]
END of mixing
[ ]
Total Mixing Time
[ ] min
Ed Number:
01
Ed. Status:
New

Effective Date:
DD/MM/YY

Handbook of Pharmaceutical

APPROVED
____________
Department

__________
R &D

Chapter: 6.12
12

_______________
RA

_________/________
QC / QA

Generic Development

SEMISOLIDS

MANUFACTURING

CHAPTER 6

Manufacturing Instructions
MANUFACTURING INSTRUCTION COMMERCIAL
PRODUCTION
Page 2 of 4 pages

MANUFACTURING INSTRUCTIONS

Machine

Sign
A+B

Date

PART THREE AQUEOUS PHASE
Step 6. Heating the Water Phase

(i) WEIGH or MEASURE 000.0 Kg [PURIFIED WATER USP] into a
stainless steel mixing kettle fitted with a high speed variable mixer. (#0)
(ii) OPERATE the mixer while HEATING to NMT [95]ºC (Target: [95]º
C).
(iii) HOLD the heated Water at the target temperature for NLT60
minutes
Target Temperature
Time of Heating
Total Process Time

[ ]º C).
[ ]
[ ] min

Step 7. Cooling the Water Phase
COVER and Cool Step 6 [PURIFIED WATER USP] to a target
temperature while slowly stirring - Target Temperature 280C [±20C]
Target Temperature
Start of Cooling Time
End of Cooling Time
Total of Cooling Time

NMT [
[
[
[

NOTE
Each action
is
CAPITALIZED

]º C
]
]
] min

PART FOUR - ADDITION OF OILY PHASE
Step 8. ADD the Active Oily Phase STEP 4 to the Bulk Oil Phase STEP
2 and mix at speed [III] until homogeneous. RINSE active material twice
with heavy mineral oil. Drain container fully after each RINSE procedure.
Start of Mixing
End of Mixing
Total of Mixing Time

[ ]
[ ]
[ ] min

Step 9. CHECK that the oil phase after the mixing period is a
homogeneously dispersed oily suspension - if necessary mix for an
additional 20 minutes
Start of Mixing
[ ]
End of Mixing
[ ]
Additional Mixing Time
[ ] min
Ed Number:
01
Ed. Status:
New

Effective Date:
DD/MM/YY

Handbook of Pharmaceutical

APPROVED
____________
Department

__________
R &D

Chapter: 6.13
13

_______________
RA

_________/________
QC / QA

Generic Development

SEMISOLIDS

MANUFACTURING

CHAPTER 6

Manufacturing Instructions
MANUFACTURING INSTRUCTION COMMERCIAL
PRODUCTION
Page 3 of 4 pages

MANUFACTURING INSTRUCTIONS

Machine

Sign
A+B

Date

ADDITION OF AQUEOUS PHASE

Step 10. RECORD the Aqueous and Oil Phase temperatures.
Temperature of AQUEOUS Phase NMT [30]º C (Target: 280C [±20C])
Temperature of OIL Phase
NMT [30]º C (Target: 280C [±20C])
Step 11. ADD the aqueous phase to STEP 8 while continuously mixing
at mixer speed III.
Start of Mixing
[ ]
End of Mixing
[ ]
Total Mixing Time
[ ] min
Step 12. ATTACH the mixing kettle temperature graphs (Type & No) to
the manufacturing instructions. Add the batch number to the temperature
graph and Immediately date and sign it..

COOLING OF COMBINED PHASES
Step 13. COOL Step 11 to a target temperature while slowly stirring
[Set I].
Target Temperature 250C [±20C] Record Temperature ______0C
Step 14. PASS the SEMISOLID through an HOMOGENIZER (Type &
No) fitted with a [0.0 mm] screen into an ultra clean holding bin.
Step 15. CHECK pH [25]º C of a sample of the homogenized
SEMISOLID).
Record pH Result: _________ [Units]
DETERMINE the viscosity using (Type & No) Brookfield Viscometer;
Spindle No [3]
RPM [5]
Temperature [25]º C
Record First result: __________ [Cp]
Cp Limits:
[4000 to 6000]
Step 16. If necessary, CONTINUE to Homogenize the bulk material (recirculate) under the same conditions as STEP 14, until the viscosity is
close to the midpoint of the given range limits and check viscosity again.
Record Second result: __________ [Cp]
Step 17. PUMP the semisolid into (Type & No) [000] liter container.
Pumping Stop Time: _________
Step 18. WEIGH the bulk material ______Kg.
Step 19. Immediately ADD the batch number to the scale print-out, and
attach to the manufacturing instructions, date and sign the print-out.
Ed Number: 01

Effective Date:

Ed. Status:
New

DD/MM/YY

Handbook of Pharmaceutical

APPROVED
____________
Department

__________
R &D

Chapter: 6.14
14

_______________
RA

_________/________
QC / QA

Generic Development

SEMISOLIDS

MANUFACTURING

CHAPTER 6

Manufacturing Instructions
MANUFACTURING INSTRUCTION COMMERCIAL
PRODUCTION
Page 4 of 4 pages

MANUFACTURING INSTRUCTIONS

Machine

Sign
A+B

Date

YIELD CALCULATION
Step 20. Theoretical Weight [00.0] Kg.
Yield ___________ %
(Yield Limits: NLT 95% of Theoretical Weight.) No of Bins ______
Step 21. COLLECT 10 samples, each equivalent to the approximate
weight of 10 g in labeled sample containers. Collect samples from upper,
middle and lower part of the container. Send the samples to the QC
laboratory for Content Uniformity Testing.

The ingredients
are rewritten for
each sub-lot. Up to
three sublots are
common

Step 22. WEIGH the final material
Actual weight:
[00.0] Kg.
Theoretical Weight
[00.0] Kg.
Yield __________ %
No. of containers _____ .
(Yield Limits: NLT 98% of total actual weight

PART FIVE - FILLING PROCEDURE
Step 23. IDENTIFY and verify the cleanliness of the filling equipment in
use.
FILL the material according to the written specifications into air blown
tubes WITHIN 24 hours after manufacture.
CAUTION: (Do not leave standing over weekends/holidays.)
CHECK filling weight every 15 minutes.
CHECK end-crimp every 30 minutes.
CHECK Lot No and Expiration Date over stamping at start and end of
run.
CHECK Lot No and Expiration Date after reset or replacing type.
Air Blowing machine: (Type & No).
Filling machine:
(Type & No).
Machine Speed
_______ Tubes per minute.
Limit of output NLT _______ units; NMT _______ units.
Step 24. COUNT the total units produced:
Actual production count:
[00.0] Units.
Weight of Samples taken:
[00.0] Units.
Vacuum and rejects number:
[00.0] Units.
Total Units
[00.0] Units
Theoretical Weight
[00.0] Kg.
Yield _________ %
(YIELD
YIELD Limits: NMT 3% unexplained loss compared to the final bulk
weight from STEP 20.
Ed Number:
01
Ed. Status:
New

Effective Date:
DD/MM/YY

Handbook of Pharmaceutical

APPROVED
____________
Department

__________
R &D

Chapter: 6.15
15

_______________
RA

_________/________
QC / QA

Generic Development

SEMISOLIDS

MANUFACTURING

CHAPTER 6

Manufacturing Instructions
MANUFACTURING INSTRUCTION COMMERCIAL
PRODUCTION
FLOW CHART
Chart One

Water Phase Heating

Purified Water USP
Water Soluble
Excipients
Nitrogen blanket
Solvent NF
Antioxidant NF
Active USP

880-920C

MIXER
Water Phase Cooling
0
0
60 -62 C

Water USP
Purified Water
Lipophyllic Emulgent

1st RINSE

2nd RINSE

Nitrogen blanket

3rd RINSE
(microgram Actives )

OIL PHASE
MIXER
(S/S

Inlet temp.
up to 62°C
(target 60°C)

Mixing vessel)

Oily Solvent
Lipophobic Emulgent
Emulsifier
(Ross

IPQC Testing
pH
Viscosity
Content Uniformity
Microbial limits

mixer)

Viscosity Agent

Cool to 280C

(Specify Type)
at controlled temp - T 0C

DE-AERATOR
Homogeneous
Semisolid

Target Temp.
0
0
50 -52 C
HOLDING TANK
Under Nitrogen
Fill tubes according
to specifications

Ultra-clean FILLING
YIELDS
Overall Production Yields

Handbook of Pharmaceutical

Chapter: 6.16
16

Generic Development

SEMISOLIDS

MANUFACTURING

CHAPTER 6

Manufacturing Instructions
MANUFACTURING INSTRUCTION COMMERCIAL
PRODUCTION

ATTACHMENTS:
THE FOLLOWING ATTACHMENTS ARE PLACED HERE:

Process
Attachment # 1
Attachment # 2

Weight Print-Outs of the raw material / solvents.
Temperature Print-Outs of manufacturing process stage .

In-process
Attachment # 3

pH Print-Outs of Bulk.

Attachment # 4

Viscosity Print-Out of Bulk material.

Final Bulk

Mixing Process.
Attachment # 5
Attachment # 6

Mixing time Print-Out(s) of the Final Bulk.
Weight Print-Out of the Final Bulk.

Weight Control

Filling Process.
Attachment # 7

In-process weight Print-Outs of the filled material

NOTE:
Where automatic print-outs are not available, Statistical Data Work Sheets are filled
out, during the filling process. Suitable Semisolid Filling machines are highlighted
below.
Filling process:

Handbook of Pharmaceutical

[ALL-FILL \ KING]

Chapter: 6.17
17

Generic Development

SEMISOLIDS

MANUFACTURING

CHAPTER 6

Manufacturing Instructions
IN-PROCESS CONTROL SPECIFICATION
BULK MATERIAL
SUMMARY
Product: [Generic name] SEMISOLID [USP] [000.0] mg / g Lot No: 000
Quantity 000000
Yields
Bulk Yield

MNF Date:

Month DD, YY

Limit: NLT 98.0%

Total Final Yield

Limit: NLT 98.0% (based on actual quantities
processed).

Overall Production Yield

NLT 95.0%

1

Target Fill Weight
Limits 5.0%

____________ g.
NLT 00.000g

Target Cap Torque (jars)
Cap Torque Check (jars)

- NMT 00.000g

____________ Kg
____________ Kg

¹ Recorded on Statistical Data Work Sheets.

Handbook of Pharmaceutical

Chapter: 6.18
18

Generic Development

SEMISOLIDS

MANUFACTURING

CHAPTER 6

Manufacturing Instructions
IN-PROCESS CONTROL
SPECIFICATIONS
SUMMARY
PRODUCT: [GENERIC NAME] SEMISOLID [000.0] mg.
Labeled Amount: EACH gram contains [000.0] mg [Active Material]
In-process Specifications
Description

Opaque uniform homogeneous Semisolid
with a [type] color and [type] odor.

Active Fill Weight (±5.0%)

Target 000

Limit: 000 - 000 mL

pH
(±1.0 / 0.5 unit)
Viscosity

Target 0.0
Target 0000

Limit: 0.0 - 0.0
Limit: 0000 - 0000 cp.

Brookfield, Spindle #[ 0] After [ 0] rpm

In-Process
Semisolid Content Uniformity

Limit: 94.0 - 106.0% of labeled amount
RSD ≤ 6.0% (as per attached specifications)

Particle Size (microns)

Median 000µ

Limit: 000 - 000 µ

Yields
Actual Bulk Weight

Limit: NLT 98.0% (based on actual quantities
processed)

Calculated Filling Yield

Limit: NLT 100.0% (based on bulk weight/
target fill weight).

Actual Filling Yield

NMT 2.0% unexplained loss from the
previous final blend step

Overall Filling Yield

NLT 95.0%

Note: Exact Decimal points have been set for each specification

¹ Recorded on Statistical Data Work Sheets.

Handbook of Pharmaceutical

Chapter: 6.19
19

Generic Development

SEMISOLIDS

MANUFACTURING

CHAPTER 6

Manufacturing Instructions
IN-PROCESS CONTROL SPECIFICATION
SUMMARY
Product: [Generic name] SEMISOLID [USP] [000.0] mg / g
Quantity 000000

MNF Date:

Lot No: 000

Month DD, YY

Lowest

Mean

Highest

¹Target Fill weight 000.0 (g)

000.0

000.0

000.0

¹Weight of 10 Containers #1 (g)

000.0

000.0

000.0

¹Weight of 10 Containers #2 (g)

000.0

000.0

000.0

¹Weight of 10 Containers #3 (g)

000.0

000.0

000.0

¹Weight of 10 Containers #4 (g)

000.0

000.0

000.0

¹Weight of 10 Containers #5 (g)

000.0

000.0

000.0

¹Weight of 10 Containers #6 (g)

000.0

000.0

000.0

¹Weight of 10 Containers #7 (g)

000.0

000.0

000.0

¹Weight of 10 Containers #8 (g)

000.0

000.0

000.0

Weight Controls

In-Process Yields
¹Yield after filling vs. bulk material
¹Yield after filling to theoretical
Semisolid Yield

00.0 %
00.0 %
NMT 2.0% unexplained loss
from the previous step

¹ Recorded on Statistical Data Semisolid Filling Work Sheets.

Handbook of Pharmaceutical

Chapter: 6.20
20

Generic Development

SEMISOLIDS

MANUFACTURING

CHAPTER 6

Manufacturing Instructions
RELEASE SPECIFICATION FOR SEMISOLID [USP]

SUMMARY
Product: [Generic name] Semisolid [000.0] mg / g
Labeled Amount: Each gram contains [000.0] mg [Active Material]
Description

[Opaque] uniform homogeneous Semisolid
with a [type] color and [type] odor.

Identification A:

The Infra Red Absorption Spectrum conforms
to the Reference Standard

Identification B:

The Chromatogram of the sample solution
exhibits a peak with the same retention time
as the standard solution.

Fill Volume (±5.0%)

Target 000

Limit: 000 - 000 mL

pH
(±0.5 / 1.0 unit)
Viscosity

Target 0.0
Target 0000

Limit: 0.0 - 0.0
Limit: 0000 - 0000 cp.

Brookfield, Spindle #[ 0] After [ 0] rpm

Uniformity of Dosage Units:
Content Uniformity

Conforms to the current USP

Total Microbial Count
Total Aerobic Count

NMT 100
NMT 100

Objectionable Organisms

Absent: S aureus; E coli; P aerugenosa;
Salmonella species; Indicator orgs

Impurities /Degradation
Products determination
- Each Individual:
- Any other Individual:
- Total:
Assay (Preservative)
(Where Appropriate)

Assay (Active)

Handbook of Pharmaceutical

CFU / g
CFU / g

NMT 0.5% of the labeled amount
NMT 0.5% of the labeled amount
NMT 2.0% of the labeled amount

Limit: 50.0 - 105.0% of labeled amount
[00.0] - [000.0] mg / g
Limit: 90.0 - 110.0% of labeled amount
[00.0] - [000.0] mg / g

Chapter: 6.21
21

Generic Development

SEMISOLIDS

MANUFACTURING

CHAPTER 6

Manufacturing Instructions
RELEASE SPECIFICATION FOR SEMISOLID [USP]

OUTLINE of
IN-HOUSE ANALYTICAL SOP
Content Uniformity
The requirements for content Uniformity are met if the amount of the active ingredient in
each of the 10 samples, as determined from the Content Uniformity Analytical Method, lies
within the range of 90.0 - 110.0% of the labeled amount and the Relative Standard
Deviation is less than or equal to 6.0%.
If 1 sample is outside the range of 90.0 - 110.0% of labeled amount and no sample is
outside the range of 80.0 - 120.0% of labeled amount, or if the Relative Standard Deviation
is greater than 6.0%, or if both conditions prevail, test 20 additional samples.
The requirements are met if not more than 1 sample of the 30 is outside the range of 90.0 110.0% of labeled amount and no sample is outside the range of 80.0 - 120.0% of labeled
amount, the Relative Standard Deviation of the 30 samples does not exceed 7.8%.

Preservative Efficacy
Preservative Efficacy Testing (USP) is omitted as a routine QC test when fully qualified with
justification during the formulation development, process qualification AND pivotal batch lot
testing.
Preservative Efficacy Test USP are evaluated on stability testing at time of manufacture, 12;
24; and 36 months for PQ, Pivotal and validation batches only.

Preservative Efficacy / Preservative Assay
Preservative Efficacy Testing (USP) and Assay is omitted as a routine QC test when fully
qualified with justification during the formulation development, process qualification AND
pivotal batch lot testing.
Preservative Efficacy / Preservative Assay are evaluated on stability testing at time of
manufacture, 12; 24; and 36 months for PQ, Pivotal and validation batches only.

Regulatory Requirements - Preservative Assay
In cases of regulatory requests or insistence Preservative Assays are performed on every
5th production batch or at least once per year where only one batch is made.

Handbook of Pharmaceutical

Chapter: 6.22
22

Generic Development

SEMISOLIDS

MANUFACTURING

CHAPTER 6

Manufacturing Instructions
COMPARISON OF PIVOTAL AND PRODUCTION FORMULAE
Product: [Generic name] q [Semisolid] [000.0] mg per g. Lot: S-000

INGREDIENT

Amount per

Executed

Production

[0] mL

Batch

Batch

(mg)

0000

0000

(Kg)

(Kg)

Miconazole USP

00.00

00.00

00.00

Micronized

00.00

00.00

00.00

Pegoxol 7 Stearate [Tefose

00.00

00.00

00.00

63™]

00.00

00.00

00.00

Heavy Mineral OIL NF

00.00

00.00

00.00

Benzoic Acid USP

00.00

00.00

00.00

Butylated Hydroxyanizole

00.00

00.00

00.00

Peglico 5 Oleate

00.00

00.00

00.00

Edetate Disodium USP

00.00

00.00

00.00

Purified Water USP

00.00

00.00

00.00

000.000

000.000

Total

000.000

Adjust where applicable (i.e. if moisture content of active is greater than 0.5-1.0%):

Handbook of Pharmaceutical

Chapter: 6.23
23

Generic Development

SEMISOLIDS

MANUFACTURING

CHAPTER 6

Manufacturing Instructions
COMPARISON OF EQUIPMENT AND MANUFACTURING CONDITIONS
BETWEEN PIVOTAL AND COMMERCIAL BATCHES
Product: [Generic name] q [Semisolid] [000.0] mg per g. Lot: S-000

Equipment and
Manufacturing Conditions

Executed
Batch
000 Kg

Production
Batch
000 Kg

PROCESSING KETTLE

Production

Production

MIXER I

Production

Production

MIXER II

Production

Production

KING AIR MACHINE JD / BB

Production

Production

ZANASSI FILLING MACHINE
LA-60

Production

Production

ALL FILL FILLING MACHINE
SMR / 14

Production

Production

KING CAPPER C80

Production

Production

YAMATO CHECK WEIGHER

Production

Production

Equipment Variation

NONE

NONE

Manufacturing Area

Production

Production

Staff

Production

Production

SOP

Production

Production

Handbook of Pharmaceutical

Chapter: 6.24
24

Generic Development

SEMISOLIDS

MANUFACTURING

CHAPTER 6

Manufacturing Instructions
PACKAGING OPERATION DESCRIPTION
Product: [Generic name] q [Semisolid] [000.0] mg per g. Lot: S-000
Stage One.
PACKAGING COMPONENTS:
1. Bulk Product
2. HDPE / Aluminum / Glass Containers
3. Package Outsert (Product Leaflets)
4. Container Label
5. Master Cartons
6. Carton Shipping Labels
Stage Two
PACKAGING PROCEDURE:
HDPE Containers & Bulk Feed

Tube/Jar Cleaning Process
(Air and Vacuum)
Count & Fill

Capping
(Tube/Jar)

Jar Closure Torque Test

Container Label
and Outsert Attachment

Packed in Master Shipping
Cartons

Handbook of Pharmaceutical

Chapter: 6.25
25

Generic Development

SEMISOLIDS

MANUFACTURING

CHAPTER 6

Manufacturing Instructions
PACKAGING OPERATION - EQUIPMENT LISTING:
Product: [Generic name] q [Semisolid] [000.0] mg per g. Lot: S-000
Machine

Operation

Manufacturer

Type

Serial #

Supplier
1

Schenck

HDPE Bottle

Schenck Process

1000-S

or Amber

GMBH Darmstadt

AccuRate

No:

Output
CONTAINERS
per min2
50 Low

543123

100 High

Glass
Feeding
2

King

Air Cleaning

C.E. King Ltd, UK
SuperKleen

3

Cream

ALLFILL
KING

FILLER(1)

Filling
4

5

6.

7.

Capper

Torque

Groninger

Prestek

Capping

Torque

KING CAPPER

H.G.Kalish Inc.,
Canada
Groninger & Co

DFVK

KarlsHeim,
Germany

3000

Labelling &

Prestek Ltd

Printing

Science Park

SmartDate
Intelligent
Thermal
Transfer
Printer

Outserter

Nottingham UK

(1)

(2)

CAP 80

MK-

50 Low

2994

100 High

L-333

Count

L-334

50
50*

100
100*

2232-

50 Low

2234

100 High

2234-

50 Low

9987

100 High

5664

50 Low
100 High

53342

50 Low
100 High

Average figures for containers per minute output for Slow and High Speed.
All indicated machine outputs are adjusted to the Filling rate.

Handbook of Pharmaceutical

Chapter: 7.26
26

Generic Development

SEMISOLIDS

MANUFACTURING

CHAPTER 6

Manufacturing Instructions
BATCH RECORDS FOR EXECUTED BATCH
TYPE OF SEMISOLID
Lot No
Enclosed are the batch records of the executed batch
labeling).

(master, packaging and

Note:
Translation Policy - (Foreign Manufacturing Plants):
All documents provided are authenticated photocopies of the executed batch
document.
The documents are written in (local language) with parts of the data and information
presented in English.
Where information is provided in the (local language), a verified English translation
is provided together with the original document in the local language. Where, only
English is used in a document, the original copy document is provided.
Executed batch of [Generic Name] SEMISOLID was manufactured on production
equipment under actual production conditions.

ACTIVE MATERIAL
The active material is manufactured by [BPC] Pharmaceutical and Chemical
Manufacturing Company - [Address].

Handbook of Pharmaceutical

Chapter: 7.27
27

Generic Development

SEMISOLIDS

MANUFACTURING

CHAPTER 6

Manufacturing Instructions

REPROCESSING STATEMENT
(Delete statement where appropriate)

The COMPANY is unable to anticipate what manufacturing qualifying factors, if any,
may lead to the need for reprocessing at this time. If reprocessing of a batch is
required once the product has been marketed, the reprocessing procedure as well
as the relevant supporting data will be submitted, (according to the SUPAC
guideline, where appropriate), for supplementary review and approval of the Office
of Generic Drugs prior to implementation.

[Signature of Responsible Person]
------------------------------------------------

---------------------------------------

[Name of Responsible Person]

Date

Plant Manager
Pharmaceutical Manufacturing Division

[Generic Company Name Inc. / Ltd.]

[Signature of Responsible Person]
------------------------------------------------

----------------------------------------

[Name of Responsible Person]

Date

Director Quality Assurance Unit
Pharmaceutical Manufacturing Division

[Generic Company Name Inc. / Ltd.]

[Signature of Responsible Person]
------------------------------------------------

[Name of Responsible Person]
Director Pharmaceutical Research & Development
Pharmaceutical Division

----------------------------------Date

[Generic Company Name Inc. / Ltd.]

Handbook of Pharmaceutical

Chapter: 7.28
28

Generic Development

SEMISOLIDS

MANUFACTURING

CHAPTER 6

Manufacturing Instructions

REPROCESSING STATEMENT
(Delete statement where appropriate)

The following manufacturing stages have been reworked during the full size process
Qualification batch (essentially similar to the pivotal batch shown) and the finished
product specifications were evaluated.
At time of manufacture (Time zero):
No detectable change was recorded for the following test studies
pH
Viscosity
Content Uniformity
At 3 months stability station (40o C / 75% RH):
The above parameters showed no detectable changes. The full re-work study is
presented in the “Product Development Report” and a Summary outline is given in
Section XXI.
Conclusion:
It is concluded that an additional 20 minute mixing (last stage) may be repeated
once as shown, without affecting or impacting on the products physical parameters
as shown in the in-process, release or stability (check) specifications.
[Signature of Responsible Person]
------------------------------------------------

--------------------------------------

[Name of Responsible Person]

Date

Plant Manager
Pharmaceutical Manufacturing Division

[Generic Company Name Inc. / Ltd.]
[Signature of Responsible Person]
------------------------------------------------

-------------------------------------

[Name of Responsible Person]

Date

Director Quality Assurance Unit
Pharmaceutical Manufacturing Division

[Generic Company Name Inc. / Ltd.]

Handbook of Pharmaceutical

Chapter: 7.29
29

Generic Development

SEMISOLIDS

IN-PROCESS CONTROLS

CHAPTER 7

In-process
Quality Controls
…‘A critical stage of the overall development validation choosing process and product in-process controls…’

Manufacturing In-process Controls
anufacturing parameters and
in-process controls are set in
order to produce consistent
batch-to-batch product lots.
During the development stages of the
manufacturing process the principal
parameters that need to be evaluated
are:
◊ Sieving of dry powders (state sieve #).
◊ Dissolving times for actives & semi
actives in the solvent system
(Aqueous or alcoholic solvent).
◊ Specifying the order of addition for all
critical ingredients.
◊ Grouping of 'like' excipients (viscosity
agents) into a single manufacturing /
processing step.
◊ Adding the viscosity agents under
vacuum (FRYMA™) at a specific
vehicle mix temperature and product
de-aeration while mixing.
◊ specifying the rate of addition for
critical ingredients (and rinsing).
◊ Identifying mixing speeds/settings
length of mixing.
◊ Identifying cooling parameters (inlet
& outlet water temperatures, cooling
times & target cooling values).
◊ Specifying cooling parameters..

M

Identify the critical stages, temperatures,
times and optimal mixing speeds and
settings of the manufacturing process.
Qualify ranges and limits:
If any range is indicated, manufacture the
batch at the lower and upper limits and
test for compliance in meeting the
Finished Product Specifications e.g.
Qualification of viscosity/rheology/Ph.
.

Product in-process controls

In-process

control specifications of the
bulk material is generally set at
marginally tighter control limits than the
Handbook of Pharmaceutical

finished product release specifications.
This procedure prevents the finished
product from being released at the
extremes of the release specifications.
This permits a safety margin for product
aging (shelf life).
Standards governing in-process controls
to:◊ ensure the bulk product will
adequately pass the finished product
release specifications;◊ ensure the product remains in
specification for the entire shelf life.
◊ Minimum parameters are;
♦ Description + Appearance
♦ Color & Odor
♦ pH
♦ Viscosity
♦ Tube Weight (limits)
♦ Content Uniformity
♦ Assay
♦ Microbial Limit Test

Diffusion
Diffusion profile, is not a compendial
requirement, may be omitted. It is an
useful test for demonstrating similarity
between
the
pivotal
and
three
commercial validation batches. It is an
official requirement for scale-up and
post approval changes (SUPAC-SS)
Manufacturing In-process Controls
n controls are those routine tests
performed on each lot that are
intended to ensure the completion of a
given manufacturing step or the
suitability of the intermediate material for
subsequent steps. The tests used and
subsequent parameters and in-process
controls set in order to produce
consistent batch-to-batch

I

Chapter: 7.1
1

Generic Development

IN-PROCESS CONTROLS

SEMISOLIDS

CHAPTER 7

ØC H E C K L I S T ×
CL # P-000-03-01YY

In-process controls during the
manufacturing process
‘ well developed manufacturing procedures with good in-process
controls…
…will ensure a failure-free end product...’

1. All dry powders are screened (state mesh size) prior to processing?

qYes qNo

2. Mixing of small weight excipients in plastic bags is not permitted ?

qYes qNo

3. The active material is dissolved in part of the solvent (at a specific
temperature) with a clearly defined mixing and dissolving times?

qYes qNo

4. The active container is rinsed at least twice to remove all active
residue? Use multiple rinses (x3/x4) for low potency active materials.

qYes qNo

5. The order of addition of excipients is clearly identified?

qYes qNo

6. The rate of addition for critical ingredients (e.g. solution) is clearly
identified and documented in the manufacturing procedure?

qYes qNo

7. Compatible excipients are grouped into a single manufacturing step
where suitable?

qYes qNo

8. Mixing times are identified and recorded by ‘start and stop’ entries?

qYes qNo

9. Mixing speeds (rpm) and blade settings are identified ?

qYes qNo
0

10. Heating and cooling rates to target temperatures (±2 C) are
identified.

qYes qNo

10. Critical Range limits have been qualified by manufacturing the
product at the lower and upper specification limits?

qYes qNo

11. The bulk pH value is tested by a sample portion and evaluated via a
calibrated pH electrode?

qYes qNo

12. Homogenization (rpm) sieve size (mm) and orifice settings are
identified ?

qYes qNo

13. Warning and Action limits have been established for microbial limit
testing?

qYes qNo

Footnote : The procedure for selecting approved suppliers for non active ingredients will minimize
inter-batch excipient variation significantly. This variation, if present, may impact upon the in-process
controls.
The absence of
adequate GMP (cleaning procedures) may adversely affect the microbial
bioburden of the bulk material during the manufacture and the filling process.

Handbook of Pharmaceutical

Chapter: 7.2
2

Generic Development

IN-PROCESS CONTROLS

SEMI SOLIDS

CHAPTER 7

ØC H E C K L I S T ×
CL # P-000-03-01YY

In-process controls during the
manufacturing process
‘the test result is only as good as the sampling procedure...’

Routine in-process quality controls on the Final Product consists of testing the bulk
semisolid and the in-process fill weights during the tube filling stage: The following
parameters should be evaluated in the at the in-process and finished product stage:
14. Maximum processing times are stipulated for key stages and the
overall manufacturing time is controlled and documented ?

qYes qNo

15. Routine IPQC testing on the material is controlled by:

qYes qNo

viscosity control on sample (after homogenization stage)

qYes qNo

content uniformity (after homogenization stage)

qYes qNo

16. pH testing unit uses a calibrated electrode.

qYes qNo

17. pH values are qualified by manufacturing the product at the lower
and upper limits of the Intermediate Product Release Specification
during the product development stage.

qYes qNo

18. Viscosity testing type and equipment used is documented.

qYes qNo

19. pH testing unit type and unit model number documented.

qYes qNo

20. Qualification - Range limits (e.g. pH) have been suitably qualified by
manufacturing the product at the lower and upper limit of the Finished
Product Release Specification during the product development stage?

qYes qNo

21. In-process limits are set marginally tighter than the product
release specifications?

qYes qNo

22. Maximum time period between sanitation of filling line and filling
operation is clearly stated in documentation?

qYes qNo

23. Target fill weight for the filling procedure, is established during the
product development stage and then qualified as a filling parameter ?

qYes qNo

Handbook of Pharmaceutical

Chapter: 7.3
3

Generic Development

IN-PROCESS CONTROLS

SEMI SOLIDS

CHAPTER 7

ØC H E C K L I S T ×
CL # HBGD-03-01YY

In-process controls during the
manufacturing process
‘the test result is only as good as the sampling procedure...’

24. Routine In-Process Quality Control testing are performed:

qYes qNo

Validated Manufacturing Process
⇒ Appearance

(After homogenization)

qYes qNo

⇒ Color and odor

(After homogenization)

qYes qNo

⇒ Viscosity

Target Limit + NMT 1000 centipoise.

qYes qNo

⇒ Content Uniformity

(Top, middle, bottom kettle)

qYes qNo

⇒ Individual Weight

(10 units during filling)

qYes qNo

⇒ Average Weight

(20 units) Limits NMT 5%

qYes qNo

Validated Filling Process

Non-validated Manufacturing Process - (Additional Tests Required)
⇒ pH

Limits NMT ±0.5 to 1.0 unit

qYes qNo

⇒ Microbial Limit test

(Prior to packaging)

qYes qNo

⇒ Preservative Efficacy Test

(Prior to packaging)

qYes qNo

Notes:Setting the limits may be achieved by manufacturing at the extreme ends of the viscosity range (lowest and
highest values) and measuring the resulting values. The range may be skewed to the right, if necessary. As
an example viscosity - is set a range of say 5000 [lower] - 6000 [target] - 8000 cP [upper], especially if there is
a possibility of a significant variation in raw materials producing a more viscous semisolid. The range
specification may be reviewed in the forthcoming annual report after several batches have been produced
commercially. pH ranges are ±0.5 units for acidic or basic target values and ±1.0 units for near neutral
preparations. E.g. 4.0 - 4.5 -5.0 (acidic) and 5.5 - 6.5 -7.5 (around neutral pH)

Handbook of Pharmaceutical

Chapter: 7.4
4

Generic Development

IN-PROCESS CONTROLS

SEMI SOLIDS

CHAPTER 7

STANDARD OPERATING
PROCEDURES
SOP #

Page 1 of 1.

HBGD-03-01YY

In-process Quality Controls
The following Standard Operating Procedures are recommended for a generic
development unit :

In-process Quality Control
(Development Phase QC)
P-000-02-01YY

Choosing appropriate In-process Quality Control Limits.

P-000-02-01YY

Qualification of Manufacturing In-process Controls.

P-000-02-01YY

Qualification of Product In-process Controls.

P-000-02-01YY

Time Limitations on Manufacturing Processing Stages.

P-000-02-01YY

Reserved.
----------------

A R&D Quality Control unit in a development or R& D department is an essential
requirement for well controlled and audited pharmaceutical drug development. Such
units may consists of only one or two experienced personnel who review all
documentation and raw data produced by the project researchers and analysts (i.e.
development lab books; analytical methods; procedures and all protocols).
When the development has progressed to a Process Qualification stage the regular
plant QC department should also review and sign all key documentation
Ü Master formula
Ü Process Instructions
Ü Product Specifications (In-process; Release; and Stability)
Ü Validation protocols
(Analytical; Process; and Cleaning )

4
[End of Document]

Edition No.:02

Effective Date :

Ed. Status : 01

Handbook of Pharmaceutical

APPROVED
___________ ____________
Department
RD

Chapter: 7.5
5

____________
RA

__________/___________
QC
/
QA

Generic Development

CHAPTER 8

FINISHED PRODUCT SPECIFICATIONS

SEMISOLIDS

Finished Product Specifications
…‘these are the product specifications
indicating the product quality throughout the shelf life…’

Finished Product Specifications

A rugged and validated manufacturing

consist of a group of three sets of
specifications of the drug product. The
difference in these specification values
depends on the time the actual
measurement is made.
These end-product specifications are:• the release specifications
• the stability (check) specifications
• the Finished Product Specifications
Finished Product Specifications (FPS)
are the specifications the product must
maintain for the full length of the allocated
shelf life.
Stability (Check) Specifications are a
sub-set of the FPS and are the monitored
specifications of the Finished Product that
tend to change with aging and may or do
impact on the overall product quality.
Since only a few specifications have a
aging significance there are always less
check specifications. Check specifications
ranges may not be greater that the
Finished Product Specifications.
The Release Specifications are the
values required for
batch release
purposes only.

procedure requires Content Uniformity at
the manufacturing in-process control
stage only. In semi-solids this is a bulk
mixing variable and not a filling variable.

The Assay of a drug product, for example,
is usually set at:
⇒ Release 95.0 - 105.0%
⇒ Check -

90.0 - 110.0%

⇒ Finished 90.0 - 110.0%
of labeled amount.
Check & Finished Product Specifications
are usually the same values & ranges.
Not all finished product specifications are
stability indicating, with the result that
there are less specifications in the stability
testing protocol than in the overall finished
drug product specifications.
Reduced Testing Programs
A well structured drug development
program can reduce the number of
specifications tests required for release,
check, and finished product.

Handbook of Pharmaceutical

Preservative efficacy is established with
development and process qualification (PQ)
lots, and demonstrated with pivotal (and
possibly validation) batches.
Total microbial count and microbial
limit tests are a release specification
(after filling stage) and not a routine
product
stability
or
in-process
manufacturing quality control test.
Non-buffered topicals may exhibit pH
changes with aging and pH monitoring
may be present in the in-process, release,
and stability specifications.

PET is established with the development
and PQ lots. If a consistent PET profile is
exhibited during all development stages it is fully excluded from the product
release specification.
Viscosity may exhibit changes with aging
and monitoring may be present in the inprocess,
release,
and
stability
specifications.
The choice and rationale of correctly
placing the product specification in either:




in-process
release
finished product
stability

[bulk]
[ T0 ]
[overall]
[shelf life]

categories with appropriate limit values
depends on when the test is performed
and whether it is of a stability indicating
value.

A well developed and validated product
formula and manufacturing process will
significantly reduce the amount of release
testing
that
would
otherwise
be
necessary.
Note:
Compendial
requirements are Finished Product
Specifications.

Chapter: 8.1
1

Generic Development

CHAPTER 8

FINISHED PRODUCT SPECIFICATIONS

SEMISOLIDS

ØC H E C K L I S T ×
SOP # P-000-03-01YY

FINISHED PRODUCT SPECIFICATIONS
‘…release, check and finished product specifications all have minor
c h a n g e s - the difference is in the size of the ranges…‘

1. The Finished Product Specifications have both release and a stability qYes qNo
check specifications that allows for appropriate product aging
throughout the allocated shelf life ?
2. All the stability specifications are shown to be - stability indicating ?
qYes qNo
3. The Description allows the minor changes in color from release to qYes qNo
end of shelf life (i.e. - smooth white to off-white homogeneous
cream?)
4. Release specifications have narrower limits than the stability check qYes qNo
specifications, allowing an appropriate margin of safety as the product
ages?
qYes qNo
5. The assay release specifications are set at 95.0 - 105.0% ?
qYes qNo
6. The assay check specifications are set at 90.0 - 110.0%
7. The firm performs specified critical in-process controls to insure that
the finished product testing is always in specification (e.g. content
uniformity testing or with older environments, Microbial Limit Tests)?
8. Uniformity of Content is tested at the end of bulk manufacture ?
9. Batches released at <97.0% are investigated and monitored for
stability, (if development studies show that the active loss is >7% for
the claimed shelf-life)?
10. Development and qualification lots show content uniformity does not
change after the filling process (i.e. cracking, breaking or splitting).
11. Viscosity is tested in-process (bulk) prior to filling?
12. Total Microbial Count and Limit tests are performed after filling ?
13. Total Fungal Count is performed after filling ?
14. Preservative Efficacy Test USP was tested in the development and
qualification batches and demonstrated for regulatory purposes in the
pivotal and if deemed necessary, validation lots?
15. If Q14 answered yes then preservative assay monitoring is
unnecessary for routine commercial lots?
16.The microbial limits test includes pathogens specific to the local
environment and water contaminants ?

Handbook of Pharmaceutical

Chapter: 8.2
2

qYes qNo

qYes qNo
qYes qNo

qYes qNo
qYes qNo
qYes qNo
qYes qNo
qYes qNo

qYes qNo
qYes qNo

Generic Development

CHAPTER 8

FINISHED PRODUCT SPECIFICATIONS

SEMISOLIDS

ØC H E C K L I S T ×
SOP # P-000-03-01YY

FINISHED PRODUCT SPECIFICATIONS

‘…release, check and finished product specifications all have minor
c h a n g e s - the difference is when you measure the ranges…‘

17. Viscosity testing is not performed as a finished product release test qYes qNo
as this test is routinely addressed during the in-process controls?
18. Content uniformity (U of C) is not evaluated as a check specification, qYes qNo
if development studies shows no changes in U of C with aging studies
(see globule size studies)?
19. Stability Studies show an absence of weeping, bleeding, cracking, qYes qNo
(splitting) or granular effects in the semisolid matrix ?
20. Antioxidant Optimization (either with or without a chelating agent, qYes qNo
where deemed necessary) was performed to establish that the Finished
Product Specification (Stability Check) Assay and Impurities remained
within the specification range?
21. The Preservative Efficacy Test (PET) and final Antioxidant qYes qNo
concentration was evaluated in the development and qualification
batches and demonstrated to produce consistent results in the pivotal
and three full size commercial validation lots?
22. If yes to #13, then PET and Antioxidant monitoring is unnecessary for qYes qNo
routine commercial lots, if neither a USP compendial monograph
requirement?
23. The Description allows for possible minor changes in appearance qYes qNo
from product release to end of shelf-life (i.e. off-white to creamish color)?
24. Where Test failures occur in parameters that have been optimized or qYes qNo
qualified, re-qualification studies must be investigated?
Footnote: Where the product batch history shows test failures due to environmental or raw material
variations is a clear indication that both these parameters should be further investigated and
addressed

Handbook of Pharmaceutical

Chapter: 8.3
3

Generic Development

FINISHED PRODUCT SPECIFICATIONS

SEMISOLIDS

CHAPTER 8

GLOSSARY OF TERMS
Approved Target Composition: The components and amount of each
ingredient for a drug product used in an approved pivotal clinical study or
bioequivalence study.
Batch: A specific quantity of a drug or other material produced according to a
single manufacturing order during the same cycle of manufacture and intended to
have uniform character and quality, within specified limits. (21 CFR 210.3(b)(2)).
Contiguous Campus: Contiguous or unbroken site or a set of buildings in
adjacent city blocks.
Creams/Lotions: Semisolid emulsions that contain fully dissolved or suspended
drug substances for external application. Lotions are generally of lower viscosity.
Diluent: A vehicle in a pharmaceutical formulation commonly used for making up
volume and/or weight (e.g., water, paraffin base).
Drug Product: A drug product is a finished dosage form (e.g., cream, gel, or
ointment) in its marketed package. It also can be a finished dosage form (e.g., tablet,
capsule, or solution) that contains a drug substance, generally, but not necessarily,
in association with one or more other ingredients (21 CFR 314.3(b)).
Drug Release: The disassociation of a drug from its formulation thereby allowing
the drug to be distributed into the skin or be absorbed into the body where it may
exert its pharmacological
effect.
Drug Substance: An active ingredient that is intended to furnish pharmacological
activity or other direct effect in the diagnosis, cure, mitigation, treatment, or
prevention of a disease, or to affect the structure or any function of the human body,
but does not include intermediates used in the synthesis of such ingredient (21 CFR
314.3(b)).
Emulsion: Emulsions are two phase systems in which an immiscible liquid
(dispersed phase) is dispersed throughout another liquid (continuous phase or
external phase) as small droplets. Where oil is the dispersed phase and an aqueous
solution is the continuous phase, the system is designated as an oil-in-water
emulsion. Conversely, where water or an aqueous solution is the dispersed phase
and oil or oleaginous material is the continuous phase, the system is designated as
a water-in-oil emulsion.
Emulsions are stabilized by emulsifying agents that prevent coalescence, the
merging of small droplets into larger droplets and, ultimately, into a single separated
phase (bleeding and cracking). Emulsifying agents (surfactants) do this by
concentration in the interface between the droplet and external phase and by
providing a physical barrier around the particle to coalesce.
Surfactants also reduce the interfacial tension between the phases, thus increasing
the ease of emulsification upon mixing. Emulsifying agents substantially prevent or
delay the time needed for emulsion droplets to coalesce. Emulsification is the act of
forming an emulsion. Emulsification can involve the incorporation of a liquid within
another liquid to form an emulsion or a gas in a liquid to form a foam.

Handbook of Pharmaceutical

Chapter: 8.4
4

Generic Development

FINISHED PRODUCT SPECIFICATIONS

SEMISOLIDS

CHAPTER 8

GLOSSARY OF TERMS
Formulation: A listing of the ingredients and quantitative composition of the
dosage form.
Gel: A semisolid system in which a liquid phase is constrained within a three
dimensional, cross-linked matrix. The drug substance may be either dissolved or
suspended within the liquid phase.
Homogenization: A method of atomization and thereby emulsification of one
liquid in another in which the liquids are pressed between a finely ground valve and
seat under high pressure (e.g., up to 5,000 psi).
Internal phase: The internal phase or the dispersed phase of an emulsion
comprises the droplets that are found in the emulsion.
In Vitro Release Rate: Rate of release of the active drug from its formulation,
generally expressed as amount/unit area/time . 0.5
Lot: A specific quantity of a drug or other material produced according to a single
manufacturing order during the same cycle of manufacture and intended to have
uniform character and quality.
A Lot may comprise of several sublots, - each sub-lot representing the quantity of
material of the smallest manufacturing unit's capacity in the overall manufacturing
process.
Ointment: An unctuous semisolid for topical application. Typical ointments are
based on petrolatum. An ointment does not contain sufficient water to separate into
a second phase at room temperature. Water soluble ointments may be formulated
with polyethylene glycol.
Pilot Scale Batch: The manufacture of drug product by a procedure fully
representative of and simulating that intended to be used for full manufacturing
scale.
Preservative: An agent that prevents or inhibits microbial growth in a formulation
to which it has been added.
Process: A series of operations, actions and controls used to manufacture a drug
product.
Scale-up: The process of increasing the batch size.
Scale-down: The process of decreasing the batch size.
Shear: A strain resulting from applied forces that cause or tend to cause contiguous
parts of a body to slide relative to one another in direction parallel to their plane of
contact.
In emulsification and suspensions, the strain produced upon passing a system
through a homogenizer or other milling device.
• Low shear: Processing in which the strain produced through mixing and/or
emulsifying shear is modest.
• High shear: Forceful processes which, at point of mixing or emulsification place
a great strain on the product.

Handbook of Pharmaceutical

Chapter: 8.5
5

Generic Development

FINISHED PRODUCT SPECIFICATIONS

SEMISOLIDS

CHAPTER 8

GLOSSARY OF TERMS
Homogenization, by its very nature, is a high shear process which leads to a small
and relatively uniform emulsion droplet size. Depending on their operation, mills and
mixers are categorized as either high shear or low shear devices.
Significant Body of Information: A significant body of information on the
stability of the product is likely to exist after five years of commercial experience for
new molecular entities, or three years of commercial experience for new dosage
forms.
Structure Forming Excipient: An excipient which participates in the formation
of the structural matrix which gives an ointment, cream or gel etc., its specific
semisolid character. Examples are gel forming polymers,
• petrolatum,
• certain colloidal inorganic solids (e.g., bentonite),
• waxy solids (e.g., cetyl alcohol, stearic acid)
• emulsifiers used in creams.
Strength: Strength is the concentration of the drug substance (for example,
weight/weight, weight/volume, or unit dose/volume basis), and/or the potency, that is,
the therapeutic activity of the drug product as indicated by appropriate laboratory
tests or by adequately developed and controlled clinical data (expressed, for
example, in terms of units by reference to a standard) (21 CFR 210.3(b)(16)).
For semisolid dosage forms the strength is usually stated as a weight / weight (w/w)
or weight / volume (w/v) percentage.
Suspending agent: An excipient added to a suspension to control the rate of
sedimentation of the active ingredients.
Technical grade: Technical grades of excipients differ in their specifications
and intended use. Technical grades may differ in:
(1) specifications and/or functionality,
(2) impurities
(3) impurity profiles.
Validation: A procedure to establish documented evidence that provides a high
degree of assurance that a specific process or test will consistently produce a
product or test outcome meeting its predetermined specifications and quality
attributes. A validated manufacturing process or test is one that has been proven to
do what it purports or is represented to do.

The proof of process validation is obtained through collection and evaluation of data,
preferably beginning with the process development phase and continuing through
the production phase. Process validation necessarily includes:
• process qualification
• the qualification of materials,
• equipment
• systems
• building
• personnel,
but it also includes the control of the entire processes for repeated batches or runs.
Handbook of Pharmaceutical

Chapter: 8.6
6

Generic Development

CHAPTER 8

FINISHED PRODUCT SPECIFICATIONS

SEMISOLIDS

STANDARD OPERATING
PROCEDURES

Page 1 of 1.

SOP # HBGD-03-01YY

FINISHED PRODUCT SPECIFICATIONS

The following Standard Operating Procedures are recommended for a generic
development unit :

Finished Product Specifications
P-000-02-01YY

Choosing Finished Product Specification limits.

P-000-02-01YY

Qualifying Finished Product Specification limits.

P-000-02-01YY

Choosing release Specification limits.

P-000-02-01YY

Choosing Check Specification limits.

# P-000-02-01YY

Reducing stability specifications by developing rugged
generic product formulations.

REFERENCES
1. Shah, V. P., J. Elkins, J. Hanus, C. Noorizadeh, and J. P. Skelly,"In Vitro Release of Hydrocortisone from
Topical Preparations and Automated Procedure," Pharmaceutical Research, 8:55-59, 1991.
2. Shah, V. P., J. S. Elkins, and R. L. Williams, "In Vitro Drug Release Measurement of Topical Glucocorticoid
Creams," Pharmacopeial Forum, 19, 5048-5059, 1993.
3. Corbo, M., T. W. Schultz, G. K. Wong, and G. A. Van Buskirk, "Development and Validation of In Vitro
Release Testing Methods for Semisolid Formulations," Pharmaceutical Technology 17(9):112-128, 1993.
4. Li, J. B. and P. C. Rahn, "Automated Dissolution Testing of Topical Drug Formulations Using Franz Cells and
HPLC Analysis," Pharmaceutical Technology 17(7):44-52, 1993.
5. Shah, V. P. and J. S. Elkins, "In Vitro Release from Corticosteroid Ointments," Journal of Pharmaceutical
Sciences, 84:1139-1140, 1995.
6. Zatz, J.L., "Drug Release from Semisolids: Effect of Membrane Permeability on Sensitivity to Product
Parameters," Pharmaceutical Research 2:787-789, 1995.

4
[End of Document]

Edition No. 03

Effective Date :

Ed. Status :
Supersedes - 02

Handbook of Pharmaceutical

APPROVED
_____________ __________________ _____________
Department
RD
RA

Chapter: 8.7
7

_______________
QC / Q A

Generic Development

SEMISOLIDS

P R O C E S S - O P T I M I Z A T I O N

CHAPTER 9

Process
Optimization
‘…choosing the right formula and process specifications
prior to qualification…'

Qualification of Limits
Formula and Process Optimization are
utilised in establishing formula &
processing target values pertaining to
the manufacturing procedure finally
adopted as well as establishing correct
specification limits for key mfg stages.
Semisolid Key Formula parameters are:
Ü Antioxidant concentration
Ü use of a chelating agent (synergism)
Ü preservative(s) and concentration
Ü target pH (and range) - unbuffered
Semisolid Key Process parameters are:
Ü target
heating
and
cooling
temperatures of oil, aqueous, and
the combined phases.
Ü optimum
PHASE
mixing
or
emulsifying TEMPERATURES.
Fine tuning the formulation involves
selecting the correct antioxidant and
where
necessary,
a
synergistic
chelating agent (EDTA) or establishing
the optimum antioxidant concentration
or synergistic combination and then
evaluating the overall formula and
process capability in maintaining assay
and impurity/degradant limits.
Choosing
the
most
effective
preservative is a basic formula development but evaluating its' most effective
concentration in the formula in order to
effectively withstand a challenged by
the Preservative Efficacy Test falls into
process qualification frame, as the
whole overall process is involved.
.

Handbook of Pharmaceutical

The resulting 'qualified' formula and
process will be rugged and robust and
adequately control both biological and
chemical impurity / degradant growth.
The Optimization Procedures adopted:Optimization batches P-06 P-07, P-08
P-09, P-10 were manufactured in a
Fryma™ unit (Vacuum, De-aerator)
homogenised and packed in flexible
HDPE tubes and placed on stability at
25°C/60%RH for 6 months and
30°C/75% RH for 3 months.

Optimization Batches:
Batch 06 - BHA Study + Preservative
Batch 07 - BHA Study + Preservative
Batch 08 - EDTA Study + Preservative
Batch 09 - EDTA Study + Preservative
Batch 10 - Control

The formula and physical properties
obtained are presented in Table No. 0809 and stability results outlined in Table
No. 10-16.

All

four
batches
re-evaluated
increasing concentrations of the
preservative while Lot P-10 acted as a
control batch.

Only four experimental batches and a
control were necessary to optimise the
formula and select the final batch for
Process Qualification namely lot P-08.

The stability results highlight the
acceptable
qualification
of
the
appropriate BHA - EDTA concentration.

Chapter: 9.1
1

Generic Development

SEMISOLIDS

P R O C E S S - O P T I M I Z A T I O N

The

Preservative Qualification

P

rocess Optimization (PO) involving
the fine tuning of the preservative
concentration
or
preservatives
combinations takes place either during or
after the antioxidant-chelating Studies.
Checking the preservative efficacy of the
formula is usually performed as the last
formulation
decision.
As
inhibiting
microbial growth are affected by:
Ü Correct preservative in final formula
Ü Correct concentration of preservative
Ü Sanitized manufacturing process
(Excipients, Pur. Water, cGMP)
Ü Ultra Clean filling procedure
Ü Sanitized containers / closures
Thus the order of process optimization
and qualification studies are as follows:

♦ Physical characterization (PO)
♦ pH (unbuffered)

(PO)

♦ Antioxidant

(PO)

♦ Chelating agent
♦ Content Uniformity
♦ Preservative Efficacy
Process Optimization
Qualification (PQ) -

Formula

cleaning procedure, cGMP,
manufacturing technique and filling and
microbial-clean containers (i.e. with
very low residual contamination) impact
on the Preservative Efficacy, while
formula, phase temperatures, mixing
times, de-aeration and homogenisation
steps impact on the semisolid, content
uniformity values.

CONTAINERS
Containers do not have to be sterile just ultra clean (i.e. with low microbial
contamination
levels.)
Microbial
sampling containers should always be
sterile, as not to bias the testing.
NOTE: The preservative may inhibit or
possibly (with time after ~30 days),
chemically sterilize the semisolid
preparation in the tube. It can be
demonstrated in Preservative Efficacy
Testing, that after 28 days incubation,
many or all of the spiked organisms
introduced in the test are not detected
for growth (i.e. chemically sterilized).

PRESERVATIVES-pH

(PO)
(PQ)
(PQ)
& Process
Differences.

optimization, such as target
pH or antioxidant-chelating studies are
Optimization Studies as the choice of
the final formula, ingredients or
manufacturing
controls
are
not
established and are in the ongoing
process of being developed.
Preservative Efficacy and bulk Content
Uniformity Qualification are Process
Qualification parameters as both the
formula and process are final and the
PQ studies are in fact challenging and
verifying Content Uniformity and
preservative Efficacy on the final
formula and final overall manufacturing
process.

Handbook of Pharmaceutical

CHAPTER 9

Certain preservatives function at an
optimum pH thus preservative efficacy
and manufacturing target pH often go
hand-in-hand in the development
formula planing.

ANTIOXIDANTS-CHELATES
Antioxidant(s) and chelating agents are
generally synergistic and are qualified
together.

AQUEOUS-OIL PHASE
Oil phase and the aqueous phase ratios
and phase-mixing temperature affects
the diffusion test results (Hanson), Fix
O/W ratios during early development.

ACTIVE SOLUBILITY
The active may be soluble in one of the
phases, but if insoluble, it is suspended
and homogenised as a 'semisolid
suspension'.
(Note:pastes
are
semisolid suspensions with a relatively
high suspended solids i.e. viscosity).

Chapter: 9.2
2

Generic Development

SEMISOLIDS

P R O C E S S - O P T I M I Z A T I O N

CHAPTER 9

ØC H E C K L I S T ×
SOP # HPGD-03-02YY

FINISHED PRODUCT SPECIFICATIONS
‘…release, check and finished product specifications all have minor
c h a n g e s - the difference is in the size of the ranges…‘

1. If the active is oil soluble, then an oil soluble antioxidant is evaluated?
qYes qNo
2. If the active is (partially) water soluble water and oil soluble, dual antioxidants qYes qNo
are evaluated?
3. The antioxidant was evaluated so as to limit impurities generated from the qYes qNo
active substance and (possibly) the oil phase, in the case where the oil may
tend to rancidify with time?
4. If 'natural sourced' excipients are present in the oil and water phases, then qYes qNo
both oil and water soluble preservatives (dual preservative system e.g. methyl /
propyl parabens) need to be evaluated?
5. If the 'natural sourced' excipients are water soluble, then a water soluble qYes qNo
preservative is used?
6. If the 'natural sourced' excipients are oil soluble, then an oil soluble
preservative is used?
7. Preservative function and the optimum preservative pH level is evaluated?
8. pH values close to neutral have a pH range of ±1.0 unit ?
9. Acidic or basic pH values have a pH range of ±0.5 unit?
10. Buffered semisolid preparations containing a preservative should allow the
preservative to function optimally within the selected pH buffer range?
11. Where actives are insoluble - use of micronized material is evaluated?
12. The Uniformity of Content of 'insoluble active materials' has been
appropriately qualified in the PQ batch?
13. Strict specifications as to ultra clean manufacturing and filling lines set in
order not to challenge bulk with higher bioburden?
14. Sampling containers for microbial testing are sterile and over-wrapped.
15. Strict filling specifications for ultra-clean tubes / jars set in order not to
compromise preservative efficacy results with excessive starting bioburden ?
16. The oil and water phases exhibit target heating temperatures and cooling
temperatures - prior to phase mixing?
17. Viscosity or thickening agents such as Avicel RC 591 is evaluated in order to
improve Uniformity of Content - performed where necessary?

Handbook of Pharmaceutical

Chapter: 9.3
3

qYes qNo
qYes qNo
qYes qNo
qYes qNo
qYes qNo
qYes qNo
qYes qNo
qYes qNo
qYes qNo
qYes qNo
qYes qNo

Generic Development

SEMISOLIDS

P R O C E S S - O P T I M I Z A T I O N

CHAPTER 9

Qualification of Antioxidant & Chelating Agent
20 mg / g Miconazole USP
Optimization Batch Stage
Table No. 10

Formulae Ingredients
ò
Batch No. è

Amount per gram (mg)
P-06

PART ONE - OIL PHASE

P-07

EDTA STUDY

Pegoxol 7 Stearate [Tefose 63™]

P-09

P-08

P-10

BHA STUDY

180.0

180.0

180.0

180.0

180.0

25.0

25.0

25.0

25.0

25.0

Benzoic Acid USP

1.0

1.5

2.0

2.0

0.0

Butylated Hydroxyanisole NF
(BHA).

0.05

0.15

0.05

0.05

0.0

Low

High

Heavy Mineral OIL NF

PART TWO - Oily Suspension

Low

Mixing

Miconazole USP Micronized

20.0

20.0

20.0

20.0

20.0

Peglico 5 Oleate
[LABRAFIL M 1944™]

30.0

30.0

30.0

30.0

30.0

1.5

0.5

1.5

1.0

0.0

High

Low

Edetate Disodium USP
Heavy Mineral OIL

20.0

PART THREE - AQUEOUS PHASE

Purified Water USP

20.0

Intermediate

20.0

20.0

20.0

Heating and Cooling
722.45

722.85

721.45

721.95

725.0

Total Weight 1000.0

1000.0

1000.0

1000.0

1000.0

PART IV - PHASE MIXING

pH

5.0

Viscosity

4000.0
Total

4.5
4000.0

0.0

FORMULA
FOR
OPTIMISING
ANTIOXIDANT
AGENT

Handbook of Pharmaceutical

0.0

4.0

4.0

4000.0

4000.0

0.0

0.0

6.8
3800.0
0.0

FORMULA
FOR
OPTIMISING
CHELATING
RANGE

Chapter: 9.4
4

Generic Development

SEMISOLIDS

P R O C E S S - O P T I M I Z A T I O N

CHAPTER 9

Qualification of Antioxidant & Chelating Agent
Physical Characterization of Bulk Semisolid
20 mg / g Miconazole USP
Optimization Batch Stage
Table No. 11

Ø Optimization Batch Stage - Semisolid Physical Characterization
containing 20 mg/g of Active Material
BATCH NO. è

P-06

P-07

P-08

P-09

P-10

Results:
Description / Color / Odor

Conforms

Conforms

Conforms

Conforms

Conforms

Preservative Efficacy test

Fails

Just Fails

PASS

PASS

Fails

Spreadability / Skin feel

Elegant

Elegant

Elegant

Elegant

Secondary

Analysis
Percentage (micron size)

Solid Particles

Microscopic Method
or Coulter Counter

<10

4

6

4

6

3

<20

8

10

8

7

11

<30

20

17

20

17

18

<40

18

16

18

15

15

<50

10

12

10

16

16

<60

22

22

21

22

20

0

0

0

1

0

>60

Semisolid
Physical Parameters

Weeping

MILD

Absent

Absent

Absent

Present

Bleeding

MILD

MILD

Absent

Absent

MILD

Splitting

Absent

Absent

Absent

Absent

MILD

Granular Appearance

Absent

Absent

Absent

Absent

MILD

Samples examined
after maximum
holding time
in bulk stage

Physical
Parameters
evaluated

NOTE: Preservative Efficacy Test re-evaluated with chelating agent.

Handbook of Pharmaceutical

Chapter: 9.5
5

Generic Development

SEMISOLIDS

P R O C E S S - O P T I M I Z A T I O N

CHAPTER 9

Qualification of Antioxidant & Chelating Agent
20 mg / g Miconazole USP

Optimization Batch Stage - Stability studies
Container / closure system
Fill size

:
:

HDPE tube + Cap (110 mL)
100 grams

Storage conditions

:

30°C / 75% Relative Humidity
Table No. 12

Assay and Impurities (%)
Batch P-06 - Containing BHA 0.05 + EDTA 1.5 mg per gram
Parameters
Storage Appearance
(months)

BHA
%

Thin Layer (TLC)

HPLC

ANY TOTAL
Assay Impurity Impurity Impurity ANY TOTAL Impurity
Impurity Impurity
Impurity TLC
I
II
II
III
TI
H
II
TLC
TLC
HPLC
TLC

NMT
Specs. Off White to 50- 90.0 Cream
110 110.0

NMT
1.0

NMT
0.5

NMT
0.5

NMT
0.1

NMT
3.0

NMT
0.5

NMT
0.1

NMT
1.0

0

Conforms

90

102.2

<0.1

<0.1

<0.1

<0.1

0.3

<0.02

<0.02

<0.02

1

Conforms

60

99.7

<0.1

<0.1

<0.1

<0.1

0.3

<0.02

<0.02

<0.02

2

Conforms

65

101.3

0.1

<0.1

<0.1

<0.1

0.4

0.1

0.05

0.15

3

Conforms

55

100.8

0.3

<0.1

<0.1

<0.1

0.4

0.1

0.05

0.2

Table No. 13

Assay and Impurities (%)
Batch P-07 - Containing BHA 0.15 + EDTA 0.5 mg/gram
Thin Layer (TLC)

Parameters
Storage
(months)

HPLC

Appear
ance

BHA
%

0

Conforms

98

103.2

<0.1

<0.1

<0.1

<0.1

<0.1

<0.01

<0.01

<0.01

1

Conforms

92

101.6

<0.1

<0.1

<0.1

<0.1

<0.1

<0.01

<0.01

<0.01

2

Conforms

85

101.0

<0.1

<0.1

<0.1

<0.1

<0.2

<0.01

<0.01

<0.02

3

Conforms

70

102.2

0.3

0.1

0.4

0.1

0.9

0.15

0.05

0.2

Specs

Assay Impurity Impurity Impurity
ANY
TOTAL Impurity ANY TOTAL
Impurity
Impurity Impurity
TLC
I
II
III
II
TI
H
II
TLC
TLC
TLC
HPLC
NMT
NMT
NMT
NMT
NMT
NMT
NMT
Off White NMT 90.0 - NMT
501.0
0.5
0.5
0.1
3.0
110.0
0.5
0.1
1.0
to Cream
110

Key:
Assay % of Label Claim of Active.
BHA
Butylated Hydroxyanisole NF (GRAS)
Impurity I ; II ; III - Known impurities (by TLC)
ANY T = Any other impurities (by TLC)
TOTAL TLC = Total impurities (by TLC)
Impurity spot III separated by horizontal TLC development of impurity spot II using new edition TLC method.
Impurity II HPLC - Known impurities (by HPLC)
ANY II = Any other impurities (by HPLC)
TOTAL H = Total impurities (by HPLC)

Handbook of Pharmaceutical

Chapter: 9.6
6

Generic Development

SEMISOLIDS

P R O C E S S - O P T I M I Z A T I O N

CHAPTER 9

Qualification of Antioxidant & Chelating Agent
20 mg / g Miconazole USP

Optimization Batch Stage - Stability studies
Container / closure system
Fill size

:
:

HDPE tube + Cap (110 mL)
100 grams

Storage conditions

:

30°C / 75% Relative Humidity
Table No. 14

Assay and Impurities (%)
Batch P-08 Containing BHA 0.05 + EDTA 1.5 mg per gram
Parameters
Storage Appearance
(months)

BHA
%

Thin Layer (TLC)

HPLC

ANY TOTAL
Assay Impurity Impurity Impurity ANY TOTAL Impurity
Impurity Impurity
Impurity TLC
I
II
II
III
TI
H
II
TLC
TLC
HPLC
TLC

NMT
Specs. Off White to 50- 90.0 Cream
110 110.0

NMT
1.0

NMT
0.5

NMT
0.5

NMT
0.1

NMT
3.0

NMT
0.5

NMT
0.1

NMT
1.0

0

Conforms

96

100.2

<0.1

<0.1

<0.1

<0.1

0.3

<0.02

<0.02

<0.02

1

Conforms

85

99.9

<0.1

<0.1

<0.1

<0.1

0.3

<0.02

<0.02

<0.02

2

Conforms

78

101.5

0.1

<0.1

<0.1

<0.1

0.4

0.1

0.05

0.15

3

Conforms

69

101.4

0.3

<0.1

<0.1

<0.1

0.4

0.1

0.05

0.2

Table No. 15

Assay and Impurities (%)
Batch P-09: Containing BHA 0.05 + EDTA 1.0 mg/gram
Thin Layer (TLC)

Parameters
Storage
(months)

HPLC

Appear
ance

BHA
%

0

Conforms

90

103.2

<0.1

<0.1

<0.1

<0.1

<0.1

<0.01

<0.01

<0.01

1

Conforms

75

100.6

<0.1

<0.1

<0.1

<0.1

<0.1

<0.01

<0.01

<0.01

2

Conforms

65

99.0

0.2

<0.1

<0.1

<0.1

<0.3

<0.01

<0.01

<0.02

3

Conforms

53

97.2

0.4

<0.1

0.1

<0.1

0.5

0.2

0.05

0.3

Specs

NOTE:
P-08
P-09

Assay Impurity Impurity Impurity
ANY
TOTAL Impurity ANY TOTAL
Impurity
Impurity Impurity
TLC
I
II
III
II
T
H
II
TLC
TLC
TLC
HPLC
NMT
NMT
NMT
NMT
NMT
NMT
NMT
Off White NMT 90.0 - NMT
501.0
0.5
0.5
0.1
3.0
110.0
0.5
0.1
1.0
to Cream
110

BHA Assay higher than P-09 ; Impurities marginally lower than P-09
BHA Assay lower than P-08 ; Impurities marginally higher than P-08
BHA is greater irritant and/or toxicant than EDTA - therefore presents a greater safety

factor.

Handbook of Pharmaceutical

Chapter: 9.7
7

Generic Development

SEMISOLIDS

P R O C E S S - O P T I M I Z A T I O N

CHAPTER 9

Qualification of Antioxidant & Chelating Agent
20 mg / g Miconazole USP

Optimization Batch Stage - Stability studies
Container / closure system :
Storage conditions
:
Packaging Date:

HDPE container = cap (110 mL)
Fill size: 110 mL
30°C / 75% Relative Humidity
Mfg. Date:
Expiration Date:
Stability Start Date:
Table No. 16.

Storage

in

(%)

P-06

Batch
ð

months P-06

Specs.

Assay & Content Uniformity

Appearance
of
Semisolid

P-08

Off-white to
Cream color
smooth appearance
non gritty feel

0

Conforms

1

Conforms

Conforms

2

Conforms

Conforms

3

Conforms

Conforms

Assay
ð

Top

P-08

Middle Crimp

Top

Middle

Crimp

CONTENT
UNIFORMITY

CONTENT
UNIFORMITY

(RSD)

(RSD)

103.5

102.1

102.5

101.9

100.1

(1.9)

(0.9)

100.5

101.8

99.9

101.5

101.0

101.9

102.4

97.8

101.5

(1.0)
Conforms

97..5

98..5

100.5
(2.1)

(2.3)

Range fully
within
specification

CONTENT
UNIFORMITY
in Specification

Handbook of Pharmaceutical

99..5

Chapter: 9.8
8

Generic Development

SEMISOLIDS

P R O C E S S - O P T I M I Z A T I O N

CHAPTER 10

SCALE-UP

P rocedures
‘…Scale-up is a development procedure pivotal and validation lots are demonstration procedures…’

S C A L E - U P

O F

D E V E L O P M E N T

T

he scale-up of the manufacturing
procedure remains a development
procedure and should be applied
initially to:

• the process qualification batch

♦ weighing the ingredients
♦ adding or transferring materials
♦ rinsing procedures
♦ mixing / stirring speeds

• the pivotal batch

♦ maximum torque value (if available )

• the full size validation lots.

The Process Qualification batch should
mimic the pivotal batch in all its
aspects. Ideally it is the same size or
about 70% of the market batch and is
seen as a prototype test run for the
pivotal procedures, QC controls and full
processing documentation package.

Batch size considerations:The pivotal batch must be 10 % or
greater than the size the corresponding
validated commercial batch lot (OGD’s
Regulation).
The pivotal size may in fact be equal in
size to the validated commercial lots
and since every commercial lot size
must be separately and individually
validated - scale up procedures need to
consider both the pivotal batch and the
commercial lots.
Ten standard guidelines for scale-up of
topical
procedures
are:-

Handbook of Pharmaceutical

L O T S

♦ time/temperature/vacuum
requirements
♦ requirements of time / temperatures
♦ Processing times;

◊ in-process
◊ prior to filling
◊ total manufacturing time
♦ sampling procedures / protocol

Scale-up procedures
Net ingredient weight
The addition of bulk liquids or
semisolids to large processing vessels
may require pumping or hand /
mechanical transfer. The recording of
the net ingredient weight from each
drum or container requires specific
documentation and signatures. Drum
transfer require individual gross, net
and tare weights to be recorded.

Chapter: 10.1
1

Generic Development

SEMISOLIDS

P R O C E S S - O P T I M I Z A T I O N

SCALE-UP

Procedures
Where indirect measurements using
specific gravity and temperature
measurements are used to calculate
mass transfer - check signatures are
required for each calculation.
Significant decimal points recorded with
respect to the calibrated measuring
instruments must be relevant to each
recording.

Bulk transfers
Drums and containers may require
preheating to liquefy contents prior to
transfer. Record preheating steps in
batch manufacturing instructions.

Rinsing procedures
Potent active or semi active ingredients
may be transferred directly into the
processing vessel or may require to
undergo a rinsing procedure to remove
trace
amounts.
Processing
documentation must indicate the
quantity of rinse solvent reserved and
the exact number of rinse procedures.
A two rinse procedure is essential and
an efficient practice. Note that the
rinsing fluid is recorded in the master
formula as 1st Rinsing Fluid and 2nd
Rinsing Fluid. Where micrograms of
active material are present an
additional 3rd Rinsing stage is
performed.

Stirring and mixing speeds
The stirring speed (rpm) for each
processing step and each critical
processing stage requires complete
documentation of mixing speeds and
settings to insure complete in-process
mixing and content uniformity.
Mixing efficacy may differ from pilot
kettles and small scale reactors to large
processing vessels and large scale
reactors.
Handbook of Pharmaceutical

CHAPTER 10

Manufacturing equipment for pivotal
and commercial batch sizes must have
operating principles that differ only in
scale.
Since mixing speeds and mixing times
impact significantly on the uniformity of
content of the bulk batch, both
operations are considered critical
process parameters.

Stirring and mixing times
The processing time for each
manufacturing step requires a ‘start and
stop’
documentation entry. Where
possible automatic recording control
charts should be in place for monitoring
processing times and temperatures.

Time / temperature requirements
Slow continuous stirring may be
required during in-process cooling or
heating. When the rate of heating and
cooling is significant or critical, the
stirring rates, processing parameters
and times should be documented to
achieve the desired heating or cooling
function.
Caution or warnings statements must
be documented to circumvent excessive
heating or cooling rates,
where
appropriate.

General Scale-up concepts
The processing time for each
manufacturing step requires a ‘start and
stop’ document entry. Where possible
automatic recording control charts
should be in place for monitoring
processing times and critical process
temperatures.

End-point temperatures
Temperature end-points for heating or
cooling are documented in the format of
a range, i.e. ‘cool to 250 C (± 20 C) or
heat to 700 C (± 10 C).’
It is not necessary to qualify such
narrow operating temperature limits (as
there is no significant impact on the
process).

Chapter: 10.2
2

Generic Development

SEMISOLIDS

P R O C E S S - O P T I M I Z A T I O N

PROCESSING TIMES

SCALE-UP

The following pre-processing and
processing
controls
require
documentation in order to minimize or
totally
prevent
microbial
growth
between the various manufacturing
filling steps and stages:
Where possible the minimum period
should elapse between:-

Procedures
Re-mixing a step
Repeating a mixing step is acceptable,
if the re-mixing procedure has been
qualified
during
the
product
development phase.
To qualify a re-mixing step manufacture the batch with the initial
mixing step.
Sample the bulk at the different
sampling levels and positions. Do not
composite any samples for content
uniformity tests.
With the same batch immediately
repeat the exact mixing step and resample exactly as before. (sampling
procedures and sampling positions
must be recorded). The content
uniformity, viscosity etc. should not
differ in both sampling sets.

Revalidation
Infrequent re-mixing should only occur
in incidences of mechanical breakdown
or due to excipient variation. Where the
re-mixing process becomes more
frequent - revalidate the manufacturing
process to optimize the mixing steps
and review raw material ingredient
specifications.
Do not composite any samples for
content uniformity tests.
Sampling Procedures:-

• Use the same sampling unit every
time you sample.
• Sample the same levels (top,
middle, bottom)
• Use the same angle of entry, thief
orientation and sampling motion
every time you sample.

Handbook of Pharmaceutical

CHAPTER 10

è Line Cleaning
[Manufacturing
and
filling
lines
including pumps and transfers lines ]

è Product manufacture
[Time from weighing and dispensing to
final in-process bulk control]
W here bulk creams are held for several
weeks or longer prior to filling - stability
and microbial limit tests of the bulk
material must be qualified and
documented during its holding storage
in the bulk containers.

è Product filling
[Continuous filling without stoppages or
over week-end breaks]
Manufacturing
&
Processing
documentation controls include:

ÜMaximum time period between
equipment cleaning and batch
processing

ÜMaximum

time period to
complete
a
critical
manufacturing step

ÜThe overall manufacturing time
and the overall filling time

ÜMaximum time period between
sanitation of filling line and start
of filling operation

ÜThe

maximum time period
allowed
between
end
of
manufacture and start of filling
operation

Chapter: 10.3
3

Generic Development

SEMISOLIDS

P R O C E S S - O P T I M I Z A T I O N

CHAPTER 10

ØC H E C K L I S T ×
CL # HBGD-03-02YY

SC AL E

UP P ROCEDURES

‘ the order is clear:- develop - scale-up - process qualification
- pivotal and validation lots ’

1.

The process qualification batch is a ‘carbon copy’ of the pivotal lot?

qYes qNo

2.
The process qualification batch is manufactured under normal production qYes qNo
facilities ?
3. The process qualification batch documentation is similar or identical to the qYes qNo
pivotal lot documentation, which is identical to the commercial lots?.
4.
Where two commercial batch sizes are manufactured, the equipment used qYes qNo
differs only in capacity or size?
5.

Each batch size has a dedicated set of processing documentation?

qYes qNo

6.

All mixing/granulating times have a ‘start and stop’ entry?

qYes qNo

7.

All end-temperatures are documented with the recorded entries?

qYes qNo

8.
Speed, temperature and time control charts attached to manufacturing qYes qNo
instructions clearly identify batch, vessel, and processing step #?
9.

qYes qNo

Documentation records overall manufacturing and filling times ?

10. Special instructions exist to prevent product contamination during normal qYes qNo
processing breaks and temporary work stoppages?
11.

Filling instructions document equipment cleaning and filling times?

qYes qNo

12.

Adequate controls exist to prevent over week-end/holiday manufacture?

qYes qNo

13.

Containers are air blown to reduce particulate matter and bioburden?

qYes qNo

14.

Line screen covers protect open containers from aerial particle settling?

qYes qNo

15. Control procedures in place to minimize environmental contamination qYes qNo
during tablet filling (bioburden reduction)?
Footnote :
The Process Qualification Batch Documentation is the basis for the Pivotal manufacturing
documentation. Pivotal and commercial batch manufacturing instructions and procedures are in fact
identical in all respects with exceptions in
equipment size changes. Both the process and the
manufacturing
documentation
under
goes
appropriate
scale-up
procedures.

Handbook of Pharmaceutical

Chapter: 10.4
4

Generic Development

SEMISOLIDS

P R O C E S S - O P T I M I Z A T I O N

CHAPTER 10

ØC H E C K L I S T ×
CL # HBGD-03-02YY

S CA LE

U P P ROCEDURES

The following selected model Standard Operating Procedures are RECOMMENDED
in the SOP appendix :

Scale-up Procedures
SOPs
P-000-01-02YY

Preparing a scale-up report for pivotal and validation batches.

P-000-01-02YY

Time limitations between equipment cleaning and batch processing.

P-000-01-02YY

Time limitations for completing overall granulation procedures.

P-000-01-02YY

Maximum time between end of granulation and start of tabletting
operation.

Processing Times:
The following pre-processing and processing controls have SOP documentation:

maximum time period between equipment cleaning and batch processing.

maximum time periods to complete a critical manufacturing steps.

the maximum period allowed between end of processing and start of the filling
operation.

the overall manufacturing time and the overall packaging time.

4
[End of Document]

Edition No. 01

Effective Date :

Ed. Status : New

Handbook of Pharmaceutical

APPROVED
______________ __________ ______________ ________________
Department
RD
RA
QC / Q A

Chapter: 10.5
5

Generic Development

SEMISOLIDS

CL
L E A N I N G

L I M I T S

CHAPTER 11

CLEANING
LIMITS
…‘Check the baby not the bath rinse water
Check the pot not the dish water…’

C

leaning validation has become a
focal point of inspection for
regulatory agencies throughout
the world.
For pre-approval
inspections conducted by the FDA
for any product ultimately directed to
the US market, many companies
have been denied approval because
of deficiencies in their cleaning
program or a lack of cleaning
validation for their products.
This chapter reviews and highlights
key regulatory expectations for a
satisfactory pre-approval inspection
program.

Validation Protocol

A cleaning validation program is an
essential part of the generic product
development program.
Product approval has been denied
during
pre-approval
inspections
(PAIs) conducted by the FDA due to
the absence of appropriate scientific
rationale
and
documented
acceptance criteria for cleaning
program.
Residue types

A

well structured cleaning validation
plan requires the removal after
manufacture of the following principle

Handbook of Pharmaceutical

contaminants from process equipment,
piping and hoses used.
∗ active material residues (limit)
∗ excipient residues (non-soluble)
∗ Detergent and solvent residues
∗ microorganisms (bioburden
reduction)
∗ machinery lubricants

Solubility factors

Non

soluble active and insoluble
excipient residues require specific
cleaning mechanisms to prevent cross
contamination or adulteration of the
next batch product. Maximum Residual
limits are required to be established for
each active.

Adulteration
Zero adulteration for penicillin's has
been
regulated.
Steroids
(e.g.
hydrocortisone and estrogen) as well
as sulfa drugs require extremely low
levels of active residues remaining in
the equipment after cleaning.

Written procedures
Written cleaning procedures (SOPs)
are required detailing the cleaning
process for each piece of equipment
used in the manufacturing and filling
process.

Chapter: 11.1
1

Generic Development

SEMISOLIDS

CL
L E A N I N G

L I M I T S

Clean to remove
extraneous peaks
to below their LQ
in the next batch, if
they affect your assay

Parameters evaluated
Written procedures detail the cleaning
procedures are required:

♦ between different batches of the
same product (minor cleaning).

♦ between different product changes.
♦ for water soluble product residues.
♦ for

non-water
residues.

soluble

product

♦ for dedicated equipment and hoses.
Each cleaning validation protocol
needs to address the following:-

♦ Responsible person for approving
the cleaning protocol.

♦ Responsible person for performing
the actual cleaning procedures.

♦ The

specific
procedure.

written

cleaning

♦ Sampling procedures.
♦ Analytical

methodology

(and

♦ Acceptance

criteria
and
establishment of residual limits after
cleaning.

♦ Protection after cleaning and time
limits.

♦ A revalidation period.
♦ The final validation cleaning report.
cleaning procedures in a
development / production department
need to assure that the residual levels
of the active drug substance, after the
cleaning process does not introduce
extraneous HPLC peaks in the next
development / production batch (for
non-serial product lots).

Handbook of Pharmaceutical

Extraneous HPLC peaks may result in
the analytical testing laboratory if active
materials
from
the
previous
manufacturing lot are carried-over in
the next non-serial batch (i.e. when a
different active product is manufactured
as the following batch).
Where extraneous peaks do occur, the
HPLC procedure needs to establish the
exact peak position and its possible
origins from the previous manufactured
batch product.
Peak purity needs to be established to
ensure that the main peak of the next
active has no underlying minor
extraneous peaks of the previous
product, thus augmenting the assay
results erroneously.

Limits and Acceptance Criteria

sensitivity.)

Routine

CHAPTER 11

Establishing the criteria for acceptance
of a cleaning procedure requires that
the procedure consistently cleans to a
chosen target value residue or limit.
Choosing the residual target value
limits vary between individual firms
manufacturing the same products.
This standard method highlights an
exceptionally elegant and simple
procedure for choosing the appropriate
clean limit using a scientifically derived
‘clean formula’.
Chosen residue values need to be
based on good scientific rationale and
appropriate medical opinion that
evaluates and takes into account the
total daily dose that may be prescribed
to the patient. This dose should be
'free' to a limit of the previous material
manufactured.

Chapter: 11.2
2

Generic Development

SEMISOLIDS

CL
L E A N I N G

Contaminating

materials
in
a
pharmaceutical Master Cleaning Plan
fall into two to three main types for
evaluation and limit testing. These are:
• the active material
• the cleaning detergent
• colored and/or insoluble excipients

Strongly

colored
or
insoluble
excipients should be removed by
cleaning to a pre-set limit value for
active
materials
and
cleaning
detergents.
If excipients are not remove to a ‘zero
visible level’ a further residue limit
should be set for the problematic
ingredient. Generally water soluble and
easy-to-clean excipients do not require
analytical limit testing to a pre-set limit
value.

Establish acceptance
criteria
and residual limits
for the cleaning
process
Maximum cleaning limits
The maximum residual limits of

active
material A is acceptable when it is
present at a 1 in 1000 part in product B
and when expressed as a function of
the therapeutic ratio (TR) of product B.
What is the TR of a product ?
The therapeutic ratio is the lowest
marketing dose (LMD) divided by the
maximum daily dose for the intended
purpose (i.e. LMD / MDD). The LMD is
in fact for all purposes the lowest
therapeutic dose of the active drug
substance, for the intended clinical
indications.
Steroid
hormones
such
as
betamethazone are available for widely
varying clinical indications. Both 25 mg
per gram and 100mg / g are available.

Handbook of Pharmaceutical

L I M I T S

CHAPTER 11

The TR for the lower dose is
1:4 The TR is therefore defined for its
intended medical indication profile.

Clean to leave
1 in 1000
active residuals in
the next dosage unit
Cleaning levels per next unit dose may
readily be achieved down to 0.5-1
microgram contamination limits or
better.
Firms cleaning to a maximum residual
limits of 1/2000 would be well within the
pharmaceutical industry standard while
residual limits of 1/10000 could be
considered a possible cleaning over-kill
and a costly sanitation procedure for
standard routine drug manufacturing
processes.

The purpose of a cleaning validation is
to obtain documented evidence that the
cleaning procedure of the firm will
provide a high degree of assurance
that the overall cleaning process will
effectively remove, to a predefined
limit, active product and cleaning agent
residues from all the processing
equipment used, for the purpose of
establishing the absence of product-toproduct cross-contamination.

Set detergent
residual limits to
1 in 1000 of its
lowest toxic dose
This implies that the cleaning methods
used are effective in removing all
product and cleaning residues that are
in direct contact with the equipment
surface areas during the manufacturing
process.

Chapter: 11.3
3

Generic Development

SEMISOLIDS

CL
L E A N I N G

For cleaning detergent limits, a similar
end point marker is used by
substituting toxic dose for therapeutic
dose. The cleaning detergent limit may
be defined or written as:
“the maximum contamination of detergent
residuals in the maximum daily dose for the
next product will not be more than 1/1000
of its lowest toxic dose (LTD ”
The LTD is the recorded LD50 of the
detergent’s active material obtainable
from the published literature.
Using the above wording as a standard
written format, the acceptance criteria
for the residual limits of any active raw
material after the cleaning process has
been completed may be defined as:

“the maximum contamination limit of
the residual active drug from the
previous product (A) expressed in terms
of the maximum daily dose for the next
product (B) will not be more than 0.1%
of Product A’s lowest labeled strength
(LLS) ”
In the case where the next batch lot is
not known (in R&D / development units)
or production cleaning is performed
independently of the production
scheduling, the QA department should
apply a worst case product scenario.
The calculation variables for the firm’s
granulation-tabletting line would be:
• the Lowest Label Strength of
previous product A
• the largest therapeutic ratio [TR]
• calculated at 1/1000 parts.
Cleaning Limit
(in mcg)

=

LLSA x
1000

TR

TR = The Lowest Marketed Dose
(LMD) divided by the Total Daily Dose
(TDD). Obtained from the medical
literature for the products intended
indication profile.
The state-of-the-art scientific rationale
using the concept of the therapeutic
ratio employs current medical opinion
Handbook of Pharmaceutical

L I M I T S

CHAPTER 11

along with appropriate safety factors
and allows a firm to defend its overall
cleaning program during regulatory
review.
Furthermore it allows the R&D to
development and coordinate and
standardize the scientific rationale for a
cleaning validation program in all future
product development.

Residual limits
are always based
on the lowest
therapeutic dose

It

is essential that cleaning limits are
independent of the dosage strength of
the contaminating material - thus a 0.25
1.0 and 5.0 mg per gram semisolid
preparation, all have the same cleaning
limits.
This is a further safety factor as the
clean formula uses the lowest
marketing dose (i.e. 0.25 mg per gram
calculation and is known as the lowest
labeled strength (LLS)).

The

amount of residual Active
contaminating the next batch will be the
same for of 0.25 to 5.0 mg/g strength.
To simplify the cleaning validation
program the firms products may be
grouped
according
to
common
parameters (the active’s solubility and
specific dosage form - i.e. topicals with
water insoluble actives) and an
appropriate limit for a worst case
cleaning model evaluated using the
above safety ratios for developing limits
based on the medical risk assessment
of the firms current products.
From these worst case variables a
target cleaning limit may be calculated
with ease and presented in a simplified
form as shown.

Calculations-

The calculation to
determine the limit of residuals in the
next known product for dosage forms is
given below:

Chapter: 11.4
4

Generic Development

SEMISOLIDS

CL
L E A N I N G

CLEAN Equation. No II.

Clean Limits
(in mcg / dose)

= LLSA
1000

x
LSB
x MDD

Where:
CL
LLSA
LSB
(mg)
1000
MDD
A
B

= Residuals of A in mcg per
dosage unit of Product B
= Lowest Label Strength of
product A expressed in mg.
= Label strength of product B
= Reduction factor of 1/1000
= Maximum Daily Dose of B (mg)
= Last manufactured product
= Next manufactured product

Calculations for a ‘worst case’
scenario.
The calculation to determine the limit of
residuals in the next unknown product
(N) for oral dosage forms is given as
follows:
CLEAN Equation. No III.

Clean Limits
(in mcg/dose)

= LLSA x
1000
x

LSN
MDD

Where:
CL
LLSA
(mg)
LSN
1000
MDD
A
N
LMD

= Residuals of A in mcg per
dosage unit of Product N.
= label strength of product A
= label strength of product N (mg)
= Reduction factor 1/1000
= Maximum Daily Dose of N
= Last Manufactured Product.
= Product with largest therapeutic
ratio (LMD / MDD).
= Lowest Marketing Dose

Firms

can rapidly establish from their
product lists the largest therapeutic
ratio (LMD / MDD) of products
processed in the plant.
Lets show how simple this formula
works in practice. The Company
examines its product profile and finds
that it markets a potent 1.0 mg/g anti-

Handbook of Pharmaceutical

L I M I T S

CHAPTER 11

inflammatory cream in which the
products package insert allows for a
maximum administration of 2g cream
application every 6 hours - i.e. a total of
8 mg active in 24 hours. Thus the MDD
is 8 mg.

Worst case calculation:
The therapeutic ratio for the firms
‘worst case’ scenario is thus 1:8 which
is a fixed value.
Therefore the equation II simplifies to:
CLEAN Equation. No IV.

Clean Limits
(in mcg/dose)

=

LLS(A)
8000

The

equation may be expressed in
words as:
The limit of residuals (expressed as
mcg per dose) in a ‘worst case’
scenario for the next manufactured
product is 1/8000th of the last
manufactured product’s lowest labeled
strength expressed in milligrams.

The equation may be further expressed
for daily use in the cleaning and QA
departments as a much simplified
arithmetic formula - the limit of
allowable residuals after cleaning,
stated in micrograms is 1/8 of the last
manufactured
product’s
milligram
labeled strength.
Establishing the largest therapeutic
range (LMD / MDD) and expressing as
a ratio may seldom exceed the value of
1: 8.
This procedure permits the QA
department to evaluate the cleaning
procedure to a routine standard limit
(mcg / dose) of 1/8000th of the last
batch’s lowest labeled strength. 3
References:
1. USP/NF XXIII USPC Rockville Maryland USA 1994.
2. Scale up and Post approval Changes Manufacturing
and Controls In vitro Dissolution and In Vivo
Bioequivalence Documentation CDER 1995 (SUPAC)

Chapter: 11.5
5

Generic Development

SEMISOLIDS

CL
L E A N I N G

L I M I T S

CHAPTER 11

ØC H E C K L I S T ×
CL # HBGD-03-02YY

Cleaning Limits & Procedures
ACTIVE AND EXCIPIENTS
‘...Set active and detergent residual limits
and clean to this target level...’

1. Is there is a written cleaning procedure for every processing unit?

qYes qNo

2. Is there a written cleaning procedure for all auxiliary equipment?

qYes qNo

3. Cleaning procedures require rapid equipment flushing, immediately qYes qNo
after manufacture to prevent products from drying and becoming more
difficult to clean?
4. After each manual cleaning procedure a quantitative rapid test qYes qNo
procedure is used to evaluate the cleaning process ?
5. When ever there is a detergent; formulation; cleaning equipment or qYes qNo
procedures change, the cleaning process requires to be re-validated ?
6. Operators are initially qualified and periodically thereafter re- qYes qNo
qualified to ensure satisfactory cleaning procedure performances ?
7. Cleaning procedures are performed after maintenance / calibration qYes qNo
periods?
qYes qNo

8. Cleaning procedures are performed after shut-down periods?

9. Cleaning re-validation is performed after persistent microbial levels qYes qNo
are obtained, in excess of ‘alert’ or ‘warning’ limits ?
10. Visual examination, surface swabs and final rinse water analysis are qYes qNo
collectively used to test for permissible residual limits?
11. Final rinse water analysis is only used for soluble active materials as qYes qNo
a routine QC monitoring procedure?
12. Aqueous (Purified Water USP) and non-aqueous (alcohol) solvents qYes qNo
are used to wet the swabs - dependent on the nature and solubility of the
active and excipients?
13. Standard swabs (e.g. Whatmans™ #4, 9.0 cm filter paper) are used?

qYes qNo

14. A standardized surface area (approx. 0.1 - 0.2 m2 ) is wiped in a qYes qNo
unidirectional manner with the swab?
15. Cleaning procedure manuals or SOPs highlight ‘hard to clean’ areas qYes qNo
such as valves, threads, seals, shafts and mixer blades - where product
may accumulate and remain static after cleaning? These ‘hard to clean’
areas are evaluated during the cleaning validation procedure ?

Handbook of Pharmaceutical

Chapter: 11.6
6

Generic Development

SEMISOLIDS

CL
L E A N I N G

L I M I T S

CHAPTER 11

ØC H E C K L I S T ×
CL # P-000-03-02YY

Cleaning Limits & Procedures
ACTIVE AND EXCIPIENTS
‘Detailed visual checking by cleaning operator and
supervisor is a cGMP requirement

16. The 1/1000 of the lowest marketing dose (LMD) are the acceptable
active material residue limits ?

qYes qNo

17.The 1/1000 of the LD50 are the acceptable detergent residue limits?

qYes qNo

18. Wiping-solvents for cleaning swabs are specifically pre-determined qYes qNo
for each active material - depending on whether it is water soluble or
insoluble ?
19. Purified Water USP is the wiping solvent for most detergents?

qYes qNo

20. Rapid assessment of equipment cleanliness after manual procedures qYes qNo
is achieved by simple analytical test methods ?
21. High pressure hot water jets and steam jets are available in the qYes qNo
cleaning area?
qYes qNo
22. The final rinse water is Purified Water USP ?
23. Maximum time limits prior to cleaning have been established ?

qYes qNo

24. Maximum time limits between equipment cleaning and sampling have qYes qNo
been established to avoid post-cleaning sampling errors ?
25. Maximum time limits between equipment cleaning and next batch qYes qNo
production have been established?

Use a combination of swabs and rinse waters tests
26. Equipment covers are used to protect exposed cleaned surfaces qYes qNo
during storage between batches (portable mixers etc.)?
27. Detergent concentration is standardized for soluble and non-soluble qYes qNo
active materials ?
28. Where applicable detergents and chlorine bleach are used together? qYes qNo
29. Where applicable detergents and hydrogen peroxide are used
qYes qNo
together?
30. Disposable clean cloths or filtered hot air is used for drying qYes qNo
equipment ?
qYes qNo
31. Residual rinse waters are completely removed, after cleaning ?

Handbook of Pharmaceutical

Chapter: 11.7
7

Generic Development

SEMISOLIDS

CL
L E A N I N G

L I M I T S

CHAPTER 11

STANDARD OPERATING
PROCEDURES

Page 1 of 1.

SOP #HBGD-03-02YY

CLEANING VALIDATION
Cleaning Validation Requirements
The following Standard Operating Procedures are recommended for a generic
development unit :
…‘Time limits before and after cleaning must be laid down
in writing…’

Cleaning Validation SOPs
P-000-01-02YY

Cleaning validation requirements for non-sterile manufacturing.

P-000-01-02YY

Aspects of semisolid cleaning validation.

P-000-01-02YY

Equipment cleaning verification.

P-000-01-02YY

Serial (minor) and non-serial (major) equipment cleaning.

P-000-01-02YY

Setting Cleaning limits in semisolid preparations.

4
[End of Document]

Edition No. :
01
Ed. Status : New

Effective Date :
DD/MM/YY

Handbook of Pharmaceutical

APPROVED
______________ ____________ ______________ ________________
Department
RD
RA
QC / Q A

Chapter: 11.8
8

Generic Development

SEMISOLIDS

ANALYTICAL

Analytical

However

Validation
Analytical Validation - a working
validation protocol for HPLC system.

A

nalytical assay validation of the
generic drug active material
requires to be evaluated
reasonable
early
in
the
drug
development process. In many cases
the Official USP assay (if available at
the time) is not really a stability
indicating testing procedure.
This article provides an example (for
tablets) of a typical hand-on analytical
validation for in-house HPLC methods
that may or

Official USP
Analytical method
for well known
actives are not
generally stabilityindicating test
methods as well

validation of new generic
products in the pipeline may not have
an official assay method.
A totally new assay method possibly
based on a Pharmacopeial Forum
methodology is adapted in-house for
assay as well as for stability indicating
testing methodology.
New HPLC methods require complete
validation
whether
the
method
originates
from
an
outside
manufacturer, whether developed inhouse or adapted from the literature.

What to validate?
⇒ Assays
⇒ Stability Assays
⇒ Impurity Package
⇒ Dissolution
when in-house
These

procedures ensure that the
Product Development Process of the
generic drug up to the Process
Qualification Batch testing is based on
a foundation of Good Laboratory
Practice, using validated test method
procedures.

may not be based on official USP
methodology, as well as showing that
these methods are stability-indicating.
Validation terms used frequently by
different pharmaceutical and analytical
researchers may have different
meanings
in
different
research
departments. Terms used here are
defined in a real-life HPLC context.
When a methods is based on the USP
official method but is modified inhouse for stability indicating test
purposes, it requires a full in-house
validation procedure. This is often the
preferred route most generic labs
follow.
Handbook of Pharmaceutical

CHAPTER 12

Analytical Product Development.
Ruggedness testing validates the
technical transfer of the methodology
to the Quality Control laboratory at the
commercial manufacturing site.

In-house

analytical validation applies
to each non-compendial analytical
assay method intended for ANDA (or
OTC-ANDA) manufactured products.

Validation

also applies to StabilityIndicating Assays and limit testing of
impurities based on compendia
methods.3

Chapter: 12.1
1

Generic Development

SEMISOLIDS

ANALYTICAL

Analytical
A spects

E

ach Product strength will follow a
full method validation procedure.
One general all purpose analytical
validation is not sufficient for multiple
dosage strengths (e.g. 200, 400
800mg tablets) as sample aliquots,
ranges and linearity data may change
as a function of the dosage strength.

Method Validation
Non-compendial method validation
usually follows the USP direction for
parameters needed for the validation
of test methods.
Typical parameters for validating
assays and other non-compendial
analytical methods designed for
providing quantitative reproducible
results include:

Accuracy

Recovery

Precision
(Repeatability, Reproducibility and
Intermediate precision (ruggedness)

Specificity

Linearity

Range

Ruggedness1 & Robustness

and the assay value the analyst should
obtain. It simply implies freedom of
error. In a development laboratory
validation protocol, accuracy may
often be expressed simply as the
percent recovery (with a zero bias) by
the assay of known added amounts of
the active analyte.
Bias needs to be understood in
analytical accuracy. Drawing an
example from the game of throwing
darts, accuracy is an all important
factor, this means getting all the darts
tightly clustered around the bulls-eye right in the center 50-point ring!
Placing all the darts in a neat tight
circle at three-0-clock is precise
throwing but not accurate. There is a
positive bias in the true mean of the
dart's results and the real true value
actually required - i.e. the bulls-eye!
Thus bias is simple the error between
the mean of the analytical HPLC assay
results obtained and their true value.
Bias may be positive or negative
(assays with a mean of 102.4% show a
positive bias while an assay reading
97.9% yields a negative bias).
Bias is important for release and
stability check specifications assays as
the product may indeed fail, not due to
a sub-potent assay, but simply a
biased analysis.

Frequent revalidation

of analytical assay
methods is an

1

(Two analysts on different days using
different equipment models / columns).
Terms used in analytical validation
should be defined as the reviewer may
need a clear definition from the author
for all values submitted. Typical
definitions are:
Accuracy - This is the degree of
correlation of the HPLC assay result to
the true value (also called trueness)

Handbook of Pharmaceutical

CHAPTER 12

essential procedure

for detecting bias

Precision - may be of a method - or
the precision of the HPLC system
i.e. system precision.
The precision of the system
removes the potential sampling
error.

Chapter: 12.2
2

Generic Development

SEMISOLIDS

ANALYTICAL

Analytical
A spects
The Precision of the System
Is defined as the degree of
agreement among the individual
assay results when the assay step
is applied to replicates of the
standard (volumetric) preparation
(i.e. the variation due to sampling is
eliminated) - this sampling variation
may be significant in tablet
granulation material or semi-solid
dosage forms.

Method precision
includes
sampling error
The ‘precision of a method’ is
challenged
by
including
the
sampling error in an homogeneous
sample or composite of samples.
No granulate material is perfectly
homogeneous thus the ‘precision of
the method’ is detecting both the
minor variations in the homogeneity
of the sample and the precision of
the HPLC system, due to minor
detector, pump, mechanical and
electronic fluctuations.
Precision of a method is defined as
the degree of agreement between
individual HPLC test assay results
when
the
analytical
method
procedure is applied repeatedly to
multiple samplings of a homogeneous sample of composite.
A frequent error cited by the agency
inspectors deals with linearity and
range. Laboratory HPLC analysts
inject amounts that are outside the
range for which the linearity of the
test
method
has

Handbook of Pharmaceutical

CHAPTER 12

been demonstrated in the method
validation.
In most cases the
injected volume will display a linear
response - however the need to
demonstrate the full range in the
method linearity is essential.
Linearity of an HPLC test method is
its ability of the HPLC detector to
elicit a response that is directly
proportional to the concentration of
the analyte in the sample in the
chosen range e.g. 50-150%.
Linearity may require a transformation
equation
to
show
proportionality.
The range of a test method is
demonstrated as the interval
between the upper (150%) and
lower levels (50%) of the analyte to
be injected into the HPLC that
shows linearity as well as accuracy
and precision. A fixed volume loop
must be within the chosen range.

Peaks must be
homogeneous.
Not
a mixture of
co-eluting peaks
Peak

Homogeneity
is
a
chromatographic term. A peak is
homogeneous if it corresponds to a
single chemical entity i.e. it is not a
mixture of co-eluting peaks possibly
derived from impurities or the
placebo excipients.

Placebo Analysis.
A mixture of non-actives (placebo)
is prepared and subjected to HPLC
analysis.
Normally no interfering peaks are
observed in the graph of the
placebo chromatogram.

Chapter: 12.3
3

Generic Development

SEMISOLIDS

Where

During the production process in the

interfering
peaks
are
observed, their position should be
noted as well as checked that no
reinforcement of the active peak is
present - resulting in biased or
skewed assay results.
Standard Solution - Stability. - Take
care to evaluate the stability of the
Standard solution. It is assessed by
re-injection of the standard solution
again after the said period of days
the standard will be used and

manufacture of the drug product,
abnormal heat stress may be present
due to heat produced by fluidized
bed dryers, tray ovens, or heat
generated by high shear mixers, at
maximum settings.

Take care that the
product and the placebo
are stressed to realistic
abnormal production
heat or hydrolysis
stresses to detect
extraneous HPLC peaks

comparing with the original values.

Standard Solutions must be stored at
controlled temperatures and light
conditions and so labeled on the flask.

Stability Indicating Procedures.

Processing Heat Stress
The Manufacturing process can

For the Stability Indicating Method,
the product sample shall include
forced degradation by stressed
analysis. Conditions such as the
concentration and reaction times
may vary depending on the stability
of active drug substance as to
whether it is thermo or chemolabile.

cause ingredient breakdown, giving
new extraneous peaks.
Care needs to be taken that the
manufacturing process does not
introduce high heat stress factors
into the in-process bulk product. High
speed mixer may create hot spots for
a brief time period, while FBD / Tray
drying procedures, or maintaining hot
oils, waxes or purified water for a
lengthy period, during topical semisolid processing, may cause the
appearance of new HPLC peaks.

------------------------------------------

Routine stressed conditions tested
are
generally
the
following
categories:


Oxidation Stress
[H2O2] plus length of standing time.

Base Hydrolysis

It may be important in a heat stress

[NaOH] plus length of standing time.

evaluation to run a test to mimic the
highest manufacturing operating
temperature (plus an extra 20-30%
degrees C margin) for the duration
equal to the maximum time period
required for the largest batch size,
processing step (plus 20 - 30%
added process stress time).

Acid Hydrolysis
[HCl] plus length of standing time.

Sun light Stress
6 to 24 hours standing time.


Heat Stress I
@ T1 oC - abnormal production.

Heat Stress II
@ T2 oC - active breakdown.

Edition Number:
03
Ed. Status :
Supersedes 02

CHAPTER 12

ANALYTICAL

Effective Date:
DD/MM/YY

Handbook of Pharmaceutical

APPROVED
_____________
Department

___________
R &D

Chapter: 12.4
4

______________
RA

_________/________
QC / QA

Generic Development

SEMISOLIDS

Analytical

Identify known
degradants, and label
and tag unknown
degradants and
impurities

A spects
Specificity and Suitability
Resolution and Tailing Factors.

The peak purity of the main peak is

W hen

a satisfactory separations of
all the degradation peaks have been
achieved
through
the
forced
degradation reactions, a Resolution
Factor (according to the USP
requirements) between the main
active peak and the nearest
degradant peak is calculated using
the USP formula.

normally given for each stressed
analysis (determined by peak-slicing
using diode-array UV detection and
comparing
with
stressed
and
standard references).

Validation of limit testing for
impurity methods shall include :
Specificity and Selectivity
Limit of Detection
(LOD / DL)
Limit of Quantitation (LOQ / QL)
The Detection Limit (DL) is the lowest
concentration of analyte in a sample
that can be reliably detected, but not
necessary accurately quantified with
the method used. DL and QL are
specific to the actual method used.
The Limit of Quantitation or
Quantitation Limit (LOQ or QL) is a
more valuable tool and represents the
lowest concentration of analyte in a
sample that can be determined at a
defined precision and accuracy for the
test method employed.
The LOD and LOQ limit values have
become important parameters in
analytical aspects of cleaning
validation protocols and reports.
Frequently firms presenting a master
validation cleaning plan or specific
major or minor cleaning protocols for
the various soluble and non-soluble
classes of active material processed
by the firm - ignore the analytical
aspects of the trace amounts they are
trying to detect or quantify.
3

Stressing
the placebo is often
ignored when searching
for extraneous HPLC
peaks in stability
indicating methods
A Tailing Factor (according to the
USP formula) is also calculated for
the main active substance peak.
Both the resolution and tailing factors
are standard procedures and should
be presented in a standard format in
every method validation protocol and
report.
Relative Retention Time of Main and
Additional peaks:
In each stressed analysis routinely
indicate the percentage by which the
Main peak Is decreased as well as
the relative retention time (RRT) for
any other Additional peaks.

If the RRT of an Additional Peak
corresponds to a known degradant /
impurity etc. it is stated in the
analytical validation report.

Edition Number:
03
Ed. Status :
Supersedes 02

CHAPTER 12

ANALYTICAL

Effective Date:
DD/MM/YY

Handbook of Pharmaceutical

APPROVED
_____________
Department

___________
R &D

Chapter: 12.5
5

______________
RA

_________/________
QC / QA

Generic Development

SEMISOLIDS

CHAPTER 12

ANALYTICAL

Analytical

Aspects I

Validation of analytical methodology
for an HPLC system.
1.
PURPOSE
The purpose of this Standard Analytical Procedure is to demonstrate the procedure
required to validate in-house HPLC analytical methods and to show that the methods
are stability-indicating. Methods based on the USP but modified for stability
indicating test purposes require full in-house validation.
This procedure ensures that the Product Development Process and Process
Qualification Batch analysis is based on a foundation of Good Laboratory Practice
using validated test procedures.
2.
RESPONSIBILITY
The Head of Analytical Development in coordination with the managers of QC and
Regulatory Affairs at the proposed manufacturing site.
3.
FREQUENCY
For each non-compendial analytical method intended for ANDA (or OTC ANDA)
manufactured products.
For Stability-Indicating Assays and limit testing of impurities that may be based on
compendial methods. Each Product strength will follow the full method validation
procedure.
4.
PROCEDURE
[a]. Method Validation
Non-compendial methods validation will follow the USP direction for parameters
needed for the validation of test methods.
Typical parameters for validating assays and other non-compendial analytical
methods designed for providing quantitative results shall include :






Accuracy
Recovery
Precision ( System reproducibility, Method reproducibility )
Specificity
Linearity
Range
Ruggedness (different analysts / days /different equipment models / columns)

[b]. Placebo Analysis.
A mixture of non-actives (placebo) shall be prepared and subjected to analysis.
No interfering peaks shall be observed in the graph of the placebo chromatogram.
[c]. The stability of the Standard solution is assessed by re-injection of the
standard solution after 24 x n hours (where n = number of days the Standard will be
used).

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Standard Preparation for Assay
Comparison of standard solutions for Assay of Active material, injected after say 3
days / one week and freshly prepared solutions demonstrate that the standard
solutions are stable and do not lose its potency after the above period of
refrigeration.
Standard Preparation for Impurity
Comparison of standard solutions of (say Guanine) an impurity, injected after one
month and freshly prepared demonstrate that the standard solutions are stable and
do not lose their quality after 1 month if refrigerated.
Name of standards

Storage conditions

Difference. relative
to freshly prepared
standard

[Active] 100%

4°C

<2%

[Impurity] 100%

4°C

<2%

Standard Solutions are stored at controlled temperatures and light conditions as per
labeling.
[d]. Stability Indicating Procedures.
For the Stability Indicating Method, the product sample usually includes forced
degradation by stressed analysis. Conditions of concentration and reaction time
may vary depending on the active drug substance and drug product - e.g:




Oxidation
Base Hydrolysis
Acid Hydrolysis
Sun light
Heat

-

[H2O2] plus a fixed exposure time
[NaOH] x N a fixed plus exposure time
[HCl] conc. a fixed plus exposure time.
(24 hours exposure time).
(T oC a fixed plus exposure time).

Summary of Stability Indicating Results
Stressed Conditions

Temp.
o

( C)

Time
(hr)

Raw Material;
Remaining
Substance.
(%)

Peak Purity,
(Figure)

Tablets
Remaining
Substance

(%)

Peak
Purity,
(Figure)

Solution heating

90

12

100.2

pure

98

pure

Solid heating

160

2

101.3

pure

92

pure

Sunlight 765 w/m2

40

14

101.1

pure

84.8

pure

3,3N Sodium Hydroxide

70

10

99.8

pure

100.2

pure

10%Hydrogen Peroxide

37

3

77.5

pure

90.5

pure

5% Hydrochloric Acid

Room

20

79.7

pure

78.6

pure

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[e]Specificity and Suitability.
(Resolution and Tailing Factors).
When a satisfactory separations of all the degradation peaks have been achieved
through the forced degradation reactions, a Resolution Factor (according to the USP
requirements) between the main active peak and the nearest degradant peak is
calculated using the USP formula.
A Tailing Factor (according to the USP formula) is calculated for the main active
peak.
[f] System Suitability Test
A mixture of [Active] AS. standard at the concentration about [0.1]mg/mL and of
[Impurity] AS. standard at the concentration about [0.01]mg/mL according to Method
SI-1000 was prepared and injected into the HPLC system.
For chromatogram obtained the following values were calculated (according to
USP):
1. Relative Retention Time for [Impurity] peak
RRT = RT [Impurity]
RT [Active]

=

2.65 = 0.31
8.45

2. Tailing factor for [Active] peak
Tf =

W0.05
9
=
= 1.1
2f
4.2

The values depict the specificity of the method for resolution between the main peak
and impurity peak. (values shown for demonstrations purposes).

Peak Purity
The photo diode-array is used for the evaluation of the stability indicating nature of
the assay method number SI-1000 for [000]mg and [000] mg tablets using a Waters
996™ Unit, controlled by the chromatography manager Millennium 2010™.
Peak purity and match results are reported as:
Purity Angle is a measure of spectral non-homogeneity across a peak - i.e. the
weighed average of all Spectral Contrast Angles calculated by comparing all spectra
in the integrated peak against the peak apex spectrum.
Purity Threshold is the sum of Noise Angle and Solvent Angle. It is the limit of
detection of shape differences between two spectra.
Match Angle is a comparison of the spectrum at the peak apex against a library
spectrum.
Match Threshold is the sum of the Match Noise Angle and Match Solvent Angle.
Noise Angle is a measure of spectral non-homogeneity caused by system noise.

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Solvent Angle is a measure of spectral non-homogeneity caused by solvent
composition.
It the purity angle is smaller than the purity threshold and the match angle is smaller
than the match threshold, this indicates that no significant differences between
spectra are detected. There is no spectroscopic evidence for co-elution and the
peak is considered pure.

[f] Relative Retention Time of Main and Additional peaks.
Each stressed analysis shall indicate the percentage by which the Main peak is
decreased as well as the RRT for any other Additional peaks.
If the RRT of an Additional peak corresponds to a known degradant/impurity etc. it
shall be stated.
The peak purity of the main peak shall be given for each stressed analysis (where
possible).

[g]. Validation of limit testing for impurity methods shall include :

Specificity

Detection Limit (DL)

Quantitation Limit (QL)
Detection Limit (DL)
The detection limit of an individual analytical procedure is the lowest amount of
analyte in a sample which can be detested but not necessary quantitated as an
exact value.
Quantitation Limit (QL)
The Quantitation limit of an individual analytical procedure is the lowest
amount of analyte in a sample which can be quantitatively determined with
suitable precision and accuracy. Used in the determination of impurities and or
degradation products.
[h]. Contents of a typical HPLC Analytical Validation Protocol
Part II of this article deals with the typical validation attributes that need to be
addressed in the development of a new drug's. overall analytical validation
package. Three separate development protocols are impacted. These are;
• The active bulk substance analytical validation package
• The finished product stability indicating assay and impurity profile
◊ The finished product impurity profile (quantitative or limit tests)
◊ The finished product dissolution assay
• Clinical sample assay for active and metabolites during the biostudy (this
assay development and validation is performed by the CRO undertaking the
study).

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Analytical

Aspects II

Validation of analytical methodology
for an HPLC system.
1.

Introduction

2. System Repeatability
Precision

A brief description pertaining into the
following test method specifications:

Ten replicate (single) injections of the
standard solution at the nominal
concentration described in the method
is performed by the same analyst and
the RSD calculated.
The Results
(sample number and peak areas) are
tabulated. The Average Peak Area,
S.D., and R.S.D are shown in the
table. Target values for R.S.D lie
between 0.5 to 1.0
(Keep this standard solution for the
stability of Standard Solutions - Point
nine [9]).

♦ Method

and Edition #
used.
Batch # of samples tested (test
the lowest and the highest label
strength.

♦ Type

of detector used to analyze
stressed samples.

♦ Stress

testing of Standard solution
to determine origin of Additional
peaks

Precision - Table 1.
System Repeatability
[Also called intra-assay precision]

SYSTEM

REPEATABILITY

SAMPLE No.

PEAK AREAS

1
2
3
4
5
6
7
8
9
10

Repeatability shows
precision
under the same operating
conditions over a short
interval of time - same day
same morning

Average Peak Area
Standard Deviation
Relative Standard Dev.

=
=
=

0.5 - 1.0

W here

possible standard expected statistical values have been entered as an
numerical guide. Depending on the active material and equipment used, these
values may differ slightly in specific case studies.

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[3] Method Reproducibility - Precision

The full analytical method # is carried out and repeated Ten

times on the finished
product (batch #) and the RSD is calculated. Two HPLC injections are performed
per method assay and the peak areas are averaged.

♦ The Results (assay %) are tabulated.
♦ The Average Assay %, SD and RSD are calculated and shown in the tabulations.
♦ Target values for RSD = 1.5 to 3.0.
METHOD

REPRODUCIBILITY

SAMPLE No

ASSAY %

Batch No:
1
2
3
4
5
6
7
8
9
10

Method
Reproducibility
monitors the sample-tosampling variation of the
same drug product by
evaluating
the
full
analytical
method over
and over again.
(same operator - same
equipment)

Average Assay %
Standard Deviation
Relative
Standard
Deviation.

=
=
= 1.5 - 3.0

[4] Accuracy

The

Accuracy of an analytical procedure expresses the closeness of agreement
between the true value and the value found.
Ten replicate (single) injections of the standard solution at the nominal concentration
of x mg/100 mL as described in the Analytical Method / Ed is made and the percent
deviation from the true values as determined from the linear regression line is
calculated.

♦ The Results (Peak areas and % accuracy) are tabulated.
♦ The Mean, SD and C.of.V are shown in the tabulations

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[4] Accuracy (continued)
Accuracy may be termed trueness as well

ACCURACY
INJECTION
No

PEAK
AREA

CALCULATED
CONC.

%
ACCURACY

1
2
3
4
5
6
7
8
9
10
Mean (% Accuracy) =
Standard Deviation =
% Coef. of Variation =

[5] Recovery (Extraction time)
The
extraction
efficiency
is
demonstrated by varying the extraction
time of prepared sample solutions as
described in the analytical method
Two HPLC injections are performed per
method assay and the peak areas are
averaged.

Not less than three different extraction
times are used namely:
♦ T (half)
♦T
♦ T (one & half)
(where T is the extraction time of the
method).

Peak values from

Peak values from

the SAME
sample solution may
be averaged

DIFFERENT
sample solution
may not be

The extraction time suitable to ensure
complete extraction is highlighted.

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[5] Recovery

(Extraction time - tabulations continued).

The Results (Extraction time and Assay %) are tabulated as shown.

RECOVERY - EXTRACTION

TIME IN MINUTES
Batch No:

% ASSAY

0.5 T

Run at between
3 and 5
extraction times
to
demonstrate
recovery

0.75 T
T
1.25 T
1.5 T

[6] Recovery
(of spiked placebo samples)

VALIDATE THE ANALYTICAL
METHODS FOR THE
ACTIVE SUBSTANCE
AND
FINISHED DOSAGE FORM
SIDE-BY-SIDE.

Five

spiked admixtures of the active
substance and the non-active vehicle
(placebo) at concentrations of about
50% to 150% of the stated
concentration required by the assay
procedure is prepared and analyzed to
show the percentage active recovery.

Two HPLC injections are performed per
method assay and the peak areas are
averaged.
The Results (Theoretical conc. Actual
conc. and % recovery ) are tabulated.

RECOVERY
TESTING
ALSO
DEMONSTRATES
DETECTOR
LINEARITY



The Average Recovery
SD and the
% Coefficient of Variation

are tabulated.

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[6] Recovery (spiked placebo samples tables - continued).
The recovery results are shown graphically (peak area Vs conc. (mg/100 mL).
These results also show extraction method and detector linearity.

R E C O V E R Y
Standard solution mg/100mL
Peak Area =
CONC.
Theoretical
(mg/100ml)

PEAK AREA
FOUND

CONC.
FOUND
(mg/100ml)

PERCENTAGE
RECOVERY

50
75
100
125
150

Mean (% Recovery) =
Standard Deviation =
% Coef. of Variation =

Display values
The Linear Regression value, Slope and Y-Intercept are shown in the GRAPH. The
placebo chromatogram (vehicle only) is shown to highlight the absence of Additional
Peaks

[7] Linearity and Range.

The

linearity on an analytical procedure is its ability (within a given range) to obtain
test results which are directly proportional to the concentration (amount) of the
analyte in the test sample.

Five Standard solutions in a concentration range of (about) 50 % to 150 % of the
stated concentration required by the assay procedure are prepared and analyzed by
the stated method.
Two HPLC injections are performed per method assay and the peak areas are
averaged.

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[7] Linearity and range - (continued).
The Area count and concentration range is plotted. Linear regression analysis will
demonstrate the acceptability of the method for quantitative analysis over the full
spectrum of the concentration range. Detector linearity is also demonstrated
between the upper and lower analyte concentrations.
The Results (Range conc. and peak areas ) are tabulated.

LINEARITY

AND

CONC.
Batch No:

RANGE
PEAK AREAS

50 %
75 %
100 %
125 %
150 %

Linear Regression
Y-Intercept
Slope

=
=
=

The results are shown graphically (peak area Vs range conc. (mg/100 mL).

GRAPH OF LINEARITY
120000
P
e 100000
a
80000
k
60000
A
40000
r
e 20000
a
0
0

25

50

75

100 125

150

Conc. mg/100mL

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[8] Robustness.

Internal

and external variations are
often mixed together in analytical
validation packages erroneously, under
the heading of one or the other. Internal
and external analytical parameters
should be separated and appraised
individually.

Ruggedness and Robustness.
The USP defines ruggedness as "the
degree of reproducibility of test results
obtained by the analysis of the same
samples under a variety of normal test
conditions such as:-

♦ Different laboratories
♦ Different analysts
♦ Different instruments
♦ Different reagent lots
♦ Different analysis days
♦ Different elapsed assay times
♦ Different assay temperatures …"

Ruggedness
is a USP
Requirement
Robustness
is not.
The

Robustness of an analytical
procedure is a measure of its capacity
to remain unaffected by small but
deliberate
variations
in
method
parameters thus providing an indication
of its reliability under normal usage.
The method may be evaluated for
specificity using two different columns.
No differences in specificity, selectivity
or column performance should be
observed.
Robustness
determinations
are
essential when transferring analytical
methods
from
the
development
laboratory to the commercial quality
control laboratory. There may usually
be a difference in columns or HPLC
machine models used.

These factors are all external to the
written analytical method and each
parameter should show a lack or indeed
absence of influence on the test results
obtained.

Ruggedness
Measures External
Robustness
Internal Variations.
Ruggedness measures the lack of
external influence on the test results
whereas robustness measures the
lack of internal influences on the test
results.

Robustness is defined by both the USP and the ICH Tripartite guidelines as "a
measure of its capacity to remain unaffected by small but deliberate variations in
method parameters and provides an indication of its reliability during normal use "
Robustness is defined both in the USP and ICH, but is not required.
Robustness variations.
Deliberate variations according to the following table were made to the critical
parameters of the method such as column, flow rate and concentration of [organic
acid] in the mobile phase. Using the System Suitability solution and LOQ (also QL)
solution as the Test Solutions the performance of the method was evaluated.

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Robustness variations (Tabulated ).
Column 1: Phenomenex Bondclone 10µ, C-18, 300 x 3.9mm (OOH-2117-CD)
Column 2: Waters µ-Bondapak
10µ, C-18, 300 x 3.9mm (27324)
CONDITION
Condition Column
No.

Flow Rate
mL/min

RESULTS
Buffer
Conc. (%)

RRT

Tf

RSD
RSD
bet. LOQ of bet. LOQ of
[Active]
[Impurity]

1
2

1
1

2.5
2.2

0.1
0.1

0.3
0.3

1.1
1.1

<10
<10

<10
<10

3
4
5

1
1
2

2.8
2.5
2.5

0.1
0.15
0.1

0.3
0.3
0.3

1.1
1.1
1.1

<10
<10
<10

<10
<10
<10

[8] Ruggedness - (Tabulations).
The Results (Average assay % for Analyst 1 and 2 ) are tabulated.

RUGGEDNESS
ANALYST
No 1

%
ASSAY
Column I

ANALYST
No 2

%
ASSAY
Column 2

1
2
3
4
5
6
7
8
9
10
Mean (% Accuracy) =
Standard Deviation =
% Coef of Variation =
Notes on different terms frequently used:
The analytical variation expressed between laboratories on different days; with
different equipment; or different analysts is known as - intermediate precision. This
intra-laboratory precision or the precision between laboratories is known as
reproducibility or more specifically - intra-laboratory reproducibility. Both the above
are ruggedness - and a USP requirement.

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Ruggedness & Robustness Evaluation.
The evaluation of ruggedness and robustness (where necessary) should
be finalized at the end of the development phase - around the time of the
process qualification lot manufacture.
The robustness evaluation should be developed with the commercial
laboratory equipment in mind. It should show the reliability of an analysis
with respect to deliberate variations in the method parameters.

A consequence of robustness evaluation is that a series of system
suitability parameters are established to ensure that the validity of the
analytical procedure is maintained whenever used.

[9] Stability of Standard solutions
Re-chromatography of ten replicate single injections of the same standard
solution (which have been allowed to stand for x hours ) against freshly
prepared Standards showed no significant differences from the original
results.

STABILITY OF
THE STANDARD SOLUTION
mg/100mL
Initial Analysis
(Date)

mg/100mL
Repeat Analysis
2nd (Date)

1 injection
2 injection
3 injection
4 injection
5 injection
6 injection
7 injection
8 injection
9 injection
10 injection

1 injection
2 injection
3 injection
4 injection
5 injection
6 injection
7 injection
8 injection
9 injection
10 injection

Mean
Standard Deviation
Relative Standard Dev.

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=
=
= NMT 2.0 %

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[10] Typical Chromatograms.
Representative chromatograms of the following traces are routinely provided:-




System Suitability
Standard Solution
Drug Product
placebo

When Representative Chromatograms are displayed - all peaks are LABELED with
the peak name and RRT.

Representative chromatogram
Drug Product

Label the peak
clearly
Name and Retention
time (8.78 min)

[11]Conclusion.

It

is important to emphasize that
analytical validation applies to a drug
formula and a set manufacturing
procedure. Extraneous peaks and
processing stresses are specific to a
manufacturing procedure, equipment
used and the nature of the excipients.

(Closing Statement)
An appropriate conclusion should be
given stating clearly that:
“The method # 005 Ed. No 00 is shown
to be accurate and precise for carrying
out assay analysis as part of the Assay
and Stability Studies for the Drug
Product conforming to the formula as
shown in Appendix 1” .
[12] References & Appendixes.

Where

there is a formulation or
excipient change as well or a new
processing
principle
of
the
manufacturing procedure, the analytical
validation package should be amended
to account for appropriate changes.
Frequently this involves a full
revalidation of the overall methodology.

Acknowledgment to references as well
as attachments such as the drug
product formula are attached at the end
of the validation protocol.

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Revalidation
An entire validation procedure should

Validation Checklist
1. Are all in-house methods validated?
2. Is the dissolution method for
development, release and stability
validated.
3. Are the different validation editions
comparable with the previous
edition?
4. Was the stability assay and
dissolution method validated at the
time of process optimization
5. Was the stability assay and
dissolution method validated at the
time of process qualification
6. Is the validated stability assay,
impurity profile and dissolution
method used in the pivotal essential
similar to the commercial validation
lots so that data is comparable.
7. When a new edition is not
comparable to the previous edition is a new method number allocated?
8. Has the lab an historical track record
of all assay dissolution etc. methods
used from early development to
commercial validation?

be repeated again for new approved
sources of the active material as the
new active may well display a different
impurity profile and an altered
degradation pattern under stressed
conditions.

All

of the above validation parameters
are mentioned in the SUPAC (3) guide
for analytical methods, developed for
bioequivalence blood sample testing:
i.e.







Accuracy
Specificity
Recovery
Precision (interday & intraday)
Linearity (of standard curves)
Sensitivity
Stability (Storage & handling)

Bioequivalence studies
Linearity and range at the extreme
lower ends of the active analyte or
metabolite(s) in sera are important
parameters in assaying blood serum
concentrations.
Range studies MUST be linear at the
lower and upper limits as found in the
serum samples or those used for
calibration curves, a point sometimes
frequently overlooked by analytical
method
developers
in
clinical
environments when dealing with very,
very dilute concentrations.

References:
1. "Validation of compendial methods" USP 23
<1225> USPC Rockville Maryland USA
1994.
2. USP/NF XXIII USPC Rockville Maryland
USA 1994.
3. Scale up and Post approval Changes
Manufacturing and Controls In vitro
Dissolution and In Vivo Bioequivalence
Documentation CDER 1995 (SUPAC)
4. International Conference on Harmonization
"Guidelines on validation of Analytical
Procedures: Definitions and Terminology;
Federal Register (March 1, 1995.)
5. ASTM Standard Guide For Conducting
Ruggedness Tests E1169 American Society
for testing Materials Philadelphia 1989.
6. G. Kateman and L. Buydens, The
Ruggedness Test Quality Control in the
Analytical chemistry John Wiley and Sons
NY 2nd Edition 1993, pp118 125.

All

analytical validation attributes
require to be taken into account,
including ruggedness. No robustness
tests are officially required for USP and
ICH, however prudent analytical
method developers should build in a
robust test, whether official or not.

Edition Number:
03
Ed. Status :
Supersedes 02

CHAPTER 12

ANALYTICAL

Effective Date:
DD/MM/YY

Handbook of Pharmaceutical

APPROVED
_____________
Department

___________
R &D

Chapter: 12.20
20

______________
RA

_________/________
QC / QA

Generic Development

SEMISOLIDS

ANALYTICAL DEVELOPMENT

CHAPTER 12

OUT-OF-SPECIFICATION
TEST RESULTS
‘…Investigate all Out-of-Specification Results routinely and immediately,
the findings may well be in the firms commercial interests...’

Out Of Specification
(OOS) Retesting and
Product failures based
on the 1993 Judgment

P

racticing the correct do’s and don’t
procedures in out-of-specification
decisions making is a central
requirement for an analytical laboratory
personnel. The FDA 1998 draft OOS
guidelines applies to all drug product
manufacturers and may be a useful tool
for the day-to-day administration and
decision making in a research or routine
quality control analytical laboratory (see
OOS checklist).
Judge Alfred M Wolin’s original 1993
interpretation of Good Manufacturing
Practice (GMP) issues embedded in the
landmark US court ruling five and half
years ago is the underlying basis of the
FDA's September 1998 DRAFT Out-ofSpecification guidelines for the generic
and innovative pharmaceutical industry.
Notwithstanding that the court ruled in
April 1993 on important OOS laboratory
practices, FDA EIRs and 483 Inspection
observations, still cite non-compliance
practice with respect to product retesting
and Out-of-Specification (OOS) test
results in both Generic and Innovative
drug firms.
The interpretation and application of the
Good Manufacturing Practices (GMP) Act
have set practical ‘hands-on’ guidelines
that support the industry rules for handling
out-of-specification test results, retesting
procedures
and
product
failure
investigations.
These rules are now incorporated in the
draft 'guidance for industry investigating
out-of-specification
test
results
for
pharmaceutical industry'.

Handbook of Pharmaceutical

Drug

developers and manufacturers
should be thoroughly conversant with the
FDA's September 1998 draft 'Out-ofSpecification' guidelines and current
thinking which may provide an appropriate
base for decisions in routine QC and
production OOS investigations.

An Out of Specification
(OOS) Result
may or may not
be a product failure

Out-of-Specification

results are not
necessary product failures, a term FDA
investigators commonly use in PAI and
GMP
inspections.
Handling
out-ofspecification lab data has become a
primary GMP inspection focal point.
The failure for some firms to conduct an
adequate data investigation has become a
frequent citation in PAIs and routine GMP
Agency Inspections.

Where is my data
invalidating
an Out-of-Specification
(OOS) Result?
Out-of-Specification

results
must
not
become
‘un-investigated
failures’. The maxim “we investigated but
didn’t write it down” is often heard and
carries little weight with an agency official.

Sect: 12.21
12.21

Generic Development

SEMISOLIDS

What the PAI investigator really hears is,
“we didn’t bother to investigate and don’t
have any SOP requiring us to do so”.
Such an attitude is in violation of the new
draft guidelines and the firm needs to
address its investigation procedures
impacting on product retesting and
evaluating drug product approvals.

Out-of-Specification Test Results (OOS) may
be:- Reversible due to a:-

Ü
Ü

genuine laboratory error
sampling error
manufacturing processing error
manufacturing operator error

Genuine Laboratory Error.
Laboratory errors can occur when
analysts make analytical mistakes. All
laboratory technicians and analysts may
mistakes at times in their career. There is
no such concept as an error-free
laboratory analyst or that all standard
solutions are always correct and that data
is never miscalculated. Samples may be
incorrectly prepared, diluted, injected or
stored at inappropriate environmental
temperatures or quite simply that
containers where not properly closed or
even placed in the correct designated
sampling container.
A suspected laboratory error must be
investigated and if found genuine can
immediately be invalidated and the result
simply filed and disregarded completely.
The investigation or ‘failure investigation’
should where ever possible identify the
cause of the OOS and its impact.

Retest procedures
must follow
pre-written rules

Where

an error is investigated and the
result of the investigation is inconclusive
the following rules apply to the retest
procedure.

Inconclusive errors retest

An

inconclusive error is an OOS where
the 'supervisor-analyst investigation' did
not draw a firm conclusion and the reason
for the error was not clearly identified.
What to do: Answer - Retest with new
aliquot (replicates, if required) from the
same sample, if the sampling procedure
was proven OK by investigation. If the
sampling procedure was found to be in
error, then re-sample the target material
and perform a new duplicate analysis.

For process failures
confirmed by laboratory
testing - means the
product has failed?
DECISION TREE

Once the nature of the OOS has been
identified - as an laboratory error - a
repeat test must be performed and the
initial test totally ignored. (Remember this
initial test result is invalid - it was an error

Handbook of Pharmaceutical

and has no scientific merit or statistical
value).
For practical purposes this invalid result
was technically never done and should
not be used for any calculation or
statistical evaluation.
However the
analyst error must be thoroughly
documented and properly invalidated with written reasons, supervisor and
analyst
signatures
and
date
of
invalidation process.

Investigate according
to a set procedure
and then retest if the
error is conclusive?
Inconclusive errors

Or non- reversible due to a :-

Ü
Ü

CHAPTER 12

ANALYTICAL DEVELOPMENT

An overview of Out-of-Specification
Results procedures is provided by the
decision tree. Re-sampling the material for
a new representative sample should take
place only when the original procedure
was found to be clearly non-representative
of the whole.

Sect: 12.22
12.22

Generic Development

SEMISOLIDS

CHAPTER 12

ANALYTICAL DEVELOPMENT

Do’s
Don’ts

&

Retest procedures
must follow
pre-written rules.

The ‘Retesting Rules’:
Do

insure that the firm has a written
Retest SOP.

Do insure the retest SOP indicates when
testing stops and the product is evaluated.

Do retest only after;

The Don’ts
Don’t
- use the outlier test for a
dissolution test or profile.
Don’t
- use the outlier test for an
Assay or a Content Uniformity test.

⇒ reporting,
⇒ classifying and

Don’t
- use the outlier test frequently
to reject non-chemical test results.

⇒ investigating jointly.
sample

Don’t
- use the outlier test outside
the USP specifications prescribed.

Do feel free to prepare a second aliquot

Don’t
- retest before an investigation
is completed and closed.

Do retest

on

the

same

collected.
from the same sample as the first.

Do use a larger portion of the first
sample, if required.

Do know when you can and can’t use
the outlier test.

Do re-sample if the original sampling
procedure is proven by investigation, as
not representative.

Do re-sample if the original sample was

Don’t
- retest before reporting to
your supervisor and conducting an
informal investigation - together.
Don’t
- ignore ever the rules for
governing a single or multiple OOS result.
Don’t
- re-sample unless the sample
procedure was proved to be faulty.
Don’t
- re-sample
without
your
supervisor permission obtained only after
an informal investigation.

improperly prepared (clearly shown after
the required investigation).

Do investigate and then close the
investigation within 30 days after the
OOS.
Do keep a

‘Failure Report” or an
‘Investigation Report’ log.

Handbook of Pharmaceutical

Averaging passing and
OOS results together
is not GMP
Don’t
- Average
good and bad
results - as they simply hide the true test
values.
3

Sect: 12.23
12.23

Generic Development

SEMISOLIDS

CHAPTER 12

ANALYTICAL DEVELOPMENT

ØC H E C K L I S T ×
CL # P-HGD-03-069Y

OUT-of-SPECIFICATION RESULTS
‘…Averaging passing and OOS Test Results together
is not permitted as it conceals the full analytical picture…’

IDENTIFYING OOS TEST RESULTS
1. Does the firms have a clear SOP spelling out the procedure and qYes qNo
investigations required when ever an OOS result is obtained?
qYes qNo

2. Are all firm's 'rejected batch' OOS results investigated as well?

3. Are the previous (or related) batches associated with the failed batch qYes qNo
specification reviewed and the overall impact (on quality) evaluated?
4. Are written investigations undertaken and then follow-up procedures qYes qNo
recommended in writing?
5. Are the investigations performed in a timely manner and follow a qYes qNo
defensible scientific logic (see attached Decision Tree)?
6. Does the companies 'Investigation SOP' include the three key tenants qYes qNo
i.e. TO INVESTIGATE - TO CONCLUDE - TO FOLLOW-UP?
7. Have the laboratory analysts been instructed to keep the original qYes qNo
'suspect test solutions' for possible reanalysis (Ref. Decision Tree)?
8. When an OOS has been detected does the initial review, before the qYes qNo
investigation, check for instrument or system suitability malfunction,
faulty reagents, calculation, documentation or transcribing errors?
9. If no clear analytical errors are detected in a 'suspect result' does a qYes qNo
comprehensive 'failure investigation' ALWAYS follow?
10. Where malfunctions are identified and detected are all prior 'suspect qYes qNo
data' evaluated and reviewed for a possible related (or similar) errors?
11. Are analytical failures tracked back to their original point of failure?

qYes qNo

12. When a faulty lab procedure is detected, is the analytical test qYes qNo
procedure immediately terminated (as a matter of routine)?
13. Have the analysts been trained to immediately report to their qYes qNo
supervisors an obvious error or an analytical fault?
14. Are obvious errors (spilling, incorrect dilution, injection volume etc.) qYes qNo
documented in the lab book and a brand new test restarted?

Handbook of Pharmaceutical

Sect: 12.24
12.24

Generic Development

SEMISOLIDS

CHAPTER 12

ANALYTICAL DEVELOPMENT

ØC H E C K L I S T ×
CL # P-HGD-03-069Y

OUT-of-SPECIFICATION RESULTS
‘…failure investigations are conducted to determine
what caused the unexpected OOS result…’

INVESTIGATING OOS TEST RESULTS
1. Does the supervisor's 'initial assessment' follow the abbreviation qYes qNo
' DECIDED procedure ' (See box)?
2. Are the retained 'suspect' sample preparations examined during the qYes qNo
'initial assessment' and then retested promptly on initiating the
'failure investigation'?
3. Where a clear error is identified, is the result immediately invalidated?

qYes qNo

4. Where clear error is NOT identified, is a failure investigation qYes qNo
conducted immediately?
5. Is the firm's full scale failure investigation fully predefined in writing?

qYes qNo

6. Does the firm's own QC Unit perform the 'full scale failure qYes qNo
investigation'?
7. Does the general review include a list of related batches - impacted?

qYes qNo

8. Does the full scale failure investigation include the production side qYes qNo
and the laboratory side?
9. Does the laboratory protocol include the two key steps - retesting the qYes qNo
original sample and testing a new sample from the batch lot?
10.Retesting the original sample with a new analyst, is generally the first qYes qNo
step after the 'initial assessment' is completed?
11.Are the number of retests (usually duplicates) specified and not qYes qNo
exceeded?
Averaging 'original suspect' and retest results is
forbidden.
12. When improperly prepared samples are proved, then the original qYes qNo
results may be immediately invalidated?
13. The firm may re-sample when the investigation highlights that the qYes qNo
original sample was unrepresentative?
14. Where the investigation concludes that the sampling method is in qYes qNo
error a new sampling method must be developed and qualified ?
15. To prove the original aliquot is faulty, the analyst prepare two qYes qNo
additional aliquots and compares the three sets of results?

Handbook of Pharmaceutical

Sect: 12.25
12.25

Generic Development

SEMISOLIDS

CHAPTER 12

ANALYTICAL DEVELOPMENT

ØC H E C K L I S T ×
CL #

P-HGD-03-069Y

OUT-of-SPECIFICATION RESULTS
‘…Batches must be formulated with the intent to provide 100%
of the labeled amount…'

AVERAGING IN OOS RESULTS
1. Averaging results from a standard solution or a test aliquot is qYes qNo
acceptable (i.e. averaging replicate results).
2. Averaging results from microbial count plates are quite acceptable.

qYes qNo

3. Averaging a set of results, where some are OOS is not acceptable.

qYes qNo

4. Hiding an OOS result in any average is not acceptable.

qYes qNo

5. When the intent is to highlight variability within the product then qYes qNo
averaging is not acceptable, but RSD (CV) values are generally
reported to show statistical significance.
6. Replicate peak responses whether test or standard should be qYes qNo
averages as one result.
7. Are analysts trained, not to average passing and OOS results together qYes qNo
in order to hide the failing results?
8. Composite assays, require only one assay result and are in fact qYes qNo
average assay values, as opposed to individual content uniformity
values.

OUTLIER USE IN OOS RESULTS
1. Where 'control' and 'specification' lower and upper limits are used in qYes qNo
QC criteria an OUTLIER may be outside the control limits but inside
the specifications limits? [i.e. an example of OUTLIER use.]
2. Analyst are trained not to assume OUTLIERS as testing errors but qYes qNo
inherent variability in the sample.
3. The firm has an OUTLIERS SOP detailing the use of OUTLIER qYes qNo
TESTS.
4. OUTLIERS are not permissible in Content Uniformity and Dissolution qYes qNo
tests.
5. Where the intent is to measure the variability, OUTLIERS should not qYes qNo
be used.

Handbook of Pharmaceutical

Sect: 12.26
12.26

Generic Development

ANALYTICAL

SEMISOLIDS

CHAPTER 12

ASSAY VALIDATION

Ruggedness
and

Robustness

R

uggedness and robustness testing is
applicable to pharmaceutical R&D and
QC Laboratories, especially when
methods are transferred and distinguishes
the similarities and differences between the
two analytical concepts and how they are
applied in the laboratory.

Analytical methods are usually developed in
an R&D laboratory and eventually
transferred to the production quality control
laboratory for routine product analysis. This
process of technical data transfer from one
lab to the other requires a clear
demonstration that the methodology can be
successfully transferred. How is it done?

There is an easy-to-use procedure to meet
this regulatory and compendial requirement.

Ruggedness

is a USP
Requirement
Robustness is not.
Ruggedness and Robustness.
The USP defines ruggedness as "the degree
of reproducibility of test results obtained by
the analysis of the same samples under a
variety of normal test conditions such as:

♦ Different laboratories
♦ Different analysts
♦ Different instruments
♦ Different reagent lots
♦ Different analysis days
♦ Different elapsed assay times
Handbook of Pharmaceutical

♦ Different assay temperatures …"
These factors are all external to the written
analytical method and each parameter should
show a lack or indeed absence of influence
on the test results obtained.

But

what about the internal factors of the
written test method such as a change in the
flow rate (mL/min) or the concentration of
the organic acid in mobile phase (HPLC
systems) or better still, a change from a
Phenomenex Bondclone™ 10µ C-18
column to a Waters µ-Bondapak™ 10µ C18 column? These small but deliberate
internal variations in method parameters of
the written analytical procedure should be
evaluated to access whether the analytical
procedure remains unaffected by these slight
changes.
Robustness is defined by both the USP and
the ICH Tripartite guidelines as "a measure
of its capacity to remain unaffected by small
but deliberate variations in method
parameters and provides an indication of its
reliability during normal use " Robustness
is defined both in the USP and ICH, but is
not required.

Furthermore, ruggedness measures the lack
of external influence on the test results
whereas robustness measures the lack of
internal influences on the test results.
Internal and external variations are often
mixed together in analytical validation
packages erroneously, under the heading of
one or the other. Internal and external
analytical parameters should be separated
and appraised individually.

Chapter: 12.27
27

Generic Development

ANALYTICAL

SEMISOLIDS

A simple experimental design can evaluate
both ruggedness and robustness, as separate
distinguishable entities - together.
Table 1

Comparison Table.

Attribute.

Ruggedness. Robustness.

USP Validation
Requirement
ICH Validation
Requirement

þ

CHAPTER 12

Even more dramatic, for eleven variables
(11 x 12) a minimum of 132 one-factor-at-atime data points would be required, but via
matrix testing using an twelve-run design,
only 12 HPLC assays are needed to produce
the equivalent of 132 individual one-factorat-time assays.

ý

Few, if any HPLC assay analytical methods

ý

ý

could have more than 12-15 significant
environmental or method variations.

Internal change

ý

þ

Table 1.

External change

þ

-

Method
Variations
Environmental
Variations

-

þ

An Eight Run Design Template

þ

No

A

B C D

E

F

G

ASSAY
TEST
RESULT

1

+ + + −
− + + +

+


+

99.3


+

101.5
97.9

2

Designing Analytical Experiments
Such a designed experiment can
demonstrate
that
methodology
and
environmental factors may or may not
influence the test results. It is hoped that the
analytical method is both rugged and robust,
however a well designed experiment may
identify test conditions or specification limits
that need to be closely controlled and
tightened or even test parameters that need
further investigation and optimization.
Advantages - Designing the Experiment
A designed experiment is a simple matrix
design. The Plackett-Burman designs are
most applicable to technical transfer of a
validated
analytical
methods
from
development to quality control centres. For
the most cost-effective design, the attributes
of both R&D and QC laboratories should be
incorporated into development validation
protocol of the assay method.

The

advantages of these designs are quite
simple - the number of tests required is
simply dramatically reduced. 56 assays (i.e.
7 x 8) are needed to evaluate seven internal
and/or external variables, these can be
reduced to eight quick assays using an eightrun Plackett-Burman design.

Handbook of Pharmaceutical

External / Internal
Changes / Variations

Test

6

− − + +
+ − − +
− + − −
+
+ −

7

+ +

8

3
4
5


+
+


+

+

+


+

+

+

99.0

+

+

97.9

− − −

100.9

100.4
98.5

The (+) or (-) signs are used as variables in the 8 run
design. Assign (-) to Analyst I ; Day I; Column I and
(+) to Analyst II; Day II; Column II and so on
A to G are chosen as the external variations
(ruggedness) anticipated to arise during use in the
Development Lab.

Table 2.

8 RUN DESIGN

Template for Ranked Effect and Means
External & Internal Ranked
M
changes/variations Effects values
A - Analyst I & II

1.8

-1.35

F - Analyst III & IV

-0.76

G - Reagents I & II

-0.35

E - Week I & II

0

B - Week III & IV

+0.35

C - Column I & II

+0.76

D - HPLC No I & No II

0

+1.35

The M values are obtained from statistical design
tables. The ranked Effects are calculated by simple
addition of assay test results and then dividing by
half the number of runs (i.e. 4 in a 8 run design).

Chapter: 12.28
28

Generic Development

ANALYTICAL

SEMISOLIDS

ruggedness and robustness when transferring
a method to another laboratory.

Calculating the Ranked Effects
For A
Figure 1.
99.3
+
101.5

100.4

Sum the Assay
97.9
+
values by
98.5

assigning
99.0
+
a positive or
97.9
+
negative value
obtained from
100.9

the 8 run
-7.2

design
/4
-1.8
For D
99.3
101.5
100.4
97.9
98.5
99.0
97.9
100.9
0
0

Table 3.

An Twelve Run Design Template
External / Internal
Changes / Variations (11)
No A B C D E F G H

+

+



+
+
+
10 −
11 +
12 −
1
2
3
4
5
6
7
8
9

Figure 2.

+
+
+


+


/4

Perform this
addition for
each of the eight
variables and
divide the
sum by 4
(half the number
of runs)

Results.
A linear-linear scale is used. Plotting the
Ranked Effect on the X-axis vs. the M
values on the Y-axis produce a normal
probability plot of effects. If a value lies
outside this straight line one can conclude
that the method is not rugged / or robust, as
classified, for that particular variable (e.g.
[say] flow rate).
12 Run Designs.
A template for 12 run design is used (Tables
3 & 4), when more than seven factors are
present. This design will give 11 factors for
analysis. The M values are constant for any
given design and are actually the means of
the order statistics (3) for a sample size of
eleven. As they always remain the same, the
template can be used for any ruggedness /
Robustness validation method protocol. Use
a Eight Run for evaluating say, ruggedness
only, and a Twelve Run design for both

Handbook of Pharmaceutical

CHAPTER 12

+
+

+



+
+
+


+
+

+



+
+
+

+

+
+

+



+
+

+
+

+
+

+



+

+
+
+

+
+

+




+
+
+

+
+

+




+
+
+

+
+

+

ASSAY
TEST

I

J K




+
+
+

+
+

+

+



+
+
+

+
+

RESULT


+



+
+
+

+
+

99.3
101.5
100.4
97.9
98.5
99.0
98.8
99.9
100.6
98.9
97.9
100.9

The (+) or (-) signs are used as variables in the 12 run
design. Assign (-) to Analyst I ; Day I; Column I and (+) to
Analyst II; Day II; Column II and so on…
A to K are chosen as the external (ruggedness) / internal
(robustness) variations anticipated during the transfer from
the R&D to QC laboratory.
The assay results are entered into the table on completion of
the12 HPLC assay analyses.

Table 4.

Template for Ranked Effect and Means
External & Internal Ranked
M
changes/variations Effects values
A- R&D & QC Lab
F- Day I & II
G- Analyst I & II
E- Analyst III & IV
B- Reagents I & II
H- [Solvent] I & II
C- Heating Rate I & II
J - Column I & II
K- Temperature I & II
I - Flow rate I & II
D- Elapsed time I & II

-1.59
-1.06
-0.73
-0.46
-0.22

+0.00
+0.22
+0.46
+0.73
+1.06
+1.59

The M values are obtained from statistical design tables.
The Ranked Effects are calculated by simple addition of
(-) (+) assay test results and then dividing by half the
number of runs (i.e. divide by 6 in a 12 run design).
The effects form A - K were selected as the most
significant variables between the two labs. Templates are
available for up to 100 run variables (100 x 99).

Chapter: 12.29
29

Generic Development

ANALYTICAL

SEMISOLIDS

Method Procedure.
1. Choose the number of variables required
and select a run design template.
2. Assigning the minus (-) or plus (+) values:
These are arbitrary designations. As a
standard rule assign a 'minus' (-) to I or a
lower limit and a 'plus' (+) to II or a upper
limit. Evaluate a range limit by assign (-)
value for lower and (+) value for higher (i.e.
Flow rate 1.2 mL/min assign (-) and 1.8
mL/min assign (+)). Likewise Day I assign () and Day II assign (+) and so on…
3. Perform the HPLC assays in a random
order.
4. Tabulate the assay results in the template.
5. Calculate the Effects (Figures 1 and 2).
6. Rank the Effects from smallest to largest.
7. Plot the Effects against the M values.
8. Evaluate the plot.
Conclusion.
The results from the plot form a near
straight line. It can be concluded that the
analytical method is (a) rugged for the
external factors over the tested range and
(b) robust for the internal factors over the
tested range in the 12 run design.
Figure 3.

A Normal Probability Plot of Effects
+1.5
*
M
*
V
A
L
U
E
S

*
*
*
*
*

-1.5

-8

Ranked Effects

Handbook of Pharmaceutical

+7

CHAPTER 12

Process Qualification Stage.
The evaluation of ruggedness and
robustness should be finalised at the end
of the development phase - around the
time of the process qualification lot
manufacture.
The
ruggedness/robustness evaluation should
be developed with the commercial
laboratory equipment in mind. It should
show the reliability of an analysis with
respect to deliberate variations in the
method parameters.
Ruggedness/robustness determinations
are essential when transferring analytical
methods
from
the
development
laboratory to the commercial plant
quality control laboratory. There may
usually be a difference in columns or
HPLC machine models used.
A consequence of ruggedness /
robustness evaluation is that a series of
system suitability parameters are
established to ensure that the validity of
the analytical procedure is maintained
whenever used.
References:
1. "Validation of compendial methods" USP 23
<1225> USPC Rockville Maryland USA 1994.
2. International Conference on Harmonization
"Guidelines on validation of
Analytical
Procedures: Definitions and Terminology…;
Federal Register (March 1, 1995.)
3. "Validation of compendial methods" USP 23
<1225> USPC Rockville Maryland USA 1994.
4. USP/NF XXIII USPC Rockville Maryland USA
1994.
5. Scale up and Post approval Changes
Manufacturing and Controls In vitro Dissolution
and In Vivo Bioequivalence Documentation
CDER 1995 (SUPAC)
6. ASTM Standard Guide For Conducting
Ruggedness Tests E1169 American Society for
testing Materials Philadelphia 1989.
7. Kateman and L. Buydens, The Ruggedness Test
Quality Control in the Analytical chemistry John
Wiley and Sons NY 2nd Edition 1993, pp118
125.

Chapter: 12.30
30

Generic Development

SEMISOLIDS

PROCESS QUALIFICATION

CHAPTER 13

Process
QUALIFICATION
‘…The process qualification batch is a simulation of the forthcoming pivotal
lot
proving in-house, that the process really works…‘

Process qualification
Getting to the end point in the generic
development program is the manufacture of
the process qualification batch. All generic
development,
product
and
control
specifications are challenged in this batch.

Simulation of Pivotal
It is a full simulation of the pivotal
process
with
completed
process
documentation and fully validated analytical
methods, including stability indicating assay
analysis.
Development of the formula and
manufacturing process terminates at this
point, as all specifications and parameters
have now been qualified and optimized.

Complete Documentation
Full manufacturing instructions and
specific SOPs and all supporting analytical
documentation is complete and audited and
signed off.

Qualification of Process
The intention is to challenge every aspect
of the formula, process instructions and all
product specifications, which include full
accelerated stability tests.

Commercial conditions
The PQ batch is manufactured in the
plant’s commercial facilities where the
marketing lots will be produced, using
standard production raw materials and
personnel, as well as routine QA
procedures.

Production Equipment
The equipment used are the same
models as planned for the marketing lots
and the cleaning procedures and operation
routine production SOPs.

Handbook of Pharmaceutical

These are the conditions under which the
regulatory pivotal lot will be manufactured,
as an exhibition submission to the
Marketing Application (MA).

An Exhibition Batch
The Plant Production Director needs to
fully comprehend the importance of the
firm’s in-house Process Qualification batch
and the MA Pivotal production batch.
Although not for commercial sale both
exhibition batches are manufactured under
standard commercial conditions.

Simulating the Pivotal Batch
The Process Qualification is a full inhouse simulation of the Pivotal batch. Final
minor optimization and documentation
editing
is
performed
after
the
manufacturing and packaging of the
Process Qualification Batch.

Documentation fine-tuning
The final PQ documentation and
specifications are the data basis from which
the Pivotal Batch
manufacturing
instructions and specifications evolve.

Technical Transfer Documentation
The
Process
Qualification
Batch
manufacturing documentation, in-process
and
complete
finished
product
specifications are the principal documents
in the Technical Transfer Documentation
Dossier (TTD) that is transferred from the
Generic Development Unit to the
commercial plant production unit after the
execution of the Pivotal Batch. New
information gleaned from the pivotal
experience is added to the TTD as the final
Pivotal Batch Report.

Chapter: 13.1
1

Generic Development

SEMISOLIDS

PROCESS QUALIFICATION

CHAPTER 13

ØC H E C K L I S T ×
CL # HBGD-03-01YY

PROCESS QUALIFICATION
‘…well developed process qualification batch with good in-process controls
and excellent documentation will ensure a failure-free pivotal lot…’

1.

The Process Qualification batch is equal to the 70% or more of the pivotal qYes qNo
batch or the smallest commercial batch size that will be validated?

2.

The active material source has been verified as an ‘Approved Supplier’ ?

qYes qNo

3.

All non actives are routine production excipients or have been approved?

qYes qNo

4.

The container closure-system is the final marketing pack?

qYes qNo

5.

The Master Product Formula Record has all authorization signatures ?

qYes qNo

6.

The Master Manufacturing Batch Instructions has all authorization qYes qNo
signatures?

7.

The manufacturing flow chart (identifying all equipment and process qYes qNo
parameters) is final with all authorization signatures?

8.

In-process QC specifications and processing parameters are complete?

qYes qNo

9.

Standard packaging instruction (including sampling protocol) complete?

qYes qNo

10.

Release Specifications (with narrower lower and upper limits) complete?

qYes qNo

11.

Check Specifications (with maximum lower and upper limits) complete?

qYes qNo

12.

Overall Finished Product Specifications complete?

qYes qNo

13.

Accelerated stability protocol complete and signed-off ?

qYes qNo

14.

The analytical methods and stability indicating assay are complete?

qYes qNo

15.

The PQ is not a regulatory requirement but a in-house dry run!

qYes qNo

16.

The
Content
Uniformity
Protocol
evaluation during PQ batch manufacture.

17.

The Preservative Efficacy Test protocol will be evaluated during the PQ qYes qNo
batch manufacture?

is

prepared

for qYes qNo

Footnote: It is important to understand that no development or even minor specification changes
may take place after the pivotal production. Therefore all development is complete at the start of
the MA pivotal batch production. The pivotal batch is solely a legal demonstration or exhibition
batch for regulatory MA submission. Firms with appropriate pilot facilities may execute the process
qualification batch under pilot conditions and repeat the process, if deemed necessary, at the
commercial production site.

Handbook of Pharmaceutical

Chapter: 13.2
2

Generic Development

SEMISOLIDS

PROCESS QUALIFICATION

CHAPTER 13

STANDARD OPERATING
PROCEDURES

Page 1 of 1.

CL # HBGD-03-01YY

PROCESS QUALIFICATION
The following Standard Operating Procedures are recommended for a generic
development unit:

Process Qualification SOPs
P-000-02-01YY

Bulk Semisolid Content Uniformity Qualification.

P-000-02-01YY

Preservative Efficacy Test Protocol.

P-000-01-01YY

Documentation requirements for the Process Qualification batch.

P-000-01-01YY

Side-by-side comparison of Process Qualification and Pivotal
batch parameters

4
[End of Document]

Edition No. 01

Effective Date :

Ed. Status : New

Handbook of Pharmaceutical

APPROVED
______________ ________________ ___________ ________________
Department
RD
RA
QC / Q A

Chapter: 13.3
3

Generic Development

SEMISOLIDS

PROCESS QUALIFICATION

CHAPTER 13

Process
Qualification
‘these are the product specifications
indicating the product quality throughout the shelf life’

Sampling Bias
CONTENT UNIFORMITY
SAMPLING

J

BULK

udge Wolin's decision in the
US
vs.
Barr
Laboratories
prompted the industry to reexamine and modify its policies
and
understanding
on
blend
uniformity
and
sampling
techniques.
The
proposal
to
amend the cGMP regulations to
rule that the commercial batch
final blend be routinely tested for
active
ingredient
homogeneity
(Content
Uniformity
USP).
Although the Wolin decision
focused on solid dosage forms it
is valid for semisolid dosage
forms and especially suspension /
dispersion sampling.)
Active material particle migration
occurs the most in dry solid
material (granules) and the least
in viscous semisolids/gels during
product processing, i.e. (1) to (3)
(1) Solid granular material
(2) Suspended liquid Forms
(3) Semisolid - topical forms
W olin's ruling interpreted for
semisolids states simply that the
sample size of the final bulk
should be set at no more than
three times (3X) the application

Handbook of Pharmaceutical

(dosage) weight. In the case of
semisolids this is about 5-10g.
Sampling could be either from a
holding vessel or preferable the
mixing unit (top, middle, bottom).
The assumption that the current
technology
using
modern
sampling
devises
provide
a
means to consistently collect
minute, representative samples
from a much larger (10 5 ) static
bulk without some sampling bias
does not always hold true.
Current
sampling
technology
manifests a predominance of
varying sampling techniques with
some resulting sampling bias.

Different Sampling
thieves or dies may give
varying results with the
same bulk material
S ampling

errors are introduced
by three factors namely the:

♦ Sample thief design
♦ Sampling technique
♦ Bulk Material Properties

The physical design of the sample thief
and even the most recently developed
side-sampling or end-sampling "slug
thief" can produce sampling errors.
Sampling
technique
should
always
be
the
same
from
development to commercial lots.

Chapter: 13.4
4

Generic Development

SEMISOLIDS

PROCESS QUALIFICATION

Ø Sampling Bias
Different
sampling
techniques
with
the
same
thief
can
profoundly impact on sampling
errors in solids and suspensions,
with somewhat lesser effects in
semisolids, producing non representative results, with respect
to the true content uniformity
value.

♦ Bulk

depth
Sampling motion
♦ Sampling Angle
♦ Sampling Orientation
may bias results
the sample in different ways are:-

♦ Depth of bed (top, middle or bottom
sampling).

♦ Sampling angle (vertical, acute,
downwards).

♦ Sampling motion (smooth, twisting
jerking, or oscillating actions etc.)

♦ Sampling thief orientation in the bed
(Side-sampling probe rotation of
chamber is up (3600á), down
(1800â), or on the side (either 450 ä
; 900 à or 1350 æ).
In general, development studies show
the need for about a 3X sampling. For
semisolids a general application dose is
between 2 - 4 grams. Sampling error
increases as the sample size and/or
formulation potency decreases.
homogenisation process, is one
of the series of unit processes that
require validation. This validation
should be performed at the Process
Qualification and again at the Pivotal
batch manufacturing stage. The GMP
rules require that the process is

Handbook of Pharmaceutical

validated and consistently produces the
desired end product.
Qualifying and the bulk content
uniformity in the process qualification
(PQ stage) will insure that the semisolid
bulk is fully homogeneous prior to the
irreversible filling stage.

Bulk

density and particle size
variations of micronized active material
do not readily affect semisolid
preparations, as they may severely
distort solid dosage forms. However
routine semisolid Content Uniformity
testing is an prudent requirement prior
to unit (tube) filling.

Content

F actors that may marginally bias

Final

CHAPTER 13

Uniformity changes are
generally time dependant in semisolids
(weeping, bleeding, cracking) and are
mostly unlikely to change between the
time of the initial bulk manufacture and
the final tube filling stage !
Thus the requirement to establish both
lower (LCL) and upper control limits
(UCL) for the content uniformity of the
bulk is self evident. The final bulk assay
should conform to within the mean Ñ2
SD representing the lower & upper
control limits (See SOP).

References
1. Current Good manufacturing Practice of Certain
Requirements for the Finished Pharmaceuticals;
Proposed Rules May 3 1996 (61 FR 20103).
2. United States of America vs. Barr Laboratories
Inc., civil action for the district of N.J., Feb 1993.
3. J.T. Carstensen and M.V. Dali "Blending
Validation and Content Uniformity of low content
…powder blends " Drug development and Industrial
Pharmacy Vol. 22 Issue 4 pp. 285-290 (1996).
4.J Berman, A Schoeneman and JT Shelton, Unit
Dose Sampling - a tale of two thieves" Drug
development and Industrial Pharmacy Vol. 22 Issue
11 pp.1211-1132 (1996).
5. J Berman, and J.A. Planchard "Blend Uniformity
and Unit Dose Sampling" Drug development and
Industrial Pharmacy Vol. 21 Issue 11 pp.1257-1283
(1995).
6.J.T. Carstensen and C.T. Rhodes " Sampling in
Blending Validations" Drug development and
Industrial Pharmacy Vol. 19 Issue 20 pp.2699-2708
(1993).

Chapter: 13.5
5

Generic Development

SEMISOLIDS

PROCESS QUALIFICATION

CHAPTER 13

Sampling Record for BULK material
STRENGTH
q- LAB RECEIPT No
Batch No:
Date of Sampling:
Sampling Unit No:
Die No:
q PIVOTAL & q BIOEQUIVALENCE LOT
q PROCESS QUALIFICATION LOT
q VALIDATION LOT
q RE-VALIDATION LOT
No of
Weight of
TOP
MIDDLE
BOTTOM
Time
Signature
Bulk
Samples
Sample
g
semisolid
PRODUCT

Sampling Record for In-Process Filling
q- MACHINE TYPE:
q- LAB RECEIPT No

q Semisolids
q Liquid Filling
Machine

No:

LOW
Weight

HIGH
Weight

No of Units
SAMPLED

LEFT

RIGHT

Time

Signature

SPEED - RPM
q
q
q
q
q
q
q
q
LOW SPEED
- RPM
q
q
q
q
q
q
q
q
HIGHSPEED
- RPM
q
q
q
q
q
q
q
q
TARGET

Sampling Record for Packed Product
q Topical Semisolids
q Liquid Suspensions
Lot No:

Sample
No:

TOP

o
o
o
o

Edition Number:
04
Ed. Status:
Spds:
03

Effective Date:
DD/MM/YY

Handbook of Pharmaceutical

q Suspensions for Reconstitution
q- LAB RECEIPT No:
MIDDLE

o
o
o
o

END

Quantity
Sampled
in Grams.

Time:

Signature:

o
o
o
o

APPROVED
______________
Department

_____________
R &D

Chapter: 13.6
6

______________
RA

______/__________
QC / QA

Generic Development

SEMI SOLIDS

PROCESS QUALIFICATION

ØMaterial Sampling

In-process controls
Do remember that the variation in the

Do's and Don'ts
DEVELOPMENT
Do keep particle size distribution

of
active material as narrow as possible Use
micronized
material
where
appropriate. Do not exceed 50 microns
Do use the same sampling thief type
for all development, scale-up, and
validation sampling operations.
Do formulate with appropriate
viscosity agents to allow for similar,
rheological properties resulting in
representative samples & assays.

SOPs
Do

prepare a sampling and testing
SOP for Pivotal batches - (as shown).
Do use this SOP for sampling and
testing all key development, pivotal,
and commercial validation batches.
Do Develop a Standardised Sampling
SOP to replicate routine sampling
procedures with Sampling Record
Forms.

SAMPLERS
Do take into account that all samplers
sample dissimilarly, due to different
construction geometry.

Do

remember that the latest "endsampling slug thieves" also produce
significant sampling errors.

Do

sample 1X to 3X unit dose
application, depending on the detailed
development report recommendations.

Do

Remember that development data
supporting 3X sampling is acceptable
especially where unit dose potencies
are low.

Handbook of Pharmaceutical

CHAPTER 13

bulk material is generally greater, than
in the finished drug product. Do
demonstrate uniformity of material
adhering to the walls of the mixer.
Do compare the mean of the bulk
material with the mean of the filled
semisolid tubes / jars.
Do sample three (3) sample containers
- 1 for analysis and two more for
reserve testing, if needed later.

Sampling
Do

remember that the Wolin decision
does not take into account all inherent
problems
in
current
sampling
technology and mixing equipment.
Do use the same sampling style, thief
orientation, and hand operations when
sampling - retrain operators biannually.
Do take into account that pressures at
the bottom of bulk vessels give different
samples (and thus assays) to those
results from the top and middle
container positions.
Do sample at the same level and at the
same wall distance - every time.
Do keep the side-chambered sample
thief orifice pointing in the same
direction every time you sample, i.e.
(either at 360o ; 45o ; 90 o ; 135 o or
180o).

Don't use different sample thief types choose a suitable unit and use it
consistently, in a standardized manner.

Don't rely solely on the final bulk
assay as an in-process test; above a
well specified, process controlled and
validated manufacturing procedure
(Note: use Teflon-edged side scrapers
in processing equipment to insure
vessels are properly side scraped)

Don't forget that the assay of the final
bulk is as good as the sampling
technique - and no final bulk sampling
procedure is free of error.

Chapter: 13.7
7

Generic Development

SEMISOLIDS

PROCESS QUALIFICATION

CHAPTER 13

STANDARD OPERATING
SOP # D-000-03-03YY

PROCEDURES

PROTOCOL FOR CONTENT UNIFORMITY QUALIFICATION
(PROSPECTIVE QUALIFICATION PROTOCOL)
Page 1 of 2.

1.

PURPOSE

The purpose of this Standard Operating Procedure is to provide a protocol (• ‚) to
qualify the Content Uniformity of [semisolids / suspensions], in order to evaluate the
average semisolid / suspension assay profile of the bulk material and the profile of
the packed finished product.

2.

RESPONSIBILITY

Responsibility of actions is represented in the text by symbol:-.
• indicates Protocol is prepared by R&D Project and Process Development
Managers. Protocols are approved by the R&D and QA.
‚ indicates performed by validation team.
ƒ indicates performed by plant QA Technicians.
… indicates in-process testing performed by the plant QC Analytical Laboratory.
† indicates testing performed by the R&D Analytical Laboratory.
‡ indicates analysis and evaluation of the test data generated, performed by the
R&D Validation Team and approved by the R&D Quality Assurance.

3.

FREQUENCY

Performed with the Process Qualification and the Pivotal Lot.

4.

PROCEDURE

PROSPECTIVE CONTENT UNIFORMITY QUALIFICATION
4.1 Sampling Plan Bulk Material:
Samples (9) are collected from the top middle and bottom of the bulk processor.
Three samples are collected at each horizontal level (near mixer wall , midway point
between wall and center, near center.)
4.2 Sampling Plan Packed Material:
Samples are collected as they are filled at the target filling speed.

Sampling
Points

4.3 Testing Plan:
The bulk and filled tubes are tested ƒ † as follows:
9 units for uniformity of content (Three vertical and horizontal levels) ƒ †
10 units for uniformity of content (near cap, middle and crimp) ƒ †
3 units for Appearance / Description and Texture ƒ †
10 units for weight determination (tubes only) ƒ †

Edition Number:
03
Ed. Status:
Supercedes: 02

Effective Date
DD/MM/YY

Handbook of Pharmaceutical

APPROVED
______________
__________
______
Department ------------------R &D-----------------RA--------------------- QC / QA---------------------------

Chapter: 13.8
8

Generic Development

SEMISOLIDS

PROCESS QUALIFICATION

CHAPTER 13

STANDARD OPERATING
SOP # D-000-03-03YY

PROCEDURES

PROTOCOL FOR CONTENT UNIFORMITY QUALIFICATION
(PROSPECTIVE QUALIFICATION PROTOCOL)
Page 2 of 2.

5.0

ACCEPTANCE CRITERIA ‡

5.1 All parameters tested will be within the upper and lower control limits of the
control chart.
5.2 These limits for the in-process and finished product test shall be within the
defined specification limits for the in-process and finished product.
5.3 The overall process shall be evaluated for capability and shall be within the
process capability index for the finished product.

For In-process Product Testing:
5.4 The Upper control limit (UCL) is defined as the mean + 3 x Standard Deviation
5.5 The Lower control limit (LCL) is defined as the mean - 3 x Standard Deviation

For Finished Product Testing:
5.6 The Upper control limit (UCL) is defined as the mean + 3 x Standard Deviation
5.7 The Lower control limit (LCL) is defined as the mean - 3 x Standard Deviation
5.8 Cp ≤ 1.0
(Note: Cp = UCL - LCL / 6SD)
6.0

LIMITS and LIMITATIONS

6.1 Bulk Mix - critical step.
The content uniformity of the Bulk Mix prior to unit filling shall be tested … for <
Content Uniformity USP>. The Bulk Mix shall fall within the control limits calculated
from the ten individual sampling assay results.

Special Note:
In-process specifications for the Bulk Assay Content.
For In-process Bulk Content Testing (Content Uniformity):
6.2 The Upper control limit (UCL) is defined as the mean + 3 x Standard Deviation
6.3 The Lower control limit (LCL) is defined as the mean - 3 x Standard Deviation
7.0
DOCUMENTATION
7.1 A Qualification Report (QR-‡) including tabulation of results, statistical
evaluation, process capability evaluation, report conclusions and recommendations
will be submitted to QA Unit, Production and Development Unit Managers.

3
[End of Document]

Edition Number:
03
Ed. Status:
Supercedes: 02

Effective Date
DD/MM/YY

Handbook of Pharmaceutical

APPROVED
______________
__________
______
Department ------------------R &D-----------------RA--------------------- QC / QA---------------------------

Chapter: 13.9
9

Generic Development

SEMISOLIDS

PIVOTAL BATCH

PIVOTAL

CHAPTER 14

BATCH

‘the generic product has been developed and qualified
this is a key demonstration batch for regulatory submission.’

The Pivotal Batches

T

he Pivotal batch(es) are that
demonstration batches containing
the manufacturing documentation,
product specifications and accelerated
stability data normally submitted in the
PIVOTAL as part of the regulatory data
necessary for a successful filing.
The data is generated from the Pivotal
Batch
manufacture
and
testing
processes. Bioequivalency testing
against a reference drug is performed
with samples from this batch.
Exhibition/ Pivotal batch
The pivotal is a key exhibition batch
for legal and regulatory purposes and
serves as a model system or exhibition
batch for the agency as to the
structure
of
the
manufacturing
processing instructions, drug product
specifications
and
test
results
obtained. It is used as a reference
point.
PIVOTAL Submission
Agencies expect that the commercial
lots
will
have
the
equivalent
specifications and parameters as
specified in the PQ which has been
based on the pivotal lot.
Production Facilities
The expectation that the pivotal batch
will be manufactured, filled and
packaged under full GMP conditions
using the commercial production
equipment and staff under which the
proposed future commercial batch lots
will be manufactured.
The Bioequivalent evaluation against
the Reference Listed Drug is carried
out using the pivotal batch product. As
the pivotal batch may be for clinical
use it is in fact a small scale full GMP
commercial batch.

Handbook of Pharmaceutical

Validated pivotal batches may in fact
be marketed after approval is
obtained, if the product displays
sufficient marketable shelf life.
Analytical methods
All
analytical
development
methodology,
stability
indicating
assays and impurity profiles are
complete at this stage.
The pivotal batch is tested by the fully
validated analytical assay method and
the
accelerated
stability
tests
performed on the generic drug
product will be evaluated by the
stability indicating test analysis.
SUMMARY
The Pivotal Batch Lots are:
♦ the Pivotal submission batches
♦ the regulatory reference batches
♦ the process exhibition batches
♦ the bioequivalence batch
♦ a process qualified batch
♦ the validation-basis batches
♦ a production processed batch
♦ a full GMP batch
♦ a stability tested batch
The Pivotal Batch contains the :
◊ ingredients from ‘approved
suppliers
◊ final product formulation.
◊ final processing instructions.
◊ final in-process specifications.
◊ final release specifications.
◊ final stability specifications.
◊ final FP specifications.
◊ final filling specifications.
◊ final packaging specifications.
◊ full analytical SI methodology.
◊ full microbiological methodology.

Chapter: 14.1
1

Generic Development

CHAPTER 14

PIVOTAL BATCH

SEMI SOLIDS

ØC H E C K L I S T ×
CL # HBGD-03-01YY

THE PIVOTAL BATCH
‘…Development stops here!
After the pivotal, there are no significant specification changes…’

1.The product formula for the pivotal is the final marketing formula?

qYes qNo

2.The Manufacturing Instructions are suitable for routine production?

qYes qNo

3.The pivotal batch manufacturing equipment is standard production qYes qNo
equipment operated by production staff with routine QA personnel?
4.A side-by-side comparison of the pivotal equipment and the validation qYes qNo
batch equipment are similar, and differ in a change in scale only?
qYes qNo

5.The pivotal batch production will follow all production SOPs?

6.The pivotal batch size is 10% or greater of the largest proposed qYes qNo
commercial lot?
7.The complete pivotal batch must be 100 % filled and packaged in the qYes qNo
marketing container-closures (no part-packaging permitted)?
8.All production equipment has been physically checked for appropriate qYes qNo
recorders and control units as written in the pivotal documentation ?
9.The validation protocol for the first three full scale lots is drawn up?

qYes qNo

10.The validation protocol addresses all key processing parameters, that qYes qNo
if changed, will significantly impact on product quality ?
11.All microbiological methodology has been audited and signed-off ?

qYes qNo

12.Assays and test methods based on the pharmacopoeia, with in- qYes qNo
house modifications has been validated?
13.The active’s assay has been validated and is a stability indicating qYes qNo
test?
14.The stability
specifications ?

protocol

addresses

the

key

stability

indicating qYes qNo

15.The overall pivotal manufacturing file is audited and signed-off ?

qYes qNo

Footnote :
The Pivotal Batch is sometimes referred to as the; the Bioequivalent Batch,
the Exhibition Batch, the Demonstration Batch, the Clinical Batch, the Regulatory Batch,
or the PIVOTAL Batch. The names have all the same meaning.

Handbook of Pharmaceutical

Chapter: 14.2
2

Generic Development

CHAPTER 14

PIVOTAL BATCH

SEMI SOLIDS

STANDARD OPERATING
PROCEDURES

Page 1 of 1.

CL # HBGD-01-01YY

THE PIVOTAL BATCH
The following Standard Operating Procedures are recommended for a generic
development unit:

The Pivotal Batch
P-000-01--01YY

Documentation requirements for the Pivotal Batch.

P-000-01--01YY

Side-by-side comparison of Pivotal and Validation Batch
parameters.

P-000-01--01YY

Pivotal Batch Requirements - Topical Semisolids.

P-000-01--01YY

Do’s and Don’ts when preparing for Pivotal Batches.

P-000-01--01YY

Auditing the pivotal batch CMC documentation.

Note:
Revised FDA COMPLIANCE POLICY GUIDE NUMBER 7157.02 (1996).
The FDA has been sensitive to the need for industry to protect information
generated by internal in-house GMP auditing programs. It is the agencies intention
not to review the internal audit results, except under circumstances of litigation or a
judicial search warrant.
A firm requires to have a written quality assurance program in place at the regulated
site in order for the FDA not to review or copy the firm’s records and reports that
resulted from audits of a written quality assurance in-house program.
A written ‘Certificate of Audit’ notifying management that such audits and inspections
have been implemented, performed and documented and that all corrective action
necessary has been taken is required.
The intent of the FDA policy is to encourage firms to conduct in-house quality
assurance program audits and self-inspections that are both candid and meaningful.

4
[End of Document]

Edition No. 01
Ed. Status : New

Effective Date :
DD/MM/YY

Handbook of Pharmaceutical

APPROVED
______________ ______________ _____________ ________________
Department
RD
RA
QC / Q A

Chapter: 14.3
3

Generic Development

SEMI SOLIDS

PIVOTAL BATCH

CHAPTER 14

NOTES

Handbook of Pharmaceutical

Chapter: 14.4
4

Generic Development

SEMI SOLIDS

PIVOTAL

SOP #HBGD-04-03YY

STANDARD

BATCH

CHAPTER 14

OPERATING

PROCEDURES

IN-PROCESS SAMPLING & TESTING PROCEDURES OF
SEMISOLIDS, AND SUSPENSION FOR PIVOTAL BATCHES
Page 1 of 5.

1.

PURPOSE1

The purpose of this Standard Operating Procedure is to describe the production inprocess sampling procedure and the testing to be performed on the pivotal batch.

2.

RESPONSIBILITY

Responsibility of actions is represented by the relevant symbol in the text.
• Symbol indicates Protocol is prepared by Development Project Unit and Process
Development Managers. Protocols are approved by the Development and QA Unit.
‚ Symbol indicates performed by process validation team.
ƒ Symbol indicates sampling performed by the Plant QA Technicians.
„ Symbol indicates In-process testing performed by the Plant QA Technicians.
… Symbol indicates Batch Release Testing performed by the Plant QC Analytical
Laboratory.
† Symbol indicates testing performed by the Development Analytical Laboratory.
‡ Symbol indicates analysis and evaluation of the test data generated, performed by
the Development Unit Validation Team and approved by the Development Quality
Assurance Unit.

3.

FREQUENCY

The procedure is performed with each pivotal batch. The procedure may be used for
the Process Qualification Batch.

4. PROCEDURE
4.1 In-Process Control - Sampling and Testing
Bulk material - (prior to filling).
Physical Testing - Sampling Protocol
A total of nine samples (about 50g per sample) is collected from the bulk containers,
representing the top, middle and the end of the BULK material.
Three 50g samples are used for testing and the balance of the samples reserved for
further testing, if so required.
Chemical Testing - Sampling Protocol
Ten (10) samples, each sample equivalent to the approximate weight of one (to
three)³ dose application are collected from the bulk processor. Sampling techniques
are outlined in the written product protocol and the Batch Manufacturing Instructions
(BMI).
1

This sampling plan is structured upon the PDA Technical Report, April 30 97 & FDA's "Guidance on the Packaging of Test
Batches", of February 8, 1995 Number 41-95".

Edition Number:
04
Ed. Status:
Spds: 03

Effective Date:
DD/MM/YY

Handbook of Pharmaceutical

APPROVED
______________
Department

_____________
R &D

Chapter: 14.5
5

_______________
RA

______/__________
QC / QA

Generic Development

SEMI SOLIDS

PIVOTAL

SOP #HBGD-04-03YY

STANDARD

BATCH

CHAPTER 14

OPERATING

PROCEDURES

IN-PROCESS SAMPLING & TESTING PROCEDURES OF
SEMISOLIDS, AND SUSPENSION FOR PIVOTAL BATCHES
Page 2 of 5.

Chemical Testing - Sampling Protocol - (continued)
Where sampling procedures from the processor are not possible, the reasons are
described in the written product protocol. In this case the bulk holding container, is
sampled from the top, middle and bottom of the holding unit.
Sample collection ‚ƒ
ƒ
20 samples are collected. 10 samples, each equivalent to the approximate weight of
one (to three)³ unit applications ‚ƒ, are collected from the holding containers,
according to SOP, "Sampling for Content Uniformity - Semisolids". (³ See limits

and Limitations)
10 samples (of 50g) will be collected ‚ƒ
ƒ and stored as retention samples for
additional testing, if required.
Sampling procedure:
The samples are collected via an appropriate “Sampling Thief” equipped with the
necessary die - unless otherwise instructed in the written protocol. Samples
container shall be sterile.

4.2 Physical Testing Protocol (Bulk)
Each sample is tested for:
Ü Description
Ü Appearance
Ü Color / Odor
Ü pH
Ü Viscosity (rheology)

4.3 Chemical Testing Protocol
The samples will be assayed according to the full monograph.
Ü Assay + Impurities
Ü Content Uniformity
Ü Microbial Limit test

Edition Number:
04
Ed. Status:
Spds: 03

Effective Date:
DD/MM/YY

Handbook of Pharmaceutical

APPROVED
______________
Department

_____________
R &D

Chapter: 14.6
6

_______________
RA

______/__________
QC / QA

Generic Development

SEMI SOLIDS

PIVOTAL

SOP #HBGD-04-03YY

STANDARD

BATCH

CHAPTER 14

OPERATING

PROCEDURES

IN-PROCESS SAMPLING & TESTING PROCEDURES OF
SEMISOLIDS, AND SUSPENSION FOR PIVOTAL BATCHES

Page 3 of 5.

FINISHED PROCESSED MATERIAL
5.1 Semisolids and Suspensions
Applies to filled tubes and jars testing for semisolids and suspensions only.

5.2 Batch Testing
Sampling Protocol
Samples should be collected directly as they exit the filling tube machine, at a
minimum of three time intervals, representing the beginning, middle and end of the
filling process.
Testing Protocol †
90 Sample will be collected † per interval as follows - ¹ Tests performed on the
different units: One Sample per physical test (30) with two retention samples per test
held (60).
Ü Description (1)
Ü Appearance (1)
Ü Color / Odor (1)
Ü pH (1)
Ü Viscosity (Rheology) (1)
Ü Weight (10 Samples)
Assay:- The samples will be assayed according to the full monograph.
Ü Assay + Impurities (1)
Ü 10 units for Content Uniformity Test
Ü Microbial Limit Test (1)

5.3 QC Release/Stability Testing (Time Zero) of Finished Packed Product
A representative sample taken from the production packaging run is tested … as
per product release specifications.
Each package type (smallest and largest pack) is tested† for the initial time zero
stability assay requirements - as per product stability protocol.
Samples are submitted to the laboratory with the specific testing protocol • and
appropriate sampling record forms (refer: sampling attachment forms).
Laboratory acceptance† of the test samples is verified by signing the sampling
record forms.

Edition Number:
04
Ed. Status:
Spds: 03

Effective Date:
DD/MM/YY

Handbook of Pharmaceutical

APPROVED
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Department

_____________
R &D

Chapter: 14.7
7

_______________
RA

______/__________
QC / QA

Generic Development

SEMI SOLIDS

PIVOTAL

SOP #HBGD-04-03YY

STANDARD

BATCH

CHAPTER 14

OPERATING

PROCEDURES

IN-PROCESS SAMPLING & TESTING PROCEDURES OF
SEMISOLIDS, AND SUSPENSION FOR PIVOTAL BATCHES
Page 4 of 5.

6.0 Evaluation of Tested Parameters † ‡
The physical and chemical parameters tested are evaluated to confirm the uniformity
of the batch and where applicable to comply with the required specifications ‡.
6.1 The limits for the in-process and finished product testing shall be within the
defined specification limits for the in-process and finished product.
6.2 All parameters tested will be within the upper and lower control limits of the
control chart.
6.3 The overall process shall be evaluated for process capability and shall be
within the process capability index (CpK) for the finished product.
Special Note:
For In-process specifications for the Bulk Content Assay.
In-process Testing (Content Uniformity)4:
7.0 The Upper control limit (UCL) is defined as the mean + 3 x Standard Deviation
7.1 The Lower control limit (LCL) is defined as the mean - 3 x Standard Deviation

For In-process Product Testing:
7.2 The Upper control limit (UCL) is defined as the mean + 3 x Standard Deviation
7.3.1 The Lower control limit (LCL) is defined as the mean - 3 x Standard Deviation

For Finished Product Testing:
7.4 The Upper control limit (UCL) is defined as the mean + 3 x Standard Deviation
7.5 The Lower control limit (LCL) is defined as the mean - 3 x Standard Deviation
7.6 CpK ≤ 1.0 (Note: CpK = UCL - LCL / 6SD)

Edition Number:
04
Ed. Status:
Spds: 03

Effective Date:
DD/MM/YY

Handbook of Pharmaceutical

APPROVED
______________
Department

_____________
R &D

Chapter: 14.8
8

_______________
RA

______/__________
QC / QA

Generic Development

SEMI SOLIDS

PIVOTAL

SOP #HBGD-04-03YY

STANDARD

BATCH

CHAPTER 14

OPERATING

PROCEDURES

IN-PROCESS SAMPLING & TESTING PROCEDURES OF
SEMISOLIDS, AND SUSPENSION FOR PIVOTAL BATCHES
Page 5 of 5.

8.0

LIMITS and LIMITATIONS

8.1 Bulk Mix - critical step.
The content uniformity of the Bulk Mix prior to filling shall be tested … for < Content
Uniformity BP>. The Bulk Mix shall fall within the control limits calculated from the
ten individual sampling assay results.
This SOP is restricted to the sampling and testing of in-process controls during
pivotal batch manufacture for chemical and physical testing, and includes U. of C.
Qualification Testing. This SOP does not specify the actual number of packed units
to be representatively sampled for: QC Retention, Stability Profile, Stability Reserve
or Bioequivalence Testing and Bioequivalence Reserve.

³ Sample size may be increased to three dosage applications, where appropriately
qualified in the process development report.
4 Bulk

Mix (Content Uniformity):
Where appropriately qualified by suitable batch analysis (or clearly established
during process development), the in-process lower and upper limits for Bulk Mix
Content Testing (Content Uniformity) may be narrowed to:
The Upper control limit (UCL) is defined as the mean + 2 x Standard Deviation
The Lower control limit (LCL) is defined as the mean - 2 x Standard Deviation

9.

CORRECTIVE ACTION

Out-of-specification test results (OOS) are handled according to the firms current
Out-of-Specification SOP.

10.

DOCUMENTATION

Each protocol will be accompanied • by a manufacturing process flowchart.
The sampling record ‚ forms are filed with the manufacturing batch records.
Sampling Record Forms for data completion at the time of sampling are as follows:
Attachment 1 - " Sampling Record for Bulk Mix "
Attachment 2 - " Sampling Record for Filling"
Attachment 3 - " Sampling Record for Finished Product Release & Stability T0 Test "

3
[End of Document]

Edition Number:
04
Ed. Status:
Spds: 03

Effective Date:
DD/MM/YY

Handbook of Pharmaceutical

APPROVED
______________
Department

_____________
R &D

Chapter: 14.9
9

_______________
RA

______/__________
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Generic Development

SEMI SOLIDS

PIVOTAL BATCH

Auditing the
Pivotal Batch

CHAPTER 14

Inspecting and comparing the pivotal
batch documentation line-for-line and
page-by-page is a prudent, worthwhile
and judicious auditing operation.

Retrieving and reviewing the plant

T

he Pivotal (Regulatory or Exhibition)
Batch is the demonstration batch lot
that is submitted to the regulators
as the example and legal basis on
which the future commercial lots will be
marketed and sold. It represents a
baseline of procedures and product
specifications that are the regulatory
basis for government agency approval.
This is generally the first production
batch in which all the production and
control parameters and specifications
have been fully set. Little practical
experience has been gained so far,
from the manufacture of a minimum 100
000 units (net / packed quantity).
Production familiarity, experience and
process fine tuning, by the firm will be
gauged, only after the product has been
approved, during the many commercial
production manufacturing lots.

Error-Free Pivotal

documentation saves
time and money
Thus the need to get it right, at the very
first attempt at the production level
(pivotal lot) is paramount. Careless
omissions in the batch documentation
will eventually result in an agency
deficiency letter and thereby delaying
approval for an additional few months costing both time and valuable
development and lost sales dollars.
Experienced Pharmaceutical Firms
know the high costs of undetected
documentation omissions or data fields,
and have set up efficient development
quality assurance units that closely
examine, inspect, audit and review
every
aspect
of
the
batch
documentation
for
submission.

Handbook of Pharmaceutical

production and cleaning logs or
ingredient inventory cards are a
necessary part of the job. Checking
batch numbers, dates and signatures,
possible transposed numbers or
omitted data, require careful vigilance
by the auditor or audit team. Auditing
with a formal procedure, simplifies the
task and allows the audit checklist to
grow when new and unusual errors or
omissions are detected.

Update audit checklists
after each pivotal lot
An audit checklist that remain static
over the years, may well reflect an
ineffective inspection, analysis and
detection procedure.

The Pivotal Batch Audit Checklist.
Checklist Do's:-

♦ Divide

audit
checklist
into
representative sections portraying each
operation, manufacturing and control
procedure.
♦ Add new check points to the list,
when a new error or omission arises.
♦ Test the checklist, by evaluating
routine production batches, to get a
sense of possible omission categories.
♦ Break multiple check points into
individual audit items on the checklist.
♦ Carefully cross-reference handwritten dates and times on the
production forms against machine printouts that have immediately follow the
operational step.
♦ Remember - weighing, pH, HPLC
and temperature print-outs and charts
normally give the date and the exact
time of the operation or test procedure.
♦ Evaluate production yields and
adherence to time-limitation against
actual weighing & recording print-outs. 2

Chapter: 14.10
10

Generic Development

SEMISOLIDS

PIVOTAL BATCH
14

SOP # HBGD-02-02YY

CHAPTER

STANDARD OPERATING
PROCEDURES

CHECKLIST FOR AUDITING THE PIVOTAL BATCH
Product Name:

Dosage Strength;

Batch No.

Date of Audit:

mg
/

/YY
Page 1 of 3.
Yes

No

q
q

q
q

ü Are the batch documents equivalent to the Master documents and available for the

q

q

audit?
ü Is the batch size equal or greater than 110,000 units?
ü Are the batch document pages numbered correctly?
ü Evaluate whether some of the pages could be replaced or rewritten?
ü Is there any evidence of erasures or white-outs?
ü Are cross-outs legible and correctly signed and dated ?

q
q
q
q
q

q
q
q
q
q

3. PRODUCT MASTER FORMULA - Check MF
ü Batch number
ü Lot No of ingredients
ü Two Signatures and date(s) for each weighing
ü Check ingredients weigh-out sheets
ü Computer weighing print-outs show gross, tare and net weights.
ü Are print-outs available and accurate?

q
q
q
q
q
q

q
q
q
q
q
q

4. BATCH MANUFACTURING INSTRUCTIONS - Check BMI for
ü Batch numbers recorded in correct data fields
ü ID numbers for Processing Machine present
ü Signatures and date(s) for each separate processing step
ü pH figures correct and are in the specification limit
ü Weight of processed material and yield calculation performed
ü % yield conform to written specifications limits on BMI

q
q
q
q
q
q

q
q
q
q
q
q

5. PRINT-OUTS & ATTACHMENTS - Check for full identification:
ü 'Equipment Cleaned' labels attached to batch record
ü In-process LOD print-outs recording target moisture achieved
ü In-process weight sheets/print-outs recording in-process yields
ü Recording charts for phase temperature (mixers / kettles etc.)
ü Recording charts for time of mixing (mixers/kettles).

q
q
q
q
q

q
q
q
q
q

1. PRODUCT MASTER DOCUMENTS
ü Master documents approved and signed by appropriate personnel.
ü Master documents available during the audit for comparison.
2. ACTUAL BATCH DOCUMENTS (Executed Batch)

Edition Number:
02
Ed. Status:
Supwecedes - 01

Effective Date
DD/MM/YY

Handbook of Pharmaceutical

APPROVED
______________
Department

__________
R &D

_______________
RA

Chapter: 14.11
11

______/__________
QC / QA

Generic Development

SEMISOLIDS

PIVOTAL BATCH
14

SOP # HBGD-02-02YY

CHAPTER

STANDARD OPERATING
PROCEDURES

CHECKLIST FOR AUDITING THE PIVOTAL BATCH
Product Name:

Dosage Strength;

Batch No.

Date of Audit:

mg
/

/200Y
Page 2 of 3.

6. ROOM PREPARATION - Check for:
ü Machine Card details corresponds to batch record
ü Room Preparation Card details and dates correct
ü Check that card dates coincide with batch record dates.
ü If equipment was used in 2 sublots, were both entries recorded?
7. BATCH RUN SHEETS - Check Production sheets for:
ü All Product details are complete as per product Specifications.
ü Work station approved as clean and initialed before opening.
ü Opening of Production Work station initialed.
ü Operator and QC in-process control charts separate & identified.
ü Transferred of numbers are correct to BATCH SHEETS.
ü Operator and QC in-process on-line check results within the specifications limits
set.
ü Number of in-process checks according to current SOP.
ü In-process sampling during manufacturing as per protocol.
8. INSTRUCTIONS FOR SEMISOLID FILLING Check for:
ü All Product details are accurate, including Lot No. of empty Tubes /
Caps / Applicators.
ü Minimum, maximum and average empty tube weight
ü Minimum, maximum and average theoretical fill weight
ü Minimum, maximum and average of filled tube weight
ü Signatures of Production and Quality Control personnel
9. GENERAL MANUFACTURING INSTRUCTIONS
ü Check continual stirring of suspension premixes :
ü All Product entries are complete - including sub lot number.
ü Preheating of Purified Water to 950C for NLT 45 min.
ü Mixer parameters set-up (settings, type, distance, angle)
ü Temp/Time Recording procedures including equipment graph.
ü Percentage yield conforms to specifications and within limits.
ü Summary of manufactured sub-lots (where appropriate).

Edition Number:
02
Ed. Status:
Supwecedes - 01

Effective Date
DD/MM/YY

Handbook of Pharmaceutical

Yes

No

q
q
q
q

q
q
q
q

q
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q

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q
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APPROVED
______________
Department

__________
R &D

_______________
RA

Chapter: 14.12
12

______/__________
QC / QA

Generic Development

SEMISOLIDS

PIVOTAL BATCH
14

SOP # HBGD-02-02YY

CHAPTER

STANDARD OPERATING
PROCEDURES

CHECKLIST FOR AUDITING THE PIVOTAL BATCH
Product Name:

Dosage Strength;

Batch No.

Date of Audit:

mg
/

/200Y
Page 3 of 3.
Yes

No

q
q

q
q

11. PACKAGING CONTROL SHEET - Check:
ü All Product details required & entered are accurate
ü Cleanliness check of work station is approved
ü Product and packaging material identification is approved
ü Approval for start-up of the line
ü In-process control checks complete
ü Packaging 100% completion check
ü Quantity of the packaged product compared to the estimates
ü Sample of labels used with Lot No and Expiration Date
ü In-process QC checks of product packs
ü Representative sampling of each pack type and pack size.

q
q
q
q
q
q
q
q
q
q

q
q
q
q
q
q
q
q
q
q

12. PACKAGING MATERIALS BALANCE - Check for:
ü All Product details are accurate on reconciliation form
ü Labels are reconciled and printed material balance correct
ü Production and QA Signatures complete and dated.

q
q
q

q
q
q

13. PRODUCTION & PACKAGING SHEET - Check for:
ü All Product details required & entered are accurate
ü Yield reconciliation of each stage of manufacture
ü Time limitation at each stage of production in specification
ü Authorization signature of Quality Control Manager

q
q
q
q

q
q
q
q

q
q
q
q
q
q
q

q
q
q
q
q
q
q

10. STANDARD PACKAGING SHEET - Check for:
ü Product details required for packaging operation complete.
ü Lot numbers present of packaging components.

14. MANUFACTURING DEVIATION REPORT - Check MDR for:
ü All Product descriptive details are entered accurately
ü Full description of the deviation
ü Source of process deviation
ü Proposed solution stated precisely
ü Decision on batch disposition confirmed
ü Authorization of Quality Assurance Unit

Edition Number:
02
Ed. Status:
Supwecedes - 01

Effective Date
DD/MM/YY

Handbook of Pharmaceutical

APPROVED
______________
Department

__________
R &D

_______________
RA

Chapter: 14.13
13

______/__________
QC / QA

Generic Development

SEMISOLIDS

BIOEQUIVALENCE

CHAPTER 15

Topical
Bioequivalence
vs. Reference Listed Drug

I

n vitro release (diffusion testing) is the
current tool used during drug
development,
or
batch-to-batch
similarity by evaluating the comparative
diffusion profile of the semisolid.
This information is not required for the
bioequivalence section (VI) of the
ANDA submission in topical products,
as dissolution is an essential standard
method required in solid dosage forms.
It is essentially a reproducible test used
to evaluate the 'sameness' of two
products having the same formula and
near similar manufacturing process.
Topical corticosteriods are a specific
class of topical semisolids that have a
published FDA guidance procedure
(June 1992) on in-vivo bioequivalence
using a vasoconstrictor bioassay and
include guidelines on a Franz cell
diffusion test.

Evaluating

whether
your
firms
corticosteriods drug will pass the
vasoconstrictor bioassay at the first
time
is
a
key
requirement.
Vasoconstrictor bioassays are relatively
costly clinical evaluations.
The primary goal is to ensure that the
generic topical drug is similar to the
reference drug. Knowing the reference
drugs overall diffusion profile and
ageing parameters are critical input
data requirements to make this
decision.

Handbook of Pharmaceutical

This

chapter
combines
the
developments in diffusion testing and
the May 1997 data correlation of
SUPAC-SS to produce a working model
on accessing similarity between your
drug and the reference listed drug (i.e.
RLD.)
Two essential steps the topical
development unit can do to achieve this
goal?

♦ Drug Classification:
Classify the drug product whether it is a
corticosteroid or non-corticosteroid
product. This classification will furnish
two useful aspects;
1. The type of diffusion studies
considered necessary to fully evaluate
your formulated drug against the RLD
that has been selected (Reference.
Graph 1 & Graph 2 demonstrate
comparison diffusion studies.
2. Whether it is possible to establish an
IVIVC (in-vitro, in-vivo correlation)
between your drug and the intended
vasoconstrictor
bioassay
/
bioequivalence study necessary for
corticosteriods applications to the FDA.

♦ Validated Diffusion Method
A fully validated diffusion assay method
may obtain meaningful results from a
comparative diffusion profile (CDfP)
between the Generic and RLD. Prudent
development laboratories will evaluate

Chapter: 15.1
1

Generic Development

SEMISOLIDS

BIOEQUIVALENCE

Topical

LABORATORY WORK:

Bioequivalence
several (CDfP) using multipoint profiles
with multiple (i.e. 3) batches, hopefully
with different manufacturing dates and
thus assessing miscellaneous product
ages.
Diffusion method requirements are
highlighted in summary given.

♦ Multi-point Diffusion Profiles
A least three different batch lots of the
RLD using a multipoint diffusion profiles
should be performed. (See comparison
graphs below.)
Where possible age or stress one of
the RLD lots and evaluate with the
specified media for creams or
ointments.
Evaluate
profiles
using
the
standardised
25mm
polysulfone
membrane. Pre-treat the membrane as
specified. The marginal higher cost of a
comparative diffusion program may well
be the difference between a 'topical
biostudy' pass or failure.

♦ Bioequivalence Study - Pilot
In the case of high cost biostudies a
pilot study may give meaningful results
and enable necessary formula or
process adjustments in intricate drug
comparisons. Should the pilot study fail
or 'just' fail' - it is important to note the
full participant study would have failed
and at a significantly higher cost.

♦ Bioequivalence Study - Full
Your R&D unit should be ready to
perform a full-scale biostudy supported
with adequate CDfP data and statistical
evaluation for sameness in order to
pass the topical biostudy against the
Reference Listed Drug chosen.

Handbook of Pharmaceutical

CHAPTER 15

Evaluate Comparative Diffusion Profiles
(CDfP) using 3 different RLD batch Lots
obtained at approximately 3 month
intervals apart from the time of initial
manufacture. The test and reference
product should be approximately the
same age from initial manufacture.

Low Stressed Profiles:
Comparative Diffusion Profiles (CDfP)
using up to 3 different Reference Listed
Drug batch Lots placed on accelerated
stability at 30° C / 60% RH for 3
months. (Evaluate average Diffusion
profiles) Avoid using fresh material
directly off the production line. The
semisolid matrix should be allowed to
stabilise for about one month before
evaluation.

It

is significant to evaluate the
variability in the RLD product of
equivalent manufacturing date to the
test product (where the RLD is
purchased with a similar date of
manufacture.)
Success of a costly Bioequivalence
study may hinge or depend on the
detail of the RLD's data (i.e. Multiple
lots with real time and aged studies.)
Inter-batch variability of the RLD should
be evaluated with care.

In-vitro release tests (IVIVC)

Ü The

in-vitro release test is reliable
reproducible and is a product specific
test.

Ü The

in-vitro release test is suitable
for sameness comparisons prior to
topical bioequivalent testing (corticosteroid vasoconstrictor tests)

Ü The in-vitro release test can officially
be used during product development.
scale-up and post approval changes

Ü The in-vitro release test can be used
for assuring product sameness under
SUPAC related changes.

Chapter: 15.2
2

Generic Development

SEMISOLIDS

BIOEQUIVALENCE

CHAPTER 15

Topical Bioequivalence
DIFFUSION CONDITIONS
Used for Comparative Diffusion Profiles (CDP)
DIFFUSION CONDITIONS
(Semisolids)
System:

Six unit static Diffusion Cell
(Hanson P/N 57-VC Vertical Diffusion Cell)1

System Orifice:

15mm

Temperature:

320 C (Ñ0.50 C)

Membrane (creams):

Polysulfone (Tuffryne™)
Diameter 25mm saturated with
Isopropylmyristate/Ethomeen™

Membrane (ointments):

Polysulfone (Tuffryne™)
Diameter 25mm saturated with
Isopropylmyristate (IPM)

Receptor Phase:

Ethanol-Water Mixture

Sampling Time:

0.5; 1; 2; 4; 6 - hours

Analysis:

Reverse Phase HPLC

Mobile Phase (creams):

Water/Acetonitrile

Mobile Phase (ointments):

IPM/Water/Ethanol 10:85:5

Release Rate:

1

Determine micrgram/cm2 release
at each interval plotted versus the
square root of time the Slope of the
line is the release rate

Hanson MICROETTE SYSTEM™

Cautions:

Ü Note Difference in membrane treatment and receptor phases for creams and
ointments. Semisolids age > one month (ideally between 3-6 months.)

Ü Receptor medium is sufficient to maintain sink conditions.
Ü No medium membrane interaction.
Ü No medium formulation interaction.

Handbook of Pharmaceutical

Chapter: 15.3
3

Generic Development

SEMISOLIDS

BIOEQUIVALENCE

CHAPTER 15

Topical Bioequivalence
COMPARATIVE DIFFUSION PROFILE
FOR CORTICOSTEROID DRUG PRODUCT LOTS
USED IN TOPICAL BIOEQUIVALENCE STUDIES:
[Generic name] [Topical Preparation] [00.0] mg/gram.

Lot No:[000]

6 Unit Static Diffusion Cell
Polysulfone membrane with 30% ethyl alcohol

Real Time Study
3 months Stability at 28° C / 60% RH
Figure No. 1. Comparative Diffusion Profile
Generic Semisolid vs RLD 00mg
300
250
Cummulative
amount
penertrated
(Mt)

200
150

S-12345
RLD AA0000

100
50
0

0 0.5

1.0

1.5

2.0

2.5

3.0

Square root of TIME (Hour)

References:
1. SUPAC SS Statistics Committee Maryland USA 1997.
2. Donald J Schuirmann - QMR/OEB/CDER Maryland USA
3. Robert Dillard Ph.D. (PhRMA) USA
4. David Pearce PH.D (NAPM & GPIA) USA
5. US Department of Health and Hunam Sciences FDA CDER May 1997
6. Gordon L Flynn Ph.D. SUPAC-SS Working Group University of Michigan USA
7. USP XXIII USPC USA
8. Richard J Davis FDA Mid Atlantic Division USA
9. Jerome Elkins Dallas District Laboratory FDA USA 1997.
10.International Journal of Generic Drugs, Vol..1 No 1-8, 1997.

Handbook of Pharmaceutical

Chapter: 15.4
4

Generic Development

SEMISOLIDS

BIOEQUIVALENCE

CHAPTER 15

Topical Bioequivalence
COMPARATIVE DIFFUSION PROFILE
IN-VITRO RELEASE
THREE DRUG PRODUCT LOTS SHOWING SAMENESS PRIOR TO
BIOEQUIVALENCE STUDIES:
[Generic name] [Topical Preparation] [00.0] mg/gram.

Lot No: [000]

6 Unit Static Diffusion Cell
Polysulfone membrane with 30% ethyl alcohol

Comparison Diffusion Study
Figure No. 2. Comparative Diffusion Profile

Generic Triamcinolone acetonide 0.5% cream
120
100
S-113
80
2

(µg.cm )

S-115

60

S-116

40
20
0

(√ Time)
CERTIFICATES OF ANALYSIS REPRESENTING THE DRUG PRODUCTS USED IN
BIOEQUIVALENCY STUDY

[Generic name] Cream
[RLD] Cream

Lot: 1234
Lot: AA000

[BP] [000.0] mg.
[BP] [000.0] mg.

CoA No: 0000
CoA No: 0000

The analytical results of the Certificates of Analysis for [Generic Company Name Inc. / Ltd.] and
[RLD Company Name Inc. / Ltd.] Drug Product lots were tested the Analytical Research Laboratories
of [Generic Company Name Inc. / Ltd. & Address].

Handbook of Pharmaceutical

Chapter: 15.5
5

Generic Development

SEMISOLIDS

BIOEQUIVALENCE

CHAPTER 15

Topical Bioequivalence
COMPARATIVE DIFFUSION PROFILE
IN-VITRO RELEASE
FIVE DRUG PRODUCT LOTS SHOWING EQUIVALENT PROFILES
[Generic name] [Miconazole Nitrate] [20.0] mg/gram.

Lot No:1234

6 Unit Static Diffusion Cell
Polysulfone membrane with 30% ethyl alcohol

Comparison Diffusion Study
Figure No. 3. Comparative Diffusion Profile

Niconazole Nitrate 2.0% cream
300
250

Test
Product

200
Innovator
2

(µg.cm )

150
Product A

100

Product B

50

Product C
0

0 2 4 6 8 10 12 14 16 18 20

(√ Time)
Hours

IN-VITRO RELEASE OF TEST AND INNOVATOR MICONAZOLE NITRATE
2% CREAM




[Generic name] Cream
[Innovative] Cream
[Manufacturer A] Cream
[Manufacturer B] Cream
[Manufacturer C] Cream

Lot: 1234
Lot: AA00
Lot: S3420
Lot: EX230
Lot: C369

[BP] [20.0] mg.
[BP] [20.0] mg.
[BP] [20.0] mg.
[BP] [20.0] mg.
[BP] [20.0] mg.

CoA No: 0010
CoA No: 0020
CoA No: 0030
CoA No: 0040
CoA No: 0050

The analytical results of the Certificates of Analysis for [Generic Company Name Inc. / Ltd.] and
[RLD Company Name Inc. / Ltd.] Drug Product lots were tested the Analytical Research Laboratories
of [Generic Company Name Inc. / Ltd. & Address].

Handbook of Pharmaceutical

Chapter: 15.6
6

Generic Development

Guidance for Industry
Nonsterile Semisolid Dosage Forms
Scale-Up and Postapproval Changes:
Chemistry, Manufacturing, and Controls;
In Vitro Release Testing and In Vivo
Bioequivalence Documentation

U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
May 1997
SUPAC-SS
CMC 7

Guidance for Industry
Nonsterile Semisolid Dosage Forms
Scale-Up and Postapproval Changes:
Chemistry, Manufacturing, and Controls;
In Vitro Release Testing and In Vivo
Bioequivalence Documentation
Additional copies are available from:
Office of Training and Communications
Division of Communications Management
The Drug Information Branch, HFD-210
5600 Fishers Lane
Rockville, MD 20857
(Tel) 301-827-4573
(Internet) http://www.fda.gov/cder/guidance.htm

U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
May 1997
SUPAC-SS
CMC 7
Table of Contents

I.

INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

II.

GENERAL BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
A.
Critical Manufacturing Parameters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
B.
General Stability Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
C.
The Role of In Vitro Release Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3

III.

COMPONENTS AND COMPOSITION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
A.
Level 1 Change . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
B.
Level 2 Change . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
C.
Level 3 Change . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
D.
Preservative . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8

IV.

MANUFACTURING . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
A.
Equipment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
B.
Process . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

V.

BATCH SIZE (SCALE-UP/SCALE-DOWN) . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
A.
Level 1 Change . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
B.
Level 2 Change . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
C.
Level 3 Change . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

14
14
15
16

VI.

MANUFACTURING SITE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
A.
Level 1 Change . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
B.
Level 2 Change . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
C.
Level 3 Change . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

16
17
17
18

VII.

IN VITRO RELEASE TEST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19

VIII. IN VIVO BIOEQUIVALENCE STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
GLOSSARY OF TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26

GUIDANCE FOR INDUSTRY1
Nonsterile Semisolid Dosage Forms
Scale-Up and Postapproval Changes:
Chemistry, Manufacturing, and Controls;
In Vitro Release Testing and
In Vivo Bioequivalence Documentation
SUPAC-SS

I.

INTRODUCTION

This guidance provides recommendations to pharmaceutical sponsors of new drug applications
(NDAs), abbreviated new drug applications (ANDAs), and abbreviated antibiotic drug
applications (AADAs) who intend to change (1) the components or composition, (2) the
manufacturing (process and equipment), (3) the scale-up/scale-down of manufacture, and/or (4)
the site of manufacture of a semisolid formulation during the postapproval period. This guidance
addresses nonsterile semisolid preparations (e.g., creams, gels, lotions, and ointments) intended
for topical routes of administration. The guidance defines (1) the levels of change; (2)
recommended chemistry, manufacturing, and controls (CMC) tests to support each level of
change; (3) recommended in vitro release tests and/or in vivo bioequivalence tests to support each
level of change; and (4) documentation to support the change.
The guidance specifies the application information that should be provided to the Center for Drug
Evaluation and Research (CDER) to ensure continuing product quality and performance
chacteristics of the semisolid topical formulation for specified changes. The guidance does not
comment on or otherwise affect compliance/inspection documentation defined by the Office of
Compliance in CDER or the Office of Regulatory Affairs at FDA.

The guidance provides recommendations on application documentation for the following multiple

1

This guidance has been prepared by the Scale-Up and Post Approval Change Semisolids (SUPAC-SS)
Working Group operating under the direction of the Chemistry Manufacturing Controls Coordinating Committee (CMC
CC) and the Biopharmaceutics Coordinating Committee (BCC) in the Center for Drug Evaluation and Research
(CDER) at the Food and Drug Administration. This guidance document represents the Agency’s current thinking on
semisolid dosage forms scale-up and postapproval changes. It does not create or confer any rights for or on any person
and does not operate to bind FDA or the public. An alternative approach may be used if such approach satisfies the
requirement of the applicable statute, regulations, or both.

changes, provided appropriate test and filing documents are submitted (1) multiple level 1 changes
with level 1 test and filing documentation; (2) multiple level 1 changes; one level 2 change with
level 2 test and filing documentation; (3) multiple level 2 changes with level 2 test documentation
and a prior approval supplement (PAS) and (4) level 3 manufacturing site change and any other
level 1 change with level 3 manufacturing site change test and filing documentation. The
documentation to support the changes varies depending on the type and the complexity of the
semisolid dosage form. For those changes filed in a Changes Being Effected (CBE) Supplement
(21 CFR 314.70(c)), the FDA may review the supplemental information and decide that the
changes are not approvable. Sponsors should contact the appropriate CDER review division and
staff for information about tests and application documentation for changes not addressed in this
guidance, or for successive level 2 or 3 changes submitted over a short period.
The regulations provide that applicants may make changes to an approved application in
accordance with a guidance, notice, or regulation published in the Federal Register that provides
for a less burdensome notification of the change (e.g., by notification at the time a supplement is
submitted or in the next annual report) (21 CFR 314.70(a)). This guidance permits less
burdensome notice of certain postapproval changes within the meaning of
§ 314.70(a).

II.

GENERAL BACKGROUND

In general, semisolid dosage forms are complex formulations having complex structural elements.
Often they are composed of two phases (oil and water), one of which is a continuous (external)
phase, and the other of which is a dispersed (internal) phase. The active ingredient is often
dissolved in one phase, although occasionally the drug is not fully soluble in the system and is
dispersed in one or both phases, thus creating a three-phase system. The physical properties of
the dosage form depend upon various factors, including the size of the dispersed particles, the
interfacial tension between the phases, the partition coefficient of the active ingredient between
the phases, and the product rheology. These factors combine to determine the release
characteristics of the drug, as well as other characteristics, such as viscosity.
A.

Critical Manufacturing Parameters

For a true solution, the order in which solutes are added to the solvent is usually
unimportant. The same cannot be said for dispersed formulations, however, because
dispersed matter can distribute differently depending on to which phase a particulate
substance is added. In a typical manufacturing process, the critical points are generally the
initial separation of a one-phase system into two phases and the point at which the active
ingredient is added. Because the solubility of each added ingredient is important for
determining whether a mixture is visually a single homogeneous phase, such data, possibly
supported by optical microscopy, should usually be available for review. This

2

is particularly important for solutes added to the formulation at a concentration near or
exceeding that of their solubility at any temperature to which the product may be exposed.
Variations in the manufacturing procedure that occur after either of these events are likely
to be critical to the characteristics of the finished product. This is especially true of any
process intended to increase the degree of dispersion through reducing droplet or particle
size (e.g., homogenization). Aging of the finished bulk formulation prior to packaging is
critical and should be specifically addressed in process validation studies.
B.

General Stability Considerations

The effect that SUPAC changes may have on the stability of the drug product should be
evaluated. For general guidance on conducting stability studies, see the FDA Guideline
for Submitting Documentation for the Stability of Human Drugs and Biologics. For
SUPAC submissions, the following points should also be considered:
1.
In most cases, except those involving scale-up, stability data from pilot
scale batches will be acceptable to support the proposed change.
2.
Where stability data show a trend towards potency loss or degradant
increase under accelerated conditions, it is recommended that historical accelerated
stability data from a representative prechange batch be submitted for comparison.
It is also recommended that under these circumstances, all available long-term data
on test batches from ongoing studies be provided in the supplement. Submission
of historical accelerated and available long-term data would facilitate review and
approval of the supplement.
3.
A commitment should be included to conduct long-term stability studies
through the expiration dating period, according to the approved protocol, on either
the first or first three (see section III-VI for details) production batches, and to
report the results in subsequent annual reports.
C.

The Role of In Vitro Release Testing

The key parameter for any drug product is its efficacy as demonstrated in controlled
clinical trials. The time and expense associated with such trials make them unsuitable as
routine quality control methods. Therefore, in vitro surrogate tests are often used to
assure that product quality and performance are maintained over time and in the presence
of change. A variety of physical and chemical tests commonly performed on semisolid
products and their components (e.g., solubility, particle size and crystalline form of the
active component, viscosity, and homogeneity of the product) have historically provided
reasonable evidence of consistent performance. More recently, in vitro release testing has
shown promise as a means to comprehensively assure consistent delivery of the active
3

component(s) from semisolid products.
An in vitro release rate can reflect the combined effect of several physical and chemical
parameters, including solubility and particle size of the active ingredient and rheological
properties of the dosage form. In most cases, in vitro release rate is a useful test to assess
product sameness between prechange and postchange products. However, there may be
instances where it is not suitable for this purpose. In such cases, other physical and
chemical tests to be used as measures of sameness should be proposed and discussed with
the Agency. With any test, the metrics and statistical approaches to documentation of
“sameness” in quality attributes should be considered.
The evidence available at this time for the in vitro-in vivo correlation of release tests for
semisolid dosage forms is not as convincing as that for in vitro dissolution as a surrogate
for in vivo bioavailability of solid oral dosage forms. Therefore, the Center’s current
position concerning in vitro release testing is as follows:
1.
In vitro release testing is a useful test to assess product “sameness” under
certain scale-up and postapproval changes for semisolid products.
2.
The development and validation of an in vitro release test are not required
for approval of an NDA, ANDA or AADA nor is the in vitro release test required
as a routine batch-to-batch quality control test.
3.
In vitro release testing, alone, is not a surrogate test for in vivo
bioavailability or bioequivalence.
4.
The in vitro release rate should not be used for comparing different
formulations across manufacturers.

III.

COMPONENTS AND COMPOSITION

This section of the guidance focuses on changes in excipients in the drug product. Qualitative
changes in excipients should include only those excipients which are present in approved drug
products for the specific route of administration. Quantitative changes in excipients should not
exceed the amount previously approved in products with the same specific route of
administration.2 The chronology of changes in components and composition should be provided.
Changes in components or composition that have the effect of adding a new excipient or deleting
an existing excipient are defined as level 3 changes (see section III.C below), except as described
below. These changes generally result in the need to change the labeling.

2

FDA, CDER, Inactive Ingredient Guide, 1996, Division of Drug Information Resources.
4

Compositional changes in preservatives are considered separately and are not included as part of
the total additive effect under sections III.A, B and C.
A.

Level 1 Change
1.

Definition of Level

Level 1 changes are those that are unlikely to have any detectable impact on
formulation quality and performance.
Examples:
!

Deletion or partial deletion of an ingredient intended to affect the color,
fragrance, or flavor of the drug product.

!

Any change in an excipient up to 5% of approved amount of that excipient.
The total additive effect of all excipient changes should not be more than
5%. Changes in the composition should be based on the approved target
composition and not on previous level 1 changes in the composition. A
change in diluent (q.s. excipient) due to component and composition
changes in excipient may be made and is excluded from the 5% change
limit.

!

Change in a supplier of a structure forming excipient that is primarily a
single chemical entity (purity$95%) or change in a supplier or technical
grade of any other excipient.

2.

Test Documentation
a.

Chemistry Documentation

Application/compendial product release requirements and stability testing.
Stability testing: First production batch on long-term stability reported in
annual report.
b.

In Vitro Release Documentation

None.
c.

In Vivo Bioequivalence Documentation

None.
5

3.

Filing Documentation

Annual report (all information including long-term stability data).
B.

Level 2 Change
1.

Definition of Level

Level 2 changes are those that could have a significant impact on formulation
quality and performance.
Examples:
!

Changes of >5% and #10% of approved amount of an individual excipient.
The total additive effect of all excipient changes should not be more than
10%. Changes in the composition should be based on the approved target
composition and not on previous level 1 or level 2 changes in the
composition. Changes in diluent (q.s. excipient) due to component and
composition changes in excipients are acceptable and are excluded from the
10% change limit.

!

Change in supplier of a structure forming excipient not covered under level
1.

!

Change in the technical grade of structure forming excipient.

!

Change in particle size distribution of the drug substance, if the drug is in
suspension.

2.

Test Documentation
a.

Chemistry Documentation

Application/compendial product release requirements and executed batch
records.
Stability testing: One batch with three months accelerated stability data
reported in changes being effected supplement and long-term stability data
of first production batch reported in annual report.
b.

In Vitro Release Documentation

The in vitro release rate of a lot of the new/modified formulation should be
6

compared with that of a recent lot of comparable age of the pre-change
formulation of the product. The median in vitro release rates (as estimated
by the estimated slope from each cell, see section VII) of the two
formulations should be demonstrated to be within acceptable limits using
the testing procedure described in section VII (IN VITRO RELEASE
TEST) below.
c.

In Vivo Bioequivalence Documentation

None.
3.

Filing Documentation

Changes being effected supplement (all information including accelerated stability
data); annual report (long-term stability data).
C.

Level 3 Change
1.

Definition of Level

Level 3 changes are those that are likely to have a significant impact on
formulation quality and performance.
Examples:
!

Any qualitative and quantitative changes in an excipient beyond the ranges
noted in level 2 change.

!

Change in crystalline form of the drug substance, if the drug is in
suspension.

2.

Test Documentation
a.

Chemistry Documentation

Application/compendial product release requirements and executed batch
records.Significant body of information available: One batch with three
months accelerated stability data reported in prior approval supplement and
long-term stability data of first three production batches reported in annual
report.

7

Significant body of information not available: Three batches with three
months accelerated stability data reported in prior approval supplement and
long-term stability data of first three production batches reported in annual
report.
b.

In Vitro Release Documentation

The in vitro release rate of the new/modified formulation should be
established as a point of reference. Under this level 3 change, in vitro
release documentation is not required, but sponsors are encouraged to
develop this information for use in subsequent changes under this guidance.
c.

In Vivo Bioequivalence Documentation

Full bioequivalence study on the highest strength, with in vitro
release/other approach on the lower strength(s).
3.

Filing Documentation

Prior approval supplement (all information including accelerated stability data);
annual report (long-term stability data).
D.

Preservative

For semisolid products, any change in the preservative may affect the quality of the
product. If any quantitative or qualitative changes are made in the formulation, additional
testing should be performed. No in vitro release documentation or in vivo bioequivalence
documentation is needed for preservative changes.
1.

Level 1 Change
a.

Definition of Level

Quantitatively 10% or less change in the approved amount of preservative.
b.

Test Documentation

!

Application/compendial product release requirements.

!

Preservative Effectiveness Test carried out at lowest specified
preservative level.

c.

Filing Documentation
8

Annual report
2.

Level 2 Change
a.

Definition of Level

Quantitatively greater than 10% and up to 20% change in the approved
amount of preservative.
b.

Test Documentation

!

Application/compendial product release requirements.

!

Preservative Effectiveness Test at lowest specified preservative
level.

c.

Filing Documentation

Changes being effected supplement.
3.

Level 3 change
a.

Definition of Level

Quantitatively greater than 20% change in the approved amount of
preservative (including deletion) or use of a different preservative.
b.

Test Documentation

!

Application/compendial product release requirements.

!

Preservative Effectiveness Test at lowest specified preservative
level.

!

Analytical method for identification and assay for new preservative.

!

Validation studies to show that the new preservative does not
interfere with application/compendial test.

!

Executed batch records.

!

Stability testing: One batch with three months accelerated stability
data reported in prior approval supplement and long-term stability
9

data of first production batch reported in annual report.
c.

Filing Documentation

Prior approval supplement (all information including accelerated stability
data); annual report (long-term stability data).

IV.

MANUFACTURING

Manufacturing changes may affect both equipment used in the manufacturing process and the
process itself.
A.

Equipment
1.

Level 1 Change
a.

Definition of Level

Change from nonautomated or nonmechanical equipment to automated or
mechanical equipment to transfer ingredients. Change to alternative
equipment of the same design and operating principles.
b.

Test Documentation
i.

Chemistry Documentation

Application/compendial product release requirements. Notification
of change and submission of updated executed batch records.
Stability testing: First production batch on long-term stability
reported in annual report.
ii.

In Vitro Release Documentation

None.
iii.

In Vivo Bioequivalence Documentation

None.
c.

Filing Documentation

10

Annual report (all information including long-term stability data).
2.

Level 2 Change
a.

Definition of Level

Change in equipment to a different design or different operating principles.
Change in type of mixing equipment, such as high shear to low shear and
vice versa.
b.

Test Documentation
i.

Chemistry Documentation

Application/compendial product release requirements. Notification
of change and submission of updated executed batch records.
Significant body of information available: One batch with three
months accelerated stability data reported in changes being effected
supplement and long-term stability data of first production batch
reported in annual report.
Significant body of information not available: Three batches with
three months accelerated stability data reported in changes being
effected supplement and long-term stability data of first three
production batches reported in annual report.
ii.

In Vitro Release Documentation

The in vitro release rate of a lot of the dosage form prepared in new
equipment should be compared with the release rate of a recent lot
of comparable age of the product prepared using original
equipment. The median in vitro release rates (as estimated by the
estimated slope from each cell, see section VII) of the two
formulations should be demonstrated to be within acceptable limits,
using the testing procedure described in section VII (IN VITRO
RELEASE TEST) below.
iii.

In Vivo Bioequivalence Documentation

None.
c.

Filing Documentation
11

Changes being effected supplement (all information including accelerated
stability data); annual report (long-term stability data).
3.

Level 3 Change

No level 3 changes are anticipated in this category.
B.

Process
1.

Level 1 Change
a.

Definition of Level

Process changes, including changes such as rate of mixing, mixing times,
operating speeds, and holding times within approved application ranges.
Also, order of addition of components (excluding actives) to either oil or
water phase.
b.

Test Documentation
i.

Chemistry Documentation

None beyond application/compendial product release requirements.
ii.

In Vitro Release Documentation

None.
iii.

In Vivo Bioequivalence Documentation

None.
c.

Filing Documentation

Annual report.
2.

Level 2 Change
a.

Definition of Level

Process changes, including changes such as rate of mixing, mixing times,
rate of cooling, operating speeds, and holding times outside approved
application ranges for all dosage forms. Also, any changes in the process
12

of combining the phases.
b.

Test Documentation
i.

Chemistry Documentation

Application/compendial product release requirements. Notification
of change and submission of updated executed batch records.
Significant body of information available: One batch with three
months accelerated stability data reported in changes being effected
supplement and long-term stability data of first production batch
reported in annual report.
Significant body of information not available: Three batches with
three months accelerated stability data reported in changes being
effected supplement and long-term stability data of first three
production batches reported in annual report.
ii.

In Vitro Release Documentation

The in vitro release rate of a lot of the dosage form prepared by the
new/modified process should be compared with the in vitro release
rate of a recent lot of comparable age of the dosage form prepared
by the prechange process. The median in vitro release rates (as
estimated by the estimated slope from each cell, see VII) of the lots
prepared by the two processes should be demonstrated to be within
acceptable limits, using the testing procedure described in section
VII (IN VITRO RELEASE TEST) below.
iii.

In Vivo Bioequivalence Documentation

None.
c.

Filing Documentation

Changes being effected supplement (all information including accelerated
stability data); annual report (long-term stability data).
3.

Level 3 Change

No level 3 changes are anticipated in this category.

13

V.

BATCH SIZE (SCALE-UP/SCALE-DOWN)

This guidance recommends that the minimum batch size for the NDA pivotal clinical trial batch or
the ANDA/AADA biobatch be at least 100 kg or 10% of a production batch, whichever is larger.
Deviations from this recommendation should be discussed with the appropriate agency review
division. All scale changes should be properly validated and may be inspected by appropriate
agency personnel.
A.

Level 1 Change
1.

Definition of Level

Change in batch size, up to and including a factor of ten times the size of the
pivotal clinical trial/biobatch, where: (1) the equipment used to produce the test
batch(es) are of the same design and operating principles; (2) the batch(es) is
manufactured in full compliance with cGMPs; and (3) the same standard operating
procedures (SOPs) and controls, as well as the same formulation and
manufacturing procedures, are used on the test batch(es) and on the full-scale
production batch(es).
2.

Test Documentation
a.

Chemistry Documentation

Application/compendial product release requirements. Notification of
change and submission of updated executed batch records in annual report.
Stability testing: First production batch on long-term stability reported in
annual report.
b.

In Vitro Release Documentation

None.
c.

In Vivo Bioequivalence Documentation

None.
3.

Filing Documentation

Annual report (all information including long-term stability data).

B.

Level 2 Change
14

1.

Definition of Level

Changes in batch size from beyond a factor of ten times the size of the pivotal
clinical trial/biobatch, where: (1) the equipment used to produce the test batch(es)
are of the same design and operating principles; (2) the batch(es) is manufactured
in full compliance with cGMPs; and (3) the same standard operating procedures
(SOPs) and controls, as well as the same formulation and manufacturing
procedures, are used on the test batch(es) and on the full-scale production
batch(es).
2.

Test Documentation
a.

Chemistry Documentation

Application/compendial product release requirements. Notification of
change and submission of updated executed batch records.
Stability testing: One batch with three months accelerated stability data
reported in changes being effected supplement and long-term stability data
of first production batch reported in annual report.
b.

In Vitro Release Documentation

The in vitro release rate of a lot of the scaled-up batch should be compared
with the in vitro release rate of a recent lot, of comparable age, of the
prechange scale. The median in vitro release rates (as estimated by the
estimated slope from each cell, see section VII) of the lots of the two scales
should be demonstrated to be within acceptable limits, using the testing
procedure described in section VII (IN VITRO RELEASE TEST) below.
c.

In Vivo Bioequivalence Documentation

None.
3.

Filing Documentation

Changes being effected supplement (all information including accelerated stability
data); annual report (long-term stability data).
C.

Level 3 Change

No level 3 changes are anticipated in this category.

15

VI.

MANUFACTURING SITE

Manufacturing site changes consist of changes in location in the site of manufacture,
packaging/filling operations, and/or testing for both company owned and contract manufacturing
facilities and do not include any other level 2 or 3 changes, e.g., changes in scale, manufacturing
(including process and/or equipment), and components or composition. New manufacturing
locations should have had a satisfactory cGMP inspection within the past two years.
A stand-alone analytical testing laboratory site change may be submitted as a changes being
effected supplement if the new facility has a current and satisfactory cGMP compliance profile
with FDA for the type of testing operation in question. The supplement should contain a
commitment to use the same test methods employed in the approved application, written
certification from the testing laboratory stating that they are in conformance with cGMPs, and a
full description of the testing to be performed by the testing lab. If the facility has not received a
satisfactory cGMP inspection for the type of testing involved, a prior approval supplement is
recommended. No stability data are needed for a change in a stand alone analytical facility.

16

A.

Level 1 Change
1.

Definition of Level

Level 1 changes consist of site changes within a single facility where the same
equipment, standard operating procedures (SOPs), environmental conditions (e.g.,
temperature and humidity) and controls, and personnel common to both
manufacturing sites are used, and where no changes are made to the manufacturing
batch records, except for administrative information and the location of the facility.
Common is defined as employees already working on the campus who have
suitable experience with the manufacturing process.
2.

Test Documentation
a.

Chemistry Documentation

None beyond application/compendial product release requirements.
b.

In Vitro Release Documentation

None.
c.

In Vivo Bioequivalence Documentation

None.
3.

Filing Documentation

Annual report.
B.

Level 2 Change
1.

Definition of Level

Level 2 changes consist of site changes within a contiguous campus, or between
facilities in adjacent city blocks, where similar equipment, standard operating
procedures, (SOPs), environmental conditions (e.g., temperature and humidity)
and controls, and personnel common to both manufacturing sites are used, and
where no changes are made to the manufacturing batch records, except for
administrative information and the location of the facility.
2.

Test Documentation

17

a.

Chemistry Documentation

Location of new site and updated executed batch records. None beyond
application/compendial product release requirements.
Stability testing: First production batch on long-term stability reported in
annual report.
b.

In Vitro Release Documentation

None.
c.

In Vivo Bioequivalence Documentation

None.
3.

Filing Documentation

Changes being effected supplement; annual report (long-term stability data).
C.

Level 3 Change
1.

Definition of Level

Level 3 changes consist of a site change in manufacturing site to a different
campus. A different campus is defined as one that is not on the same original
contiguous site or where the facilities are not in adjacent city blocks. To qualify as
a Level 3 change, similar equipment, SOPs, environmental conditions, and controls
should be used in the manufacturing process at the new site. Changes should not
be made to the manufacturing batch records except when consistent with other
level 1 changes. Administrative information, location, and language translation may
be revised as needed.
Any change to a new contract manufacturer also constitutes a level 3 change.
2.

Test Documentation
a.

Chemistry Documentation

Location of new site and updated executed batch records.
Application/compendial product release requirements.

18

Significant body of information available: One batch with three months
accelerated stability data reported in changes being effected supplement
and long-term stability data of first three production batches reported in
annual report.
Significant body of information not available: Three batches with three
months accelerated stability data reported in changes being effected
supplement and long-term stability data of first three production batches
reported in annual report.
b.

In Vitro Release Documentation

The in vitro release rate of a lot of the dosage form from the new
manufacturing site should be compared with the in vitro release rate of a
recent lot of comparable age of the dosage form manufactured at the prior
site. The median in vitro release rates (as estimated by the estimated slope
from each cell, see section VII) of the lots from the two
sites should be
demonstrated
to be within
acceptable
limits, using
the testing
procedure
described in
section VII
(IN VITRO
RELEASE
TEST) below.
c.

In Vivo Bioequivalence Documentation

None.
3.

Filing Documentation

Changes being effected supplement (all information including accelerated stability
data); annual report (long-term stability data).

VII.

IN VITRO RELEASE TEST

In vitro release is one of several standard methods which can be used to characterize performance
characteristics of a finished topical dosage form, i.e., semisolids such as creams, gels, and
19

ointments. Important changes in the characteristics of a drug product formula or the
thermodynamic properties of the drug(s) it contains should show up as a difference in drug
release. Release is theoretically proportional to the square root of time (/t) when the formulation
in question is in control of the release process because the release is from a receding boundary.
In vitro release method for topical dosage forms is based on an open chamber diffusion cell
system such as a Franz cell system, fitted usually with a synthetic membrane. The test product is
placed on the upper side of the membrane in the open donor chamber of the diffusion cell and a
sampling fluid is placed on the other side of the membrane in a receptor cell. Diffusion of drug
from the topical product to and across the membrane is monitored by assay of sequentially
collected samples of the receptor fluid. The in vitro release methodology should be appropriately
validated. Sample collection can be automated.
Aliquots removed from the receptor phase can be analyzed for drug content by high pressure
liquid chromatography (HPLC) or other analytical methodology. A plot of the amount of drug
released per unit area (mcg/cm2) against the square root of time yields a straight line, the slope of
which represents the release rate. This release rate measure is formulation-specific and can be
used to monitor product quality. The release rate of the biobatch or currently manufactured
batch should be compared with the release rate of the product prepared after a change as defined
in this guidance.
One possible in vitro release study design is summarized below. Sponsors are encouraged to
review the reference articles listed here.
Diffusion Cell System:
!

A diffusion cell system with a standard open cap ground glass surface with 15 mm
diameter orifice and total diameter of 25 mm.

Synthetic Membrane:
!

Appropriate inert and commercially available synthetic membranes such as polysulfone,
cellulose acetate/nitrate mixed ester, or Polytetrafluoroethylene 70 Fm membrane of
appropriate size to fit the diffusion cell diameter (e.g., 25 mm in above case).

Receptor Medium:
!

Appropriate receptor medium such as aqueous buffer for water soluble drugs or a hydroalcoholic medium for sparingly water soluble drugs or another medium with proper
justification.

Number of Samples:

20

!

Multiple replicates (six samples are recommended) to determine the release rate (profile)
of the topical dermatological product.

Sample Applications:
!

About 300 mg of the semisolid preparation is placed uniformly on the membrane and kept
occluded to prevent solvent evaporation and compositional changes. This corresponds to
an infinite dose condition.

Sampling Time:
!

Multiple sampling times (at least 5 times) over an appropriate time period to generate an
adequate release profile and to determine the drug release rate (a 6-hour study period with
not less than five samples, i.e., at 30 minutes, 1, 2, 4 and 6 hours) are suggested. The
sampling times may have to be varied depending on the formulation. An aliquot of the
receptor phase is removed at each sampling interval and replaced with fresh aliquot, so
that the lower surface of the membrane remains in contact with the receptor phase over
the experimental time period.

Sample Analysis:
!

Appropriate validated specific and sensitive analytical procedure should be used to analyze
the samples and to determine the drug concentration and the amount of drug released.

In Vitro Release Rate:
!

A plot of the amount of drug released per unit membrane area (mcg/cm2) versus square
root of time should yield a straight line. The slope of the line (regression) represents the
release rate of the product. An X intercept typically corresponding to a small fraction of
an hour is a normal characteristic of such plots.

Design of the Rate (Profile) Comparison Study:
!

The typical in vitro release testing apparatus has six cells. For each run of the apparatus,
the two products being compared should be assigned to the six cells as follows:

±
T
±
R

±
R
±
T

±
T
±
R

or

21

±
R
±
T

±
T
±
R

±
R
±
T

where T represents the Postchange Lot (Test product) and R represents the Prechange
Lot (Reference product). This approach of including both products in each run of the in
vitro apparatus will help ensure an unbiased comparison in the event of a systematic
difference between runs.
!

The choice of the assignment of products to cells (i.e., whether the prechange lot or the
postchange lot is assigned to the “upper left corner cell” of the apparatus) may either be
made systematically (i.e., alternate the pattern for each successive run) or randomly (i.e.,
flip a coin or use some other random mechanism).

!

For the case of a nonstandard apparatus, with other than six cells, the principle of
including both the prechange lot and the postchange lot in the same run should still be
used. If the apparatus has only a single cell, the runs on the prechange and postchange
lots should be intermixed, rather than obtaining all observations on one product followed
by all observations on the other product.

Details of the In Vitro Release Comparison Test
!

The in vitro release comparison should be carried out as a two-stage test.
At the first stage, two runs of the (six cells) in vitro apparatus should be carried out,
yielding six slopes (estimated in vitro release rates) for the prechange lot (R) and six
slopes for the postchange lot (T). A 90% confidence interval (to be described below) for
the ratio of the median in vitro release rate (in the population) for the postchange lot over
the median in vitro release rate (in the population) for the prechange lot should be
computed, expressed in percentage terms. If, at the first stage, this 90% confidence
interval falls within the limits of 75% to 133.33%, no further in vitro testing is necessary.
If the test is not passed at the first stage, 4 additional runs of the (six cells) in vitro
apparatus should be carried out, yielding 12 additional slopes for each product, or 18 in all
(including the first-stage results). The 90% confidence interval (to be described below)
should be computed using all 18 slopes for each product, including the first-stage results.
At the second stage, this 90% confidence interval should fall within the limits of 75% to
133.33%.

Computation of Confidence Interval - an Example:

22

!

Because outliers are expected to occur on occasion with this testing (for example, due to
an air bubble between the product sample and the membrane), a nonparametric

method is proposed, whose performance tends to be resistant to the presence of outliers.
The computations are illustrated in the following example:
Suppose that the slope data obtained at the first stage are as follows:
Postchange
Lot (T)
1.3390

Prechange
Lot (R)
1.1331

1.3496

1.1842

1.4946

1.0824

1.4668

1.3049

1.1911

1.0410

1.2210

1.2419

The first step in the computation of the confidence interval is to form the 36 (= 6 x 6)
individual T/R ratios. This is illustrated in the following table, where the prechange lot
slopes (R) are listed across the top of the table, the postchange lot slopes (T) are listed
down the left margin of the table, and the individual T/R ratios are the entries in the body
of the table:
1.1331

1.1842

1.0824

1.3049

1.0410

1.2419

1.3390

1.1817

1.1307

1.2371

1.0261

1.2863

1.0782

1.3496

1.1911

1.1397

1.2469

1.0343

1.2964

1.0867

1.4946

1.3190

1.2621

1.3808

1.1454

1.4357

1.2035

1.4668

1.2945

1.2386

1.3551

1.1241

1.4090

1.1811

1.1911

1.0512

1.0058

1.1004

0.9128

1.1442

0.9591

1.2210

1.0776

1.0311

1.1280

0.9357

1.1729

0.9832

The second step in the computation of the confidence interval is to order these 36
individual T/R ratios from lowest to highest:
0.9128 0.9357 0.9591 0.9832 1.0058 1.0261 1.0311 1.0343 . . . 1.2863 1.2945
23

1.2964 1.3190 1.3551 1.3808 1.4090 1.4357.
In the third step, the eighth and twenty-ninth ordered individual ratios are the lower and
upper limits, respectively, of the 90% confidence interval for the ratio of the median in
vitro release rate (slope) for T over the median in vitro release rate for R. In the example,
this confidence interval is 1.0343 to 1.2863, or in percentage terms,
103.43% to 128.63%.
Because this confidence interval falls within the limits of 75% to 133.33%, the product
passes at the first stage.
If the product had not passed at the first stage, an additional 4 runs would have been
carried out, yielding 12 additional slopes per lot, for a total of 18 slopes per lot altogether
(including the first-stage slopes).
All 324 ( = 18 x 18) individual T/R ratios would be obtained, and these would be ranked
from lowest to highest. It should be evident that even the computations at the first stage
would be tedious to do by hand, and doing the computations at the second stage by hand
is infeasible. A computer should be used.
At the second stage, the 110th and the 215th ordered individual ratios are the lower and
upper limits, respectively, of the 90% confidence interval for the ratio of the median in
vitro release rate (slope) for T over the median in vitro release rate for R. If this
confidence interval falls within the limits of 75% to 133.33%, the product passes the test
at the second stage.
Further Remarks on the In Vitro Release Comparison Test
!

The statistical test described above is based on a standard confidence interval procedure
related to the Wilcoxon Rank Sum/Mann-Whitney rank test, applied to the log slopes.
References to this confidence interval procedure include:
Conover, W.J., Practical Nonparametric Statistics (Second Edition), John Wiley & Sons,
page 223ff, 1980.
Hollander, M. and D.A.Wolfe, Nonparametric Statistical Methods, John Wiley & Sons,
page 78ff, 1973.
However, as was seen in the example, it is not necessary to actually compute logs in order
to carry out the test.

!

The example illustrates the case of full data, i.e., where there are 6 slopes per lot at the
24

first stage and, if the second stage is necessary, 18 slopes per lot at the second stage. If
slopes are missing, the computations will need to be modified. For example, if a single
slope were missing from one of the lots (it does not matter if it is the prechange lot or the
postchange lot) at the first stage, there would only be 30 (= 5 x 6) individual T/R ratios,
and the limits of the 90% confidence interval would no longer be the eighth and twentyninth ordered individual T/R ratio, but rather would be the sixth and twenty-fifth ordered
individual T/R ratio. If data are missing at either stage of the test, the correct computation
should be determined either by reference to a statistical text or consultant, or by
consultation with CDER staff.
!

The statistical procedure as described above does not take the block structure of the test
(i.e., the fact that data are obtained in runs of six slopes at a time, rather than all at once)
into account. This is justified by the following:
1. In vitro release data available to the Center at this time show no evidence of an
important run-to-run effect.
2. The proposed experimental design, in which both products are included in each
run, will help to ensure unbiasedness if a run-to-run effect should occur.

VIII. IN VIVO BIOEQUIVALENCE STUDIES
The design of in vivo bioequivalence studies for semisolid dosage forms varies depending on the
pharmacological activity of the drug and dosage form. A brief general discussion of such tests
follows.
Objective:
To document the bioequivalence of the drug product for which the manufacture has been
changed, as defined in this guidance, compared to the drug product manufactured prior to the
change or compared to the reference listed drug (RLD).
Design:
The study design is dependent on the nature of the active drug. The bioequivalence study can be
a comparative skin blanching study as in glucocorticoids (FDA, Topical Dermatological
Corticosteroids: In Vivo Bioequivalence, June 2, 1995.) or a comparative clinical trial or any
other appropriate validated bioequivalence study (e.g., dermatopharmacokinetic study) for the
topical dermatological drug product.
Analytical Method:
The assay methodology selected should ensure specificity, accuracy, interday and intraday
precision, linearity of standard curves, and adequate sensitivity, recovery, and stability of the
samples under the storage and handling conditions associated with the analytical method.

25

GLOSSARY OF TERMS3

Approved Target Composition: The components and amount of each ingredient for a drug
product used in an approved pivotal clinical study or bioequivalence study.
Batch: A specific quantity of a drug or other material produced according to a single
manufacturing order during the same cycle of manufacture and intended to have uniform character
and quality, within specified limits. (21 CFR 210.3(b)(2)).
Contiguous Campus: Contiguous or unbroken site or a set of buildings in adjacent city blocks.
Creams/Lotions: Semisolid emulsions that contain fully dissolved or suspended drug substances
for external application. Lotions are generally of lower viscosity.
Diluent: A vehicle in a pharmaceutical formulation commonly used for making up volume and/or
weight (e.g., water, paraffin base).
Drug Product: A drug product is a finished dosage form (e.g., cream, gel, or ointment) in its
marketed package. It also can be a finished dosage form (e.g., tablet, capsule, or solution) that
contains a drug substance, generally, but not necessarily, in association with one or more other
ingredients (21 CFR 314.3(b)).
Drug Release: The disassociation of a drug from its formulation thereby allowing the drug to be
distributed into the skin or be absorbed into the body where it may exert its pharmacological
effect.
Drug Substance: An active ingredient that is intended to furnish pharmacological activity or
other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of a disease, or to
affect the structure or any function of the human body, but does not include intermediates used in
the synthesis of such ingredient (21 CFR 314.3(b)).
Emulsion: Emulsions are two phase systems in which an immiscible liquid (dispersed phase) is
dispersed throughout another liquid (continuous phase or external phase) as small droplets.
Where oil is the dispersed phase and an aqueous solution is the continuous phase, the system is
designated as an oil-in-water emulsion. Conversely, where water or an aqueous solution is the
dispersed phase and oil or oleaginous material is the continuous phase, the system is designated as
a water-in-oil emulsion. Emulsions are stabilized by emulsifying agents that prevent coalescence,
the merging of small droplets into larger droplets and, ultimately, into a single separated phase.
Emulsifying agents (surfactants) do this by concentration in the interface between the droplet and
external phase and by providing a physical barrier around the particle to coalesce. Surfactants
also reduce the interfacial tension between the phases, thus increasing the ease of emulsification
upon mixing. Emulsifying agents substantially prevent or delay the time needed for emulsion

3

See Workshop Report: Scale-up of liquid and semi-solids disperse systems. G. A. Van Buskirk, V. P. Shah, D.
Adair, et al. Pharmaceutical Research, 11, 1216-1220, 1994,

26

droplets to coalesce. Emulsification is the act of forming an emulsion. Emulsification can involve
the incorporation of a liquid within another liquid to form an emulsion or a gas in a liquid to form
a foam.
Formulation: A listing of the ingredients and quantitative composition of the dosage form.
Gel: A semisolid system in which a liquid phase is constrained within a three dimensional, crosslinked matrix. The drug substance may be either dissolved or suspended within the liquid phase.
Homogenization: A method of atomization and thereby emulsification of one liquid in another in
which the liquids are pressed between a finely ground valve and seat under high pressure (e.g., up
to 5,000 psi).
Internal phase: The internal phase or the dispersed phase of an emulsion comprises the droplets
that are found in the emulsion.
In Vitro Release Rate: Rate of release of the active drug from its formulation, generally
expressed as amount/unit area/time0.5.
Ointment: An unctuous semisolid for topical application. Typical ointments are based on
petrolatum. An ointment does not contain sufficient water to separate into a second phase at
room temperature. Water soluble ointments may be formulated with polyethylene glycol.
Pilot Scale Batch: The manufacture of drug product by a procedure fully representative of and
simulating that intended to be used for full manufacturing scale.
Preservative: An agent that prevents or inhibits microbial growth in a formulation to which it
has been added.
Process: A series of operations, actions and controls used to manufacture a drug product.
Scale-up: The process of increasing the batch size.
Scale-down: The process of decreasing the batch size.
Shear: A strain resulting from applied forces that cause or tend to cause contiguous parts of a
body to slide relative to one another in direction parallel to their plane of contact. In
emulsification and suspensions, the strain produced upon passing a system through a homogenizer
or other milling device.
!

Low shear: Processing in which the strain produced through mixing and/or emulsifying
shear is modest.

27

!

High shear: Forceful processes which, at point of mixing or emulsification place a great
strain on the product. Homogenization, by its very nature, is a high shear process which
leads to a small and relatively uniform emulsion droplet size. Depending on their
operation, mills and mixers are categorized as either high shear or low shear devices.

Significant Body of Information: A significant body of information on the stability of the
product is likely to exist after five years of commercial experience for new molecular entities , or
three years of commercial experience for new dosage forms.
Structure Forming Excipient: An excipient which participates in the formation of the
structural matrix which gives an ointment, cream or gel etc., its semisolid character. Examples
are gel forming polymers, petrolatum, certain colloidal inorganic solids (e.g., bentonite), waxy
solids (e.g., cetyl alcohol, stearic acid), and emulsifiers used in creams.
Strength: Strength is the concentration of the drug substance (for example, weight/weight,
weight/volume, or unit dose/volume basis), and/or the potency, that is, the therapeutic activity of
the drug product as indicated by appropriate laboratory tests or by adequately developed and
controlled clinical data (expressed, for example, in terms of units by reference to a standard) (21
CFR 210.3(b)(16)). For semisolid dosage forms the strength is usually stated as a weight/weight
(w/w) or weight/volume (w/v) percentage.
Suspending agent: An excipient added to a suspension to control the rate of sedimentation of
the active ingredients.
Technical grade: Technical grades of excipients differ in their specifications and intended use.
Technical grades may differ in: (1) specifications and/or functionality, (2) impurities, and
(3) impurity profiles.
Validation: A procedure to establish documented evidence that provides a high degree of
assurance that a specific process or test will consistently produce a product or test outcome
meeting its predetermined specifications and quality attributes. A validated manufacturing
process or test is one that has been proven to do what it purports or is represented to do. The
proof of process validation is obtained through collection and evaluation of data, preferably
beginning with the process development phase and continuing through the production phase.
Process validation necessarily includes process qualification (the qualification of materials,
equipment, systems, building, personnel), but it also includes the control of the entire processes
for repeated batches or runs.

28

REFERENCES

1.

Shah, V. P., J. Elkins, J. Hanus, C. Noorizadeh, and J. P. Skelly,"In Vitro Release of
Hydrocortisone from Topical Preparations and Automated Procedure," Pharmaceutical
Research, 8:55-59, 1991.

2.

Shah, V. P., J. S. Elkins, and R. L. Williams, "In Vitro Drug Release Measurement of
Topical Glucocorticoid Creams," Pharmacopeial Forum, 19, 5048-5059, 1993.

3.

Corbo, M., T. W. Schultz, G. K. Wong, and G. A. Van Buskirk, "Development and
Validation of In Vitro Release Testing Methods for Semisolid Formulations,"
Pharmaceutical Technology 17(9):112-128, 1993.

4.

Li, J. B. and P. C. Rahn, "Automated Dissolution Testing of Topical Drug Formulations
Using Franz Cells and HPLC Analysis," Pharmaceutical Technology 17(7):44-52, 1993.

5.

Shah, V. P. and J. S. Elkins, "In Vitro Release from Corticosteroid Ointments,"
Journal of Pharmaceutical Sciences, 84:1139-1140, 1995.

6.

Zatz, J.L., "Drug Release from Semisolids: Effect of Membrane Permeability on
Sensitivity to Product Parameters," Pharmaceutical Research 2:787-789, 1995.

29

Table 1 - Components and Composition
Level
1

2

Change

Test Documentation

C

Deletion or partial deletion of color,
fragrance, or flavor

C

Application/compendial product
release requirements

C

Up to 5% change in approved amount of
an excipient with the total additive effect
of all excipient changes #5%

C

Stability: First production batch on
long-term stability

C

Supplier of structure forming excipient
that is primarily a single chemical entity
(purity $ 95%) or change in supplier or
technical grade of any other excipient

C

Change of >5% and #10% of approved
amount of an excipient with the total
additive effect of all excipient changes
#10%

C

Application/compendial product
release requirements

C

Executed batch records

C

Change in supplier of a structure forming
excipient (not covered under level 1)

C

C

Change in technical grade of a structure
forming excipient

Stability: One batch with three
months accelerated stability data and
first production batch on long-term
stability

C

In vitro release test

C

Change in particle size distribution of the
drug substance, if the drug is in
suspension

30

Filing Documentation
C

Annual report (all information
including long-term stability data)

C

Changes being effected supplement
(all information including accelerated
stability data)

C

Annual report (long-term stability
data)

Table 1 - Components and Composition (cont.)
Level
3

Change
C

Any qualitative and quantitative changes
in an excipient beyond the ranges noted
in level 2 change

C

Change in crystalline form of the drug
substance, if the drug is in suspension

Test Documentation
C

Application/compendial product
release requirements

C

Executed batch records

C

Stability:
Significant body of information
available: One batch with three
months accelerated stability data and
first three production batches on longterm stability.
Significant body of information not
available: Three batches with three
months accelerated stability data and
first three production batches on longterm stability

C

In vitro release test (encouraged only)

In vivo bioequivalence test

Note: See text for additional information.

31

Filing Documentation
C

Prior approval supplement (all
information including accelerated
stability data)

C

Annual report (long-term stability
data)

Table 2 - Components and Composition - Preservative
Level
1

2

3

Change
C

C

C

Quantitatively 10% or less change in
the approved amount of preservative

Quantitatively greater than 10% and
up to 20% change in the approved
amount of preservative

Quantitatively greater than 20%
change in the approved amount of
preservative (including deletion) or
use of a different preservative

Test Documentation
C

Application/compendial product release
requirements

C

Preservative effectiveness test at lowest
specified preservative level

C

Application/compendial product release
requirements

C

Preservative effectiveness test at lowest
specified preservative level

C

Application/compendial product release
requirements

C

Executed batch records

C

Preservative effectiveness test at lowest
specified preservative level

C

For new preservative: analytical method
for identification and assay; validation
studies showing new preservative does not
interfere with application/compendial tests

C

Stability: One batch with three months
accelerated stability data and first
production batch on long-term stability

Note: See text for additional information.

32

Filing Documentation
C

Annual report

C

Changes being effected
supplement

C

Prior approval supplement (all
information including
accelerated stability data)

C

Annual report (long-term
stability data)

Table 3 - Manufacturing Equipment
Level
1

2

Change
C

Nonautomated or nonmechanical
equipment to automated or
mechanical equipment to transfer
ingredients

Test Documentation
C

Application/compendial product
release requirements

C

Stability: First production batch on
long-term stability

C

Alternative equipment of same design
and operating principles

C

Equipment of a different design or
different operating principles

C

Application/compendial product
release requirements

C

Type of mixing equipment: e.g., high
shear to low shear or vice versa.

C

Executed batch record

C

Stability:
Significant body of information
available: One batch with three months
accelerated stability data and first
production batch on long-term
stability.
Significant body of information not
available: Three batches with three
months accelerated stability data and
first three production batches on longterm stability.

C

In vitro release test

Note: See text for additional information.

33

Filing Documentation
C

Annual report (all information
including long-term stability)

C

Changes being effected supplement
(all information including
accelerated stability data)

C

Annual report (long-term stability
data)

Table 4 - Manufacturing Process
Level
1

2

Change

Test Documentation

Filing Documentation

C

Application/compendial product release
requirements

C

Annual report

C

Changes being effected supplement
(all information including accelerated
stability data)

C

Annual report (long-term stability
data)

C

Process changes within approved
applications ranges

C

Order of addition of components
(excluding actives)

C

Process changes outside approved
application ranges

C

Application/compendial product release
requirements

C

Process of combining phases

C

Executed batch record

C

Stability:
Significant body of information
available: One batch with three months
accelerated stability data and first
production batch on long-term stability.
Significant body of information not
available: Three batches with three
months accelerated stability data and
first three production batches on longterm stability.

C

In vitro release test

Note: See text for additional information.

34

Table 5 - Batch Size
Level
1

2

Change
C

C

Change in batch size up to and
including ten times the size of the
pivotal clinical trial/biobatch

Change in batch size beyond a factor
of ten times the size of the pivotal
clinical trial/biobatch

Test Documentation
C

Application/compendial product release
requirements

C

Executed batch records

C

Stability: First production batch on
long-term stability

C

Application/compendial product release
requirements

C

Executed batch records

C

Stability: One batch with three months
accelerated stability data and first
production batch on long-term stability
In vitro release test

C
Note: See text for additional information.

35

Filing Documentation
C

Annual report (all information
including long-term stability data)

C

Changes being effected supplement
(all information including
accelerated stability data)

C

Annual report (long-term stability
data)

Table 6 - Manufacturing Site Change
Level

Change

Test Documentation

Filing Documentation

1

C

Within a single facility

C

Application/compendial product release
requirements

C

Annual report

2

C

Within the same contiguous
campus or between facilities in
adjacent city blocks

C

Application/compendial product release
requirements

C

Changes being effected supplement

C
C

Executed batch records

Annual report (long-term stability
data)

C

Location of new site

C

Stability: First production batch on longterm stability

C

Application/compendial product release
requirements

C

Changes being effected supplement
(all information including accelerated
stability data)

C

Executed batch record
C

C

Location of new site

Annual report (long-term stability
data)

C

Stability

3

C

Different campus

C

Contract manufacturer

Significant body of information available:
One batch with three months accelerated
stability data and first three production
batches on long-term stability.
Significant body of information not
available: Three batches with three months
accelerated stability data and first three
production batches on long-term stability.
C

In vitro release test

Note: See text for additional information.

36

SEMISOLIDS

TECHNICAL TRANSFER

CHAPTER 16

TTD

Technical Transfer
Documentation-Pharmaceutical

T

he successful development and fullscale manufacture of a newly
developed generic drug represents a
difficult and complex process of
integrating the new technology into the
existing
production
and
control
infrastructure. Many steps must be
completed before the company can
successfully manufacture the product in
compliance with the specifications listed
in the application and GMP regulations.
Organizing a well structured TTD is one of
these steps.

TTDs should be
comprehensive
and well
structured
Moving
the
Technical
Transfer
Documentation from the development or
researched-based unit to manufacture will
enable production and quality control
personnel to get to know the ins and outs
of the newly developed drug product.
Such dossiers are referred to as the
‘TTDs’ and consist of :

ü Material and product specifications
ü pharmaceutical manufacturing data
ü analytical development methods
ü microbiological
results

procedures

and

ü stability profile, results and full
stability reports
Handbook of Pharmaceutical

This

section
deals
with
the
Pharmaceutical TTD content. Data reports
and results that are in the domain of the
Pharmaceutical development department.
The Pharmaceutical TTD file contains all
necessary process methods, process
qualification,
product
specifications,
technical data, reports, tabulations and
summaries based on the Pharmaceutical
development work regarding the generic
drug development from the preformulation to process qualification stage.
This data is required for manufacturing
and control of the pivotal submission
batch and the initial three full size
validation batches produced at the
commercial manufacturing site facility.

Really g o o d
TTDs will
get your product
to the market
sooner
TTD programs of excellence are more
than just transferring data. They include
an evaluation of the product development
documentation (Development Report’),
the proposed manufacturing process, the
in-process specifications, and the quality
systems used to control the product.
A guideline SOP is given.
W ell managed TTD programs are
essential to firms engaged in the
development of new products which
require regulatory approval. A structured
on-time program will improve efficiency
and effectiveness in moving the product
from development to product launch. 3

Chapter: 16.1
1

Generic Development

SEMI SOLIDS

T E C H N I C A L

T R A N S F E R

CHAPTER 16

TTD

Technical Transfer
Documentation
‘the time has come the researcher said to speak of many things
- of pivotal and protocols and to validated cleanings...’

Technical Transfer Documentation
he purpose of the TTD is to
transfer all technical data from the
R&D or generic development
sections
to
the
production,
engineering, laboratory quality control,
quality assurance and administration
personnel involved with producing the
newly developed generic drug.

T

Which Data?
The data is obtained from two preexisting sources:- the audited ANDA
Chemistry, Manufacturing and Control
section (CMC) and the Product
Development Report.
The efficient transfer of technology
from the development environment to
the
full
scale
commercial
manufacturing plant is a complex
process. The TTD documents support
this overall manufacturing and control
process. The entire spectrum initiating
from the purchasing of raw materials
from approved suppliers to the final full
size validation protocol should be
covered
by
the
transfer
documentation.
Rationale
Product development reports and
technology transfer documentation
provide final CMC technology and the
rationale of the component and
process choices made during the
product development.

Handbook of Pharmaceutical

Sect: 16.2
16.2

Structure
The technical information should be
structured in a well developed and
organized dossier containing all the
product
and
process
specific
documentation and final specifications.
The documentation should be written
in an easily understood manner and
similarly to SOPs contain a ‘read and
understood’ paragraph or certification
section.

Production and
control personnel
need to know
the new process
Technical Personnel
Production and control personnel at
the selected manufacturing site will
ensure that the technical data has
been clearly absorbed and understood
prior to commencement of full scale
commercial
or
validation
lot
manufacture.
From the inspection point of view, the
TTD file is the basic documentation
that will be needed to support the
pending PAI agency program. Since
the FDA requires that the firm be
prepared for the PAI program
(inspection-audit) at the time of file
submission to agency headquarters,

Generic Development

SEMI SOLIDS

T E C H N I C A L

it is essential to transfer the TTD to
production well before the pending onsite agency inspection.

The Pre-filing Audit.
Furthermore the firms should fully
audit all raw data and control
documentation before filing the ANDA
to allow for corrections and possible
errors that may be present in the
pharmaceutical, microbiological and
analytical raw data. This essential
pre-filing audit will be an effective
measure of the sites ability and
readiness to manufacture the newly
developed drug product as well as the
firms readiness to deal with the FDA
during the forthcoming product-specific
and GMP PA Inspection.
Firms may continue the review and
audit process after filing the ANDA to
evaluate and address the current GMP
profile specific to the filed process.
Improvements or upgrading of the
firms general GMP profile should not
impact on or alter the filed data.
The TTD process will allow the
manufacturing and control personnel
at the commercial site to be fully
updated and familiar with the CMC
section portions of the TTD package.
Since the TTD has been dove-tailed
and integrated with the submitted
ANDA application containing product
and process specifications - site
personnel will be able to manufacture
and control the initial three validation
lots
and
subsequent
routine
commercial production lots without
disparity to the filed data. This is a
critical point pertaining to current FDA
thinking and logic.

The Development
Report is
part of the
Transfer Process
Handbook of Pharmaceutical

Sect: 16.3
16.3

T R A N S F E R

CHAPTER 16

Production Know-how
The pivotal batch ends with the Pivotal
Batch Report and this report finalizes
the Technical Transfer Documentation
process. There should be no further
scale-up processing after the pivotal
lot has been manufacture other than
possible fine-tuning adjustments to the
scaled-up process. No new process or
product
specification
may
be
introduced into the documentation
after the demonstration of the pivotal
batch. In generic drug development
the pivotal batch is usually the batch
on which the bioequivalence study
against a selected reference drug
(RLD) is performed.
It is this batch that is filed in the ANDA
submission. When a biostudy has
been performed, the pivotal batch may
also be referred to as ‘the Biobatch’.

The Development Report
The Development Report is a separate
report containing all development
work, supporting information and
collated data on the newly developed
product.
The preparation of a
development report is simply good
development practice and not an
agency CFR or FDA requirement.
The Development Report and the
CMC together generally contain all
necessary
documentation
for
a
complete
technical
transfer
of
information
to
the
commercial
manufacturing and control sectors.

Development
Pharmaceutical
and
Analytical
Data
is Transferred
to the factory
floor
Generic Development

SEMI SOLIDS

T E C H N I C A L

TTD Contents

T

echnical Transfer Documentation
consists of five principle sections
targeting 10 key departments:

∗ Specifications
for
purchasing
department
(Active
material
‘Approved
Suppliers’
detailed
specifications).
∗ Manufacturing, engineering and
quality control procedures and
specifications of the generic drug
product and process.
∗ All analytical methodology and
results including stability protocol
and results.
∗ All microbiological methodology and
results.
∗ The Development Report and ANDA
File and development notes and
graphs.

T R A N S F E R

CHAPTER 16

[Master
Formula;
Instructions;
IPQC,
Product Specifications]

Process
Finished

♦ Engineering Units
[Cleaning validation ; Process
validation; Metrology (calibrationstandards) HVAC System, Air
System; Nitrogen System; Purified
Water System, Water For Injection
System;
Washing
Tunnels;
Autoclave Systems; Oven System;
Freeze Drier Systems; Sanitation
Systems. (Where appropriate).

♦ Quality Control Laboratory
[Validated
analytical
methods;
impurity profiles; stability indicating
test methods for assays, dissolution
and impurities; in-process, release
and check specifications]

♦ Microbiology Laboratory
[Validated
microbial
methods;
microbiological specifications.]

♦ Stability Unit
Operational Departments

[stability protocols; stability results
and
reports;
filed
ANDA
commitments]

All Technical Transfer Documentation
is essentially contained in the ANDA
file and the Development Report.
However the data is rearranged into
specific modules and targeted to the
following departments:

♦ Quality Assurance

♦ Purchasing and Procurement

♦ Regulatory Affairs

[Active
material;
excipients;
container-closures
purchasing
specifications to the 'Approved Raw
Material Suppliers' ].

♦ Artwork and Graphics
[Label; package insert or Outsert;
carton;
blister
strip,
printing
requirements, as specified in the
ANDA submission file]

♦ Manufacturing
Controls

Process

Handbook of Pharmaceutical

and

Sect: 16.4
16.4

[SOPs and checklists; In house and
vendor audits programs and results]

[Letters of Authorization; Approved
Suppliers update commitments etc.]

♦ Archives
[ANDA copy; Development Report;
Process Optimization Report ;
Process Qualification Report; TTD
Reports; Development Notebooks,
Pharmaceutical, Analytical, and
microbiological
Notebooks and
Logs; Analytical HPLC IR UV etc.
graphs and charts].

Generic Development

SEMI SOLIDS

T E C H N I C A L

T R A N S F E R

CHAPTER 16

ØC H E C K L I S T ×
CL # HBGD-03-01YY

TECHNICAL TRANSFER DOCUMENTATION
‘ give the production unit all your experiences
also tell them what not to do ‘

1. The buying department has purchasing specifications for the qYes qNo
procurement of approved actives, excipients and container-closure
systems ?
2. Printing specification and QA approved artwork for product labels, qYes qNo
cartons, package inserts and advertising claims are approved ?
3. The manufacturing formula and master processing instructions for each qYes qNo
commercial batch sizes are approved ?
4. Cleaning validation protocol specific to the active material is complete ?

qYes qNo

5. The validation protocol for the first three consecutive batches is qYes qNo
approved?
6. All new manufacturing equipment has been fully qualified (IQOQ)?

qYes qNo

7. The metrology department has calibrated all equipment recording qYes qNo
units?
8. Plant QC laboratory has evaluated the transferred analytical methods qYes qNo
for system suitability and robustness (ruggedness) ?
qYes qNo

9. Microbiological laboratory has all methods and specifications?
10. Physical QC
specifications?

lab

has

all

container-closure

methods

and qYes qNo

11. All product specific SOPs have been distributed and signed as ‘read qYes qNo
and understood’ by the production operators and supervisors?
12. Stability unit has the ANDA commitment stability protocol (real-time qYes qNo
study) and the validation stability protocol for three validation batches?
13. All vendor DMF deficiencies (and GMP concerns) have been qYes qNo
corrected?
14. The CMC file is compiled in full and signed-off ?

qYes qNo

15. The Product ‘Development Report’ is complete and signed-off ?

qYes qNo

Handbook of Pharmaceutical

Sect: 16.5
16.5

Generic Development

SEMI SOLIDS

T E C H N I C A L

T R A N S F E R

CHAPTER 16

STANDARD OPERATING
PROCEDURES

Page 1 of 1.

CL # HBGD-03-01YY

TECHNICAL TRANSFER DOCUMENTATION
The following Standard Operating Procedures are recommended for a generic
development unit :

Technical Transfer Documentation
P-000-01-01YY

The Pivotal Batch Report

P-000-01-01YY

Preparing The Technical Transfer Documentation

P-000-01-01YY

Checklist for a TTD File.

P-000-01-01YY

Defining the contents of a TTD File - in detail.

Footnote : In-house training must be given to all QC oratory staff, production and
QA sections on specific manufacturing and control aspects of the newly developed
drug as well as SOP training pertaining to the commercial aspects of the generic drug
manufacture

4
[End of Document]

Edition No. :
01
Ed. Status : New

Effective Date :

Handbook of Pharmaceutical

APPROVED
______________ ________________ _____________ _______________
Department
RD
RA
QC / Q A

Sect: 16.6
16.6

Generic Development

SEMI SOLIDS

T E C H N I C A L

T R A N S F E R

CHAPTER 16

STANDARD OPERATING
PROCEDURES
SOP # HBGD-02-03YY

TECHNICAL TRANSFER DOCUMENTATION FOR SEMISOLIDS
Ø PHARMACEUTICAL PART ×
Page: 1 of 3
1.
PURPOSE
The purpose of this Standard Operating Procedure is to establish the overall table of
contents for the preparation of the pharmaceutical part or section of the technical
transfer file for product information transfer to the selected commercial manufacturing
site facility. This SOP is specific for preparations covering semisolids.
2.
RESPONSIBILITY
The Head of Pharmaceutical Development together with the Responsible Researcher
for the Generic Drug Development Project.
3.
FREQUENCY
Each ANDA product formula developed for the US market.
4.

PROCEDURE or SCOPE

[4.1]. The responsible personnel for the product development will prepare the
pharmaceutical section of the technical transfer file (TTD) for process and data
information transfer to the commercial manufacturing site facility.
[4.2]. The Pharmaceutical TTD file will contain all necessary pharmaceutical master
formula, manufacturing methods, validation criteria, product specifications, technical
data, reports, tabulations and summaries based on the pharmaceutical development
work pertaining to all strengths of the generic drug development from the preformulation to process qualification stage.
This data is required for the manufacture and control the pivotal submission batch and
the three initial full size validation batches produced at the commercial manufacturing
site facility.
[4.3]. Each section of the TTD File is presented in a modular form for ease of
updating. Sections are numbered [A] to [K]. The outline of the TTD requirements is
presented in a standard operating procedure format.
[4.4]. The requirements of the Pharmaceutical Technical Transfer documentation will
be part of the Product Development SOP for the specific dosage form. This
documents is based on formulation development for semisolid dosage forms.
[4.5]. An pharmaceutical TTD SOP will be prepared for each separate generic dosage
form under product development. 3

Edition No. : 01
Ed. Status :
New

Effective Date :
DD/MM/YY

Handbook of Pharmaceutical

APPROVED
____________
Department

_____________
R &D

Chapter: 16.7
7

_____________
QC Lab

_______________
QA

Generic Development

SEMI SOLIDS

T E C H N I C A L

T R A N S F E R

CHAPTER 16

STANDARD OPERATING
PROCEDURES
SOP # HBGD-02-03YY

TECHNICAL TRANSFER DOCUMENTATION FOR SEMISOLIDS
Ø PHARMACEUTICAL PART ×
Page: 2 of 3

GUIDELINE TO PHARMACEUTICALTTD REQUIREMENTS

Section [A]. - General Data (Prior to starting pharmaceutical work)
1.0
1.1
1.2
1.3
1.4
1.5

Basis for Submission approved.
Patent Certification statement.
No Process Patent infringement.
Statement no formula infringements.
Comparison - Generic Drug and Reference Listed Drug composition performed.
Environmental Impact Analysis Report.

Section [B]. - Active Ingredient
1.0
1.1
1.2
1.3
1.4
1.5
1.6

Letter of Access from US Applicant authorizing Approved Supplier # 1 and # 2
Letter of Access from Active Supplier(s) authorizing referencing of DMF
LOA notification of "Specification change statement" from Active Supplier/s #1 and #2
Active Ingredient Release Specifications (include particle size, bulk density).
Particle Size Specifications (and range).
Bulk Density Specifications (and range).
Certificates of Analysis of Drug Substance batches over past 12 months (6 copies).

Section [C]. - Non active Ingredients
1.0
1.1
1.2
1.3
1.4
1.5
1.6
1.7

LOA from Approved Suppliers to Applicant (MA Holder).
Raw Material Release Specifications per Ingredient.
Raw Material - Full Certificates of Analysis - per Ingredient - Approved Supplier.
Raw Material - Full Certificates of Analysis - per Ingredient - Alternative Supplier.
Confirmation from Local Raw Material Availability (with C of A.).
Raw Material Data Safety Sheet per Ingredient.
Qualification of each non-active vendor (approval statement)
GMP Certification of each non-active vendor.

Section [D]. - Container Closure System
1.0
1.1
1.2
1.3
1.4

LOA from Approved Suppliers to MA Applicant (Holder).
Statement from Container Manufacturers(s) indicating GMP status of MNF plant
Market Packaging (Container-Liner-Closure) Specifications.
Component Drawing and Specifications of container-liner-closure.
Certificates and Certifications (as per Container-Closure SOP).

Edition No. : 01
Ed. Status :
New

Effective Date :
DD/MM/YY

Handbook of Pharmaceutical

APPROVED
____________
Department

_____________
R &D

Chapter: 16.8
8

_____________
QC Lab

_______________
QA

Generic Development

SEMI SOLIDS

T E C H N I C A L

T R A N S F E R

CHAPTER 16

STANDARD OPERATING
PROCEDURES
SOP # HBGD-02-03YY

TECHNICAL TRANSFER DOCUMENTATION FOR SEMISOLIDS
Ø PHARMACEUTICAL PART ×
Page: 3 of 3.

Section [E]. - Master Formula.
1.0
1.1

Master Formula and quantities (in mg per gram and per 100 000 units)
Master Formula and quantities for each DOSAGE strength.

Section [F]. - Manufacturing Procedure.
1.0
1.1
1.2
1.3
1.4
1.5
1.6

Detailed Manufacturing Procedures / method
Master Blank Batch Records for each batch size and strength
Safety Procedures and special precautions / remarks
Proposed Cleaning Validation Protocol
Proposed Process Validation Protocol
Manufacturing Standard Operating Procedures specific to new product
Reprocessing Statement.

Section [G]. - In-process Controls.
1.0
1.1
1.2
1.3

In-process Manufacturing Specifications
Frequency of In-process Test Procedures for plant QC
In-process Test Procedures for plant QC
Sampling protocol for in-process and finished product.

Section [H].- Finished Product Controls.
1.0

Finished Product Release Specifications.

Section [I]. - Stability.
1.0
1.1
1.3
1.4
1.5

Stability Check Specifications for the proposed shelf-life.
Stability Protocol.
Stability Reports and Tabulations on Development Batches.
Statement on proposed expiration date for production labeling
Post Approval Stability Protocol (continuation of MA batches).

Section [J]. - Audit and Review.
1.0
1.1
1.2

SOP Index and Checklists (read and understood - signed and dated)
Manufacturing and Control Audit Checklists (signed and dated)
Pharmaceutical Development Completion Form. (signed and dated).

Section [K] - Development Report.
1.0

Pharmaceutical Development Report.

Edition No. : 01
Ed. Status :
New

Effective Date :
DD/MM/YY

Handbook of Pharmaceutical

3

APPROVED
____________
Department

_____________
R &D

Chapter: 16.9
9

_____________
QC Lab

_______________
QA

Generic Development

SEMI SOLIDS

T E C H N I C A L

SOP #HBGD-03-01YY

T R A N S F E R

CHAPTER 16

STANDARD OPERATING
PROCEDURES

CONTENTS OF THE TECHNICAL TRANSFER DOCUMENTATION
ANALYTICAL PART
Page: 1 of 3
1.

PURPOSE
he purpose of this Standard Operating Procedure is to establish the overall
table of contents for the preparation of the analytical part or section of the
technical transfer file for product information transfer to the selected commercial
manufacturing site facility. This SOP is specific for ANDA preparations of semisolid
dosage forms.

T
2.

RESPONSIBILITY

The Head of Analytical Development together with the Responsible Researcher for
the Generic Drug Development Project.

3.

FREQUENCY

Each ANDA product formula under development intended for the US market.

4.

PROCEDURE or SCOPE

[4.1]. The responsible personnel for the product development will prepare the
analytical section of the technical transfer file (TTD) for method and data information
transfer to the commercial manufacturing site facility.
[4.2]. The Analytical TTD file will contain all necessary analytical methods, method
validations, product specifications, technical data, reports, tabulations and
summaries based on the analytical development work pertaining to the generic drug
development from the pre-formulation to process qualification stage. May include
pivotal and scale-up date when available.
This data is required for testing and analyzing the pivotal submission batch and the
three initial full size validation batches produced at the commercial manufacturing
site facility.
[4.3]. Each section of the TTD File is presented in a modular form for ease of
updating. Sections are numbered [A] to [G]. The outline of the TTD requirements is
presented in the standard operating procedure format.
[4.4]. The requirements of the Analytical Technical Transfer documentation will be
part of the Product Development SOP for the specific dosage form. This document
is based on a Q & Q formulation development for semisolid dosage forms.
[4.5]. An analytical TTD SOP will be prepared for each separate generic dosage form
under product development.
4

Edition No. 02
Ed. Status : 03

Effective Date :
DD/MM/YY

Handbook of Pharmaceutical

APPROVED
____________
Department

_____________ ______________
R &D
QC Lab

Chapter: 16.10
10

______________
QA

Generic Development

SEMI SOLIDS

T E C H N I C A L

SOP #HBGD-03-01YY

T R A N S F E R

CHAPTER 16

STANDARD OPERATING
PROCEDURES

CONTENTS OF THE TECHNICAL TRANSFER DOCUMENTATION
ANALYTICAL PART
Page: 2 of 3

GUIDELINE TO ANALYTICAL TTD REQUIREMENTS

Section [A]. - General ANDA Data (Prior to starting analytical work)
1.0
1.1
1.2
1.3

Basis for MA Submission approved.
Patent Certification clear and any exclusivity statement clear
Comparison - Generic Drug and Reference Listed Drug composition.
Innovator's Insert obtained - latest edition.

Section [B]. - Active Ingredient
1.0 Letter of Authorization from US Applicant authorizing Approved Supplier # 1
and # 2
1.1 Letter of Authorization from Active Supplier(s) authorizing referencing of DMF
1.2 LOA notification of "Specification change statement" from Active Supplier(s) #1
& #2.
1.3 Active Ingredient Release Specifications (include particle size, [bulk density].)
1.4 Pharmacopoeia Assay method (if, BP/Ph. Eur./USP).
1.5 Validated Assay Method and S-I Study Results - (if assay is not compendial).
1.6 Limit Tests on Impurities and Method Validation (when required).
1.7 Summary Report in Impurity Profile of active substance.
1.8 Certificates of Analysis of Drug Substance batches over past 12 months (6
copies).

Section [C]. - Non active Ingredients
1.0 LOA. from US Applicant authorizing selected US Approved Suppliers.
1.1 Raw Material Release Specifications per Ingredient.
1.2 Raw Material - Full Certificates of Analysis - per Ingredient - Approved
Supplier.
1.3 Raw Material - Full Certificates of Analysis - per Ingredient - Alternative
Supplier.
1.4 Confirmation on Local Raw Material Availability (with C. of A.).
1.5 Raw Material Test Methods (Compendial and Non-compendial) per Ingredient.

Section [D]. - Container Closure System
1.0

1.1
1.2
1.3
1.4
1.5

Letter of Authorization (LOA) for all component parts
LOA from Container Manufacturers(s) authorizing referencing of DMF to MA
Market Packaging (Container-Liner-Closure) Specifications.
Side-by Side Comparison of Applicant and RLD Component Specifications.
Component Drawing and Specifications of container-liner-closure.
Certifications (as per Container-Closure SOP)

Edition No. 02
Ed. Status : 03

Effective Date :
DD/MM/YY

Handbook of Pharmaceutical

APPROVED
____________
Department

_____________ ______________
R &D
QC Lab

Chapter: 16.11
11

______________
QA

Generic Development

SEMI SOLIDS

T E C H N I C A L

SOP #HBGD-03-01YY

T R A N S F E R

CHAPTER 16

STANDARD OPERATING
PROCEDURES

CONTENTS OF THE TECHNICAL TRANSFER DOCUMENTATION
ANALYTICAL PART
Page: 3 of 3.

Section [E]. - In-process Controls.
1.0
1.1
1.2
1.3

In-process Control Specifications (Bulk)
In-process Test Procedures
Results of In-process Control tests (including print-outs)
Assay method statement - i.e. same as Release Assay.

Section [F]. - Finished Product Controls.
1.0
1.1
1.2
1.3
1.4
1.5
1.6

Finished Product Release Specifications
Finished Product Test Methods
Pharmacopeial Assay method (if compendial)
Validated Assay (if not BP / Ph. Eur / USP) - same as Stability Assay.
Limit Tests on Impurities and Method Validation (where required).
Certificate of Analysis of Applicant's Product.
Certificate of Analysis of Innovator's / RLD Drug.

Section [G]. - Stability.
1.0
1.1
1.2
1.3
1.4
1.5
1.6
1.7
1.8
1.9
2.0
2.1

Stability Check Specifications for the proposed shelf-life.
Stability Protocol.
Stability Summary of Applicant's Generic Product.
Stability Summary of Innovator's / RLD Drug. (2 or 3 lot #’s)
Stability Reports and Tabulations on Drug Substance from Approved Supplier.
Stability Reports and Tabulations of Applicant's Product.
Stability Reports and Tabulations of Innovator's / RLD Drug.
Statement on proposed expiration date
Method for Drug Substance Assay.
Method for Drug Product Assay.
Assay method validation
Stability-Indicating Test Results

Section [H]. - Audit and Review.
1.0
1.1
1.2
1.3

Vendor Compliance Audit - Approved Active Supplier/s (On-site, Mail or Fax Audit).
SOP Index and Checklists (read and understood - signed and dated)
Audit Checklists (signed and dated)
Project Completion Form. (signed and dated) 3

Edition No. 02
Ed. Status : 03

Effective Date :
DD/MM/YY

Handbook of Pharmaceutical

APPROVED
____________
Department

_____________ ______________
R &D
QC Lab

Chapter: 16.12
12

______________
QA

Generic Development

SEMISOLIDS

P R O C E S S

V A L I D A T I O N

CHAPTER 17

Process Validation
‘…process validation(PV) needs to show that the data from the first
three commercial lots of each batch size are essentially similar and
compare well with product data of the biobatch…’

Validation

Parameters evaluated

The validation requirements of an
approved generic drug product requires
that at least the first three consecutive
commercial batches to be validated.

Consistency
The
validation
process
must
demonstrate
that
the
overall
manufacturing
process
performs
consistently, as expected, and that the
generic drug product consistently meets
its predetermined filed specifications
(i.e. in-process and finished product
specifications).

Validation Timing
The generic drug process must be validated
before the product is distributed and
shipped, i.e. usually the time between
approval and first marketing.
Experienced companies may well validate
the process prior to approval, if the risk is
considered minimal and it is thought the
review process will not challenge the
process or product specifications.

Cleaning Validation
Approved cleaning validation must be
performed immediately after the pivotal and
after each of the first three commercial
batches.
Cleaning validation specifications are
essentially part of the generic product
development program and are in place
before the validation process.

Validation Parameters
The following parameters generally impact
on the consistency of the bulk and finished
product and are part of the overall
development
validation
plan
from
development to process optimization to
process qualification to commercial
validation.

Handbook of Pharmaceutical

♦ Particle size control (insol. actives) [a]
♦ Purified Water USP bioburden
[a]
♦ Addition Order to mixer
[a][c]
♦ Critical process parameters - control on
temperature and mixing speed

[a][c]

♦ Critical process parameters - control on
mixing times.

[a][c]

♦ Critical process parameters - control on
phase mixing temperatures.

[a][d]

♦ pH / Viscosity Range Qualification
♦ Homogenization parameters
♦ Recording devices and charts.

[d]
[a]
[e]

Content
Uniformity:
[a][d][e]
Top, Middle, Bottom sampling [a][d][e]
Dead-spot position sampling
[d][e]
Container weight testing
[a][d][e]

♦ Re-mixing step(s)?
[a][d]
♦ Sample plan / sample tests [a][d][e]
♦ Content Uniformity Qualification [d]
♦ Antioxidant/Chelate Qualification [d]
♦ PV Assay results cf. pivotal lot [e]
♦ PV test results cf. pivotal lot results [e]
♦ pH/viscosity/rheology
[a][b]
♦ Individual tube fill-weight
[b][e]
♦ Average tube fill-weight
[b][e]
♦ Processing time limitations.
[b][e]
[a] - during product development
[b] - during product development and
QC tested in commercial validation
[c] - during process optimization
[d] - during process qualification
[e] - during initial 3 validation lots

Chapter: 17.1
1

Generic Development

SEMISOLIDS

P R O C E S S

V A L I D A T I O N

CHAPTER 17

ØC H E C K L I S T ×
CL # HPGD-03-01YY

PROCESS VALIDATION BATCH
‘…to demonstrate that the process really works... ’

1
The manufacturing product and processing controls of the commercial lots qYes qNo
are substantially the same (equivalent) as those listed in the MA filing?
2.
Before the validation process and validation batches are run, the firm has qYes qNo
conducted a thorough and comprehensive on-site review and audit of all
development and analytical raw data?
3.
The firm has performed a side-by-side evaluation of the validation protocol qYes qNo
and the submitted MA dossier to ensure that the product and process
specification and control points are common in both documents?
4.
QC conducts routine particle size analysis on the active material(s) qYes qNo
suspended (insoluble) in the drug product (a particle size range is provided)?
5.
Particle size (/bulk density) QC specifications have been established for the qYes qNo
active material(s) present in the final product formula?
6.
During the product development the finished product has been evaluated at qYes qNo
both ends of a two unit pH range (pH 5 ±1 unit) for suitability in complying with
the finished product specification?
7.
Process controls on mixers (time, rpm settings) are documented in the full qYes qNo
scale commercial process instructions?
8.
Uniformity of Content is a critical processing parameter for the bulk qYes qNo
material after the mixing/homogenization process and prior to tube filing?
9.
Bulk samples taken during sampling operations - for the assay qYes qNo
determination are equivalent to one application (3-5 grams)?
10. In the event that it is not possible to obtain the equivalent of one qYes qNo
application, the closest approximation should be sampled (a function of sampling
thief used)?
11. A tapered sampling thief may during sampling operations be unsatisfactory qYes qNo
for sampling the equivalent of one application unit uniformly (use uniform
diameter thieves)? This effect is maximum in solid dosage forms and minimum in
semisolid preparations.
12.

Uniformity of Content is evaluated after the homogenization process ?

qYes qNo

13. Manufacturing instructions clearly indicate corrective action taken where qYes qNo
older mixers (pony / ribbon) display ‘dead spots’ - where no direct mixing action
can occur (around shaft / bearing area or discharge valves) ?

Handbook of Pharmaceutical

Chapter: 17.2
2

Generic Development

SEMISOLIDS

P R O C E S S

V A L I D A T I O N

CHAPTER 17

ØC H E C K L I S T ×
CL # HPGD-03-01YY

PROCESS VALIDATION BATCH
‘…and to show equivalency with the pivotal / biobatch... ’

14. Dedicated tubing is used for drug products containing colored or qYes qNo
fragrant/pungent/odorous active drug substances?
15. All critical process parameter temperature and time controls qYes qNo
incorporate automatic recording equipment?.
16. The product batch number and date is routinely entered on the qYes qNo
automatically recording temperature and time control graphs?
17. Diffusion profiles are performed on 6 units for each of the three qYes qNo
validation lots. Note: Used to determine 'sameness' statistically.
18. Where validation batches are used for sale then routine Finished qYes qNo
Product Testing must be performed on composite sample representative
of the overall production run.
19 This sampling procedure is a routine procedure and independent qYes qNo
and separate to the validation sampling requirements?
20. Assay, Content Uniformity and microbial limit tests, are critical qYes qNo
parameters and results are compared side-by-side to the bioequivalent /
pivotal batch for equivalency?
21. Equivalency of the bioequivalent / pivotal batch with the validation qYes qNo
batch lots implies a variation < 5% from the filed Biobatch?
22. All results, including failing results (if any) have been fully qYes qNo
discussed and explained in the validation report?
23. The basis for concluding that the validation process is satisfactory, qYes qNo
particularly those batch lots with failing results has been fully evaluated
in the validation report?
24. Any out-of-specification product or process result during validation qYes qNo
will be fully investigated and an Investigation Report will be completed
and signed-off within 30 days ?
25. A separate ‘Validation Concluding Statement’ is included in the qYes qNo
validation report? (Place on the approval page).
26. The ‘validation concluding statement’ indicates that the three qYes qNo
production lots are equivalent in all aspects to the filed MA batch?

Handbook of Pharmaceutical

Chapter: 17.3
3

Generic Development

SEMISOLIDS

P R O C E S S

V A L I D A T I O N

CHAPTER 17

STANDARD OPERATING
PROCEDURES

Page 1 of 1.

CL # HPGD-03-01YY

PROCESS VALIDATION BATCH
The following Standard Operating Procedures are recommended for a generic
development unit :

The Process Validation Batches
P-000-01-01YY

Performing Validation with ‘old type‘ equipment.

P-000-01-01YY

Do’s and Don’ts when preparing for Validation Batches.

P-000-01-01YY

Documentation requirements for the Validation Batches.

P-000-01-01YY

Validation Batch Guidelines for Semisolid Dosage Forms.

P-000-01-01YY

Bioequivalency and Validation Batch comparisons.

P-000-01-01YY

Diffusion comparisons on pivotal and validation batches.

P-000-01-01YY

Handling Failed Validation Batches.

P-000-01-01YY

Preparing the Validation Concluding Statement.

Footnote:
During the pre-approval inspection the proposed commercial manufacturing
documentation (each batch size) is subject to inspection. These processing
instructions will be compared to the pivotal batch (MA) documentation and
examined
for
substantial
similarity
(comparability).
The
marketing
authorities require that the plant be ready for a PAI inspection when the
firm files the application.

4
[End of Document]

Edition No. :
01
Ed. Status : New

Effective Date :

Handbook of Pharmaceutical

APPROVED
______________ ________________ ______________ ______________
Department
RD
RA
QC / Q A

Chapter: 17.4
4

Generic Development

SEMISOLIDS

PROCESS VALIDATION

PROCESS VALIDATION

CHAPTER 17

M A S T E R PLAN.
FORMULATION
Drug Development Phase

INTRA-BATCH VARIABILITY
(Reproducibility of the
Three Validation Lots)
via:
• Assay
• Content Uniformity
• Parameters within LCL-UCL Range

INTER-BATCH EQUIVALENCY
(Equivalency of the three Validation Lots
and the Topical Biostudy Batch)
• Assay + U of C
• Microbial Limit Test
• Appearance + pH + Viscosity

O P T I M I Z A T I O N

SCALE-UP

PROCESS QUALIFICATION

The

Documentation

PIVOTAL BATCH
VALIDATION - PROTOCOL

CRITICAL STAGES
1. Controlled Mixing Time/Temp.
2. Phase Mixing Temperature
3. Homogenization
4. Filling Process

SAMPLING PLAN

VALIDATION

3 Full Size Batches

TESTING PLAN
VALIDATION REPORT

MARKETED PRODUCT
CONTROL LIMITS
Upper Control Limits
Lower Control Limits
PROCESS CAPABILITY
CP ≤ 1
Handbook of Pharmaceutical

MAJOR
CHANGE

Chapter: 17.5
5

RE-VALIDATION
of Commercial Product after;
[1] New Process Equipment Introduced
[2] Major Process Change.
Generic Development

SEMI-SOLIDS

PROCESS VALIDATION

PROCESS VALIDATION

CHAPTER 17

M A S T E R PLAN.
THE DOCUMENTATION

VALIDATION PROTOCOL
PURPOSE of STUDY
RESPONSIBILITIES of PERSONNEL
FREQUENCY
PROCESS - CRITICAL STEPS - DEFINED
CRITICAL PARAMETERS - SPECIFIED
SAMPLING PLAN
TESTING PLAN
SAMPLING PLAN - Topical Semisolids
ACCEPTANCE CRITERIA
BULK - Physical and Microbial Tests Only
HOMOGENISED BULK - Content Uniformity
FILLING Process - Fill Weights (3-4 Intervals)
TUBES - Monograph Testing.

STEP
ONE

TWO

TESTING PLAN
CREAMS
OINTMENTS
Description
Description
Bleeding/weeping/splitting/cracking
pH
Viscosity
Viscosity/Rheology
Assay
Assay
Content Uniformity
Content Uniformity
Microbial Limit Test (MLT)
(MLT - only if necessary)

THREE

VALIDATION REPORT




Handbook of Pharmaceutical

Aim and Purpose of Study
List of Raw Material used in MNF
List of MNF Equipment (Pre-Qualified)
Critical Process Steps Studied
Results of Data Collected





Acceptance Criteria Evaluation
Analysis of Results (+ statistical)
Validation Statement of Process
Validation Recommendations
Attachments (Batch Records & CoAs)

Chapter: 17.6
6

FOUR

Generic Development

SEMI-SOLIDS

Process Validation

PROCESS OPTIMIZATION

CHAPTER 17

VALIDATION M A S T E R PLAN.

Choice of

FORMULA

PROCESS
OPTIMIZATION

FORMULATION
Drug Development Phase

QUALIFICATION STUDIES
1. ANTIOXIDANT
2. PET QUALIFICATION
(VIA WRITTEN PROTOCOLS)

SCALE-UP

Choice of

PROCESS QUALIFICATION

PROCESS

The

Documentation

PROCESS OPTIMIZATION

PIVOTAL BATCH
VALIDATION - PROTOCOL
SAMPLING PLAN

VALIDATION

3 Full Size Batches

TESTING PLAN
VALIDATION REPORT

MARKETED PRODUCT

MAJOR
CHANGE

Handbook of Pharmaceutical

Chapter: 17.7
7

RE-VALIDATION
of Commercial Product after;
[1] New Process Equipment Introduced
[2] Major Process Change.
Generic Development

SEMI-SOLIDS

P R E - A P P R O V A L S

CHAPTER 18

Pre-Approval
Inspections
'…Did you do what you wrote - can you do what you said…'

P

AIs (Pre-approval inspections) may
be feared with some trepidation or
looked forward to with a knowing
assurance that the Generic or
Research-based Company will pass the
agency inspection, probably with a few
minor agency orientated requests in
order to bring the company into line
with current agency and cGMP thinking.
This chapter deals with the nuts-andbolts issues of PAIs pertaining to the
Development,
Regulatory,
cGMP
requirements of a newly developed
drug and then very briefly to the
production environment, both essential
to maintain a successful Research or
Development program from preformulation to the first validated
commercial batches.
Its purpose is to get newly developed
drug products to the market place on
time, while significantly reducing
development and research costs.
The issues concerning foreign
inspections are covered notably the
areas of where they differ from local US
Pre-Approval Inspections and the
reasons why.
Agency inspectors need to review all
aspects of drug development from preformulation to the proposed first
marketing batches, as well as obtaining
a general overview of the firms
development
Standard
Operating
Procedures (SOPs) in the R&D
departments
of
Pharmaceutical,
Analytical development, Microbiological

Handbook of Pharmaceutical

parameters, Drug Stability Programs
and key Regulatory concerns.
Prior to the PAI inspection team’s
arrival, the PAI members are expected
to carefully review the data pertaining
to the product specific PAIs and to
select those issues that may need
careful attention during the coming onsite inspection.
As a minimum requirement, every
inspection undertaken focuses on an indepth evaluation of process and
laboratory tests failures, and product
process changes.

Failures

Process and lab failures are road signs
to the agency inspection team, who in
general have a limited window-ofobservation into the firm's year round
activities, especially during foreign
visits.
Obviously, process failures are the
most important points to cover during
the inspection and these failures and
process changes have a significant
impact on the adequacy of the final
manufacturing process validation.
The inspection findings do recommend
to withhold approval of an PAI subject
to proper implementation of corrective
action. For foreign firms a follow up visit
for on-site evaluation a year or more
later may be conducted prior to the
approval of the product applications.
This is the main difference between
foreign reviews and domestic plants.

Chapter: 18.1
1

Generic Development

SEMI-SOLIDS

P R E - A P P R O V A L S

Follow-up

visits (outside the US
inspection area) not occurring within a
reasonable time period may require the
firms waits a longer period before revisit
can be scheduled, if it's deemed
necessary
Although the inspection findings and
judgments made are consistent with
those judgment formed when similar
issues are found in domestic firms, the
follow-up inspection may well be much
later.
No foreign drug firm can place its' PAI
approval program on hold for longer
periods thus the need for vital care and
detailed organization in PAI preparation
cannot be over emphasized.
Firms with a good history of GMP
credibility and effective correction
action plans may not be subject to a
follow-up PAI inspection, when based
on impressive past cGMP and audit
tract records

Last Development Milestone
The PAI is the last milestone in the drug
product approval cycle prior to MA
approval. It is a review of every aspect
of
the
drug
development
and
manufacturing process up to and
including the regulatory batch(es).
A pro-active approach is necessary to
succeed
and
pass
your
PAI.
Preparation for the newly developed
drug or reformulated drug product
applies to all personnel employed in the
pharmaceutical firm. Above all it
requires a major team effort.
Selecting the best team members and
building a near-perfect PAI action group
requires
effective
harmonization
between departments with individual
departmental responsibilities.
No single individual is not impacted or
affected during the PAI preparations. It
is simply the concern of all the
personnel.

Handbook of Pharmaceutical

Build an

CHAPTER 18

Effective

Interdisciplinary
Team for PAI
Success
Management responsible for the
operation needs to involve all
departments associated directly and
indirectly (technical services and
maintenance) with the generic or
innovative drug development - from the
pre-formulation scientists to the night
shift cleaning squads. The cardinal
need
to
build
an
effective
interdisciplinary team is a vital factor to
PAI success.

You can never be
“too prepared”.
R&D or Development Units alone can
not assure a successful Pre-Approval
Inspection. Agencies will definitely
interact with other departments to
assure that a facility is consistently
capable
of
routine
commercial
manufacturing.
Exhaustive PAI preparation is equally
valid for Generic developers as well as
NCE Researched-based units.
The rules are the same - only the
documentation changes.

Failed PAIs can
effect your
existing or
pending products
All

pharmaceutical
companies
conducting
drug
research
and
development must eventually face a
PAI review. The consequences of a
failed PAI may well impact on existing
products, especially if the deficiency is
a
major
GMP
concern.

Chapter: 18.2
2

Generic Development

SEMI-SOLIDS

P R E - A P P R O V A L S

A crash

corrective action plan may be
necessary to minimize the impact of a
failed inspection on the Company’s
approved and pending drug products, in
the agency review queue.
Essentially generic development can
be distilled into a Master Checklist of
Drug
Development
Procedures
representing the best and most widely
used methods available. In drug
product development program both the
advances and the failures of the
experimental batch lots need to be
documented and addressed.
Generic Development.
The procedures that govern foreign
sites, in development of the drug
dosage form must be carefully
structured to insure that separated
development; scale-up; pivotal and
commercial procedures are fully
dovetailed and interfaced with the
proposed product testing facility
physically situated in the EU/EEA.

Complete

integration of product
manufacturing,
Quality
Assurance,
Quality Control and technical Services
(engineering,
maintenance
&
metrology) is essential, to assure that a
facility is consistently capable of
commercial
manufacture
of
the
proposed product batches. Process
validation should be performed after
the PAI (in the EU) and before the PAI
in non-EU manufacturing plant to
prevent any extra delays

What do agencies
expect during a
PAI?
During the PAI, the agencies expect to
find that the firm complies fully with
cGMPs. No firm will pass a Preapproval Inspection if GMP is sorely
deficient or documentation is absent.
Confirmation that the firm has used
appropriate scientific data to justify

Handbook of Pharmaceutical

CHAPTER 18

process and actions must be clearly
demonstrated.

All

data must be rapidly retrievable
during the PAI audit and review. The
Biobatch or Pivotal Batch records will
be asked for - as well as the
development rationale from early preformulation to process validation
protocols.
A firm should have a well structured
and assembled Product Development
Report and Expert Reports as they will
certainly go a long way to convince the
agency reviewers of a fully justified
overall process that consistently
produces the desired end-product.
The Development Report is the basis
on which the validation protocol is
designed and structured - without it,
validation may well be incomplete or
inconclusive.

Review records need to show:
⇒ authentic, clear and accurate data.
⇒ An organized
program.

process

change

⇒ any reprocessing must be justified.
⇒ An essential similarity, within rules,
between Pivotal (MA) used for the
topical bioequivalent study and the
proposed full scale commercial
production lots.
⇒ Cleaning validation & report, and
process validation protocol.
⇒ No deviation from raw material
specifications and suppliers listed in
the application unless justified by
scientific data.
⇒ In new drug application a
substantial
connection
between
biobatch and the proposed full scale
new drug commercial production.

Chapter: 18.3
3

Generic Development

SEMI-SOLIDS

P R E - A P P R O V A L S

A

checklist of expectations during a
PAI review is provided to aid the firms
Pre-Approval preparation.
The Agency needs the assurance that a
facility is capable of commercially
manufacturing the drug product as
detailed in the file submission. Further
more the Agency expects that all
problems arising from audit inspections
are correctly promptly. Where possible,
firms should correct the omission or
fault during the actual inspection or if
not possible very shortly afterwards.

Audit

corrections given the highest
work priority, during PAIs promote
cooperation.
Remember some of the observations
may impact on other drug products
already being manufactured and may
bring
them
technically
out-ofcompliance.
If all corrections are done before the
evaluation agency asks for GMP
inspection concurrence. The PAI
inspectors will then concur with the
drug product approval.

Using Technology
Transfer (TTD) for
Process Improvements
and PAI success
Manufacturing equipment and scale-up
procedures require dove-tailing with
both facilities. Analytical and microbial
laboratory test methods are needed to
be rugged and operational in both
facilities. Great care needs to be taken
to insure and demonstrate the
ruggedness of these laboratory tests.
Testing procedure methods should be
chosen in close cooperation with the
production laboratory facilities to insure
a smooth transfer of technical
documentation

Handbook of Pharmaceutical

CHAPTER 18

(TTD operational requirements).
The testing procedures used in the
drug development unit must be
designed and dovetailed for rapid
transfer to the commercial testing QC
laboratory.
Equipment and facilities (HPLCs etc.)
should be pre-evaluated to insure test
method and analytical validation
transferability.
Comprehensive and easily understood
documentation
is
an
essential
ingredient to a successful Pre-approval
Inspection. R&D, RA,
QA and
Manufacturing must work together to
create a comprehensive development
and production documentation package
that covers all the issues and enhances
the investigator's review.
The Documentation serves as a guide
to the inspection as well as a means to
enhance
the
investigators
understanding of the submission. If the
investigator is completely satisfied it
generally means that all the correct
documentation is in place and all
essential aspects of the product
development, scale-up and cleaning
and process validation have been
thoroughly executed.

Effective Development
& Production
Documentation
speeds up the PAI
immensely
Thorough

documentation methods will
accelerate your firm’s inspection.
Provide the investigator with a complete
set of documentation that ‘feels and
looks right’ in addition to being
complete. Physical logs and notebooks
need to be seen and reviewed by the
investigator.

Chapter: 18.4
4

Generic Development

SEMI-SOLIDS

P R E - A P P R O V A L S

CHAPTER 18

cards or inventory control cards
for the active material, and finished
goods are generally called for, to check
and review the deduction quantities at
the relevant batch manufacturing or use
dates.

The ultimate Pivotal lot
is a validated batch
ready for shipping on
approval

The

(equal to the commercial lot with at
least 2 years shelf life remaining
after MA approval .)

Stock

Finished Product Inventory Cards
detail the overall drug product trail or
disposition of the dosage units.
Reserve samples, biostudy samples
and quantities, QC and stability
amounts required for testing and
evaluation are carefully deducted from
the total units packed in each
container-closure system.

Finished Product
Inventory Cards
(PICs)
are essential for
complete product trails.
In

the manufacture of the Pivotal
batch, a minimum of 100 000 (net)
dosage units is required. Many firms
prepare documentation for 100 000
dosage units gross, ignoring the fact
that there may well be 2% to 5%
production losses. The net batch yield
turns out to be 98 000 or 95 000
packed units well below the 100
thousand net required.
Semisolids may have a greater
manufacturing loss than solid forms thus it is prudent to scale the pivotal
batch for at least 110 000 packed units.
remember the pivotal batch may range
from 10% to 100% net of the proposed
commercial batch.
Experienced Generic firms who do not
anticipate any problems with the pivotal
documentation often target the pivotal
quantity to 70% of the proposed
commercial
lot
thus
achieving
appropriate scale-up and pivotal in a
single batch.

Handbook of Pharmaceutical

Packing the pivotal batch.

The

Pivotal batch needs to be fully
packed in the proposed marketing
packs. Frequently the pivotal batch is
packed into 2 to 4 different pack types
and several different pack sizes and
closure combinations. (Glass, HDPE,
Metal lined, aluminum tubes, etc.)
The packaging trail identifies the
quantity packed into each containerclosure system. The overall packaging
totals to 100% of the net pivotal batch.
At least 10-20 % of the exhibition
(pivotal) batch should be packed into
each container-closure category.

Self Inspection
Audits
are an Essential
Pre-approval
Requirement
AUDITING YOUR FIRM
BEFORE THE PAI.
Development

and
production
documentation for the newly developed
dosage form should describe the
purpose and the principles generally
needed to meet the scientific,
regulatory and GMP objectives of a well
run development and production unit.
During the PAI inspection the product is
tracked from pre-formulation to Pivotal
batch.

Chapter: 18.5
5

Generic Development

SEMI-SOLIDS

P R E - A P P R O V A L S

The

development and production
documentation is the tracking agent
used by the agency reviewers - thus the
presence of ‘holes’ or deficiencies are
the concern of the firms PAI audit team.
Finding
these
deficiencies
and
correcting them on time before the
arrival of the agency investigators is the
prime objective. No document or
inventory card should be left unturned.

Identify deficiencies
well before
the actual investigation
Carefully conducted departmental inhouse pre-PAI audits may save
research based firms and generic
developers significant review time and
thousands
of
much
needed
development funds.
The pre-PAI audit team should start
reviewing
the
generic
drug
development
departments,
namely
pharmaceutical,
analytical,
microbiological and stability units and
end with the manufacturing, packaging /
disposition of the pivotal lot.

Is your Cleaning Program
and residual limits
- ready for the
Pre-approval Inspection ?
Cleaning Validation:
The Cleaning validation protocol and
Report pertaining to the MAs under
question must be available for PAI
review.
Many firms fall short of a fully
documented
cleaning
validation
protocol
and
validation
report.
Frequently the firms omit to establish
the limits of contamination of the
previously manufactured batch to which
they are required to clean. An excellent
mathematically derived rule of thumb
for establishing the maximum allowable
residual limits (mcg/dose) is simply
1/8000 of the last batch’s lowest mg

Handbook of Pharmaceutical

CHAPTER 18

labeled strength.

Do You Have
Cleaning Validation
firmly in place ?
Remote Development
Generic
Development
of
pharmaceutical drugs may take place in
a non-EU development laboratory
facility i.e. an oversees facility. Where
product development occurs in a
remote development unit (i.e. not
attached to the proposed manufacturing
site - special SOPs dovetailing the
procedures at the remote and
manufacturing site are necessary for
such a situation.

Preparing Foreign
drug firm sites for
Pre-approval
Inspection
Emphasis

is often placed on external
development (outside the EU) while
commercial manufacturing is targeted
for a EU commercial site. In the majority
of these cases the regulatory ‘Pivotal’
batch for regulatory inclusion into the
MA submission file, is best targeted for
manufacture
at
the
EU-based
commercial manufacturing site.
Oversees developers who have
inspected / approved commercial
manufacturing facilities may produce
the pivotal batch at a non-EU small or
large scale manufacturing facility. The
manufacturing and testing facility must
be in full GMP compliance, as if it were
a EU based operation.
Non-GMP R&D or drug development
facilities are not suitable for clinical or
pivotal drug manufacturing. Full cGMP
pilot plants or to use the more
appropriate terminology ‘small scale
manufacturing’ facilities are the correct
venue for manufacturing clinical
batches.

Chapter: 18.6
6

Generic Development

SEMI-SOLIDS

P R E - A P P R O V A L S

Where

the object is to routinely
manufacture at an approved GMP
commercial production site then the
pivotal (bio) batches, for regulatory
submission to the authorities, should
always be manufactured at the same
commercial site.

Firms who have open and strong audit
programs in place inevitably do well in
PAIs. Multiple mock trail-runs prior the
anticipated inspection will iron-out the
hidden deficiencies and give valuable
training and confidence to all personnel
concerned.

What are Common
PAI
Issues and Concerns ?

Conducting Mock Inspections.
Preparing your department and firm’s
personnel for what is to come seems a
daunting challenge. It does not have to
be so! An intensive pre-approval inhouse mock inspection with QA or RA
role playing as the agency inspection
team pays excellent dividends.

Conduct an Intensive
mock In-house
Inspection
Challenge
and
dissect
the
manufacturing and controls necessary
to support approval of a new or
reformulated drug whether it be a new
active or a generic.
Asking awkward questions, before the
inspector does, may save months of
work and your companies reputation such as;
♦ Formula development

CHAPTER 18

Staff learn to answer questions directly
- and not to talk any more than
necessary or advance gratuitous
information. Where foreign languages
are involved, a good practice is to
appoint a QA/RA spokesperson to
handle all communication and remain
close to the inspectorate at all times.
Create an SOP to define AgencyCompany
Interactions
and
communications. Key personnel speak
through the designated QA and RA
Director to the inspectorate. As an
inspection has generally two or
sometimes three agency personnel the need to appoint at least three
Spokespersons e.g. QA, RA and
Production usually cover all situations.

♦ Method development

Ensure the investigation
runs smoothly
on-site

♦ Actual Process Development

The

♦ Master Specifications





active
Raw Materials
In-process
Finished Process
Cleaning
Check /Stability

♦ Stability File Submission Batch
♦ Scale-up
♦ Validation Lots
♦ Data Archiving (& Rapid Retrieval)

Handbook of Pharmaceutical

firms representatives should each
have a set of ‘runners’ - key aids, who
do not speak but rapidly retrieve
documentation requested for by the
inspectors.
Review rapidly the
requested documentation with the Head
of the relevant department as to the
correctness of the data requested.
Then present the information to the
inspector by opening the desired
page(s) - use book markers highlighting the raw data only. Don’t
allow reviewers to wander through labbooks.

Chapter: 18.7
7

Generic Development

SEMI-SOLIDS

P R E - A P P R O V A L S

Set aside the board room or
other venue
for the Inspectors
exclusive use
As
lab
books
are
confidential
documents, inspectors do not and
should not page randomly through an
analytical raw data lab book. The
opened lab book is placed in front of
the reviewer with ‘begin and end’
bookmarks designating the raw data for
the relevant batch(es) requested.
Daily Work Venue
Reserve the firms board room or a large
meeting room as a routine workplace
for the company and PAI Officials.
Display all Development Reports,
Protocols, cleaning and process
validation reports. Copies of the USP,
BP and other Official Reference works
used should be on hand.

CHAPTER 18

PAI SUMMARY:
• Pharmaceutical Development
Notebooks containing All the
experimental data

• Analytical Development Notebooks
containing all the analytical / micro
data from early active material
investigation to validation of stability
indicating assays and impurities

• A full Development Report based on
a series of development lots in a
progressive, logical manner with
scientifically valid
decisions
being made

• Full Plant Documentation of the
Pivotal Lot Manufacture
& Packing

Select what to file
after the PAI
(post approval)

• Full stability data and an operational
& functional stability unit

Display on a separate table all the
product documentation under review.
Label and group documentation and
reports together (e.g. ANDA +
Development Report + Cleaning and
process validation protocols and
Reports
represent
a
product
documentation group).

• The submitted MA is able to be
verified against the departmental
raw data

• The plant is capable of
producing the drug as specified in
the MA

• Full cGMP in place
throughout the plant and labs.

Lastly provide light refreshments. 3

• An operational and functional
SOP system

The Agency needs the
assurance
that product development
yields the following :- è

• IQOQ Equipment (calibrated)

• Process Validation Protocol
prepared

Handbook of Pharmaceutical

Chapter: 18.8
8

Generic Development

SEMISOLIDS

P R E - A P P R O V A L S

CHAPTER 18

ØC H E C K L I S T ×
CL # HPGD-03-01YY

Pre-approval Inspection Team’s Set-up and
Responsibilities
‘Pre-approval inspection preparation is part of the overall drug
development process and not a post-submission regulatory crisis'

1. The firm has selected a multifaceted pre-approval inspection team?

qYes. qNo.

2. The PAI Team has outlined its charter and team responsibilities ?

qYes. qNo.

3. The Quality Assurance Head has approved and signed the charter ?

qYes. qNo.

4. The PAI team has issued a SOP detailing regulatory procedures and qYes. qNo.
protocols to be followed during inspection procedures ?

5. The PAI team leader is the Head of Quality Assurance or his designate?

qYes. qNo.

6. The PAI team is fully updated on the Pre-approval Program ?

qYes. qNo.

7. A suitably equipped room has been dedicated for use during the PAI?

qYes. qNo.

8. A working list of documents, MA dossiers, Pharmacopoeia, raw data lab qYes. qNo.
books etc. is available on-site in the PAI audit room, during the course
of the inspection ?

9. The PAI team has reviewed all product-specific files and appropriate qYes. qNo.
documentation for accuracy, clarity, and consistency - noting logical
dates, and signatures ?

10.The PAI team has focused on the pivotal batch dossier and the qYes. qNo.
proposed commercial manufacturing documentation
evaluations of actual filed manufacturing facilities?

with

on-site

11.The PAI team has, examined the product development report, together qYes. qNo.
with the project leader, and evaluated the explanations and scientific
rationale for changes that occurred during the process development right
up to the pivotal lot manufacture?

12.The PAI team has evaluated the product(s) cleaning validation, residual qYes. qNo.
limits, acceptance criteria and actual cleaning validation results?

13.The PAI team has evaluated the product(s) process validation protocol?

qYes. qNo.

14.The PAI team is geared to provide assistance in the preparation of qYes. qNo.
written responses to the investigators concerning adverse finding - during
the actual PAI review?

15.The PAI team has established and coached a core of key personnel able qYes. qNo.
to properly respond to questions asked by investigators during the PAI
review?

333

Handbook of Pharmaceutical

Sect: 18.
18 9

Generic Development

SEMISOLIDS

P R E - A P P R O V A L S

CHAPTER 18

ØC H E C K L I S T ×
CL # HPGD-03-01YY

Pre-approval Inspection Team’s Audit
Activities
‘Pre-approval inspection preparation impacts on R&D, Manufacture
Quality Control / Assurance and Regulatory Affairs from day one of the new
product development '

1. Review submitted MA and agency correspondence, manufacturing qYes. qNo.
and controls sections (MF and MI), active and excipients (lot #s,
CoAs) as used in the pivotal formula?
2. Development
3. Review the development report in detail and assure adequate qYes. qNo.
supporting documentation for process and optimization changes
made?
4. Has the active’s particle size, bulk density and polymorphism been qYes. qNo.
fully addressed?
5. Does the development report support a scientific basis for the qYes. qNo.
process validation protocol?
6. Do individual development validation studies support formula and qYes. qNo.
process changes made?
7. Process Qualification
8. Examine Process Qualification scientific rationale in establishing qYes. qNo.
product specifications?
9. Review cleaning validation, residual limits, and acceptance criteria qYes. qNo.
for the cleaning process?
10.Review that similar water quality was used from process qYes. qNo.
qualification to commercial lots?
11.Review that any reprocessing/rework stage has been fully qualified qYes. qNo.
and evaluated?

Handbook of Pharmaceutical

Sect: 18.
18 10

Generic Development

SEMISOLIDS

P R E - A P P R O V A L S

CHAPTER 18

ØC H E C K L I S T ×
CL # HPGD-03-01YY

Pre-approval Inspection Team’s Audit
Activities
‘…Pre-approval inspection preparation is the last step in
the long chain of product development…
…A weak link can sink the whole project… '

PIVOTAL BATCH
1. Review list of manufacturing and packaging equipment used in qYes. qNo.
pivotal lot.
2. Examine machine cards and cleaning verification cards or tags.

qYes. qNo.

3. Examine room cleaning cards.

qYes. qNo.

4. Examine all pivotal manufacturing, packaging and labeling records qYes. qNo.
(review date order, signatures present manufacturing deviations,
yield accountability vs. SOPs, sampling plan / retention samples) ?
5. Review the plan/protocol for sampling and testing the pivotal lot.

qYes. qNo.

6. Examine intended production documentation.

qYes. qNo.

7. Review Manufacturing Deviation Report relevant to each pivotal qYes. qNo.
batch.
8. Review conformance and compliance to manufacturing time qYes. qNo.
limitations.
9. Review excipient monographs vs. CoAs; routine and full testing qYes. qNo.
procedures and test dates?
10.Review overall disbursement of pivotal batch - e.g. QC release, qYes. qNo.
retention, stability, biostudy samples and full reconciliation of
product trail for each pack type used, and packs placed on
stability?
11.Identify contract manufacturers or packages for documentation and qYes. qNo.
compliance auditing?
12.TECHNOLOGY TRANSFER PROCESS
13.Review the technology transfer process/ SOPs from development qYes. qNo.
to production facilities ?
14.Review data supporting rework or reprocessing procedures in qYes. qNo.
development and process qualification batches to insure that the
rework process are adequately supported and scientifically
justified?
333

Handbook of Pharmaceutical

Sect: 18.
18 11

Generic Development

SEMISOLIDS

P R E - A P P R O V A L S

CHAPTER 18

ØC H E C K L I S T ×
Pre-approval Inspection Team’s Audit Activities
‘…Pre-approval inspection preparation is a team work affair…
…All departments must pull their weight equally…
…its not a QC or RA one man show… '

SCALE-UP TO COMMERCIAL

qYes qNo

15. Review scale-up documentation and ensure all changes are within SUPAC rules ?
16. Review ANDA formula and manufacturing variations are within SUPAC limits?
17. Review side-by-side comparison of pivotal vs. commercial process, facilities and equip.?
18. Review SOPs relating to issue and review of batch records, receipt, handling and processing
of raw materials, packaging components and labeling, cleaning procedures, maintenance,
HVAC, calibration and equipment use, change control and manufacture.
19. Review site (manufacturing and labs) personnel training procedures and training records

qYes
qYes
qYes
qYes

qNo
qNo
qNo
qNo

PROCESS VALIDATION

qYes qNo
qYes qNo

20. Validation protocol for first three consecutive commercial lots on-site ?
21. Review the side-by-side comparison between pivotal and validation equipment /facilities ?
22. Review the protocol for sampling and testing the validation lots (part of validation protocol)

qYes qNo
qYes qNo
qYes qNo

ANALYTICAL
qYes
qYes
qYes
qYes

23. Perform a thorough check on the lab notebook referencing all pivotal tests ?
24. Review method validation for in-house assays, impurities and dissolution test?
25. Review stability-indicating assay and the impact of any placebo effect ?
26. Review all out-of-specification results (log) on analytical or product failures?

qNo
qNo
qNo
qNo

STABILITY
27. Does pivotal batch remains in check specifications after 3 months accelerated (40oC) testing
?

qYes qNo

28. Have samples been placed on stability within 30 days of manufacturing release CoA ?

qYes qNo

29. Insure stability testing is performed according to stability protocol ?

qYes qNo

30. Statement on proposed expiration period in accordance with obtained test results ?

qYes qNo

31. Review all stability data, in-out dates, exposure times, temperatures and humidity (RH)
including control of environmental parameters (recording devices, graphs and any OOS
conditions) ?

qYes qNo

32. Review Stability SOPs and equipment; Are chambers, probes and monitors calibrated ?

qYes qNo

MICROBIOLOGICAL
33. Microbial parameters in compendial excipients are retested every 12 months ?

qYes qNo

34. Preservative containing excipients are tested for preservative efficacy ?

qYes qNo

35. Appropriate use of validated in-house methods with proper method controls ?

qYes qNo

36. Review of microbial testing facilities, test methods, calibration and laboratory SOPs?

qYes qNo

CONTRACT FACILITIES

qYes qNo

37. Full GMP review (on-site/mail audit) of contract facilities used ?

qYes qNo

38. Review of analytical testing facilities methods, validation and laboratory SOPs ?

qYes qNo

39. All facilities listed in file submission are fully capable of performing designated tasks ?

qYes qNo

40. Review of packaging and labeling procedures, in-process controls and SOPs ?

qYes qNo

333

Handbook of Pharmaceutical

Sect: 18.
18 12

Generic Development

DRUG DEVELOPMENT

CHAPTER 19

STABILITY TESTING & STABILITY SOPs

Stability Testing of Drug
Substances and Drug Products I
OVERVIEW

N

ew draft 'stability testing of drug
substance and drug products'
guidance issued in June 1998, provides,
recommendations and guidance in a
comprehensive document that covers
some 110 pages, including glossary, and
provides information on all aspects of
stability data generation and use.
It references and incorporates
substantial text from the following five
International
Conference
on
Harmonization (ICH) guidances:

Ø ICH Harmonized Tripartite Guideline
for Stability Testing of New Drug
Substances and Products, September
23, 1994 - [ICH Q1A]
Ø ICH Guideline for Stability Testing of
New Dosage Forms - [ICH Q1C]

Ø ICH Guideline for Photostability
Testing of New Drug Substances and
Products - [ICH Q1B]

Ø ICH Guideline for Stability Testing of

The

purpose of stability testing is to
provide evidence on how the quality of a
drug substance or drug product varies
with time under the influence of a variety
of environmental factors such as:-

l Temperature
l Humidity
l Light.

Stability

testing
permits
the
establishment of recommended storage
conditions, retest periods, and shelf
lives. [ICH Q1A]
This guidance provides recommendations regarding the design, conduct
and use of stability studies that should
be performed to support all the following
categories:-

Ø

Investigational
New
Drug
Applications (INDs) (21CFR 312.23(a)(7))

Ø New Drug Applications (NDAs) for
both new molecular entities (NMEs)
and non-NMEs

Biotechnological / Biological Products
- [ICH Q5C]

Ø New Dosage Forms (21CFR 314.50(d)(1))
Ø Abbreviated New Drug

Where

Applications (ANDAs) (21CFR 314.92-314.99)

text from one of these
documents has been incorporated in this
guidance, it has been denoted by the
use of a reference in square brackets
[i.e.] in the beginning of a particular
section or at the end of an individual
paragraph.

Handbook of Pharmaceutical

Ø Supplements and Annual Reports
(21CFR 314.70, and 601.12)

Ø

Biologics License Application
(BLAs)
and
Product
License
Applications (PLAs) (21 CFR 601.2)

Chapter: 19.1
1

Generic Development

DRUG DEVELOPMENT

STABILITY TESTING & STABILITY SOPs

The

principle established in ICH Q1A -that information on stability generated in
any one of the three areas of the EU,
Japan, and the USA would be mutually
acceptable in both of the other two areas
--- is incorporated in this guidance
document.
In fact, much of the text of the guidance
on drug substances and drug products is
incorporated directly from the ICH Q1A
text (e.g. II.A. and II.B.).

The guidance is intended to replace the
12 year old, Guideline For Submitting
Documentation for the Stability of Human
Drugs and Biologics, published in
February 1987.
It applies to all drug substances and
products submitted to the Center for
Drug Evaluation and Research (CDER).
This guidance also applies to biological
products that are included in the scope
of the ICH Q5C Stability Annex, Stability
Testing of Biotechnology Drug Products
(July 1996) and all other products
submitted to the Center for Biologics
Evaluation and Research (CBER).
The
draft
guidance
provides
recommendations for the design of
stability studies for drug substances and
drug products that should result in a
statistically
acceptable
level
of
confidence for the established retest or
expiration dating period for each type of
application.
The applicant is responsible for
confirming the originally established
retest and expiration dating periods by
continual
assessment
of
stability
properties (21 CFR 211.166).

Continuing

confirmation of these dating
periods should be an important
consideration in the applicant’s stability
program.
The choice of test conditions defined in
this guidance is based on an analysis of
the effects of climatic conditions in the
EU, Japan, and the USA. The mean

Handbook of Pharmaceutical

CHAPTER 19

kinetic temperature in any region of the
world can be derived from climatic data.
(Grimm, W., Drugs Made in Germany, 28:196-202,
1985, and 29:39-47,1986). Referenced in [ICH Q1A]

The

recommendations in this guidance
are effective upon publication of the
final guidance and should be followed in
preparing
new
applications,
resubmissions, and supplements.
This guidance represents FDA’s current
thinking on how the stability section of
drug and biologics applications should
be prepared. An applicant may choose to
use alternative procedures.
If an applicant chooses to depart from
the recommendations set forth in this
guidance, the applicant is encouraged to
discuss the matter with FDA prior to
initiating studies that may later be
determined to be unacceptable.
FDA recognizes that the time necessary
for
applicants
to
establish
new
procedures, install, and commission the
new temperature and relative humiditycontrolled rooms / cabinets, carry out
appropriate stability studies on batches
of product, and submit the information in
an application may prevent some
applicants
from
generating
data
consistent with the recommendations in
the guidance for some time.
However, since this guidance represents
FDA’s current thinking, recommendations
regarding stability data submission not
conforming with this guidance is possible
with justification.
Applications
withdrawn
prior
to
publication of this guidance should not
normally have to include stability data in
conformance with the guidance upon
resubmission. However, if new stability
studies are conducted to support the
submission, such studies should be
conducted as per guidance.

A comprehensive glossary is included,
and contains definitions of the major
terms and origins of the definitions
derived either from ICH, CFR, or USP.

Chapter: 19.2
2

Generic Development

DRUG DEVELOPMENT

STABILITY TESTING FOR ABBREVIATED
NEW DRUG APPLICATIONS

M

uch of the general information
provided for NDAs in the guidance
is applicable and at times referenced to
Abbreviated New Drug Applications.
However, depending upon the availability
of significant information on, and the
complexity of, these drug products /
dosage forms, the amount of information
necessary to support these applications
may vary from that proposed for NDAs.
This section (III, A-G) is intended to
provide specific recommendations on
abbreviated applications - ANDAs.

[A] Drug Substance Stability Data
Submission
For drug products submitted under an
ANDA, including antibiotics, supporting
information may be provided directly to
the drug product ANDA or by reference
to an appropriately referenced drug
master file (DMF). Publications may be
provided or referenced as supportive
information.
For ANDA bulk drug substances, stability
data should be generated on a minimum
of one pilot-scale batch. All batches
should be made using equipment of the
same design and operating principle as
the
manufacturing-scale
production
equipment with the exception of capacity.
For ANDA bulk drug substances
produced by fermentation, stability data
should be provided on three production
batches, at least two of which should be
generated from different starter cultures.

[B] Drug Substance Testing
A program for stability assessment may
include storage at accelerated, longterm, and, if applicable, intermediate
stability study storage conditions
(refer to IV.G. of the ICH Q1A 711 Guidance and Section II.A
[i.e NDAs] of this guidance).

Stability samples should be stored in the
bulk storage container equivalent (e.g.,
same composition and type of container,
closure and liner, but smaller in size).

Handbook of Pharmaceutical

CHAPTER 19

STABILITY TESTING & STABILITY SOPs

If not previously generated or available
by reference, stress testing studies
should be conducted to establish the
inherent stability characteristics of the
drug substance, and support the
suitability of the proposed analytical
procedures.
The detailed nature of the studies will
depend on the individual drug substance,
type of drug product and available
supporting information. Any necessary
testing may be carried out as described
in the NDA section (II. A.)

[C] Drug Product
Original ANDAs should contain stability
data generated under the long-term and
accelerated stability storage conditions.
(delineated in V.E. of the ICH Q1A guidance or
Section II. B. of this guidance).

ANDAs are divided into
Simple Dosage Forms
and

Complex Dosage Forms
The

data package for ANDAs (e.g.,
number of batches, length of studies
needed at submission and at approval,
and accelerated, intermediate and longterm stability data) should be based on
several factors:
þ including the complexity of the dosage
form (i.e. MR, Aerosol, Patch),
þ the existence of a significant body of
information for the dosage form,
þ the existence of an approved
application for a particular dosage form.

[D] ANDA Data Package
Recommendations
For

Simple

Dosage

Forms

the
package is

following stability data
recommended:
ð Accelerated stability data at 0, 1, 2,
and 3 months. A tentative expiration
dating period of up to 24 months will be
granted
based
on
satisfactory
accelerated stability data unless not
supported by the available long-term
stability data.

Chapter: 19.3
3

Generic Development

STABILITY TESTING & STABILITY SOPs

DRUG DEVELOPMENT

Ø

Long-term stability data (available
data at the time of original filing and
subsequent amendments).
Ø A minimum of one batch; pilot scale.
Ø Additional stability studies (12 months
at the intermediate conditions, or longterm data through the proposed
expiration date) if significant change is
seen after 3 months during the
accelerated stability study.

Simple Solid Forms
- mean IR
Complex Solid Forms
- mean MR

be considered
general ANDA

such as
modified-release products, transdermal
patches, metered-dose inhalers.
Ø Drug products without a significant
body of information.
Ø New dosage forms submitted through
the ANDA suitability petition process
(Q1C applications).
Ø Other exceptions may exist and
should be discussed with the Office of
Generic Drugs.
An ANDA in one of the above categories
should contain a modified ICH Q1A
stability data package, including:
Ø 3-month accelerated stability studies.
Ø Long-term stability studies (available
data at the time of original filing and
subsequent amendments).
The expiration dating period for complex
dosage forms will be determined based
on available long-term stability data
submitted in the application.

Handbook of Pharmaceutical

A minimum of THREE batches
manufactured in accordance with the ICH
Q1A batch size recommendations. These
batch sizes are TWO pivotal (100 000 or
10% etc.) plus one small scale lot (1/2 or
¼ Pivotal) (Refer to V.B. of the ICH Q1A guidance
and Section II.B. of new stability guidance).

Simple Solid Forms
One Pivotal Batch

Complex Solid Forms
Ø Additional stability studies (12 months

[E] Exceptions - ANDA Data
Package Recommendations
(MR/CR, MDI and TDPs)

Ø Complex dosage forms,

Ø

Two Pivotal Batches
+ one small scale lot

The tentative expiration dating period will
be determined based on the available
data from the additional study.

The following may
exceptions to the
recommendations:

CHAPTER 19

at the intermediate conditions or longterm stability testing through the
proposed expiration date) if significant
change is seen after 3 months during the
accelerated
stability
studies
(the
tentative expiration dating period will be
determined based on the available data
from the additional studies).

[F] Data Package for Approval
Full-term stability testing of the primary
stability
batch(es)
is
suggested.
However, in the absence of full-term
stability data for the drug product,
adequate accelerated stability data
combined with available long-term data
can be used as the basis for granting a
tentative expiration dating period.

Batches for Stability
should have Release Assays
close to 100%
The batch(es) used for stability testing
should comply fully with the proposed
specifications for the product and be
packaged in the market package, and
the release assay should be within
reasonable variation (taking into account
inherent assay variability) from the
labeled strength or theoretical strength of
the reference listed drug.

Chapter: 19.4
4

Overages must mimic
the RLD Product
Generic Development

DRUG DEVELOPMENT

STABILITY TESTING & STABILITY SOPs

If

formulated with an overage, the
overage should be justified as necessary
to match that of the reference listed
drug.
Other supportive stability data may be
submitted on drug product batches that
may or may not meet the above criteria.

In Modified Release
Solid Dosage Forms
the PQ batch can be
the third stability batch
Data

on relevant research batches,
investigational formulations, alternate
container/closure systems, or from other
related studies may also be submitted to
support the stability of the drug product.
The supportive stability data should be
clearly identified.

[G] Stability Study Acceptance

CHAPTER 19

ANDA STABILITY
COMMITMENT on THREE
commercial lots until long
term testing is complete
ANDAs withdrawn prior to publication of
this guidance should not normally have
to include stability data in conformance
with the guidance upon resubmission if
the original application was withdrawn
due to non-stability related issues.
However, if new stability studies are
conducted to support the submission,
such studies should be conducted as
recommended in the guidance.

NEW RULES SUMMARY

SIMPLE ANDAs
Ø One batch of 100 000 (net) for 1, 2, &
3 months at 40oC ± 2oC / 75% RH ± 5%.

If the results are satisfactory, a tentative
expiration dating period of up to 24
months at the labeled storage conditions
may be granted.
Where data from accelerated studies
are used to project a tentative expiration
dating period that is beyond a date
supported by actual long-term studies on
production batches, then the application
should include a commitment to conduct
long-term stability studies on the first
three production batches and annual
batches until the tentative expiration
dating period is verified, or the
appropriate expiration dating period is
determined.

Ø Long Term Study started i.e. 3 or 6

Extension

months - whatever is available.

of the tentative expiration
dating period should be based on data
generated on at least three production
batches tested according to the
approved protocol outlined in the stability
commitment. Reporting of the data
should follow Section VI. of this guidance

Handbook of Pharmaceutical

months - whatever is available.

Ø Commitment to THREE production
lots until long term data complete.

Ø Significant Change clause effective.

COMPLEX ANDAs
Ø TWO batches of 100 000 net for 1, 2,
& 3 months at 40oC ± 2oC / 75% RH ±
5% PLUS Small scale (e.g. PQ) lot.

Ø Long Term Study started i.e. 3 or 6
Ø Commitment to THREE production
lots until long term data complete.

Ø Significant Change clause effective.

Chapter: 19.5
5

Generic Development

DRUG DEVELOPMENT

CHAPTER 19

STABILITY TESTING & STABILITY SOPs

Stability of Finished Dosage Form
[EXAMPLE of SECTION 16 (STABILITY) of an ANDA]

TABLE OF CONTENTS
The following example highlights the Overall ANDA Guideline Requirements for the
Stability Section of an application. Only two out of the required EIGHT stability
tabulations (stability profiles) are shown. A separate profile is required for each
strength, pack size and challenge temperature and humidity. The stability section is
divided into seven essential parts, as follows:
17.1

Section Page and Title.

17.2

Expiration Dating Period Statement

17.3
Stability Protocol for Post Approval Production Batches (This is the ANDA
stability commitment on what will be done after agency approval of the file)
17.4
Individual Stability Reports (stability profiles) indicating results obtained from
the Pivotal lot after [3] months accelerated and [X] months controlled room temperature
/ humidity studies.
17.5
Package Configuration and sizes (largest and smallest) used in stability
studies.
17.6
Stability Protocol used for Pivotal Batch lot consisting of one PIVOTAL Lot
for the marketed strength.
17.7
Stability Data Summary Report (plus graphical presentations, graphs of assay
values vs. time ).

4

Handbook of Pharmaceutical

Chapter: 19.6
6

Generic Development

DRUG DEVELOPMENT

STABILITY TESTING & STABILITY SOPs

CHAPTER 19

Stability of Finished Dosage Form
[EXAMPLE of SECTION 16 (STABILITY) of an ANDA]
This section contains:
♦ Proposed expiration date and stability commitment
♦ Stability protocol for post-approval production batches
♦ Summary of Stability Profile on ONE Batch
♦ Stability reports containing data from 3 month accelerated and 6 months controlled
room temperature studies
♦ Package Characteristic of pivotal batch

Overview
Stability testing is performed on each strength of three batches in the largest and
smallest container-closure systems proposed for marketing; i.e. in each material type,
(HDPE / HDPP) containers, collapsible tubes or glass jars.
When more than one closure for the same container material type (e.g. HDPE
container) is used in the proposed marketing containers, the largest and smallest
container-closure configuration is tested, - for both accelerated and long term studies.
In cases where plastic bottles of the same size range and shape are manufactured
from different thermoplastic resins, they exhibition different storage characteristics and
thus are considered as completely separate container-closure systems.
The number of stability tests conducted can be quite large in such cases. The example
below for the following packaging configuration highlights the number of stability tests
needed. Tests can be significantly reduced using a matrix stability protocol.
1.
HDPP (smallest) container with plastic HDPE cap / nozzle
2.
HDPP (largest) container with plastic HDPE cap / nozzle
When testing ONE strengths with 4 container-closure configuration1 at accelerated and
long term testing (2), the stability Program will produce 8 separate stability protocols
as calculated below.
CALCULATING THE NUMBER OF STUDIES REQUIRED:
Calculation is for 1 pivotal batch lot per strength (1 strengths manufactured.)
i.e. (2 container / sizes x [1 lots] x 2 closures x 1 strength x [25ÐC + 40ÐC] = 8 studies).
1

Largest and smallest size only, of each container-closure configuration to be
marketed.

4

Handbook of Pharmaceutical

Chapter: 19.7
7

Generic Development

DRUG DEVELOPMENT

CHAPTER 19

STABILITY TESTING & STABILITY SOPs

Stability of Finished Dosage Form
[EXAMPLE of SECTION 16 (STABILITY) of an ANDA]

Proposed Expiration Date
and Stability Commitment

A

ll stability data support the proposed expiration period of 2 years when the product
is stored at room temperatures.

Stability commitment
Long term commercial stability studied in accordance with the approved stability
protocol shall be carried out by [Generic Company Name Inc. / Ltd.] The stability
results of these studies shall be submitted in the annual ANDA Reports filed on the
anniversary date of the submitted product.
[Generic Company Name Inc. / Ltd.] commits to remove any batch promptly from the
market place any material falling outside the products check specifications.
Extensions to the expiration date will be made via the annual ANDA Reports as
acceptable long term stability data is obtained,
Rework procedures may be submitted for batches that fail to meet established specifications. Prior
to implementation, these procedures will be submitted in a supplement in accord with: 21 CFR
314.70 (b)(2)(x) on a lot by lot basis.

[Signature of Responsible Person]
------------------------------------------------

-----------------------------------------

[Name of Responsible Person]

Date

Regulatory Affairs Director

4

Handbook of Pharmaceutical

Chapter: 19.8
8

Generic Development

DRUG DEVELOPMENT

CHAPTER 19

STABILITY TESTING & STABILITY SOPs

Stability of Finished Dosage Form
[EXAMPLE of SECTION 16 (STABILITY) of an ANDA]

Stability Protocol for Post-approval Production Batches
SEMISOLID [000.0] mg/5g.

[Batch No: 000]

Package sizes: Smallest and largest containers
LONG TERM STORAGE CONDITIONS
Controlled Room Temperature:
25-30°C.
Test Intervals:
0,3,6,9,12,18,24 and 36 months.
Samples: First three marketable production batches and annual batch thereafter.
STRESSED STORAGE CONDITIONS
Accelerated Temperature:
40°C / 75%RH.
Test Intervals:
1, 2, 3 months.
Samples: To be submitted as appropriate in supplements to the approved application
STABILITY TESTING.
All test results will be subjected to compliance with current official requirements of the
approved applications and all supplements approved thereafter.
Test parameters will include:
TEST PROCEDURE
1
2
3
4

5

TEST METHOD
& ED. NUMBER
SI-5-000-01

SPECIFICATION

Appearance / Color / Odor
Conforms to stability protocol check
Container inner surface
specifications
pH
SI-5-000-01
NLT 0.0 NMT 0.0
Assay (Preservative)
SI-5-000-01
50.0 - 105.0% of labeled amount
[Only where necessary]
To (annually) and End of Study
Assay Active material
SI-5-000-01
90.0 - 110.0% of labeled amount
IMPURITIES / DEGRADATION PRODUCTS

6

- Each Individual
- Any other Individual
- Total:
Microbial Limit Test

SI-5-000-01
SI-5-000-01
SI-5-000-01
SI-5-000-01

7

Preservative Efficacy

SI-5-000-01

NMT 0.5% of the labeled amount
NMT 0.5% of the labeled amount
NMT 2.0% of the labeled amount
Meets USP Specifications
o
T (annually) and End of Study
Meets USP Specifications
To (annually) and End of Study

Report Format:
Results will be tabulated in the format of the Stability Report Form:
1) Product Name, and Strength
2) Batch Number and Batch size
3) Storage Conditions and Intervals
4) Container/Closure Systems - Description
5) Inventory Control Number of (4)
6) Fill Size and No of units on stability
7) Batch Manufacturing Date
8) Batch Packaging Date

Handbook of Pharmaceutical

9)
10)
11)
12)
13)
14)
15)
16)

Chapter: 19.9
9

Stability Start Date
Manufacturing Site
Manufacturer of Bulk Drug
Inventory Control Number of (11)
Manufacturer of Container/Closure
Formulation
Data profile
Methodology and Specifications

Generic Development

DRUG DEVELOPMENT

STABILITY TESTING & STABILITY SOPs

CHAPTER 19

Stability of Finished Dosage Form
[EXAMPLE of SECTION 16 (STABILITY) of an ANDA]

SUMMARY OF STABILITY STUDIES
The 3 months accelerated (40° ±2°C / 75 RH ±5% ) and 6 months room temperature
(25° ±2°C / 60 RH ±5%) stability data were examined for [Generic name] SEMISOLID
[000.0] mg / 5g.

The data indicate that the formulation is stable, with no observed degradation peaks,
under test conditions. There were no significant changes in either the physical
chemical, or microbiological specifications in any samples evaluated after the exposed
storage test conditions.

The attached tables and graphs are summaries of the results for the parameters used
to establish the stability profile of [Generic name] SEMISOLID [USP] [000.0] mg/5g for
the pivotal batch per dosage strength, where applicable.
Included, are assay chromatogram spectra of the stability tests for zero time (T0) and
the three (3) months accelerated test conditions.
[Generic name] SEMISOLID [USP] [000.0] mg/5g were stored at accelerated
conditions (40o ±2 o C / 75% RH ± 5%) and at room temperature (25° ±2°C/ 60% RH
±5%) in the proposed market container/closure system. All stability data supports the
proposed expiration period of 2 years when the product is stored at room
temperatures.

SIGNIFICANT CHANGE CLAUSE:
Where PRODUCTS fail the accelerated testing, Intermediate testing is performed
according to the following specification.
Intermediate testing
30 o ±2 oC/60 ±5%RH
0,1,2,3,6, 9 and 12 months

Significant change at the accelerated conditions is defined as:
1. Ø A 5 % potency loss from the initial assay value of a batch.
2. Ø Any specified degradant exceeding its specification limit.
3. Ø The product exceeding its pH limits.
4. Ø Dissolution exceeding the specification limits for 12 dosage units (USP Stage 2).
5. Ø Failure to meet specifications for appearance and physical properties (e.g. color)
Should significant change occur at 40oC/75% RH, the initial application should include
a minimum of 6 months’ data from an ongoing 1-year study at 30oC/60 percent RH; the
same significant change criteria shall then apply.

Handbook of Pharmaceutical

Chapter: 19.10
10

Generic Development

CHAPTER 19

STABILITY TESTING & STABILITY SOPs

DRUG DEVELOPMENT

Stability of Finished Dosage Form
[EXAMPLE of SECTION 16 (STABILITY) of an ANDA]

SUMMARY OF STABILITY STUDY RESULTS
FOR MODIFIED RELEASE DOSAGE FORMS.
HDPE Container Closure liner system
Container Size (cc) Ü

25°C 60%RH

40°C 75%RH

Smallest

Largest

Smallest

Largest

000 mL

HDPE Tube with (HDPP Cap)

þ

þ

þ

þ

000 mL

HDPE Container with (HDPP Cap)

þ

þ

þ

þ

2

Glass Container Closure Liner System

ý

ý

ý

ý

ý

ý

Bulk Packaging

Number of Pivotal Batches ('100 000+' rule)

[1]

Number of NON-Pivotal Batches (i.e. PQ Lot)

[0]

TOTAL NUMBER OF STABILITY BATCHES

1

Number of Temperature/RH Levels

2

Number of Dosage Strengths

1

Number of Container Closure Sizes

2

Number of Resins present in Containers

1

Number of Closure Systems

2

Number of Resins present in Closures

1

Number of Stability Studies Performed

8

Number of resins used in the HDPE containers = one resin from same supplier.
1

Typical Assembly : HDPE / ALUMINUM container with HDPE SCREW CAP and inner LINER.

2

Typical Assembly : HDPE TUBE / PLASTIC SCREW CAP and inner LINER

Handbook of Pharmaceutical

Chapter: 19.11
11

Generic Development

CHAPTER 19

STABILITY TESTING & STABILITY SOPs

DRUG DEVELOPMENT

Stability of Finished Dosage Form
[EXAMPLE of SECTION 16 (STABILITY) of an ANDA]
STABILITY REPORT
1
2
3
4
5
6
7
8
9
10

Product name, dosage form and strength.
Fill size
Site of Manufacture
Batch or lot number
Batch size (type)
Batch manufacturing Date and Packaging Date
Manufacturer of Active Material (approved supplier)
Date placed on stability
Batch number or receiving number of Active Material
Full details of container/closure system (type, material, resin)

Generic name] [000] mg / 5g
000 [USP]
NJ MNF SITE
000
000 000
Month DD 199Y / Month DD 199Y
LEK Chemical Co. dd
MM DD Y9Y
LK 4545
100cc HDPP (LR-8320-43) Al Tube
HDPP white cap (resin LR-7340-43)
Goods Receiving number of container-liner
GRN 96-2-02564 (body)
Goods Receiving number of closure
GRN 96-2-02227 (cap)
Manufacturer of container/closure
Wheeler Cap Co PA USA.
Objective of the stability program
þ Pivotal Batch
Site where stability test conducted
US PA MAN Site
Number of units to be sent for testing in each time interval
2 x 000
Analytical method number and Edition Number for each stability indicating test S-I 555-03 / S-I 1234 Ed . 03
Stability specifications indicating names of test required.
Tabulated
Number of packages placed on stability
70
Testing intervals required
0, 1, 2, 3 (6) months

11
12
13
14
15
16
17
18
19

40 degrees C / 75% RH

20 Stability storage conditions

Period

Date of
Analysis

Appearance
and ID

ASSAY
%

HPLC/TLC
Impurity
Profile

90.0 % 110.0%

Impurities
I
Impurities
II
Impurities
III
Total
< 3.0

White to
Creamish

Month

Method #

S-I-000 -01

S-I-000 -02

S-I 000 -03

Test performed on last day of 'Check Station '

ò SEMISOLIDS ò
n Description
n Appearance / Color / Odor
n Absence of GRITTINESS/WEEPING/SEPARATION
n Appearance of inner tube surface

MLT

PET

Viscosity

pH

Assay:

0

1/6/Y

conforms

100.3

conforms

Pass /Fail

Pass /Fail

00.0

00.0

00.0

3

5/9/Y

conforms

99.8

conforms

SKIP

SKIP

00.0

00.0

00.0

6

9/12/Y

conforms

101.3

conforms

Pass /Fail

Pass /Fail

00.0

00.0

00.0

9

15/3/Y

conforms

101.4

conforms

SKIP

SKIP

00.0

00.0

00.0

STABILITY

PARAMETERS

MLT - Microbial Limit Test / Microbial Purity
PET - Preservative Efficacy Test
21. Product Formula On Stability (Formula No: 000- Identical to ANDA Sections 6, 7, 11, & 12
1. Miconazole USP Micronized
2. Pegoxol 7 Stearate [Tefose 63™]
3. Heavy Mineral OIL NF
4. Benzoic Acid USP
5. Butylated Hydroxyanizole
6. Peglico 5 Oleate [LABRAFIL M 1944™]
7. Edetate Disodium USP

8. Purified Water USP

Handbook of Pharmaceutical

Chapter: 19.12
12

Generic Development

CHAPTER 19

STABILITY TESTING & STABILITY SOPs

DRUG DEVELOPMENT

Stability of Finished Dosage Form
[EXAMPLE of SECTION 16 (STABILITY) of an ANDA]
STABILITY REPORT
1
2
3
4
5
6
7
8
9
10

Product name, dosage form and strength.
Fill size
Site of Manufacture
Batch or lot number
Batch size (type)
Batch manufacturing Date and Packaging Date
Manufacturer of Active Material (approved supplier)
Date placed on stability
Batch number or receiving number of Active Material
Full details of container/closure system (type, material, resin)

[Generic name] [000.0] mg / 5g
000 [USP]
NJ MNF SITE
P-0000
000
Month DD 199Y / Month DD 199Y
LEK Chemical Co. dd
MM DD Y9Y
LK 4545
100cc HDPP (LR-8320-43) Al Tube
HDPP white cap (resin LR-7340-43)
Goods Receiving number of container-liner
GRN 96-2-02564 (body)
Goods Receiving number of closure
GRN 96-2-02227 (cap)
Manufacturer of container/closure
Wheeler Cap Co PA USA.
Objective of the stability program
þ Pivotal Batch
Site where stability test conducted
US PA MNF Site
Number of units to be sent for testing in each time interval
2 x 100
Analytical method number and Edition Number for each stability indicating test S-I 555-03 / S-I 0000 Ed . 03
Stability specifications indicating names of test required.
Tabulated
Number of packages placed on stability
70
Testing intervals required
0, 3, 6, 9, 12, 18, 24, 36… months

11
12
13
14
15
16
17
18
19

25 degrees C / 60% RH

20 Stability storage conditions

Period

Month

Date of
Analysis

Lab book
Ref. No

Method #

0

1/6/Y

Appearance
and ID

ASSAY
%

White to
Creamish

90.0 % 110.0%

S-I-000 -01

S-I-000 -02

HPLC/TLC
Impurity
Profile
Impurities
I
Impurities
II
Impurities
III
Total
< 3.0
S-I 000 -03

5/9/Y

ò SEMISOLIDS ò
n Description
n Appearance / Color / Odor
n Absence of GRITTINESS/WEEPING/SEPARATION
n Appearance of inner tube surface

conforms

101.3

conforms

MLT
Pass or
Fail

PET
Pass or
Fail

Viscosity
00.0

pH
0.0

Assay:
000.0

conforms

99.6

conforms

SKIP

SKIP

00.0

0.0

000.0

conforms

102.6

conforms

SKIP

SKIP

00.0

0.0

000.0

conforms

100.0

conforms

SKIP

SKIP

00.0

0.0

000.0

conforms

102.1

conforms

Pass or
Fail

Pass or
Fail

00.0

0.0

000.0

L/Book
N0: Page

3

Test performed on last day of 'Check Period'

L/Book
N0: Page

6

9/12/Y
L/Book
N0: Page

9

15/3/Y
L/Book
N0: Page

12

15/6/Y
L/Book
N0: Page

STABILITY

PARAMETERS

Additional Tests performed Annually: Microbial Limit Test USP
21. Product Formula On Stability (Formula No: 000- Identical to ANDA Sections 6, 7, 11, & 12.
1.
2.
3.
4.
5.
6.
7.

Miconazole USP Micronized
Pegoxol 7 Stearate [Tefose 63™]
Heavy Mineral OIL NF
Benzoic Acid USP
Butylated Hydroxyanizole
Peglico 5 Oleate [LABRAFIL M 1944™]
Edetate Disodium USP
8. Purified Water USP

Handbook of Pharmaceutical

Chapter: 19.13
13

Generic Development

CHAPTER 19

STABILITY TESTING & STABILITY SOPs

DRUG DEVELOPMENT

Stability of Finished Dosage Form
[EXAMPLE of SECTION 16 (STABILITY) of an ANDA]

PACKAGE CHARACTERISTICS
[Generic name] SEMISOLID [000.0] mg/5g [Batch No: 000]
[Generic name] SEMISOLID [USP] [000.0] mg per g.

[Batch No: 00]

Pivotal Lot Packaging Material Characteristics
ITEM

TYPE 1

TYPE 2

TYPE 3

TYPE 4

Container
manufacturer
Container size

Drug Plastics &
Glass Co. Inc.

Drug Plastics &
Glass Co. Inc.

Drug Plastics &
Glass Co. Inc.

Drug Plastics &
Glass Co. Inc.

00 / 000cc round,
HDPE JAR

00 / 000cc round,
HDPE JAR

00 / 000cc HDPE/

00 / 000cc HDPE/

COLLAPSIBLE TUBE

COLLAPSIBLE TUBE

(coated metal)

(coated metal)

Resin Type
Cap
Manufacturer
11087 PE
White Master
batch
Cap / Nozzle
Type
Cap Size
Closure Liner
Foam seal Mfg
Inner liner
composition
CONTAINER
CONTAINER
CAP
Nozzle / Applicator
LINER
SEAL

HDPE
Quantum LR-734043
U.S. CAN
(Penn-Wheeling
Closure Corp.)
White Ampacet
11078 Polyethylene

HDPE
Quantum LR-734043
U.S. CAN
(Penn-Wheeling
Closure Corp.)
White Ampacet
11078 Polyethylene

HDPE
Quantum LR-734043
U.S. CAN
(Penn-Wheeling
Closure Corp.)
White Ampacet
11078 Polyethylene

HDPE
Quantum LR-734043
U.S. CAN
(Penn-Wheeling
Closure Corp.)
White Ampacet
11078 Polyethylene

HDPE
LDPE

HDPE
LDPE

HDPE
LDPE

HDPE
LDPE

00 / 00 mm

00 / 00 mm

00 / 00 mm

00 / 00 mm

Tekni-Plex Inc.
Foamseal PS 22

Tekni-Plex Inc.
Foamseal PS 22

-

-

TEKNISEAL RVT
+ LF

TEKNISEAL X-14
(polyethylene/Kraft
Paper laminate)
Lot #00000
CoA #0000
Lot #00000
CoA #0000
Lot #00000
CoA #0000
Lot #00000
CoA #0000
Lot #00000
CoA #0000
Lot #00000

-

-

Lot #00000
CoA #0000
Lot #00000
CoA #0000
Lot #00000
CoA #0000
Lot #00000
CoA #0000
-

Lot #00000
CoA #0000
Lot #00000
CoA #0000
Lot #00000
CoA #0000
Lot #00000
CoA #0000
-

CoA #00000

CoA #00000

Lot #00000
CoA #0000
Lot #00000
CoA #0000
Lot #00000
CoA #0000
Lot #00000
CoA #0000
Lot #00000
CoA #0000
Lot #00000

CoA = Certificate of Analysis/Compliance
Handbook of Pharmaceutical

Chapter: 19.14
14

Generic Development

DRUG DEVELOPMENT

STABILITY TESTING & STABILITY SOPs

CHAPTER 19

Stability Testing of Drug
Substances and Drug Products II
INTRODUCTION TO ANDAs
STABILITY
TESTING
FOR
ABBREVIATED NEW DRUG
APPLICATIONS

I

n June 1998 FDA issued a lengthy
draft guidance titled 'stability testing of
drug substance and drug products', The
guidance interweaves the requirements
of NDAs and ANDAs for both drug
substance and drug product and
borrows heavily from the European
Stability Guidelines.

FDA Draft Guidance
harmonizes the
requirements for
US, EU & Japan

DRUG SUBSTANCE STABILITY
DATA SUBMISSION

For

The New Draft Guidance to industry is
extremely comprehensive and is
intended to replace the ageing 1987
guidelines, thus harmonising the
requirements for US, EU and Japan
They contain detailed recommendations
on all current aspects of stability
testing,
photostability,
including
reduced testing procedures via the use
of bracketing and matrixing protocols.
This Part II article deals only in part
(with Section III) of the proposed
guidance namely aspects affecting the
stability testing in ANDA dosage forms.
The guidance to industry covers all
drug types namely INDs, NDAs and
ANDAs.

Handbook of Pharmaceutical

Much of the general information for
New Drug Applications provided in the
guidance is also applicable to
Abbreviated New Drugs Applications
(ANDAs). However, depending upon
the availability of significant information
on, and the complexity of, these drug
products / dosage forms, the amount of
information necessary to support these
applications may vary from that
proposed for NDAs.
This section is intended to provide
specific recommendations on abbreviated (ANDAs) applications only.

drug products submitted under an
ANDA, including antibiotics, supporting
active material information may be
provided directly to the drug product
ANDA or by reference to an appropriate
drug master file (DMF). Publications
may be provided or referenced as
supportive information.
For ANDA bulk drug substances,
stability data should be generated on a
minimum of one pilot-scale batch.

Chapter: 19.15
15

Pilot-scale
or Pilot Plant Scale
means100 000 units
or 10% of full size
production batch

Generic Development

DRUG DEVELOPMENT

CHAPTER 19

STABILITY TESTING & STABILITY SOPs

Definition of Pilot-Plant Scale

The

manufacture of either drug
substance or drug product by a
procedure fully representative of and
simulating that to be applied on a full
manufacturing scale.
For oral dosage forms this is generally
taken to be at a minimum scale of one
tenth that of full production or 100,000
dosage units, whichever is the larger.
[Q1A] 3222.

For

biotechnology products, the
methods of cell expansion, harvest, and
product purification should be identical
except for the scale of production.

All

batches should be made using
equipment of the same design and
operating
principle
as
the
manufacturing-scale
production
equipment with the sole exception of
capacity.
For ANDA bulk drug substances
produced by fermentation, stability data
should be provided on three production
batches, at least two of which should be
generated
from
different
starter
cultures.

DRUG SUBSTANCE TESTING
A program for stability assessment may
include storage at:Ø accelerated,
Ø long-term, ,
Ø intermediate stability study storage
conditions (where applicable)
(Refer the stability Section II A. of the Guidance).

Section

II-A deals with the stability
testing of the drug substance in New
Drug Applications (NDAs). Stability
samples should be stored in the bulk
storage container equivalent (e.g. same
composition & type of container,
closure and liner, but smaller in size).
If not previously generated or available
by reference, stress testing studies
should be conducted to establish the
inherent stability characteristics of the
drug substance, and support the

Handbook of Pharmaceutical

suitability of the proposed analytical
procedures. The detailed nature of the
studies will depend on the individual
drug substance, type of drug product
and available supporting information.
Any necessary testing may be carried
out as described in Section II-A which
pertains to new drug applications.

DRUG PRODUCTS

Original ANDAs should contain stability
data generated under the long-term and
accelerated stability storage conditions
delineated in Section II-B of the
guidance (Section II B deals with the
stability testing of the drug products in
New Drug Applications i.e. NDAs.)

The

data package for ANDAs (e.g.,
number of batches, length of studies
needed at submission and at approval,
and accelerated, intermediate and longterm stability data) should be based on
several factors, including the complexity
of the dosage form, the existence of a
significant body of information for the
dosage form, and the existence of an
approved application for a particular
dosage form.

STABILITY DATA PACKAGE
RECOMMENDATIONS.
× Simple Dosage Forms Ø
The following stability data package is
recommended: (excludes controlled /
modified release dosage forms)
Ü Accelerated stability data at 0, 1,
2, and 3 months. A tentative expiration
dating period of up 24 months will be
granted
based
on
satisfactory
accelerated stability data unless not
supported by the available long-term
stability data.

Ü

Long-term stability data (available
data at the time of original filing and
subsequent amendments).

Ü
Ü

A minimum of one batch; pilot scale.

Additional stability studies (12
months at the intermediate conditions, or

long-term data through the proposed
expiration date) if significant change is

Chapter: 19.16
16

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STABILITY TESTING & STABILITY SOPs

seen after 3 months during the
accelerated stability study.
Ü The tentative expiration dating
period will be determined based on the
available data from the additional study.

×COMPLEX DOSAGE FORMSØ
Ø
Exceptions to the ANDA Data
Package Recommendations.
The following may be considered
exceptions to the general ANDA
recommendations:Complex dosage forms, such as
Ü Modified-release products.
Ü Transdermal patches.
Ü Metered-dose inhalers.
Ü Drug products without a significant
body of information.

Ü

New dosage forms submitted
through the ANDA suitability petition
process (Other exceptions may exist and
should be discussed with the Office of Generic
Drugs. Refer Q1C applications).

An ANDA that is determined to be one
of the above categories should contain
a modified ICH Q1A stability data
package, including:

◊ 3-month accelerated stability studies.
◊ Long-term stability studies (available

data at the time of original filing and
subsequent
amendments).
The
expiration dating period for complex
dosage forms will be determined based
on available long-term stability data
submitted in the application.

◊A

minimum of three batches
manufactured in accordance with the
ICH Q1A batch size recommendations
(refer Section II B of this guidance -NDA Drug
Products or to V.B. of the ICH Q1A guidance).

Additional stability studies (12 months
at the intermediate conditions or longterm stability testing through the
proposed expiration date) if significant
change is seen after 3 months during
the accelerated stability studies (the
tentative expiration dating period will be
determined based on the available data

Handbook of Pharmaceutical

CHAPTER 19

from the additional studies)

Complex Dosage Forms
MR/CR/ER/DR/MDIs
require THREE
Stability batches
Data Package for Approval

◊ Full-term

stability testing of the
primary stability batch(es) is suggested.
However, in the absence of full-term
stability data for the drug product,
adequate accelerated stability data
combined with available long-term data
can be used as the basis for granting a
tentative expiration dating period.

◊ The

batch(es) used for stability
testing should comply fully with the
proposed specifications for the product
and be packaged in the market
package, and the release assay should
be within reasonable variation (taking
into account inherent assay variability)
from the labeled strength or theoretical
strength of the reference listed drug.

◊ If

formulated with an overage, the
overage should be justified as
necessary to match that of the
reference listed drug.

◊ Other

supportive stability data may
be submitted on drug product batches
that may or may not

◊ meet

the above criteria. Data on
relevant
research
batches,
investigational formulations, alternate
container / closure systems, or from
other related studies may also be
submitted to support the stability of the
drug product. The supportive stability
data should be clearly identified.

Stability Study Acceptance
If the results are satisfactory, a
tentative expiration dating period of up
to 24 months at the labeled storage
conditions may be granted.

Chapter: 19.17
17

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STABILITY TESTING & STABILITY SOPs

Where

data from accelerated studies
are used to project a tentative
expiration dating period that is beyond
a date supported by actual long-term
studies on production batches, the
application
should
include
a
commitment to conduct long-term
stability studies on the first three
production batches and annual batches
until the tentative expiration dating
period is verified, or the appropriate
expiration dating period is determined.

Final Expiration Dating
means long term
stability studies on
three production lots
For Complex Dosages
Extension

of the tentative expiration
dating period should be based on data
generated on at least three production
batches tested according to the
approved protocol outlined in the
stability commitment.
Reporting of the data should follow
Section VI format of the guidance which
applies to all application types
ANDAs withdrawn prior to publication
of this guidance should not normally
have to include stability data in
conformance with the guidance upon
resubmission if the original application
was withdrawn due to non-stability
related issues.
However, if new stability studies are
conducted to support the submission,
such studies should be conducted as
recommended in the guidance.

REPORTING STABILITY DATA
A. General
Stability data should be included in the
ANDA application (or supplement) they
are intended to support. The extent of
stability data expected at the time of
submission is discussed at length
throughout the guidance.

Handbook of Pharmaceutical

CHAPTER 19

Additional

data from ongoing studies
and regular annual batches should be
included in the application’s annual
report. Annual reports should include
new or updated stability data generated
in accordance with the approved
stability protocol.
The data may include accelerated and
long-term studies for each product to
satisfy
the
standard
stability
commitment made in the original or
supplemental application, including the
annual batch(es), and to support postapproval changes.
The data should be presented in an
organized,
comprehensive,
and
cumulative format.
CONTENT OF STABILITY REPORTS
It is suggested that stability reports
include the following information and
data to facilitate decisions concerning
drug product stability:
GENERAL PRODUCT INFORMATION
• Product Name
• Source
• Manufacturing site(s)
• Date of manufacture of drug
substance and drug/biological product.
• Dosage form and strength,
• Product formulation.
• Composition, type, source, size, and
adequate description of container and
closure.,
seals,
and
desiccants
(stuffers) should be identified.
The application should provide a table
of specific formulations under study.
When more than one formulation has
been studied, the formulation number is
acceptable.

SPECIFICATIONS
AND
TEST
METHODOLOGY INFORMATION
• Physical,
chemical,
and
microbiological regulatory specifications
and attributes/limits (or specific references
to ANDA or USP).

Chapter: 19.18
18

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CHAPTER 19

STABILITY TESTING & STABILITY SOPs

• Test methodology used (or specific
reference to ANDA, prior submissions,
or USP) for each sample tested.
• Information on accuracy, precision,
and suitability of the methodology (cited
by reference to appropriate sections).
• Where applicable, a description of
the potency test(s) for measuring
biological activity, including specifications for potency determination.

STUDY DESIGN AND STUDY
CONDITIONS
• Description of the sampling plan,
including:
• Batches and number selected.
• Container/closures & number selected
• Number of dosage units selected and
whether tests were conducted on
individual units or on composites of
individual units.
• Sampling time points.
• Testing of drug or biological products
for reconstitution at the time of
reconstitution (as directed on the
labeling) as well as through their
recommended use periods.
• Expected duration of the study.
• Conditions of storage of the product
under
study
(e.g.,
temperature,
humidity, light, container orientation).

A Sampling Protocol
identifying sampling
points is necessary
STABILITY DATA/INFORMATION
• Batch number (research, pilot,
production)
and
associated
manufacturing date.
• For antibiotic drug products, the age
of the bulk active drug substance(s)
used in manufacturing the batch.
Analytical data, source of each data
point, and date of analysis (e.g., batch,
container composite, etc.) Pooled
estimates may be submitted if individual
data
points
are
provided.

Handbook of Pharmaceutical

- Individual data as well as mean and
standard deviation should be reported.
- Tabulated data by storage condition.
Summary of information on previous
formulations
during
product
development. This summary may be
referenced (if previously submitted) and
should include other containers and
closures investigated.

DATA ANALYSIS
The following data analysis of
quantitative parameters should be
provided:
• Evaluation of data, plots, graphics.
• Documentation
of
appropriate
statistical methods and formulas used.
• Results of statistical analysis and
estimated expiration dating period.
• Results of statistical tests used in
arriving at microbiological potency
estimates.

CONCLUSIONS
• Proposed expiration dating period
and its justification.
• Regulatory specifications set.
(Note: Establishment of acceptable minimum
potency at the time of initial release for full
expiration dating period to be fully justified).

Complex Dosage Form Definition
A complex dosage form is one where
quality and/or stability is more likely to
be affected by changes because the
release mechanism, delivery system,
and manufacturing process are more
complicated and thus more susceptible
to variability.
Examples of complex dosage forms
include modified-release dosage forms,
metered-dose
inhalers,
transdermal
patches, liposome preparations.
Due to the diversity of currently marketed
dosage forms and the ever-increasing
complexity of new delivery systems, it is
impossible to clearly identify simple vs.
complex dosage forms in an exhaustive
manner.
Applicants are advised to consult with the
appropriate FDA chemistry review team when
questions arise.

Chapter: 19.19
19

Generic Development

DRUG DEVELOPMENT

STABILITY TESTING & STABILITY SOPs

ANDA à

CHAPTER 19

STABILITY

DRUG PRODUCT à
SIMPLE DOSAGE FORMS
× IR Ø
Formulation for Simple Dosage Forms
Immediate Release Solids & Liquids

FLOWCHART
COMPLEX DOSAGE FORMS
× CR/MR/ER/DR/MDIs…Ø
Formulation for Complex Dosage Forms
Modified Release Solids & MDIs

Sampling Protocol
(Liquids & Suspensions)
Sampling Points

Sampling Protocol
&
Sampling Points

Stability Check Specifications
and Limits

Stability Check Specifications
and Limits

(Refer Guidance for each dosage form)

(Additional Guidance for complex dosage forms in the
FDA Pipeline)

Stability Protocol
Bracketing &
Matrixing Permitted

Stability Protocol
Bracketing &
Matrixing Permitted

THREE BATCHES PER STRENGTH
Two Pivotal 100 000 (net) or 10% rule
plus one small scale lot

ONE BATCH PER STRENGTH/SITE
100 000 (net) or 10% rule

(i.e. could be PQ or Scale-UP lots)

ACCELERATED CONDITIONS
1, 2, & 3 months @ 40 oC 75% RH
plus Real Time @ 25 oC

ACCELERATED CONDITIONS
1, 2, & 3 months @ 40 oC 75% RH

SIGNIFICANT CHANGE CLAUSE
applies if accelerated specifications go
OUT-OF-LIMITS
5% potency
Rule

SIGNIFICANT CHANGE CLAUSE
applies if accelerated specifications go
OUT-OF-LIMITS

A Problematic Rule

Reporting of Stability Data
A minimum data set and format
is required.
Expiration based on ACCELERATED
data

Handbook of Pharmaceutical

5% potency
Rule

Reporting of Stability Data
A minimum data set and format
is required.
Expiration based on REAL TIME data

Chapter: 19.20
20

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STABILITY TESTING & STABILITY SOPs

CHAPTER 19

Stability Testing of Drug
Substances and Drug Products III
SIGNIFICANT
CHANGE
CLAUSE

THE MEANING OF 'SIGNIFICANT
CHANGE' … IN ANDAs

A

s of June 1998 the FDA issued for
general comment a comprehensive
and lengthy draft guidance titled
'Stability testing of drug substance and
drug products'. The guidance interweaves the requirements of INDs,
NDAs and ANDAs for both the active
drug substance and finished drug
product. It references and borrows
heavily from the European Stability
Guidelines.

Comprehensive
US Draft Guidance
partly harmonizes
US, EU & Japan
Stability Requirements
The New Draft Guidance to industry is
extremely comprehensive and detailed.
It is intended to replace the aging,
twelve year old, 1987 guidelines,
thereby
in
one
step
partially
harmonising the requirements for US,
EU and Japan while not deviating too
much
from
the
current
ANDA
requirements.
The
EU
stability
requirements are adequately met with
additional
existing
US
ANDA
requirements. The 110 page document
contain detailed recommendations on
all current aspects of stability testing,

Handbook of Pharmaceutical

photostability, including reduced testing
procedures via the use of bracketing
and matrixing protocols.
This Part III article deals with the
significant change at accelerated
conditions and the possible pitfalls
arising from this rule, during stability
testing in finished drug dosage forms.
Past experience shows that in many
stability programs, the proposed one
year, 30oC study, may well be needed,
in addition to the normal accelerated
and real time studies, as a 5%
potency/assay loss, frequently occurs
during
the
initial
three
month
accelerated
study
period.
Neither the ICH or Draft FDA guidance
takes into account of the intermediate
precision RSD of the validated stability
indicating assay. This means that the
5% is net and overlooks a standard 2.04.0% intermediate precision RSD
thereby reducing the actual 5% assay
value in real terms.

Significant Change
clause simple means:
START a 30oC / 60%RH
one year study
from DAY ONE of the
Stability Program
Just-in-Case it's Needed

Chapter: 19.21
21

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DRUG DEVELOPMENT

Where

significant change occurs due
to accelerated testing, additional testing
at an intermediate condition (e.g.,
30oC± 2oC / 60% RH ±5%) should be
conducted.
Significant change at the accelerated
conditions is defined as:
Ü5 percent potency loss from the
initial assay value of a batch.

ÜAny

specified degradant exceeding
its specification limit.

ÜThe product exceeding its pH limits.
ÜDissolution exceeds the specification

Alternatively,

Where

a significant change occurs
during 12 months of storage at
30ºC/60%RH, it may not be appropriate
to label the drug product for Controlled
Room Temperature (CRT) storage with
the proposed expiration dating period,
even if the stability data from the full
long-term studies at 25ºC/60%RH
appear satisfactory.

Significant Change
may occur during the
30oC / 60%RH

ÜFailure

to meet specifications for
appearance and physical properties
(e.g., color, phase separation, resuspendability, delivery per actuation,
caking, hardness) [ICH Q1A].

FIVE Criteria exist
requiring an additional
30oC / 60%RH
one year study
significant change occur at
40 C/75% RH, the initial application
should include a minimum of 6 months’
data from an ongoing 1-year study at
30oC/60 percent RH; the same
significant change criteria shall then
apply. [ICH Q1A]
If any parameter fails significant change
criteria during the accelerated stability
study, testing of all parameters during
the intermediate stability study should
be performed.
If stability samples have been put into
the intermediate condition, but have not
been tested, testing these samples may
begin as soon as the accelerated study
shows significant change in the drug
product specifications.
o

Handbook of Pharmaceutical

the study at the

intermediate condition should
be started from the initial time
point.

limits for 12 dosage units for oral units
and suspensions (USP Stage 2).

Should

CHAPTER 19

STABILITY TESTING & STABILITY SOPs

intermediate study
- as well
In

such cases, alternate approaches,
should be considered during drug
development. such as the following:-

Ü

Qualifying
higher
criteria for a degradant

acceptance

Ü

Shorter expiration dating period,
or refrigerator temperature storage

Ü

More protective container and/or
closure

Ü
Ü

Modification to the formulation

Modification of the manufacturing
process.
ADDITIONAL LABELLING
If CRT storage is ultimately justified, it
may be necessary to add to the product
labeling a cautionary statement against
prolonged exposure at or above 30ºC.
The long-term testing will be continued
for a sufficient period of time beyond 12
months to cover shelf life at appropriate
test periods.

Chapter: 19.22
22

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CHAPTER 19

STABILITY TESTING & STABILITY SOPs

ADDITIONAL DATA

STABILITY TESTING PROTOCOL

The

additional or further accumulated
data should be submitted to the FDA
during the assessment period of the
drug application. [ICH Q1A.]
The first three production batches
manufactured post approval, if not
submitted in the original application,
should be placed on accelerated and
long-term stability studies using the
same stability protocol as in the
approved drug application. [ICH Q1A.]

Place sufficient stability samples for
all three temperature ranges within
30 days from manufacturing date

250C

PLACE & HOLD

FOUR TEST STATIONS
A minimum of 4 test stations (e.g., 0, 2,

Test for 0, 1, 2, 3
months

4, and 6 months) are recommended for
the 6-month accelerated stability study.

DEFINITION (FDA / ICH)
Significant Change

[1] 5 percent potency loss from the
initial assay value of a batch
[2] Any
specified
degradant
exceeding its specification limit
[3]

Product exceeding its pH limits

[4] Dissolution
exceeding
the
specification limits for 12 dosage units
[5] Failure to meet specifications for
appearance and physical properties, for
example.
Tablets:Color, hardness
Suspensions:- Color, phase separation
Re-suspendibility, and
caking
Semisolids:- Color, phase separation
Liquids:Color,
Aerosols:Delivery per actuation
phase separation.

Handbook of Pharmaceutical

Start testing if any
of the 5 accelerated
conditions fail.
TEST for up to
12 months

[ICH-Q1A]

Significant change for a drug product at
the accelerated stability condition and
the intermediate stability condition is
defined as:

Chapter: 19.23
23

400C

300C

Full Monograph
testing required

Continue
until
either
400C
or

any
300C
study
FAILS
then
STOP
all Test

FAIL
PASS

0, 2, 4, 6, 12 months
sampling periods

If
significant
change
occurs
again
Re-formulate
Re-qualify
Re-view
alternative
approaches

All
400C
tests
pass for
Three
months
þ
Product
OK

If Real Time 25oC PASS
but additional 30oC study
shows Significant Change
as well - then a Cautionary
Labeling Statement is required.

Generic Development

CHAPTER 19

STABILITY TESTING & STABILITY SOPs

DRUG DEVELOPMENT

When Applicable
1

2

Initial To
Assay decreases
> 5% during
1, 2, or 3 months
of 30/40o C Study
Initial assay must be
'close to 100% rule'

Specification
Limit of any
drug product
degradant is
exceeded during
o
30/40 C Study

3

4 +5

Drug Product
exceeds it pH
limits during
o
the 30 or 40 C
Study

SIGNIFICANT CHANGE

Dissolution
exceeds 12
dosage unit
specification
or
Appearance
or
Physical
properties

IMPACT ON TESTING
Ü Three Study Temperatures in stability protocol
Ü Evaluate stability profile in PQ batch to access and eliminate significant change
Ü Qualify and document check specifications precisely accounting for relevant
aging (e.g. white to gray-white, or cream/light yellow/light gray colored etc.)
Ü Critical Parameter Qualification Protocol for PQ or Pivotal Batch Lot
Ü pH range Qualification Protocol for liquids, suspensions and semisolids
Ü Rugged Assays with low RSD values for intermediate precision (day-to-day)
Ü SOP to define 5% change as meaning net value change (i.e. 5% ± RSD1)
Ü More detailed Investigation procedures to evaluate, if >5% change is not due to
an analytical procedure or technician error.
RSD1 values for actual full assay method's intermediate precision calculated on
different days, with different lab technicians and equipment, under routine
conditions.
IMPACT ON DRUG DEVELOPMENT

Ü
Ü
Ü

Longer times required for overall stability study evaluation - more costly studies.

Ü
Ü

Viscosity Qualification Study 2 essential in either PQ or Pivotal Batch lots.

Formulations to be rugged / robust to withstand potential 5% assay change.

Enhanced antioxidant / chelating formula optimization studies1 necessary
during product development stages.

Full Analytical Assay Validation must be performed at the PQ stage or earlier to
sufficiently evaluate potential significant change parameters.
1 Refer: International Journal of Generic Drugs, Volume 01; No 08; 1997.Locum Press.
2 Refer: International Journal of Generic Drugs, Volume 01; No 06; 1997. Locum Press.

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Chapter: 19.24
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CHAPTER 19

STABILITY TESTING & STABILITY SOPs

STANDARD OPERATING
PROCEDURES

Total Pages 4.

EVALUATION OF SIGNIFICANT CHANGE
RESULTS IN STABILITY TESTING PROCEDURES
PURPOSE

T

he purpose of this Standard Operating Procedure is to define the procedure to
be observed in the case of questionable laboratory results being obtained due to
significant change occurring during stability testing programs. This SOP is designed
to fully address the impact of potential significant change in stability analytical results
due to laboratory error causes (Ref. Draft Stability Guidance to Industry, June 1998.)
Significant change analytical results are defined as the following:
[1]. Analytical results which falls outside of the Stability Check Specifications.
[[2]. >5 percent potency loss1 from the initial analytical assay value of the batch
(i.e. values outside the >5% ± RSD2 range)
[3]. Any specified drug product degradant exceeding its specification limit.
[4]. Dissolution assay results for oral units or oral suspensions exceeding the
specification limits for 12 dosage forms (USP Stage 2 criteria).
[5]. Failure to meet product CHECK specifications for appearance and physical
properties or where the product exceeds its CHECK SPECIFICATION pH limits.

RESPONSIBILITY

◊ Laboratory Analysts are responsible for immediately informing their supervisor of
any significant change or questionable analytical result obtained.

◊ Laboratory Supervisors are responsible for conducting a laboratory investigation
together with the appropriate analyst.

◊ After

such investigation is complete the supervisor shall determining whether
repeat analytical testing is necessary and the Quality Assurance Manager
(Development) shall be informed of the investigation's conclusions.

FREQUENCY
Applies to laboratory analysis where a questionable stability result or a significant
change in a previous test result has been obtained.

PROCEDURE (Ref. - Appendix 1 - GENERAL FLOW CHART)
[1]. The Analytical testing Laboratory shall maintain and keep current a Significant
Change Logbook. The Logbook shall record all Significant Change results and retest
procedures and investigations.
1

2

Adjusted Significant Change that includes analytical variance value. Relative Standard Deviation
(RSD) values for test assay method's intermediate precision. Calculated from assays performed on
different days, with different lab technicians and equipment, under routine testing conditions.
ED. N0: 01
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STANDARD OPERATING
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EVALUATION OF SIGNIFICANT CHANGE
RESULTS IN STABILITY TESTING PROCEDURES

[2]. Where a questionable analytical result is obtained during routine laboratory
testing, the testing analyst shall immediate inform the appropriate supervisor.
[3]. The supervisor and the analyst shall then conduct a laboratory investigation
which shall include a review of the analytical principles using the “Checklist For
Laboratory Investigation Report” (See “Out of Specification Result SOP.”)
[4]. Where the laboratory investigation reveals that the cause of the questionable
result is a LABORATORY ERROR, i.e. one of the principles mentioned in the
checklist was at fault, the supervisor shall invalidate the original test results. The
supervisor shall record the conclusions and scientific rationale in the analyst's
laboratory notebook. The comments shall be signed and dated.
[5]. Where the cause is found to be faulty analytical technique, the test is repeated
(in duplicate from the beginning) on the same sample (i.e. from the same stability
sample container initially used for sampling and testing).

Ü If the sample passes the retest, then the result may be released and accepted.
Ü In cases of retest failure, proceed as per paragraph [9].
[6]. Where the cause is due to faulty analytical methodology, a new edition
methodology revision shall be prepared.
[7]. Where the laboratory investigation is INCONCLUSIVE, and the cause cannot
definitely be ascribed to laboratory error, proceed as follows:
[8]. If the relevant pharmacopoeia specifies acceptance criteria guidelines for the
particular type of test involved (Viscosity, microbial limits etc.), the analyst shall
proceed with the testing according to the official method. If the retest passes, it is
reported according to the pharmacopoeial requirements. If the compendial retest
fails, the Quality Assurance Unit inform for further investigation, where appropriate.
[9]. Where, the relevant pharmacopoeia does not specify retesting procedures for
the particular type of test involved, TWO re-tests will be performed by TWO analysts
(that is, the sample shall be tested in duplicate).
The final result is calculate as the average of the THREE analysis (e.g. 6 results
which include the results from two re-tests and the original test result). No individual
analysis of the retest results shall fail the specifications.
ED. N0: 01
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Chapter: 19.26
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CHAPTER 19

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DRUG DEVELOPMENT

STANDARD OPERATING
PROCEDURES

Total Pages 4.

EVALUATION OF SIGNIFICANT CHANGE
RESULTS IN STABILITY TESTING PROCEDURES

[10]. In cases that the results are within the specified limits, the results are accepted.
[11]. If the retest result still remains questionable, the supervisor will inform the
Quality Assurance Unit for further investigation, if so required.
[12]. The Quality Assurance Unit shall fully review the data and decide if the test
results should be reported as is, or additional action is required.

LIMITS & LIMITATIONS
Retesting may not be performed until an investigation is completed or the laboratory
supervisor's permission has been given. The results of the investigation shall
determine at what point re-testing is appropriate (if, at all).
In the case of a proposed analytical methodology revision, retesting with the new
edition method may proceed, but the results shall not be accepted or utilized until
the method is fully validated, approved and duly authorized.

CORRECTIVE ACTION
Retesting is performed on the same sample container originally used, (obtaining
new samples, new sample stock or performing new sampling procedures from bulk
material or stability stock is prohibited.)

DOCUMENTATION
Laboratory investigations shall be fully documented, and the conclusions signed and
dated by the Laboratory Manager.
In case where the investigation is passed on to the Quality Assurance Unit Manager,
an Investigation Report shall be prepared.
All analytical re-testing of stability tests is to be reported and documented in the
Significant Change Log. The Log book is held under the responsibility of the
Analytical Laboratory Manager and the Stability Unit Manager.
A “Checklist For Laboratory Investigation Reports” is filed in all cases of
questionable or significant change results following a laboratory investigation.
The Investigation Report Number is recorded in the Significant Change Log.

ED. N0: 01
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APPROVED:

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Chapter: 19.27
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CHAPTER 19

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DRUG DEVELOPMENT

STANDARD OPERATING
PROCEDURES

SOP # S-435-01-089Y

Total Pages 4.

EVALUATION OF SIGNIFICANT CHANGE
RESULTS IN STABILITY TESTING PROCEDURES

Appendix 1 FLOW CHART
Significant Change with
Questionable Lab Result
Immediate Notification
Investigation Started

LABORATORY INVESTIGATION
FINDINGS in LOGBOOK
NON CONCLUSIVE
RESULTS

LABORATORY ERROR
Invalidate original results
and RETEST on the SAME
sample in duplicate.

Specific Pharmacopoeial
Retest Procedures allowed
Retesting

Not Specified
PASS
Retest TWICE (duplicates) on
Same Sample - TWO analysts

FAIL

PASS
FAIL
PASS
FAIL

Report Average of all
three analysis (6 results)

LOG
RESULT

LOG
RESULT

QA INVESTIGATION

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R&D

Chapter: 19.28
28

RA

QC / QA

Generic Development

DRUG DEVELOPMENT

STABILITY TESTING & STABILITY SOPs

CHAPTER 19

Stability Testing Storage
Conditions
STORAGE
PARAMETERS

TEMPERATURE/HUMIDITY

STABILITY GUIDELINES
LONG TERM, INTERMEDIATE &
CONTAINER-CLOSURE SYSTEMS

S

tability data should be developed for
the drug product in each type of
immediate container and closure
proposed for marketing, promotion, or
bulk storage.
The possibility of interaction between
the drug and the container and closure
and the potential introduction of
extractables into the drug product
formulations during storage should be
assessed
during
container/closure
qualification studies using sensitive and
quantitative procedures.
These studies are recommended even
if
the
container-closure
meet
compendial suitability tests, such as
those outlined in the USP for plastic
containers and elastomeric or plastic
closures.
A draft guidance is available on this
topic entitled; Submission of Documentation
in Drug Applications for Container Closure
Systems Used for the Packaging of Human
Drugs and Biologics (June 1997).

Solutions

(i.e., oral, SVPs, LVPs, oral
and nasal inhalations, and topical
preparations), dispersed systems (oral,
MDIs, injectables), and semi-solid drug
products (topical, ophthalmics, and
otics) should be stored in both the
upright and either inverted or on-theside positions until contact with the
container/closure system has been
shown not to impact on drug product
quality.

Handbook of Pharmaceutical

ACCELERATED CONDITIONS
The

comparison between upright and
inverted or on-the-side position is
important to determine whether contact
of the drug product (or solvent) with the
closure results in extraction of chemical
substances
from
the
closure
components
or
adsorption
and
absorption of product components into
the container/closure.
The evaluation should include the set
of
test
parameters
(check
specifications) that are listed in
Considerations for Specific Dosage
Forms in Section VIII of the draft
Guidance

Development Stability
Studies Include

Upright & Inverted
Positions
Upright

versus inverted/on-the-side
stability studies should be performed
during the pre-approval and postapproval verification stages of the
stability program.
Once it has been demonstrated that the
product in maximum contact with the
primary pack does not have a
significantly greater impact on drug
product quality than the upright
orientation, stability studies may be
continued only in the most stressful
orientation, which is generally the
inverted or on-the-side position.

Chapter: 19.29
29

Generic Development

DRUG DEVELOPMENT

CHAPTER 19

STABILITY TESTING & STABILITY SOPs

LONG TERM, INTERMEDIATE & ACCELERATED CONDITIONS
Tabulated storage conditions detailing temperature, humidity and orientation as
recommended in the proposed June 1998 stability testing guidance document.

Container-Closure

CONDITIONS

TIME at File

Storage Orientation áâ

Long Term Stability
Solid Oral Dosage Forms
Glass Containers (solid oral)
Glass Containers (liquids) áâ
Semi Permeable á â

25oC ±2oC
o

o

25 C ±2 C
25oC ±2oC
25oC ±2oC

Optional

60% RH ±5%

12+

3+

[60%RH ±5%]
[60%RH ±5%]

12
12+
12+
NDA

3+
3+
3+
ANDA

6
6
6
NDA

3
3
3
3
ANDA

6+
6+
6+
6+
6+
6+

6+
6+
6+
6+
6+
6+

40% RH ±5%
Optional

Accelerated Stability
Solid Dosage Forms
Glass Containers (solid oral)
Glass Containers (liquids) áâ
Semi Permeable Containers á â

40oC ±2oC
40oC ±2oC
40oC ±2oC
40oC ±2oC

75% RH ±5%
[75%RH ±5%]
[75%RH ±5%]
15% RH ±5%
Optional

Intermediate Stability
Solid Dosage Forms
Glass Containers (solid oral)
Glass Containers (liquids) áâ
Semi Permeable (SP) áâ
Ophthalmics + Otics (SP) áâ
Nasal Sprays (SP) áâ

30oC ±2oC
30oC ±2oC
30oC ±2oC
30oC ±2oC
30oC ±2oC
30oC ±2oC

Submission
NDA
ANDA

60% RH ±5%
[60%RH ±5%]
[60%RH ±5%]
40% RH ±5%
40% RH ±5%
40% RH ±5%

Stability

Storage Conditions for container-closures which may be susceptible to
water loss are defined as: Semi-Permeable & Permeable containers for: þ Large
volume parenterals (LVPs); þ Small volume parenterals (SVPs); þ Ophthalmics;
þ Otics, & þ Nasal sprays packaged in semi-permeable containers, such as plastic
bags, or semi-rigid plastic containers e.g., ampoules, vials and bottles with or without
droppers or applicators.

LOW TEMPERATURE - LONG TERM & ACCELERATED
CONDITIONS
CONDITIONS

DOSAGE FORM
Container-Closure
Long Term Stability - Refrigerator
5oC ±5oC

TIME
At Submission

No Control

Accelerated Stability - Refrigerator
25oC ±2oC

60% RH ±5%

Long Term Stability - Freezer
-15oC ±5oC

No Control

Accelerated Stability - Freezer
5oC ±3oC

Handbook of Pharmaceutical

Chapter: 19.30
30

Ambient RH

NDA

ANDA

12+
NDA

3+
ANDA

6
NDA

3
ANDA

12+
NDA

3+
ANDA

6

3

Generic Development

DRUG DEVELOPMENT

CHAPTER 19

STABILITY TESTING & STABILITY SOPs

Setting-up
a Functional
Stability Unit

I

n setting-up a stability unit it is
necessary to highlight some current
deficiencies found in Pharmaceutical
Stability Departments, as well as
indicating
the
necessary
control
structures required for the efficient
operation of a functional Stability
Department. The structure of a practical
and
operational
proven
stability
department is herewith described.
Stability Control.
Stability control is achieved through
standard operational systems - namely
proper
stability
documentation,
sufficient control SOPs and acceptable
monitoring equipment and laboratory
facilities.
The
analytical
testing
section
(personnel and equipment) must be of
sufficient size to adequately perform the
stability tests in the required time.
Stability testing depends on good
timing. Consistently late drug product
testing is of little scientific or regulatory
value.
Number of SOPs required
Stability SOPs number about 45 to 50
for a well managed and organized
stability
department
to
operate
efficiently within current GMP.
A comprehensive list of the stability
control
SOPs
and
some
SOP
summaries, controlling key functions
are included in this issue to highlight
the many operational details required.
In Generic and Researched-based
analytical laboratories, stability testing
is performed in three target areas.

Handbook of Pharmaceutical

Each area is fundamental to the longterm success of the firms products,
whether the products are New Drugs
(NDAs), ANDAs or simply OTCs.
Departments Impacted
The stability department(s) must service
the Development Department (or
R&D), the Regulatory Batches (those
submitted to the authorities) and the
Production Department (where each
commercial product is placed on
stability once a year - i.e. only one
batch of each strength and largest pack
size).

The Stability Requirements
The main stability operations are:
⇒ Development Stability
• Stability testing during the key
product development stages (i.e.
stability testing prior to the pivotal
batch used for regulatory filing).
⇒ Regulatory Stability
Stability testing of ANDA / AADA FDA
filed batch(es):♦ Original
Generic
Applications
submitted to FDA.
♦ Amended Applications (before file
approval.)
♦ Supplementary
Applications
(changes after approval.)
⇒ Production Stability
Stability testing - annually on a
representative full production batch.
♦ One production batch per product,
per strength, per year.
♦ Annual Reports - ongoing stability
commitments per filed application.

Chapter: 19.31
31

Generic Development

DRUG DEVELOPMENT

Stability Facilities
Adequate stability facilities

are
required. The number of stability tests
increase every year. Thus facilities are
required to be sufficiently large in order
to accommodate the annual growth.
Firms need to invest adequately in the
stability department facilities and
equipment.
The stability data on development,
regulatory, or production lots constitute
critical review data during ANDA file
review and Pre-approval Inspections
(PAIs.)
The minimum stability facilities required
are:

The Environmental System:
◊ A large 25oC - 30oC controlled
environment stability room with
generous multilevel shelving.
◊ dedicated
room(s)

controlled

temperature

◊ continuous recording of temperature
and humidity in the stability room(s)

tape or disc system).
• A rapid/high speed printer with
continuous paper or sheet feed .
This is a minimum acceptable system.
Review chemists and Scientific Officers
conducting GMP or pre-approval
inspections regard a suitable structured
and efficiently established stability
department as a critical factor in the
evaluation program. Therefore the
following areas should be properly
reviewed:

♦ correctly formatted Stability Reports
(for agency review chemists).

♦ adequate environmental control on
temperature and humidity (review of
recording graphs) - reviewed by PAI
site inspectors.

♦ skillfully written Stability SOPs - for
efficient daily operation (reviewed
during PAI site visits).
Meticulous care is necessary to pass a
ANDA product specific pre-approval
site inspection.

77

◊ a validated environment - (room
probes and periodic room validation)

Do’s & Don’ts

◊ 30o and 40oC climatic chamber
cabinets with automatic recorders.
◊ a light chamber cabinet (optional)
[Drug Products need to be properly
exposed to the controlled environment
- this requires orderly storage on
appropriate and spacious shelving.
Products
may
not
be
stored
indiscriminately in cardboard boxes].

The Minimum
Set-up
Requirements
The Computer system
• A stability computer (Pentium) with a
validated stability software program.
• A computer back-up system (e.g.

Handbook of Pharmaceutical

CHAPTER 19

STABILITY TESTING & STABILITY SOPs

for Managing
Stability
Departments.
Formal SOP monitoring
Do - insure that Stability SOPs

are
or bi-

regularly updated annually
annually.
Do - monitor and approve proposed
changes to Stability SOPs.
(Avoid stability and quality control
laboratory personnel displaying a nonawareness of the departmental SOPs in
their essential day-to-day work).

Chapter: 19.32
32

Generic Development

DRUG DEVELOPMENT

STABILITY TESTING & STABILITY SOPs

Do

- train and re-train staff in the
correct use and understanding of
current SOPs.
Do - check the firms SOPs adequately
cover all aspects of stability operations
required by the FDA or Agency.
Do - insure the instructions and details
in the SOPs are adequate and sufficient
to assure consistent and repeated
operation by staff, reading the SOPs.
Do - check staff are aware of latest
edition of the Stability SOPs, affecting
their day-to-day work.
Do - provide frequent departmental
training in ‘reviewing and understanding’ the principles of the SOPs.

ALWAYS KEEP
DEPT. SOPs
ON SITE
(Electronically
If possible)

Do -

insure operational personnel are
aware of the latest editions of the SOPs
and where they can be located in their
stability department (All SOPs on Site).
Do - insure they are able to refer to the
SOPs for rapid guidance in performing
their routine daily duties and tasks.
Do - insure supervisors and personnel
have signed a ‘Read and Understood’
form annually indicating full awareness
of the SOP contents.
Do - insure SOP distribution is
adequate and the SOP Change Control
System really works and is consistently
on time.
Do - insure the 25oC climatic area for
storing the ANDA / NDA and OTC
stability samples at 25o C (±
± 2o) is a
controlled environment room.

Do

- insure access is through an
controlled-access door, that does not
affect the environmental temperature every time the door is opened.
Handbook of Pharmaceutical

CHAPTER 19

Don’t - allow the stability

room to be
used as a stability office, where
personnel are continually entering and
leaving the controlled facility.
Don’t - allow an air-conditioned 22o 25oC stability office to function as a
25oC climatic room.
Don’t - store the 25oC long term
stability samples in an office.
(In terms of GMP compliance such a
facility
is
inadequate
and
the
environment cannot be controlled).
Don’t - install unreadable chart
temperature recorders due to the
smallness of the rotating chart.
(Out-of-specifications temperatures are
not adequately shown on these charts,
as the range divisions on the chart are
cramped and often too small. Narrow
chart sensitivity scales are generally
unsuitable and unreadable. The
compliance value of such a temperature
recording system is of minimal value
and open to agency challenge).
Do - insist that current recording
devices are fitted with larger chart
recorder so that the daily temperatures
and OOS values can be read with
accuracy and precision.
Do - insure there is a system for 60%
RH control (environmental humidity).
Do - insure the stability room has
sufficient temperature probes at the
upper and lower levels of the room
where the stability samples are being
stored.
Do - construct a dedicated stability
room with controlled environmental
facilities that maintain the temperature
at 25o C (± 2o C) and the relative
humidity at 60% RH (± 5%).
Do - install the 30o and 40o C climatic
chamber units inside the controlled
stability areas or rooms.
Don’t - allow stability samples for
ANDA/NDA and OTC (development, or

Chapter: 19.33
33

Generic Development

DRUG DEVELOPMENT

STABILITY TESTING & STABILITY SOPs

production samples) to be stored in
cardboard boxes on cramped shelving
(i.e. stacked one on top of the other).
(Reason - the samples are not exposed
to the environment uniformly as they
are protected by the insulating
cardboard boxes in which they are
stored.
Thus the lower samples are screened
by the newer samples and a uniform
controlled exposure to temperature and
humidity is not generally achieved.
The older stability samples at the
bottom of the cardboard box will be
temperature and humidity screened by
the several upper sample layers.)
Do - avoid product exposure to large
seasonal variations which do not keep
the temperature in (non-insulated)
stability rooms within a ±2o C range of
25o C, in either winter or summer.
Do - avoid
uneven
room
temperature exposures (near doorways,
vents, fans.)
Do - insure the samples are arranged
on the shelving in a neat, orderly
manner.
Do - insure there is not a large across
room-variation in temperature and
humidity. Both these variables must be
adequately controlled (<5 %).
Do - insure the upper and lower
shelves have been challenged for
temperature compliance.
(A single
chart recorder probe does not record
the temperature accurately at which all
the stability samples are stored.
Multiple probes are necessary - i.e. > 2
upper and 2 lower.
Do - insure the room temperature
validation studies have been conducted
to insure the firm is aware of the actual
storage parameters of the stability
ANDA/NDA and OTC test samples.
Do - insure there is a substantive
review and control of stability
temperature recorders or charts.

Handbook of Pharmaceutical

CHAPTER 19

Do - insure temperature/RH charts are
reviewed for out-of-specification (OOS)
temperature and RH values.

Review Recording
Charts for OOS
Values - Daily
Do

- insure the monitoring control
charts are adequately signed and filed
in an rapid retrieval system.
Do - insure adequate quality
assurance evaluation is performed on
the recording charts.
Do - insure there is corrective action
taken when the stability temperature
goes out of the specifications (OOS).
Do - insure that is possible for the firm
to conclusively assure the FDA that the
filed drugs were held at 25o C, 40o C (
±2o C) for the required storage periods
of 3, 6, 9, 12, 18, + etc. months.
Do - insure a corrective action SOP
exists - to determine the procedures to
follow after a failure of the recording
equipment or power supply during an
ongoing stability study.
Do - insure corrective actions are
carried out, documented and closed.

Have emergency
procedures in place
Do

- insure there are written
emergency procedures for the use of
calibrated hand-thermometers and
recording logbooks due to recorder or
stability probe failures.
Do - insure air-condition failures or
equipment shutdowns are recorded.
Do - insure periodic revalidation and
temperature distribution studies of the
climatic chambers are carried out
(every two years or when there is a
change).

Chapter: 19.34
34

Generic Development

DRUG DEVELOPMENT

Do

STABILITY TESTING & STABILITY SOPs

- insure Original Data Summary
Sheets are never replaced with
unauthorized "corrected versions".
Do - outlaw the use of "White-Out
tapes or liquids" in stability and other
reports.
Do - review of the annual report
prepared for the FDA to show that the
ongoing stability testing has been met,
as per the filed ANDA commitment.
Agency Case-History I. - Data values
go unrecorded.
Investigations highlighted that one set
of data values had not been recorded.
The appearance that the stability data
sheets are a direct and accurate
transfer procedure of the raw data in
the laboratory notebooks is open to
question and further investigation.
This technique appears to be used to
alter raw data when the original
worksheet data was not in compliance.
Case History II - Lost raw data
The 6 month data point for the product
potency was required to be evaluated
by microbial assay. However the raw
data to support this assay value in the
stability data sheet was not able to be
found. Further investigation highlighted
that this raw data was untraceable.
Do - insure there is no lost data and
full traceability of stability test points.
Do - insure summary data sheets
containing ‘failed analysis results’ are
meticulously signed and filed.
Do - insure there exists a well
documented reporting system for the
repeat testing of stability data,
according to written SOPs.
Do - insure traceability of ALL tests
performed via the laboratory worksheets, resulting in full credibility of the
laboratory test results.
Do - investigate thoroughly if it
appears that the stability data is tested
and repeat tested until it passes.

Handbook of Pharmaceutical

CHAPTER 19

Do

- insure established procedures
for investigating abnormal assay
fluctuations
or
out-of-specification
(OOS) results in the analytical and
microbial stability testing program, is
both operational and functional.

Investigate OOS
Results
- Daily
Do

- insure OOS SOPs are written
and the principles of the Judge Wolin’s
decisions are followed and properly
investigated.
Do - review and audit stability
documentation in order to establish the
authenticity of the stability test results
reported to the FDA in ANDAs or
Supplements or Annual Reports.
Insure there is a formal pre-submission
internal auditing program.
Do - insure the firms does verify the
transfer of raw data values from the
laboratory workbooks to the final
computer stability print-out reports.
(Where intermediate summary sheets
and analysis request forms are used,
these intermediate data sheets should
be signed and stamped as bona fide
and accurate by Quality Assurance).
Do - insure the final stability study is
signed off by the Director of Quality
Control and the firm has a SOP
specifying the acceptance and sign-off
procedure for a completed stability
study, to ensure that the study is
complete and accurate.
Do - insure that no laboratory raw
data is unavailable or missing in
support of the Stability Summary Data
Reports.
Do - insure proper cross-referencing
of
laboratory
notebooks
and
worksheets
with
computerized
documentation prior to data being
submitted
to
the
FDA.

Chapter: 19.35
35

Generic Development

DRUG DEVELOPMENT

Do

STABILITY TESTING & STABILITY SOPs

- insure retrospective audits trails
of ANDA stability reports to summary
data sheets and back to laboratory
workbooks clarify that the FDA filed
data can be supported by the raw
laboratory test data.
Do - insure the firm does have a
comprehensive and functional laboratory data reporting system for test
results.
Do - insure that data points are not
missing (e.g. pH values; missing
potency from crimp-end of semi solid
tubes etc.).
Do - insure stability test values are
not different from the filed values.
Do - insure the use of bound and
numbered laboratory notebooks.
Note - The use of unnumbered
analytical worksheets for recording
analytical data should be discontinued
and is not in GMP compliance).
Do - insure that stability data is not
selectively
screened
prior
to
computerisation.
Do - insure the absence of
discrepancies and different values in
ANDA Annual Reports and the original
laboratory raw data.
[Case study:- Review of the annual
report prepared for the FDA showed
that the ongoing stability testing as per
ANDA commitment showed an original
report in the stability files with a test
data line covered with “white tape”.
This data report was photocopied and
sent to the FDA. The photocopy did
not reveal the ‘white-out’ data in
question.]
Do - insure traceability of workbook
reference page numbers and dates
relating to the original raw data in
laboratory workbooks.
Do - insure the traceability of any
repeat testing performed on the stability
samples is clearly referenced on the
stability documentation used to prepare

Handbook of Pharmaceutical

CHAPTER 19

the

computerized stability reports.
Do - insure the need to prepare an
SOP for cross-referencing laboratory
note-book data with computerized
stability test result documentation.
Do insure all repeating testing
performed at the same test interval
must be cross-referenced - all together.
Note: a reviewer requires to audit all
testing performed on the stability test
sample and not only the raw data in the
laboratory notebooks that have passed
the stability check specifications.
Do - insure all stability data points are
present and are in full compliance with
the pre-written stability protocol.
Do - insure a full review of the stability
protocol and a comparison of the test
procedures carried out on the stability
samples - at each test station - to
highlight any incidence where stability
data points may be absent or OOS.
Do - insure that no raw data is
omitted from the stability reports or in
the Annual Reports submitted to the
FDA.

Review and Audit
SOPs
- Annually
Do

- insure stability SOPs are
adequate and routinely reviewed for
GMP compliance by written in-house
audits.
Do - insure the existing SOPs do
control the functions of the stability
department. (45-50 SOPs presented
are a prerequisite to operate a stability
department for an innovative or generic
drug manufacturing company).
Do - insure is that SOPs are not
deficient both in the content and detail.
The lack of suitable SOPs in a stability
department may result that much of the
stability management and testing of the
stability samples are erratic and out-ofcontrol - resulting in a failed PAI review

Chapter: 19.36
36

Generic Development

DRUG DEVELOPMENT

Do

- insure that SOPs are readily
available and routinely followed and
updated (i.e. after a change or
annually).
(The lack of a full set of stability SOPs
and the fact that the SOPs are
incomplete or that stability personnel
are poorly trained on the contents of the
SOPs is strong evidence to an agency
that the firm’s stability testing program
is not in current GMP compliance).
Do - insure that it is not possible, for a
sample in a stability program to remain
untested after the ‘due date’ and thus
skip the designated ‘testing interval’.

Do - insure the Certificate of Analyses
are not out of date for time zero when
the sample is eventually placed on
stability at a ‘start date’ several months
after the initial C. of A. was performed.
[Reason - the sample assay value
potency may have degraded by several
months aging which would not be
reflected by the initial certificate of
analysis - some time earlier].

ØPAI×
OBSERVATIONS
on
Stability
♦ Traceability

of retested stability
samples difficult and inconsistent.

♦ Traceably of raw data inconsistent.
♦ No

written procedures for reporting
stability results precisely.

♦ ‘Corrected’

data substituted on FDA
summary data sheets.

♦ Use

of ‘white-out liquid’ in stability
reports to obscure test results.

♦ Annual

reports to FDA not accurate
or authentic.

♦ Lack of stability and analytical

Insure
all
C of A's
are
in-date

SOPs

to insure GMP compliance.

Avoid
any
White-0uts
♦ Stability

data reports not internally
audited and reviewed.

Do

- insure the presence of stability
SOPs controlling the maximum time
period [30 days] between initial testing
(Certificate of Analysis at time zero)
and the ‘Start Date’ of the stability study
in order not to invalidate the initial
stability results.

Do -

CHAPTER 19

STABILITY TESTING & STABILITY SOPs

insure that all the stability SOPs
are updated according to the firm’s
SOP index.

♦ Data transfer from raw documents to
final report not verified.

♦ No review of temperature/RH charts.
♦ Uncontrolled storage of charts makes
retrospective temperature/RH chart
review, difficult and time consuming.
No written emergency procedures
after
equipment
breakdowns.

3

Handbook of Pharmaceutical

Chapter: 19.37
37

Generic Development

DRUG DEVELOPMENT

♦ No

corrective action taken after
stability system failures.

♦ Stability

storage
recording
temperature procedures not in cGMP
compliance.

♦ Stability

climatic room must be
dedicated to stability sample storage.

CHAPTER 19

STABILITY TESTING & STABILITY SOPs

Stability room general office area
for multipurpose use.

♦ Single-probe

recorders are
suitable for temperature control.

not

♦ No

periodic revalidation of stability
chambers.

♦ Inadequate

temperature validation
studies performed in stability room.

♦ Uneven

temperature distribution and temperatures are out of the
stated specification range in stability
rooms.

♦ No

controlled storage of stability
samples before testing.

♦ Upper

and lower sample
temperatures
have
not
validated.

room
been

♦ Overall

stability facilities in violation
GMP compliance.

♦ Absent

pH values and missing data
test points.

♦ Sample

re-tests and to-be-repeated
procedures violate Wolin’s rules.

♦ Missing data points with only passing

Stability Room for 25o C samples
used as a working office with
inadequate environmental controls.

♦ No

substantive review of stability
temperature recorders or charts.

♦ Original

Data Summary Sheets
replaced with "corrected versions" including the use of "White-Out tape"
in stability reports.

♦ LIMS

(Laboratory
Information
management System) data not
accurately reported.

♦ LIMS

data excluded from Annual
reports and selectively screened in
ANDA Applications.

♦ Ignoring LIMS data results at specific
intervals when OOS results obtained

♦ Out-of-Specifications

LIMS stability
results not reported after a full
investigation performed.

♦ Laboratory

raw data unavailable or
missing to support the Stability
Summary Data Reports.

♦ Rewriting

stability protocol testing
requirements
retrospectively
to
remove unwanted results obtained

♦ Discrepancies and different values in
Annual Reports and laboratory raw
data of ANDA tested product.

♦ Stability

data points are not in
compliance with stability protocol.

♦ Missing

accelerated stability data
points on impurities at 3 and 6 month
intervals

stability test values selected.

♦ Stability reports not signed of by

QA

♦ Inadequate

controls on the overall
stability testing program.

Director.

Handbook of Pharmaceutical

Chapter: 19.38
38

Generic Development

DRUG DEVELOPMENT

CHAPTER 19

STABILITY TESTING & STABILITY SOPs

Stability
SOP
Development
‘…operating a functional stability unit…

This

section deals with the Stability
Units’ Standard Operating Procedures
(SOPs).
Handling SOPs in an ordered manner
may well be the solution to the effective
development of a generic or innovative
drug development program, not only to
place the newly formulated drug
product on the fast track to approval but
hopefully
to
save
embarrassing
moments
during
a
pre-approval
inspection (PAI) should the agency
investigator stumble onto failing drug
product stability results in a productspecific PAI review.
Key Standard Operating Procedures
are summarized to highlight the myriad
of procedures required for the correct
handling of stability results and stability
failures in an ongoing drug stability
study, - be it a developmental or a final
formula i.e. a finished product ready to
go for submission.
How does your firm shape up in this
stability line-up? If you don’t have the
Stability SOP in place, - what is the firm
doing about it? How is the stability
department handling the specific
stability requirements?
Have all
stability programs and protocols
involving the following subject matters
been thoroughly aired and discussed
in your firms stability unit ?

Handbook of Pharmaceutical

Handling

the standard procedures
correctly may well establish the validity
or non-validity of the firms stability
programs and the actual
stability
results obtained.
The following SOP summaries,
represent a minimum number of
essential stability study SOPs required
to maintain an operational stability
department for either a generic or
innovative (researched-based) drug
development program and in full GMP
compliance for the stability testing of
developmental, regulatory and once a
year commercial production batch lots.

4
S-005-02-06YY Indexing
procedure for Stability Studies.
The purpose of this standard operating
procedure is to establish an index and
an annual supplementary index for
stability
study
SOPs.
The
supplementary index allows for new
SOPs, or updated existing SOPs, to be
indexed in the supplement and
distributed in real time.

4
S-010-02-06YY Index for
Stability Studies.
The purpose of this standard operating
procedure is to index the Stability SOPs
as shown above. 4

Chapter: 19.39
39

Generic Development

DRUG DEVELOPMENT

CHAPTER 19

STABILITY TESTING & STABILITY SOPs

S-015-02-06YY Initiating a
Stability Study.
The purpose of this standard operating
procedure is to define the stages and
documentation required in order to start
or initiate a development, pivotal, or
commercial stability study.

4
S-020-02-06YY Contents of a
Stability Protocol.
The purpose of this standard operating
procedure is to define the parameters
needed in the stability protocol that
meet the specific FDA regulatory
requirements.

4
S-025-02-06YY Setting limits for
check specifications in a
Stability Study.
The purpose of this standard operating
procedure
is
to
establish
the
development procedures for setting
upper and lower specification limits for
the release and stability (check)
specifications for a Stability Study.

4
S-030-02-06YY Number and size
of batches for stability testing.
The purpose of this standard operating
procedure is to establish the procedure
for determining the number and sizes of
batches commonly required from
development to commercial batch,
stability study purposes.

4
S-035-02-06YY Number of
samples required for performing
stability tests.
The purpose of this standard operating
procedure is to establish the number of
samples required for performing the
analytical tests in a Stability Study. This
SOP is specific for each dosage form
under evaluation.
4

S-040-02-06YY Storage
configuration of samples in a
stability environment.
The purpose of this standard operating
procedure is to determine the storage
configuration of the stability samples in
the climatic controlled rooms or
chambers during the course of the
stability study.

4
S-045-02-06YY Stress testing
the bulk drug substance for
stability analysis.
The purpose of this standard operating
procedure is to determine the stress
testing procedures and parameters for
an approved supplier of the active drug
substance. The data is used for
impurity
evaluation
and
method
validation.

4
S-050-02-06YY Intervals and
climatic and storage conditions
for a US development Stability
Study.
The purpose of this standard operating
procedure is to define the intervals and
storage conditions for conducting
formulation stability studies intended for
ANDA/OTC
formulations
for
US
approval in accordance with the FDAEU-Japan ICH Guidelines.

4
S-055-02-06YY Intervals and
climatic conditions for a US
Pivotal /Bioequivalence Stability
Study.
The purpose of this standard operating
procedure is to define the intervals and
storage conditions for conducting,
Pivotal and commercial stability studies
intended
for
ANDA
and
OTC
formulations for US approval in
accordance with the FDA-EU-Japan
ICH Guidelines.

4

Handbook of Pharmaceutical

Chapter: 19.40
40

Generic Development

DRUG DEVELOPMENT

STABILITY TESTING & STABILITY SOPs

CHAPTER 19

S-060-02-06YY - Intervals and
climatic conditions for a US
validation/PM Stability Study.

S-080-02-06YY - The initial
Certificate of Analysis at To for a
Stability Study.

The purpose of this standard operating
procedure is to define the intervals and
storage conditions for conducting
Validation and Post Marketing stability
studies intended for ANDA / OTC
formulations for US approval.

The purpose of this standard operating
procedure is to initiate appropriate time
frames for starting a Stability Study not
later than 30 days (according to current
guidelines), after the sample has been
fully QC tested and a regulatory valid
certificate of analysis (C-of-A at time
zero (To)) has been issued. Where
samples exceed this period new C-of-A
are issued

4
S-065-02-06YY - Placing the
Reference Listed Drug (RLB) on
Stability.
The purpose of this standard operating
procedure is to establish the procedure
for placing batch lots of the reference
listed drug on stability in order to
evaluate
the
RLD’s
analytical
parameters, aging and impurity profile
at different time intervals and different
RLB manufacturing dates in order to
produce an overview of the reference
drugs
stability
parameters
(e.g.
especially dissolution and impurities)
(produces a set of mean curves over a
year).
4

S-070-02-06YY - Determining the
‘Due dates’ for a Stability Study
protocol.
The purpose of this standard operating
procedure is to determine the ‘due
dates’ (individual testing stations) at
which samples are taken from the
controlled storage environment for the
purpose of analytical testing according
to the stability protocol.
4

S-075-02-06YY - Setting the
‘Start date’ for a Stability Study.
The purpose of this standard operating
procedure is to determine the ‘start
dates’ at which samples are placed in
controlled climatic condition according
to the stability protocol. This procedure
determines the time limitations between
each step in the procedure.
4

Handbook of Pharmaceutical

4
S-085-02-06YY - Packaging
procedures on Formulation lots
for a stability study.
The purpose of this standard operating
procedure is to determine the
packaging procedures and quality
control functions on development
formulation lots for a Stability Study.
The number of units packed and the
sampling protocol is clearly established.

4
S-090-02-06YY - Packaging
procedures on the Process
Qualification Batch for a
stability study.
The purpose of this standard operating
procedure is to determine the
packaging procedures and quality
control functions on the final process
qualification lots for a Stability Study.
The number of units packed and the
sample protocol is clearly established.

4
S-095-02-06YY - Representative
sampling procedures during
batch packaging of stability
samples.
The purpose of this standard operating
procedure is to define the sampling
protocol
used
during
packaging
procedures in order to accomplish a

Chapter: 19.41
41

Generic Development

DRUG DEVELOPMENT

STABILITY TESTING & STABILITY SOPs

CHAPTER 19

fully representative sampling operation
of the entire batch.

S-120-02-06YY Reporting test
results of a Stability Study.

4
S-100-02-06YY - ContainerLiner-Closure systems for a
Stability Study.

The purpose of this standard operating
procedure is to determine the
procedure for reporting and recording
of the stability test results at each test
interval in the analytical laboratory. The
procedure for averaging, reviewing and
distributing
the test results are
documented.
4

The purpose of this standard operating
procedure is to specify the containerclosure-liner parameters required for
product
testing
from
product
development
to
the
process
qualification stage and the final
validation/commercial lots.

4
S-105-02-06YY - Certification of
a Container -Liner-Closure
system.
The purpose of this standard operating
procedure is to establish the vendor
and
in-house
documentation
requirements in order to meet the FDA
documentation filing requirements for
container-liner-closure systems. The
contents of each document is briefly
described.

4
S-000-02-06YY Labeling of
Stability Study Samples.
The purpose of this standard operating
procedure is to specify the procedure
and exact label data requirements for
labeling stability study samples.

4
S-115-02-06YY Storing the
stability study samples under
controlled conditions prior to
analysis.
The purpose of this standard operating
procedure is to establish the storage
conditions
under
which
stability
samples are kept during the interim
period between the sample “due date”
and the time
prior to laboratory
analysis to prevent sample spoilage.

4

Handbook of Pharmaceutical

S-125-02-06YY Procedures for
handling abnormal or OOS results
in a Stability Study.
The purpose of this standard operating
procedure is to establish the procedure
for investigation into abnormal assay
fluctuations
or
out-of-specification
(OOS) results in the analytical and
microbiological
stability
program
testing.

4
S-130-02-06YY The control of
Analytical methods #’s and
Edition #’s in stability
documentation.
The purpose of this standard operating
procedure is to ensure that the correct
analytical methods numbers and edition
numbers are used in the analytical and
microbiological testing laboratory, and
are
specified
in
the
stability
documentation during the course of a
Stability Study. This SOP insures that
method changes are updated in the
stability documentation.

4
S-135-02-06YY Crossreferencing laboratory
notebooks with computerized
stability documentation.
The purpose of this standard operating
procedure
is
to
cross-reference
laboratory
analytical
and
microbiological notebooks containing
the raw data at each specific test
interval with the computerized stability
documentation.
4

Chapter: 19.42
42

Generic Development

DRUG DEVELOPMENT

S-145-02-06YY Auditing stability
data in laboratory notebooks.
The purpose of this standard operating
procedure is to determine the method of
auditing the stability testing raw data in
the laboratory notebooks (analytical
and microbiological) and to ensure the
precise computerization of the stability
data reports.

4
S-150-02-06YY Recording
stability study climatic
conditions
The purpose of this standard operating
procedure is to ensure the correct
recording procedures, of temperature
and humidity control charts for the
climatic
chambers
or
controlled
environment
rooms.
Breakdown
procedures of chart recorders and
corrective action are documented.

4
S-155-02-06YY Review and
control of temperature and
humidity recording charts.
The purpose of this standard operating
procedure is to ensure the correct
review, audit and record keeping of
temperature and humidity control charts
for a climatic chambers or controlled
environment rooms.

4
S-160-02-06YY Periodic
revalidation of climatic rooms
and chambers.
The purpose of this standard operating
procedure is to ensure the periodic
revalidation of the climatic rooms and
chambers
to
secure
that
the
temperature and humidity is within limits
at all points where samples are stored
in the controlled area.

4
S-170-02-06YY Sanitation and
house-keeping requirements of
climatic
chambers.

Handbook of Pharmaceutical

CHAPTER 19

STABILITY TESTING & STABILITY SOPs

The purpose of this standard operating
procedure is to specify appropriate
sanitation and house-keeping practices,
conditions and requirements of climatic
chambers and controlled environment
rooms.

4
S-175-02-06YY Fault correcting
procedures (after breakdowns)
during a Stability Study.
The purpose of this standard operating
procedure is to determine the
procedures to follow after a breakdown
or failure of the equipment or power
supply during an ongoing stability
study. The use of hand thermometers
and recording logbooks
and the
corrective
action
procedure
is
documented.
4

S-180-02-06YY - Emergency
procedures during a Stability
Study.
The purpose of this standard operating
procedure is to is to determine the
procedures to follow after a permanent
breakdown or failure of the climatic
chambers
equipment
(motor
burnout/probe
failure)
during
an
ongoing stability study. Corrective
action procedures are documented.

4
S-185-02-06YY Reserved.
The purpose of this standard operating
procedure is to identify specific inhouse SOPs due to unique conditions,
methods or equipment operating within
the companies development operational
procedure.

4
S-190-02-06YY Conditions for
stopping a Stability Study.
The purpose of this standard operating
procedure is to define the precise
conditions subject to which an ongoing
stability study will be terminated.

Chapter: 19.43
43

4

Generic Development

DRUG DEVELOPMENT

STABILITY TESTING & STABILITY SOPs

S-200-02-06YY - The layout and
format of a Regulatory Stability
Report
(i.e. the filed FDA report)
The purpose of this standard operating
procedure is to define the contents and
data fields as well as the document
layout and format of a regulatory
stability report ready for filing with an
FDA agency.

4
S-210-02-06YY- Self inspection
procedures in a stability
department.
The purpose of this standard operating
procedure is to provide for self
inspection procedures according to the
written in-house compliance program
specific for the stability department.
4

S-220-02-06YY - Using stability
SOPs and compliance program
as stability training tools.
The purpose of this standard operating
procedure is to highlight the training
tools established in order that
appropriate training procedures are
provided to the departmental personnel
with specific respect to standard
operating procedures and in-house
compliance programs.

4
S-225-02-06YY - The Do’s and
Don’ts of a Stability Study - a
departmental training tool.
The purpose of this standard operating
procedure is to document a check list
for departmental training purposes of
common practice to follow and to avoid
when performing stability studies.

4
S-230-02-06YY - Stability
department compliance staff
training
The purpose of this standard operating
procedure is to provide a written
Compliance and stability procedure,

Handbook of Pharmaceutical

CHAPTER 19

detailing specific training programs and
frequency for the stability department
personnel.

4
S-235-02-06YY - Documentation
requirements for a Stability
Study - contents of a Stability
Dossier
The purpose of this standard operating
procedure is to provide a check list and
explanation of all the documentation
and data forms required to make up the
complete contents of a Stability Study
Dossier.

4
S-240-02-06YY - Job description
of stability department
personnel
The purpose of this standard operating
procedure is to document and provide
appropriate job descriptions (and a
training outline) for the personnel in the
stability department or personnel
involved in the performance of stability
related functions.

4
S-245-02-06YY - Review and
auditing stability study
documentation.
The purpose of this standard operating
procedure is to review and audit and
review each stability study performed in
order to ensure that all documentation
from
laboratory
Notebooks
to
computerized stability reports are
accurate and complete.

4
S-250-02-06YY- Accepting and
Signing-off a Completed
Stability Study.
The purpose of this standard operating
procedure is to specify the acceptance
and signing-off procedure by the
Quality Assurance Unit for a completed
stability study to ensure that the study
is in fact complete.
4

Chapter: 19.44
44

Generic Development

SEMISOLIDS

S O P s

CHAPTER 20

Development
SOPs
‘…the essential internal standard system of a
successful drug development unit…'

S

tandard
Operating
Procedures
(SOPs) for drug development
applies to individuals or groups
responsible for the management and
operation of the innovative/generic drug
development unit. It is equally valuable
for the operation and control of the
CMC (chemistry, manufacturing and
control) section of a NDA researchedbased unit.

All

pharmaceutical
companies
conducting
drug
research
and
development
must
have
understandable SOPs. The primary
purpose of the SOP is to translate the
various regulations and guidelines,
which are open to interpretation, into
clear and concise sets of instructions.

Don't Do
Without
Development
SOPs

A researcher conducts work according
to a documented set of procedures which hopefully represents the best and
most current methods available i.e.
drug development via “state-of-the-art”
techniques.
A drug researcher must keeps a record
of every detail of the product
development - both the advances and
the failures of the experimental batch
lots. SOPs also demonstrate that you
are following a key rule of a good
researcher - that the research
procedures are fully described so that
they
can
be
replicated
where
necessary.

Remote-US Drug Development.

The

Essentially

generic development can
be distilled into standard development
procedures which any development
scientist could apply. These procedures
may be electronically circulated as a
read-only documents. Master copies
authorized and stored by QA using the
new electronic signature procedure (esig rule of 20 October 1997).

Handbook of Pharmaceutical

Distribute
e-SOPs
electronically

Sect: 20.
20 1

Standard Operation Procedures
that govern Non-US drug development
of the innovative/generic dosage form
must be carefully structured to insure
that the development procedures are
fully understood and interfaced with the
US manufacturing facility.

Manufacturing equipment and scale-up
procedures require dove-tailing at both
facilities. Analytical and microbial
laboratory test methods need to be
rugged and operational in both
facilities. Great care needs to be taken
Generic Development

SEMISOLIDS

S O P s

to insure and demonstrate the
robustness of these laboratory tests
and analyses.

Testing

procedure methods should be
chosen in close cooperation with the
production laboratory facilities to insure
a smooth transfer of technical
documentation
(TTD
operational
requirements).
The Standard Operation Procedures
chosen, must fully represent a crosssection of the SOPs needed for a drug
development unit to operate efficiently
and to produce drug products on time.
The SOP index in this journal supplies
all the major procedures required, while
the summary SOPs chosen describe
the purpose and the principles
generally needed to meet the scientific,
regulatory and at times GMP objectives
of a well run stability unit.
Carefully written SOPs will save
research based firms and generic
developers time and hard pressed
development dollars.

Standard Operation Procedures
The SOP index of about three hundred
development SOPs provides the reader
with a full overview of the written SOP
requirements for functional drug
development
departments,
namely
pharmaceutical,
analytical,
microbiological and lastly the key
stability unit.

Regulatory Audit
SOPs are
an Essential
Pre-submission
Requirement
Regulatory

SOPs are a specialized
area and should cover all regulatory
aspects of Drug Development. Presubmission file review and presentation
of the Product Annual Report are two
key examples of Regulatory SOPs.
Handbook of Pharmaceutical

Sect: 20.
20 2

CHAPTER 20

Generic

Development
of
pharmaceutical drugs may take place in
a Non-US development laboratory
facility.
W here product development occurs in
a remote development unit (i.e. not
attached to the proposed manufacturing
site - special SOPs dovetailing the
procedures at the remote and
manufacturing site are necessary for
such a separated situation.
Emphasis has been placed in certain
SOPs on external development (outside
the
US)
while
commercial
manufacturing is targeted at a US
commercial site. In the majority of the
SOP examples the regulatory ‘Pivotal’
batch for regulatory inclusion into the
NDA/ANDA submission file, is targeted
for manufacture at the US commercial
manufacturing site.
Oversees developers who have FDA
inspected / approved commercial
manufacturing facilities may produce
the pivotal batch at a non-US small or
large scale manufacturing facility. The
manufacturing and testing facility must
be in full GMP compliance, as if it were
a US based operation.
Non-GMP R&D or drug development
facilities are not suitable for clinical or
pivotal drug manufacturing. Full cGMP
pilot plants or to use the more
appropriate terminology ‘small scale
manufacturing’ facilities are the correct
venue for manufacturing clinical
batches.
Although this procedure may be within
the OGD framework of regulations, it is
not a recommended route, if the object
is to routinely manufacture at an
approved US commercial production
site.
Pivotal batches for regulatory
submission to the authorities should
always be manufactured at the US
commercial site - if the intended generic
market is the USA.
3

Generic Development