Pharmaceutical Development

Training Workshop on
Pharmaceutical Development
with focus on Paediatric
Formulations
Protea Hotel
Victoria Junction, Waterfront
Cape Town, South Africa
Date: 16 to 20 April 2007
Slide 1

Walters

April 2007

Pharmaceutical Development

Quality Specifications & Testing of the

Finished Pharmaceutical Product
(FPP)
Presenter:

Susan Walters

Email:

susanw@netspeed.com.au

Slide 2

Walters

April 2007

Quality Specifications & Testing of the FPP

My background
Pharmacist
PhD Pharmaceutical Chemistry
2.5 years pharmaceutical manufacturing
27 years regulation of prescription medicines (TGA Australia)
Now:
Teaching pharmaceutical development of medicines (UNSW)
Ad hoc consultancies for WHO and others

Slide 3

Walters

April 2007

Quality Specifications & Testing of the FPP

Outline of presentation
We will:
Discuss the meaning of quality in the context of FPPs
Define key terminology
List relevant pharmacopoeias & guidelines, & discuss their roles
Outline typical tests for finished products
Discuss the development & validation of dissolution test
methods & acceptance criteria

Slide 4

Walters

April 2007

What does quality mean in the context of FPPs? - 1

Quality:
The suitability of either a drug substance [=API] or drug
product [=FPP] for its intended purpose
ICH Q6A (1999)
Some of the elements of FPP quality:
Meets suitable criteria for content of active(s)
Meets suitable criteria for content of impurities
Does not contain toxic excipients or unexpected
contaminants
Slide 5

Walters

April 2007

What does quality mean in the context of FPPs? - 2

The product:
Is reproducible from batch to batch in terms of all characteristics
that may affect the patient
Has container labelling & prescribing information that is clear,
contains all the necessary information, & accurately represents
the FPPs efficacy & safety profile
For FPPs containing new APIs: Has the same efficacy & safety
profile as the batches used in pivotal clinical studies
For generics: Has the same plasma concentration/time profile as
the innovator whose efficacy & safety profile is known

Slide 6

Walters

April 2007

Quality Specifications & Testing of the FPP

How to ensure the quality of FPPs
: ICH
Specifications are
Ensure you have the results of pharmaceutical development studies
part of a total quality
Validate:
strategy designed
Manufacturing
toprocedures
ensure product
Test methodology quality &
Acceptance criteria
consistency
: The message
End-product
testing
Implement Good Manufacturing Practice at all
sites of manufacture
is one element of the
Undertake appropriate end-product testing for conformance
to specifications
quality package
Know your API!

Conduct stability studies on the FPP exactly as it is to be marketed

Validate any subsequent variations

Slide 7

Walters

April 2007

Quality Specifications & Testing of the FPP

Some terminology

Slide 8

Walters

April 2007

Specification - 1
A list of tests, references to analytical procedures, ranges
or other criteria for the tests described.
[The specification] establishes the set of criteria to which
[an API or FPP] should conform to be considered
acceptable for its intended use.
[and for excipients, containers, intermediates & others]

Conformance to specifications means that the [API or

FPP], when tested according to the listed analytical
procedures, will meet the listed acceptance criteria.
ICH Q6a (1999)

Slide 9

Walters

April 2007

Specification - 2
Specifications are critical quality standards that are
proposed & justified by the manufacturer &
approved by regulatory authorities.
Specifications are chosen to confirm the quality of
the [API or FPP] rather than to establish full
characterization, & should focus on those
characteristics found to be useful in ensuring
safety & efficacy.
ICH Q6a (1999)
Slide 10

Walters

April 2007

Acceptance criteria
Numerical limits, ranges or other suitable
measures for acceptance of the results of
analytical procedures
ICH Q6a (1999)
Quantitative acceptance criteria are sometimes
referred to as limits.

Slide 11

Walters

April 2007

A typical monograph for an FPP might

include: - 1
Description
Eg size, shape, colour

Identity tests for API(s)

Assay of API(s)
Purity tests
API-related impurities
Solvents (often water)

Physicochemical properties as appropriate to the dosage

form (includes performance/functionality testing)
Eg particle size of API(s) in suspensions
Dissolution rate of tablets

Slide 12

Walters

April 2007

A typical monograph for an FPP might

include: - 2
Identification & assay of any critical excipients
Eg antimicrobial preservatives, antioxidants

Uniformity of dosage units for solid dosage

forms
Eg uniformity of weight (high dose tablets)
Content uniformity (low dose tablets)

Microbiology
Eg sterility (injections etc)
Microbial load (non-sterile oral products &
others)
Slide 13

Walters

April 2007

The monograph as a whole

A product is not of
pharmacopoeial quality unless it
complies with all the
requirements stated in the
[relevant monograph] my emphasis
WHO TRS 908 (2003)
Slide 14

Walters

April 2007

Sources of guidance as to the content of

monographs for FPPs
Pharmacopoeias
General monographs
Eg for parenteral products, capsules

Specific monographs
Eg dapsone tablets, artemether injection

Guidelines
WHO PQP
Especially p16/26 Control of the FPP
ICH
Technically ICH guidelines apply only to new APIs. In practice
regulators apply them more widely (eg PQP)
Slide 15

Walters

April 2007

Internationally recognised pharmacopoeias

International Pharmacopoeia (Ph Int)
Published by WHO

United States Pharmacopeia (USP)

Japanese Pharmacopoeia (JP)
European Pharmacopoeia (EP)
British Pharmacopoeia (BP)

Slide 16

Walters

April 2007

Pharmacopoeias PQPs view?

PQP has not published a formal decision
as to acceptable pharmacopoeial
monographs for FPPs
But precedents suggest that monographs
of all of the preceding pharmacopoeias
would be acceptable, with the caveat that
monographs in Japanese are not easily
understood outside Japan

Slide 17

Walters

April 2007

ICH guidelines & FPP specifications

From ICHs early days, there have been working groups that focussed on
harmonisation of pharmacopoeial requirements among the three ICH regions
But to date no harmonised monographs have been published on the ICH
website
These are the three relevant topics that appear on the ICH website
Q4 Pharmacopoeias
Q4A Pharmacopoeial Harmonisation
Q4B Regulatory Acceptance of Analytical Procedures and/or Acceptance Criteria
(RAAPAC)

Of these, only Q4B has published a draft consensus guideline. It deals with
bureaucratic processing of documentation.
Keep an eye on the ICH website for updates

Slide 18

Walters

April 2007

An important ICH guideline

Q6A: Specifications: Test procedures & acceptance criteria for
new [APIs] & new [FPPs]: Chemical substances
Applies to products containing synthetic APIs (including
antibiotics), semi-synthetic antibiotics, & synthetic peptides of
low molecular weight, but not to higher molecular weight
peptides, & complex biotechnological or biological APIs.
This ICH guideline is referenced by PQP in its guidelines for
generics, & is a key guideline for this training course.
I recommend that you read it in detail !

Slide 19

Walters

April 2007

Other relevant ICH guidelines

Q3A(R2) Impurities in new [APIs] (2006) Q3B(R2)

Impurities in new [FPPs] (2006)

Q3C Impurities: Guideline for residual solvents (1997)

Impurities in non-new APIs

Pharmacopoeial monographs
Review route of synthesis
Compare chromatographic profiles with those of innovator

Slide 20

Walters

April 2007

Impurities in non-new FPPs

Generally specifications for impurities in an existing API
&/or an associated finished product are acceptable if
one or more of the following criteria are met:
Levels of impurities are below ICH qualification thresholds
Nature of impurities & their limits match those of a
transparent [pharmacopoeial] monograph
The new product does not contain impurities in
concentrations that exceed those in a market leader
(normally the innovator)
TGA (2004)
Slide 21

Walters

April 2007

Deciding acceptance criteria

The justification (for acceptance criteria) should refer
to relevant development data, pharmacopoeial
standards, test data for [APIs & FPPs] used in
toxicology & clinical studies, & results from long term
stability studies, as appropriate.
Additionally a reasonable range of expected
analytical & manufacturing variability should be
considered.
Adapted from ICH Q6A (1999)
Slide 22

Walters

April 2007

Parametric release & end product testing

Sterility testing is probably the most well known example
of the parametric release option
Q6A describes it as an operational alternative to routine
release testing
In the case of sterility, release of each batch is based on
satisfactory results from monitoring specific parameters,
eg temperature, pressure & time during the terminal
sterilization phases of... manufacturing (Q6A)
In principle parametric release can be substituted for
other end product testing, but there are few examples
All batches must nevertheless meet the full product
specification if tested
Slide 23

Walters

April 2007

Periodic & skip testing - 1

Periodic or skip testing is the performance of specified tests
at release on preselected batches &/or at predetermined
intervals, rather than on a batch-to-batch bases
All batches must nevertheless meet the full product
specification if tested
Once a manufacturer has developed confidence in the
manufacturing process & a number of consecutive batches
have passed the test in question, testing may be reduced to
one in every x batches, or once every x months, where x is a
number that varies with the test in question

Slide 24

Walters

April 2007

Periodic & skip testing - 2

Certain tests are considered critical in terms of GMP,
& must be conducted on every batch. Examples
include identification & assay of the active(s).
Regulatory approval must be obtained (on a productspecific basis) before periodic testing may be
implemented
In the event that a batch is tested & fails to meet
acceptance criteria, regulatory authorities must be
immediately informed. The batch may be recalled.
The reason for the failure must be identified in order
to assess the consequences for other batches.
Slide 25

Walters

April 2007

Release & expiry limits

Manufacturers (almost always) have separate release & expiry limits
for tests that have a quantitative result. The main reasons are:
To allow for any observed deterioration of the measurement during
stability studies
To incorporate a safety margin so that batches are less likely to be
recalled in the event of testing by a regulatory laboratory
Effect on product image

Immediately after a batch has been released, the expiry limits

apply.

Some regulatory authorities consider this in-house information & do

not require disclosure of the release limits. Most do.
PQP seeks both sets of limits.
Slide 26

Walters

April 2007

Alternative test procedures

Pharmacopoeias & regulators allow manufacturers to use
alternative test methodology
In the event of a dispute, the approved methodology must be
used.
Why?
Science moves on ! Methodology improves. Regulators should not
discourage improvements.
Alternative methodology may be simpler &/or cheaper to conduct, but
equally effective. For example if the product has been shown not to
degrade during manufacture, a titration method may be more
accurate, precise & cheaper to perform than HPLC/MS, although less
specific for the target analyte.

Slide 27

Walters

April 2007

Dissolution
testing
Slide 28

Walters

April 2007

Dissolution test methods & acceptance criteria:

Available guidelines
Dissolution Testing of Immediate Release Solid Oral Dosage
Forms
FDA, CDER (1997)

<1092> The Dissolution Procedure: Development & Validation

USP
Dissolution testing of solid oral dosage forms
BP, Supplementary Chapter E
FIP Guidelines for Dissolution Testing of Solid Oral Products
http://www.fip.org/www2/statements/index.php

Dissolution testing
WHO PQP: Guideline on Submission of Documentation for
Prequalification of Multisource (Generic) FPPs: Supplement 1.
Slide 29

Walters

April 2007

For what purposes are dissolution studies

conducted?
During product development, selecting formulations for further
development
During end-product quality control, determining whether each batch
meets predetermined in vitro release criteria
During stability studies, determining whether in vitro release rate
changes with product age
In the context of bioequivalence studies, to determine the extent to
which in vitro dissolution results mirror in vivo results.
During the products market lifetime, determining whether variations
affect in vitro release rate
Eg change of manufacturing site or equipment

Slide 30

Walters

April 2007

What constitutes a good dissolution test?

Repeatability
Within & between equipment, analysts, labs etc
Over time (eg this year vs next year)

Discriminatory power
Discriminates between batches that perform well in
vivo & those that do not

Slide 31

Walters

April 2007

Formal validation of dissolution test

methodology
Examples:
Repeatability studies
System suitability tests
Eg using USP dissolution calibrators

Manual vs automated procedures

Analytical methodology

Slide 32

Walters

April 2007

What should we take into account when choosing

dissolution test methods & acceptance criteria? - 1
The APIs in question & their characteristics
Especially solubility in aqueous media
Known history of dissolution &/or bioavailability problems
Biopharmaceutical classification (see FDAs Waiver of In Vivo
Bioavailability & Bioequivalence Studies for Immediate-Release Solid Oral Dosage
Forms Based on a Biopharmaceutics Classification System, 2000)
The purpose for which the test is being conducted [this affects
acceptance criteria]
Routine batch release
Stability testing
For registration purposes
To support results of a bioequivalence study
To justify a waiver of in vivo BE data

Slide 33

Walters

April 2007

What information should we take into account when choosing

dissolution test methods & acceptance criteria? - 2
Recommendations made by FIP, by pharmacopoeias & in regulatory
guidelines
Regulatory requirements for registration
Eg those of WHOs PQP

Whether an in vivo/in vitro correlation (of any type) has been

established

May or may not have been published

See especially the website for the FIP Special Interest Group for BABE at
http://www.fip.nl/www2/sciences/index.php?
page=pharmacy_sciences&pharmacy_sciences=sciences_bioavail_groupbcs

Precedents

Concerning the API in question, related APIs or related dosage forms

Published
Or known only to you
But only if there are facts/data that you can cite in support

Slide 34

Walters

April 2007

Dissolution testing: Decisions to make

Apparatus
Medium (solvent)
Sampling times
Acceptance criteria

Slide 35

Walters

April 2007

Dissolution test methods: Apparatus - 1

Options (all described in the Ph Int, BP & USP):
Stirred methods
Rotating paddle
Rotating basket
Modifications
For floating dosage forms, especially capsules
May need to change medium during the test, eg pH for enteric coated products

Flow through methods

Reciprocating cylinder (USP only)
Useful for modelling media changes & predicting in vivo profiles of modified
release products (Personal Communication David Elder 2007)

Slide 36

Walters

April 2007

Dissolution test methods: Apparatus - 2

In general milder agitation conditions are
preferred
More likely to be able to discriminate
between good & bad batches
May have to increase speed in some cases
in the event of coning due to insoluble
excipients

Slide 37

Walters

April 2007

Dissolution test methods: Apparatus - 3

Recommendations by PQP for immediate
release products:
Paddle (USP Apparatus 2) usually at 50 or 75
rpm
Basket (USP Apparatus 1) usually at 100 rpm

Slide 38

Walters

April 2007

Dissolution test methods: Medium/solvent

Prefer media that are:
Not dissimilar to physiological conditions
Eg avoid 50% acetone!

Discussed in pharmacopoeias
Defined in regulatory requirements
Eg WHOs PQP Dissolution testing: Guideline on Submission
of Documentation for Prequalification of Multisource
(Generic) FPPs: Supplement 1.
FDA/CDERs Dissolution Testing of Immediate Release Solid
Oral Dosage Forms

Water is now out of favour because pH is uncontrolled

Slide 39

Walters

April 2007

Dissolution test methods: Sampling times - 1

Prefer sampling times that are:
Recommended in pharmacopoeias
Defined in regulatory requirements

Prefer:
Profiles (multipoint) vs one or two point tests
Profiles are more discrimating than one or two point tests
Formulation comparisons should normally be profiles
One or two point tests may be adequate for routine batch release if fully
justified

Slide 40

Walters

April 2007

Dissolution test methods: Sampling times - 2

Some relatively recent (but non-official) nonnumerical terminology:
Very rapidly dissolving
85% in 15 minutes

Rapidly dissolving
85% in 30 minutes

Slide 41

Walters

April 2007

Dissolution test methods: Sampling times - 3

The FDA guidance describes three categories
of dissolution test:
Single-point specifications
Two-point specifications
Dissolution profile comparison
From: Dissolution Testing of Immediate Release
Solid Oral Dosage Forms FDA (1997)

Slide 42

Walters

April 2007

Dissolution test methods: Sampling times - 4

Single-point specifications. Can be used:
As a routine quality control test for highly soluble and rapidly
dissolving drug products
Definition of rapidly dissolving?
Recently defined as >85% in 30 minutes but the FDA dissolution guideline did
not define the termSingle-point specifications. Can be used:
As a routine quality control test for highly soluble and rapidly
dissolving drug products
Definition of rapidly dissolving?
Recently defined as >85% in 30 minutes but the FDA dissolution guideline did
not define the term

Slide 43

Walters

April 2007

Dissolution test methods: Sampling times - 5

Two-point specifications. Can be used:
For characterizing the quality of the drug product.
As a routine quality control test for products that contain
slowly dissolving or poorly water soluble APIs such as
carbamazepine.
Dissolution profile comparison. Can be used:
For accepting product sameness in the context of variations.
To waive bioequivalence requirements for lower strengths of
a dosage form.
To support waivers for other bioequivalence requirements,
especially for BCS #1 APIs.
Slide 44

Walters

April 2007

Dissolution test methods: Sampling times - 6

So for routine quality control of immediate release products:
Either specify a dissolution profile
Acceptable for most types of product

Or specify a two point dissolution test

Acceptable for most immediate release products

Or specify a single point dissolution test

Acceptable for most immediate release products that contain highly soluble &
rapidly dissolving APIs

But each case must be considered individually

Slide 45

Walters

April 2007

Deciding acceptance criteria - 1

Approaches for setting dissolution

specifications for a new chemical entity
Approaches for setting dissolution
specifications for generic products
From: Dissolution Testing of Immediate Release
Solid Oral Dosage Forms FDA (1997)

Slide 46

Walters

April 2007

Deciding acceptance criteria - 2

Considerations when setting dissolution
specifications for a new chemical entity:

pH solubility profile
pKa of active
GI permeability or octanol/water partition
Dissolution characteristics of batches used in pivotal
clinical trials and/or in confirmatory bioavailability
studies.
If the formulation intended for marketing differs
significantly from the drug product used in pivotal
clinical trials, dissolution and bioequivalence testing
between the two formulations are recommended .

From: Dissolution Testing of Immediate Release

Solid Oral Dosage Forms FDA (1997)

Slide 47

Walters

April 2007

Deciding acceptance criteria - 3

Considerations when setting dissolution

specifications for a generic product:
Has a pharmacopoeial dissolution test been
published?
Is a dissolution test publicly available for a reference
listed drug product?
Conduct comparative dissolution testing using test &
reference products under a variety of test conditions

Slide 48

Walters

April 2007

Comparing dissolution profiles

When comparing two immediate release products:
If both are >85% dissolved in 15 minutes, the profiles
may be considered similar. Statistical calculation is not
required.
PQP (2005 )
Calculate the similarity
factor f2 where

Need minimum
of 3 points

f2

Walters

April 2007

R (t ) T (t )
t n

Slide 49

100

t 1

Summary and conclusion

It is important to understand the place of end-product
testing in the total quality context
Monographs for FPPs should be based on:
Pharmacopoeial general monographs
Pharmacopoeial precedents
ICH & PQP guidelines
Characteristics of the API & FPP in question

The bottom line is safety, efficacy & reproducibility for

the patient
Slide 50

Walters

April 2007