HANDBOOK OF

PHARMACEUTICS Compiled & Edited:

Masih Jaigirdar

For Pharmaceutical Scientists & Regulatory

Reviewers

(Second Edition)

1
Preface

Pharmaceutics is the discipline of pharmacy that deals with the process of turning a new chemical entity
(NCE) or old drugs into a medication to be used safely and effectively by patients. It is also called the
science of dosage form design. There are many chemicals with pharmacological properties, but need
special measures to help them achieve therapeutically relevant amounts at their sites of action.
Pharmaceutics helps relate the formulation of drugs to their delivery and disposition in the body.
Pharmaceutics deals with the formulation of a pure drug substance into a dosage form. Branches of
pharmaceutics include:

Pharmaceutical formulation
Pharmaceutical manufacturing
Dispensing pharmacy
Pharmaceutical technology
Physical pharmacy
Bio-Pharmaceutics
Pharmaceutical jurisprudence
Pure drug substances are usually white crystalline or amorphous powders. Before the advent of
medicine as a science, it was common for pharmacists to dispense drugs as is. Most drugs today are
administered as parts of a dosage form. The clinical performance of drugs depends on their form of
presentation to the patient.

Though the subject Pharmaceutics is only studied or in the educational curricula of the College of
Pharmacy in different universities across the globe, but its use and at least some knowledge is needed or
essential for the other technical disciplines personnel in the pharmaceutical industry as a formulator,
analyst, process engineer and regulatory affairs. It is also very important for a reviewer in the regulatory
agency, going through the section P.3 Drug Product and Process Development of the application, to
understand the basics of pharmaceutics for authentic endorsement or approval of an application from
quality perspective.

This Hand book of Pharmaceutics is a reference work containing a compilation of information collected
and edited by the initiator and made it easy by using his education in pharmaceutics and 45 years of
professional experience; with over 10 years in the public service as USFDA/CDER CMC reviewer and 35+
years in the private sector (Pharmaceutical Industry) as Product Development Scientist, writing and
collecting many scientific articles and giving many presentations to the audience at the scientific
seminars of ISPE and AAPs and for the training as a mentor of the FDA CMC reviewers . For this task of
compilation the editor has utilized his own education, exposure and experience in the field by covering
multiple subjects and technologies in a way that would not be merely a review of the literature but in
depth review and interpretation. Each chapter begins by assuming either the reader is not very familiar
with the subject or would be a refresher.
P.S: This version of the Handbook of Pharmaceutics is only for the use of academic and scientific purpose and only
its electronic or printed copies may be distributed among the user but not to be published by anybody for their
financial benefit without the permission of the editor.

2
Acknowledgements:

Grateful thanks also go to the two reputed professors of Pharmaceutical Sciences (Pharmaceutics) for
their review the draft copy of this book; Dr. Abu T. M. Serajuddin, PhD, FAPhA, FAAPS Professor of
Industrial Pharmacy St. John's University, has his recommendation for the publication of this handbook
at a relatively low price so that the book gets wide circulation and acceptance by the pharmaceutical
community. Dr. Larry Augsburger, Emeritus Professor at University of Maryland Baltimore, commented;
this excellent reference book that benefits from his extensive knowledge and experience will be of
particular interest and value to graduate students preparing for careers in industrial pharmacy and
beginning product development specialists.

Thanks are also gratefully extended to the staffs of the AAPS Open Editorial Office who are being
involved in the production of the Handbook of Pharmaceutics.

Reviews and Notice to Readers:

It is a very nicely written handbook; Concise, yet very informative with current information. I suggest
that every scientist working in the pharmaceutical industry involved in dosage form development,
especially one relatively new in the field and without much formal training in pharmaceutics, should
read the book. Indeed, since there are not many pharmaceutics programs in the academia teaching
physical pharmacy and drug formulation, most of the new formulators in the industry and regulatory
agencies do not have pharmaceutics background. I believe that they will be much benefitted by reading
this book. I recommend the publication of this handbook at a relatively low price so that the book gets
wide circulation and acceptance by the pharmaceutical community.

From: Abu Serajuddin

Sent: Monday, February 15, 2021 1:42 PM
Abu T. M. Serajuddin, PhD, FAPhA, FAAPS
Professor of Industrial Pharmacy
St. John's University
8000 Utopia Parkway, Queens, NY 11439, USA
Tel: 718-990-7822

Congratulations on compiling a very nice, concise compilation of useful information in pharmaceutical

development and manufacture. This excellent reference book that benefits from your extensive
knowledge and experience will be of particular interest and value to graduate students preparing for
careers in industrial pharmacy and beginning product development specialists.

From: Larry Augsburger

Emeritus Professor at University of Maryland Baltimore
University of Maryland Baltimore
Severna Park, Maryland, United States
Forwarded Oct 4 at 10:42 PM

3
About the Compilation and Editor

Masihuddin Jaigirdar by profession a Pharmaceutical Scientist, before retiring, was a senior Quality
Reviewer, US Federal Government (G.S-14-8) with FDA/OPQ/OPMA Division III. Beside his quality
reviews of many applications including INDs, NDAs and over 500 ANDAs/Amendments for a period of
over ten years; he has also contributed/participated in FDA OGD/OPMA various scientific working
groups as a team member. In October 2020 for his dedication to the FDA through his 10 years of
exemplary service as an exceptional employee and mentor, received the certificate of appreciation from
the CDER; FDA.

He has M. Pharm and Post Graduate Education in Pharmaceutical Science/Technology and over 35 years
of diverse experience in the Pharmaceutical Industry in the field of Formulation Development, Process
Technology Transfer, Process Optimization, and Scale-up of products and Manufacturing for Brand and
Generic Pharmaceuticals in US and Overseas (Europe & Middle East).
As a formulation scientist he has proven success of generating many Abbreviated New Drug Applications
(ANDAs) of Paragraph IV Paradigm defending them at litigation and got agency approval. He has worked
for many worlds reputed Pharmaceutical Companies.

He was the Associate Director and Research Leader of R&D Product Development; expertise in Modified
Release Technology for Actavis (former Watson) Pharmaceuticals in Corona, California.
Masih was Senior Principal Scientist, for the generic division of Marion Merrill Dow (MMD), Hoechst
Marion & Russel, Aventis; (Chelsea Laboratories), in Cincinnati, Ohio.

Just before joining FDA in September 2010, he was with the Product Development Group of Mylan, in
Morgan Town, West Virginia.

GLOBAL EXPOSURE:

Masih started his professional career in early 70’s, joining the then E.R.Squibb & Sons in their overseas
pharmaceutical plant in Bangladesh. In the 80’s was trained by ASTRA Development AB, Sodertalje,
Sweden, for the position of Head of Process Technique/Technology Transfer, for the newly build
pharmaceutical plant KPICO of the Kuwait (Middle East) government. He was responsible and conducted
the Validation Program for Product’s Process: Installation Qualification (IQ), Operational Qualification
(OQ) and Performance Qualification (PQ) in conjunction with technical experts from ASTRA Sweden for
all pharmaceutical dosage forms.
Provided technical support and troubleshooting to existing products and process.
Has written and revised production methods, batch production records, SOPs and validation protocols.

4
Field of Knowledge/Experience/Exposure/Expertise
Solid Oral Dosage: Immediate Release, Modified Release (Controlled Release & Delayed Release)
Semi Solids: Ointment, Cream, Gel and Suppositories Technologies

Liquids: Internal-Liquid (Oral Solution, Suspension, Elixirs, and Emulsion); Injectable: SVP & LVP,
Peritoneal Dialysis and Hemodialysis solutions, ophthalmic preparations and Nasal Spray etc.

Contribution and Accomplishments

Masih was routinely sought out by his peers for his insight on both scientific and regulatory challenges
when reviewing applications (e.g., scale-up considerations for a variety of finished dosage forms) and
has trained and mentored a number of Chemistry Reviewers. He has been a routine trainer for new
reviewers in multiple offices within the Office of Pharmaceutical Quality (OPQ); and has presented
training sessions on many manufacturing process related topics.

He provided valuable input and actively participated in a number of important working groups and
committees that had a direct impact on review work being completed in OGD, and OPQ, including OGD’s
Quality by Design (QbD) Working Group and OGD’s Risk Assessment Team, and OPF’s Continual Learning
Committee.

Masih was also well regarded for his mentorship and training abilities which have been shared across
multiple offices. When in the Office of Generic Drugs (OGD) he presented and participated in Study
Lunch Series, served on the Training Faculty for new review chemists that formally trained
approximately 65 new chemists, and served as official mentor for his division.

During his tenure in the Office of Pharmaceutical Quality (OPQ), he continued to serve on a Continual
Learning Committee that emphasizes and enhances review and inspection processes. For this endeavor
he received a Leadership Excellence Award in 2016.

In 2017, Masih gave a manufacturing training for solid oral dosage forms that crossed all sub-offices
within the larger OPQ super-office. He continues to serve as official mentor for his office and is routinely
sought out for his insight on both scientific and regulatory challenges when reviewing applications (i.e.,
NDAs and ANDAs). While in OGD, Mr. Jaigirdar provided significant contributions to the generic drug
program which have translated to the larger organization in OPQ and helped advance the Agency’s
mission of approving safe and effective generics that meet the same standards as the brand drug. He
was actively involved in the advancement of a formal Risk-based Review (RbR) program for the
evaluation and assessment of ANDAs which focuses reviewers on product risk and patient impact. It
ensures high risk areas in an application receive the appropriate level of scrutiny and streamlines the
review process for low risk areas. Through his work on the RbR program he has helped ensure more
effective and consistent risk-based decisions on generic drug quality and in 2014 he was presented with
a Regulatory Science Excellence Award in recognition. In summary, Masih has made significant overall

5
contributions to the Agency’s mission of approving safe and effective high quality drug products.
Through his excellent working knowledge and his personal desire to share and impart that knowledge
to others through mentorship and educational opportunities, he is a valued contributor and supporter
of
the Agency’s drug review program.

Awards: Masih has received many awards during his 10 years’ service with the agency.

• Certificate of Appreciation for dedication to the FDA through his 10 years of exemplary service as an
exceptional employee and mentor, October 14, 2020.

 Award received (group): In Recognition of the OPF Training and Development Team
sponsoring cross-OPQ training and development activities, December 13, 2016.

• Leadership Excellence; OPF Continual Learning Committee, September 16, 2016.

• Certificate of Appreciation: Risk Based Review Pilot Program, February 10, 2014

• Excellence in Mentoring: Training Faculty for New Chemist Reviewers; For outstanding efforts in
training over 65 new chemists in the review of Chemistry, Manufacturing, and Control portion of
the ANDA in 2013

• OGD Chemistry Risk-Based Review Groups; for demonstrating the feasibility, effectiveness and
efficiency of risk-based review in the chemistry evaluation of ANDAs

• Speaker at OPF Knowledge Sharing Seminar Series.

• CDER Office of Generic Drugs, Certificate of Appreciation; “Role of Scale-up Strategy in Product
Development and Formulation, March 14, 2011.

Arrangement of Contents

Chapter 1: Background Information

Chapter 2: Generic New Product Introduction & Product Development Process Solid Dosage (Tablet)

Chapter 3: Solid Dosage Form

Chapter 4: Mixing and Granulation Solid Dosage (Powder, Tablet and Capsules)

Chapter 5: Hard Gelatin Capsule Chapter

Chapter 6: Soft Gelatin Capsule

Chapter 7: Pharmaceutical Coating

Chapter 8: Solid Dosage Manufacturing Process Testing and Sampling Considerations

6
Chapter 9: Pharmaceutical Excipients for Solid Dosage

Chapter 10 Semi-Solids Dosage

Chapter 11: Liquid Dosage

Chapter 12: Parenteral Medications

Chapter 13: Lyophilization Process

Chapter 14: Typical Pilot-scale Lab Apparatus & Equipment

Chapter 15: Role of Scale-up Strategy in Product Development

Chapter 16: Practical Example of Product Development (Case History)

Chapter 1: Background Information

Drugs/Medicines are used for: against disease, medical or health conditions.

They either come from chemical or biological source.
Can be broadly classified into two main as per therapeutic (Pharmacological) category:
1. Chemo-therapeutic agents (drugs),
2. Biological-drugs
Chemo-therapeutic drugs: Drugs made of chemicals. A few examples are of the following groups:
Analgesics/Antipyretics; Analgesic/Hypnotics; Anti-hypertensive; Anti-diabetics; Anti-depression; Anti-
cholesterols, etc.

Biologicals: Drug derived from biological source or fermentations: Anti-biotic, Vitamins etc.
These are well known as drug substance and are produced in bulk quantities by their manufacturer.
However, for doctor/physician/Nutritionist prescribe them to a patent or individual in specific quantity
(dose) to be taken/used/applied per recommendation.
Many of these doses can be as little as a few micrograms and up to 1000mg or more. The question arise
how to deliver them to such specific quantity/quantities?
Pharmaceutical Dosage form became the media/mode of delivery to the patient/user to take/use/apply
specified quantity one time or multiple times depending on the requirement

Pharmaceutical Dosage Form: Dosage forms (also called unit doses) are essentially pharmaceutical
products in the form in which they are delivered for use, typically involving a mixture of active
pharmaceutical ingredient (API) and inactive ingredient (excipients).

7
Depending on the method/route of administration, dosage forms come in several types. These
include in general broadly in following main three groups: Solids, Liquid and Semi-solids
Solids: Powder, Powder for reconstitution as solutions or suspensions, Pill, Tablet, and Capsule
Semi-Solids: Ointment, Cream & Gels
Various dosage forms may exist for a single particular drug: due to different medical conditions or
patient population (Pediatric, adult and geriatric) can warrant different routes of administration.
Liquids: Internal & External Liquids
Internal Liquids: Oral Solution & Suspension, Emulsion, Dialysis solution, Parenteral and Ophthalmic
liquids
External Liquid: Disinfectants, Sanitization Liquid, Hospital Germicidal Liquids, etc.

Chapter 2: Generic New Product Introduction & Product DevelopmentProcess

Solid Dosage (Tablet)
Generally Generic Firm will have a New Product Selection Committee (NPSC). This committee
evaluate/explore before selecting and finalizing to introduce a new drug product into market.

These are:

1. Strategies: Pharmaceutics, Analytical and Bio-Pharmaceutics

2. Market Barriers: Patient & Exclusivities

3. Market Analysis: Projected Forecast (Units, Dollars), anticipated market share based on being number
1, 2, 3 and so forth player

4. API availabilities

5. Time line

Stage 1: Literature Search

 Literature Search  USP, BP, JP, EP, Merck, Florey etc.

 FDA-FOI  Summary Basis of Approval

 Data Base guidelines for test methods,
 On-line search of FDA/CDER info.
dissolution, impurities, Bio-study
parameters. etc.
 Patent Evaluation
 Orange Guide + FDA/CDER www.patent
consultant

8
Stage 2: API Sourcing

 Sourcing of Active Pharmaceutical  US & International Suppliers from

Ingredient (API); Drug Substance
(Europe, Asia, etc.)
 Have Potential Supplier lists  Request Technical Binder & DMF

 US agent for API Information

 Request samples & CoA and
Specifications
 At least two suppliers for full evaluation

Stage 3: API Evaluation and Procurement

 Evaluation of Active Pharmaceutical  At least 2-3 potential API supplier

Ingredient (API)
 DMF availability & Status
 Compliance with USP monograph
 Purchase of API
 Impurity profile and stability
 Potential polymorphic forms
 Commitment for physical specification
(micronized)
 Statement of non-patent infringement
 In g/kg quantities for method
development & pre- formulation study

Stage 4: API Testing (Early Sample Quantity)

Chemical testing by R&D Analytical Laboratory  Chemical testing as per:

 USP monograph (if present)
 Pharmacopeia Forum (if available)
 In-house method (based on API
manufacturer.
Stage 5: Bulk API Testing

Chemical testing by R&D Analytical Laboratory  Polymorphism

(Full physical & chemical characterization)  Particle size distribution & method
development

9
  Assay
 Stress study (Heat, Acid, Base, Oxidative
and Photolytic)
 Relative substances/Impurity profile,
Degradants
 Optical rotation
 Enantiomeric purity
 O.V.I. Testing
Stage 6: Pre-Formulation

1. Drug substance  Physico-chemical evaluation for:

 Physico-Chemical testing by R&D
Pharmaceutics Laboratory
2. Drug Product
Physico-chemical evaluation of Innovator’s
Product by R&D Pharmaceutics Laboratory
 Moisture sorption/desorption
 Flowability, Particle size, B/T Density
and Compact-ability study
 Drug-Excipient Compatibility study
 At least 3 different lots in smallest and
largest pack size
 Evaluation of physical parameters
(Shape, Size, Dimension, Score, Color,
Embossing for Logo)
 Container/Closure system (packaging
materials, dunnage: cotton, polyester,
rayon; desiccant; odor absorbent,
oxygen scavenger etc.).
 Physical testing for:
 Weight, Thickness, Hardness, LOD,
Friability, Disintegration etc.
 For MR Tablets: Evaluation of tablet’s
disintegration behavior:
 Erosion Vs Congealing characteristics

Microscopic observation of Innovator’s  By slight crushing of tablet with a

Product by R&D Pharmaceutics mortar & pestle and observing under
microscope for:
 Particles Vs granules for particle size,

10

Dissolution profile of Innovator’s Product
by R&D Analytical Laboratory
Phases of Product Development
Stage 7: FEASIBILITY STUDY BATCHES
 Drug-Excipient compatibility using DSC methods and stability assessment
 Accelerated Stability: 40°C/75% RH ; Time points 0 up to 3 months
 Stress Stability: 60°C up to 3 weeks
 Qualitative and Quantitative Composition
 Matching dissolution with RLD.
 All excipients within IIG limits.
 Process and Equipment Train Identified.
 Container/Closure with either accelerated or stress stability established.
 IVIVC or BE by Pilot Bio.
crystal shape & habit.
 Differentiation on the presence specific
excipients can be verified from
microscopic observation. e.g., Lactose
modified Vs Anhydrous Lactose,
Cross-linked cellulose, Starch and
Avicel have a specific shapes and
morphology and maybe detected.
 USP monograph and FDA method -
(where present) Dissolution; 12 unit
Dissolution Profile.
 In case of Modified Release Tablet: In
Water, 0.1N HCl, pH 4.5 Buffer, and pH
6.8 Buffer
 Prototype Batch (Feasibility study)
 Optimized Batch (Characterization study)
 Exhibit Batch (ANDA Submission)
 Production Batch (Commercialization)
11
Stage 8: Manufacturing Process

 EVALUATION SUITABLE Wet granulation (aqueous or non-aqueous)

high shear mixing / low shear mixing
MANUFACTURING PROCESSES
• FBD spray procedure), or
 Direct Compression
• Dry mixing, dry granulation and/'or Slugging
 Wet Granulation • Determination of order of mixing

 Dry Granulation by Slugging or Roller • Determination of pre-mixing (in Granulator)

Compaction
 Moisture Activated Dry (MAD) Granulation
• Determination of fluid addition (if relevant)
• Determination of granulation time
(chopper I & II)
• Determination of torque end-point value
• Determination of Drying parameters
• Determination of LOD limits
• Determination of testing temperature for
checking LOD limits
(State machine used e.g. Mettler™,
Computrac™).

Stage 9: Container Closure System

Evaluation of suitable Container-Closure System

Choice of container-closure-liner system

including:

• Material composition,

• Type of thermoplastic resin and resin pigments,

• Manufacturers and suppliers,

• Liners and seals used by closure manufacturer,

• Dunnage :( cotton, polyester, rayon), odor absorbent and desiccants.

• Manufacturer's DMF numbers for all component parts.

12
 Stage 10: Scale-up

Process
Scale-upCharacterization
batch prepared ifbatch
largerand Scale-up
batch batch
size scale upmay be evaluated
problems as a single batch.
anticipated.

Stage 11: Process Characterization (Optimization)

GRANULATION OPTIMIZATION
 Effect of granulation parameters

 Granulation time

 Speed of choppers (I & II) or mixer blades

 Solvent addition rate and overall amount

 Ratio of intra-granulate Disintegrant and

DRYING binders agents
 Milling Configuration & Screen size

 Adjusting mill screen size up or down to fine

 tune hardness
 Evaluation of optimized granulate and tablet
attributes
 FB Drying temperature versus target LOD and
 range limits and the effect on granulate and
tablet properties (flow, capping, sticking).

BLENDING Effect of level of lubricant

 Lubricant Split into two parts (pre-blending and

 final blending)
COMPRESSION
 Effect of Blending Time
P.C. REPORT
 Response: Content Uniformity and Dissolution
 Profile.

 Evaluation of unit dose sampling vs. Content

 Uniformity

13
  Effect of hardness on tablet properties
 (Aging, dissolution, friability).

 Evaluation of Hardness Range Limits

 Evaluation of stability results of optimized mfg. process

 Prepare PC Report. This Process Characterization Report forms

product Development Report

Stage 12: ESTABLISHING AND IN-VITRO IN-VIVO CORRELATION

IVIV Correlation • Dissolution - in USP medium (Multipoint

profiles) and other relevant media versus
Innovator's product.

• Perform IVIV Bioavailability Study

(where relevant)

Establish a Level A or C correlation without

adjusting dissolution parameters and time scale

• Adjust the dissolution parameters or time

scale to achieve a Level A or C correlation
(adjust only if necessary)

Level A correlation:

An IVIVC that correlates the entire in vitro and in vivo profiles has regulatory relevance and is
called a Level A Correlation .This level of correlation is the highest category of correlation and
represents a point-to-point relationship between in vitro dissolution rate and in vivo input rate of
the drug from the dosage form.

Level A correlation is the most preferred to achieve; since it allows bio waiver for changes in
manufacturing site, raw material suppliers, and minor changes in formulation. The purpose of
Level A correlation is to define a direct relationship between in vivo data such that measurement
of in vitro dissolution rate alone is sufficient to determine the biopharmaceutical rate of the
dosage form.[1]

14
Level C correlation:

Level C correlation relates one dissolution time point (t50%, t90%, etc.) to one mean
pharmacokinetic parameter such as AUC, Tmax or Cmax. This is the weakest level of
correlation as partial relationship between absorption and dissolution is established since it
does not reflect the complete shape of plasma drug concentration time curve, which is the
critical factor that defines the performance of a drug product.

Due to its obvious limitations, the usefulness of a Level C correlation is limited in predicting in
vivo drug performance. In the early stages of formulation development Level C correlations can
be useful when pilot formulations are being selected while waiver of an in vivo bio-equivalence
study (bio-waiver) is generally not possible.

CRITICAL AND IMPORTANT FACTORS CONSIDERED DURING PRODUCT

DEVELOPMENT

Developers are encouraged to develop IVIVC for IR dosage forms, where applicable
to the BCS, (Biopharmaceutical Classification System) in the expectation that the
information will be useful in establishing appropriate dissolution specifications and
thus permit certain post approval formulation and manufacturing changes to be
effected, - without additional bioequivalence studies.

The objective of developing an IVIVC is to establish a predictive mathematical

model describing the relationship between in-vitro dissolution settings and the actual
in-vivo drug-plasma parameters found, (such as AUC, Cmax, Tmax).

The in-vitro dissolution settings are adjusted (via media, pH agitation) until a I : I
correlation is achieved (Level A) or a single dissolution point and a plasma
parameter is shown to correlate (Level C).
When more than one point correlates a multiple Level C is obtained - which may
possibly be upgraded to a Level A with additional development work.

This matching of dissolution settings with plasma levels, that are derived from a
specific IR formula and its corresponding manufacturing process, is in fact simply an
arbitrary set of values that establish the so called 'predictive mathematical model'.

An IVIVC should be evaluated to demonstrate that predictability of the in-vivo

performance of the drug product (i.e. derived from the plasma parameters) from its in
vitro dissolution characteristics (e.g. equipment s e t t i n g s / and
manufacturing changes) is maintained over the product's dissolution profile

15
Biopharmaceutics Classification System (BCS)

BCS represents a convenient way to look at solubility and permeability characteristics of

drug substances. The BCS is a scientific framework for classifying drug substances
based on their aqueous solubility and intestinal permeability.

When combined with the dissolution of the drug product, the BCS takes into account
three major factors that govern the rate and extent of drug absorption from immediate-
release (IR) solid oral dosage forms: dissolution, solubility, and intestinal permeability.
According to the BCS, drug substances are classified as follows:

Class 1: High Solubility—High

Permeability Class 2: Low Solubility—High

Permeability Class 3: High Solubility—Low

Permeability Class 4: Low Solubility—Low

Permeability

The recommended methods for determining solubility, permeability, and in vitro

dissolution are discussed below.

A. Solubility

The solubility class boundary is based on the highest dose strength of an IR product
that is the subject of a bio-waiver request. A drug substance is considered highly
soluble when the highest dose strength is soluble in 250 ml or less of aqueous media
over the pH range of 1–7.5. The volume estimate of 250 ml is derived from typical
bioequivalence study protocols that prescribe administration of a drug product to fasting
human volunteers with a glass (about 8 ounces) of water.

B. Permeability

The permeability class boundary is based indirectly on the extent of absorption (fraction
of dose absorbed, not systemic bioavailability) of a drug substance in humans and
directly on measurements of the rate of mass transfer across human intestinal
membrane. Alternatively, nonhuman systems capable of predicting the extent of drug
absorption in humans can be used (e.g., in vitro epithelial cell culture methods). In the
absence of evidence suggesting instability in the gastrointestinal tract, a drug substance
is considered to be highly permeable when the extent of absorption in humans is
determined to be 90 percent or more of an administered dose based on a mass balance
determination or in comparison to an intravenous reference dose.

16
C. Dissolution

In this guidance, an IR drug product is considered rapidly dissolving when no less than
85 percent of the labeled amount of the drug substance dissolves within 30 minutes,
using U.S. Pharmacopeia (USP) Apparatus I at 100 rpm (or Apparatus II at 50 rpm) in a
volume of 900 ml or less in each of the following media: (1) 0.1 N HCl or Simulated
Gastric Fluid USP without enzymes, (2) a pH 4.5 buffer, and (3) a pH 6.8 buffer or
Simulated Intestinal Fluid USP without enzymes. A review of the approved products
indicates that most of the oral solutions and syrups are developed for BCS Class 1 and
BCS Class 3 APIs. This is to be expected because the compounds are highly soluble in
water or gastrointestinal pH media. However, it is noted that there are a few BCS class
2 and class 4 compounds that are formulated as oral solutions or syrups. These
products utilize special techniques such as salt formation, micronization, and
complexation with resins, cosolvents, or surfactants for solubilization in order to
formulate as homogeneous oral liquid dosage forms. Table 1 shows the list of all 382
products and their BCS classification based on the values obtained from literature. This
table will be updated as more information becomes available.

Stage 13: Exhibit Batch (ANDA Submission)

PRODUCTION FACILITIES
 Batch size at least 100,000 units or 1/10th
 Pivotal batch MUST be compressed in a
of the commercial batch. Minimum three
production tableting machine (or
batches.
production type with same principle and
 Formula & Process Optimized.
operation)
 Matching dissolution with RLD.
 All excipients within IIG limits.
BATCH DOCUMENTATION
 Process and Equipment Train Selected.
 Preparation of FINAL Master Formula and
 Container/Closure with 3 months
Processing Instructions
accelerated stability established.
 BE by Pivotal Bio or IVIVC.
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.

17
 OPERATING CONDITIONS
 Operation of production and control
personnel during Pivotal manufacture,
aided by development team.

TECHNOLOGY TRANSFER REPORT

 The preparation of a Technology Transfer
Document (TTD). This TTD forms part of
the overall Product Development Report.

Stage 14: BIOEQUIVALENT STUDY

BE STUDY Fasted Perform Fasted / Food Effect Biostudy on Pivotal Lot Samples

BE STUDY [Food Effect] Perform Food Effect Biostudy on Pivotal Lot Samples (See food
effect guidelines, where appropriate)

HIGHEST DOSAGE Biostudy generally performed on highest strength of product

One or two studies Fasted and Food Effect Study may be required

Stage 15: Process Validation

 Protocol  Process Validation Protocol for 3

 Execution of process validation batches consecutive marketing lots
 Report  Process Validation of 3 consecutive
 Similarity marketing lots
 Bio-Validation Similarity  Process Validation Report
 Showing intra-batch similarity
 Showing inter-batch similarity
between Bio-batch (Pivotal) and the
Commercial Validation Lots

18
Stage 16: Production Batch (Commercial)

 Batch size not more than 10 times of ANDA batch.

 Qualitative Composition same as ANDA batch.
 Process and Equipment Train Same or Scale-up size (within 10 times of ANDA batch
equipment).

Chapter 3: Solid Dosage Form

By the very name/description it is understood that both the drug and its mode of delivery is through/by
a solid medium. Generally pharmaceutical solid dosage comes into following categories:
Powder, Pills, Tablets, Capsules and Medicated Lozenges, etc.
Powder: As a dosage form can be of a single drug substance, or combination of multiple drug
substances. They can be for either internal or external use.
Powders for internal use: Can be powder for re-constitution with water as solution or suspension taken
orally or as injection given IM.

Tablets: Is the most common and widely used pharmaceutical dosage form and very popular for its
convenience of use mostly orally or inserted into other body cavity, sublingual, buccal, vagina or rectum
and Chewable tablets.
Based on their release in the stomach tablets can be classified into two main groups.

1. Immediate Release Tablet (IR Tablet): Immediate release tablets are made to disintegrate and
release their dosage form with no special rate controlling features, such as special coatings and
other techniques. Immediate release tablets are those which disintegrate swiftly and get dissolved
to release the medicaments. Generally these types of tablets after taken orally releasing its active
into stomach within a maximum of 30 to 90 minutes.

2. Modified Release Tablet (MR Tablets): This can be again re-classified into three different
categories; a) Delayed Release Tablet, b) Sustained Release Tablet, and c) Extended Release
Tablet.

Delayed Release Tablet: The release of the drug is delayed to either: Partial delay to by-pass the
esophagus or full delay to by-pass the stomach.

19
Sustained Release Tablet: The release of the drug is sustained for at least 12 hours, so that patient can
take the daily dose in twice daily regimen.
Extended Release Tablet: The release of the drug is extended for more than 20 hours, so that patient
can take the medicine once daily regimen.

Capsules: Hard Gelatin Capsule (HGC) and Soft Gelatin Capsule (SGC)
Formula design for Multi Strength Tablets; Based on drug load (% API content) in the final formula, it
could be as follows:

 Dose Proportional Design: Typically this formula design is used when the drug load is moderate to
high. Where the final weight of the tablet for any strength would be proportional to the % API
concentration in the formula, i.e. as the strength goes low the final tablet weight will also be low.
E.g., for a drug product having three strengths; 5mg, 10mg and 15mg, if the final weight of the 5mg
tablet is 50mg. Then for the 10mg and 15mg to be dose-proportional has to be 100mg and 150mg
respectively. The dose proportional formula design gives the advantage of making a common blend
for all the strengths and then divides it proportionately to make the final tablet. Their tablet shape
can be round but of different diameter. No need of using color for identification.

 Formula Similar Design: In this case the final tablet weight is same irrespective of its strength.
Generally, this type of formula design is used for the low to moderate drug load (%API) in the
formula. The advantage of this system design is the drug load being low to moderate; the main
formula design is based on the excipient load. The functional excipient concentration and amount
remains the same. The final weight is adjusted by the main diluent q.s. by subtracting the API
amount. The disadvantage of this formula design is, unlike dose-proportional formula design, it
does not allow making a common blend. However, as the final tablet weight is same irrespective of
the strength, to identify each of the strength, typically different colors or shape is used to
differentiate among them, e.g. (round, triangle and oval).

 Neither dose-proportional Nor Formula Similar: Although it is very uncommon but there are a few
drug products in tablet form for its multi strength did not follow the above two design. Their each of
the strength has its own final weight; is neither proportional nor same as the other strength. This is
mostly found with some Brand Product. However, by its Physico-chemical characterization the
generic formulator would be able to identify the main reason. Typically, this is may be as follows:

 For its multi strength tablets mostly for the low to moderate drug load the formula design has two
separate common blends. I) A dose-proportional high concentrate (% API) blend for the API with a
portion of the main diluent, also some time with the dissolution enhancer (for BCS II type DS). Ii) A
separate common blend made of mostly all functional excipient and rest of the main diluent. The
final blend for the each strength is made taken dose-proportional amount from the blend 1 having
the API and taking same amount of the 2nd blend irrespective of the strength. Thus the final weight
of the table become different from each other but not dose proportional.

20
Example: Say a firm for its multi strength tablet 10mg, 15mg and 20mg tablets has made a formula
design neither dose-proportional nor formula-similar. They have made 100,000 tablets, two separate
common blends as follows:

A. API concentrate blend (Dose-Proportional): 45kg and divide it proportionately into 10kg, 15kg
and 20kg.

B. A separate common blend of other functional excipient of another 300kg and divide it into
three separate lots of 100kg each. Then they mix this two sub lots of blend as follows:

a. For the 10mg Tablet: Blend A 10kg + Blend B 100kg = 110kg

b. For the 15mg Tablet: Blend A 15kg + Blend B 100kg = 115kg

c. For the 20 mg Tablet: Blend A 20kg + Blend B 100Kg =

120kg Now the final weight of the tablets would be as follows:

10mg Tablet: 110mg, 15mg Tablet: 115mg and the 20mg Tablet: 120mg. Hence, neither dose
proportional nor formula similar. For identity they could be differentiated by their shape. However, this
type of formula design is very uncommon and confusing to a formulator.

Chapter 4: Mixing and Granulation Solid Dosage (Powder, Tablet and Capsules)

Mixing is a unit operation that involves manipulation of a heterogeneous physical system with
the intent to make it more homogeneous. Mixing can be achieved by the following processes.

 Hand Mixing (Using Spatula)

 Mortar & Pestle (Trituration)
 Tumbling & Shaking (Diffusion)
 Shear Mixing (Low Shear: Planetary Mixer, High Shear- Mixer-Granulator)
 Fluid Bed Process

Type of Mixing:

 Diffusion Mixing : by Random movement (Using Blender or Bin)

 Convection Mixing: Displacement of group of particles from one place to another (Auger
Mixer, Ribbon Mixer)
 Shear Mixing: By effecting mechanical energy to change the configuration of ingredients
(High Shear Intensive Mixer).

21
Mode of Mixing:

Geometric Dilution: In Pharmaceuticals this is mostly used for making an intermediate

concentrate pre-mix for actives, colors or any other ingredient in a very small amount in the
product composition.

Ordered Mixing; It is a non-randomized process. In this process materials are selectively mixed
based on their physical characteristics (cohesive, adherence, ruggedness, irregular shape,
coating, and/or flow properties) this process is widely used in the Pharma Industry and can be
achieved in a number of ways:

Mechanical: By Dividing and Recombining, Mixing & Screening

 Selective mixing of the low drug load <5% API with a carrier with irregular surface area (e.g.
Anhydrous Lactose, Mannitol etc.). Thus the career excipient due to its rugged irregular
surface attaches the low amount drug substance forming an API-carrier mixture concentrate
for ultimate BU and CU of the drug product.

 Selective mixing of high drug load >50% API of non-cohesive property with a cohesive
ingredient to induce compaction for a Direct Compression (D.C) Process.

Mixing Equipment

Diffusion Mixing • V-Blender, Slant-cone Mixer, Double-cone Mixer &

Bin Blender
Convection Mixing • Auger Mixer & Ribbon Mixer
Shear Mixing • Low-shear Planetary Mixer
• High-shear Intensive Mixer

Testing for Compressibility & Flowability of Powder, Blend and Granules:

Compressibility = Tapped Density - Bulk density X 100

Tapped Density

Compressibility (%) Flowability (Quality)

5 – 15 Excellent
12 – 16 Good
18 – 21 Fair-passable
23 – 35 Poor
33 – 38 Very poor
> 40 Very, very poor

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Granulation: In this process powder particles are adhered into larger, multi-particle entities
called granules. This bondage between particles is achieved either by compression/compaction
or by using a binding agent. Pharmaceutical granules typically have a size range between 0.2
and 4.0 mm, depending on their subsequent use.

In the majority of cases this will be in the production of tablets or capsules, when granules will
be made as an intermediate product and have a typical size range between 0.2 and 0.5 mm,

Reasons for granulation:

To prevent segregation of the constituents of the powder mix:
Segregation is due to differences in the size or density of the components of the mix, the
smaller and/or denser particles concentrating at the base of a container with the larger and/or
less dense ones above them. An ideal granulation will contain all the constituents of the mix in
the correct proportion in each granule, and segregation of the ingredients will not occur. It is
also important to control the particle size distribution of the granules because, although the
individual components may not segregate, if there is a wide size distribution the granules
themselves may segregate. If this occurs in the hoppers of capsule-filling machines or tablet
machines, products with large weight variations will result. This is because these machines fill
by volume rather than weight, and if different regions in the hopper contain granules of different
sizes (and hence bulk density), a given volume in each region will contain a different weight of
granules. This will lead to an unacceptable distribution of the drug content within the batch of
finished product.
To improve the flow properties of the mix:

Many powders, because of their small size, irregular shape or surface characteristics, are
cohesive and do not flow well.

Poor flow will often result in a wide weight variation within the final product owing to variable fill
of tablet dies etc.

Granules produced from such a cohesive system will be larger and more isodiametric, both
factors contributing to improved flow properties.

To improve the compaction characteristics of the mixture:

Some powders are difficult to compact even if a readily compactable adhesive is included in the
mix, but granules of the same formulation are often more easily compacted and produce
stronger tablets. This is associated with the distribution of the adhesive within the granule. Often
solute migration occurring during the post granulation drying stage results in a binder-rich outer
layer to the granules. This in turn leads to direct binder–binder bonding, which assists the
consolidation of weakly bonding materials.

23
To reduce the hazard of toxic dust powders:

The granulation of toxic materials will reduce the hazard associated with the generation of toxic
dust that may arise when handling powders.

Suitable precautions must be taken to ensure that such dust is not a hazard during the
granulation process. Thus granules should be non-friable and have a suitable mechanical
strength.

Dry Granulation: In the dry methods of granulation the primary powder particles undergo;

Granulation: (aggregation) under high pressure without the use of a liquid using one of the
following processes. Generally conducted by: Making large size tablet (Slug) in a tablet
press/slugging or passing the powder material between two counter rotating rollers producing
sheet or ribbon by a roller compactor/Chilsonator. Then the intermediate products are broken
using a suitable milling technique to produce granular material, which is usually sieved to
separate the desired size granules. The unused fine material may be reworked to avoid waste.

Roller compactors

24
Moisture Activated Dry Granulation (MAD-Granulation): This process involves moisturizing
the powder blend to a pre-determined LOD to achieve compaction for a direct compression
(D.C) method of manufacture.

Hot-Melt Granulation: In these process molten materials is used as the granulating liquid.

API is either co-melted or dispersed in the molten stage of the vehicle and then cooling it to
solidification. This process is used mainly for the following purpose.

 For poorly soluble API for enhancing solubility and dissolution

 To protect moisture sensitive API
 To achieve sustained or extended release
 API or formulation ingredients are moisture sensitive
 Unable to withstand elevated drying temperature
 Formulation ingredients has sufficient inherent binding cohesive properties
 To improve flow property and die filling.

Process Parameters, In-process Tests & Scale-up factors for Dry Granulation

 Process Parameters, & In-process  Scale-up factor

Tests • For mixing blender: Equipment
• Particle size distribution occupancy in volume (%)
• Bulk & Tap Density • Total Revolutions
• LOD or Moisture • For Roller Compactor:
• Hardness of slugs. • Feed, Augur speed, Screen Size, Tip-
• Ribbon Thickness speed
• Roller Pressure & Gap

When Moisture Activated Dry Granulation (MAD-Granulation)?

• High load API with efflorescence, becoming powder with no compaction property

• Needs moisture to keep its crystallinity

• Usually a mixture of humectant with water is sprayed in a Fluid Bed Processor or High
Shear Mixer Granulator to achieve desired LOD without involvement of drying process

• Finally lubricant is added to obtain a blend for direct compression

25
Wet granulation

Granules are formed by addition of granulating liquid onto a substrate in a mixing bowl of:
(LSMG, HSMG or FBPD)

The substrate (intra-granular ingredient) may include the API and/or a binder: Mixed intensively
before addition of the granulating liquid to achieve uniformity.

Granulating liquid: Aqueous or Solvent with or without binder and may contain API in solution or
in dispersion state.

While the mixing process is continued either in the bowl of High-Shear Mixer Granulator with an
impeller and chopper mixing or in the Fluid Bed Processor Dryer the granulating liquid is added
at a constant rate until all is added

Further mixing is continued until pre-determined granulation end-point is reached (by measuring
the resistance/constrain on the impeller (ohms) or consumption of the electric energy (watts).

In the fluid bed processor both granulation and drying is achieved in a continuous process. The
end point is reached by achieving the desired LOD and product temperature.

Steps in Wet Granulation Process

Dry Mixing: Intra-granular ingredients with or without the API is intimately mixed in the bowl of
LSMG, HSMG or FBPD

Wet granulation involves the massing of a mix of dry primary powder particles using a
granulating fluid. The fluid contains a solvent which must be volatile so that it can be removed
by drying, and be non-toxic. The granulation liquid may be used alone or, more usually, as a
solvent containing a dissolved adhesive (binding agent) which is used to ensure particle
adhesion once the granule is dry. Further mixing of the wet mass is continued to achieve
granulation end-point

In the traditional wet granulation method the wet mass is forced through a sieve to produce wet
granules which are then dried. A subsequent screening stage breaks agglomerates of granules
and removes the fine material, which can then be recycled.

Typical liquids include water, ethanol and isopropanol, either alone or in combination. The
primary advantages of water are that: it is non-flammable, which means that expensive safety
precautions not be taken. Water is commonly used for economic reasons. The disadvantages of
water as a solvent are that:

 It may adversely affect drug stability, causing drug hydrolysis.

 It needs a longer drying time than do organic solvents, that
 Increases the length of the process and again may affect stability because of the extended
exposure to heat.
Organic solvents are used when water-sensitive drugs are processed, as an alternative to dry
granulation, or when a rapid drying time is required. Fluidized-bed granules are similar to those

26
prepared by the wet granulation, but possess greater porosity and the granule surface is
covered by a film of binding agent.

Wet granulators: There are many types of granulator used in the pharmaceutical industry for
wet granulation.

 Shear granulators: i) Low Shear and ii) High shear

 Fluidized-bed granulators
 Spray granulation and drying
 Spheronizer /Pelletizers

Low-Shear Mixer granulators: A low shear

planetary mixer with a grilled-beater is used
for initial powder mixing. The paddle of the
mixer agitates the powders followed by wet
massing of the mixed substrate by adding the
granulating liquid continuing the agitation.

High-Shear Mixer granulator:

Generally, this type of granulator has a

stainless steel mixing bowl containing a three-
bladed main impeller, which revolves in the
horizontal plane, and a three-bladed chopper
(breaker blade) which revolves either in the
vertical (Collette Gral) or the horizontal plane
(Diosna or T.K. Fielder).

 The unmixed dry powders are placed in the bowl and mixed by the rotating impeller for a
few minutes.

27
 Granulating liquid is then added using either a pressurized pot or peristaltic pump via a port
in the lid of the granulator while the impeller is turning.
 The granulating fluid is mixed into the powders by the impeller.
 The chopper is usually switched on when the moist mass is formed, as its function is to
break up the wet mass to produce a bed of granular material.
 Once the granules have been produced, the granular wet-mass is discharged, passing
through a wire mesh which breaks up any large aggregates, into the bowl of a fluidized-bed
drier.

Advantages of High-Shear Mixer/granulation:

Mixing and granulation are all performed within a few minutes in the same piece of equipment.

Disadvantages of High-speed mixer/granulation:

The process needs to be controlled with care as the granulation progresses so rapidly that a
usable granule can be transformed very quickly into an unusable, over-granulated mass. It is
also sensitive to variations in raw materials. However, these situation or problem is over come
and or controlled using a suitable monitoring system to indicate the end point of the granulation
process, i.e. when a granule of the desired properties has been attained. Usually monitoring the
amperage or resistance (torque) measuring ohm by a strain gauge installed within the impeller.

Process Parameters, In-process Tests & Scale-up factors for Wet-Granulation

 Process Parameters, & In-process Tests o Scale-up factor

 Dry Mix : Impeller & Chopper speed, Mixing Time o Same Tip speed of impeller
 Granulating Liquid Making: Impeller speed, o Same granulating liquid
mixing time addition time
 Addition of granulating liquid: Amount, Rate of o Same or close to same
addition, Impeller & Chopper speed initial LOD for the wet mass

Drying Process
Drying is a mass transfer process consisting of
 Tray Drying: (Convective forced air helps
the removal of water /solvent by evaporation
in heat transfer)
from a solid
 Fluid Bed Drying: (material for drying is on
a lifted fluid bed (air) with continuous heat
transfer)
 Freeze Drying: (is a drying method where
the solvent is frozen prior to drying and is
then sublimed) (Used for biologicals).

28
Tray Drying: The granules are collected on trays and transferred to a drying oven.

Tray drying has following three major disadvantages;

1. The drying time is long.

2. Dissolved material can migrate to the
upper surface of granules’ bed, as the,
solvent is only removed from the upper
surface of the bed on the tray, popularly
known as “Case Hardening” effect.
3. Granules may aggregate owing to bridge
formation at the points of contact of the
granules.

Fluid Bed Processing and Drying

Fluidized-bed Processor (Glatt)

 The powder particles are

fluidized in a stream of air.
 Granulating fluid is pumped
from a reservoir and sprayed
using pressurized pot or a
peristaltic pump from a nozzle
on to the bed of powders.
 Heated and filtered air is blown
through the bed of unmixed
powders to fluidize the
particles and mix the powders.

29
Advantages of fluidized-bed granulation

 In the conventional method of the wet-granulation processes, require separate equipment

for granulation, wet milling and drying. However, for the fluid-bed processing all these are
performed in one unit, saving time, transfer losses and time and labor costs. Thus very
convenient and economic.
 The process can be automated once the conditions affecting the granulation have been
optimized.

Disadvantages of fluidized-bed granulation

 The equipment is expensive.

Optimization of process parameters affecting granulation needs extensive development work.

Spray granulation and drying process: Spray drying is the process of converting a
solution of an API and polymer into a dry powder

 Granular product is made from a

solution or a suspension rather than
initially dry primary powder particles.
 The resultant granules are free-
flowing hollow spheres and the
distribution of the binder in such
granules results in good compaction
properties.
 Spray-drying can convert hard elastic
materials into more ductile ones.
 The primary advantages of the
process are the short drying time and
the minimal exposure of the product
to heat owing to the short residence
time in the drying chamber.
 This means that little deterioration
of heat-sensitive materials takes
place.
 Spray-dried particles are influenced
by equipment design, solution
characteristics and feed rate as well
as drying kinetics.

30
Process Parameters, In-process Tests & Scale-up factors for Drying

 Inlet temperature
 Exhaust temperature
 LOD
 For FBD also product temperature
 Air volume
 Inlet air dew point
 Scale-up is linear

SPRAY DRYING PROCESS PARAMETERS

Identifying Critical Process Parameters and their impact on Critical Quality Attributes in early
development can help ease the transition from early to late stage manufacture

Critical Process Parameters Critical Quality Attributes

Nozzle Type and Size Atomization Gas Type Particle Size Bulk Density
Spray Rate Atomization Flow Rate Physical State Yield
Inlet Temperature Drying Temperature and Time Residual Moisture Content
Outlet Temperature Drying Gas Type and Flow Rate Solvent

Spray Drying for Bioavailability Enhancement

Spray drying is an effective and popular method to manufacture the ASDs that increase the
bioavailability of low solubility APIs. Amorphous solid dispersions (ASDs) improve the solubility
of Develop-ability Classification System (DCS) class IIb compounds. Spray drying technology is
one method of manufacturing high-quality ASDs. Drug developers have found that the solubility
of DCS class IIb compounds can be enhanced by mechanization and related techniques that
expand the surface area of the drugs’ molecules. To improve the solubility of DCS class IIb
compounds, drug developers produce ASDs of the drugs. Spray drying is one of two methods
used to create ASDs. The spray drying process begins with the dissolution of the API and one
or more polymer excipients into an organic solvent. Polymers stabilize the API’s amorphous
state by physically separating the drug’s molecules. Because of the random order of the API
molecules inside the polymer matrix, ASDs completely release drugs without inducing re-
crystallization.

31
Spheronizer /Pelletizers

For some applications it may be desirable to have a dense, spherical pellet of the type difficult to
produce with the previous equipment. Such pellets are used for controlled drug release.
 A commonly used process involves:
 Separation of wet massing.
 Extrusion of this wet mass into rod-shaped
granules and subsequent Spheronization
of these granules.

Advantages of granulation using Extrusion/Spheronization

 Extrusion/Spheronization process is used to make uniformly sized spherical particles.

 It is used primarily to produce multi-particulates for controlled drug release applications.
 The major advantage over other methods of producing drug loaded spheres or pellets are
the ability to incorporate high levels of active ingredients without producing excessively large
particles (minimal excipients).
 Ideal flow behavior and dosability
 Compact structure
 Low hygroscopicity
 High bulk density
The main steps of the process are:

32
1. Dry mixing of ingredients to achieve homogenous powder dispersion

2. Wet massing to produce a sufficiently plastic wet mass

3. Extrusion to form rod-shaped particles of uniform diameter

4. Spheronization to round off these rods into spherical particles

5. Drying to achieve the desired final moisture content

6. Screening to achieve the desired narrow size distribution

Extrusion

Schematic representation of production extruder

Spheronization

 The function of Spheronization is to round off the rods produced by extrusion into spherical
particles.
 This is carried out in Spheronizer which consists of a bowl with fixed side walls and a rapidly
rotating bottom plate or disc.
 The rounding of the extrudate into spheres is dependent on frictional forces generated by
particle–particle and particle equipment collisions.

33
Comminution (size reduction) Milling

 Size reduction/milling of the dried granules is required for:

 Eliminate segregation during mixing by producing uniformity of particle size between
granules and extra-granular material
 Improve flow property and die/capsule shell filling

Size reduction Process & Equipment

1. Sifting
 Hand or Mechanical sifter using sieves:
Sieve size and Shaking
 Feed; Speed, Sieve Size & Configuration
2. Mills with revolving knives of Knives or Hammer
 Sieve size and speed
3. Oscillating Mills
 Scale-up is linear

Diffusion Mixing/Blending

Mode of Mixing: by Random movement; tumbling

Equipment: V-Blender, Slant-cone Mixer, and Double-cone Mixer & Bin Blender
It is mostly used for the following steps of mixing during drug product manufacturing.

34
Pre-Lube Mixing:
 In this stage generally the dried/milled granules is mixed with extra-granular ingredients in a
diffusion type of blender or within the primary mixer i.e., HSMG or FBPD
 Extra-granular ingredients: (Disintegrant, Anti-adherent, Glidant, Colorants, Flavors,
etc.).[For Modified Release tablets, Natural or synthetic Polymers]
 At Development Phase: (Sample is taken @ different mixing time to determine pre-lube
mixing time for blend uniformity).

Lube-Mixing:
 In this stage finally the lubricant is mixed with the blend to achieve the final blend for
compression or Encapsulation.
 Blend sample is taken for: BU, Assay, B/T Density, Sieve Analysis and LOD
 Scale-up factor: To have same total number of revolutions.
Process Parameters, In-process Tests & Scale-up factors for Blending

 Bulk & Tap Density

 % Capacity utilization
 Sieve Analysis for particle size
 Total revolutions
distribution
 LOD or Moisture (KF)
 Blend Mixing Time
 Blend Uniformity

Compression: (Tableting)

Materials or substrate processed/used for tablet compression:

After the preparation of granules (in case of wet granulation) or milled slugs/compacts after
commination/size reduction process (in case of dry granulation) or mixing of ingredients (in case
of dry blend-direct compression), they are compressed to get final product. The compression is
done either by single punch machine (stamping press) or by multi station machine (rotary
press). The tablet press is a high-speed mechanical device. It 'squeezes' the ingredients into the
required tablet shape with extreme precision. It can make the tablet in many shapes, although
they are usually round or oval. Also, it can press the name of the manufacturer or the product
identification into the top of the tablet.

Compressed tablets can be round, oblong, or unique in shape; thick or thin; large or small in
diameter; flat or convex; unscored or scored in halves, thirds, or quadrants; engraved or
imprinted with an identifying symbol and/or code number; coated or uncoated; colored or
uncolored; one, two, or three layered.

35
Tablet diameters and shapes are determined by the die and punches used in compression. The
less concave the punches, the flatter the tablets; conversely, the more concave the punches,
the more convex the resulting tablets. Punches with raised impressions produce recessed
impressions on the tablets; punches with recessed etchings produce tablets with raised
impressions or monograms. Logos may be placed on one or on both sides of a tablet,
depending on the punches.

Type of Tablet Press: There are Manual and Automatic Tablet Press

Manual Tablet Press: Generally, is of single punch or multi-tip single punch. They are mostly
used for research and/or initial pharmaceutical product development work for evaluating API’s
compaction characteristics for direct compression or dry granulation method of tablet
manufacturing. Making disc of API for intrinsic dissolution test, etc. e.g. Carver Press, Natoli
Laboratory Tablet Press. The compression force is generally exerted by spring load pressure,
pneumatic pressure or hydraulic pressure.

Automatic Tablet Press:

Based on their design and running principle can be of two types; i) Single punch Tablet Press
and ii) Rotary Tablet Press

i) Single punch Tablet Press: These single punch automatic tablet press are
generally used for making slugs for dry-granulation process or for low volume
production of some shaped tablet for body cavity (vaginal or anal) insertion. e.g.
Manesty or Stokes, F3 Tablet Press: Single station, 4-ton compression pressure,
7/8" max tablet diameter, 11/16" max depth of fill, rated 42-85 tablets per minute.

ii) Rotary Automatic Tablet Press: is a mechanical device that unlike the single
punch tablet press has several tooling station which rotates to compress
granules/powder mixture into tablets of uniform size, shape (depending on the
punch design) and uniform weight. It was developed to increase the output of tablets

There are many stages that occur during tablet production on the rotary tablet press and a full
understanding of their functions is crucial to the success of producing a quality tablet.

Compression stages in a rotary tablet press:

36
Stage 1 Filling: Top punch is withdrawn from the die by the upper cam Bottom punch is low in
the die, so powder falls in through the hole and fills the die. The punch-die cavity is made of die
and lower punch. Then the position of lower created the volume of the cavity. This volume is
appropriately adjusted for the weight of granules to be compressed to make the tablets.

Stage 2 Metering: Bottom punch moves up to adjust the powder weight-it raises and remove
the excess granules from the compression machine. At this stage, the required weight (volume)
of the granules to be compressed into tablets is controlled by the height of the lower punch in
the die and the height of the lower punch is controlled by the fill cam.

Stage 3 Compression: Top punch is driven into the die by upper cam Bottom punch is raised
by lower cam Both punch heads pass between heavy rollers called compression roller to
compress the powder. The compression rollers push the punches towards the die to form the
product.

Stage 4 Ejection: Top punch is withdrawn by the upper cam Lower punch is pushed up and
expels the tablet is removed from the die surface by surface plate

Rotary Tablet Press based on tooling size is of two type, D tooling Tablet press and B
tooling Tablet Press:

There are two internationally recognized standards for tablet compression tooling, the “TSM”
and the “EU” standards. Both “TSM” and “EU” standards identify the physical tool configuration
for “B” and “D” type tablet compression tools, their critical dimensions, and associated
tolerances assuring tablet quality and an efficient tablet press operation.

The “TSM” tooling standard is recognized in the Americas and is considered exclusive in the
United States. “TSM” stands for the Tablet Specification Manual and is published, revised, and
distributed by the American Pharmacist Association in Washington, DC. The “TSM” standards,
once known as the “IPT” standards, were originally developed in 1968 by a committee
consisting of major US pharmaceutical companies. Their motivation was an attempt to maintain
standardization for “B” and “D” tablet compression tooling, which provides interchangeability
between tablet presses. The “TSM” provides engineered drawings that are a valuable reference
for troubleshooting and tool inspection. Today, the “TSM” committee consists of professionals
from the tablet press, tooling, and tablet manufacturing industries. The “TSM” also includes
useful information such as standard cup configurations for round tablets and a reference to
common bisects for breaking tablets into multiple uniform dosages.

37
The “EU” tooling standard is internationally recognized and is more widely used than its counterpart,
the “TSM” standard. “EU,” which is the acronym for “Euro-standard” and “Euro norm,” is considered
the European standard for interchangeable “B” and “D” type compression tools. The “EU” standards
were created by Trevor Higgins in an attempt to establish a tooling “norm” that provides tool
interchangeability with the most common “B” and “D” type European tablet presses. The “EU”
standard is printed and distributed by I Holland Ltd, Nottingham, UK. Drug Product CQAs Impacted
by Tablet Compression Process
Critical Process Parameters Critical Quality Attributes Additional points to check in the
Batch Records

 Type of Tablet Press (model,
geometry, number of stations)
 Hopper design, height, angle,
vibration
 Feeder Mechanism
(gravity/forced feed, shape of
wheels, direction of rotation,
number of bars)
 Feed frame type and speed
 Feeder fill depth
 Tooling design (e.g.
dimension, score configuration,
quality of the metal)
 Maximum punch load
 Press speed/dwell time
 Pre-compression force
 Main compression force
 Punch penetration depth
 Ejection force
 Dwell Time
 Tablet appearance
 Tablet weight
 Weight uniformity
 Content uniformity
 Hardness/Tablet
breaking force/Tensile
strength
 Thickness/dimensions
 Tablet
porosity/density/solid
fraction
 Friability
 Tablet defects
 Moisture content
 Disintegration
 Dissolution
Records the following: During Set-
up and Compression Run
Machine Type/ Single
punch/Rotary; Double sided/Bi-
layer
Tooling Type, Description, # of
Stations
Press Speed (Low and High.
Feeding of the press: Gravity or
Force
Sampling for: Weight, Thickness,
Hardness, and Friability
Challenges tests: (During product
development to set hardness
range)
High weight/Low hardness:
Friability & Thickness
Low Weight/High Hardness:
Thickness, & Dissolution profile
Uniformity of dosage unit (By
content uniformity/AV value)

Dissolution Test (Disintegration

Test if required)

Assay

38
Measuring of Compression Force

Although the compression force is one of the main CPP for making a tablet by applying
pressure to a material/substrate (powder or granules). However, in the tablet press this is not a
unit measurement for the recording in the Batch Manufacturing Record, rather its output the
CQA tablet hardness is measured/tested and recorded as the in-process control. Typically, the
compression force is obtained/provided in a tablet press is by a) coiled spring load pressure, b)
Pneumatic pressure or c) Hydraulic pressure. In the tablet press the pneumatic pressure or
hydraulic pressures (PSI) are recorded in a meter located at the pressure application pump.
This meter has a green and red area with middle. Typically, at the start of compression process
the operator of the tablet press will either open the air vent or pump the handle to obtain the
required compression force by pneumatic or hydraulic pressure respectively. However, for the
spring-loaded pressure the operator will screw the wheel of the spring-load plunger to get the
pressure on to the lower compression roller.

However, for the research purpose or in the product development of a very special project a
tablet press would be instrumented with a strain gage at some practical position of the machine
that would undergo a force proportional to the force exerted by the upper punch and recorded in
a chart recorder. Now-a-days some modern tablet press have facilitated measuring/recording
the compression force and even has a printer chart recorder or electronic monitor. As stated in
the above recording this CPP, the tablet compression force should not be a hard and fast
requirement for the BMR.

Instrumentation

Modern rotary production tablet presses are typically equipped to measure pre-compression
and main compression forces. Additionally, measurement and monitoring of tablet ejection
force can prove to be beneficial for specific problem products and for production
troubleshooting.
However, for most pharmaceutical products’ proper product development and optimization work
eliminate the need to instrument a production machine for ejection force. Rotary tablet presses
can also be equipped to measure both upper punch and lower punch pull-down forces. These
measurements are primarily made to detect tight- running punches and are necessary on
production machines only if the machine monitoring system uses direct force measurement for
these functions. Tablet scrape-off force can also be measured, but this is only recommended on
development machines. Scrape-off forces are typically below 6 N. Therefore, instrumentation of
a tablet stripper requires highly sensitive instrumentation that is easily damaged.
Pre-compression and main compression forces are normally measured for the upper punches
These forces are typically measured using strain gauges arranged in a full Wheatstone bridge
Strain gauges are basically resistors applied to the metal surface in a specific orientation. Under
load, the member deflects and the strain change the resistance of the gauge. The change in
resistance is proportional to the applied force. However, due to design differences, some
39
machines measure the lower compression forces as opposed to upper compression forces. The
compression force should be measured as close to the compression event as possible. For the
most accurate and reproducible readings, the strain gauge should be in line with the
compression event as opposed to off center at a remote location. This is easily accomplished
on most rotary tablet presses by using a shear pin to support the compression rollers. However,
the pin must not be rotated when the position of the compression rollers is changed. Therefore,
this system is ideally suited for machines that change roller position by a vertical slide
mechanism as opposed to an eccentric mechanism. Shear pins are typically custom
manufactured, where quality depends not only on the pin design but also on the strain gauge
receptivity and arrangement.

Tablet Press Scale-up:

In tableting applications, the process scale-up involves different speeds of production in what is
essentially the same unit volume (die cavity in which the compaction takes place). Thus, one of
the conditions of the theory of models (similar geometric space) is met.
However, there are still kinematic and dynamic parameters that need to be investigated and
matched for any process transfer. One of the main practical questions facing tablet formulators
during development and scale-up is whether a particular formulation will sustain the required
high rate of compression force application in a production press without lamination or capping.
Usually, such questions are never answered with sufficient credibility, especially when only a
small amount of material is available, and any trial-and-error approach may result in costly
mistakes along the scale-up path.
When developing a new formulation scientists are equipped with a small scale tablet press to
study and understand their product’s tabletability. These small scale systems are very useful at
the research level but do not always successfully transfer to the larger scale manufacturing
machines. Ideally, developing the product on a manufacturing press would eliminate the transfer
challenges, but the amount of powder required to operate such a machine is very high and not
cost effective.
As tablet formulations are moved from small-scale research presses to high- speed machines,
potential scale-up problems can be eliminated by simulation of production conditions in the
formulation development lab. In any process transfer from one tablet press to another, one may
aim to preserve mechanical properties of a tablet (density and, by extension, energy used to
obtain it) as well as its bioavailability (e.g., dissolution that may be affected by porosity).

40
A scientifically sound approach would be to use the results of the dimensional analysis to model
a particular production environment. Studies done on a class of equipment generally known as
compaction simulators or tablet press replicators can be designed to facilitate the scale-up of
tableting process by matching several major factors, such as compression force and rate of its
application (punch velocity and displacement, in their dimensionless equivalent form.

 Experience has shown that both tablet weight consistency and integrity improve as feed
times and compression times (dwell) increases. (Impact on tablet’s integrity to be
established during Product Development).
 Dwell times are calculated on the basis of how much time is spent at maximum
compression.
 Dwell Time: length of punch head flat and linear punch speed are the determining factor.
 Note: Comparing turret RPM between machines is not a valid measure of relative dwell
times.
 To have same dwell time between the Tablet Press

Calculation of Dwell Time for Scale-up

DT = Dwell Time; Time = Distance ÷ Velocity; Distance = Punch Head flat diameter; TPM =
tablet per minute; PCD = Turret Pitch Circular Diameter; Π = 3.14159 Number of
Stations = # of stations in the tablet press turret

Velocity = TPM x Π X PCD = TPM x 3.14159 x 228.6 = 0.748 TPM (mm/sec)

(#Stations) x 60 16 x 60

Dwell Time = Head flat diameter ÷ Velocity = m ÷ m/sec = sec

Example: for a BETAPRESS 16 station

PCD = 228.6mm

Length under the feeder = 214 mm

Therefore, Velocity = TPM x 3.14159 x 228.6 = 0.748 TPM (mm/sec)

16 x 60

Time = Distance = 214 = 286.1

Velocity 0.748TPM TPM

Dwell time = the amount of time that the head flat is under the compression roller.

DT = Head flat dia. = 12.7 mm = 17

Velocity 0.748 TPM

41
Head Flat Diameter for a B tooling = 12.7 mm; Head Flat Diameter for a D tooling = 18.2 mm

DT = 12.7mm = 16.978 = 17

0.748 TPM

For Press Speed of 1400 TPM: DT = 17÷1400 = 0.73 seconds

42
HOW CRUCIAL IS COMPACTION DWELL TIME?

43
44
45
46
47
Selection of Logo position in a round shaped Biconvex Tablet
Generally by default a formulator will chose the crown area of a round bi-convex tablet to place
the logo inscription on the tablet, without thinking its implication. A few years ago the editor
being an R&D formulator himself of the generic industry learned the following with product’s
logo definition issues on the final compressed tablets.

In the past while formulating the generic version Ranitidine tablets he learnt it very hard way,
that placing the logo definition on the perimeter of a round bi-convex tablet as opposed to at the
crown area would not only remove potential picking problem, specially of the island and
peninsula areas but also it will remove any bridging problem for film-coating.

The following alphabets and digits have island and peninsula which have potential for picking
problem. They are differential into following three categories:

Item I. No Problem II. Moderate Problem III. High Problem

Alphabets C, I, J, L, S, T, U, E, F, G, H, K, M, N, A,B, D, O, P, Q, R,
V,W, X, Y, Z
Digits 1, 2, 3 5, 7 4, 6, 8, 9, 0

Category I:
Alphabets, C, I, J, S, T, and U due to not having any island or very sharp peninsula in
them would not give any problem for in the tablet product definition for trade dress
tooling design for engraving, producing it’s mirror image debossed tablet.

Digits, of this category are 1, 2, 3, and most likely 5 if designed properly should not have
any potential problem for “Picking”

Category II:
Alphabets, E, F, G, H, K, M, N, V,W, X, Y, and Z although they do not have any island
but due to having very sharp peninsula areas in them would give moderate problem of
“Picking” for the debossed tablets produced using their trade dress tooling design with
engraving.

Similarly digits, of the category II are 5 and 7 if not designed properly would have some
potential problem for “Picking”

Category III:
The most problematic Alphabets are A, B, D, O, P, Q, and R all of them have at least
one island and Q has also a very sharp peninsula area. They would give highest
problem of “Picking” for the debossed tablets produced using their trade dress tooling
design with engraving.

Similarly digits, of the category III are 4, 6, 8, 9, and 0. Like the alphabets with island
these digits would have potential problem for “Picking”

48
How to resolve and/or avoid this “Picking” problem:

 Logo design and NDC number with island or very sharp peninsula areas of
alphabets and digits has to be considered very carefully during product design,
especially for small tablet.
 30 to 50% pre picked tooling design for the island areas in the tooling may be
used. Sharp peninsula should be rounded if possible.
 For bi-convexed tablet small tablets with debossing, their tooling design for the category
III type engraving should not be placed at the crown area. Rather, it should be placed
on around the perimeter of the punch. Concave tooling at a given hardness would have
the weakest area for compression is CROWN. Therefore, placing an engraving in that
area is potential for "picking”
 Another very important point for the placement of engraving between Upper and Lower
punch. It would be always good the put the engraving on the upper punch and only for
scoring a bisecting bar can be placed on a lower punch.
Comparative similar case

Dentist will tell there is potential for the upper teeth to have problem as opposed to lower ones. Why?

This is due to low of gravity. An upper tooth for its weight (mg) would like to fall into the ground “like
that of the apple” Newton’s low of Gravity. Thus, the muscle of the upper gum is always going through a
strain to keep the upper tooth in place. Whereas, a lower tooth for its weight (mg) due to gravitational
pull will remain sitting in the lower gum, less likely to fall apart unless one has an infection. Sometimes a
loose lower tooth would set in by itself due to this gravitational advantage.

This law of Gravity also applies in the case of granules during compression. Upper punch will have
fewer problems of sticking and or adherence. The Engraving of a lower punch after running for a while
has potential for sticking and filling into the engraved areas, especially for adhesive materials. Hence, a
good formulator or tooling designer will never put engraving on to the lower punch, unless it is very
much needed and have been found satisfactory with the specific product during development stage.

With this knowledge the comparator/editor of this handbook as a formulator; for a pharmaceutical
company in Cincinnati made all its R&D generic tooling placing “BBBB” or “8888” on the upper
perimeter of the upper punch.

The lower punch was made plain to avoid this ‘picking’ as well as “sticking” potential and placed only
a bi-sector when it was needed for the drug product.

With that firm ordered tooling from Natoli Engineering and received at least 20 sets of tooling of
following description.

49
 Set Shape Size in inch Upper Upper Lower
Number Punch (1) Punch (2) Punch

1 Round 15/16” 0.9375” “BBBB” “8888” Bisector

2 Round 7/8” 0.875 “BBBB” “8888” Bisector

3 Round 13/16” 0.8125 “BBBB” “8888” Bisector

4 Round 3/4” 0.750 “BBBB” “8888” Bisector

5 Round 11/16 0.6875” “BBBB” “8888” Bisector

6 Round 5/8” 0.625” “BBBB” “8888” Bisector

7 Round 9/16” 0.5625 “BBBB” “8888” Bisector

8 Round 17/32’ 0.53125” “BBBB” “8888” Bisector

9 Round ½” 0.500 “BBBB” “8888” Bisector

10 Round 7/16” 0.4375 “BBBB” “8888” Bisector

11 Round 3/8” 0.375” “BBBB” “8888” Bisector

12 Round 11/32” 0.34375” “BBBB” “8888” Bisector
13 Round 5/16” 0.3125” “BBBB” “8888” Bisector
14 Round 9/32” 0.28215” “BBBB” “8888” Bisector
15 Round ¼” 0.2500” “BBBB” “8888” Bisector
16 Round 7/32” 0.21875” “BBBB” “8888” Bisector
17 Round 3/16” 0.1875” “BBBB” “8888” Bisector
18 Round 5/32” 0.15625” “BBBB” “8888” Bisector
19 Round 1/8” 0.125” “BBBB” “8888” Bisector

With all these sets available at R&D tooling room, the Product Development was able to formulate at
least all the needed generic tablet sizes for the round shaped tablet with or without a bisector and
made its life easy. Then following establishing a proto type formula, the project key formulator would
always order trade dress tooling but to follow the same concept of design of the tooling i.e., placing the
logo and NDC number on the perimeter of the tooling avoiding any picking potential in the scale-up
ANDA batches.

Unfortunately a specific case had happen with ANDA batch tablets of 100mg and 200mg weight. The
formulator made the batch in R&D using the tooling with engraving on the perimeter, but passed and
ordered trade dress tooling with “LOGO” and NDC number at the crown position of upper and lower
punch respectively. The experimental and Process Optimization batches had no picking problem but
the ANDA batch due to its wrong tooling design resulted with picking. This was negligence from both
Product Development and Technology Transfer due to oversight. They should not have made this
change of engraving position placement on the crown area as opposed to perimeter area without
proper evaluation, which has resulted in picking in tablets.

50
Examples of Pharmaceutical Unit Operations, Material Attributes, Process Parameters,
Quality Attributes, Comments and points to check in the Submitted Batch Record(Solid
Dosage)

51
Chapter 5: Hard Gelatin Capsule

1. Hard Gelatin Capsules: Formulation and Manufacturing Considerations

Hard gelatin capsules also known as hard-shell gelatin capsules or two-piece capsules are solid dosage
forms in which one or more medicinal agents and/or inert materials are enclosed within a small shell.
They are a well-established dosage form that provides solutions to many of today’s drug delivery and
nutraceutical formulation challenges.

A hard gelatin capsule shell consists of two prefabricated, cylindrical sections (a cap and a body) each
of which has one rounded, closed-end and one open end. The body has a slightly lower diameter than
the cap and fits inside the cap

Hard gelatin capsule shells are fabricated and supplied empty to the pharmaceutical industry by shell
suppliers and are then filled in a separate operation. During the capsule filling unit operation, the body is
filled with the drug substances and the shell is closed by bringing the body and the cap form the final
dosage form.

Components of hard gelatin capsules

Hard gelatin capsule shell is composed largely of gelatin. Other than gelatin, it may contain
materials such as plasticizer, colorants, opacifying agents, and preservatives which either
enable capsule formation or improve their performance. Hard gelatin capsules also contain 12–
16% water, but the water content can vary, depending on the storage conditions.

Capsule sizes and shapes

Empty hard gelatin capsule shells come in a variety of sizes ranging from an arbitrary
numbering of 000 to 5 with 000 being the largest size and 5 being the smallest. The shape has
remained virtually unchanged since its invention except for the development of the self-locking
capsule during the 1960s when automatic filling and packaging machines were introduced.

52
The size of hard gelatin capsule selected for use is determined by requirements of the
formulation, including the dose of the active ingredient and the density and compaction
characteristics of the drug and other components. The first step to estimating the optimal
capsule size for a given product is to determine the density of the formulation using tapped
density for powders and bulk density for pellets, mini-tablets, and granules. The appropriate
capsule size may then be calculated using the measured density of the formulation, the target
fill weight, and capsule volume. The fill weight for liquids is calculated by multiplying the specific
gravity of the liquid by the capsule body volume multiplied by 0.9.

To accommodate special needs, some intermediate sizes (‘elongated sizes’) are produced. These capsule
sizes typically have an extra 10% of fill volume compared to the standard sizes
e.g. elongated size 00 capsules (00el), elongated size 0 capsules (0el), elongated size 1 capsules (1el),
elongated size 2 capsules (2el) etc. The table below shows capsule volumes and typical fill weights for
formulations with different tapped densities.

2. Manufacture of empty hard gelatin capsules

Hard gelatin capsules are manufactured using a dip-coating method and the various stages
involved are as follows:

Step 1: Preparation of the gelatin solution (dipping solution)

Step 2: Dip-coating the gelatin solution on to metal pins (molds)

Step 3: Rotation of the Dip-coated pins

Step 4: Drying of the gelatin-coated pins

Filling of hard gelatin capsules

The filling of hard gelatin capsules is an established technology, with equipment available
ranging from that for very small-scale manual filling (e.g., Feton capsule filling machine),
through intermediate-scale semi-automatic filling to large-scale fully automatic filling. Hard
gelatin capsules can also be hand-filled one at a time, as done in a compounding pharmacy.
The difference between the many methods available is the way in which the dose of material is
measured into the capsule body.

53
The basic steps in filling hard gelatin capsules include:

1. Rectification of capsules (placing empty gelatin capsules on the removable plate with bodies
facing downward).
2. Separation of caps from bodies.
3. Dosing of fill material (The body is filled with the formulation manually using a plastic
spatula, and the excess powder is removed).
4. Replacement of caps/ closing capsule shells and
5. Ejection of filled capsules.

Filling of powder formulations into hard gelatin capsules

Hard gelatin capsules can be filled by hand for research or experimental purposes or when
filling a small number of capsules in the pharmacy. This is done by placing the powder to be
filled on a sheet of clean paper or on a pill tile or porcelain plate and pressing the open end of
the capsule downward until it is filled. The cap is then placed to close the capsule.

On a small-scale manufacture, hard gelatin capsules can be filled manually using a manual or a
hand-operated capsule machine. This is done by directly filling the powder into the capsule shell
and relying on the bulk/tapped density of the powder to get the correct dose for the volume of
the capsule shell used. The various types of hand-operated capsule machines have capacities
ranging from 24 to 300 capsules and, when efficiently operated, are capable of producing about
200 to 2,000 capsules per hour.

Large scale production involves the use of machines that come in great variety of shapes and
sizes, varying from semi- to fully automatic and ranging in output from 3000 to 150 000 per
hour. Powder filling is accomplished by either of the two dosing devices: dosator device or
dosing disk/tamping.

The dosator device uses an empty tube that dips into powder bed, which is maintained at a
height approximately two-fold greater than the desired length of the plug. The dosator piston’s
forward movement helps form the plug, which is then transferred to the body of the capsule, and

Dosator filling principles

54
 The tamping device operates by filling the cavities bored into the dosing disk, similar to the die- filling
operation during tableting. A tamping punch slightly compresses the filled powder by repeated action,
which is followed by the ejection of the plug into the capsule body.

Tamping/ Dosing disk filling principle

Large scale filling of hard gelatin capsules follow the same basic steps of filling two-piece
capsules with two significant improvements:

1. Capsule alignment and separation are driven by vacuum, instead of mechanical interlocking.
2. Powder filling may require a soft compact (plug) formation depending on the formulation weight
and capsule fill volume. This compact is usually much softer than a typical tablet. The
compaction force used for plug formation is typically 20–30 N, compared to 10–30 kN typically
used for tableting.

Filling of tablets into hard gelatin capsules

Tablets are placed in hoppers and allowed to fall down tubes, at the bottom of which is a gate
device that will allow a set number of tablets to pass. These fall by gravity into the capsule
bodies as they pass underneath the hopper. Most encapsulators used for this purpose have a
mechanical probe that is inserted into the capsule to check that the correct number of tablets
has been transferred.

Tablets for capsule filling are normally film-coated to prevent dust generation and are sized so
that they can fall freely into the capsule body but without turning on their sides.

A recent innovation is the filling of coated Minitab lets, which have a significantly smaller surface
area than the equivalent quantity of pellets, thus, reducing the amount of coating required and
improving its uniformity.

55
Filling of multi-particulates and mini-tablets into hard gelatin capsules

Capsules formulated to give modified-release patterns are often filled with granules or coated
pellets using machines adapted from powder use. These materials can be filled via volumetric
filling and dosator filling using aspirational air flow.

Multi-particulate volumetric chamber filling principle for multiple products

Pellet dosing based on volumetric filling by the moving dosing disk principle

Volumetric filling can be achieved in a number of ways. The dosing disk method can be adapted
in a way that the filled dosing chambers are not tamped and the filled dosing chamber is
transferred above the capsule body, where a sliding plate opens the chamber to release the
multi-particulates. Similarly, the dosator filling principle is adapted, whereby the dosator strikes
in the multi-particulate bed to vacuum transfer the multi-particulates by air and transfers them to
the capsule body.

56
In the double-slide method, a chamber is opened and closed by a moving plate. A second plate
then opens and closes at the bottom of the chamber to fill the metered pellet dose into the
capsule.

The piston dosing systems are based on the gravimetric principle where a dosing piston is
underneath the multi-particulate bed. The dose is adjusted by the moving piston and a
mechanical closure before the piston moves further down to reach to open a channel through
which the multi-particulates flow into the capsule body. This principle is also used for the filling
of two different multi-particulates whereby the first filling and closing of the piston is followed by
lowering of the piston to collect second filling before moving to the release stage of the multi-
particulates into the capsule body in the dosing disk principle the dosing disk principle the
dosing chamber is closed at the bottom and gravimetrically filled with the pellets.

Multi-particulate dosator capsule filling principle

When the dosing disk moves the upper end closes und the dosing chamber moves directly
above the capsule body to release the pellets. Filling of multi-particulates by dosator-type
machines is achieved by the dosator driving into the pellet bed and sucking in the pellets by
vacuum.

Because pellets are not compressed during the filling process, it is necessary to make an
allowance for their size when calculating the weight of particles that can be filled into a capsule.
Unlike powders, which have a much smaller size, pallets cannot fill as much of the available
space within the capsule because of packing restrictions. The degree of this effect will be
greater the smaller the capsule size and the larger the particle diameter.

57
Filling of liquids/semisolid formulations into hard gelatin capsules

As drug discovery continues to yield poorly water-soluble molecules, there is an increasing need
for formulation techniques that can improve drug solubility. One such approach is the use of
liquid-based formulations containing lipids, solvents, or surfactants, usually in combination, to
improve drug solubility and bioavailability. The final formulation may be filled through piston
pump systems into hard gelatin capsules as a room temperature liquid, or as a molten
semisolid.

The filling of a liquid or semi-solid formulation is dependent on the viscoelastic properties of the
formulation and the need to fulfil certain characteristics at the filling temperature. As a general
rule, the formulation should have a viscosity of between 50 and 1000 Centipoise (cP) (although
formulations of much higher viscosity can be suitable for manufacturing) and should not exceed
70 °C

The particle size in suspension should ideally be less than 20 µm and formulations should be
such that no stringing, dripping, splashes or solidification of the formulation should occur at the
dosing nozzle. Unless a hot-melt is filled that completely solidifies below 40 °C, hard capsules
are recommended to be band or fusion sealed using separate band sealing or Liquid
Encapsulation Micro-spray Sealing (LEMS®) sealing equipment. For research purposes, a
machine that is capable of filling and sealing 1500 capsules an hour (e.g. CFS® 1500) has been
developed.

Note: If hard gelatin capsules cannot be used because of any formulation, preference, or
cultural reason, alternative materials such as polymer-based shells or hypromellose may be
used.

Liquid Excipients Compatible with Hard Gelatin Capsule Shells

Lipophilic excipients Vegetable oils e.g., Peanut oil, Castor oil, Olive oil,
Fractionated coconut oil, Corn oil, Sesame oil, Hydrogenated
vegetable oil, Soybean oil
Esters e.g., Glycerol Stearate, Glycol Stearate, Isopropyl
myristate, Ethyl oleate
Fatty Acids e.g., Stearic acid, Laurie acid, Palmitic acid, Oleic
acid, Oleic acid
Fatty Alcohols e.g., Cetyl alcohol, Stearyl alcohol
Hydrophilic excipients PEG 3000–6000 MW
Amphiphilic Poloxamers, Lecithin, PEG esters (e.g., Gelucir 44/14; 50/13;
excipients Labrafil)
Abbreviations: PEG, polyethylene glycol; MW, molecular weight.

58
 Drug Product CQAs Impacted by Encapsulation Process (Hard Gelatin Capsule)
Critical Process Parameters Critical Quality Attributes Additional points to check in the
Batch Records
Machine type Capsule appearance Records the following in the
Machine fill speed Weight application:
Tamping Force Weight uniformity Type of Encapsulators used
No. Of Tamps Content uniformity Speed (Low and High), If batch size
Auger screw design/speed Moisture content does not allow run at one speed
Powder bed height Slug tensile strength Type of Feed: Powder, plug, pellet,
tablet etc.
Disintegration
In-Process weight: Empty capsule
Dissolution Weight, Filled Capsule weight
Set-parameters
Dosator, Tamping pressure, spring
size etc.
Uniformity of dosage unit (By
content uniformity)
Dissolution & Assay

Chapter 6: Soft Gelatin Capsule

Softgel Capsule Manufacturing Steps

 Gel Mass Compounding: The process of blending and heating granulated gelatin and
other ingredients in warm water in a gelatin melting tank. With appropriate heat, mixing and
vacuum, the ingredients form thick syrup called a "gel mass" for use in encapsulation. Color
may be added during the melting process or in a separate machine.
 Fill Mass Compounding: The process of preparing the non-aqueous oil or dispersion that
will be encapsulated. Preparation equipment may include: processing tanks, mixers,
vacuum homogenizers, sieves and mills. Heated and unheated transfer tanks may be used
for the fill material and gelatin while waiting for encapsulation.
 Encapsulation: The process of converting the gel mass into a thin layer of gelatin and
wrapping it around the fill material to form a softgel.
 Drying: The process which removes excess moisture from the gelatin shell to shrink and
firm up the softgel. Drying occurs either by tumbling or by a combination of tumbling and tray
drying.
 Cleaning/Polishing, Inspection and Sorting: This is often required prior to packaging
based upon the intended use of the softgel.

Gel Mass Compounding:

 Charging of Purified Water, Glycerin and/or Sorbitol into a jacketed stainless steel melting
tank while mixing and heated until temperature reaches 85°±10°C.
 Mixing is continued until completely dissolved.

59
 Vacuum is applied to de-aerate the gel mass.
 Opacifier and color is added to the gel mass and mixed until uniform.
 De-aeration of the gel mass by applying Vacuum until complete de-aeration is achieved.
 Gel Mass is hold in tanks at 55±5°C for 12 to 72 hours.

Critical Process Parameters & In-Process Control for Gel Mass Compounding

 Gelatin Cooking Temperature: 85 ± 10 °C

 Gelatin Cooking Time: Until completely dissolved
 Opatint addition and Mixing Time: Until uniform
 Gel Hold Time: 6-72 hours
 Gel Hold Temperature: 50-60°C to keep Gelatin in Melted State
 Moisture Content: Between 16 – 25%
 Viscosity: 5000 – 28000 cP

Process Equipment for Soft Gelatin Capsule

 Gel Melter
 Jacketed Gel Holding Tank
 Soft Gel Encapsulation Machine
 Capsule Drying Chamber & Trays
 Capsule Sorter
 Capsule Polishing Pan
 Capsule Printing Machine

Fill Mass Compounding

 Generally the API either dissolved or dispersed in a non-aqueous system; oil or PEG 400
 A suspending or emulsifying agent with/without an anti-oxidant is used.
 Homogenization is employed for de-agglomeration and uniformity of the dispersion
 Fill Mass is mixed in transfer tanks (Heated /Unheated) at slow speed until encapsulation.
 De-aeration of the fill mass by applying Vacuum until complete de-aeration is achieved

Process Parameters & In-Process Control for Fill Mass Compounding

 Fill Mass Temperature: °C Product dependent

 Fill Mass Mixing Time: Until completely dissolved or dispersed
 Processing Aids addition and Mixing Time: Until uniform
 API addition, Mixing and Dispersion
 Homogenization: Colloid Mill Gap Width
 High Pressure Homogenizer: Up to 150 MPa
 Post milling mixing

60
Encapsulation

 The process of converting the gel mass into a thin layer of gelatin and wrapping it around
the fill material to form a softgel.
 Gel mass tank is connected to the encapsulation machine.
 Transferring the fill mass into the hopper with or without heating. Blanket with nitrogen if
needed.
 Molten gel is released to produce a ribbon. Adjust Ribbon thickness is adjusted using
spreader box knobs.
 The fill mass is injected into an oval/round shape die set, to obtain desired target fill weight.
 Soft gel capsules is collected in a tumble drying basket containing lint-free wipes and rotated
for the initial drying phase.
 Semi-dried soft gel capsules are spread on trays and transferred to the drying room for 48
hours or longer until the soft gel capsules reaches desired a hardness and moisture content

Process Parameters & In-process Control for Drying Capsules

 Drying Time: Until moisture content specifications are met.

 Drying Temperature: 22°C - 25°C
 Humidity: 14% - 22% RH
 Fill Moisture content: NMT 10.00%
 Shell Moisture Content: NMT 10.00%
 Average Hardness: kN

Process Parameters for Encapsulation, In-process Controls

 Machine Speed: Operating range ( 2 – 5 rpm)

 Fill Mass Hopper Temperature: 29-35°C
 Ribbon Thickness: 0.70 ± 0.05 mm
 Seam Thickness: NLT 0.25 mm
 Spreader Box Temperature: 65 °C (±15°C)
 Wedge Temperature: 40 °C (±10°C)
 Drum Cooling Temperature: 4-24°C
 Ribbon Thickness: Thickness to deliver target shell (0.75-0.95 mm)

Sorting, Printing, Polishing & Packaging

 The capsules are sorted using capsule sorting machine

 Polish with Isopropyl Alcohol 99% to remove residual oil in a polishing pan
 Often the capsules are printed using Printing Machine with Opacode® Black, using printing
aids n-Butyl Alcohol and Propylene Glycol if needed
 Printed capsules are oil polished with 3% Lecithin in Medium Chain Triglycerides
(Miglyol 812N) in a polishing pan and then inspected
 Package the capsules.

61
 Drug Product CQAs Impacted by Soft Gelatin Capsule Process
Critical Process Parameters
Gelatin Cooking Temperature:
85 ± 10 °C
Gelatin Cooking Time
Opatint addition and Mixing Time:
(Until uniform)
Gel Hold Time: 6-72 hours
Gel Hold Temperature: 50-60°C to
keep Gelatin in Melted State
Moisture Content: Between 16 – 25%
Viscosity: 5000 – 28000 cP
Critical Quality Attributes
For Gelatin cooking Time;
Complete dissolution
For Opatint: Until uniform
Moisture Content
Viscosity
Fill Mass Temperature: °C
Product dependent
Fill Mass Mixing Time: Until
completely dissolved or
dispersed
Processing Aids addition and
Mixing Time: Until uniform
API addition, Mixing and
Dispersion
Homogenization: Colloid Mill
Gap Width
High Pressure Homogenizer:
Up to 150 MPa
Post milling mixing
Additional points to check in the
Batch Records
Records the following in the
application:
Machine Speed: Operating range (2 – 5
rpm)
Fill Mass Hopper Temperature: 29-
35°C
Ribbon Thickness: 0.70 ± 0.05 mm
Seam Thickness: NLT 0.25 mm
Spreader Box Temperature: 65 °C
(±15°C)
Wedge Temperature: 40 °C (±10°C)
Drum Cooling Temperature: 4-24°C
Ribbon Thickness: Thickness to deliver
target shell (0.75-0.95 mm)

Chapter 7: Pharmaceutical Coating

What is Coating?

Coating is a covering that is applied to the surface of an object, usually referred to as the
substrate. The purpose of applying the coating may be aesthetic, functional, or both.

For the Pharmaceuticals it is applied to the surface of a solid-dosage form in order to confer
specific benefits over uncoated substrate (particle, granules pellets, tablets and capsules etc.)

Pharmaceutical Coating

Tablet coating is one of the oldest pharmaceutical processes still in existence.

Sugar Coating:

Since the development of film coating in the 50s and attention has been focused increasingly
on it, the use of sugar coating technology has faded out due to its multistep process, intensive
labor and a fair degree of skill require.

Film Coating: A film coating is a thin polymer-based coat applied to a solid dosage form such
as a tablet. The thickness of such a coating is usually between 20-100 µm. It is widely practiced
for various reasons.

62
Aesthetic Coating: In Pharmaceuticals this is mostly used for providing visual and/or appealing
appearance of the drug product from consumer acceptance perspective.

Functional Coating: There could be several reasons for functional coating

Taste Masking: many drugs tastes unpleasant or bitter

Protective: drug product sensitive to environmental conditions; light, air, moisture/humidity, etc.

Modified Release: This is again classified into two main category; a) Extended Release b)
Delayed Release

Solubility Enhancement: (This by itself is a separate technology not elaborated in this

presentation).

Types of Coating

Taste Masking: Separating taste receptors, usually by applying a thin film of coating of polymer
resistant to neutral pH of saliva in the mouth is 6-7

Protective: Many drugs are sensitive to light, air, and humidity; degrades due to hydrolysis or
oxidation; several polymers including shellac, PVP, HPMC, HPC and Methacrylate are used.

Extended Release (sustained release) Coating

 To deliver the API over up to 24 hours for a longer-lasting therapeutic effect. This is
achieved by laying a film of diffusion-controlled membrane
 Several polymers available; Ethyl cellulose, Methacrylic acid pH independent polymers;
Eudragit® RL and RS or NE/NM systems.
 Ethocel with a pore former has been widely used in the Pharmaceutical industry for
extended-release coating; both as solution or dispersion in organic solvent or water
respectively. Many ready mixed aqueous dispersion are available, e.g. Surelease® from
Colorcon

Components used for Extended Release

 Substrate: (Particle, pellets, tablets or capsules)

 Solvent: IPA, Ethanol, Propanol etc.,
 Film-former: (various pH independent hydrophobic polymers); Ethyl Cellulose or Methyl
acrylate
 Pore former: ( Various soluble ingredients; e.g., micronized lactose, mannitol, NaCl or
hydrophilic ingredients; e.g., Natural gum, PVP, Na-CMC, HPMC, HPC, pH independent
methacrylate, etc.,
 Opacifier: Titanium Dioxide
 Colorant: FDC Dye pigment or their Lakes®
 Plasticizer: e.g., PEG, Tweens, etc.,

63
Organic Solvent based Extended-Release Systems

 Ethylcellulose is widely used for modified-release dosage form. Initially emphasis was of
using organic-solvent based solutions.
 EC is dissolved into an organic solvent (IPA, Dehydrated Ethanol etc.,) to produce a viscous
solution.
 Then the pore former (in-soluble in the organic solvent) along with opacifier, colorant
(pigment) are dispersed into it using a rotor-stator type homogenizer ( Silverson or Ross
Homogenizer)
 Finally a plasticizer is added and mixed together to form the extended-release coating
system.

Aqueous based Extended-Release System

 Although EC is insoluble in water; however it can be dispersed into an alkaline media

(usually ammonium hydroxide) or making an emulsion as an aqueous latex dispersion.
These systems are available as concentrate from suppliers and are readily miscible with
water for dilution and addition of a pore former; (HPMC/HPC/PVP etc.) at any ratio for
adjusting permeability of the membrane for desired drug release.
 Methacrylic pH independent polymers Eudragit® RL/RS and NE/NM formulation are flexible.
They have quaternary ammonium group; can be mixed at any ratio to adjust permeability of
the formed membrane as per specific need.

Delayed Release Coating

 The purpose of delayed release coating is to prevent the release of the API mostly in the
stomach; due to various reasons:
 To protect drug unstable in acidic pH
 To protect esophagus or stomach from irritation: e.g., doxycycline-Hyclate, acetylsalicylic
acid, iron compounds, etc.
 Delaying drug release due to food effect
 GI targeting at different sections of the small intestine or the Colon.

Delayed Release System

 The pH-dependent polymer is the key element in controlling the dissolution of coated
membrane.
 Drug can be released in a precise manner in specific sections of the GI tract or specific time
after intake (specifically for food affect)
 Among the pH dependent polymers, Polyvinyl Acetate Phthalate and Methacrylate
Eudragit® L and Eudragit® S are used.
 Sodium Alginate, from natural source due to its unique property of congealing in acidic
media is also used alone as a clear suspension or with opacifier for enteric coating.

64
Equipment & Technologies

 Fluid Bed Coating: Mostly for particles/substrate ≤ 2 mm is coated in a fluid bed processor
with top spray or bottom spray with a Wurster column.
 Pan Coating: Usually for tablets or capsules using film-coating pan equipment.

Coating Dispersion & Process Parameters

 Organic base coating system usually contain 5 – 10% solids

 Aqueous coating dispersion usually contains 15 – 25% solids
 To achieve uniformity of the coating dispersion it is homogenized using rotor/stator type
homogenizer.
 To prevent settling/sedimentation; continuous stirring with a impeller type stirrer is employed
during coating process
 Prepared dispersion usually used within 24 hours after preparation.

Spraying Process- Pan Coating

 Perforated Pan of adequate size to allow uniform cascading of the tablets during its rotation.
 Depending on size of the Pan 2 – 4 spraying guns are used
 Generally a minimum distance of 10 – 25 cm is maintained between the substrate bed and
spray nozzle at a 90° angle at cascading motion.
 Product Bed Temperature is an important CPP and is usually: 20-30°C and 25-35°C; for the
organic and aqueous coating respectively.

Coating Process Parameters

 Spray Rate: For most substrate; Initially at a slow rate (60-70%) of the recommended spray
rate of the equipment. After about 30-60 minutes it is increased to the optimum spray rate
with proper checking of the substrate wetness and drying
 Atomization & Air pressure: Usually 1- 2 Bar (15 – 30 psi); usually flow meters are used to
check if any blockage during the coating process.
 Inlet Air humidity: Specifically for aqueous coating humidity plays a significant role. Based
on humidity condition the spray rate and inlet air temperature is adjusted.
 Air Volume: Sufficient air to evaporate the solvent or water efficiently; usually the Pan
pressure not to exceed – 150 Pa (~ 1.5 mbar, ~ 1.1 mm Hg, ~ 0.02 psi)
 Air capacity of about 0.3 – 0.5 m3/min/kg tablets
 Pan rotation: At an optimum speed for gentle rotation/cascading of the substrate bed
 Pump: Mostly peristaltic pumps with silicon tubing or sometimes gear pumps are also used.

65
Technology used for weight gain calculation during the pellets coating process

Q: Why is there a need for pellets coating, and pellets in general?

A: This technology is used usually for modified release drugs in order to produce complex dissolution
profiles. The coating creates an active pharmaceutical ingredient around an inert core, layering it with
insoluble substances to form a film. Additional layers determine the dissolution rate of API. This creates a
more consistent and replicable dissolution rate that can be conveniently used in tablets and capsules
production. Simply put - pellets coating is used for drugs that create a long lasting effect (4-20 hr.) rather
than an immediate one.

Q: How did you set the spraying profile in the past?

A: Due to the fact that during the pellets coating there are few unwanted processes (e.g. the coating
materials tend to stick to the equipment, spray drying etc.) which produce too many variables for the
accurate control of the amount of active material ( and other materials) coated on the pellets.

The industry faced a big problem; how to control the required active material to be used during the pellet
coating process?

Prior to the pellet counter, we relied on quite a bit "trial and error". For example, we took 10 kilograms of
active material and started spraying using Wurster - a process that can take up to 20 hours. We also used
many complicated calculations, eventually reaching only an approximation of the amount of required
API and the exact results eventually came from the analytical test.

Q: How would you summarize the added value you got from our machine?

A: Well, the impact can be seen in many fields: we no longer need to rely on "trial and error" so we saved
a lot of valuable development and manufacturing time.

The spraying profile itself is now precise, resulting in less API loss, both in the R&D lab and during the
large scale manufacturing process.

We also use this as a scale-up tool and can quite easily determine the end point of spraying and coating
efficiency on different scales. The machine is also used by QC during the manufacturing stage.

In their site; you can find a video to see an example where the PH Device counts pellets, granules and
mini tablets

For more information, contact: sorin@data-technologies.com

66
Chapter 8: Solid Dosage Manufacturing Process Testing and Sampling Considerations:
Standardization of Sampling, Testing and Protocol Content in the Manufacturing of Exhibit
Batch
Process Modules
 Dry Blend for Direct Compression/Encapsulation
 Size Reduction & Comminution
 Granulating Liquid Preparation for Wet Granulation
 High Shear Granulation
 Fluid Bed Granulation
 Oven Drying
 Fluid Bed Drying
 Roller Compaction/Chelsonation
 Extrusion and Spheronization
 Tableting/Compression
 Encapsulation
 Coating: Pan Coating & Fluid Bed Coating
 Packaging ( Bottle or Blister)

Dry Blend for Direct Compression Sampling & Testing

 Blend Uniformity in Blender: Minimum 10 samples, Record Sampling Thief, Cavity size,
Angle of insertion, Visual observation
 Blend Homogeneity (Assay) of final blend in Drums. Sample T, M. B of every drum or a
composite. Sampling Thief, Cavity size, Angle of insertion, Visual observation
 LOD Testing: Composite of each drum, Analyzer used, Temperature and Sample size
 Particle size Testing: Tester used, Sieves used, Vibration/Shake time
 Bulk and Tap Density (Composite of each drum or overall composite) [also provides an idea
about compressibility].

Twin Shell V-Blender

10 Sampling Points (Diagram 1)
Unit Dose = 2x ± 40%; for 100mg (200 ±80) = between 120 and 280mg

67
68
Fiber Drum Double Polyethylene lined Sampling Points (Diagram 2)

Sampling
Point Location

TR 1/3 down top of blend, 2 inches from right side

TL 1/3 down top of blend, 2 inches from left side

MR 2/3 down from top of blend, 2 inches from right side

ML 2/3 down from top of blend, 2 inches from left side

BR 2 inches from bottom of blend, 2 inches from right side

BL 2 inches from bottom of blend, 2 inches from left side

Dry Blend for DC Sampling & Testing

 Blend Sampling Amount of Samples:

 If the number of drums is ≤ 3, collect a composite sample from Top, Middle , and Bottom of
each drum
 If the number of drums is > 3, collect a composite sample from Top, Middle, and Bottom of
square root n+1 drums (include 1st and last drum).
 Bottom of square root n+1 drum (include 1st and last drum).
Granulating Liquid (Solution/Dispersion) Preparation for Wet Granulated Products-
Sampling & Testing

Record the following:

 Tank including capacity and Mixer Type: Impeller/Shear

 Order of addition of ingredient
 Mixer speed, temperature, etc. at number of intervals
 End point of solution/dispersion Preparation – By: Visual, Specific Gravity/Viscosity
measurement
 Bulk holding time – viscosity/microbial testing/impurity profile/stability at x # of hours
 Special consideration: N2 blanketing, storage conditions, etc.

69
High Shear Mixer/Granulator- Wet Granulated Products: Sampling & Testing

 Record the following:

 Type of HS-Mixer-Granulator used and Capacity
 Order of addition
 Mixing Configuration (Impeller & Chopper) and Time
 Granulating liquid delivery: Pressure vessel/Type of pump, pump speed, Tubing type,
diameter, and length, nozzle diameter, delivery rate, and total time to deliver.
 End point of granulation: torque or power consumption
 Method of discharge: Gravity, Suction or Scooping
 Visual observation of dry mix and LOD
 Visual observation of wet mass and LOD
 Bulk density of wet mass ( to determine capacity utilization)
 Record temp, pressure, amperage, ohms etc.

Oven Drying: Sampling & Testing

 Record the following:

 Type of oven/dryer, Number of trays, racks, lining of the tray
 Air flow, Purge time, Pre-heat conditions and timing
 Sample at least T, M, B trays of each rack at x interval to establish drying curve
 Transfer of wet mass to the trays: Record approximate amount (number of scoops per tray),
bed height, intermittent raking
 Visual observation of the wet mass
 Sample for LOD from each rack as follows:
 Top - composite
 Middle - composite
 Bottom - composite
 Overall - composite

70
Fluid Bed Granulation/Coating & Drying: Sampling & Testing

 Order of addition
 FBD bowl screen size and filter bag opening size – (if determined as critical by R&D)
 Spray Gun position, Number of spray guns, nozzle type and size, bowl capacity
 Type of Processor: GPCG or WSG
 Granulation: Record inlet and exhaust temperature, Atomization pressure, Air volume,
shaking time and interval, drying time etc. During processing time.
 Granulating liquid delivery: Type of pump, pump speed, Tubing type, diameter, and length,
nozzle diameter, delivery rate, and total time to delivery.
 Dew point and Product temperature
 End point of granulation and drying
 Visual observation of the dry mix
 Visual observation of the wet mass
 Loading capacity to be calculated
 Sample for LOD at different interval in order to establish a drying curve (from the sampling
ports) – composite sample
 End of drying: Test for LOD – Sampling at least 3 points (Top, Middle, and Bottom) and test
individual and a composite
 Weight gain Vs Dissolution (for functional coating)

Roller Compaction/Milling: In-process Sampling & Testing

 For Roller Compaction

 Machine Type
 Roller Configuration: Gap and Pressure
 Feeding: Gravity or Auger
 In-process Testing for Ribbon/slug thickness and strength
 For Milling:
 Type: Oscillating or Revolving blades
 Screen: Size
 Configuration: Knives Forward / Impact Forward
 Speed: Slow, Medium and High
 Bulk and Tap Density
 Particle size

71
Tableting/Compression: Sampling & Testing

 Record the following: During Set-up and Compression Run

 Machine Type/ Single punch/Rotary; Double sided/Bi-layer
 Tooling Type, Description, # of Stations
 Press Speed (Low and High), If batch size does not allow can be run at one speed
 Feeding of the press: Gravity or Force
 Sampling for: Weight, Thickness, Hardness, and Friability
 Challenges tests:
 High weight/Low hardness: Friability & Thickness
 Low Weight/High Hardness: Thickness, & Dissolution profile
 Uniformity of dosage unit (By content uniformity/AV value)
 Dissolution Test ( Disintegration Test if required)
 Assay

Encapsulation: Sampling & Testing

 Record the following:

 Type of Encapsulators used
 Speed (Low and High), If batch size does not allow run at one speed
 Type of Feed: Powder, plug, pellet, tablet etc.
 In-Process weight: Empty capsule Weight, Filled Capsule weight
 Set-parameters
 Dosator, Tamping pressure, spring size etc.
 Uniformity of dosage unit (By content uniformity)
 Dissolution
 Assay

Film Coating: Sampling & Testing

 Record the following:

 Bulk Density of charging substrate (tablet); to determine capacity
 Pan Loads
 Pan speed, Inlet/Exhaust temp: Pre-warming, Coating, Polishing (if applicable), Cooling,
 Product Bed Temperature ( by IR gun)
 Spray rate, Coating time, Coating dispersion amount used to get theoretical weight gain.
 Final tablet weight gain variability, appearance
 Coating efficiency: Weight gain Vs solution amount used
 AQL during coating (Visual inspection).

72
 For Non-Functional Coating:
 Dissolution profile of each pan
 For Functional Coating:
 Dissolution profile of each pan
 Dissolution profile – Composite of coated tablets
 Assay composite of finished product
 Moisture ( by KF)

Bottle Packaging: Sampling & Testing

ISTA (International Safe Transit Association) Transportation Testing (Vibration and Drop testing)

Document/Check for the following:

 Bottle type, (Glass, Polypropylene, Viscose, etc.)

 Moisture permeation/Oxygen barrier/Odor adsorber: Desiccant type, size and how many per
bottle
 Dunnage: Type (Cotton, Polyester, Rayon) Yes or No
 Closure: CRC or Non-CRC
 Seal: Type- Aluminum induction heat seal or torque seal
 Visual inspection
 Speed, Count, Torque, Removal Torque
 Slats: Type and Number
 Temperature of heat tunnel, Stability, Shrink wrapping.

Blister Packaging: Sampling & Testing

ISTA (International Safe Transit Association) Transportation Testing (Vibration and Drop testing)

Document/Check for the following:

 Set up parameters
 Visual inspection (AQL)
 Physical Testing:
 Temperature
 Pressure
 Color change
 Pac vision challenge (Color, missing, broken tablets) If not performed during the IQ, OQ of
the equipment.
 Leak testing
 Push through testing

73
Record observations in packaging Analytical Testing:

 Dissolution (Beginning, Middle and End run)

 Assay (Beginning, Middle and End run)
 Impurities (Beginning, Middle and End run)
 Stability after blistering
 Pouch leak test

Bulk Holding Time: Sampling & Testing

Manufacturers should ensure that the products that they manufacture are safe, effective and of the
quality required for their intended use. Systems should be in place to ensure that pharmaceutical
products are produced according to validated processes and to defined procedures. Manufacturing
processes should be shown to be capable of consistently manufacturing pharmaceutical products
that are of the required quality and that comply with their specifications.

Good manufacturing practices (GMP) require that arrangements should be made to ensure that the
dispensed raw materials and packaging materials, intermediate products, bulk and finished products
are stored under appropriate conditions. Storage arrangements should not have deleterious effects
on the subsequent processing, stability, safety, efficacy or quality of starting materials, intermediate
products and bulk products prior to final packing. Maximum acceptable holding periods should
therefore be established to ensure that intermediates and bulk product can be held, pending the next
processing step, without producing results outside the acceptance criteria for the quality of the
material. Normally, intermediate and bulk products should not be stored beyond the established hold
time.

The choice of maximum holding period should be supported by relevant data. Studies may extend
beyond the chosen maximum but it is not necessary to extend testing to determine the extreme
limits at which failure occurs.

 Bulk Tablets prior to packaging

 Document the following in a separate protocol:
 Test intervals
 30 days, 60 days, 90 days
 Separate a tote, box or shipper and test at intervals above
 Analytical Testing as per Stability program
 After 6 months package and place in bottle/blister for the remaining shelf-life

World Health GENERAL GUIDANCE 6 ON “HOLD-TIME” STUDIES

Organization REVISED DRAFT FOR COMMENT 9 (August 2014)
Hold-Time General Guidance Followed by Pharma Industry during Product Development
Physical Nature of Intermediate Direct Aqueous-wet Non-aqueous / Solvent
component/substrate Stages Compression / granulation granulation
Dry Granulation /
Hot-melt
Granulation

74
Major Substrate Dispensed Raw 30 days w/o 30 days w/o 30 days w/o micro-limit

75
 containing/made of Material micro-limit test micro-limit test test
Hydroscopic and Pre-lube Mixing 15 days 7 days w/o micro- 15days w/o micro limit
Hydrophilic
limit test test
Components
15 days with 30 days with micro-limit
micro-limit test test
Lube-Mixing 15 days 7 days w/o micro- 15days w/o micro limit
limit test test
15 days with 30 days with micro-limit
micro-limit test test
Binder Solution N/A 24-48 hours w/o 72 hours w/o micro-limit
micro-limit test test
Dried Granules N/A 7 days w/o micro- 15days w/o micro limit
for comminution , limit test test
size-reduction 15 days with 30 days with micro-limit
micro-limit test test
Final Blend 15 days 7 days w/o micro- 15days w/o micro limit
limit test test
15 days with 30 days with micro-limit
micro-limit test test
Core Tablets 30 days 7 days w/o micro- 15days w/o micro limit
before Film limit test test
Coating 15 days with 30 days with micro-limit
micro-limit test test
Blend for 30 days 7 days w/o micro- 30 days w/o micro limit
Encapsulation limit test test
15 days with 90 days with micro-limit
micro-limit test test
Tablets / HGC 30 days 7 days w/o micro- 30 days w/o micro limit
before packaging limit test test
15 days with 90 days with micro-limit
micro-limit test test

1. Hydroscopic material: API or Excipients tendency of absorbing moisture. in normal storage condition.
e.g. Lactose Monohydrate, Avicel PH102 etc.

2. Hydrophilic material: Generally, would not absorb moisture in normal storage condition but it would
at stress condition.

3. In case of major component/substrate containing hydrophobic or material that would not have any
tendency of absorbing moisture in both normal and stress conditions; APIs, Calcium and Magnesium
salts, Anhydrous Lactose, Avicel PH 112, Waxes, Celluloses, polymers etc. This would be same as the
last column material i.e., Non-aqueous granulation.

76
Pharmaceutical Example input Critical
Unit Operation Material Attributes
 Drug load
Pre-sifting /
 API physical properties
Co-sifting
 Particle size
 Particle size distribution
 Fines/Oversize
 Particle shape
 Bulk/Tapped/True
density
Blending/Mixing
 Cohesive/Adhesive
properties
 Electrostatic properties
 Moisture content
 Blend homogeneity
Dry-Granulation  Blend physical properties
By slugging
 Particle/Granule size
 Particle/Granule size
distribution
 Fines
 Particle/Granule shape
 Bulk/Tapped/True
density
 Adhesive properties
 Electrostatic properties
 Hardness/Plasticity
Size Reduction
/Comminution  Viscoelasticity
 Brittleness
 Elasticity
 Solid form/Polymorph
 Moisture content
 Granule porosity/density
Ribbon milling
 Ribbon dimensions
 Ribbon density
 Ribbon porosity/solid
Additional points to check
Example Critical Process Parameters Example Critical Quality Attributes
in the BPR/ Application
 Co-sifting with excipient  See Blending & Mixing -Check for the same CPPs
 Hand Vs Mechanical Sifter between exhibit Vs
 Sieve size and Shaking parameter commercial batch
 Type (Diffusion, Convection or High-  Blend uniformity - Fill Volume (%)
Shear) and geometry of mixer  Potency - Same revolutions
 Mixer load level  particle size - Larger blender lower
 Order of addition  Particle size distribution speed but higher
 Number of revolutions  Bulk/Tapped/True density mixing time
(time and speed)  Moisture content - Mixer Design Impeller Vs
 Agitating bar (on/off pattern)  Flow properties Disintegrator
 - Mixing Mode: High,
Discharge method  Cohesive/Adhesive properties
 Medium or Low
Holding time  Powder segregation
- Same Tip speed for High
 Environment temperature and RH  Electrostatic properties Shear Mixer
Granulation Endpoint
Making large size tablet (Slug) in a tablet  Slug hardness -Check if proposed same
press/slugging : Type of Press and Tooling: process parameter for
Usually Tablet Press with D type Flat Faced the commercial batch
Tooling
Impact/Cutting/ Screening mills  Particle/Granule size - Check for any
 Mill type difference for the process
 Particle/Granule size distribution
 Speed parameters between
 Blade configuration, type, orientation  Particle/Granule shape exhibit Vs commercial
 Screen size and type batch.
 Particle/Granule shape factor - Reporting if any screen
 Feeding rate
(e.g. aspect ratio) breakage and remedy.
Fluid energy mill - Use of metal detector
 Particle/Granule density/Porosity during tableting stage.
 Number of grinding nozzles
 Feed rate  Bulk/Tapped/True density - Validation by positive
 Nozzle pressure control.
 Flow properties
 Classifier
 API polymorphic form -Check for Feed; Speed,
Sieve Size & Configuration:
Granule/Ribbon milling
 API crystalline morphology Knives Forward Vs
 Mill type
Hammer Forward
 Speed  Cohesive/Adhesive properties
 Blade configuration, type, orientation  Electrostatic properties
 Screen size and type
 Feeding rate  Hardness/Plasticity
77
 fraction
 Particle size distribution
 Fines/Oversize
 Particle shape
 Bulk/Tapped/True
density
 Cohesive/Adhesive
properties
 Electrostatic properties
 Hardness/Plasticity
 Viscoelasticity
 Brittleness
 Elasticity
 Solid form/polymorph
 Moisture content
Wet Granulation
 Viscoelasticity
 Brittleness
 Elasticity
High/Low shear granulation  Endpoint measurement (e.g. Check for the proposed
 Type of granulator (High/low shear, commercial batch:
top/ bottom drive) power consumption, torque, etc.) - Same Tip speed of
 Fill level impeller irrespective of
 Pre-granulation mix time  Blend uniformity size of equipment
 Granulating liquid or solvent quantity
 Impeller speed, tip speed,  Potency -Same granulating liquid
configuration, location, power addition time
consumption/torque  Flow irrespective of size of the
 Chopper speed, configuration, batch
location, power consumption  Moisture content
 Spray nozzle type and location -Same or close to same
 Particle size and distribution initial LOD for the wet
 Method of binder excipient
mass irrespective of
addition (dry/wet)
 Granule size and distribution batch size.
 Method of granulating liquid
addition (spray or pump)
 Granule strength and uniformity -Rationale and/or
 granulating liquid temperature justification for a process
 granulating liquid addition rate and time loss/overage
 Wet massing time (post-granulation mix  Bulk/Tapped/True density
time) PS: Overage is a
 Bowl temperature (jacket temperature)  API polymorphic form
misnomer it should be;
 Product temperature excess amount API used
 Post mixing time  cohesive/adhesive properties
due to adjustment for the
 Pump Type: Peristaltic, Gear type API quantity for assay,
 Electrostatic properties
 Granulating liquid vessel (e.g.: water content and
pressurized, heated) process loss (if any and
 Granule brittleness justified).
Fluid bed granulation
 Type of fluid bed  Granule elasticity
 Inlet air distribution plate
 Solid form/polymorph
 Spray nozzle (tip size,
type/quantity/
pattern/configuration/position)
 Filter type and orifice size
78
 Fill level

79

 Particle size, distribution
 Fines/Oversize
 Particle shape
 Cohesive/Adhesive
properties
 Electrostatic properties
 Hardness/Plasticity
 Viscoelasticity
 Brittleness
 Elasticity
 Solid form/polymorph
Drying
 Moisture content
 Bottom screen size and type
 Preheating temperature/time
 Method of binder excipient addition
(dry/wet)
 Granulating liquid temperature
 Granulating liquid quantity
 Granulating liquid concentration/viscosity
 Granulating liquid holding time
 Granulating liquid delivery method
 Granulating liquid spray rate
 Inlet air, volume, temperature, dew point
 Atomization air pressure
 Product and filter pressure differentials
 Product temperature
 Exhaust air temperature, flow
 Filter shaking interval and duration
Fluidized Bed  Granule size and distribution For tray drying; Check
 Inlet air volume, temperature, dew point
 Granule strength, uniformity for any information on
 Product temperature
 Exhaust air temperature, flow  Flow Hot Spot and Cold Spot
 Filter type and orifice size in the dried material
 Bulk/Tapped/True density
 Shaking interval and duration
 Total drying time  Moisture content and/or casehardening
and how addressed.
 Residual solvents
Tray
 Type of tray dryer  API polymorphic form
 Bed thickness/tray depth (depth or transition Check for required
of product per tray)
 Purity profile Critical Moisture Content
 Type of drying tray liner (e.g. paper,
plastic, synthetic fiber, etc.) or LOD to achieve final
 Moisture profile (e.g.
 Quantity carts and trays per chamber drying
 Quantity of product per tray product temperature vs.
 Drying time and temperature LOD)
 Air flow Check for, to be the same
 Inlet dew point  Potency
product Bed
 Cohesive/Adhesive properties
Vacuum/Microwave Temperature between
 Jacket temperature  Electrostatic properties
exhibit and
80

 Particle size, distribution
 Fines/Oversize
 Particle shape
 Cohesive/Adhesive
properties
 Electrostatic properties
 Hardness/Plasticity
 Bulk/Tapped/True
Roller compaction density
/Chelsonation
 Viscoelasticity
 Brittleness
 Elasticity
 Solid form/polymorph
 Particle size, distribution
 Fines/Oversize
Extrusion-
 Particle shape
Spheronization
 Cohesive/Adhesive
properties
 Condenser temperature commercial batch?
 Impeller speed Fluid-bed
 Bleed air volume
 Vacuum pressure granulation/drying
 Microwave power process have potential
 Electric field
 Energy supplied for process loss, due to
 Product temperature material adherence in the
 Bowl and lid temperature
expansion-chamber and
 Total drying time
filter assembly of the
fluid bed dryer. If there is
any batch yield record
after this major process
step?
 Type of roller compactor  Ribbon appearance (edge Check, there should be a
 Auger (feed screw) type/design attrition, splitting, lamination, pre-mix step before this
(horizontal, vertical or angular) color, etc.) step. This is to insure
 Deaeration (e.g. vacuum)  Ribbon thickness & strength uniformity for the in-put
 Auger (feed screw) speed  Ribbon density (e.g. envelop density) material before its
 Roll shape (cylindrical or interlocking).  Ribbon porosity/solid fraction compaction.
 Roll surface design (smooth,  Ribbon tensile For very low drug load
knurled, serrated, or pocketed) strength/breaking force API or a functional
 Roll gap width (e.g. flexible or fixed)  Throughput rate excipient (e.g.
SLS/Polysorbate to
 Roll speed  API polymorphic form and transition
enhance dissolution).
 Roll pressure
How its CU in the blend
 Roller temperature
is insured?
 Fines recycled (yes or no, # of cycles) Check for required
Critical Moisture Content
or LOD to achieve
compaction
 Type of Extruder (screw or basket) Extrudate Extrusion: Check for
 Screw length, pitch, and diameter o Density Drug Load, Physical
o Length/Thickness/Diameter characteristics,
 Screw channel depth
o Moisture content Solubility, etc.
 Screw blade configuration
 Number of screws (single/dual) o API polymorphic form and Feed, Augur/Screw
81
  Electrostatic properties
 Hardness/Plasticity
 Bulk/Tapped/True
density
 Viscoelasticity
 Brittleness
 Elasticity
 Solid form/polymorph
 Particle size, distribution
 Fines/Oversize
 Particle shape
 Melting point
 Density
 Solid form/polymorph
Hot Melt Extrusion
 Moisture content
 Die or screen configuration (e.g. radial transition speed, Screen Size,
or axial) o Content uniformity Screen Pressure.
 Die length/diameter ratio o Throughput
 Roll diameter (mm) In-process control for
 Screen opening diameter (mm) Pellets after Spheronization Cohesion; Tensile
 Screw speed (rpm) o Pellets size and distribution strength, Screen
 Feeding rate (g/min) o Pellets shape factor (e.g. Temperature.
aspect ratio)
 Type and scale of Spheronizer
o Bulk/Tapped density Spheronization: Check
 Spheronizer load level
o Flow properties for Chamber/Bowl
 Plate geometry and speed o Brittleness Load/Fill; Plate Grove
 Plate groove design (spacing and pattern) o Elasticity Size, Spinning rotation
 Air flow o Mechanical strength (Speed); Number of
 Residence time o Friability revolutions.
In-process control for:
Pellet size: % yield of
18 and 25 Mesh cut,
Pellet shape: Spherical
Vs Cylindrical,
Friability, crushing
strength, Bulk and Tap
Density.
 Screw design (twin/single)  Extrudate density Temperature must be
higher than the melting
 Screw speed  Length/Thickness/Diameter temperature of the
 Screw opening diameter (mm)  Polymorphic form and transition polymer (at least 20°C
higher) for complete
 Solid and liquid feed rates  Content uniformity conversion to amorphous
 Feeder type/design  Throughput form and ease of
processing (reduce
 Feed rate viscosity)
 No. of Zones Risk associated with
chemical stability –
 Zone temperatures thermo-labile compounds
High Tg of commonly
 Chilling rate
used polymers (150-160
°C) – need suitable
plasticizers; temperature
must be > Tg
Lack of miscibility
82

In this stage generally the
dried/milled granules is
mixed with extra-granular
ingredients in a diffusion
Pre-Lube Mixing
type of blender or within the
primary mixer i.e., HSMG or
FBPD
In this stage finally the
lubricant is mixed with the
blend to achieve the final
Lube-Mixing
blend for compression or
Encapsulation.
 Particle/granule size
and distribution
 Fines/Oversize
 Particle/Granule shape
 Cohesive/adhesive
properties
 Electrostatic properties
 Hardness/Plasticity
Tableting
 Bulk/Tapped/True
density
 Viscoelasticity
 Brittleness
 Elasticity
 Solid form/polymorph
 Moisture
between drug and
polymer
 Same as Mixing/Blending  Same as Mixing/Blending Check for any
reported process loss
for milled granules
Need for any adjustment
for the in-put extra-
granular ingredients due
to above cause.
 Same as Mixing/Blending  Blend sample is taken for: Check for blender
BU, Assay, B/T Density, Capacity utilization
Sieve Analysis and LOD And Total revolutions
 Scale-up factor: To have
same total number of
revolutions
 Type of press (model,  Tablet appearance Records the
following: During Set-
geometry, number of stations)  Tablet weight up and Compression
 Hopper design, height,  Weight uniformity Run Machine Type/
Single punch/Rotary;
angle, vibration  Content uniformity Double sided/Bi-layer
 Feeder Mechanism (gravity/forced  Hardness/Tablet breaking Tooling Type,
Description, # of Stations
feed, shape of wheels, direction of force/Tensile strength Press Speed (Low and
rotation, number of bars)  Thickness/dimensions High. Feeding of the
press: Gravity or Force
 Feed frame type and speed  Tablet porosity/density/solid fraction Sampling for: Weight,
 Feeder fill depth  Friability Thickness, Hardness, and
Friability
 Tooling design (e.g. dimension,  Tablet defects Challenges tests: (During
score configuration, quality of the product development to
 Moisture content
set hardness range)
metal)
 Disintegration High weight/Low
 Maximum punch load hardness: Friability &
 Dissolution Thickness
 Press speed/dwell time Low Weight/High
 Pre-compression force Hardness: Thickness, &
Dissolution profile
 Main compression force Uniformity of dosage
83
  Punch penetration depth
 Ejection force
 Dwell Time
 Particle/Granule size
and distribution
 Fines/Oversize
 Particle/Granule shape
 Cohesive/Adhesive
properties
 Electrostatic properties
 Hardness/Plasticity
 Bulk/Tapped/True
Encapsulation
density
 Viscoelasticity
 Brittleness
 Elasticity
 Solid form/polymorph
 Moisture
 Gel Mass Compounding
 Fill Mass Compounding
Soft-Gelatin
Capsule
 Machine type  Capsule appearance
 Machine fill speed  Weight
 Tamping Force  Weight uniformity
 No. Of Tamps  Content uniformity
 Auger screw design/speed  Moisture content
 Powder bed height  Slug tensile strength
 Disintegration
 Dissolution
 Gelatin Cooking Temperature: 85 ±  For Gelatin cooking
10 °C
Time; Complete
dissolution
 Gelatin Cooking Time  For Opatint: Until uniform
 Moisture Content
 Opatint addition and Mixing
 Viscosity
Time: (Until uniform)  Fill Mass Temperature:
 Gel Hold Time: 6-72 hours °C Product dependent
 Fill Mass Mixing Time:
 Gel Hold Temperature: 50-60°C to Until completely dissolved or
dispersed
keep Gelatin in Melted State
 Processing Aids addition
 Moisture Content: Between 16 – and Mixing Time: Until
uniform
25%
 API addition, Mixing
and Dispersion
unit (By content
uniformity/AV value)
Dissolution Test
(Disintegration Test if
required)
Assay
Records the following in
the application:
Type of Encapsulator
used
Speed (Low and High),
If batch size does not
allow run at one speed
Type of Feed: Powder,
plug, pellet, tablet etc.
In-Process weight:
Empty capsule
Weight, Filled Capsule
weight Set-parameters
Dosator, Tamping
pressure, spring size etc.
Uniformity of dosage
unit (By content
uniformity)
Dissolution & Assay
Machine Speed:
Operating range (2 – 5
rpm)
Fill Mass Hopper
Temperature: 29-35°C
Ribbon Thickness: 0.70 ±
0.05 mm
Seam Thickness: NLT
0.25 mm
Spreader Box
Temperature: 65 °C
(±15°C)
Wedge Temperature: 40
°C (±10°C)
Drum Cooling
84
  Viscosity: 5000 – 28000 cP  Homogenization: Colloid Temperature: 4-24°C
Mill Gap Width Ribbon Thickness:
 High Pressure Homogenizer: Thickness to deliver
Up to 150 MPa target shell (0.75-0.95
 Post milling mixing mm)
 Tablet dimensions  Type of pan coater (conventional  Coating efficiency Records the following
 Tablet defects or side-vented)  Core tablet weight before in the application:
 Pan (fully perforated or partial and after preheating Bulk Density of charging
 Hardness/Plasticity
perforated)  Moisture (gain/loss) substrate(tablet/pellet);
 Density  Baffle (design, number, location) during preheating to determine capacity

 Porosity  Pan load level  Environmental Pan Loads

 Pan rotation speed equivalency factor Pan speed, Inlet/Exhaust
 Moisture content
 Spray nozzle (type, quantity,  Coated drug product (e.g. temp: Pre-warming,
pattern, configuration, spray pattern) tablet or capsule) appearance Coating, Polishing (if

 Nozzle to bed distance  % weight gain applicable), Cooling,

 Distance between nozzles  Film thickness Product Bed Temperature

Pan Coating (by IR gun)
 Nozzle orientation  Coating (polymer and /or
color) uniformity Spray rate, Coating time,
 Total pre-heating time
 Hardness/Breaking Coating dispersion
 Inlet air flow rate,
force/Tensile strength amount used to get
volume, temperature, dew
point  Friability theoretical weight gain.

 Moisture (gain/loss) Final tablet weight gain

 Product temperature
during overall process variability, appearance
 Individual nozzle spray rate
 Residual solvent(s) Coating efficiency:
 Total spray rate
 Disintegration Weight gain Vs solution
 Atomization air pressure
amount used
 Pattern air pressure  Dissolution
Acceptable Quality Limit
 Exhaust air temperature, air flow  Tablet defects
(AQL) during coating
 Total coating, curing time and drying

85
 time  Visual attributes (Visual inspection).
check impact of film
coating polymer
thickness (weight gain)
on drug release profile
 Tablet dimensions  Type of fluid bed coater  Coating efficiency Bulk Density of charging
 Tablet defects  Fluid bed load level  Core tablet weight before and substrate(tablet/pellet);
 Hardness/Plasticity  Partition column diameter after preheating
 Density/Porosity  Partition column height  Moisture (gain/loss) to determine capacity/
 Moisture content  Number of partition columns during preheating Load
 Air distribution plate type and size  Environmental equivalency factor
 Filter type and orifice size  Coated drug product (e.g. tablet
 Filter differential pressure or capsule) appearance
 Filter shaking interval and duration  % weight gain
 Spray nozzle (type, quantity,  Film thickness
pattern, configuration)  Coating (polymer and /or color)
 Nozzle port size uniformity
 Total pre-heating time  Hardness/Breaking
 Spray rate per nozzle force/Tensile strength
Fluid Bed Coating  Total spray rate  Friability
 Atomization air pressure  Moisture (gain/loss) during
 Inlet air flow rate, volume, overall process
temperature, dew point  Residual solvent(s)
 Product temperature  Disintegration
 Exhaust air temperature, air flow  Dissolution
 Total coating, curing and drying time  Tablet defects
 Visual attributes
 Tablet size/dimensions  Conveyor type  Opening diameter (internal  Rationale for
 Polymer type  Conveyor speed and external) these factors.
 Membrane thickness  Laser power  Depth
Laser Drilling  Number of pulses  Shape of the opening
 Type(s) of lens(es)
 One or two sided
 Number of holes

86
FDA Guidance for Industry: Size, Shape, and Other Physical Attributes of Generic Tablets and Capsules

87
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90
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93
94
95
96
Chapter 9: Pharmaceutical Excipients for Solid Dosage

A drug product as a dosage form would contain both drug substance (Active Pharmaceutical Ingredient)
and excipients added to aid the formulation and manufacture of the dosage form for administration to
patients. In fact, the properties of the final dosage form (i.e. its bioavailability and stability) are, in major
case highly dependent on the excipient used, their concentration and interaction with both the API and
each other. Hence, excipients should not be considered as inert or inactive ingredients. It is therefore,
needed to know and understand not only their Physico-chemical properties but also the role play
chosen (novel forms of delivery) for the formulation.

Excipients used for Immediate Release Solid Dosage (Tablets):

Diluents/Fillers

 To increase the mass/volume/size of a dosage unit for ease of dispensing/delivery or ultimate

patient use
 Inert but could be of specific function desired and included in product design
 Generally Lactose, Starch, Sucrose, Mannitol, Cellulose, Calcium Phosphate, Calcium Sulfate, etc. are
used as diluent for tablets.

Disintegrant/Dissolution Enhancer

 To break apart the tablet into particulates for dissolution and drug release
 Commonly used disintegrant are: Starch, Modified Starch, Microcrystalline Cellulose, Sodium Starch
Glycolate, Cross Povidone, Cross Carmelose,Na-alginate, Polymeric Resin (Amberlite), Veegum, SLS,
etc.
 Sometimes Na or K – bicarbonate is used as disintegrant cum dissolution enhancer
 Sodium Lauryl Sulfate (SLS) with a very high HLB value of 40 is mostly used as dissolution enhancer
at a very low concentration. (0.05 % t0 0.5%).

Binders

 Bring bondage between particles to help compaction/compression into tablet.

 Commonly used binders are: Starch paste, Povidone, Gelatin, Gum Acacia, Guar Gum, Methyl
Cellulose, HPMC, HPC, Na-CMC, etc.

Anti-adherent & Glidant

 Materials used to correct sticking property

 Materials used to improve flow property
 Materials belonging to this group are:
 Talc, Colloidal Silicon Dioxide, Silica, Syloid, Magnesium-Aluminum Silicate, etc.

97
Lubricants

 Materials used to eliminate die wall sticking & picking of tablet surface during tableting
 Materials belonging to this group are: Talc, Stearic Acid & its salts of Mg, Ca & Zn, Sodium
Stearyl Fumarate, Sodium Acetate and Glyceryl Behenate(Compitrol-888)

Colorants, Flavors & Humectants

 Materials used to provide distinct product identification

 Materials belonging to this group are: Iron Oxide, Titanium Dioxide, Pigments, FD&C Colors and
their Aluminum Lakes, etc.
 Various flavors are also used for chewable & effervescent tablets
 Humectants are used to provide/keep moisture in the product where there is a tendency of
losing moisture making product to become powdery: Propylene Glycol, PEG, Glycerin, etc.

Functional Excipient Used for Modified Release Tablets/Capsules

 Modified Release group is divided into two major classes: Extended Release & Delayed Release
 Excipients for Extended Release group can be classified into two major group
 1) hydrophilic and 2)hydrophobic
 Hydrophilic Materials: Cellulosic Polymers, Gums, PVP, PEG, etc.
 Hydrophobic Materials: Ethyl Cellulose, Wax. Eudragit (RL/RS) etc.
 These polymers are generally pH-independent

Delayed Release Excipient: This is usually desired to bypass the stomach and or release of the drug to a
specific site e.g. Colon

 Polymers generally used are mostly pH dependent

 Various Methacrylic Acid polymers called “Eudragit” are used. They can be An-ionic, Cationic or
Neutral. e.g. Eudragit L30D-55 is soluble ≥ pH 5.5 suitable for intestinal delivery
 Eudragit FS30D is soluble above pH 7, hence unique for colonic delivery
 Also Polyvinyl Acetate Phthalates & Succinates.

98
Chapter 10: Semi-Solids Dosage

What are Semi-Solids?

These products have semisolid consistency and applied to skin or mucous membranes for therapeutic or
protective action or cosmetic purpose. The following preparations belong to semisolid dosage products:
creams, ointments, gel and pastes having viscous consistency.

Definitions:

 Ointment: An ointment is hydrocarbon based semisolid preparation, translucent in appearance

and greasy in nature for topical use.
 Creams: A viscous semisolid emulsion (Oil in Water (O/W) or Water in Oil (W/O) with opaque
appearance for topical use (on the skin) that contains a water base. Oil in water are non-
greasy water washable, good for drug delivery
 Pastes: Is a high insoluble solid content stiff ointment. However, its appearance unlike ointment is
opaque.
 Gel: It is a solid, jelly-like material with properties ranging from soft and weak to hard and tough.
Made of substantially dilute cross-linked system, which exhibits no flow when in the steady-state. By
weight, gels are mostly liquid, yet they behave like solids due to a three-dimensional cross-linked
network within the liquid.

Route of Administration:

Primary routes of administration for semisolids are Topical and Ophthalmic.

Semisolid drug products, depending on their use, can be sterile or non-sterile.

Advantage of Transdermal Drug

 No hepatic first pass effect

 Drug delivery is continuous
 Relatively few side effects
 Easy to terminate therapy at anytime
 Favorable patient compliances
Manufacturing Process

 By trituration: Using Glass Slab and Spatula or Mortar and pestle (in Compounding Pharmacy or
Hospitals)
 By Melting/fusion: In a jacketed mixing tank with mixer: Types(Anchor; Impeller or Disintegrator)
 By Milling: Using Triple roller ointment mill
 Emulsification: Bringing two immiscible phase (Water and Oil) together mixing with an emulsifying
agent and homogenization

99
Manufacturing involves following steps:

1. Bulk Manufacturing/Mixing: ASTM standards for 316/316L Tank/Vessel

2. Mixing/Dispersion (Convection or Shear Mixing): (Using Anchor, Impeller or Disintegrator type

of blades)

3. Heating/Cooling: Jacketed vessel/tank or Heat Exchanger connected with steam and chilled water

4. Homogenization: Colloid Mill (rotor-stator principle) or Forced Pumping through a restricted orifice
principle

5. De-aeration: By passing inert Nitrogen gas or Vacuum

6. Transfer and Filling: Vacuum or Pump into single or multiple unit containers such as rigid bottles or
jars, collapsible tubes or flexible pouches.

Manufacture/Preparation

Compounding: Creams/ointments typically contain one or more drug substances dissolved or dispersed
in aqueous, oil or a suitable base. They are either oil-in water or water-in oil emulsions. They also could
be dispersions of long-chain fatty acids or alcohols that are water washable or miscible.

Homogenization: Homogenization requires the ingredients to be processed until of a uniform globule or

particle size. For most products, including creams, ointments, sauces, flavoring emulsions and
pharmaceutical suspensions, this requires a globule or droplet size in the range of 2 – 5 microns.

High pressure homogenizers

Various types of high pressure homogenizer are

available for use in the food and chemicals
industries but the design which has been very
extensively used for cell disruption is the Manton-
Gaulin APV type homogenizer. This consists of a
positive displacement pump which draws cell
suspension (about 12% w/v) through a check valve
into the pump cylinder and forces it, at high
pressures of up to 150 MPa (10 tons per square
inch) and flow rates of up to 10,000 L hr-1,
through an adjustable discharge valve which has a
restricted orifice (Figure 2.5). Cells are subjected
to impact, shear and a severe pressure drop across
the valve but the precise mechanism of cell
disruption is not clear. The main disruptive factor
is the pressure applied and consequent pressure
drop across the valve. This causes the impact and
shear stress which are proportional to the
operating pressure.

100
High pressure homogenizer with Restricted Orifice Principle

 The basic principle of homogenization is the control of velocity through an adjust-able, restricted
orifice. The product at high pressure enters a controlled clearance area between the homogenizing
valve (A) and seat (B). At this point, energy which has been stored as pressure is instantaneously
released as a high velocity stream. Velocity is a function of homogenizing pressure and may be in
excess of 57,000 ft. per min. In the high velocity area, between A and B, the product is subjected to
intense turbulence, hydraulic shear and cavitation.
 The product then emerges from the controlled clearance area and impinges with shattering force
and change of direction on the impact ring (C). This series of actions, occurring in as short an interval
as a micro-second, is the homogenizing process.
 Manton-Gaulin Homogenizer

Rotor-Stator
Principles

The precision-machined Silverson work head generates exceptionally high shear rates in a three stage
mixing/homogenizing process; the high speed rotor draws materials into the work head where they are
intensely mixed. Centrifugal force then drives the materials to the periphery of the work head and
subjects them to mechanical shear in the precision gap between the rotor and stator. This is followed by
intense hydraulic shear, as the product is forced through the stator screen at high velocity and circulated
back into the mix. Fresh material is continually drawn into the work head, progressively reducing globule
or particle size and quickly resulting in a homogeneous, uniform product.

101
Colloid Mill

Critical Manufacturing Step Critical Process Parameter

 Dissolving  Mixing Speed
 Melting  Mixing Time
 Homogenizing  Rate of Addition of polymer
 De-aeration /Vacuum  Fill Volume
 Transfer /Filling  Homogenizing Speed
 Rotor stator gap (mµ)
 Heating /Cooling Temp, Rate and Time
 Pumping Speed (Flow Rate)
 Vacuum and/or N2 Pressure

In-Process Tests/Specifications

 Appearance and color (Colorimetric, color chart).

 Homogeneity, Phase separation, solid sediment, Foreign matter
 Test for pH, viscosity
 Specific gravity
 Particle size
 Weight loss/gain: for filled container
 Tube/pump uniformity and leak test
 Holding time; in-compliance with 21 CFR §211.111
 BATCH RECONCILIATION (Accountability) as per 21CFR186 (b)(7) and 21CFR192.

102
Release Tests

 In-house more tighter for the release than stability specifications for assay and impurity
 Compendial: Wherever they are appropriate, pharmacopeial procedures (testing and
acceptance criteria) should be utilized
 Identification: for the drug substance
 Visual test for homogeneity of drug product
 pH, viscosity, specific gravity
 Antioxidant content.
 Microbial test: microbiological examination of
 Non -sterile products, for., USP <61>, <62>, and <111.
 Manufacturing are compliant with USP <87>, USP <88> and conforms to 21 CFR 177 and 178.

Mixer and Homogenizer

Lab-scale Production-scale

103
 Tube Filling Machine

In-Process Tests/Specifications

 Machine Cycle Time: Tube/Minute (tpm)

 Fill Weight
 Visual Inspection: Crimp and Print/Debossing
 Leak test

Ingredients used for semisolids

 Drug Substance (API)

 Bases; ( Hydrocarbon, Hydrophobic and/or Hydrophilic polymers)
 Humectants (PEG, Glycerin, Propylene glycol, etc.)
 Emulsifiers
 Gelling agent (Carbomer, gum. Veegum, hydrophilic polymer)
 Fragrances
 Antioxidants
 Antimicrobial preservatives
 Permeation enhancer
 pH adjuster

104
Functional Excipients;

 Antioxidant: Vitamin E, BHA & BHT

 Humectants: PEG, Propylene glycol, Glycerol or Sorbitol
 Anti-microbial agent/Preservatives: Methyl paraben, Propyl paraben, Benzoic acid, Benzalkonium
chloride, Benzyl alcohol, Phenyl mercuric nitrate, etc.
 Emulsifier: With HLB (hydrophilic-lipophilic balance) values to reduce surface tension for to form
stable emulsion system and preventing coalescence. (SLS, Tween & Spans)
 pH adjusting agent: diluted solution of HCl or NaOH.

Advantage & Absorption of Semi-Solid Drug Products

 They allow for local treatment of a number of dermatological conditions with very little systemic
exposure. Also can be absorbed through the outer part of the epidermis, the stratum corneum,
and the epidermis.
 High drug load can be applied on the actual site.
 Reduced risk of unwanted side effects.
 Easy to apply; the moisturizing effect may be beneficial for several skin conditions

Surfactant Basics - Definition of HLB, and How It Applies to Emulsions

What is HLB? How is it applied to formulate emulsions?

HLB (Hydrophile-Lipophile Balance) is an empirical expression for the relationship of the

hydrophilic ("water-loving") and hydrophobic ("water-hating") groups of a surfactant. The HLB
system is particularly useful to identify surfactants for oil and water emulsification. There are two
basic emulsion types:

Water-in-oil (w/o): water is dispersed in oil

Oil-in-water (o/w): oil is dispersed in aqueous phase, most common emulsion type.

Water-in-oil emulsions (w/o) require low HLB surfactants. Oil-in-water (o/w) emulsions often require
higher HLB surfactants.

Surfactant selection for an o/w emulsion can be simplified if the HLB system is applied. Oils have
required HLB numbers that identify the HLB necessary to give good o/w emulsification. Often the oil
supplier can provide the required HLB value. Alternatively, there are a number of compiled lists in the
literature on the required HLB for common waxes and oils. Since overall chemical structure (e.g.,
branched, linear, aromatic) is also a variable, a number of different surfactants with the required HLB
should be examined. Not all surfactants having the same HLB value may be acceptable for an o/w
emulsion. HLB values for surfactants can be calculated for simple alcohol ethoxylates. If a surfactant is
not a simple alcohol ethoxylate, the HLB value must be determined experimentally. HLB values are

105
additive; therefore, if two different surfactants or oils are present, the HLB will be the weighted average
of the HLB values for each component. Example: An oil (HLB = 10.5) is a component in an aqueous
cleaning solution.

There are several choices for surfactants. TRITON X-45 might be considered since it has an HLB value of
9.8; however, it is dispersible (not soluble) in water. Another choice is a blend of TRITON X-35 (HLB =
7.8) and TRITON X-100 (HLB = 13.4), a combination that will be water-soluble. HLB values are
additive, so to achieve the required HLB value, use the weighted average of the HLB values for each
surfactant. Required HLB = 10.

106
Chapter 11: Liquid Dosage

What are Pharmaceutical Liquid Preparations?

Liquid dosage forms are designed to provide the maximum therapeutic response in a target population
with difficulty swallowing tablets and capsules and/or to produce rapid therapeutic effects.

Liquid dosage forms are either, internal, parental or external use. They are available in monophasic and
biphasic forms. Monophasic liquid dosage forms are true or colloidal solution. Water is mainly used as a
solvent for majority of monophasic liquid dosage forms. The liquid which consists of two phases are
known as biphasic liquids.

Classification

 Pharmaceutical liquid preparation can be classified mainly into two major class based on their site of
application; Internal or external
 Internal Liquids: Oral Liquid preparations (Syrups, Elixirs, Linctus, Drops, Injectables, and Dialysis
solutions.
 External Liquids: Liquid to be applied to the skin: Liniments and lotions. Liquids meant for body
cavity: Gargles, throat paints, mouth washes, eye drops, eye lotions, ear drops, nasal drops,
sprays and inhalations
 Also based on routes of administration, Liquid preparations can be either sterile or non-sterile
 Parenteral Medications: Sterile products administered by injection or infusion in order to bypass
the gastrointestinal tract. Administration involves the use of a needle to penetrate the skin.

Mono Phasic Internal Liquid Preparations

Monophasic liquid dosage forms: It contains only one phase.

 Syrups: A liquid preparation typically containing a high concentration of sugar (or sugar substitute),
usually the concentration of sugar is 66% (w/w), a flavoring agent, and active drug ingredients.
Syrups are a popular delivery vehicle for anti-tussive drugs because they feel more soothing to
swallow than a tablet or capsule, and the medication is more quickly absorbed. Syrups are used in
formulation of antibiotics, saline drugs, vitamins, antitussives, sedatives, etc.

 Elixirs: Are hydro-alcoholic sweetened solutions, but a bit less sweet and viscous than syrups. Thus,
the main purpose for the preparation containing alcohol is for dissolving alcohol-soluble drug
components in the solution. Main Ingredients of elixir are ethyl alcohol, water, glycerin, propylene
glycol, flavoring agent, sugar and preservatives. Medicated elixir contains very potent drug such as
antibiotics, antihistamines, sedatives. Flavoring elixirs used as flavors and vehicles.

107
 Linctus: Viscous liquid and oral preparations that are generally prescribed for the relief of cough.
They contain medicament which have demulcent, sedative or expectorant action. linctus should be
taken in a small doses sipped and swallowed slowly without diluting it with water in order to have
maximum and prolonged effect of medications. Simple syrup is used a vehicle for most of the
linctus. Tulu syrup is preferred in certain cases because of its aromatic odor and flavor.

 Drops: Liquid preparations meant for oral administration. The oil soluble vitamins such as vitamin A
and D concentrations in fish liver oil are presented as drops for administration. Since these
preparations contain potent medications the dose must be measured accurately.

 Liniments: Liquid and semi liquid preparations meant for application to the skin. Liniments are
usually applied to the skin with friction and rubbing of the skin. Liniments may be alcoholic or oily
solutions or emulsions. Alcohol helps in penetration of medicament in to the skin and also increases
its counterirritant or rubefacient action. Arachis oil is used in some liniments which spread more
easily on the skin. Soap is also included as ingredients in some of the liniments which help in easy
application of liniment on the skin. Liniments contain medicaments possessing analgesic,
rubefacient, soothing, counter irritant or stimulating properties. Liniment should not be applied to
broken skin it may cause excess irritation.
 Lotions: Liquid preparations meant for external application without friction. They are applied direct
to the skin with the help of some absorbent material such as cotton, wool or gauze soaked in it.
Lotions may be used for local action as cooling, soothing or protective purpose. They are generally
prescribed for antiseptic action ex: Calamine lotion.
 Gargles: Aqueous solutions used to prevent or treat throat infections. They are usually available in
concentrated for with direction for dilution with warm water before use. They are brought in to
contact with mucous membrane of the throat and are allowed to remain in contact with it for a
few seconds.
 Mouth washes: Aqueous solutions with a pleasant taste and odor used to make clean and
deodorize the buccal cavity. Generally they contain antibacterial agents, alcohol, glycerin,
sweetening agents, flavoring agents and coloring agents.
 Throat paints: Viscous liquid preparations used for mouth and throat infections. Glycerin is
commonly used as a base it adheres to mucous membrane for a long period and it possesses
a sweet taste.
 Nasal drops; solutions of drugs that are instilled in to the nose with a dropper. They are usually
aqueous and not oily drops. Nasal drops should be isotonic having neutral pH and viscosity similar
to nasal secretions by using methyl alcohol.

108
 Eye drops: Sterile solution or suspensions of drugs that are instilled in to the eye with a
dropper. The eye drops are usually made in aqueous vehicle. It should be sterile isotonic with
lachrymal secretions, buffered and free from foreign particles to avoid irritation to the eye.

 Eye lotions: Aqueous solutions used for washing the eyes. The eye lotions are supplied in
concentrated form and are required to be diluted with warm water immediately before use.
It should be isotonic and free from foreign particles to avoid irritation to the eye.

 Ear drops: solutions of drugs that are instilled in to the ear with a dropper. These are generally
used for cleaning the ear, softening the wax and for treating the mild infections.

Bi-Phasic Liquid Dosage Preparations

Biphasic liquid dosage forms: It contains two phases.

Examples: Suspension/Dispersion and Emulsion

Suspensions/Dispersions: Biphasic liquid dosage form of medicament in which finely divided solid
particles are dispersed in a liquid or semisolid vehicle. The solid particles act as disperse phase whereas
liquid vehicle acts as the continuous phase. Suspensions are generally taken orally or by parental route.
They are also used for external application.

Many suspensions are supplied as dry powders which are converted in to suspensions by adding the
specified amount of vehicle before use. This is done to ensure the stability of suspension

Example: Antacid Suspensions, Ampicillin for oral suspensions, Barium sulfate suspensions, Insulin zinc
suspension

Emulsion: Biphasic liquid preparation containing two immiscible liquids, one of which is dispersed as
minute globules in to the other. The liquid which is converted in to minute globules is called the disperse
phase and the liquid in which the globules are dispersed is called the continuous phase. Normally two
immiscible liquids cannot be dispersed for a long period. So an emulsifying agent is added to the system.
It forms the film around the globules in order to scatter them indefinitely in the continuous phase, So
that a stable emulsion is formed.

Emulsions are of two types

I. Oil in water type (O/W): Emulsion in which oil is the dispersed phase whereas water is in the
continuous phase. The O/W type emulsions are preferred for internal use. In these emulsions gum
acacia, tragacanth, methyl cellulose, saponins synthetic substances and soaps formed from
monovalent bases like sodium, potassium are used as an emulsifying agent.

109
II. Water in oil type (W/O): Emulsion in which water is in the dispersed phase whereas oil is in
continuous phase. Wool wax, resins, beeswax and soaps formed from divalent bases like calcium,
magnesium and zinc are used as an emulsifying agent. The W/O emulsions are mainly used for
externally as lotions or creams.

III. Intravenous emulsion: The oil soluble hormones vitamin A,D and K are administered as intravenous
injection. The emulsified oils are also injected as diagnostic aids. The emulsion should have small globule
size and must be sterile.

IV. Emulsion for external use: The emulsions for external application may be both O/W or W/O type but
O/W type emulsion is preferred. When a drug is emulsified its rate of penetration through the skin may
get reduced. It helps to prolong the action of a drug. Generally the emulsions for application to the skin
are semisolid at room temperature and are considered to be an excellent vehicle.

Liquid Manufacturing Process

Involves following steps:
Bulk Manufacturing/Mixing: ASTM standards for 316/316L Tank/Vessel
2. Mixing/Dispersion (Convection or Shear Mixing): (Using Anchor, Impeller or Disintegrator type of
blades)
3. Heating/Cooling: Jacketed vessel/tank or Heat Exchanger connected with steam and chilled water
4. Filtration: For solutions
Homogenization (for suspension/dispersions): Colloid Mill (rotor-stator principle) or Forced Pumping
through a restricted orifice principle
5. De-aeration: By passing inert Nitrogen gas or Vacuum
6. Transfer and Filling: Vacuum or Pump into single or multiple unit containers such as rigid bottles or
jars, collapsible tubes or flexible pouches.

Homogenization (Suspension/dispersion)
Homogenization requires the ingredients to be processed until of a uniform globule or particle size.
For most products, including liquids for suspension/dispersion, sauces, flavoring emulsions and
pharmaceutical suspensions, this requires a globule or droplet size in the range of 2 – 5 microns.

High pressure homogenizer with Restricted Orifice Principle

The basic principle of homogenization is the control of velocity through an adjust-able, restricted orifice.
The product at high pressure enters a controlled clearance area between the homogenizing valve (A)
and seat (B). At this point, energy which has been stored as pressure is instantaneously released as a
high velocity stream. Velocity is a function of homogenizing pressure and may be in excess of 57,000 ft.
per min. In the high velocity area, between A and B, the product is subjected to intense turbulence,
hydraulic shear and cavitation.

110
The product then emerges from the controlled clearance area and impinges with shattering force and
change of direction on the impact ring (C). This series of actions, occurring in as short an interval as a
micro-second, is the homogenizing process. Manton-Gaulin Homogenizer
High Pressured Restricted Orifice Principle

Rotor-Stator Principles
The precision-machined Silverson work-head generates exceptionally high shear rates in a three stage
mixing/homogenizing process;
The high speed rotor draws materials into the work-head where they are intensely mixed. Centrifugal
force then drives the materials to the periphery of the work-head and subjects them to mechanical
shear in the precision gap between the rotor and stator.
This is followed by intense hydraulic shear, as the product is forced through the stator screen at high
velocity and circulated back into the mix.
Fresh material is continually drawn into the work-head, progressively reducing globule or particle size
and quickly resulting in a homogeneous, uniform product.

Colloid Mill

111
 Critical Manufacturing Step Critical Process Parameter
 Mixing  Mixing Speed
 Dissolving  Mixing Time
 Homogenizing  Rate of Addition of polymer
 De-aeration /Vacuum  Fill Volume
 Transfer /Filling  Homogenizing Speed
 Rotor stator gap (mµ)
 Heating /Cooling Temp, Rate and Time
 Pumping Speed (Flow Rate)
 Vacuum and/or N2 Pressure
In-Process Tests/Specifications

 Appearance and color (Colorimetric, color chart).

 Homogeneity, Phase separation, solid sediment, Foreign matter
 Test for pH, viscosity
 Specific gravity
 Particle size
 Weight loss/gain: for filled container
 Tube/pump uniformity and leak test
 Holding time; in-compliance with 21 CFR §211.111
 BATCH RECONCILIATION (Accountability) as per 21CFR186 (b)(7) and 21CFR192.

Release Tests

 In-house more tighter for the release than stability specifications for assay and impurity
 Compendial: Wherever they are appropriate, pharmacopeial procedures (testing and
acceptance criteria) should be utilized
 Identification: for the drug substance
 Visual test for homogeneity of drug product
 pH, viscosity, specific gravity
 Antioxidant content.
 Microbial test: microbiological examination of
 Non -sterile products, for., USP <61>, <62>, and <111.
 8. Manufacturing are compliant with USP <87>, USP <88> and conforms to 21 CFR 177 and 178.

In-Process Tests/Specifications for filling process

 Machine Cycle Time: Bottle/container/Minute

 Fill Weight:
 Visual Inspection: Capping torque for un-screwing
 Print/Debossing
 Leak test

112
Ingredients used for Liquids Preparations

 Drug Substance (API)

 Sweetening Agent: Sucrose, Dextrose, Sorbitol, Mannitol, Glycerin, Aspartame
 Vehicles/Solvents: Water, Ethanol, Glycerin, Sorbitol, Isopropyl Alcohol, Chloroform, etc.)
 Emulsifiers
 Suspending agent/Thickening agent: (Carbomer, gum. Veegum, Hydrophilic polymers)
 Fragrances
 Antioxidants
 Antimicrobial preservatives
 pH adjuster
 Buffers: To resist any change in pH

Functional Excipients

 Antioxidant: Vitamin E, BHA & BHT

 Humectants: PEG, Propylene glycol, Glycerol or Sorbitol
 Anti-microbial agent/Preservatives: Methyl paraben, Propyl paraben, Benzoic acid, Benzalkonium
chloride, Benzyl alcohol, Phenyl mercuric nitrate, etc.
 Emulsifier: With HLB (hydrophilic-lipophilic balance) values to reduce surface tension for to form
stable emulsion system and preventing coalescence. (SLS, Tween & Spans)
 pH adjusting agent: diluted solution of HCl or NaOH

Advantage & Absorption of Liquid Drug Products

 Easier to swallow therefore easier for: children - old age - unconscious people.
 More quickly effective than tablets and capsules, as drug become available immediately for
absorption
 Liquid dosages as solutions are homogenous therefore give uniform dose than suspension
or emulsion which need shaking.
 May be designed for any route of administration
 Flexible dosing

Surfactant Basics - Definition of HLB and its application in Emulsions

What is HLB? How is it applied to formulate emulsions?

 HLB (Hydrophilic-Lipophilic Balance) is an empirical expression for the relationship of the

hydrophilic ("water-loving") and hydrophobic ("water-hating") groups of a surfactant. The table
below lists HLB values along with typical performance properties. The higher the HLB value, the
more water-soluble the surfactant.

113
 The HLB system is particularly useful to identify surfactants for oil and water emulsification. There
are two basic emulsion types:
 Water-in-oil (w/o): water is dispersed in oil : e.g. Common Cold Cream
 Oil-in-water (o/w): oil is dispersed in aqueous phase, most common emulsion type.
 e.g.: Milk, Vanishing Cream
 Water-in-oil emulsions (w/o) require low HLB surfactants. Oil-in-water (o/w) emulsions often
require higher HLB surfactants.

Selection of Surfactant

Surfactant selection for an o/w emulsion can be simplified if the HLB system is applied. Oils have
required HLB numbers that identify the HLB necessary to give good o/w emulsification.

Often the oil supplier provides the required HLB value.

Literature search for compiled lists on the required HLB for common waxes and oils.

Since overall chemical structure (e.g., branched, linear, aromatic) is also a variable, a number of
different surfactants with the required HLB should be examined.

Not all surfactants having the same HLB value may be acceptable for an o/w emulsion. HLB values for
surfactants can be calculated for simple alcohol ethoxylates.

If a surfactant is not a simple alcohol ethoxylate, the HLB value must be determined experimentally. HLB
values are additive; therefore, if two different surfactants or oils are present, the HLB will be the
weighted average of the HLB values for each component. Example: An oil (HLB = 10.5) is a component in
an aqueous cleaning solution.

There are several choices for surfactants. SLS has a very high HLB value of 40 it can emulsify easily an oil
to form oil in water emulsion

Bi-Phasic Liquid Dosage Preparations

Biphasic liquid dosage forms: It contains two phases.

Examples: Suspension/Dispersion and Emulsion

Suspensions/Dispersions: Biphasic liquid dosage form of medicament in which finely divided solid
particles are dispersed in a liquid or semisolid vehicle. The solid particles act as disperse phase whereas
liquid vehicle acts as the continuous phase. Suspensions are generally taken orally or by parental route.
They are also used for external application.

Many suspensions are supplied as dry powders which are converted in to suspensions by adding the
specified amount of vehicle before use. This is done to ensure the stability of suspension

114
Example: Antacid Suspensions, Ampicillin for oral suspensions, Barium sulfate suspensions, Insulin zinc
suspension

Emulsion: Biphasic liquid preparation containing two immiscible liquids, one of which is dispersed as
minute globules in to the other. The liquid which is converted in to minute globules is called the disperse
phase and the liquid in which the globules are dispersed is called the continuous phase. Normally two
immiscible liquids cannot be dispersed for a long period. So an emulsifying agent is added to the system.
It forms the film around the globules in order to scatter them indefinitely in the continuous phase, So
that a stable emulsion is formed.

Emulsions are of two types

I. Oil in water type (O/W): Emulsion in which oil is the dispersed phase whereas water is in the
continuous phase. The O/W type emulsions are preferred for internal use. In these emulsions gum
acacia, tragacanth, methyl cellulose, saponins synthetic substances and soaps formed from
monovalent bases like sodium, potassium are used as an emulsifying agent.

II. Water in oil type (W/O): Emulsion in which water is in the dispersed phase whereas oil is in
continuous phase. Wool wax, resins, beeswax and soaps formed from divalent bases like calcium,
magnesium and zinc are used as an emulsifying agent. The W/O emulsions are mainly used for
externally as lotions or creams.

III. Intravenous emulsion: The oil soluble hormones vitamin A,D and K are administered as intravenous
injection. The emulsified oils are also injected as diagnostic aids. The emulsion should have small globule
size and must be sterile.

IV. Emulsion for external use: The emulsions for external application may be both O/W or W/O type
but O/W type emulsion is preferred. When a drug is emulsified its rate of penetration through the skin
may get reduced. It helps to prolong the action of a drug. Generally the emulsions for application to the
skin are semisolid at room temperature and are considered to be an excellent vehicle.

Liquid Manufacturing Process

Involves following steps:
Bulk Manufacturing/Mixing: ASTM standards for 316/316L Tank/Vessel
2. Mixing/Dispersion (Convection or Shear Mixing): (Using Anchor, Impeller or Disintegrator type
of blades)
3. Heating/Cooling: Jacketed vessel/tank or Heat Exchanger connected with steam and chilled water
4. Filtration: For solutions
Homogenization (for suspension/dispersions): Colloid Mill (rotor-stator principle) or Forced Pumping
through a restricted orifice principle
5. De-aeration: By passing inert Nitrogen gas or Vacuum

115
6. Transfer and Filling: Vacuum or Pump into single or multiple unit containers such as rigid bottles or
jars, collapsible tubes or flexible pouches.

Homogenization (Suspension/dispersion)
Homogenization requires the ingredients to be processed until of a uniform globule or particle size.
For most products, including liquids for suspension/dispersion, sauces, flavoring emulsions and
pharmaceutical suspensions, this requires a globule or droplet size in the range of 2 – 5 microns.

High pressure homogenizer with Restricted Orifice Principle

The basic principle of homogenization is the control of velocity through an adjust-able, restricted
orifice. The product at high pressure enters a controlled clearance area between the homogenizing
valve (A) and seat (B). At this point, energy which has been stored as pressure is instantaneously
released as a high velocity stream. Velocity is a function of homogenizing pressure and may be in excess
of 57,000 ft. per min. In the high velocity area, between A and B, the product is subjected to intense
turbulence, hydraulic shear and cavitation.

The product then emerges from the controlled clearance area and impinges with shattering force and
change of direction on the impact ring (C). This series of actions, occurring in as short an interval as a
micro-second, is the homogenizing process.
Manton-Gaulin Homogenizer

High Pressured Restricted Orifice Principle

Rotor-Stator Principles
The precision-machined Silverson work-head generates exceptionally high shear rates in a three
stage mixing/homogenizing process;
The high speed rotor draws materials into the work-head where they are intensely mixed.
Centrifugal force then drives the materials to the periphery of the work-head and subjects them to
mechanical shear in the precision gap between the rotor and stator.
This is followed by intense hydraulic shear, as the product is forced through the stator screen at high
velocity and circulated back into the mix.
Fresh material is continually drawn into the work-head, progressively reducing globule or particle
size and quickly resulting in a homogeneous, uniform product.

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 Colloid Mill

Critical Manufacturing Step Critical Process Parameter

 Mixing  Mixing Speed
 Dissolving  Mixing Time
 Homogenizing  Rate of Addition of polymer
 De-aeration /Vacuum  Fill Volume
 Transfer /Filling  Homogenizing Speed
 Rotor stator gap (mµ)
 Heating /Cooling Temp, Rate and Time
 Pumping Speed (Flow Rate)
 Vacuum and/or N2 Pressure
In-Process Tests/Specifications

 Appearance and color (Colorimetric, color chart).

 Homogeneity, Phase separation, solid sediment, Foreign matter
 Test for pH, viscosity
 Specific gravity
 Particle size
 Weight loss/gain: for filled container
 Tube/pump uniformity and leak test
 Holding time; in-compliance with 21 CFR §211.111
 BATCH RECONCILIATION (Accountability) as per 21CFR186 (b) (7) and 21CFR192.

Release Tests

 In-house more tighter for the release than stability specifications for assay and impurity
 Compendial: Wherever they are appropriate, pharmacopeial procedures (testing and
acceptance criteria) should be utilized
 Identification: for the drug substance
 Visual test for homogeneity of drug product
 pH, viscosity, specific gravity
 Antioxidant content.
 Microbial test: microbiological examination of
 Non -sterile products, for., USP <61>, <62>, and <111.
 Manufacturing are compliant with USP <87>, USP <88> and conforms to 21 CFR 177 and 178.

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In-Process Tests/Specifications for filling process
 Machine Cycle Time: Bottle/container/Minute
 Fill Weight:
 Visual Inspection: Capping torque for un-screwing
 Print/Debossing
 Leak test
Ingredients used for Liquids Preparations

 Drug Substance (API)

 Sweetening Agent: Sucrose, Dextrose, Sorbitol, Mannitol, Glycerin, Aspartame
 Vehicles/Solvents: Water, Ethanol, Glycerin, Sorbitol, Isopropyl Alcohol, Chloroform, etc.)
 Emulsifiers
 Suspending agent/Thickening agent: (Carbomer, gum. Veegum, Hydrophilic polymers)
 Fragrances
 Antioxidants
 Antimicrobial preservatives
 pH adjuster
 Buffers: To resist any change in pH

Functional Excipients

 Antioxidant: Vitamin E, BHA & BHT

 Humectants: PEG, Propylene glycol, Glycerol or Sorbitol
 Anti-microbial agent/Preservatives: Methyl paraben, Propyl paraben, Benzoic acid, Benzalkonium
chloride, Benzyl alcohol, Phenyl mercuric nitrate, etc.
 Emulsifier: With HLB (hydrophilic-lipophilic balance) values to reduce surface tension for to form
stable emulsion system and preventing coalescence. (SLS, Tween & Spans)
 pH adjusting agent: diluted solution of HCl or NaOH

Advantage & Absorption of Liquid Drug Products

 Easier to swallow therefore easier for: children - old age - unconscious people.
 More quickly effective than tablets and capsules, as drug become available immediately for
absorption
 Liquid dosages as solutions are homogenous therefore give uniform dose than suspension
or emulsion which need shaking.
 May be designed for any route of administration
 Flexible dosing

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Surfactant Basics - Definition of HLB and its application in Emulsions

What is HLB? How is it applied to formulate emulsions?

 HLB (Hydrophilic-Lipophilic Balance) is an empirical expression for the relationship of the

hydrophilic ("water-loving") and hydrophobic ("water-hating") groups of a surfactant. The table
below lists HLB values along with typical performance properties. The higher the HLB value, the
more water-soluble the surfactant.
 The HLB system is particularly useful to identify surfactants for oil and water emulsification. There
are two basic emulsion types:
 Water-in-oil (w/o): water is dispersed in oil : e.g. Common Cold Cream
 Oil-in-water (o/w): oil is dispersed in aqueous phase, most common emulsion type.
 e.g.: Milk, Vanishing Cream
 Water-in-oil emulsions (w/o) require low HLB surfactants. Oil-in-water (o/w) emulsions often
require higher HLB surfactants.

Selection of Surfactant

Surfactant selection for an o/w emulsion can be simplified if the HLB system is applied. Oils have
required HLB numbers that identify the HLB necessary to give good o/w emulsification.

Often the oil supplier provides the required HLB value.

Literature search for compiled lists on the required HLB for common waxes and oils.

Since overall chemical structure (e.g., branched, linear, aromatic) is also a variable, a number of
different surfactants with the required HLB should be examined.

Not all surfactants having the same HLB value may be acceptable for an o/w emulsion. HLB values for
surfactants can be calculated for simple alcohol ethoxylates.

If a surfactant is not a simple alcohol ethoxylate, the HLB value must be determined experimentally. HLB
values are additive; therefore, if two different surfactants or oils are present, the HLB will be the
weighted average of the HLB values for each component. Example: An oil (HLB = 10.5) is a component in
an aqueous cleaning solution.

There are several choices for surfactants. SLS has a very high HLB value of 40 it can emulsify easily an oil
to form oil in water emulsion.

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Chapter 12: Parenteral Medications: Sterile products administered by injection or infusion in
order to bypass the gastrointestinal tract. Administration involves the use of a needle to
penetrate the skin. Parenteral administration technically means non-oral administration, but it
typically refers to the injection of drugs into the body intravenously, intramuscularly, or
subcutaneously. Parenteral drug delivery bypasses the body’s natural defenses against bacteria
and viruses, which increases the risk of infection to patients. Consequently, parenteral drug
products and biologics must undergo sterilization to destroy any potential contaminants and
ensure patient safety.

There are two ways a sterile drug product can be manufactured: They are manufactured by
either terminal sterilization or aseptic technique process.

Procedures for Pre-entering Sterile/Aseptic Manufacturing Area

Personal Hygiene Procedures and Requirements

In Locker Room: Change from personal clothes, shoes and other personal wares to the
following:

Protective Uniforms: Non-sterile clean, single or two-piece, white (other light color) uniforms
without pockets made from lint-free weave, e.g. polyester/cotton (67/33).

Footwear: Non-sterile special/separate white snickers/clogs and worn at all times within the
area.

Head Gear: Non-sterile disposable headgear totally enclosing hair and facial hair

Face Mask: Non-sterile, non-linting face mask be worn before entering Personnel Air Lock.

Access to the area: Only authorized specially trained personnel are permitted to enter the
sterile and aseptic manufacturing area. Any condition which may cause the shedding of
abnormal numbers or types of organisms (e.g. coughs, colds or any other type of infection) must
be reported by the employee to the supervisor who will decide on suitable tasks for that
employee Access to Sterile/Aseptic Manufacturing Area is only via the two steps personnel air
lock system.

A mirror must be used to ensure that the protective garments have been put on in a complete
and proper manner.

On entering the outer part of the personnel air lock the non-sterile area uniform, shoes,
socks/stockings must be removed.

Hands must be thoroughly washed and then disinfected by rubbing in the disinfectant
solution/gel

Clean, sterilized socks must be put on and then enter into inner- air lock and protective
garments must be put on in the following order

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Sterilized head gear made of lint-free, non-particle sheading (100% polyester)

Sterilized face mask, non-lint type, must totally cover the nose and mouth to prevent shedding
of droplets. Touching the face mask must be avoided. If so, the hand must be thoroughly
disinfected.

After use face mask must be disposed of in a waste bin placed in the outer part of the air lock.

Hygiene of the Hands: The hands must be well-tended. No open lesions shall be discernable.
Small lesions/infections must be thoroughly covered with a Band-Aid or bandage. The nails
must be clean and cut. Nail polish or other cosmetics which can shed particles must not be
used. Hands must be thoroughly washed and disinfected before entering the Sterile/Aseptic
Manufacturing Area, before starting a work operation or when the hands have become dirty.
Sterile, disposable gloves must be worn within the areas intended for aseptic preparation of
drug products. The sterile gloves must be changed prior to each working operation. Damaged
gloves must be exchanged immediately. Used gloves must be disposed of in a waste bin placed
in the outer part of the air lock.

Protective Uniforms: Sterilized, one-piece, light color (different to white color) uniforms gathered
at the wrists and ankle and provided with a high neck without pockets made from lint-free, non-
particle shedding materials (100% polyester).

For terminal sterilized production area sterilized uniforms must be changed at least every day.
For the aseptic filling area the sterilized garments must be changed at every entry.

Footwear: When entering the Sterile/Aseptic Manufacturing Area shoes of non-sterile area
must be changed to specially designated shoe preferably of another color for distinction. The
shoe must be clean and when not used, kept at a fixed place within the inner part of the air lock.
In addition, clean socks shall be worn totally enclosing the feet and with the trouser-bottom
tucked inside the socks.

Head Gear: Sterilized, lint-free, non-particle shedding must totally enclose hair/beard and worn
tucked inside the neck of the uniform

Face Mask: A non-lint face mask be worn covering nose and mouth to prevent shedding
droplets. Touching the face mask must be avoided. If so, the hand must be thoroughly
disinfected.

After use face mask must be disposed of in a waste bin placed in the outer part of the air lock.

Other Hygiene Percepts for Sterile/Aseptic Manufacturing Area

Wristwatches and jewelry must not be worn within this area

Cigarettes, money etc. must not be kept in the garments

Excessive shedding of particles and organisms due to over vigorous activity must be avoided as
well as whistling and unnecessary talking must be avoided.

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Raw materials, primary packaging materials, drug products or sterilized machine parts must not
be directly touched by the operators.

Aseptic Sampling and Dispensing of Sterile Materials

Aseptic Sampling & Dispensing Area: The aseptic sampling and dispensing of raw materials
must be carried out in the Laminar down Flow / Cross Flow Unit (LAF cabinet / Down Flow
Hood) within the dispensing room. Access to the aseptic area is permitted only via the
personnel air lock. Only one batch at a time must be sampled or dispensed within the aseptic
area.

The aseptic LAF-unit must be cleaned sanitized every day after use.

When sampling or dispensing has been completed the operator must vacuum-clean the cubicle.
Package containing materials for aseptic sampling or dispensing must be sanitized before
moving into aseptic area.

The operators must change into garments, including head and foot wear. A disposable non-
linting face mask and disposable powder-free gloves must be worn.

Preferably hygiene packed glass jars or glass bottles should be used as sample container.
Once a package of containers is opened all jars or bottles must immediately be fitted with lids.

Samples intended for biological analysis must be transferred into sterile sample glass
containers. Only sterile equipment (spoons, spatulas, scoops etc.) must be used.

Aseptic Manufacturing

Researchers and drug innovators rely on processes like aseptic manufacturing to ensure that
their parenterally administered therapies and biologics are safe and of high quality for the
patients who need them. Aseptic manufacturing is a uniquely challenging process that requires
expertise and careful planning for successful execution.

Aseptic Fill/Finish

This is a process where the drug product, container, and container closure are first sterilized
separately and then brought together. Combining the product, container, and closure is done in
a cleanroom and often uses special equipment that is self-contained in a sterile environment.
The aseptic fill/finish process is challenging and complex, and it is usually chosen when terminal
sterilization is not suitable. The terms ‘aseptic fill/finish’ and ‘sterile fill/finish’ are often used
interchangeably

Challenges Faced in Aseptic Fill/Finish Processes:

Aseptic manufacturing of parenteral drugs is fraught with many challenges — with the growing
diversity in drug product composition exacerbating some of them. From start to end, sterile
fill/finish requires deliberate planning, skilled technical personnel and project managers, and

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specialized and modern equipment and facilities. Here are some challenges commonly faced
during sterile fill/finish projects:

Maintaining product stability: Many biopharmaceuticals are volatile or sensitive, and their
structure, potency, and stability can be altered during processing and filling. Extra care must be
taken, especially during stages involving significant temperature changes, to maintain the drug
product’s stability

Maintaining personnel sterility: Specialized personnel are essential for the sterile fill/finish
process, but they present the most significant risk of contamination to the drug product. The use
of robots to automate aseptic processing can help reduce the number of personnel needed in
the cleanroom (and consequently the risk of contamination). Still, it cannot completely eliminate
the need for them.

Conducting effective inspections: Drugs and biologics vary in appearance and viscosity and
are packaged in containers that also vary in transparency, color, and thickness — all of which
can make visual inspection challenging. More, the non-uniformity associated with manual
inspection (which is often the chosen method) impacts the effectiveness and pace of
inspections.

Sterile Manufacturing Process:

Sterile fill/finish involves harmonization and complex interactions between specialized

personnel, sterilized drug products, fill/finish equipment, containers, cleanroom, support
components, and sterilized filling components.

BUBBLE POINT TEST

Membrane filters have been used successfully for many years to remove yeast, bacteria and
particulate from fluid streams. The ultimate integrity test for a sterilizing grade membrane filter is
the bacterial challenge. Unfortunately this is a destructive test; the filter cannot be used
afterwards to filter a product. As a result, one of the most important aspects of the use of filters
to remove bacteria is to have a non-destructive integrity test, which is correlated to the
production of effluent in a bacterial challenge test. It is this correlation, rather than the non-
destructive integrity test alone, that provides assurance that the filter will perform as intended.
During production of sterile product, the filter should be subjected to such an integrity test before
and after filtration. This is done to ensure that the filter meets specification, is properly installed
and intact during filtration, and to confirm the rating of the filter.

There are 3 major tests used to determine the integrity of a membrane filter: the Bubble Point
Test, the Forward Flow Test, and the Pressure Hold Test. All three tests are based on the same
physics, the flow of a gas through a liquid-wetted membrane under applied gas pressures. They
differ in which part of the flow/pressure spectrum they examine. In this paper, we will focus on
the Bubble Point Test.

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Background

A bubble point test is a test designed to determine the pressure at which a continuous stream of
bubbles is initially seen downstream of a wetted filter under gas pressure. To perform a Bubble
Point Test, gas is applied to one side of a wetted filter, with the tubing downstream of the filter
submerged in a bucket of water. The filter must be wetted uniformly such that water fills all the
voids within the filter media. When gas pressure is applied to one side of the membrane, the
test gas will dissolve into the water, to an extent determined by the solubility of the gas in water.
Downstream of the filter, the pressure is lower. Therefore the gas in the water on the
downstream side is driven out of solution. As the applied upstream gas pressure is increased,
the diffusive flow downstream increases proportionally. At some point, the pressure becomes
great enough to expel the water from one or more passageways establishing a path for the bulk
flow of air. As a result, a steady stream of bubbles should be seen exiting the submerged
tubing. The pressure at which this steady stream is noticed is referred to as the bubble point.

Bubble Point Test Procedure

A forward bubble point integrity test is a procedure

which measures the pressure needed to be applied
to the upstream side of a filter causing bulk or open
pore flow through the largest pores of a wetted
filter.

This measurement is taken from the downstream

side of the filter housing where a flexible piece of
tubing has been attached and the other end
submerged into a beaker of water.

The bubble point is indicated by vigorous bubbling

from the tubing. The accuracy of this test will rely
on the operator’s ability to successful recognize
this point.

Materials required to perform test: Test Method

 Record the filter part number(s), lot number,
 Compressed air or nitrogen and product information. Also include physical
observations.
 Pressure regulator
 Wet the filter to be tested with water.
 Filter, Filter housing  Place the wetted filter in the appropriate
housing.
 Hose barbs
 Connect the outlet fitting from the compressed
 Beaker air pressure regulator to the upstream side of
the test filter. Check that the gauge which is
 Tubing connected to the pressure regulator has
 Filter adapters subdivisions of at least 0.5 psig, and has the
capacity to measure up to 100 psig. A digital
pressure gauge can also be used.
 Connect the outlet fitting from the compressed
air pressure regulator to the upstream side of
the test filter.

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  Connect a piece of flexible tubing from the
downstream port of the test filter into a beaker
filled with water.
 Starting from zero pressure, gradually increase
the pressure to the test filter using the pressure
regulator.
 Observe the submerged end of the tubing for
the production of bubbles as the upstream
pressure is slowly increased in 0.5 psig
increments. Note the rate that the bubbles
appear for the end of the submerged tube.
 9. The bubble point of the test filter is reached
when bubbles are produced from the tube at a
steady rate. Record the pressure to the nearest
0.5 psig as indicated on the pressure gauge.

Container Closure Integrity Testing (CCIT)

PTI’s non-destructive inspection technologies verify container closure system integrity.

Deterministic quantitative test methods for vials, ampoules, syringes, cartridges and auto-
injectors. Applications include stability studies, clinical trials, quality assurance testing and
statistical process control (SPC). PTI’s leading technologies are referenced in the new USP
<1207> Chapter on package integrity testing.

Electronic Scanning

 High Voltage Leak Detection (HVLD)Technology

 Applications include liquid based products, especially products containing proteins or
suspensions
 Non-conductive container materials can be glass, plastic or poly laminates
 Detects small pinholes, micro cracks and seal imperfections.
 Defect detection down to single digit microns

Vacuum Decay PERMA-Vac Technology

 ASTM Test Method F2338 and FDA

 Consensus Standard
 Defect detection down to 0.05 ccm
 Measures seal integrity of entire container or
 package
 Tests for gas leaks for dry products
 (lyophilized vials, powder filled)
 Tests for liquid leaks (liquid filled vials, ampoules, cartridges and pre-filled syringes)

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Excipients for Parenterals

Parenteral excipients are substances used in the formulation of injectable drugs. They are an important
component of parenteral products as they help to stabilize, solubilize, and enhance the delivery of active
pharmaceutical ingredients (APIs) to the patient.

Definitions of Parenteral Excipients

As per the United States Pharmacopeia-National Formulary (USP-NF), a parenteral excipient is defined
as “any substance, other than the active ingredient(s), added to a parenteral product.”

Similarly, the European Pharmacopoeia (EP) defines parenteral excipients as “all constituents of a
medicinal product, other than the active substance, that are intentionally added to the product with the
aim of enhancing its stability, bioavailability or tolerability, or to facilitate its administration.”

Source: Seppic Parenteral Excipients

Quality Attribute of parenteral Excipients

The quality attributes of excipients are critical since they impact the quality attributes of the final
formulations. The excipient attributes for parenteral excipients include:

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1. Purity: Parenteral excipients must be of high purity, typically meeting compendial standards such as
those set by the United States Pharmacopeia (USP), European Pharmacopeia (EP), or Japanese
Pharmacopeia (JP).

2. Compatibility: Excipients must be compatible with the active ingredient and other excipients in the
formulation to prevent any adverse reactions, such as precipitation or degradation.

3. Sterility: Excipients must be sterile to prevent microbial growth and contamination in the
formulation.

4. Stability: Excipients must be stable throughout the shelf-life of the drug product, preventing any
degradation or loss of activity of the active ingredient.

5. Safety: Excipients must be safe for use in humans and not cause any adverse effects or toxicity.

6. Functionality: Excipients must perform their intended function, such as solubilizing or stabilizing the
active ingredient, without interfering with its activity.

7. Traceability: Excipients must be traceable to their source and manufacturing process to ensure
quality and safety.

8. Regulatory compliance: Excipients must comply with regulatory requirements in the countries
where they are used, such as those set by the U.S. Food and Drug Administration (FDA) or the
European Medicines Agency (EMA).

9. Consistency: Excipients must be consistent in their physical and chemical properties, ensuring
reproducibility of the drug product from batch to batch.

Overall, parenteral excipients must meet high standards of quality and safety to ensure the efficacy and
safety of the final drug product.

Functional excipients in parenteral formulations

Functional excipients are substances added to pharmaceutical formulations to enhance the

performance of the active ingredient or to improve the stability, bioavailability, or pharmacokinetic
properties of the formulation. In parenteral formulations, functional excipients play a critical role in
ensuring the safety and efficacy of the drug product.

Here are some commonly used functional excipients in parenteral formulations:

 Buffering agents: These agents help to maintain the pH of the formulation, which is critical for the
stability and activity of the active ingredient.

 Solubilizing agents: These agents improve the solubility of poorly soluble drugs in the
formulation, enhancing their bioavailability.

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 Preservatives: These agents prevent microbial growth and contamination in the formulation, helping
to maintain the integrity and sterility of the drug product.

 Stabilizers: These agents protect the active ingredient from degradation or oxidation, improving the
shelf-life of the drug product.

 Viscosity modifiers: These agents control the viscosity and flow properties of the formulation, which
is important for the ease of administration and drug delivery.

 Tonicity adjusters: These agents help to adjust the osmotic pressure of the formulation, which is
important for minimizing discomfort at the injection site.

 Complexing agents: These agents form stable complexes with the active ingredient, improving
its solubility, stability, and bioavailability.

 Antimicrobial preservatives: These are specific types of preservatives that are used to prevent the
growth of microorganisms in the formulation.

 Antioxidants: These agents protect the active ingredient from oxidation, which can cause
degradation and loss of activity.

 Chelating agents: These agents bind to metal ions, preventing them from catalyzing the
degradation of the active ingredient.

 Suspending agents: These agents help to suspend insoluble particles in the formulation, improving
the uniformity and stability of the drug product.

 Surfactants: These agents reduce the surface tension between the formulation and the container,
improving the wetting and spreading properties of the drug product.

 Water for injection: This is a highly purified form of water that is used as a solvent or diluent in
parenteral formulations.

 Solvents: These are other types of solvents that can be used in parenteral formulations, such as
ethanol, propylene glycol, and glycerin. They can improve the solubility and bioavailability of
the active ingredient, but they must be chosen carefully to avoid toxicity or other adverse
effects.

Excipients used in parenteral formulations

Common parenteral excipients used in pharmaceuticals include:

1. Water for Injection (WFI): A purified form of water that is used as a solvent and diluent in parenteral
products. It is prepared by distillation or reverse osmosis and is free from pyrogens.

2. Sodium Chloride Injection: A sterile solution of sodium chloride in water for injection. It is used as a
tonicity adjuster and diluent for parenteral products.

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 3. Lactose: A disaccharide that is used as a bulking agent in freeze-dried parenteral products.

4. Mannitol: A sugar alcohol that is used as a bulking agent and tonicity adjuster in injectable products.
USP Monograph Mannitol.

5. Polysorbate 80: A nonionic surfactant that is used as an emulsifying agent and solubilizer
in parenteral products.

6. Propylene Glycol: A solvent that is used as a co-solvent and co-surfactant in parenteral products.

7. Benzyl Alcohol: A preservative that is used to prevent microbial growth in multi-dose vials of
parenteral products.

8. Citric Acid: An organic acid that is used as a pH adjuster in parenteral products.

9. Sodium Citrate: A sodium salt of citric acid that is used as a pH adjuster and anticoagulant
in parenteral products.

10. Glycine: An amino acid that is used as a buffer and stabilizer in parenteral products.

In addition to the above-mentioned excipients, there are several other excipients that are used in
parenteral products. These include preservatives, antioxidants, buffers, chelating agents, and viscosity
modifiers. It is important to select appropriate excipients based on the specific needs of the drug
product to ensure its safety, efficacy, and stability.

Excipients for parenteral Drug Delivery on pharmaexcipients.com in alphabetical order

Product Manufacturer

Ammonium sulfate EMPROVE® EXPERT ChP,NF,ACS Merck KGaA

Benzalkonium Chloride EMPROVE® EXPERT Ph Eur,NF Merck KGaA

Benzalkonium chloride solution EMPROVE® Expert, Ph. Eur., NF Merck KGaA

Benzyl alcohol EMPROVE® ESSENTIAL Ph Eur,BP,JP,NF Merck KGaA

Benzyl Alcohol EMPROVE® EXPERT Ph Eur,ChP,JP,NF Merck KGaA

Captisol Ligand

Cavitron Cyclodextrins Ashland

Cavitron W7 HP5 Pharma Ashland

Cavitron W7 HP7 Pharma Ashland

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Citric acid anhydrous powder EMPROVE® EXPERT Ph Eur,BP,JP,USP,ACS Merck KGaA

Citric acid monohydrate cryst. EMPROVE® EXPERT Ph Eur,BP,JP,USP,ACS Merck KGaA

Gangwal Healthcare Private

Complexol-HP®
Limited

D(-)-Mannitol EMPROVE® EXPERT Ph Eur,BP,USP,JP Merck KGaA

di-Potassium hydrogen phosphate anhydrous EMPROVE® EXPERT Ph Eur,BP,USP Merck KGaA

di-Sodium hydrogen phosphate dihydrate EMPROVE® EXPERT Ph Eur,BP,USP Merck KGaA

di-Sodium hydrogen phosphate heptahydrate EMPROVE® EXPERT DAC,USP Merck KGaA

Ethanolamine EMPROVE® EXPERT Ph Eur,BP,NF Merck KGaA

Glycerol 85% EMPROVE® Expert, Ph. Eur., BP Merck KGaA

Glycerol anhydrous (vegetable) EMPROVE® EXPERT Ph Eur,BP,JP,USP,ACS Merck KGaA

Glycine granulated EMPROVE EXPERT Merck KGaA

KLEPTOSE® HP ORAL GRADE Roquette

KLEPTOSE® HP Parenteral Grade Roquette

KLEPTOSE® HPB Oral Grade Roquette

KLEPTOSE® HPB Parenteral Grade Roquette

KLEPTOSE® HPB-LB Parenteral Grade Roquette

Kolliphor® ELP BASF

Kolliphor® HS 15 BASF

Kollisolv® PYR BASF

Labrafac Lipophile WL 1349 Gattefosse

Labrafac PG Gattefosse

Labrafil M 1944 CS Gattefosse

LYCADEX® PF Roquette

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Maltose PH Hayashibara

MIGLYOL® 812 N IOI Oleo

MONTANE 20 PHA PREMIUM SEPPIC

MONTANE 20 PPI SEPPIC

MONTANE 60 PHA PREMIUM SEPPIC

MONTANE 80 PHA PREMIUM SEPPIC

MONTANE 80 PPI SEPPIC

MONTANE 85 PPI SEPPIC

MONTANOX 20 PHA PREMIUM SEPPIC

MONTANOX 20 PPI SEPPIC

MONTANOX 60 PHA PREMIUM SEPPIC

MONTANOX 80 API SEPPIC

MONTANOX 80 LPI SEPPIC

MONTANOX 80 PHA PREMIUM SEPPIC

MONTANOX 80 PPI SEPPIC

MONTANOX 80 VG DF RPRD SEPPIC

NEOSORB® PF Roquette

Parteck® SI 400 LEX (Sorbitol) Merck KGaA

PEARLITOL® PF (Mannitol PFG) Roquette

Plasdone C-17 Ashland

Plasdone C-30 Ashland

Plasdone S-630 Ashland

Potassium chloride EMPROVE® EXPERT Ph Eur,BP,USP,JP Merck KGaA

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Potassium chloride granulated EMPROVE® EXPERT Ph Eur,BP,JP,USP Merck KGaA

Potassium dihydrogen phosphate cryst. EMPROVE® Expert Ph Eur,BP,JPC,NF Merck KGaA

REFINED OLIVE OIL IV ADM

REFINED SESAME OIL IV-1 ADM

REFINED SOYBEAN OIL IV ADM

Sodium acetate anhydrous EMPROVE® EXPERT USP Merck KGaA

Sodium acetate trihydrate EMPROVE® EXPERT Ph Eur,BP,JP,USP Merck KGaA

Sodium dihydrogen phosphate dihydrate EMPROVE® EXPERT Ph Eur,BP,USP,JPE Merck KGaA

Sodium dihydrogen phosphate monohydrate EMPROVE® EXPERT BP,USP Merck KGaA

SODIUM GLUCONATE PHARMA Roquette

Sucrose EMPROVE® EXPERT Ph Eur,ChP,JP,NF Merck KGaA

Super Refined™ Benzyl Alcohol Croda

SUPER REFINED™ CASTOR OIL Croda

Super Refined™ DEGEE Croda

SUPER REFINED™ OLEIC ACID Croda

Super Refined™ P35 Castor Oil Croda

SUPER REFINED™ PEANUT OIL Croda

SUPER REFINED™ PEG 400 Croda

SUPER REFINED™ POLYSORBATE 20 Croda

SUPER REFINED™ POLYSORBATE 80 Croda

Super Refined™ Polysorbate 80 POA Croda

SUPER REFINED™ SESAME OIL Croda

SUPER REFINED™ SOYBEAN OIL Croda

Transcutol HP Gattefosse

132
Transcutol V – veterinary Gattefosse

Trehalose dihydrate EMPROVE® EXPERT Ph Eur,NF,JP Merck KGaA

Trehalose SG Hayashibara

tri-Sodium citrate dihydrate cryst. EMPROVE® EXPERT Ph Eur,BP,JP,USP,ACS Merck KGaA

Triethanolamine (Trolamine) EMPROVE® EXPERT Ph Eur,NF Merck KGaA

Tris(Hydroxymethyl)aminomethane (Trometamol) high purity EMPROVE® EXPERT Ph

Merck KGaA
Eur,BP,ChP,JPC,USP,ACS

TWEEN 20 HP Croda

TWEEN 80 HP Croda

Parenteral Drug Delivery

Parenteral drug delivery refers to the administration of drugs via injection directly into the body,
bypassing the gastrointestinal tract. This method of drug delivery is typically used for drugs that cannot
be taken orally or when immediate and precise drug delivery is required.

The United States Pharmacopeia-National Formulary (USP-NF) defines parenteral drug products as
“pharmaceutical preparations that are intended for injection through the skin or other external
boundary tissue, rather than through the alimentary canal.” Similarly, the European Pharmacopoeia (EP)
defines parenteral products as “medicinal products intended for injection, infusion or implantation into
the body.”

There are several types of parenteral drug delivery methods, including:

1. Intravenous (IV) Injection: This involves injecting the drug directly into a vein, allowing for rapid
onset of action. IV injection is typically used for drugs that require immediate effects, such as
emergency medications or chemotherapy drugs.

2. Intramuscular (IM) Injection: This involves injecting the drug into a muscle, allowing for slower
absorption and longer-lasting effects. IM injection is commonly used for vaccines, antibiotics, and
hormone therapies.

3. Subcutaneous (SC) Injection: This involves injecting the drug into the fatty layer beneath the skin,
allowing for slower absorption and longer-lasting effects. SC injection is commonly used for insulin
and some vaccines.

133
4. Intradermal (ID) Injection: This involves injecting the drug into the skin, just below the surface,
allowing for slow absorption and localized effects. ID injection is commonly used for allergy testing
and some vaccines.

The FDA and EMA both require that parenteral drug products be safe, effective, and free from harmful
contaminants. To ensure the safety and efficacy of parenteral drug products, strict regulations and
guidelines have been established, including requirements for quality control, manufacturing practices,
and labeling.

There are advantages and disadvantages of parenteral drug delivery compared to oral dosage forms.

Advantages of parenteral drug delivery:

1. Faster onset of action: Parenteral administration allows drugs to be delivered directly into the
bloodstream, resulting in a rapid onset of action.

2. Higher bioavailability: Parenteral administration bypasses the first-pass metabolism in the liver,
which can result in higher bioavailability of the drug.

3. Precise dosing: Parenteral administration allows for precise dosing of drugs, which can be critical for
drugs with a narrow therapeutic index.

Disadvantages of parenteral drug delivery:

1. Increased risk of infection: Parenteral administration requires the use of needles and syringes, which
can increase the risk of infection if proper aseptic techniques are not followed.

2. Requires trained healthcare professionals: Parenteral administration requires trained healthcare

professionals for proper administration, which may not always be available.

3. Higher cost: Parenteral administration is typically more expensive than oral administration due
to the need for specialized equipment and healthcare professionals.

Parenteral drug delivery may be the preferred method of administration for drugs that cannot be
administered orally, such as drugs that are poorly absorbed or metabolized in the gastrointestinal tract
or drugs that are rapidly degraded by stomach acid. Parenteral administration may also be preferred for
drugs that require rapid onset of action or precise dosing.

Examples of drugs that are commonly administered via parenteral routes include vaccines, antibiotics,
insulin, chemotherapy drugs, and emergency medications such as epinephrine for anaphylaxis.
However, the choice of drug delivery method ultimately depends on the specific drug, its intended use,
and the patient’s individual needs and preferences.

134
Chapter 13: Lyophilization Process

Lyophilization, or freeze-drying, is a process in which water is removed from a product after it is frozen
and placed under a vacuum, allowing the ice to change directly from solid to vapor without passing
through a liquid phase. The process consists of three separate, unique, and interdependent processes:
freezing, primary drying (sublimation), and secondary drying (desorption). Products are manufactured in
the lyophilized form due to their instability when in solution and the impact of a solution on the
container closure system The quality of biopharmaceutical products like antibodies, vaccines, peptides,
enzymes, chemical API, and others remains unchanged once it undergoes freeze-drying, which enables
an increase in the shelf life of the product

The advantages of Lyophilization include:

 Ease of processing a liquid, which simplifies aseptic handling

 Enhanced stability of a dry powder
 Removal of water without excessive heating of the product
 Enhanced product stability in a dry state
 Rapid and easy dissolution of reconstituted product
 Disadvantages of lyophilization include:
 Increased handling and processing time
 Need for sterile diluent upon reconstitution
 Cost and complexity of equipment

The lyophilization process generally includes the following steps:

 Dissolving the drug and excipients in a suitable solvent, generally water for injection (WFI).
 Sterilizing the bulk solution by passing it through a 0.22 micron bacteria-retentive filter.
 Filling into individual sterile containers and partially stoppering the containers under aseptic
conditions.
 Transporting the partially stoppered containers to the lyophilizer and loading into the chamber
under aseptic conditions.
 Freezing the solution by placing the partially stoppered containers on cooled shelves in a freeze-
drying chamber or pre-freezing in another chamber.
 Applying a vacuum to the chamber and heating the shelves in order to evaporate the water from
the frozen state.
 Complete stoppering of the vials usually by hydraulic or screw rod stoppering mechanisms
installed in the lyophilizer.

135
Drug Product Manufacturing Process: Generally involves the following stages
Compounding Procedure: Preparation of Excipient Solution
Slurry Preparation: Slurry addition to the Compounding Tank
Bulk Solution Filtration: Online Filtration/Aseptic Filling and Half Stoppering
Lyophilization and Full Stoppering
Before Lyophilization, VHP sanitization of Mobile Trolley Isolator and Lyophilizes Interface Isolator is
performed and the leak test is done. The half stoppered vials are loaded onto the Lyophilizes Interface
Isolator from Mobile Trolley Isolator and then loaded into the Lyophilizes.

Lyophilization Cycle

• Freezing – Filled vials are loaded at 5°C (shelf temperature) and the product freeze by reducing
the shelf temperature to -45°C (at 0.2°C/min). Then hold at -45 °C for a duration of not less than
240 minutes.
• Annealing - After freezing, the product is subjected to heat annealing by increasing the shelf
temperature to -15 °C (at 0.5°C/min). Then hold at -15°C for a duration of not less than 240
minutes.
• Refreezing - Refreeze the product by reducing the shelf temperature to -45 °C (at 0.5°C/min).
Hold at -45 °C for a duration of not less than 360 minutes.
• Cool the condenser and evacuate the chamber to not more than 100 mTorr throughout
primary drying by pyranic gauge.
• Primary Drying – Sublime the ice by adjusting the shelf temperature to -10°C (at 0.2°C/min)
while maintaining chamber pressure at 100 mTorr. for a duration not less than 2520 min.
• Secondary Drying – Desorb bound water by increasing the shelf temperature to final
secondary drying temperature of 35°C (at 0.2°C/min), with an intermittent ramp at 0°C. Hold at
35°C for not less than 600 minutes.
• Stoppering – At the completion of drying, aerate the chamber with sterile filtered nitrogen, until
a pressure of 650 ± 50 Torr, and fully insert the stoppers into the vials by collapsing the shelves.
• Unload the stoppered vials and move the vials to the capping area.

Lyophilized Vials Unloading, Sealing, External Vial Washing and Coding

After completion of Lyophilization, fully stoppered vials are unloaded from the shelves of lyophilizer to
the Mobile Trolley Isolator and transferred to the Filling and Sealing machine Isolator for sealing activity.
Generally, sealing is performed at 30 vials per minute speed or as per validated optimized speed
(vials/min). Leak test is performed for the initial 5 sealed vials from each sealing head to ensure proper
sealing and noted in the batch record. External vial washing was performed in Room IP-046. Sealed vials
are externally washed with purified water and dried.

136
Visual Inspection

Vials are transferred to visual room for inspection. During visual inspection, vials are checked by tray
wise for sealing, cracks in vials, melt back, cake height, black particle, glass particle, slanted cake and
observations are recorded in the batch record. After inspection of each tray, the inspected vials are
immediately loaded at 2-8°C condition.

Labeling and Secondary Packaging

Vials are sent for labeling and for secondary packaging. The vial, carton and shipper labels approved by
QA are only used in the labeling operation. Generally, each labeled vial is placed in a single carton, a
dozen (12) single cartons are then placed in one multi-carton and 3 multi-cartons are placed in a
corrugated box for shipment.

Parenteral Container Packaging Systems: Choosing the correct container is crucial for the stability of
the drug and the safety of the patient. Types of container systems include: RTS (Ready to Sterilize) and
RTU (Ready to Use), also known as pre-sterilized. Some examples of vials, prefilled syringes, and
cartridges used during the aseptic manufacturing process include: Glass Borosilicate Glass for its
excellent barrier properties, chemical resistance, regulatory acceptance, and a broad range of
applications served.
Polymeric materials such as cyclic olefin copolymer (COC). This combines glass and COC for greater
formability, break resistance, lightweight, glass-like transparency, strong barrier, and chemical
compatibility. These systems are ideal for high-value, complex molecules. - Crystal Zenith® CZ system.

FDA Manufacturing Guidelines:

• GLP/GMP compliance means having a validated designing, manufacturing, and testing facility for
pharmaceutical and biopharmaceutical products. These guidelines contain the validation of the
lyophilization process and equipment. As per these guidelines, the lyophilization equipment requires
Performance Qualification.

• FDA governs all inspection guidelines for the lyophilization of drug products. The Lyophilization of
Parenterals (7/93) is the guide for the lyophilization of parenterals. This references material for
investigators and other FDA personnel.

• The Center for Biologics Evaluation and Research (CBER) of the FDA regulates freezedried biological
products in its section pertaining to residual moisture, as published in Title 21 of the Code of Federal
Regulations for Food and Drugs. FDA Regulatory Considerations for Pharmaceutical Lyophilization • Hold
Time and Equipment Compatibility

• Fill Volume/Fill Volume Tolerances

• Product-specific Characterization/Development Studies
• Establishing the Critical Process Parameters
• Establishing the End Points for Primary and Secondary Drying
• Sampling Plan • Critical Quality Attributes
• Scale-up
137
• Post-Approval Lifecycle Perspective

138
Chapter 14: Typical Pilot-scale Lab Apparatus & Equipment

No. Name of the Machine/Equipment/Apparatus Suggested Make & Model

1 Balance, 1 to 100 gm

2 Balance, 0.1 to 2 kg

3 Balance, 0.1 to 2 kg

4 Balance, 1 to 10 kg

5. Pharmaceutical Powder Control by Anton Paar (Pharmaceutical Powder Characterization )

6 Multi-Shell 'V' Blender: 0.5 qt, 1qt, 2 qt., 4qt, 8qt, and 16 qt, from Globe Pharma, NJ or P.K.
Blend Master.

7 Fitz Mill with all size screens Model L1A type

8 Multi-Bowl high shear granulator, 0.5 kg to 5 kg Diosna PL6 Type

9 Table top Tablet compression machine; 10 stations Piccola Rotary Tablet Press, 10 stations
2-in1 (B & D) turret with or without instrumentation

10. Perforated coating pan – High-Coater: Multiple pan; 0.5 kg to 5 kg LDCS type

11 Fluid Bed Multi- Processor; spray granulation, spray coating as well as drier Glatt Fluid Bed Dryer
GPCG-1 & GPCG-3 with Wuster Column

12 Multi-Sieve or Russell sieve, with all typical screens

13 Tray Oven (R&D size) Memmert UFP 500 Drying Oven

14 Bench Top Semi-automatic Capsule Filling Machine

15 Capsugel Encapsulating Machine for Liquid Filling in HGC and sealing bending machine.

16. HDPE Bottle Induction Sealer: Automate Technologies Induction Sealer

17. Bench Top Blister Packaging Machine Dott Bonapace type

18. Utensils Different sizes S.S Mixing pots, Scoop, Spatula,

19. Bottle Cap Torque Tester

20. Lab. Mixer (Electric and/or Pneumatic) Lightnin type bench top stirrers

21. Peristaltic Pump Small Capacity: 1g – 500g/min

22. Pressure Pots 0.5 L, 1L, & 5 L

139
In-Process Testing Equipment & Apparatus

1 Powder density apparatus

2 Sonic sifter with all typical screens, #20, 40,60,80,100,140,200,325,400 & Pan Sieve Shaker
3”Model

3 Loss on drying Computrac or similar type

4 Powder Flow Meter

5 pH Meter

6 Infrared IR Gun

7 Tablet Friabilator

8 Tablet Hardness tester Dr. Schleuniger Model 6D or Similar

9 Tablet Thickness measurement Micrometer or Slide Caliper

10 Tablet disintegration tester Hankel or Ewereka 6 stations

11 3M dissolution/disintegration Apparatus; Hankel 2 baths

Miscellaneous requirements.

1 Portable Temp/RH Recorders

2 Torrit Dust Collectors

3 Self-contained HEPA filter Canopy (Portable)

4 Vacuum (dry & wet)

5 Peristaltic Pumps

6 Stereo Microscope

7 Benches SS Portable

8 RM Storage Racks/Shelving (Heavy Duty)

9 Stop Watches

10 Tablet Press Tooling (Generic)

11 Capsule Tooling

12 Tablet/Capsule Deduster

140
I. Pre-Formulation Study (Solids) & In-Process Testing

1. Weighing scale: Various ( mg - g capacity) ; ( g - kg capacity); weighing papers, boats etc.

2. Tablet Hardness tester

3. Tablet Friabilator

4. Tablet Disintegration Testing Apparatus

5. Sieve Shaker with 3" size screen of following mesh sizes; (20, 40, 60, 80, 100, 140, 200, 325,
400, & Pan)

6. Bulk and tap Density tester

7. Carver Press with tooling

8. pH Meter tester

9. Powder Flow Meter

10. Table top Temperature/Humidity Chamber for 40degC/75% RH for Accelerated

Stability; 50degC/75% RH for Stress Stability

11. Glass Desiccators with temperature monitor and Petri Dishes for moisture sorption study of
API, formulation cock tail mixture etc.

12. Bench top Magnifying Glass with light

13. Glass and Stainless Steel Utensils (Cylinder, Beaker, Mixing Pots, Scoop, Spatula etc.)

14. Infrared Gun for temperature measurement

15. IR Tachometer for rpm measurement

16. Slide Calipers

II. For Solid Dosage (Tablet, Capsule, Powder)

1. Mixers (Blender type) (2qt - 16qt)

2. Bench Top Lab Mixer and Homogenizer (Electric or Pneumatic)

3. High Shear Mixer-Granulator ( 2 - 10 L)

4. Peristaltic Pump or Pressurized Pot

5. Table Top Drying Oven (10 - 15 trays)

6. Fluid Bed Dryer: GPCG 1 - 5 with Wurster Column

141
7. Rotary Tablet Press: at least 8 to 16 stations with pre-compression and preferably instrumented.

8. Bench Top Semi-Automatic capsule Filling Machine with change parts to handle at least sizes: 0,
1, 2, 3, & 4

9. R&D Small scale (9") Coating Machine Vector: Laboratory Development Coating System (LDCS)
with 1 spray gun

10. Bench Top HDPE bottle induction sealing machine

11. Bottle Cap Torque measuring apparatus

12. Bench Top Blister Packaging Machine

III. For Liquid and Semi-Solid (Oral Liquid, Suspension, Emulsion, Ointment, Cream & Jelly)

1. Jacketed Mixers (Electric or Steam) 2 - 10 L)

2. Bench Top Lab Mixer and Homogenizer (Electric or Pneumatic)

3. Colloid Mill (Silverson, Fryma, Ross etc.)

4. Triple Roll Ointment Mill

5. Color Matching Apparatus

6. Bench Top Semi-Automatic Cream/Ointment Collapsible Tube Filling Machine

7. Brookfield Viscometer

8. Specific Gravity Measuring bottles and jars

9. Bench Top HDPE bottle induction sealing machine

10. Bottle Cap Torque measuring apparatus

142
Chapter 15: Role of Scale-up Strategy in Product Development
[Solid Dosage]

Scale-up factors for Diffusion Mixers

Patterson & Kelley Blender

Unit Size Cubic Feet Blend Time Factor*

1 1.2
2 1.3

3 1.43

5 1.50

10 1.70

20 1.85

30 2.00

40 2.10

50 2.20

60 2.30

75 2.50

100 2.70
• Scale Up Factor for Standard Tumble Blenders
• (Provided by Patterson & Kelley)

Scale-up for P.K blenders is accomplished by applying the scale-up factors from the previous
table, to the formula below:

Blending Time (Blender 2) = Factor (Blender 2) ÷ Factor (Blender1) x Blending Time (Blender 1)

143
Example: Scale up from a 5ft3 blender with 5 minutes blending time to a 30ft3 blender, the
blending time will be: (2 ÷ 1.5) x 5 = 6.66 minutes ~ 7 minutes

For P.K. blenders a consistent blend can be expected in a range from +5% to 30% of the rated
volume, although this will vary by product.

Gemco Blender:

Another simple “rule of thumb” for diffusion type blenders is to count vessel revolutions

 Example: Using a 1 cft blender, with a vessel RPM of 23. If the blend is accomplished in 10
minutes the vessel will complete 230 revolutions.
 Moving to a larger blender the same number (230) revolutions will be required.
 A 40 cft blender turning at 12 RPM will need (230÷12) = 19.5 minutes to blend. The blend
time will increase due to the fact that the larger the blender, the slower the vessel rotation.

So, for scale-up, matching of rpm or time of the two blenders will be incorrect.

For Gemco Blender: SC: 33 -100% and DC: 50-100% capacity

High-Shear Mixer Granulator

 Rotational speeds (RPM) in combination with vessel/impeller diameter give almost the same
circumferential speed (Tip Speed).
 For scale-up, it is very important to have same or almost same Tip speed. (meter/second) of
the mixer/impeller between the equipment.

Scale-up Parameters: For scale-up in a high-shear mixer it is important to check the

same tip speed of the impeller between the equipment.

144
Collette Gral 10 25 75 150 300 400 600 1200
Working 7 17 50 100 200 267 400 800
Capacity (L)

Impeller radius (cm) 11.9 18 25.4 33.5 40.0 46.0 52.5 72.5

Impeller Speed (rpm) 420/ 285/ 200/ 145/ 125/ 105/ 95/135 75/115
Low/High 630 425 305 225 185 155

Impeller Tip 5.5/ 5.4/ 5.5/ 5.4/ 5.4/ 5.06/ 5.4/ 5.8/
speed(m/sec) 8.4 8.2 8.4 8.2 8.2 7.47 8.0 8.9

Chopper Speed Speed I : 1500 1300/ 1200/

rpm Speed II: 2600 2400
3000 rpm

T.K. Fielder 10 25 65 150 300 400 600 1200

Working Volume (L) 2, 4.5 15 40 100 240 320 480 900

&6

Impeller Speed (rpm) 334/ 261/ 209/ 130/ 108/ 98/ 86/172 68/136
Low/High 668 522 418 260 216 196

Impeller Tip 5.2/ 5.6/ 5.5/ 5.0/ 5.3/ 5.3/ 5.3/ 5.3/
speed(m/sec) 10.4 11.2 11.0 10.0 10.6 10.6 10.6 10.6

Chopper Speed Speed I : 1800 rpm

Speed II: 3600 rpm

Diosna 10 25 50 100 250 400 600 1250

Working Volume (Kg) 3-5 8-12 15-25 35-50 80-100 180-220 280-350 560-710

Impeller Speed (rpm) 215/ 162/ 133/ 98/ 88/ 64/ 57/ 55/
Low/High 433 325 265 196 176 129 114 75

Impeller Tip Not Available

speed(m/sec) Note: Impeller Speed is slower going from small to large Equipment. This is to
keep same tip speed.

145
Scale Up Factors in Fluid Bed Processing (Granulation and Drying)

Granulating

1. A. Critical Parameters

▪ Air flow - ft.3 /min

▪ Air velocity ft. /min

▪ Air temperature degrees F or C

▪ Total amount of liquid - kgs

▪ Spray rate - g/min

▪ Atomizing pressure - psi

▪ Fluidized bed depth - inches/mm

▪ Nozzle height above bed

146
2. B. Theoretical Scale Up

▪ Use same inlet temperature

▪ Use same velocity - velocity calculation Air flow ft.3 /min Ft.2 of distributor plate = ft./min
▪ Calculate total amount of liquid per kg of product processed and maintain
▪ Calculate spray rate per CFM and maintain
▪ Maintain same liquid droplet size by adjusting air pressure as required
▪ Maintain same bed height ▪ Maintain nozzle height above bed

3. C. Practical Tips

▪ visually achieve same fluidization level

▪ Note that deeper bed will result in denser granule

▪ In small R&D machines (up to 20 liters) the nozzle may be closer to the bed. The lower liquid
addition rate and smaller nozzle will produce a smaller droplet size to compensate. The nozzle height
may need to be adjusted upwards when scaling up from small R&D to larger systems.

Tablet Press Scale-up: To have same dwell time between the Tablet Press

Calculation of Dwell Time for Scale-up

DT = Dwell Time
Time = Distance = Punch Head flat diameter TPM = tablet per minute
Velocity
PCD = Turret Pitch Circular Diameter
Π = 3.14159 Number of Stations = # of stations in the turret
Velocity = TPM x Π X PCD = TPM x 3.14159 x 228.6 = 0.748 TPM
(mm/sec) (#Stations) x 60 16 x 60
Dwell Time = Head flat dia = m ÷ m/sec = sec
Velocity

Example: BETAPRESS 16 PCD = 228.6mm

Head Flat Dia for a B tooling = 12.7 mm; Head Flat Dia for a D tooling = 18.2 mm
DT = 12.7mm = 16.978 = 17
0.748 TPM
For Press Speed of 1400 TPM: DT = 17÷1400 = 0.73 seconds

Scale-up Pan Coating

RPM for Larger Pan = (Pan rpm small) x [ (diameter of small pan) ÷ (diameter of large pan) ]

Thermodynamic Analysis of Aqueous Coating (used for scale-up)

147
Chapter 16: Practical Example of Product Development (Case History)

An interesting story that the firm only knows half of how to do the Scale-up (to maintain total
revolution), but does not understand the why and how to get there.

Background
Question and seeking Scientific Opinion Request

Hi Masih,

I know you are the expert on this topic. Could you help evaluate if the following scale up strategy
proposed by a generic firm is scientifically sound?

The formulation: Drug load 3%, spray dried lactose monohydrate 69%, Avicel 102, 20%, and other
commonly used tablets excipients such as disintegrant, glidant and lubricant. A blending –direct
compression process is used. Let’s assume it is a free-flowing formulation.

The exhibit batch size is 25 kg and a 100L bin blender was used (rotation speed 5 rpm, blending time 30
min). For the intended commercial scale: 150 kg (6x as exhibit scale) using 600L bin blender (i.e. loading
level is the same).

The firm’s proposal is to keep the rotation speed and time the same (5 rpm and 30 min) and therefore to
maintain the total number of revolutions for scale up. Keeping the total revolution the same is the
commonly used scale up rule for blending. However, to use this rule, my understanding is that the
rotation speed should be engineeringly scaled down due to the linear dimension increase.

Any thoughts on the firm's scale up strategy?

Thank you very much for your help in advance.

Best regards,

Daniel

Reply/Answer/ Scientific Resolution

Hi Daniel,

Please find attached my calculation for what should be the comparative scale-up between 100 L and 600
L Blender.

Generally, for any equipment as the size goes up (be it a blender) the shaft speed will go down. As per
my calculation it should be of 4.3 rpm and 35 minutes of blending to achieve the same 150 revolutions.

For detail please see below the attachment.

148
Subject/Issue ANDA Batch Proposed Production Batch
Formula Composition: Drug Load: 3% Same
Lactose Monohydrate: 69%
Avicel PH 102 20%

Method of Manufacture Dry Blend, Direct Compression Same

Batch Size 25 kg 150 kg
Scale-up factor 150/25 = 6 6x
Blender 100L 600 L
Blender Speed 5 rpm 5 rpm
Blending Time 30 minute 30 minutes
Number of revolutions Calculated Revolutions: Calculated Revolutions:
5 x 30 = 150 revolutions 5 x 30 = 150 revolutions

Though from the above table it looks OK, but following is my deduction for what should be the
actual scale-up.

28.5 L = 1 cu.ft Therefore, 100 L ≡ 100 ÷ 28.5 = ~ 3.51 cu.ft

600 L = 3.51 x 6 = 21.05cu.ft

I am comparing this with scale-up factors given by P.K V-Blender

Using their scale-up chart the Blend Time Factor:

 3 cu.ft Blender is: 1.43

 20 cu.ft Blender is : 1.85

Therefore, for a 3.51 we can calculate the approximate blend time factor would be:
3.51 ÷ 3.0 = 1.17
So, it blend time factor would be 1.43 x 1.17 = 1.67
Similarly the blend time factor for a 20 cu.ft P.K. V-Blender is: 1.85
Therefore, for a 21.05 it can be calculated as follows:

21.05 ÷ 20 = 1.053; 1.85 x 1.053 = 1.948 or ~ 1.95

Hence, calculated scale-up between 100L and 600L blender is

1.95 ÷ 1.67 = 1.16766 or = ~ 1.168

Hence time of blending in the 600 L Blender should be,

30 minutes x 1.168 = 35.04 minutes, or ~ 35 minutes.

To achieve the same revolutions, i.e. 150

The speed (RPM) of the 600 L blender should be = 150 ÷ 35 ~ 4.286 rpm or 4.3 rpm

149
Response to scientific opinion:

Masih,

You are the Master for this!! I totally agree with your detail calculation. So, we are on the same page.

This is somehow an interesting story that the firm only knows half of the story (to maintain total
revolution), but does not understand the why and how to get there.

Thank you very much for the timely help.

Daniel

Chapter 16: Practical Example of Product Development (Case History)

Product Development Practical Examples:

Critical aspects of Product Development (Solid Dosage) by D.C method of manufacture;
Choice and role of Excipient

A drug product as a dosage form would contain both drug substance (Active Pharmaceutical
Ingredient) and excipients added to aid the formulation and manufacture of the dosage form
for administration to patients. In fact, the properties of the final dosage form (i.e. its
bioavailability and stability) are, in major case highly dependent on the excipient used, their
concentration and interaction with both the API and each other. Hence, excipients should not
be considered as inert or inactive ingredients. It is therefore, needed to know and understand
not only their Physico-chemical properties but also the role play chosen (novel forms of
delivery) for the formulation.

3. Drug substance
 Physico-chemical evaluation for:
 Physico-Chemical testing by R&D  Moisture sorption/desorption
Pharmaceutics Laboratory  Followability, Particle size, B/T Density
and Compact-ability study
 Drug-Excipient Compatibility study
API solid–form screening and characterization is a crucial part of drug substance development
and pre–formulation. Knowledge of the underlying fundamentals of polymorphism,
hydrates/solvates, salts, and co-crystals is essential to establish an understanding of a drug
substance and its solid–form throughout the drug development lifecycle.

Critical factors considered for the Formula and Process design for solid dosage

Drug load and API Physico-chemical characteristics/attributes evaluated by the R&D

Pharmaceutics.
150
 I. Low drug load < 5.0% in the product formula for a D.C. method of manufacture

In such case it is very important to evaluate the APIs cohesiveness and/or binding property.
Depending on this characteristic the formulator has to Selective mixing of the low drug load
<5% API with a carrier with irregular surface area (e.g. Anhydrous Lactose, Mannitol etc.). Thus
the career excipient due to its rugged irregular surface attaches the low amount drug substance
forming an API-carrier mixture concentrate for ultimate BU and CU of the drug product.

Thus, a pre-mixing step is introduced with mostly 1:1 or a maximum 1:10x API: drug carrier to
achieve binding and ultimate blend uniformity and final product content uniformity. However,
one should not make a bulk of this pre-mixture then its flow will be a problem.

In the next step a flow property enhancer; either Lactose Monohydrate or combination with
Microcrystalline Cellulose (Avicel) of right grade depending on the pre-formulation study of the
API is ad-mixed by ordered mixing operation with other functional excipients, disintegrant and
lubricant. This will provide not only the flow property but also maintain the blend uniformity.

II. Moderate drug load > 5.0% --- 50% of low compaction property

In such case either a pre-mix with a binder and/or cohesive property excipient either pre-
mixed, dry granulated under high pressure without the use of a liquid using one of the
following processes. Generally conducted by: Making large size tablet (Slug) in a tablet
press/slugging or passing the powder material between two counter rotating rollers producing
sheet or ribbon by a roller compactor/Chilsonator. Then the intermediate products are broken
using a suitable milling technique to produce granular material, which is usually sieved to
separate the desired size granules. The unused fine material may be reworked to avoid waste.

In the next step a flow property enhancer; either Lactose Monohydrate or combination with
Microcrystalline Cellulose (Avicel) of right grade depending on the pre-formulation study of the
API is ad-mixed by ordered mixing operation with other functional excipients, disintegrant and
lubricant. This will provide not only the flow property but also maintain the blend uniformity.

III. High drug load > 50% with not only very low compaction property but also
efflorescence property

In such case, a selective mixing of high drug load >50% API of non-cohesive property with a
cohesive ingredient is done to induce compaction for a Direct Compression (D.C) Process,
mostly by two processes; a) Moisture Activated Dry Granulation (MAD-Granulation): This
process involves moisturizing the powder blend to a pre-determined LOD to achieve
compaction for a direct compression (D.C) method of manufacture. b) Hot-Melt
Granulation: In these process molten materials is used as the granulating liquid.

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 API is either co-melted or dispersed in the molten stage of the vehicle and then cooling it to
solidification. This process is used mainly for the following purpose.

• For poorly soluble API for enhancing solubility and dissolution

• To protect moisture sensitive API
• To achieve sustained or extended release
• API or formulation ingredients are moisture sensitive
• Unable to withstand elevated drying temperature
• Formulation ingredients has sufficient inherent binding cohesive properties
• To improve flow property and die filling.

An Example of Product Development Employing Moisture Activated Dry-Granulation

Drug Substance: Metformin HCl

Drug Load: ~ 94%

Evaluated Pre-formulation Physio-chemical Properties:

 Metformin HCl drug substance by itself is a white, clumpy powder, with no flow-ability and/or
compactibility characteristics. (for all vendors)
 Pre-milled API from the supplier had comparatively a better flow-ability. It is was found critical to
use milled metformin HCl with the particle size, particle size distribution and the bulk density that
was found with the latest material from the supplier FarmHispania. “Milled” metformin HCl
supplied by FarmHispania had the following particle size, particle size distribution and bulk density.
 50.2 % ≤ 180 um
 32% ≤150 um
 2.8% ≤75 um
 Bulk density of 0.36/mL.
 Use of the milled material achieved process ease tablet formula for the drug product.
 Blending with 1% colloidal silicon dioxide has radically improved the flow property; however it did
not improve its compactibility characteristics significantly.
 Microcrystalline Cellulose, Avicel PH 112 of a nominal mean particle size of 100µm and moisture
content ≤ 1.5% was used for the MAD process to ultimate moistened it to ≤ 5.0%; which is same as
the Avicel PH 102. Hence, there was about (5.0 – 1.5) 3.5% moisture (water) available for the
moisture activated dry granulation.
 A few experiments were made using a small scale PMA-I high-shear mixer using formulation with
drug and excipient except lubricant and spraying water to obtain a dry granulation with moisture
content of approximately 2-4%. This granulation without further processing (i.e. drying & milling
etc.) was blended with a lubricant and then compressed into tablets.
 Incorporating a liquid type of humectant (polyethylene glycol 400 or Glycerol) in the formula
would also help to keep the required moisture for efflorescence type of API, e.g. Escitalopram.

Since metformin HCl being almost 94% in the formula and does not have any compactibility, this is also
attributed to its very low moisture content. Therefore, a moisture activated drygranulation method was

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employed to make some tablets. Following was the method and adjuvant that were tried for the
approach.

Method: Moisture Activated Drygranulation/Direct Compression

Binder: Hydroxypropylcellulose, povidone and methylcellulose

Dissolution aid: Sodium starch glycolate
Lubricant: Magnesium stearate or Stearic acid
Bulking Agents: Microcrystalline cellulose, Avicel PH 112 finally converting it into
PH102 by MAD process.
Tablet Coating agents: Hydroxypropyl methylcellulose
Polyethylene glycol
Water
Physio-chemical characterization at Product Development Stage; specifically for solid dosage drug
products.
API solid–form screening and characterization is a crucial part of drug product development and pre–
formulation. Knowledge of the underlying fundamentals of polymorphism, hydrates/solvates, salts, and
co-crystals is essential to establish an understanding of a drug substance and its solid–form throughout
the drug development lifecycle. These are as follows:

Moisture sorption/desorption
Followability
Particle size & Particle size Distribution
Bulk and Tap Density
Compact-ability study
Drug-Excipient Compatibility study

The challenges faced for API with very low and high bulk densities for formulation of tablets by direct
compression method of manufacture.

Case History 1. Ranitidine HCl: The API had Low bulk density: 0.22g/mL

The API related problem and their resolution

It was found that the API ranitidine HCl by itself is compactible and it is possible to make a direct
compression formula. It is also sticky in nature but had a low bulk density of ≤ 0.22g/mL. Because of the
relatively high dose of the API and its low flow-ability it is likely to cause some significant problems for a
direct compression formula. However, introducing a pre-mix step for the API with 1% Colloidal Silicon
Dioxide and screening through a 14 mesh changed the angle of repose from 42° to about 27 ° improved
its flow property and ultimate tablet machine die filling to get the right weight and final content
uniformity.

Case History 2. Galantamine HBr: API of high density (~0.6g/mL).

Segregation Characteristics of Galantamine HBr and resultant dry blend for direct compression had
blend uniformity problem resulting in tablet’s Content Uniformity problem.

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 Selectively mixing Galantamine HBr with a right proportion of Microcrystalline Cellulose, (Avicel PH
301) with a bulk density of about 0.45g/mL and colloidal silicon silicone dioxide.
 Avicel PH 301 grade of microcrystalline cellulose in the formula provided/mitigated for BU &CU.

Hence, the Physio-Chemical Evaluation & testing of Drug Substance by R&D Pharmaceutics Laboratory
was found for these two projects.

Modified Release Technology (Solid Dosage)

Modified-release dosage is a mechanism that (in contrast to immediate-release dosage) delivers for a
prolonged period of time (extended-release [ER, XR, XL] dosage) or to a specific target in the body
(targeted-release dosage) or a drug with a delay after its administration (delayed-release dosage).

Sustained-release dosage forms are dosage forms designed to release (liberate) a drug at a
predetermined rate in order to maintain a constant drug concentration for a specific period of time
with minimum side effects. This can be achieved through a variety of formulations, including liposomes
and drug-polymer conjugates (an example being hydrogels). Sustained release's definition is more akin
to a "controlled release" rather than "sustained".
Extended-release dosage consists of either sustained-release (SR) or controlled-release (CR) dosage. SR
maintains drug release over a sustained period but not at a constant rate. CR maintains drug release
over a sustained period at a nearly constant rate.[1]
Sometimes these and other terms are treated as synonyms, but the United States Food and Drug
Administration has in fact defined most of these as different concepts.[1] Sometimes the term "depot
tablet" is used by non-native speakers, but this is not found in any English dictionaries and is a literal
translation of the term used in Swedish and some other languages.
Modified-release dosage and its variants are mechanisms used in tablets (pills)
and capsules to dissolve a drug over time in order to be released slower and steadier into the
bloodstream while having the advantage of being taken at less frequent intervals than immediate-
release (IR) formulations of the same drug. For example, extended-release morphine enables people
with chronic pain to only take one or two tablets per day.
Most commonly it refers to time dependent release in oral dose formulations. Timed release has several
distinct variants such as sustained release where prolonged release is intended, pulse release, delayed
release (e.g. to target different regions of the GI tract) etc. A distinction of controlled release is that not
only it prolongs action but it attempts to maintain drug levels within the therapeutic window to avoid
potentially hazardous peaks in drug concentration following ingestion or injection and to maximize
therapeutic efficiency
Functional Excipient Used for Modified Release Tablets/Capsules

 Modified Release group is divided into two major classes: Extended Release & Delayed Release
 Excipients for Extended Release group can be classified into two major group
 1) hydrophilic and 2)hydrophobic
 Hydrophilic Materials: Cellulosic Polymers, Gums, PVP, PEG, etc.
 Hydrophobic Materials: Ethyl Cellulose, Wax. Eudragit (RL/RS) etc.
 These polymers are generally pH-independent

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Delayed Release Excipient: This is usually desired to bypass the stomach and or release of the drug to a
specific site e.g. Colon

 Polymers generally used are mostly pH dependent

 Various Methacrylic Acid polymers called “Eudragit” are used. They can be An-ionic, Cationic or
Neutral. e.g. Eudragit L30D-55 is soluble ≥ pH 5.5 suitable for intestinal delivery
 Eudragit FS30D is soluble above pH 7, hence unique for colonic delivery
 Also Polyvinyl Acetate Phthalates & Succinates.

Various Systems Used for Modified Release Technologies:

Matrix System: In this system the medium or the substrate is either a dry mix or wet granulated
substrate is made with the API and the polymer or combination of different type or grade of polymer to
get the desired rate of release with or without other tablet compression or encapsulation aids. [Flow-
enhancer (SiO2 and lubricant (MgS)]. There could be in either hydrophilic or hydrophobic matrix
formulation systems.
For the generic product development it is very important to conduct the Physio-chemical properties are
conducted to study stability and erosion property of the blend and tablets of the brand and generic
formulated subject product. For in specific cases even the pH has to be evaluated at these stages.

Major hydrophilic polymers have the property of swelling in water and forming a gelatinous like
substance and provide sustained drug release by both diffusion out of the gel and erosion of the tablet.

A case study history using acidified hydrophilic system: For the generic drug product it was needed to
maintain a specific acidic pH for the granulated substrate and the final tablet for its final stability.

This was made with an acidified granulating liquid with the following variables

The tablets formulated with the high molecular weight hydroxypropyl cellulose (HPC-HXF), and
combination of talc, magnesium stearates as lubricant, maintained the required pH and got the required
gel forming and erosion characteristics for the tablets sustained release characteristics. Their initial
dissolution results confirmed the affirmative effect of the polymer HPC-HXF in the hydrophilic-matrix
formulation. However, these tablets in their stress and accelerated stability condition observed dose
dumping, but there was no degradation of the product.

Thus, this dissolution failure at stability study needed further evaluation. Therefore, studies were
required on the product formulation in conjunction with the use of HPC as the matrix polymer. Aqualon
the manufacturer of the polymer hydroxypropyl cellulose was contacted. Aqualon and the Generic’s
R&D conducted series of physio-chemical testing to investigate and find the root cause of dissolution
failure and/or physical popping of the tablets in the dissolution apparatus.

Acid catalyzed hydrolysis is a mechanism that can occur with all cellulose ethers. Celluloses are
sufficiently stable towards hydrolysis for most uses including film coating and wet granulation followed
by oven drying at moderate temperature conditions e.g. 50-70 deg C. However, they can be susceptible

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to hydrolysis by acids and, to a lesser extent, by alkalis. Acids attack the acetyl linkages, cleaving the 1-4-
glycosidic bonds. The hydrolysis mechanism is catalyzed by the presence of water and the rate is
increased by increasing temperature. The result of hydrolysis is chain cleavage, which translates to a
polymer with reduced molecular weight and reduced viscosity. Thus, there is a very fast in-vitro drug
release.

There are a number of variables, which influence cellulosic hydrolysis:

1) Water - Water is needed to catalyze the reaction without the presence of water the hydrolysis
reaction cannot start. Increased moisture and humidity levels will increase the rate at which hydrolysis
proceeds.

2) Temperature - It is possible that in the presence of dilute acid that at low temperatures (such as
room temperature) one will not observe the hydrolysis mechanism either because it is not
thermodynamically favorable or it is kinetics very slow. As one goes to higher temperature the rate of
hydrolysis increases. This would mean that it is possible not to see a loss of polymer chain length at low
temperature but only at higher temperatures. Temperature is secondary as a direct variable. The
degradation kinetics is temperature dependent, but since everything is done at a defined relative
humidity, the focus should be on the temperature dependence of the water load in the system, which
just provides a greater reservoir of moisture to the system.

3) Time - If the hydrolysis reaction is thermodynamically possible then the time at which the polymer is
subjected to the increased temperature conditions is a variable. The longer the polymer is exposed to
the increased temperature conditions is the presence of the dilute acid and water at a high temperature
the faster the hydrolysis rate.

New formulation Approach due to the problem encountered with the initial formulation in which there
was a dose dumping phenomenon, which had HPC of 5% intra-granular and 5% extra granular.
Therefore, this 5% intra-granular HPC is more susceptible to acid catalyzed hydrolysis. In the new
experimental design, a minimum quantity of the HPC in the intra-granular portion of the granulation was
used. The reason was that more HPC extra granular will not be in contact with the dilute HCl solution
and will also not be subjected to the drying process. This should improve the likelihood of the polymer
not cleaving due to non-exposure to moisture; dilute acid, increased temperature or drying time. All of
these as described earlier increase the rate of hydrolysis of the polymer.

Batches were made with HPC-HXF 1% intra granular and 9% extra granular in conjunction with reduced
amount of diluted HCl to 2.0% w/w in the formula. Tablets made with this process were subjected to
both stress (50°C/75%RH) and accelerated (40°C/75%RH) stability conditions. They were physio-
chemically tested for both pH and dissolution behavior characteristics. Studies revealed that tablets of
stress stability up to 2 weeks were holding together without any popping. Tablets of accelerated
stability up to three months were not only holding together but also their dissolution profile matched
with that of the initial time point.

Studies were also conducted to optimize the following factors for the core tablet:

1) Effect of amount of diluted HCl on product’s stability

2) Influence of LOD (dried granulation) on pH /stability

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 3) Effect of Polymer level on tablet’s drug release
4) Effect of polymer viscosity on tablet’s drug release.
5) Effect of lubricant on the drug product’s physio-chemical attributes
I. Coating system: There are many film coating employed to achieve modified release, both
sustained-release i.e., releasing by 12 hours, need to take two dosages a day or long term
extended-release of 24 hours needs just one unit of the dosage to be taken daily. These can
be achieved by the following techniques:

a. Making a film with a screen with required porosity: Using mostly the hydrophobic polymer
ethyl cellulose as the film maker and either lactose or other soluble but inert excipient by
either milling, micronizing and selective sieving process for desired PSD and final porosity or
door opening. In most case the substrate in the unit dose itself have some matrix polymer
in its formula.

b. The CPP and CQA for these processes are;

i) Molecular weight and/or viscosity of the film polymer and its amount
ii) Particle size and particle size distribution of the pore former
iii) Rate of addition and Speed of mixing for the pore former and the film
former respectively.

c. Making a semi-permeable membrane film; this system does not have pore former or a
particular size door opening, rather the film formed itself is a semi-permeable allows the
film coated unit dosage substrate to come out or dissolve into the media at a desired
regulated rate based on the dissolution specification. In such system requires selecting of
polymers of hydrophobic and hydrophilic nature, at a specific combination, determined by
optimization experiment trials, when applied to core tablet as a film coat forms a semi-
permeable membrane that has a regulated drug release. This will result in an extended drug
release profile for about 24 hours in the selected bio-relevant dissolution media matching to
that of reference tablet. That would ultimately help to get bio equivalency of the formulated
product.

d. Generally for the hydrophobic polymer either dehydrated ethanol, IPA or a ready-mix
aqueous dispersion of Ethyl Cellulose is used. Sometimes talc or MgS are used as anti-
tacking agent. . In almost most every case the substrate in the unit dose itself is of
immediate release formula.
The CPP and CQA for these processes are;

iv) Molecular weight and/or viscosity of the film polymers and their amount in
the desired ratio.
v) Rate of addition and Speed of mixing

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 e. Another type of secondary coating systems is also used based on food effect or a specific
requirement to introduce the drug product at a specific site of the GI system. A second
coating is applied to the extended release coated unit dosage tablet, pellets or capsules that
would will delay and/or have a lag time in the release profile of the finished unit dosage
drug product in the selected bio-relevant dissolution media. That will help to nullify any food
effect on drug absorption and or to get it releases at the desired site of the GI system.

f. Example: A second coating system consists of Methacrylic acid co-polymer [Eudragit L-100-
55] is usually applied on top of the first coat to induce a delayed-release effect (lag time of ~
2 hours in 0.1N HCl) for nullifying in-vivo food effect of the drug absorption.

Studies were also conducted to optimize the following factors for the coated tablet:

1) Effect of level of hydrophobic and hydrophilic polymer on permeability of film-coat membrane

affecting drug release

2) .Effect of coating level (% weight gain) on drug release

3). Effect of coating thickness on finished tablet drug release.

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159
Amorphous Solid Dispersions and Accelerating Drug Development

Integrated approaches improve drug bioavailability and enable more rapid advancement to clinical proof
of concept.

INTRODUCTION:

Drug development pipelines are well-populated with poorly soluble active pharmaceutical ingredients
(APIs), increasing demand for formulation technologies such as amorphous solid dispersion (ASD), which
can address solubility challenges and provide scalable drug products for clinical evaluation faster.
However, formulation technologies alone may not significantly impact development timelines. In this
paper, we outline how data-driven strategies and integrated approaches simplify development and
reduce costs, using case studies to demonstrate how spray drying can solve solubility challenges and
how integrating good manufacturing practice (GMP) manufacturing and clinical testing can rapidly
screen formulations and advance molecules into the clinic while also considering downstream process
development.

DRUG SOLUBILITY AND BIOAVAILABILITY:

Drug development is rife with challenges in optimizing bioavailability, particularly related to poor API
solubility. A recent review calculated 65% of oral oncolytic APIs are poorly soluble in water and 47% are
poorly absorbed from the gastrointestinal tract (1). Overlying this, many of these APIs are weak bases
that show reduced solubility at high gastric pH, which can result from being taken with food or from

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treatment with gastric acid reducing agents (ARA), which occurs in 33% of cancer patients (2). The ideal
formulation can mitigate these API limitations. The Develop-ability Classification System (DCS) (3) has
helped drive formulation strategies to improve clinical outcomes, particularly for low solubility
compounds where there is distinction between dissolution-limited Class IIa and solubility1limited Class
IIb. This subdivision can be used as part of a formulation roadmap which focuses on technologies having
kinetic versus thermodynamic influences on absorption; thus, lipidics are a logical starting point for Class
IIb, while size reduction is favored for Class IIa via particle engineering methods such as ASD.

RAPID FORMULATIONS DEVELOPMENT: Reiterative formulations development can be time-consuming,

while parallel development pathways are costly. A thorough understanding of the technologies and
potential models involved can suggest an accelerated pathway to formulation. The following case study
demonstrates use of a technology1based pathway we developed in order to most efficiently evaluate
ASD formulations with limited iteration, resulting in confident selection of the drug product
intermediate and final ASD tablet

Case Study: ASD and pH-Dependent Bioavailability:

Calquence (acalabrutinib) is an API formulated as a crystalline free base in a gelatin capsule. Absorption
is decreased by ARA, and its solubility in water is <50 mcg/ml (4). However, its relatively low
crystallization tendency and low lipophilicity lend themselves to ASD formulation. ASD formulation has
recently been used to improve bioavailability of acalabrutinib in the presence of ARA.

First, a solvent shift assay was used to examine multiple drug/polymer solutions in simulated intestinal
fluid (SIF). Acalabrutinib showed decreased crystallization in polymer solutions, with hypromellose
acetate succinate (HPMCAS)-H and -M maintaining super-saturation of acalabrutinib, indicating
improved solubility (5). Intermediate dissolution testing in fasting state SIF showed sustained super-
saturation for ASD using HPMCAS-H compared to M and L grades (5). The 50% drug load HPMCAS-H ASD
tablet reduced tablet size 60% compared to Calquence and demonstrated good compression properties,
rapid in vitro disintegration, and good stability during a 6-month test (6). Next, an in vitro gastric
transfer model was utilized, where gastric disintegration/solubility was measured in the upper gastric
chamber, then the solution was pumped to the lower intestinal chamber and simulated absorption in
SIF was recorded. Gastric solubility and intestinal absorption were equivalent between the ASD tablet
and Calquence at pH 2. At pH 6, Calquence solubility and absorption were greatly reduced, as expected,
while the ASD tablet demonstrated less effect of increased pH (FIGURE 1). In silico modeling was
performed using fasted beagle physiology in GastroPlus software; input parameters.

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included surface versus bulk pH measurements and pH dependent dissolution rates to more accurately
reflect tablet surface conditions (4). Predicted absorption and area under the curve (AUC) of the ASD
tablet were similar between pH 2 and 6 and similar to Calquence at pH 2, but had three-fold
improvement over Calquence at pH 6 (5), consistent with in vitro modeling. An in vivo beagle study
(FIGURE 2) found that these in silico results (lines) were a good predictor of in vivo pharmacokinetic (PK)
data (markers). The streamlined ASD formulation development method described here led to rapid,
successful ASD tablet generation without significant iteration. We predict that this method can be
applied to other weak base drugs to rapidly assess the potential utility of multiple ASD formulations for
addressing similar solubility-limited, pH dependent bioavailability issues.

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EXTRAPOLATION LIMITATIONS:

While formulations technologies can be used to increase bioavailability, they cannot fully address
bioavailability related roadblocks in clinical testing, due in large part to discrepancies between animal
models and human outcomes. Meta-analysis studies have previously examined drug bioavailability in
rodents, dogs, and non-human primates, and found a lack of generalizable correlation with human
bioavailability (7-8). Unfortunately, a drug-specific correlation, or lack thereof, is only observable after
clinical studies are performed, during which suboptimal results are likely. A holistic approach to
development requires tools which better anticipate the drug product performance in human biological
systems and hence inform clinical development. These include more bio relevant in vitro methodologies,
such as use of simulated gastrointestinal fluids to study dissolution and precipitation, and the gastric
transfer model utilized above which can model fed and fasted states. Physiologically based PK modeling
software can also be used to predict human outcomes. Most importantly, human data must be used to
drive decision making in a way that de-risks outcomes from the clinical study.

AN INTEGRATED DEVELOPMENT PARADIGM:

Traditional drug development separates chemistry, manufacturing, and controls (CMC) from clinical
activities, resulting in a temporal and frequently geographical gap for clinical drug product evaluation.
The consequences of this paradigm drive time and cost inefficiencies and result in a lack of within-study
flexibility to respond to emerging clinical data. Translational Pharmaceutics accelerates drug
development by fully integrating formulation, GMP manufacturing, and clinical testing. In this
paradigm, drug products are developed with data from technical batches used to support regulatory
submissions and clinical batches manufactured and released in response to clinical demand. Complete
workflow integration results in products being released and dosed in short cycles. Clinical data such as
safety and PK inform in real time which drug product composition to make and dose next. Meanwhile,
parallel
stability data assure product quality and drive development efficiencies. One aspect of this paradigm’s
flexibility lies in the formulation design space, a set of bracketed ranges of critical-to-performance
formulation attributes within which one can select compositions to make and dose during clinical study
(FIGURE 3). Regulatory submissions contain data from technical batches at each of the composition
extremes, providing assurance that all formulations within the approved design space can be
manufactured and dosed to meet clinical program needs without further regulatory amendment. It is
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important to note that Translational Pharmaceutics encompasses GMP manufacturing, so although drug
dose is the most common attribute, the design space can also investigate polymer load, excipient
content, and more.

Tufts University researchers recently estimated that an average of 12 months is saved using
Translational Pharmaceutics versus a traditional development paradigm, yielding a potential financial
gain of $200 million per approved drug (9). Importantly, development risk is reduced because decisions
are made based on evolving human data, maximizing the potential for success across the entire
development life cycle, from first-in-human (FIH) studies to life cycle management. The following case
studies illustrate the principles of Translational Pharmaceutics and demonstrate how its use can
accelerate timelines at two different stages of clinical development.

Case Study: FIH Study of a Poorly Soluble Compound:

Physicochemical and nonclinical PK data for R552 suggested enabling formulations were required to
achieve systemic exposure in the therapeutic range. An integrated FIH study was designed to determine
the most appropriate formulation, manage the risk of suboptimal bioavailability, and do so without
compromising clinical characterization of PK, safety, and tolerability. Based on in vitro screening, three
formulation prototypes were identified - a lipid solution with multiple R552 concentrations, and two
powder-in-bottle (PiB) spray-dried dispersions (SDDs) containing fixed drug loading of polymer alone or
with lipidic co-solvent. The study schematic contained a typical single ascending dose (SAD) study
(FIGURE 4) initiated with lipid solution; however, the protocol allowed evaluation of alternative
formulations should dose-limiting effects be observed. Based on emerging PK data, the option to
manufacture and evaluate the PiB SDDs was exercised at dose level 3, allowing direct comparison of all
three formulations, which led to selection of one PIB SDD for evaluation in the remaining SAD levels
and MAD study. A key advantage of Translational Pharmaceutics in this study was the ability to react to

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emerging data from the SAD study and initiate in-parallel development of a solid dose tablet containing
the lead SDD, which was included in Part 3 of the FIH study via CMC amendment, enabling PK bridging to
the PiB SDD (FIGURE 4). Clinical data showed linear, dose-proportional PK over the evaluated dose range
using SDD formulations. All three SDD formulations showed comparable Tmax, and for the lead

SDD, no significant differences in exposure were observed between PiB and tablet formats. Inter-subject
variability was low, and exposure was comparable in fasted and fed states, aside from expected effects
on Cmax and Tmax arising from delays in gastric emptying (10). The primary objectives of assessing
safety, tolerability and PK were met in this FIH study, while enabling human data to drive formulation
selection in real time,, in <15 months. Additionally, the ability to transition from fit-for-purpose to
patient-ready drug forms during this study alleviated the need for additional critical path CMC
development and clinical bridging, resulting in seamless transition of drug product into clinical POC
studies.

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Case Study: Tablet Formulation for Phase II:

An FIH study was previously completed for IDX-719 using an SDD suspension, with a solid dosage form
then required for Phase II clinical trials. Multiple formulations had been screened in in vitro models and
in animal PK studies, but a lack of correlation in these studies and lack of a reliable dissolution assay
yielded great uncertainty and risk in selecting a formulation for clinical PK. A Translational
Pharmaceutics study was designed that efficiently and effectively used human data to identify and
optimize a solid dosage form for clinical validation ahead of Phase II clinical trials. Formulation design
spaces for two fixed ratio SDD polymers, designated P1 and P2, used bracketed ranges for a pH modifier
and a surfactant, which enabled adjustment of their quantitative levels during the clinical study.
Regulatory submission included data for the extremes of each composition. The study design included
two parallel cohorts dosed with P1 versus P2 formulations for six dosing periods. The initial three
periods used reference polymer suspensions, followed by tablets with high surfactant and then tablets
with high surfactant and pH modifier. The protocol for the remaining periods allowed flexibility in tablet
composition based on emerging PK data, with new tablets manufactured and dosed within two weeks.
These data revealed that design space variations in P1 SDD tablet composition had significant effects on
its bioavailability, which was 39-98% compared to lipid solution, while variations in P2 SDD tablet
composition had minimal effect on its low bioavailability (11). The use of Translational Pharmaceutics
allowed optimization of an SDD tablet formulation for use in Phase II studies within 8 months – a
reduction of 6 months compared to traditional approaches. Furthermore, data generated during this
study enabled development of a discriminating in vitro dissolution method to support downstream
process development.

CONCLUSION:

New technologies such as amorphous solid dispersions can address bioavailability issues using simple,
scalable formulations, and bio-relevant in vitro and in silico evaluation models can be used to rapidly
advance these formulations to the clinic. Employing a holistic, integrated approach to clinical drug
development via Translational Pharmaceutics can further accelerate development timelines by
empowering and de-risking decision making for these formulations, with the ultimate goal of getting
new treatments to patients faster.

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