Handbook Of Pharmaceutics Scientists And Reviewers.pdf

HANDBOOK OF
PHARMACEUTICS

Compiled & Edited:
Masih Jaigirdar

For Pharmaceutical Scientists and Reviewers

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 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 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


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 KIPICO
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.
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.

3

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

Certificate of Appreciation for valuable service to the AAPS Modified Release as Learning
Opportunity Manager, in November 2020 – November 2021.
Certificate of Appreciation for dedication to the FDA through his 10 years of exemplary service as an
exceptional employee and mentor, October 13, 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.
4


Review 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


5


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
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 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; Anticholesterols, 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.

6


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).
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
7




Literature Search



USP, BP, JP, EP, Merck, Florey etc.



FDA-FOI



Summary Basis of Approval




On-line search of FDA/CDER info.

Data Base guidelines for test methods,



Patent Evaluation

dissolution, impurities, Bio-study
parameters. etc.


Orange Guide + FDA/CDER www.patent
consultant

Stage 2: API Sourcing


Sourcing of Active Pharmaceutical
Ingredient (API); Drug Substance





Have Potential Supplier lists





US agent for API

US & International Suppliers from
(Europe, Asia, etc.)
Request Technical Binder & DMF
Information



Request samples & CoA and
Specifications



At least two suppliers for full evaluation

8


Stage 3: API Evaluation and Procurement




Evaluation of Active Pharmaceutical
Ingredient (API)

Purchase of API



At least 2-3 potential API supplier



DMF availability & Status



Compliance with USP monograph



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



Pharmacopeia Forum (if available)



In-house method (based on API

(if present)

manufacturer.
Stage 5: Bulk API Testing
Chemical testing by R&D Analytical Laboratory



Polymorphism

(Full physical & chemical characterization)



Particle size distribution & method
development



Assay



Stress study (Heat, Acid, Base, Oxidative
and Photolytic)



Relative substances/Impurity profile,
Degradants



Optical rotation



Enantiomeric purity



O.V.I. Testing

9


Stage 6: Pre-Formulation
1. Drug substance


Physico-Chemical testing by R&D
Pharmaceutics Laboratory



Physico-chemical evaluation for:



Moisture sorption/desorption



Flowability, Particle size, B/T Density
and Compact-ability study

2. Drug Product



Drug-Excipient Compatibility study



At least 3 different lots in smallest and
largest pack size

Physico-chemical evaluation of Innovator’s
Product by R&D Pharmaceutics Laboratory



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:

Microscopic observation of Innovator’s
Product by R&D Pharmaceutics



Erosion Vs Congealing characteristics



By slight crushing of tablet with a
mortar & pestle and observing under
microscope for:



Particles Vs granules for particle size,
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.
10


Dissolution profile of Innovator’s Product



by R&D Analytical Laboratory

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)

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.

Stage 8: Manufacturing Process


Wet granulation (aqueous or non-aqueous)
high shear mixing / low shear mixing

EVALUATION SUITABLE
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
Compaction

or Roller

• Determination of pre-mixing (in Granulator)
• Determination of fluid addition (if relevant)
• Determination of granulation time

11




Moisture Activated Dry (MAD) Granulation

(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.

Stage 10: Scale-up

Scale-up batch prepared if larger batch size scale up problems anticipated.
Process Characterization batch and Scale-up batch may be evaluated as a single batch.

Stage 11: Process Characterization (Optimization)
Documented verification that the process and/or total process related system performs as
intended throughout all anticipated operating ranges.
GRANULATION OPTIMIZATION



Effect of granulation parameters



Granulation time



Speed of choppers (I & II) or mixer blades

12


DRYING



Solvent addition rate and overall amount



Ratio of intra-granulate Disintegrant and
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

COMPRESSION
P.C. REPORT

Effect of level of lubricant




Lubricant Split into two parts (pre-blending and
final blending)
Effect of Blending Time




Response: Content Uniformity and Dissolution
Profile.




Evaluation of unit dose sampling vs. Content
Uniformity




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

13


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]
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.

14


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

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 immediaterelease (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
15


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.
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
16


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



of the commercial batch. Minimum three

Pivotal batch MUST be compressed in a
production tableting machine (or

batches.

production type with same principle and



Formula & Process Optimized.



Matching dissolution with RLD.



All excipients within IIG limits.

BATCH DOCUMENTATION



Process and Equipment Train Selected.





Container/Closure with 3 months

operation)

Preparation of FINAL Master Formula and
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.

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.

17


Stage 14: BIOEQUIVALENT STUDY
Bioequivalence: A scientific basis on which generic and brand name drugs are compared with
one another. Drugs are bioequivalent if they enter circulation at the same rate when given in
similar doses under similar conditions. Proof of bioequivalence is crucial for generic drugs, and
must be demonstrated in ANDAs.

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:
Establishing through documented evidence, a high degree of assurance that a specific process
will consistently yield a product that meets predetermined specifications and quality
characteristics.


Protocol



Execution of process validation batches



Report



Similarity



Bio-Validation Similarity



Process Validation Protocol for 3
consecutive marketing lots



Process Validation of 3 consecutive
marketing lots



Process Validation Report



Showing intra-batch similarity



Showing

inter-batch similarity between

Bio-batch (Pivotal) and the Commercial
Validation Lots

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).

18


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: A solid dosage form prepared from powders or granules by compaction. It 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.
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)

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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.

Example: Say a firm for its multi strength tablet 10mg, 15mg and 20mg tablets has made a formula
design not dose-proportional or 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.

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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.

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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).

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.

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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

Direct Compression: Producing tablets using a mixture of dry API powder and excipients that
have not been granulated (wet or dry).
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
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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.
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/chelsonator. 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.

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Roller compactors

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.

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