INTRODUCTION

CHAPTER I
Introduction
1.1 Generic Drugs
A generic drug or generics is a copy that is the same as a brand name drug in
dosage, safety, strength, route of administration, quality, performance and intended use. It
does not have any patent protection for active ingredient
Generics simply means that the drug is not sold as the brand name but it has the
identical strength, dosage and route of administration and the same active ingredient as
the brand name drug.
According to the US Food and Drug Administration (FDA), ‘generic drugs are
identical or within an acceptable bioequivalent range to the brand name counterpart with
respect to pharmacokinetics and pharmacodynamic properties’. Therefore generics are
considered identical in dose, strength, route of administration, safety, efficacy and
intended use. A generic drug must be shown to give blood levels that are very similar to
those of the reference product. If blood levels are the same, the therapeutic effects will be
the same and there is no need to carry out a clinical effectiveness study.
The main reason behind promoting the use of generic drugs by Government
agencies is their cost effectiveness. There is a big difference between generics and brand
name drugs. On average, the cost of a generic drug is 40 to 80% lower than the brand
name product. This low cost factor sometimes lead people think that it is of inferior
quality but it is not true. The principal reason for relatively low price of generics is that
competition increases among producers when drugs no longer are protected by patents.
Generic companies incur fewer costs in creating the generic drug and are therefore able to
maintain profitability at a lower cost to consumers. Unlike innovator companies Generic
manufacturers do not incur the cost of drug discovery and instead are able to reverse
engineer known drug compounds to allow them to manufacture bioequivalent versions
also they do not have to bear the burden of proving the safety and efficacy of the drug
through clinical trials.

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Generic drug companies also receive the benefits of the previous marketing
efforts of the brand name drug company including media advertising, presentations by
drug representatives and distribution of free samples. Many of the drugs introduced by
generic manufactured have already been on the market for decade or more and may
already be well known to patients and providers.

1.2 Generic Product Development Cycle

Development of generic product may pass through several stages. They may be:-
 Literature Search
 Active Sourcing
 Active Evaluation
 Active Purchasing
 Active Testing
 Innovator's Product Purchasing
 Innovator's Product Testing
 Bulk Active Testing
 Excipients compatibility testing
 Container Closure System selection
 Manufacturing Process selection
 Analytical Evaluation
 Process Optimization
 Analytical Evaluation of optimized formulas or products
 Scale-up
 Process qualification and Pivotal Production
 BIOSTUDY Evaluation
 ANDA Pre-Submission Auditing
 ANDA Submission
 Process Validation

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 Process Re-validation

1.2.1 Literature Search

After identification of project literature review is done regarding already available
products (innovator and other generic products). Literature search in the electronic data
base i.e. articles and publications on test methods, dissolution, synthesis procedure, drug
impurities, pharmacokinetics and pharmacodynamics are done. Bio study parameters and
dissolution methods can be evaluated from the information available in FDA CDER.
Availability of patent on the proposed drug substance is also to be checked with orange
guide and FDA CDER patent consultant.

1.2.2 Active Sourcing and Evaluation

Active raw materials (active drug substance) sample are requested with
specifications from different raw material suppliers. At least two suppliers must be fully
evaluated on the basis of DMF availability, compliance with USP monograph, Impurity
profile and stability, potential polymorphic forms, commitment for physical
specifications and also the active supplier must provide a statement of non-patent
infringement.

1.2.3 Active Purchasing and Testing

Actives are purchased in small quantity from potential active material suppliers
for active testing. Chemical testing is done by analytical R & D lab as per pharmacopeial
monograph (if present), pharmacopoeia forum (if available), in-house method or by
supplier’s test methods and specifications.

1.2.4 Innovator's Product Purchasing and Testing

For testing of innovators product at least three different lots in smallest and
largest pack size of each product strengths are purchased. Physical parameters of
innovator product like tablet shape, tablet color, code for punch embossing, pack sizes,
containers materials, closure types, cotton and desiccants are evaluated. Other physical

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parameters like weight, thickness, hardness, OD, friability, disintegration, evaluation of

tablet punch, size, score, embossing and shape are also tested.
Formula ingredients of innovator product are evaluated from summery formula in
PDR, international PDRs and innovators product’s insert. Microscopic observations on
particle size, crystal shape, and habit are performed. Differentiation on the presence of
specific excipients can be verified from microscopic observation. For example cross
linked cellulose’s starch and Avicel have a specific shapes and morphology and may
easily detectable.
Dissolution profile is derived from USP monograph and FDA dissolution method.

1.2.5 Preformulation and Bulk active Testing

First batch of bulk active from approved supplier are characterized chemically
and physically. Physical characters like polymorphism, BET, particle size distribution,
bulk density, microscopic characterization are tested. Chemical characters like assay,
stressed analysis, expected degradants, impurity profile, optical rotation, enantiomeric
purity and O. V. I. testing.

1.2.6 Excipients compatibility study and Formulation

Proposed excipients are evaluated along with actives for their compatibility by
DSC, IR studies or other suitable methods. Then formulate with compatible excipients to
get desired formulation characteristics.

1.2.7 Evaluation of Suitable Container-Closer System

Suitable container closer system for storage and dispensing of in-process and
finished products are selected. Selection is based up on:
 Material composition
 Compatibility with drug substance and drug product or other materials used in
product
 Type of thermoplastic resin and resin pigments present

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 Manufacturer and suppliers (DMF availability and trust worthiness)

 Amount and type of desiccants and cottons to be used
 Letters of access for regulatory authorities to view DMF dossiers
1.2.8 Manufacturing Process Selection and Evaluation
In manufacturing a immediate release tablet dosage forms main manufacturing
processes involved are granulation, blending, compression and coating. Among these
process a verity of steps to be followed, these steps are crucially evaluated and selected
for manufacturing. For example type of granulation processes to be followed chosen i. e.
wet granulation, dry granulation or slugging and dry granulation. Other manufacturing
steps like
 Determination of order of mixing
 Determination of premixing
 Determination of rate and amount of fluid addition
 Determination of granulation time
 Determination of torque end point value
 Determination of drying parameters
 Determination of LOD limits
 Determination of testing temperature for checking LOD limits

Physical properties of granulate like flow properties, density, particle-size

distribution and compressibility are to be tested. Physical properties of compressed
tablets like weight, hardness, thickness, friability, disintegration and dissolution are
tested.
Final formula is established based on test results and 1-3 months accelerated
stability results.

1.2.9 Analytical Evaluation of Developed Product

Analytical evaluation is done on the formulated drug products. The tests include

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 Dissolution in USP medium and other relevant media (a multipoint evaluation)

and compared versus Innovator’s product.
 Uniformity of content test for low active concentrations products.

Validation of analytical package i. e. assay; Dissolution; content uniformity

completed prior to process Qualification.

1.2.10 Process Optimization

This step involves optimization of process parameters during the manufacturing
process.
1.2.10.1 Granulation optimization:
The process of granulation is optimized with adjusting granulation control
parameters like:
 Granulation time
 Speed of choppers or mixer blades
 Solvent addition rate and overall amount
 Ratio of intra granular disintergant and binder agent
 Screen size for milling
 Adjusting mill screen size up or down to fine tune hardness
 Evaluation of optimized granulate and tablet attributes
 Fluid bed drying temperature versus target LOD and rang limits and their effect
on granulate and tablet properties

1.2.10.2 Blending Optimization

While blending following parameters to be considered: -
 Blending time
 Pre-blending and final blending
 The effect on content uniformity, granule lubrication and dissolution profile
 Evaluation of unit dose sampling versus content uniformity

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1.2.10.3 Compression Optimization

While compression optimization following: -
 Evaluation of compression machine RPM and it’s effect on tablet properties (wait
variation)
 Effect of hardness on tablet properties (aging, dissolution, friability)
 Evaluation of hardness range limits
 Evaluation of stability results on the basis of optimized manufacturing process
After this optimization trials are over, process optimization report are prepared and are a
part of the product development report.

1.2.11 Analytical Evaluation

Analytical evaluation is done on optimized drug products to show similarity with
the innovator product.
 Dissolution in USP medium and other relevant media (a multipoint evaluation)
and compared versus Innovator’s product.
 IVIVC Bioavailability study
 Establish a level A or C correlation without adjusting dissolution parameters and
time scale
 If necessary adjust dissolution parameters and time scale to get a level A or C
correlations

1.2.12 Process Qualification and Pivotal production

The process qualification batch is manufactured in order to detect any problems
that may arise during the manufacture of production size batches, allowing a solution

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prior the manufacture of pivotal batch. Scale up to the pivotal batch size or 70% of the
pivotal batch may be combined with qualifying the manufacturing process. At this stage
full manufacturing documentation is prepared alone standard procedures.
Process qualification batch should be compressed in a production type tableting
machine. In this stage batch size of pivotal and marketing batch are conformed that is
NLT 100000 net/packed at target parameter or 10% of proposed marketing batch.
Master formulas with processing instructions are prepared by discussion with
production and QA staff. Review of proposed formulas and processing instruction are
done by concerned department heads and approved for further execution.
During the process critical manufacturing steps are identified and sampling and
testing parameters are specified to detect and control any problem during manufacturing
process. Presence of production and control personals are necessary during qualification
batch execution. Upon completion of the process a complete process qualification report
is prepared which is part of overall development report.
Pivotal production batch may be same as process qualification batch. Pivotal
batch must be prepared in production tableting machine and must be of at least 100000
units or 10% of commercial batch which ever is greater. Before production final master
formula and processing instructions are prepared and approved by Research and
Development, Quality control, Production and Quality assurance department after
through review. Pivotal report is also a part of overall development report.

1.2.13 Bioequivalent Study

Pivotal lot samples are used for biostudy evaluation. Biostudy is performed in
fasted or with food generally on highest strength of products in case of multiple strength
products. For multiple strength products in-vitro dissolution testing is to be conducted in
three different pH media on lower dosage forms and similarity test (F2 test) is to be
performed on dissolution results.

1.2.14 ANDA Pre Submission Auditing

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Pre submission auditing is required for successful auditing by FDA. In this

process audit all raw data supporting development report, plant and laboratory
documentation as per ANDA.
Review SOP system and cGMP of manufacturing process. Evaluate biostudy
report and develop an IVIVC correlation with RLD (reference listed drug).

1.2.15 ANDA Submission

Like NDA submission prior to market a new drug product, documents to be
submitted to US FDA according to CTD (Common Technical Document) requirements.
Unlike NDA application the ANDA applicant need not to submit clinical data to prove
safety and efficacy.
According to CTD system there are five modules. In the module 1, administrative
information are submitted and in module 2 summery of all the information that is to be
submitted in subsequent modules are submitted. In module 3 all the data required to
ensure the quality of drug substance and drug product are submitted. Module 4 describes
the non-clinical report, which a ANDA applicant no need to submit because the data
generated during development by the innovator is in hand of US FDA. In module 5,
which describes about the recruitment of clinical data to be submitted to FDA to prove
safety in human use, a ANDA applicant only submits bioequivalent data to prove their
product is just similar to innovator’s product or RLD. So ANDA applications need not to
include safety data. In some cases where a Level A correlation is obtained bio-waiver can
be granted for the drug product.

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Figure 1: Common technical Document Modules

1.2.16 Validation Batches

For an approved product, process validation protocols are prepared for 3
consecutive marketing scale batches and process validation is performed. After
successful validation, validation reports are prepared and are required to submit to FDA.
The validation batches must show inter-batch and intra batch similarity between
bio-batch and the commercial validation lots.

1.2.17 Process Re-Validation

Process revalidation is required when there is change in formula, manufacturing
process or change in process equipments. For any minor changes SUPAC rules are
followed.

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Project Identification & Literature

search
Active sourcing And Evaluation

Active purchasing And Testing by AR&D

Innovator product purchasing And Testing

Preformulation study On Bulk active

Excipients compatibility study And Formulation

Evaluation of container closer system

Evaluation of manufacturing process

Evaluation of formulated products

Reformulation Formulation
meets with
proposed
specificatio
ns

Scale up

Process optimization
Granulation optimization
Process qualification
Drying
Blending
Compression Pivotal production or Bioequivalent
Coating batch production
( At least 100000 units or 10% of
proposed mkt. batch)

Formulation meets with proposed specifications ANDA pre-submission Auditing

ANDA submission
Reconsider the process
and process parameters Meet all the
quality
attributes Process validation
predetermined
Commercialization

Process revalidation
Scale up

Flow Chart 1: Flow Chart Generic Product Development

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1.3 Technology Transfer

In recent years, there is a growing awareness that an appropriate transfer of
manufacturing technologies (technology transfer) is important to upgrade drug quality as
designed during R&D to be a final product during manufacture as well as assure stable
quality transferred for many reasons between contract giver and contract acceptor during
manufacture. The drug quality, it is desired to make sure 5 W’s and 1 H, that is what,
when and why information should be transferred to where and by whom and how to
transfer, then share knowledge and information of the technology transfer each other
between stake holders related to drug manufacturing.
Transfer of Technology (TT) is defined as “a logical procedure that controls the
transfer of an established process together with its documentation and professional
expertise to a site capable of reproducing the process and its support functions to a
predetermined level of performance”.
The ever-changing business strategies of pharmaceutical companies increasingly
Involve intra- and inter-company transfers of technology for reasons such as the need for
additional capacity, relocation of operations or consolidations and mergers.

1.3.1 Reasons for Technology Transfer

There may be many reasons why a developer of the technology might consider
making its technology available to another person to exploit, instead of exploiting the
technology itself. Some of theses are:
A. Forming alliances with partners that can progress the development of the
technology to take it to market.
The developer of the technology might have the resources to take the technology
to particular state of development, such as up to animal studies and toxicology studies,
but dose not have the resources to take the technology through its clinical and regulatory
phases, and must collaborate with another organization to take it through these phases,
and into the market.

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B. Forming alliances with partners with manufacturing capability.

The developer of the technology may have taken the technology to a state of
development so that it is near market ready, but dose not have the clean room
manufacturing capability or resources to manufacture the product, and must partner with
another organization that dose have that capability.
C. Forming alliances with partners with marketing and distribution capability.
The developer of the technology may have fully developed the technology and
even have obtained regulatory approvals and product registrations for the product to be
sold, but it lacks the marketing and distribution channels to give it a marking capability
and must collaborate with another organization that doses have that capability.
D. Exploitation in a different field of application.
The developer of the technology might be capable of exploiting the technology
itself in the field of diagnostic applications, and may grant exploitation right to
commercial partner for the exploitation of therapeutics applications.
By transferring the technology for the use in another field of application to
another person, the developer of the technology creates another income stream from the
exploitation that takes place on that takes place in that other field.
E. No Commercial capability.
The developer of the technology may be research institute of a university, which
doses not have the capability to exploit commercially at all, and need to collaborate with
another organization that does have that capability.
1.3.2 Importance of Technology Transfer in Pharmaceutical Industry:
A. To elucidate necessary information to transfer technology from R&D to actual
manufacturing.
B. To elucidate necessary information to transfer technology of existing products
between various manufacturing places.

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1.4 Scale-Up from R&D Laboratory to Production Scale

Pharmaceutical Process Scale-Up deals the procedures of transferring the results
of R&D obtained on laboratory scale to the pilot plant and finally to production scale.
Scale-up is generally defined as the process of increasing the batch size. Scale-up of a
process can also be viewed as a procedure for applying the same process to different
output volumes. There is a subtle difference between these two definitions: batch size
enlargement does not always translate into a size increase of the processing volume. In
mixing applications, scale-up is indeed concerned with increasing the linear dimensions
from the laboratory to the plant size. On the other hand, processes exist (e.g., tableting)
for which “scale-up” simply means enlarging the output by increasing the speed.
In moving from R&D to production scale, it is sometimes essential to have an
intermediate batch scale. This is achieved at the so-called pilot scale, which is defined as
the manufacturing of drug product by a procedure fully representative of and simulating
that used for full manufacturing scale. This scale also makes possible the production of
enough products for clinical testing. However, inserting an intermediate step between
R&D and production scales does not in itself guarantee a smooth transition. A well-
defined process may generate a perfect product in both the laboratory and the pilot plant
and then fail quality assurance tests in production.
Scale up can be done based in dimensional analysis. Dimensional analysis is a
method for producing dimensionless numbers that completely characterize the process.
The analysis can be applied even when the equations governing the process are not
known. According to the theory of models, two processes may be considered completely
similar if they take place in similar geometrical space and if all the dimensionless
numbers necessary to describe the process have the same numerical value. The scale-up
procedure, then, is simple: express the process using a complete set of dimensionless
numbers, and try to match them at different scales. Dimensionless numbers, such as
Reynolds and Froude numbers, are frequently used to describe mixing processes. Scale-
up problems may require postapproval changes that affect formulation composition, site,
and manufacturing process or equipment (from the regulatory standpoint, scale-up and
scale-down are treated with the same degree of scrutiny). In a typical drug development

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cycle, once a set of clinical studies has been completed or an NDA/ANDA has been
approved, it becomes very difficult to change the product or the process to accommodate
specific production needs. Such needs may include changes in batch size and
manufacturing equipment or process.
Postapproval changes in the size of a batch from the pilot scale to larger or
smaller production scales call for submission of additional information in the application,
with a specific requirement that the new batches are to be produced using similar test
equipment and in full compliance with CGMPs and the existing SOPs. Manufacturing
changes may require new stability, dissolution, and in vivo bioequivalence testing.
Scale up of a process may be done in a such a way that all the problems that may
arise in production are identified and steps are taken to eliminate all problems to avoid
extra cost of development and regulatory constraints.

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