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

Process Re-validation

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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

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

tablet punch, size, score, embossing and shape are also tested.

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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

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

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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

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.

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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

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.

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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

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).

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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.

Figure 1: Common technical Document Modules

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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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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

Process optimizationGranulation optimization DryingBlending CompressionCoating

Formulation meets with proposed specifications

Formulation meets with proposed specifications

Meet all the quality attributes predetermined

Scale up

Process qualification

Pivotal production or Bioequivalent batch production( At least 100000 units or 10% of proposed mkt. batch)

Process validation

Commercialization

ANDA submission

ANDA pre-submission Auditing

Project Identification & Literature search

Process revalidation

Active sourcing And Evaluation

Reconsider the process and process parameters

Scale up

Flow Chart 1: Flow Chart Generic Product Development

INTRODUCTION

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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