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 -3-

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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 -6-

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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 Drying Blending Compression Coating

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

Formulation meets with proposed specifications

ANDA pre-submission Auditing

Reconsider the process and process parameters

ANDA submission Meet all the quality attributes predetermined

Process validation Commercialization Process revalidation

Scale up

Flow Chart 1: Flow Chart Generic Product Development - 11 -

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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 welldefined 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. Scaleup 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 - 14 -

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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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