Overview Of Generic Formulation Development For US Market

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Generic Drug Development for US Market


1.1 IPR
1.8 Stores
1.9 Purchase
1.10 Engineering
1.11 CRO
2. Selection and qualification of vendors for API, RM, PM
3. Procurement of innovator products
4. Procurement of API, RM, PM
5. Analytical method development assay, RS, dissolution, UOD and validation
6. Literature review regarding patents
7. Selection of filing Para I para II para III para IV
8. Planning of development strategy
9. Selection of excipients (vendors) API (Vendors) PM (vendors)
10. Quality by design
11. Design of experiments in small scale (X)
12. Finalization and reproducibility of formula in size (approx. X)
13. Scale up (approx. 10X)
14. Charging for stability
15. Process optimization and validation
16. Validation batches (100X)
17. Bioequivalence studies
18. Preparation of protocols
19. ANDA preparation
20. Filing Procedure and Duration

1.0 Departments involved and their role:

1.1 Intellectual property rights:

Patent infringement is a very big issue in generic product development. It involve in collecting the information from patent searching databases for a particular product. Detailed interpretation will be done on the product so that infringement should not happen during product filing.

1.2 Formulation R&D

It involves in the development, optimization of the formulation for the innovator product. The sequential flow of the activities are as follows.

O Literature searches and review of the Reference listed drug (RLD) (chemical, pharmaceutical, pharmacological, pharmacokinetic and patents)

O Reverse engineering of RLDs and check for inactive ingredients (IIG) limits, office of generic drugs (OGD) dissolution database.

O Identification of new raw materials

O Performing preformulation studies of the physical and chemical nature of innovator drug products

O Characterization of pharmaceutical components (physical, chemical, pharmaceutical, pharmacokinetic) and drug substances prior to formulation

O Identify and evaluate the critical formulation factors (e.g., components and process)

O Identify and evaluate Quality target product profile (QTPP), Critical quality attributes (CQA), Critical process parameters (CPP) and critical material attributes (CMA).

O Coordinate development with AR&D, Engineering, Validation, Production, Non clinical, Clinical, Regulatory, and QA, to ensure uninterrupted progress

O Design and development of prototype trials

O Documentation of product development activities

O Develop manufacturing process and prepare cGMP and non GMP batches

O Conduct QbD and Validate processes for the trial batches

O Prepare process evaluation, scale-up, execute batches as per the protocols, analyze data, and prepare summary reports. Understand material characteristic and product quality attributes thoroughly and identify the most suitable processes to manufacture the product meeting all intended quality attributes.

O Suggest process improvements, perform trouble shooting and changes to improve quality

O Prepare project summary, reports and presentations and make recommendations to managements

1.3 Analytical R&D

Analytical R&D involves mainly evaluation of the formulation sent by formulation, production and quality assurance department during the product development. The key activities are as follows.

1.3.1 Pre-formulation Studies

O Design of preformulation protocols, review and monitor drug excipient, drug compatibility studies

O pH dependent solubility profiles

O Intrinsic solutbility

O Hygroscopicity studies etc...

1.3.2 Stability Studies

O Design, Review and approval of stability protocols

O Plan and Monitor Stability Studies as per ICH Guidance conditions or specified conditions

O Plotting of Trend Charts

O Review of Reports, Investigation of Incidents, OOS, OOT and Investigation

1.3.3 Analytical Method Transfer

O Lead Transfer of Validated analytical Methods to customer QC, Manufacturing Sites as per specified protocols

1.3.4 Raw Materials Analysis

O Monitor and Review Analysis of Raw Materials as per Pharmacopoeial Requirements

1.3.5 Equipment Calibrations

O Ensure Equipment or Instrument Calibration as per Master Calibration Schedule and Compliance

1.3.6 Good laboratory practice (GLP)

O Ensure the Laboratory complies to the current GLP.

1.3.7 Technical Requirements

O Expertise with working on Analytical Instruments like HPLC, GCHS, Dissolution Tester, UV-Vis Spectrophotometer, Titrators etc.

O Possess excellent Troubleshooting Skills, Guide, Train and work with the Team in situations of Crisis.

O Develop and validate analytical methods for finished products for regulated markets (US and Europe market)

O Handling equipments like HPLC, UPLC, dissolution tester, UV/Vis spectrophotometer, IR, KF titrator etc

O Trouble shoot in existing methods and support regular and stability analysis for formulation development

O Preparing reports like method development report, validation protocols and reports, specifications, stability protocols etc

O Following good laboratory and documentation practices

O Preparation of Instrument and system SOPs for development.

1.4 Quality assurance

1.4.1 To establish the quality system

O Establish the quality management system to describe how the firm follows CGMPs and operates to maintain a state of control

O Keep the quality management system current with good industry practices, and applicable to the mission of your operation.

1.4.2 To audit compliance to the quality system

O Audit for compliance to policies and procedures: on paper vs. practice.

O Report quality system performance metrics, including trends, that help decision-making and taking proactive targeted actions

1.4.3 To establish procedures and specifications

O Ensure that procedures and specifications are appropriate and followed

O Ensure that the procedures and specifications of firms under contract are also appropriate and followed, i.e., maintain control and take responsibility for third-party services providers (contract manufacturers, contract laboratories, etc.)

1.4.4 To establish manufacturing controls

O Ensure that appropriate manufacturing in-process controls are implemented

O Ensure in-process controls are performed during manufacturing operations and results are satisfactory

1.4.5 To perform laboratory tests or examinations

O Perform laboratory testing of components, containers, in-process materials, packaging materials and drug product using validated methods against scientifically-derived, fit-for-purpose specifications

O Approve or reject drug products manufactured, processed, packed, or held under contract by another company, i.e., final product release is not delegated to a contractor.

O Perform retests or reexamine approved components, drug product containers and closures after long storage or exposure to adverse conditions

1.4.6 To review and approve or reject all things cGMP

O Review and approve/reject any document that gives work instructions and set requirements such as procedures, protocols, test methods, and specifications--including changes to these documents

O Review and approve/reject reprocessing and rework procedures

O Review and approve/reject production batch records and make the final decision to release a product lot into commerce.

1.4.7 To ensure investigation of nonconformance

O Ensure investigation is conducted and root cause is eliminated for production and control record errors, discrepancies, and failure to meet specification, including quality attributes

O Review complaints to determine if it relates to a failure to meet specification, if so investigate and report to FDA if it is serious and unexpected

1.4.8 To keep management informed

O Report on product, process and system risks--and keep management informed

O Report on outcome of regulatory inspections and ensure responses are complete and managed to verifiable closure--and keep management informed.

O Keep management informed--get it?

1.5 Quality control

O Excipients and Raw Materials Analysis

O Microbial test for purified/processed water

O Compendial analysis covering a range of pharmacopeia methods (USP, EP and JP)

O Client specific method

O Pharmaceutical Analytical Research and Development

O Proteins and Biotechnology Product Batch Release Testing

O Intermediates & Finished Product Testing:

O Organic Volatile Impurity & Residual Solvent Analysis

O GMP batch Release Testing covering a wide range of technology

O Degradation Studies and Pharmaceutical Impurity Identification

O ICH Stability Testing & Storage

O Dissolution

O Physical Characterization

1.6 Regulatory affairs

O Ensuring that a company's products comply with the regulations of the USFDA

O Keeping abreast of international legislation, guidelines and customer practices in all countries that the company is exporting to;

O Collecting, collating and evaluating scientific data that has been researched by colleagues;

O Developing and writing clear arguments and explanations for new product licenses and license renewals;

O Preparing submissions of license variations and renewals to strict deadlines;

O Monitoring and setting timelines for license variations and renewal approvals;

O Working with specialist computer software and resources;

O Writing clear, accessible product labels and patient information leaflets;

O Planning and developing product trials and interpreting trial data;

O Advising scientists and manufacturers on regulatory requirements;

O Providing strategic advice to senior management throughout the development of a new product;

O Project managing teams of colleagues involved with the development of new products;

O Undertaking and managing regulatory inspections;

O Reviewing company practices and providing advice on changes to systems;

O Liaising with, and making presentations to, regulatory authorities;

O Negotiating with regulatory authorities for marketing authorization;

O Specifying storage, labelling and packaging requirements

1.7 Production

O Prepares for production by reviewing production schedule; studying and clarifying specifications; calculating requirements; assembling and weighing materials and supplies.

O Prepares equipment by performing sterile cleaning-in-place (CIP), servicing-in-place (SIP), and cleaning out-of-place (COP); conducting operator inspections; performing preventive maintenance checks

O Produces requirements by operating and monitoring equipment; observing varying conditions; adjusting equipment controls; calculating concentrations, dilutions, and yields; adhering to aseptic filtering and filing procedures.

O Maintains safe and clean work environment by following current good manufacturing practices (cGMP), and standard operating procedures; complying with legal regulations; monitoring environment.

O Keeps equipment operating by following operating instructions; troubleshooting breakdowns; calling for repairs.

O Documents production by completing forms, reports, logs, and records of equipment and batches.

O Updates job knowledge by participating in training opportunities.

O Enhances organization reputation by accepting ownership for accomplishing new and different requests; exploring opportunities to add value to job accomplishments.

1.8 Technology transfer

This department is interlink between product development from R&D scale to production level. Based on the technical transfer dossier (includes BMR, MFR, in process, finished product, stability Specifications...) provided by R&D department, technology transfer department makes a report to implement in production scale at affordable cost. It includes a team having persons from Technology transfer associate, QC, R&D, Engineering, QA. [1]

1.9 Stores

It involve in the dispensing the raw materials (API, RM, PM) as per the master formula record during batches with large scale. The items are dispensed under cGMP conditions in presence of QA professionals. It will document all inward and outward materials, update concerned department regarding expiry/retest of the materials.

1.10 Purchase

It involves purchasing all the items like API, RM, PM, equipment, instruments, daily usage chemicals and solvents in a proper manner as per the industry guidelines. In case of API, RM, PM as per the assigned item code, purchase order has to be raised in order to meet consistency and accuracy in getting the materials.

1.11 Engineering

It involves in maintenance of all the equipments and instruments in the facility. It assigns proper calibration due and record it as per the SOP designed. Heating, ventilation and air-conditioning (HVAC) are maintained regularly using Air handling units. Maintain distilled water plant for producing purified/processed water regular usage for all the department. It plays important role in breakdown of any equipment, power supply. All the activites are documented properly as per standard operating procedures.

1.12 Clinical research organization (CRO)

Clinical research organization involve the evaluation of innovator and generic samples in humans. Generally samples are outsourced from the generic industry to clinical research organization.

2.0 Steps involved in the product development

2.1 Selection of filing

Generic filing can be classified into following types based on the patent protection of the innovator product. A generic drug is a drug which is produced and distributed without patent protection. The generic drug may still have a patent on the formulation but not on the active ingredient. A generic must contain the same active ingredients as the original formulation. Generic drugs can be legally produced for drugs where:
1) the patent has expired,
2) the generic company certifies the brand company's patents are either invalid, unenforceable or will not be infringed,
3) for drugs which have never held patents, or
4) in countries where a patent(s) is/are not in force.

The generic approval process is called Abbreviated New drug Application (ANDA). While filing an ANDA, the generic company has to choose one of the following four options (referred to as paras)

O Para I filing is made when the innovator has not made the required patent information in the Orange Book.

O Para II filing for the launch of a generic drug is made when the drug is already off patent.

O Para III filing is made when the patent for the product exists but the generic company wants to enter the markets after the date of patent expiry passes.

O Para IV filing is made when the ANDA applicant believes its product or the use of its product does not infringe on the innovator's patents listed in the Orange Book or where the applicant believes such patents are not valid or enforceable.

In all the generic filings, the FDA has 180 days to deem the generic application complete and accept it for review, or incomplete and reject for filing. In case of Para I and Para II filing, once the application is deemed complete, it is simply processed for approval.
In case of Para III the application is processed for approval, however its approval status depends upon the products patent expiry. Apparently Para IV filings are the most lucrative, tedious, time consuming and expensive of the above.

2.1.1 Filing for generic drugs

505(j) Filing Requirements

O Same active ingredient

O Same conditions of use (labeling)

O Same dosage form

O Same strength

O Same route of admin

O Bioequivalent

O Patent Certification

505(b2) Filing Requirements

O Dosage form. An application for a change of dosage form

Example: change in solid oral dosage form to a transdermal patch

O Strength. An application for a change to a lower or higher strength.

O Route of administration. An application for a change in the route of administration

Example: from an intravenous to intrathecal route.

O Substitution of an active ingredient in a combination product. An application for a change in one of the active ingredients of an approved combination product for another active ingredient.

2.2 Literature review regarding patents

All patents related to the product like manufacturing method, excipients, packing materials used in the formulation development are studied. Patent infringement has to be avoided by not following the claims provided in the patent.

2.3 Procurement of innovator products

After identifying the product to be developed, innovator products have to be imported as per the import licensing guidelines framed by DCGI. After procuring, innovator products have to be recorded and documents. They have to be kept in controlled conditions for future use. They have to be issued to the formulation/Production departments officially as per the internal standards. Further samples have to be kept in stability chamber in accelerated, intermediate and long term condition to get the data for physical parameters, assay, Related substances, dissolution etc...

2.4. Procurement of API, RM, PM

All the said materials have to be procured after getting instruction from the concerned department (like Formulation, analytical, production) by the purchase departments as per the item codes assigned.

2.5 Selection and qualification of vendors for API, RM, PM

During product development, vendors should be identified as per the regulatory guidelines for active pharmaceutical ingredient, raw materials and packing materials. The vendor should submit the all supporting documents to the quality assurance department. After scrutinizing all the documents (specifications, COAs, Approvals), vendors will be qualified as per the internal proceedings by quality assurance department. QA department issues particular item codes for the particular materials as per the internal SOPs. These item codes are used for making uniformity and faster tracking of the procured materials.

2.6. Analytical method development assay, RS, dissolution, UOD and validation

For the targeted Active pharmaceutical ingredients analytical method developments has to be carried for determination of assay, related substances, dissolution, uniformity of dosage units and validation etc... for the developed methods validation has to be carried out and documentation has to be done. Standard test procedures and standard operating procedures have to be prepared for avoiding interpersonal variations. These prepared SOPs, STPs are strictly followed during analysis by all the analysts.

2.7 Quality by design

Quality by Design (QbD) is a systematic approach to pharmaceutical development that begins with predefined objectives and emphasizes product and process understanding and process control, based on sound science and quality risk management. QbD requires an understanding how formulation and process variables influence product quality. Relevant documents from the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), ICH Q8, Pharmaceutical Development, along with ICH Q9, Quality Risk Management, and ICH Q10, Pharmaceutical Quality Systems, indicate on an abstract level how quality by design acts to ensure drug product quality.

Especially for ANDA sponsors, who were not actively involved in the ICH processes, there is a need for more concrete descriptions of quality by design. These discussions have generally focused on the development of new drugs. Drawing on these discussions and some specific aspects of the development of generic products, a QbD development process may include

O Begin with a target product profile that describes the use, safety and efficacy of the product

O Define a target product quality profile that will be used by formulators and process engineers as a quantitative surrogate for aspects of clinical safety and efficacy during product development

O Gather relevant prior knowledge about the drug substance, potential excipients and process operations into a knowledge space. Use risk assessment to prioritize knowledge gaps for further investigation

O Design a formulation and identify the critical material (quality) attributes of the final product that must be controlled to meet the target product quality profile

O Design a manufacturing process to produce a final product having these critical material attributes.

O Identify the critical process parameters and input (raw) material attributes that must be controlled to achieve these critical material attributes of the final product. Use risk assessment to prioritize process parameters and material attributes for experimental verification. Combine prior knowledge with experiments to establish a design space or other representation of process understanding.

O Establish a control strategy for the entire process that may include input material controls, process controls and monitors, design spaces around individual or multiple unit operations, and/or final product tests. The control strategy should encompass expected changes in scale and can be guided by a risk assessment.

2.8 Design of experiments in small scale (X)

DoE is a structured, organized method for determining the relationships among factors affecting a process and its output. It has been suggested that DoE can offer returns that are four to eight times greater than the cost of running the experiments in a fraction of the time that it would take to run one-factor-at-a-time experiments. Application of DoE in QbD helps companies

O Gain maximum information from minimum number of experiments

O Study effects individually by varying all operating parameters simultaneously

O Take account of variability in experiments, operators, raw materials, or processes themselves

O Identify interactions among process parameters, unlike with one-factor-at-a-time experiments

O Characterize acceptable ranges of key and critical process parameters contributing to identification of a design space, which helps to provide an "assurance of quality."

2.9 Finalization and reproducibility of formula in size (approx. X)

In small scale the finalized formula has to be checked for reproducibility and robustness. The main evaluation tests are dissolution, assay, uniformity of dosage units, related substances, physical appearance, hardness, friability.

2.10 Scale up (approx. 10X)

After attaining proper robust formula, it has to be scaled up in controlled conditions. Proper records have to be maintained for the all unit operations. After attaining the finished product, . The samples will be sent to AR&D for dissolution (multimedia if necessary), assay, RS method developments. All the developed methods will be documented and STPs will be determined for the developed methods.

2.11 Charging for stability

Samples have to be packed in suitable conditioners and sent for charging in stability as per the approved protocols designed based on ICH guidelines. Stability conditions include photo stability, long term, intermediate and accelerated conditions. As per the schedule mentioned in the protocol, the samples have to be withdrawn and the tests like assay, dissolution, RS, Uniformity of dosage units, physical appearance, hardness, friability etc. will be performed. The results will be interpreted scientifically to draw the conclusion for shelf life.

2.12 Process optimization and evaluation

After attaining the stable formulation as per ICH guidelines in the scale up batch, process optimization and validation will be performed. Process optimization include tuning the processing conditions slightly higher and lower sides so as to determine its effect on the produce quality and performance. For example, granulation time, mixing time, compression speed are the variables to optimize. Process optimization report has to be prepared by formulation department along with production, quality assurance departments.

2.13 Validation batches (100X)

Validation batches (3) have to be performed on commercial scale with the final formulation and process parameters under fully controlled conditions. Full batch has to be packed in the proposed commercial packaging materials. Stability data has to be generated for innovator and generic products comparatively to prepare packaging development report. [2]

2.14 Bioequivalence studies

The samples from validation batches will be sent to clinical research organization (CRO) to evaluate bioequivalence as per the guideline given by USFDA.

2.15 Documentation

Main documentation include preparation of laboratory notebooks, product development report, master formula record, batch manufacturing record, packaging development report, batch packaging record.

2.16 Abbreviated new drug application (ANDA) preparation

Regulatory affairs department involves in preparation of ANDA. Abbreviated new drug application has to be prepared as per the e-Common Technical Document which include 5 modules. Briefly,

Module 1: Administrative information and prescribing information

Module 2: Common technical document summaries

Module 3: Quality

Module 4: Safety (nonclinical study reports)

Module 5: Efficacy (clinical study reports)

All the data has to be compiled according to the modules mentioned and electronic copy can be sent to USFDA for approval. [3],[4]

2.17 Filing Procedure and Duration

On July 9, 2012, the Generic Drug User Fee Amendments of 2012 (GDUFA) introduced into law to speed access to safe and effective generic drugs and reduce costs to industry. According to this law, Industries has to pay user fees ($ 51,520) to supplement the costs of reviewing generic drug applications and inspecting facilities. This will enable the FDA in the following aspects

O Reduce Current backlog of pending drug applications

O Cut the average time required to review them for safety

O Increase risk-based inspections.

O Enhance global supply chain safety by requiring generic drug facilities/sites worldwide to self-identify and meet FDA standards for safety, purity and effectiveness.[5]


About the Author

Omkara Swami Muddineti's picture

I have two years experience in Formulation R&D after completion of my M.Pharm (Pharmaceutics) from BITS Pilani. I Qualified GATE-2009 with 98.68 percentile. Currently I am pursuing Ph.D from BITS Pilani. My area of interest is development of lipid based nanocarriers for delivery of chemotherapeutics.

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