Product Development and Selection Generic Drug

The aim of pharmaceutical development is to design a quality product and its manufacturing process to consistently deliver the intended performance of the product. The information and knowledge gained from pharmaceutical development studies and manufacturing experience provide scientific understanding to support the establishment of the design space, specifications, and manufacturing controls.

Information from pharmaceutical development studies can be a basis for quality risk management. It is important to recognize that quality cannot be tested into products; i.e., quality should be built in by design. Changes in formulation and manufacturing processes during development and lifecycle management should be looked upon as opportunities to gain additional knowledge and further support the establishment of the design space. Similarly, the inclusion of relevant knowledge gained from experiments giving unexpected results can also be useful. Design space is proposed by the applicant and is subject to regulatory assessment and approval. Working within the design space is not considered a change. Movement out of the design space is considered to be a change and would normally initiate a regulatory post-approval change process.

At a minimum, those aspects of drug substances, excipients, container closure systems, and manufacturing processes that are critical to product quality should be determined and control strategies justified. Critical formulation attributes and process parameters are generally identified through an assessment of the extent to which their variation can have an impact on the quality of the drug product.

In addition, the applicant can choose to conduct pharmaceutical development studies that can lead to an enhanced knowledge of product performance over a wider range of material attributes, processing options, and process parameters. The inclusion of this additional information in this section provides an opportunity to demonstrate a higher degree of understanding of material attributes, manufacturing processes, and their controls. This scientific understanding facilitates the establishment of an expanded design space. In these situations, opportunities exist to develop more flexible regulatory approaches, for example, to facilitate:

1. Risk-based regulatory decisions (reviews and inspections);
2. Manufacturing process improvements, within the approved design space described in the dossier, without further regulatory review;
3. Reduction of post-approval submissions;
4. Real-time quality control, leading to a reduction of end-product release testing.

To realize this flexibility, the applicant should demonstrate an enhanced knowledge of product performance over a range of material attributes, manufacturing process options, and process parameters. This understanding can be gained by application of, for example, formal experimental designs, process analytical technology (PAT), and/or prior knowledge. Appropriate use of quality risk management principles can help prioritize the additional pharmaceutical development studies to collect such knowledge.

The design and conduct of pharmaceutical development studies should be consistent with their intended scientific purpose. It should be recognized that the level of knowledge gained, and not the volume of data, provides the basis for science-based submissions and their regulatory evaluation.

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Components of the Drug Product

Drug Substance

• The physicochemical and biological properties of the drug substance that can influence the performance of the drug product and its manufacturability, or were specifically designed into the drug substance (e.g., solid state properties), should be identified and discussed. Examples of physicochemical and biological properties that might need to be examined include solubility, water content, particle size, crystal properties, biological activity, and permeability. These properties could be interrelated and might need to be considered in combination.

• To evaluate the potential effect of drug substance physicochemical properties on the performance of the drug product, studies on the drug product might be warranted. The knowledge gained from the studies investigating the potential effect of drug substance properties on drug product performance can be used, as appropriate, to justify elements of the drug substance specification.
• The compatibility of the drug substance with excipients should be evaluated. For products that contain more than one drug substance, the compatibility of the drug substances with each other should also be evaluated.

Excipients

• The excipients are chosen by their concentration and the characteristics that can influence the drug product performance (e.g., stability, bioavailability) or manufacturability should be discussed relative to the respective function of each excipient. 
• This should include all substances used in the manufacture of the drug product, whether they appear in the finished product or not (e.g., processing aids). Compatibility of excipients with other excipients, where relevant (for example, a combination of preservatives in a dual preservative system), should be established. 
• The ability of excipients (e.g., antioxidants, penetration enhancers, disintegrants, release controlling agents) to provide their intended functionality, and to perform throughout the intended drug product shelf life, should also be demonstrated. 
• The information on excipient performance can be used, as appropriate, to justify the choice and quality attributes of the excipient, and to support the justification of the drug product specification.
• Information to support the safety of excipients, when appropriate, should be cross-referenced.

Drug Product

Formulation Development

• A summary should be provided describing the development of the formulation, including identification of those attributes that are critical to the quality of the drug product, taking into consideration intended usage and route of administration. Information from formal experimental designs can be useful in identifying critical or interacting variables that might be important to ensure the quality of the drug product.
• The summary should highlight the evolution of the formulation design from the initial concept up to the final design. This summary should also take into consideration the choice of drug product components (e.g., the properties of the drug substance, excipients, container closure system, and any relevant dosing device), the manufacturing process, and, if appropriate, knowledge gained from the development of similar drug product(s).
• Any excipient ranges included in the batch formula should be justified in this section of the application; this justification can often be based on the experience gained during development or manufacture.
• A summary of formulations used in clinical safety and efficacy and in any relevant bioavailability or bioequivalence studies should be provided. Any changes between the proposed commercial formulation and those formulations used in pivotal clinical batches and primary stability batches should be clearly described and the rationale for the changes provided.

• Information from comparative in vitro studies (e.g., dissolution) or comparative in vivo studies (e.g., bioequivalence) that links clinical formulations to the proposed commercial formulation should be summarized and a cross-reference to the studies (with study numbers) should be provided. 
• Where attempts have been made to establish an in vitro/in vivo correlation, the results of those studies, and a cross-reference to the studies (with study numbers), should be provided in this section. A successful correlation can assist in the selection of appropriate dissolution acceptance criteria, and can potentially reduce the need for further bioequivalence studies following changes to the product or its manufacturing process.
• Any special design features of the drug product (e.g., tablet score line, overfill, anti-counterfeiting measure as it affects the drug product) should be identified and a rationale provided for their use.

Overages

• In general, the use of an overage of a drug substance to compensate for degradation during manufacture or a product’s shelf life, or to extend shelf life, is discouraged.
• Any overages in the manufacture of the drug product, whether they appear in the final formulated product or not, should be justified considering the safety and efficacy of the product. 
• Information should be provided on the 

1. amount of overage, 
2. reason for the overage (e.g., to compensate for expected and documented manufacturing losses), 
3. justification for the amount of overage. 

• The overage should be included in the amount of drug substance listed in the batch formula.

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Physicochemical and Biological Properties

• The physicochemical and biological properties relevant to the safety, performance, or manufacturability of the drug product should be identified and discussed. This includes the physiological implications of drug substance and formulation attributes. 
• Studies could include, for example, the development of a test for the respirable fraction of an inhaled product. Similarly, information supporting the selection of dissolution vs. disintegration testing, or other means to assure drug release and the development and suitability of the chosen test, could be provided in this section.

To develop a generic drug product following eight points are to be considered.

1. Patent expiration, exclusivity, and legal issues.
2. Active Pharmaceutical Ingredients (API) availability.
3. Sales and potential market share/volume.
4. Technology.
5. Formulation.
6. Experience.
7. Timing.
8. Cost.

Patent expiration, exclusivity, and legal issues:

• The expiration date of the patents for Active ingredients, Formulation composition, and Process. The generic firm must be considered.
• For any exclusivity that the innovator firm has filled, the generic firm must be considered.
• Legal issues must be considered. e.g.: Narcotic drugs

Active Pharmaceutical Ingredients (API) Availability:

• DMF availability
• Impurity profile and stability
• Potential Polymorphic forms
• Commitment to physical specifications e.g. Bulk density and Particle size distribution
• Statement of non-patent infringement
• Cost of API and Impurities.

Sales and potential market share/volume:

• The selection of generic drug products for development is to be estimated sales volume of the branded product and other generic drug product manufacturers.
• The potential market share that the firm is expected after approval.

Technology:

• The availability of technology and the cost of acquiring technology for the development and manufacture of generic drug products will also impact the choice of generic drugs.
• e.g. If the technology required a fluidized bed processor, Hot melt extrusion, or any special equipment then it must be considered whether the equipment is available or required to be acquired.

Formulation:

• Formulation considerations include the availability of active ingredients, special excipients, and any critical process in the innovator formulation.

Experience:

• The expertise of the research and development employees, employed by the company.

Timing:

• The predicted profitability of the generic product with required will require strategic planning for the subsequent lunch timing, which must take into account the expected generic price knowledge of the anticipated competition.

Cost:

1. Cost of active pharmaceutical ingredient(s) (API).
2. Cost of excipients.
3. Cost of packing materials.
4. Special equipment is required for development and Manufacturing.
5. Cost for analysis. (Method development, routine analysis, and Validation).
6. Facility requirements e.g. Low Relative Humidity.
7. Special bioequivalence (BE) related study. e.g. BE study type and Population.

Industries must consider the cost of developing a generic drug product.

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