QbD Validation Strategies: The Process Design Phase Part 1

By Anil Doshi, R.Ph., Ph.D, President, Infinity Pharmaceutical Consulting

Process validation comprises three stages that take place over the life cycle of the pharmaceutical drug product.[1]  (See Figure 1.)  Stage 1, which will be the focus of this column, is referred to as process design, and encompasses pharmaceutical drug products in early development. Stage 2 is referred to as process qualifications, and includes pharmaceutical drug products at a stage prior to commercialization or prior to submitting a New Drug Application (NDA) or Abbreviated New Drug Application (ANDA).  Stage 3 is referred to as continued process verification and includes pharmaceutical drug products that are commercialized and currently marketed products with completed prospective validation. Products that fall in between these categories will need to be assessed on a case-by-case basis and can be placed in the appropriate stage using a "gateway" approach.

Documents for process validation studies at each stage are described in Table I.  To proceed from stage 1 to stage 2 (gateway 1), the following documents must be completed and approved internally by the company[2]: a development report, a risk assessment, a control strategy document, and a final manufacturing process description.  To proceed from stage 2 to stage 3 (gateway 2) an approved process performance qualification report must be completed and approved as well.

Documents for Process Validation

Table 1

Process Design (Stage 1)

Process design is achieved through well-defined and established internal processes that are based on Quality by Design (QbD) guidelines.[3]  While QbD is not a mandated FDA requirement, it is recommended to implement a systematic process to evaluate and understand formulation and manufacturing processes using prior knowledge, experimentation and risk assessment. The following describes the key action elements to process design:

1. Develop Quality by Design (QbD) Comprehensive Evaluation:  A company should develop consistent internal evaluation systems and identify material attributes (e.g., API and critical excipient) and process parameters, to product critical quality attributes (e.g., CQAs).

2. Identify Critical Quality Attributes (CQAs):  All quality attributes for the product should be evaluated by a company based on a quality target product profile (QTPP).  Potential CQAs should be identified based on an evaluation of the severity of the attribute in terms of the impact, which is based on clinical experience and in-vitro studies.

3. Provide Risk Assessment:  A company must assess the impact of material, process, and environmental variables on the potential CQAs. A risk assessment enables the synthesis of important information for the development of control strategy. This strategy can be revised on an ongoing basis to continue to enhance the company's understanding of its product and processes.

4. Execute Product/Process Development:   A company should conduct process design experiments on generally accepted scientific principles. Only those experiments that result in material being used for clinical trials need to be conducted under cGMP conditions. The subjectivity within a process, such as different API lots, production operators, limitations of commercial manufacturing equipment, environmental conditions, and measurement systems should be considered in the product design process. While validating analytical methods is not necessarily required, analytical methods adopted by the company should be well-defined and provide accurate and consistent results that can be relied upon.

5. Develop Critical Process Parameters (CPPs):  CPPs should be developed based on the knowledge gained during process development.  CPPs should be consistent with corresponding CQAs.

6. Establish Product/Process Design Space:  While not necessary for each operation, design space is developed by relying on knowledge gained from the process development studies and input from is a specific defined process that have been demonstrated to provide quality.

7. Plan Control Strategy:  A control strategy is a planned set of controls, derived from product and process understanding which assures process performance and product quality. Control strategies should consider material quality, equipment monitoring and environmental conditions. Control strategies are expected and are needed for stage 2.

In summary, in the process design phase, the process development will develop the manufacturing process. This manufacturing process will yield products with consistent quality that is sufficiently characterized so that the process can be successfully validated to stage 2 process qualification.

In my next communication, I will be addressing Stage 2 process qualification and Stage 3 continued process verification.

About The Author:

Anil is the president of Infinity Pharmaceutical Consulting, which provides product and process development, technical transfer, manufacturing, regulatory, and management strategies to the life science industries. For any questions, please contact anilinfinity@optonline.net, or call 973-538-1725