Process validation and aspects of Process Qualification and Process Performance Qualification (PPQ) c gmp guidelines
During the process qualification (PQ) stage of process validation, the process design is evaluated to determine if it is capable of reproducible commercial manufacture. This stage has two elements: (1) design of the facility and qualification of the equipment and utilities and (2) process performance qualification (PPQ). During Stage 2, CGMP-compliant procedures must be followed. Successful completion of Stage 2 is necessary before commercial distribution. Products manufactured during this stage, if acceptable, can be released for distribution.
Design of a Facility and Qualification of Utilities and Equipment
Proper design of a manufacturing facility is required under part 211, subpart C, of the CGMP regulations on Buildings and Facilities. It is essential that activities performed to assure proper facility design and commissioning precede PPQ. Here, the term qualification refers to activities undertaken to demonstrate that utilities and equipment are suitable for their intended use and perform properly. These activities necessarily precede manufacturing products at the commercial scale. Also see ( process validation in pharma )
1.Qualification of utilities and equipment generally includes the following activities:
Selecting utilities and equipment construction materials, operating principles, and performance characteristics based on whether they are appropriate for their specific uses.
Verifying that utility systems and equipment are built and installed in compliance with the design specifications (e.g., built as designed with proper materials, capacity, and functions, and properly connected and calibrated).
Verifying that utility systems and equipment operate in accordance with the process requirements in all anticipated operating ranges. This should include challenging the equipment or system functions while under load comparable to that expected during
routine production. It should also include the performance of interventions, stoppage, and start-up as is expected during routine production. Operating ranges should be shown capable of being held as long as would be necessary during routine production.
Qualification of utilities and equipment can be covered under individual plans or as part of an overall project plan. The plan should consider the requirements of use and can incorporate risk management to prioritize certain activities and to identify a level of effort in both the performance and documentation of qualification activities. The plan should identify the following items:
1. the studies or tests to use,
2. the criteria appropriate to assess outcomes,
3. the timing of qualification activities,
4. the responsibilities of relevant departments and the quality unit, and
5. the procedures for documenting and approving the qualification.
The project plan should also include the firm’s requirements for the evaluation of changes. Qualification activities should be documented and summarized in a report with conclusions that address criteria in the plan. The quality control unit must review and approve the qualification plan and report (cfr 211.22).
2. Process Performance Qualification (PPQ)
The process performance qualification (PPQ) is the second element of Stage 2, process qualification. The Process Performance Qualification (PPQ) combines the actual facility, utilities, equipment (each now qualified), and the trained personnel with the commercial manufacturing process, control procedures, and components to produce commercial batches. A successful Process Performance Qualification PPQ will confirm the process design and demonstrate that the commercial manufacturing process performs as expected.
Success at this stage signals an important milestone in the product lifecycle. A pharmaceutical manufacturer must successfully complete Process Performance Qualification PPQ before commencing commercial distribution of the drug product. The decision to begin commercial distribution should be supported by data from commercial-scale batches. Data from laboratory and pilot studies can provide additional assurance that the commercial manufacturing process performs as expected.
The approach to Process Performance Qualification PPQ should be based on sound science and the manufacturer’s overall level of product and process understanding and demonstrable control. The cumulative data from all relevant studies (e.g., designed experiments; laboratory, pilot, and commercial batches) should be used to establish the manufacturing conditions in the pharmaceutical manufacturing process performance qualification PPQ. To understand the commercial process sufficiently, the manufacturer will need to consider the effects of scale. However, it is not typically necessary to explore the entire operating range at commercial scale if assurance can be provided by process design data. Previous credible experience with sufficiently similar products and processes can also be helpful. In addition, we strongly recommend firms employ objective measures (e.g., statistical metrics) wherever feasible and meaningful to achieve adequate assurance.
In most cases, Process Performance Qualification PPQ will have a higher level of sampling, additional testing, and greater scrutiny of process performance than would be typical of routine commercial production. The level of monitoring and testing should be sufficient to confirm uniform product quality throughout the batch. The increased level of scrutiny, testing, and sampling should continue through the process verification stage as appropriate, to establish levels and frequency of routine sampling and monitoring for the particular product and process. Considerations for the duration of the heightened sampling and monitoring period could include, but are not limited to, volume of production, process complexity, level of process understanding, and experience with similar drug products and processes.
The extent to which some materials, such as column resins or molecular filtration media, can be re-used without adversely affecting product quality can be assessed in relevant laboratory studies. The usable lifetimes of such materials should be confirmed by an ongoing process Performance Qualification PPQ protocol during commercial manufacture.
A pharmaceutical manufacturing process that uses PAT may warrant a different process performance qualification PPQ approach. PAT processes are designed to measure in real time the attributes of an in-process material and then adjust the process in a timely control loop so the process maintains the desired quality of the output material. The process design stage and the process qualification stage should focus on the measurement system and control loop for the measured attribute. Regardless, the goal of validating any manufacturing process is the same: to establish scientific evidence that the process is reproducible and will consistently deliver quality products. This article is a part of current good manufacturing guidelines on process validation published by US FDA on Jan 2011. Following are the links for next topics on process validation.
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