Pharmaceutical Process Validation: Emplication of New FDA Guidelines

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B. Stage 1 ? Process Design
Process design is the activity of defining the commercial manufacturing process that will be reflected in planned master production and control records. The goal of this stage is to design a process suitable for routine commercial manufacturing that can consistently deliver a product that meets its quality attributes.

1. Building and Capturing Process Knowledge and Understanding
Generally, early process design experiments do not need to be performed under the CGMP conditions required for drugs intended for commercial distribution that are manufactured during Stage 2 (process qualification) and Stage 3 (continued process verification). They should, however, be conducted in accordance with sound scientific methods and principles, including good documentation practices. This recommendation is consistent with ICH Q10 Pharmaceutical Quality System. Decisions and justification of the controls should be sufficiently documented and internally reviewed to verify and preserve their value for use or adaptation later in the lifecycle of the process and product.

2. Establishing a Strategy for Process Control
Process knowledge and understanding is the basis for establishing an approach to process control for each unit operation and the process overall. Strategies for process control can be designed to reduce input variation, adjust for input variation during manufacturing (and so reduce its impact on the output), or combine both approaches.

FDA expects controls to include both examination of material quality and equipment monitoring. Special attention to control the process through operational limits and in-process monitoring is essential in two possible scenarios:
1.      When the product attribute is not readily measurable due to limitations of sampling or detectability (e.g., viral clearance or microbial contamination) or
2.      When intermediates and products cannot be highly characterized and well-defined quality attributes cannot be identified.

C. Stage 2 ? Process Qualification
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.

1. 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.

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).  

2. Process Performance Qualification
The process performance qualification (PPQ) is the second element of Stage 2, process qualification. The 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 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 manufacturer must successfully complete PPQ before commencing commercial distribution of the drug product.16 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.

3. PPQ Protocol
A written protocol that specifies the manufacturing conditions, controls, testing, and expected outcomes is essential for this stage of process validation. We recommend that the protocol discuss the following elements:

  • The manufacturing conditions, including operating parameters, processing limits, and component inputs.
  • The data to be collected and when and how it will be evaluated.
  • Tests to be performed and acceptance criteria for each significant processing step.
  • Criteria and process performance indicators that allow for a science- and risk-based decision about the ability of the process to consistently produce quality products. The criteria should include:
  • A description of the statistical methods to be used in analyzing all collected data.
  • Provision for addressing deviations from expected conditions and handling of nonconforming data. Data should not be excluded from further consideration in terms of PPQ without a documented, science-based justification.
  • Design of facilities and the qualification of utilities and equipment, personnel training and qualification, and verification of material sources (components and container/closures), if not previously accomplished.
  • Status of the validation of analytical methods used in measuring the process, in-process materials, and the product.
  • Review and approval of the protocol by appropriate departments and the quality unit.

4. PPQ Protocol Execution and Report
Execution of the PPQ protocol should not begin until the protocol has been reviewed and approved by all appropriate departments, including the quality unit. Any departures from the protocol must be made according to established procedure or provisions in the protocol. Such departures must be justified and approved by all appropriate departments and the quality unit before implementation.

A report documenting and assessing adherence to the written PPQ protocol should be prepared in a timely manner after the completion of the protocol. This report should:

  • Discuss and cross-reference all aspects of the protocol.
  • Summarize data collected and analyze the data, as specified by the protocol.
  • Evaluate any unexpected observations and additional data not specified in the protocol.
  • Summarize and discuss all manufacturing nonconformances such as deviations, aberrant test results, or other information that has bearing on the validity of the process.
  • Describe in sufficient detail any corrective actions or changes that should be made to existing procedures and controls.
  • Include all appropriate department and quality unit review and approvals.

D. Stage 3 ? Continued Process Verification
The goal of the third validation stage is continual assurance that the process remains in a state of control during commercial manufacture. A system or systems for detecting unplanned departures from the process as designed is essential to accomplish this goal. Adherence to the CGMP requirements, specifically, the collection and evaluation of information and data about the performance of the process, will allow detection of undesired process variability. Evaluating the performance of the process identifies problems and determines whether action must be taken to correct, anticipate, and prevent problems so that the process remains in control.

An ongoing program to collect and analyze product and process data that relate to product quality must be established. The data collected should include relevant process trends and quality of incoming materials or components, in-process material, and finished products. The data should be statistically trended and reviewed by trained personnel. The information collected should verify that the quality attributes are being appropriately controlled throughout the process.

In most cases, the PPQ study needs to be completed successfully and a high degree of assurance in the process achieved before commercial distribution of a product. In special situations, the PPQ protocol can be designed to release a PPQ batch for distribution before complete execution of the protocol steps and activities, i.e., concurrent release. FDA expects that concurrent release will be used rarely.

Concurrent release might be appropriate for processes used infrequently for various reasons, such as to manufacture drugs for which there is limited demand or which have short half lives (e.g., radiopharmaceuticals, including positron emission tomography drugs). Concurrent release might also be appropriate for drugs that are medically necessary and are being manufactured in coordination with the Agency to alleviate a short supply.

Documentation at each stage of the process validation lifecycle is essential for effective communication in complex, lengthy, and multidisciplinary projects. Documentation is important so that knowledge gained about a product and process is accessible and comprehensible to others involved in each stage of the lifecycle.

The degree and type of documentation required by CGMP vary during the validation lifecycle. Documentation requirements are greatest during Stage 2, process qualification, and Stage 3, continued process verification. Studies during these stages must conform to CGMPs and must be approved by the quality unit in accordance with the regulations. Viral and impurity clearance studies, even when performed at small scale, also require quality unit oversight.

Process knowledge depends on accurate and precise measuring techniques used to test and examine the quality of drug components, in-process materials, and finished products. Validated analytical methods are not necessarily required during product- and process-development activities or when used in characterization studies. Nevertheless, analytical methods should be scientifically sound (e.g., specific, sensitive, and accurate) and provide results that are reliable. There should be assurance of proper equipment function for laboratory experiments. Procedures for analytical method and equipment maintenance, documentation practices, and calibration practices supporting process-development efforts should be documented or described. New analytical technology and modifications to existing technology are continually being developed and can be used to characterize the process or the product.



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