FDA's Pharmaceutical Quality Initiatives: Implementation of a Modern Risk-based Approach - Pharmaceutical Technology

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FDA's Pharmaceutical Quality Initiatives: Implementation of a Modern Risk-based Approach
The US Food and Drug Administration announced its Pharmaceutical GMPs for the 21st Century initiative six years ago. This article reports on the outcome of a recent workshop on this topic and the action plan set forth.


Pharmaceutical Technology


Case-by-case applications. A case-by-case approach to biotech and biological products was considered appropriate, depending on several factors including manufacturing process control, mechanism of action, level of characterization, and linkage to clinical studies. Platform technologies may be helpful to allow experience from related processes and products to be used to help define design space, but risk assessments need to be product-specific. Some process-specific data may also be needed for each product.

Comparability protocols. Workshop participants felt that such protocols were useful and appropriate, especially for unit operation changes or more involved new-facility or large-scale changes. The relationship of product quality attributes to clinical experience can affect the design space. In establishing a design space, one must consider that process capability and process robustness that may limit the design space. For implementation of QbD with biopharmaceutical products, uncertainty should be identified and controlled to establish a meaningful design space.

Reduction of CMC supplements. Reduction of CMC supplements was considered a good area to apply QbD principles in the short term via expanded use of comparability protocols. For changes to unit operation design space, session participants thought that examination of quality attributes specific to that unit operation plus linkage to downstream unit operations was an adequate approach. Discussants appreciated that some aspects of design space are specific to facilities and equipment.

Process validation breakout report

Pharmaceutical process validation requires a comprehensive understanding of a manufacturing process and a demonstration of adequate control throughout its life cycle. Product life cycle begins with pharmaceutical development. As introduced in ICH Q8, quality can be designed into the manufacturing process from process understanding through establishment of a design space and using a risk-based control strategy. The life cycle begins with product and process development and continues through validation activities to confirm that the developed process works as intended and reproducibly produces the desired product at commercial scale. Because the product is manufactured commercially, the process design is verified with ongoing assessments of process performance. Variability is identified and controlled using existing and emerging tools such as process analytical technology (PAT) applications and risk mitigation strategies. The result is confidence in quality and advances in process understanding so that effective improvements may be implemented.

The decisions that must be made throughout a product's life cycle such as the considerations in establishing design space and the approach to validation, can be based on a risk assessment that considers the degree of confidence required with respect to potential patient impact and supply. The level of confidence or assurance that should be obtained from various studies and evaluations should correspond to the level of risk identified.

Validation consists of process development, process confirmation and continual verification. The traditional three- batch approach to validation is not meaningful—sometimes it provides too much, sometimes too little. Although approaches to process validation may be changing, the principles of process validation have not changed. Participants in this breakout session identified these core principles as:

  • Identifying and controlling what is critical
  • Using in-process measurements as part of evaluation
  • Demonstrating a state of control
  • Demonstrating reproducibility over time
  • Justifying and documenting changes in controls

Process validation confirms the design space and control strategy. The validation approach should be flexible and risk- based dependent upon level of process knowledge and understanding. The challenge often is how to demonstrate knowledge gained at a smaller scale through limited full-scale batches. Consequently, full-scale confirmation should focus on scale-dependent aspects that impact CPQAs.

Session participants felt that risk assessment is valuable to establishing a validation strategy. By using risk assessment, one will be able to identify critical attributes and predict effect of changes, use prior knowledge, and reduce "over validation" for a well-understood process. Risk assessment should be used to determine impact of changes on CPQAs. It is critical that changes are documented and tracked.


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