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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