FDA answers questions to ICH Q8, Q9, and Q10

The FDA has published a new Guidance for Industry: Q8, Q9, and Q10 Questions and Answers*. Since the Q8, Q9, and Q10 guidances were made final, experiences implementing them in the ICH regions have given rise to requests for clarification. This new question and answer (Q&A) document is intended to clarify the key issues. The guidance reflects the current working procedure of the ICH Quality Implementation Working Group (Q-IWG) for implementing the Q8, Q9, and Q10 guidances:

  • Q8 (R2) Pharmaceutical Development (includes the Q8 parent guidance (Part I) and the annex (Part II), which provides further clarification of the Q8 parent guidance and describes the principles of quality by design)
  • Q9 Quality Risk Management
  • Q10 Pharmaceutical Quality Systems

In the first part, a few Q&As strive for general clarification regarding a minimal approach (sometime also called "baseline" or "traditional" approach) and the appropriate approach for process validation using ICH Q8, Q9, and Q10 elements. In this context it is also discussed how information from risk management and continuous process verification can provide for a robust continual improvement approach as, like the product itself, process validation also has a lifecycle (process design, process qualification and ongoing process verification).

A rather big part of the document is dedicated to Quality by Design (QbD) topics. Eight questions and answers on Design Space give quite a good overview of the current expectations regarding getting a desired operational flexibility. It is also discussed that it is possible to develop a design space for existing products. Relevant information should be utilised from e.g., commercial scale manufacturing, process improvement, corrective and preventive action (CAPA), and development data. However there is no regulatory expectation to develop a design space for an existing product unless the applicant has a specific need and desires to use it as a means to achieve a higher degree of product and process understanding, which may increase manufacturing flexibility and/or robustness.
It is also outlined that set of proven acceptable ranges alone does not constitute a design space. However proven acceptable ranges continue to be acceptable from the regulatory perspective (but are not considered a design space).

Another hot topic at the moment is Real-Time Release Testing (RTR) and eleven Q&As are addressed in this section. Differences and relationships between real time release, real-time release testing and control strategies are explained. It is also again emphasised that real-time release testing does not necessarily eliminate all end-product testing. For example, an applicant can propose RTR testing for some attributes only. But if all critical quality attributes (CQAs) (relevant for real-time release testing) are assured by in-process monitoring of parameters and/or testing of materials, then end-product testing might not be needed for batch release. However some product testing will still be expected for certain regulatory processes such as stability studies or regional requirements.

This is followed by a section of Q&As on Control Strategy as defined in the ICH Q10 glossary. Differences in a control strategy for products developed using the minimal approach vs. a quality-by-design approach are discussed and information is given on the relationship between a design space and a control strategy.

A third part is dedicated to the Pharmaceutical Quality System (PQS) in accordance with ICH Q10. These elements are also currently implemented in EU-GMP Guideline. First of all the benefits are outlined like for example:

  • Facilitated robustness of the manufacturing process
  • Transparency of systems, processes, and organizational and management responsibility
  • Reducing risk of product failure and incidence of complaints and recalls
  • Better process performance
  • Increased compliance with GMPs, which builds confidence in the regulators and may result in shorter inspections

Although a company should demonstrate the use of an effective PQS through its documentation (e.g., policies, standards), its processes, its training/qualification, its management, its continual improvement efforts, and its performance against pre-defined key performance indicators, it is not necessary to describe the PQS in a regulatory submission and there will be no specific ICH Q10 certification program developed by the regulatory agencies.

Very interesting is also the fourth part: Impact of new ICH Quality Guidance on GMP Inspection Practices where it is described how inspections might run in the future. There is likely to be greater focus on enhanced process understanding and understanding relationships, e.g., critical quality attributes (CQAs), critical process parameters (CPPs). Inspections might also focus on the application and implementation of quality risk management principles. The inspection process itself will remain similar. However, upon the implementation of ICH Q8, Q9, and Q10, inspections will have greater focus on (but not only focus on) how the PQS facilitates the use of e.g., quality risk management methods and the implementation of design space.

Last but not least a fifth part is dealing with Knowledge Management, which is not a new concept. However it is expected that more complex information generated by appropriate approaches (e.g., QbD, process analytical technology (PAT), real-time data generation, and control monitoring systems) should be better captured, managed, and shared during product life-cycle

*The guidance, which can be found here, was developed within the Quality Implementation Working Group of the ICH and has been subject to consultation by the regulatory parties, in accordance with the ICH process. The Q&As in this document have been endorsed by the ICH Steering Committee at Step 4 of the ICH process, April 2009, June 2009, and October 2009. At Step 4 of the process, the final draft is recommended for adoption to the regulatory bodies of the European Union, Japan, and the United States.

Summarised by
Wolfgang Schmitt
On behalf of the European Compliance Academy (ECA)

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