The History of Phase Appropriate Quality

The FDA first began discussing risk and risk-based strategies in the late 1990s resulting in the publication of the report Pharmaceutical CGMPs in the 21st Century – A Risk-Based Approach (FDA, 2004).  Building on this, the EU soon introduced ICH Guideline Q8 (R2) on Pharmaceutical Development (ICH, 2004) introducing the concept of risk-based Quality by Design (QbD) which was then followed by ICH Guideline Q9 on Quality Risk Management (ICH, 2006).

With the risk foundation firmly established, FDA then applied these concepts to Phase Appropriate GMP which was first formalized in FDA’s Guidance for Industry: CGMP for Phase 1 Investigational Drugs (FDA, 2008). This guidance offered a risk-based path to the application of the GMPs for drugs manufactured for use in Phase 1 clinical studies.

Although the guidance was issued in 2008, today surprisingly few manufacturers are taking advantage of this offered flexibility.  Instead, they continue to apply the time-consuming and costly practices of the full GMPs regardless of their phase of drug development. 

Why, when a regulatory agency offers regulatory flexibility, would manufacturers not take advantage of the reduced requirements?

The answer to this question is critically important and surprisingly simple.  People (and companies) are comfortable with what they already know and what they have previously done.  Add to this the fact that many quality people do not know how to ‘reduce’ requirements (even when they are encouraged to do so) and the result is a slow or total reluctance to adopt a phase appropriate GMP approach. 

Also, as we all know, change in the pharmaceutical industry occurs at a glacial pace. As the guidance was issued in 2008, it is frustrating, but somewhat understandable that many companies still are not taking advantage of this available flexibility.

The Difficulties with Implementing Phase Appropriate GMP – It’s all about Risk!

Why is the concept of phase appropriate so difficult to adopt and implement?

For a quality person or team, one problem with implementing a ‘phase appropriate quality system’ is that doing so typically requires the establishment of more than one quality approach.

Designing a QMS to be phase appropriate requires the QMS process design team to build a risk-based model into the workflow of the system. This means for example that one of the first questions asked in a quality workflow process is “what is the stage of development for the product in question”?  Based on the stage of development the workflow will then typically need to take a different risk-based approach to resolving the problem.  This necessarily creates additional complexity.

Phase Appropriate QMS

The design of a QMS intended to be used for all stages of pharmaceutical production needs to apply risk-based principals in order to determine the appropriate quality approach for the given problem.  For example, the selection and auditing of a raw material or component supplier used in the production of a phase 1 product has a lower risk than for a later phase product.  In such a case, a paper audit may be required, but it is unlikely that a physical audit would be appropriate.  In fact, for many materials even a paper audit may not be required. Instead, it may be appropriate to rely simply on a CofA from the supplier to use the material.

Similarly, changing a step in the manufacturing process is different based on the product stage.  For early phase products, often only changes likely to impact the final dosage form or product safety need to be considered.

The design of the QMS needs to incorporate product phase as one of the very first questions when it comes to making a quality decision. Based on the clinical phase application, the workflow paths apply a graded quality risk approach.

While it is easier to design phase-appropriate quality into a QMS during the design of the QMS, it is possible to ‘retrofit’ these concepts into an existing QMS.