Objective 4
FDA’s “Compliance Program Guidance Manual” (CPGM) 7346.832, which provides an in-depth guide for the investigator on factors to consider when performing a “Pre-Approval Inspection” (PAI), was revised in October 2022 with little fanfare. This is surprising, considering the significance of this CPGM to the overall application approval process. The previous guidance had been released in August 2019, and was effective for just over three years (a very short lifespan for regulatory guidance!). Interestingly, the PAI program was an outcome of serious fraud and corruption uncovered in the mid 1980’s, commonly referred to as the “generic drug scandal”. The program was designed to prevent fraudulent applications from gaining approval via a vigorous on-site inspection. The inspection outcome performed according to the CPGM, combined with the expert review of the various application components, come together near the end of the process to inform the overall approval decision. The PAI process has long included the following three traditional objectives:
Objective 1 - Readiness for commercial manufacturing: is the firm capable of producing the drug at commercial scale, or will the site struggle to maintain a consistent supply, resulting in drug shortages?
Objective 2 – Conformance to Application: was the process, equipment, and other factors consistent with what is observed during the on-site inspection?
Objective 3 – Data Integrity: were the data submitted in the application accurate and complete?
Firms have traditionally prepared for evaluation of these three objectives the best they can, considering the investigator will likely take a risk-based approach to coverage of each objective.
What stands out in this new revision is the addition of a new objective, titled “Objective 4 - Commitment to Quality in Pharmaceutical Development”. This objective is a break from the traditional compliance approach to inspection, and is aligned with other recent FDA whitepapers, namely FDA’s vision for Quality Management Maturity (QMM). This objective appears to be an attempt to gauge the level of maturity within the firm’s product development program, with two keywords standing out: knowledge management and quality risk management. For the regulator (and patient), these ingredients are important, considering the approval process is largely based on trust: the expert review and inspection activities only evaluate the tip of the much larger product development iceberg. Has the firm been transparent with all relevant development outcomes? Again – the process is largely built on trust, which can be tricky considering human nature – namely the universal faults with regard to conflict of interest and cognitive dissonance!
How can we limit these universal human flaws? The answer comes in the form of systematic tools for capturing knowledge (knowledge management) and evaluating that knowledge through the patient safety lens (quality risk management). Without firmly established and mature tools, bias is allowed to creep in like the cockroaches of central Texas… and the result is unpleasant for everyone involved.
Speaking of systematic tools, ICH Q8 “Quality by Design”, which has been around since 2006, provides a harmonized guide for building quality into the development process, so in reality the addition of objective 4 and the evaluation of a firm’s maturity should come as no surprise… Any grace period needed to adapt the concepts behind Q8 into a given development program has long since passed.
A quick self-evaluation can be performed to gauge one’s inspection readiness for 2024:
Knowledge Management: Has management provided the solutions necessary to ensure information gathered during development can be transformed to knowledge via digitization? To gauge one’s maturity, use the FAIR principles as the standard for success.
Quality Risk Management: Has management updated the overall QRM program in line with last year’s revisions to ICH Q9? To gauge one’s maturity, use the spectrum of formality with regard to available QRM tools (from a risk memo to FMEA) as the standard for success.
This is already a long post for a blog, and my flight is landing soon, so I will wrap it up here: In summary, management investment in the product development program should be sufficient to allow adaption to updated regulatory guidance. If data are still captured on paper (or paper on glass), your firm runs the risk that a poor maturity evaluation may lead to a loss in confidence regarding the accuracy and completeness of your application. This will likely lead to delays in product approval until additional verification can be completed either through written correspondence or a follow-up secondary on-site/remote inspection. Consider the approval process from the regulatory/patient perspective and the iceberg analogy, and it really is a “no-brainer” – a mature quality system within development (don’t worry, this is different than commercial GMP) is no longer optional. It’s time to implement flexible and risk-based tools that will unleash critical thinking throughout your organization and bring high-quality medicines to patients without regulatory delays.
Pete
