Subcommittees of the House Committee on Energy and Commerce heard testimony last week from the Government Accountability Office’s Mary Denigan-Macauley and from Janet Woodcock, Director of FDA’s Center of Drug Evaluation and Research, about the state of FDA’s foreign drug establishment inspection program.
ICH Q12 “Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management” was adopted by the ICH in Singapore, which means Q12 is now in Stage 5, Implementation. Implementation should be interesting as concepts like “established conditions” and “product lifecycle management” which sit at the core of Q12 are still open for interpretation as Q12 is implemented in specific regulatory markets.
This draft guidance is now in a review period by regulatory agencies. Which means no public comments, but it will be applied on a 6-month trial basis by PIC/S participating authorities, which include the US Food and Drug Administration and other regulators across Europe, Australia, Canada, South Africa, Turkey, Iran, Argentina and more.
This document is aligned to ICH Q10, and there should be few surprised in this. Given PIC/S concern that “ongoing continual improvement has probably not been realised to a meaningful extent. The PIC/S QRM Expert Circle, being well-placed to focus on the QRM concepts of the GMPs and of ICH Q10, is seeking to train GMP inspectors on what a good risk-based change management system can look like within the PQS, and how to assess the level of effectiveness of the PQS in this area” it is a good idea to start aligning to be ahead of the curve.
“Changes typically have an impact assessment performed within the change control system. However, an impact assessment is often not as comprehensive as a risk assessment for the proposed change.”
This is a critical thing that agencies have been discussing for years. There are a few key takeaways.
The difference between impact and risk is critical. Impact is best thought of as “What do I need to do to make the change.” Risk is “What could go wrong in making this change?” Impact focuses on assessing the impact of the proposed change on various things such as on current documentation, equipment cleaning processes, equipment qualification, process validation, training, etc. While these things are very important to assess, asking the question about what might go wrong is also important as it is an opportunity for companies to try to prevent problems that might be associated with the proposed change after its implementation.
This 8 page document is really focusing on the absence of clear links between risk assessments, proposed control strategies and the design of validation protocols.
The guidance is very concerned about appropriately classifying changes and using product data to drive decisions. While not specifying it in so many words, one of the first things that popped to my mind was around how we designate changes as like-for-like in the absence of supporting data. Changes that are assigned a like-for-like classification are often not risk-assessed, and are awarded limited oversight from a GMP perspective. These can sometimes result in major problems for companies, and one that I think people are way to quick to rush to.
It is fascinating to look at appendix 1, which really lays out some critical goals of this draft guidance: better risk management, real time release, and innovative approaches to process validation. This is sort of the journey we are all on.
The FDA has posted the 2019 483 observations as an excel file. The FDA has made these files available every year since 2006 and I find them to be one of my favorite tools for evaluating regulatory trends.
So for example, looking at change related 483 I see:
The Pharmaceutical Inspection Convention Cooperation Scheme (PIC/S) on 01-Jan-2019 released a long-awaited guidance to help regulators harmonize the classification and reporting of good manufacturing practice (GMP) deficiency outcomes from inspections. The guidance is designed as a “tool to support the risk-based classification of GMP deficiencies from inspections and to establish consistency amongst inspectorates.”
On 30-Nov-2018 PIC/S published the third draft of guidance PI 041-1 “Good Practices for Data Management and Data Integrity in regulated GMP/GDP Environments“. The first draft was published back in 2016, and the third draft is subject to a focused stakeholder consultation seeking substantive comments from trade and professional associations on specific questions relating to the proportionality, clarity and implementation of the guidance requirements. In parallel to this stakeholder consultation, the new draft is applied by PIC/S Participating Authorities on a trial basis for a new implementation trial period (3 months).
In short, you can expect inspectors to have reviewed and be reviewing against this. Do your gap analysis now and have plans in place to address the gaps. Yes, there will be a little while before this is finally published, but at this point this guidance neatly triangulates with other guidances on data integrity and we can expect most of this to be in the final version.
This document is a great place to start and can be used to develop whole sections of the quality management system. I find it very actionable. For example this table from 9.5 “Data capture/entry for computerised systems”: