Regulatory Focus on Change Management

November was an exciting month for change management!

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.

And then, to end the month, PIC/S published draft 1 of PI 054-1 “Recommendation on How to Evaluate / Demonstrate the Effectiveness of a Pharmaceutical Quality System in relation to Risk-based Change Management.”

This draft guidance is now in a review period by regulatory agencies.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.

  1. 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.
  2. 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.
  3. 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.

Much of my thoughts on implementing this can be found in my presentation on change management and change control.

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.

FDA launching pilot program on established conditions

The FDA has announced a pilot program to “propose explicit established conditions (ECs) as part of an original new drug application (NDA),
abbreviated new drug application (ANDA), biologics license application
(BLA), or as a prior approval supplement (PAS) to any of these.”

As the FDA mentioned, this is a followup of two draft guidances: The 2015 FDA ‘‘Established Conditions: Reportable CMC Changes for Approved Drug and Biologic Products’’and the draft Q12.

It is exciting to see Q12 move forward. We can argue about its imperfections, but at the end of the day this is a big step for the industry.

ICH charts a course

Last week the ICH published a reflection paper “Advancing Biopharmaceutical Quality Standards to Support Continual Improvement and Innovation in Manufacturing Technologies and Approaches.”

The ICH contines to move beyond the prescriptive guidances of Q1-7 and focus more on strengthening the conceptual framework of Q8-Q11 (see some of my thoughts here). There is a lot of talk about strengthening relationships and alignment between regulatory agencies, which is definitely needed. Q12 has had a bumpy road of it (EU saying they might not implement, US FDA issuing a guidance that’s not all that aligned). We see a firm commitment to continuing the QbD work with Q13 (continuous manufacturing) and Q14 (Analytical methods).

Interesting timing with the FDA recent announcement on generics.

FDA issues new guidance on Post Approval Changes

This past week the FDA issued a draft guidance “Post Approval Changes to Drug Substances” from the Center for Drug Evaluation and Research on post-approval changes for drug substances to provide clarity to holders of drug master files and holders of new and generic drug applications on which reporting category manufacturing changes fall into as well as the information required to support these changes.

Like any guidance this is supposed to “describe the Agency’s current thinking on a topic” and in this case this is a pretty important guidance as it is the first on the subject of change management published after the draft of Q12. It also clearly builds on the concepts of Q11 and is the first time the agency has published a guidance on drug substance post approval changes.

The guidance covers changes to facility; scale and equipment changes; specification changes to starting materials; synthetic manufacturing process changes; and, changes to the container closure systems for the drug substance.

It uses the traditional breakdown of major changes (prior approval supplement category), Moderate changes (changes-being-effected-30 (CBE-30) category) and Minor changes (annual report).

The guidance provides some solid requirements for risk assessments, and requires the risk assessment be included with the filing of change. This will require some companies to improve their risk management process, and may cause some to question decision making about their internal formulas for level of effort and the formality of risk management.

The deadline for public comment on the draft is Nov. 13. Submit comments to the docket at: https://www.regulations.gov/docket?D=FDA-2018-D-3152.