Interpreting Q7

The latest version (version 14) of the “How to do” Document – Interpretation of ICH Q7 Guide and “Review form” for APIs was published a few months back. It is intended to facilitate the implementation of the ICH Q7 Guideline and provides recommendations on interpretation.

In this version, the responsible Task Force of the Quality Group of APIC, which is a sector group of the European Chemical Industry Council (CEFIC), mainly made additions and updates in chapters 11 –  Laboratory Controls, 15 – Complaints and Recalls, and in section 16 – Contract Manufacturers (incl. Laboratories).

The addition in section 11.11 for “Approval/rejection of materials” is pretty striaghtforward – have an SOP.

The changes in section 15 for recalls is pretty cosmetic.

I would re-read section 16 on contract manufacturers. Not much substantial here, but the rewrite makes it a good time to ensure compliance.

Rocky Road to ICH Q12 Implementation

Prior to the adoption of Q12 in Singapore at the end of 2019 there was a lot of rumbling from regulatory agencies on how Q12 would be more aspirational in many ways. In the last few weeks we’ve started to see just what that will mean.

FDA to release a guidance

The FDA’s Mahesh Ramanadham, from the Office of Pharmaceutical Quality in the FDA’s Center for Drug Evaluation and Research, provided an update on the agency’s implementation of ICH Q12 in the US on 25 February at the annual IFPAC meeting in North Bethesda, Md. He started that the FDA will soon be issuing guidance implementing the International Council on Harmonization’s Q12 guideline in the US that will, among other things, translate ICH post-approval change classification categories to FDA supplement categories, and address how to file established conditions (ECs).

This Q12 guidance will replace the agency’s 2015 draft guidance for industry on established conditions and reportable chemistry, manufacturing and controls changes to approved drug and biological products. It is expected to be issued in May 2020. The guidance will also discuss the relationship between FDA comparability protocols and the post-approval change management protocol (PACMP) established by the ICH Q12 guideline.

EU says not so fast in their adoption

However, additional scientific risk-based approaches to defining Established Conditions and
associated reporting categories, as described in Chapter 3.2.3, and the Product Lifecycle
Management (PLCM) Document, as described in Chapter 5, are not considered compatible with the
existing EU legal framework on variations.

It is important to note that the legal framework always takes precedence over technical and
scientific guidelines. More specifically this means that the definition of Established Conditions and
their reporting categories must follow the requirements laid down in the current EU Variations
Regulation and associated EU Variations Guidelines. With respect to the Product Lifecycle
Management (PLCM) document, in case such a document is submitted, it cannot be currently
recognised in the EU due to the fact that it is not referred to in the EU legal framework.

EMA/CHMP/ICH/78332/2020

In an explanatory note accompanying the adoption of ICH Q12 and related annexes, the European Commission and the European Medicines Agency point out that there are “some conceptual differences” between the ICH guideline and the EU legal framework on managing post-approval changes, ie, the variations regulation (Regulation (EC) No 1234/2008).

The EU authorities offer no clarity on when and how ICH Q12 would be fully implemented in the EU. The note merely states that the new “tools and concepts in the ICH Q12 guideline that are not foreseen in the EU legal framework will be considered when this framework will be reviewed.” The EU regulators said they would continue to work on the implementation of the ICH Q12 within the existing EU legal framework. The explanatory note also points out that despite some conceptual differences between ICH Q12 and the EU framework, there is also considerable common ground. In fact, some tools and concepts in ICH Q12 tools can already be applied by industry by following the current EU variations framework.

Next Steps

Companies should be ensuring that their knowledge management and risk management processes and understanding continue to grow. ICH Q12 will be a rocky road and I’m not sure we’ll see some of the potential streamlining of regulatory processes for a long time.

ICH Q12 pathway for established conditions

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.

Driving for Mature Quality Organizations – FDA recent perspective

Theresa Mullin, FDA’s Associate Director for Strategic Initiatives for the Center for Drug Evaluation and Research recently gave a presentation “Update from FDA CDER” at GMP by the Sea (I need to go to that that some-year).

As in other FDA presentations this presentation summarized the Quality Metrics Research Final Report by the University of St. Gallen as the appropriate steps to ensure quality maturity:

  1. Optimized set-up and cleaning procedures are documented as best practice process and rolled out throughout the whole plant.
  2. A large percentage of equipment on the shop floor is currently under statistical process control.
  3. For root cause analysis, the firm has standardized tools to get a deeper understanding of the influencing factors for problems.
  4. Goals and objectives of the manufacturing unit are closely linked and consistent with corporate objectives and the site has a clear focus.
  5. Manufacturers have joint improvement programs with suppliers to increase performance.
  6. All potential bottleneck machines are identified and supplied with additional spare parts.
  7. For product and process transfers between different units or sites,standardized procedures exist that ensure a fast, stable and compliant knowledge transfer.
  8. Charts showing the current performance status such as current scrap rates and current up times are posted on the shop floor and visible for everyone.
  9. The firm regularly surveys customers’ requirements.
  10. The firm ranks its suppliers and conducts supplier qualifications and audits.

This are some pretty low hanging fruit. They are also the pretty necessary in any organization, not just pharmaceuticals.

There was also a little discussion on the use of Q10 that really makes me wish I had been there to hear exactly what was said. I hope it was “Just freaking implement it already.”

In general, useful slides, I recommend going and checking them out.

Q13 and Q14 path forward

Final concept papers have been published for the next two ICH quality guidelines. In both cases we can hope to see drafts in the first half of 2020. Both guidelines are intended to supplement the existing documents ICH Q8 – ICH Q12, reinforcing the principles of a risk based quality by design (QbD).

ICH Q13: Continuous Manufacturing of Drug Substances and Drug Products

Final concept paper and business plan. This new quality guideline will:

  • capture key technical and regulatory considerations including certain CGMP elements specific to continuous manufacturing
  • allow drug manufacturers to employ flexible approaches to develop, implement, or integrate continuous manufacturing for the manufacture of small molecules and therapeutic proteins for new and existing products
  • provide guidance to industry and regulatory agencies regarding regulatory expectations on the development, implementation, and assessment of continuous manufacturing technologies.

ICH Q2/Q14: Analytical Procedure Development

Concept paper and business plan. Q14 will bring the QbD principles to analytical development.

In the course of the preparation of this new guideline, ICH Q2 (Validation of Analytical Procedures) will also be revised. It will be adapted to the state of the art to include modern analytical methods in the future..

It’s stated that the Expert Working Group (EWG) will evaluate combining Q2 and Q14 into one document. Here’s hoping.