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This Q12 guidance will replace the agency’s 2015 draft guidance for industry on established conditions and reportable chemistry, manufacturing and controls changes to approved drug and biological products.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

How can anyone keep up with all that information?

I hear this from colleagues all the time, how do you keep on top of so much news? How have are you always the first person to know this thing?

Keeping on top of trends, of regulatory changes, of new event is critical. This is a big part of content, and from that we bring context. It is part of what makes us Subject Matter Experts.

But let’s be honest, there is a lot out there to stay aware of, and it can eat a lot of unproductive hours up, especially with so much new content on the web being added daily, it can be tough to keep up with what’s happening online. But if you rely on visiting specific websites every day, doing Google searches, or relying on social media to keep them informed you will get overwhelmed and miss important things. The best solution I have found is pretty old-school: The RSS feed.

About every site you need to follow, from a trade publication to a government agency to a professional society to all those blogs publishes an RSS feed (including this one). Often they publish more than one which can compartmentalize the reading and help you narrow down to specific topics that interest you.

You then use a reader to aggregate these feeds into compartments that make sense to you, skim the headlines at your leisure and read those items that seem relevant to you. This gives you a comprehensive, regularly updated look at all the content your favorite sites publish throughout the day. Think of it as the ultimate aggregator; every morsel from every source you care about, fed directly to you.

I use Feedly, but there are several good ones out there, most free to use. A lot of friends tell me I should move to Inoreader.

Do not be afraid of the massive amounts of information out there. Like anything, it’s all about getting the right tool for the job.

System failures are rarely due to the employee

Between January 2016 and May 2019, you recorded approximately 397 customer complaints related to container closure issues (e.g., approximately 60%), product separation, lack of effect and adverse events. Your quality unit failed to adequately review these complaints, identify trends, and implement effective CAPAs. During the inspection you explained that these lapses in quality system performance were due to underperforming staff, who had since been dismissed. In your response, you attributed these and other quality related issues to under staffing of the quality unit as your business expanded.

Your response is inadequate because you failed to appropriately address your quality unit not performing their required duties. Your firm must provide the quality unit with the appropriate authority, sufficient resources, and staff to carry out its responsibilities to consistently ensure drug quality.

FDA Warning Letter to Teligent Pharma, Inc. dated 26-November-2019

Continuing the trend of making me petrified about generics, this warning letter is a roller coaster read. One big set of failures to actually investigate and apply appropriate resources to the quality unit. And then the management had the gall to blame the employees.

80+ years of quality principles ignored. I personally thought the FDA was being overly nice.

There are basically three questions to answer:

  • Do you have a properly established, staffed, and managed Quality Unit?
  • Does your Quality Unit have appropriate responsibilities and authority?
  • Does your Quality Unit have access to the data it needs to make informed decisions?

New Report Exposes MBTA’s “Questionable” Approach to Safety

A “debilitated” safety department and too-thin maintenance crews are just two of the revelations surfaced by a new report on the MBTA’s safety culture.

Read on www.bostonmagazine.com/news/2019/12/09/mbta-safety-report/

Let’s cut right to the heart of the report’s recommendations:

The panel makes six policy recommendations that are intended “to move the organization to a place where safety is a priority and is culturally integrated into every aspect of their mission.” They include establishing better safety performance indicators, identifying the areas where maintenance is being deferred, implementing stronger data collection, and strengthening the MBTA’s leadership team with “more seasoned” transit professionals.

Where does that seem familiar?

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.