International Council of Harmonization Q7-Q14

The Pharmaceutical GMP Professional certification from the ASQ body of knowledge has, as its first area, Regulatory Agency governance, as it should, as a solid understanding of not only what the regulations and guidances say is important, it is pretty important to understand the why, and how they work together.

The subsection Regulations and Guidances states: “Interpret frequently used regulations and guidelines/guidances, including those published or administered by the Pharmaceutical Inspection Convention and Pharmaceutical Inspection Cooperation Scheme (PIC/S), Health Canada, the World Health Organization (WHO), the International Conference on Harmonization (ICH), the European Medicines Agency (EMA), the Food & Drug Administration (FDA), the USDA 9CFR, the International Pharmaceutical Excipients Council (IPEC), and Controlled Substance Act (CSA) 21 CFR 1300. (Understand)”

The ICH is on my mind this week as I’ve had a few different conversations with folks as part of development conversations and other places about understanding regulations, and this post is my jotting down a few thoughts for future development and thought.

I am focusing on Q7 to Q14 (Q7-Q11 are published, Q12 in draft, Q13 and Q14 just recently announced). There are other Qs and there are certainly other aspects of the ICH, those just are not what I am interested in here.

Q7-Q14, in many ways, involves the development of a philosophy between the ICH member nations and the various observers. Like any harmonization and guidance process, it has a few difficulties, but the developing philosophy has been developed to establish a more proactive and risk-based approach to the industry. As such, being well versed in the principles is good for a pharmaceutical quality practitioner.

Quality trio ICH

Q7

ICHQ7 “Good Manufacturing Practice Guide for Active Pharmaceutical” was a fairly late product of the ICH. Founded in 1990 it was not until 1998 that it was determined that a GMP document was needed. It took another 2 years to complete and then another year or two for adoption by the member nations of the time. Which for the ICH is rocket speed.

Q7 is basically a solid list of what makes a functioning pharmaceutical quality system. Its the great big giant check-box of stuff to make sure you have. Personnel Qualification! Check! Production Controls? Check! Cleaning Validation? Check (well….)

Q7 covers API and has a great table on page 3 that covers applicability for types of API and the increasing GMPs. That said, Q7 is pretty much a great stopping place for anyone evaluating their quality system in a GMP environment. Most of the principles are universal, for example stating about master production records “These records should be numbered with a unique batch or identification number, dated and signed when issued. In continuous production, the product code together with the date and time can serve as the unique identifier until the final number is allocated.”

The Q&A released for Q7 in 2015 is telling. It is either all narrow specifies (including a definition of terms) or it is “Can I use risk management with X”, such as “To what extent can quality risk management be used in establishing appropriate containment measures to prevent cross-contamination?” To which the answer is basically “That is why we wrote Q9”

A good document to have around when setting standards.

Q8

ICHQ8 “Pharmaceutical Development” is the place where quality by design really starts coming into its own a solid concept. Finalized in 2005, it started being adopted in 2009/2010 (with Canada adopting it in 2016).

Q8 is all about setting forth a systematic, knowledge-driven, proactive, science and risk-based approach to pharmaceutical development. And at its heart, this is the philosophy that these ICH guidances rest on.

Q9

ICHQ9 “Quality Risk Management” was finalized in 2005 and quickly adopted in 2006 (except in Canada). This guidance pretty much recognizes that nothing the ICH was going to do would work without a risk-based approach, and it is arguable that the pharma industry might not have been all on the ball yet about risk. Risk management is without a doubt the glue that holds together the whole endeavor.

Q10

ICHQ10 “Pharmaceutical Quality System” was finalized in 2008 and adopted from 2008-2010 (except Canada). Q10 lays out a quality system approach that, based on a science and risk-based approach, establishes 4 pillars: Process Performance and Product Quality Monitoring; CAPA; Change Control; and, Management Review. Your welcome pharmaceutical industry, the ICH has now told you how to do your job and after Q10 we are getting serious about figuring out how to get ready for new technologies and be nimble and stuff.

The Pharmaceutical lifecycle is set out in 4 phases: Pharmaceutical Development, Technology Transfer, Commercial Manufacturing and Product Discontinuation; with the requirements of each pillar being explained at a high level for each phase.

Knowledge management gets poked at as a key enabler.

Q9 and Q10 together basically set out to demonstrate just how to do the things that are a requirement in order to have quality by design (Q8) but also show how to move from Q7 to a proactive, risk-based approach to running your pharmaceutical lifecycle. We are moving from a set of discrete compliance requirements (which Q7 is sort of a bow-tie around) to a comprehensive quality systems approach over the lifetime of the product to establish and maintain a state of control and facilitate continual improvement. Breaking down silos this approach united product development with manufacturing, with distribution. I feel almost like I am having a mystic experience when I contemplate what this path we are on can do. Because frankly, we are still on the path.

Q11

ICHQ11 “Development and Manufacture of Drug Substances” was finalized in 2012 and adopted in the next 4 years. This is a bow guidance as it shows how to implement Q8, with the support of Q9 and Q10. This is based on six principles that stem from the three previous guidances: Drug-substance quality linked to drug product; Process-development tools; Approaches to development; Drug-substance CQAs; Linking material attributes and process parameters to drug substance CQAs; and, Design space.

Q11 is our blueprint, drug substance manufacturers. Others can learn a lot of how to implement Q8-10 through reading, understanding and internalizing this document.

Q12

In November of 2017 the long-anticipated draft of ICHQ12 “Technical and Quality Considerations for Pharmaceutical Product Lifecycle management” was published. Q12 provides a framework to manage CMC changes across the lifecycle of the product. In short, it utilizes Q8, Q9, and Q10 and says if you do those things then here are how post-marketing changes will work and the expected regulatory benefits. Which means getting changes to market faster. Knowledge management is expanded upon as a concept.

Q12 enshrines established conditions, which is a term that wraps a few QbD concepts and provides a regulatory framework. Still, in draft, there is a fair share of controversy (for example, the EMA can’t adopt it as is it appears) and I am certainly curious to see what the final result is.

At this point we have: Q7 – summary of GMPs; Q8 – QbD; Q9- risk management; Q10 – quality systems; Q11 – a roadmap for drug substances; and in draft, Q12 – lifecycle management.

The ICH primary exists as a way for regulatory bodies to align and work out the thorny issues facing the industry. The process is not perfect, but it’s much better to be involved then to ignore.

Q13 and Q14

This last June the ICH met and, amongst other things, announced the roadmap for what is next:

Analytical Procedure Development and Revision of Q2(R1) AnalyticalValidation (Q2(R2)/Q14)
Continuous manufacturing (Q13)

Q2 is desperately in need of revision. It was finalized back in 1996 and does not take advantage of all the thought process expressed in Q8-Q11. Apply QbD, risk management, and quality systems will hopefully improve this guidance greatly.

Q13 appears to be another in the line of how to apply the Q8-Q10 concepts, this time to everyone’s favorite topics – continuous manufacturing. Both the FDA and EMA have been taking stabs at this concept, and I look forward to seeing the alignment and development through this process.

I look forward to seeing formal concept papers on both.

Likelihood of occurrence in risk estimation

People use imprecise words to describe the chance of events all the time — “It’s likely to rain,” or “There’s a real possibility they’ll launch before us,” or “It’s doubtful the nurses will strike.” Not only are such probabilistic terms subjective, but they also can have widely different interpretations. One person’s “pretty likely” is another’s “far from certain.” Our research shows just how broad these gaps in understanding can be and the types of problems that can flow from these differences in interpretation.

“If You Say Something Is “Likely,” How Likely Do People Think It Is?” by by Andrew Mauboussin and Michael J. Mauboussin

Risk estimation is based on two components:

The probability of the occurrence of harm
The consequences of that harm

With a third element of detectability of the harm being used in many tools.

Often-times we simplify probability of the occurrence into likelihood. The quoted article above is a good simple primer on why we should be careful of that. It offers three recommendations that I want to talk about. Go read the article and then come back.

I. Use probabilities instead of words to avoid misinterpretation

Avoid the simplified quality probability levels, such as “likely to happen”, “frequent”, “can happen, but not frequently”, “rare”, “remote”, and “unlikely to happen.” Instead determine probability levels. even if you are heavily using expert opinion to drive probabilities, given ranges of numbers such as “<10% of the time”, “20-60% of the time” and “greater than 60% of the time.”

It helps to have several sets of scales.

The article has an awesome graph that really is telling for why we should avoid words.

W180614_MAUBOUSSIN_HOWPEOPLE

II. Use structured approaches to set probabilities

Ideally pressure test these using a Delphi approach, or something similar like paired comparisons or absolute probability judgments. Using the historic data, and expert opinion, spend the time to make sure your probabilities actually capture the realities.

Be aware that when using historical data that if there is a very low frequent of occurrence historically, then any estimate of probability will be uncertain. In these cases its important to use predicative techniques and simulations. Monte Carlo anyone?

III. Seek feedback to improve your forecasting

Risk management is a lifecycle approach, and you need to be applying good knowledge management to that lifecycle. Have a mechanism to learn from the risk assessments you conduct, and feed that back into your scales. These scales should never be a once and done.

In Conclusion

Risk Management is not new. It’s been around long enough that many companies have the elements in place. What we need to be doing to driving to consistency. Drive out the vague and build best practices that will give the best results. When it comes to likelihood there is a wide body of research on the subject and we should be drawing from it as we work to improve our risk management.

Move beyond setting your scales at the beginning of a risk assessment. Scales should exist as a library (living) that are drawn upon for specific risk evaluations. This will help to ensure that all participants in the risk assessment have a working vocabulary of the criteria, and will keep us honest and prevent any intentional or unintentional manipulation of the criteria based on an expected outcome.

Risk Filtering – A popular tool that is easy to abuse

An article titled “ICE Modified Its ‘Risk Assessment’ software So It Automatically Recommends Detention” is probably guaranteed to reach me, for a myriad of ways.

I believe strongly in professional codes of conduct, and the need to speak out. In this case, I am thinking of two charges:

Hold paramount the safety, health, and welfare of individuals, the public, and the environment.
Avoid conduct that unjustly harms or threatens the reputation of the Society, its members, or the Quality profession.

Reading this article, and doing some digging, tells me that the tools of quality that I hold dear have been abused and I believe it is appropriate to call that out.

Now, a caveat, risk assessment, and management have some flavors out there and I’ll be honest that I once made the mistake of getting into a discussion with a risk management expert from a bank and realizing we had very different ideas of risk management. But supposedly we’re all aligned (sort of) to ISO Guide 73:2009, “Risk management. Vocabulary.” And as such, I’ll try to stick pretty close to those shared commonalities. I also assume that ISO Guide 73:2009 is a shared point between me and whoever designed the ICE risk assessment software.

Risk assessment is one phase in risk management, and I’ll focus on that here. Risk assessment is about identifying risk scenarios. What we do is:

Establish the context and environment that could present a risk
Identify the hazards and considering the hazards these risks could present
Analyze the risks, including an assessment of the various contributing factors
Evaluate and prioritize the risks in terms of further action required
Identify the range of options available to tackle the risks and decide how to implement risk management strategies.

A look at the decision making around this found in the Reuters article, leads me to believe that what ICE is using meets these criteria and we can call it a risk assessment (why it is in quotes in the Motherboard article mystifies me).

There are a lot of risk assessment tools out there. it is important to know that risk assessment is not perfect, and as a result, we are constantly developing better tools and refining the ones we have.

My guess is we are seeing a computerized use of the risk ranking and filtering tool here. Very popular, and something I’ve spent a great deal of time developing. This tool involves breaking a basic risk question down into as many components as needed to capture factors involved in the risk. These factors are then combined into a relative risk score for ranking. Filters are weighting factors used to scale the risks to objectives.

And that is where this tool can often go wrong. It appears ICE under the Trump administration has determined its objective is to jail everyone. By adjusting the filters, the tool easily drives to that conclusion. And this is a problem. Here we see a quality tool being used to excuse inhumane policy choices. It is not the ICE agents separating families and jail people over a misdemeanor, it is the tool. And if that doesn’t strike to the heart of the banality of evil concept I’m not sure what does.

I could go deeper into the tool, how I would have built it, the ways you validate the effectiveness of it. And that all probably will make an excellent follow-up someday. But the reason I’m writing this post is primarily that I read this article and it dawned on me that someone very similar to me in skill set probably created this tool. Someone who maybe I’ve sat across the table at a professional conference, who has read the same articles, probably debates the same qualitative vs. quantitative debates. And this is a great example of when its necessary to speak up and criticize a tool of my profession being used for evil. I probably will never talk to the team who developed this tool, but we all see instances of companies around us being asked to build similar applications, using the tools of our profession, that will be used for the wrong results. And we owe it to our code of ethics to refuse.

Risk Management enables Change

Every change has a degree of risk. We cannot understand that unless we utilize risk management as a key enabler. Change management utilizes risk management to appropriately evaluate knowledge management.

Not everything we do in a change is a risk. There are also impacts.

Impacts are the things that will be impacted by the change. if I revise my HVAC system, my air monitoring program will be impacted. Subject matter experts can easily identify these, they can be checklisted, they are easy to standardized. If I can X, Y needs to happen. All of these impacts end up on the action plan.

Risk management instead looks at what could happen as a result of the change. In change control it is important to evaluate both the future state and the process of implementing the future state.

In the diagram above the four major aspects of change are linked to the risk management activities we do.

When we propose a change we often are using an already existing risk assessment to drive the decision making. We can also conduct risk assessments as part of our option analysis, and design activities.

In change plan development (evaluation), we also add in the risk of implementing the change. Depending on the risk management activities that happened in propose the formality of this risk assessment will change. Our risk assessment drives an action plan, which manages the mitigations, the risk control.

In Implement, we do the work to mitigate the identified risks. By accepting the change we accept the mitigated risks. How we break the change into pre-implementation, implementation and post-implementation activities will be driven heavily by risk mitigation.

And in closure, we come back to ensure risks are appropriately mitigated. If formal risk assessments (such as an FMEA) drove the change, we return and rescore the risks against their new, mitigated, state.

Effectiveness reviews can be tied back to risk review activities.

Risk Management and Quality Intelligence

Kris Kelly on the Advantu blog brought to my attention a February post he wrote titled “Medical Device Recalls – Do You See the Pattern…?“

While specific in intent to medical devices, the content is very relevant to my last post. Risk Management is a major enabler of quality system, and a big part of risk assessments is moving beyond the expected to find the unexpected.

The other part of the article that stood out to me was how this was a great example of regulatory intelligence as a part of knowledge management. Kris took a trend of medical device recalls and evaluated the need for action. And you should too. Regulatory intelligence should be informing your quality system, it needs to be an input to decision making from design through change management activities and every step of the way. Regulatory intelligence should be an input to your organization. This idea can be expanded to quality intelligence, which also looks at best practices, pharmacopeias and a whole assortment of inputs from agencies to industry associations to benchmarking with other companies.

To bring this post around to one of my long-term preoccupations, change management, the following request is found in 3 of the drug cGMP warning letters on the FDA website since the 01Mar2018.

A comprehensive, independent evaluation and remediation of your change management system. The evaluation should include, but not be limited to, assuring changes are appropriately justified, approved by your quality unit, and evaluated for effectiveness. Also, include a retrospective assessment of all changes executed outside an appropriate change management process.

Is your quality system strong enough? Have you evaluated the risks of your change management system? Are you prepared for your next regulatory inspection? How do you ensure you are evaluating these trends as they develop? Do you have a process in place to make sure you are not surprised?