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


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.


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.


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.



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.


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.


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.

Master and Transactional Data Management

Mylan’s 483 observation states that changes were being made to a LIMS system outside of the site’s change control process.

This should obviously be read in light of data integrity requirements. And it looks like in this case there was no way to produce a list of changes, which is a big audit trail no-no.

It’s also an area where I’ve seen a lot of folks make miss-steps, and frankly I’m not sure I’ve always got it right.

There is a real tendency to look at use of our enterprise systems and want all actions and approvals to happen within the system. This makes sense, we want to reduce our touch points, but there are some important items to consider before moving ahead with that approach.

Changes control is about assessing, handling and releasing the change. Most importantly it is in light the validated and regulatory impact. It serves disposition. As such, it is a good thing to streamline our changes into one system. To ensure every change gets assessed equally, and then gets the right level of handling it needs, and has a proper release.

Allowing a computer system to balkanize your changes, in the end, doesn’t really simplify. And in this day of master data management, of heavily aligned and talking systems, to be nimble requires us to know with a high degree of certainty that when we apply a change we are applying it thoroughly.

The day of separated computer systems is long over. It is important that our change management system takes that into account and offers single-stop shopping.

Mylan gets a 32 page 483

The FDA’s April 483 for Mylan Pharmaceuticals has been in the fore-front of a lot of conversations in the last week. Let’s be honest, the FDA posts a 32 page, 13 observation 483 report on any manufacturer and it will be news. One as prominent as Mylan and doubly so. On the same day, the FDA also posted a 2016 483 and 2017 warning letter against a Mylan facility in India.

The 483 is a hit parade of observations, like the 1st observation of failure of the quality unit, including a reference to lack of quality approval of change controls.

What everyone has been intensely focusing on is the strong emphasis on cleaning, with 11 pages dedicated to failures in cleaning validation.

Which to be frank, is a big deal in a multi-product facility.

Read the 483, and when doing so evaluate your site’s cleaning program. Ask yourself some of these questions:

  • Are there appropriate cleaning procedures in place for all products-contact equipment, product contact accessories?
  • Are there appropriate cleaning procedures in place for facility cleaning (dispensing, sampling room…)?
  • Do your procedures include the sequence of the cleaning activities? Is it significantly detailed?
  • Do the procedures address the different scenarios (cleaning between different batches of the same product, cleaning between products changes, holding time before and after cleaning…)?
  • Do the procedures address who is responsible for performing the cleaning?
  • Does the validation study, the acceptance criteria and when revalidation justification and keys documentation approved by Quality? Does it include a clear status on the cleaning process?
  • Is the strategy used for the cleaning validation clearly established? (matrix approach, dedicated equipment, worst case scenario, grouping equipment, equipment train…)
  • Are batches that come after the cleaning validation run, released after completion of the cleaning validation?
  • Are the acceptance criteria (products, detergents, cleaning agent, micro… ) scientifically established and followed? Do these acceptance criteria include a safety margin?

Approval of cleaning validation is a key responsibility of the quality unit that involves some very specific requirements. These requirements should be built into the quality systems, including validation, deviation, and change management.

FDA Repays Industry by Rushing Risky Drugs to Market — ProPublica

As pharma companies underwrite three-fourths of the FDA’s budget for scientific reviews, the agency is increasingly fast-tracking expensive drugs with…
— Read on

This is worth reading. I remember when I first started it was easier to get European approvals before US, and have been surprised by the switch over the last few years.

I also watch all these companies struggle with QbD and wonder if these two trends go hand in hand.

No answers from me, but I do recommend reading this article.

Data Integrity Thoughts

At the MHRA Blog, a GDP Inspector has posted some thoughts on Data Integrity. As always, it is valuable to read what an agency, or a representative, of an agency in this case, is thinking.

The post starts with a very good point, that I think needs to be continually reiterated. Data Integrity is not new, it is just an evolution of the best practices.

Data Integrity

It is good to see a focus on data integrity from this perspective. Too often we see a focus on the GCP and GMP side, so bringing distribution into the discussion should remind everyone that:

  • Data Integrity oversight and governance is inclusive of;
    • All aspects of the product lifecycle
    • All aspects of the GxP regulated data lifecycle, which begins at the time of creation to the point of use and extends throughout its storage (retention), archival, retrieval, and eventual disposal.

Posts like this should also remind folks that data integrity is still an evolving topic, and we should expect more guidance from the agencies from this in the near future. Make sure you are keeping data integrity in your sites and have a process in place to evaluate and improve.

I recommend starting at the beginning, analyzing the health of your current program and doing a SWOT.

data integrity SWOT




Quality Metrics – Not Dead yet

Pink Sheet has an update this week on the FDA’s Quality Metrics initiative – US FDA Quality Metrics Initiative Continues Moving Forward … Quietly.

This is behind a firewall so may not be viewable by all.

The major takeaways were:

  1. The initiative is still happening
  2. the FDA wants to remind companies why they are doing this in the first place
  3. They are starting a pilot real “soon” now

These metrics have been a hard sell within Pharma. I’ll be curious what steps the FDA will be taking to rebrand the effort.