DIY medicines -another compounding pharmacy disaster?

“Meet the Anarchists Making Their Own Medicine” mostly avoids bringing the typical “technology can solve anything” silicon-valley messianic fevor to an interesting idea, that of micro-pharmaceutical manufacturers.

“Unless the system is idiot proof and includes validation of the final product, the user is exposed to a laundry list of rather nasty stuff,” DeMonaco told me in an email. “Widespread use [of Four Thieves’ devices] would provide an entire new category for the Darwin Awards.”

Discussing at the high level the risks of DIY drug synthesis, the article points to compounding pharmacies as a lesson on how to do this right. Not sure I agree, as compounding pharmacies have had a slew of problems in recent years, and frankly quality systems still need improving.

I do think we will see more and more hospitals turn to small scale manufacturing. Hopsitals are more used to the idea of quality systems and can build the encessary systems and processes to do this safely.

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.

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 www.propublica.org/article/fda-repays-industry-by-rushing-risky-drugs-to-market

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.

Changes become effective

Change Effective, implementation, routine use…these are all terms that swirl in change control, and can mean several different things depending on your organization. So what is truly important to track?

regulatory and change

Taking a look at the above process map I want to focus on three major points, what I like to call the three implementations:

When the change is in use
When the change is regulatory approved
When product is sent to a market

The sequence of these dates will depend on the regulatory impact.

	Tell and Do	Do and Tell	Do and Report
Change in use	After regulatory approval. When change is introduced to the ‘floor’	When change is introduced to the ‘floor’	When change is introduced to the ‘floor’
Regulatory approval	Upon approvals	After use, before send to market	Upon reporting frequency (annual, within 6 months, within 1 year)
Sent to market	After regulatory approval and change in use	After regulatory approval and change in use	After change in use

I’m using ‘floor’ very loosely here. “Change in use” is that point where everything you do is made, tested and/or released under the change. Perhaps it’s a batch record change. Everything that came before is clearly not under the change. Everything that came after clearly is.

You can have the same change fit into all three areas, and your change control system needs to be robust enough to manage this. This is where tracking regulatory approval per country/market is critical, and tracking when the product was first sent.

A complicated change can easily look like this (oversimplification).

building actions

Is this 1, 2 or 3 processes? More? Depends on so many factors, the critical part is building the connections and make sure your change control system both receives inputs and provides outputs. Depending on your company, the data map can get rather complicated.

Regulatory Impact of Changes

In a regulated industry, such as pharmaceuticals or medical devices, knowing your changes impact your regulatory partners is a critical aspect of change management. For example, the MHRA in their yearly summarizations of GMP inspection deficiencies consistently cites failure to perform adequate review of need of regulatory notification (for example, see 2016 trends). And to be frank, we in the industry are often looking for more guidance, which drives responses like ICHQ12 and the FDA’s March 2018 draft guidance CMC Changes to an Approved Application: Certain Biological Products and all the other similar guidances out there.

These all follow a similar risk-based approach, and this approach should be built into your change management system (and applicable change control process).

regulatory structure2

The major difference between Supportive Information and Do-and-Record is usually what goes in your product quality report (APR/PQR). Fro example, I often see qualification of facility fit into the Do-and-Record area. These changes may not be fillable, but you certainly want to review and account for.

Many companies manage this through their regulatory affairs organization, but that can be time consuming. It is better to take the time to identify the supportive and do-and-record categories out front, thus removing the need for an extra assessment. The PQR review process is a great tool for ensuring consistent execution.

This risk based approach should look at the dossiers, taking into account any special market considerations, as well as current best practices in the regulations. For those companies lucky enough to be more towards the QbD model, established conditions will greatly help here.

Then build a matrix to help guide your changes. An example could include items like these:

Facility, Equipment, Manufacturing Systems, Utilities & Automation	Equipment/instrument maintenance
	Decommissioning of equipment not classified as critical equipment
	Computer programming that affects non-production equipment
	Alarms (i.e., notification system for out of tolerances)
	Cleaning and Sanitization of Manufacturing facilities and non-product Contact equipment
	Upgrade of Application Software or operating system
	Alarm setpoint changes
	Creating user groups and modifying user group privileges
	Tuning parameter, adjustment to the gain, reset and rate of a PID controller
Manufacturing Processes	In-process labeling
	Changes to Process Control and Operating Parameters (tightening/shifting) within current non-established conditions
	Change in equipment sterilization times
	The addition of in-process or final product samples
	Changes to sample volume for in-process or finished product samples
	Addition of new ancillary equipment (e.g. no product contact, does not control process steps) to the process

You can then further delineate between Supportive Information and Do-and-Record on a few other criteria, such as qualification/validation impact.

Like many areas of good system management, this is an area where a forethought and design can reap dividends in making your changes more nimble while preventing a compliance mishap. Tapping into the PQR makes all this part of your knowledge management system, and allows you to grow as your needs grow. This is definitely not a once-and-done process.