GMP in Clinical Development: Does GMP "Meet" Development?
"GMP Meets Development" - a catch phrase many have heard. And for plenty of GMP staff this has triggered a virtual stampede to seminars, trainings, webinars and so forth. Why is that?
Quite simple: because there is a legacy of timidity when it comes to certain GMP aspects to be applied or not to be applied during the manufacture of drugs / medicinal products for clinical trials. Few companies I met have a firm grasp what GMP in development should or literally must look like. It is clearly less codified and the expectations are less clear than in the commercial GMP area. And this is true or for sure lived(!) in some of the major Western GMP-contexts - EU GMP and US FDA cGMP.
And in my experience, clinical trial supply manufacturing and all its surrounding quality management body are among the messiest things in the GxP cosmos. The GMP-differences are huge between IMP manufacturers - and don′t even get me started on development API manfacturing(!).
While some companies apply essentially all commercial GMP aspects to IMP manufacturing (rare but real examples are out there), others work based on the presupposition that GMP in development is the "only the absolut must" version of GMP. And then there is a third kind of company that for lack of understanding of either one of the those two lifecycle stages overdo GMP to such an extreme that no product ever sees clinical trial use and for sure never matures to commercial level - such is the hindrance in those companies. It may even ruin a company financially.
If You have never seen a "development-GMP" system but are used to commercial GMP You will likely go into GMP-culture shock when You enter this mysterious world the first time.
Although there is a lot to most of these bullet points - bottom line is "Development GMP" is a misleading and unprofessional expression. There is no such thing as that. And: GMP does not "meet" development - no, but development must meet GMP! There is GMP and that′s it. And: GMP does not and does not need to "meet" development or its hopes for reduced GMP-effort or investment or resources - no, but development must meet GMP! For medicinal products used in clinical development as trial medication there are only very few differences in the GMP to be applied - and even those are for the most part debatable. The situation is quite similar even for GDP.
And commercial GMP vs IMP GMP should be seen by its differences in their goal - not by the difference in required manufacturing or quality assurance hustle and cost. For example, just because a full process validation is not required for IMP manufacturing and because this seems to make IMP GMP less intensive - this is misleading because other GMP aspects are added to IMPs that commercial GMP never has to implement (e.g. GMP conform blinding Operations).
A lot of equirements are absolutely expected in IMP GMP just as they are for commercial production - sometimes even in a more sophisticated manner - here just a few pointers:
Some of the actual key differences are:
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Within the EU GMP system these two aspects can be differentiated rather clearly in terms of their function in the pharmaceutical quality system.
For IMP manufacturing and a process that is under development a process freeze would be necessary to do a reasonable process validation. Or so is the common understanding. The EU GMP text in Detailed Commission guideline of 8 December 2017 on the good manufacturing practice for investigational medicinal products pursuant to the second paragraph of the Article 63(1) of Regulation (EU) No 536/2014 however points to the reality of a process validation being necessary (section 6.2) - even though its extent can depend in the stage of the product and process development. But it is(!) necessary - although surprisingly noone does it. This issue is typically covered by the fact that the historical expectation from supersiving bodies is not so. The GMP culture controls the interpretation - for the benefit of the manufacturers - and that may be ok.
In the US this may be a bit more tricky to circumvent once an IMP (IND) has entered use in clinical phase 2. Then there is formally no exception any more for such a product from 21 CFR 211 - and this should technically also be quite clear from 21 CFR 210 2 (c). But here again - noone validates manufacturing processes for a Phase 2 product - and again this is commonly accepted or looked past by US FDA.
The common understanding is that during development a process validation can be substituted by a sound control strategy and product testing rather than process robustness studies. And that′s the reason why everyone looks away in spite of the current texts. Now in commercial production the patient risk of a non-validated process is considered too high - it is that simple. It is a shared common perspective, but without too much of a scientific or ethical reason behind it. Because let′s be honest: Aren′t clinical trial subjects people who deserve the same degree of quality assurance as everyone else does? Maybe even more even because they agree to enter a trial...?
Change control on the other hand has a truely different function when comparing a production process development cycle to change control in a validated commercial manufacturing environment. Change control is essentially there to keep the validated state of a commercially marketed product in its manufacturing process and quality assurance. During IMP production Change Control does serve the function of controling the GMP activities too - for sure! But its true value in development - since there isn′t yet a validated process to defend - is to catch, track and make transparent the process development knowledge and information - for later regulatory submission and due to the expectation and usefulness of knowledge management (Q10 Guideline.pdf (ich.org)). So here is a textbook example of a classic GMP QM workstream taking on not a more lean but actually a more pivotal function in development than in commercial. So it′s not less GMP because it′s development - but more!
Some understand IMP manufacturing as a playground for the human GMP intellect to decide what is enough GMP and what is not for a given IMP or clinical supply phase or even for a given patient.
Pressure to do so comes from the medical realm which is driven by project timelines and investment tracking.
So in summary one could say: "GMP meets development" where it is pressured to do so. But in reality the product development and its realization in manufacturing of trial medication for real patients - must meet GMP!