The recent FDA warning letter (recipient was DuPont Nutrition USA Inc.) has triggered a new round of discussion about GMP for Excipients. And curiously enough many of those who have commented on this issue publicly have expressed their surprise at the standards FDA has applied in this for-cause inspection.

But how can this be a surprise to anyone? First of all, it has been a long-standing requirement for excipients to be manufactured in accordance with cGMP principles. Excipients are drug components and thus naturally subject to cGMP – this is the US viewpoint at least. Come on – that is not new! This has been around the block for a while. Even a pharmacopeial batch certification (PhEur, USP, etc.) depends(!) not on testing according to the monograph alone but on cGMP applied during manufacturing. „Complies with USP“ without cGMP is not legitimate. But even this seems not clear to all excipient stakeholders out there. And even some GMP inspectors are not aware of it.

None of this is new. The fact that the US or the EU have no standalone GMP-guide for excipients does not change the general cGMP requirement the slightest bit. The only reason why excipient manufacturers have not been in the spotlight as much is that they were not and still are not subject to regular inspections by regulatory authorities – compared to for example API manufacturers. They have been flying under the radar a bit for decades and decades. From today´s perspective on drug quality assurance a little outrageous some would say.

Was the FDA too tough with their GMP expectations?

As much as I stand critical toward some of the FDA´s doings and guidance, I am with them in this case.

One consulting company has commented publicly that FDA was essentially wrong in applying next-to API GMP and their inspection standard in the DuPont inspection. Instead, the FDA – in the opinion of that company – should have applied IPEC / Excipact GMP since those would be adequate for excipients. Well, I couldn´t disagree more with this assessment.

Excipient industry – at least some representatives of it – has kept playing hide and seek when it comes to GMP. The fear of a clear and defined Excipient GMP Guide from the legislators has brought forth quite interesting fruit. Still such a guide is yet to come. But make no mistake: one key reason why e.g. the EU has not yet put anything of the like into place until today is mostly economical. Drug product pricing is a problem for any healthcare system – and the Excipient industry has in some way benefitted from the regulators hesitancy for a long time now. And so, the entire matter developed quite differently – as all readers of this article would know:

One very prominent organization (obviously) is IPEC with its whole set of GMP-standards – and of course the Excipact(TM) certification scheme. It is our experience that one of the most important goals of a company attaining to the Excipact certification is to reduce the load of on-site customer audits. For one because it takes time, and resources to receive such audits, and secondly because every client requires something different when it comes to Excipient GMP (which is absolutely understandable) – and that is a lot of extra work driving ultimately the excipient price.

Screnshopt snippet of FDA Warning Letter page.

What must be understood though is that any certification – even full governmental GMP certifications for drug product manufacturers – does not obviate the need to audit for example a GMP-certified contract manufacturer. So it is short-sighted to believe that a certification such as Excipact(TM) would in any way be better than even governmental inspection-based GMP-certificates when it comes to the supplier audit matter. In fact, no certification scheme I know – be it in the GMP area or in the ISO standards realm – has ever succeeded to assure all risks or product quality aspects are under control. This is simply wishful thinking. Those schemes are very useful and clearly have an overall improving effect on the industry at large, but they are non-exhaustive in assuring things entirely. That is just an empirical fact.

I certainly consider the IPEC standard(s) extremely helpful and good concerning its content as well – on paper. But the EU GMP Guide with its Annexes is also really good, so is 21 CFR 210/211 with all its attached guidances and other CFR sections – but still many drug substance and drug product companies run with GMP deficiencies and have product quality assurance gaps. How much worse will it be in the area of essentially non-officially inspected raw material industry? Wherever there is no governmental pressure to comply, failure and negligence is more likely – because there is less accountability! It is as simple as compliance with a speed limit on a freeway – most people simply do not comply unless there is local enforcement to make them. This not any different in the industry. It has been true also even in the medical device sector (EU) – where the government does not themselves conduct inspections (at least within the EU) – but notified bodies do. And no matter how well ISO 13485 is written – the reality is: people have died from medical devices due to lack of quality assurance. And ultimately in my opinion due to the lack of direct governmental supervision. And although I am not one for blindly believing in governmental authority – in this context this is my stance, founded by experience.

If anyone says API GMP is over the top for an excipient manufacturer, then this is either due to lack of experience with API and Excipient quality assurance alike or due to ulterior motives – I couldn´t imagine any other reasons. The truth is: the API GMP standard is significantly less intense than some excipient GMP approaches. How can anyone seriously complain that FDA is too tough when they don´t accept a lobby GMP standard? How cheap a position. When You read the particular warning letter You will find some deficiencies that are not at all limited to API quality assurance system requirements – but should even be covered in the simplest ISO 9001 QMS. Clumsy complaint management, sloppy handling of OOS results – gosh those are such basic things that I could tell my 8-year-old daughter and she would understand the brunt of it. And this is not in any way meant to speak against the company that received the warning letter – but addresses those who say FDA was too tough. That is simply not true and shows a lack of understanding.

Summary of Deficiency Headers from USA FDA, accessed Feb 11, 2023.

What could or should be the consequences for the Excipient-GMP cosmos?

DuPont received the warning letter – to the best of my understanding – despite being Excipact(TM) certified at the time. And the reason as it seems was not that the Excipact standard in and of itself was not strict enough (I mean take a look for example into NSF-363 – this is massive!) but that the way it was enforced did not protect the company from what the FDA found. And of course, quite a few eyes will now turn toward IPEC, Excipact(TM) and their certifying bodies – and hopefully also to the regulators.

It also must be considered that the receiver of the warning letter had a fair chance to provide an answer that could have satisfied the FDA – usually none receives a warning letter right off the bet, but this did not work here. The response was „inadequate“ as FDA mentions in the Warning letter. How can a company which – in the eyes of so many who deal with excipient GMP – is adequate GMP-wise but is still not able to write an adequate reply? And especially toward these kinds of findings? Those were not the most complex issues to respond to. How much is this kind of excipient GMP worth if it can be accredited to companies who have such trouble to address GMP issues in writing and in suggesting adequate CAPA?

It is really instructive that FDA would literally recommend a cGMP consultant – not another certification by whatever self-appointed certification body – but a cGMP consultant. Independence. Qualification. Experience. Objectiveness. Not Norm-Clause- but Quality-Oriented. This speaks volumes.

All things considered: Consequences from this could (and in my view will be) that:

  • Excipient manufacturing companies may think twice whether they want to buy into the reliance on an Excipact certification, but rather set up their GMP system in their own GMP-understanding. Certifications can be a valuable addition to market standing, but it might simply not win the day.
  • Drug product manufacturers might greatly reconsider to all too quickly add certificates from industry organizations as an acceptance criterium in their supplier and material qualification workflows – because this is not guaranteed protection from regulatory fallout and significant market and possibly even legal consequences. By now everyone should have realized this.
  • Certifying companies will hopefully accept and not deflect the reality that they are part of the mess when warning letters such as this one happen – and not blameshift any of what (as in this case) the FDA might find wrong in a certified company. A certifying body will always inject a sense of security to the certified company that things are ok now. Such trust should not be broken.
  • The regulators might (and in my opinion should!) consider to finally provide clear minimum QMS requirements for excipient manufacturers including its official supervision, and not leave the excipient GMP-battlefield in the hands of the industry alone. There is no plausible reason to handle excipients in any way less diligently than APIs when it comes to quality assurance. Consequently, the guidance with the excipient industry as direct addressee is required – not indirect controls via „formalized risk assessments only.

The excipient industry lobby must stop playing games and grow up. You are part of the pharmacotherapy of human beings. You cannot expect to wing it forever – most don´t – but some really do. And of course, several excipient manufacturing companies we have gotten to know continue to do an excellent job in assuring excipient quality with their processes and quality systems. Some even with higher degrees of quality assurance than a few API manufacturers I have seen.

Excipient GMP must peel out of its part-political nature and turn its attention to „real GMP“ and to those who will take medicines – namely all of Us!

Dr. Dietmar Gross

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