In High Potency Regulations in the November/December 2013 issue of Contract Pharma, Stephanie Wilkins wrote, “While other areas of pharma manufacturing are embracing science- and risk-based approaches, some in industry are back trying to define ‘certain’ in terms of where dedicated facilities may be required.”

We disagree with that statement, from a perspective of risk management. Surely the very essence of risk assessment is to encourage the use of any appropriate approach, where a written rationale is supported by objective evidence. We would like to remind people of the pharmacology behind the industrial manufacture of medicinal products. It is actually unscientific to rule out the “1/1000th of the therapeutic dose” approach. This approach, if supported by documented analysis of preclinical toxicology studies in animals, Phase I, Phase II and Phase III studies in humans and post-marketing pharmacovigilance data, provides a far greater, evidence-based, amount of data regarding toxicity than any arbitrary equation based on theoretical “uncertainty factors” and “modifying factors.”

Ms. Wilkins mentioned the EMA workshop, but neglected to mention the statements made there by one of the most experienced regulators present, who was on the original GMP/ GDP Inspector’s Working Group charged with the mandate of revising the approach to dedicated facilities. That statement effectively said that when the ship set sail, the mandate was to provide a risk-based tool to define what was meant by “certain” highly potent products in the existing text of Chapter 3 of the EU GMPs. That same regulator reminded industry — as did one of our co-authors, Karen Ginsbury, who was also present at the Workshop — that the argument regarding less containment or less rigorous cleaning measures for non-potent drugs is negated by the existing GMPs whereby no facility that is following GMPs should ever be able to justify the presence of visible powder residues either in the facility or on equipment. Thus, for non-potent drugs in older facilities, even where containment may be less rigorous, the existing GMPs already address this issue.

In response to the argument that Risk-MaPP solves all, Ms. Ginsbury audited a facility that claimed to be using Risk-MaPP. It had placed the client’s (non-potent) product in a highly potent manufacturing area based on its Risk-MaPP calculations, but the result was that the supposedly  “clean” room (according to records and signage) showed visible residues on the equipment. Therefore, an approach is needed that leaves emotions aside and is based on all relevant scientific considerations, not just a toxicological evaluation.

It is certainly appropriate to separate the issues of operator safety from patient safety. Operator safety is based on a toxicological evaluation. Patient safety is based on a health-based evaluation as well as other product quality issues related to carryover of residues. Considerations for a risk assessment in each situation may be different.

When the initial revision to the GMPs was proposed (in 2005), the EMA concept paper did indeed require a better definition of “certain” highly potent drugs. That was when the paper was with the GMP/GDP Working Party. Subsequently, it was transferred to the Safety Working Party for their input and they took it to toxicologists. Unfortunately, different toxicologists tend to come up with different Acceptable Daily Exposure (ADE) values. We are in complete agreement that a patient should never be subjected to adverse events, or even to non-therapeutic but possibly cumulative effects of active substances that may lead to harmful effects.

If we use the same approach we use for solvents and that ICH is proposing for elemental impurities — both of which have limited available human toxicity data because they are not intended for human administration and have never been studied in controlled clinical trials — we will drive down the allowable limits for residues and further drive up the cost of medicines. In many cases it is the most critical drugs that will fall into still shorter supply as lack of availability of sufficiently sensitive analytical methods will drive them to dedicated facilities. The cost of building such a facility will not be financially viable.

As for the assertion that one should consider the possible interaction of therapeutic effects between a residue and the next drug product containing that residue, the original article mentions the possible effect of a blood pressure-lowering active as a residue in a diabetes medicine (presumably leading to possible lower blood pressure in the diabetic). It is maintained that safety factors such as 1/1000th dose may not be adequately protective. We question whether an ADE evaluation, as proposed in Risk-MaPP, would provide a higher level of protection. Indeed, as suggested by Risk-MaPP advocates, the most likely scenario would be that much higher levels of residue of the blood pressure-lowering active would be allowed in the diabetic medicine under an ADE determination.

The original article also implies that there may be significant cost saving in utilizing the new ADE paradigm. However, as several highly experienced toxicologists pointed out at the EMA workshop, it takes one toxicologist approximately two weeks to calculate an ADE value. If industry needs to do this for every medicinal product being manufactured and for multinational companies with hundreds if not thousands of products, we are looking at 10 to 20 person-years of work. The issue of efficiency and cost savings should be considered after first determining what the limit is for acceptable residues. If ADE values do adequately provide for patient safety and product quality, let the manufacturers decide for themselves whether to use the 1/1000th criterion or the ADE/PDE approach.

However, Ms. Wilkins claimed, “It is true that for approximately 90% of products, the traditional cleaning limits of 1/1000th LCD and/or 10 ppm will be lower (much lower) than when determined using the ADE or PDE” [emphasis added]. If that is the case, shouldn’t we be focusing our limited resources on the 10% where those criteria are not protective enough? Those are specifically the highly hazardous actives, such as actives with reproductive or genotoxic hazards. It is precisely those other 10% where the use of ADE or PDE calculations may allow manufacturers to avoid dedicated facilities/equipment. It is these 10% (the so-called “certain” products) where the toxicological evaluation may be truly appropriate.

Many manufacturers are producing a broad spectrum of products, including contract manufacturers whose services are in short supply. We believe that requiring them to perform an across-the-board risk assessment using the ADE calculation is a massive burden. If science demanded this, they should have to do it. It does not. We would like to see EMA take a bold step back and return the issue to where it belongs — in the hands of the GMP/GDP working group, addressing “certain” highly potent products. There is no scientific justification for applying the ADE/PDE tool to products that everyone seems to agree have been safely made since the 1/1000th criterion was adopted in the early 1990s. This approach is not one of turning the clock back; it is recognizing what we have learned about safety, efficacy and quality of products during the past 20 years and is a genuinely risk-based approach. CP

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Karen Ginsbury is founder and chief executive officer of PCI Pharmaceutical Consulting Israel Ltd. She can be reached at karen@pcipharma.com. Destin A. LeBlanc is a consultant at Cleaning Validation Technologies. He can be reached at destin@cleaningvalidation.com. Both of these authors were on the PDA’s commenting team on the EU revisions to Chapters 3 and 5 and the Health-Based Exposure Limits Guidance. The views expressed here are the authors’ views and do not necessarily represent PDA’s opinions.