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Relationships, Communication Gaps for Atypical Actives Aired at PDA/FDA Workshop

The relationships and the communication gaps between ingredient producers, distributors, dosage form manufacturers and regulators when atypical actives are involved received a public airing at a workshop cosponsored by PDA and FDA in March in Bethesda, Maryland.

The workshop brought together the players involved to develop a clearer understanding of the issues raised and a road map of how to address them when ingredients commonly used as excipients take on the role of an active ingredient in the dosage form.

A primary issue is the applicability of the API GMP requirements provided in ICH Q7 in the atypical active context.

Excipients may be manufactured with quality standards suitable for their intended use without complying with Q7, and the International Pharmaceutical Excipients Council has produced a significant body of well-accepted guidance on what is needed in the excipient context and how the requirements differ. In turn, a move to apply the API GMPs more strictly to excipients when they are used in the atypical actives context could be disruptive to the supply chain for these primarily OTC products and create unnecessary burdens for all the parties involved.

In her opening remarks, meeting co-chair Janeen Skutnik-Wilkinson, who is a director of quality strategy at Pfizer, underscored that the workshop was “the first…anywhere in the world” that has focused on the issues arising from atypical actives.

She stressed that the participants in the chain must all work together to understand and address the challenges posed by the uncertain regulatory expectations and a lack of communication between the players.

[An analysis of the workshop discussions on the current challenges that atypical actives present for supply chain participants and regulators is normally provided only for subscribers. By special arrangement, IPQ is making the full story available on a complimentary basis to workshop participants and involved industry association members. Also see the IPQ “In the News” March 21 companion story for the recommendations that emerged from the PDA/FDA workshop.]

While there was a mix of excipient makers, users, and FDA regulators at the workshop, only one distribution company was represented.  Skutnik-Wilkinson acknowledged the distributor present, but stressed that more engagement from that sector is critical.

“If we as makers, users and regulators were to go off and try and solve this challenge without bringing the distributors into the discussion on how to move forward, we are not going to be successful.  I think it is a really strong barrier that we need to consider.  We have to engage with distributors on whatever solutions we come up with going forward.”

Atypical Active Issues Impact Many Products

At the two-day workshop, excipient makers, users, US and EU regulators and industry associations provided their perspectives and case studies on the issues around atypical actives. The presentations were followed by breakout sessions to discuss the concerns and brainstorm solutions.

On the morning of the first day, Skutnik-Wilkinson, speaking from the user perspective, and workshop co-chair David Schoneker (Global Regulatory Affairs Director for Colorcon), speaking as a supplier of excipients, provided their insights on the current challenges.  Both play active roles in related standard setting at USP and they have served as the last two chairs of IPEC Americas. Skutnik-Wilkinson is currently vice chair of the IPEC Federation.

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Highlighting the scope of atypical actives on the market, she pointed to a study performed by the European self-medications group, AESGP, which determined that there are over 100 known atypical actives that are currently used in thousands of products – frequently as the sole ingredient.

She pointed to glycerin suppositories as an example, in which glycerin is the active ingredient.  The AESGP study listed over 15,000 known uses for glycerin across industries.

Other common examples include dimethicone/simethicone anti-gas tablets, kaopectate, kaolin, rubbing alcohol and mannitol.  Mannitol is used in an injection as a last chance effort to jumpstart the kidneys during severe kidney failure.

On a personal note, Skutnik-Wilkinson commented that “there is less than a 50% chance that [the mannitol injection] will work.  I can tell you that when you are in the situation where that is the only choice, you are not concerned whether or not this is being made to Q7.  I have been in that position before and I can tell you the only thing you are thinking is ‘please, please let this work,’ and that is your biggest concern.”

She pointed out that the mannitol product is “made to GMPs, made to the right requirements, but certainly not under the conditions of Q7,” and that not having that material available would have a detrimental impact on the life of the patient undergoing kidney failure.

“It is important to remember that in a lot of these cases these formulations have been around for decades” with no patient safety issues, she emphasized, noting that many “certainly existed long before ICH Q7 was written.”

Q7 was written for materials being developed and made as active ingredients, and those involved have said that the special case of atypical active ingredients “never crossed their minds,” the Pfizer director commented.

“There is no guidance, there is no regulation specifically on this material,” she pointed out.  However, the Q7 guidance has been applied when inspecting some atypical actives with detrimental effect.  Manufacturers using the atypical active have been forced to find a new supplier or reformulate – both problematic – or to discontinue the product.

“We cannot realistically expect all excipients used as atypical actives to comply with Q7.  We need to remember that the use of these  materials in pharmaceuticals is of minute quantities compared to their major uses. We are a very, very small player for most of these materials.”

Skutnik-Wilkinson pointed to cellulose as an example.  Although cellulose is widely used in the manufacture of tablets, the pharmaceutical industry’s share of the market is “less than 0.02%,” so the possibility of impacting how it is manufactured is remote, at best.

Another consideration is the potential to create a black market for products that may be taken off the market. If this were to happen, “there will be people out there waiting in line to jump into this, and to put products out there on the black market,” she cautioned.

Makers Often in the Dark on Use

Introducing the maker’s perspective, Colorcon’s Schonecker began with a definition of an atypical active from that perspective.

“An atypical active, in our book,” he explained, “is a chemical that is normally produced for use as an excipient, food additive, or industrial product that some customer decides, usually without our knowledge, to use as an API in drug products.”

He reiterated his co-chair’s point that the use of these materials is small compared to their use in other industries, adding that the prices and margins are low.

“You might have a chemical plant that is ten stories high, producing millions of pounds of material per week. The amount that goes into the pharma industry as an API might be the first five minutes of the first day of production, on the first day of the year.”

The shipping methods and supply chains for these materials also look different from those normally seen for APIs.  They are usually shipped in bulk containers by rail car, barges, trains, tankers or boats, with different levels of control than are expected for APIs, Schoneker noted.  He explained that it would be “very difficult and costly” to set up API GMPs around this kind of supply chain, and likely not worth the cost for such small market shares.

Because the material is manufactured for excipient and industrial purposes, it is generally manufactured using either excipient or food GMPs, he noted, which provide the “appropriate level of control” and specification ranges for their intended uses.  However, API is not an anticipated use.

Schoneker drew on his experience at Colorcon and discussions at IPEC in explaining the pharmaceutical industry’s use of excipients as active ingredients even though they are not manufactured for that purpose.

Many pharmaceutical companies who need these actives are “not quite sure what do”, he said, when they can find no suppliers that manufacture their API using Q7.  “But they also realize there is little existing guidance out there with what to do with this situation, and that is when everybody starts interpreting things.  And different people interpret things in different ways, depending on what sort of price pressure is coming down from upper management many times.”

Many decide to use the excipient grade or the food grade material and try to simply test the materials to show compendial compliance.  Although testing is important, “testing everything to meet the monograph in no way, shape, or form shows that you meet appropriate GMPs.  In many cases, it might meet the monograph and not even meet the food GMPs or the excipient GMPs” the Colorcon director emphasized.

“Testing cannot substitute for knowing about the GMPs and having real audit information about what the supplier is actually doing,” he pointed out.  “There is way too much confusion..about how important testing is, at the agency and in the industry. Testing is relied upon by all parties as if it is somehow good enough, and it simply is not.”

The use of excipients as atypical APIs “in many cases” is not divulged to the maker because the pharma firm using it is “afraid they might stop supplying it to them once they know.”  Schoneker pointed to increasing regulatory and industry focus on supply chains as a reason this cannot continue.

“As there is more and more attention being given to supply chains and the need for supplier qualification…there is going to be no excuse for [pharma firms] not having that discussion with every single supplier and having audit information on every single supplier.”

A user needs to be accountable for any atypical active uses of their material, he emphasized. “Ultimately, if you are going to use it as an atypical active, you better have talked to your supplier about it.  You better be fully aware of the risks and understand that you have got those under control.”

It is also a responsibility of the user to “discuss their API uses with their suppliers and assess, using risk management techniques, what must be done to meet appropriate regulatory requirements and assure safety,” Schonecker commented.  “Whether it is Q7 or not, if you understand how it was made, you can come to some reasonable risk management decisions about what is acceptable for your application.”

Involving regulators in discussions about appropriate level of GMPs is also key, he stressed.  “We can do the best job we can doing risk management in industry, but if FDA, or EMA, or some other regulators come in and say ‘well that is great, I see you did all this risk management, but our expectation is Q7,’ and they do not accept the fact that good science is trying to dictate an outcome here, that is going to be a problem.”



What is really happening today? I have kind of set up what we have seen that pharmaceutical companies might do. I can talk from experience from the discussions we have had at IPEC, within the maker’s side of what the other customers actually seem to be doing in this scenario.  And I can speak myself from a Colorcon perspective.

Pharmaceutical companies will tend to incorporate an atypical active in the drug product and not tell their supplier. Very typical. I see some of the excipient manufacturers in the room nodding their heads right now.

Then what happens is that material gets listed in a drug application.  FDA then shows up at the excipient manufacturing facility to perform their preapproval Q7 API inspection of the API manufacturing plant.

The excipient company goes to the lobby when FDA comes in and says ‘what do you mean you are here to do a Q7 inspection, we don’t make APIs. I am not sure why you are here, and we are not aware of anybody who is using the product in that manner.’  FDA then usually says ‘well, that is nice, but…you are listed in a drug application, you are listed as the API manufacturer, and since we are here and you are listed in the application, I think we will go ahead and do the inspection anyway.’

Usually then what happens, as you might expect, [is that] the company is utilizing IPEC excipient GMPs.  There are certain issues within Q7 that they are addressing in different ways, perfectly adequate for an excipient, but the excipient company then gets a 483 with many observations related to those areas of difference between Q7 that go beyond the IPEC excipient GMPs.

So then usually what happens is the excipient company tells FDA that they will not supply material for use as an atypical active any longer to anybody that they know is using the product in that manner.  FDA will then come to a position to say ‘O.K., well if that is the case, then we won’t expect you to meet Q7A observations.’

Then usually what happens is the FDA then goes to revisit that pharmaceutical company who happened to list them as an API in their application to discuss with them how they came to that conclusion, and why they did not talk to their supplier about it. And in some cases this might end up with a rejection of their drug application or a citing of GMP violations.

Then the excipient company [is now] worried.  They have got this outstanding 483 and they have committed to say they will not sell to any users who are using this as an API, but they are not quite sure who that might be.

They will start searching their database of customers, and every once in a while they will see a name that has a ‘pharmaceutical company’ at the end of it, and say, ‘well, they never told us they were doing this, but that makes me a little suspicious, so let me go out to all my customers and tell them I need to know what they are doing with it.’ Many times those customers refuse to tell them, or just never answer the request.  But usually the excipient company does its best to try to show the due diligence that they tried to find out if anybody was using this as an API, so they could stop it.

Many times they cannot assure themselves of that, and so since they promised FDA they would cease supplying in the future, sometimes the best they can do is say ‘O.K., we’re going to label all of our material now on the C of A or on the drums or both places to say ‘excipient use only.’  Or they are going to put things out on their website to say ‘this material is not for medicinal use, cannot be used for API uses.’  That is what a lot of excipient companies do because they know they cannot assure themselves sometimes that their customers are not abusing the material without telling them. That is what is really happening.  Many of you guys who are here are probably here because you know this, or you lived this or you have been through it.

So what is the outcome?  The excipient manufacturer must make costly improvements to meet Q7 GMPs if they do want to stay in the market, but they probably will have to raise prices – it is not going to be the road grade prices that everyone liked before. But that probably will not happen in most cases.  It may happen in a few cases where the market is sizable enough and the users are willing to pay top-dollar, but in most cases the excipient manufacturer is going to exit the market so they will not supply it anymore under any circumstances, and in some cases they may even close the plant if it turns out that that was a major use of the product.

You will hear more about this in the case studies tomorrow. The pharma companies must find, as Janeen [Skutnik-Wilkinson] said, another supplier, if one exists that meets Q7 GMPs, and in many cases there will not be any, unless they turn a blind eye.

So then what happens is that the drug cannot be produced, and that is a major problem for patients. If you really look at risk-management – not having the drug available for patients that need it is probably our bigger risk. It is certainly a much bigger risk than saying something was made using excipient GMPs, especially when you consider the fact that the excipient, in a tablet application, is usually 80% or 90% of the tablet. The API is that silly few little milligrams that are in there, kind of important, but a few little silly milligrams that are there in the dosage form. The majority of the dosage form you are taking is the excipient.

Let’s say it is 90% of the drug.  If it is O.K. to use excipient GMPs for 90% of the tablet, why aren’t those GMPs O.K. for the three milligrams that are not? So I think we have got to keep it in perspective.  We are not talking about saying no GMPs here – we are talking about GMPs for excipients which are already pretty high standard materials.

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