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Insights from Atypical Actives Workshop Could Drive Needed Technical/Regulatory Guidance, Participants Affirm

The insights that emerged at a PDA/FDA workshop on atypical active ingredients could form the basis for guidance that would clarify the regulatory expectations involved and help close the existing communication gaps in the manufacturing and distribution chain.

The two-day workshop, held in early March in Bethesda, Maryland, brought together the industry and regulatory players involved to develop a clearer understanding of the issues 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.

Two central themes that emerged during the workshop were: ● the lack of communication and understanding between the players of the issues involved, and ● the need for clear expectations that both industry and regulators can agree upon.

The FDA participants recognized the gaps in their own understanding that the workshop was helping to fill.

“I definitely want to be sure that FDA is aware of this,” CDER Office of New Drugs Quality Assessment (ONDQA) Reviewing Chemist Jeffrey Medwid commented.  “I do not think it was really that hot of a topic until this [workshop] came along.”  He added that the other FDA attendees will be interacting with higher management on the issue as well.

[The analysis of insights and recommendations from the workshop 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 more on the challenges in the relationships and communication gaps in the producer/user/regulator chain when atypical actives are involved.]

CDER Office of Pharmaceutical Sciences (OPS) Associate Director for Policy Development Jon Clark described his experience in listening to the discussions at the preceding workshop session as “an epiphany,” leading him to revise his presentation during the break “a little more toward the center of the target” – in particular, regarding the applicability of ICH Q7 in the atypical active context.

FDA Guidance Could Follow Industry Effort

During the Q&A after Clark’s talk, workshop co-chair David Schoneker (Global Regulatory Affairs Director for Colorcon) queried him on the possibility of the agency producing guidance for atypical actives.

“Certainly one of the things we thought about in putting this conference together,” Schoneker explained, was that “if we can come up with good ideas on how to handle this situation and clarify some of the uncertainty – that sounds like guidance.  What is the potential, as we all work together on this, that over some period of time maybe we could see some sort of guidance document from the agency that could, in fact, reflect some of this thinking?”

Clark responded that such guidance is a “very high possibility.”  However, he cautioned that “guidance processes are unpredictable.”  Those projects that seem up-front to be a “train wreck” may get done in a few years, while others may be 15 years old and not completed.

Schoneker pointed out that the International Pharmaceutical Excipients Council (IPEC), which he is active in and has formerly chaired, has worked with its members to develop industry guidances on various topics related to the manufacturing and control of excipients that have become broadly accepted in the regulatory community.  He expressed interest in Clark’s position on whether that approach would be appropriate in the case of atypical actives.

The CDER policy official voiced support for the idea, pointing to the National Technology Transfer and Advancement Act (NTTAA) of 1995 which directs federal agencies to adopt private sector standards whenever possible in lieu of creating proprietary non-consensus standards.

Clark explained that when a consensus standard is brought to FDA, under the NTTAA “you have to respond, you cannot ignore it.”  He noted that the agency has a staff manual guide, 9100.1, that directs its activities on standards brought forward.  “The important thing,” he emphasized, is that if IPEC were to develop consensus standards in this area “you are on firm ground” in getting FDA’s recognition.

Asking the agency to develop a guidance before that consensus process has unfolded can be counterproductive, Clark explained.

“When the FDA starts writing a guidance, there is an information collection time…when we are not supposed to interact.  We are looking for comment through the docket system.  If you ask us to write a guidance, you might literally be shutting down the conversation.”  In the case of atypical actives, ”I am not sure we are ready to do that.”

On the other hand, he pointed out, “if you have written a document, it is a standardized document and you have gone through this public discourse process…then we have to respond to it in a way that makes that guidance go quicker, makes the public comment coming in easy to deal with.”

The CDER official provided an example of how using this process is helpful in during the public comment phase.  “When I get in a public comment from a guy who says, ‘no, there is no way the practice allows for this,’ and yet there is a completely public standard sitting somewhere in ASTM, ISO or IPEC that says the industry wants to control its community in this way, I have a powerful tool to put that comment where it belongs.  Without that tool, I could be dealing with that for years.”

Breakout Groups Offer Recommendations

On the second day of the workshop, separate breakout sessions were held to discuss technical and regulatory considerations for atypical actives.  The attendees rotated between the two session topics.

At the workshop conclusion, co-chairs Schoneker and Janeen Skutnik-Wilkinson (Pfizer Quality Strategy Director) provided summaries of the breakout discussions (see box below).

In the technical considerations sessions led by Schoneker, participants came to general agreement that the IPEC excipient GMPs are appropriate for atypical actives and that additional technical requirements are not really needed.  They also agreed that other IPEC guides – for example, on GMP, stability, validation, composition and significant change – should be acceptable for use with these materials.

The group emphasized the need for a pathway between maker and user to discuss design criteria.  “Talking about the design criteria that the drug product manufacturer needs vs. what the excipient supplier can do – that alone is a major step forward,” Schoneker commented.

Communication, in general, was identified as a primary challenge in resolving the current issues around atypical actives.

“The challenge that has come across loud and clear throughout is that communication between the maker and the user must be improved,” Schoneker emphasized.  “We have to find a way to force that discussion to take place if we stand any chance of resolving some of these issues.”

Additional challenges identified include: ● regulator understanding of the issues ● regulatory flexibility around what standards are applied, and ● the industry rationale for the controls they have in place for their processes.

High on the list of recommendations coming from the technical considerations groups was the use of a decision tree process to define when excipients qualify as atypical actives and the consequences of that decision.

“A lot of what we are trying to do is to make sure that everybody is asking the right questions at the right time so we can come up with a good scientific conclusion and not run into a lot of regulatory hurdles that are not based on science,” Schoneker explained.

On the communication front, the participants stressed the value of leveraging confidentiality and quality agreements to share technical and use information between makers and users.

The value of risk mitigation plans in creating a viable and proportional solution to the regulatory challenges that atypical actives present was another key theme.

Participants noted that these plans provide a pathway for regulatory buy-in to excipient-level control systems regarding: ● composition and variability ● process capability/validation ● stability ● specs ● change control, and ● cleaning validation.

Overcoming Regulatory Barriers Addressed

The inapplicability of the ICH Q7 API GMPs to atypical actives was also addressed at the regulatory breakout sessions.  In her summary, Skutnik-Wilkinson identified the “misperception, misunderstanding, and misuse of ICH Q7” as a “strong barrier” to moving forward with resolving the issues around atypical actives.

The problem is that Q7 is “being applied verbatim as law,” when in fact it is guidance, she said – one indication that “there really needs to be a refresher on the use of guidance across the board.”  She added that the workshop is “beginning to raise awareness” of this issue.

In general, the Pfizer quality policy official commented, the lack of “clear understanding on the expectations of FDA could be a barrier going forward” and create inconsistency in handling atypical actives during inspections.  Participants felt that further guidance from FDA would be useful in this regard.

Other hurdles identified by the group include the need to train excipient manufacturers on how to deal with FDA inspections, the defining and handling of “legacy products,” and engagement of distributors in the discussions.

Addressing the hurdles will require communication with and education of all of the foreign and domestic players involved, Skutnik-Wilkinson emphasized.  There needs to be “a mechanism to inform drug manufacturers, regulators and excipient manufacturers on the use of excipients as atypical actives.  We really need a mechanism to help educate people on any differences that we see.”

Participants in the regulatory discussions also pointed to confusion around: pharmacopeial monographs and whether they apply to the materials as excipients or actives; and a lack of awareness by both foreign inspectorates and FDA about what the issues are with these materials.

“I think just the fact that FDA agreed to partner on this workshop means that they want to address this,” the Pfizer official commented.

The breakout discussions encompassed the problems that not addressing the atypical actives could cause, including increased costs, regulatory risk to the companies involved, and the potential for drug shortages and counterfeiting.

“The overwhelming response has been that we cannot just walk away today and forget about this issue,” Skutnik-Wilkinson emphasized.  “We need to take action.  We need education.  We need more discussion and communication.  The risk is creating some real issues with our suppliers if we just walk away.  It is unfair to them to not have that discussion because you are putting them at risk.  You are putting them at risk for inspections, for FDA to show up at their door without their knowledge that they are supplying an API.”

Potential avenues discussed at the workshop for advancing the atypical actives discussions and guidance included ICH – possibly by making Q7 more flexible to cover atypical actives or through focusing directly on excipients – WHO, IPEC, the American National Standards Institute (ANSI), and consumer health organizations such as the Consumer Health Products Association (CHPA), which discussed their involvement in the area at the workshop.



Technical Considerations (Schoneker)

We are going to talk about: ● issues discussed ● shared understandings and agreements – and I say shared understandings, not always on the agreement side, but certainly shared understandings in some cases…. ● some remaining challenges that we identified from the discussion that we think are going to be hurdles that we are going to have to overcome to  move forward, and ● some recommendations that we took out of the discussion as maybe a place to start putting some attention to and figuring out how, along with what Janeen is going to present, we can make some sense out of this, and then have further discussion with the regulators and throughout industry.

Issues Discussed

We had several topics that we threw out there on the technical considerations piece – not so much saying these were issues that had to be addressed as being different between atypical actives and excipients, but saying here are some areas where we know there is controversy and discussion that comes up: ● composition and variability ● specifications ● stability ● change control ● risk management

Shared Practices and Improvements

It seemed that most everybody is saying excipient GMPs are appropriate for atypical actives.

We felt that there is a real need to discuss design criteria before going into specification setting and into further determinations.  Those design criteria are something that really can get at a lot of the technical issues we are talking about.  It is not necessarily that they have to be different between excipients and atypical actives.  But the fact that you are talking about the design criteria that the drug product manufacturer needs vs. what the excipient supplier can do – that alone is a major step forward.  The specs and everything else can come out of that as to whether there actually are any additional technical requirements or not for a specific application….

[We need to] make a path so that discussion can occur in a more proactive way between maker and user, and ultimately lead to an agreed-upon design criteria….  It was brought up that [getting agreement and signatures] may be difficult when you have long distribution chains.  We have got to find a way to solve that problem, because without an agreed-upon design criteria to talk about, a lot of this stuff gets really hairy and difficult.

It seemed for a lot of the discussion – although I do not know that everybody agreed – that really no additional technical requirements should be necessary across the board that is any different for atypical actives than it is for excipients, unless there is a very specific application need that has been identified in negotiating between the maker and user.

In general, since most of these excipients have been made under excipient GMPs and have always met excipient standards and have not necessarily met any special requirements for years and years, why is there really any reason to think that they need any special requirements just because we are calling them APIs today?  That may not be popular in the way some regulators might look at this, but I can tell you that certainly came out strongly….  Just because you call it an API does not change the fact that there are not really any technical needs that are different.  There may be some exceptions to the rule, but we should not stress that there needs to be something more across the board.

There is certainly a lot of feeling that the use of IPEC guides that exist today for GMP, stability, validation, composition, and significant change, should be acceptable for use with atypical actives as well.  There really does not seem to be a need to have additional stability data for the excipient, and not necessarily more information on composition, unless you have a specialized need for your particular application – but not necessarily across the board for atypical actives.  When we talked about a significant change, we [thought] the same level of change notification is needed between user and maker whether it is an excipient or an API.

Remaining Challenges

The challenge that has come across loud and clear throughout is that communication between the maker and the user must be improved.  We have to find a way to force that discussion to take place if we stand any chance of resolving some of these issues.  And if we want to get regulators to have any flexibility in terms of how atypical actives need to be handled, that communication is going to be a key part of justifying why flexibility exists.

We feel there is a significant challenge in regulator understanding of the issue.  As much as the realities exist out there today, there are many barriers to that in terms of guidances that exist that people tend to use as checklists – people who come from a certain environment and say, ‘this is what we always expect,’  Is that necessary?  There are going to be some educational aspects in working together to make sure that everyone is on the same path with this.

There needs to be flexibility in interpretation.  If something is not a law, it is not a requirement.  If it is a guidance, it is guidance.  It means it can be interpreted and good science should rule the day.  If you have a good science argument, that should rule the day, regardless of what you do in another circumstance.  That flexibility in interpretation is going to have to both be justified by industry and accepted by regulators if there is a good scientific argument.  That is not going to be easy – it is going to be a challenge.  We are talking about a paradigm change as soon as you put the term ‘active’ on there.

The next challenge we talked about was to develop an appropriate rationale to apply to controls that we feel are justified, when in fact those controls might be less than what might be interpreted as Q7 expectations.  We cannot ignore the fact that Q7 is out there, but we are going to have to have a rationale to justify if we have controls at lower levels – why and how does that play out scientifically.  That rationale should be documented.


From a recommendations standpoint, [Iain Moore, Product/QA Manager from Croda Europe] brought a really interesting idea, both in his talk and in the [breakout session], and we really think this makes a lot of sense to think about in our path forward:  we really need to have some sort of decision tree process to define an atypical active in a specific circumstance.

That is a difficult thing – how we define it.  There is not going to be a list out there.  In each of your situations you are going to have to define when it is an atypical active vs. an excipient vs. a typical or standard API.

Iain mapped out a few ideas on how a decision tree process could be put together, and what information might be then available to determine appropriate control depending on different circumstances…   This would tie in nicely with some of the thinking that is happening in Europe already.  We could put it into a process that we could all start to think about in the right way.  A lot of what we are trying to do is to make sure that everybody is asking the right questions at the right time so we can come up with a good scientific conclusion and not run into a lot of regulatory hurdles that are not based on science….

Trying to develop a decision tree might not be easy.  But trying to develop something that seems to make sense, that can be very easy for industry to understand how they came to this conclusion and for a regulator to look at and say, ‘ok, that makes sense, you went through this process, you thought about this and that, you looked at the data and came to this conclusion’ – it starts to standardize the approach, which is what this is all about.

Another recommendation was that we have to maximize how we utilize confidentiality and quality agreements to improve the sharing of technical and use information, and recognize that this is a two way street.  A confidentiality agreement is not just about the user signing a confidentiality agreement so the maker will tell them everything about the process.  It needs to be a confidentiality agreement that also has the user telling the maker what they are doing with it, and why.  That is critical to this whole understanding and how all these things play out.

So we may have to take a look at how we handle confidentiality and quality agreements – add some information into the templates.  We talked yesterday a little bit about the quality agreement – maybe having a section where you could tick off what kind of application you are using this material in, at least as an indicator to get the discussion going.  Good idea.  Maybe there are some other things that we can do.

Finally, to sum it all up…a big part of what we need to accomplish here is to find a way to develop an appropriate risk mitigation plan template, which walks you through the process – and this might tie in nicely with the decision tree concept – that addresses the key differences that we think exist between excipient GMP and Q7.  That would include some discussion of the various design criteria where, in fact, controversy sometimes exists.

The areas that we came up with that need to be incorporated in the risk mitigation plan in terms of what are the key areas a rationale needs to be built for: If you are going to say you are not Q7 or whatever, how are you addressing this?

● If we do not feel there is any need for additional composition and variability information, justify why we do not think there is any need for that – why, in fact, what we know about the excipient is what we need to know about the API.

Process capability vs. validation:  we have got to have a better discussion that is documented about why we are using process capability data and how – rather than getting into this idea of validation studies all the time, which does not compute to many of the chemical manufacturers.

Stability:  why we believe the stability information – I say information as opposed to data – that we have on an excipient is good enough for the use that we have.  If it is not, then let’s recognize it and say we need more.  But if it is, and it has been a stable excipient and a stable atypical active for a hundred years, and nobody has ever had a problem with the level of stability information you have, do you really need to have to have ICH condition proactive studies?  If not, explain why not as part of your risk mitigation plan.

● For specifications, the same thing.  Do we really need tighter specs?  Probably not.  You never had them before.  You have been using this as an atypical active all along, you are probably meeting the specs that you have always met.  Just because now it is defined as an API does not mean that it changes things.  There might be some circumstances where it does.  Discuss that and justify why you are doing what you do….

● For change control, the same thing….  There is really no difference between a need for change control for excipients and atypical actives.  That may need some explanation in your risk mitigation plan, and maybe not in some circumstances, but it needs to be addressed….

Cleaning validation tends to be discussed a lot when people talk about Q7.  That does not really come into play many times with a lot of these dedicated manufacturing facilities where…you would not want to clean out the lines – that would cause all kinds of problems that you do not want to cause.  But because it is a little different than what people are used to in a Q7 environment, there may be a need to explain how cleaning is handled in the risk mitigation plan, and why maybe a true cleaning validation is not a good idea all the time.

Those are the areas that we think need to be added into the risk mitigation plan.  I am sure there are others, but these were the ones that came out of the discussion points that we had up for this particular session.

Regulatory Considerations (Skutnik-Wilkinson)


First we started with the barriers.  What are some of the barriers that we heard from everybody?  I think across the board we heard a real strong barrier which, interestingly enough we also heard from [Schoneker’s group] is a real misperception, misunderstanding, and misuse of Q7 from both regulators and industry.  A lot of it is being applied verbatim as law, when perhaps that is not necessarily the case, and in some cases not necessarily even needed.  I think there really needs to be a refresher on the use of guidance across the board.

[There is] a real lack of understanding of the actual issue that we are trying to resolve.  I do not think that is surprising, because one of the key things that we thought would be an outcome from this workshop is really raising awareness of what the issue is, and that there is an issue….  Certainly from the perspective of this meeting we are beginning to raise awareness.

Perhaps an audit guide from FDA would be useful.  [The lack of] clear understanding on expectations of FDA could be a barrier going forward and whether there is consistency in terms of atypical actives on inspections.

The training of excipient manufacturers on how to deal with FDA, what to expect, and what the whole situation is [is important].  If you think about, on the pharma side, how much training do you have within your company on how to handle an FDA inspection, how to work with FDA?  We do an awful lot.  But obviously if you are an excipient supplier and you do not even know FDA could ever show up at your door, you are not going to have programs in place.  Even if you were to try to, if you have never had experience with it, it could be very difficult to accomplish that – so really trying to help everybody help each other.

There has been a lot of discussion about legacy products, and actually that we need to define what a legacy product is and what does that encompass.  Are we talking about solely everything that is already on the market?  Or are we talking about the formulations that are on the market, in terms of if another company comes to put on the market a similar formulation, is that a legacy product?  There needs to be some further clarification.  That could be a barrier for us moving forward….

We have a lot of distributors, and it is very difficult to know all the key players.  Also, at the moment, we do not have distributors engaged.  We have one distributor here today, which I am happy about, but [for the most part] they are not engaged in this discussion at this time.  That could be a barrier, because 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….

The education of quality units came up as a barrier.  There is a lot of discussion…about this box-checking mentality that we need to continue to move away from.  We have certainly moved away from it a bit over the last couple of years, but it is something that we need to continue to work on.

There was a lot of discussion about the Colorcon situation [with] CalCarb.  We do not want to end up in situation where we have products discontinued – and not just atypical actives, but [also] excipients.  We need to be very careful in the approach that we take or we could be creating a significant barrier in terms of the availability of materials and medicines.

Addressing the Barriers

[There were] some really good ideas for helping to address some of the barriers for education and training, [for example] using webinars to get the issues out to regulators and industry….  There was a lot of good discussion about using technology, using webinars as ways to get out this information to industry and regulators.

We need a clear rationale for why atypical actives of legacy products do not need Q7 scrutiny, which I think is quite similar to what we heard from session A, and clear criteria checklists based on risk assessment to decide how to deal with them….

There was a lot of concern raised about foreign sourcing overseas, not focused so much on just the quality, but in terms of how we engage them in this discussion, how we make sure they are aware of the use of materials as atypical actives, what are the expectations, and so forth.

The need to educate regulators on how excipients are made, and that it is different from an API – there still seems to be a misunderstanding of how the chemical industry functions and how excipients are made.  If we want to be truly successful – not just here with atypical actives, but also in terms of this evolution that we have going on with supply chain and with Q8, Q9 and Q10 – we really need to make sure that all the players and all the actors understand each others’ business better.

Help the excipient manufacturers to understand the new excipient regulations or anything that may come out from an atypical actives perspective.  Make sure that they are aware of expectations coming out from regulators.

[We need a] mechanism to inform drug manufacturers, regulators and excipient manufacturers on the use of excipients as atypical actives.  We really need a mechanism to help educate people on any differences that we see.  So if we are involved with a decision tree, if we are going to come up with criteria, we need a mechanism to make sure all the parties are educated.

Regulatory Hurdles

The next topic that we addressed was the regulatory hurdles….

This is not an issue solely within the US and Europe.  We need to engage foreign regulators.  We need to not only educate them on what the issues are, but also make sure that they are part of the solution going forward.

There are some issues from the pharmacopeial perspective that were raised.  We also heard some discussions during the plenary sessions about whether both USP and NF monographs are needed for all of these materials.  If you have a USP and NF monograph and a PharmEur monograph, then how do you know if the PharmEur monograph is meant to be for an API or an excipient?  There are still some challenges and concerns there that we need to look at.

There is a real strong request for FDA to acknowledge that atypical actives exist.  [Jeff Medwid, CDER ONDQA Review Chemist] did volunteer to take this back and follow up with FDA.  And I think just the fact that FDA agreed to partner on this workshop means that they want to address this issue….  I think it was just never really raised, so there really was not an awareness of what this issue is.  I do thank FDA for partnering with PDA on this….

Another hurdle is that we have emerging markets.  Their regulators are starting to ask a lot of questions, and the questions may not necessarily be appropriate or work with these materials.  We need to address the hurdles in those markets as well and recognize that their knowledge and understanding of the state of play in Europe and the US may not be what we think it is.

We have seen this when we work with regulators.  They may have been led to believe that there is a current situation in certain markets, and that may not be accurate.  Not only do you have to work with them, but you also have to figure out what they understand about the current situation.  Unless you understand where they are coming from, you cannot possibly work with them.  That is a key thing that we have noticed in the work we have done in emerging markets.

[Also a hurdle is] the availability of excipient manufacturers’ processes and the information on GMP, providing that information to drug manufacturers, and what type of information is available.  A lot of times companies ask their suppliers for certain information that just does not exist, so we need to understand how we communicate that and how we understand what information is critical.

There are GMP differences between various different countries, which everyone in this room is well aware of.

The issuance of GMP certificates is another hurdle that we need to address.  It is already a problem for other situations, but it is also an issue here for us to address – not just the fact that we do not get GMP certificates in the US, but specifically for atypical actives we know that countries are expecting to see those certificates.   How do we handle that in this specific situation?  Not only the fact that you may not be able to get a certificate, but what GMPs are you certifying it to?  That needs to be clear along with the process that we go through.  Again, distributors need to be in the loop, because if they are not part of the development of the solution we are not going to be successful.

Risks with the Status Quo

There was a broad understanding that the risk to the patient was not so much from a safety perspective, really more from a legal perspective.  What we mean by that is that there is not a safety issue for the products out there now in terms of the way they have been manufactured for years and the way that they have been used.  We recognize that the quality has been good enough.

But we have to recognize that if we do not address this issue somehow, if we are not active in working with regulators trying to solve this problem, we could potentially lead to encouraging counterfeit drugs and illegal actors to enter the market for a lot of different reasons.  [For example], cost pressures:  if the prices of these drugs on the market go up solely because everybody says ‘we have to implement all these new standards’ so the prices double for those materials, that creates a counterfeit situation because it becomes very profitable and people do not want to pay double for what they paid for their Kaopectate yesterday….  And there is the potential risk of people saying, ‘the liability for us is too severe and we can no longer supply the market.’

There is the potential to lead to drug shortages, which is something that we need to be aware of.

Increased costs we need to be aware of.  Every single country in the world is concerned about the cost of drugs.  So we need to make sure that every step that we take makes sense and benefits the patients.

There could be a drive for sponsors to seek production overseas at questionable facilities, depending on the cost of materials.  So there is a risk if we just forget about this issue and all go home that this could drive companies to seek lower cost suppliers with more risk to the patient.

There was a really interesting discussion about innovation.  Perhaps if we just bury our heads in the sand after today we could have an impact on innovation with these products.  One of the key issues there was, if we pretend there is no issue, we could then prevent people from…changing their processes, enhancing their processes, because they are concerned about opening the door with the agencies.  They do not want to remind an agency that they have an atypical active.  So that can prevent that whole process.  Innovation can have a positive impact on the economic situation with drugs.  It can reduce costs.  It can reduce the resource drain….

This can put drug manufacturers at significant regulatory risk to the company reputation.  If we reflect on some of the things that have happened [recently], one of the key things I have always had to think about is kind of ‘the New York Times test.’  Do you want this to show up, do I want my company to show up [in the New York Times] because of a decision I made?  Do you want to risk a recall?

Think about the situation if we do nothing.  If you decide not to talk to your supplier and tell them they are supplying an atypical active, and tomorrow FDA shows up at their door to do an audit.  They do not comply with Q7.  They do not even know they are supplying an API.  Perhaps then they are not allowed to supply you anymore.  That then becomes a product recall.  So now you have created this whole media issue – for what?  At the end of the day, is there really a patient safety issue for that material that has been on the market?  Of course, if there is a real patient safety issue, that is a different story.  But I am talking about just by the letter of the law, it there was a non-compliance issue and someone made that decision….

The overwhelming response has been that we cannot just walk away today and forget about this issue.  We need to take action.  We need education.  We need more discussion and communication.  The risk is creating some real issues with our suppliers if we just walk away.  It is unfair to them to not have that discussion because you are putting them at risk.  You are putting them at risk for inspections, for FDA to show up at their door without their knowledge that they are supplying an API.

One of the biggest risks that we talked about is the ripple effect of not only your APIs no longer being available as an atypical active, but also the excipients no longer being available, and how many products that could affect.  We are not just talking about a situation where somebody does not want to supply you. If those materials are not allowed to be imported into the country because of a potential issue based on an inspection to Q7, how does that impact all of our patients?


Certainly ICH was brought up as a potential avenue.  There were some concerns that they are very finished-drug oriented, and that they are not [as familiar] with excipients.  There are some ways to address that….  There was some discussion about making Q7 more flexible to cover atypical actives.

How do we work with CHPA and follow up with them on what processes they are taking, and on whether they are engaging with the other consumer health organizations?

We had some discussion about whether WHO would be a suitable option going forward.

We also had a lot of discussion about what IPEC can do.  We have heard some things already in terms of the guidances that IPEC has and how we can make some modifications to guidances to help this going forward.

[There was] a proposal to put this into ANSI, which would permit FDA to reference this as a consensus-based standard.  [Maybe] first some development by industry and then putting it into one of the other processes….

Key Messages

One of the things that I heard in every single discussion and session, both in the breakouts as well as in the plenary sessions, is that transparency in communication is essential.  It needs to occur between users, makers, regulators and distributors.

Specifically, if you are using a material as an atypical active and you have not told your supplier, they need to be aware of that.  That can start now.  It is not something that needs to wait for guidance.  We really do have an obligation, even if we do not do anything else, just because of the fact that FDA can show up at their door.  I think that is an obligation that we have – to make sure that they are aware of that.

There is a strong need for education.  Users and regulators need to understand the excipient chemical business.  Makers of excipients need to understand the FDA process – how audits are done and what the expectations are.  Inspectors and auditors need to know what to expect when they walk into a chemical company.

We heard a lot about gap analysis that needs to be done between the IPEC PQG and Q7.  I know that there is some work that has already been done on that, but I do not think that is has been published formally.

Next Steps

The slides will be available.  We will take the information from this session today and give you additional information from the breakouts.  I realize some of the language and verbiage here may not be as clear, so that will be cleaned up.  The planning committee will reconvene and we will discuss all of the feedback and start planning for some next steps.

FDA specifically will be discussing this issue further in terms of what actions they intend to take.

Additional information based on our decisions about next steps will be provided to the attendees as it becomes available.

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