Medical Device Link.

Originally Published PMPN September 2002

Discussing DMFs

In this exclusive roundtable discussion, PMP News explores the challenges facing both drug manufacturers and material suppliers in referencing, maintaining, and updating Drug Master Files.

Any time a pharmaceutical company sends a New Drug Application (NDA) or other submission to FDA, it must provide certain information about packaging, as specified in the 1999 guidance "Container Closure Systems for Packaging Human Drugs and Biologics." The problem is, much of this information is not readily available to pharmaceutical firms; instead, it lies with their packaging suppliers for proprietary or other reasons. The suppliers provide this information to FDA in a Type III Drug Master File (DMF), where agency reviewers can reference it every time it is included in an application, as long as a Letter of Authorization (LOA) is provided.

However, it is a challenge for pharmaceutical companies and their packaging suppliers to make sure that all appropriate packaging information is included, between the NDA and the DMF. In fact, FDA has determined in recent years that many DMFs are deficient, leaving the agency to spend extra time reviewing packaging information, potentially slowing down the application process. Such issues came to light during a workshop on DMFs sponsored by Michigan State University's School of Packaging for pharmaceutical companies, packaging suppliers, consultants, and FDA. It was held in March 2002, and a white paper was then published on what should be in a Type III DMF. The paper can be viewed at dmfworkshop.msu.edu.

But more work needs to be done before all DMFs are in order. In this excerpt of PMP News's exclusive roundtable discussion moderated by senior editor Erik Swain, four of the workshop organizers discuss some of the DMF-related issues that FDA wants industry to address and the challenges that still lie ahead. The organizers are Robert E. Bergeson, senior operations investigator, analytical R&D, stability administration and packaging for Pfizer Inc. (New York City); Perry Fan, consultant with Montesino Associates LLC (Wilmington, DE); Ron McManus, consultant with Pharma-Pack Inc. (Fort Myers, FL); and Dwain L. Sparks, associate regulatory consultant for Eli Lilly & Co. (Indianapolis).

Why has FDA made addressing DMF deficiencies a pretty significant priority in recent years?

Robert E. Bergeson, senior operations investigator, analytical R&D, stability administration and packaging for Pfizer Inc. (New York City)

Bergeson: It's connected to the container closure guidance that was issued in 1999. FDA raised the bar with the amount of information required to prove that the container closure system is suitable for its intended use. The information is critical for the reviewer to determine whether or not there are safety, quality, suitability, or interaction issues with the dosage form, and once all the reviewers were trained on the container closure guidance, they realized through the review process that some of the DMFs have not kept up to the standards set by that guidance, which resulted in some deficiencies.

Sparks: During 1998, we started seeing increased activity prior to FDA's publication of the container closure guidance. It was evident at that time that, prior to release of the guidance, FDA was headed toward the expectations described in that guidance.

Fan: I have to agree completely with both Bob and Dwain. I think the other interesting thing from my perspective is that 1989 saw the original DMF guidelines, and there really had been nothing of substance put out in print until 1999, a full 10 years later, and I think this has caught some suppliers by surprise.

McManus: During the mid-1990s, postapproval changes and the concept of interchange protocols were being used more frequently, for example, the change from glassine inner seals to heat induction seals. This encouraged the review of DMFs to look for equivalency support. Then came the new container closure guidance with its additional DMF requirement. These were not well publicized to the suppliers and they were caught with subsequent NDAs.

How much packaging information are you generally able to include in an NDA, and how much has to go into the DMF?

Bergeson: The amount of information we include in the application is directly tied to the type of dosage form we are filing. Typically, we would include basic descriptive information, along with some supportive qualification data. The rest of the information we would refer back to the DMF. But again, this is dosage-form dependent. If you have a larger safety concern with an IV, for example, we would do more up-front testing and include that information in the actual filing.

Sparks: One significant issue is when there is no DMF or when a DMF lacks information that is not typically provided in the NDA. Those gaps need to be filled. When we are aware that the DMF does not contain specific, pertinent component information, we will include it in the NDA or ask the DMF holder to amend its DMF.

Drug firms do not always have adequate information about the content of a DMF. They may find out what is, or is not, in the DMF via deficiencies in the DMF. I agree that the amount of information that is needed for packaging components varies with dosage form. The amount of information FDA wants is fairly well spelled out in the container closure guidance. Whether that information is in the DMF or whether it is in the NDA doesn't really matter to FDA. At the DMF conference, we heard FDA state clearly that it doesn't matter where container closure information is, as long as FDA gets it.

Even though the container closure guidance is clear on what information needs to be provided for an application, there are still some gaps in the amount of information being provided.

One example that comes to mind is treatment of a packaging component. I would say that the information on the treatment of packaging components is not fully elaborated in some DMFs. This is one example where the container closure guidance describes the information that is expected, but, I don't think FDA is always getting; the drug companies do not have that information. And right now, FDA is not really asking for it or hasn't identified that as an issue. But, I would suspect that if a treatment issue arose, the drug firms and FDA may point to the container closure guidance and ask why that information has not been provided. So, industry is attempting to provide information like this to FDA, up front.

Perry Fan, consultant with Montesino Associates LLC (Wilmington, DE)

Fan: This illustrates that some suppliers are not aware of or have not looked at the container closure guidance or the "Changes to an Approved NDA" guidance. Or, they've looked at it but not read it carefully, and they don't see that there's a listing for treatments. So, in our experience in talking to suppliers, a lot of them are unaware that the bar has been raised by FDA.

What procedures do you have to coordinate with your suppliers as to what information isn't going to be in the NDA and thus needs to be in the DMF, or for them to tell you what's not in the DMF so that you know to put it in the NDA?

Bergeson: That question was one of the driving forces for us to issue the white paper. I think there was a lack of awareness out there on both parts, the end-user and the supplier, as to what do we actually put in the NDA versus what's required in the DMF. Since the DMF workshop, we've had additional conversations with our suppliers to ensure that they're aware of this guidance, the white paper, as well as the container closure guidance, that the bar has been raised, and that they need to fall into compliance.

Sparks: We have made our suppliers aware of the white paper and the DMF workshop Web site. As soon as the Q&A feature is active on the working group's Web site, we will initiate another communication to our packaging component vendors to remind them of the importance of working together and using the Web site as a tool.

Perry, is this an issue that you can be of assistance with as a consultant?

Fan: Oh, absolutely. Personally, I've done a lot of work in the last year either writing new DMFs or auditing, revising, or updating existing DMFs. "Staggering" is the best way I can describe it in terms of seeing firsthand what is and isn't in existing Type III DMFs that are "in good standing," in other words, that haven't had deficiencies in the last few years. Really basic information is missing in terms of raw material suppliers, raw material grades, manufacturing processes, quality control programs. I've seen all of that either blatantly missing or just substandard in existing DMFs. One of the services we offer is to make people aware that these guidances exist.

Is there any way that you can ensure that your packaging suppliers have given FDA everything it needs, or is it always going to be a guessing game?

Bergeson: That's another question that prompted the issuing of the white paper, because we can't guarantee it. We can have conversations with our suppliers, we can ask if the information is there. We may or may not get a positive answer from them depending on the proprietary nature of the information. So, in most cases, we have to wait until it goes through the review process and see if we get any inquiries from FDA. The bottom line is we can't ensure that the DMF has everything FDA needs. I am aware that there are consultants who are doing third-party DMF audits and, although we haven't partaken of that yet, they are a good way to reassure drug companies that the DMFs are up to standard.

Sparks: We've spent quite a bit of time recently doing as much auditing of vendor DMFs as we can. As we bring on new DMF holders, our bar has been raised significantly. Four years ago, our goal was to obtain an LOA. Since that time, we have come a long way. A new DMF holder will be scrutinized and be expected to demonstrate that its DMF is in good shape. Or, if the holder is writing a new DMF, then it's going to have to meet certain expectations that we would have, particularly if the holder is writing it for us. If it's writing it for the general industry, the DMF holder will want other firms to provide input to provide the best interface with their NDAs, related to content about the subject component of the DMF.

Fan: One thing we've noticed when we're doing these third-party DMF audits is that it's usually apparent very quickly who really looks at this as an opportunity and has bought in to the program versus who's going to be brought in kicking and screaming.

Ron McManus, consultant with Pharma-Pack Inc. (Fort Myers, FL)

McManus: The third-party audits have been initiated in different ways. Sometimes suppliers take the initiative for the independent audits to upgrade and show clients that they intend to meet any and all FDA and customer expectations. In other instances, a pharmaceutical company that is about to submit an NDA may ask for an audit to avoid any surprises. In any case, there typically are adjustments that have to be made to the DMF.

Sparks: DMF holders that are repeatedly receiving deficiency letters on their DMFs or are unwilling to cooperate with NDA owners are very quickly going to fall out of favor with most drug companies.

Do you have a system in place to handle LOAs?

Sparks: Yes, we do, and it has worked quite well. Like everything else, it must be maintained, and it takes manpower to maintain. It is a database that allows us to track our current LOAs. It's very searchable and user-friendly. Anyone that has anything to do with an NDA can access the database and find an LOA. And, each LOA is linked to our internal part numbers.

Bergeson: That was one of the biggest complaints from the suppliers that were at the workshop. They don't really know who to send these LOAs to.

Sparks: We found that we had too many people asking suppliers for LOAs. So, we went the extra mile and put a process in place that's really worked quite well.

Fan: There's no one contact that suppliers can always go to. Every time suppliers get another request, basically they roll their eyes and just send it out. But, my gut feeling is that the system at Lilly is ahead of other companies' systems. It seems like other companies that we talk to have a system of updating the letters, making sure they have one at least no more than one year old. But, I haven't heard of a system like what I know you have at Lilly.

Dwain L. Sparks, associate regulatory consultant for Eli Lilly & Co. (Indianapolis).

Sparks: I want to go back to the previous question. There was some disagreement at the workshop pertaining to DMF deficiencies. When a supplier gets a deficiency letter, it was not clear how much information the NDA company receives. There is not strong evidence that every time a supplier gets a deficiency letter that it is sharing the deficiency with drug companies that reference the DMF.

And, related to that, if the DMF holder receives a deficiency related to an NDA submitted by one company, which results in a change to its DMF, the DMF holder may not notify other companies referencing the DMF. Those are the kinds of things that can happen if the DMF holders are not communicating to all their NDA holders when they make a significant update. The DMF holders need to communicate on a more regular basis, not just at annual report time.

Fan: I don't think that's an exaggeration. I believe it is fairly common that if a deficiency is received and an amendment or an update is made to part of the DMF, that company would probably notify the customer directly. But it would be rare to find a company that would then take the proper step and notify all people who have received their LOAs in the past for the product that has been updated. It's not that difficult to do. But, it's not done that often.

Bergeson: I agree with both of you. My experience has been that when in the process of reviewing one of our applications, we probably would be notified if there was a deficiency in a DMF in conjunction with a review of our NDA. However, as Dwain said, if it was somebody else's and there's a change being made, we wouldn't know about that, and that is still an issue.

McManus: Probably one of the bigger overlooked issues as it relates to DMFs is the lack of SOPs [standard operating procedures] at suppliers to manage and maintain DMFs. In audits done so far, I have seen very few. Without SOPs, people do not know who, what, how, where, or when activities need to take place. This includes proper customer notification of a change. This is the greatest challenge ahead.

Have you had an NDA or other submission held up because of Type III DMF deficiencies? If so, how long of a delay?

Bergeson: I'm not aware that we've ever had an approval held up. However, when we've encountered a number of deficiencies in DMFs that we had to address, we had to devote a lot of resources to it, and it took away from other things that could have been done. So, in that respect, it's a costly exercise to go through. But, we also receive inquiries on other things in the application. So, for us, it's been part of that inquiry and responding within the appropriate time frame.

Sparks: Yes, I agree. At the workshop, FDA stated that they do not generally hold up approval of an application for a packaging related issue because those issues are resolved prior to that stage of the process. If the reviewer had to take that time away from his desk to deal with a DMF issue for a day, and, in the end, it added to the final review time, then that's a delay. And we'll never know that because CMC [Chemistry, Manufacturing, and Controls] review usually is done well in advance of the medical review. Most reviewers today are getting their CMC portion done ahead of time. A delay of an NDA is probably not necessarily an issue so much as it is the cost of the resources. A lot of it comes down to not knowing what's in the DMF. The questions that come generally are surprises and not anticipated. We will not knowingly leave gaps when we know a DMF is deficient. We deal with DMF issues head-on, before we make a submission.

When the deficiency is resolved, is it then a simple process? Did you find later that it could have been easily prevented? Further, did you ever change any procedures after being notified of a DMF deficiency?

Bergeson: What we would do is discuss a resolution strategy and the timing with the supplier. The information that the FDA is looking for, of course, could be confidential, so we may or may not be able to get involved. But, we certainly would emphasize with our suppliers that timing is critical and we need to get a resolution.

Fan: Bob, were deadlines or target dates set on those type of things?

Bergeson: Oh, definitely. Usually when we get inquiries, you have a specific amount of time in which to respond, whether it's 30 days or 60 days. It depends. But we have to wrap that up. Otherwise, you are going to get into a situation where you could delay the approval. So, we discuss those issues with our suppliers and say, we would like to have this resolved in a reasonable time frame, and complete the strategy and the timing. Here again, the actual specific information is not something we would necessarily be privy to. But, at least they would realize that they could potentially be holding up an approval process, and to me, the best way to prevent this from happening is by partnering up with our suppliers right up front and making sure that they understand what needs to be in their DMFs.

Fan: It doesn't seem like part of the normal commercial discussion when you're talking to a supplier.

Bergeson: I think you're going to see it as more of the norm as we raise awareness by holding this discussion, by having more workshops, by getting the word out. The more that we do it, and the more that some suppliers may lose business, I think you're going to see it turn around a little bit.

Sparks: I agree with all of that. We continue to work with our quality control auditors of our vendors to ensure their knowledge of DMF processes. The answer to the last part of your question is, yes, this LOA database we have was a direct outgrowth of issues; that's why it was put into place. And yes, we did change some practices. We have more works in progress. We have a policy, which describes, very specifically, the role of the LOA; why we have them and the importance of them. It is very clear, and people are required to train on it that have anything to do with an NDA. We definitely have changed some practices here.

Has the postapproval changes guidance that came out at the end of 1999 had any effect on how you and your packaging suppliers have addressed DMFs?

Sparks: The postapproval changes guidance is very specific. And, as far as regulatory relief is concerned, which is what they were touting that all these guidances would provide, this one definitely did it. There are a few changes that require supplements that may not have required supplements before the guidance was published. And, today, whether it's in the NDA or not, we're going to report a change that is clearly described in the guidance. The guidances do reduce some of the reporting categories, and this helped. Also, there are some things that now we have to include in annual reports that did not require reporting in the past. So, the postapproval change guidance definitely had an impact on our business. It helped us, but I don't know that it's really helped the DMF holder as much.

Fan: For some suppliers, it has helped clarify or confirm what they've been told by customers. But, there are a large number of established pharmaceutical packaging suppliers that have not even read the documents in detail. It's surprising to me how many haven't.

Bergeson: Until it hits the suppliers at the bottom line, they're not going to pay too much more attention to it.

Sparks: Quality is our driver, and we want to put quality information out there. We want FDA to see the quality systems that we have and be satisfied and confident that we are making quality drugs with quality systems. And, we want them to see that there is a link, then, between what we do and what we expect from our suppliers in every facet.

The line between quality and regulatory is really diminishing. Regulatory must be involved in the decisions about changes more up front than we used to be and try to make sure everything fits together for a submission.

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