Episode Summary
If you are in the consumer healthcare industry, you probably know about GMPs, or Good Manufacturing Practices. But what do they specifically mean when it comes to dietary supplements, and how do VMS companies prepare for an FDA inspection?
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Anita Brikman: Coming up on CHPA Chat, a lively and in-depth conversation on GMPs. If you're in the consumer healthcare product industry, you probably know that means good manufacturing practices. But what do they specifically mean when it comes to dietary supplements? And what do companies in that space need to do to be ready for an FDA inspection? Coming up.
Speaker 2: Welcome to CHPA Chat, conversations in the consumer healthcare industry with Anita Brikman.
Anita Brikman: Hello everyone on CHPA Chat. Today we have a great panel discussion with a dietary supplement journalist and lawyer, an industry expert, and our own Larisa Pavlick, Senior Director of Product Quality and Technical Affairs, that's quite the title, at CHPA. They're discussing dietary supplement good manufacturing practices, GMPs, what this means to industry and the consumer buying these products in the context of current hot topics related to dietary supplement quality and compliance. Larisa, I'll turn it over to you to welcome your esteemed guests.
Larisa Pavlick: Thank you, Anita. Very excited to be here today. We have Asa Waldstein and Josh Long, and the two of them are going to talk with me today about good manufacturing practices. Josh, I'm going to turn it over to you to do a brief introduction. Tell us about yourself and your experience in the dietary supplement industry.
Josh Long: Oh, hey, thank you very much for having me, Larisa. I am associate editorial director of Natural Products Insider, which is a B2B publication that covers the dietary supplement industry. I'm also an employee of Informa. We put on the largest industry trade shows in the world, including in our industry, SupplySide West, SupplySide East, Expo West, and Expo East. I'm also a lawyer by training, and I have been covering this industry for over a decade, and I have been looking at GMP numbers and talking to experts like yourself for over a decade. Time flies. Thanks again for having me.
Larisa Pavlick: Thank you for being here. Asa, can you go ahead and introduce yourself and tell us about your experience in this industry?
Asa Waldstein: Sure. Thanks so much for having me, Larisa and CHPA Chat. I'm really excited to be here. I'm a fan of the podcast, so really honored to be here. So I started making dietary supplements 20 years ago, so I've really grown up in the industry. So over the years, I've seen the implementation of many laws such as the common allergen labeling law, adverse event reporting law, and of course GMPs for dietary supplements, which we're talking about today. I also have the great honor of being chair of the Cannabis Committee for AHPA, the American Herbal Products Association, and I am principal of the Regulatory Consulting Company Supplement Advisory Group.
Larisa Pavlick: Perfect. It's great to have both of you with us. And I know that you, and we have all worked together for a lot of years. So Asa and Josh and I've been in the industry for 26 years in the dietary supplement industry and in food safety. And so we've encountered one another in a few different pathways during my career. But within that time, we've talked about GMPs often, and I respect both of you for your education and your background and all of the experience that you have in this industry. So I wanted to talk to you a little bit about GMPs.
Asa Waldstein: Sure, I'll jump in. So for dietary supplements, cGMPs, current good manufacturing practices, they're really a term used to describe regulations which cover the manufacturing and labeling of dietary supplements. So GMPs, they're really a framework of regulations that leave a lot of room for interpretation. So this is one of the important reasons to follow enforcement trends because by following enforcement trends, this can really show us what FDA investigators are focusing on. So I know we'll talk a little more about enforcement trends later today.
Josh Long: Right, thanks, Larisa. From my standpoint, just in plain English, I think GMPs, they're designed to ensure that products in the marketplace are made consistently to quality standards, and that what is declared on the label is in the bottle. It's really as simple as that, and it doesn't contain anything else, including contaminants, and you're really the expert, Larisa. I'm going to turn it back over to you. We talked about GMPs, but there's a C in cGMPs. Why is that important, the C in GMPs. What does it mean?
Larisa Pavlick: Well, when we're talking about GMPs, we're usually looking at the acronym only, and you'll see usually a small letter c in front of GMP. That's referring to current. So when we're talking about current, that means that things change. The regulation hasn't changed in some time, but when we talk about cGMP, we're talking about the current regulations. And the regulation started in 1994, and I had the honor of working with Loren Israelsen. He founded another trade association that we work closely with, but we talked to him during our CHPA Chat number six on the history of DSHEA. So hopefully we can share that link with all of the listeners to re-listen to that. But he talks about the history and how the industry really came together in the... it was about 1991, I think he refers to, when it was considered the Wild West, and there was an unregulated space.
It was referred to as unregulated. But was that FDA didn't understand the products, and they started becoming very mainstream products. And the FDA wanted to ensure that these products were safe. With the turmoil at the time between FDA and industry, eight major brands came together in Utah to say, "What do we need the FDA to understand about our industry?" And that started forming the framework of what we know of now as the Dietary Supplement Health and Education Act, which passed in 1994. And with the GMPs, or with DSHEA, which is common really referred to in the acronym, it led to FDA needing to develop good manufacturing practices for the industry. Those sat in a draft form for quite some time, but the final regulation came to us in 2007, and we'll talk more about that today.
Josh Long: Thanks, Larisa. I wanted to pick up on that. So the final rule was adopted in 2007, and then FDA had compliance dates that were staggered based on the size of your company, 2008, 2009, and 2010 for the smallest firms. In 2010, I believe they also put out a small entity compliance guide on cGMPs to give industry guidance on these regulations. So it's been a number of years since the guide was published, and it's been a number of years, obviously, since the final rule was adopted. I'd like to hear from you and Asa. Are the cGMPs today truly current, or are they not current given what we know about the modern science?
Larisa Pavlick: Well, depending on who you talk to in the industry, the regulation itself has been kind of the foundation of the industry. And without a champion in Congress, it's up for debate on whether or not we want to modernize and update the regulation. But under most regulatory professionals' opinions, it seems that it is probably time to update and modernize the Dietary Supplement Health and Education Act. And there's a few key points that the industry agrees on, and of course there are other points that are not agreed on or a little bit more controversial based on the membership of different trade organizations. I think at this time, there's a lot of room for improvement and a lot of opportunity that we could talk about. Asa, how about you?
Asa Waldstein: Yeah, there's always room for improvement. We can't implement a regulation and then 20 years later, say, "Hey, everything's A-okay, we got to keep going." We have things like social media, digital marketing, that are all considered an extension of label and therefore are covered by FDA in many respects that weren't around in 1994 or not even really around in 2007 when GMPs, the final rule came out. So there's certainly a lot of room for, or potentially some room for improvement. Now, strictly with GMPs for dietary supplements, I think in general the rules are pretty darn good. They're a framework.
Anita Brikman: And, Asa, I was wondering, or maybe this is a question for any of you, are there some repeat violations we see more often than not that consumers should be aware of?
Asa Waldstein: Yeah, I'm going to defer to Josh on that one because he's written a lot about this for Natural Products Insider.
Anita Brikman: Josh?
Josh Long: Yeah. So for a number of years, we at Natural Products Insider have filed Freedom of Information Act requests from the FDA to ascertain which observations or so-called violations of these regulations are most common, most predominant, are being cited most frequently. And in the most recent fiscal year, many of those observations had to do with setting specifications for identity, purity, strength and composition of the dietary supplement. And I want to turn it over to Larisa because she was the FDA investigator. And, Larisa, you can explain to the audience what exactly does it mean to set specifications for our identity, purity, strength, and composition, and why is it paramount?
Larisa Pavlick: The biggest challenge that we see in the dietary supplement industry and actually in the food space as well, is the ability to set regulatory specifications. So there's a difference between what you'll see in operations department and a manufacturing department in their specifications versus what the FDA is looking for. So when I was conducting trainings, I used to always help people to understand that a regulatory specification may look different than what they would be using in their own organization. It's okay to combine the information. It's important to know the bulk density, the particle size, the moisture, the color, the smell. Those are all very important characteristics to develop a dietary supplement product or any product that's being consumed. But what the FDA is looking for is identity, purity, strength, composition and limits for potential contaminants. I call those the big five, and those must be listed on your specification, or the investigator could and probably will cite you for deficiency.
Now, GMPs were originally established in 1969, and that was really referring back to drug specs. And when you compare a drug specification to a dietary supplement specification, they're very similar, but the words are used a little bit differently. So in a drug spec, we're looking for identity, strength, quality, and purity. So most of those are comparable to what you would see in the dietary supplements, which is identity, purity, strength, composition and limits for potential contaminants. The two differences in those are quality in the drug spec and composition in the dietary supplement specification.
Now, when you're working in the dietary supplement space, the five that I referred to as the big five, identity, purity, strength, composition and limits for potential contaminants, those are the definition of quality when you look at the regulation. The difference when I look at drug specifications to try to make the correlation is that even though the specification states that you'll have identity, strength, quality, and purity, I don't find a definition for quality. So I think those differences make it difficult at times for companies expanding into the dietary supplement space or for those that are entering the dietary supplement space to really understand how to appropriately write the specifications to include all those necessary elements, and then using those terms appropriately.
Anita Brikman: So, Larisa, is this a nomenclature issue or sometimes is it the way it's reported that is often the problem, or are there lapses in manufacturing as well that need to be addressed? Have you seen both?
Larisa Pavlick: It depends on the organization. A lot of small companies don't have the resources. Sometimes the mid-size companies I would find didn't interpret the regulation the same as what was intended. And then a lot of the large companies have more resources and more ability to put the manpower into their specifications. I think that difference and the challenge for a lot of companies is that when we're talking about a drug specification, typically we're referring to product that's at 98% purity. It's a lot easier to write a specification for a product that's that pure. You only have to identify 2% of the product, which might fall into impurity, but the composition is very easy to define. When we're talking about an herbal product or a gummy or some of these other complex matrix, it's very difficult to define a specification in the same manner that we would define a drug spec.
Anita Brikman: Asa, I saw you nodding your head, even though we have listeners who don't see you nodding your head. Did you want to add something?
Asa Waldstein: Yeah, I really love what Larisa said. It can be difficult for a company of potentially limited resources to develop a specification for a finished herbal product. So back to what Josh said earlier, one of the most commonly cited violations is setting specifications. We all know companies should set specifications. We want to know what's in the product. We want to know what's on the label. We want to know what's in the blend. But what about if there is an herbal blend of products? So here's just a hypothetical here that I'd like to just throw out to the group for discussion.
Let's say there's a group of herbal products. I've done my identity, strength, purity, composition, contaminants on all five of my botanical products. Now, if I mix those together in a blend and I've got a validated blending procedure, then how do I test that? How do I test that bulk botanical ingredient or that bulk botanical blend? Really the only way to do that is to develop a specification, which can be really expensive to develop that with a lab.
So I've kind of seen a trend of FDA investigators, at least based on what I'm hearing from my clients and what I'm seeing in warning letters, is FDA investigators are now really holding company's feet to the fire with these bulk botanical blends saying, "Hey, we know that you've tested everything properly on the way in. You've blended it properly, but maybe you're not proving your composition because you didn't develop a $2,000 method at a lab." So I guess my question, or it's more of a comment for the group, any thoughts on that, either Larisa or Josh?
Josh Long: Larisa, that is your expertise. I'm going to defer.
Larisa Pavlick: Botanical blends or any vitamin blend or proprietary blends, all of those have a huge challenge. As a former FDA investigator, we would pick apart the composition of those products, and we would want to know from the manufacturer how they could verify what they stated was in that blend was actually present. Now, one thing that we have to recognize is most FDA investigators, all FDA investigators, have to have a bachelor's degree. And it's required to be in a science field. I believe it was 20 or 30 credit hours that were required in science. So these are very smart, knowledgeable individuals that are conducting the investigations, but very often they do not have experience in dietary supplements, herbal products, or in manufacturing. So what we have to understand when they investigate our products is we have to do a lot of explaining to them. They don't understand the standard business practices that we use, or as Asa mentioned, our blending studies.
So when I approached an organization with my 12 years in industry prior to joining the FDA, I could look at the product and understand that we could evaluate composition by looking to see how well we qualified the raw materials, how well written the specifications for the raw materials were, and verifying that all those specifications were being met. Then through good manufacturing practice, we can verify that the appropriate ingredients were added to the blend. We can verify the weights. We can verify the addition. We can look at the blending operation. We can verify that the blend is appropriate. We didn't lose any materials. We can ensure the composition of that product based on documentation.
However, some of those investigators that don't have background and experience in our industry, they're going to look for analytical techniques or chemistry to verify the composition of those goods. And that creates a big challenge for the industry because you will see that often on warning letters, and we'll see that often on 483s where the investigator is citing the facility for not verifying the composition of those finished product blends. And those blends are very, very difficult to pull apart once you've placed them in that blending operation or into a finished product matrix.
Josh Long: I'm going to switch gears to an entirely different topic here at a very high level. So as I was obtaining some of this other data. Recently, we learned according to the data I obtained from FDA, that the FDA had conducted 517 inspections for compliance with the cGMPs. 500 of those were domestic. 17 were foreign. That was an improvement compared to the prior year, which was 277 domestic, four foreign at the height of COVID. And then I had previously reported the number of inspections in FY20 was down 52% from 598 in the prior fiscal year.
Cara Welch, who oversees the Office Of Dietary Supplement Programs at FDA, she's the head honcho in terms of overseeing supplements for the country. She has said that typically the agency inspects 500 to 600 facilities annually. We know there are upwards of 10,000 registered food facilities. So we know only a small fraction of dietary supplement facilities are inspected annually. Here's my question for you or Asa. Is that a problem? And if so, what's the solution? Is there a solution?
Larisa Pavlick: Well, at CHPA and my personal opinion, when only a small fraction of the industry is being inspected, and right now we're thinking that based on Cara's numbers for the number of registered facilities, about 7% of facilities were in inspected in 2022. And in the years prior to that, they were slightly lower due to COVID and the investigators not being in the field. So really, we've always been in the single digits for the percentage of facilities being investigated. When we looked at the top 10 citations and the top citations issued to the industry, meaning the deficiencies found during a regulatory inspection, it's only giving us a snapshot of a very small number of facilities. And we have to remember that some of those facilities are being reinspected because they were a violative inspection. So they have to have a regulatory follow-up.
I think it would be valuable for the industry and for the consumer if we could expand the number of facilities covered per year, and I think it would give a better picture of what the industry is doing. I think we would see more of the responsible industry reflected in the top 10 citations, and I think it would be helpful for the industry if we could come up with solutions to fill that investigational gap. And at CHPA, we have a couple of ideas with the DSHEA modernization and some suggestions for potentially looking at third-party certifiers, maybe implementing systems like the vQuip, which is a paid program used in foreign supplier verification programs, or maybe some of these third-party certifiers like GRMI. Asa, I'll throw it over to you.
Asa Waldstein: Yeah, I like it. I'd really love to see that number up, as we all would. Is it simply a funding issue? I don't think it ever is simply a funding issue, but I'm always a big fan of giving the agency more funding to help them do their job. Also, I don't know if it plays a role into this discussion, but RRAs, remote regulatory assessments, I don't know how... I think they're a pretty good idea. They help manufacturers work with FDA and then FDA can quickly or somewhat quickly screen the manufacturer to make sure that the processes are in place. RRAs might play a role in this so FDA could then simply touch base with the manufacturer, say, "Oh, your paperwork's in line. I'm going to go down to the next company," rather than having to spend the resources to go in and do an in-person 111 or 117 inspection. Josh, what do you think about that?
Josh Long: In terms of RRAs?
Asa Waldstein: Yeah.
Josh Long: I'm all for filling the quote regulatory gap. I think the more oversight the better, obviously, and that may provide a more accurate representation of the industry in terms of compliance. Obviously the devil's in the details, and I did want to mention for CHPA members for example, that approximately half of companies that are inspected for compliance with cGMPs do not receive a quote form 483. In other words, the FDA inspectors go into the facility and they find that they are in compliance with the manufacturing rules. And I'd love to get your thoughts Asa and/or Larisa on just that statistic, on that fact.
Asa Waldstein: Yeah, I think that's a pretty good number. I'm pretty lucky. I've had three CFR 111 GMP inspections and received no 483s, which is pretty rare, means I'm pretty lucky. And we had a really nice robust quality management system. So with 483s, and I think people that have worked for the agency know this as much as anyone, but some investigators really love to give 483s. One investigation that I had, the investigator said, "Hey, this is the first time that I haven't given out a 483 in a very long time." So the fact that 50% or so of the companies haven't received 483, I think clearly shows that based on the inspection data we have, we've got a very, very compliant industry. Not to imply that a 483 means that a company is egregious and not following the rules, but I think that's a pretty good number.
Josh Long: What are your thoughts, Larisa?
Larisa Pavlick: 483s are the investigator's opinion, and if you read the fine print on a 483 right under the company name, you'll notice that there's a little bit of legal fine print. And as an investigator, we were required to read that information when we issued a 483. It is only the investigator's opinion. It's not in the opinion of the agency, and it is just documenting what the investigator sees.
Another issue if we talk, bring it back to 483s, is making sure that... Industry takes those very seriously, and they are public. So I think we just need to come into some collaboration with the agency to make sure that we're truly issuing 483s where it's appropriate and to make sure that we're helping the public to continue access to safe, quality products.
Anita Brikman: And that's what we are all about. Any final thoughts as far as for industry as we talk about GMPs and compliance? I would love for each of you to leave our listeners with a tidbit of advice before we wrap up this episode.
Asa Waldstein: Sure. I'll start here. Well, half the battle with GMP inspections is preparation. So half the battle is before FDA shows up at your facility, make sure that you have all your proper documentation, your website's clean. You have an SOP for what to do when the FDA arrives, that you're ready. So when that investigator shows up, you know exactly how it's going to go. You have the call list of who to call. You know where the FDA is going to sit. This is really important. And so just be prepared for the FDA.
Josh Long: I would just say this stuff is complicated. So you need to retain the appropriate experts. You need to retain the likes of a Larisa Pavlick. And if you do receive a bunch of 483s, you probably should be retaining counsel and following up in an appropriate manner because you don't want to be subject to what's known as official action indicated because that could ultimately result in an injunction and a warning letter, just not great publicity. So always retain the appropriate experts, and you should be fine.
Anita Brikman: So kudos to Larisa. High marks there. Last words from you?
Larisa Pavlick: Thank you, Anita, and thank you, Asa and Josh. I appreciate your time being here today and for sharing your knowledge. My piece of information for the listeners is being prepared for your GMP inspection is essential, and I always share with my friends and those that I train, is to make sure that you Google Dietary Supplement Compliance Program Guide. And that is an FDA document that'll tell you exactly what the investigator is looking at when they enter your facility and what is required of them to include in their report. So if you can go through the compliance program and understand the expectations in that guide, you should be well on your way to understanding the process of that inspection. And if you need any help, let us know. We're here to help you.
Anita Brikman: Great note to end on. Larisa, Asa and Josh, thank you for joining for this episode of CHPA Chat.
Speaker 2: Thank you for joining us here at CHPA Chat. For more information and to hear our entire catalog of shows, please visit chpa.org.
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