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Manufacturing vs Pharmacy: An Interview With Patrick Stone

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What is an FDA warning letter, and how should your company respond once it has received one? In today’s episode, Darshan Kulkarni talks with former FDA inspector Patrick Stone about the auditing process in compounding pharmacies, and how companies should address warning letters issued by the FDA. Plus, we’ll discuss the repercussions of ignoring FDA Form 483 findings.

Narrator: This is the DarshanTalks Podcast. Regulatory guy, irregular podcast, with host Darshan Kulkarni. You can find the show on Twitter @darshantalks or the show's website at

Darshan: Hey, everyone. Welcome to another episode of DarshanTalks. We have Patrick Stone, as always. Patrick, as you guys know, is the Auditor Extraordinaire, and he's an ex-FDA Inspector.

Patrick, what did I miss? Tell us more about yourself.

Patrick: Right. So, 13 years with the FDA. Most of that time with the bioresearch monitoring project program area. In 2004, they had me doing international audits. So, for the past I'd say 18 years, we've gone international every year. That was good. The FDA only sends high level individuals able to maybe speak a few languages. So, I did a lot of that.

Then, after my 13 years at FDA, the past almost 10 years now as a Consultant, I've assisted with a GMP, a lot of GMP, a lot more than what I did at FDA. Just now I'm starting to get a lot more BIMO, Bioresearch Monitoring, in the way of electronic trial master file reviews. I have done quite a few paper ones, but now that FDA is not accepting anything paper, it's all been eTMFs, and the review of them. Not just the TMF, a lot of times they'll say, "Oh, can you just review the TMF?" And I'm like, "Well, we should look at your quality systems."

Darshan: Yeah.

Patrick: We should look at every aspect that FDA will be reviewing, not just the eTMF. A big part of that is the data integrity. Also, we look at the project level oversight, right? A lot of times they miss that they need to look at sites, they need to look at project, and they have to be heavily involved in the safety, because the oversight of that is critical to FDA's review cycle.

Darshan: Let me ask you this question before we get into BIMO stuff: have you done any audits of pharmacies?

Patrick: Compound pharmacies? Yes.

Darshan: Yes.

Patrick: Many, many compound pharmacies. Some of the biggest compound pharmacies on the West Coast, I've assisted with.

Darshan: Okay.

Patrick: Some that were innovators in vaccines. We can't talk about names, but-

Darshan: Sure.

Patrick: ... obviously if you know about certain vaccines, they innovated a few vaccines, and now they're wanting to do more compounding. So, when we talk about compound, we talk about the sterile add mixtures, but also the dietary ones, where you have 18-

Darshan: Yup.

Patrick: ... or 16-

Darshan: TPNs.

Patrick: ... Yes, TPNs.

Darshan: Kinds of TPNs.

That's Total Peripheral Nutrition, or Partial Peripheral Nutrition. Yeah.

Patrick: The sterility aspect is where I come in. I do the USP 797 audits on them. FDA does have compound pharmacy, GMP, rags, but they're very shallow, and they pertain a lot more to vet meds. So, we look at more of the USP aspect for compound pharmacies. I would say there's still probably at a 70 or 80% failure rate. Even at the highest levels I've even had to go to...

Just say, the NIH. They asked me to come in and look at their compound pharmacy after the FDA shut them down. That's all public information, but I've seen the smallest to some of the largest premiere compound pharmacies, and two of my bigger FDA cases were from 2009-2010 area time.

Dallas District has three or four really big compound pharmacies, and they were typically in trouble for either doing things with vet meds they weren't supposed to, or using vet meds as human meds. Just all kinds of stuff, yeah. We got some things.

Darshan: I just gave a talk literally in the last two days on compounding pharmacies, and I do about a bunch of work in compounding pharmacy, so that's full disclosure. Having said that, one of the big pushbacks you get when you talk to compounding pharmacies are the following. Well, some of the push backs.

Number one: they say, "You know what? It's normal to get a 483 from the FDA. That's nothing to be surprised by. One of the explicit things I heard was a warning letter is the lowest form of a notification the FDA can give you, so I wouldn't worry too much about warning letters. My first question is: what is your opinion about those statements?

Patrick: It sounds like the folks that are giving those output from getting those type of 483s, don't understand what a warning letter is for one, and how to avoid one, right? It's not a badge of honor to get a warning letter because it's actually hurting your brand, right? Anyone can look up and see, "Hey, maybe I don't want to do business with this warning letter brand."

That's kind of where they don't get that part of it, like the marketing. But, when we talk about compliance and the possible safety issues, right? A lot of people can say, "Oh, yeah. We give out a lot of 483s, but some of them are small and minor in nature and you can tell right away, but some of them you need to read between the lines and see what the market impact, what the safety impact.

That's how you measure how bad a 483 is. If there's market impact, if there's patient safety issues, you better believe there will be some litigation. There will be lawyers involved. There will be courts involved, and people have short-term memory, so they forget how big the mold in the syringe episode was that went on for four years. Because it was six seven years ago, whatever it is now, the short-term memory kicks in and they forget.

Also, some of the bigger issues aren't just with the sterility part. It's the presumptive making of drug, right? Instead of being a compound pharmacy, you step into GMP, and when FDA starts handing out GMP 483s, you're in trouble because those are well-defined and you have now been looked at not as a pharmacy, you are a manufacturer. That's where they miss that importance that you leave the shelter of your State Pharmacy Board Harbor, and that Harbor is not so safe anymore that FDA is saying, "You're in trouble to State Board Pharmacy for allowing this New England business to occur and not reacting to it nationally."

Darshan: I'll give you, again, the feedback I've gotten, which is... the statement was that after 483s or the warning letters that are received, the feedback that was provided back by the pharmacies, very rarely looked at, but 100% of the customers are happy with the steps taken to address the 483 findings and the warning letter findings. My question for you is: is that because those steps are adequate or because the customers don't know what to look for?

Patrick: Yeah. I would say customer information for compound pharmacy is definitely lacking and the importance of pharmacies not pushing in and doing things in the wrong way. But, even when I go in to do effectiveness checks, I find that the effectiveness of things still isn't all there, because not everyone's on board or the appetite to spend the money to remediate isn't all there, right? Because maybe you're in a basement of a hospital system, or you're always in some sort of utilities closet or something, and you're not treated very well, right? Because space is premium and obviously your drugs are important, but the way you get them maybe isn't. So, yeah. I've seen some vacuum tube system still in use. That's cool.

Darshan: That's totally normal.

Patrick: I'm starting to see more robots carrying things around in a big chest, they just go through and take the meds wherever they need to go. But, I wouldn't necessarily say that, by client, are we talking about the clients that maybe are affected by these issues that are ongoing at the pharmacies? Because we're going to talk about them too, not just the clients that are helping them make the drugs. They can't have too many clients that are getting these tailgates compounding or presumptive compounding, right? You don't want to be in that position where you have that situation, but if you do, you better be ready to be called a manufacturer.

Darshan: Well. So, 503Bs facilities are by definition, as you know, subject of GMP. The question I have at that point, and I'm sorry, I know we had a very different topic planned, but this is fascinating to me. We can always do the other topic later on. But this one, in the context of being a 503B facility, our first question would be: do you think that the GMPs that are applied to pharmacies are the same as they're applied to manufacturers, or is there even a higher standard? One of the conversations I had was on how easy is it for a 503B facility to start making an AMBA? What is your take on that?

Patrick: Well. It depends on the class of drug it is, right? Is it a sterile injectable, or is it an oral formulation?

Darshan: It's an injectable.

Patrick: Injectable. Right. Traditionally, look at what FDA did to our vaccine manufacturing, okay? We pushed them out. We over audited them. FDA wanted to be a part of almost every campaign for certain vaccines like flu or typical vaccines that would be manufactured every year and distributed in large numbers. I think that when they apply them to compounding, they try to be fair and regimen, but understand that maybe compound pharmacies cannot react or don't have the amount of resources to correctly remediate. I think there may be a little bit of leeway in that, but typically FDA has reacted. Look at how they reacted to the outbreak of contamination, right? Since then, they did a real big blitz of compound pharmacy audits and found that many failed-

Darshan: Okay.

Patrick: ... but that tapered off, right?

Darshan: Yeah. I think the last report I read was the 2017 report, I want to say. They said 29 out of 30 failed.

Patrick: Yeah, but it's tapered off. In the past three four years, the appetite for that has changed, and now obviously everything is centered around what? Right? I don't even want to say because we talk about it too much and everything else, but if it's not that current thing, FDA, it seems they're too reactive in this case, right? They need to be even keel on all the issues, right? You can't just say, "Oh, let's put every resource into this one thing." It doesn't necessarily work so well that way, but I think compounders are still going to be getting away with some things that maybe they shouldn't be. I think they don't understand the ramifications for a large scale issue or some sort of contamination. Then, they need to be on board with understanding.

First of all, do I see quality by design in a compound pharmacy? That is the law of the land. You must have quality by design principles embedded in your GMPs and your process, right? Your process risk assessment. I don't see compounders doing what GMP operations are doing. They don't have that level of process risk assessment, process risk control. Even the batch record review, I find is somewhat lacking in the compound pharmacy because they don't have the same principles or background. If you don't have a process risk assessment, how are you going to design a batch record that looks at and has risk mitigation that is looking at critical control points, CQAs, your specificities, right? I think they're still getting a pass and that they should understand they need to bring their operations up.

Darshan: If I was a large compounding pharmacy and I said, "I have already put in," I'm making up numbers here, "a million dollars to upgrade my facilities. I am making $30 million worth of compounded medications every single month or every single year. I think I want to start an AMBA facility and maybe do contract manufacturing," what would you say to them? Do you think that they're ready? Or do you, and again we're not talking to a specific pharmacy, obviously.

Patrick: Right. Right. In general.

Darshan: In general, do you think that these facilities are ready, or do you think that they need work? If so, what kind of work do they need?

Patrick: In general, if you said you put in anywhere between one million and ten million, I'd say that's a good start. That's a great start. What is your long-term plan? Do you have longer term goals? Do you have metrics to meet those goals? Then I would ask, "Did you use a risk mitigation plan to invest that million dollars?" Right? You can do a lot of building enhancements, or philosophy type corrective actions, or small things that cost a lot of money, but when you don't focus them on the process, when you don't focus on building a quality system that you have data integrity, and a lot of GMP 483s are having data integrity issues because you're lacking training, you're lacking understanding of the computer systems in use.

Darshan: Mm-hmm (affirmative).

Patrick: You don't have validation plans in place. We can kind of equate this to an orphan drug sponsor, right? They start with 11 folks, they think that's enough. Next thing you know, I come around and hit them with the biggest 483 and tell them, "Look, you probably need 60 to 70 folks for this, and you're going to need them to do this, this, this, this, this in all these areas."

So, yeah. I also would ask compound pharmacies what their quality system is like now, because typically these operations are QC focused, QC centric. Their QA is probably non-existent, it probably doesn't exist. So, to build a QMS with QA in it, you're talking about possibly millions of dollars, because now you have to have a training capture system that isn't paper, right? Or, you have to have all of these oversight systems, internal audits, audit plans, right? Because when we talk about QC, we're talking about just focusing on one task or one series of tests. You're not talking about the entire process. Then, to assure sterility, right? To the area, environmental controls and upkeep of HEPA and all of these things like this, you could be talking easy tens of millions of dollars to just for the samples, right? To analyze the samples. If you don't do that internally, if you say something like, "Are you going to be sending this out to third-party?" Because if you are, the cost is going to be triple or minimum double.

Environmental monitoring is a big deal, and what type of a one pass system are you going to put in place, right? Don't tell me you're going to have someone from a clean corridor able to go into a dirty corridor and come back and forth, and this and that. What's your cross-contamination plan? There's so much involved that I don't know that a regular compound pharmacy has that, right? They have certain aspects of it. They have rudimentary type aspects, but full GMP aspect? I rarely see it.

Darshan: Fair enough. Well, I'm going to ask you to explain something as the manufacturing expert for let's just call it a mutual friend, because I had a conversation with a mutual friend about this. I need you to define a few terms for me in general approximately: the difference between QA and QC.

Patrick: Sure. ICH is very clear in many of the Q9 E6(R2) when we talk about GCP, because QA was not necessarily a defined. So, quality control is, from a GMP perspective, is like your analysis of environmental monitoring tests. They're the ones that will take the samples and analyze them either in the microlab or in other labs. They're heavily involved in the analytical part QC, but other parts of QC, each area of a process line will have someone come in and check the line. That's a QC function. Sometimes it's the operator, sometimes it's a third party. So, from that perspective, QC is focused on a series of items or one type of tests, right?

When we talk about QA, QA doesn't have a focus on one or two. It has kind of an omnipotent focus of the full process from drug substance to drug packaging, and every step in between. There are more gathering the some parts to evaluate the whole as a batch and to release that batch, right? Because when we talk about QA and QC, QC does not release a batch. They do not have a responsibility authority, and if they do it's backwards, right? That we would write that up. We would say, "Hey. Wait a minute. What qualifications do you have as QC as an analyst to review an entire batch from start to finish?"

Darshan: Right.

Patrick: Not just the process, right? When we talk about batch record review, hopefully we're talking about training of the operators to make sure they're trained up. If they're not trained up, that's a data integrity issue we're talking about. Also, the line clearance, checking the line clearance pre-start post-campaign, things of that nature. So, there's a lot involved there and the QA part is looking at every aspect.

Darshan: Does the distinction between QA and QC matter in clinical research?

Patrick: It does now, because ICH defines it. In the old days, you could get away with more QC than QA, right? Some of these rare sponsors that start with nothing. They have a QC functions, right? Because when we talk about clin ops, when we talked about regulatory affairs, we talk about data management, even when we talk about medical monitoring, that's QC functions. Medical monitors aren't a QA function in the sense that they're not looking at the entire project level safety.

Now, there should be a QA medical monitor in the background taking every site, all the information, right? So ICH E6(R2), now coming up R3, clearly defines in section 5.0 5.1, the QA QC paradigm, and it defines the separation. It also gives a bit of the expectation that QA is... I try to explain to sponsors, right? That QA drives the quality boat, right? They drive the system of QMS. They don't drive the company, right? Because that's why you have a CEO, but that CEO is relying on QA to have deliverables, to have market output that is safe and effective, and the only way to do that is to review every aspect.

Darshan: Okay. Can you explain process controls and validation?

Patrick: Right. Validation has different meanings in the sense that you have a reproducible event, that you have a processing line, we're talking process line, right? The validation of that process line includes the cleaning of it. It includes the maintenance of it. It includes the operation of it during the campaign, and also includes any electronic systems that are attached to it. Validation for a process and electronic system are two different things because the validation of a process includes the computer system, whereas the validation of a computer system, we're talking about principles of GAM or we're talking principles of installation qualification, operation qualification, performance qualification, user acceptance testing, and a compliance matrix when it comes to, let's say, we're talking a US FDA market, part 11 compliance.

Now that everything is ICH, you kind of want to go with GAM because if you just stick with part 11 compliance and EU comes in says, "Hey. We're going to look at your inspection and we're going to share your inspection." If you want to market in EU, which most operations plan on starting either US or EU and then branching out to everyone else, you want that higher level of validation for the computer systems.

Now, process of validation is different because now we're focusing strictly on the manufacturing process line alone. We're talking about the manipulation of compounds or chemicals or even biological that go through the equipment, okay? So, the process of the chemicals or biologics, or even a device because it's the same in devices-

Darshan: Mm-hmm (affirmative).

Patrick: ... going through that manufacturing line. The way you validate that process is through QC testing at the beginning. For drug manufacturing obviously to say a process is valid, you have to have three campaigns in sequence, and they all have to be within a certain theoretical yield, even with all the testing samples, the extra QC, right? Built in, because obviously you're going to have more testing for these three validation runs. So, after you have that, then you have a process that is valid because you've proven at least three times that you can reproduce the drug substance and drug packaging set up. Now, a lot of times when we talk about process validation, we're only talking about one part: the drug substance part. We're only talking about that one process of getting to the API.

Darshan: Mm-hmm (affirmative).

Patrick: Then, there's another process validation of going from the drug substance to the drug product. Now, in Biologics, the Center for Biologics, CBER, only looks at it as all one thing. It's all a drug product, so you don't separate drug substance. Let's say, you have cell therapy, right? You have a vector, and then you have a plasma that infects here, or whatever. So, it's all drug substance. There is a drug product, it's not drug substance. Anyway, that's just for the biologics part. Does that answer the process validation and-

Darshan: The question I was really trying to figure out is: do compounding pharmacies in your experience having audited them, do they understand these basics? Do they have processes in place to maintain the quality? And, if so, based on your experience, what advice would you give them as parting words?

Patrick: Yeah. I have not seen them have a good quality by design a system or a robust. I haven't seen that level of process risk assessment like it's demanded in Q9, because they feel like they're treated differently, right? There's somehow insulated. I believe they feel protected almost from the State Board, and they shouldn't rely on that thought process because it's a bad thought process. FDA will not stop looking at GMP the way they should based on State Board discussions. Actually, they won't even discuss anything with the State Board because it's between the manufacturer and the federal government. So, there's kind of a Trump there. They're like, "Hey. You're above your pay grade, buddy. Sorry."

The compounders need to really either get consultants or hire individuals that understand the quality system approach, the quality approach, which is good but they also need to understand now the quality by design, which is a much higher order of sensitivity of information. They want anatomical, molecular, whatever's available technology-wise today to specify a molecule or to understand a chemistry, they want to know the best and all of it.

There cannot be any unknowns in your output, right? Whether it's a QC sample, where you're looking at what's inside of every product, like the final product release, right? If there's any unknowns in there, there's a lot of issues related to that lately, because quality by design mandates there are no unknowns.

Now, it could be a class of chemicals that they hybridized, or they switched between two different isomers or something. And, that's okay as long as you know that's happening. But, if these peaks or these other items pop up that are not related to that, there should be no, "Oh, I don't know what that is." I think that's where compounders kind of stop focusing on the quality by design part.

Darshan: You mentioned an important question, which is they should reach out to consultants who can help. How can people reach you?

Patrick: Well. I'm all over LinkedIn. There's a lot of us on LinkedIn. is my portal. There are a lot of groups out there that I've worked with and go-betweens that find work. I've never really asked those guys, "Hey. Where do you find these clients? Do they just come to you?" Because sometimes I'll get three or four of these go-betweens asking me to do the same contract. Sometimes even I've heard, if I get a job, "Well, three outfits sent me you and your information. So, we figured, since we were getting your name so much, we wouldn't even interview you, just take you." And I'm like, "Oh, okay. Cool. Thanks. That's awesome." Right?

I don't know. I always wondered, "How are three different competing outfits offered the same stuff?" There must be some sort of message boards, leader boards. I don't know. There's something, but I haven't needed to find how that is thankfully, because I have been so busy that I don't typically look for new work. Just like this job, I just did this eTMF. I did these past three days. This was actually like a two for one, because I had a sponsor look for me based on a guru video. Then, one of their contractors was in search of someone that could do high-level work and for rare disease, because there's not a whole lot of contractors out there that really understand that pathway. This pathway was weird because they did a Phase One Two, right? Never heard of that. The adaptive design only applies to Phase Two Three, as you know. So, this would be my second Phase One Two design that I review based on FDA saying, "We like this so much that you need to apply now. We're not waiting for your Phase Three," and I'm like, "Since when is FDA picking winners and losers?"

Then, I look at the efficacy, right? Of this thing. Okay, it's a small sample, right? There's a small amount of these subjects, but we're talking over 70% effective, my friend. I was like, "Wait. No. No. No." I was like, "Okay. 40 to 50 to 60, but above that range..." And you're like, "Hey. That's borderline curative, man."

Darshan: [inaudible 00:36:18] company that is, so we can stay away from issues.

Patrick: Yeah. No joke. Yeah. So, we wouldn't say anything about who it was and I never will.

Darshan: We said that we do need to do another talk. I was really actually hoping to interview you about virtual audits, which is something [inaudible 00:36:37] soon.

I'm actually going to talk and see if I can get you back on, if that's okay with you.

Patrick: That's fine. Yeah. Yeah. I'll have a lot more time coming up here. These past four weeks were grueling. I had two to three audits a week, and then the TMF audit was like having two audits because it's just a massive amount of information to sift through.

Darshan: Well. It was wonderful having you on again, Patrick. Thank you so much for coming on.

Patrick: Appreciated.

Darshan: We're going to have you on soon again.

Patrick: Appreciate your time. Thank you so much.

Darshan: Take care.

Narrator: This is the DarshanTalks Podcast. Regulatory guy, irregular podcast, with host Darshan Kulkarni. You can find the show on Twitter @darshantalks or the show's website at

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