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Agnes Shanley

FDA Fields Tough Questions About Inspections, Challenges Pharma to Be Open, Honest
by Agnes Shanley, Editor in Chief, PharmaManufacturing.com


Aug 30, 2012 | Free Downloads | email | Print

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Note: The views expressed in this article are those of the author and do not necessarily represent those of his/her employer, GxP Lifeline, its editor or MasterControl, Inc.


This article was originally published in pharmamanufacturing.com. Reprinted with author's permission.


Last month in Bethesda, at a conference on the Current Challenges of GMPs, presented by Pharma Conference, Inc., FDA officials took FDA's transparency mandate to new levels, by discussing some of the issues they are seeing at pharmaceutical manufacturing and quality operations.

They also addressed some critical questions from industry involving the consistency of field inspections, individual inspector styles, and problems with the review process.

This openness was particularly evident in an audience Question and Answer session chaired by Rick Friedman, Director of FDA's Division of Manufacturing and Product Quality, Barry Rothman, Supervisory consumer safety, and Steven Wolfgang consumer safety officer.

Questions ranged from quality management and contractor oversight, to issues of risk management and the need to "do more with less." Friedman noted the need to staff QA units with more seasoned professionals, especially those with manufacturing experience. He also noted that the drug industry still underreported internal QC issues, a fact that can come back to haunt any manufacturer during a recall.

All three connected today's drug shortages to insufficient supplier oversight.

Here is some of what they had to say. (For more, and some video clips, stay tuned).

Q - Recently there seems to be an increased concern about particulate matter, especially glass particles and metal fragments, in oral and liquid solid dosage forms. Has there been a shift in the Agency's perception of risk presented by very small, low levels of particulates?

Rick Friedman: Risk hasn't changed. It never changes. Perceptions and assessments of risk include people's expert opinions and you look at probability, severity, detectability.

Part of it also depends on what type of particle is present, what type of metal, and how large the particles are.

There is also a question about patient population, for instance, whether it's a pediatric medication, and dosage type (tablet or injectable). These factors affect risk severity.

When investigators see [particulate issues at a facility] and we see there is a trend, at FDA we start to get worried.

When manufacturers see that components are coming in that contain metal and glass particulates, we wonder how they are responding to their supplier. Are they returning the API lot to the vendor, saying 'This is not my standard, I don't want metal and glass in my API,' or are they simply forward processing the faulty materials?

These are the kind of things that we want you to think about from the good manufacturing practice and prevention point of view.

We want you to be thinking about the prevalence of the problem and whether there is a pattern, and also, how you work with the supplier when you get a product that is below your standards.

We want to know 'What was your reaction to that API, what do you do?'

Q - Does the FDA have a policy about the number of the investigators that can be assigned to an inspection? The number assigned continues to increase. When more than three investigators are present, it really taxes a company's ability to support the inspection.

Barry Rothman: This phenomenon has become prevalent recently. In the past three years, we've hired about 600-800 new inspectors, and what better experience can a new investigator get than to be out in the field with another investigator? You're seeing teams of three, four, or sometimes even five.

This trend should slow as these new investigators become more experienced and start to work more independently.

If you are being taken in too many directions at one time and don't have enough employees to fulfill the requests and when you start to hear complaints from clients that you're not being timely with fulfillment, you need to connect with a lead investigator, there is always a lead investigator assigned who should identify him or herself at the onset of the inspection.

Tell him or her that you are being stretched beyond your capabilities. Discuss when you can reasonably provide the records that are being requested. Respond to the inquiries that they are making.

If you don't get resolution there, then you should go to the District Office and contact a supervisor. If you don't feel comfortable calling the District Office, call me, I am always happy to take your call.

Q. - What is causing drug shortages today?

Barry Rothman: At Team Biologics, we inspect a lot of single-source suppliers. Keep in mind that there is a difference between policy and investigation.

An investigator is a fact witness. He or she is going to conduct the inspections and gather evidence to determine whether or not you are in compliance with regulation, and, at the bottom line, whether or not you are in a state of control.

He or she will do this, whether or not you are a single-source supplier. It is going to be the same every time.

The rest of us will then get together and talk about the potential impact of having to take the product off the market.

Rick Friedman: There are many factors causing the shortages. Half of the cases are not drug quality problems that occur specifically at the facilities. Sometimes they reflect sourcing problems for API, or issues like that.

Factors that have to do with quality or manufacturing practice typically involve problems that aren't brand new to the company that haven't been resolved over time. There can, rarely, be total "out of the blue" surprises, which are rare but can occur due to polymorphs, precipitation or some other chemical physical phenomena that the manufacturer is dealing with.

Still the bottom line is manufacturing practices that are not adhered to, whether at contractors' facilities or within the company. It's very much about the need to build quality in.

In one case, for instance, an excipient used for one parenteral product, a medically necessary and important product at that, had high endotoxin loads.

You must build in upstream controls for the process and with your supplier.

In this case, we were dealing with an oil-based formulation, using a natural oil, and the oil permitted, or even actively promoted, the growth of endotoxins.

These are the types of things you want to look at in your supply risk management manual, for instance, potential endotoxin levels for natural vs. synthetic. Natural products can be more difficult to control.

The company ultimately discontinued the product, leaving a void in the market place rather than try to fix the problem with their supplier. Again, these are the kinds of issues that we are seeing; they are basically GMP staples.

Steven Wolfgang: Many of the shortages have to do with products of marginal quality that have been on the market for a long period of time. Whenever there is a realization that the quality of the product is marginal such that something needs to be done, it can take a fairly significant effort to bring that product back up to the level of expectation.

It is clearly not a single one-time occurrence; I think we have a problem that has been around. Glass delamination, for instance, is nothing new.

Another thing that is prompting the shortages is the change in the management of the pharma supply chain, which is not yet robust enough to withstand hiccups. As pharma's supply chain becomes more globalized it is very important that from one end to the other that the manufacturers have a good understanding of where potential bottlenecks or short circuits can occur or a short circuit in the supply chain. As we look at these problems, down the road, we want to consider some of the things Richard was talking about regarding supply chain risk.

Rick Friedman: Pricing does play a part. The company discontinued the product that I was just talking about in the anecdote about the endotoxins.

I think it was about a fifty-cent-per-bottle product, so maybe they didn't feel that it was going to be profitable to invest in the remediation of the process and work with the supplier.

That is a shame because it's an important product that needs to be on the market and it is pretty tight these days. But there are pricing realities.

There have to be some solutions discussed by the Rx 360's of the world, the IPEAs, concerning uniform excipient GMPs. Such systemic improvements will make a difference for manufacturers and purchasers of raw materials because this is a systemic problem.

Q - The reporting policy under the field alert regulation is inconsistently applied across the field offices. Is anything being done to define or clarify the reporting end of the field alert regulation and to establish a consistent policy?

Barry Rothman: I am not clear on where inconsistency is, but I believe the question is expressing the concern that, during an onsite investigation, reviewing adverse events, an investigator may make a decision that something should have been reported, which wasn't. If you read the regulation literally, anything that could cause product to be adulterated or misbranded should be reported.

I think that you're going to see a little bit of variation between investigators as long as we are using human investigators. It's also going to be part of "what are we seeing at the firm. Are these isolated incidents? Maybe there wasn't a report that should have been there. Was the risk less than significant?"

If there are more significant things that investigators are finding that aren't being reported by the company, the investigators are not discussing these findings in a vacuum, but bringing issues up with supervisors.

We're encouraging earlier communication with Center partners. These are the types of things we're doing to encourage consistency.

The reports themselves reflect communication with D.O. We have started recent teleconferences to discuss across the field, Center, my office and the field to discuss reporting timeframes, mechanism and consistent processes for reviewing adverse effects in the field during inspections.

The reports themselves, as they come in, are reviewed both by the district office as well and we have communications about significant issues that are discovered.

Rick Friedman: Consultations during inspections are sometimes difficult in cases where we don't have the chance to do some frontloading and proactive communications. The Center, as part of regulatory recommendation, still looks at all potential adulterations to determine whether or not they're violations. In some cases, we determine that they didn't violate regulations, but in a lot of cases, they do.

There's probably underreporting, in many cases, within the industry.

Richard Davis: I have the benefit of having worked in the FDA and I've also been on the industry side and running quality organizations, and I've seen this in consulting as well. When I get a call about a particular issue and the question, 'Do I need to report this?' My first question is: What do you think? What's the violation, what's the issue, what's the root cause?

You may not have all the answers, in which case there's a provision that says, 'File it anyway, since you have time to do the investigation and communicate with the Agency.'

I've seen situations where we have submitted something, sometimes thirty days or forty five days from the event, but we had already submitted an alert so the Agency knew what we were doing. We were talking with them and telling them when we were going to send the report in.

If you're saying, 'I don't know if I really want to send this. We haven't done enough to get the information we need.' Six months later when product is out there, you don't want to be in a [bad] position...it is better for both sides to get the things filed, do all of our work, make sure we get it documented, and make sure there is communication on both sides.

Barry Rothman: You need to form the relationships with your District Offices so that you can pick up the phone and say, 'This is what we are seeing. Do you think it is reportable? These are the things we are doing to investigate it and make our determination.'

If you have had that discussion, then it's likely you're not going to have a problem.

This approach will open lines of communication. If we think there is a significant issue that we think needs to be reported, we will tell you.

Q - Risk-based supply management means doing the right level of management, in some cases more and in some cases less. However, management often means doing more with the same resources. Do you expect supplier oversight, in general, to require more effort and resource than are typically [allocated] today?

Richard Davis: We need more resources associated with risk management because the whole supply chain has been globalized.

Years ago, when companies were manufacturing their own APIs and most of the excipients were from well-known companies, this was not such a problem. Today, however, you could do some really detailed mapping [on ingredients for your product] and still be surprised by where product is coming from and who is touching it.

Rick Friedman: No organization is successful with risk management, unless it supports it, both philosophically and financially.

Quality assurance sometimes gets short shrift or there are not enough qualified personnel. Sometimes it is good to have people with a production background or other experience in the industry, in QA, so they can ask the tough questions.

It has to do with qualifications, but also a lot to do with resources because you actually have to pay more for better people in QA.

In inspections in Europe and the U.S., I have seen some cases where a quality assurance associate with one or two years' experience with a pharmaceutical degree was thought to be qualified enough to ask the tough questions in a complex laboratory OOS or manufacturing investigation.

You need qualified personnel in QA overseeing the operations and asking the tough questions. If you don't have a strong quality management system, and address problems as they come up, then, ultimately, they will come back up later on—we all know that. That is when you really need to have good QA people in sufficient numbers and I think that it is lacking right now in the industry. External audits need to be improved.

Q - What is FDA's position with regard to Rx-360, IPEA and third-party quality auditors? I don't think industry will accept third-party audits without formal comments from FDA.

Steven Wolfgang: This question suggests that the industry is not poised to use third parties until the FDA speaks out on what the ground rules are for doing that. If that is the case then I believe that FDA will, at some point, make some kind of formal statement.

But the third party has to meet your expectations. In other words, you would need to qualify them as if they were one of your suppliers. I'm not really sure what [additional] FDA guidance you would need in order to use that kind of an approach.

Q - Briefly discuss the difference between Annual Product Reviews and Stage-Three Process Verification. APRs are done only once a year, so, presumably, they wouldn't meet requirements set for continuous process verification.

Rick Friedman: Annual verifications aren't sufficient. While FDA has only sporadically asked those questions in inspections over the years, I remember a manufacturer that lacked about three months of process control and recently was subject to a regulatory action.

211.110 has always said that a company is responsible for looking at a valid history of batches to determine what the proper limits are and whether they are remaining within those limits. This control is basic to any industry that produces.

So if you take 211.110 and marry that to 211.180, which says that you should review your procedures and specifications at least once a year to make sure they are still valid. There is an annual review, but there's also the ongoing need to evaluate and monitor process performance, which can be a near-term trend of two or three weeks where everything's going out of control.

Over the years, I've seen situations at a number of places where a process is running along really well for years, even five to ten years, where it has great history and then suddenly, control goes awry.

A root cause analysis is really important and often problems can be traced to raw materials.

Sometimes problems are due to untested attributes of the raw materials that are certainly not named in the USP or other compendia, which focus on chemical and microbiological but don't look at physical attributes.

Sometimes it is physical attributes or it can be a chemical property like another component of an excipient that causes dissolution problems. You have to know what it is that makes your excipient or active ingredient tick, and understand what physical attributes you need to check for or evaluate your supplier for.

You can use third parties such as IPEA and Rx360 as long as they are qualified.

Q - After initiating inspection, it has become more common for investigators to request that documents be faxed or emailed to them at their office for review rather than returning to the site to review them at the facility. Sometimes the document requests are voluminous and the inspector only returns to the site to read and issue the 483. Is this practice condoned by field office management? Is it consistent with the statutory requirement that inspections proceed in a reasonable manner?

Barry Rothman: We certainly do not condone that kind of activity. Reflecting on it though, we live in a different world today. We are living in this new generation, with what I once called "electronic-based" investigators who grew up in the Twitter age and are used to and may prefer electronic communication media.

It is our responsibility in field management to educate our investigators on how to conduct an inspection in a reasonable manner. It is industry's responsibility to let us know when investigators are [over-relying on electronic and digital communication].

I know there's a fear of retaliation, but you really need to communicate with FDA management. Several years ago, I received a complaint about an investigator, but this communication came only after several years of a series of inspections that this investigator had been conducting.

We knew nothing about what was going on in the field because we didn't see it. As in any environment, individuals don't always act the same way in the field as they do when [management is] there, or when they are in the office.

Once we found out about it, we met with the company, interviewed them, took affidavits, and that investigator was removed. There was no retaliation against that firm and we had a good discussion about how much we appreciated their willingness to come forward.

We do not condone faxing or emailing as primary means of communication, but there may be situations where a faxed document or email document may be sent in. That normally will be during a recall event; you could send it to an investigator but you may send it to the R&E coordinator in the District Office. In fact, that may be the most efficient way to provide distributor lists and that kind of information, but during the course of an ongoing inspection, that is not appropriate.

Some documents may be requested before the inspection.

Rick Friedman: [Using that approach for some documents] could even shorten the time required for inspection. You want inspectors visiting your site to read up on [background information] and understand your processes before they are in your conference room.



Agnes Shanley, Editor in Chief, Pharmaceutical Manufacturing, joined Putman Media in June, 2003. Agnes was previously a senior editor and project manager for Chemical Week Associates and for McGraw-Hill, where her work won awards for editorial excellence. While at McGraw-Hill, she ran a continuing education program for scientists and engineers, and subsequently launched a magazine focused on Web-based technologies for the process industries. With a B.A. in liberal arts from Barnard College, Columbia University, and a B.S. in chemistry and life sciences from the City University of New York, she has covered the pharmaceutical, biotech, and chemical industries extensively for publications that include Chemical Engineering, Chemical Processing, Chemical Business, Chemical Marketing Reporter, and the Homeland Defense Journal. She has also worked as a research analyst, focusing on industrial applications of IT, for FIND/SVP.


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