IPQ The News in Depth, April 3, 2012

FDA GMP Compliance Spotlight Will Remain Centered on Conventional Aseptic Processing
FDA is putting industry on notice that conventional aseptic processing lines not employing isolators or restricted access barrier systems (RABS) will get heightened scrutiny from agency investigators and that a convincing justification will have to be provided for their ability to consistently produce sterile product. The agency has been making clear its concerns with the conventional lines during inspections and enforcement follow-up in the injectable arena and will soon be releasing a revision of its aseptic process inspection program to formalize this risk-based focus across its field operations. During a discussion of regulatory concerns in the aseptic processing arena that capped the late February/early March ISPE Tampa meeting, Center For Drug Evaluation and Research (CDER) compliance official Richard Friedman explained that the forthcoming inspection program revision will direct field investigators to spend more time on lines that have more contamination risks associated with them. Investigators will be directed to scrutinize them more from a design control operational perspective, with the realization that our historical experience with those lines has been very sketchy, Friedman commented. The compliance official pointed out that a review of the recent warning letters reveals that the major aseptic processing observations FDA has been making involve the older lines. Explaining that he has had the opportunity to participate in reviewing nearly all of the drug GMP warning letters that the agency has issued over the past eight years, Friedman noted that he does not remember once seeing an isolator being cited as a line found to be non-compliant and out of a state of control. But what we are seeing is old conventional lines which are problematic. And as a result, for our risk-based approach we will require investigatorsto focus most on those lines. Included on the FDA panel with Friedman to discuss the current aseptic processing regulatory issues and the advancing isolator and barrier technologies were Tara Gooen, who also works in the drug compliance office, and Destry Sillivan from CBERs compliance office. Gooen serves with Friedman in CDERs Office of Manufacturing and Product Quality (OMPQ) and leads the team responsible for evaluating establishments named in applications and their preapproval inspection review. Sillivan serves a similar role in CBERs DMPQ with responsibilities for preapproval and prelicensing inspections and review of post-licensure compliance actions, as well as development and implementation of regulatory policy. Scrutiny Extends to Clinical Suppliers Asked about the GMP expectations for clinical production, the panel made clear that clinical supply operations have not been and will not be immune from the heightened scrutiny FDA is giving to traditional processing lines.

Gooen noted that this year, we have enforced a number of IND holds on sterile products made in facilities that were not maintained under current good manufacturing practices. These holds generally involve facilities drawing an official action indicated (OAI) rating on an inspection and a subsequent warning letter. CDER then follows up to make sure that appropriate actions are being taken not only for the commercial product, but for the clinical product as well where appropriate, Gooen explained. FDA, she stressed, will expect commercial GMP aseptic practices for all sterile products that are going to be injected into humanswhether it is Phase 1, 2, 3 or commercial. The 210 and 211 regulations may not apply the same way in the clinical context, but we do want to make sure that the products are sterile and you are assuring the safety and the quality of these products. The concept FDA has espoused of phase-appropriate GMPs, Friedman added, does not mean that the safety of the patient should be compromised by poor sterility assurance practices. Phase appropriate GMPs means cleaning verification instead of validation. It means in some cases lesser documentation requirements other things like that. But as Tara said, it does not mean that the lines should be unreliable in terms of producing sterile units. Teetering on the Border of Compliance In a follow-up question, the panel was asked if FDA is accepting new/abbreviated new drug applications (NDAs/ANDAs) or Biologic License Applications (BLAs) that call for the use of conventional clean room equipment. Sillivan explained that the agency is seeing fewer of these and that the situation is very product dependent. CBER regulates a lot of products that may be produced in very small quantities. They may be manually filled [under] a hood. We have been struggling lately with requirements for filling cord blood products, which are now required to be licensed. For some of these newer technologies, CBER has had to push just to get filling done in a Class 100 laminar airflow environment and the environment monitored, he said. Noting the different situations that arise, Sillivan explained that CBER would review a BLA calling for a conventional aseptic approach. We cant tell you what you are going to submit to us. If the data are robust enough to support that your operations wont impact negatively the quality and purity of that product, then we likely will have to approve it. On the other hand, this approach would be different from any recommendations that we might actually be making [and] our hope that the industry goes towards what works better. If you are talking about filling of large scale parenterals in large batch sizes, one would hope you would invest in the proper system. Friedman concurred, commenting that CDER also has a variety of product types in its purview and still sees a few older technology approaches, even though the evidence is clear that they are much closer to the edge of failure. For CDER, we really are expecting to see highly protected lines with modern approaches to risk mitigation. This does not foreclose the possibility of a conventional line being found acceptable by FDA. However, when you ask us for a recommendation, we would tell you that it is probably teetering on the border of compliance. A lot of these older facilities, older operations, are not so robust. They dont incorporate the learning and the science that provides some of the public health protection that we see with RABs and isolators.

While CDER does have to make allowance for the older-style, small-scale operations in some of the niche areas it regulates, they are also very carefully scrutinized, he said. Echoing Sillivan on the less accommodating approach the agency is taking on the larger scale industrial operations, Friedman cautioned that there is going to be a point where the clean room that was acceptable in the 70s and 80s and there is still a decent amount of them out there will no longer be considered meeting minimum cGMP requirements. The CDER compliance official, who is well-versed in current quality systems theory and literature, noted that, like several FDA colleagues, he has on his shelf at work a copy of Demings Out of the Crisis. The books focus on risk and making sure the system is designed to work from the beginning, rather than on trying to perfect the people involved, is highly relevant to the challenges of aseptic processing, he explained. Everything you are talking about with restricted access barrier systems or isolator systems is designing it right so that you can make people successful. By contrast, an exposed sterile vial is imperiled by the activities of humans and is on the edge of failure, frankly, with older operations. With that human a direct vector of contamination, when you close that human out of the process, close the system, then you design for success. That is how you dont have surprises and crises that you have to address because you have designed things so well from the outset. This recognition, he affirmed, is why you are all here at this conference this week. All of you understand how important modernization is. The industry is ready for it. There have been so many successes with isolators and RABS for about 15 years now. The recognition is also why FDA scrutiny of the older lines will be much more intense than the modern lines in our ongoing surveillance. The old paradigms certainly wont provide the quality and safety and reliability that is feasible and valuable in the year 2012. The panel was asked if FDA expects a company that has a mixture of conventional and RABS processing lines to convert them all to RABS. Industry consultant Jack Lysfjord, a long time participant in PDA and ISPEs effort to expand the available guidance on the new aseptic technologies and the leader of the panel discussion, echoed the caution expressed by the panelists on trying to retrofit conventional lines into RABS. Speaking from many years in the equipment business, Lysfjord emphasized that there are filling lines that should not have an enclosure over them, because they are the 40-year-old variety that require a lot of tweaking all the time. And if you put an enclosure around that, it is going to be totally ineffective. You need to replace the line. FDA Reviewing Aseptic Practice Guidances The panel was also asked to comment on FDA efforts to update or revise its current aseptic practice guidance documents in particular, to incorporate the expectations for RABS as was done for isolators in Appendix 1 of its aseptic processing guideline. Friedman pointed out that there was a tremendous amount of outreach and collaboration with the industry to revise the 1987 aseptic processing guidance. The last revision, he commented, took the document from 20 to 50 pages and included additional coverage of the new aseptic technologies, but without using the term RABS and the related terminology specifically,

although the "Design" section includes a discussion of barriers. The upcoming sterile processing inspection program, however, will reference RABS. The compliance official mentioned that CDER and CBER together did publish a Q&A in late 2009 that allowed for a lesser burden in the number of media fills per year for isolators, but not for RABS. The Q&A indicates that a conventional aseptic processing line that operates on two shifts should be evaluated twice per year per shift, resulting in four media fills annually. However, for aseptic filling conducted in an isolator over two shifts, performing fewer than four media fills per year may be justifiable, if the line is reviewed semiannually to assure a continued state of aseptic processing control. The FDA panel was asked specifically about the agencys view and planned usage of Technical Document No. 15 on RABS, released by the UK-based Pharmaceutical & Healthcare Sciences Society (PHSS) in 2011. Friedman responded that the effort was very ambitious and strongly encouraged by his office, which did not provide exhaustive input but did share some comments for consideration by PHSS. As authoritative RABS and isolator references like the PHSS document, ISPEs baseline guide on sterile product manufacturing and PDAs technical report on isolators (TR 34) are published, he explained, we consider them in our regulatory interpretations. Inspection Hotspots for RABS Highlighted Along with their perspective on the conventional lines, the FDA panelists were also asked at the forum to provide their insights on some of the key inspection focal points for isolators and RABS. Explaining that he does visit facilities for CBER fairly frequently, Sillivan noted that he sees more RABS than isolators. In the RABS context, he said, I am going to focus a lot more on your set-up and what you are doing there. I am going to focus on where your environmental monitoring is. I am going to focus on how often you do environmental monitoring. I am going to focus on laminar or unidirectional airflow. Compared to isolators, there are a lot more factors that could go wrong, and Sillivan wants to see how operators behave accordingly. Obviously if you have removed the people, then you have removed a lot of those things that I have to watch for with respect to RABS in comparison to isolators. Friedman commented that media fills will be looked at more intensively in the RABS context, along with disinfection programs and door openings. The compliance official stressed the importance of giving close consideration when something atypical is done that could disturb the RABS and determining the risk to the system. In that context, investigators will expect that every door opening in a RABS will be documented as part of the quality system. It is supposed to be a restricted access barrier. That means it is restricted. If it is open, that should be an exceptional occasion, with documentation on why it was opened, the extent of the deviation, the time of the deviation, what kind of intervention took place.

When the door in a closed RABS has been opened, companies treat it as a new operation you have toabort the current operation, disinfect again and start over. Friedman has seen several drug companies that follow this closed RABS approach and have been very successful. Lysfjord echoed Friedman in emphasizing that the FDA terminology for a closed RABS is that the doors are only open for changeover and cleaning/sanitization, etc, but otherwise they are closed throughout the run. If you open the door, you scrub the rest of the batch. Friedman added that the decontamination is not going to be as robust in the RABS context as for an isolator, but a sporicidal would need to be used, and a lot more effort spent for multi-day campaigns determining whether or not the quality of the environment could be maintained, including the surfaces. FDA investigators, he said, would also look at the procedures for operating that RABS [and] watch the personnel in doing the disinfection and in doing the aseptic assembly putting the equipment into the RABS. For Isolators, Media Fills and Gloves are Focal Points For isolators, Sillivan explained that he will look closely at decontamination cycles and their validation. He will also want to examine how interventions are handled in media fills and that the types and maximum done in practice are reflected therein. Isolators provide some interesting permutations towards media fills, the CBER compliance official commented. With campaigns that last seven to ten days or even longer, the question for the investigator is have you adequately captured the media fill over the course of that long a campaign, and how is it meaningful? Sillivan would probably turn that right back around to the company and say, you tell me defend what you have done. As in any inspection of filling lines, the CBER reviewer will focus very closely on what actually happens when I am observing. Among the factors are the checks that are being made within the filling: Are you monitoring for pressure continuously? How are you monitoring? Friedman noted that the big control points identified by his CBER colleague were also those that CDER is interested in. He commented further on the expectations for media fills, explaining the flexibility allowed in the isolator context. Once you start to get confidence in your line through initial media fills, the program can be adjusted. But you probably need to do more up front on your initial media fills to really have a good amount of information to justify a campaign length, for example. He echoed the concern that the risks and the interventions need to be incorporated in a proper design so that media fills are not best case. Friedman pointed to gloves including materials of construction, SOPs, frequency of changes and integrity tests and transfer ports as two focal points in an isolator inspection. Gooen added to the isolator watch list the maintenance of pressure during manufacturing and making sure that unexplained deviations are appropriately investigated. What if the Glove Leaks? The issues, expectations, experiences, and practices around gloves in isolator and RABS use received a fair amount of attention at the ISPE forum and were addressed during the panel discussion as well.

The consequences of the discovery of a glove leak was one tack of the discussion. Sillivan commented that obviously, if you have a leak in your glove it should not be treated lightly. We saw recently that some people are experiencing glove failure rates in an isolator of one to two every batch vs. almost never. Obviously we would prefer the later. The discussion prompted the CBER compliance official to mull over the question in his mind of whether a leak in a glove at some point during a campaign constituted a failure of the isolator system. The answer is not an easy one, he proposed, and is probably situation and event dependent. Are you going to likely want to pitch the batch for a pinhole leak? Probably not but potentially. You have to do an investigation. He referenced one slide by an earlier presenter indicating that if there is a compromise in the isolation you would want to do a decontamination event. A leak in a glove, Sillivan observed, is like you are potentially compromising your isolation. But you have positive pressure going out for an isolator. You have got protection in having unidirectional air. Those are all built in system controls that ought to be considered. Discussion leader Lysfjord added the comment that if it is a glove that is not being used and you discover after a run that it is just hanging there, it probably didnt participate in any risk. What Drives You to Smoke? The FDA panel was asked to comment on what interventions in an isolator need to be covered in a smoke study. Gooen pointed out that smoke studies are intended to characterize the airflow within the isolator, and so from that perspective, any significant interventions that could be done during manufacturing must be represented in [the] studies to the extent that it is practical to ensure that you know what happens with the airflow. Another question fielded by the panel regarding isolator air handling was under what operational conditions non-uniform, non-laminar airflow is permissible. Friedman took the first crack at it, commenting that some turbulent airflow can be acceptable for example, for isolators used in sterility testing. If you have a sterility test isolator, turbulence is expected probably, and it is not absolutely required to have unidirectional air. In other cases, some microturbulence in an isolator might be tolerated as compared to a classic line, but we still are expecting unidirectional air in general. Sullivan advised on the need to be very careful if you didnt have laminar flow in an isolator. You would have to justify it very well. Lysfjord noted that the rewrite of FDAs aseptic processing guideline refers to unidirectional airflow and no longer uses the term laminar, which is not so true in Europe. From an engineering perspective, he pointed out, if the walls are brought in close to equipment such as feeder systems, fillers and nozzle motion devices, you will not have laminar flow in my opinion. You are going to have to get around those obstructions. But in general you are going to have unidirectional flow, like a piston pushing downwards with an air return.

Gooen commented that issues around the first air rule usually come up when we are talking about isolator gloves, because the gloves are usually situated very close to the equipment because of the compressed clean room situation. She stressed that, while the gloves could be close to the equipment, they shouldnt be hanging over the exposed sterile product. Lysfjord added his perspective as an industry trainer. When I do training, he said, I like to create the knowledge that even thought the gloves have been sterilized or have a bioburden reduction on them because of the process, the way you use them should be as if they were contaminated that is, dont go over the open vial. It is just like in an operating room: You dont want to have 15 people putting their hands over the open body cavity when they are doing surgery one or two people, or you use tools to do the touching. Sullivan summed up the point: You dont forget good aseptic technique because you are in an isolator. Smoke studies and the demonstration of unidirectional airflow was the first issue raised in a pair of warning letters issued in late February to two sterile drug manufacturers Bangalore, India-based Wintac and Gulf Pharmaceutical Industries, located in Ras al Khaimah, United Arab Emirates. The Gulf letter maintains that the firm had failed to perform smoke studies for an ampoule filing line. The firm had also been cited in 2004 for not doing the unidirectional airflow studies on a vial line. The studies that were subsequently done on the vial line, the letter notes, showed turbulent airflow in several critical aseptic areas that was not addressed by the quality unit. At Wintac, FDA also found that the smoke study did not demonstrate unidirectional airflow and sweeping action over and away from the critical processing areas under dynamic conditions. Nor did the firm provide a detailed interim plan describing additional steps taken in an effort to ensure that these areas were suitable for aseptic manufacturing of sterile drug products. A warning letter issued a year earlier to Sanofi Aventis regarding its injectable facility in Frankfurt am Main, Germany, which was signed by Friedman, contained similar language. The agency referenced Sanofis smoke studies as confirmation that the airflow velocity inside critical areas of the aseptic operations in a line was not acceptable. The letter stressed to the company that proper design and control prevents turbulence and stagnant air in the critical areas and that it is crucial that airflow patterns are evaluated for turbulence that can act as a channel for contamination. Qualify Disposable Bag Vendors The panel also took a look at the concerns that need to be addressed from a regulatory perspective in the move toward disposable components such as stopper bags. Lysfjords co-moderator for the session Ryan Hawkins, drug product operations VP for Cook Pharmica, commented that the integrity testing of bags seems to be a very hot topic of conversation, but I dont know that we have got a whole lot of action from an industry perspective. He noted that not a lot of the ready-to-use components coming in for vial-type applications are vacuum sealed, eliminating the ability to definitely determine whether or not the bag is integral.

Sillivan suggested that periodic testing should be done to determine that the stopper bag that comes in from the vendor is sterile and remains so as part of the incoming raw material checks if it is considered a critical attribute. In turn, if you think it is that critical, perhaps you should test a subset of each batch, he suggested. While the issue definitely presents a concern from a review perspective, requiring each batch to be tested would be kind of onerous. I think that should be really dealt with under your testing procedures for incoming raw materials. Gooen agreed that it comes down to a supplier qualification issue. So often we talk about supplier qualification in terms of the ingredients that go into the product. But certainly when there are other parts of equipment that need to be sterile, etc., you really need to make sure that your suppliers are qualified and that you have assurance that what you are getting in is really what you are purchasing. Also see related IPQ stories: Merck Serono Biotech API, Injectable and Testing Sites in Europe Draw FDA Warning Letter Role of Drug GMP Compliance Problems in Drug Shortages and Plant Market Devaluation Explored at ISPE Conference Generic Injectable GMPs Again Prompt FDA Warning APP Added to Non-compliance Watch List Generic Drug Manufacturing Issues Draw FDA Warning Letters at Sandoz and Mylan Ranbaxy Consent Decree Fires FDA Warning Shot for Ex-US Pharma on Data Integrity

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