Guidance for Parenteral Packaging

Industry remains divided over the validity of a new guidance document on aseptic processing. 

Erik Swain

, Editor

As FDA prepares to publish a guidance on aseptic processing, pharmaceutical companies are evaluating whether or not the new document will prompt changes in some of their aseptic processing procedures.

Industry has seen FDA's initial ideas after the agency, in an unprecedented move, made public a draft concept paper in order to receive input before a draft guidance was published. While a new guidance document is expected to encourage some newer technologies and practices, to what extent it does so remains to be seen. Aseptic processing is an extremely complex process. There remain differences of opinion over how detailed a guidance should be and how strongly certain technologies and practices should be endorsed. 


One source of discussion has been an eye-opening chart FDA has been using in its presentations about the draft concept paper. Using figures provided by the recall staff of the agency's Center for Drug Evaluation and Research (CDER), the chart shows that there were 50 or more individual product recalls due to lack of sterility assurance in each of fiscal years 1999, 2001, and 2002. There were more than 30 in fiscal year 2000 (see Figure 1). But the chart shows that between fiscal years 1993 and 1998, there were fewer than 10 such product recalls each year.
FDA is using the chart to underscore why a new guidance recommending better practices is needed. But does the significant jump, starting in 1999, indicate a public health problem, a statistical anomaly, or something else?

"Why has there been an increase in recalls? It's tough to say," says Richard L. Friedman, a sterile products compliance officer for CDER. Friedman will serve on the panel that authored the concept paper and will write the guidance. "Problem detection appears higher than normal, either by the firms or the FDA investigators. Sometimes we are alerted to a serious quality problem by the firm, in other cases inspections have found such problems. I have heard some say that both small and large firms have experienced a loss of qualified technical and quality personnel, and that may be detrimental to their ability to maintain a state of compliance. I hope that people will remain attentive to opportunities for technological improvement and other advances in GMP science in order to avert sterility issues."

Some in industry have questioned the validity of the chart, saying it offers a misleading picture of a rampant problem that is not borne out in reality. 

Figure 1. The number of product recalls by year due to lack of sterility assurance. (Click to enlarge).

"That's a misleading chart," says Russell E. Madsen, senior vice president of science and technology at the Parenteral Drug Association (PDA; Bethesda, MD). "Close examination of the data regarding the true nature of the recalls shows that the observed increase is more likely attributed to a few isolated events and not reflective of a negative trend for the pharmaceutical industry as a whole. A detailed analysis revealed 128 recalls attributed to a lack of sterility assurance during the period of FY 1999 through FY 2001. Of that total, 47 were attributed to the recall of a disposable alcohol wipe that was manufactured for third parties and included in drug product kits. Another 38 resulted from a single third-party contract manufacturer of SVP [small-volume parenteral] products. It has been reported that this manufacturer had not been inspected by FDA and was sterilizing vials in a microwave oven, a practice unlikely to be effective. Review of another nine enforcement reports showed the recalls were due to issues that were not directly attributed to aseptic processing of finished products. These issues included cracked vials, crimp or seal problems, bulk drug contamination, and filter validation. Factoring in the processing issues not directly related to aseptic processing, the change in the recall performance metric for recalls due to a lack of sterility assurance is much less significant."

Madsen says he does not see much in the draft concept paper that will lead to a significant decrease in sterility-assurance-related recalls for aseptically produced products. Rather, he says, the numbers should be more affected by FDA's enforcement practices and in the way the agency keeps statistics. 

Jim Agalloco, president of Agalloco & Associates (Belle Mead, NJ), notes that "contamination at low levels is inherent in aseptic processing. There have been about 3000 complaints over the course of the last 10 years. But billions of units have been filled successfully. Do we have a public health problem? FDA has said no. There is a general trend of improvement. PDA surveys have shown that firms are doing a much better job, production is better, and limits are tighter."
Training should have more of an impact in the long run, says Jack Lysfjord, vice president of consulting for Valicare, a division of Bosch Packaging Technology (Minneapolis). Firms should keep their employees trained in the proper procedures.

"A conclusion is being drawn because of the (recall) numbers," he says. "I would say that we are putting people who have been poorly trained into the wrong positions. If you do that with an isolator, the consequences will be even worse. The key is not only training but continued training. You may spend one or two days on it, but have you properly retained it?"

"One explanation could be that FDA can look at things more closely," he continues. "Their tools are better and their techniques have improved. It can also have to do with communication between the end-user and FDA and the need for management to give proper oversight capabilities to their employees. You need proper quality control that is in a position to shut down if it's not done right. Maybe the checks and balances have not been correct."

Friedman says the document will strongly encourage proper training. "It's very important to incorporate a risk-based approach in the guidance," he says. "This is epitomized by talk of [improper] personnel behavior in the cleanroom, aseptic technique, and gowning. We will state a need for a firm to have CGMP systems that detect trends before the process is finished and improve quality."


It's too early to tell how a guidance document would change the way in which pharmaceutical firms perform aseptic processing. Likely it will call for more-extensive environmental monitoring and give more specifics on media fills.

Some believe it could lead to greater use of isolators, which have never before been formally addressed in an FDA guidance. The concept paper's appendix on isolators begins with a statement endorsing them, though some wonder whether the rest of the appendix backs up those words.

"I hope the use of isolators will be encouraged. They should be," Madsen says. "We will try to get FDA to get rid of some of these requirements they are placing on the use of isolator technology. There are tighter controls for isolators than for conventional aseptic processing. We think there is no data to support those tighter controls. For example, it says it is necessary to use redundant HEPA filters for an isolator. A conventional cleanroom can use a single HEPA filter. There is no rationale for that that we can see."

The handling of closures and other packaging components could also be affected. 

"Maybe transfer port devices will be more encouraged," says Lysfjord. "It may change methods of sterilization or container handling. It could get firms up to the state of the art in what they are doing with these things."

If isolators do come into greater use as a result of the guidance, "that adds to the importance of closures and how to get them into an isolator," says Fran DeGrazio, vice president of quality assurance for the Americas at the pharmaceutical systems division of West Pharmaceutical Services (Lionville, PA). "There are a number of options on how to do that, and they should get a closer look. There's a lot of talk about rapid transfer ports, but it's still an open-ended question as to what is the best way."

Because the document is likely to go into great detail about validation, "I see the potential for pharmaceutical and biotechnology customers to evaluate the use of ready-to-sterilize closures for use in the process," DeGrazio says. "Then they would need to audit their closure suppliers to make sure they were doing what was appropriate and no longer need to go through that kind of minutiae in their own validations."

Also, she says, "they've recommended in greater detail how the customers need to evaluate their process, even looking at variations in the line speeds. I had not seen that before. That has implications on how stoppers can run on the line. If customers are planning to run at different line speeds, they need to evaluate their closures in conjunction with that, and set up validations with those considerations."


How practices change will also be affected by how much detail the agency chooses to include in the guidance. 

Surprisingly, much of the initial reaction from industry to the concept paper focused on needing more specific recommendations on how to conduct certain practices.

"Industry is looking for something firm," says Lysfjord. "Industry sees variability with preapproval incidents, and it's causing severe trauma, sometimes after millions of dollars and many years of time. Surrounding room classification for isolators of Class 100,000 or Class 10,000, FDA does not give the limit to what it will allow under best conditions."

Agalloco, however, argues for more flexibility. "I find it very restrictive in terms of what it asks you to do," he says. "The problem is that there are a mind-boggling number of variables, from the product to the formulation to the container to the manufacturing technology. Fitting everything that applies to all of these in 50 pages is a lot tougher than some may think. There is a tremendous diversity of technologies and issues that are not consistent with what the document offers."

Instead, he says, "You need five things in a nutshell: a cleanroom environment, the sterilization of all the product and its components, well-trained people, an environmental monitoring program, and a process that works in harmony to keep things sterile. Leave it to the manufacturer to develop systems that give them the results that they want to see. But I don't see that forthcoming. Some think it's too vague; I don't see how this document enhances the flexibility we need. It's stifling to innovation."

Lysfjord says he hopes that an end result is "better training, for both FDA and industry, as to the black-and-white rules, so everyone uses the same rule book. The bottom line is, there needs to be better communication between FDA and industry. It helps to learn firsthand from FDA what it expects and to be sure you are not making incorrect assumptions. It is better to spend this energy at the drawings stage, rather than when the plant is built."

Friedman says his panel is very sensitive to the calls for both detail and flexibility. "No matter what you do, some people will say they want more detail, and others less. If we get equal complaints, that probably means we've done a good job."

Madsen says he would prefer to see a focus on solving "a major problem, which is inconsistency with FDA investigations. Inspector A wants to see something different from Inspector B, who wants to see something different from Inspector C. That constantly ratchets up the controls that firms have to put in place. They will do anything to make those problems go away. The guidance document can't be specific enough."


The first round of input is coming to a close, and FDA expects to issue a draft guidance in the near future that addresses some of the concerns and further clarifies how firms should conduct aseptic processing. 

The Product Quality Research Institute (PQRI; Arlington, VA), a consortium of industry, FDA, and academic experts, has an aseptic processing work group that conducted a survey and will be making recommendations. At press time, the 40-member group was scheduled to complete its work by February 28, 2003.

"The group is not working on all areas of the document but rather on specific areas within the environmental monitoring, process simulations (media fills), isolators, and sterilization sections," says Glenn Wright, director of global regulatory affairs for Eli Lilly & Co. (Indianapolis) and a member of the work group. "The work is focused on eight clarifications to the existing text of the concept paper and 10 recommendations. FDA has indicated it will work to incorporate the clarifications and recommendations made by the working group into the draft guidance."

That, and other industry input, will hopefully make the document one that will remain relevant for years, says Lysfjord. "PQRI is a good vehicle, with technical resources from many aspects," he says. "As you increase the number of people involved, there are more communication channels. The guidance is not finished yet, but it is a step in the right direction that will ultimately paint a picture of what you can and can't do."

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