Aseptic Processing Draft Available Soon

by Erik Swain, Senior Editor

Richard L. Friedman

Industry reaction to FDA's draft concept paper on aseptic processing has been generally positive. But there have been some criticisms that the agency hopes to address by the time the document becomes a draft guidance in the near future. 

FDA had never before released a paper in its pre-draft-guidance form to the public, but now the draft concept paper, "Sterile Drug Products Produced by Aseptic Processing," can be viewed at 

"This is an unprecedented outreach to industry," says Richard L. Friedman, sterile products compliance officer for FDA's Center for Drug Evaluation and Research (CDER), who is heading the agency workgroup that will produce the guidance. "We hope that this will lead to a more rapid publication of the final guidance. We need everyone's support to get it out while it is still most relevant."

The last aseptic processing guidance was published in 1987, but the technology and the science has evolved so fast that producing a new guidance has become an urgent priority. Also, lack of sterility assurance has become an increasing concern. According to the CDER recall staff, there were 52 product recalls in fiscal year 2002 for that reason, compared to less than 10 each year between fiscal years 1993 and 1998.

The draft concept paper in many cases contains flexible language. It shows what the agency expects industry to achieve but does not delineate exactly how to go about doing it. Ironically, many of industry's criticisms focused on the document not being detailed and prescriptive enough in certain places. 

These criticisms were voiced mainly at the October 22, 2002, meeting of FDA's Advisory Committee for Pharmaceutical Science and at a workshop held at the Parenteral Drug Association's (PDA; Bethesda, MD) annual meeting on November 9, 2002.

"We took special, perhaps even extraordinary, measures to avoid overprescriptiveness in this document. And we've now been told [from industry reaction] that too much latitude can sometimes mean too little guidance," Friedman says. "We are trying to make it more specific, detailed, and precise where necessary without adding superfluous content. Our goal is to produce a document that is effective in facilitating industry compliance while also allowing latitude to foster promising innovations. Both are consistent with our public health aims."

Some of the industry's concern about too much latitude was spelled out in FDA's comments prepared for the October 22 meeting. "The concept paper contains technical inaccuracies; it also fails to define several important terms and uses others unconventionally," the association states. "Successful aseptic processing relies on strict adherence to specific, well-defined procedures and an accurate knowledge of the critical factors that could result in nonsterile product if not properly controlled. Correct and consistent use of terminology within the industry and by FDA is critical to success."

In addition to the FDA and PDA forums, input will come from a task force of the Product Quality Research Institute (PQRI), a consortium of government, industry, and academic experts. 

One frequent criticism was that the section on media fills was too vague because it did not present any concrete acceptance criteria. 

"We have already started work on that," Friedman says.

Another area to be addressed is the lack of mention of rapid-test methods, which many in the industry believe are more precise than classic culture methods. "That did not mean FDA does not welcome those methods, but the industry has asked us to explicitly acknowledge their availability because they believe it will encourage firms to more quickly adopt them," Friedman says.

Clean-area classifications mentioned in the document will likely be revised to harmonize with ISO 14644 (Cleanrooms and associated controlled environments: Classification of air cleanliness) and Annex 1 to the European Union GMPs. 
There was also little mention of clean-in-place and sterilize-in-place technologies for stoppers and other components. Friedman says FDA "is looking at fleshing out that area."

The appendix on isolators has proved controversial, especially since FDA had not previously published any formal guidance on the technology. At the PDA workshop, James E. Akers, PhD, consultant with Akers Kennedy & Associates, Inc. (Kansas City, MO), said, "the authors [of the concept paper] raise to an apparently high level of concern technical issues that have not proved problematic in actual use," and that "if the requirements given for isolators were necessary to make parenterals that are safe, logically we should be closing down all human-scale cleanrooms."

Friedman says, however, that all of the agency's recommendations for isolators are based on science, including inspectional data, and "we have to go where the data brings us. One or two of the opinions we've heard are contrary to the overall consensus of the data and scientific literature. But we are working on a number of revisions to the isolator section, and I should add that we have seen exceptional results with these systems. More and more firms are adopting isolation technology. In addition to the significantly increased product protection offered by the technology, we are being told it can also be attractive because of economies like greatly increased throughput due to multiday campaigns, overall air-handling reductions, and lower cleanroom apparel requirements."

A draft guidance could be published for public comment shortly. "PQRI is set to complete its work product at the end of February [2003]," Friedman says. "I anticipate that some time in the months following, there should be a draft for public comment."

Indeed, the agency's outreach effort has been so well received that Dave Miner, who spoke on behalf of the Pharmaceutical Research and Manufacturers of America (PhRMA; Washington, DC) at the October 22 meeting, wondered if it could "serve as a pilot for a better process."


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