Isolator Technology: Industry Wants Revised Regulations To Encourage Use

FDA should encourage the use of isolator technology by ensuring an open regulatory environment, committee guests agreed at the Pharmaceutical Science Advisory Committee meeting on Oct. 22.

"The uptake of that technology in this country has not been very good and a lot of it is somewhat because of perceptions, through various 483s or meetings, that it's actually a very difficult technology to validate," committee guest and Alkermes VP-Regulatory Affairs Don Burstyn, PhD, said.

"The standards for an isolator are much more rigorous than that for a conventional cleanroom. I think we certainly need to dispel that perception and do everything we can do to actually get people to use technology such as isolators."

FDA convened the meeting to discuss a ¹ concept paper on "Sterile Drug Products Produced By Aseptic Processing" that was released by the agency Sept. 27.

Industry called upon FDA to revise and update its guidance on aseptic processing, which was issued in 1987 (² 'The Pink Sheet' Aug. 26, In Brief). The 1987 guidance made no mention of barrier isolator and other advanced aseptic processing technologies.

The concept paper includes appendices on barrier isolator and blow-fill-seal technologies. FDA's decision to release a concept paper instead of a draft guidance presumably reflects a desire to receive additional input on some of the document's underlying principles.

The concept paper states that barrier isolator technology has a sterility advantage over conventional aseptic processing for sterile drug products. "A well designed positive pressure barrier isolator, supported by adequate procedures for its maintenance, monitoring, and control, appears to offer an advantage over classical aseptic processing, including fewer opportunities for microbial contamination."

Although the concept paper opens the possibility for increased uptake of isolator technology, industry representatives said that companies need to be reassured about the implementation of new technology.

"Many of us go back to older technology because we're used to it, and it's very safe for us. And we do avoid new technology because none of us really want to be a pioneer, the first one out there, and risk the chance of our approvals being delayed," Burstyn said.

FDA has not issued specific guidance on isolator technology, but a number of industry organizations have, including the Pharmaceutical Inspection Convention Scheme, the ISPE, the International Standards Organization, and the PDA.

Industry representatives also noted that the concept paper made no reference to rapid microbiological testing, which is seen as a more reliable and efficient technology for measuring product sterility.

"This document will be extremely detrimental to the already negative perception that people have that FDA will not support rapid microbiology," committee guest Jeanne Moldenauer, PhD, Vetech Pharmaceutical Consultants, cautioned.

The agency indicated that it would likely incorporate principles for rapid microbial testing into its upcoming guidance on process analytical technologies (³ , p. 8).

Other industry concerns with the concept paper were related to its level of specificity. Quality Systems Consulting President Sandra Lowery highlighted media fills as one area lacking detail in the paper.

"I think there are instances where specifics are needed and they're actually wanted. And really in terms of media fills, duration and yield are certainly one aspect of it, but really acceptance criteria" need definition. "While the target is of course zero, what would be the acceptable number of units? This is a big deal and it needs to be defined."

However, Mikkor Enterprises Senior VP Michael Korczynski, PhD, said the document should not "become a detailed roadmap." Companies should be able to "use technical alternatives if they have the wherewithal and confidence to defend" their choices.

Acting PDA President Russ Madsen recommended that FDA replace the word "limit" with "level" in regard to process monitoring. "Limits...are applicable to specifications, while levels apply to process monitoring....Exceeding an alert or action level does not produce an out of specification result."

Pfizer Global Quality Operations VP Gerry Migliaccio, PhRMA's representative at the meeting, suggested that the new manufacturing subcommittee could take the lead on developing guidance on aseptic manufacturing practices (see ⁴ (Also see "FDA Manufacturing Subcmte. Should Track Industry/Agency Disputes – PhRMA" - Pink Sheet, 4 Nov, 2002.)).