Biologics Error Reports May Include Events Not In Validation Protocols - FDA

Unvalidated biologics manufacturing errors and accidents may need to be reported to FDA even if a firm determines the lapses do not affect the safety, purity or efficacy of the product.

Incidents that a company believes do not affect the product's safety and efficacy may be indicative of a larger problem and should be reported, FDA Emergency Investigational Operations Division National Biologics Expert Marsha Major indicated during a March 31 workshop in Washington, D.C.

"When you tell me that a product is validated," Major said, "you're telling me that you've reviewed the component and the process, and you meet all your critical parameters."

"If you miss an appearance specification - say you have a specification of color that is wrong - then that's a failure," Major explained. "Something is perhaps deteriorating or reacting with that product."

The workshop, co-sponsored by the Pharmaceutical Research & Manufacturers of America and FDA, was held to discuss the guidance under development by the Center for Biologics Evaluation & Research for use in conjunction with the final rule on reporting errors and accidents. The rule and guidance are expected by fall 2000, the agency said.

FDA said it would use the information collected through error and accident reports to build a better surveillance system. "We could build in things that could allow the industry to put in place more process controls to prevent having to submit every single thing that happens," CBER Consumer Safety Officer Sharon O'Callaghan said.

The September 1997 proposed rule "Biological Products: Reporting of Errors and Accidents in Manufacturing" says industry must make a report if the safety, purity or potency of a biological product "may" have been affected by a deviation from current Good Manufacturing Practices, applicable standards, established specifications or an unexpected event.

"That 'may' is going to cause a lot of problems," Major said. "You would interpret it your way, and I would interpret it my way."

Major said that one company told the agency that it did not report a stability test failure because the firm determined that product safety was unaffected. "We would struggle with that in inspection," Major said, cautioning industry that this is information that is important to the agency.

"If you empower yourselves to make that decision, that it didn't affect the safety" of the product, Major said, "then on inspection all you have to do is defend that."

"My concern," she added, "is that if you don't report certain details, then during inspection, those really critical points that I would like to know are missing."

O'Callaghan said that, if the industry interpretation was followed, "the only things we are going to be seeing as errors and accidents would be recalls, because in determining that the product quality was affected chances are that you are going to recall the product."

Another "subset" exists in cases where industry is unable to decide whether a manufacturing glitch negatively affected a product. Reports of that nature also would not be adequate to establish the surveillance mechanism that FDA desires, O'Callaghan said.

"If we are getting stuff that is really, really significant that constitutes recalls, there is not surveillance there," she remarked. "But, on the other hand, if we had everything reported, that...may overload the system. So we have to find some kind of happy medium in that area."

Industry suggested that reporting was already being done through NDA field alerts.

"In an NDA field alert it's straightforward," Major said. "It says that if you have a bacterial contamination, chemical or physical change or deterioration then you need to report. On the error and accident side, we have an unexpected or unforeseeable event that may affect the safety, purity and potency of the product."

The problem with older products is that the inherent process is not validated, Major said. "That's a key consideration when I'm looking at your products."

Companies should look for errors and accidents arising from changes to components or a change in a processing step, such as time or temperature, that may affect the product, Major suggested.

"One of my favorite cases is one in which the components aren't made anymore....These are things that are going to affect your product," she said. "Perhaps missing time, or holding time needs to be defined....There was one product that was held too long and that actually caused the problem itself." Changes in the support system of a process such as sterilizers, filters or lyophilizers may also affect a process.

For new products, she cited inadequate development data as a major source of problems. "GMP requires the developmental work," Major said.

"Critical parameters aren't being identified so that ultimately you get to production and you find that you can't identify something or you've inadequately defined something," she said.

Major suggested that companies establish standard operating procedures for error and accident reporting as a first step towards approaching the guidance, and encourage "a sense of urgency about it."

In the case of biologics, "there may be more reporting...due to the 'may affect' but even though the rule says that, through our guidance we can try and limit the scope of that," O'Callaghan said.

CBER Office of Compliance & Biologics Quality Director Steven Masiello said the agency "would like to...issue guidance on not only what is reportable but also what is not reportable, so that we don't get the ones that shouldn't be reported."

O'Callaghan added that, due to differences in errors and accidents for blood products and non-blood biologics, the agency may develop a separate flowchart for each industry to describe the reporting process.

Though E&A reports have come predominantly from the blood products industry, FDA has already received 73 non-blood product reports in 2000, O'Callaghan reported. In fiscal 1999, the agency received 98 reports from non-blood manufacturers and 15,433 reports from blood and plasma establishments.

FDA is working on a web-based standardized form for error and accident reports that would include an e-mail account to allow notification of extra or missing information. Currently, the agency is unable to respond or acknowledge every report that is made by a company, O'Callaghan said.