FDA and industry are in the middle of working out their differences on an update to the 1987 aseptic processing guidance

By Sheila Galatowitsch

Disappointment was the general industry reaction last fall when the U.S. Food and Drug Administration (FDA) released a preliminary follow-up to its 1987 aseptic processing guidance. While manufacturers praised the effort that went into the agency's 50-page preliminary concept paper, they nevertheless called for significant improvements.

And that's just what the agency had in mind.

The intention behind releasing a “concept paper” instead of a draft guidance was to offer the industry a preview into agency thinking and solicit feedback for a subsequent draft guidance. The action, which has been hailed as an unprecedented outreach to the industry on behalf of the FDA, accomplished its mission. Feedback was quick to materialize.

It came in the form of comments mailed in to the agency and from a substantive face-to-face discussion between stakeholders at an all-day pharmaceutical science advisory committee meeting at the Center for Drug Evaluation and Research (CDER; Rockville, Md.).

At that meeting, held less than a month after the concept paper's release, the Parenteral Drug Association (PDA; Bethesda, Md.) submitted a seven-page response to CDER outlining numerous examples where the paper had technical inaccuracies and confusing terminology, failed to reflect current industry best practices and left unanswered key questions. The 27-member task group that drafted the response also recommended creation of an agency/industry ad hoc committee to conduct a formal review.

That's where dialogue continues today, under the auspices of a Product Quality Research Institute (PQRI; Arlington, Va.) aseptic processing working group. The three-year-old PQRI acts as a neutral meeting ground for the FDA, industry and academia to conduct research and generate scientific information to support regulatory policy.

Headed up by Glenn E. Wright, director of global regulatory affairs for marketed products at Eli Lilly & Company (Indianapolis, Ind.), the working group is mulling over recommendations and clarifications and tabulating results from an industry survey conducted earlier this year. This month, the working group expects to submit its findings to the FDA.

PDA's initial response

Last fall, members of the PDA aseptic processing task group found little to praise and much to criticize in the concept paper “Sterile Drug Products Produced by Aseptic Processing: Draft,” a joint product of CDER, the Center for Biologics Evaluation and Research, the Office of Regulatory Affairs and the Office of Pharmaceutical Science (OPS).

Among the positives is the document's attempt to modernize the 1987 guidance, its support of isolators and the fact that it provides a good platform for final draft guidance.

But chief among its drawbacks are a lack of focus and specificity, says Russell E. Madsen, the PDA's senior vice president of science and technology. For example, certain topics included in the concept paper, such as sterility testing, endotoxin control and equipment qualification, are not germane to an aseptic processing guidance document.

“The other big problem with this document is that it is open to interpretation by FDA field investigators. It doesn't give them enough specific information to use when they go in to audit a facility. It doesn't provide for fairly firm expectations. For instance, the media fill criteria, including how many units should be filled and how many positives are allowable, is still too open to interpretation. The FDA hasn't adequately answered those questions,” says Madsen.

The PDA task group itemized its concerns in four main categories: best practices and current good manufacturing practices (cGMP), technical issues and unconventional terminology, scope and harmonization. The group also noted that many of the comments it submitted in response to the 1987 guidance are still relevant, including apparent departures from current industry practice, which could lead to disagreements between the FDA and manufacturers and ambiguity over microbial control limits (See “Excerpts from PDA's response”). The complete text version is available in .pdf format at www.pda.org/scireginfo/index.html. The FDA concept paper is located at http://www.fda.gov/cder/dmpq).

“To essentially repeat many of the old and incorrect ideas—given the amount of more contemporary information on aseptic processing that's out there—was surprising to many of us,” says James Agalloco, president of Agalloco & Associates (Belle Mead, N.J.) and a member of both the PDA and PQRI working groups.

Calling the agency's expectations excessive, Agalloco says the paper reflects a view of aseptic processing that suggests manufacturers “are so good as to never have an environmental isolate, a positive media fill unit or a contaminant on a gown surface. Industry environmental performance is superior to what we had in 1987, but it can never be perfect.”

In the agency's defense, it's extremely difficult to write a document that will please all parties because not everyone agrees on all the particulars surrounding aseptic processing, says Art Vellutato, Jr., president of the Delaware Valley Chapter of the PDA and a PDA Training and Research Institute faculty member. He is also vice president of technical sales and marketing for Veltek Associates Inc. (Phoenixville, Pa.).

“A guidance can't be too specific or too general. It has to be vague enough to allow for some flexibility among processes,” says Vellutato, who is moderating a session on the aseptic guidance proposal at CleanRooms East 2003, March 17-19, at Boston's World Trade Center.

“The concept paper at least identified critical points in aseptic processing—and that's a dramatic improvement over the 1987 document,” he adds. “The inconsistency comes in from what is written in the guidance and what inspectors request in the field. The people writing the document are not the people doing the inspections. There's a big division between those in review and approval and the actual inspectors in the field.”

The PQRI effort will make the document better, but it won't appease everybody, says Vellutato.

Science focus of PQRI

Many of the same industry representatives who serve on association aseptic processing working groups are part of the 38-person collaborative effort at PQRI, which counts some eight FDA representatives as members, including Joseph Famulare, director of the manufacturing and product quality division within CDER's Office of Compliance; Richard Friedman, a compliance officer with CDER's Office of Compliance; and David Hussong, Ph.D., an OPS review microbiologist.

While serving on the PQRI working group, however, these government participants act as “individual scientists rather than representatives of FDA. They are not wearing their FDA regulatory hats,” says Tobias Massa, Ph.D., chairman of the PQRI steering committee and executive director of global regulatory affairs at Eli Lilly.

The same goes for industry and academia group members. No person at PQRI is there to represent his or her corporation or institution. Everyone assembled around the table is there in the interest of science, says Massa.

“The review process comes into play once the working group sends the agency its final recommendations. PQRI has an agreement with the FDA that the agency will either accept and incorporate our recommendations into the draft guidance, or if it does not accept them, it must provide written comments on what the deficiencies are and what we need to address.”

The PQRI working group developed a three-part plan, which began with an industry survey on current aseptic processing practices related to filling lines and media fills, environmental monitoring, isolators and sterilization options. The objective was to collect information on how individual manufacturers run their aseptic processing operations. The data is being blinded and tabulated for use in developing the recommendations to the concept paper.

“The survey is just one way we are trying to understand what current practices are today,” says group chair Wright. “The survey data does not necessarily lead us to answers, but it's useful as we discuss these issues.”

The second part of the plan includes eight clarifications to the current text of the concept paper. The clarifications will be presented to the FDA in the form of redlined revisions to the text.

For example, the working group will clarify validation of environmental monitoring methods referenced in line number 981 in the concept paper, which states, in part, “evaluating the quality of air and surfaces in the cleanroom environment should start with a well-defined written program and validation methods.” Other clarifications center on revalidation runs, sampling test limits, disinfectants, sanitization efficacy, active air monitoring, rapid transfer ports and atypical microorganisms.

The third part of the plan calls for developing recommendations on 10 points related to process simulations (media fills), environmental monitoring, aseptic processing isolators and sterilization options (See “PQRI to recommend changes in concept paper”). Perhaps the biggest issue on the table is determining the appropriate limits for positives on media fills, says Massa.

Not all of the industry's concerns with the concept paper will be addressed in the PQRI forum, which has a three-month time limit to address the major sticking points, says Wright. Still, the industry is benefiting from the agency's “courageous” move to release the concept paper, he says. “The FDA knew the amount of information coming back to them would be enormous given the 15 years since the last guidance was released.”

By the time a draft guidance is released, it is often difficult to affect change, adds Massa. “Communication beforehand is really key, and that's why we are happy the agency opted to give us a preliminary look into their thinking.”

Consensus still in question

The neutral PQRI forum will allow all stakeholders to openly discuss the issues, clear up misunderstandings of perception and hopefully, come to an agreement on the scientific principles underpinning good aseptic processing practice.

Yet even though the PQRI represents the only opportunity for the stakeholders to have a meaningful dialogue that could result in resolution, it doesn't mean resolution is guaranteed. It's still too early to know whether consensus can be achieved, says Massa.

What everyone does agree on is the burning need for an updated guidance document that will prevent inspection inconsistencies. “Companies are being inspected every day, and they don't know what to expect when the FDA comes in. Compliance is a moving target, and they feel vulnerable,” says Madsen.

Perhaps it is unrealistic to expect that any written guidance could be widely applicable given the many variables in aseptic processing, including the breath of technologies, scales of production and variations from firm to firm and site to site, says Agalloco. “A 5,000-page effort might be enough to define it all, but certainly not a 50-page brief. There are a few broad principles we must all adhere to to make a product aseptically, but beyond that the circumstances are too diverse to allow for a simplistic position paper to define it all.”

The agency will take up to two months to review the PQRI conclusions and send comments back to the working group. Look for new developments, and possibly a draft guidance, to materialize later this spring.

Bringing aseptic guidance into the 21st century

The Center for Drug Evaluation and Research's (CDER) approach to updating the aseptic processing guidance reflects the bigger agency move to encourage innovation and strengthen the consistency of its oversight. These aims, outlined in the “Pharmaceutical cGMPs for the 21st Century: A Risk-Based Approach” initiative released last year, will help CDER strike a balance between both general and specific guidance language.

“We want to be flexible in the sense that the aseptic processing guidance doesn't inhibit technology enhancements,” says Joseph Famulare, director of the manufacturing and product quality division within CDER's Office of Compliance. “We want to motivate the industry to enhance product quality and make manufacturing improvements rather than be reactionary to what it feels the regulators want.”

Yet at the same time, the agency will try to answer industry pleas for greater specificity in certain areas, like media fills. “We're looking at the scientific data and will use the PQRI forum to help us in our thinking and improve clarity” in the document, Famulare says.

Moreover, by involving field personnel in every step of the guidance-making process, CDER is also striving to “have the best information for our investigators and foster consistent approaches to inspections.” CDER's goal is “to enhance the science that we put into inspections, and put properly trained people in the field.”

PQRI recommends changes on key issues in concept paper

In addition to clarifying points in the U.S. Food and Drug Administration's (FDA) concept paper, the Product Quality Research Institute (PQRI) plans to make recommendations on 10 key issues. The recommendations will be based on good scientific principals and forwarded to the FDA for consideration. The agency must either accept the recommendations or provide formal comment back to PQRI on why it rejects them. Here are the 10 questions up for consideration under their respective categories.

Process simulations:
1. What is an appropriate number of units to be filled during a process simulation (media fill)?
2. What is an acceptable temperature range for the incubation of media fill units using trypticase soy broth (TSB) and fluid thioglycollate medium (FTM)? If alternative practices are used, what type of justification is required?3. What is an appropriate limit for the contamination rate in a process simulation (media fill)? What is an appropriate target for contaminated units in a process simulation (media fill)?

Environmental monitoring:
4. When should critical surfaces be monitored? What are appropriate expectations in regard to results obtained?
5. What data should be considered when establishing monitoring limits? What is an appropriate frequency for re-evaluating monitoring limits?
6. Regarding air classifications: What is the maximum number of viable organisms allowed in air samples for the various classifications?

Aseptic processing isolators:
7. What type of airflow is required in closed isolators?
8. What is the appropriate requirement for air handling systems in isolators?
9. What are appropriate methods for use in the development of decontamination cycles?

Sterilization options:
10. With respect to terminal sterilization and adjunct processing, what flowcharts represent the most risk-based and scientifically developed approach?

Excerpts from PDA's response

New guidance to replace the 1987 document is “urgently needed” by both manufacturers and field investigators, the Parenteral Drug Association (PDA) noted in its Oct. 22 response to the release of the U.S. Food and Drug Administration (FDA) aseptic processing concept paper. “The current patchwork of 'requirements' has little relevance to what is actually needed to manufacture a sterile product by aseptic processing.”

Stressing that a final guidance document should be based on appropriate technology, science and best practices, the task group listed its concerns with the concept paper in some detail. Following are excerpts from the document.

Best practices/cGMP

Examples where the concept paper fails to reflect best practices and current good manufacturing practice (cGMP):

*The PDA task group took issue with lines 146-147 in the concept paper, which state, “Active air monitoring of critical areas should normally yield no microbiological contaminants. Contamination in this environment should receive investigative attention.” The PDA response: This implies that there is a limit of 0 in ISO Class 5 areas for airborne monitoring, while the table on the previous page lists a specification of 0.1 CFU per cubic foot.

In lines 982-984: “The monitoring program should cover all production shifts and include air, floors, walls and equipment surfaces, including the critical surfaces in contact with the product and container/closures.” The PDA response: Critical surface monitoring is not advisable because these surfaces are sterilized using validated processes. Monitoring of these surfaces provides little meaningful information. If the results are positive, it could mean the surface contained one or more microorganisms or that it was contaminated by the act of sampling. Even if negative, the result many not be meaningful because of less than perfect recovery efficiency.

Technical issues

Successful aseptic processing relies on strict adherence to specific, well-defined procedures and on accurate knowledge of the critical factors that could result in non-sterile product if not properly controlled, the PDA noted before describing several technical inaccuracies and unconventional terminology in the FDA document. Examples include:

The concept paper's section on air filtration indicates that hot air sterilizer vents should be equipped with membrane filters. The PDA writes that HEPA filters should be used for this purpose. In addition, the agency indicates that HEPA filters should be integrity tested; the PDA says that installation and periodic evaluation of HEPA filters is accomplished by leak testing, not integrity testing.

Scope and harmonization

Important questions regarding media fills, such as how many units should be filled and how many positives are allowed, are not addressed in the concept paper, according to the PDA. Other questions on the topic remain unanswered.

Moreover, there is little guidance offered relative to performance of the remainder of the aseptic processing area, outside of the critical zone (Class B or C), where personnel are located.

The PDA also criticizes the FDA's use of outdated Federal Standard 209E cleanroom classifications and its ambiguity in defining guidance information vs. regulatory requirements.