FDA to build cGMPs with science-based guidelines

by Sheila Galatowitsch

Industry ponders impact of the FDA decision to reassess cGMPs, encourage innovation and strengthen the consistency of its oversight

The U.S. Food and Drug Administration's (FDA) announcement that it plans to reassess current good manufacturing practices (cGMPs) took many pharmaceutical manufacturers by surprise, but it was welcome news to an industry that has complained for years about agency inconsistencies.

Associations such as the Parenteral Drug Association (PDA; Bethesda, MD) and Pharmaceutical Research and Manufacturers of America (PhRMA; Washington, DC) were quick to commend the FDA action. “Right now there is a great deal of praise for the FDA taking this step,” says PhRMA spokesman Jeff Trewhitt. “The agency has clearly signaled that it wants feedback and recommendations. This is like a shot in the arm for our ongoing cGMP task force.”

In its August announcement, the FDA said it plans to encourage use of the latest manufacturing innovations, place greater emphasis on risk management and quality systems in cGMPs, and improve the consistency and predictability of its oversight—all general philosophical shifts that will lead to greater protection of public health, says Paul D'Eramo, International Society for Pharmaceutical Engineering (ISPE) secretary and former FDA inspector and manager of technical operations.

Even those regulatory observers who were expecting the initiative found its scope larger than anticipated. “Industry was seeking science-based guidances to the existing cGMP framework, but the FDA has taken some additional steps to look at the entire framework to make sure it is suitable for contemporary pharmaceutical manufacturing operations,” says Gerry Migliaccio, vice president of global quality operations for Pfizer Inc. (New York, NY). “This is a once-in-a-lifetime chance to bring the cGMPs up to the current state of science and technology. It's a great opportunity for all of us.”

But the lack of specificity in the agency's statement leaves some observers wondering what, if any, impact the agency's plans will have on industry, especially aseptic manufacturing operations.

“This is really just the beginning. The initiative will be evolving for the next few years,” says ISPE secretary D'Eramo, who is now executive director for worldwide policy and compliance management at Johnson & Johnson (New Brunswick, NJ). “There are not enough specifics that tell us how it will affect cleanroom design. We're not at that stage.”

Bill Stoedter, PDA's director of regulatory affairs, agrees. “I think industry doesn't know what to expect right now. The announcement in and of itself is plain vanilla with a lot of general statements.”

More details will be released on the FDA's immediate steps by the end of February, says Dr. Janet Woodcock, director of the agency's Center for Drug Evaluation and Research (CDER). “We have come together with a will and enthusiasm to get this done. I'm amazed at how fast things are moving along,” says Woodcock. In fact, at press time, the agency had scheduled an October workshop to discuss cGMP issues related to aseptic processing.

Until specifics emerge that will clarify exactly what changes are in store, some see the FDA's announcement as a restatement of old ideas that have been tried before. “I read and re-read the announcement, and although it is well-intentioned, I don't see anything new in it,” says Peter D. Smith, a former FDA inspector who is now a principal consultant at KMI (Rockville, MD), a compliance consulting firm.

To Paul Heldman, a health analyst who follows healthcare regulatory issues for institutional investors at Schwab Washington Research Group (Washington, DC), the initiative is further evidence of the FDA's determined mission to hold drugmakers accountable for their manufacturing practices. But it also reflects the Bush administration's response to industry complaints about inconsistencies and overzealous inspectors, complaints the agency has “tried to address in the past without success. So the jury is still out on whether this will improve consistency and make it easier for industry to ensure compliance,” says Heldman.

One message Johnson & Johnson's D'Eramo says he heard loud and clear in the statement is that the FDA has a “continued commitment to strong enforcement of existing regulatory requirements, and they will prosecute companies with poor compliance.” A second recurring theme is the focus on high-risk products and processes.

D'Eramo also says that the FDA plan to team product specialists from headquarters with regional field inspectors will mean tougher inspections. “Down the road, there will be a greater expectation that processes are more rugged and better designed, and that will show up in the pre-approval inspection.”

The FDA also signaled its intention for greater cooperation with industry associations, international regulators, academia and consumer groups. “They want to increase the level of their own knowledge of manufacturing quality control and improve consistency in this area, so they will be looking for help from the experts,” says D'Eramo.

The agency realizes it must be more collegial with industry, rather than confrontational, if it is to keep pace with technological advancements, adds Francis McAteer, vice president of Microbiology Research Associates Inc. (Acton, MA), an FDA-registered contract testing lab. “This will be good for business because it will open up innovation in the industry and bring more products to bear.”

Supporting innovation

The FDA announcement came as Congressional pressure mounts for industry to lower the cost of medicines, but that was not one of the official reasons listed for launching the initiative at this time. Fewer agency resources coupled with an ever-multiplying number of pharmaceutical products demands a new approach to cGMP regulations, the FDA said, especially since the last major cGMP revision was nearly 25 years ago.

The agency also cited increasing globalization of the pharmaceutical industry as a key motivator, as well as advances in quality assurance techniques and manufacturing technologies, which it now wants to actively encourage. For years, manufacturers have resisted implementing new technologies because of the time-consuming process of filing a supplement requesting approval for the change. “Supplements are a major issue for the industry,” says D'Eramo.

But in the past year, the agency has shown interest in technology that would provide continuous monitoring of manufacturing processes. Process analytical technology (PAT), which uses laser and infrared sensors to analyze both active and inactive ingredients in a drug product, would replace the inefficiencies of batch testing-now required by cGMPs with real-time, inline and online testing.

“The FDA likes PAT because, theoretically, you could test every tablet that comes down a packaging line,” says Stoedter. “It's a big advantage to the safety of public health and also to the pharmaceutical industry, because batch testing requires a lot of downtime.”

PAT may prove the model for helping government and industry devise a better process for the approval of supplements containing new technology. “The process being built around PAT should be applicable to any other new innovation, such as barrier technologies in sterile products manufacture. Those have been a real challenge to implement because the elements required for gaining approval are currently not developed,” says Migliaccio. “Most companies do not want to risk product approval by introducing new technology in new drug applications if there is no clear guidance on what the FDA expects for that technology. What we are doing now is developing a process and standards for introducing new technology and getting approval for it.”

In a concept paper on the initiative, the FDA said it wanted to begin immediately to encourage innovation within the existing framework of statutory provisions and regulations by allowing certain changes in the manufacturing process without prior review and approval. A group within the agency is already discussing how to implement this objective, says Woodcock, with details expected in February.

Focusing on high-risk products, processes

More efficient manufacturing technologies will help the agency make better use of its limited resources, which are straining under the weight of an overwhelming inspection workload. Another goal of the initiative-implementing a risk-based approach to inspection that will match the level of effort against the magnitude of risk-will also make inspections faster and more efficient.

Woodcock says manufacturers can expect to see this approach in action for the 2003 drug inspections.

Risk-based inspections will focus on the products and processes that pose the greatest danger to public health if not adequately controlled. Inspectors will examine the infrastructure a manufacturer has in place in the six systems under cGMP regulations: quality, facilities and equipment, materials, production, packaging and labeling and laboratory control.

“If there are flaws in any one of these systems, inspectors will make assumptions that there are flaws in the processes,” says D'Eramo. Companies that raise red flags will be targeted for more frequent inspections, warning letters and even closure, while companies with a good track record of quality systems may be bypassed altogether.

This approach will give the agency “the most bang for their buck and put resources where the greater risk to health would be,” says Stoedter. It will end the current labor-intensive practice of reviewing batch records and procedures. “Today's inspectors look at everything, and that wastes too much time. Each year, they perform fewer inspections because some of the inspections they do perform last two months instead of two days.”

However, the risk-based approach could mean “more inspections of drug plants and fewer of toothpaste manufacturers,” says Heldman. And that poses a danger for the drug and biotech industries. “Any time an inspector walks into a drug plant, there is a chance that they will find some sort of problem that will end up being costly to the company.”

Improving consistency

The cGMP initiative also calls for teaming field investigators with product specialists from headquarters for more comprehensive pre-approval inspections (PAIs). Coordinating the product submission review program with the field inspection organization will improve consistency in reviewing applications, the agency maintains.

This “holistic” approach should yield more informed reviewers and investigators, says Migliaccio. “In the new drug approval (NDA) process, there is little interaction between the reviewing division—the chemistry, manufacture and control section—and the separate field inspection division doing the pre-approval inspections. There can be issues that develop where a reviewing chemist has accepted a procedure in the NDA but an investigator disagrees with it. That is not uncommon.”

Integrated inspection teams could make PAIs more rigorous, says D'Eramo. “The chemist from center headquarters has a different perspective from the field investigator, and that means industry will have to pay even greater attention to how it designs a product early in research and development.”

As with the other immediate goals of the initiative, more details on these inspection teams, including the training each side will receive, will be forthcoming in February.

In another bid to improve uniformity, the agency said that CDER and the Center for Biologics Evaluation and Research (CBER) would provide a scientific and technical review of all drug cGMP warning letters. The centers will also develop a technical dispute resolution process that integrates technical experts from the centers and addresses perceived inconsistencies between the centers.

Applying science to cGMPs

Providing the foundation to each of these goals is the FDA's plan to bolster cGMPs with science-based policies and standards. While a product's safety and efficacy are both rooted in science, cGMPs are general, empirical-based guidelines. “One of the industry's concerns in the past has been that field inspectors have had a lot of power in terms of how they interpret implementation of cGMP standards, and interpretations can vary from region to region,” says PhRMA's Trewhitt.

What industry, government and academia need to do is “agree on the science and then develop guidances or regulations based on the science,” says Migliaccio. “If we can do that, there will be general agreement on what is needed to comply to cGMPs.”

Establishing science-based cGMP guidances for aseptic operations is critical, adds Migliaccio. “It is certainly one of the top priorities in my mind for this initiative, and it may bear the greatest fruit.”

Woodcock agrees, citing the October workshop on the topic where the agency hoped to get academic input for writing a draft guidance. The agency's “initial thought is to put out update guidances and other new guidances on different aspects as we introduce current scientific thinking,” she says. “Long-term, we may need to revise the regulations, but we are not promising to revise the regulations as part of this initiative, but rather assess whether they need to be revised.”

In the interim, the agency will award contracts for benchmarking of quality systems and regulatory programs, and perform an external process review of its programs. “These types of steps will really help move us along,” says Woodcock. “I'm committed to bringing the highest level of science into this dialogue.”

Sheila Galatowitsch is a special correspondent to CleanRooms magazine.

FDA says initiative not ratchet in manufacturing wheel

Enhancing current good manufacturing practices (cGMPs) will make “even a very good system better,” says U.S. Food and Drug Administration (FDA) deputy commissioner Dr. Lester M. Crawford when he unveiled “Pharmaceutical cGMPs for the 21st Century: A Risk-Based Approach.”

The initiative does not represent a “ratcheting up” of manufacturing standards, but rather the FDA's plan to implement the most up-to-date concepts of risk management and quality systems approaches and ensure that the agency's resources are used most effectively.

Covering veterinary and human drugs, including human biological drug products such as vaccines, the initiative will be overseen by a steering committee that includes representatives from the Office of Regulatory Affairs, the Center for Drug Evaluation and Research, the Center for Biologics Evaluation and Research, the Center for Veterinary Medicine and the Office of the Commissioner.

The committee will examine the existing cGMP inspection and product review programs for potential inconsistencies and redundancies. It will also reevaluate the agency's current scientific approach to both programs to achieve a consistent, integrated systems approach to product quality regulation. Finally, the agency wants to enhance the scientific approach of cGMPs to emphasize risk-based control point analysis and to facilitate the latest innovations in pharmaceutical engineering.

Accomplishing these broad actions may take up to two years or more, but to get the process started the agency will first seek to expand its own knowledge of pharmaceutical technologies. It will organize scientific workshops with key stakeholders and increase training and hiring. A concept paper detailing the FDA initiative is available at http://www.fda.gov/oc/guidance/cGMP.html.

cGMPs: Protecting public health

A Congressional mandate more than 40 years ago created what is now known as current good manufacturing practice (cGMP) requirements, which were intended to address concerns about substandard drug manufacturing practices by applying quality assurance and control principles to drug manufacturing.

The requirements ensure that the American public does not have to wait until there are injuries and deaths before the U.S. Food and Drug Administration (FDA) can intervene to assure drug safety and effectiveness and protect public health. The cGMPs are intended to prevent harm by building quality into product design and production, thereby reducing the risks that deficient products will be produced. —Source: FDA


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