Moving Toward Automation
03/01/2005
New aseptic processing technologies are advancing rapidly, but in the meantime, training and validation are more crucial than ever
BY STEVE SMITH
During last fall’s much-publicized case of flu vaccine contamination at Chiron Corp.’s Liverpool, U.K., manufacturing facility, the Food and Drug Administration’s Center for Biologics Evaluation and Research (FDA CBER; www.fda.gov) issued a warning letter to the company that summarized numerous deviations from current good manufacturing practices (cGMP)-including several aseptic processing sterilization failures.
Inadequate environmental monitoring and failure to conduct validation studies for critical processes were among the key factors in the FDA’s action to render Chiron’s Fluvirin vaccine “adulterated…and not safe, pure and potent.”
While no one can guarantee that a similar crisis won’t occur in the near future, the good news is that rapid advances in pharmaceutical aseptic processing technologies are moving the industry away from contamination risks caused by human error. Rick Friedman, team leader of guidance and policy in the FDA’s office of compliance, believes the trend in aseptic processing is moving “toward products protected by isolator and barrier systems, and increased automation.” If broadly implemented, he stated, the latter “promises to make personnel-intensive processing a distant memory.”
And according to Hank Rahe, director of technology for EnGuard Systems (a division of Containment Technologies Group; Indianapolis, Ind.; www.mic4.com),“To move drugs into the early phases of clinical trials and maintain control of the regulatory schedule, small companies can now use such equipment as closed-system isolators to produce clinical batches.”
The clarification of expectations for such modern aseptic processing technologies appears in the FDA’s updated Guidance for Industry: Sterile Drug Products Produced for Aseptic Processing-Current Good Manufacturing Practice. Rahe says, “The recognition that the use of properly designed isolator systems offers tangible advantages over classic aseptic processing methods shows the FDA’s continued effort to provide safer products through partnerships with industry,” and will “dramatically increase the use of this technology, both in large and small companies.”
Rahe is hopeful that the trend will result in increased overall quality and sterility assurance. But for many pharmaceutical companies, getting advanced aseptic processing technologies online may take time, says Ken Christie, senior director of consulting services at VTS Consultants (Westborough, Mass.; www.vtsconsultants.com), a company that services the validation and regulatory requirements of pharmaceutical, biotechnological and medical devices industries.
Automation isn’t automatic
“Barrier technology, blow-fill-seal machines, isolators, etc., is the direction the FDA would like to see the industry pursue, but the industry sees delays in getting the new systems qualified, reviewed and approved before they can be fully implemented,” says Christie, a former validation manager for the Parke-Davis Sterile Products Division of Warner-Lambert.
Jerold Martin, senior vice president and global technical director at Pall Life Sciences (East Hills, N.Y.; www.pall.com), adds: “Lack of guidance on new technologies, such as isolators and blow-fill-seal systems, as well as rapid microbiology systems for bioburden monitoring, has retarded their implementation.” But with the new FDA Guidance, Martin says “inclusion of recommendation on isolators and blow-fill-seal systems is encouraging.” Like Christie, however, he believes that actual implementation of advanced systems won’t be immediate, but “will occur in the coming years.”
Nevertheless, Martin is optimistic that the FDA’s inclusion of these technologies in the new Guidance will “encourage pharmaceutical companies to introduce these as a means of achieving higher levels of sterilization assurance.”
Indeed, some companies are already pressing through the qualification approval steps and unveiling breakthrough aseptic processing innovations.
Absolute Control Systems (Golden, Colo.; www.absolutecontrolsys.com), for example, recently introduced a barrier system for Class 100 cleanroom use in pharmaceutical packaging, designed to provide a simple method of separating the aseptic process from personnel and the surrounding environment. The barrier is designed with round tubing rather than square tubing found on similar barrier systems, which the company says results in higher performing airflow.
Earlier this year, Millipore unveiled its Steritest EZ next-generation sterility-testing tool for large-volume parenterals and synthetic drugs. The device’s needle adapters are designed to fit most test containers, maintaining a closed-concept system that virtually eliminates contamination risk. Its 850 mm of tubing is designed to give aseptic processing workers more room to perform manipulations involved in sterility testing, and a canister inlet design is built to minimize foaming and enhance faster filtration.
Pall Corp.’s Martin, noting that the new FDA Guidance “is now encouraging the automation of pharmaceutical process steps, including the use of technologies such as robotics that can further reduce risk to the product,” says his company has developed a number of automated systems-including the Palltronic integrity test instruments-to reduce the risk of “performing the wrong test or turning the wrong valve.”
Last October, InTact Filling System-a subsidiary of Medical Instill Inc. (Stamford, Conn.; www.medinstill.com)-granted exclusive, long-term rights to GlaxoSmithKline Biologicals for its proprietary contamination-free filling process for injectables. GlaxoSmithKline intends to use the InTact technology in its own manufacturing processes, and plans to offer it to the rest of the industry through its Belgian subsidiary, Aseptic Technologies.
Reflecting on last fall’s flu vaccine crisis, Dr. Daniel Py, Sc.D., chairman of MedInstill, said in an article published in the December issue of CleanRooms: “One of the factors contributing to the flu vaccine shortage is the inability of companies to guarantee a sterile environment for the injectables. Our process solves this problem by allowing manufacturers to have greater confidence in sterility, turn around new vaccines quickly, and respond to shortages without fear of contamination.”
The InTact process is an automated closed-filling system that features pre-assembled and sterilized glass or plastic containers that are filled through a stopper by a noncoring and sterile needle. The stopper is then resealed with a low-energy laser to create a pure barrier. Medical Instill says its system has achieved third-party performance qualification and microbiological validation, with no microbiological contamination found in tested media fills.
GlaxoSmithKline President Jean Stephenne believes Medical Instill’s modern aseptic technology will “totally change the way terminally sterilized injectable products are manufactured in the pharmaceutical industry.”
The FDA hopes its current aseptic processing Guidance, which updates and clarifies cGMP guidelines that had been written in 1987, can make things more efficient and productive for pharmaceutical manufacturers. “By providing FDA’s current thinking on these topics,” says Friedman, “pharmaceutical manufacturers can more readily adopt appropriate new technologies that improve sterility assurance, with reduced apprehension of the ‘regulatory uncertainty’ that the industry has said is attendant to such changes.”
Reducing the intensity and extent of personnel involvement in the aseptic process, says Friedman, is clearly one of the most critical issues facing pharmaceutical and biotherapeutic manufacturers today. Among other key issues are:
The need for a suitable, modern facility design (including material and personnel flow, room pressure cascades, airlocks, etc.);
Choosing the most appropriate equipment design, including a sound product protection plan (i.e., isolators, barriers);
Carefully choosing and managing contracting relationships to ensure awareness of all issues and trends related to the product, process and raw materials.
A solid, quality-assurance system is another critical issue, and is a major focus of the FDA’s updated Guidance. “Integration of a strong quality system,” Friedman adds, is crucial “to making sure each of these concepts is implemented.” Quality system elements such as change control, supervisory oversight, responsive investigations, batch release, and training are some key elements of a robust quality system.
Accordingly, Friedman explains, the FDA’s goal in presenting the updated Guidance is “to provide clear communication of regulatory expectations to promote voluntary compliance with current FDA requirements. It updates the industry on cGMP expectations for aseptic processing facilities, reflects the latest science in the area of sterile drug quality, and promotes manufacturing innovation to achieve increased sterility assurance.”
After years of input from the industry, Friedman believes the final version of the Guidance is “a pragmatic document that answers many recurring questions asked by industry professionals over the years on topics such as facility design, cleanroom control, environmental monitoring, personnel training and qualification, as well as various validation matters.”
Rahe believes that the make-up of the biotech and pharmaceutical industries is moving toward an increased concentration of large companies, with more and more small companies becoming product innovators.
“The trend has been for the small companies to find a large company partner to help with the movement of new drug entities through the long and torturous path to approval of a new product,” says Rahe, a 30-year veteran of the pharmaceutical industry. “The new Guidance offers help to the smaller companies that will allow them to move their new drugs further along the approval path by giving better and more complete descriptions of expectations.”
Filtering through the language
For pharmaceutical device manufacturers like Pall Corp., a key issue has been the validation of sterilization by filtration. “Overall, the FDA Guidance serves to reinforce many of the concepts of sterilizing filtration presented in the 1987 Guidance,” says Martin. “Perhaps the most significant change is to the definition of ‘sterilizing grade filter’.” In the former document, a sterilizing filter was defined as “…one which, when challenged with the microorganism Pseudomonas diminuta (P. diminuta), at a minimum concentration of 107/cm2 of filter surface, will produce a sterile effluent.”
Martin notes that “FDA reviewers commonly believed that such filters were universally sterilizing for bacteria, though perhaps not mycoplasma or viruses. In the ensuing years, however, FDA became aware of several incidents where drug product bioburden organisms were suspected of penetrating integral 0.2-µm or 0.22-µm filters previously qualified by filter manufacturers for retention of Brevundimonas diminuta-the current name for P. diminuta-under standard challenge conditions.”
In its updated Guidance, Martin says the FDA has abandoned the original definition of sterilizing filter for a new one that describes it as “a filter that, when appropriately validated, will remove all microorganisms from a fluid stream, producing a sterile effluent.”
“The primary significance of this change,” says Martin, “is that filter users can no longer rely on standard challenge data and integrity test correlation provided generically by filter manufacturers to assure that a filter will be sterilizing for a given product. Sterilization filtration process validation is a must for all new products.”
According to Martin, “While B. diminuta is still widely used as a model challenge organism, filter users must now justify its selection on the basis of studies demonstrating that smaller or potentially more penetrative bacteria are not present in the prefiltration bioburden or, in some cases, environmental samples.”
Such clarifications, notes Rahe, reflect “the efforts of the pharmaceutical industry and societies such as ISPE (International Society for Pharmaceutical Engineering) to continue to communicate with the FDA concerning improvements in technology.”
Friedman concurs: “The final document is the product of extensive listening and feedback. This interaction has yielded a modern manufacturing guidance that puts us all-industry and FDA-in a good position to address the coming years in aseptic manufacturing.”
The essentials of following procedure
While outdated approaches to aseptic processing methods are rapidly improving, as sterilization technologies advance and production demands increase, FDA and pharmaceutical industry officials agree that until automation is the norm, companies must both understand and carry out the details of aseptic processing cGMPs to ensure sterile pharmaceutical production.
Christie says that “the greatest challenge with aseptic processing has always been to have in place the needed procedures dealing with training, sterilization, media fills, audits, CAPA [compliant corrective and protective action], change control, equipment operation, etc., and then assuring the work force is properly trained on them-and that the training itself is documented and evaluated to be sufficient. The new Guidance does not change this requirement.” (See sidebar, “Focused on training.”)
“In my 26 years within the sterile products industry, procedure has always been one of the greatest challenges to control and implement-and then to assure that everyone is properly trained on it,” says Christie. “No matter how detailed and well-written procedures are,” he adds, “they are worthless without people being trained on them and understanding what they require-and operators [need to] abide by them.”
In the Chiron incident, for example, the quality control unit at the Liverpool manufacturing facility was cited for failing to thoroughly investigate environmental monitoring irregularities during filling of lots of its Fluvirin vaccine.
Troubleshooting strategies
While industry experts say it’s hard to pinpoint exactly when the impact of the new guidelines will be felt, or when aseptic processing automation will be the norm, there is agreement as to what the immediate course of action should be: troubleshoot your current aseptic processing practices, see how they measure up to the new recommendations, then devise a plan to correct problem areas.
“As an interpretation of current best practice,” says Pall Corp.’s Martin, “most drug manufacturers will already be applying these recommendations to one degree or another. Any actual issues will depend on what the manufacturer’s current practices are with respect to these recommendations.”
Christie concurs: “As far as what manufacturers must address immediately, this is simple-whatever items are listed that a company knows they do not have in place.” These could include everything from the extent of environmental monitoring to personnel monitoring.
“It may involve the lack of all typical manipulations in media fills or the number of units run in a media fill,” Christie adds. “It may also be a lack of procedures covering the main areas of aseptic processing.”
A visit to the FDA’s Web site, say Christie and others, could be a beneficial starting point for pharmaceutical companies wanting to make sure they are in compliance with the updated aseptic processing guidance-not only downloading and studying the document itself, but also reading examples of FDA warning letters and FDA-483 forms used by investigators for recording noncompliance of cGMPs.
“Be familiar with the main areas of 483 citations and/or warning letters,” says Christie, “then review the status of where your company stands in relation to having procedures in place to address the area of citation, or verify that current practices are not deficient in some manner.”
Christie also suggests that companies establish a risk factor for each segment of the aseptic filling process, making sure that the practices can be defended, and that they comply with regulatory requirements. “Companies must be able to defend the practices they use, understand the regulations, and not be afraid to challenge citations that they might feel are unfair,” Christie adds.
The FDA’s Friedman acknowledges that inadequate approaches to the aseptic manufacturing operation in recent years have led to costly product loss, extensive failure investigations, critical supply issues, significant customer complaints and, in some cases, product recalls.
But he concludes optimistically, “Clear and current regulatory standards for sterile drug products should make the daily job of both industry and the Agency a bit easier and help reduce the incidents of manufacturing problems with this class of pharmaceuticals.” III
Focused on training
Numerous pharmaceutical companies and organizations offer training for aseptic processing procedures and validation. Among them:
Millipore Corp. (Billerica, Mass.; www.millipore.com) has established an Aseptic Processing Validation School at selected European sites and at its facilities in Massachusetts. The full-day program provides pharmaceutical workers with instruction on validation, filter testing and sterilization, documentation, and bioburden monitoring. Among the things companies will learn, says Millipore, is “how to acquit yourself when a regulatory audit takes place in your premises, and how to interpret and answer questions asked by the auditor.”
The Parenteral Drug Association (PDA; Bethesda, Md.; www.pda.org) is offering its pharmaceutical-industry members a series of week-long aseptic processing training programs that are a combination of hands-on laboratory and lecture training. After being trained in the fundamentals of aseptic processing, workers focus on all required elements for producing a sterile product, with an emphasis on documentation. (A complete schedule of the PDA’s courses can be found at its Web site.)
The Pharmaceutical Training Institute (New York, N.Y.; www.pti-international.com) is sponsoring a series of aseptic processing training opportunities in the coming weeks: April 18-19 in Research Triangle Park, N.C.; May 12-13 in Boston; June 16-17 in San Francisco. (Visit the PTI Web site for details.)
3Dsolve (Cary, N.C.; www.3dsolve.com), a simulation learning company, is appealing to manufacturers’ concerns for the time and expense required for on-site or observation-based instruction in aseptic processing techniques. With its virtual training program, pharmaceutical companies can train their employees via computer, using learn-by-doing methodologies that are designed to equip workers for knowing aseptic processing techniques before stepping into the work area. In its literature, 3Dsolve points out that “students are typically expected to observe cleanroom operations from outside and imitate the aseptic techniques they have seen upon cleanroom entry. In practical terms, this is equivalent to having a student pilot observe a seasoned aviator and then solo without ever having taken the controls.”
Is everybody happy?
While the FDA’s updated Guidance on aseptic processing has been generally applauded throughout the pharmaceutical industry for its comprehensiveness, there remains concern and controversy in some of the details.
“Air quality classifications, pressure gradients, and testing requirements for media fills are always topics where a number of individuals have opinions,” notes Hank Rahe, director of technology for EnGuard Systems. “The one recommendation that will continue to cause debate is the size of media runs and the value they create. Active air monitoring for microbial quality may also be new for some companies.”
Regarding media runs, the updated FDA Guidance says: “Simulation run sizes should be adequate to mimic commercial production conditions and accurately assess the potential for commercial batch contamination…A generally acceptable starting point for run size is in the range of 5,000 to 10,000 units…Media fill size is an especially important consideration because some batches are produced over multiple shifts or yield an unusually large number of units. These factors should be carefully evaluated when designing the simulation to adequately encompass conditions and any potential risks associated with the larger operation.”
As for monitoring air quality, the FDA suggests “a well-defined, written program and scientifically sound methods. The monitoring program should cover all production shifts and include air, floors, walls, and equipment surfaces, including the critical surfaces that come in contact with the product, container and closures… It is important that locations posing the most microbiological risk to the product be a key part of the program. It is especially important to monitor the microbiological quality of the critical area to determine whether or not aseptic conditions are maintained during filling and closing activities…All environmental monitoring locations should be described in SOPs with sufficient detail to allow for reproducible sampling of a given location surveyed.”
Ken Christie, senior director of consulting services at VTS Consultants, points out that “while some companies might claim the new guidelines don’t impact them much, others might consider them to be more definitive and now more burdensome to comply with. I think the industry looks for clarification in those guidelines that were open to too much interpretation-not directing what the overall process should entail for companies.”
To assist pharmaceutical manufacturers big and small to comply with the detailed, often time-consuming FDA validation procedures, numerous companies around the country-including Christie’s VTS Consultants-provide complete validation services and consultation. A nationwide sampling includes:
American Technical Consultants (Langhorne, Pa.; www.atccorp.net)
PharmaSys (Cary, N.C.; www.pharma-sys.com)
Pharmaceutical Systems Inc. (Mendelein, Ill.; www.pharmasystems.com)
R. Donnelly & Associates (St. Charles, Mo.; www.rda-group.net)
Pharmaceutical Services Corp. (Pasadena, Calif.; www.biotech.com)
While Christie agrees that “there will always be issues that some companies will take exception to, the FDA is committed to assuring the greatest safety is provided to the consumer and, as a result, there will be issues where there is little room for debate.” He believes that the majority of pharmaceutical companies will not only comply with the Guidance but also will eventually suggest improvements and offer further changes to the FDA’s guidelines.
“Because these are recommended guidelines,” Christie adds, “companies can still choose another course of action, provided the intent of the guideline is maintained and the practice can be defended as to why it is considered acceptable.”