PACKAGING FORUM Concept Paper Discusses Update of Aseptic Processing Guidelines

Hallie Forcinio

ifteen years have passed since FDA published tors, which have gained a strong position among guidelines for aseptic processing. During those parenteral drug makers during the past decade. The Fyears, technology advanced rapidly, and the second discusses blow–fill–seal technology, and a number of products being aseptically processed grew third describes processing before filling–sealing op- substantially. Isolator-equipped filling lines also erations. The concept paper concludes with lists of evolved into an alternative to traditional cleanrooms. references and relevant guidance documents followed In an effort to meet the expanding needs of today’s by a glossary that defines approximately 30 terms re- pharmaceutical manufacturers, FDA has been work- lated to aseptic processing. ing to update its guidelines for What has not changed is FDA’s stance that “ster- The recently issued aseptic processing, and it fi- ile drugs should be manufactured by aseptic pro- nally issued a concept paper cessing only when terminal sterilization is not fea- FDA concept paper on 27 September 2002. The sible.”To find support for this policy, one need look much-anticipated draft docu- no further than the years between 1980 and 2000 about aseptic processing ment, “Sterile Drug Products when nearly all of the recalls for nonsterility or lack Produced by Aseptic Process- of sterility assurance involved aseptically processed shows how the current ing,” has been the talk of the products. industry ever since. Reaction to the long-awaited draft has been gen- guidelines could be At approximately 50 pages, erally favorable, although some concerns and modi- this concept paper is consid- fications have been suggested in comments submit- expanded and makes erably longer than the exist- ted to the agency. Considerable discussion also ing guidelines that were issued ensued at a day-long meeting organized by the Paren- recommendations for in 1987. It also takes a more teral Drug Association (PDA) on 9 December 2002, risk-based management ap- during which attendees emphasized the importance alternatives to proach, a strategy the agency of familiarizing FDA field personnel with any new has been adopting in other guidelines to ensure consistent treatment from in- traditional cleanroom areas, including revisions of spector to inspector. installations such as CGMPs. New subjects include Comments submitted by PDA’s ad hoc Subcom- guidance for personnel quali- mittee on Aseptic Processing comprise four main isolator-equipped fication, cleanroom classifica- subject areas: numbers and limits, media fills, envi- tions under dynamic condi- ronmental monitoring, and sterility testing. aseptic filling lines tions, room design, quality Numbers and limits. The subcommittee advocates control, environmental moni- building flexibility into the guidelines to accommo- and blow–fill–seal toring, and reviews of pro- date advancing technology and the individual pro- duction records, isolators, and cedures followed by various companies, and it notes equipment. blow–fill–seal systems. that any numbers and limits stated in the guideline Other sections feature a should be supported by scientific data. This approach lengthy discussion of container–closure prepa- is particularly necessary for microbial control lim- Hallie Forcinio ration and inspection, endotoxin control, process its because, according to the subcommittee, “stan- is Pharmaceutical validation and equipment qualification, batch- dard sample collection and microbiological meth- Technology’s Packaging record review for process-control documenta- ods for these environmental tests have not been Forum editor, 4708 tion, and laboratory controls. The latter includes defined.” The comment letter proceeds to explain Morningside Drive, topics such as process simulation, filtration effi- that “in actual practice, it is extremely difficult to es- Cleveland, OH 44109, tel. (216) 351-5824, cacy, sterilization of equipment, and containers tablish microbial limits that are statistically valid. fax (216) 351-5684, and closures. For example, FDA suggests a limit of one viable or- [email protected]. Concluding the work are several related appen- ganism per 10 cubic feet of air. However, there is no dices. The first focuses on aseptic processing isola- reason to believe that a finding of two or three or-

38 Pharmaceutical Technology MARCH 2003 www.pharmtech.com Packaging Forum

ganisms per cubic foot on a single sample tion supervision, and operator training would indicate that product quality had been practices. FDA’s concept jeopardized.” Environmental monitoring. The subcom- paper emphasizes Media fills. Requirements for media-fill mittee also maintains that environmental tests also should be flexible, according to monitoring should focus on critical sites system integrity and the subcommittee. Such tests shouldn’t be rather than on critical surfaces because many given undue significance because they don’t of the critical surfaces listed “are inaccessi- maintenance. necessarily provide an improved level of ble … or not readily sampled … without quality assurance in operations with ap- jeopardizing the quality of the material being propriate environmental control, produc- filled.” Sterility testing. The sterility testing sec- tion of the subcommittee’s comment letter discusses the choice of methods, media, per- sonnel, sampling and incubation, and in- vestigation of sterility positives. Although the PDA subcommittee’s comments are quite detailed, the group makes the following basic points: ● Sterility-test problems should be addressed in the compendia. ● The investigation of a first-stage failure will in most cases not be definitive. ● Microbial identification data may not re- liably establish the source of a contami- nant. ● The technical limitations of sterility tests are not adequately discussed. Because so much confusion exists about the interpretation of sterility-test results, PDA’s Research Committee is conducting a survey to determine how industry responds to evi- dence of a first-stage failure.

Aseptic processing isolators Unlike the 1987 guidelines document, the 2002 concept paper addresses isolator tech- nology, whereby the filling line is enclosed in a controlled environment rather than set up in a cleanroom. The agency states that a well-designed isolator system “appears to offer an advantage over classical aseptic pro- cessing, including fewer opportunities for microbial contamination during process- ing.” It also warns that “users should not adopt a ‘false sense of security’ with these systems,” and adds that “manufacturers should also be aware of the need to estab- lish new procedures addressing issues unique to these systems.” FDA’s concept paper emphasizes system integrity and maintenance as well as regular replacement of items such as gloves, half-suits, seams, gaskets, and seals, which, if breached, can allow contamination into the system. Gloves, which typically are mounted to allow operators to manipulate items inside an iso- lator enclosure without breaking the seal, Circle/eINFO 31 40 Pharmaceutical Technology MARCH 2003 www.pharmtech.com Packaging Forum should be inspected at every use.“The choice be separated and fully extended during the Finally, because human operators gener- of durable glove materials coupled with a decontamination cycle. ally pose the biggest contamination threat to well-justified replacement frequency are two ● Decontamination cycles should include an isolator-based system,“meticulous asep- aspects of good manufacturing practice that an extra margin of kill time to ensure that tic technique standards must be observed.” should be addressed,”the paper states. In ad- viable microorganisms are eliminated. dition,“due to the potential for microbial mi- ● Biological indicator (BI) challenges should Blow–fill–seal technology gration through microscopic holes in gloves be used to validate the decontamination Appendix 2 of the FDA document ac- and the lack of a highly sensitive glove in- process. “For most production applica- knowledges the advantages that blow–fill– tegrity test, the inner part of the installed glove tions, demonstration of a six-log reduc- seal technology offers. A system that forms, should be sanitized regularly, and the opera- tion of the challenge BI is recommended,” fills, and seals containers in a controlled en- tor should also wear a second pair of thin the paper states. vironment demonstrates economies in gloves.” ● Decontamination should be completed container–closure processing as well as re- Appendix A also reiterates FDA’s con- according to a validated schedule or when- duced human intervention. However, equip- tention that isolators should not be located ever a breach in isolator integrity occurs ment must be designed to control the parti- in unclassified rooms. “A Class 10,000 or because of a power failure, glove/seam tear, culates generated by the plastic extrusion, Class 100,000 background is appropriate de- air leak, loss of pressure, or other problem. cutting, and sealing processes. Process moni- pending on isolator design and manufac- “Breaches of integrity should be inves- toring and environmental monitoring are turing situations.” tigated, and any product that may have been particularly important. FDA states that The concept paper’s overview of decon- impacted by the breach should be rejected.” “samples should be taken during each shift tamination procedures includes several Other isolator requirements that are de- at specified locations under dynamic con- requirements: scribed in the paper include the establish- ditions.”Continuous monitoring of particu- ● Written procedures for decontamination ment of an environmental monitoring pro- lates can help control the system. should be established. gram to periodically check the micro- Companies that use blow–fill–seal sys- ● The decontamination process must fully biological quality of air, surfaces, and gloves tems must ensure that containers are ster- expose all surfaces to the sterilant. To en- and monitoring of particulate levels in the ile and nonpyrogenic. In addition,“the plas- sure that this happens, glove fingers should interior and at the exit port. tic polymer material chosen should be pharmaceutical grade, safe, pure, and pass USP criteria for plastics. Polymer suppliers should be qualified and monitored for raw- material quality.” In addition, each sealed container should be inspected to identify and reject any problem containers such as leakers. FDA concept papers are not binding to either the agency or industry. However, it is likely that this document, with some revi- sions based on industry comments, will form the foundation for any future guidelines re- lated to aseptic processing. PT FYI Updated resource available The updated and revised Standard for the Use of the International System of Units (SI):The Modern Metric System is available from the American National Standard for Metric System (ASTM).The 69-page document provides information that defines and comments on SI quantities and units used to describe such properties as mass,force,weight, temperature,pressure,angle,moment of inertia, and kinetic energy.Rules for conversion and rounding and various easy-to-understand tables are included. For more information,visit www.astm.org or contact ASTM Customer Service at 610.832.9585 or via e-mail at [email protected]. Circle/eINFO 34 44 Pharmaceutical Technology MARCH 2003 www.pharmtech.com