Differences in sterility assurance for manufacture vs. compounding
Comparing and contrasting requirements for facilities, components and gowning
By Hank Rahe, Containment Technologies Group
The following statement by the FDA highlights the critical factors that are required to perform aseptic manipulations, whether it is in pharmaceutical manufacturing or compounding preparations in a pharmacy setting: “In an aseptic process, the drug product, container, and closure are first subjected to sterilization methods separately, as appropriate, and then brought together. Because there is no process to sterilize the product in its final container, it is critical that containers be filled and sealed in an extremely high-quality environment. Aseptic processing involves more variables than terminal sterilization. Before aseptic assembly into a final product, the individual parts of the final product are generally subjected to various sterilization processes. For example, glass containers are subjected to dry heat; rubber closures are subjected to moist heat; and liquid dosage forms are subjected to filtration. Each of these manufacturing processes requires validation and control. Each process could introduce an error that ultimately could lead to the distribution of a contaminated product. Any manual or mechanical manipulation of the sterilized drug, components, containers, or closures, prior to or during aseptic assembly, poses the risk of contamination and thus necessitates careful control.”
Aseptic manipulations in either manufacturing or compounding are difficult. The level of success in delivering a drug that is safe to use on a patient is described as the sterility assurance level (SAL) of the final package. Sterility assurance is a theoretical number set so that the probability of a nonsterile product making it through the validated sterilization process is one unit per million sterilized. This is referred to as a SAL of 10-6.
In many ways, aseptic manufacturing, as it occurs in pharmaceutical facilities, can be contrasted and compared to compounding preparations in pharmacy. The major areas of each activity are the facilities, components and gowning used. The FDA guidance for aseptic manufacturing is presented in the form of non-binding recommendations that support compliance to cGMPs, while the aseptic compounding of sterile preparations requirements come in the form of a standard issued by the U.S. Pharmacopeia (USP). A USP standard is not a regulation or law but can be adopted into law. As a standard it must be followed as written.
The facilities for pharmaceutical processing can be of several different configurations, from conventional ISO Class 7 cleanrooms, supporting a critical manufacturing zone of ISO Class 5 where the combining of all components come together to provide a sealed package, to an ISO Class 8 environment surrounding and supporting an isolator. The FDA guidance regarding facilities is described in Sterile Drug Products Produced by Aseptic Processing-Current Good Manufacturing Practice (2004): “This guidance represents the Food and Drug Administration’s (FDA’s) current thinking on this topic... You can use an alternative approach if the approach satisfies the requirements of the applicable statutes and regulations.”
The facility requirements for aseptic compounding of preparations as described in USP <797> are a work in progress. The USP process allows for annual revisions to its standard and has presented a moving target to healthcare institutions falling under the standard. USP <797> was first published and became enforceable as a standard of practice in 2004. The facility requirements outlined in the chapter mirror the physical requirements for cleanrooms outlined in the FDA 2004 guidance in terms of materials of construction. The USP standard calls for ISO Class 8 for air quality and uses an example showing two options for construction style, the first being a conventional anteroom and the second a single room with no physical separation between the ante-area and the compounding area.
Acceptable ISO Class 5 environments identified in the USP <797> chapter are laminar flow benches, Class II biological safety cabinets (BSC) and barrier isolators. The barrier isolators are not required to be supported by an ISO Class 8 environment.
In 2006, as part of the annual revision process, USP issued a number of revisions to USP <797>, including major changes in the physical requirements. One major change was the requirement for ISO Class 7 cleanrooms and a series of facilities for hazardous drugs. The proposed requirements for hazardous drugs include negative-pressure cleanrooms with cascading pressure differentials leading to an adjacent positive-pressure cleanroom.
In aseptic manufacturing processes, the vials, syringes and patient delivery bags are also produced, in many cases, by aseptic processing. Those products that are able to withstand it are terminally sterilized. In the majority of cases, after being filled, the vials are not terminally sterilized.
The supporting components for filled vials, including the glass vial and stoppers, are sterilized and the liquids are sterile filtered. The SAL of vials is documented to be from 10-3 to 10-5. Syringes, needles and patient delivery bags are typically terminally sterilized to a SAL of 10-6.
The components used in aseptic compounding of preparations have a high SAL on the inside of the packages. However, the outside of the packages are not enclosed in a protective aseptic environment and, after manufacture, are held in corrugated shippers in a warehouse before being then shipped to a wholesaler’s warehouse until they are ordered by and shipped to a healthcare institution. Neither the facilities nor the shippers are aseptically protecting the exterior of the packages. Upon arrival at the healthcare institution, the packages containing the “sterile” components may be placed in another warehouse or general storage area. The net result is that the exterior of the components used in aseptic compounding are likely to have been contaminated with microorganisms.
The decontamination processes for compounding components is typically either a wipe- or spray-down with nonsterile alcohol. Nonsterile alcohol is the environment used to support spores and is documented as not being an effective decontaminant. FDA has discouraged manual sanitization because it is not a consistent and repeatable process. However, in the USP <797> chapter, the definition of decontamination excludes spores.
A major difference between aseptic manufacturing and aseptic compounding is the starting point, in terms of the sterility assurance level, of the components being placed into the ISO Class 5 environment.
Several studies have shown that it is likely that touch contamination is the leading factor in the dramatic differences in the sterility assurance levels between aseptic manufacturing and aseptic compounding. Two studies published in the American Journal of Heath-System Pharmacy (AJHP) help to support this conclusion.1, 2
The first study showed a 5.2 percent contamination rate of medium-risk simulations and that the use of sterile gloves greatly reduced the rate of contamination. Manipulation of contaminated components would, however, result in contamination of the sterile glove after the first contact. The second study compared simulations in and out of a conventional cleanroom. It showed a similar contamination rate of less than 10-3 in both cases.
Both studies indicate a difference in individual performance that would seem to invalidate the idea that good aseptic technique is the answer to reducing the high contamination rates. There is no means to assure good aseptic technique when the contamination rate is dependant on individuals performing the activity in the same way.
Gowning requirements for aseptic manufacturing facilities require that individuals working in the aseptic core be fully covered with a “bunny suit.” Individuals are trained in proper gowning and degowning technique and it should be noted that gowns are sterile and intended for one-time use.
USP <797> allows for a much lower level of personal gowning, including the use of nonsterile gowns and the reuse of gowns.
Biodecontamination of the exterior of materials used in aseptic manipulations is the major factor in determining the SAL, given a properly maintained and sanitized ISO Class 5 environment.
Isolators have increased the dependability of the ISO Class 5 environment for aseptic processing by minimizing personnel contact during processing. This has been demonstrated in studies showing increased sterility assurance levels as compared to conventional cleanrooms.
Biodecontamination by automated decontamination systems has made it possible for pharmaceutical manufacturers to sterilize components and environments and has enabled them to aseptically produce products having a SAL greater than 10-4.
Compounded preparations, on the other hand, are not routinely tested for sterility due to the nature of the activities surrounding their preparation. Feedback on the lack of sterility comes in the form of adverse patient reaction, reported as secondary infections. An indication of contamination rate can be determined by simulated media activities if repeated a number of times.
The surfaces of components used in compounding must be properly decontaminated, as well as the ISO Class 5 environment, including any glass, sleeves or body parts entering the environment. If we are to see a reduction in the number of contaminated IVs going to patients, standards such as USP<797> must focus on the biodecontamination of preparations.
Hank Rahe is director of technology for Containment Technologies Group and is a member of the CleanRooms Editorial Advisory Board. He can be contacted at firstname.lastname@example.org.
- Thomas, M., M. Sanborn, R. Couldry. “I.V. admixture contamination rates: Traditional practice site versus a class 1000 cleanroom,” American Journal of Health-System Pharmacy, Vol. 62 , Issue 22, pp. 2386-2392.
- Trissel L., J. Gentempo, R. Anderson, J. Lajeunesse. “Using a medium-fill simulation to evaluate the microbial contamination rate for USP medium-risk-level compounding,” American Journal of Health-System Pharmacy, Vol. 62, Issue 3, pp. 285-288.