Event-Based Sterility Assurance

Robert Westney, Founder and President of Cryologics Inc., Principal Consultant for Westney & Associates Consulting LLC

Introduction 

Event-related sterility assurance is, simply put, any event that compromises the integrity of the barrier enclosing the sterilized material. Such events may occur just subsequent to sterilization, during transport, and during storage (including repeated handling of the packaged material), leading to breaches, punctures, holes, rips, tears, dampness, crushing, etc. This includes materials that are sterilized in-house, or those that are purchased pre-packaged and pre-sterilized. 

The scope of this article includes materials that have been subjected to a sterilization process, followed by their transport and storage. Many factors should be considered when determining how long these materials remain sterile (e.g., time limit, hold time, expiration, etc.). For example, the following factors should be considered: the type and configuration of material packaging; how frequently a sterilized material is handled before use; storage conditions, such as an open shelf or a closed cabinet; the method and environmental control of the transportation; the environment of the storage area, such as an International Organization for Standardization (ISO) area classification, temperature, humidity, disinfection regimen, etc. This article introduces the concept of event-based sterility assurance and provides guidance for implementing an event-based sterility assurance program.  

Discussion 

Limited regulatory guidance can be gleaned from the U.S. Code of Federal Regulations (CFR) requirements related to the prevention of contamination of materials:  

• 21 CFR 211.42(b): “Any such building shall have adequate space for the orderly placement of equipment and materials to prevent mix-ups between different components, drug product containers, closures, labeling, in-process materials, or drug products, and to prevent contamination. The flow of components, drug product containers, closures, labeling, in-process materials, and drug products through the building or buildings shall be designed to prevent contamination.” [emphasis added] 
• 21 CFR 211.80(a): “There shall be written procedures describing in sufficient detail the receipt, identification, storage, handling, sampling, testing, and approval or rejection of components and drug product containers and closures; such written procedures shall be followed.” [emphasis added] 
• 21 CFR 211.80(b): “Components and drug product containers and closures shall at all times be handled and stored in a manner to prevent contamination.” [emphasis added] 

These CFR sections alone are insufficient to detail the approach for establishing time limits for sterilized materials. However, it is clearly an expectation of the U.S. Food and Drug Administration (FDA) that material sterility time limits be qualified. For example, its Guidance for Industry, Sterile Drug Products Produced by Aseptic Processing, contains two relevant statements: 

1. Section VI (B): “Written procedures should specify the frequency of revalidation of these processes as well as time limits for holding sterile, depyrogenated containers and closures.” [emphasis added] 
2. Section VIII: “Time limits should include, for example, the period between the start of bulk product compounding and its sterilization, filtration processes, product exposure while on the processing line, and storage of sterilized equipment, containers and closures.” [emphasis added] 

These two guidance document statements provide further clarification of 21 CFR 211.42(b) and 21 CFR 211.80(a) and (b), and represent the agency’s current thinking on this topic. For example, in a 2020 Warning Letter,2 the FDA stated, “The investigators observed that your firm has not established a hold time for sterilized stoppers, vials and seals used in sterile drug production”. In a 2017 Warning Letter,3 the FDA stated, “... your firm did not provide supporting documentation to demonstrate how these items will be protected from contamination while awaiting use in aseptic drug protection [sic]. Furthermore, we remain concerned with the lack of a hold time for these items. Storage of sterilized items for extended periods of time increases the risk of them becoming contaminated. Your firm should ensure that these items are protected from contamination while awaiting use in sterile drug production ...” 

While limited regulatory or compendial guidance exists in the Good Manufacturing Practices (GMP) industries for addressing event-related sterility assurance, several papers have been published by academic and medical organizations. In 2016, the Centers for Disease Control and Prevention answered Frequently Asked Questions for packaging and storage, stating, “Storage practices for wrapped sterilized instruments can be either date- or event-related. Although some facilities continue to date every sterilized package and use shelf-life practices (first in, first out), other facilities have switched to event-related practices. This approach recognizes that the product should remain sterile until some event causes the item to become contaminated (e.g., a package becomes torn or wet)”.4  In its document “Event-Related Sterility”, The University of Rochester Medical Center states, “Recent studies suggest that current standards for sterility testing can be improved by the addition of event-related testing, and that contamination of wrapped trays may occur within days, instead of weeks”.5  It recommends a review of “technical documentation on barrier quality of packaging materials”, and developing a policy that includes defining “events that would require reprocessing of packages”. 

The Association of periOperative Registered Nurses (AORN) is an excellent resource for understanding the principles of event-related sterility assurance. AORN states in its “Recommended Practices for Sterilization in the Perioperative Practice Setting”, “The shelf life of a packaged sterile item is event related”.6  It further describes that an “event must occur to compromise package content sterility. Events that may compromise the sterility of a package include ... multiple handling that leads to seal breakage or loss of package integrity, moisture penetration, and exposure to airborne contaminants”. It asserts, “Sterile packages should be stored under environmentally controlled conditions”. The document contains the important recommendation, “Transportation of sterile items should be controlled”.  

AORN again provides informative guidance in its “Recommended Practices for Selection and Use of Packaging Systems for Sterilization”. Among its recommended practices: 

• “Packaging systems should be evaluated before purchase and use to ensure that items to be packaged can be sterilized by the specific sterilizers and/or sterilization methods to be used. 
• Packaging systems should be compatible with the specific sterilization process for which it is designed.
• Package contents should be assembled, handled, and wrapped in a manner that provides for an aseptic presentation of package contents. 
• Sterilized packages should be considered sterile until an event occurs to compromise the package barrier integrity.” 

Following each of its 12 recommended practices, AORN succinctly describes guidelines for addressing that practice. These guidelines can easily be applied to GMP processes and environments. 

Drawing from guidelines published in numerous papers, this author proposes the following. Rather than qualifying a hold time for a sterilized material, a GMP firm may author a “position paper” that can be defensible to regulatory scrutiny. The elements of the paper include (a) method of sterilization, (b) evaluation of the packaging material, (c) method of wrapping and protecting the item, (d) transport and storage conditions, and (e) personnel training. The “position paper” may present a holistic approach, representing a “family” of materials/items requiring sterilization, or may be authored on a per-material basis. 

Method of Sterilization 

Describe the sterilization method, including physical and/or chemical conditions. Extreme physical conditions may include temperature, pressure, radiation, etc. Chemical conditions may represent a risk to the packaging material. Summarize information relating to validation of the sterilization cycle. Consideration should be given to not only the packaging material (see below), but also to the item itself to be sterilized. Detail the requirements for inspecting sterilized materials subsequent to sterilization for any breaches of packaging integrity. 

Evaluation of Packaging Material 

Describe the rationale for selection of the packaging material. Packaging materials must be compatible with the method of sterilization in order to ensure that not only are they not degraded (either immediately, or long-term), but also that they permit sterilization of the target item. For example, packaging materials for steam sterilization should provide adequate air removal, permit steam penetration and direct contact with the item’s surfaces and permit adequate drying. Packaging materials for ETO should be permeable to ETO, moisture, and air, and permit aeration. Packaging materials for VHP sterilization should be permeable to the process, be made of a material recommended by manufacturers and used according to the manufacturers’ instructions. Packaging systems for heat sterilization should permit heat penetration and direct contact with the item’s surfaces. Finally, prior to use in sterilizing items, packaging materials should be maintained according to the manufacturer’s recommended storage conditions. 

This section of the “position paper” allows for inclusion of empirical data. While it pertains to sterile pharmaceutical products, USP <1207>8 and related chapters provide detailed guidance for assessing and testing packaging integrity. Related chapters include Package Integrity Testing in the Product Life Cycle - Test Method Selection and Validation <1207.1>, Package Integrity Leak Test Technologies <1207.2>, and Package Seal Quality Test Technologies <1207.3>. These tests can be performed, and the data presented in the “position paper”. These tests can also be performed subsequent to long-term (e.g., years) storage. 

Method of Wrapping and Protection 

Describe the size of the wrapping material that is adequate to completely enclose the item, including techniques for sealing the package. The item should be wrapped securely to prevent gapping, billowing, and air pockets from forming, conditions which may adversely impact the sterilization process. Sequential wrapping using two barrier-type wrappers is a common technique employed to provide an additional barrier to microbial contamination and to facilitate introduction of the item into aseptic processes. 

Transport and Storage Conditions 

Describe the process of transporting sterilized material from the point of sterilization to the storage destination. Facility layout maps are an excellent means of illustrating transportation flows and area classifications. Detail the measures that are taken to protect the sterilized material from incidental contamination during transport. The description of the storage area should include emphases on environmental conditions and security. The storage area should be of a design that facilitates “first in-first out” usage and minimizes excessive movement of items by personnel. 

Although it pertains to finished drug products, USP <1079>9 is an excellent resource for mitigation of risks associated with transportation and storage. It describes four “pillars” of a Quality Management System (QMS) that “facilitate the identification of risk”: Documentation and Procedures; Training; Resources for Storage, Transportation, and Personnel; and Qualification and Validation. The chapter provides detailed guidance for identifying a hazard, evaluating its effect, and developing a strategy to mitigate its risk. 

Personnel Training 

Training is critical for ensuring that the above-described controls are maintained. Summarize Standard Operating Procedures (SOPs) associated with each of these controls, including relevant details. Department-specific responsibilities may be outlined. 

Conclusion 

While event-related sterility assurance is prominent in the medical industry, in this author’s experience it is not prevalent in the GMP  industries. There is ample science-based information from the medical industry to adopt this practice. The guidelines for a “position paper” provided in this article are robust and very likely to survive regulatory scrutiny. Given the proper controls, a sterilized material can remain sterile virtually indefinitely. Consider this: Johnson & Johnson reported that samples of absorbent gauze sterilized in 1917 were tested in January 1962.10 Forty-five years later, the gauze was still sterile.  

Author Biography 

Robert Westney is the Founder and President of Cryologics Inc., which specializes in preparation of in-house isolates for use in compendial testing. He is also Principal Consultant for Westney & Associates Consulting LLC. He has more than 30 years of experience in the GMP industry, including Quality Control Microbiology, Quality Assurance and Regulatory Affairs. He holds a Master of Science degree from Temple University in Quality Assurance / Regulatory Affairs. He is Regulatory Affairs Certified (RAC) and is a Certified Manager of Quality / Organizational Excellence (CMQ / OE). He is a member of the American Society for Microbiology (ASM), the Parenteral Drug Association (PDA), the Regulatory Affairs Professional Society (RAPS), and a Senior Member of the American Society for Quality (ASQ).  

Acknowledgment 

Many thanks to Eric Staib and Mark Fosbenner for contributing to an earlier concept of this topic many years ago.  

References 

1. FDA Guidance for Industry. Sterile Drug Products Produced by Aseptic Processing – Current Good Manufacturing Practice. September 2004. 
2. FDA Warning Letter; Tailor Made Compounding LLC. April 1, 2020. 
3. FDA Warning Letter; Pharmacy Plus, Inc. dba Vital Care Compounder. April 9, 2017. 
4. Centers for Disease Control and Prevention. Sterilization: Packaging & Storage, FAQs. February 26, 2016. 
5. University of Rochester Medical Center. “Event-Related Sterility”. https://www.urmc. rochester.edu/sterile/event.aspx. Accessed January 24, 2022. 
6. Association of periOperative Registered Nurses. Recommended Practices for Sterilization in the Perioperative Practice Setting. AORN Journal. (83)3:700-722, March 2006. 
7. Association of periOperative Registered Nurses. Recommended Practices for Selection and Use of Packaging Systems for Sterilization. AORN Journal. (85)4:801-812, April 2007. 
8. United States Pharmacopeia <1207>, “Packaging Integrity Evaluation – Sterile Products” 
9. United States Pharmacopeia <1079>, Risks and Mitigation Strategies for the Storage and Transportation of Finished Drug Products 10. Gaughran, E.R.L, and Morrissey, R.F, Ed. (1981). Sterilization of Medical Products, Volume II. Multiscience Publications Limited.

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