AABB24: Understanding the Finer Points of Sterility Testing

Transfusion medicine professionals are well-acquainted with federal regulations intended to ensure that communicable diseases are not transmitted by blood components. Traditional concerns have focused on transmission by contamination, cross-contamination or the risk for errors. Regulations regarding cellular therapies may not be as well-understood because the human cells used in cellular therapies are regulated as either human cell and tissue-based products (HCT/Ps) or as biological drug products. Currently, different sterility testing procedures are used for products in these two different categories. Thus, confusion may result.

The Saturday AABB Annual Meeting session “Sterility Testing for Cellular Therapies: Updates and Challenges” gave attendees a clearer idea of what they should be doing. Presenters discussed updates to the regulations for sterility testing of HCT/Ps and biological drug products, as well as the challenges in maintaining compliance.

A Complex Issue

J. Wade Atkins, MS, MLS(ASCP)SBB, CQA, CABP(H) from the National Institutes of Health (NIH) in Bethesda, Md. presented an overview of just how complex the regulations can be. The regulations governing HCT/Ps are found in 21 CFR 1271.10(a) as a list of criteria that, if met, will exempt the HCT/P product from the federal requirement for premarket regulatory review, approval or clearance. All other cellular therapy products are regulated as biological drugs and are governed by regulations found not only in 21 CFR 1271 (current good tissue practice requirements), but also in the following sections:

• 21 CFR 207.9, Which facilities these regulations apply to
• 21 CFR 210, Current good manufacturing practice in manufacturing, processing, packing or holding of drugs; general
• 21 CFR 211, Current good manufacturing practice for finished pharmaceuticals
• 21 CFR 220, Processing and process control
• 21 CFR 610.12, Sterility
• 21 CFR 807.20, Which facilities must register and submit a device list
• 21 CFR 820.1, Scope of quality system regulation

After more discussion of the requirements in the CFR, Atkins also touched on the contents of a 2011 Guidance for Industry issued by the Food and Drug Administration (FDA) that gave additional information to consider.

Sterility Testing Methods

Anna F. Lau, PhD, D(ABMM), also from NIH, focused her presentation on the performance characteristics of, and updates to, the applicable sterility testing requirements in the United States Pharmacopeia (USP). She outlined two contamination events at NIH in 2015 that resulted in published reports, changes in executive leadership and the creation of a sterility testing service.

She emphasized that clinical testing of sterility for blood components is not equal to the current good manufacturing practice (cGMP) sterility testing for biological products. Specifically, clinical sterility testing methods are not accurate in detecting fungi, which may give those who use clinical methods for sterility testing of cellular therapy products a false sense of security.

Lau identified several variations in testing parameters that add to the complexity of sterility testing, including the following:

• The use (or not) of sterile gloves
• The correct use of a biological safety cabinet
• The equipment used
• The media formulations
• The temperature differences
• The cleaning products and methods used
• The process controls in place

Lau noted three key take-aways from her presentation: 1) lessons learned through the NIH experience may help others avoid some of the pitfalls, 2) USP sterility testing is the “gold standard” and 3) updated USP regulations are expected to be released in the near future.

Risk-Based and Data-Driven Decision-Making

Liz Lessey-Morillon, PhD, from the FDA Center for Biologics Evaluation and Research in Silver Spring, Md., presented the FDA perspective on rapid microbial methods for cellular therapy products. Her overview included identification of several challenges, including the small lot sizes typically involved, the medical need to administer some products before testing has been completed and the inherent variability in the characteristics of the cellular starting material.

She described the decision-making process for cellular therapy product review as risk-based and data-driven. Noting that the FDA considers some flexibility in reviewing products created under an investigational new drug (IND) application, Lessey-Morillon emphasized that there are more aspects to sterility than aseptic techniques and spoke about the FDA’s expectations. She advised the attendees to plan ahead and consider the work being performed from the perspective of the impact on the particular patient as well as the impact on the entire lot of product involved.