Guest Editorial: What Might Have Been

In October 1991, the U.S. FDA published a Proposed Rule, “The Use of Aseptic Processing and Terminal Sterilization in the Preparation of Sterile Pharmaceuticals for Human and Veterinary Use,” to amend the CGMP regulations to require the use of terminal sterilization of sterile drug products unless that process would adversely affect the drug product. (1)

The Proposed Rule would have amended 21 CFR § 211.113 Control of Microbiological Contamination by adding paragraph (c) to read:

(c)(1) Drug products purporting to be sterile shall be sterilized by terminal sterilization unless such process will adversely affect those drug products. In cases where terminal sterilization is determined by the manufacturer to be inappropriate, the written procedures described in paragraph (b) of this section shall include a justification for this determination.

(2) Biological products for human use are exempt from the requirements of paragraph (c)(1) of this section.

At that time, it was common for manufacturers to employ steam sterilization “overkill” cycles, e.g., 121 °C and 15 minutes, for terminal sterilization processes. Many drugs could not tolerate such conditions and manufacturers pushed back, essentially saying the proposal was burdensome in requiring justification for something that was already well known. However, the proposed rule did not specify the terminal sterilization conditions or method, leaving the way open to alternatives such as using the product bioburden as the basis for evaluating the lethality of the applied sterilization process in lieu of resistant biological indicator microorganisms, yielding contamination rates equivalent to the one in one million [10-6] units filled afforded by the overkill approach.

One of FDA’s justifications for amending the CGMP regulations was the lower contamination rates which could be achieved by terminal sterilization as compared with aseptic processing. The proposed rule stated, “… current aseptic processing methods, even when performed under optimal conditions, can only be validated to ensure that the contamination rate is no greater than 1 contaminated unit per 1,000 [10^-3] filled.”

PDA commented on the proposed rule, concluding “the proposed ruling is a beneficial action on the part of the [FDA] that will surely enhance the level of sterility assurance associated with sterile drug products.” (2) To address FDA’s concern that aseptic processing did not provide sterility assurance levels equivalent to terminal sterilization, PDA’s comments stated, “With knowledge and control of the indigenous bioburden, and its resistance to the sterilization process, sterility can be consistently achieved by processes which will not adversely impact product quality. Where an aseptic process is followed by a terminal sterilization procedure, a modest moist heat treatment would be sufficient to assure that the fluid is sterile.”

In its comments, PDA had captured the key issue inhibiting the use of terminal sterilization for many sterile products: “It is the PDA’s belief that the focus on overkill cycles has contributed to a narrower application of terminal sterilization in the industry than would otherwise be the case.”

In any event, FDA’s proposed rule was never adopted.

Another impediment to the widespread use of terminal sterilization was the release for consultation in 1998 and publication in 2000 of the CPMP “Decision Trees for the Selection of Sterilisation Methods.” (3) This document specified as a starting point for aqueous products terminal sterilization at 121 °C and 15 minutes, with identified alternatives if this was not achievable. The document reflected the standard moist-heat sterilizations specified in the European Pharmacopoeia.

This leads to the current sterile pharmaceutical manufacturing situation. Terminal sterilization is not widely used because of unrealistic expectations regarding overkill cycles and the resulting detrimental effects on product quality. In terms of sterility assurance, terminal sterilization is the best option, but it is not being used to the degree it should.

It is the author’s opinion that had the CGMP regulations been amended as proposed in 1991, leading to the use product bioburden-based terminal sterilization in lieu of overkill sterilization, it is likely that terminal sterilization would today be the method of choice, followed by advanced aseptic processing technologies and the abandonment of manned cleanrooms. This scenario would have increased patient safety, simplified the design of manufacturing processes, and eliminated much of the cleanroom space and operational inefficiencies and activities (e.g., extensive and expensive-to-operate HVAC systems and environmental monitoring programs) which simply increase costs without product quality and patient safety benefits.

Let’s not be so quick to reject a good regulatory proposal when we see it. Perhaps we should revisit this one with the perspective of over twenty years hindsight.

References

1. Federal Register, Vol. 56, No. 198, October 11, 1991, 51354-58.
2. Akers, J.E., et al, PDA Response FDA Proposal to Amend cGMP’s Entitled–Use of Aseptic Processing and Terminal Sterilization in the Preparation of Sterile Pharmaceuticals for Human and Veterinary Use. J Pharm Sci Technol 1992, 46 (3), 65-8.
3. EMEA Committee for Proprietary Medicinal Products (CPMP), Decision Trees for the Selection of Sterilisation Methods (CPMP/QWP/054/98 Corr), 5 April 2000.