Terminal Inertia

Terminal sterilization should be used wherever possible when manufacturing sterile medicines; not only does it provide a higher level of sterility assurance than other sterilization processes, it is also the preferred approach of regulators, both in the US and Europe. The FDA indicates in its Aseptic Processing Guidance that “it is a well-accepted principle that sterile drugs should be manufactured using aseptic processing only when terminal sterilization is not feasible” (1). Similarly, the European Medicines Agency’s Decision Tree provides guidance on the sterilization parameters to be evaluated prior to determining that a product should be sterilized using aseptic processing. It states: “Those products intended to be sterile should be terminally sterilized in their final container as clearly stated in the European Pharmacopoeia, and in the CPMP Notes for Guidance. Where it is not possible to carry out terminal sterilization by heat due to formulation instability, a decision should be taken to utilize an alternative method of terminal sterilization, filtration and/or aseptic processing,” (2).

And so it continues to amaze me that surveys show no significant change in the number of drugs aseptically processed versus terminally sterilized. Approximately 80 percent of sterile drugs manufactured use aseptic processing versus just 20 percent for terminal sterilization (3-6).

Apart from a few exceptions, manufacturers of large-volume parenteral medicines (those with container sizes of 100 mL or more) must terminally sterilize their products. However, many of these medicines are also manufactured in vials or syringes in smaller volumes, which are not terminally sterilized. Some companies think that terminal sterilization cannot be used for their products because of a misunderstanding that 121 °C for at least 15 minutes is the only acceptable cycle. In reality, you can select cycles with lower temperatures and longer times, or higher temperatures with shorter times, and still meet the regulatory requirements for terminal sterilization. For example, some products that cannot be successfully sterilized using standard steam cycles can withstand high temperatures for very short periods of time. As long as this provides a probability of a non-sterile unit of less than 0.000001, it is considered successful terminal sterilization. Depending upon the product formulation and its packaging configuration, you could also choose other types of moist heat sterilization, such as saturated steam, air–steam mixtures, air–steam–water mixtures, water immersion or rotary sterilization to meet the necessary sterilization requirements.

There is a lot of guidance to help manufacturers. The Parenteral Drug Association updated their technical report on moist heat sterilization in 2007 (7) to provide a significant level of detail on the various types of sterilization approaches that can be performed, including overkill cycles, or product-specific cycles (formerly called combined bioburden biological indicator based cycles or absolute bioburden cycles). Despite the detailed methods provided, companies have been reluctant to pursue product-specific cycles. In some cases, they do not want to perform the additional biological indicator testing to determine spore log reductions – they prefer total kill cycles.

Another roadblock is that companies often don’t want to evaluate terminal sterilization for existing products because a regulatory submission is required to approve the new cycle. When the submission is made, it will also be evaluated for compliance with all current regulatory requirements, and the company may be concerned whether all the various chemistry and microbiology parameters will be met. In some cases, there are also costs associated with making the submissions, which may be prohibitive.

Yes, there are hurdles – some real, some perceived – but the huge advances made in sterilization science and methods in the last 35 years allow the terminal sterilization of even challenging formulations. With so many cycles available, and so much guidance at hand to develop and implement them, it is disconcerting to see how few companies are moving towards terminal sterilization of more of their products. Companies need to accept that terminal sterilization ultimately benefits patient safety – and that’s something we should all be striving for.