Ensuring Sterility of Parenteral Products - Pharmaceutical Technology

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PharmTech Europe

Ensuring Sterility of Parenteral Products
Experts describe best practices for sterility assurance in parenteral drug manufacturing. This article contains bonus online-exclusive material.

Pharmaceutical Technology
Volume 37, Issue 4, pp. 62-67

PharmTech:What are the limitations or challenges to current sterilization methods?

Agalloco (Agalloco & Associates): The obstacle we face is the expectation for higher F0 values, increased doses, and tighter filters. There a belief that if we just make the process a little more lethal or more robust, it will be better. That ignores the whole other side of the process—what it does to the materials we are processing. There is degradation, increased particles, extractables, less mechanical strength and other impacts that oversterilization can cause. There needs to be more consideration of the negative consequences of what sterilization does. We only need kill or remove the bioburden once. Overprocessing is rampant and aside from making things look better on the surface, it’s actually not something we should be doing. The half-cycle approach to sterilization should be used rarely and unfortunately its use is becoming more prevalent rather than less.

Sandle (Bio Products Laboratory): The main limitation with any sterilization method relates to the validation, the way it has been executed, and the way the validated sterilization technology is used in practice. One only has to look at the major pharmaceutical contamination scandals of the past 40 years to see this limitation, from the Devonport incident in the early 1970s (which was partly the basis of modern GMPs) (4) to the issues surrounding the New England Compounding Center last year, where three lots of methylprednisolone acetate, intended to be injected into the spinal cord as a treatment for arthritis, were contaminated with Exserohilum rostratum (5). This incident led to more than 700 reported infections and some 48 deaths, based on figures from the US Centers for Disease Control and Prevention. In both these cases, the sterilization equipment was involved and it was not operated correctly, which is largely a practical matter of engineering and systematic checks (6, 7).

Besides validation issues, various factors (e.g., economic, space, time-to-release) drive the use of different sterilization technologies. The factor, however, is the product and whether it is compatible with the technology. The lower-risk technologies are terminal sterilization methods, especially for medical devices that can be gamma irradiated or treated with ethylene oxide.

Terminal sterilization is most commonly carried out using steam (moist heat). Risks are often low provided the cycles have been validated thermometrically and biological indicators have been used to show that sterility-assurance levels are at 10-6 as a minimum. A number of quality attributes must, however, be carefully checked for each run. Most important is air removal. It is crucial to ensure that all of the trapped air is removed from the autoclave before activation as hot air is a very poor medium for achieving sterility.

The biggest challenge is aseptic filling. There are complications around product filtration relating to the validation of the product through the filter (where the filter needs to be challenged with 10,000,000 cells of a diminutive bacterium); product bioburden; and issues relating to filter failure (for which post-use integrity checks are crucial). There are also the complications of bringing together a sterile product and sterile components (vials, stopper, crimpers) and attempting to fill thousands of vials under a clean air zone.

Verjans (Aseptic Technologies): We need to distinguish between terminally sterilized and aseptically filled products. For the first category, products are sterilized shortly after fill–finish, therefore eliminating contamination that could potentially put patients at risk. On the contrary, for aseptically filled products, there is a real concern of contamination because the last safety barrier provided by terminal sterilization is not there. From now, I will exclusively talk about aseptic processing, in particular fill–finish.

The following is a list of contamination sources, among others:

  • The product may have been contaminated during formulation so all precautions during fill–finish are useless as the contaminant is already there
  • Contamination may occur during product transfer
  • Product contact parts, such as paths or stoppers, may be contaminated
  • The environment may be contaminated during introduction of various elements (e.g., tools)
  • The quality of the environment may be at risk due to a tiny leak in high-efficiency particulate air (HEPA) filters or in barrier integrity
  • The operator can bring a contaminant, especially if he is in close contact with the processing area

To have safe aseptic processing, it is mandatory to address all these aspects carefully, which therefore makes aseptic processing perhaps the most complex pharmaceutical manufacturing process. The challenges are to:

  • Prevent the contamination from coming in contact with the environment: The best approach is to optimize equipment design, set up clear and sound procedures, and train operators. Training is crucial as, even with the highest quality of equipment and procedures, the process is at risk without good operators.
  • Detect the contamination: Can we identify the contamination and eliminate it before it reaches and affect the patient?
  • Reduce the probability of transforming a contaminant into a contamination: The lower the exposure, the lower the risk.


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