Ensuring Sterility of Parenteral Products - Pharmaceutical Technology

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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/challenges to current testing methods for microbial control?

Agalloco (Agalloco & Associates): We’ve exhausted the ability of microbial sampling and test methods to help us. The expected quantities of microorganisms are at or below the threshold of detection for most sampling methods. The only acceptable result in Class 100 (Grade A) is less than 1 colony-forming unit (CFU). There are problems with this because it suggests that aseptic processing has to be conducted under essentially sterile conditions, which is not possible, especially with the manned filling technologies in use. Aseptic processing can be successfully performed in less than sterile condition, and that creates severe tensions between what we can provide in the way of environmental and process control, and the extreme regulatory expectation of those same controls. Rapid microbial methods aren’t the answer, because they only provide the results somewhat sooner.

Sandle (Bio Products Laboratory): Monitoring methods are divided into viable monitoring and nonviable particle monitoring. The objective of viable environmental monitoring is to enumerate the numbers of microorganisms present at a location within a cleanroom, to allow incidents to be recorded and, ideally, to permit species level identification. This type of monitoring is undertaken using a range of different air and surface counting methods, namely active air-sampling using volumetric air-samplers; so-called passive air monitoring using settle plates; the surface methods—contact plates and swabs; and the monitoring of personnel in terms of gloved hand prints and suit gown plates, taken on exit from the cleanroom suite.

Concerns with these classic methods was highlighted in the recent update to the USP chapter <1116>, which argued that we need to get away from seeing these methods as somehow “super accurate” such as an analytical instrument in a chemistry laboratory (9). The methods are limited because they can only be used periodically and thus serve as “spot checks” only. They cannot pick up all the culturable microorganisms present for example, due to weaknesses in collecting all the microorganisms that adhered to surface when using a contact plate. Recovery is also affected by temperature and agar variations.

As another example, with active air-samplers, these devices are only designed to pick up 50% of the viable particles that are drawn in. There are risks with the method of drawing the air in, such as by impaction or through centrifugal forces, damaging or stressing the microorganism to the extent that it will not grow. It has been estimated that many of the micororganisms present in cleanrooms will not grow using the conventional methods. These are termed the viable but nonculturable (VBNCs) organisms.

These same issues also affect in-process bioburden monitoring, used to measure contamination build-up in process areas, even with end-product sterility tests. There are, however, things that can be done to improve detection. With settle plates, it is important that the plates are tested to show that after exposure, due to the inevitable weight loss from drying out, they can still grow microorganisms. With contact plates used on surfaces, these plates should contain neutralizers to ensure that any residues from cleaning agents do not mask any microorganisms present. With swabs, the method will always be limited. However, there are new types on the marketplace that give better recoveries. Finally, with active air-samplers, tests should be conducted to show that the sampler does not disrupt the air-flow, especially at ISO Class 5.

The use of risk assessment and putting together a well-thought of environmental monitoring plan can also help. Monitoring should be orientated towards the main activities within an area and directed to where product is exposed. Historical data can help to set appropriate monitoring frequencies.

Verjans (Aseptic Technologies): Let’s compare between large particle detection in containers and environmental monitoring. Particle detection is a systematic monitoring that screens all containers. The efficacy of the particle-monitoring process, even if not 100% perfect, is good enough to eliminate all or almost all containers containing a large particle, which is a potential source of embolism for the patient. This approach is not yet feasible with small living organisms and one way to address the contamination risk issue is to have environmental monitoring. This control is essential but presents the disadvantage of being based on samples. For example, contact plates and active air sampling are only targeting one sample of air. Therefore, the probability of detecting bacteria in the processing environment remains low.

It has been estimated that approximately 28 dm of air are in contact with each 2R glass vial (8). Therefore, classical microbial air monitoring systems collecting 1 m of air are only representative of 35 vials. Knowing that a batch may represent few hundreds of thousands of vials, statistical calculation demonstrates that the probability of detecting a CFU during microbial environmental monitoring is much lower than having one or few contaminated vials.

Another aspect is that monitoring is limited in terms of location. Monitoring is usually done at positions where the impact of a contamination may be serious such close to the filling needle, close to the stopper or plunger bowl, or close to the stoppering area. Nevertheless, it is difficult to monitor everything, which hence, leaves room for contamination in an area other than the scrutinized ones.


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