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 :Can you identify recent advances in process analytical technology (PAT) or other analytical testing methods (such as rapid microbial testing) that can help improve testing for microbial control.

Agalloco (Agalloco & Associates): We have exhausted the current technologies for confirmation of classical environmental controls for aseptic processing. New technologies with the ability to detect in near real-time the presence of viable microorganism’s are becoming available. These technologies have promise, but the concern I have with respect to their use is that while they will detect what cannot be detected using the classical practices, they will confirm the presence of viable microorganisms at a lower level of sensitivity. That is not necessarily good, in that it may result in higher expectations for even better control of environmental controls. The sterile products we manufacture are certainly safe at the microbial levels that we have already established. We do not need ‘sterile’ environments for the manufacture of aseptic products, and striving to do so will result in substantially increased cost without any meaningful improvement in patient safety.

Sandle (Bio Products Laboratory): Rapid microbiological methods are being developed in earnest by most of the major vendors, although adoption by the pharma industry remains slow, but I suspect that will change over the next five years. In relation to PAT, measuring critical process parameters during manufacturing, as well as current quality risk management and spectrophotometric methods look very promising. There is essentially a development of the particle counter, where air is drawn in through an instrument and passed through a laser. The instrument software is able to differentiate the particle size and to count the number of particles.

Other advances with rapid methods are focused on the time-to-result. Most cultural based methods require incubation times of five-to-seven days. Technology has been developed for testing process water. One system uses an ATP-releasing reagent, added to microbial cells, followed by the addition of luciferin and luciferase. The system then scans for fluorescence.

With in-process bioburden, there is a method which uses digital imaging technology to automatically enumerate micro-colonies. This method has cut the time-to-result down by half. An alternative is quantitative real time polymerase chain reaction (qPCR), which allows amplified microbial DNA to be detected as the reaction progresses in real time. However, there is concern whether the methods can detect a wide range of microorganisms, especially when they are bound to the product.

Other areas have centered on accuracy, most notably with microbial identification methods. Knowing the correct ID is important for corrective and preventive action (CAPA) investigations. For me, the most exciting developments here are with MALDI-TOF, which is almost instantaneous, and the genotypic methods that can pin-point different strains. With each method, there are difficulties with validation, cost, and in gaining regulatory acceptance. Nevertheless, the case for implementation will soon be sufficiently strong and I'm sure we will see many of these methods in place five to ten years from now.

Verjans (Aseptic Technologies): PAT is defined as mechanisms to design, analyze, and control manufacturing process by measuring critical process parameters. It can be separated into three categories: PAT on the environment, PAT on the quality, and PAT on the equipment operation. All three have their own importance and may contribute to the quality of the product.

PAT on the environment allows release of the production in a timely manner and minimize risk of missing a deviation. For example, a particle counter may be connected to the filling equipment and may dispense a warning signal when exceeding an alert level or an action level. With appropriate procedure, the operator may act to correct the issue if possible, or he may interrupt the production of the batch if the problem cannot be solved without being disruptive. The value of such rapid information is increasing with the price of the product because it reduces the risk of batch rejection thanks to correction of a deviation.

PAT on particle monitoring can be easily standardized. PAT on viable monitoring is more complex as most of approved methodologies are based on bacterial growth. Nevertheless, a new technology emerged recently, combining viable monitoring and total particle monitoring. This technology combines classical particle count with laser-induced fluorescence and therefore detects all particles that contains excitable molecules such as nicotinamide adenine dinucleotide (NADH) and riboflavines. These molecules are characteristic of living organisms so this technology is able to detect in real time the presence of a living particle (10).

PAT on product quality relies on container inspection. Besides the classical particle count, new technologies include vacuum testing, high-voltage testing, and headspace analysis (to detect e.g., lack of closure integrity, poor nitrogen flush, or inappropriate lyophilization).

PAT on equipment operation allows the elimination of badly/poorly processed containers. One of the PAT processes that has been used for long is weight measurement. What is changing in recent years for weight measurement is the move from sample measurement to 100% measurement, even on machines with high-speed production.

Other more sophisticated PAT on equipment operation are emerging in parallel with new processing technologies. For example, in the case of the closed-vial technology, the container-closure integrity is ensured by laser re-sealing of the piercing trace left by the needle in the stopper. To ensure that the laser is effective, all the vials are checked for laser shot, both in terms of shot time and shot intensity. This measurement process is directly coupled with the automation system, leading to automatic reject of containers with laser beam out of specification. By optimizing PAT, the pharmaceutical industry improves its capability to ensure that only well-processed containers are released for use to the patient.


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