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 equipment design, operation, filtration, or processes that are addressing some of these problems?

Agalloco (Agalloco & Associates): The operational improvements made by increased use of closed RABS and isolators are well known. Increased use of robotics and automation are making aseptic processing safer. Other technologies such as closed-vial filling, gloveless isolators, and single-use systems will further enhance performance of aseptic manufacturing. Understanding the importance of bioburden destruction as opposed to biological indicator destruction would help as well.

Sandle (Bio Products Laboratory): Most of the technologies that we are using have been around for quite a long time. Scientists experimented with heat under pressure to improve food preservation in the mid-19th century, for example. Many other sterilization processes began to be more widely used post-World War II, such as irradiation.

Cleanroom technology did not advance greatly until the late 1990s. This pace of transformation has accelerated more quickly in recent years, notably with barrier technology. Aseptic filling risks have been lowered through the use of isolators and RABS. RABS create a physical and aerodynamic barrier to protect the product, but they are not all enclosing. Isolators are the most effective as they create a complete barrier (isolation) between the products and people. Where isolators can be placed around filling machines, it allows for the entire space to be decontaminated using hydrogen peroxide (either as a vapor or in the ionized state). This approach allows for the sporicidal sanitization of all exposed surfaces. Isolators are not risk free, however, due to issues such as air leakage.

There has been some conceptual changes with cleanroom design, using computer-aided engineering software that can help pinpoint contamination risks. There are also big advancements in the use of risk management, supported by initiatives from regulators such as FDA. Risk assessment tools such as HACCP (hazard analysis and critical control points) have become more common.

Also with cleanrooms, various items of equipment and surfaces are now manufactured with antimicrobial coatings. One example is the incorporation of silver, which is effective against a range of microorganisms, into implements such as forceps. With processing, the most important recent advances have come from single-use disposable technologies. Such technologies have reduced risks by allowing pharma organizations to move away from equipment that need to be sterilized or consumables that are recycled or pose a risk with their transfer into cleanrooms. Single-use items are typically sterilized using gamma rays, which kill microorganisms by destroying cellular nucleic acid.

Examples of single-use systems include aseptic connections for the connection of a vessel or filter to another item of equipment for the transfer of fluid. Here, a big contamination risk is from the hand of the operator; the connector effectively eliminates this risk. Another example relates to disposable bag technologies for holding the product. These technologies have huge potential economic benefits since plastic technology can reduce validation and clean-in-place requirements, lower the requirements for pure water, clean steam, and water for injection (WFI), as well as cut costs (e.g., from reduced set-up times). Other examples include consumables and disposable filling manifolds, each of which reduces the need for operator involvement.

Verjans (Aseptic Technologies): In the last decade, multiple improvements have been introduced to mitigate the risk of contamination. The first one is to improve gowning of operators moving from classical laboratory coats in the fifties to fully gowned operators. The second one is to use filters with extremely good efficacy in retaining living organisms, even the smallest ones and the mobile ones. The quality of these filters is improving regularly. The third one is to separate the operators from the processing area. Processing equipment can now be protected by advanced barriers such as the RABS and the most advanced ones such as the closed RABS and the isolators. The isolators offer complete separation of the processing area from the environment, combined with an automated sanitization system using sporicidal agents, which are usually hydrogen peroxide.

Beside these improvements, there is a new category of improvements that consists of the reduction of exposure to the environment. Reducing the time when a container is open reduces the probability of having a living organism penetrating into the container. The same concept applies to contact of the inside part of the container. For example, a stopper or a plunger being in contact during a significant period of time with a stopper bowl and various ramps may accidentally capture a living organism and bring it inside the container when closing it. Two new technologies that aim to reduce this exposure include:

  • Blow-fill-seal technology, based on the concept of forming the container from heated polymer, filling it immediately after cooling and closing it without involving contact with another product part. The process takes a few seconds, therefore minimizing the probability of entry of living organism.
  • Closed-vial technology, based on the concept of using a closed sterile container. The stopper, instead of being exposed to the environment, is already in place. Filling is done with a needle piercing the stopper and dispensing the liquid. Immediately after these two operations, the container closure integrity is restored by laser re-sealing of the stopper.

These technologies have demonstrated reduction in contamination risks by at least 2 log (100 times) compared to the classical glass vial filling process (8).


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