Achieving Zero Particulates In Parenteral Manufacturing: What Needs To Be Done?
By Jahanvi (Janie) Miller, PDA
There are numerous novel types of medications on the market today. As many of these are parenteral products, concerns with particulate matter typically associated with these types of products have also increased.
In relation to particulate matter, size does matter. The particulate matter you can easily see has a higher likelihood of being intercepted during visual inspection procedures. It’s the particulate matter you can’t detect during inspection processes that can cause potential risk to patients. Particulate matter has also become a growing concern given the fact that there are better inspection processes, both automated and manual, which allow the industry to better identify product contaminated with particulate matter. This, coupled with increasingly stringent requirements, leads to a very challenging goal for industry overall in achieving zero particulates in parenteral product.
There is an expectation to not only reduce particles, but also to control them, including those that fall within the subvisible category. The ability to identify the source of particulate matter contaminants can potentially support the industry in its efforts to reduce particulate contamination. Pharmaceutical manufacturers, suppliers, and regulators are expected to produce safe and effective injectable drug products. Particle detection and identification are significant parts of regulatory compliance and product quality assurance.
In a short four-year time frame (2008 to 2012), 22 percent of recalls for injectable products were due to visible particles, according to the FDA. Manufacturers are being extremely vigilant in the release and recall of their products in hopes of reducing the release of products that may cause potential risks due to visible particulates. The amplified vigilance has the potential to cause drug shortage issues. This necessitates the production of injectable pharmaceuticals to the highest standards of quality and purity, including being essentially free of extraneous matter such as particles; however, this is not very feasible given current industry practices.
Current State Of Industry
The pharmacopeias provide standards for manufacturing pharmaceutical products and guidance on sourcing of particles in relation to their risk; however, processes still tend to vary across manufacturers. Variances in product rejection can be due to the differences in processes, as opposed to the overall quality of the product. A common understanding of the manufacturing process and where particles could potentially be introduced into the product is important in assessing the overall risk to the sterility of the product.
Manufacturers are instructed to take a life cycle approach to understanding where particles may be generated, detected, and removed in a production process. Identification of defects at the time of manufacture can provide valuable insights into the overall understanding of particle generation and subsequent mitigation to reduce the level of particles in products. Even though the primary endeavor for manufacturers is to produce injectable products within the required standards to ensure their safe and effective use, the lack of consistency in manufacturing processes can impede this effort.
Multiple considerations need to be taken into account if companies are to manufacture particle-free injectable pharmaceuticals. As noted in the PDA 2015 Visual Inspection Survey, of the companies surveyed, 60 percent classify glass particles as “Critical.” The shift to a Critical classification for particles is likely due to regulatory pressure, but this may not be exactly aligned with the new pharmacopeia. A consensus is needed on how particles are classified based on their size, type, and quantity present so that risk is being assessed in a uniform manner for those factors.
Alignment of manufacturing processes, visual inspection methods, and risk assessment approaches is also critical since there can be variations in all those aspects within multiple sites of a single organization. The lack of harmonization among terminology, along with detailed specifications within the relevant guidance and regulatory requirements, also continues to challenge the industry. The regulations provide guidance, but not exact specifications, for setting acceptance criteria for injectable products and the primary packaging used in their preparation.
This circumstance, coupled with the normal variability of manual processes of visual inspection, has led to a wide range of methods and limits applied to particles in injectable drug products. A shift to uniform approaches could potentially increase the feasibility of products being manufactured essentially free of particulate matter.
Aspects such as the inspector’s visual acuity and the potential for fatigue make visual inspection a very subjective process. Detection and removal of all particulate matter is not an achievable target for pharmaceutical manufacturers. The considerable differences in manufacturing processes, inspection practices, and assessments across the industry and within organizations don’t allow for this level of detection. Even with the best inspection technology/processes, such an outcome would be an unrealistic feat in the current industry environment.
Although there have been significant improvements in compendial guidance, it can still be unclear where specification details are needed, which creates challenges for pharmaceutical manufacturers. Limits should be practical, based on patient risk and process capability. Collaboration and open communication channels between pharmaceutical manufacturers, suppliers, and regulatory agencies will help the parenteral manufacturing industry get closer to reaching the goal of zero particulates.
About The Author:
Janie Miller is the staff liaison to the Science Advisory Board from the Science and Regulatory Department within PDA. She works collaboratively with PDA members and governing bodies to facilitate the production of PDA Technical Reports, Points to Consider, and Training Courses. Prior to joining PDA in 2012, Janie was a clinical manager for Otsuka, primarily working on Phase 3 trials for Sativex. From 2006 to 2010, Janie worked at as an account manager for a startup that is now a global consulting firm with offices located in New York, Beijing, and Europe. During her time at Johnson & Johnson from 2002 to 2006, she worked as a researcher developing chemotherapeutics and submitted two publications on those drugs to Science Direct during her time there. Janie received her master’s degree in business management in 2009 and bachelor of science from Drexel University in 2004.