This article is based on a presentation given at a recent Engineers Ireland seminar on biopharmaceuticals in Ireland, ‘A Global Perspective: Facility Design, Trends & Positioning for Growth’. It will outline the importance of process closure in biopharmaceutical production and how to undertake a risk assessment, process closure analysis, to support both a process design and operational procedures.
Before examining process closure, one must understand the importance of bioburden control in biopharmaceutical manufacture.
Biological systems operate in aqueous-based environments at ambient temperatures and pressures and therefore are often unstable to solvents and extremes of pH or temperature. Biological molecules are a food source for microbes and the processing conditions are generally ideal for microbial growth. Thus, biological medicinal products are susceptible to microbial contamination.
If a process or product becomes contaminated with microorganisms, the ensuing microbial growth may destroy the product and/or produce metabolic by-products which will not be removed by subsequent processing and could be toxic to the patient. Thus, bioburden control of biopharmaceutical processes is of paramount importance.
This control is achieved by ensuring that the process equipment is clean and sanitary before processing starts, controlling the bioburden of all process contact raw materials and utilities, including in-process bioburden reduction steps (primarily filtration) where required, and then ensuring contact between the process and the environment is minimised to prevent adventitious contamination.
In order to have bioburden control, one needs bioburden limits and specifications. Bioburden limits are set by the requirements of the product and the ability of the process to remove or inactivate bioburden.
In most biopharmaceutical processes, the final drug product will be sterile and impact of bioburden contamination of the process will be significant. Whilst the bulk drug substance (or active pharmaceutical ingredient (API)) will be defined as ‘low bioburden’ there is, in reality, zero tolerance of bioburden contamination.
In terms of the process requirements for bioburden specifications, the upstream process (fermentation or cell culture) will be axenic (free from living organisms other than the species required), with bioburden free media and additives, with the subsequent process steps, and associated solutions, defined as low bioburden.
In order to prevent microbial contamination of the process, the equipment must be sanitary (free from contamination) and the process protected from adventitious environmental contamination. Therefore, it is necessary to: