Manufacturing B
y definition, a sterile product is sterile if it doesn’t contain more than the defined limits for bacterial endotoxins and/or pyrogens, and if it is free of visible particles. To ensure this level of sterility, the manufacture of pharmaceutical products, and more precisely sterile preparations, is subject to special requirements by different regulations. This includes pharmacopoeias – collections of standards and quality specifications that apply to specific countries or regions – as well as guidelines that relate to Good Manufacturing Practices (GMPs).
Having published draft versions of European Commission GMP Annex 1 for Manufacturing of Sterile Products, the pharmaceutical industry is currently focused on a key principle of the sterility best practices for the manufacture of sterile products: Contamination Control Strategy (CCS).
Is CCS a new paradigm? Yes and No. No because for the pharmaceutical industry contamination control is a key driver for the manufacture of sterile products with the objective of minimising contamination risks from microbial, pyrogen and particles sources. Yes, because contamination control should not be considered individually for each element (For example, process, premises, equipment, personnel, raw materials, components) but collectively – which is what appears to be happening now. CCS as a concept is about holistically considering all potential risks of contaminations in order to do the right thing the first time for your product and your process. One example of taking a holistic approach is the frequency of environmental monitoring, which must be more frequent for open processes and less so for closed processes. Another example is seen with sterilisation or decontamination, with sterilisation carried out for all product contact surfaces and decontamination carried out for other surfaces to prevent the transmission of microbes from surface to product.
An effective CCS should include the following elements: personnel knowledge; the quality culture and pharmaceutical quality system; contamination controls; validation of controls and monitoring of controls. An effective CCS should be in continuous improvement mode, applying a life cycle approach with a periodical review with changes implemented as necessary.
Main sources of potential contamination
The development of the CCS requires access to all technical details and the assurance that personnel involved in this programme will have the necessary knowledge and information concerning the process and the product. This is in order to evaluate the potential sources and risks of microbial, pyrogen and
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particulate contaminations. For microbes, the main source of contamination is humans, which account for about 80% of all contaminations. The other contributing factors include the environment in which products are manufactured, water used in the process and raw materials.
Pyrogens, including bacterial endotoxins, are substances that can cause fever in humans. Bacterial endotoxins are lipopolysaccharides produced by gram-negative bacteria, generally waterborne microorganisms such as Escherichia coli. These microorganisms are known to generate biofilms. Concerning particulate contamination, particles can be visible if their size is at least 50µm, or sub- visible particles if they are unable to be observed by the naked eye.
Particles exist in huge diversity; they can be classifi ed in the three following categories according to their sources, characterisation, and properties: ■ Extrinsic particles are particles that are foreign to the manufacturing processes and could involve high risks for sterility of the manufactured products.
■ Intrinsic particles may come from the manufacturing process including production equipment and primary packaging materials.
■ Inherent particles are particles related to the dosage form of the product and may be acceptable when their presence is measured, characterised, and determined to be part of the clinical profi le.
Barriers and isolators
The manufacture of sterile products should be carried out in an appropriate environment that ensures the absence of microbes, endotoxins/pyrogens and particulates risk for the process, the products and the patient. That is why the pharmaceutical industry has, since the past decade, moved to switch from conventional clean rooms to barrier technologies that include the use of isolators to secure the environmental conditions of manufacturing sterile products, and specifically those that cannot be terminally sterilised. Isolator technology is designed to avoid and prevent the ingress of contamination from the surrounding environment, including the absence of direct contact of the operators to the inside isolator barrier (Grade A zone).
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A representation of the holistic Contamination Control Strategy.
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