Cleanroom Technology: Contamination Control of Sterile Medicinal Products

Patrick Nieuwenhuizen, Director Senior Consultant, PharmaLex

The manufacturing of medicinal products brings many challenges when it comes to control of contamination. Contamination can present itself as chemical, microbial, particulate or product cross-contamination. Medicinal products such as parenteral, ophthalmic and some inhalation preparations are required to be sterile, i.e., entirely free from undesired living organisms of all types or their by-products. This article delves into contamination control from a microbiological perspective.

When a pharmaceutical product reaches Clinical Phase I, the pharmaceutical product is administered to humans. Therefore, current Good Manufacturing Practice (cGMP) compliance is mandatory as set out by regulatory bodies such as the European Medicines Agency (EMA) according to the EudraLex, and the US Food and Drug Administration (FDA) Code of Federal Regulations (CFR) part 210 and 211.

From this phase of the product lifecycle, a holistic view of the entire product and its manufacturing process, including Quality Control and Quality Assurance processes, must be taken with the objective of achieving a high level of proactive contamination control.

Contamination control is the primary aim of pharmaceutical microbiology. This includes the control of microbiological contamination throughout manufacturing systems, environment, utilities and, finally, the pharmaceutical product itself. As per the regulations, terminal sterilization of medicinal products in their final container is the preferred option, where possible, as it gives the highest level of assurance that a product is free from viable microorganisms. In some cases, this is an option for small-molecule products. However, because of the heat labile nature of many medicinal products, particularly for large molecules or “biologics” this is not an option. Hence, the manufacture of these products has specific requirements to minimize the risk of microbiological contamination, i.e., aseptic processing.

As pharmaceutical manufacturing generally comprises of complex and multi-step processes, it is important to understand which sources increase contamination risk. Sources of contamination include raw materials, personnel, equipment and utilities, the manufacturing environment, and container closures to name a few. Biologics come with additional challenges as the molecules are protein based and far less stable than small molecules.

"Contamination control is the primary aim of pharmaceutical microbiology. This includes the control of microbiological contamination throughout manufacturing systems, environment, utilities and, finally, the pharmaceutical product itself"

Prevention of contamination is more important than detection and removal; therefore, establishment of a contamination control strategy (CCS) based on the principles of Quality Risk Management (QRM) should be implemented to protect the product. Quality Risk Management is imperative in obtaining and maintaining a good understanding of the process and its challenges. Internationally, it is well recognized that an effective QRM approach can ensure the high quality of the drug product to the patient by providing a proactive means to identify and control potential quality issues during manufacture.

Several questions must be considered to understand the key elements required in order to meet the quality system requirements detailed in ICHQ10 in addition to ICHQ9 and EudraLex Volume 4 Annex 1 for a CCS.

• What points need to be considered to support the implementation of such a program within any manufacturing facility?

• What makes it robust?

• Should it be multifaceted to ensure its effectiveness? When assessing the risk of microbial contamination, the additional important questions should be considered:

• What are potential contamination ingress points?

• Can micro-organisms proliferate?

• Process removal or reduction points of micro-organisms and their by-products, for example endotoxins?

• Contamination history?

Using the historical data and information gathered throughout the manufacturing life cycle, knowledge can be obtained about these processes and systems and their performance. The design and management of the manufacturing environment, utilities and production process itself are important aspects in the contamination control strategy for a pharmaceutical product. Information and data gathered allows for identification of design flaws or short comings, equipment vulnerabilities or practices that could pose a contamination risk, which allows identification of proposals for control measures and process improvements that enhance the overall control of contamination. The Contamination Control Risk Assessment and the associated strategy provides an opportunity to assess if the current process design still meets regulatory expectations and highlights the most critical or urgent issues to be addressed. The disparity between the perceived level of control and the reality of their robustness when involved in a comprehensive risk review process can be surprising and this disparity can emphasise the need for objective definitions for the appropriate level of contamination control. For stakeholders and decision makers, a robust CCS program presents scientific justification for investments to be made in selected areas and allows for a structured remediation plan where necessary. Such a plan can include interim control measures to reduce existing risks before longer-term solutions can be implemented. For regulators, the CCS demonstrates the level of understanding an organisation has of their manufacturing process and associated vulnerabilities This provides the company with an opportunity to present a robust and risk-based remediation plan to address any identified vulnerabilities.

It is not uncommon within companies to see contamination control documents scattered and disjointed across the system resulting in information and knowledge being siloed and thus preventing a holistic approach. A well-developed contamination control strategy brings all these individual elements together in one overarching document, summarizing all control practices and their rationales in one place. It provides visibility as to where various parts are supporting or augmenting each other, or where the potential gaps are that require remediation to reduce identified risks. A well-established CCS does not rely on a single point of failure but has redundant elements in place as back-up.

In the end, contamination control is not a single item, but an amalgamation of various elements that together determine the effectiveness of the program as a whole.

Contamination control is a continuous process in which data trends, product information and new regulatory requirements are to be evaluated on an ongoing basis. Based on the information gathered it must be determined if the current microbiological aspects associated with the manufacturing of a product are still adequate to guarantee quality, safety and efficacy of the medicine or if adjustment is required.