Medicinal quality risk management: A holistic view

Contamination control is a continuous process in which data trends, product information and new regulatory requirements should be evaluated on an ongoing basis. Patrick Nieuwenhuizen from PharmaLex delves into the microbiological perspective

The manufacturing of medicinal products brings its challenges when it comes to control of contamination. When contamination occurs it can present itself as chemical, microbial, particulate or product cross-contamination. This article delves into contamination control from a microbiological perspective.

Microbiological considerations for medicines are far greater from Clinical Phase I onward as it is at this point the pharmaceutical product is administered to humans and current Good Manufacturing Practice (cGMP) compliance is mandatory as set out by the 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.

Potential microbial ingress points or “hot-spots” must be identified

From this stage 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. It includes the control of microbiological contamination of utilities, manufacturing systems & environment and, finally, the pharmaceutical product itself. As pharmaceutical manufacturing generally comprises of complex and multi-step processes, it is important to understand which contamination sources increase risk. These include raw materials, personnel, equipment & utilities, the manufacturing environment, and container closures to name a few.

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. This is not a new concept and has been a regulatory expectation since the revision of EudraLex Volume 4 Part 1 Chapter 5 in 2015. A common misunderstanding is that the requirement for a CCS only applies to aseptic or sterile manufacturing; the publication of the draft text of the EU Annex 1 revision will raise awareness of these regulatory expectations across the industry to all drug manufacturers.

Theory and reality are often not a perfect match

QRM is imperative in obtaining and maintaining a good understanding of the process and its challenges. 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 development and manufacturing.

When assessing the risk of microbial contamination, the following important questions should be considered:

  • What are potential contamination ingress points?
  • Can micro-organisms proliferate?
  • Process removal or reduction points of microorganisms and their by-products, for example endotoxins?
  • Contamination history?

Product and process knowledge play an important role. To fully understand this complexity, strong collaboration between different parties is imperative to acquire a holistic understanding of the product and process.

The design and management of the manufacturing environment, utilities and production process itself are important aspects in the contamination control strategy of a pharmaceutical product.

There are many engineering concepts and technologies available and there is no "one-size-fits-all", it depends on the type of product and manufacturing scale. It would be redundant and a waste of effort and money to put the same design specifications and control measures in place for a non-sterile oral dose product as for a parenteral drug that is manufactured under aseptic conditions and cannot be terminally sterilised.

Map it out

The microbiological contamination risks to a pharmaceutical product are present throughout the entire manufacturing process. To obtain a good understanding of the potential points of ingress, process mapping is an important activity.

High-level flow maps of personnel, (intermediate) products and waste streams in the facility are a useful tool to visualise and identify potential microbial ingress points or "hot-spots" where different process streams cross over each other. These are particularly useful in a multi-product facility where different parts and components are used and mix-up risk of mix-up is greater.

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The same applies for the process-design, by mapping out the various process steps and equipment involved, microbial risk factors can be pinpointed. Physically walking the facility and process with Subject Matter Experts and Operators is of great value as it enables one to see the actual process and supporting activities working and interacting together.

One would be surprised at how often theory and reality are not a perfect match, especially with ageing facilities where changes implemented throughout the years might not always bring the best results from a contamination control perspective! It gives a good opportunity to "recalibrate" the current state and identify potential issues.

A comprehensive in-process sampling and testing plan of the manufacturing environment and utilities is necessary to monitor and control the manufacturing processes and supporting elements. These are not limited to microbiological data as physical data such as temperature, pressure and flow rates also give early indications if the performance of a system is slipping. If set-up correctly, it allows for timely identification of emerging trends and implementation of actions to correct or prevent further deterioration.

Process mapping is an important activity

The worst thing one can do is generate significant amounts of data without knowing or understanding how to use this data to their benefit for improvement.

It is not uncommon within companies to see contamination control documents scattered across the system resulting in information and knowledge being siloed. A well-developed contamination control strategy brings all these individual elements together in one overarching document, summarising 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 that all together determine the effectiveness.

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.

One can design the most sophisticated manufacturing facility with state of the art utilities and process design; however, it is the people element that make these work. Besides all the scientific sound design, the most difficult element to control is the human factor. A comprehensive continuous training and awareness programme is often overlooked but is imperative as part of a contamination control strategy creating a Quality Culture that the company can rely on.