Microbiological Contamination Control of Non-Sterile Medicinal Products – EMA Q&A

Particularly in relation to the manufacture of non-sterile medicinal products, questions regarding contamination control measures are currently arising with increasing frequency. The available regulatory guidelines do not provide as much detail on the requirements for surveillance measures – such as environmental monitoring – or preventive measures – such as the cleaning and disinfection of production areas – as they do on the manufacture of sterile medicinal products. However, current documents, such as Annex 1 for sterile products, indicate that the principles set out in the Annex can certainly be applied appropriately to the field of non-sterile medicinal products. In particular, the QRM and CCS approaches can be applied to various critical products.

On 13 July, the EMA published a brief Q&A paper entitled ‘What technical and organisational measures should be considered to prevent microbial contamination of non-sterile medicinal products?’, which addresses issues relating to contamination control in non-sterile medicinal products. In addition to questions and answers, the document provides some background information on the issue. The contents are summarised below:

Background

Microbial contamination of non-sterile medicinal products is closely linked to manufacturing processes, in particular to the effectiveness of cleaning and gowning protocols. Even if the product is non-sterile, microbial contamination can pose a significant risk to the product and the patient – for example, through opportunistic or multi-resistant microorganisms. EU GMP Chapter 5, as well as Annex 1 and Annex 15 therefore emphasise the protection of products and starting materials from contamination at all stages of manufacture. These requirements must be implemented by applying quality risk management principles (including those set out in ICH Q9 and Chapters 5.17–5.22 of EU GMP Part 1), with a particular focus on validated cleaning procedures and their complete, traceable documentation.

Technical Measures

The selection of technical measures is based on the results of a systematic quality risk management process.The focus here is on room and equipment design and use, material flow, process characteristics, microbiological controls, and cleaning process design. Manufacturers may refer to the principles of a Contamination Control Strategy (CCS) set out in Annex 1, even in the case of non-sterile products.

Key technical aspects include the management of cleaning agents and solutions (including supplier involvement, expiry dates, and hygienic manufacturing), cleaning validation using suitable microbiological samples from product-contacting parts, and consideration of critical process parameters, such as the drying phase, to prevent residual moisture. In addition, validated methods for microbiological testing must be used for active substances, excipients, water, primary packaging materials, equipment, the environment and the finished product; the suitability of the water used for its intended purpose must be demonstrated. If microbial contamination occurs, validated cleaning and disinfection procedures must be applied and their suitability for the respective intended use must be demonstrated.

Organisational Measures

Organisational measures are also derived from the risk assessment. The focus is on an appropriate gowning protocol – including the use of protective clothing, gloves and face masks during critical activities – as well as, where necessary, the disinfection of gloves before entering critical areas. In addition, the training and regular practical instruction of staff are of central importance, particularly for employees who carry out gowning and cleaning or are involved in critical production steps. These training sessions should teach correct behaviour, hygiene rules and how to deal with critical situations appropriately.

Furthermore, the hygiene and health status of staff must be closely monitored and regularly assessed in order to identify potential sources of contamination at an early stage. Appropriate environmental monitoring ensures that the production premises remain suitable for manufacturing and that there is no risk of uncontrolled contamination. These organisational requirements are set out in EU GMP Chapter 5 and Annex 1 and are implemented as part of an integrated quality and risk management approach.

Further details can be found directly in the EMA Q&A on prevent microbial contamination of non-sterile medicinal products.