Notes on Annex-1 Part three

Impact of new EU-GMP Annex-1 to manufacture of non-parenteral medicinal products

In 2021 Progress has begun publishing a series of articles on the new EU-GMP Annex-1 (for which consultations started in 2020 and ended in 2021; at this moment the guidance is still in draft). This series examines different aspects of the changes to this important GMP document. The first article focuses on the concept of contamination control strategy and the selection, qualification and validation of disinfectants. The second article discusses the ins and outs of Contamination Control Strategy in more detail, and this article will examine the potential impact of the Annex-1 to the manufacture of non-parenteral / non-sterile medicinal products.

In the new version of the Annex-1 the principles of QRM and the principle of Contamination Control Strategy are introduced as required parts of the Pharmaceutical Quality System. Another major change concerns the scope of the document. Whereas in the past non-parenteral products appeared to be entirely excluded from the scope of the Annex-1, in the updated document non-parenteral products are explicitly included, especially when contamination poses a serious risk. Therefore not only manufacturers of sterile products, but also producers of non-parenteral medicinal products will have to adhere to the principles and requirements as listed in the new Annex-1.

In the previous versions of Annex-1 emphasis was completely on the production of sterile products, and only non-aseptic process steps related to the manufacture of precursors of the sterile product were discussed. Production of non-parenteral / non-sterile products was not mentioned and hence all requirements concerning cleanrooms, personnel gowning, training and other information that could be of interest to all manufacturers of medicinal products was not considered mandatory for non-parenteral products, which left a gap and a large grey area in the EU-GMP guidelines.

With the new Annex-1 this gap has been resolved and non-sterile products are explicitly included. In particular products prone to contamination and for which low levels of bioburden are considered critical should be assessed on  applicability of Annex-1 principles. There is now a reference to requirements and measures for non-parenteral products, to ensure a low, acceptable level of microbial contamination. Manufacturers of non-parenteral medicinal products can also expect to face inspections focusing on the requirements as laid down in annex-1.

Previously the control of potential microbial contamination for non-parenteral products was discussed in other parts of the EU-GMP, although mostly in very limited terms and without clear reference to requirements such as qualified cleanrooms, personnel gowning, etcetera. It was therefore left to the good intentions and compliance aspirations of the manufacturers to decide how to implement cleanroom controls, personnel training, gowning and validation. However, in the new version of Annex-1 the control of potential microbial contamination for non-parenteral products is included in the scope and in the specific guidance instructions.

The timing of the EU-GMP to rewrite the Annex-1 is not unique; recently also the US FDA have issued a Guidance for Industry on ensuring microbiological quality for non-sterile products (FDA; Microbiological Quality Considerations in Non-Sterile Drug Manufacturing; September 2021). The FDA guide discusses considerations with regard to product development, risk assessments, manufacturing process design and analytics. Like the new Annex-1, it emphasizes the use of a risk-based approach, the prevention of contamination, and the execution of risk assessments in order to ensure the safety, quality, identity, purity and efficacy of medicinal products. The FDA has explicitly stated that this document was issued as a reaction to reports of adverse events and observed non-compliances during FDA inspections.

Principles discussed in the new Annex-1 for manufacture of non-sterile products
In the scope of the revised Annex-1 it is stated that the primary purpose of the document is to provide guidance for the manufacture of sterile products, but it also indicates that the document should be considered by manufacturers of non-sterile products, especially if it concerns products for which control and reduction of microbial, particulate and pyrogen contamination is deemed important. From a patient safety point of view this should encompass all medicinal products. Principles and guidance specifically referred to in this respect include the use of risk assessments, the design of premisses, cleanroom classification and qualification, cleaning and disinfection validation, as well as environmental monitoring and personnel gowning. All these aspects converge in the requirement to have an effective Contamination Control Strategy in place.

There is a clear expectation for a formal, risk-based, holistic Contamination Control Strategy (CCS) to minimise contamination risks. In the past, parts of such a risk-based control strategy were already expected to be in place, but requirements for CCS were not clearly stated in the guidelines and the concept was not discussed in the all-encompassing manner it is now. It is highly advisable to study and apply these concepts well before the new Annex-1 becomes effective. Progress can help you in defining, setting up and executing new policies and procedures.

At minimum the CCS should cover all processes and process steps where (very) low levels of microbial, pyrogenic and particulate contamination are required to ensure the safety, quality, identity, purity and efficacy of the manufactured products. The CCS should address facility design, cleanroom classification and personnel gowning. There should also be a program for risk assessment of all factors that could contribute to contamination, including risk-based procedural measures to limit the chance of contamination, an environmental monitoring program, and testing of raw materials, intermediates and products for the presence of particulate or microbiological contamination. This does not mean that there should be no contamination present in the non-parenteral / non-sterile products, but bioburden levels in the materials and products should be under control and preferably as low as possible. Special attention should be paid to the potential presence of micro-organisms considered objectionable.

The notion that products may contain a low level of contamination puts even more emphasis on proper risk assessments than for sterile products. A proper risk assessment requires a multi-disciplinary team, who should be knowledgeable about the execution of risk assessments and on the product and processes in question, in order to understand all potential risks. All evaluations / risk assessments performed for the CCS shall be properly documented. For non-sterile products at least the following points should be evaluated on potential contamination risks:

  • Facility design, qualification and validation,
  • Process design, qualification, validation and monitoring,
  • Personnel behaviour and gowning, training and qualification,
  • Equipment and Utility Systems management; design, maintenance, calibration and qualification,
  • Raw materials / components and their suppliers; selection, qualification and control,
  • Cleaning and Disinfection processes; design, qualification and validation,
  • Environmental monitoring system; design, qualification, validation and evaluation.

Include all processes and process steps where (very) low levels of microbial, pyrogenic and particulate contamination are deemed necessary, and list all process steps where contamination could occur. Identify, justify and document the critical process steps, critical process parameters and the related critical attributes of the resulting products.

What does this mean for the manufacture of non-sterile products?
Anyone involved in the manufacture of non-sterile medicinal products, or planning to manufacture such products, should carefully consider the nature of their products. Are these products considered non-sterile but potentially susceptible to contamination, and should there be controls in place to support safe and consistent manufacture to ensure a sufficient level of control on microbial, particulate and pyrogen contamination? If the products in question meet these criteria it is highly advisable to apply the principles of Annex-1 and begin conducting risk evaluations of the above-mentioned areas.

What to do:

  • Establish a risk-based Contamination Control Strategy spanning all facilities and activities. The CCS should cover all successively linked events and procedural instructions that define the critical control points for the facilities and processes, monitor such controls and evaluate their effectiveness to manage the risks associated with any form of potential contamination of the manufactured products, from raw material up to the distribution of the final product.
  • Use risk evaluation techniques as defined in the current version of ICH Q9 (Quality Risk Management) and evaluate in detail the risks to, or posed by the facility, equipment, utilities, personnel, materials and operations with impact to your products in order to define and implement a suitable CCS.
  • Identify, evaluate, reduce, eliminate and control the defined contamination risks. Define critical control points to mitigate such risks and assess the effectiveness of the controls (design, procedural, technical and organisational) and monitoring measures in place to manage risks associated with potential contamination.
  • Ensure the CCS is maintained and actively updated. The CCS should drive continuous improvement of the manufacturing and control methods, and it should contain robust explanations or rationales for the acceptance of residual risks.
  • Ensure that the CCS properly explains where and how the principles of Annex-1 have been applied, and ensure that compliance with those principles is consistently demonstrated. This acknowledgement of compliance can be included in the Product Quality Reviews and / or the Annual Management Review for the facility in question. Please note that based on the outcomes of such reviews your CCS may require attention and updating; it is a living document.
  • Ensure that production is carried out in appropriately clean areas that meet the requirements as discussed in Annex-1. In general, validated and well maintained Grade D and C cleanrooms will suffice for the manufacture of non-sterile products. Regular environmental monitoring by means of qualified monitoring processes and regular evaluation of monitoring results are required to ensure continuous verification of the validated state of monitored areas. Also a procedure should be in place to follow in case the cleanroom ventilation is out of order.
  • Ensure that personnel is knowledgeable of the products, processes, engineering, equipment and the policies and procedures of the Quality System. Implement training in hygiene and proper cleaning, disinfection and gowning practices and ensure training is refreshed regularly. The training of personnel in the ins and outs of the CCS should be a continuous effort.
  • Ensure that the manufacturing processes are designed with potential contamination risks in mind and that the processes are properly qualified, maintained and validated. Perform process monitoring and regularly evaluate the results.
  • Design and validate suitable programs and procedures for cleaning and disinfection. Their efficacy should be verified by means of appropriate validation studies.
  • Ensure that all process equipment and utility systems are fit for purpose, well maintained, regularly calibrated, properly qualified and validated where necessary. Ensure that the qualified / validated state is maintained throughout the lifecycle.
  • Ensure that all materials and components used in the manufacture of products are selected based on pre-defined criteria, and that the materials and components and their suppliers are properly qualified. Also ensure that the quality of each batch of materials and components is well controlled and that the qualified state of the materials is maintained throughout the lifecycle of the product.

As discussed, a new version of the EU-GMP Annex-1 is currently in review and is expected to become effective relatively soon. This new version of the Annex-1 contains several important changes. One crucial difference compared to previous versions is that the production of non-parenteral products is now included in the scope of the document. And another important change is that an active Contamination Control Strategy will be expected for all manufacturing facilities and processes.

Progress can help you in all aspects of assessing your operations, and developing a suitable CCS for both Active Pharmaceutical Ingredients and Medicinal Products vulnerable to contamination. Progress consultants can help you assess the situation, perform risk assessments, perform critical control point assessments and develop and execute a suitable Contamination Control Strategy.