The impact of GMP Annex 1 changes and the role of single-use technology

The European Commission's revision of its Good Manufacturing Practices (GMP) Annex 1 for sterile drug products will have implications for pharmaceutical companies that market their sterile drug products in the EU, whether manufactured in the U.S. or elsewhere in the world. The revised Annex 1 was released last year after 14 years of development and will take effect on August 25, 2023, except for section on 8.123 on lyophilizer sterilization which will take effect 12 months later.

The revision includes changes in several areas of pharmaceutical manufacturing, including risk management, personal hygiene, environmental monitoring, and sterility assurance. It harmonizes sterile drug manufacturing principles with those of the World Health Organization (WHO) and Pharmaceutical Inspection Cooperation Scheme (PIC/S) standards of sterile drug manufacturing, as well as better aligning with the US Food and Drug Administration’s (FDA) 2004 guidance on sterile drug products manufactured by aseptic processing. The changes include a new section on pharmaceutical quality systems, which incorporates the principles of quality risk management (QRM) into sterile drug manufacturing; a new section addressing the concept of a contamination control strategy (CCS) in reducing contamination; and sections which incorporate recent advances in sterile processing technology in manufacturing, such as restricted access barrier systems (RABS) and isolators.

This focus on contamination control and sterile processing technologies means there is likely to be an increase in demand for plug and play solutions that enable manufacturers to meet the new requirements with minimal effort. We sat down with Watson-Marlow’s Claire Hutchison and Nicole Hunter to get their perspective on the role of single-use systems in satisfying GMP demands.

1. How will the proposed changes impact pharmaceutical companies that manufacture sterile products and will they require significant investment?

Nicole Hunter:

The pharmaceutical industry has changed dramatically in the 14 years since the last revision of the GMP guidelines and the rise of novel biologic therapies has outgrown existing GMP requirements. Many pharmaceutical companies will have therefore worked closely with regulators to put their own safety and contamination control measures in place. These new GMP revisions stem from extensive consultation with regulators and industry, so while companies will need to ensure that their processes are compliant, many will already meet these needs or only require minimal amends.

Perhaps the most widely discussed novel requirement in the new Annex 1 is Pre-Use Post-Sterilisation Integrity Testing (PUPSIT). Many biopharma manufacturers are already adding PUPSIT testing capability to existing production lines and incorporating PUPSIT in their designs for new production lines in preparation for this.

Another big change with the introduction of the new Annex I is that pharma companies will be required to have a documented CCS implemented across their facilities. The CCS must consider all aspects of contamination control and its life cycle with ongoing review resulting in documented updates within the quality system. The new requirements encourage the implementation of innovative sterile manufacturing technologies.

Claire Hutchison: For those developing new manufacturing processes or needing to update their systems in order to achieve compliance, there are standardized solutions already available on the market that can be easily integrated into manufacturing lines to facilitate the process. Pre-validated, GMP compliant single-use assemblies offer an ideal solution that can be designed for bespoke manufacturing needs and supplied fully irradiated with a sterility assurance claim. These plug and play systems are ideal to accelerate set up and change over to increase productivity, making use of single-use technology in accordance with regulatory guidelines in order to mitigate risk.

2. Will the changes affect the release of new drug products in the European Union and will they impact ongoing clinical trials or marketing authorisation applications?

Claire Hutchison: These changes may impact the release of new drug products and ongoing clinical trials or marketing authorisation applications in a number of ways.

Firstly, the revised GMP Annex 1 includes new requirements related to the manufacture of sterile medicinal products, which may impact the design of manufacturing processes and the validation of new products. This could result in longer lead times for the development and approval of new drug products.

Secondly, the changes may require pharmaceutical manufacturers to modify their existing manufacturing processes or equipment, which could impact ongoing clinical trials or marketing authorisation applications. If a manufacturer needs to modify their manufacturing process during an ongoing clinical trial, it may require the trial to be put on hold until the changes are implemented and validated.

Lastly, the revised GMP Annex 1 places greater emphasis on risk management and environmental monitoring, which may require more extensive testing and documentation. Regulatory authorities may need additional time to review the documentation and ensure compliance with the new requirements, potentially resulting in longer lead times for the approval of marketing authorisation applications.

Overall, the specific impact will depend on the individual circumstances of each product and application. It is important for pharmaceutical manufacturers and sponsors to carefully review the new requirements and assess the impact on their processes and timelines.

3. What impact will this have on the cost of pharmaceutical products, and will they result in changes to pricing or reimbursement policies?

Nicole Hunter: It is difficult to predict with certainty how the changes in the 2022 GMP Annex 1 will impact the cost of pharmaceutical products, as it will depend on various factors such as the type of product, the manufacturing processes involved, and the extent of the changes required to meet the new requirements.

However, it is likely that implementation will require investment in new equipment, technology, and personnel training, which could increase production costs. Additionally, the increased focus on risk management and environmental monitoring may require more rigorous testing and monitoring procedures, which could also contribute to higher costs.

Whether or not these increased costs will result in changes to pricing or reimbursement policies will depend on differences between regions, the competitive landscape of the market, and the willingness of payers to increase reimbursement.

4. What steps can pharmaceutical professionals take to prepare for the implementation of the changes to Annex 1, and what resources are available to support their efforts?

Claire Hutchison: To prepare for the implementation of these changes, pharmaceutical professionals can take several steps:

1. Familiarize: Take the time to review the revised GMP Annex 1 carefully and understand the changes it contains.
2. Conduct a gap analysis: Identify any areas where current processes and procedures may not align with the new requirements. This will help identify any necessary changes that need to be made before the implementation deadline.
3. Develop a plan for implementation: This plan should include timelines, resources required, and responsibilities for each task.
4. Train personnel: All personnel involved in manufacturing processes need to be made aware of the changes in the revised GMP Annex 1 and trained on the new requirements and minimize the risk of non-compliance.
5. Consider technology and collaborations: The use of new technology or the modification of existing technology may be required. Pharmaceutical professionals should ensure that any necessary changes are made to manufacturing processes.
6. Think about the complete supply chain: Assessment of suppliers is critical to compliance. For sterile single use systems, verification of sterility assurance should be performed as part of the supplier qualification process and evidence of sterilisation should be checked on receipt.
7. Conduct regular audits: Regular audits will ensure ongoing compliance and help identify any issues early to allow for corrective actions to be taken before they become major problems.

“Assessment of suppliers of disposable systems including sterilization is critical to the selection and use of these systems. For sterile SUS, verification of sterility assurance should be performed as part of the supplier qualification and evidence of sterilization of each unit should be checked on receipt.”

Annex 1

5. How will these changes affect the supply chain for pharmaceutical products and how can we mitigate against any disruptions?

Nicole Hunter: As with any changes to manufacturing systems, new supply chains may be needed which may introduce delays in the production process. With less than six months left to implement these changes, new suppliers will need to demonstrate that their supply chains can withstand this demand. But these changes may also provide opportunities for manufacturers to rationalize and refine their supply chains.

Claire Hutchison: Incorporating pre-assembled single-use products can result in a reduction of the number of items required and a simplified supply chain compared to ordering components separately and assembling in-house. This reduces inventory and facilitates the ordering process for manufacturers. It can also lead to a reduction in waste as the manufacturer only orders the assemblies they need rather than additional lengths of tubing or other components. Waste reduction brings cost benefits as well as being an important component of companies’ sustainability goals.

Dr Nicole Hunter is the Head of Global Regulatory & Validation Services at Watson-Marlow Fluid Technology Solutions (WMFTS). Prior to joining Watson Marlow, Nicole held the position of R&D Manager at Thermofisher Scientific leading a team of chemists and microbiologists developing in vitro diagnostic devices. Her PhD in the area of pharmaceutical materials science was undertaken at the University of East Anglia, UK. Nicole also has pharmaceutical industry experience gained from working in the Drug Discovery department of Pfizer Animal Health. She is an active member of several industry working groups and committees including Biophorum, BPSA, ISO and BSI.

Claire Hutchison is a highly experienced Life Science Sector Specialist for Watson-Marlow Fluid Technology Solutions. With an honors degree in Biomedical Science and over 10 years in the industry, Claire has developed a deep understanding of the complex requirements of the industry. Claire began her career in the clinical trials field, where she developed expertise in manufacturing autologous cell therapy treatments for cancer. She then moved into vaccine manufacturing, where she gained valuable experience in vaccine production processes and quality control. Transitioning into biosafety testing, she performed a wide range of in vitro testing while developing her understanding of safety and regulatory compliance in the industry. Throughout her career, Claire has also focused on the validation of quality management systems and is passionate about developing solutions that improve efficiency, quality, and safety in the life sciences sector.