Impact of Revisions to Good Manufacturing Practices Annex 1 on Sterile Drug Products

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 US or elsewhere in the world. The changes, which focus on contamination control and sterile processing technologies, mean there is likely to be an increase in demand for plug and play, single use solutions that enable manufacturers to meet the new requirements with minimal effort.

GMP Annex 1 Changes to Pharmaceutical Manufacturing

The revised Annex 1 was released in 2022, after 14 years of development. Most changes took effect in August 2023 with the exception of lyophiliser sterilisation (8.123), which went into effect in August 2024. 

The revision includes changes to risk management, personnel hygiene, environmental monitoring, and sterility assurance rules. The revised rules harmonise sterile drug manufacturing principles with those of the World Health Organization (WHO) and Pharmaceutical Inspection Cooperation Scheme (PIC/S) sterile drug manufacturing standards, and better align with the US Food and Drug Administration’s (FDA’s) 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 that incorporate recent advances in sterile processing technology in manufacturing, such as restricted access barrier systems (RABS) and isolators. 

Impacts on Pharmaceutical Companies that Manufacture Sterile Products

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. As a result, many pharmaceutical companies have already worked closely with regulators to put updated safety and contamination control measures in place – so they may already meet new rules or require only minimal changes to ensure their processes are compliant.

As an example, the most widely discussed novel requirement in the new Annex 1 is pre-use post-sterilisation integrity testing (PUPSIT). Many biopharma manufacturers have already been preparing for this change by adding PUPSIT testing capability to existing production lines and incorporating PUPSIT in their designs for new production lines.

Another big change is the requirement for the implementation of a documented CCS across a company’s facilities, which 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.

Many looking to develop new compliant manufacturing processes or update their systems to ensure compliance are facilitating the process by incorporating available standardised solutions that can be easily integrated into manufacturing lines. 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 to mitigate risk.

Impact of Changes on Release of New Drug Products in the European Union

The changes outlined in GMP Annex 1 may have several different impacts on the release of new drug products, ongoing clinical trials, or marketing authorisation applications.

Firstly, the revised GMP Annex 1 includes new requirements on the manufacture of sterile medicinal products, which may have an impact on 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 modification of existing pharmaceutical manufacturing processes or equipment, which could affect ongoing clinical trials or marketing authorisation applications. If required to modify a manufacturing process during an ongoing clinical trial, the trial may have 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.

The specific impact will depend on the individual circumstances of each product and application. That makes it especially important for pharmaceutical manufacturers and sponsors to carefully review the new requirements and assess the impact on their processes and timelines.

Potential Cost, Pricing, and Reimbursement Implications for Pharmaceutical Products

It is difficult to predict with certainty how pharmaceutical product costs will be affected by changes in the 2022 GMP Annex 1 because impacts will vary depending on product type, manufacturing processes involved, and the extent of changes required. However, it is likely that implementation will require investment in new equipment, technology, and personnel training, which could increase production costs. In addition, the increased focus on risk management and environmental monitoring may require more rigorous testing and monitoring procedures, which could also contribute to higher costs.

But will these increased costs result in changes to pricing or reimbursement policies? That will depend on differences between regions, the competitive landscape of the market, and the willingness of payers to increase reimbursement.

Preparing for Implementation of Annex 1 Changes

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

1. Familiarise: 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 an implementation plan: Include timelines, resources required, and responsibilities for each task.

4. Train personnel: Make all personnel involved in manufacturing processes aware of the changes in the revised GMP Annex 1 and train them on the new requirements to minimise the risk of non-compliance.

5. Consider technology and collaborations: If changes are needed to manufacturing processes, evaluate and select any necessary new technology or modification of existing technology.

6. Evaluate the complete supply chain: Conduct an assessment of suppliers to evaluate compliance. For sterile single use systems, perform verification of sterility assurance as part of the supplier qualification process and check evidence of sterilisation on receipt. [Note: this is specifically called out in Annex 1].

7. Conduct regular audits: Regular audits ensure ongoing compliance and help identify any issues early to allow for corrective actions to be taken before they become major problems.

Mitigating Effects of Annex 1 Changes on Pharmaceutical Product Supply Chain

Any changes to manufacturing systems that involve new supply chains may introduce production process delays. New suppliers must demonstrate that their supply chains can withstand this demand. By the same token, these changes may also provide opportunities for manufacturers to rationalise and refine their supply chains.

For example, incorporating pre-assembled single-use products can reduce the number of items required and simplify the 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.

Stay Updated on Additional Changes to Annex 1

It is unlikely that there will be significant further changes to Annex 1 before its final August 2024 implementation date, as the document has already undergone an extensive review and revision process. There may of course be minor clarifications or corrections, so pharmaceutical manufacturers would be well advised to keep up to date with any changes. Process and regulatory experts can provide helpful guidance to facilitate this transition and strong partnerships with suppliers will be key in strengthening the sterility of processes globally.