What to consider for successful GMP Annex 1 implementation

By Kevin Robinson | Published: 19-May-2023

In advance of her presentation at Manufacturing Chemist Live, Dr Nicole Hunter (NH), Head of Global Regulatory and Validation Services at Watson-Marlow Fluid Technology Solutions, and colleague Claire Hutchison (CH), Life Science Specialist, provide their insights on the updates to the European Commission’s Good Manufacturing Practices (GMP) Annex 1 and the role of single-use systems

After 14 years in development, the updated GMP Annex 1 for sterile drug products was released in August 2022. It’s to be implemented one year after publication or two years for section 8.123 on lyophiliser sterilisation. With this deadline fast approaching, pharmaceutical professionals need to understand the implications and put any additional measures in place.

The revision harmonises 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. 

It includes a new section on pharmaceutical quality systems, incorporating the principles of quality risk management (QRM), a new section addressing contamination control strategies (CCS) and recent advances in sterile processing technology, such as restricted access barrier systems (RABS) and isolators.

There is therefore likely to be an increase in demand for plug and play solutions, including single-use systems, that enable manufacturers to meet the new requirements with minimal effort. Dr Kevin Robinson got in touch to find out more.

KSR: How will the proposed changes impact pharmaceutical companies that manufacture sterile products and will they require significant investment?
NH: The pharmaceutical industry has changed dramatically since the last revision of the GMP guidelines, especially with the rise of novel biologic therapies. These new GMP revisions stem from extensive consultation with regulators and industry, so although companies will need to ensure that their processes are compliant, many will already meet these needs or only require minimal amends.

What to consider for successful GMP Annex 1 implementation

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 it into designs for new production lines.

Pharma companies will also be required to have a documented CCS implemented across their facilities, which considers all aspects of contamination control and its lifecycle, with ongoing reviews resulting in documented updates within the quality system. 

CH: There are standardised solutions already available on the market that can be easily integrated into manufacturing lines to facilitate compliance. Prevalidated, 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 changeover to increase productivity, making use of single-use technology in accordance with regulatory guidelines to mitigate risk.

KSR: 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?
CH: The new requirements related to the production of sterile medicinal products 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.

What to consider for successful GMP Annex 1 implementation

Existing manufacturing processes or equipment may also require modification, which could impact ongoing clinical trials or marketing authorisation applications. 

With greater emphasis on risk management and environmental monitoring, more extensive testing and documentation may be required. Regulatory authorities may need additional time to review and ensure compliance, potentially resulting in longer lead times for the approval of marketing authorisation applications.

KSR: What steps can pharmaceutical professionals take to prepare for the implementation?
CH: To quote from Annex 1: “Assessment of suppliers of disposable systems including sterilisation 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 sterilisation of each unit should be checked on receipt.”

  • Familiarity: Review the revised GMP Annex 1 carefully and understand the changes.
  • Gap analysis: Identify any areas where current processes and procedures may not align and identify any necessary changes that need to be made.
  • Implementation plan: Include timelines, resources required, and responsibilities for each task.
  • Personnel training: All personnel involved in manufacturing processes need to be aware of the changes and trained to minimise the risk of non-compliance.
  • New technology: Ensure that any necessary technology changes are made to manufacturing processes.
  • Supply chain: Assessment of suppliers is critical to compliance. Verification of sterility assurance for sterile single use systems should be performed as part of the supplier qualification process and evidence of sterilisation should be checked on receipt.
  • Regular audits: Ensure ongoing compliance and help identify any issues early to allow for corrective actions.

KSR: How will these changes affect the supply chain for pharmaceutical products and how can we mitigate against any disruptions? 
NH: As with any changes to manufacturing systems, new supply chains may be needed that may introduce delays in the production process. New suppliers will need to demonstrate that their supply chains can withstand this demand, but these changes may also provide opportunities for manufacturers to rationalise and refine their supply chains.

CH: Preassembled single-use products can result in a simplified supply chain compared with ordering components separately and assembling in-house. This reduces inventory and facilitates the ordering process for manufacturers and can lead to a reduction in waste. Waste reduction brings cost benefits as well as being an important component of companies’ sustainability aims.

And, finally, stay up to date! It is unlikely that there will be significant further changes, but minor clarifications or corrections may be made to the document to address any issues.

Staying aware of these recent changes and any additional amends will be vital for regulatory compliance and help pharmaceutical manufacturers deliver the highest quality medicines to patients. Process and regulatory experts can provide helpful guidance to facilitate this transition and strong partnerships with suppliers will be key in strengthening the sterility. 

For further insights on the regulatory concerns facing the industry, join Dr Nicole Hunter at Manufacturing Chemist Live on 24 May for her talk: Cell and Gene Therapies: On the Brink of Commercialisation. 

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