New Annex 1: what is the impact on the pharmaceutical sector?
- Liselotte Herbert
- Project Engineer
On 25 August 2022, the final version of the revised Annex 1 was published. While the previous 2008 revision counted 16 pages, the new version is 59 pages. We can therefore conclude that many new guidelines have been added. These directives take effect on 25 August 2023 (except for section 8.123 on manual loading of freeze dryers, which takes effect on 25 August 2024).
Find out the biggest changes by chapter here.
Chapter 1: Scope
Chapter 1 describes that the guidelines are written for sterile drug production but can also be used to support non-sterile production. This should not be misinterpreted, certain sections, e.g. gowning principles, are considered good practices for any cleanroom. So even if non-sterile production uses cleanrooms according to classes A to D, these rooms must comply with the principles of Annex 1.
Chapter 2: Principle
This chapter breaks down the general principles behind Annex 1. Three principles are emphasised:
- Since personnel is a major source of contamination, processes should be automated wherever possible.
- All processes, equipment, utilities and production activities should be done according to the principles of quality risk management (QRM).
- A contamination control strategy (CCS) should be developed, setting out all possible sources of contamination and ways to contain or control it.
Chapter 3: Pharmaceutical Quality System (PQS)
This chapter emphasises the importance of quality systems. It sets out specific requirements for sterile production that control all activities and reduce the risk of contamination:
- There should be a risk management system covering the entire life cycle of the product with the aim of minimising contamination.
- The producer must have sufficient knowledge of the product and processes.
- In case of failures, a root cause analysis must be done after which applicable CAPAs are drawn up.
- The CCS is drawn up on the basis of risk management.
- Management should be involved in monitoring and revising the risk management.
- Finishing, storage and transport of product should not cause contamination.
- Those responsible for batch release should have access to production and quality information. They should also have knowledge of the process so that errors are detected.
Chapter 4: Premises
Chapter 4 specifies expectations around cleanroom design. To contain contamination from materials and personnel, several new requirements are proposed. These include making the use of Restricted Access Barrier Systems (RABS) and isolators mandatory at new facilities. Furthermore, there must be a uni-directional process for transfer of materials in and out of Grade A and B, and the entrance and exit dressing room for Grade B must be separate.
The next major part of the changes in this chapter relates to cleanroom qualification. For this, the new guidelines are in line with ISO 14644. Important changes include:
- Videos of smoke studies must be added to the validation report.
- Cleanroom qualification must be done 'at rest' and 'in operation'.
- Re-qualification of grade A and B must happen every 6 months, re-qualification of grade C and D every 12 months.
Furthermore, cleaning and disinfection should be done through a written, validated procedure. Disinfection with spore-killing agents should be done regularly.
Chapter 5: Equipment
Chapter 5 describes how equipment and processes are properly described, qualified and documented. It emphasises the importance of cleaning equipment and how equipment should be used in cleanrooms. Parts that come into direct or indirect contact with product should be sterilised. Alarms should also be evaluated for trends.
Chapter 6: Utilities
Chapter 6, which focuses on utilities, is almost entirely new. Guidelines have been formulated for four utilities: Water for injection (WFI), pure steam, compressed gases (compressed air and nitrogen) and heating and cooling systems.
Some important guidelines in this chapter are:
- WFI systems should be continuously monitored for Total Organic Carbon (TOC) and conductivity.
- Gases in contact with product should be monitored at each user point.
- Heating and cooling systems should be located outside the cleanroom whenever possible.
Chapter 7: Personnel
This chapter sets out the guidelines for personnel, gowning and training.
Compared to the previous Annex 1, more emphasis is placed on training and qualification of operators. In case of trends on monitoring of personnel or a failed media fill, an operator can be denied access to the cleanroom until he is re-qualified.
There are also new specifications for gowning. For example, operators must wear company clothing (including socks) before entering the gowning area. For reusable clothing, 'wash' procedures must be qualified. In addition, the maximum number of times clothing can be worn has been determined.
Chapter 8: Production and Specific Technologies
Chapter 8 sets out the guidelines for sterile production and associated technologies. A maximum hold-time must be determined for each aseptic step. More details have also been added to the requirements for 'pre-use post sterilisation integrity testing' (PUPSIT).
The chapters on sterilisation and blow-fill-seal have been significantly expanded and new chapters have been added on Form-fill-seal, freeze-dryers and single-use-sytems (SUS).
Chapter 9: Environment and process monitoring
This part of Annex 1 outlines how cleanrooms should be monitored and how this should be documented. Environmental monitoring consists of particle counts, microbial monitoring, monitoring of environmental parameters and media fill. The guidelines for environmental monitoring have been significantly expanded. Important changes are:
- More emphasis is placed on trend analysis.
- Monitoring of personnel should be done at every critical intervention and every exit from Grade B.
- Microbial limits for Grade A cleanrooms have been clarified to 'no growth'.
- If microbial growth is recovered for Grade A, an investigation should be initiated.
- The use of rapid analysis techniques for microbial sampling is suggested.
- For media fill, at least 5000 - 10000 vials should be filled and any growth should lead to a failed media fill and an investigation.
Chapter 10: Quality control (QC)
The last chapter deals with quality control. This chapter reiterates that personnel must be adequately trained and experienced in the processes and specifies the requirements for sterility testing of a product.
GxP Academy training courses have been supplemented with the latest information from Annex 1. Many parts of the new Annex 1 have a direct impact on the operational management of a cleanroom. Just think of QRM, CCS, cleanroom classifications, ect.
Advipro can also support the implementation of the new Annex 1 through its various areas of expertise.
Be sure to take a look at our GxP Academy website and the Advipro website:
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