· 11 min read
The final version of the revised Annex 1 was published on August 25, 2022, seven years after the revision process started. The revised annex becomes effective on August 25, 2023, except for section 8.123, which contains the requirement for lyophilizers that are manually loaded or unloaded with no barrier technology separation to be sterilized before each load, which becomes effective one year later, on August 25, 2024.
At 50 pages, the 2017 draft was considerably longer than the 16-page 2008 version, and the final version is even longer, at 59 pages. This revision is a complete rewrite of the annex and was a joint EU, PIC/S and WHO project, with U.S. FDA personnel actively involved.
This section describes how the annex is written for the manufacture of sterile medicinal products but that it may be used to support the manufacture of other products that are not intended to be clean. This should not be misinterpreted as it must be used. Some aspects of the annex may be useful, as it gives detailed guidance. However, as stated in the annex, "where a manufacturer elects to apply guidance herein to non-sterile products, the manufacturer should clearly document which principles have been applied and acknowledge that compliance with those principles should be demonstrated." So if you claim you are working to Grade A, that should be complied with and demonstrated.
This section is a good introduction to the thinking behind the revised annex, reinforcing quality risk management (QRM) principles and mentioning the contamination control strategy (CCS). The CCS is probably the most significant requirement introduced in the revised annex, which companies should already be aware of, as it was in the December 2017 draft. This is not an entirely new concept, and the requirements to control contamination (and cross-contamination) are not new. However, the need to combine the various elements into one “strategy” document that describes how different elements interact may be new for some sites. It should be performed with thought and care to help ensure that it is a useful and valuable document. The revised annex states, “Its effectiveness should form part of the periodic management review,” so thought should be given to how this is performed in practice to help ensure that the management team has sufficient oversight of how the CCS is operating, but without it becoming unnecessarily burdensome.
This section should be read in conjunction with Chapter 1, as it is designed to supplement the main chapter with specific requirements for sterile products.
In the revised annex, while using RABS and isolators is encouraged, it is not mandated, and other options can be used as long as they are justified within the CCS. However, for new facilities or installations, there would need to be clear reasons why RABS or isolators weren’t the preferred options. More details are given in the “Barrier Technologies” section on RABS, isolators and gloves. 4.22i now specifically requires bio-decontamination of the interior surface of isolators to be automated and validated. For some small-scale manufacturers, this may require changes to current practices.
Paragraph 4.11 requires a unidirectional process for the transfer of materials, equipment and components into the Grade A/B areas, and whereas before, "the use of separate changing rooms for entering and leaving clean areas was sometimes desirable, this has now been strengthened to the use of different change rooms for entering and leaving the grade B area is desirable. Where this is not practical, time-based separation of activities (ingress/egress) by procedure should be considered. Where the CCS indicates that the risk of contamination is high, separate change rooms for entering and leaving production areas should be used."
Paragraph 4.15 clarifies air visualization studies (smoke studies) and includes the requirement to record (video) the studies. Although most sites were already doing this, it is now a specific requirement.
More detail is given regarding clean room qualification tests, although this remains in line with ISO 14644. The CCS and historical data now drive the decision whether to monitor particles of 5µm or greater. The sampling locations for both viable and nonviable particles should be assessed and documented. This now includes reference to knowledge of the process and smoke studies in this assessment.
This includes water for injection (WFI) generated from reverse osmosis and discusses minimizing biofilms. In keeping with advances in technology, in-line monitoring of WFI systems is referred to due to "the better indication of overall system performance than discrete sampling."
Additional emphasis is put on training and, in particular, aseptic operators. This includes qualification to enter Grade A/B areas. Further clarification on gowning requirements includes several additional requirements, such as the requirement to change socks to facility socks for entry to Grade C and above and the need for sterile goggles in Grade B. The requirement to define a maximum time clean room garments can be worn in Grade A/B is now stipulated.
Of specific note are paragraphs 8.18, which stipulates requirements around aseptic hold times, and 8.27, which gives additional requirements for room classification of capping activities.
Paragraph 8.87 refers to filter integrity testing and pre-use, post-sterilization integrity testing (PUPSIT), which is not a new requirement as required by the 2008 Annex 1 under section 113. The revised annex details what to do if PUPSIT is impossible, for example, at those sites making very small volumes, requiring a thorough risk assessment. Details of what to include in the risk assessment are given.
A new subsection around form-fill-seal has been added, and the subsection on blow-fill-seal has been expanded.
The subsection on lyophilization has been significantly expanded and clarified, and paragraph 8.123 has an extended implementation time (August 25, 2024) to allow manually loaded lyophilizers to be sterilized before each use.
In line with the increase in use throughout the industry, a subsection on single-use systems (SUS) has been added. As most of this with regard to manufacture and sterilization is outsourced, this places additional requirements on the supplier management processes, and sites should help ensure that these are appropriately considered and assessed.
Environmental and process monitoring is significantly expanded and clarified. The requirement to assess the design of the EM program is specified, although this should not be new for most sites. Monitoring of personnel should also be assessed by risk assessment, and the annex discusses consideration of the requirement to monitor after each critical intervention (gloves minimum) and on each exit from the Grade B area (gloves and gown). Limits for Grade A monitoring are clarified as “no growth,” and the requirement for all Grade A recoveries requires an investigation. Reference is made to sites considering using rapid technologies. The annex is written to encourage sites to consider viable and nonviable monitoring together rather than as discrete entities.
The subsection on aseptic process simulations (APS) (also known as media fills) has been significantly expanded and clarified. This includes much more detail, although this should not pose any significant challenges for most sites. The section in the current annex regarding the numbers of units to fill and investigations has been revised to a more appropriate standard approach, with all contaminated units resulting in a failed APS and investigation.
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