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Annex 1 Revision, FDA Biosimilar Workshop & More – September Update

In the September update, we provide a comprehensive look at the Annex 1 revision, and more.

Annex 1 Revision Published

The final version of the revised Annex 1 was published on 25 August 2022, some 7 years after the revision process started. The revised annex becomes effective on 25 August 2023; except for section 8.123 which contains the requirement for lyophilisers that are manually loaded or unloaded with no barrier technology separation to be sterilised before each load, which becomes effective one year later on 25 August 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 in total. This revision is a complete re-write of the Annex and was a joint EU, PIC/S and WHO project, with the US FDA personnel being actively involved.

Phil Rose, NSF Principal Consultant, who is an expert on sterile products and was a Senior MHRA Inspector before he joined NSF on 1 June this year, has provided the following assessment of the revised annex:-

The annex has been revised primarily to remove ambiguity; to come in line with other chapters that have been revised and to take account of advances in technology however there are very few significant changes overall. This is by no means a full gap analysis of changes between the different versions of the annexes as that should be performed at a site level dependant on previous interpretation and implementation.

The scope 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 sterile. This should not be misinterpreted as it must be used as I have recently seen some interpreting it as. Some aspects of it may be useful as it does give a lot of 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 it’s claimed you are working to Grade A, that should be complied with and demonstrated, although as below, quality risk management principles could be applied to how it is implemented.

Quality Risk Management (QRM) is now fully embedded within the annex. Although this is by no means a new concept, this stands as a good reminder that QRM should be included in all aspects of medicinal product manufacture and especially for higher risk products such as sterile medicinal products.

The “Principle” section has been clarified and expanded significantly. This section now sets a good introduction, reinforcing QRM principles and mentioning the Contamination Control Strategy (CCS). Now, most companies that were inspected by me during my time at the MHRA will have known that this is not a new concept and the requirements to control contamination (and cross-contamination) is not new. However, pulling the various elements together into one “strategy” document and how different elements interact may be new for some sites and should be performed with thought and care to ensure that it is a useful and valuable document. Paragraph 2.5 gives a non-exhaustive list of elements to include in the CCS so even for sites that had existing controls in place, it is worth reviewing the list to ensure all elements are covered. Interestingly the Annex states that, “Its effectiveness should form part of the periodic management review”. Again, thought should be given to how this is performed in practice to ensure that the management team have sufficient oversight of how the CCS is operating but without it becoming unnecessarily burdensome.


Section 3 is for the Pharmaceutical Quality System (PQS). This should be read in conjunction with Chapter one and is not a replacement, but more is designed to supplement the main chapter with specific requirements for sterile products. Hopefully to most sites these are not new requirements but should be good reminders of what should be included and that QRM around the products and methods of manufacture should form a basis for all aspects, both planned and unplanned.


Section 4 is for premises. There was some discussion within industry before publication that the draft was mandating RABs and Isolators. This is incorrect and although use of RABs and Isolators is encouraged, other options can be used so 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 section on “Barrier Technologies” on both RABs, isolators and gloves. 4.22i now specifically requires bio-decontamination of the interior surface of isolators to be automated and validated. For some of the 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 is sometimes desirable this has now been strengthened to the use of separate 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 gives more clarification around air visualisation 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 with regards to cleanroom qualification tests although this remains in line with ISO 14644. The decision whether to monitor 5µm or greater particles is now driven by the CCS and historical data. The sampling locations for both viable and non-viable locations should be assessed and documented. I am pleased to see that this now includes reference to knowledge of the process and smoke studies in this assessment as often this is overlooked.


Section 6 refers to utilities. This now includes water for injection (WFI) generated from reverse osmosis and also includes discussion around minimising biofilms. In line 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.


Section 7 refers to Personnel. Additional emphasis is put onto training and in particular aseptic operators. This includes qualification to enter Grade A / B areas. Additional clarification on gowning requirements is included including several additional requirements such as the requirement to change socks for facility socks for entry to Grade C and above and the requirement for sterile goggles in Grade B. The requirement to define a maximum time that cleanroom garments can be worn in Grade A / B is now stipulated.

Production and Specific Technologies

Section 8 is specific to production activities. Of specific note are paragraphs 8.18 which stipulates requirements around aseptic hold times and 8.27 gives additional requirements for room classification of capping activities.

Paragraph 8.87 refers to filter integrity testing and pre-use, post sterilisation integrity testing (PUPSIT). Again, there has been a lot of discussion around this being a new requirement although it was a requirement in the current version under section 113. I think that the clarification on wording may have caused some confusion on it being a new requirement although as a former inspector, we were trained to inspect for requirements of PUPSIT prior to this annex update. I am pleased to see that it specifically details what to do if PUPSIT is not possible, for example at those sites making very small volumes and this requires a thorough risk assessment to be performed. Details on what to include are given in this paragraph however as currently is the case, this should be a product by product assessment and not a site general statement.

A new sub-section around Form Fill Seal is in place and the section on Blow Fill Seal is expanded.

The sub-section on Lyophilisation has been significantly expanded and clarified and paragraph 8.123 has an extended implementation time (25th August 2024) to allow manually loaded lyophilisers to be sterilised before each use.

In line with the increase in use throughout the industry, a section on single use systems (SUS) is in place. As most of this with regards to manufacture and sterilisation is outsourced, this places additional requirements on the supplier management processes and sites should ensure that these are appropriately considered and assessed.

Viable and Non-Viable Environmental and Process Monitoring

Section 9 covers Viable and non-viable environmental and process monitoring and is significantly expanded and clarified compared to the previous version. The requirement to assess the design of the EM programme 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 is clarified as “no growth” and the requirement for all Grade A recoveries require an investigation. Reference is made to sites considering using rapid technologies. The annex is written in a way that encourages sites to consider viable and non-viable monitoring together rather than as discrete entities.

The sub-section on Aseptic Process Simulations (APS) (also known as media fills) has been significantly expanded and clarified. This includes a significant amount more detail although for most sites this should not pose any significant challenges. The section in the current annex with regards to numbers of units to fill and investigations has thankfully been revised to a more appropriate standard approach with all contaminated units resulting in a failed APS and investigation. One section which is too specific for me personally now is around only risk assessing as far back as the last successful APS. Due to the inherent weakness with any APS, my personal preference would be not to limit this just to the last six months depending on what the most probable root cause was attributed to and rather consider the risk of the process as a whole to the product and patient.

FDA Draft Guidance on “Conducting Remote Regulatory Assessments”

In July 2022, the U.S. FDA issued draft guidance on “Conducting Remote Regulatory Assessments” in the form of a Q&A document. This new draft has the following main headings:

  • Remote Regulatory Assessment (RRA) Fundamentals
  • Remote Regulatory Assessment Expectations
  • Requests for Records or Other Information as Part of Remote Regulatory Assessments
  • Completion of a Remote Regulatory Assessment

The draft guidance says that the FDA will not be conducting hybrid inspections that combine RRAs and on-site inspections. However, an RRA could precede, prompt or be a follow-up to an inspection, in which case the FDA may combine any information gained from the RRA with any resulting observations from the inspection.

You can read the draft document on the FDA website here.

EMA Concept Paper on Proposed Changes to Guideline on Chemistry of Active Substances

On July 26, 2022, the EMA published a concept paper proposing to revise its guideline on the chemistry of active substances in response to lessons learned from the nitrosamine issue. Responses to this consultation should be sent to the EMA by October 31, 2022. The concept paper proposes the following changes to the current guideline:

  • Guidance on appropriate process development to mitigate as much as possible the potential presence of N-nitrosamines or other “cohort of concern” (CoC) compounds as well as of other potent toxins (if applicable). The selected manufacturing process should be justified accordingly.
  • Guidance on the need to provide clear information on all the materials used in the process (including raw materials, starting materials and intermediates) in relation to their function in the corresponding manufacturing step, their applied quantities, their potential contaminants and their overall quality.
  • Guidance on the required discussion regarding presence or formation of N-nitrosamines or other CoC compounds as well as of other potent toxins. Clarify the new systematic approach suggested by ICH M7 on mutagenic impurities.
  • Guidance on the use of recycled materials.
  • Guidance on specific control options for N-nitrosamines or other CoC compounds as well as for other potent toxins, including possible control points and acceptance criteria.
  • Guidance on the need to consider formation of N-nitrosamines or other CoC compounds as well as of other potent toxins during storage.

You can read the draft document on the EMA website here.

EMA and MHRA Extend the Step 3 Deadline for Nitrosamines

The deadline for completing step 3 of the nitrosamine review process for medicines with chemically produced APIs has been extended from September 26, 2022, to October 1, 2023.

Step 3 is when MA holders must apply for any necessary changes to the manufacturing process resulting from their steps 1 and 2 review by requesting a variation to the marketing authorization via standard regulatory procedures.

The step 2 confirmatory testing deadlines for completion remain as follows:

  • Chemical medicinal products: September 26, 2022
  • Biological medicinal products: July 1, 2023

The step 3 deadline for medicines with biologic APIs remains July 1, 2023.

The revised EMA Q&A is attached, and the revised MHRA guidance can be found here.

FDA To Hold Public Workshop To Discuss Biosimilar Product Development

The U.S. FDA is hosting a one-day virtual public workshop entitled “Increasing the Efficiency of Biosimilar Development Programs” on Monday, September 19, 2022. Registration is now open, and details are here.

This workshop will discuss statistical, scientific and clinical methods for streamlining comparative clinical studies associated with biosimilar product development programs. This virtual workshop is open to the public; however, registration is required.

Dipti Gulati, NSF Executive Vice President, Pharma and Biotech, is an acclaimed expert on the issue of biosimilars.

FDA Issues Two Draft Guidances Related to the Drug Supply Chain Security Act

The U.S. FDA is announcing the availability of two guidances to help trading partners comply with the Drug Supply Chain Security Act (DSCSA). These documents are critical steps toward implementing the DSCSA enhanced drug distribution security requirements that will go into effect on November 27, 2023. Details are available here.

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