Annex 1 Flashcards
What is the scope of Annex 1
Section 1: Scope - written for the manufacture of sterile medicinal products. May be used to support the manufacture of other products that are not intended to be sterile.
What are the principles of annex 1
ection 2: Principles - reinforcing Quality Risk Management (QRM) principles and mentioning the Contamination Control Strategy (CCS). Paragraph 2.5 gives a non-exhaustive list of elements to include in the CCS, so even for sites that have existing controls in place, it is worth reviewing the list to ensure all elements are covered.
The revised Annex states that, “Its effectiveness should form part of the periodic management
review”, so 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.
What section of Annex 1 is PQS
Section 3
Overview of Annex 1 - premises
Section 4: Premises - 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 RABs, isolators and gloves. 4.22i now specifically requires bio-decontamination of the interior surface of isolators to be automated and validated. 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 particles should be assessed and documented. This now includes reference to knowledge of the process and smoke studies in this assessment.
Overview of Annex 1 - Utilities
Section 6: Utilities - 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.
Overview of Annex 1 - personnel
Section 7: 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 a number of 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 cleanroom garments can be worn in Grade A / B is now stipulated.
Overview of Annex 1 - production and specific technologies
Section 8: Production and specific technologies - 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-sterilisation integrity testing (PUPSIT), which is not a new requirement as it is required by the 2008 annex 1 under section 113. The revised annex 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 of what to include in the risk assessment are given. A new sub-section around Form Fill Seal has been added and the sub-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 (25 August 2024) to allow manually loaded lyophilisers to be sterilised before each use. In line with the increase in use throughout the industry, a sub-section on single use systems (SUS) has been added. 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.
Overview of annex 1 - Viable and non-viable environmental and process monitoring
Section 9: Viable and non-viable environmental and process monitoring - Environmental and process monitoring is significantly expanded and clarified. 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). Limit for Grade A monitoring is clarified as “no growth” and 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 been revised to a more appropriate standard approach with all contaminated units resulting in a failed APS and investigation.
Describe an annex 1 environmental monitoring programme
Annex 1
An environmental monitoring programme should be established and documented. The purpose of the environmental monitoring programme, is to:
i. Provide assurance that cleanrooms and clean air equipment continue to provide an environment of appropriate air cleanliness, in accordance with design and regulatory requirements.
ii. Effectively detect excursions from environmental limits triggering investigation and assessment of risk to product quality.
Risk assessments should be performed in order to establish this comprehensive environmental monitoring programme, i.e. sampling locations, frequency of monitoring, monitoring methods and incubation conditions (e.g. time, temperature(s), aerobic and/or anaerobic conditions).
These risk assessments should be conducted based on detailed knowledge of; the process inputs and final product, the facility, equipment, the criticality of specific processes and steps, the operations involved, routine monitoring data, monitoring data obtained during qualification and knowledge of typical microbial flora isolated from the environment.
The risk assessment should include the determination of critical monitoring locations, those locations where the presence of microorganisms during processing may have an impact upon product quality, (e.g. grade A, aseptic processing areas and the grade B areas that directly interface with the grade A area).
Consideration of other information such as air visualisation studies should also be included.
These risk assessments should be reviewed regularly in order to confirm the effectiveness of the site’s environmental monitoring programme.
The monitoring programme should be considered in the overall context of the trend analysis and the CCS for the site.
Monitoring procedures should define the approach to trending. Trends should include, but are not limited to:
i. Increasing numbers of excursions from action limits or alert levels.
ii. Consecutive excursions from alert levels.
iii. Regular but isolated excursion from action limits that may have a common cause, (e.g. single excursions that always follow planned preventative maintenance).
iv. Changes in microbial flora type and numbers and predominance of specific organisms. Particular attention should be given to organisms recovered that may indicate a loss of control, deterioration in cleanliness or organisms that may be difficult to control such as spore-forming microorganisms and moulds.
The monitoring of grade C and D cleanrooms in operation should be performed based on data collected during qualification and routine data to allow effective trend analysis. The requirements of alert levels and action limits will depend on the nature of the operations carried out.
The size of monitoring samples taken using automated systems will usually be a function of the sampling rate of the system used. It is not necessary for the sample volume to be the same as that used for formal classification of cleanrooms and clean air equipment. Monitoring sample volumes should be justified.
