This is part 1 of a series of blogs which will address the draft annex 1 in full. This series will be presented over the next few weeks, with a focus on individual chapters. For a quick overview and context, you can read our initial blog on the draft here.
This first part discusses the draft Annex 1 Chapters 1 and 2, the Scope and Principle sections:
New draft Annex 1 – Chapter 1 – Scope
The scope section is entirely new – there was no scope statement in previous versions of Annex 1. As should be expected, it defines the scope primarily in terms of manufacture of sterile medicines. However, in line with the 2015 concept paper, the new scope gives some context to where the annex may be used apart from sterile production.
The additional scope is limited to manufacture of low microbial or low particulate products, and the steps referenced are limited to contamination control strategy, room classification, environmental monitoring and gowning.
New draft Annex 1 – Chapter 2 – Principle
The 2007 version of Annex 1 had a principle statement of approximately 110 words. The update contains a principle with approximately 700 words – a substantial increase in detail.
The previous principle focused on the special requirements for manufacturing sterile products, and focused on people and procedures as the areas requiring special attention.
The update expands the focus to include facilities and processes, but also takes a further step in defining what the “special” attention might include. The embedding of Quality Risk Management (QRM) as a key principle for Annex 1 starts here, and the principle includes the statement
“Risk assessments should be used to justify alternative approaches to those specified in this Annex only if these alternative approaches meet or surpass the intent of this Annex.
Point of Contention: Who decides what the intent of the Annex is? Past experience tells us that different inspectors, let alone different inspectorates, have different views on intent. The wording of this sentence is open to misuse where disagreement occurs.
The other key concept introduced in this section is “Contamination Control Strategy”, a new and specific documentation requirement.
Contamination Control Strategy (CCS)
CCS is mentioned 16 times in the update, and it is defined within the principle. The CCS is defined as a multi-element, formally documented strategy, which is implemented site-wide. Most organisations will already have many of the elements of a CCS as described by the Annex, but they may not be collated through a single source, as appears to be the intent of this requirement.
The Annex requires organisations to understand the sources and control mechanisms for contaminants, which are defined as microbiological and cellular debris, as well as particulate matter.
The key purpose of a CCS is to allow assessment of the strategies implemented. The Annex is not merely asking for a collation of risk assessments, validations, procedures and other information, there must be ongoing evaluation of the effectiveness of the strategy, and correction were necessary.
The new Annex provides a detailed list of elements expected to be covered within a CCS. The list below is republished directly from the draft Annex, Principle section:
- Design of both the plant and facilities
- Equipment and facilities
- Raw Materials Control – including in-process controls
- Product containers and closure
- Vendor approval – such as key component suppliers, sterilization of components and single use systems, and services
- For outsourced services, such as sterilization, sufficient evidence should be provided to the contract giver to ensure the process is operating correctly
- Process risk assessment
- Process validation
- Preventative maintenance – maintaining equipment and premises (planned and unplanned maintenance) to a standard that will not add significant risk of contamination
- Cleaning and disinfection
- Monitoring systems – including an assessment of the feasibility of the introduction of scientifically sound, modern methods that optimize the detection of environmental contamination
- Prevention – Trending, investigations, corrective and preventive actions (CAPA) root cause determination and the need for more robust investigational tools
- Continuous improvement based on information from the above systems
In addition to the details provided in the Principle section, throughout the Annex, several specific topics are identified as requiring inclusion in the CCS:
- Justifications for the maximum number of operators in critical areas
- Risk evaluation and mitigation strategies for transfer of materials into Grade A/B areas
- Isolator disinfection
- Aseptic processing controls, and associated acceptance criteria
- Consideration to minimization of not just microbiological contamination, but also pyrogen and particulate contamination
- BFS machine design and operational controls (and a further list of specific considerations is provided at clause 8.94)
- Control of lyophilization processes
- Environmental and process monitoring programs, including the sampling quantity and frequency.
- The risk assessments which define environmental monitoring programs
- The approach to managing hazards such as live organisms or radioactive materials.
- The risk based requirements for identification of organisms detected in Grade C and D (note, ID of organisms located in A or B is mandated by the Annex)
- Strategy for monitoring/managing microbiological quality of starting materials
- Monitoring requirements for CNC areas adjacent to classified areas
For those organisations who do not yet have a single source document describing their contamination control strategy, there is considerable work to do. Thankfully, the annex gives reasonably detailed information on the expectations for CCS, and manufacturers should see the benefit of collating this information and ensuring their strategy is free of gaps.
Draft Annex 1 – Part 1 (this post)