How successfully are pharma manufacturers adapting to EU GMP Annex 1 requirements?
Summary
EU GMP Annex 1 requirements related to the Manufacture of Sterile Medicinal Products have come into force. Anna Cluet of Rephine delves into the challenges faced by certain manufacturers when implementing effective Contamination Control Strategies and practical Quality Risk Management, sharing valuable insights and tips for addressing the issues.- Author Company: Rephine
- Author Name: Anna Cluet, Pharmaceutical Consultant and Senior Auditor
- Author Email: anna.cluet@rephine.com
- Author Website: http://www.rephine.com
In August, the revised EU GMP Annex 1 requirements related to the Manufacture of Sterile Medicinal Products came into force, with implications for contamination control strategies and, by extension, for plant facilities, equipment, manufacturing processes and Quality systems.
The updated requirements are designed to increase confidence in these products. Now that they are live, the expectations of auditors have adapted accordingly which will have a bearing on audits and their findings from this point on. The new requirements under Annex 1, relate to a fit-for-purpose Contamination Control Strategy (CCS), and associated policy, to ensure that consistent standards are upheld, end to end, across manufacturing operations.
It is here that many manufacturers have struggled. Although the focus of Annex 1 is very clearly on microbial, particulate and pyrogen contamination, some companies have inadvertently broadened their Policy scope to cover product residue (as per Annex 15 of EU GMP). This in turn introduces the concept of cross-contamination – e.g. if the same equipment is being used for different products. Although this is important, it is not within the scope of Annex 1 and is a distraction here.
We’ve also seen policy documents be drawn up at too high and theoretical a level. In many cases, companies have drawn up a document which merely explains the current control measures and monitoring plans - without evaluating their level of compliance and any gaps with the expectations of the new Annex 1.
A further issue involves the links between the various different contamination controls. Here, too many companies are failing to provide a holistic overview of potential risks which is essential to achieve the required sterility assurance level. Evaluating each component individually can mean that companies fail to take into account interdependencies between and with other systems, processes and considerations.
Seven targeted improvements
Bearing in mind some of the shortcomings we have encountered with companies’ CCSs and associated policy implementations relating to existing (rather than new) products/facilities, we have developed the following specific guidance to close the identified gaps:
- Objective/scope: e.g. include/don’t include product residue contamination in the policy
- Compile all controls and monitoring systems
- Gap assessment of the existing control measures and monitoring systems vs the requirements of the new Annex 1 (see table below for example scenarios):
- Check the following:
- People
- Facilities, equipment, utilities
- Process
- Close/open
- Cleaning methods
- Disinfection, sterilisation methods
- Product and container closure
- Raw materials
- Sterility Assurance performance metrics
- Ongoing evaluation
- Check the following:
Gap analysis – example scenarios:
|
Item |
Current measure |
Reference (Annex 1) |
Identified gap & resolution |
|
Facilities |
Filling machine (class A), people |
4.30 |
No smoke test to verify homogeneous of the air- Non speed measure on the working position Unidirectional airflow systems should provide a homogeneous air speed in a range of 0.36 – 0.54 m/s (guidance value) at the working position, unless otherwise scientifically justified in the CCS. Airflow visualization studies should correlate with the air speed measurement.
|
|
|
Differential pressure monitoring, recorded once per day No alarm system |
4.16 |
Install visual and sound alarm |
|
HVAC |
Definition of number and location of sample points |
4.28 |
Assessment to identify critical points that must be sampled and monitored |
|
|
Enter to class B from to a non-classified area |
4.12 |
Personnel enter Grade B area from unclassified change room → Grade C change room → Grade B change room, which does not comply with “increasing cleanliness” defined in Annex 1 article 4.12. |
|
|
A list with the materials approved to enter to grade A or B is not in place |
4.12 |
Material airlocks: used for materials and equipment transfer. Only materials and equipment that have been included on an approved list and assessed during validation of the transfer process should be transferred into the grade A or grade B areas via an airlock or pass-through hatches. |
|
|
Separation between personnel and material flows |
4.12 |
No gap |
|
Equipment |
Some indirect contact parts are not sterilized |
5.5 |
For aseptic processes, direct and indirect product contact parts should be sterilised. Direct product contact parts are those that the product passes through, such as filling needles or pumps.
Indirect product contact parts are equipment parts that do not contact the product, but may come into contact with other sterilised surfaces, the sterility of which is critical to the overall product sterility (e.g. sterilised items such as stopper bowls and guides, and sterilised components). |
|
Utilities |
Monitoring plan does not include non-condensable gases, dryness value (dryness fraction) and superheat |
6.17 |
Other aspects of the quality of pure steam used for sterilisation should be assessed periodically against validated parameters. These parameters should include the following (unless otherwise justified): non-condensable gases, dryness value (dryness fraction) and superheat |
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|
|
|
|
- Correct gaps identified in the gap analysis
- Implement new control measures/actions
- Close CCS policy
- Review periodically, on an ongoing basis.
To remain effective and contain risk over time, provisions must be periodically reviewed – the determined risk should dictate how often measures and readings should be reviewed. At the same time, as inspectors begin to offer their insights on the ongoing development of manufacturers' CCS, companies will be better able to focus their on product sterility compliance efforts.
