Anna CluetPharmaceutical Consultant and Senior AuditorRephine
In August 2023, 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.
In a previous article some months ago, we detailed the confirmed new requirements under Annex 1, in particular relating 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, with some of the main issues (and remedial advice) set out below.
Inadvertent Broadening of Scope
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.
Lack of Detailed Gap Analysis
We’ve also seen policy documents drawn up at a too high and theoretical 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. Without a detailed gap analysis, these companies risk not fulfilling the new measures that are required to control contamination risks, especially in Class A or Class B production areas. The whole point of Annex 1 was to force pharma manufacturers to review their contamination controls, and make, document, and measure targeted improvements.
Failure to Take a Holistic View of Risk
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. The expectation under Annex 1 is that Contamination Control Strategies consider facilities/ equipment, utilities such as water management, and people-related risk controls as a whole, because any weakness in the chain could compromise all other measures.
Ongoing Review
As we have noted previously, devising the Contamination Control Strategy, associated Policy and identified measures is and should not be viewed as a one-time event. To remain effective and contain risk over time, provisions must be periodically reviewed – and once a year may not be sufficient. It is the determined risk that should dictate how often measures and readings should be reviewed. If there is deemed to be a medium risk level, for instance, reviews and evaluation of raw data must be conducted at more regular intervals. If the evaluated data shows a negative trend, meanwhile, the risk level will need to be modified and the data evaluated more frequently still.
To check that water microbial content remains within safe limits not just in the cooler months but also throughout the summer when temperatures can soar in southern Europe, for instance, adapted control measures may be needed (the capacity to control the temperature of water, or to increase the sanitization process during peak temperatures), along with increased frequency of sampling and analysis.
Similarly, training those working in Class A and Class B facilities to understand human contamination risks won’t mitigate eventualities such as holiday cover when other employees or temporary staff may be covering that work.
Closing the Gaps
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:
1. Objective/scope: e.g., include/don’t include product residue contamination in the policy
2. Compile all controls and monitoring systems
3. Gap assessment of the existing control measures and monitoring systems versus 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, sterilization methods
- Product and container closure
- Raw materials
- Sterility Assurance performance metrics
- Ongoing evaluation
4. Correct gaps identified in the gap analysis
5. Implement new control measures/actions
6. Close CCS policy
7. Review periodically, on an ongoing basis.
It is likely that guidance and recommendations will continue to undergo refinement as inspectors work through the process of offering their insights and feedback on the ongoing CCS measures implemented by manufacturers. This iterative process aims to ensure that companies can strategically allocate their resources and budgets to areas that will yield the most significant positive outcomes for product sterility and quality assurance.
Author Biography
Anna Cluet is a Pharmaceutical Consultant and Senior Auditor at Rephine. She has been a qualified GMP auditor since 2005. She studied Chemical Engineering at the Instituto Químico de Sarrià and Industrial Engineering at Ramon Llull University, both in Spain.
Contact: [email protected], www.rephine.com
Publication Detail
This article appeared in American Pharmaceutical Review:
Vol. 26, No. 8
Nov/Dec 2023
Pages: 68-69
Subscribe to our e-Newsletters
Stay up to date with the latest news, articles, and events. Plus, get special
offers from American Pharmaceutical Review delivered to your inbox!
Sign up now!