A few weeks ago, the revised EU GMP Annex 1 requirements related to the Manufacture of Sterile Medicinal Products came into force, with implications for contamination control strategies – affecting plant facilities, equipment, manufacturing processes and Quality systems.
Now that the requirements are live, auditors have adapted their expectations accordingly with a bearing on audits and their findings.
Having a fit-for-purpose Contamination Control Strategy (CCS), and associated policy, is key to companies’ new measures, ensuring that consistent standards are upheld, end to end, across manufacturing operations. But it is here that we have seen many manufacturers struggle.
Here’s what’s tying them in knots, and what they should do next.
Matters of scoping
Although the focus of Annex 1 is specifically 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 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.
Too much focus on documenting vs analysing existing measures
We’ve also seen policy documents be drawn up at too theoretical a level. In many cases, companies have put together a document that merely explains the current control measures and monitoring plans – without assessing their level of compliance and any gaps with the needs of 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 is to prompt pharma manufacturers to review their contamination controls, and make, document and measure targeted improvements.
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 CCSs consider facilities/equipment, utilities such as water management, and people-related risk controls as a whole, because any chink in the chain could compromise all other measures.
Failure to track & adjust over time
Devising a CCS, associated Policy and identified measures 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 (the determined risk should dictate how often measures and readings should be reviewed).
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 sanitisation process during peak temperatures), along with increased frequency of sampling and analysis.
Bearing in mind some of the shortcomings we’ve seen, we suggest the following remedial actions:
Stay in scope: e.g. include/don’t include product residue contamination in the policy
Review all controls and monitoring systems
Perform a gap assessment of the existing control measures and monitoring systems against the requirements of Annex 1; Correct gaps identified in the gap analysis
Implement new control measures/actions
Close the CCS policy
Review all of this periodically, on an ongoing basis.