Background

Continuing our brief assessment of the 2022 version of Annex 1, we focus on the Contamination Control Strategy. One of the most critical additions to Annex 1 is the section that captures the requirement for a formal Contamination Control Strategy (CCS) within the drug product/facility. The four, relatively short, clauses (2.3 through 2.7) have set into motion a whole series of personnel intensive, potentially expensive activities intended to ensure sterility. As one person has said, “It’s not difficult to see how this will become the standard for all manufacturing activities including simple processes for solid oral dosage forms in dedicated facilities.” Then asking, “Will there ever be a time when ‘enough is enough?”

One concern that companies have relates to the “design” component of the CCS. How will older systems, which have operated successfully for years, be judged when a single failure or just an Inspector/Investigator might suggest the system was related to the cause of the failure or obsolete, respectively. The Annex gives little assurance that older designs won’t be challenged but attempts to assuage some fears by saying it shouldn’t happen “Where existing control systems are in place and are appropriately managed, these may not require replacement but should be referenced in the CCS and the associated interactions between systems should be understood (clause 2.3).” A single, related event might be an outlier event not indicative of failure, but will the company be put into a situation where unnecessary or expensive changes might be forced upon them by an aggressive inspector or investigator. Ultimately, companies must be able to demonstrate compliance and sterility assurance now that the CCS is an essential component of the data set. Its clarity and depth must be such that it is a true working document.

The CCS must:

1. Be a living document that evolves with process changes.

2. Consider all potential sources of contamination (human, environmental, material, and process-related).

3. Be integrated with the Pharmaceutical Quality System (PQS).

4. Be backed by scientific rationale and risk assessments.

What you need to know

The elements of the CCS are familiar to many of us who have been in the industry for an extended period of time. In fact, it is likely that many of them have already been developed as part of well-defined control systems. The challenge may be to reassess the concerns and comments considering the element of Quality Risk Management (QRM, ICH Q9). Elements to be considered within a CCS should include (but are not limited to):

1. Design of both the plant and processes including the associated documentation.
2. Premises and equipment.
3. Personnel.
4. Utilities.
5. Raw material controls – including in-process controls.
6. Product containers and closures.
7. Vendor approval – such as key component suppliers, sterilisation of components and Single Use Systems (SUS), and critical service providers.
8. Management of outsourced activities and availability/transfer of critical information between parties, e.g., contract sterilisation services.
9. Process risk management.
10. Process validation.
11. Validation of sterilisation processes.

Elements outside a company’s control will also cause concern, such as the status of vendors who refuse to cooperate or who ignore the significance of their products to drug product quality. The challenge for all who are part of the process is to create an honest assessment that fairly critiques the facility, the personnel, the relationships, and the process. No small task in itself.

What You Need to Do:

Think of the CCS as your company’s sterility Quality Manual; your starting point. If you haven’t already developed one it’s time to create a team that has the mandate and authority to create the document, maintain it, and enforce it. The team should conduct a full review of your existing contamination control measures and ensure they are captured. Creating a map of potential contamination points is a good second step. It is important to conduct a retrospective review of issues encountered in the manufacturing process and facility. Don’t overlook all of the incidents, actions, activities, concerns, aberrant results, etc. (regardless of what you call them, they are still deviations) for every product that has gone through the sterile corridor. The worst thing you can do is to create it and then ignore or forget it. Full reviews and staff training should occur using the CCS as a focal point for product/facility control. Regulators will expect evidence that your CCS is actively used and continuously updated. In the long run, awareness of the potential contamination points in the process will be critical to minimizing such events in the future.

A simple stepwise process could include:

1. Create a team of internal experts. You may need to think outside your organization and bring in a consultant to help.
2. Assess Your current practices: Review your existing contamination control measures and identify any gaps or areas for improvement.
3. Develop a comprehensive CCS: Document all potential contamination sources and the controls in place to manage them. This should include facility design, equipment maintenance, personnel training, SOPs, and environmental monitoring.
4. Implement Quality Risk Management (QRM) Principles: Apply QRM to systematically identify, assess, monitor, and control contamination risks throughout the manufacturing process.
5. Train Your Personnel: Ensure all staff involved in the manufacturing process are adequately trained and understand their role in contamination control.
6. Regularly Review and Update Your CCS: Continuously monitor and review your CCS to ensure it remains effective and up to date with regulatory requirements and industry best practices.

Points for Comment:

While all comments are welcome, we would like to ask some questions to stimulate conversations.

1. Does the Contamination Control Strategy represent a significant hurdle with your company? Why?

2. Is the CCS a promising idea with positive impact or is it just another regulatory requirement that has little benefit?