Is your facility up to date with new Annex 1 Contamination Control Strategy (CCS) guidance?
The newly revised version of Annex 1 will go into effect in August of 2023. So, what does this mean for your facility’s contamination control strategy (CCS)? A contamination control strategy is a scientifically formulated action plan that is tailored for each pharmaceutical manufacturing facility to address and monitor potential risks to the product or facility. It is no secret that additional measures are routinely added to guidance due to the ongoing challenges associated with the manufacture of sterile pharmaceutical products and the main goal of each CCS is to ensure that the facility remains microbial, pyrogen, and particle free. To achieve this, a monitoring and ongoing review system is also put into place to look for potential lapses in the aseptic environment and identify contamination points in the facility.
Implementing New Annex 1 Guidance
Guidance on 2023 contamination control strategies remains largely unchanged, with minor adjustments added in the revised version of Annex 1 compared to the previous 2020 update. However, a stronger emphasis has been placed on developing a CCS due to increases in drug recalls and deaths related to contaminated sterile pharmaceutical products in recent years. Drug recalls also place a financial burden on pharmaceutical manufacturing facilities and lead to hefty fines. For example, in 2009, drugs produced by Fabrazyme and Cerezyme were found to be contaminated and led to a loss of $300m in revenue for the company (Christou, 2018). In addition to this, the FDA imposed a fine of $175m, further adding to the losses (Christou, 2018). To prevent this from happening, facilities should first determine their critical control points to help tailor their CCS accordingly.
Critical Control Points to Consider when Implementing the New Annex 1 Revision
Annex 1 (EU, 2022) highlights the importance of considering the design of both the plant and the processes when developing a CCS in any pharmaceutical manufacturing facility, including the associated documentation of:
- Premises and equipment Certain equipment and machinery have been known to spread particulates in pharmaceutical manufacturing facilities and should be taken into consideration when developing a CCS. For example, isolators are a known weak link in the glove areas due to cleaning challenges of the gloves (ISPE, 2015).
Personnel
Personnel have been linked to over 80% of contamination in pharmaceutical processing cleanrooms, and necessary measures must be taken to combat this, like adopting the use of full PPE (suit, hood, boots, and gloves) in sensitive areas (Smith, 2021). Providing training and implementing automated processes can further reduce the risk of microbial contamination in aseptic processing areas of the facility.
- Raw material controls, including in-process controls Raw materials have a high potential of introducing microbial contamination into pharmaceutical manufacturing facilities and each should be evaluated carefully to determine adequate control strategies. This may include the use of high-level decontamination or sterilization of areas, surfaces, and equipment where materials are processed before entering aseptic processing areas of the facility.
- Validation of sterilization processes Biological indicators can help provide tangible, biological evidence of a vaporous decontamination and help ensure sensitive areas have been treated with a 6-log sporicidal treatment.
Preventative maintenance
Ensuring the accuracy of the current SOP for maintenance may ensure simple traceability of challenging areas.
- Cleaning and disinfection Various methods of disinfection and sterilization may be implemented in one area within a facility and understanding the roles of water PH, concentration, chemistry interaction, and particle sizes may help ensure a more successful outcome.
Various other components should be considered as well in a well-rounded CCS plan, including utilities, product containers, enclosures, vendor approval, management of outsourced activities and availability/transfer of critical information between parties, process risk management, process validation, monitoring systems, prevention mechanisms, and continuous improvement based on information derived from above (EU, 2022).
Building a Proactive Process
A major downfall of previous CCSs was that they were not proactive. Many facilities continue to identify the source of contamination after it has already occurred and then begin treating it. However, this fails to prevent it from occurring. New Annex 1 guidance encourages facilities to be proactive and determine potential areas that are at higher risk for contamination to allow for continuous monitoring and prevention strategies while taking into account the key components listed above. If contamination is found, facilities should alter their CCS to prevent further infractions and combat the spread of microorganisms.
Validating Your Sterilization Processes
An important addition to this version of Annex 1 is the validation of the sterilization processes. This simple addition can mean the difference between a contaminated and non-contaminated cleanroom. With no validation process, which includes the use of sporicidal biological indicators, it is impossible to know whether a sterilization treatment was efficacious.
The Dangers of Not or Under-Validating Decontamination Cycles
One ongoing practice possibly leading to lapses in bio-decontamination in pharmaceutical manufacturing facilities is the utilization of unverified or unvalidated sterilization products. Implementing these products can lead to contamination control concerns if the product does not actually achieve sterility consistent with current guidelines. Contamination can lead to costly implications and damaged products. This is why it is first important for every facility to determine areas in which contamination remains a concern and develop sterilization treatments to target those areas.
Recommendations for Ideal Decontamination Validation Practices
Current guidelines in the EU state that sterilization treatments must be validated on three sterilization runs achieving 6-log sporicidal efficacy (European Medicines Agency, 2019). Validation studies should use 1x10^6 biological indicators with compatible microorganisms. Although a 3-log reduction is the minimum acceptable criteria, a 6-log reduction of bacterial spores is the commonly approved standard for sterilization (EPA, 2022). Such biological indicators include Geobacillus stearothermophilus, which is best paired with hydrogen peroxide-based sterilization systems and steam sterilization, while Bacillus atrophaeus is best paired with ethylene oxide and dry heat sterilization methods. Common use of biological indicators recommends placement to be in the room or inside the RABS/containment isolators in multiple locations during the sterilization treatment cycle, as per facility-approved SOPs. A triplicate successful run can help determine strong SOPs for targeting sterilization. Incorporating 6-log validation can improve the health of your facility and ensure your sterilization products are sufficient to support your CCS.
The Shift Towards Automation
It is no secret that the new version of Annex 1 heavily emphasizes the use of technology and automated processes during aseptic processing in the manufacturing space. This is critical in reducing the risk of microbial and particulate contamination in pharmaceutical manufacturing facilities. With automation comes the reduction of human involvement during the manufacturing process (Glasure, 2020). This is pivotal, considering human involvement increases the risk of contamination by leading to the transfer of bacteria commonly found on the skin, like S. aureus and Propionibacterium, into the manufacturing space (Smith, 2021). Facilities should consider adding automated processes in areas like filling lines with vaporous high-level disinfection to help eliminate human error when developing a proactive CCS.
The Benefits of Using CURIS HHP Automated Bio-decontamination
CURIS System Hybrid Hydrogen Peroxide (HHP) devices provide portable, fully automated, and 6-log validatable sporicidal treatments that can be easily incorporated into any CCS. This innovative technology can be employed in cleanrooms to combat microbial contamination on surfaces air touches. Patented Pulse™ technology maintains optimal dwell times without leaving behind corrosive residues like traditional peroxide methods from 35-59% legacy devices. Production spaces, labs, and isolators can be easily treated using CURIS fully automated devices which are federally approved to achieve 6-log repeatable efficacy. CURIS systems are proven effective even in areas such as gloves, where contamination is commonly found, and CURIS automation can reduce human involvement, which misses critical control areas, leading to lapses in contamination control.
A Look Toward the Future
Annex 1’s additions to CCS guidance will continue to improve the health of pharmaceutical manufacturing facilities by implementing proactive strategies that can stop contamination before it occurs and improve remediation steps. Validation, automated processes, and risk management all play a large role in ensuring that sterile pharmaceutical products remain safe for the consumer and maintain the utmost quality.
How will your facility use these resources to improve the outcomes of your products?
References
“Active Substance, Excipient and Primary Container Guideline on the ...” European Medicines Agency, Committee for Medicinal Products for Human Use (CHMP), 9 Mar. 2019, https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-sterilisation-medicinal-product-active-substance-excipient-primary-container_en.pdf.
Christou, L. (2020, January 16). The high cost of contamination in drugs manufacturing. Pharmaceutical Technology. Retrieved January 25, 2023, from https://www.pharmaceutical-technology.com/sponsored/high-cost-contamination-drugs-manufucaturing/
Committee for Medicinal Products for Human use (CHMP). (2019, March 9). Guideline on the sterilisation of the medicinal product, active substance, excipient and primary container. European Medicines Agency . Retrieved January 24, 2023, from https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-sterilisation-medicinal-product-active-substance-excipient-primary-container_en.pdf
Glasure, A. (2020, November 25). Cleanrooms, contamination and the realities of Pharmaceutical Automation. BioSpace. Retrieved December 20, 2022, from https://www.biospace.com/article/cleanrooms-contamination-and-the-realities-of-pharmaceutical-automation/
“Protocol for Room Sterilization by Fogger Application - US EPA.” Environmental Protection Agency, EPA, https://www.epa.gov/sites/default/files/2015-09/documents/room-sterilization.pdf.
Smith, L. M., Lamb, A. J., & O’ Driscoll, N. H. (2021, October 13). A comparison of the bacterial contamination of the surface of cleanroom operators' garments. EJPPS. Retrieved December 24, 2022, from https://www.ejpps.online/post/vol26-3-a-comparison-of-the-bacterial-contamination-of-the-surface-of-cleanroom-operators-garments
The Rules Governing Medicinal Products in the European Union Volume 4 EU Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use. European Commission. (2022, August 22). Retrieved January 24, 2023, from https://health.ec.europa.eu/system/files/2022-08/20220825_gmp-an1_en_0.pdf
“Risk of Contamination through Pinholes in Gloves and How ... - NemtilmeldI.” ISPE Nordic, 10 July 2015, https://ispenordic.nemtilmeld.dk/images/descriptions/13540/2_Scholler_Risk_of_contamination_through_pinholes_in_gloves_ISPE.pdf.