The importance of the contamination control strategy (CCS) in relation to Annex 1
8 June 2023
Commissioning & QualificationThe concept of CCS – Contamination Control Strategy is defined in the Annex 1 glossary (not present in the previous version) as:
“A planned set of controls for microorganisms, endotoxins/pyrogens, and particles, derived from the current understanding of the product and the process, ensuring both process performance and product quality. The controls may include parameters and attributes related to the active substance, excipients, materials and components of the pharmaceutical product, operational conditions of the plant and equipment, in-process controls, finished product specifications, and related methods and frequencies of monitoring and control.”
The CCS concept permeates the entire Annex 1 document (sometimes specifically, other times in a cross-cutting manner) and is a fundamental principle. It is mentioned multiple times and indicates examples and topics that need to be addressed.
It can be a single document (quite extensive) or a collection of documents, procedures, assessments, rationales, and/or references to them; we could call it a CCS dossier.
Therefore, it is a strategy that needs to be implemented throughout the production structure to define all critical control points and evaluate the effectiveness of the implemented controls and monitoring measures used to manage risks to the quality and safety of medicines.
The implemented (or to be implemented) controls will depend not only on design (Quality by Design) but also on procedural steps, technical solutions, and organizational aspects.
To compose the CCS dossier, it is necessary to have knowledge of the product (competence in it), the process to obtain it, and the contamination risks related to manufacturing (in order to prevent/avoid them). In effect, the CCS document set is essential for companies to demonstrate their knowledge and control of their processes (it supports the entire production process). It describes in detail how a site knows, controls, and minimizes risks to the quality of the product(s). It is a comprehensive view that allows the implementation of controls ensuring product quality but, above all, patient safety.
All process experts (SMEs, Quality Assurance, Quality Control, Sterility Assurance, Production Operations, Designers, Logistics, Packaging, etc.) must analyze (understand and evaluate) all potential sources of microbiological, particulate, and chemical contamination that the product (and all associated parts/processes) may encounter during its journey (from raw materials and their suppliers to the manufacturing plants, every process machine and related work phases, analysis of operations and interventions – both automated and manual – packaging and shipment, etc.).
Therefore, interdisciplinary collaboration and integration among different parts of the company are necessary to identify potential sources of contamination (microbiological/particulate/pyrogenic).
The CCS dossier is considered a living document (to be reviewed/updated throughout the product/process lifecycle). Any changes to the systems involved in the process require a reevaluation of the validity of the CCS. The periodic review could be annual (although Annex 1 does not specify it).
Minimum elements to be considered when structuring the CCS dossier
| Minimum points to be addressed in a CCS dossier | Relationships and interrelationships within Annex 1 |
|---|---|
| Plant and process design | Part of the CCS dossier will be the documentation of the project and/or changes related to it regarding: - Facility, specific departments, process design, selection of layouts and environmental classifications, cross-contamination controls, bio-contamination controls, sanitization processes, automation and/or procedural controls designed and implemented during the design phase, but also the rationale that led to that design choice to control and mitigate contamination risks (along with the methods for monitoring these controls). Where there is a high risk of contamination, the dossier must have evaluated appropriate layouts (e.g., IN and OUT separation for production areas) and the introduction of control methods for incoming materials in production zones (e.g., checklists for materials that can enter, their cleaning/disinfection, and environmental monitoring plan - viable and non-viable, temperature and humidity, pressures) - Point 4.12 Air flow visualization studies - which are an integral part of the design, and subsequently, during C&Q, the air flow pattern tests - play a fundamental role in demonstrating that critical areas are protected by the UDAF (Unidirectional Air Flow). |
| Facilities and Equipment | The documents comprising the CCS must contain at least the following information: - Set pressure setpoints for cleanrooms, the need for continuous monitoring, and alarms if they are deemed critical (assessment and justification of assigned delays - for example, associated with a qualification study related to the operations to be performed, clean-up period, etc.) - Point 4.16 - Frequency of glove change in RABS and isolators - Point 4.21 - Analysis and evaluation for the use of RABS and isolators in the process flow - Point 4.3. RABS and/or isolators are useful for minimizing microbial contamination associated with direct human interventions in the critical zone (if possible, they should be eliminated from the process). Otherwise, their risk needs to be analyzed and controlled (possible risk reduction actions). - Analysis and evaluation for the use of robotics and process automation, always aiming to eliminate/reduce human interventions for critical operations (e.g., loading/unloading of lyophilizers, SIP). |
| Personnel | Personnel at all levels must be experienced and qualified - a concept reiterated multiple times within Annex 1. Training must be continuous, documented, and monitored. In general, personnel should be trained and instructed in: - Hygiene - Basic elements of microbiology and sources of contamination. - How to prevent contamination during process operations (aseptic behaviors and techniques) - Gowning (to be confirmed at least once a year, and for sterile gowns accompanied by visual and microbiological evaluation) - Understanding personnel and material flows - Understanding the process in which they are actively and integrally involved Furthermore, the CCS dossier must specify the number of people allowed to operate in the cleanroom. It should be sufficient to manage the process, but the maximum number must be established to not compromise sterility (to be determined during initial qualification and APS, based on both "In Operation" classification tests, both viable and non-viable, clean-up time, and other parameters considered important for containing contamination). SOPs should specify the maximum number of personnel. |
| Utilities | The CCS should indicate: - Whether it is necessary to measure air velocity in classes B, C, and D (not just the supply air volume) - Point 4.32 - Furthermore, Annex 1 indicates that the air velocity test (for non-unidirectional flows) could be replaced by the recovery test. - Based on risk assessment and rationale, what controls should be performed on Utilities that have an impact on product quality, and the corresponding sampling plans, with alert and alarm limits. The impact of the controls on the utility itself should also be evaluated - Point 6.1 and 6.13. |
| Controls on raw materials, including in-process controls (IPC). | Not only do all raw materials contributing to the process and materials for laboratories (point 10.2) need to be controlled and identified, but also personnel garments. They must be qualified and controlled for material quality, particle retention efficiency, washing processes, maximum number of rewashings and sterilizations, and packaging. For glove materials, chemical and mechanical resistance is explicitly required. |
| Containers and Closures of Products | All glass containers, BFS (Blow-Fill-Seal) containers, and those with a capacity of less than 100 mL sealed by fusion must undergo 100% integrity verification using a validated method (CCI validation). For containers with a larger volume (greater than 100 mL), also sealed by fusion, a reduced sampling integrity test is allowed if it has been scientifically proven to provide a high level of process control and test data consistently demonstrate process consistency. Note: Visual inspection is not considered an acceptable integrity test. Where possible, in-process tests (IPC) should be correlated/validated with CCI. CCI validation should also consider variations (pressure, decompression, temperature) that the container-product undergoes during transportation. |
| Supplier Approval - (e.g., for critical components, sterilization of single-use systems - SUS, and critical services) | The evaluation of suppliers of single-use systems, including their sterilization, is crucial for the selection and use of these systems. For sterile SUS, verification of sterility assurance must be conducted as part of supplier qualification. Specific risks associated with SUS (and their suppliers) should be assessed in the CCS - Point 8.132. For example, it is necessary to evaluate: - The interaction between the product and the product-contact surfaces under real process conditions (e.g., leachables and extractables), and any potential impact on product quality, especially if the system is made of polymer-based materials. - The fragile nature of the system compared to reusable fixed systems. |
| Management of outsourced activities and availability/transfer of critical information between parties, such as contract sterilization services | Qualification of suppliers and their processes: It is necessary to conduct an evaluation and qualification of suppliers, including their processes, to ensure they meet the required criteria. For example, if external tests or culture media provided by third parties are used, it is important to justify their use and consider transportation and shipping conditions. It is also important to establish a confidentiality agreement to protect critical information shared between the parties. |
| Process Risk Management | - The CCS (Controlled Change System) must identify if there are specific risks during the filling of products intended for terminal sterilization (slow filling, wide-neck containers, a significant amount of time - more than a few seconds - between filling and vial closure). In such cases, the filling must be performed in a Class A environment with a minimum background of grade C - Point 8.4. - The CCS must clearly define acceptance criteria for controls associated with aseptic process risks, as well as requirements for monitoring and reviewing their effectiveness. Accepted residual risks must be formally documented. The CCS should indicate precautions taken to minimize microbial contamination, endotoxins/pyrogens, and particles during the preparation of the aseptic environment, throughout all processing stages (including pre- and post-sterilization of bulk product), and until the product is sealed in its final container. The presence of materials capable of generating particles and fibers must be minimized - Points 8.7 and 8.8. - The CCS should prescribe whether or not to use a sterile, sterilizing filter as close as possible to the filling point (for products that cannot be terminally sterilized in their final container) - Point 8.80. - For Form-Fill-Seal (FFS) and Blow-Fill-Seal (BFS) processes, the CCS must define the sampling frequency for required tests, bioburden levels, and (where applicable) endotoxins/pyrogens for packaging films and associated components. - The frequency of sterilization for lyophilizers loaded and unloaded by automatic systems or protected by closed barrier systems must be justified and documented in the CCS - Point 8.123. - Adequate measures must be taken to ensure the integrity and sterility of components used in aseptic connections of closed systems. The means to achieve this goal must be determined and included in the CCS. Appropriate integrity tests of the system should be considered. Supplier evaluation should include the collection of data on potential failure modes that could lead to a loss of system sterility - Point 8.129. - All possible holding times must be evaluated and challenged with dedicated qualifications. - There should be a list of permitted and qualified aseptic interventions, both related to production itself and corrective operations. - During the Aseptic Processing Simulation (APS), all interventions must be re-executed. - Non-qualified interventions should be pre-evaluated and used only in exceptional cases, requiring approval from Quality Assurance and evaluation/consideration during batch disposition. |
| Process Validation and Sterilization Process | - For each sterilization process, the loads must be validated (subject to periodic revalidation). The validation strategy for loads should include both minimum and maximum load configurations. Sterilization cycles for worst-case loads should be revalidated at least annually. The need for validation confirmation for other load types should be evaluated and justified in the CCS (Controlled Change System) - Point 8.39. - Annex 1 provides minimum validation requirements for different processes and/or types of sterilization. |
| Preventive Maintenance | Having a CMMS (Computerized Maintenance Management System) that allows monitoring of GMP (Good Manufacturing Practice) deadlines and criticality for equipment, services, and premises, including periodic validations. Fit & finish, housekeeping, pest control. Cleaning & sanitization of Facility and Utilities. Following maintenance (and/or periodic revalidation) on equipment, components, and/or utilities, their return to use - Return to Service - must be approved (involving relevant personnel such as qualification, engineering, maintenance, production, and quality). The execution of unplanned maintenance on critical machinery must be evaluated and approved by QA (Quality Assurance) as it may have an impact on product sterility. |
| Cleaning and Disinfection | The documents comprising the CCS should consider the following aspects: - Validation of disinfectants and their action on surfaces. - Procedure for the use and disinfection of electronic devices (e.g., tablets required for monitoring/implementing the process itself) to be brought into and used in the cleanroom - Point 7.9. - Rotation and differentiation of disinfectants. - Monitoring (to verify disinfectant efficacy and identify new types of microbial flora). - Evaluate whether disinfectants used in Grade C and D areas need to be sterile - Point 4.35. - If there are operations in Grade C and D areas considered to have a high risk of contamination (assessment performed in the CCS document), wearing gloves and facial masks may be required - Point 7.13. - How to sterilize (prior to use) the detergents and disinfectants used in Grade A and B areas. - How to demonstrate that cleaning and bio-decontamination agents do not impact the product (including accompanying components such as caps, seals, etc.) that will be processed within the RABS and/or Isolator. |
| Monitoring Systems (Environmental and Process Monitoring) | EM and PM are essential parts of CCS and are responsible for confirming the effectiveness of controls that have been designed (and therefore implemented) to minimize the risk of contamination, or rather to keep it under control – Point 9.1. EM and PM allow for effective detection of deviations from environmental limits and initiate investigations and risk assessment for product quality. Establishing a good EM/PM program. Risk assessment is necessary, for example, for sampling locations, monitoring frequency, monitoring methods, and incubation conditions (e.g., time, temperature, aerobic and/or anaerobic conditions). Alert and action limits should be based not only on regulatory requirements but also on historical and qualification data and the nature of one's own process, as well as what is written in the CCS - they should be periodically reviewed based on trend data. Action limits must adhere to regulatory limits (Table 5 - Non-viable total particles - and Table 6 - Viable), but based on CCS/historical data, they may be lower. The use of new and appropriate technologies to enhance product safety and reduce contamination is encouraged, provided they are equivalent (or superior) to traditional methods (equivalence/superiority must be demonstrated through validation). When using rapid and automated microbial methods, these methods must be validated for the relevant products/processes. CCS should indicate whether to consider 5-micron particles during the classification of Zones A and B and whether to consider different limits from 0.36-0.54 m/s (scientifically justified) for working positions/stations - Point 4.27 and 4.30. When performing aseptic operations, microbial monitoring (viable particles) must be frequent using a combination of methods such as settling plates, volumetric air sampling, sampling on gloves, garments, and surfaces (e.g., swabs and contact plates). The sampling method used must be justified within the CCS, and it must be demonstrated that it has no negative impact on Grade A and B AFPs - Point 9.22 - therefore, sampling positions, plate placement, and replacement will be part of the AFP tests. The number of units processed (filled) for APS must be sufficient to effectively simulate all representative activities of the aseptic production process. The justification for the number of units to be filled must be clearly stated in the CCS. Typically, at least 5000-10000 units are filled. For small batches (e.g., those less than 5000 units), the number of units processed in APS must be at least equal to the batch size of production - Point 9.40. |
| Prevention Mechanisms | It is necessary to collect data and trends from production processes in order to analyze and evaluate whether there are any preliminary indications of process control loss (determining the root cause, corrective and preventive actions - CAPA - and the need for comprehensive investigation tools). |
| Continuous Improvement based on the information obtained from the above. | Having a strong quality system and documentation management. Knowledge, experience, adherence to regulatory aspects. |
In conclusion, it is necessary to have a set of documents that demonstrates in-depth knowledge of one’s processes and stating, for each aspect of them, the control strategy applied.
Thus, it must contain at least the following:
- Design requirements
- Design documentation
- Rationales supporting design choices.
- Validation master plans with rationale supporting the chosen tests and acceptance criteria.
- Documentation illustrating the processes (process flow diagrams, layouts, etc.) and controls implemented in the design.
- Process analysis and identification of risk points for contamination.
- Criticality analyses for plants, components, alarms, and associated actions.
- Maintenance and return to service management programmes.
- Periodic validations
- Cleaning/sanitisation/sterilisation practices
- Utilities sampling plans with rationale, control strategy
- Staff training
- Vendor and material management and qualification
- Closure system qualification (CCI validation)
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