USP publishes Draft Chapter on Contamination Control Strategy

With the new chapter on Contamination Control Strategy (CCS), the USP builds a bridge between the requirements of CFR and the current 1st edition. In its introduction, the USP states that microbiological contamination control is a crucial part of drug manufacturing. In the USA, this is regulated by legal requirements such as CFR §211.113. A contamination control strategy (CCS) is required to minimise the risk of microbial contamination. It includes a holistic view of the entire production facility and is based on quality risk management (QRM). The most important sections are listed below, whereby the USP emphasises that this overview does not represent a 100% list of all relevant aspects.

Planning and operation of the plant

• Cleanroom design: minimisation of microbial contamination through cascading pressurisation and appropriate cleanroom classifications (ISO standards).
• Air control systems: Temperature, ventilation and humidity control, use of HEPA filters.
• Material flow & process flow: Unidirectional processes to avoid cross-contamination.
• Cleanroom qualification: Regular testing of particles, airflow and filter integrity.
• Maintenance: Planning of building maintenance taking microbial risks into account.

Equipment and process

• Equipment design: Cleanable and sterilisable production equipment with validated cleaning efficiency.
• Process design: Closed systems are preferred; open processes require ISO 5 environment.
• Material transfer: Validated methods for transfers to ISO 5 areas.
• Hold times: Must be validated to prevent microbial growth.

Personnel

• Training: Fundamentals of microbiology, aseptic technique, environmental controls and cleaning.
• Garbing: ISO 8 areas require protective suits, ISO 5 areas require additional sterile bonnets, masks and gloves.
• Qualification: Includes training, monitoring and microbiological testing.

Supply facilities

• Water: Must be pharmaceutical grade and regularly tested for microbial contamination.
• Process gases: Direct contact with products requires sterile filters (0.2 µm) and regular testing.

Raw material controls

• Risk assessment: Takes into account origin, manufacturing processes and storage.
• Incoming inspections: Inspection of materials by suppliers and manufacturers required.

Product containers and closures

• Integrity assurance: Container and closure integrity testing.
• Storage and transport validation: Ensuring microbial barrier function.

Management of outsourcing activities

• Quality assurance of external service providers: audits, quality agreements and regular inspections.
• Examples: Sterilisation, environmental monitoring and cleaning of outsourced areas.

Risk management and process validation

• QRM approach: Identifying, analysing and assessing microbial risks.
• Process validation: Continuous evaluation of sterilisation and production processes.

Cleaning and disinfection

• Regular disinfection: Based on cleanroom classification and microbial trends.
• Validation: Documentation of the effectiveness of cleaning agents and disinfectants used.

Verification of monitoring controls

• Environmental and personnel monitoring: Evaluation of microbial control in production areas.
• Alternative monitoring methods: Faster detection of contamination using new technologies.
• Trend analyses: To identify microbial hotspots and optimise the CCS.

Aseptic process simulations (APS)

• Regular tests: Worst-case scenarios to ensure aseptic conditions.
• Validation of media fill tests: Proof of the effectiveness of the aseptic process.

Investigation of deviations

• Root cause analysis: Determining the cause of microbial contamination.
• Corrective and preventive actions (CAPA): Implementation and effectiveness testing.

A more detailed presentation of the individual points and the associated content can be found after prior registration on the website of the USP.