Cleanroom Cleaning: A Comprehensive Guide for Pharmaceutical Facilities

With the formal release of EU-GMP Annex 1 "Sterile Products Manufacturing" (effective August 25, 2023), pharmaceutical companies face a significant change: implementing contamination control strategies (CCS) throughout their facilities to define all critical control points. To help clients better understand specific issues in cleanroom cleaning processes, this guide provides detailed answers to common questions.

I. Disinfectant Management

When changing disinfectant suppliers, facilities must follow a three-step approach:

1. Evaluation: Assess whether the disinfectant type has changed and evaluate disinfectant rotation schemes and associated risks

2. Commercial Audit: Review and assess supplier qualifications

3. Verification: Most critically, confirm the disinfectant's antimicrobial efficacy through validation. Only after passing verification can the supplier's disinfectant be approved for purchase

4. Change Control: Implement subsequent change control measures

II. Production Area Cleaning Schedules

For Grade B areas with production cycles exceeding one week, cleaning schedules must be carefully considered:

• For cycles slightly over one week, cleaning should be performed immediately after production ends

• Two different levels of cleaning may be required

• For significantly longer cycles, additional operations must be considered

• Any human intervention requires immediate cleaning afterward

• Cleaning cycles should correspond to production cycles, with a second cleaning after production completion

III. Equipment Cleaning Classifications

Major and minor cleaning distinctions are based on equipment cycles and material processing:

• Particularly important for continuous API production

• Minor cleaning focuses on internal equipment cleaning

• Major cleaning includes both internal and external equipment cleaning

• Special equipment may require specific considerations based on process requirements

IV. Environmental Monitoring

Environmental monitoring exceedances aren't solely due to cleaning issues. Contributing factors include:

1. Cleanroom design rationality

2. Environmental control capabilities

3. Human activities

4. Material movement

5. External particles and microorganisms introduced with materials

6. Cleaning measures

V. Complex System Cleaning

For complex systems like fermentation equipment with wall-mounted valves and pipework:

• Systems should not be directly against walls to allow cleaning access

• Even small cleaning spaces should be maintained

• Cleaning strategies should match ceiling cleaning protocols

• For areas below two meters in sterile environments, daily cleaning isn't recommended

• High-mounted pipework should follow ceiling cleaning protocols

VI. Cleaning Procedures

1. Large particle removal comes first

2. Followed by cleaning agent application (not necessarily water)

3. Commercial sterile cleaning agents like 70% ethanol or IPA are acceptable

4. Cleaning must precede disinfection

5. Pressure differentials must be considered even during routine cleaning

VII. Material Management

For cleaning tools and materials:

• Different grade areas require different cleaning materials

• Grades A/B require sterile wiping materials

• Grades C/D can use non-sterile materials

• Pre-moistened disposable sterile wipes must be used according to manufacturer specifications

VIII. Documentation Requirements

1. Cleaning records require:

•   Operator signatures

•   Verification signatures

•   QA and management signatures for inspection records (not routine cleaning)

2. Material transfer SOPs must specify:

•   Types of materials and tools entering clean areas

•   Entry points and transfer windows

•   Cleaning and sterilization methods

IX. Special Applications: CAR-T Production Facilities

For CAR-T production areas:

1. Critical operation rooms:

•   Require cleaning after each operation

•   Higher cleaning frequency due to long cultivation periods

2. Auxiliary corridors:

•   Cleaning frequency depends on usage patterns

•   Daily cleaning may be required for high-traffic areas

•   For low-volume operations (1-2 weeks between batches), clean after each use

3. Sterile product areas:

•   General recommendation for cleaning at the end of each shift

•   Frequency adjustments based on production schedule and facility utilization

This comprehensive guide ensures all aspects of cleanroom cleaning are addressed while maintaining compliance with current regulations and ensuring proper cleanliness standards for pharmaceutical production.

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