In this all-encompassing article, Subroto Mukherjee, Vice President & Head – Administration & Facilities Management, Cipla lays down the law for how pharma FM heads and service providers must work together to meet the stringent domestic and international regulatory Good Manufacturing Practices (GMP) requirements.
Pharma GMP standards
GMP standards apply in all geographies across the globe and are defined by the local regulatory authority, such as the US FDA’s Code of Federal Regulations Part 21 or the UK MHRA’s Orange Guide. According to Indian CDSCO and Schedule M, as per Section 9 (Sanitation in the Manufacturing Premises):
9.1 The manufacturing premises shall be cleaned and maintained in an orderly manner, so that it is free from accumulated waste, dust, debris and other similar material. A validated cleaning procedure shall be maintained.
9.2 The manufacturing areas shall not be used for storage of materials, except for the material being processed. It shall not be used as a general thoroughfare.
9.3 A routine sanitation program shall be drawn up and observed, which shall be well recorded and which shall indicate (a) specific areas to be cleaned and cleaning intervals; (b) cleaning procedure to be followed, including equipment and materials to be used for cleaning; and (c) personnel assigned to and responsible for the cleaning operation.
According to the US FDA, ‘Facilities should be appropriately cleaned and disinfected to ensure sufficient microbial control. The firm should have established, validated cleaning and sanitising procedures and be able to provide justification for established residual limits using validated analytical testing methods.’
Working with service providers
- Shortlist and select the service provider, preferably one with a proven and verifiable track record in international pharma GMP operations and having a robust QMS and in-house training team.
- Carefully curate an SLA that ticks all the pharma GMP boxes and ensures self-performance by the service provider. We need to put in place methodology to ensure availability of accurate and real-time delivery history, and deterrents and quick cures for non-adherence.
- Strict adherence to SOPs and procedures through training and robust governance is a must. So are quarterly/half yearly audits by GMP experts to identify gaps, proactively implementing effective CAPAs, training teams to avoid deviations and audit observations.
They are site specific and relevant to the manufacturing equipment in use. Use of Isopropyl Alcohol (IPA) and purified water are common in most cleaning procedures, along with lint-free cloth.
Some points to be borne in mind when devising cleaning SOPs for manufacturing equipment include:
- Compatibility of cleaning agents with chemicals used for manufacturing.
- Corrosiveness of equipment surface.
- Cleaning-in-Place to be validated as part of process validation and ‘Dirty Hold time’ and ‘Clean Hold time’ parameters as defined by the site.
- Sensitive electrical connections and tubings of instruments need special care while cleaning.
Disinfectant selection criteria depend on relative types of microorganisms in the viable count (Gram negatives, gram positives, yeasts, spore-forming organisms etc.), level of control required, and compatibility with other disinfectants/cleaning agents.
The sequence of disinfection is very important:
- Cleanest to dirtiest (closest to HEPA to furthest from HEPA).
- Ceilings > walls > floors.
- Grade A > Grade B > Grade C.
- Unidirectional wiping: back to front, top to bottom.
- ‘S’ method may be used to disinfect floors.
Site SOP instructions should include:
- Equipment used and list of agents.
- Storage of cleaning materials and equipment.
- Preparation of disinfectants: dilution and water requirements.
- Labeling of agents, documentation.
- Sequence, frequency, and methodology.
- Rotation scheme for disinfectants, equipment preparation.
- Area specific methods (e.g. double bucket method).
- Equipment/area to be disinfected.
- Equipment storage and preparation for storage.
- Disposal of used cleaning/disinfecting agents.
- Hazards and safety precautions required (e.g. PPE).
- Reference to gowning and trafficking/flows procedures.
- Drain cleaning, expiry date of a disinfected area.
- Actions to be taken in case of an unplanned event.
Working around production process
- Based on scope of work, the frequency of cleaning and area to be cleaned should be defined. E.g. Prior to the start of production and at the end of shift.
- Need-based cleaning during process spills with defined PPE and cleaning equipment.
- In the event a manufacturing process is ongoing and entry of housekeeping personnel is necessary, it should be done in compliance with the gowning procedure for the area and also post permission of the area supervisor. This is necessary to avoid contamination of the product if an open process is being carried out.
- Restricted to yellow line in case of hazardous drug manufacturing.
Choice of cleaning solutions
- Grade A/B areas: Sterile water, purified water or better (WFI)
- Grade C/D areas: Purified water or better (WFI). Does not have to be sterile
- Disinfectants: Validated disinfectants based on environmental isolate study or approved disinfectants.
- Tools for sterile equipment: Mop handles, mop heads (discarded after use), buckets – autoclaved prior to each use or sterile pre-packaged bucket, low particulate shedding wipes
- Machines: Walk-behind or ride-on scrubbers, vacuum cleaners, single disc machines.