| Department | Validation/Technical Services | Document no | VAL-120 | ||
| Prepared by: | Date: | Supersedes: | |||
| Checked by: | Date: | Date Issued: | |||
| Approved by: | Date: | Review Date: | |||
1.0 OBJECTIVE
The purpose of cleaning validation is to provide documented evidence that the cleaning process is effective in removing residues of a product, cleaning agent or microbial contamination to below a predetermined level.
The objective of this guideline is to describe the approach and methods, which will be used to validate cleaning and sanitation procedures involved in GMP processes employed in GMP Site Manufacturing facilities.
2.0 BACKGROUND
Cleaning procedures are established in order to reduce cross contamination between products, cleaning agents and microbial contamination to acceptable levels. The cleaning procedures define the frequency of cleaning, the cleaning method, the type and concentration of cleaning agents used or the automatic cycles employed for Cleaning In Process (CIP) systems.
Applicable equipment qualifications and all supporting method validation must be completed prior to execution of cleaning validation studies.
3.0 SCOPE
This guideline applies to all major and minor manufacturing equipment at a GMP facility where automated or manual cleaning procedures are employed.
This guideline should be read in conjunction with this guidance documents for cleaning validation.
4.0 RESPONSIBILITY
Validation / Technical Services
Validation / Technical Services is responsible for establishing and maintaining cleaning validation programs and for developing and approving all cleaning validation policy, plans, protocols and reports. Technical Services is responsible for verifying that all cleaning validation programs are in compliance with this guideline and current GMP
Manufacturing
Manufacturing is responsible for ensuring that validated cleaning procedures are used to clean all major manufacturing equipment.
Quality Assurance
Quality Assurance is responsible for ensuring that the GMP aspects of the cleaning validation programs are in accordance with relevant procedures and that critical parameters and report conclusions are supported
5.0 VALIDATION POLICY
5.1. Equipment changeover cleaning procedures must be validated for all major and minor product contact equipment used for multi-product production, subdivision and sampling of drug products and in process materials.
5.2. Equipment cleaning validation shall be based on a worst-case product with the minimum calculated acceptable carryover limit using the calculation model for Residue Acceptability Limit. For Non-Therapeutic materials the Residue Acceptability Limit for Non-Therapeutic materials based on toxicity applies. The minimum calculated acceptable carryover will be used as the cleaning validation criteria for all products manufactured in the specified equipment.
5.3. Three consecutive successful applications of the cleaning procedure are required to demonstrate that the procedure is validated. Batches of another product cleaned by a different cleaning procedure may intervene the three applications of the procedure undergoing validation trials shall be executed using one or more of the following options:
Cleaning validation trials performed at the end of a regularly scheduled campaign; and/or
Cleaning validation trials conducted at campaign lengths less than the maximum campaign length, so long as at least one trial is at full campaign length. Additional cleaning validation trials, using the next most difficult to clean product, may be conducted prior to completion of the three validation trials of the most difficult to clean product. For retrospective cleaning validation studies, a second worst case product should be considered if the worst case product is manufactured infrequently. Failure of a validation trial for the next most difficult to clean product is equivalent to a failure of the validation trial for the most difficult to clean product
5.4. When there is a deviation from the planned cleaning procedure on one of the replicate runs, it may be removed from the sequence if an assignable cause can be determined and the deviation is unrelated to the cleaning procedure. e.g., power loss, cleaning utility malfunction. In situations where an assignable cause can not be determined a review of the procedure should be conducted, followed by three successful cleanings.
5.5. Where acceptance criteria has not been met, a complete review of the cleaning procedure should be conducted, followed by three successful cleanings. In this situation the cleaning run cannot be removed from the sequence.
5.6. The effectiveness of the cleaning procedure must be evaluated by visual inspection and if required, testing for drug residue, cleaning agent residue and microbial bioburden. Where evaluation demonstrates that routine cleaning procedures are not acceptable, cleaning SOPs and equipment will be reviewed and revised or modified as necessary.
5.7. A product grouping or equipment bracketing strategy can be used to avoid the need to validate all combinations of equipment, processes and products in the program. A representative range of similar products (product-based or family approach) and equipment train (equipment-based) is selected to rationalize the validation program.
5.8. Equipment with the same design and operating principles and with the same cleaning procedures can be grouped for the purposes of cleaning validation. These groupings should be documented and justified. Cleaning validation shall be performed using three executions of the same cleaning procedure using any combination of equipment within a group. Care must be taken not to negate worst case scenarios defined as a part of the product grouping strategy.
5.9. Equipment which is new to the facility must be thoroughly cleaned before use and during equipment qualification. This type of cleaning does not generally require validation but assurance of the removal of oily residue, detergents, solvents or other cleaning agents before use needs to be ascertained by visual inspection. Use and Cleaning History must be determined for product contact equipment that has been used by third parties or by another Site facility (e.g., trials, rentals, borrowed). The history must be documented, and it must be verified that previous product residues were removed prior to any new cleaning or use.
5.10. Identification of worst case (hardest to clean) swabbing locations must also be identified if uniform distribution of contamination is assumed. The exact location of swabbing must be identified in the protocol if there is potential to swab more than one location at the area identified.
5.11. Analytical Methods used for Cleaning Validation must be validated and have detection limits with sufficient sensitivity to detect the established acceptable level of residue.
5.12. Training and qualification in the use of validation sampling and analytical methods shall be part of the training record for personnel performing these functions.
5.13. Two types of cleaning can be conducted. Campaign, that is between batches of the same product, and change over that is between batches of different product. In campaign cleaning consideration should be given to microbiological contamination and product build up.
The cleaning procedures for campaign manufacture equipment must specify the number of batches which can be campaigned and the length of time the equipment can be operated before a full clean is performed. Campaign cleaning should be performed according to cleaning procedures and will form a subset of the full cleaning validation.
Campaign Validation trials shall be executed using one or more of the following options:
a. Cleaning validation trials performed at the end of a regularly scheduled campaign; and/or
b. Cleaning validation trials conducted at campaign lengths less than the maximum campaign length, so long as at least one trial is at full campaign length.
5.14. Cleaning Validation will include any or all of the following. It must include visual. Visual inspection should include all accessible product contact parts of manually cleaned systems and pre-defined parts of automated cleaning systems. Special attention should be paid to areas that are difficult to clean, observe or reach and where residue may accumulate.
Swab analysis may be used to quantitatively determine the presence of worst case products or cleaning agents on the surface of the equipment. Appropriate methods will be developed and validated for each target residue prior to the validation of the equipment cleaning procedures.
Rinsing volume analysis is used to assess the cleanliness of surfaces which cannot be reasonably accessed for accurate assessment via swabbing. Rinse methods must be validated.
Microbial Acceptability Limits for Equipment Cleaning shall be established and validated, when required.
5.15. For many OTC products the residue carryover limit will be above the visual limit of detection per standard surface area. Under these circumstances full swab and rinsate testing may not be justified and visual inspection is acceptable. In order to utilise visual inspection only, limits of detection for visual inspection should be established and validated.
5.16. Dirty Holding Time is defined as the interval between use and cleaning and must be specified in the protocol and validated using at least one cycle. If the validated Dirty Holding Time is exceeded a risk assessment must be performed and if necessary the equipment must be assessed for product and microbial contamination following cleaning.
5.17. Clean Holding Time is defined as the interval between cleaning and use and must be specified in the protocol and validated. If the Clean Holding Time is exceeded the equipment shall be cleaned again prior to use and verified as clean
5.18. Validation of the removal of cleaning agent and/or sanitizing agent residue is required for dedicated equipment campaign cleaning or interval cleaning whenever major cleaning is performed. Full cleaning validation is not required for product dedicated equipment if cleaning/sanitizing agents are not utilized; visual examination and microbial testing only will apply. Dedicated equipment includes:
a. Equipment used to manufacture one or more strengths of the same product
b. Different products or dosage forms with the same active ingredient and excipients
5.19. Contract manufacturers that produce and/or control site products are to use practices that are validated to standards equivalent to those specified in this guideline.
5.20. Prior to introduction of any new cleaning agent an assessment report must address the probable impact on the current equipment cleaning validation plan
6.0 CLEANING VALIDATION DOCUMENTATION
6.1 Validation Project Plans
A Cleaning Validation Project Plan must be available for all product contact equipment and must be approved by the site validation authority, site production authority and site quality authority. Individual equipment trains or manufacturing areas may have their own cleaning plans. Typically a cleaning validation project plan should contain the following:
Description of equipment/equipment evaluation and cleaning procedures
Grouping strategies
Product/Formula Attributes
Worst case analysis
Calculation of the equipment train surface area
Calculation of acceptance limits
Procedure for recovery qualification
Analytical and sampling methods to be used
Documentation required for completion of validation study
Reference cleaning equipment qualification
Cleaning parameters and applicable ranges
Equipment surface finish
Suitability of cleaning agents
Potential for degradation by products or conversion products
6.2 Cleaning Validation Protocols
Equipment Cleaning Validation Protocol must be prepared and approved by the relevant Site Validation Committee (SVC) members or their designee and shall include or reference at least the following:
Approval Page with approval signatures and date of final approval;
Approved Cleaning Procedure/Instruction-Records to be validated;
Products addressed by the protocol;
Description of equipment and cleaning cycle;
Reference to qualification of all major equipment involved;
Campaign lengths, if applicable;
Residue materials to be removed;
Cleaning parameters to be evaluated;
Cleaning and sanitizing materials to be used;
Analytical Methods;
Microbiological Test methods
Sampling Plans;
Sampling Methods; and
Acceptance criteria.
6.3 Cleaning Validation Reports
A cleaning validation report will be written and approved for each protocol. An interim report will be written if consecutive cleaning validation trials are more than three months apart. Typically a report will contain the following:
Summary
Introduction
Scope
Results
Deviations from the protocol (Failures during cleaning validation are to be documented as deviations and reviewed by the relevant SVC members)
Acceptance Criteria
Conclusions
7.0 CLEANING VALIDATION ACCEPTANCE CRITERIA
Residue acceptability limits for cleaned equipment must be established using an approved method of calculation. Determination of acceptance criteria must be based on a careful evaluation of equipment, procedure, associated risk of contamination and sound scientific judgment. Limits should be logical, practical, achievable and verifiable.
7.1 Visual Inspection
No quantity of residue will be visible on the equipment after the cleaning procedures are performed and when the equipment is dry.
7.2 Therapeutic and Non Therapeutic Residues Removal
Equipment cleaning validation for each cleaning procedure shall be based upon the most difficult to clean product using the calculation model for the Residue Acceptability Limits (RAL).
The minimum calculated carryover limit for all product combinations will be used as the residue cleaning validation criteria for all products manufactured in the specific equipment train, item or unit and cleaned using the equipment cleaning practice and specified materials.
7.3 Microbiological Acceptance Criteria
7.3.1 Rinse Water
TPC: The microbiological acceptance criteria for Total Plate Count is based on maximum allowable count of 1/cm2 as for swabs and expressed as maximum count per 100mL for each sampling point.
TPC ≤ 1 c.f.u / cm2
Pseudomonas spp: Not Detected/ 100ml
Coliforms: Not Detected/ 100ml
E.coli: Not Detected/ 100ml
Salmonella spp Not Detected/ 100ml
7.3.2 Swabs
TPC: ≤ 1 c.f.u / cm2
Yeast & Mould: ≤ 1 c.f.u / cm2
Pseudomonas spp.: Not Detected/ swab
Coliforms: Not Detected/ swab
E.coli: Not Detected/ swab
Salmonella spp Not Detected/ swab
8.0 SUPPORT AND CONTROL ACTIVITIES
8.1 Maintaining the Validated State
All cleaning procedures once validated will be maintained in a validated state. Maintaining the validated state will be achieved by change control, re-qualification, training, SOPs, calibration and engineering maintenance programs. Revalidation of the cleaning procedure will be required if any of the following occur:
Change in cleaning instructions and/or cleaning agent
Introduction of a new product (if it reduces the worst case limit) or changes to a production process
Changes to the equipment being cleaned
Sampling, analytical or microbiological methods
Number of batches in a campaign
Maximum time interval between use and cleaning
8.2 New Product Introduction
When a new product is introduced to equipment an assessment is made to determine if cleaning validation is required. If the new product carry over limit is above the previously determined residue carry over limit AND the new product is more soluble than the target component of the previous product then cleaning validation is usually not required. This will be documented in the cleaning validation plan.
8.3 Periodic Evaluation – Cleaning Verification Programs
Each cleaning program should be reviewed on a two yearly basis or in the case of a failure of a critical parameter to assure the procedure remains in a validated state. The review should at minimum include change control documentation and deviation reports. The review should be documented in a report.
Cleaning effectiveness after each cleaning episode will be verified as a minimum via visual inspection of the cleaned equipment and or review of automated cycle printouts. Results must be recorded in batch records
8.4 Training
Training and Qualification in the use of validation sampling (swabbing and rinsate techniques) and analytical methods shall be part of the training record for personnel performing these functions.
Swab recovery must be validated at ≥50% . The recovery value must be used as a correction factor in the calculation of results.
Trained operators will be used for performing a cleaning procedure during the validation program. Their records should document that their training is complete and up to date.
The facility requires a cleaning SOP for each item of manufacturing equipment. These will form the basis of the cleaning procedure for cleaning validation.
8.5 Document Management
During the validation effort any documentation which is integral to the final certification of cleaning validation is to be collated by the Validation Project Team and is to be registered.
9.0 REFERENCES
None.
8.0 SUPPORT AND CONTROL ACTIVITIES
| Version # | Revision History |
| VAL 125 | New |