Department | Validation/Technical Services | Document no | VAL-215 | ||
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Part A – Rationale and General Principles
1. Introduction
[Enter company name] manufactures and distributes a range of sterile and non-sterile, liquid, veterinary biological and pharmaceutical products from their sites [address].
The GMP facility has Code of Good Manufacturing Practice (cGMP) licenses with the [List all licenses].
[Enter company name] core business focus is manufacturing and packaging pharmaceuticals and veterinary medicines in various forms. These include oral and pour–on drenches, powders, creams, ointments, lotions, pastes and tablets.
This document aims to summarise the overall intentions and approach to the validation of the facility, equipment and processes.
It is intended to be a working document and will be periodically updated by site management responsible for the execution of validation.
2. Responsibilities
Validation Manager | Validation | Engineering Manager | Engineering | Production Manager | Production | QC Manager | QC Laboratory | Development Manager | Development | Quality Manager | Quality Assurance | |
Validation study design | P | P | I | I | I | I | I | I | I | I | I | I |
Identifying and providing the appropriate level of resource in order to execute the cleaning validation exercises | P | P | (P) | (P) | (P) | (P) | (P) | |||||
Identification of process equipment trains and selection of worst case products for validation | P/A | P | I | I | I | I | I | I | I | I | I/A | I |
Calculation of cleaning limits for equipment / processes | P/A | P | I | I | I | A | I | |||||
Training of Operators in Cleaning SOPs | I | I | P | P | ||||||||
Writing and execution of protocols | P/A | P | I | I | A/I | I | I | I | I | I | A/I | I |
Review of QC results and final report writing | P/A | P | A | A | ||||||||
Rinse and Swab Sampling | P | P | I | I | A | I | ||||||
Conduct analytical test method validation | (P)/A/I | (P) | P/A/I | P | A/I | |||||||
Testing of swab and rinse samples | (P) | I/(P) | I | I | A/P | P | ||||||
Validation cleaning studies discrepancy resolution | P/A | P | I | I | I | I | I | I | I | I | A/I | A/I |
Update of this CVMP when required | P | P | I | A/I | I | I | A/I |
Where A = Approver P = Primary Ownership (P) = Joint Ownership I = Input
3. Rationale and General Principles
3.1 Rationale
Pharmaceutical products can be contaminated by other products (cross contamination), by cleaning agents, by micro-organisms or by foreign matter. In a multipurpose facility the same (common) equipment may be used for many different products and therefore to avoid cross contamination of the next product adequate cleaning is essential.
The objective of cleaning validation is to verify the effectiveness of the documented cleaning procedure for removal of product residues, degradation products, preservatives, excipients and/or cleaning agents so that the analytical monitoring may be reduced to a minimum in the routine phase. In addition, one needs to ensure there is no risk associated with cross contamination of active ingredients.
3.2 General Principles
The following general principles apply to cleaning validation:
3.2.1 Only cleaning procedures for product contact surfaces are subject to validation. Only cleaning procedures for “product to product” changeover (common equipment) will be fully validated.
3.2.2 Cleaning procedures for products and processes which are very similar do not need to be individually validated. Documented grouping or bracketing of similar products and similar equipment trains is acceptable provided a documented risk assessment is undertaken.
3.2.3 Dedicated equipment is confirmed as visually clean following “same product to same product” cleaning procedures. The verification is documented on the batch record prior to commencing subsequent batches.
3.2.4 Cleaning validation must, where relevant, address removal of cleaning agents and micro-organisms as well as active drug substances/products.
3.2.5 Where cleaning validation is required, a combination of analytical testing for residues on equipment surfaces, analysis of flush volumes and visual inspection is required. A successful validation must pass all three criteria.
3.2.6 Equipment cleaning validation may be performed concurrently with actual production steps during process development and clinical manufacturing. Validation programs should be continued through full scale commercial production.
3.2.7 The primary methods of analytical testing will be based on swab analysis (of predefined “worst case” locations) and or rinse sampling. It will be assumed that all contamination detected will be incorporated into the subsequent batch and that it will be uniformly distributed.
3.2.8 Where sampling detects no residues, calculations of residue will assume residues to be at the limit of detection of the test method. This “worst case” value will be used in residue calculations.
3.2.9 Bracketing of products may be used to validate a common cleaning procedure. In such cases, the acceptance criteria and swab analysis will be based on “worst case” combinations as detailed below.
3.2.10 A maximum (dirty hold) time between end of use of equipment and cleaning must be defined and included in the validation study.
3.2.11 Analytical methods used to validate cleaning must also be validated at least for recovery levels and limit of detection.
3.2.12 Due to their inherent solubility in water, cleaning agent residues will be assessed from rinse samples. Specific analytical methods for cleaning agent residue analysis are often not available due to the proprietary nature of formulations. Since cleaning agents, by their ionic nature, affect pH and/or conductivity at low concentration non specific methods such as final flush water conductivity may be used to verify removal of the agent.
3.2.13 Due to their inherent solubility in water, cleaning agent residues will be assessed from rinse samples where applicable. Specific analytical methods for cleaning agent residue analysis may not available due to the proprietary nature of formulations. Non-specific analytical techniques may be utilised where justified or where appropriate recovery and correlation studies have been conducted.(e.g. conductivity, TOC).
3.2.14 Consumer exposure to cleaning agent residue will be calculated as a cumulative value from the entire equipment train distributed in a subsequent batch, as for active residues.
3.2.15 Cleaning validation should consider impacts of contaminants from the entirety of the product equipment trains.
3.2.16 Routine monitoring of cleaning efficacy shall be undertaken on a periodic basis to demonstrate that cleaning efficiency is being maintained. Such monitoring shall be performed on a limited number of locations. The locations for monitoring shall be identified in the results of the initial cleaning validation and shall be selected on the basis of locations showing high residue levels, i.e. difficult to clean locations.
3.3 Cleaning SOP or Instructions
The study should be executed in accordance with a cleaning procedure or set of instructions. These instructions in their entirety should at a minimum identify the physical setup of the system to be cleaned and guidance on how to perform the cleaning. These should be “walked through” by the system owner prior to execution to ensure that the intended usage is encompassed in the study.
Cleaning operation steps may be in their own cleaning procedure or be part of a larger SOP encompassing other operational instructions.
In order to proceed when any prerequisites are not at the minimum specified status, a written assessment must be made and approved noting the outstanding issues, the impact on the testing and the rationale for proceeding.
Note: All executing personnel must be trained on the applicable SOPs.
The purpose of the Cleaning Validation program is to demonstrate that a given cleaning method is consistently effective for a given piece of equipment for cleaning a given residue.
Therefore, to optimize Validation testing, the following issues may be considered and identified for Cleaning SOP’s:
– Equipment to be cleaned and location
– Product to be cleaned
– Maximum anticipated residence time
– Condition in which a system may be held prior to cleaning
– Maximum dirty hold time in that condition before cleaning
– Physical set up – Piping/circuit paths for flowthrough systems
– Cleaning agent identity and concentration
– Time, temperature, flow rates, pressures, volumes for cleaning or soak cycles (and technique for manually cleaned systems)
– Time, temperature, flow rates, pressures, volumes for rinse cycles
– Sequence of cleaning, soak and rinse cycles or steps
– Additional Operating Instructions
– Routine data, samples to be collected during normal operation, including any end of cycle analytical samples
– Assay methods for sample testing
– Maximum hold time after cleaning – Clean Hold Time
3.4 Risk Based Approach
Selection of “Worst Case” – Product Bracketing Strategy
3.4.1 A risk-based matrix approach will be used to determine the worst-case product for each cleaning procedure. Cleaning validation will be performed for all equipment cleaning procedures associated with that worst-case (highest risk) product. Acceptable validation of a cleaning procedure for the worst-case product shall constitute validation for all other products that utilise the same cleaning procedure. Cleaning validation will be performed on additional products, as necessary, to verify performance of any cleaning procedures relating to equipment, which was not utilized during the manufacture of the worst-case product.
3.4.2 The risk-based matrix takes into account the following factors (refer Diagram “Risk Matrix”):
Solubility – solubility of the active ingredients in water, as noted in the Merck Index.
Toxicity and Concentration – either based on available toxicology information or based on LD50 Oral (rat) – the amount of a substance required to kill half a given population and percentage of the active ingredients in the formulation residue.
Figure: Risk Matrix Diagram
3.4.3 Carry- over calculations for the permissible residue quantities will be based upon available toxicology information for the identified substance(s) of greatest toxicity, highest potency or suitability as in indicating agent for common production equipment.
3.4.4 Swab analysis will generally be performed using the most difficult to remove active drug substance or the most toxic substance, whichever is determined to be of greatest cross-contamination risk. The most difficult to remove substance must be identified based on a combination of solubility in the cleaning agent, and also on first hand experience. In instances where the most potent active used to calculate the acceptance is potentially harmful as a contaminant in other products, swabbing for residues of this active will be conducted as well as on the identified worst case (most difficult to clean active) as an added precaution.
3.4.5 Where swabbing is performed on a worst case active, the acceptance criteria will still be based on the most potent active, not the active being swabbed. This combination provides a high level of safety margin and ensures that all active residues would meet the most stringent possible acceptance criteria. This assumption eliminates the need to perform swab analysis on any products other than that which is identified as the most difficult to clean (except in the case of potentially harmful actives as discussed above).
3.4.6 Applicable substances will be considered in the determination of the permissible daily exposure quantity limits in residues based on the toxicity of the formulations. The identified target substances may also be chosen on the basis that it is unique to the formulation and present a greater cross-contamination that other substances listed in the product formulation (for the respective state of manufacture).
3.4.7 Permitted exposure level criteria will be applied as a cumulative value of the surface area of the entire applicable equipment train to which a product may be exposed, during manufacture assuming a worst possible case exposure level. The cumulative value will thus over-estimate the maximum possible residue to which a consumer could be exposed.
3.4.8 Justification of worst case active substance and calculation of worst case acceptance criteria should be attached as an appendix to this document.
3.4.9 If the results of the validation exercise fail to meet the acceptance criteria due to the accumulation of several over estimations of potential residue in a “worst case” approach, then the results shall be reviewed to assess if the failure is due to one or more locations with extraordinarily high residue levels. If this is the case, then the applicable cleaning procedures will be revised to ensure l residue levels are achievable and revalidated. If no locations are found to be unusually contaminated, and the failure is attributed to excessive overestimation due to the assumptions made, then the acceptance criteria may be recalculated to reflect actual common surface areas rather than total estimated applicable surface areas.
3.5 Assessment of New Products
3.5.1 When a new product is introduced it must be assessed for content of “worst case” substances, against existing worst case substances and also the acceptance criteria (permitted exposure quantities) determined in previous validation activitites to ascertain if additional cleaning validation is warranted. If the worst case new product components are considered not to be any more potentially harmful than the previously justified worst case materials, then minimal, or no additional cleaning validation will be required.
3.5.2 Additional validation must be undertaken where a new product contains potentially harmful substances to demonstrate that it is capable of being cleaned to residue levels lower than the previously identified worst case (most difficult to clean/highly toxic/Low ADI) substances. Such verification shall only be undertaken in a limited number of “difficult to clean” indicator locations (as used for routine cleaning validation monitoring).
3.6 Preparation and Approval of Protocols and Reports
3.6.1 The protocol should define the following:
– The specific cleaning methods/equipment combination under validation
– Contaminants to be monitored eg. nominated active drug substance, microbiological, cleaning agent residues
– Tests (and test methods) to be used
– Location, size and number of samples to be taken
– Number of replications of the validation (normally three episodes are required)
– Acceptance criteria
3.6.2 The Validation Report should contain the following:
– Individual swab results
– Estimated total contamination, calculated by multiplying swab results by surface area
– A statement of acceptability of the cleaning method
– Recommendations for a routine monitoring schedule
3.7 Acceptance Criteria
3.7.1 Product and Detergent Residue
The product residue limits should also consider the cleaning criteria:
Visual Inspection:
No quantity of residue will be visible on any equipment surface post-cleaning when the equipment is dry.
Product Residues – the most scientifically justifiable residue quantity applicable from following criteria.
a. A toxicology based calculation specifically, a heath based exposure limit for residual active substances that pose a cross contamination risk. The limit is termed the Permitted Daily Exposure (PDE) (a unit quantity which is applicable when considering the target patient weight). This quantity varies depending on the available data to support the No-Observable Effect Level (NOEL). The NOEL should be based on available toxicology data.
b. Where toxicological data is not available, no more than 1/1000th of the minimum therapeutic dose of any product is to be present as a potential contaminant in the maximum allowable daily dose of a subsequent product. (Note: A safety factor of 1/100th may be used for products or product components of less risk with suitable justification (e.g. product intermediates or product intermediates which share common manufacturing equipment which are recombined in the final product).
c. No more than 10ppm of any product will appear in a subsequent product.
Permitted Daily Exposure (PDE) or Maximum Acceptable Carry-Over (MACO) Limits
The permitted carry over quantity (of previous product or detergent residues) on common product contact surfaces, may be calculated based on the potential exposure of the target animal subsequently taking the largest allowable daily dose (where toxicological data is not available).
For calculation purposes, the worst case should be used, that being a subsequent batch with the least number and/or quantity of maximum daily doses per batch. The carry-over calculations may be applied over the respective equipment, however detergent residues should be considered over the entirety of the manufacturing process where a detergent is utilized on multiple pieces of product contact equipment/systems as part of the manufacturing process. Refer to VAL-195 Maximum Safe Carry-Over (MSCO) Determination for evaluation.
3.7.2 Microbiological Contamination
The requirement for microbial testing shall be determined on a case by case basis and shall be appropriate for the products to be cleaned. Where microbial testing is not required justification shall be made in the validation protocol.
The microbiological acceptance criteria for Total Plate Count (TPC) is based on a maximum allowable count of 1/cm2 as for swabs and expressed as maximum count per 100mL for each sampling point.
TPC : £ 1 cfu / cm2
Pseudomonas spp: Not Detected/ 100ml
Coliforms: Not Detected/ 100ml
E. coli: Not Detected/ swab
Salmonella spp Not Detected/ swab
Swabs
TPC: £ 1 cfu / cm2
Yeast & Mould: £ 1 cfu / cm2
Pseudomonas spp.: Not Detected/ swab
Coliforms: Not Detected/ swab
E.coli: Not Detected/ swab
Salmonella spp Not Detected/ swab
The target limits shall be:
a. Less than, or equal to, 1 cfu per cm2 for product contact surfaces.
b. Absence of E. coli., mould, yeast
3.8 Priority, Schedules and Documentation
3.8.1 Schedules for equipment cleaning validation must be based on the following priority:
Assessment of all new products before initial manufacture (refer Part 3 above)
Product or product groups assessed as having a high clean ability risk
Product or product groups assessed as having a medium clean ability risk (if required)
Product or product groups assessed as having a low clean ability risk (if required)
3.8.2 Schedules must be prepared listing line/equipment (groups) train, product(s) or product group(s), and SOP(s) or procedure(s).
3.8.3 The following minimum documentation should be available for review on the completion of validation:
Cleaning validation protocol, including location maps of swab sampling
Published cleaning procedure used in the validation
Validation report referenced to raw data
Reference to method validation and active product surface recovery studies
3.9 Cleaning Strategies
Hold times are the times a piece of equipment or system is allowed to remain idle, either after it has been utilized for production processes (dirty-hold time) or after an equipment or system has been cleaned (clean hold-time).
3.10 Clean Hold Time
Clean hold times are the maximum time a piece of equipment or systems are allowed to remain idle between the end of the cleaning process and the beginning of usage. The primary concern is with an adverse change in the cleanliness of the equipment over a period of time.
Clean hold times will be evaluated where the equipment or system is considered to be at risk of change of the cleanliness state when left idle for extended periods of time. Equipment or systems have acceptable hold times evaluated via microbiological or chemical testing as appropriate. Where equipment is sterilized prior to use, a validated overkill sterilization cycle for the equipment or system would be considered sufficient justification to negate the necessity for microbiological evaluation of a hold time.
The requirement to conduct microbiological studies for the clean hold time should be risk assessed for the application and equipment usage style. Similarly, chemical residues will be evaluated based on risk of the processes. Cleaning validation minimizes the concern by verifying systems are free of residual soil and cleaning agents via challenging the cleaning processes under worst case conditions and that they are free of excess standing water (which could promote microbiological growth).
The period between equipment usage and commencement of the cleaning procedure is considered to constitute the dirty hold time (unless sufficient justification is provided otherwise).
3.11 Dirty Hold Time
The dirty hold time is defined as the period between completion of equipment usage and commencement of the cleaning operations. Certain types of soil may become more difficult to remove from the equipment when left for extended periods. Evaluation of the necessity to establish a dirty hold time should be addressed in the individual validation protocols. The dirty hold time should be evaluated where it is deemed that there is potential risk for the cleaning of the equipment to become more difficult to clean when left in a dirty state over an extended period of time.
3.12 Campaign Cleaning
The word “campaign” with reference to production refers to production of goods of similar nature immediately following a preceding batch of similar formulation. In such cases, the cross-contamination risk may be reduced as a result of the subsequently manufactured product containing the same components at the same or greater concentration, or the same components and additional ones. In cases of “campaign” manufacture, a reduced cleaning regime may be considered, following appropriate risk assessment and validation activities.
3.13 Re – Validation
Re-validation of cleaning procedures are to be conducted, based on the risk of the cleaning operations and the product risk to the end-user. Re-validation may also be considered when existing cleaning procedures have been modified where there is significant impact of the change of the validated system and the risk of the change assessed during the change process.
3.14 Manual Cleaning Procedures – Monitoring
Manual cleaning procedures are considered to be of greater risk than automated cleaning procedures.
Manual cleaning procedures are defined as cleaning procedures which require a degree of production technician intervention, such that cleaning efficacy and reproducibility is dependent on operator knowledge and understanding of the cleaning standard operating procedure or operating instructions.
The re-validation requirements of the manual procedures are based on risk to the end-user and product risk.
Re-validation activities may include reduced testing (as compared with the original validation testing) based on the risk of the process.
3.15 Cleaning Validation Program – Required Documents Table
The following table describes documents (and some important definitions within documents) that together describe the cleaning validation system.
Document / Definition (Definitions may be found in specific documents) | Purpose |
Cleaning Validation (Master) Plan (CVMP) This Document | The cleaning validation plan itemises the specific requirements as defined in regulatory and other guidelines along with an analysis of resources, definition of responsibilities and allocation of responsibilities for the writing of protocols, execution of validation and review of data. The CVMP provides the specific rationale concerning- selection of allowable carry over limits, grouping of products and equipment, rationale for selection of “marker” or exhibit products. It also defines who is responsible. |
Cleaning Validation Schedule (Attached to CVMP) | The schedule itemises and prioritized the cleaning validation activities and any supporting activities which are required to achieve the cleaning validation program. Schedules usually cover a 2 – 3 year period. |
Cleaning Validation Protocol | A document which documents the process of evaluating the effectiveness of a specific cleaning procedure. This protocol is specific to a cleaning procedure, the marker product (representing a group) and the equipment train. |
Risk Assessment (Protocol) | The risk assessment reviews the risks associated with the cleaning program i.e. what level of cleaning needs to be achieved, toxicity of actives, worse case scenarios of cross contamination potential. |
Identification of Equipment Train (Protocol) | An assessment of all equipment used during the manufacture of a particular product (or group of products) identifying worse case scenarios and equipment trains. |
Clean Limit – Rational for setting Limit | A limit for acceptable level of “clean”, which is defined in the cleaning validation protocol, and defined in terms of (a) maximum carryover levels to the next product and (b) allowable residues per unit are of equipment surface. |
Validated Analytical Methods | Methods used for cleaning analysis must be appropriately validated i.e. Limit of Quantitation (LOQ) and Limit of Detection (LOD) must be assessed for each analyte and possibly degradant. An assessment of the precision, accuracy and linearity must also be performed at the LOD and LOQ. Pre-requisites to analytical method validation include qualification and calibration of all equipment/lab instruments used in the analysis. |
Procedure for Sampling | In order to ensure consistent and reproducible recovery, a procedure for the sampling (be it swabbing, rinse collection or placebo approach) must be written and trained to. |
Recovery Studies – Swabbing Protocol | When swabbing is used as a sampling technique, as well as training to the procedure, it is a requirement to perform recovery studies which evaluate the ability of the sampling procedure to recover a specific analyte from specific surfaces. The recovery study is also used to quality the analysts or samplers performing the swab per the protocol. |
Qualification of Swabbers | This may be achieved in the above document Recovery Study – Swabbing protocol. Its purpose is to show the effectiveness of training of “swabbers” to take samples in a reliable and reproducible manner. |
4. References
1 | PIC/S Guide to Good Manufacturing Practice for Medicinal Products Part II and the Appendices | January 2009 |
2 | PDA Technical Report Number 29-Points to Consider for Cleaning Validation | August 1998 |
3 | United States Pharmacopeia | Edition 34 |
4 | European Pharmacopeia | 7th Ed. |
5 | EU Guidelines for GMP for Medicinal Products for Human and Veterinary Use (Draft) CH3/ CH5 | Aug 2014 |