1. Purpose
The Purpose of this guideline is to define the minimum requirements for cleaning and validation of cleaning processes for formulated product. It also covers post validation monitoring of the effectiveness of cleaning processes.
2. Scope and Applicability
This document is applicable to all commercial and investigational formulated products manufactured within a R&D and Operations facilities. It sets standardsfor cleaning and cleaning validation that suppliers of formulated products shouldbe assessed against. Cleaning for primary packaging operations is also included.
This guideline applies to the validation of cleaning procedures for equipmentused in manufacture of pharmaceutical products, but excludes ActivePharmaceutical Ingredients (API) and their intermediates.
Microbiological aspects of cleaning and determination of effectiveness are not considered in this document. Such activities should be treated on a case-by-case basis with due consideration given to manufacturing operations, area classifications, dosage forms etc.
3. Definitions
3.1 Hot Spot
A surface which is judged to be difficult to clean, or where microbiological growth may be foreseen, such as bends, valves, feed controls, sleeve couplings, bushing and hidden surfaces.
3.2 Limit of Detection
The lowest amount of a given substance in a sample that can be detected but not quantified with the selected analysis procedure.
3.3 Limit of Quantification
The lowest amount of a given substance in a sample that can be quantified with suitable accuracy and precision with the selected analysis procedure.
3.4 Cleaning Validation
Establishing documented evidence that a specified cleaning procedure will provide a high degree of assurance that it can be used to consistently clean a piece of equipment or a facility to a predetermined acceptable level of cleanliness.
3.5 Acceptable Carryover Quantity (ACQ)
The maximum allowable quantity of a guiding substance that can be carried over into subsequent manufacture.
Notes:
The guiding substance is generally the contaminant within the equipment train that is considered to have the greatest potential impact on patient safety. This is assessed by taking into consideration information on toxicity, ease of removal and pharmacological activity. Often the guiding substance will be the active ingredient, but it may be another component in the formulated product or the cleaning agent.
A guiding substance (or substances) should be selected such that verification of the removal of the guiding substance(s) to an acceptable level will assure that any residual contamination from other materials in the contamination matrix is also below an acceptable level.
There may be a need to define more than one guiding substance if there is more than one active component in the formulated product with a significant toxicological/pharmacological activity that is removed by a different cleaning method.
3.6 Critical Site
A surface in contact with a product from which possible contamination may find its way into an individual dose or packaging unit. An example is a filling needle.
3.7 Cleaning Verification
Specific evidence that the cleaning procedure is proven by documented verification through appropriate testing that demonstrates contaminants (processes or cleaning process related) are below a predetermined level that may affect the safety and quality of the next product.
3.8 Equipment Train
All process equipment, including flexible hoses and pipe work, that is in direct contact with the product during manufacture of a specific product, e.g. granulation, drying, milling, mixing, compaction and coating. Used to identify the total surface area potentially at risk to cross-contaminate a product. Disposable or dedicated product specific parts are excluded.
3.9 Minimum Therapeutic Dose (MTD)
The minimum amount of active substance typically given to a patient on each occasion as referenced in the Core Data Sheet. Note: The MTD differs to the MED when the lowest observable pharmacological effect is not the desired therapeutic effect.
3.10 Nil Effect Dose (NED)
Based on human data, is the maximum (single or repeated) dose at which there are no observable pharmacological effects in man. Note: The NED is expressed as a weight of active substance (usually mg or g) per day.
3.11 Minimal Effect Dose (MED)
The minimum dose at which there is an observable pharmacological effect in man. Note: The MED is expressed as a weight of active substance (usually mg or g) per day.
3.12 Maximum Daily Dose (MDD)
The maximum dose of product typically administered to a patient in any 24hr period. Note: The MDD is normally expressed as a weight of active ingredient (usually mg or g) per day. For the purpose of the ACQ calculation it may be more appropriate to use the gross weight of drug product (mg or g) per day if the minimum batch size used in the ACQ calculation is based on weight of drug product rather than weight of active ingredient.
3.13 Safety Factor
The Safety Factor is the safety margin used when defining an acceptance limit for product carryover. It is applied during calculation to ensure that the level of product carryover is sufficiently low that there will not be a pharmacological effect due to any product carried over into the subsequent product.
3.14 Swab
Swab means a piece of inert absorbent material used for sampling a predetermined surface area of equipment.
3.15 Visibly Clean/
Absence of visible residues A state of cleanliness characterized by the absence of any residues visible to the naked eye assessed following a written procedure. This can be quantified (e.g. as part of analytical method validation) where a quantitative result (based on the worst case level for visibly clean) is required for carry over calculation.
4. Responsibilities
4.1 All Sites/Plants
Each site/plant shall document the rationale for their adopted approach (e.g. product/plant matrices, revalidation frequency etc.) and for the setting of maximum acceptable limits for carryover, including the medical rationale. Each site/plant shall ensure that the analytical methods used for the determination of residual contaminants are validated. Each site/plant shall issue and maintain procedure(s) based upon this guideline. +
4.2 Operations Sites
Each Operations site/plant shall put in place validated cleaning procedures and generate data to confirm the validation of all product/equipment changeovers.
4.3 R&D Sites
Each R&D site/plant shall put in place appropriate cleaning validation or cleaning verification (including appropriate analytical method validation) that provide a high degree of assurance that cross contamination is avoided.
5. Guideline
5.1 General Principles
In Operations records for each changeover, confirming compliance with the pre-determined acceptance criteria shall be produced and retained. In R&D, during early development phases, when a worst-case cleaning validation approach (see section 5.2) or cleaning verification is employed, records for each changeover should be documented in process equipment log books to confirm that the equipment has been cleaned using the validated procedure or that verification has been successful before it can be used for the next product. During later development phases, when replicate clinical trial batches of the same product are being manufactured and the formulation and process are fixed validated cleaning procedures should be undertaken and recorded more formally. The exact approach taken shall be described in R&D SOPs.
When Operations facilities are used to manufacture products for clinical trials the approach adopted shall be documented and include a supporting rationale. Each site/plant shall consider all product/equipment combinations. Grouping into product families (e.g. utilizing highest active agent variant, or other worst case example) and identical equipment groups is acceptable.
For product dedicated equipment, a rationale and supportive data shall be generated to justify time limits or maximum campaign lengths between cleaning. ‘Test until clean’ (i.e. cleaning until an Acceptable Carryover Quantity (ACQ) is achieved) procedures should not be used.
The level of cleaning required/number of repeat washings should be established during the technology transfer phase of product development, and cleaning validation work for the product and equipment in question. Cases where additional cleaning is required following the routine cleaning procedure should be reported via the site/plant deviation reporting system. Cleaning procedures should be designed to provide the simplest, practical and reproducible process that results in carryover remaining below a scientifically derived limit.
Whilst attempts should be made to optimize the efficiency of all cleaning processes, it is not necessary to clean until the carryover is below the analytical limit of detection (i.e. none detected). The acceptance criteria for carryover must be related to the pharmacological effect of the carryover product or to a defined default limit if this pharmacological effect information is not available.
If the acceptance limit for a changeover is lower than the analytical limit of detection, the equipment must either be dedicated, or an alternative, more sensitive method of detection be developed. Cleaned equipment should be stored dry and protected against contamination. Cleaning validation for packaging operations shall be considered in the same manner as for manufacturing or processing operations. Cases where cleaning validation is not undertaken shall be justified. Cleaning from a microbiological viewpoint is not considered within this document.
The need for microbiological evaluation should be considered within the cleaning protocol. When not undertaken, justification should be supported by a documented rationale. For certain products (e.g. penicillin, cytotoxics) it may not be permissible or practical to routinely perform cleaning to the required levels for prevention of cross contamination.
For new products introduced to an Operations site/plant, cleaning information (e.g. validated analytical methodology for determination of product residues, outline cleaning methods, etc.)shall be part of the technology transferred from the development function to the site/plant, and form the basis of the site validation. For established product technology transfer, the transferring Operations site shall ensure data is available for inclusion in receiving Operations site cleaning validation protocols.
5.1.1 Design Requirements
Design documents, such as piping and instrument diagrams, equipment specifications and product contact material specifications, should be reviewed to evaluate that the equipment can be cleaned and that the design meets current GMP requirements. Such review shall be documented and should include identification of potential hotspots or critical sites requiring evaluation during cleaning.
5.1.2 Cleaning Methods
The preferred methods of cleaning are vacuum or wet cleaning methods, using water or the most appropriate solvent and cleaning agent for the product. Site/plants should develop specific procedures during the transfer process. All cleaning procedures shall specify the cleaning parameters, such as wash and rinse solvent quality, volume and temperature, cleaning agent quality and concentration, time of sequence of various cleaning steps, specific equipment hot spots, time of drainage and drying, and use (and controlled re-use) of any mechanical devices and/or cleaning devices.
The extent to which any equipment should be disassembled should be specified. The maximum period of storage (i.e. ‘worst case’ hold times) of equipment before cleaning and the maximum time between cleaning and equipment re-use should be specified and formally documented.
5.1.2.1 Clean in Place
Clean in Place (CIP) systems provide a reproducible method of cleaning, with less exposure to the operator. CIP equipment shall be fully qualified prior to undertaking cleaning validation. For CIP systems, well-defined specifications should be established and documented for the CIP process (i.e. water volume, velocity, number of rinses, temperature, equipment settings, etc.).
5.1.2.2 Manual Cleaning
Where manual cleaning is employed the cleaning procedure should be sufficiently detailed in order to minimize operator-to-operator variations in performance. Manual cleaning procedures should be reassessed and monitored at more frequent intervals than cleaning-in-place procedures to safeguard against variations in operator performance.
5.1.2.3 Cleaning Agents
Cleaning agents such as detergents and other chemical aids may be used when a practical, reproducible cleaning process using water or solvents is not readily achievable (eg owing to the requirements of certain materials, equipment or environmental factors). Cleaning agents, where required, should be readily removable.
Sufficient information shall be known about their formulation and toxicity to determine a calculated ACQ. The acceptance criterion for cleaning agent carryover should be minimized, taking into account the limit of detection of the analytical method as well as the calculated safe ACQ. Note: Reasonable effort should be applied to the development of an analytical method with a suitable limit of detection to minimize carryover.
5.1.3 Sampling Methods for Cleaning
A number of different sampling methods to determine the effectiveness of the cleaning procedure may be used (see below). The cleaning method should utilize the most appropriate combination of these sampling procedures to confirm the adequacy of the specific cleaning procedure.
5.1.3.1 Visibly Clean
Although not strictly a sampling technique visual inspection is a key requirement and the foundation of the cleaning process, during cleaning verification, during validation and for all subsequent routine cleaning operations. Diagrams and/or checklists to represent areas to be cleaned/examined should be developed and completed during the cleaning operation/inspection. Ancillary equipment such as UV lamps may be used to detect fluorescent compounds. Cameras may be used to examine inaccessible areas such as pipes and hoses.
5.1.3.2 Swab Testing
Surface sampling via swab testing is a direct method for assessment of cleanliness. This technique permits the hot spots and critical sites to be sampled and measures the actual residues left on the equipment. Swab procedures should define the area to be monitored and solvent, if used.
Procedures shall be in place for quantitative calculation of the residue product result, taking into account area swabbed, recovery of product from the surface and swab, total area of the equipment. The time between cleaning and swabbing also needs to be considered. The swab technique can be used to assess effectiveness of Clean In Place (CIP) systems after defined CIP cycles.
5.1.3.3 Rinse Wash Testing
Rinse solutions are an indirect method for assessment of cleanliness. This technique samples a greater surface area but measures removal rather than residual product (hence indirect). This approach assumes that residual product is not greater than product removed. This method allows larger areas/more complex equipment/CIP systems to be evaluated. Analytical methodology should measure the product specifically, however following validation non product- specific measures may be employed as part of routine monitoring.
5.1.4 Testing Methods
A suitable quantitative method should be selected appropriate to the sampling method and acceptance criterion. The limit of detection must be lower than the ACQ. Preferably, the limit of quantification should also be below the ACQ otherwise it is necessary to clean to ‘none detected’. Qualitative methods are generally not acceptable. Non-specific techniques such as Total Organic Carbon (TOC) determination may be applied for certain products, providing there is scientific justification that these will give worst-case results (i.e. they could detect additional contamination).
5.1.5 Acceptance Criteria for Carryover
The scientific rationale for derivation of ACQ for a changeover is based upon the premise that ‘The maximum daily dosage of one product must not contain a level of residue of previous product that would have any clinically significant Pharmacological or Toxicological effect’ Acceptance criteria for carryover shall include absence of visible residues.
The most stringent of the following limits shall also be applied.
Either:
ACQ = (Therapeutic Dose of residue product) x (Smallest batch size of next product) (Safety factor) x (MDD of next product)
Therapeutic Dose of residual product = NED, MED or MTD, in this order of preference depending on availability of the relevant therapeutic dose information. Safety factors for equipment train or individual equipment respectively:
Equipment Train | Individual Equipment | |
NED (This allows for the uncertainty associated with the carryover measurement) | 10 | 100 |
MED (This allows for uncertainty associated with carryover measurement and makes an additional allowance of 10 fold for use of MED instead of NED) | 100 | 1,000 |
MTD (This allows for uncertainty associated with carryover measurement and makes an additional allowance 10- 100 fold for use of MTD instead of NED) | 100 – 1,000a | 1,000 – 10,000 a |
“ppm” Allowed carryover of previous product to appear in any subsequent product | 10ppm | 1ppm |
a An appropriate safety factor within the range should be selected if MTD is used. For some products the therapeutic effect is the lead pharmacological effect and the MTD is effectively the same as the MED hence the lower safety factor (same as MED) is appropriate.
For other products the lead pharmacological effect may not be the therapeutic one and the MED is lower value than the MTD and hence the higher safety factor is appropriate. The use of the lower safety factors should be justified, however in R&D (for development compound cleaning where NED and MED are most often not available) the lower safety factors can be used without justification.
5.1.5.1 Acceptance Limits for Dedicated Equipment
Cleaning between batches of the same stage for the same product (e.g. several granulation batches later blended together in a tablet process) or for dedicated equipment used for one stage of one product, should not normally be required, unless there is evidence from Development or Technology Transfer of any problems (e.g. degradation). In both these cases, time limits should be established defining intervals between cleaning. Where cleaning is carried out in dedicated equipment, visibly clean is the minimum acceptance criterion.
5.1.6 Determination of Carryover Levels
Surface sampling (swab testing) provides quantitative data for residues remaining on a given surface. Individual swab test results should be combined to yield an overall Measured Carryover (MC) for comparison to the calculated ACQ for the product changeover. The MC must be less than ACQ. Usually swabs will be taken from different equipment surfaces and the individual swab results are then combined to obtain the final MC. The following guidance should be used to calculate the MC. Note: Swab test results must be corrected for recovery
5.1.6.1 Permitted Amount for Each Swab
Based on the assumption of uniform distribution of carryover product in the equipment it is possible to calculate the amount of product that would be obtained for each swab if the carryover amount equal the ACQ. Permitted amount = ACQ x Area of equipment sampled (per swab) (Per swab) Total surface area of equipment If all swab results are below this permitted amount then the MC is also below the ACQ and the equipment is clean. Where individual swab result(s) is/are greater than this amount it is then necessary to calculate the MC to demonstrate cleanliness.
It is allowable for individual swabs results to be greater than the permitted amount so long as the MC is less than the ACQ. However, it is recommended that no individual swab should be greater than x10 the permitted amount for each swab (x10 is safety factor built into the ACQ calculation to cover uncertainty in the sampling and determination of carryover).
5.1.6.2 Measured Carryover (MC)
Measured Carryover is calculated by adding the individual swab results.
This may be done on an equipment basis:
MC = (Sum of swab values) x (Total surface area of whole equipment) (Total surface area sampled by all swabs) Or, this may be done on an individual surface basis:
MC = Sum of: (Swab value) x (Total surface area of the individual surface) (Total surface area sampled by individual swab) The sum of the total individual surface areas must equal total surface area of the equipment.
5.1.6.3 Swab Acceptance Criteria not met – Non-Validated Cleaning
Process If the MC exceeds the ACQ then the acceptance criteria for carryover has not been met. Additional cleaning or other action shall be taken. It may not be necessary to repeat all the cleaning process. Before any additional cleaning is carried out the cleaning documentation should be updated to justify any additional cleaning activities.
5.1.6.4 Swab Acceptance Criteria not met – Validated Cleaning Process
If the cleaning process is validated there should be an evaluation of validated cleaning status, the cause of the failure and impact should be investigated in order to establish if the cleaning process has to be changed and revalidated.
5.2 Cleaning Validation
There shall be an approved written cleaning procedure before any validation study can begin. The cleaning procedure may be updated based on the outcome of the validation work. Normally, only cleaning procedures for equipment or surfaces in contact with product need to be validated.
However, other equipment parts, into which product could migrate, must be considered and this review documented. Three (3) consecutive changeovers should be undertaken to complete validation. It is acceptable to complete an interim validation report following the first changeover, provided the commitment is documented to monitor and report the next two (2), to complete the validation activity.
Where practical, validation of cleaning should follow typical campaign lengths, to reflect normal operating conditions. Release of product may proceed as normal following review of each changeover against acceptance criteria. Where product/equipment changeovers occur which are unlikely to be repeated, cleaning validation on a ‘one off’ concurrent basis (Operations) or cleaning verification (R&D) should be performed.
Placebo processed through the equipment and monitored for contaminants should not be used alone as proof of validation. This method can only provide limited additional assurance to validation.
Revalidation should be considered if problems are encountered with the routine procedure or when changes are made to cleaning method, materials, cleaning agents, equipment, campaign length, etc.
5.2.1 Sampling Methods
Surface sampling via swabs is the preferred method for assessment of cleanliness during validation. Visibly clean must apply. Rinse testing may be used to provide additional assurance or to indicate readiness for swab sampling. Following successful completion and documentation of validation, it is not necessary to routinely use all these methods (e.g. use visual inspection only), provided that the documented cleaning procedure is followed.
5.2.2 Analytical Methodology
Analytical methodology shall be appropriately validated and documented in order to provide sufficient assurance of cleanliness relative to the acceptance criterion for the product changeover.
During the Technology Transfer of a new product from R&D to Operations, R&D shall provide the validated analytical methods to Operations for use in Cleaning Validation.
The analytical method validation should take into account the method of sampling, proven level of recovery from swabs and surfaces, and interactions with other materials present in the sample matrix (e.g., solvents, swab extractives, cleaning agents, other active ingredients, etc.).
5.2.3 Bracketing (Matrixing) of Products, Equipment and Cleaning Methods
It is acceptable, with documented rationale and data, to group (also known as ‘bracket’ or ‘matrix’) together product ‘families’ (i.e. different strengths of the same formulation), or products/active ingredients with similar physico-chemical characteristics (e.g. solubility) to perform cleaning validation studies on the ‘worst case’ example, where the same equipment and cleaning method is used.
Bracketing studies may also be based upon other criteria. Examples of such criteria could be: type of equipment, type of material in contact with product, type of process (e.g. wet or dry manufacturing), ability to perform visual inspection, method of cleaning (eg manual or automated), etc. The rationale and criteria for any use of bracketing shall be justified and documented and the validation of such bracketing must encompass worst- case conditions (e.g. active ingredients, equipment etc).
5.2.4 Cleaning Validation Documentation
Operation or R&D sites shall have a procedure describing how to validate cleaning. Cleaning validation should be included in the Validation Master Plan. The cleaning validation documentation shall explain how the validation of the cleaning procedure shall be conducted. The documentation shall, as a minimum, include the following:
– The objective of the validation
– Description of the equipment and material specifications
– Cleaning procedure to be used including all cleaning parameters and cleaning agents
– The carryover product to be detected
– Worst case conditions, including the rationale for selection
– Sampling methods, including the rationale for selection
– Sampling plan covering identified sampling spots, including the rationale for selection
– Validated test methods
– The acceptance criteria including the rationale for ACQ
– Responsibilities for performing the validation work
– A statement requiring that a validation report shall be written
5.2.5 Post Validation
Requirements for Cleaning Processes This should be taken into account in the relevant Cleaning Validation report. Following cleaning validation, there should be a periodic reassessment of the continued suitability and validity of the cleaning against the original validation. Manual cleaning processes should be evaluated more regularly than a CIP process.
The frequency of periodic monitoring for different cleaning operations should be documented including how it will be performed. This may include repeating all or selected parts of the original validation, or by monitoring by alternative methods.
Note: Visual checks for absence of visible residues are mandatory for every changeover. Each site/plant should aim to routinely achieve the standards of cleaning demonstrated during cleaning validation. This may result in setting action limits below the scientifically derived acceptable limits. To aid consistency of routine operations a common action limit may need to be applied to similar cleaning procedures on a site/plant.
5.2.5.1 Change Control
Cleaning routines, analytical methods, equipment, cleaning solutions and production process should be defined and documented in connection with the validation.
In case of changes, change control in accordance with local procedures and Quality & Compliance international procedures and guidelines should be applied. Revalidation should be evaluated on a case-by-case basis following formal changes to plant.