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SOP for Cleaning Validation – Manufacture of APIs

This SOP describes the strategy and basic requirements for validation of cleaning procedures in the manufacture of APIs and intermediates in order to avoid chemical and microbiological contamination.

The preparation of a cleaning validation master plan, a worst-case concept, and a matrix approach are included, together with acceptance criteria, a minimum number of cleaning runs, preparation of validation protocols, and a report are also described.

It is the responsibility of the management of the third party to be in substantial compliance with this assessment standard and to ensure that manufacturing processes are validated, and maintained in a validated state.


Process Summary

General Requirements
To enable validation, the following documents are to be established and approved in the following order:
  • Validation Master Plan
  • Validation Protocol
  • Validation Report

Changes can influence the validation status. To control these changes, change control procedures must be in place. Revalidation may be necessary if a new worst case is introduced or the cleaning procedure is changed.

Cleaning Validation Strategy (Risk Assessment)
Risk Assessment
Reference is to be given to the validation strategies in the respective local validation policies. A risk assessment is necessary to determine the level of validation for each cleaning procedure. The criteria to be considered in the risk assessment are:
  • Solubility of APIs and intermediates
  • Dosage levels/toxicity/potency
  • Equipment design and construction (including direct/indirect surface contact area to product)
  • Dedicated/non-dedicated equipment
  • Critical equipment parts
  • Adsorption to surface material of the equipment
  • Non-sterile/sterile special consideration of microbiological, endotoxin, and particulate risks
  • Location of step within an overall process
  • Manufacturing campaigns
  • Batch size and possible changeovers
  • Processing time scales
  • Cleaning intervals
  • Idle time and idle conditions
  • Safety risks for the patient
  • Number of products covered by the respective cleaning procedure
  • First versus re-validation

The cleaning validation risk assessment will also identify any APIs that are considered to be beta-lactam penicillin, steroid, and cephalosporin, oncological, Ames positive, mutagenic, or allergenic in nature. Cleaning procedures for equipment on which very similar APIs / intermediates and processes are handled, may not need to be individually validated. 

Following the risk assessment worst case situations are to be identified and a matrix approach with groups of products may be selected for validation. In the matrix approach, either 3 elements of the same group are tested once or the worst case of the group is tested 3 times.

Matrix Approach
The same may be applied to equipment, i.e. groups of similar or equivalent equipment can be treated as a matrix and grouped according to risk assessment (same material, size, complexity, configuration etc.)

The critical parameters that are used to select the products from each group that makes the worst case are (list non-exhaustive):
  • Lowest solubility in the specified solvent or in the specified detergent
  • Complexity (relevance) of plant items used in the process
  • Past experience and history of cleaning difficulties
  • API
  • Oral toxicity as applicable
  • Dosage level

It is acceptable to select a range of similar APIs / intermediates or processes concerned and to justify a validation study, which addresses the worst case regarding the selected APIs / intermediates and corresponding cleaning procedures.

A single validation study may be carried out which takes account of the relevant criteria. If a new API / intermediate is brought to a site/building, the risk assessment for cleaning of the equipment used for this API / intermediate must be re-evaluated. If the new API / intermediate is shown to be a new worst case, a revalidation must be performed with it. If the new product is not a worst case, cleaning is only verified following the normal cleaning SOPs, and no additional validation is required (e.g. 3 successful cleanings using the new product.

A number of Cleaning Runs:
Three predetermined runs of the cleaning procedure must be performed and shown to be successful in order to prove that the cleaning procedure is validated. Refer to Section (The Cleaning Validation Process) for details on what is involved in a cleaning procedure. In the matrix worst-case approach, only one cleaning run for each of three different APIs / intermediates of the same category (or combination thereof) or three runs utilizing the worst-case product of the same category is acceptable.

Dedicated Equipment:
For dedicated equipment cleaning validation may be reduced to the validation of the removal of detergents/disinfectants and microbiological/endotoxin contamination (if applicable). According to the result of the risk assessment, cleaning intervals must be set up in order to prevent the building up of residues or decomposed substances.

Detergents and Disinfectants:
It is desirable not to use complex detergents or disinfectants containing surfactants etc. (i.e. preferably NaOH, H3PO4, H2O2, or other well-defined components). If their use cannot be avoided, only detergents or disinfectants should be used for which the composition is known. If such information is not available, an alternative should be selected. 

A procedure should be established to get information about critical changes in the formulation of the detergent or disinfectant from the manufacturer. The removal of detergents/disinfectants should be considered in the cleaning validation. In such cases, methods detecting single elements shown to be the worst case (e.g. phosphate) may be applied.

Microbiological Contamination:
Microbiological contamination is possible if the last cleaning step is performed with water or mixtures of organic solvents with water. For equipment that is cleaned by refluxing organic solvents the risk of relevant contamination is minimal.

Issue and Approval of the Cleaning Validation Master Plan
A Cleaning Validation Master Plan must be prepared, authorized, and approved by Quality Assurance and management of the areas involved, showing the extent of the validation program.

The need for training, particularly for new processes or e.g. manual cleaning steps must be assessed and executed.

Organizational Structure of all Cleaning Validation Activities
The documentation of all cleaning validation activities comprises of or is contained in the validation master plan, the validation protocol, the validation report, outlining the validation strategy, the validation process, the cleaning procedures, key acceptance criteria, sampling methods, the change control procedures applied and the approval procedures.

Cleaning Procedures
There are three types of cleaning procedures as follows:

1. Manual Cleaning
This is performed manually by an operator using specified cleaning material which might include high-pressure jetting. It is equipment specific and therefore equipment such as dryers, solids discharge equipment, solids charging equipment, and bulk binds will have different cleaning procedures. Manual cleaning practices are subject to operator variability and therefore should only be performed by properly trained operators.

2. Clean Out of Place (COP)
This involves disassembling process equipment and cleaning using manual methods or recirculation washers.

3. Clean In Place (CIP)
This is typically a procedure in which the process equipment is cleaned without disassembly by circulation or refluxing of cleaning solutions along the process flow path. The procedure is not generally equipment specific (an exception would be a short path still or bulk storage tank) but depends on the manufacturing process.

The CIP procedure employed may involve manual cleaning (if applicable), preliminary cleaning, main cleaning, and final rinse, also called analytical cleaning if samples are taken for routine analysis. A pre-use rinse may be used after the CIP procedure is completed in case it is not included in the normal CIP sequence after the plant is re-configured for a new product. The definitions for these types of cleaning methods are given below.

Post Campaign Flush
Initial installation cleaning after the end of a campaign in case longer holding times occur before the next one using a defined solvent mixture and/or acid or alkaline solutions. Alternatively, a standard CIP cycle may be applied between campaigns.

Pre-Use Rinse
A solvent wash is used to rinse out the plant immediately before the start of a new product campaign using the solvent of the new process

Cleaning Sequence
Preliminary Cleaning:
The preliminary cleaning is performed using designated solvents, solvent mixtures, and acid or alkaline solutions.

This can be achieved using a defined series of cleaning runs or manual cleaning with brushes or high-pressure jetting and steam or cleaning until visually clean or cleaning to a specific limit.

Main Cleaning:
The final rinse is done with an adequate solvent and there must be a system in place to demonstrate that the plant is acceptably clean. A sample of the last rinse (sometimes called Analytical Cleaning) is analyzed and based on a satisfactory analysis the equipment is released for further use.

Sampling Methods

Rinse Samples
Rinse samples are used for closed equipment or difficult-to-access equipment. Wherever possible the entire equipment train or equipment module is boiled out with an appropriate solvent. Equipment that cannot be heated is rinsed through with the same solvent, preferably hot.

Swab Samples
Where solvent rinsing is not possible to direct surface sampling with swabs is used based on a risk assessment. If various areas of specific equipment are swabbed then the highest residue is used to calculate the contamination. These individual equipment results are combined with the rinse samples to give the residual contamination left in the entire plant.

For cleaning validation studies swabbing of solvent-rinsed equipment is carried out where possible, to confirm the validity of rinse samples.

Key Acceptance Criteria
The acceptance criteria for the cleaning procedures are to be defined before performing the cleaning validation. Criteria will include acceptable amounts of chemical (APIs, intermediates, detergents, disinfectants) and microbiological (microbial and biological) contaminants.

Cleaning Limits
The limits of these contaminants are:
Primarily the equipment must be visually clean. If not a deviation report must be issued and follow-up action decided.

Final API Purification
The last step in the API purification process is defined as being immediately after the isolation equipment used to separate the crystalline product from its crystallization mother liquors or appropriate purification procedures. This is immediately after the final centrifuge, nutsche or nutsche dryer.

Dedicated Equipment
  • Dedicated equipment must be visually clean and must meet microbiological requirements (if applicable).
  • The contamination by highly toxic (allergenic, cytostatic, hormone, mutagenic or teratogenic properties) compounds in the following compound must be no more than 10 ppm.
  • The minimum therapeutic dose should be estimated for development substances that are not yet fully characterized regarding their potency.
  • Additional assumptions are to be considered for the calculation of the limits: the entire residue (worst contamination found calculated for the total surface area of equipment module) of the previous product in the processing equipment will contaminate one batch of the following product (worst case assumption). The acceptable contamination at each product changeover should be calculated on the basis of the batch size of the following product, or on the basis of the minimum batch size manufactured on the respective equipment. The complete calculation, with all the assumptions made, must be documented.
  • The minimum therapeutic dose (lowest single dose produced) and the unit dose (highest single dose produced e.g. In case if there are three strengths, e.g., 10mg, 20mg & 30mg Tablets, “single dose” means 30mg) are required for the calculation of cleaning limits.
  • Carry-over of detergents/disinfectants must be no more than 10 ppm within the next batch of API manufactured in the equipment. A limit of 100 ppm is accepted if supported by respective safety data of the detergent/disinfectant (e.g. Acute Toxicity).

In addition to visually cleaning, the following criteria must be applied:

After Final Purification

API to API Dryer/Mill/Blender
For carry-over of API residues in drying, blending, milling equipment, and further equipment used after the last purification step (e.g. freeze dryers) in an API to API sequence processed in multipurpose equipment, one of the two following criteria applies based on the risk assessment:
  • Not more than 1/1000 (0.1%) of its minimal therapeutic dose in the single dose of the following API
  • Not more than 20 ppm contamination by an API in the following API. This limit is derived from the 10 ppm limit being valid for drug products and considers the mixing of APIs with considerable amounts of other ingredients during pharmaceutical processing.

Intermediate to API Dryer/Mill/Blender
The following criteria apply for the carry-over of intermediate residues in drying, blending, milling equipment, and further equipment used after the last purification step (e.g. freeze dryers) in an intermediate to API sequence processed in multipurpose equipment:

The contamination by an intermediate in the following API must not be more than 20 ppm. This limit is derived from the 10 ppm limit being valid for drug products and considers the mixing of APIs with considerable amounts of other ingredients during pharmaceutical processing.

Prior to Final Purification
For carry-over of API residues in an API to API sequence processed in multipurpose equipment, one of the two following criteria applies based on the risk assessment:
  • Not more than 1/1000 (0.1%) of it's minimal therapeutic dose in the single dose of the following API
  • Not more than 1000 ppm contamination by an API in the following.

Intermediate to Intermediate
  • The following criteria apply for carry-over of Intermediate residues processed in multipurpose equipment in an Intermediate to Intermediate sequence prior to the last purification step:

The contamination by an intermediate in the following intermediate must be no more than 1000 ppm.

Intermediate to API NOT Dryer/Mill/Blender
The following criteria apply for the carry-over of Intermediate residues processed in multipurpose equipment in an Intermediate to API sequence prior to the last purification step:

The contamination by an Intermediate in the following API must be no more than 1000 ppm.

API to Intermediate
The following criteria apply for the carry-over of API residues processed in multipurpose equipment in an API to Intermediate sequence prior to the last purification step:

The contamination by an API in the following Intermediate must be no more than 1000 ppm.

Intermediate to Intermediate - Same API
The following criteria apply for carry-over of intermediate residues processed in multipurpose equipment in an Intermediate to Intermediate sequence of the same API:

The contamination by an intermediate in the following intermediate of the same API must be no more than the carry-over by the process itself. The equipment must be visually clean.

Microbiological Contamination
Microbiological and endotoxin (as applicable) contamination of the API by the equipment must be prevented. Also, the time between cleaning and equipment re-use must be considered in the cleaning validation procedure. The limits for the microbiological and endotoxin contamination of equipment surfaces in contact with APIs must be in accordance with the existing module “Cleanliness Zoning in the Manufacture of APIs” (Non-sterile/sterile).

Where open handling of product occurs, the surrounding areas (floors and walls) must be "visibly clean" of the API /intermediate and detergent/disinfectant. It may be necessary to do an initial evaluation of the floors and walls to show that they are in fact clean following the cleaning procedure.

The Cleaning Validation Process
Several requirements must be met before the validation of a cleaning procedure is started.

Equipment must be qualified, computerized systems used for CIP / COP must be validated and qualification/validation documentation approved. The design of the concerned equipment must be fully established, especially the contact surface area and its material must be known. The equipment/facilities concerned must be examined carefully with respect to the contact surface area. The areas hardest to clean must be identified. The total contact surface area must be known before performing the validation.

Cleaning Procedure
The cleaning procedure must be prepared and approved by Production and QA, before starting the validation study. These may be updated as a result of the cleaning validation.

Personnel involved in the validation of a cleaning procedure must be trained for cleaning requirements and cleaning validation requirements. Training records must be available on any training received.

Analytical Procedure
Any analytical procedures used in the validation study must be validated. The analytical procedures must be challenged in combination with the sampling methods used in order to show that the contaminants can be recovered from the equipment surface and to show the level of recovery as well as the consistency of recovery. This is necessary before any conclusions can be drawn based on the analysis of the samples.

Method Challenge
Recovery rates should be established for samples of the concerned API / intermediate. The recovery rate from the concerned equipment materials (e.g. stainless steel, glass, Teflon, plastics) which have contact with the API / intermediate or detergent/disinfectant should be determined. The recovery tests may be conducted with material plates, not on the equipment itself. The grouping may be applied based on risk assessment.

The recovery rate from the material plate should exceed 50%. Otherwise, the sampling procedure and/or the swab material/rinse solution should be optimized. If it is not possible to reach higher recovery values than 50 % the use of the sampling procedure has to be explained in the validation protocol or report, or the method must be replaced

All recovery tests should be conducted in triplicate at least. The lowest recovery is used as a correction factor when calculating the contamination (i.e., if the swab sampling is found to recover 50%, the correction factor for the actual equipment swab samples would be 2).

The intervals between production and cleaning and between cleaning and use should be considered to ensure that the validation study covers the worst case occurring for the respective equipment/facilities.

Documents for cleaning validation e.g. cleaning validation master plan, site cleaning policy, and equipment cleaning procedures must be available and approved prior to conducting cleaning validation activities.

All cleaning procedures which are applied to a specific process, product, system or item of equipment must be described and evaluated. Any decision to validate must be based on a thorough risk analysis, and the decision must be taken by Quality Assurance and Production.

Cleaning Validation Protocol
A validation protocol must be available prior to conduct the validation study and must be authorized by Production and QA. The cleaning validation protocol must cover the following topics:
  • A detailed description of how the validation of a specific cleaning procedure will be performed.
  • A list of cleaning procedures, sampling plans, and reference to the analytical methods to be used
  • The risk assessment of the critical cleaning parameters for each cleaning method or the reference to the separate document (as necessary)
  • Acceptance criteria and calculation formula of the equipment cleaning being validated
  • The timelines and dates when the study will be performed and completed and when the report will be available
  • The calculations to be used to determine the contamination
  • The equipment and APIs / intermediates concerned are identified.
  • Responsible for the execution, review, approval, and documentation is stated.

  • Three runs of the cleaning procedure must be performed and shown to be successful.
  • The critical steps of the respective cleaning procedure (the critical parts of the equipment regarding cleaning, and the worst case are determined, APIs / intermediates based on their solubility, toxicity, dose, and production volume) are identified by a risk assessment.
  • The interval between the last production run and cleaning of the equipment, the campaign length, and the idle time of the equipment between cleaning and use in production needs to be considered in the risk assessment
  • The validation study described must be rationalized with the findings of the risk assessment. The validity of the results of this validation study for other equipment and APIs / intermediates is to be stated.

Sampling Procedures
The sampling must follow a rationalized plan to fully characterize the cleaning process for validation purposes. The sampling procedures used (i.e. rinsing and/or direct surface sampling by swabbing) should be determined based on their suitability, considering the accessibility of the equipment contact surface area and the solubility of the contaminant in the rinse solution. For cleaning validation studies, swabbing should be carried out on all major items of equipment after they have been boiled or rinsed out with solvent, e.g. reactors, filters, and dryers. These swab results are to demonstrate that the equipment is acceptably clean and confirm the validity of the rinse sample results.

Analytical / Microbiological Procedures
Reference to the analytical/microbiological/endotoxin procedures used for analyzing API / intermediate, detergent/disinfectant, and microbiological contamination are to be given together with their validation status. For the measurement of active ingredients, in nondedicated plants, a selective method should be used (i.e., HPLC, GC, CE) while measurement of the cleaning agent may utilize either a selective method or a nonselective method (for example TOC). The sensitivity of the analytical procedures must assure that the limit of quantification is suitable to meet the acceptance criteria for the training of equipment.

Key Acceptance criteria
The acceptance criteria together with their limits for the concerned equipment and API / intermediate, the detergent/disinfectant, and the microbiological/endotoxin contamination (if applicable) should be determined based on the requirements stated in this module. All processes must be validated to visibly clean status.

Cleaning Validation Report
Validation activities can be considered functionally complete when all raw data has been generated, reviewed, and found acceptable. This determination is to be documented in the cleaning validation report. The cleaning validation report is to cover the following topics:

Documentation of validation activities performed. It presents all pertinent findings and conclusions, especially the validation status. Any deviation from the protocol or from the acceptance criteria is to be described and rationalized, and the consequence of validation is stated.

Description of Tests carried out / Expected Results
Reference to the respective validation protocol should be given, and the acceptance criteria together with their limits are to be stated.

Detailed Summary of Results
The result of all tests is to be summarized for all contaminants considered including the results of failed tests. The reference to all raw data must be provided.

Additional Tests / Deviations
All deviations and changes that occurred during the validation must be reviewed and approved. Deviations in the analytical laboratory (out-of-specification (OOS) test) must be subject to investigations according to applicable SOPs.

Review / Comparison of Results
The obtained results must be reviewed in regard to validation ranges of critical cleaning parameters and acceptance criteria. The results should be compared with the expected values. The outcome of the investigation performed for any deviation or analytical OOS results must be reviewed, the effects on the product quality must be discussed and the appropriate conclusions are drawn.

Acceptance / Rejection Decision
The acceptance/rejection decision is to be stated after all activities are completed, including any corrective actions and repetitions.

Conclusion / Recommendations
Recommendations for the extent of routine testing after cleaning, the interval between production and cleaning, the interval between cleaning and use, and campaign length should be stated on the basis of experience of the cleaning runs performed during the validation. Criteria for re-validation should be specified. This report must be approved by Quality assurance and the VMP amended accordingly.


To maintain the validation status of a cleaning procedure despite planned changes to the cleaning procedure, the equipment/facilities or the APIs / intermediates may need revalidation.

There are two types of re-validation, periodic routine evaluation of validation status and re-validation if necessary and re-validation due to a change or due to observations in the annual product review. The kind of re-validation considered should be stated as the reason for it. Periodic routine evaluation of validation status is performed by ongoing monitoring or analysis of samples following each cleaning after either a defined time or a defined number of production campaigns. The degree of re-validation due to a change or an observation in the annual product review should be based on the risk assessment of the change/observation regarding the quality characteristics.

Variables to be monitored
Re-validation may not need to cover all variables monitored in the initial validation study, depending on the results of the risk assessment. Evaluation of the influence of the change observed on the cleaning efficiency determines what variables require monitoring. The validation documentation for re-validation is to be established in the same way as for the initial validation. The variables/systems not considered in the re-validation should be stated together with the reason for not monitoring them.

Change Control
Changes to any aspect of the above-described process must be authorized through a formal change control procedure. This should include also quality and regulatory issues.

Changes that may have an influence on the API / intermediate quality could be for example:
  • Changes in the cleaning procedure
  • Changes in the equipment contact surface (material, geometry, size)
  • Addition/removal of equipment
  • Change of batch size
  • Changes in the APIs / intermediates processed on the equipment

As a result of a request for such a change re-validation may be necessary before the change is implemented.


Revision History

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