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Cleaning Validation : Procedure & Protocol

Standard operating Procedure & Protocol for Cleaning Validation to prove that the equipment cleaning procedure can repeatedly and reproducibly remove residue of the previous product below established acceptance limit.

The acceptance limit is maximum allowable quantity of product residue, which does not affect quality and safety of the subsequent product to be manufactured, by using same equipment and facility.

Cleaning Validation

1.0   PURPOSE :

    • The purpose of this Standard Operating Procedure (SOP) –

    • To prove that the equipment cleaning procedure can repeatedly and reproducibly remove residue of the previous product below established acceptance limit.
    • The acceptance limit is maximum allowable quantity of product residue, which does not affect quality and safety of the subsequent product to be manufactured, by using same equipment and facility.
    • To establish acceptable time limit for storage of used Equipment before cleaning (Dirty Equipment Hold Time study).

2.0   SCOPE :

    • This SOP is applicable for validating of cleaning procedures followed for process equipment and accessories used in manufacturing pharmaceutical products.
    • To identify the new worst case molecule / product based on matrix prepared based on LD 50/ Potency & Solubility.

3.0   RESPONSIBILITY :

    • Production Manufacturing :

    • Performing of cleaning activity as per standard operating procedure.
    • Review of Protocols and Summary Reports.
    • The preparation and approval of SOP for cleaning of equipment(s).
    • Execution of Cleaning Activities as per SOP during cleaning validation .
    • Training on equipment and area cleaning SOPs.
    • Checking of cleaning activities.

    • Quality Control :

    • Responsible for ensuring the validation of analytical methods and recovery study used to analyze cleaning validation  samples.
    • Review of Protocol and Report.
    • The approval of SOPs, STPs and GTPs.
    • Analysis of cleaning validation  samples and report submission.
    • Initiation of Deviations pertaining to analysis.

    • Microbiology :

    • Review of Protocol and Report.
    • Sampling of Swab/rinse samples for microbial analysis during cleaning validation.
    • The approval of SOPs and testing procedure.
    • Incubation of swab or rinse sample taken during execution of cleaning validation protocol.
    • Initiation of Deviations pertaining to testing.

    • Quality Assurance :

    • Preparation, Review of Cleaning validation master plan.
    • Preparation, Review of Protocol and Report.
    • Execution and Sampling of swab/rinse samples for chemical analysis during cleaning validation  as per approved protocol.
    • Verifying the cleaning activities.
    • The Authorization of SOPs, STPs, Protocol & Report.
    • Handling of Deviations.
    • Training of team involved in cleaning validation .
    • Updation of cleaning validation matrix, to understand / identify the new worst case molecule/ product if any addition/deletion of product from the facility.

    • Engineering :

    • Calculation of equipment contact surface area.

4.0   PROCEDURE – CLEANING VALIDATION

    • Prerequisites for cleaning validation:

    • The procedure of cleaning validation  shall be based on the policy and philosophy of cleaning validation mentioned in Cleaning Validation Master Plan.
    • Approved equipment cleaning SOPs involved in manufacturing shall be available.
    • The cleaning validation procedures involves the review of cleaning procedures Manual cleaning, automated cleaning, cleaning–in-place, cleaning out of place of manufacturing equipment coming in contact with the product and can pose a potential risk of cross contamination in other products manufactured on the same line.
    • The Cleaning Validation Master Plan and cleaning validation protocol shall be available before execution of cleaning validation.
    • Validated analytical method for estimation of cleaning agent (if any) in the rinse/swab.

    • Cleaning of Equipment(s)

    • Clean the equipment(s) as per respective approved SOP of equipment cleaning and ensure the followings:
      • The number of cleaning steps and/or cycles shall be performed as per respective equipment cleaning SOPs.
      • Volume of water shall be used for final rinsing of equipment/equipment parts as per individual SOPs or respective annexure of cleaning validation.
      • Water for injection shall be used as the final rinse for equipment to be used in production of sterile products and purified water shall be used for equipment to be used in production of non-sterile products.

    • Types of cleaning levels:

      • For Injection:
      • Type ‘A’ cleaning shall be done in the following situations:
      • Batch to Batch changeover of same product on same day.
      • Strength to strength changeover of same product on same day.
      • Type ‘B’ cleaning shall be done in the following situations:
      • Batch to Batch changeover of same product on different day.
      • Strength to strength changeover of same product on different day.
      • Product to product change over.
      • For Oral
      • Type ‘A’ cleaning shall be done in the following situations:
      • Batch to Batch changeover of same product.
      • Lower to higher strength of same product.
      • After preventive maintenance of non-contact parts.
      • Type ‘B’ cleaning shall be done in the following situations:
      • Product to product change over
      • Different colour of same product
      • Higher to lower strength of same product
      • After preventive maintenance of contact parts.
      • Re-cleaning after stipulated storage period (CEHT)
      • Batch to Batch changeover of same product campaign (If applicable).

  • Preparation and Approval of Cleaning Validation Protocol

    • For preparation of protocols, following considerations shall be taken.
    • Cleaning validation protocol shall be specific for Injection and oral.
    • Protocol shall be numbered as per the current version SOP for protocol numbering system.
    • Product matrix shall be available w.r.t. details of solubility, dosage, toxicity of active ingredient(s) and batch sizes of products manufactured in existing facility.
    • All the products in a particular line shall be enlisted in the form of matrix incorporating their active pharmaceutical ingredients (API), strength, smallest therapeutic dose, batch size (in Kg.), Fill weight in mg (Dry powder Injection) /average weight of the tablet (in mg.), solubility, maximum daily dose.
    • Product contact surface area of equipment(s) involved in manufacturing of pharmaceutical product (The basic information or contact surface area of equipment pieces may be taken from manufacturer documents also).
    • Approved sampling plan (for both chemical and microbiological sampling) for taking the sample from complexity (Hard to clean) and design of equipment into consideration.
    • Approved Swab/Rinse locations for equipment(s) involved in manufacturing of pharmaceuticals product.
    • Product verses Equipment matrix with contact surface area.

    • Preparation of cleaning analytical method validation protocol

    • Cleaning analytical method validation protocol shall be product specific.
    • Protocol shall be numbered as per the current version SOP for protocol numbering system.
    • Protocol shall include but not limited to the following
    • Method of analysis, detailed analytical method including instruments and reagents to be used.
      • Accuracy
      • Precision
      • LOQ (Limit of Quantification)
      • LOD (Limit of Detection)
      • Recovery Study (Recovery of contaminant from cleaning sample & equipment surface)

    • Approach for calculation of Acceptable Residual Limit:

    • Acceptable residual limit (ARL) is determined by a comparative calculation of one product against all other product (Subsequent product) sharing the equipment train.
    • For ARL the following residual limit calculations shall be utilized and other criteria shall also consider (If applicable).
    • The first calculation, referred to as the Dose Criterion, is based on assuring that less than 1/10000 (For Injection) and 1/1000 (For Oral) of Single Unit Dose of the contaminating product will appear in the maximum daily dosage of any subsequently manufactured product utilizing any aspect of the shared equipment train.
    • The Second calculation, referred to as the Ten (10) Part per Million Criterion, is based on assuring that less than ten milligrams of contaminating product will appear per kilogram or liter of subsequently manufactured product utilizing any aspect of the shared equipment train.
    • The Third calculation, referred to as the Toxicological Data, The ARL calculation is based on assuring that less than 1/10000 of NOEL (No Observed Effect Level) For Injection and 1/1000 (for oral) of NOEL of the contaminating product that will appear in the maximum daily dosage of any subsequently manufactured product.
    • Visually clean criteria. The equipment(s) should be visually inspected for cleanness before taking swab/ rinse sample.
    • For all the products, the above residual limits calculation will be determined, and the lower of the determined calculation will typically be applied as the product specific ARL.

  • Execution and Sampling for Cleaning Validation 

    • Following procedure shall be followed during execution and sampling:
      • Validation study shall be conducted on three consecutive batches or end of three campaigns of considered product (In case of oral).
      • In case of Injectable products cleaning shall be performed after completion of each batch and three consecutive batches shall be considered for cleaning validation study.
      • The cleaning of the equipment(s) (CIP / COP) shall be done in all the three validation runs by different operators to verify the ruggedness of the cleaning procedure.
      • Completion of cleaning, production officer/technical staff shall inform QA officer/technical staff to carry out sampling.
    • After getting the requisition from the production, QA officer/technical staff shall examine the cleaned equipment visually for its cleanliness as per procedure defined in the respective protocol for its cleanliness.
    • After satisfactory observation, QA officer/technical staff shall collect the samples from different locations as per the sampling plan mentioned in the cleaning validation protocol/CVMP.

    • Collection of samples for chemical & Microbial analysis

    • Swab/Rinse samples shall be collected after final cleaning as per approved sampling plan of each equipment which is involved in the manufacturing.

    • The sampling plan shall be defined considering the followings:

    • The selection of sampling techniques and solvent shall be depending upon solubility of residue and cleaning agent (If any).
    • Design of the equipment(s).
    • Locations of sampling.
    • Difficult to clean sites.
    • Samples shall be taken in the form of swab or rinse or the combination of these two.
    • The surfaces where swabbing of 25 cm² area or as specified in the protocol is not possible, equally divide the area to take swab sampling for microbial and chemical analysis or consider the rinse sampling.
    • Stainless steel/Teflon/PVC template should be used for determining the surface area of the swab.

    • Swab sampling for chemical analysis

    • Swab individually various parts of the equipment after cleaning and final rinsing of parts as detailed in the sampling plan.
    • Selection of swabbing sites shall be hard to clean sites with justification. Refer individual sampling plan of different equipment’s parts to be swabbed (as per cleaning validation protocol).
    • Before collection of swab sample visual inspection of the equipment shall be done to check the cleanliness.
    • Selection of sample position shall be based on difficult to clean equipment surface area, as specified in the sampling plan.
    • The swab shall be wet by the solvent before sampling.
    • Swab sample shall be collected from 5 x 5cm (25cm²) or as specified in the protocol.
    • Swab sample shall be collected in dry test tube.
    • Each test tube shall be identified with the label indicating sampling.

    • Swab Sampling for Microbiological Analysis

    • Sampling for Microbial analysis shall be performed as procedure defined in the protocol or as per the current version of SOP for “Sampling and Microbial Monitoring of Cleaned Equipment(s)”.
    • Microbial swab samples shall be collected prior to chemical swab sample.
    • Sterile prepared swabs or ready to use sterile swabs should be used for swabbing of equipment surfaces for microbiological analysis.

    • Selection of swabbing sites should be hard to clean and difficult to sanitize the sites.

    • Swab sample for microbiological analysis shall be collected prior to swab sample for chemical analysis and swab sample should be adjacent to microbial swab.
    • For Microbiological analysis swab stick should be sterile prior to use and dipped in 0.9 % w/v sterile saline solution.
    • The surface area should be swabbed is 25 cm² or as specified in the protocol. If the surface area less than the 25 cm², complete surface area should be swabbed.
    • Swab sample should be taken after the final cleaning cycle from hard to clean location of equipment.
    • In case of swab sampling of pipes, do the swabbing in circular motion from outer edge to inner surface in clockwise direction and return the swabbing in similar procedure i.e. from inside to outside in anticlockwise direction.
    • Wherever dismantling of such equipment/components is possible, dismantle and wash then do the sampling.

    • Rinse Sampling (where it is applicable):

    • The final rinse sample shall be collected in such a way that the sample is representative of entire rinse volume.
    • Perform the rinse sampling for chemical and microbiological analysis from pre-defined locations as per protocol/CVMP.
    • The quantity of rinse shall be collected as procedure defined in cleaning validation Protocol.
    • Visually inspect the final rinse of equipment/each part of equipment to ensure that it is clean, clear and colorless.
    • All samples shall be sent to Q.C. along with the test request forms for analysis and results shall be verified with respect to the set acceptance criteria.
    • All results shall be compiled and reviewed during preparation of cleaning validation report.
    • Any kind of discrepancies or deviations shall immediately be noted down and information shall be given to Head-QA/ Manger.

  • Labelling and storage of cleaning validation samples

    • Label each swab and rinse sample appropriately.
    • The rinse sample shall be stored in depyrogenated vials/bottles and swab sample in appropriately covered glass test tube with proper labelling so as to prevent contamination or alteration during storage.
    • Microbial swab sample shall be stored in sterile well closed test tube with proper labeling as per current version of SOP for “Sampling and microbial monitoring of cleaned equipment”.
    • Transfer all the swabs/rinse samples to the Microbiology lab for further analysis. Analysis of the samples shall be done as soon as possible by the microbiologist.
    • In case of expected delay beyond 2 hours, store the samples at 2-8ºC and analyze the samples within 6 hours of sampling as per current version of SOP for sampling and microbial monitoring of cleaned equipment.

  • Hold time study

    • Dirty equipment hold time study
    • The objective of hold time study is for establishing time limit for Dirty Equipment Hold time (DEHT) i.e. time from the end of manufacturing until the beginning of the cleaning process.
    • DEHT time period for holding equipment should be decided on the basis of microbiological analysis data.
    • A separate protocol shall be prepared having details of hold time, sampling plan, method for conducting Dirty Equipment Hold Time study and its acceptance criteria.
    • After successful completion of hold time study, a summary & conclusion report shall be prepared & the same shall be incorporated in the respective cleaning SOPs.

    • Clean Equipment Hold time study

    • Cleaned Equipment Hold Time (CEHT) i.e. time from the end of the cleaning process until the beginning of the use.
    • CEHT is carried out to establish the expiry of cleaning in view of microbiology, equipment shall be kept idle after cleaning.
    • Microbiological swab samples shall be taken and analyzed starts from zero hour immediate after completion of equipment cleaning till the end of the hold time as per frequency defined in the protocol.
    • A separate protocol shall be prepared having details of hold time, sampling plan, analytical method for conducting Cleaned Equipment Hold Time study and its acceptance criteria.
    • After successful completion of hold time study, a summary & conclusion report shall be prepared & the same shall be incorporated in the respective cleaning SOPs.

    • REPORT PREPARATION (CLEANING VALIDATION)

    • Each test results shall continuously be verified against final acceptance criteria.
    • Cleaning validation (CV) reports shall be prepared by collecting and compiling of all Q.C. results, observations and deviations.
    • Report shall be numbered as per the current SOP of numbering system or as mentioned in the Cleaning Validation Report.

    • ANNUAL VERIFICATION

    • Regular validation review must be established to maintain the validated status of the cleaning procedure.
    • Cleaning verification of the worst case product shall be carried out once every year.

    • REVALIDATION CRITERIA

    • The need for carrying out re-validation of cleaning procedure shall be assessed in the following situations.
    • Change / Modification in cleaning method/ cleaning agent and equipment.
    • Evidence of cleaning failure e.g. batch failure due to cross contamination etc.
    • At the time of introduction of a new product/ revision of Batch size/ change in formulation or Change of Equipment/modification in the existing equipment / equipment chain shall be assessed for evaluation of product A and product B (Subsequent product).
    • The matrix of the product grouping for worst-case determination shall be revised to include the new product based on manufacturing process and compared against the worst case of the earlier matrix.
    • If the worst-case product changes, Matrix of the ARL shall be revised to include the new product.

    • The ARL limit of the matrix shall be compared against ARL limit of the earlier matrix.

    • If the revised ARL value is less than the earlier determined ARL value, acceptance criteria shall be revised based on revised ARL value.
    • If the revised ARL value found more than the earlier reported ARL value, then no cleaning validation shall be performed, as the earlier study proved that the cleaning procedure followed for each equipment stands effective and consistent to reduce previous product residue to acceptance level.
    • Revised ARL value (acceptance criteria) is less than the observed highest ARL value obtained during the previous study then perform re-validation study using the same cleaning procedures.
    • If the above revalidation studies do not pass the revised ARL value (acceptance limit), the cleaning validation shall be repeated with the revised cleaning procedure through Change Control procedure.

5.0   REFERENCES – CLEANING VALIDATION

    • Code of federal regulation -211, sub part 211.67
    • Guidance on aspects of cleaning validation in active pharmaceutical ingredient plants (APIC).
    • WHO Technical Report Series, No. 937, 2006, Appendix 3 and 4, Annex 4 Supplementary guidelines on good manufacturing practices: validation.

6.0   ABBREVIATIONS AND DEFINITION

    • CIP         : Clean in Place
    • COP       : Clean out of place
    • ARL        : Acceptable residual limit
    • STP        : Standard Test Procedure
    • GTP        : General Test Procedure
    • LD 50     : Lethal dose 50
    • TRS        : Technical Report Series

    • Cleaning Validation :

    • Cleaning validation  is the methodology used to assure that a cleaning process removes residues of the active pharmaceutical ingredients of the previous product manufactured in a piece of equipment, the cleaning aids utilized in the cleaning process and the microbial attributes.

    • Worst case:

    • A product or set of conditions encompassing the upper and lower processing limits for operating parameters and circumstances with SOP which pose the greatest chance of product or process failure when compared to ideal conditions. Such conditions do not necessarily include product or process failure.

    • Worst case product:

    • The product selected from a group of products that represents a greatest risk of carry over contamination to other products made in the same equipment by virtue of its poor solubility, potency and toxicity or a combination of these factors.

    • Acceptance criteria:

    • To demonstrate during validation that the cleaning procedure, routinely employed for a piece of equipment, limits potential carryover to an acceptable level.

    • Revalidation:

    • The repeat of initial validation either after changes/introduction to equipment, new product or periodically to provide assurance that the changes done, do not affect the cleaning effectiveness.

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Janki Singh

Mrs. Janki Singh is the professional pharmaceuticals Blogger. She has already posted more than #1000 articles on varrious topics at different blogging plateforms. Contact : guideline.sop@gmail.com