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SOP on Cleaning Validation in pharmaceutical company

  • To establish  and explain the procedure to be followed for the cleaning Validation of
  • Standard Cleaning Procedures (SCP)s, in order to
  •  Assure that  fitness of the equipment is adequately protected for every product.
  •  Demonstrate that no cross contamination will be observed on shared equipment between drug product to be cleaned  and Drug product to be manufactured.
  • Demonstrate and validate that current Standard Cleaning Procedures can consistently clean the equipment to a pre – determined  level of cleanliness.
  • Establish the length of time between the end of cleaning process and the use of the equipment, as  cleaned equipment hold time.
  • Officer of the concerned department to initiate the  SCPs and Officer validation, in co-ordination with the Officer of the concerned department, if required  to prepare the Cleaning Validation Protocols for various equipments.
  • Officer Analytical R&D (AR&D) to develop analytical methods for estimation of residue of active ingredient, cleaning agents and validate the methods.
  • Officer – Analytical R&D / Quality Control (QC),  to sample and analyse as per cleaning validation protocol.
  • Heads of user department, Quality Control / Analytical  R&D and Quality Assurance (QA), to approve and certify Cleaning Validation Protocols.
  • The Cleaning validation program is designed to demonstrate the effectiveness of SCP to remove residual drug active substance as well as cleaning agents used in SCP.
  • After the process equipment is used for the manufacture of a product, it shall be cleaned as mentioned in respective SCP.
  • All the SCPs of process equipments used to manufacture more than one product shall be validated, for each product.
  •  If the product  contains multi active drug substances, the active substance least soluble in potable water and /or highly toxic is tested, unless the method validation data provides for testing of all active drugs in the combination.
  • Before  initiating any cleaning validation, a cleaning validation protocol shall be prepared by Officer Validation and submitted for approval, to the concerned Head of the Department (HOD) Head – QC/ AR&D  and Head – QA.
  • The cleaning validation protocol in general, shall contain the following:
  1. Objective: Describe the objective and scope of the validation
  1. Procedure:
  • a) Describes the activities  comprising  the  cleaning validation  and  personnel responsible for carrying out the activities.
  • b)Provides procedure for Preparation of Swabs and swabbing pattern.
  • c) Calculates and provides surface area of the equipment in common along  with sampling locations, swab numbers and type of sample (Residue of drug active, Cleaning agent, Microbial)
  1. Acceptance Criteria: Specifies the acceptance limits for the active drug substance, the cleaning agent and microbial attributes, if any.
  1. Annexures :The protocol contain the summary of analytical results for Drug  active, Cleaning agent and microbiological attributes as Annexures.
  • A copy of the analysis report given by  QC / AR&D  laboratory shall also be enclosed to the  protocol.
  • Each Cleaning Validation Protocol shall be certified by the approving authorities after it’s satisfactory execution.
  • Cleaning Validation shall be performed on a minimum of three (3) production size batches.
  • Any drug active or cleaning agent failing results shall be investigated and a corrective action shall be taken.
  • If acceptance criteria is not met and / or  cleaning found not satisfactory, during visual inspection, the following steps shall be taken for remedial action.
  • Investigate the execution of the SCP of that particular process equipment.
  • If found to be incorrect and deficient during investigation, clean the equipment again as per that SCP. Sample again and analyse as per the cleaning validation protocol.
  • If execution of SCP is found proper, revise the SCP to ensure proper cleaning of locations/parts which are found to be not satisfactorily cleaned during visual inspection or analysis of the swab samples.
  • Cleaning Validation Acceptance Criteria:
  • For each drug active an Exposure Control Level (ECL) will be calculated, mg/Sq.Inch. using the following formula: X = 0.001 x d x B x 1/D x 1/A x F
  • Where X = the residue of the drug active in mg/ Sq.Inch
  • d = Dose in lowest label strength available for the product in mg  to be cleaned.
  • B = Minimum Batch size (or Smallest  batch size) of the all strengths for host product.
  •  A = Cumulative surface area of the equipments in common to the product to be cleaned and product to be manufactured, in Sq. Inch.
  • D= Maximum dosage units taken per day of the product to be   manufactured.
  • F = Recovery factor (Specific to each product, shall be established  by AR&D – Officer)
  • Calculate the residue in swabbing solvent, in ppm,( X in ppm) by using the following formula
  • X in ppm =  X in mg/Sq. inch x 16 Sq. inch x 1/V x 1000
  • V = Volume of solvent used for Extraction of Swabbed contents.
  • 16 Sq. inch = area of the equipment surface to be swabbed.
  • The value obtained for X in ppm is the maximum amount of residue of drug active permitted in any swab sample.
  • Follow the below steps before performing the ECL drug active calculations :
  • Prepare a matrix with all possible combinations of manufactured products which share equipment in common with the compound under study. List manufactured products, maximum daily dose, maximum dosing units/day, batch size (units), equipment surface area (for typical matrix refer annexure-1).
  • Make  these  calculations  in  accordance  to  the  formula  above  for  all
  • manufactured  products  which  share the equipment with product to be cleaned.
  • Compare results of above calculations for each product sharing equipment with the drug active to be cleaned.
  • The lowest calculated permissible residue per Sq. inch obtained among all strengths of products evaluated with the drug active under study is to be used as the ECL.
  • Calculate an ECL for Cleaning agent (Detergent)  in µg/Sq. Inch  using the
  •  following formula: (Wherever LD50 value is available).
  •  Y = (Q x R x T x B)/ (S  x  D x A)
  • If LD50 value is not available a maximum of 5 ppm/swab is allowed unless otherwise
  • specified in the individual cleaning validation protocol.
  • Q = LD 50 of cleaning agent (1000g/kg )  x 50 kg of body weight of a human (small adult).
  • R = % of active ingredient in total dose of cleaning agent.
  • S= Safe daily exposure factor = 5 x 106 (constant)
  • T= 1 x 106 µg/g (conversion factor)
  • D = Maximum number of dosage units taken per day of product to be manufactured.
  • B = Minimum batch size (or smallest batch size)
  • A = Total equipment surface area used in process.
  • Follow the below steps before performing the ECL for cleaning agent calculations : using the product matrix procedural description, calculate the cleaning agent ECL in accordance to the formula above. List manufactured product, maximum dosing units/day, batch size (units), equipment train surface area, LD50 and percent of active ingredient of cleaning agent as in Material Safety Data Sheets  (MSDS)
  • Compare  results  of  above calculations for the cleaning agent under study with  each  product  strength  evaluated. The  lowest  calculated permissible residue per square inch obtained among all strengths of products evaluated with the cleaning agent under study is to be used as the ECL.
  • Alert Limit : For each product an alert limit for Active Drug substance shall be established  during  cleaning  Validation. The  alert  limit  shall   be  60% of the calculated limit.
  • When ever the cleaning validation results are differing significantly from the regularly observed results, for the drug active, the same shall be investigated.
  • The ECL values for drug active and detergent shall be referred to a review committee comprising of Heads of R&D and QA. The limits shall be reviewed for their acceptance by considering the toxicity, sensitivity levels in all the possible subjects of different age groups.
  • In case the calculated ECL values are not acceptable, the committee shall recommend the alternative ECL values and same shall become effective.
  • Revalidation of Cleaning Procedures :
  • A Revalidation of the cleaning procedure is required if any of the following occur and revalidation of SCPs shall be performed on a minimum of three(3) Production batches.
  • Modification of MOC/surface area of Product contact parts of the equipment, or any modification to the equipment.
  • Change in cleaning agents.
  • Change in SCP
  • Change in  Formula of the Product.
  • Major non – traceable contamination occurrence.
  • Periodic Monitoring Program:
  • Monitor the validation status of Cleaning procedures once in a year, unless otherwise specified in the individual cleaning validation protocol of the product.
  • “UNDER CLEANING VALIDATION – DO NOT USE” label shall be kept after collecting the swabs
  • Unless the interim report/analysis report is released by Quality Control to Quality Assurance department for chemical and detergent swabs results, clearance for the equipment usage shall not be given by Quality Assurance for the next product.
  • In case of microbial analysis results of swab samples, no need to wait for the release of results.
  • Numbering of Validation Protocol :
  • Each validation protocol shall have a unique number.
  • The number consists of eight characters.
  • The third and fourth characters shall be follows :
  • PD  – Production
  • The fifth character shall be a dash.
  • The sixth, seventh and eighth characters indicates the serial number.
  • The first protocol belonging to PD shall be VCPD-001.
  • Details shall be recorded in the register.
  • Forms and Records (Annexures)
  • Not Applicable
  • Distribution
  • Master copy –  Quality Assurance
  • Controlled copies- Quality Assurance, Production, Quality Control.engineering
  • History
    Date Revision Number Reason for Revision
    00 New SOP


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