SOP on Cleaning Validation in a 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 the fitness of the equipment is adequately protected for every product.
Demonstrate that no cross-contamination will be observed on shared equipment between the drug product to be cleaned and the Drug product to be manufactured.
Demonstrate and validate that current Standard Cleaning Procedures can consistently clean the equipment to a predetermined level of cleanliness.
Establish the length of time between the end of the 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 coordination with the Officer of the concerned department, if required to prepare the Cleaning Validation Protocols for various equipment.
Officer Analytical R&D (AR&D) to develop analytical methods for estimation of the residue of the active ingredient, and cleaning agents and validate the methods.
Officer – Analytical R&D / Quality Control (QC), to sample and analyze 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 substances 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 the respective SCP.
All the SCPs of process equipment 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 – of QC/ AR&D, and Head – of QA.
The cleaning validation protocol in general, shall contain the following:
Objective: Describe the objective and scope of the validation
a) Describes the activities comprising the cleaning validation and personnel responsible for carrying out the activities.
b)Provides a procedure for the Preparation of Swabs and swabbing pattern.
c) Calculates and provides a surface area of the equipment in common along with sampling locations, swab numbers, and type of sample (Residue of drug active, Cleaning agent, Microbial)
Acceptance Criteria: Specify the acceptance limits for the active drug substance, the cleaning agent, and microbial attributes, if any.
Annexures: The protocol contains the summary of analytical results for Drug active, Cleaning agent, and microbiological attributes as Annexures.
A copy of the analysis report given by the QC / AR&D laboratory shall also be enclosed in the protocol.
Each Cleaning Validation Protocol shall be certified by the approving authorities after its 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 corrective action shall be taken.
If acceptance criteria are not met and/or cleaning is found not satisfactory, during a 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 the investigation, clean the equipment again as per that SCP. Sample again and analyze 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 all strengths for the host product.
A = Cumulative surface area of the equipment 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 the 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 that share equipment in common with the compound under study. List manufactured products, maximum daily dose, maximum dosing units/day, batch size (units), and equipment surface area (for typical matrix refer to annexure-1).
Make these calculations in accordance with the formula above for all manufactured products which share the equipment with a product to be cleaned.
Compare the results of the above calculations for each product-sharing equipment with the drug activity 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 the active ingredient in a total dose of the cleaning agent.
S= Safe daily exposure factor = 5 x 106 (constant)
T= 1 x 106 µg/g (the conversion factor)
D = a 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 the 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 with the formula above. List manufactured product, maximum dosing units/day, batch size (units), equipment train surface area, LD50, and percent of the active ingredient of cleaning agent as in Material Safety Data Sheets (MSDS)
Compare the results of the 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 substances shall be established during cleaning Validation. The alert limit shall be 60% of the calculated limit.
Whenever 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 activity 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, and sensitivity levels in all the possible subjects of different age groups.
In case the calculated ECL values are not acceptable, the committee shall recommend alternative ECL values and the 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 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 the 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 the 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 as follows :
PD – Production
The fifth character shall be a dash.
The sixth, seventh, and eighth characters indicate the serial number.
The first protocol belonging to PD shall be VCPD-001.
Details shall be recorded in the register.
Forms and Records (Annexures)
Master copy – Quality Assurance
Controlled copies- Quality Assurance, Production, Quality Control. engineering