SOP for Cleaning Validation | Cleaning Validation in Pharmaceutical Industry |
- Cleaning Validation SOP covers below points:
- Cleaning Validation definition
- Cleaning Validation purpose
- Cleaning Method / Procedure for cleaning validation
- Cleaning Validation protocol
- Cleaning Validation Report
- Sampling procedure for cleaning Validation
- Rinse sampling procedure for cleaning validation
- 10-PPM criterion for cleaning validation
- Analytical Methods for cleaning validation
- Revalidation Criteria for cleaning validation
- Acceptance criteria for cleaning validation
- Precaution for cleaning validation
- Cleaning Validation protocol format
- Cleaning Validation Report format
1.0 OBJECTIVE :
- To define the procedure for Cleaning Validation carried out at manufacturing site.
2.0 SCOPE :
- This SOP is applicable to all the critical cleaning procedures used for the cleaning of the surfaces of the processing Equipments and Machines (manufacturing facility) that comes into direct contact with products and APIs at the time of manufacturing of one product and to be used for the manufacturing of another product after cleaning.
3.0 RESPONSIBILITY :
- Q.C. officer / Executive is responsible to prepare the Cleaning Method Validation Protocol and Report. He / She is also responsible to perform the validation activity with the help of Production, Quality Control, Engineering Personnel.
- Q.C. Head is responsible to check the Cleaning Method Validation Protocol and Report. He / She is responsible to monitor the validation activity and testing and reporting of the validation samples.
- Engineering Head is responsible to provide all the technical support required for validation regarding Facility, Equipments / Instruments, Utilities etc.
- It is the responsibility of Q.A. Department that this SOP is followed at the time of the cleaning method validation.
- Validation Team is responsible for overall co-ordination and execution of Cleaning Method Validation as per the approved protocol and also for the preparation of report with the help of Production personnel.
4.0 ACCOUNTABILITY:
- Q.A. Head
5.0 PROCEDURE :
5.1 Cleaning Method Validation is the generation of documented evidence that the cleaning procedures consistently remove residues of pharmaceutical actives and the contaminants from the manufacturing facility and equipment to predetermined level to protect the follow up pharmaceutical product from cross contamination.
5.2 Pharmaceutical products can be contaminated by other pharmaceutical products, by cleaning agents or by other material (e.g. air-borne particles, dust, lubricants, raw materials, intermediates, auxiliaries).
5.3 These guidelines describe the validation of cleaning procedures for the removal of contaminants associated with the previous products, residues of cleaning agents and other material. (e.g. air-borne particles, dust, lubricants, raw materials, intermediates, auxiliaries, micro contamination).
5.4 Written SOPs exits detailing the cleaning process for Equipments and Machines which are to be validated.
- Surfaces that comes into contact with product.
- Cleaning after product changeover (When one pharmaceutical formulation is being changed for another).
- Between batches in campaigns (When the same formula is being manufactured over a period of time).
- Bracketing products for cleaning validation. (Where product contains same substance but different strength. An acceptable strategy is to first manufacture the lowest strength and then the highest strength).
5.5 At least three consecutive applications of the cleaning procedure are performed and shown to be successful in order to prove that the method is validated.
5.6 Periodic re-validation is required once in five years or whenever there is change in procedure or introduction of new API.
5.7 Cleaning Method
- The cleaning method validation is initiated and monitored by Q.A. Head with the help of the individual department head and validation team members.
- The cleaning method validation is carried out by validation team as per the cleaning method validation protocol.
- Validation Protocol :
- A written plan stating how validation will be conducted, including test parameters and the Acceptance criteria.
- The validation protocol provides a synopsis of what is hoped to be accomplished. The protocol should list the selected process and control parameters, state the number of batches to be included in the study and specify how the data are assembled, will be treated for relevance. The date of approval by the Q.A. Head should be noted.
- In the case where a protocol is altered or modified after its approval, appropriate reasoning for such a change must be documented.
- The Cleaning Method Validation Protocol should be numbered as follows:
- CMVP/XXX/YY/ZZZ
- Where,
- CMVP : Cleaning Method Validation Protocol
- XXX : Formulation Type or Facility used for
- TAB : Tablet
- YY : Lat two digits of the Calendar Year
- ZZZ : Serial number of Process Validation
5.8 The validation protocol should be signed and dated by respective authorities and should contain the following minimum information:
- The objective and scope of the validation process,
- Responsibilities for performing and approving the validation study,
- Product Composition,
- Rationale,
- Cleaning procedures for products and processes which are very similar do not need to be individually validated. A validation study of the “worst case” may be considered acceptable. There should be justified validation program for this approach referred to as “bracketing” addressing critical issues relating to the selected product, equipment or process.
- Analytical Method
- Acceptance Criteria and Revalidation
- Sampling Locations
- Description of Sampling procedure,
- Cleaning Validation Report,
- Recovery Study
- Reference Documents
- Common Product Sharing equipments
5.9 Validation Report :
- When the validation carried out, the actual data is recorded, compared with the requirement and acceptance criteria and a conclusion is made and authorized in the form of report.
- The validation report should be signed and dated by respective authorities and should contain the following minimum information :
- Rationale,
- Cleaning procedures for products and processes which are very similar do not need to be individually validated. A validation study of the “worst case” may be considered acceptable. There should be justified validation program for this approach referred to as “bracketing” addressing critical issues relating to the selected product, equipment or process.
- Reference Documents,
- Acceptance Criteria,
- Visual Inspection Summary Report,
- Product Residue results compliance,
- Summary of microbial analysis,
- Summary ,
5.10 Following things are also plays a very important role and having a major impact on cleaning method validation and may be a part of cleaning method validation.
- Personnel:
- Personnel or operators who perform cleaning routinely should be trained and should be effectively supervised.
- Equipment :
- Normally only procedures for the cleaning of surfaces of the equipment that come into contact with the product need to be validated. But the consideration is also be given to the “non-contact” parts of the equipments into which product or any process material may migrate.
- Dedicated equipment should be used for product which are difficult to clean, equipment which is difficult to clean or for products with a high safety risk where it is not possible to achieve the required cleaning acceptance limits using a validated cleaning procedure.
- There should be one process for cleaning a piece of equipment or system with the cleaning occurs between the batches of same product or whether cleaning occurs between the batches of different products.
- The design of the equipment may influence the Effectiveness of the cleaning process. Therefore the design of the equipment should be taken in consideration while preparing the cleaning method validation protocol.
- Microbiology :
- The preventive measures to be consider to stop microbial growth and to remove contamination during cleaning.
- There should be documented evidence that the cleaning and storage of the equipment does not allow microbial proliferation.
- The period and conditions for the storage of unclean equipment before the cleaning and the time between the cleaning and equipment reuse, should be the part of cleaning validation.
- Equipment should be stored in dry condition after cleaning. Stagnant water should contaminate the equipment after cleaning.
5.11 Sampling procedure:
- Samples are drawn according to the Cleaning Validation Protocol.
- There are two methods of sampling that are considered to be acceptable, direct surface sampling (swab method) and indirect sampling (use of rinse solutions). A combination of the two methods is generally the most desirable, particularly in circumstances where accessibility of equipment parts can mitigate against direct surface sampling.
- Swab method:
- This method is used for Swab samples shall be taken as per locations given in cleaning validation protocol. Swab stick shall be used for sampling. Defined volume of solvent (about 20-30ml) in which active ingredient is soluble, shall be taken in test tube. Deep the swab stick (1 gm of cotton) into it and wipe on 5 x 5 cm2 surface area of equipment in the manner given below. Deep the swab sticks into test tube and cover the test tube. Repeat the procedure for the other locations.
- A minimum of 3 points should be swabbed per equipment which should include at least one dead spot and these swabs per equipment should be collected individually in a suitable, clean, covered container. Swabbing should be done for all the equipment, which is common for the products manufactured and product to be manufactured. Swabs of different equipments should be collected in separate container.
- Milligrams of active ingredients in the swabs should be estimated quantitatively using a validated analytical technique. The quantity of residue over the swab area will be estimated, by determining the quantity of residue in the 100 ml of solvent, and finally correlated to the entire area of the equipment. Declare the results of estimation in terms of % and in PPM (Results for calculations).
- Rinse Sample:
- Rinse samples allow sampling of a large surface area. In addition, inaccessible areas of equipment that cannot be routinely disassembled can be evaluated. However, consideration should be given to the solubility of the contaminant and the appropriate volume of the samples.
- A direct measurement of the product residue or contaminant in the relevant solvent is made when rinse samples are used to validate the cleaning process.
- In the rinsed technique, the final water quantity for rinsing the equipment is 50 liters. The quantity of residue present in the 50 lit of rinsed water will be the quantity of resides in the equipment.
- 10-PPM criterion:
- This criterion is based on the principles of maximum allowable parts per million (PPM) Ref : Fourmann and Mullen, Pharmaceutical Technology, 54 (1993)
- Milligrams of active ingredient of product A permitted in product B
- = R x S x U / T
- R = 10 mg active ingredient of product A / kg of product B
- S = Number of Kilograms per batch of final mixture of product B
- T = Equipment surface area in common between product A and B expressed as meters2.
- U = 0.01 meters2 / swab
- Calculations:
- In the swab analysis swab report for ACTIVE is for the area 5 x 5 cm. i.e % of Active estimated in 5 x 5 cm area. (Z PPM)
- The surface area for the equipment is known. Thus residual % or PPM of Active in the equipment under study will be
- Z X Surface area in Sq. cm / 5 X 5 = Y PPM
- Compare the Y PPM obtained with the limit of residue allowed.
- If the results are within the acceptance limit of the equipment, the cleaning process is validated for the equipment under study.
- Carry out the experiment for all equipment for the swab technique and conclude the results of cleaning validation.
- Analytical Methods :
- The analytical methods should be validated before the cleaning validation is performed.
- The methods chosen should detect residuals or contaminants specific for the substance being assayed at an appropriate level of cleanliness (sensitivity).
- Validation of the analytical method should include.
- Precision, linearity and *Selectivity (* : If specific analyses are targeted)
- Limit of Detection (LOD)
- Limit of Quantitation (LOQ)
- Recovery, by spiking with the analyte
- Reproducibility
- The detection limit of each analytical method should be sufficiently sensitive to detect the established acceptable level of the residue or contaminants.
- Suitable methods that are sensitive and specific should be used where possible and may include the chromatographic methods (Eg. HPLC, etc.). Other methods may include ( alone or in combination ), UV Spectroscopy etc.
- Establishing Acceptable Limits :
- The acceptance criteria established for contaminant levels in the sample should be practical, achievable and verifiable. The rational for the residue limits established should be logical and based on the knowledge of the material involved.
- In establishing the residual limits it should be consider that there should be no residue from the previous product, from reaction by-products and degradants or from the cleaning process itself (eg. Detergents or solvents).
- The limit setting approach can be,
- Product specific
- Group products into families and choose a worst case product
- Group products into groups according to risk, eg. Very soluble products, products with similar potency, highly toxic or difficult to detect products.
- Use different safety factors for different dosage forms based on physiological response (this method is essential for potent material)
- Limits may be expressed as a concentration in a subsequent product (PPM), limit per surface area (mcg/cm2), or in rinse water as PPM.
- The three most commonly used criteria for cleaning validations are given below, the most stringent of three options should be used.
- Visually clean (No residue should be visible on equipment after cleaning.) Spiking studies should determine the concentration at which most active ingredients are visible. The criteria may not be suitable for high potency, low-dosage drug.
- No more than 10 PPM of one product will appear in another product.
- No more than 0.1% of the normal therapeutic dose of one product will appear in the maximum daily dose of a subsequent product.
- Once the cleaning process is validated there should not be any change in the cleaning SOP of equipments. Any change would lead to revalidation of cleaning process. Cleaning validation should be reviewed regularly after every 24 months.
- Revalidation Criteria :
- Change in cleaning procedure.
- Change in solvent used for cleaning.
- Modification / change in processing equipment.
- Change in equipment sequence.
- Acceptance criteria:
- Visually, clean, dry, odorless and colorless.
- This is first step acceptance criterion which should be included in every cleaning validation procedure. The test should be performed and recorded after every cleaning exercise and before start of every campaign.
- No more than 1/1000 PPM of therapeutic dose any product will appear in another product.
5.12 Precaution:
- Cleaning SOP should be available for every equipment.
- Before commencing any cleaning operations, ensure that all the electrical connections are disconnected.
- If persons are required to go inside the tank or manufacturing vessel for cleaning the equipment, proper care should be taken to prevent cross contamination. Also another person should be present near the manhole of the tank till the persons come out of the tank.
- Product wise equipment list used for manufacturing should be available.
- Before proceeding for cleaning validation, each of the equipment should be visually checked for cleanliness.
- Swab stick should be used for taking swabs.
- Solvent used for swabbing should be of analytical grade.
- Equipment should be cleaned thoroughly with water after taking the swab samples so that there is no residual solvent left on the equipment surface.
6.0 ABBREVIATIONS:
| Abbreviation | Expanded form |
| SOP | Standard Operating Procedure |
| QA | Quality Assurance |
| GMP | Good Manufacturing Practices |
7.0 ANNEXURES:
| Annexure No. | Title |
| 01 | Cleaning validation Protocol |
| 02 | Cleaning validation Report |
8.0 SOP REFERENCES
- GMP Guidelines
END OF THE SOP
ANNEXURES :
Annex. No. 01 Cleaning validation Protocol
Annex. No. 02 Cleaning validation Report
