· General concept
Ø Three consecutive validations will be performed to prove that the method is validated.
Ø Whenever a new product is introduced, equipment usage and nature of potential contaminant will be studied to assess whether it poses a challenging study for cleaning validation.
Ø If the new product represents worst case, study/ identify/develop method of cleaning to be employed. Simultaneously develop Analytical method for cleaning and validate the same.
Ø Revalidation Policy.
· Level of cleaning:
Ø Levels of cleaning during processing depends on:
o Equipment usage (e.g. dedicated or not)
o Stages of manufacturing
o Nature of contaminant (e.g. solubility, toxicity, color etc.)
Ø Our policy is to carry out cleaning after the end of each process, so that the equipment is clean and ready for the next use.
· Elements of cleaning validation:
· Cleaning validation study includes:
Ø Cleaning Procedure
o Identification of equipment
o Characterization of products
o Determination of cleaning agents
Ø Analytical method and its validation
Ø Sampling procedure
Ø Establishment of acceptance criteria
Ø Validation protocol
Ø Validation Reports
· Cleaning Procedure:
Ø Prior to developing cleaning validation study, evaluate the following:
o Identification of Equipments:
ü Identify equipments to be cleaned.
ü Identify difficult to clean areas
ü Check for ease of dismantling
o Characterization of products:
ü Study activity/toxicity, solubility of the active substance of current batch and dosage and batch size of next product to be taken on the equipment.
o Determination of Cleaning Agents:
ü Identify cleaning agents to be used
ü Identify number of cleaning cycles
ü Identify equipments / materials to be used for cleaning.
o Based on above, prepare detailed written cleaning procedures for each equipment.
· Analytical Methods and its validation:
Ø In order for the analytical testing of the cleaning validation samples to yield meaningful results, the analytical methods used should be validated.
Ø Analytical method validation for cleaning should include limit of detection, limit of quantification, acceptance criteria and rationale for setting the specified limits.
· Sampling Procedure:
Ø Sampling plan for validation study should be drawn which includes:
Ø Sampling technique: Type of Sampling methods to be used are,
o Direct surface sampling by swab.
o Rinse water sampling (for equipment cleaning).
o Plate exposure (for area cleaning).
Ø Sampling Locations:
o Two easy to clean and two hard to clean areas should be clearly defined in Protocol.
Ø Sampling Procedure:
o Should mention how many samples are to be taken
ü Swab samples should be taken separately for chemical and microbiological studies
ü For each of chemical and microbiological analysis take 2 swabs from easy to clean hard to clean locations
ü How the samples are to be taken
Ø Sample Numbering:
o Swab samples should be numbered numerically and sequentially like 01, 02 etc for identification.
Ø Establishment of Acceptance Criteria:
o Based on the data available calculate acceptance criteria for both Pharmacological dose method and limiting the level of product to 10 ppm which appear in the following product.
o Of these two, choose the criterion with stringent limits and detectable by analytical method.
o Microbiological limit is 50 CFU/100 cm2. Per swab
· Validation Protocol
Ø Validation protocol defines protocol number.
Ø Protocol defines a validation team that will be responsible for carrying out validation studies. Validation team comprises of at least one responsible person from production, QC & QA department.
Ø Responsibilities of team member are:-
o Production – Carrying out cleaning methods & implementing validation protocol.
o Quality Control – Developing analytical method for cleaning, sampling, testing & recording the results.
o Quality Assurance – Issuing & reviewing of protocol, supervision of validation activities.
Ø Validation protocol given details location, product manufactured, profile of active ingredient, cleaning agents used, testing equipment to be used, sampling points, sampling procedures, limit of detection acceptance calculation, surface area, validation report etc.
Ø Responsible persons from Production, QC and QA should formally approve the cleaning validation protocol.
Ø After approval Validation protocol is issued to QC Department.
Ø QC will perform validation studies in accordance with protocol and record results in validation report.
· Validation Procedure:
Ø After completion of the manufacturing process, workman will clean the equipment.
Ø If the cleaned equipment is listed in the protocol, production person will inform QC Department to collect samples for testing and QA department for supervision.
Ø QA/QC chemist will first check visually for cleanliness of equipment.
Ø If it observed not clean, instruct for re-cleaning.
Ø If it observed visually cleaned, collect samples separately for both chemical and microbial analysis (if required) from locations given in the protocol as per sampling procedure.
Ø Samples are carried to QC, where testing of the samples will be done using validated Analytical method.
· Validation Report:
Ø QC will record the results of testing in the protocol.
Ø QC will return the protocol with documented results and attachments like work sheet, graphs, chromatograms etc. to QA for review.
Ø After completion of documented studies, QA will write conclusions regarding acceptability of the results and status of procedures considered for validation.
Ø Any recommendations based on the documented results will be mentioned.
Ø References to the procedures used for cleaning, sampling and testing should be mentioned in the validation report.
Ø All the members of validation team should approve conclusion
Ø In cases where it is unlikely that further batches of the product will be manufactured for a period of time, it is advisable to generate interim reports on batch-to-batch basis till such time the cleaning validation study is complete.
Ø If the results of validation of any of the three studies are non-conforming to set limits of acceptance criteria, QC should inform immediately to QA.
Ø Further manufacturing process on the equipment/in the area should be suspended.
Ø Re-validation should be performed.
Ø Prior to re-validation, cleaning methods/procedures, sampling methods/ procedures and analytical procedures employed should be re-checked and reviewed.
· Re-validation Policy:
Ø Revalidation of validated cleaning procedures will be considered –
o Once in a year, three replicate studies will be performed.
o In case of changes in equipment/process of product
Ø If the new product represents worst-case challenge
1.0 The result of inadequate cleaning procedures is that any of a number of contaminants may be present in the next batch manufactured on the equipment such as:
o Precursors to the Active Pharmaceutical Ingredient
o By-products and/or degradation products of the Active Pharmaceutical
o The previous product
o Solvents and other materials employed during the manufacturing process.
This is particularly the case where microbial growth may be sustained by the product.
o Cleaning agents themselves and lubricants
2.0 Cleaning techniques to be evaluated
o Manual cleaning
o CIP (Clean-in place)
o COP (clean-out-of-place)
o Semi automatic
o Time considerationso Number of cleaning cycles.