Cleaning validation
- 1. Cleaning validation Presented by:-Ram Kumar M.Pharmacy (1st semester) Department of pharmaceutical analysis ISF College Of Pharmacy, Moga, Punjab
- 2. Contents • Introduction • Objective • Possible contaminants • Levels of cleaning • Analytical method used in cleaning process • Validation of analytical methods • Validation of cleaning process • Acceptance criteria
- 3. Cleaning validation • It is a documented evidence that assures us that a cleaning process removes residues of API of manufactured product from a piece of equipments, cleaning aids utilized in the cleaning process and the microbial attributes • By cleaning all the residues are removed to a predetermined level
- 4. Objective • The objective of cleaning validation is to prove that the equipment is properly cleaned of products, detergents and microbial residues to an acceptable level,to prevent contamination and cross contamination.
- 5. Possible contaminants • Product residue • Cleaning agent residue • Airborne matter • Lubricant, ancillary method • Decomposition residue • Bacteria, mould, pyrogens
- 6. Levels of cleaning • Level 1 cleaning: It is used only between steps in the same manufacturing process • Level 2 cleaning: It is used when cleaning between steps in the same manufacturing process. Level 2 cleaning would be used if step B was to be performed immediately after step A for the same product line.
- 7. Levels of cleaning • Level 3 cleaning: It would be performed when cleaning after an intermediate or final product step or one product in preparation of an intermediate step of another product. • Level 4 cleaning: It would be used after final product is ready.
- 8. Analytical methods used in cleaning • Analytical methods used for cleaning validation should be validated before the cleaning validation is performed • The detection limit for each analytical method should be sufficiently sensitive to detect the established acceptable level of residual or contaminants. • Some of the analytical methods used for cleaning validation are as follows
- 9. Analytical methods • HPLC • HPTLC • GC • UV spectroscopy • Ph • Conductivity • Elisa • These methods can be used alone or in combination depending upon the need.
- 10. Analytical method validation Parameters for analytical method validation:- a) Linearity and range b) Specificity c) Precision d) Accuracy e) LOD f) LOQ g) Robustness h) System suitability
- 11. Analytical method validation • Linearity and Range:-The range of an analytical procedure is the interval between the upper and lower levels of analyte (including these levels) that have been demonstrated to be determined with a suitable level of precision, accuracy, and linearity. • For establishment of linearity, minimum 5 concentrations are recommended. • Linearity results should be established by appropriate statistical methods.
- 12. • The Range of the procedure is validated by verifying that the analytical procedure provides acceptable precision, accuracy, and linearity when applied to samples containing analyte at the extremes of the range as well as within the range.
- 13. Analytical method validation • Precision:-The precision of an analytical procedure expresses the closeness of agreement (degree of scatter)between a series of measurements obtained from multiple sampling of the same homogeneous sample under the prescribed conditions. • Precision may be considered at three levels:- a. Repeatability b. Intermediate precision c. Reproducibility
- 14. Analytical method validation • Accuracy:- it is defined as the nearness between the True value/Reference value and the experimentally observed value. • Accuracy should be assessed by using o minimum of 9 concentration over a minimum of 3 concentration levels covering the specified range.
- 15. Analytical method validation Limit of Detection:-It is the lowest amount of analyte in a sample which can be detected but not necessarily quantitated. Limit of Quantitation:- It is the lowest amount of analyte in a sample which can be quantitatively determined with suitable precision and accuracy.
- 16. Analytical method validation • Robustness:-The robustness of an analytical procedure is a measure of its capacity to remain unaffected by small, but deliberate variations in method parameters and provides an indication of its reliability during normal usage. • If measurements are susceptible to variations in analytical conditions, the analytical conditions should be suitably controlled or a precautionary statement should be included in the procedure, such as:- 1. Use solution within 24 hours 2. Maintain temperature below 25 degree
- 17. Analytical method validation • Specificity:- The ability to detect the analyte in the presence of interfering substances (typically impurities, degradants, matrix)is called as specificity. • Suitable identification tests should be able to discriminate between compounds of closely related structures which are likely to be present.
- 18. Analytical method validation • System suitability:-System suitability testing is an integral part of many analytical procedures. The tests are based on the concept that the equipment, electronics, analytical operations and samples to be analyzed constitute an integral system that can be evaluated as such.
- 20. Cleaning process validation • Cleaning process validation should be performed in order to confirm the effectiveness of a cleaning procedure Parameters of cleaning validation:- • Equipment • Personal • Microbiological consideration • Documentation • Sampling • Acceptance criteria
- 21. Cleaning process validation • It is usually not considered acceptable to test-untill-clean. This concept involves cleaning, sampling and testing with repetition of this sequence untill an acceptable residue limit is attained . Equipments:-any equipment used for processing should be specifically designed to facilitate cleanability and permit visual inspection and whenever possible, the equipment should be made of smooth surface of non-reactive materials. Personal:- it is difficult to validate a manual cleaning procedure,Therefore operator carrying out manual cleaning procedures should be adequately trained, monitored, and periodically assessed.
- 22. Cleaning process validation Microbial consideration:- equipment should be dried before storage and under no circumstances should stagnant water be allowed to remain in equipment subsequent to cleaning operations • The aim should be to prevent excessive microbial contamination.
- 23. Cleaning process validation Documentation :-Detailed cleaning procedure should be documented in SOPs Cleaning validation protocol should include:- • Objective of cleaning validation • Responsibilities for performing and approving the validation study • Description of the equipment to be used • The interval b/w the end of production and the beginning of the cleaning procedure • Sampling procedure
- 24. Cleaning process validation • Detail cleaning procedures to be used for each product , each manufacturing system or each piece of equipment • The number of cleaning cycles to be performed consecutively • Clearly defined sampling locations • A final validation report should be prepared .The conclusion of this report should state that cleaning process has been validated successfully
- 25. • The report should be approved by the plant manager Sampling Method of sampling:-There are two methods of sampling 1. Swabbing method 2. Rinse sampling swabbing method:-this method of sampling is the most commonly used and involve taking an inert material (Such as cotton wool) on the end of probe and rubbing it methodically across the surface
- 26. Sampling • Then these swabs are added to diluted solvents and these solvents and these solvents are than analysed by suitable analytical instruments to check the presence of residues of previous products • Multiple swabs can be taken to improve surface recovery • An area of 10 cm by 10 cm and located in the most problematic region of the apparatus is scrutinized
- 27. sampling Rinse sampling :- In this method ,a measured area of clean surface is rinsed or washed with solvent and the solvent is collected and tested for traces of contaminants. • Rinse sampling method should be used along with other sampling methods such as surface sampling • This method can be used for large surface area and inaccessible areas of equipment that can not be routinely disassembled
- 28. Acceptance criteria Chemical determination:- 1. Nmt 0.1% of the normal therapeutic dose of any product will appear in the maximum daily dose of subsequent product 2. Nmt 10 ppm of any product will appear in another product 3. For certain allergic ingredient ,penicillin, cephalosporin, steroid and cytotoxic , the limit should be below the limit of detection
- 29. Acceptance criteria Physical determination:- No quantity of residue should be visible on the equipment after cleaning procedure are performed Microbial contaminant:- Total aerobic count 1. Bacterial count:-NMT 20 CFU 2. Molds :- NMT 02 CFU
- 30. References • Kumar Satinder, Shashikant, & Prashar Bharat: “A Review on Concept of Cleaning Validation in Pharmaceutical Industry.” International Research Journal of Pharmacy, 2012; Vol. 3(7): 17-19. • www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfCFR/CFRSearch.cfm?CFRPart=211 • www. hsa.gov.sg . • Babita Lodhi, Poonam Padamwar, & Arif Patel: “Cleaning Validation for the Pharmaceuticals, Biopharmaceuticals, Cosmetic and Neutraceutical Industries.”Journal of Innovations in Pharmaceuticals and Biological Sciences, 2014; Vol 1(1): 27-38. • Kumar V.S., Sanjeev T., & Sharma P.K.,: “Overview of Cleaning Validation in Pharmaceutical Manufacturing unit.” International Journal of Advanced Research in Pharmaceutical & Bio Sciences, 2012; Vol.2(2): 154-164. • P.V. Waghmare, A.S.Chinchole, B.N.Poul, & O.G.Bhusnure: “A Brief Review on Cleaning Validation and its Significance in Pharmaceutical Industry.” an International Journal of Pharmaceutical Sciences, 2013; Vol 4(4): 165-192 • Dipak k. Sarker, A Quality Systems and Control For Pharmaceuticals, p. no.- 39-41 10/13/2015