Cleaning validation

COMPLETE INFORMATION CLEANING VALIDATION

1. CLEANING VALIDATION Presented by G.Vinay jain M.Pharmacy 1 st year 2 nd sem Department of Pharmaceutical analysis and QA Malla reddy college of pharmacy

2. Validation The process of providing documented evidences which provides a high degree of assurance that specific process, method, will consistently produce a result with pre – determine specification and acceptance criteria Types of validation Analytical method validation Process validation Software validation Cleaning validation

3. Types of validation Analytical validation Process validation

4. Software validation Cleaning validation

5. CLEANING VALIDATION

6. Cleaning validation : It is an documented evidence which provide high degree of assurance that an approved cleaning procedure will provide equipment that is suitable for processing of pharmaceutical products or API Importantance Heart of pharmaceutical activity Related to safety and purity of the products Level of cleaniness is achieved by clean procedure which depends on its validation C leaning method if performed confidently, method produced reproducible results

7. Cleaning validation plan Cleaning validation plan must define the following What is to be validated How it is to be validated Who is to validate it Who is to approve the validation When it must be revalidated

8. Cleaning technique Aqueous cleaning Solvent cleaning Manual cleaning Ultrasonic cleaning E xtraction Vapour degreasing Ultrasonic cleaning

9. Ultrasonic cleaning Ultrasound creates waves of compression and expansion in the liquid. In the expansion phase, the molecules are pulled apart rapidly, causing the formation of microscopic vapour bubbles. Subsequently, these cavitation bubbles implodes releasing tremendous energy. Extreme temperature (~5000°C), combined with high velocity jets provides the cleaning action.

10. Vapour degreasing Extraction

11. LEVEL OF CLEANING The equipment usage (dedicated use or not) The stage of manufacture (early , intermediate or final) The nature of potential contaminants (toxicity , solubility etc ) Each of the above three bullets must be evaluate based on the next product.

12. LEVELS ATTRIBUTES CLEANING VALIDATION LEVEL - Batch to batch cleaning in an identical process (same intermediate and same API ) . Change in the early stage of another process Not required LEVEL - 1 Changeover between intermediate of one product to final intermediate of another product. Changes in early steps to intermediate of another product ( API to intermediate ) Required but not necessary LEVEL - 2 Changeover from one API to another API. Changeover any intermediate to any API. Changeover from early step to final step of same product Essential

13. Level of cleaning differ from each other in the following aspects Level – 0 Level – 1 Level – 2 RISK Lowest Moderate Highest ACCEPTANCE LIMIT Highest Moderate Lowest DEGREE OF CLEANING Less extensive More extensive Much extensive VERIFICATION OF CLEANING Visual inspection No t required Analytical testing required

14. ELEMENTS OF CLEANING VALIDATION Establishment of acceptance criteria Product , equipment , facilities to be clean Cleaning agents Cleaning procedure Cleaning mechanism Sampling Analytical methods Establishment of limits Documentation Validation report

15. Acceptance criteria CHEMICAL DETERMINATION Limiting the level on toxicity data Pharmacological dose method NMT 1/1000 of residue present in the next product run in equipment Limiting the level of product appear in another product upto 0.1% of unknown material may be present in the product being tested PHYSICAL DETERMINATION visual examination of equipment MICROBIOLOGICAL DETERMINATION

16. Types of cleaning agents Detergents

17. Surfactants Anionic and Non-ionic: used as components for detergent Cationic and amphoteric : used in the formulations of disinfectants for their microcidal e effect Complexing agents – complexing with minerals and inorganic components Sequestering agent – EDTA Anti foaming agents:- mineral oil , vegetable oli Oxidizing agents – H 2 O 2 Corrosion inhibitors - Silicates

18. Cleaning validation process It mainly include 4 stages Stage 1 :- Determine the most appropriate cleaning procedure for the equipment Develop and validate the sampling and chosen analytical method for the compound being cleaned Evaluate equipment surface and determine

19. Stage 2 :- Develop a cleaning validation protocol for the product and equipment being cleaned Stage 3 :- Generate interim(time) cleaning validation report on a clean by clean basis Stage 4 :- Generate a cleaning validation report detailing the acceptability of cleaning procedure for the product and equipment

20. Cleaning mechanism Mechanism totally depends on selection of cleaning agents and type of residue to be cleaned Method involved in cleaning of residue are Dissolution Saponification Wetting agents Emulsifying agents Dissolution mechanism involved is solubility of residue in cleaning agents. eg :- SLS , chelating agents etc

21. Saponification mechanism involved is breakage of ester bond in fat residue to form fatty acid and glycerol which is soluble in water. eg ;- NAOH, KOH etc Wetting agents mechanism involved is lower the surface tension of cleaning solution so that it can easily penetrate in to residue eg ;- surfactants

22. Sampling methods Equipment should normally be cleaned as soon as possible after use This may be especially important for operation with topical products, suspensions where the drying residue will directly effect the efficiency of a cleaning procedure Two methods of sampling 1.Swab 2.Rinse Swabbing method This method of sampling is the most commonly used and involved taking an inert material ( eg :-cotton wool) on the end of the probe(referred as swab) and rubbing it methodically across the surface

23. The swab are added with dilution solvent and these solvent were analysed by suitable analytical instruments for the presence of residue of previous products Advantages Disadvantages Dissolve and physically remove sample Adaptable to wide variety of surfaces May allow sampling of a defined area Applicable to active, microbial and cleaning agent residue An invasive technique that may introduce fibre Complex and hard to reach areas difficult

24. Rinse sampling A measured area of a cleaned surface is rinsed or solvent washed and solvent is collect and test for traces of contaminants Advantage Disadvantage Allow the sampling of large surface area Allows the sampling of unique ( poros ) surfaces Applicable for actives, cleaning agents and excipients Limited information about actual surface cleanliness in some cases Inability to detect location of residue Usually use for rising an entire piece of equipment

25. Analytical method The analytical method should be validated before the cleaning validation is performed The method chosen should detect residuals or contaminates specific for the substance being assayed Validation of analytical method should include precision linearity accuracy limit of detection limit of quantitation ruggedness robustness Method selected should be specific and sensitive

26. Specific and Non-specific methods A specific method detects unique compounds in the presence of potential contaminants. eg ;- HPLC Non-specific methods are those methods that detect any compound that produces a certain response eg ;- pH and conductivity. Others 1. Thin layer chromatography (TLC): TLC is widely used for the qualitative determination of surfactants. 2. Atomic absorption spectroscopy (AAS): AAS is used for the determination of inorganic contaminants. 3. Bioluminescence: It is useful for biologicals

27. Establishing acceptable limit The acceptance limit established for contaminant levels in the sample should be practical , achievable and verifiable NMT 10 ppm of any product will appear in other product NMT 0.1% therapeutic dose of any product will appear in the maximum daily dose of the following product No quantity of residue should be visible on the equipment after cleaning procedure are performed For certain allergenic ingredients the limit should be below the limit of detection

28. DOCUMENTATION The cleaning process should be documented in an SOP Documentation should be in such a way that the following Information is readily available: The area or piece of equipment cleaned The person who carried out the cleaning When the cleaning was carried out The SOP defining the cleaning process The product, which was previously processed on the equipment being cleaned

29. VALIDATION REPORT A validation report is necessary to present the results and conclusions and secure approval of the study. The report should include the following, Summary of procedures used to clean , sample and test. Physical and analytical test results or references. Conclusions regarding the acceptability of the results. Revalidation practices if applicable. Approval of conclusions. Review any deviations for the protocol that occurred

30. Revalidation Revalidation of the cleaning process is to be done if Cleaning procedure is changed Raw material are changed Change in formulation New detergents Modification of equipment Cleaning process validation should be checked at regular intervals

31. CONCLUSION Clean environment and clean operations is the heart of pharmaceutical activities. Four basic requirements of cGMP are safety, identity, strength and purity which can be achieved by cleaning process and its proper validation

32. References S.W. Harder, ‘The validation of cleaning processes’, pharmaceutical technology.(1984) James Agalloco , ‘Points to consider in the validation of equipment cleaning procedures’, Journal of parenteral science and technology. (October 20 Richard J.Forsyth ; Equipment Hold Time for Cleaning Validation: Time to come cleans for a dirty little secret; Pharma Times Vol 40 No 6, June 2008; Page No: 15-18. Manohar A. Potdar : pharmaceutical quality assurance: cleaning validation: page no: 8.22 – 8.28 08)