1. 2005.06.28. Dr. Pogány - WHO, Pretoria 1/35 Supplementary Training Workshop on Good Manufacturing Practices (GMP) CLEANING VALIDATION János Pogány, pharmacist, PhD, consultant to WHO Pretoria, South Africa, 28 June 2005 E-mail: pogany@t-online.hupogany@t-online.hu

2. 2005.06.28. Dr. Pogány - WHO, Pretoria 2/35 WHO GMP  4.11 It is of critical importance that particular attention is paid to the validation of... cleaning procedures.  16.11 Contamination of... a product by another material or product must be avoided. This risk of accidental cross contamination arises from... products in process, from residues on equipment. Among the most hazardous contaminants are highly sensitizing materials... and highly active materials.

3. 2005.06.28. Dr. Pogány - WHO, Pretoria 3/35 WHO GMP  16.15 Before any processing operation is started, steps should be taken to ensure that the work area and equipment are clean.  16.18 Time limits for storage of equipment after cleaning and before use should be stated and based on data.

4. 2005.06.28. Dr. Pogány - WHO, Pretoria 4/35 Why do we validate cleaning processes?  The cleaning process is an integral part of the pharmaceutical manufacturing process.  Industry should view cleaning of equipment as the first manufacturing step. ( It will have effect on the safety, efficacy and quality of the batch to be manufactured.)  A cleaning process must be chosen based on products (e.g., ARVs, solid dosage forms), objectives, resources, and limitations within each manufacturing company.

5. Pharmaceutical Process Validation: Second Edition, Revised and Expanded, edited by Ira R. Berry and Robert A. Nash, Marcel Dekker, Inc., New York – Basel – Hong Kong (1993). GENERAL CONSIDERATIONS

6. 2005.06.28. Dr. Pogány - WHO, Pretoria 6/35 Potential Contaminants  Chemical contamination  Product residues  Decomposition residues  Cleaning or disinfecting agent residues  Microbiological contamination  Bacteria, moulds, pyrogens  Unintended materials  Airborne (particulate) matter  Lubricants, ancillary material (e.g. pieces of brushes)

7. 2005.06.28. Dr. Pogány - WHO, Pretoria 7/35 Manual Cleaning Procedures  Equipment disassembly ( if required )  Prewash and inspection ( most visible material removed )  Wash ( cleaning agent, temperature, multiple steps until visually clean)  Initial rinses ( rinse water, temperature )  Final rinse ( minimum dissolved solids, microorganisms )  Reassembly ( if required )

8. 2005.06.28. Dr. Pogány - WHO, Pretoria 8/35 Automated Cleaning Procedures  Clean-in-place (CIP) systems ( dishwasher-type equipment)  portable (tank and pump assemblies on wheels)  stationery, cabinet-type  Control system qualification (IQ, OQ and PQ: reproducibility, water, temperature control)  Sampling ( sampling port, pause capability)  Material supply ( hard-plumbed supply lines, volume and dispensing controls, potential impact of long storage periods )

9. 2005.06.28. Dr. Pogány - WHO, Pretoria 9/35 Documentation and Traceability  Equipment identification  Equipment use, maintenance and cleaning records  Labeling  Cleaning equipment maintenance and calibration  Utilities (water for injection (WFI), purified water, steam and compressed air systems) qualified and validated.  Standard Operating Procedure(s) [SOP(s)]  Personnel training

10. 2005.06.28. Dr. Pogány - WHO, Pretoria 10/35 Cleaning Materials and Tools  Solvents (source and quality controlled )  Cleaning agents (acids, bases, surfactants, etc., qualified type and brand QC controlled)  Ancillary utilities (steam and compressed air qualified)  Scrubbing agents (compression of placebo tablets to clean punches and dies)  Cleaning tools (standard sets of brushes, rags, sponges)  Equipment (thermometers, CIP systems consisting of tanks, metering pumps, heat exchangers, etc. maintaned and kept in calibrated status)

11. 2005.06.28. Dr. Pogány - WHO, Pretoria 11/35 Frequency of Cleaning  Cleaning between batches of the same product (abbreviated procedures)  Cleaning between batches of different products  Cleaning after maintenance  Cleaning after accidental contamination

12. Cleaning Validation Guidelines, Health Products and Food Branch Inspectorate, Canada http://www.hc-sc.gc.ca/hpfb-dgpsa/inspectorate/clean_val_gui_entire_e.html http://www.hc-sc.gc.ca/hpfb-dgpsa/inspectorate/clean_val_gui_entire_e.html PRESENTATION IS LIMITED TO SOLID PHARMACEUTICAL DOSAGE FORMS

13. 2005.06.28. Dr. Pogány - WHO, Pretoria 13/35 Validation of cleaning processes  Equipment cleaning validation may be performed concurrently with actual production steps during process development and clinical manufacturing. Validation programs should be continued through full-scale commercial production.  All pertinent parameters should be checked to ensure the process, as it will ultimately be run is validated. Therefore, if critical temperatures are needed to effect cleaning, then these should be verified. Any chemical agents added should be verified for type as well as quantity. Volumes of wash and rinse fluids, and velocity measurements for cleaning fluids should be measured as appropriate.

14. 2005.06.28. Dr. Pogány - WHO, Pretoria 14/35 Validation of cleaning processes  Validation of cleaning processes should be based on a worst-case scenario including:  challenge of the cleaning process to show that the challenge soil can be recovered in sufficient quantity or demonstrate log removal to ensure that the cleaning process is indeed removing the soil to the required level, and  the use of stress cleaning parameters such as overloading of contaminants, overdrying of equipment surfaces, minimal concentration of cleaning agents and/or minimum contact time of detergents.

15. 2005.06.28. Dr. Pogány - WHO, Pretoria 15/35 Validation of cleaning processes  At least three (3) consecutive applications of the cleaning procedure should be performed and shown to be successful in order to prove that the method is validated.

16. 2005.06.28. Dr. Pogány - WHO, Pretoria 16/35 Approach for setting limits 1.Product specific cleaning validation for all products; 2.Grouping into product families and choosing a worst case product; 3.Grouping into risk categories (e.g., very soluble products, similar potency, highly toxic products or difficult to detect); 4.Setting limits on not allowing more than a certain fraction of carryover; 5.Different safety factors for different dosage forms.

17. 2005.06.28. Dr. Pogány - WHO, Pretoria 17/35 Carry-over of product residues  NMT 0.1% of the normal therapeutic dose of any product to appear in the maximum daily dose of the following product (may not be acceptable for parenterals).  NMT 10 ppm of any product to appear in another product (may not be acceptable for parenterals).  No quantity of residue to be visible on the equipment after cleaning procedures are performed. ( Spiking studies should determine the concentration at which most active ingredients are visible.)

18. 2005.06.28. Dr. Pogány - WHO, Pretoria 18/35 Carry-over of product residues  Residues levels that do not interfere with subsequent manufacturing processes.  For certain allergenic ingredients, penicillins, cephalosporins or potent steroids and cytotoxics, the limits should be below the limit of detection by best available analytical methods. In practice this may mean that dedicated plants are used for these products.  Acceptable limits should be defined for detergent residues after cleaning (there is no normal therapeutic dose, thus e.g. the limit of detection of the most toxic component).

19. 2005.06.28. Dr. Pogány - WHO, Pretoria 19/35 Analytical methods  The analytical methods used to detect residuals or contaminants should be specific and be validated before the cleaning validation study is carried out.  The specificity and sensitivity of the analytical methods should be determined.  The analytical method and the percent recovery of contaminants should be challenged in combination with the sampling method(s).

20. 2005.06.28. Dr. Pogány - WHO, Pretoria 20/35 Sampling and related issues  Direct surface sampling (swab method)  Indirect sampling (use of rinse solutions)  Indirect testing such as monitoring conductivity may be of some value  In terms of cross-contamination, the main concern is residue left on the internal product-contact surfaces of the manufacturing equipment.

21. An Illustrative Approach to Cleaning Validation ANTIRETROVIRAL FPP(s)

22. 2005.06.28. Dr. Pogány - WHO, Pretoria 22/35 Cleaning validation (master) plan  Validation plan is based on risk analysis.  Cleaning of individual pieces of the manufacturing and packaging equipment is validated with products selected as the worst case.  The three regulatory consecutive batches can be extended to include potentially the last batches of one or more campaign productions  Water solubility, toxicity and risk analysis data of all ARV APIs.

23. 2005.06.28. Dr. Pogány - WHO, Pretoria 23/35 Risk Analysis WATER SOLUBILITY LOWMODERATEHIGH TOXICITYTOXICITY High Moderate MODERATE HighModerate LOW Moderate Low RISK FACTORS

24. 2005.06.28. Dr. Pogány - WHO, Pretoria 24/35 Illustrative Indicators for Toxicity LD 50 (rat or /mouse/)Category < 200 mg/kgHigh 200 – 2000 mg/kgModerate > 2000 mg/kgLow Composite toxicity indicators may take into account high activity, hypersensitizing indicators, etc.

25. 2005.06.28. Dr. Pogány - WHO, Pretoria 25/35 Illustrative Categories for Solubility Descriptive Term for Solubility (Ph.Eur.)Category Very soluble (< 1 ml/g) Freely soluble (1 – 10 ml/g) Soluble (10 – 30 ml/g) High solubility (<30 ml/g) Moderately soluble Sparingly soluble (30 – 100 ml/g) Slightly soluble (100 – 1000 ml/g) Moderate solubility (30 – 1000 ml/g) Very slightly soluble (1000 – 10000 ml/g) Practically insoluble (> 1000 ml/g) Relatively insoluble Insoluble Low solubility (> 1000 ml/g)

26. 2005.06.28. Dr. Pogány - WHO, Pretoria 26/35 Illustrative Risk Analysis of ARV APIs API TOXICITY INDICATOR SOLUBILITY IN WATER AbacavirModerateHigh77 mg/mL at 25 o C EfavirenzLow Indinavir sulfateLowHigh100 mg/ml LamivudineLowHigh NevirapineLow 90 μg/ml at 25°C RitonavirLow SaquinavirLow StavudineLowHigh ZidovudineLowHigh20 mg/mL at 25 o C

27. Pharmaceutical Technology Europe, 1 February 2004 Griet Van Vaerenbergh Griet Van Vaerenbergh Cleaning Validation Practices: Using a One-Pot Processor

28. 2005.06.28. Dr. Pogány - WHO, Pretoria 28/35 Summary This article describes the use of a one-pot processor for the cleaning and cleaning validation of two drug compounds: water-soluble theophylline and water-insoluble mebendazole. Both substances were produced using wet granulation and microwave drying, after which the processor was cleaned using its clean-in-place (CIP) system. Swab samples were taken from areas considered critical during processing and analysed for remains of active ingredient. It was concluded from the results that the processor's CIP system is capable of removing both APIs to a level well within accepted regulations.

29. 2005.06.28. Dr. Pogány - WHO, Pretoria 29/35 One-pot processor

30. 2005.06.28. Dr. Pogány - WHO, Pretoria 30/35 Acceptance criteria  10-ppm criterion  absolute mass criterion: NMT 1 µg/cm 2  for residual detergent traces: the conductivity of the final rinsing water should be lower than the conductivity of a 1:1000 dilution of the detergent solution.

31. 2005.06.28. Dr. Pogány - WHO, Pretoria 31/35 Acceptable quantity of an API per swab Initial trials on the swab determined that the theophylline recovery was between 95–100%. Nevertheless, the Factor 2 for swab yield was maintained in the formula for calculating the acceptance criteria, to account for any operator influence.

32. 2005.06.28. Dr. Pogány - WHO, Pretoria 32/35 Theophylline sample analysis

33. 2005.06.28. Dr. Pogány - WHO, Pretoria 33/35 Mebendazole sample analysis

34. 2005.06.28. Dr. Pogány - WHO, Pretoria 34/35 Study conclusions This study has shown that the CIP system of this one-pot processor is capable of removing both water-insoluble mebendazole and water-soluble theophylline from the system to a level significantly less than acceptable maxima. Although certain areas show a larger variation in results than others, the reproducibility of the cleaning cycle can be considered good, as the results for all areas were always consistent.

35. 2005.06.28. Dr. Pogány - WHO, Pretoria 35/35 Main Points Again  Validation of equipment cleaning processes is critical to safety, efficacy and quality of FPPs.  There is no generally accepted approach to cleaning validation.  One possible approach is risk analysis and selection of worst case for each item of equipment.  CIP equipment must be qualified and the cleaning processes must be validated.