Cleaning validation

about the methods of cleaning validation

1. ANALYTICAL AND SAMPLING METHODS FOR CLEANING VALIDATION ( PQA-MQA-202T. Pharmaceutical Validation) Presented by Guided by T V Sarath Chandra Dr. Sudheer Moorkoth 170609008 Associate Professor M Pharm I year ( Sem II) DEPARTMENT OF PHARMACEUTICAL QUALITY ASSURANCE MANIPAL COLLEGE OF PHARMACEUTICAL SCIENCES MAHE 1

2. Contents Analytical Methods Specific Methods Non Specific Methods Method Validation Sampling Methods Direct Surface Sampling Swab Sampling Rinse Sampling Placebo Sampling Recovery Studies Summary Reference 2

3. Analytical Methods Specific Methods: They are the methods that target a specific molecule or species and are designed so that possible interferences are eliminated. They are HPLC, Ion chromatography, Atomic Absorption and SDS PAGE etc. The second way is to use a non specific method. 3

4. Non Specific Methods They measure a gross property that results from contributors form a variety of chemical species. They are conductivity and total organic carbon (TOC). This generally involves expressing property as if all the measured property is due to target species. If the amount calculated by this method is below acceptance criteria, then we can say that residue is less than the acceptance criteria. If the amount is above the acceptance criteria, then one should develop a specific method or use a more robust cleaning procedure. 4

5. Method Validation Analytical methods used for measuring residue in cleaning validation protocols should be validated. This includes evaluation of Specificity Linearity Range Precision Accuracy LOD/LOQ 5

6. Specificity Specificity is a measure of the validity of the result based on expected interferences. Interferences may include changes in retention time, peak height, or peak shape (in HPLC). Methods such as TOC or an alkalinity titration are generally considered nonspecific because, in most cases, there is more than one species that can contribute to the measured property. 6

7. Range Range is a series of values of the measured species or property over which the analytical procedure was evaluated. It is only necessary to assure that the procedure is valid over a range of expected values. LOD/LOQ LOD is the assay value at which it is still possible to say that the material is present, but it may be not possible to quantify with a specific value. LOQ is the lowest assay value for which a reasonable confidence exists that the value is precise. 7

8. Linearity Linearity refers to the characteristic of the relationship of the measured property to the level of analyte present. Linearity is an indication that the measured signal is directly proportional to the concentration of the analyte over the range. Accuracy Accuracy refers to the trueness of the measurements to known values. This is determined by analysing known standards. However, more accurate methods are preferred over less accurate methods. 8

9. Precision Precision refers to the reproducibility of the method and is often measured by standard deviation. Simple precision is the reproducibility of the results in the same lab over a series of replicate assays using the same operator, the same equipment, and usually on the same day. Intermediate precision is the reproducibility of results in the same lab using different operators, different pieces of equipment, and generally done on different days. Ruggedness is interlab reproducibility, involving reproducibility in different labs. 9

10. Sampling Methods The sampling procedure refers to the selection of which surfaces are targeted for collecting residues for measurements and to the method of collecting the residues from the surface so that they can be measured The sampling methods are Direct surface sampling Swab sampling Rinse sampling Placebo sampling 10

11. Direct Surface Sampling Direct surface sampling involves an analytical instrument directly "applied to" the cleaned surface. The most common example of direct sampling is visual evaluation. In that case, the eye is the means of both analysis and sampling. The key items to consider: Eyesight of the viewer: The viewer should have suitable vision, or such vision should be correctable by glasses or contact lenses. The available light for viewing: Particularly inside equipment, external lighting may have to be introduced to adequately sample the surface. It may also be helpful to use ultraviolet light (black lights) to assist in viewing residues that may fluoresce under UV light. 11

12. The distance of the viewer from the surface: It is generally the case that the farther away from the viewer, the less sensitive visual examination will be. A surface 1 ft in front of you may appear dirty, while the same surface 12 ft away may appear visually clean. The angle of the Light and the viewer to the surface: These factors can also affect whether a surface is rated clean or dirty. The nature of the surface: This includes both the material of construction as well as its surface texture, roughness and may be different for different residues. 12

13. The nature of the residue: One figure used in the literature for the dividing line between visually clean and visually dirty is 4 µg/cm2. Particulate residues, such as from powders, can produce visually dirty surfaces at levels considerably below 4 µg/cm2. The availability of the surface: Surfaces that are readily visible can be easily examined. Other surfaces (such as the interior surfaces of ball valves) may require disassembly of the equipment in order to examine them. 13

14. Swab Sampling A swab is a fibrous material that is used to wipe a surface to remove residues from the surface. Typically, the swab is a textile fabric of some kind attached to a suitable handle. The swab "head" (the fabric portion) is typically wetted with a solvent (water, an organic solvent, or a mixture). 14

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16. The nature of the swab: For microbiological swabbing, the swab head is generally cotton fibres attached to a handle. In some cases for microbiological sampling, the sampling head is made of calcium alginate fibres. Microbiological swabs should be sterilised prior to use. The most common are made of a knitted polyester fabric head, which is then attached to a plastic handle by a suitable welding process so that adhesives are avoided. 16

17. Use of solvent for wetting and desorption of the swab: The solvent used should be appropriate for assisting in the removal of the residue from the surface. In addition, it should be compatible with any subsequent analytical procedure. The number of swabs used: Generally, only one or two swabs are used per target surface area. The concept behind using more than one swab is to increase the recovery of the target residue. One swab cannot pick up all of the residues, but it will leave behind a finite amount of solvent, which probably contains some of the target residue. A second swab will pick up an additional amount of the target residue. 17

18. The surface area swabbed: The surface area typically swabbed per site varies from about 25 sqcm to about 100 sqcm . There is no number in terms of what is best. One is to use a template placed over the surface to be sampled. Swabbing location: The locations selected for swabbing are generally those locations that are the most difficult to clean, representative of different material and representative of different functional locations. It is most important to identify those locations that are the most difficult to clean . If these locations are swabbed, and if the residues in these locations are acceptable, then residues in other locations should also be acceptable. 18

19. The swabbing pattern: This includes the pattern the swab head makes as it goes across the surface, whether the swabbed pattern is repeated at a 90" angle, as well as any "flipping" of the swab head. Swab handling and transport: Proper handling will depend to a given extent on the analytical procedure utilized. If the analytical method is TOC, then extreme care needs to be used in handling. 19

20. Rinse Sampling Rinse sampling involves using a liquid to cover the surfaces to be sampled. There are two cases of this: single point final rinse sampling and a sampling rinse separate and distinct from the final rinse. There are two objections for the FDA. The water which is collected after the rinsing is containing the potent drug in unacceptable levels, still it is meeting the USP specifications. The rinse water is examined for the target residues, not the equipment. 20

21. Single point Final Rinse Sampling In single point final rinse sampling, a sample is obtained at the end of the final rinsing process. If the rinsing medium is water, then it is a water sample; if a solvent is used for the final rinse, then it is a solvent sample. The volume of rinse sample taken will depend on the analysis done but it is commonly 500-1000ml. This is the most common method of rinse sampling. 21

22. Separate Sampling Rinse A separate and distinct rinse is performed with a fixed amount of sampling medium after the process rinsing is completed. The only function of the sampling rinse is to sample the equipment for analytical purposes. This rinse sampling procedure can either be done on a batch or continuous basis. The sampling solution is different from the washing solution. The solution used for the sampling purpose will have a fixed volume. 22

23. PLACEBO SAMPLING Placebo sampling involves manufacturing a placebo batch of the subsequently manufactured product in the cleaned equipment. Following manufacture of the placebo product, the placebo is analysed for the target residue. For example, the active in the drug product that was cleaned from the equipment. If it is having X ppm of the target residue then it is assumed that there is contamination of X ppm. 23

24. Recovery Studies In a recovery study, a fixed amount of the target residue is spiked onto a model surface, the surface is sampled with the sampling procedure. The amount of target residue is then expressed as a percentage of the amount spiked to give the "percent recovery." This percentage must then be used to adjust the analytical results obtained to accurately reflect potential contamination. 24

25. Summary 25 The analytical methods include specific and non specific methods. Specific methods give the results specifically without interferences. Non specific methods give results which include all the results of targeted species. The sampling methods include direct observation sampling which involves eye observation. Swab sampling includes the use of swab through which the sample is analysed. Rinse sampling includes analysing the wash solution for contaminants. Placebo sampling includes analysing the placebo which is without the drug for the contaminants.

26. Reference LeBlanc D. Validated cleaning technologies for pharmaceutical manufacturing. 2nd ed. new york : crc ; 2000. p.151-190 . 26

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