Article

Cleaning Validation and its importance in Pharmaceutical Industry

1

S. Lakshmana Prabu1*, T.N.K. Suriyaprakash2 Dept. of Pharm. Technology, Anna University-Tiruchirappalli, Tiruchirappalli - 620 024. 2 Dept. of Pharmaceutics, Periyar College of Pharmaceutical Sciences for Girls, Tiruchirappalli-620 021.

Pharmaceutical manufacturers must validate their cleaning process to ensure compliance with cGMP regulations. Minimizing equipment downtime has the potential to impact the efficiency and economics of pharmaceutical production. The main purpose of cleaning validation is to prove the effectiveness and consistency of cleaning in a given pharmaceutical production equipment to prevent cross contamination and adulteration of drug products with other active ingredients like unintended compounds or microbiological contamination, leads to prevent several serious problems and also useful in related studies like packaging component cleaning validation. So it is necessary to validate the cleaning procedures to ensure safety, efficacy, quality of the subsequent batches of drug product and regulatory requirements in Active Pharmaceutical Ingredients (API) product manufacture. The benefits due to cleaning validation are compliance with federal regulations, identification and correction of potential problems, previously unsuspected which could compromise the safety and efficacy of drug products. In this article cleaning, validation and importance are discussed in brief.

Introduction
Cleaning validation is a documented process that proves the effectiveness and consistency in cleaning a pharmaceutical production equipment 1 . Validations of equipment cleaning procedures are mainly used in pharmaceutical industries to prevent cross contamination and adulteration of drug products hence is critically important2. The prime purpose of validating a cleaning process is to ensure compliance with federal and other standard regulations. The most important benefit of conducting such a validation work is the identification and correction of potential problems previously unsuspected, which could compromise the safety, efficacy or quality of subsequent batches of drug product produced within the equipment. This paper provides a review of the current trends in cleaning validation and its related importance.

important to do a step-by-step evaluation of API process to determine the most practical and efficient way to monitor the effectiveness of the cleaning process. It is necessary to validate cleaning procedures for the following reasons3 1. It is a prime customer requirement since it ensures the purity and safety of the product. It is a regulatory requirement in Active Pharmaceutical Ingredient product manufacture. It also assures the quality of the process through an internal control and compliance.

equipment parts, lubricants, chemical cleaning agents and pieces of cleaning tools such as brushes and rags. 3. Microbiological contamination

Maintenance, cleaning and storage conditions may provide adventitious micro organisms with the opportunity to proliferate within the processing equipment.

2.

FDA requirements4
1. FDA expects firms to have written standard operating procedures (SOP) detailing the cleaning process used for various pieces of equipment. If firms have a specific cleaning process for cleaning between different batches of the same product and use a different process for cleaning between product changes, FDA expects the written procedures to address these different scenarios. If firms have one process for removing water-soluble residues and another process for non-water soluble residues, the written procedure should address both scenarios and make it clear when a given procedure is followed. It is required by the FDA, in the general validation procedure, that the personnel responsible for performing and approving the study should comply with the acceptance criteria and the revalidation data. FDA expects firms to prepare specific written validation protocols in advance for the studies to be performed on each manufacturing system or piece of

3.

Types of contaminations
1. Cross contamination with active ingredients

2.

Objective
The objectives of equipment cleaning and cleaning validation in an Active Pharmaceutical Ingredient (API) area are same as those in pharmaceutical production area. In both these areas efforts are necessary to prevent contamination of a future batch with the previous batch material. The cleaning of 'difficult to reach' surface is one of the most important consideration in equipment cleaning validation. Equipment cleaning validation in an API facility is extremely important as cross contamination in one of the pharmaceutical dosage forms, will multiply the problem. Therefore, it is * E-mail:slaxmanvel@gmail.com

Contamination of one batch of product with significant levels of residual active ingredients from a previous batch cannot be tolerated. In addition to the obvious problems posed by subjecting consumers or patients to unintended contaminants, potential clinically significant synergistic interactions between pharmacologically active chemicals are a real concern. 2. Contamination with unintended materials or compounds

3.

4.

While inert ingredients used in drug products are generally recognised as safe or have been shown to be safe for human consumption, the routine use, maintenance and cleaning of equipments provide the potential contamination with such items as

5.

Pharma Times - Vol 42 - No. 07 - July 2010

21

6.

7.

equipment which should address such issues as sampling procedures, and analytical methods to be used including the sensitivity of those methods. It is expected that firms conduct the validation studies in accordance with the protocols and document the result of studies. Final validation report is to be approved by the regulatory board which states whether or not the cleaning process is valid.

product residues which are to be removed, the available cleaning agents and cleaning techniques, when determining the optimum cleaning procedure for the equipment. Cleaning procedures should be sufficiently detailed to remove the possibility of any inconsistencies during the cleaning process. Following parameters are to be considered during cleaning procedures. A. Equipment Parameters to be evaluated 1. 2. 3. 4. 5. B. 1. 2. 3. C. Identification of the equipment to be cleaned 'Difficult to clean' areas Property of materials Ease of disassembly Mobility Cleaning limits Solubility of the residues Length of campaigns

should be compatible with the active ingredients and should not interfere with the assay. They should not cause any degradation of the compound. The solvent used for swabbing should provide good solubility for the compound and should not encourage degradation. 3. Rinse sampling

Current approaches in determining the acceptance limits for cleaning validation6-8

Acceptance limits for pharmaceutical manufacturing operation 1. Approach 1 (Dose criterion) Not more than 0.001 of minimum daily dose of any product will appear in the maximum daily dose of another product. Milligrams of active ingredient = I x K x M in product A permitted per JxL 4 inch2 swab area I = 0.001 of the smallest strength of product A manufactured per day expressed as mg/day and based on the number of milligrams of active ingredient. J = Maximum number of dosage units of product B per day K = Number of dosage units per batch of final mixture of product B L = Equipment surface in common between product A & B expressed as square inches. M = 4 inch2/swab. 2. Approach 2 (10 ppm criterion)

Residues to be cleaned

Sampling and testing of rinse samples for residual active ingredient is a commonly adopted method to evaluate cleaniness. This is a fairly convenient method in many cases and requires control over the solvent used for rinsing, the contact time and the mixing involved. The solvent used should be selected based on the solubility of the active ingredient and should either simulate a subsequent batch of product or at least provide adequate solubility. A disadvantage of rinse samples is that the residue or contaminant may not be soluble or may be physically occluded in the equipment. An analogy that can be used is the "dirty pot." In the evaluation of cleaning of a dirty pot, particularly with dried out residue, one does not look at the rinse water to see that it is clean; one looks at the pot.

Cleaning agent parameters to be evaluated 1. 2. Preferable materials that are normally used in the process Detergents available (as a general guide, minimal use of detergents recommended unless absolutely required) Solubility properties Environmental considerations Health and safety considerations Manual cleaning CIP (Clean-in-place) COP (Clean-out-of-place) Semi automatic procedures Automatic procedures Time considerations Number of cleaning cycles

Testing methods
The basic requirements of the analytical methods should have the following criteria. 1. Testing method should have the ability to detect target substances at levels consistent with the acceptance criteria. Testing method should have the ability to detect target substances in the presence of other materials that may also be present in the sample. The testing analytical method should include a calculation to convert the amount of residue detected in the sample to 100% if the recovery data generated indicates a recovery outside the allowed range.

3. 4. 5. D. 1. 2. 3. 4. 5. 6. 7.

Cleaning techniques to be evaluated

2.

3.

Sampling Technique9-15
Generally there are two types of sampling that are accepted. The most desirable is the direct method of sampling the surface of the equipment, another method being the use of rinse sampling. 1. Direct surface sampling It involves the determination of the type of sampling material used and its impact on the test data to check the interference of the sampling material with the test. Therefore, early in the validation programme, it is crucial to assure the sampling medium and solvent if they are satisfactory and be readily used. Advantages of direct sampling are that, areas hardest to clean and which are reasonably accessible can be evaluated, leading to establishing a level of contamination or residue per given surface area. Additionally, residues that are "dried out" or are insoluble can be sampled by physical removal. 2. Swab sampling

Any active ingredient can be present in a subsequently manufactured product at a maximum level of 10 ppm. Milligrams of active ingredient = R x S x U in product A permitted per T 4 inch2 swab area R = 10mg active ingredient of product A in one kg of product B S = Number of kilograms per batch of final mixture of product B T = Equipment surface in common between product A & B expressed as square inches. U = 4 inch2/swab. 3. Approach 3 (Visually clean criterion)

Analysing cleaning validation samples

There are many analytical techniques available that can be used in cleaning validation24. But choosing the appropriate analytical tool depends on a variety of factors15-17. The most important factor is to determine the specifications or parameters to be measured18. The limit should always be established prior to the selection of the analytical tool19-20.

No quantity of residue should be visible on the equipment after cleaning procedures are performed.

Specific and non-specific methods

A specific method detects unique compounds in the presence of potential contaminants. Ex: HPLC. Non-specific methods are those methods that detect any compound that produces a certain response Ex: Total Organic Carbon (TOC), pH and conductivity.

Cleaning Procedures
Standard cleaning procedures for each piece of equipment and process should be prepared. It is vital that the equipment design is evaluated in detail in conjunction with the

After cleaning the equipment, product contact surfaces could be swabbed to evaluate surface cleanliness. Swabs used

22

Pharma Times - Vol 42 - No. 07 - July 2010

High performance liquid chromatography

Almost every pharmaceutical company has an HPLC instrument, utilising a variety of detectors. These include UV, fluorescence, electrochemical, refractive index, conductivity, Evaporate light scattering detector (ELSD) and many others. The vast majority of techniques described in the literature are for the determination of surfactants in concentrated products 21-22. Therefore, the limits of quantitation and the limit of detection are rather high. Analysis of anionic and cationic surfactants is done by HPLC and Capillary electrophoresis (CE), where as amphoteric surfactants are analysed by HPLC, CD and ELSD23-25.

qualitative and quantitative manner in this regard. 5. Portable mass spectrometer Portable mass spectrometer can be used to detect ultra sensitive measurements and identification of the residue.

5. 6.

Additional techniques
Apart from the above mentioned techniques the biopharmaceutical industry utilises a wide variety of techniques45. These include Enzyme-Linked Immuno Sorbent Assay (ELISA)46 and Limulus amaebocyte lysate (LAL) technique.

7.

practices if applicable. Review of any deviations from the protocol. When it is unlikely that further batches of the product will be manufactured for a period of time, it is advisable to generate reports on a batch by batch basis until such time. The report should conclude an appropriate level of verification subsequent to validation.

An effective cleaning validation maintenance programme5, 53

When a minimum of three cleaning validation runs get completed and if the results meet the acceptance criteria, then the cleaning procedures would be demonstrated sufficiently and consistently to remove chemical and detergent residues from equipment surfaces during the study in order to meet the pre-established criteria. However, overtime and certain other factors can decrease the efficiency and consistency of the cleaning program. They are, 1. 2. 3. 4. Operator variability Equipment aging and repair Potential non representative results and monitoring programmes Changes to the product, equipment and process.

Method validation
It is very important to scientifically establish the residue limit prior to choosing the method of analysis. This includes the limit in the analytical sample and the limit in the next product. This will ensure the ability of the chosen method to detect and quantitate the limit present. Once the technique for analysis has been chosen, it is very important to validate the method used47-50. The validation of a method is very different from validation of recovery. A validated method is one that is rugged and robust enough to measure the residue limit established. Whereas, the validation of a recovery helps to determine the amount that can be recovered from a surface.

Capillary electrophoresis
Capillary electrophoresis can be used for many different types of analysis, viz; separation, detection and determination of sodium lauryl sulphate in cationic, anionic and non-ionic surfactants 26-28 . Another technique known as Micellar electro kinetic capillary chromatography is used for the separation of non-ionic alkyl phenol polyoxy ethylene type surfactants29.

Total organic carbon (TOC)

Presently total organic carbon is used widely in the pharmaceutical industries for various purposes30-32. TOC is determined by the oxidation of an organic compound into carbon dioxide. The oxidation can occur through a number of mechanisms depending on the instrument being used. TOC is used for the analysis of detergents, endotoxins, biological media and poly ethylene glycol33.

Data analysis for estimating possible contamination51-52

To support the cleaning validation study, an appropriate analytical method must be developed to produce a sensitivity level, at least equal to that of the acceptable residual level. For each analytical method, values defined as 'minimum quantifiable quantity' (MQQ) and 'non-detectable' (ND) are applied. A test result greater than or equal to the MQQ is considered reliable, whereas if it lies between ND and MQQ it is considered unreliable. Therefore values reported as ND or between ND and MQQ can be manipulated to apply for the possible contamination.

Operator variability
Additional questions to be asked when evaluating the cleaning process: 1. Does the equipment have to be scrubbed by hand? 2. What is accomplished by hand scrubbing as opposed to just a solvent wash? 3. How variable are manual cleaning process from batch to batch and product to product? These questions are all related to manual cleaning. The last question focuses on sources of variation associated with a manual cleaning process that is operator variability. Many companies rellay on intensive training programme to reduce operator variability. These programmes train operators on equipment disassembly procedure, detergent preparation, step-bystep cleaning procedures and drying processes. It is difficult to train an operator to perform certain elements, the same each time, such as strength applied, adherence to detailed instructions on the correct scrubbing procedure (up and down or side to side) and scrubbing time. It is even more difficult to train different operators to perform these functions the same. Hence, the problems of within operator variability and operator-to-operator variability are to be rectified by sufficient training programmes.

Ion chromatography
Ion chromatography can be used for the analysis of inorganic, organic and surfactants present in the cleaners34-39. Most cleaners contain sodium and/or potassium. The ion chromatography detection technique of suppressed conductivity is more sensitive to potassium ions than to sodium ions. Very low levels of cleaning agents can be detected by using this technique.

Others 40-44
1. Thin layer chromatography (TLC): TLC is widely used for the qualitative determination of surfactants. Atomic absorption spectroscopy (AAS): AAS is used for the determination of inorganic contaminants. Bioluminescence: It is useful for biologicals. This type of analysis usually uses ATP-bioluminescence. Optically simulated emission (OSEE) electron

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 information: 1. 2. References to all the procedures followed to clean the samples and tests. Physical and analytical test results or references for the same, as well as any pertinent observations. Conclusions regarding the acceptability of the results, and the status of the procedures being validated. Any recommendations based on the results or relevant information obtained during the study including revalidation

2.

3.

4.

3.

In some cases the limits of residue are very less that they can't be detected by conventional methods. OSEE is a very sensitive method that can be used for both

4.

Pharma Times - Vol 42 - No. 07 - July 2010

23

Equipment aging and repair

Through normal use, the smoothness and structural integrity of the equipment surfaces can change over time. As the surface becomes rougher, it is more difficult to clean because it has a greater contact area that can adsorb and could trap more chemical residues. Repairing a piece of equipment or installing new parts could create new stress centres, leading to difficulty in cleaning the surfaces. To make an equipment maintenance programme, the following points could be considered 1. 2. 3. 4. Enforcement of standard operating procedures (SOPs). A routine functionality check. Mechanical maintenance. A cleanability evaluation programme for equipment repair.

The monitoring programme provides a mechanism to verify the capability of the cleaning procedures, the efficiency of the training programme and the effectiveness of the equipment maintenance programme. Changes to the products, equipment & process When new products and equipments are added to the cleaning validation programme, revalidation of the acceptance limits for all of the products and equipments involved in the original cleaning validation study may be necessary. The acceptance limits for a cleaning validation programme usually take into account parameters viz; the product, equipment matrix, potency, daily dose and batch size. A well designed cleaning validation expansion programme provides a scientific and systematic process for managing new product, new equipment and changes in manufacturing process and batch sizes after the cleaning validation study has been completed.

6.

7.

8.

9. 10.

11.

Potential non-respective results and monitoring programme

However, cleaning validation resulting from three runs does not provide a high degree of confidence, especially for manual cleaning procedures. Operators may introduce a bias in their cleaning during cleaning validation process. To confirm the validity of extrapolating validation results to future operations, a monitoring programme can be implemented to ensure a consistent cleaning capability after the cleaning validation has been completed. Monitoring programme can be done in either of the following two ways. 1. 2. Difficulty in cleaning the equipment Difficulty in cleaning the product and equipment.

12.

Conclusions/Summary
A cleaning validation programme should contain the assessment of equipment and products, assessment of the impact of a process on routine process, determination of an appropriate cleaning agent and method, determination of acceptance criteria for the residues, determination of a degree of evaluation required to validate the procedure, decisive on the residues to be tested based on solubility and toxicity, development of sampling and analytical methods for recovery and detection of residues. acceptance criteria for the validation, compilation and approval of the validation protocol, scope for the validation studies to be performed in accordance with the protocol, compilation and approvals of validation reports, documented studies, conclusions, recommendations and revalidation policy.

13.

Validation. 2nd ed. New York: Marcel Dekker; 1993. p. 319-349. Fourman GL, Mullen MV. Determining cleaning validation acceptance limits for Pharmaceutical manufacturing operations. Pharm Tech. 1993; 54-60. Vitale KM. Cleaning validation acceptance criteria, 15th Annual Pharm Tech conference, East Brunswi New jersey, September 1995. Brewer R. Regulatory aspects of cleaning validation, ISPE seminar, Rockville, Maryland, March 1996. FDA, Guide to inspection of validation of cleaning process, July 1993. Jenkins M, Vanderweilen AJ. Cleaning validation: An overall perspective. Pharm Tech. 1994; 18(4): 60-73. Hyde JM. Cleaning validation strategies, ISPE CIP/SIP seminar, Atlanta-Georgia, June 1994. Leblane DA. Rinse sampling for cleaning validation studies. Pharm Tech. 1998; 22(5): 66-74. James A. Validation of equipment cleaning procedures, PDA congress, Basel- Switzerland, February 1992.

Difficulty in cleaning the equipment

The most 'difficult to clean' pieces of equipment require the most intensive monitoring schedule. 'Easier to clean' pieces require a moderate monitoring schedule. 'Easiest to clean' pieces of equipment require only a periodic monitoring schedule. Difficulty in cleaning the product and equipment: It is divided into three groups based on the degree of difficulty in cleaning the product and equipment. 1. Most 'difficult to clean' product and equipment requires the most intensive monitoring schedule. 'Easier to clean' product and equipment that requires a moderate monitoring schedule. 'Easiest to clean' product and equipment that requires only periodic monitoring.

References
1. Galatowitsch S. The Importance of Cleaning Validation. Cleanrooms. 2000; 14(6): 19-22. Parenteral Drug Association. Points to Consider for Cleaning Validation. Technical Report No. 29, 1998. Cleaning Validation in Active Pharmaceutical Ingredient manufacturing plants by Active pharmaceutical ingredients committee. September 1999. FDA, Guide to inspections of validation of cleaning process division of investigations, Office of regional operations & Office regulatory affairs. July 1993. McCormick PY, Cullen LF. Cleaning validation In: Berry, I.R., and Nash, R.A. editor. Pharmaceutical Process

2.

3.

4.

2.

3.

5.

14. James A. Points to consider in the validation of equipment cleaning procedures. J Parental Sci Tech. 1992; 46 (5): 163-168. 15. Phillips GF. The need for impurity control. Die Pharm Ind 1989; 51(11): 1282-1286. 16. Jenkins KM, Vanderwielen AJ. Cleaning Validation: An Overall Perspective. Pharm Tech. 1994; 18: 60-73. 17. Gavlick WK, Ohlemeier LA, Kaiser HJ. Analytical Strategies for Cleaning Agent Residue Determination. Pharm Tech. 1995; 19: 136-144. 18. Kaiser HJ, Tirey JF, LeBlanc DA. Measurement of Organic and Inorganic Residues Recovered from Surfaces. J Valn Tech. 1999; 6(1): 424-436. 19. LeBlanc DA. Establishing Scientifically Justified Acceptance Criteria for Cleaning Validation of Finished Drug Products. Pharm Tech. 1998; 22(10): 136-148. 20. Fourman GL, Mullen MV. Determining Cleaning Validation Acceptance Limits for Pharmaceutical Manufacturing Operations. Pharm Tech. 1993; 17: 5460. 21. Schmitt TM. HPLC Analysis of Surfactants In: Katz E, Eksteen R, Schoenmakers P, Miller N. editor. Handbook of HPLC. New York: Marcel Dekker; 1998. p. 789-804. 22. McPherson BP, Rasmussen HT. "Chromatography of Cationic Surfactants: HPLC, TLC, and GLC." Cationic Surfactants. In: Cross J, Singer E. editor. Surfactant Science. New York: Marcel Dekker; 1994. p. 289-326.

24

Pharma Times - Vol 42 - No. 07 - July 2010

23. Lin W, Lin S, Shu S. Comparison of Analyses of Surfactants in Cosmetics Using High-Performance Liquid Chromatography and High Performance Capillary Electrophoresis. J surfactants and detergents. 2000; 3(1): 67-72. 24. Heinig K, Vogt C, Werner G. Determination of Linear Alkylbenzene-sulfonates in Industrial and Environ-mental Sample by Capillary Electro-phoresis. Analyst. 1998; 123: 349353. 25. Heinig K, Vogt C. Determination of Surfactants by Capillary Electro-phoresis. Electrophoresis. 1999; 20: 3311-3328. 26. Kelly MA, Altria KD. Clark BJ. Quantitative Analysis of Sodium Dodecyl Sulphate by Capillary Electrophoresis. J Chrom. 1997; 781: 67-71. 27. Shamsi SA. Danielson ND. Individual and Simultaneous Class Separations of Cationic and Anionic Surfactants Using Capillary Electrophoresis with Indirect Photometric Detection. Analytical chemistry. 1995; 67(22): 4210-4216. 28. Heinig K, Vogt C, Werner G. Determination of Cationic Surfactants by Capillary Electrophoresis with Indirect Photometric Detection. J Chrom. 1997; 781: 17-22. 29. Heinig K, Vogt C, Werner G. Separation of Nonionic Surfactants of the Polyoxyethylene Type by Capillary Electrophoresis. J Anal Chem. 199; 357: 695-700. 30. Jenkins KM, Vanderwielen AJ, Armstrong JA. Application of Total Organic Carbon Analysis to Cleaning Validation. J Sci Tech. 1996; 50: 6-15. 31. Biwald CE, Gavlick WK. Use of Total Organic Carbon Analysis and Fourier-Transform Infrared Spectroscopy to Determine Residues of Cleaning Agents on Surfaces. J AOAC Inte. 1997; 80: 1078-1083. 32. Westman L, Karlsson G. Methods for Detecting Residues of Cleaning Agents During Cleaning Validation. J Pharm Sci Tech. 2000; 54(2): 365-372. 33. Guazzaroni M, Yiin B, Yu JL. Application of Total Organic Carbon Analysis for Cleaning Validation in Pharmaceutical Manufacturing. American Biotech Lab. 1998; 16(10): 66-67. 34. Hoeft CE, Zollars RL. Direct Determination of Anionic Surfactants Using Ion Chromatography. J Liq Chrom. 1994; 17(12): 2691-2704. 35. Pan N, Pietrzyck DJ. Separation of Anionic Surfactants on Anion Exchangers. J Chrom. 1995; 706: 327-337. 36. Takeda T, Yoshida S, Ii T. Analysis of Sulfonate- and SulfateType Anionic Surfactants by Ion Chromatography. Chem Exp. 1992; 7(6): 441-444. 37. Nair LM, Saari-Nordhaus R. Recent Developments in Surfactant Analysis by Ion Chromatography. J Chrom. 1998; 804: 233239. 38. Weston A. Ion Chromatography in the Pharmaceutical Industry. American Biotech Lab. 1998; 16(3): 32-33. 39. Murawski D. Ion Chromatography for the Analysis of Household Consumer Products. J Chrom. 1991; 546: 351-367. 40. Bosdorf V, Krmann H. Analysis of Detergents and Cleaning Agents with Thin-Layer Chromatography. Fourth World Surfactants Congressional Association. Barcelona, Spain. 1996; 4: 92-95. 41. Read H. Surfactant Analysis Using HPTLC and the Latroscan. Proceedings of the International Symposium on Instrumental High Performance Thin-Layer Chromatography. 3rd ed. Kaiser R. editor. Institute of Chromatography. Federal Republic of Germany. 1985. 157-171. 42. Henrich LH. Separation and Identification of Surfactants in Commercial Cleaners. J Planar Chrom. 1992; 5(2): 103-117.

43. Raghavan R, Mulligan JA. Low-Level (PPB) Determination of Cisplatin in Cleaning Validation (Rinse Water) Samples. I. An Atomic Absorption Spectrophotometric Technique. Drug Device Ind Pharm. 2000; 26(4): 423-428. 44. Davidson CA, Griffith CJ, Peters AC, Fielding LM. Evaluation of Two Methods for Evaluating Surface Cleanliness ATP Bioluminescence and Traditional Hygiene Swabbing. Luminescence. 1999; 14: 33-38. 45. Inampudi P, Lombardo S, Ruezinsky G. An Integrated Approach for Validating Cleaning Procedures in Biopharmaceutical Manufacturing Facilities. Annals of the New York Academy of Sciences. 1996; 782: 363-374. 46. Rowell FJ, Miao ZF, Neeve RN. Pharmaceutical Analysis Nearer the Sampling Point, Use of Simple, Rapid On-Site Immunoassays for Cleaning Validation, Health and Safety, and Environmental Release Applications. J Pharm & Pharmacology. 1998; 50: 47. 47. Kirsch RB. Validation of Analytical Methods Used in Pharmaceutical Cleaning Assessment and Validation. Pharm Tech. (Analytical Validation Supplement). 1998; 40-46. 48. Brittain HG. Validation of Nonchromatographic Analytical Methodology. Pharm Tech. 1998; 22(3): 82-90. 49. Ciurczak E. Validation of Spectroscopic Methods in Pharmaceutical Analyses. Pharm Tech. 1998; 22(3): 92-102. 50. Swartz ME, Krull IS. Validation of Chromatographic Methods. Pharm Tech. 1998; 22(3): 104-120. 51. Mendenhall DW. Cleaning validation. Drug. Dev Ind Pharm. 1989; 15(13): 2105-2114. 52. Kowalski DL. Process Design and data analysis for cleaning validation. Pharm Tech. 1997; 21(1): 62-69. 53. Hwang RC. How to establish an effective Maintenance program for cleaning validation. Pharm Tech. 2000; 24(1): 62-72.

Proposed IPA Building

IPA Building Fund

Appeal for

The President of Indian Pharmaceutical Association (IPA) appeals to all members of IPA to contribute minimum of Rs. 1000/towards the proposed IPA building at Mumbai. Kindly send your contribution through D/D or local cheque in favour of IPA Building Fund on the following address. Executive Secretary,

Indian Pharmaceutical Association

C/o. Bombay College of Pharmacy, Kalina, Santacruz (E), Mumbai 400098. All donations towards this fund will get tax exemption u/s 80G of Income Tax Act.

Pharma Times - Vol 42 - No. 07 - July 2010

25