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
.
.
What Is Cleaning Validation?
Cleaning validation is a requirement in industries such as pharmaceutical manufacturing which adhere to Good Manufacturing Practice (GMP) and Quality Systems Regulations (QSR), and is specific to the cleaning method and cleaner employed.
Simply stated, validation is a documented guarantee that cleaning can be performed reliably and repeatedly to satisfy a predetermined level of cleanliness. Validation is achieved by demonstrating at least three times that the cleaning process removes residues down to acceptable levels.
Testing for acceptable residues includes:
• Residue identification
• Residue detection method selection
• Sampling method selection
• Setting residue acceptance criteria
• Methods validation and recovery studies
• Writing a procedure and training operators
After establishing three or more times that a process can be repeated reliably to remove residues down to acceptable levels, a program can be implemented to maintain the state of validation where only periodical retesting is required. Changing any part of the cleaning procedure, including the cleaner, mandates revalidation. This entails first cleaning the new cleaners or methods, collecting data, and then cleaning the equipment with the prior validated process before using the equipment. These previously validated steps need to be followed until the new procedure is fully validated.
Generally, process validation is comprised of three parts: Installation Qualification (IQ), Operational Qualification (OQ), and Performance Qualification (PQ) of manufacturing equipment and operations. Cleaning validation can be incorporated in part in to the PQ process. Cleaning validation is done when it’s impractical to verify cleaning on 100% of the production equipment used in high-volume manufacturing operations. Larger-volume manufacturing, such as in the pharmaceutical industry, therefore relies upon validation, which is performed on critical cleaning steps effecting the quality or safety of the final product.
Find more related topic:
A) Different types of contamination’s in pharmaceutical industry
B) Identifying Residue and Selecting a Detection Method
C) Cleaning Acceptance Limits for APIs
D) Statistical Evaluation of Cleaning Validation Residue Data
Finding worst case molecule:
Many practitioners evaluate worst-case residues based on the solubility and toxicity of the compound of interest. While this approach may be acceptable when all products manufactured at a site are relatively easily cleaned, such as aqueous parental solutions containing soluble ingredients, it is not adequate for more complex dosage forms. Active ingredients that have the lowest solubility are considered worst-case for the validation of multi product equipment.
|
Parameter
|
Level 0 Risk
|
Level 1 Risk
|
Level 2 Risk
|
Level 3 Risk
|
Level 4 Risk
|
Level 5 Risk
|
|
Product Difficulty to clean – lab study or subjective
|
Very easy to clean – water effective
|
Easy to clean and high mobile in liquid state
|
Moderately easy to clean – some viscosity issues
|
Moderately hard to clean – viscous or gelatinous residue
|
Difficult to clean oily substance, builder or excipient
|
Very Difficult to clean such as denatured protein, carbopol, titanium dioxide
|
|
Toxicity – LD50 (oral rat)
|
≥ 2500 mg/kg
|
> 2500 mg/kg and ≤ 1250 mg/kg
|
>1250 mg/kg and ≤ 500 mg/kg
|
>500 mg/kg and ≤ 250 mg/kg
|
>250 mg/kg and ≤ 25 mg/kg
|
≥ 25 mg/kg
|
|
Solubility – g/100mL of water
|
Very soluble 100% in water
|
Freely Soluble 99.9 % in water
|
Soluble 99% in water
|
Slightly Soluble >10% but
|
Very Slightly Soluble < 10% in water
|
Practically Insoluble < 0.01% in water
|
Figure 01: Risk categorization table
For more detail : Qualifying Disinfection for Critical Environments and Clean rooms
For further reference see also:
For further reference see also:
1. Galatowitsch S. The Importance of Cleaning Validation. Cleanrooms. 2000; 14(6): 19-22.
2. Parenteral Drug Association. Points to Consider for Cleaning Validation. Technical Report No. 29, 1998.
3. Cleaning Validation in Active Pharmaceutical Ingredient manufacturing plants by Active pharmaceutical ingredients committee. September 1999.
4. FDA, Guide to inspections of validation of cleaning process division of investigations, Office of regional operations & Office regulatory affairs. July 1993.
5. McCormick PY, Cullen LF. Cleaning validation In: Berry, I.R., and Nash, R.A. editor. Pharmaceutical Process Validation. 2nd ed. New York: Marcel Dekker; 1993. p. 319-349.
6. Fourman GL, Mullen MV. Determining cleaning validation acceptance limits for
Pharmaceutical manufacturing operations. Pharm Tech. 1993; 54-60.
7. Vitale KM. Cleaning validation acceptance criteria, 15th Annual Pharm
Tech conference, East Brunswi New jersey, September 1995.
8. Brewer R. Regulatory aspects of cleaning validation, ISPE seminar, Rockville, Maryland, March 1996.
9. FDA, Guide to inspection of validation of cleaning process, July 1993.
10. Jenkins M, Vanderweilen AJ. Cleaning validation: An overall perspective.
Pharm Tech. 1994; 18(4): 60-73.
11. Hyde JM. Cleaning validation strategies, ISPE CIP/SIP seminar,
Atlanta-Georgia, June 1994.
12. Leblane DA. Rinse sampling for cleaning validation studies. Pharm
Tech. 1998; 22(5): 66-74.
13. James A. Validation of equipment cleaning procedures, PDA congress,
Basel- Switzerland, February 1992.
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: 54-60.
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
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-sulf
onates in Industrial and Environ-mental Sample by Capillary Electro-phoresis. Analyst. 1998; 123: 349-353.
onates in Industrial and Environ-mental Sample by Capillary Electro-phoresis. Analyst. 1998; 123: 349-353.
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 SodiumDodecyl 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 Sulfate-Type 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: 233-239.
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, Krüßmann 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.
Very well written.As the latest validation guidance is having terms like verification and testing its good to add ISO documents also in the requirements list.
The whole article gave a clear path where and how to start.
I thank the moderator for sharing such a good article.- See more at:
>equipment validation
After completion of worst case selection, how can we start calculation