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New Perspectives on Cleaning . Rizwan Sharnez, Coordinator
Cleaning Vali alidation dation Challenges Paul L. Pluta and Rizwan Sharnez
“New Perspectives on Cleaning” is an ongoing series of articles dedicated to cleaning process development, cleaning validation, and post-validation monitoring. This column addresses scientific principles, strategies, and approaches associated with cleaning that are faced in everyday work situations. Reader questions, comments, and suggestions are requested for future discussion discussion topics. These can be submitted to column coordinator Rizwan Sharnez at
[email protected] or to journal coordinating editor Susan Haigney at
[email protected].
KEY POINTS The fo foll llowin owingg key poi points nts are discu discussed ssed in this articl article: e: Cleaning methodologies have evolved significantly over the past 20 years; nonetheless, some practices are not adequately defensible, and many of the approaches are not not tru truly ly science-bas science-based. ed. Additionally, relevant information is not always fully integrated to facilitate the development of sound validation strategies Physical and chemical properties of the residue as well as data from small-scale studies should be the basis for determining worst-case soils for cleaning validation Historical data at full scale and experience with actual process equipment should be considered in the development of cleaning procedures Physical and chemical properties of the cleaning c leaning solution, such as pH, temperature, and surfactant concentration, can significantly affect the solubility of the residue and should be considered considered in determining worst wo rst-case -case soi soils ls The stability stability of the residu residuee should should be considered considered when devel developin opingg analytical analytical metho methods ds for for cleani cleaning ng validati vali dation on The ass assump umptio tion n that that res resid idues ues are unif uniforml ormlyy distri distribbuted in filling equipment can result in an erroneous •
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INTRODUCTION Cleaning methodologies methodologies have evolved significantly over the past 20 years. Cleaning validation is universally addressed in regulatory guidances g uidances and regulations regu lations (1-6), (1-6), and fundamental concepts and principles have been widely published (7-19 (7 -19). ). Despite the avail availabilit abilityy of of regulations and technical technica l information, certain areas of cleaning are not truly sci-
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estimate of worst-case worst-case carryover. carr yover. Non-uniform concontamination sites increase the risk of underestimating carryover Most difficult-to-clean locations for swab sampling should be determined based on a systematic system atic and scientifically defensible de fensible approach approach Residue recovery studies are the basis for quantitating swab and rinse samples for cleaning validation Personnel who perform swab sampling for cleaning valida val idatio tion n sh shoul ould d be be forma formally lly train trained ed Manual cleaning processes are high-risk operations that must be adequately controlled through a comprehensive program that includes robust procedures, clear documentation, and thorough inspections and training Organizations should recognize recognize the characteristic charac teristic differences between dirty dirt y hold time and clean hold time, and validate these parameters parameter s accordingly Valida Va lidatio tion n perform performanc ancee is onl onlyy a brief sna snapsh pshot ot in time during the entire prod product uct lifecycle. Upon successful completion of validation, robust monitoring and maintenance programs should be implemented Prospective involvement of technical groups (such as product technical support, engineering, process development, and analytical sciences) in support of cleaning validation is critical for developing and maintaining robust cleaning procedures throughout the product lifecycle.
ABOU T THE AU THORS Paul L. Pluta, Ph.D., is a pharmace pharmaceutical utical scientist with ex tensive industrial development, development, manufacturing, and management experience. He may be contacted at
[email protected]. Rizwan Sharnez, Ph.D., is principal engineer at Amgen Colorado. He has more than 15 15 years experience in the pharmaceutical industry. He may be cont acted at
[email protected].
OF V ALIDATION T ECHNOLOGY ECHNOLOGY [S PRING 2010 2010]] V
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ence-based. Approaches to address various issues are not always fully developed, and relevant information is often not integrated to foster good decisions. For example, it is well accepted that the most difficult-to-clean locations should be sampled during cleaning validation to verify the efficacy of the cleaning process; however, approaches to logically determine appropriate sampling sites have not been described. Also, active ingredients that have the lowest solubility are considered worst-case for the validation of multiproduct equipment; however, the effect of critical cleaning parameters (such as pH and temperature) on solubility, and their impact on the cleanability of the residue, is not always considered. This commentary addresses questions and concerns in cleaning validation raised by attendees at recent industry forums and through communication to the journal. These topics have come from a wide spectrum of pharmaceutical companies, including big pharma, small star t-ups, small molecule manufacturers, and biotech companies. The following issues are briefly discussed in this article: Physical and chemical properties of the residue as a basis for cleaning Considerations for determining the most difficultto-clean residue Residue solubility in determining worst-case soils Stability of the residue in developing analytical methods Non-uniform contamination of equipment surfaces Most difficult-to-clean locations in the equipment Recovery studies for quantitating residues Swab sampling technique, reliability, and training Risk in manual cleaning procedures, evaluation, and training Dirty and clean hold times Monitoring and maintaining the validated state. Topics identified in this article are primarily technical issues that should be addressed prior to executing cleaning validation. This suggests the need for enhanced technical support and integration of the various stages of the validation lifecycle. The US Food and Drug Administration identified three distinct stages in the lifecycle of a pharmaceutical product: stage 1, process design; stage 2, process qualification; and stage 3, continued process verification (20). Technical development and support activities in stage 1 and 2, and monitoring and maintaining the validated state in stage 3, should be integrated and coordinated for cleaning programs to be effective. Other topics of concern are related to compliance (e.g., manual cleaning and training for swab sampling). All of these issues have the potential to greatly impact the integrity of a cleaning program. •
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PHYSICAL AND CHEMICAL PROPERTIES OF THE RESIDUE AS A BASIS FOR CLEANING We all agree that there should be sound scientific and technical basis for cleaning processes. Nonetheless, organizations tend to revert to their standard or historical cleaning methods without fully evaluating the properties of the residue they are trying to clean. There are many factors that contribute to this practice. New cleaning agents, possible qualification of new suppliers, developing new cleaning procedures, additional training, and validation are costly—consuming valuable time and resources. In practice, however, significantly more time and resources are required to solve the problems that arise when established procedures are marginal. Consider the following actual occurrence.
Example A small molecule pharmaceutical company was validating the cleaning processes for its products. Cleaning validation for a suspension product was initiated. The active pharmaceutical ingredient (API) was a basic compound that was insoluble in neutral and alkaline pH. The cleaning method for all products comprised agitated immersion cleaning of the mixing tank with water. Associated equipment including the impact mill, transfer lines, and filling equipment were also cleaned using only water. Cleaning was accomplished by extensive soaking and rinsing, and required a large volume of water and an extensive amount of time. Despite this extensive time, effort, and use of resource, it was difficult to remove residual solid from some problematic areas of the equipment. When cleaning validation was initiated, analytical testing of the cleaned equipment indicated presence of residual formulation ingredients. A second lot was manufactured and cleaning with water was completed. Again the analytical testing failed. Management then decided to restart the cleaning validation using the “best” cleaning procedure available in the plant using an alkaline cleaning agent. The new cleaning procedure was implemented, but the cleaning validation failed once again. Technical personnel were then consulted and conducted laboratory studies using acidic, neutral, and alkaline cleaning agents. The acidic cleaning agent completely dissolved the basic drug. The neutral and alkaline cleaning agents did not have this same effect and were much less effective. Dissolution of the basic drug with the acidic cleaning agent significantly improved cleaning efficacy, and essentially all insoluble residue was eliminated. Cleaning validation was eventually successfully completed. A systematic development program based on the chemical properties of the residue provided a greatly J OURNAL
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improved cleaning method. This approach was far superior of pH is shown in the Figure. Compound A contains an to “hit or miss” approaches or using historical information ionizable acid moiety and is highly soluble in alkaline that was not relevant. The new cleaning procedure was solutions. Its solubility at neutral pH in water is low. Comfaster, required less water, and was much more effective. pound B does not contain ionizable groups; therefore, its Organizations should commit to a science-based solubility is relatively independent of pH. approach to cleaning. This strategy will result in sound When comparing the respective solubilities of these and defendable cleaning processes and will minimize fail- compounds in water, compound A has lower solubility and ures and investigations, which in turn will free up valuable would be considered the worst-case compound. However, resources for planning and execution. the equipment used to manufacture these products was cleaned with an alkaline cleaning agent. The pH of the CONSIDERATIONS FOR DETERMINING THE cleaning solution was 12. At this pH, compound A is very soluble, and compound B is clearly the worst-case product MOST DIFFICULT-TO-CLEAN RESIDUE Many practitioners evaluate worst-case residues based on for cleaning. If the cleaning agent used for these residues the solubility and toxicity of the compound of interest. contains surfactants, solubilization by micelle formation While this approach may be acceptable when all products should also be considered. The solubility data alone may not provide sufficient manufactured at a site are relatively easily cleaned, such as aqueous parenteral solutions containing soluble ingre- information to determine the worst-case compound for dients, it is not adequate for more complex dosage forms. cleaning validation. Solubility data in the cleaning liquid The cleanability of products containing polymers such are necessary for these assessments. The selection of a as controlled release tablet products may be significantly worst-case compound for cleaning validation is a critiaffected by inactive excipients. For example, consider two cal element of any program that supports the cleaning formulations containing the same active ingredient but of multiproduct equipment. These assessments must be having different inactive formulations. One may have carefully made considering all relevant technical informaprimarily soluble ingredients and be rapidly dissolving tion, including bench and pilot-scale data, as well as the while the other is designed to slowly dissolve and provide physical and chemical properties of the residues under prolonged release of drug over an extended time period. actual cleaning conditions. The cleanability of these two formulations could be markIdentifying worst-case soils for cleaning validation incoredly different even though they contain the same active rectly undermines the credibility of a cleaning program ingredient. In addition to the solubility and toxicity of the and exposes an organization to significant risk. API, the relative cleanability of each product must also be considered. Consultation with manufacturing personnel RESIDUE STABILITY IN CLEANING RESIDUE who perform actual cleaning is recommended. Their input ANALYSIS in determining the most difficult-to-clean residues and Most cleaning validation protocols require quantitative product groupings can be very valuable. analytical determination of the analyte of interest, and Cleanability assessments for complex process soils comparison of the analytical result to predetermined should not be based solely on solubility and toxicity; input acceptance criteria. Residues containing small molecule “from the f loor” coupled with bench-scale data (8, 17) are API are often quantitated using a specific HPLC method. also critical for success. Biotech residues are typically analyzed using product-specific immunological assays such as ELISA, or non-specific assays such as total organic carbon (TOC). RESIDUE SOLUBILITY IN DETERMINING Analytical methods are validated to measure the active WORST-CASE SOILS It is widely accepted that the solubility of the residue must ingredient at levels consistent with its acceptable carryover be considered when determining the worst-case soil for into a subsequent batch of the next product. However, it is cleaning validation. Cleaning practitioners often obtain also important to consider whether the active ingredient aqueous solubility data from United States Pharmacopeia degrades under the imposed cleaning conditions (21). Wet (USP), Merck Index, or other references for comparative residues may remain in the equipment for an extended evaluation. However, they often neglect the effect of pH period of time before cleaning is initiated. Depending on solubility—an omission that can lead to serious con- on its stability, the residue may undergo hydrolytic, ox idasequences. Consider the following example. tive, or photolytic decomposition prior to and during the A piece of equipment is used to manufacture two com- cleaning process (22). Swab sampling is then performed, pounds. The solubility of these compounds as a function and the recovered residue is analyzed. If there was API 32
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residue remaining on the equipment, would it be active ingredient or a breakdown product? There must be good understanding of the stability of the residues so that appropriate analytical methods are developed. The analytical methods must be able to detect degradation products if the cleaning conditions (such as high temperature or extreme pH) may cause degradation of the active ingredient. Analytical methods should be designed to detect degradants. There is little value in testing for an active ingredient that is known to completely degrade when exposed to cleaning conditions.
Figure: Solubility as a function of pH.
NON-UNIFORM CONTAMINATION Contamination control in cleaning validation focuses on minimizing carr yover between successive products manufactured in the same equipment (i.e., the amount of a contaminant from one product that can be transferred into a subsequent different product manufactured in the same equipment must be less than a predetermined acceptable limit). Calculation of the maximum residue level that is acceptable for transfer is based on the approach of Mullen and Foreman (23); whereby, the common surface area of manufacturing equipment is used to estimate the maximum allowable carr yover (MAC). This approach assumes uniform contamination across all surfaces, and complete and uniform transfer of one product residue into the next product. While this approach is valid and defendable for most equipment, it falls short when considering equipment with residue that is not uniformly transferred to the subsequent lot being manufactured (24-26). For example, for liquid filling equipment, the amount of residual active ingredient from the previously filled product that gets transferred to vials of the subsequent product decreases with every vial that is filled. Consequently, the residual active ingredient will not be transferred uniformly to all the vials of the subsequent lot. Equipment with non-uniform contamination across product-contact surfaces pose the greatest risk of excessive contamination of initial dosage units. This includes equipment after the final mixing or blending step in the equipment process train such as transfer lines or chutes, filling equipment, tablet compressing equipment, encapsulation equipment, etc. The possibility of non-uniform contamination is often neglected. This is a serious risk, both with respect to patient safety and regulatory compliance.
MOST DIFFICULT-TO-CLEAN LOCATIONS IN EQUIPMENT There is general agreement that sampling of equipment for cleaning validation should include most difficult-to-clean gxpandjvt.com
areas of equipment. How these locations should be determined has not been thoroughly discussed in the literature. Often selections of sampling sites are arbitrary and based on the expertise of one or more individuals. The approach to determine most difficult-to-clean sites should be documented in a policy or procedure. Thereafter, the actual determination of sampling sites for each system along with appropriate justification should be documented. The following considerations are proposed as part of a systematic approach to determine the most difficult-toclean sampling locations in manufacturing equipment: Equipment technical analysis. The type of surface, interfacial effects, and shadowed areas should be considered. Materials of construction (MOC) and geometrical configurations, type of processing (wet or dry), and problematic hard-to-clean areas of the equipment are noted. For example, stainless steel is generally harder to clean than glass or Teflon. Additionally, for a specific MOC, the smoothness of the surface can significantly affect its cleanability. Observation of equipment after processing. The equipment is observed after processing typical pharmaceutical products. Areas of excessive process residue accumulation are noted. Equipment disassembly review. The equipment is observed after disassembly. Product contact areas that are the most difficult to clean are noted. Equipment components that are disassembled for cleaning and subsequent evaluation pose a much lower risk than components that are part of the fixed equipment assembly and are cleaned in place. Accessibility of components on the fixed equipment assembly is noted. Cleaning procedure review. The cleaning procedure for the equipment is reviewed. Ability to visu•
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ally observe equipment and components is noted. Tip at sometime in their lives they must be qualified to Parts and equipment locations previously identified perform swab sampling. as difficult to clean may not be difficult to clean after For analytical results of the swab samples to be reliable, equipment disassembly. the cleaning personnel must be able to recover residue from Operator interviews. Discussions with operators equipment surfaces consistently. It is therefore important experienced with cleaning the equipment of inter- that personnel who perform swab sampling for cleaning est are utilized to determine difficult-to-clean loca- validation be formally trained. The training procedure tions. Their recommendations of difficult-to-clean should simulate appropriate worst-case conditions related areas of the equipment based on actual experience to the product residues that are sampled at the site. The are noted. training should include appropriate quantitative acceptance criteria to demonstrate the competence of the trainee. A cleaning validation program should include a sci- Periodic recertification of personnel is recommended to ence-based approach for identifying worst-case locations reinforce and maintain the manual dexterity and skills required for swab sampling. If an auxiliary implement for sampling. such as an extension pole is used in sampling, the training should verify that the residue can be adequately recovered RECOVERY STUDIES FOR QUANTITATING when the implement is used. RESIDUES Residue recovery studies are a frequent topic of discusIf personnel performing swab sampling are not qualision at cleaning forums. It is widely accepted that recov- fied through appropriate training, test results from swab ery studies should be performed to demonstrate that samples are questionable. residue can be adequately and consistently recovered from equipment surfaces as part of cleaning validation RISK IN MANUAL CLEANING PROCE(1). Considerations in recovery studies that are often DURES, EVALUATION, AND TRAINING overlooked include the need to perform st udies on pre- Manual cleaning processes are widely used in the pharmadominant MOCs that are swabbed or rinsed. Recoveries ceutical industry. Manual cleaning may also be used in from electropolished stainless steel surfaces should not conjunction with automated cleaning for small parts and be assumed to be representative of recoveries from cast equipment components. Because human involvement iron, elastomers, and other materials in the equipment is the basis for manual cleaning, organizations develop train. Recovery studies should be conducted on materials methods to control performance parameters (1), document provided by the equipment manufacturer—ideally these performance, and maintain competence through training. materials should be identical to those used to fabricate Manual cleaning processes cannot be taken for granted. the equipment. Variability in recovery is more likely with As risk analysis becomes common practice in pharma“soft” or porous materials such as elastomers. Solubility ceutical manufacturing, manual cleaning procedures are of the residue analyte is critically important for rinse increasingly being recognized as a high risk activity. When sampling. Extractants used for swab sampling often products containing a highly potent API are involved, the contain alcohol or other organic solvents to enhance risk is significantly increased. The Viracept cleaning issue the solubility of surface residues. Thus, the solvents are in Basel in 2006-2007 (27) and its dire consequences are formulated to maximize recover y. This may not be pos- testament to the need to control cleaning processes and sible with rinse sampling. The analyte of interest must retrain cleaning personnel on a regular basis. be recoverable in the rinsing solvent. Cleaning processes performed by manufacturing personResidue recovery studies are the basis for swab and rise nel must be given more scrutiny than automated cleaning sampling in cleaning validation. If recovery studies are processes. This should include more detailed and restrictive not done correctly, cleaning validation is undermined. cleaning procedures, more thorough visual evaluation of cleaned equipment, and a greater level of sampling during cleaning validation. Thorough training of personnel SWAB SAMPLING TECHNIQUE, who perform cleaning and inspect cleaned equipment RELIABILITY, AND TRAINING Swab sampling is an important component of most clean- (including periodic retraining), greater level of monitoring ing validation programs; nonetheless, some organiza- post validation, and periodic revalidation even when no tions consider swab sampling to be a mundane activity process changes have occurred are recommended. The that can be performed without any training. Perhaps collective procedures and controls, inspection, documentatheir rationale is that because everyone has used a Q- tion, and training associated with manual cleaning should •
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demonstrate that the organization clearly recognizes risks associated with manual cleaning. If manual cleaning processes are not adequately controlled through a comprehensive program, the reliability of such processes is questionable.
DIRTY AND CLEAN HOLD TIMES
result, many organizations do not have a defensible monitoring program. The FDA draft process validation guidance (19) clearly states the need for monitoring and maintaining the validated state. A fundamental requirement of maintaining the validated state is change control. Organizations must have a strong change control program for all processes, equipment, and other critical manufacturing systems. Organizations should develop a monitoring plan based on risk—types of products, potencies of products, automated vs. manual cleaning, and other considerations should be the basis for maintenance and monitoring. Non-conformances, deviations, and other unexpected occurrences associated with cleaning must be periodically reviewed according to a defined review schedule. Historical data may be compiled and trended for signs of process drift. When manual cleaning processes are involved, additional monitoring including enhanced training of personnel is recommended. Cleaning processes must be appropriately monitored and maintained. Validation performance is only a snapshot in time.
Practitioners in cleaning and cleaning validation have a general understanding of hold times. Approaches to limit the time between manufacturing and cleaning (dirty hold time) are more widely developed than those used to limit the time between cleaning and subsequent use (clean hold time). Some organizations determine these hold times by policy, but have no data to support them. Others specify time limits that are too long to be of any practical value. For example, “equipment may be stored for one year without re-cleaning.” Another important point is that equipment sampling locations for dirty hold time are based on worst-case locations for removing process residues. Equipment sampling locations for clean hold time are not necessarily the same as those used to assess dirty hold time; typically, these are based on worst-case locations for harboring and removing microbial residues. Organizations should recognize the critical differences CONCLUSIONS between dirty hold time and clean hold time. There should This article discusses selected topics raised by attendees at be clear policies addressing each of these parameters. The recent cleaning forums. Topics identified are significant effect of dirty hold time on cleanability can be studied at issues with potentially serious ramifications for cleaning small-scale. These studies should simulate drying condi- programs. Cleaning practitioners acknowledge the importions in the equipment as well as changes in the chemical tance and need to thoroughly and correctly address these composition of the residue as a function of time. Based on issues in their cleaning programs. However, reasonable the results of the small-scale studies, the appropriate dirty approaches to do so have not been adequately developed hold time can be scheduled during the cleaning valida- and all relevant information is often not considered and tion conformance runs. If the dirty hold time needs to be integrated. extended after validation, an additional run can be perCleaning practitioners and their organizations should formed at full scale based on the data from the small-scale adopt a lifecycle approach to cleaning validation. This studies. Storage conditions for clean equipment should be approach emphasizes scientific and technical development thoughtfully considered when designing validation studies work as the basis for developing and validating cleaning for clean hold time. Equipment sampling locations should procedures. It also emphasizes monitoring and maintebe based on the most likely locations for contamination nance of the validated state post validation. Prospective during storage. Testing should include visual inspection involvement of technical groups (e.g., product technical and samples for quantifying bioburden and endotoxin. support, engineering, process development, and analytical sciences) in support of cleaning is necessary for MONITORING AND MAINTAINING THE the successful implementation of this approach. A good understanding of the chemical and physical properties VALIDATED STATE Post validation monitoring of cleaning is a topic that has of the residue (particularly solubility and stability under elicited many comments and questions from attendees at appropriately simulated cleaning conditions) is necessary cleaning forums. Post validation monitoring is a regulatory to develop sound cleaning procedures. Thorough equipexpectation (1); however, it is seldom considered during ment evaluations including consideration of non-uniform cleaning validation. Practitioners may agree that moni- contamination and logical identification of most difficulttoring should be done but are unsure of how to approach to-clean locations in equipment are frequently overlooked monitoring or to what extent monitoring is required. As a areas. Areas of concern regarding residue analysis include gxpandjvt.com
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adequacy of residue recovery studies and swab sampling technique, reliability, and training. Organizations should develop an integrated approach to cleaning (i.e., characterization, validation, in-process controls, monitoring, and training), especially for manual procedures.
REFERENCES 1. FDA, Guide to Inspections of Validation of Cleaning Processes , 1993. 2. Health Canada, Drugs and Health Products,Cleaning Validation Guidelines (GUIDE-0028), January 10, 2008. 3. PIC/S, Pharmaceutical Inspection Convention,Recommendations on Validation Master Plan, Installation and Operational Qualification, Non-Sterile Process Validation, Cleaning Validation. July 2004. 4. World Health Organization, WHO Guideline of Transfer of Technology , Draft Document for Comment , June 2008. 5. ICH, Q7A, Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients, November 10, 2000. 6. European Commission,EU Guide to Good Manufacturing Practice, Annex 15, July 2001. 7. LeBlanc, Destin A.,Validated Cleaning Technologies for Pharmaceutical Manufacturing , Interpharm/CRC, 2000. 8. Sharnez, R., et al., “In Situ Monitoring of Soil Dissolution Dynamics: A Rapid and Simple Method for Determining Worstcase Soils for Cleaning Validation,” PDA Journal of Pharm. Sc. & Tech.; Vol 58, No. 4, p. 203-214, July-Aug 2004. 9. LeBlanc, Destin A., Cleaning Validation. Practical Compliance Solutions for Pharmaceutical Manufacturing , Volume 1, PDA and DHI Publishing. 10. LeBlanc, Destin A., Cleaning Validation. Practical Compliance Solutions for Pharmaceutical Manufacturing , Volume 2, PDA and DHI Publishing, 2010. 11. Sharnez, R., and VanTrieste, M., “Quality-by-Design for Cleaning Validation,” Pharmaceutical Cleaning and Cleaning Validation, Vol 1, Chapter VI, Davis Healthcare International & PDA, 2009. 12. LeBlanc, Destin A., www.cleaning validation.com. 13. Sharnez, R., “Validating for the Long Haul,” Journal of Validation Technology , Vol. 14, No. 5, 2008. 14. Bismuth, Gil, and Shosh Neumann, Cleaning Validation: A Practical Approach, Interpharm Press, 2000. 15. PDA, “Points to Consider for Cleaning Validation,”Technical Report #29. August 1998.
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16. Voss, Jon R., editor. Cleaning and Cleaning Validation: A Biotechnology Perspective, PDA, 1996. 17. Sharnez, R., “Leveraging Small-Scale Models to Streamline Validation,” Journal of Validation Technology , Vol. 14, No. 4, 2008. 18. Pluta, Paul L., editor. Cleaning and Cleaning Validation, Volume 1. Basics, Expectations, and Principles, PDA and DHI Publishing, 2009. 19. Sharnez, R., and Klewer, L., “Parametric Release for Cleaning, Part I: Process Characterization,” Journal of Validation Technology , Vol. 14, No. 8, p. 30, 2009. 20. FDA, Process Validation: General Principles and Practices, Draft Guidance, November 2008. 21. LeBlanc, Destin A., “Analytical Methods for Cleaning Validation,” Validated Cleaning Technologies for Pharmaceutical Manu facturing , Interpharm/CRC, p. 151-152, 2000. 22. Porter, William R., “Residues and Clean ing Chemistr y,” Cleaning and Cleaning Validation, Volume 1. Basics, Expectations, and Principles, PDA and DHI Publishing, p. 153-175, 2009. 23. Fourman, Gary L. and Michael V. Mullen, “Determining Cleaning Validation Acceptance Limits for Pharmaceutical Manufacturing Operations,” Pharmaceutical Technology , 17 (4), 54-60, 1993. 24. LeBlanc, Destin A., Setting Acceptance Criteria: in Validated Cleaning Technologies for Pharmaceutical Manufacturing , Interpharm/CRC, 2000, p.145-147. 25. Jenkins, K.M., and A.J. Vanderweilen, “Cleaning Validation: An Overall Perspective,” Pharmaceutical Technology , 18 (4), 60-73, 1994. 26. Agalloco, J., “Points to Consider in the Validation of Equipment Cleaning Procedures.” J. Parenteral Science and Technology , 46 (5), 163-168, 1992. 27. Lewcock, Anna, “Viracept: Lessons to be learnt?” In-Pharma Technologist.com , June 14, 2007. JVT
ARTICLE ACRONYM LISTING API FDA HPLC MAC MOC TOC USP
Active Pharmaceutical Ingredient US Food and Drug Administration High Performance Liquid Chromatography Maximum Allowable Carryover Materials of Construction Total Organic Carbon United States Pharmacopeia
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