CLEANING VALIDATION PROBLEMS GLOBAL PERSPECTIVE

Transcription

1 CLEANING VALIDATION PROBLEMS GLOBAL PERSPECTIVE Paul L. Pluta, PhD Journal of Validation Technology and Journal of GXP Compliance University of Illinois at Chicago (UIC) College of Pharmacy Chicago, IL, USA 1

2 OUTLINE OVERVIEW OF IDENTIFIED PROBLEMS PRODUCT PROBLEMS Residue chemistry as basis for cleaning Solubility in worst-case residue determination Cleanability in worst case residue determination EQUIPMENT-RELATED PROBLEMS Non-uniform contamination transfer Most difficult-to-clean locations CLEANING PROCESS PROBLEMS Manual cleaning qualification Cleaning procedure documentation Dirty hold time (time to initiate cleaning) LABORATORY PROBLEMS Residue stability in cleaning residue analysis Residue recovery studies Swab sampling technique, reliability, and training 2

3 OVERVIEW CLEANING VALDIATION PROBLEMS Problems or deficiencies identified by questions and discussions with cleaning professionals at domestic and international pharma cleaning meetings. Confirmation by multiple experts Four groupings of problems / deficiencies identified Product residue problems Equipment problems Cleaning process problems Laboratory problems 3

4 AUDIT QUESTIONS Is residue chemistry considered in developing cleaning procedure? Is ph-solubility profile considered in worst-case matrix analysis? Is residue cleanability considered in worst-case residue determination? Is non-uniform contamination considered in residue calculations? Are most difficult-to-cleanto clean equipment locations proceduralized? Are manual cleaning personnel qualified and requalified? Are cleaning procedures quantitative and documented? Are dirty hold times controlled? Is residue stability considered in cleaning residue analytical? Have analytical recovery studies been conducted? On representative materials? Are swab sampling personnel trained / qualified? 4

5 LIFECYCLE APPROACH TO CLEANING VALIDATION FDA identified three stages of process validation 1. Process design and development (understanding) 2. Process qualification (performance) 3. Continued process verification (maintenance) Problems discussed indicate most cleaning deficiencies in Stage 1 process understanding, i.e., pre-work for traditional validation. Three problems are identified for Stage 2 processing. Problems in Stage 3 validation not identified. Almost no companies have a stage 3 program other than change control. 5

6 LIFECYCLE APPROACH TO PROCESS VALDIATION KEY CONCEPTS Stage approach Design and development General approaches Specific cleaning methods Process demonstration Continued process verification Scientific and technical basis Risk Variation identification and control 6

7 1. PRODUCT RESIDUE PROBLEMS Physical and chemical properties of residue as a basis for cleaning Residue chemistry, cleaning agent chemistry, and process must be consistent. Would you clean an acid with a base or with another acid? Residue solubility in most-difficult-to-clean matrix Determination of the true worst-case residue is critical for the cleaning matrix. The consequences of incorrect identification of worst-case products are disastrous. Cleanability in determining the most-difficult-to-clean residue Solubility and toxicity not only considerations for determination of worst-case compounds 7

8 PHYSICAL AND CHEMICAL PROPERTIES OF RESIDUE AS BASIS FOR CLEANING PROBLEM: No basis for cleaning procedure Arbitrarily chosen Best method at site Methods used for years for all products Bought soap at local store sale price 8

9 PHYSICAL AND CHEMICAL PROPERTIES OF RESIDUE BASIS FOR CLEANING PROCEDURE Case study #1: Antibiotic suspension containing insoluble API (base) Original cleaning method: Water, PurW, dry No documented cleaning validation for many years Unknown peaks on original cleaning validation attempts API insoluble Second method: Alkaline soap wash, water, PurW, dry Unknown peaks again API insoluble Final method: Acid wash, alkaline soap wash, water, PurW, dry Significant improvement No residues. Unknown peaks determined to be flavors. API dissolves (acid-base neutralization) Consider active drug and other residue chemistry in development of 9 cleaning process

10 CLEANING METHOD 1. Three lots with new cleaning procedure Acid cleaning liquid, drain Significant improvement in process Alkaline cleaning liquid, drain Water rinse Purified water rinse Dry 2. Swab sampling in worst case locations 3. No detectable residue, no unknown peaks 4. Unknown peaks from past trials determined to be formulation flavors (hydrophobic oils) 5. Documentation 10

11 PHYSICAL AND CHEMICAL PROPERTIES OF RESIDUE BASIS FOR CLEANING PROCEDURE Case study #2: Small molecule l API oral liquid id product. API insoluble Original cleaning method Alkaline cleaning agent with manual intervention Acid cleaning agent (full strength) when white residue noted. Small parts soaked in acid cleaning agent (full strength) Cleaning method difficult, ineffective, and unsafe Liquid product alcohol / glycol solvent system Change cleaning method to alcohol initial rinse. API soluble Final method: Alcohol rinse/soak, alkaline wash, water, PurW, dry Significant improvement No residues Easy and safe method Consider active drug and other residue chemistry in development of cleaning process 11

12 EXPERIMENTAL DEVELOPMENT PROCEDURE 1. Evaluate formulation and chemical properties 2. Laboratory comparison 2 L beaker and mixer Small amount of product into beaker + water to disperse Add cleaning agents to be screened acid, neutral, alkaline, solvent Visual observation 3. Coupons with residue in beaker 4. Simulated cleaning procedure. Swab sampling Analytical determination 5. Conclusions and recommendations 6. Confirmation in pilot equipment 12

13 CLEANING PROCEDURE DEVELOPMENT PROCESS Stage 1 R&D 1. API technical analysis. 2. ph solubility profile ph Solubility in proposed cleaning liquid. 4. ph-stability profile ph Laboratory cleaning studies confirmation. 6. Analytical method development based on stability data. 7. Testing of all excipients with analytical method. Source of unknown peaks CLEANING PROCEDURE TECHNICAL BASIS ph-solubility AND Ph-STABILITY IS BASIC R&D WORK ANALYTICAL METHOD MEASURES ACTUAL RESIDUE ANALYTICAL METHOD DETECT OTHER EXCIPIENTS 13

14 BIOTECH CLEANING CHEMISTRY -- API Protein molecules degrade in alkaline conditions Degradation rate is milder in acidic conditions Degradation rate increases with temperature API residues typically consist of protein fragments and aggregates Analytical method: Non-specific analysis Reference: Kendrick, Canhuto, and Kreuze. Analysis of Degradation Products of Biopharmaceutical API Caused by Cleaning Agents and Temperature. Journal of Validation Technology, V15, #3, Summer

15 BIOTECH CLEANING CHEMISTRY GROWTH MEDIUM Medium Composition Acids or bases Monovalent salts Polyvalent salts Amino acids Proteins (polypeptides) Carbohydrates Aqueous soluble organics Non-aqueous soluble organics Consider medium composition at end of cycle. Reference: Azadan and Canhoto. A Scientific Approach to the Selection of Cleaning Validation Worst-Case Soils for Biopharmaceutical manufacturing. Cleaning and Cleaning Validation, Volume

16 CLEANING AGENT OPTIONS Water Commodity alkalis and acids Organic solvents Surfactants Anionic Cationic Amphoteric Nonionic Formulated detergents 16

17 COMPONENTS OF FORMULATED DETERGENTS Surfactants Alkalis Acids Sequestrants / chelants Dispersants / anti-redeposition agents Corrosion inhibitors Oxidizing agents Enzymes Buffers / builders Preservatives 17

18 RESIDUE SOLUBILITY IN MOST DIFFICULT TO CLEAN MATRIX BASIS FOR CLEANING PROGRAM PROBLEM: Wrong basis for worst-case residue Water solubility USP Tables Is this adequate? Depends on cleaning procedure ph effect API with ionizable groups? Solubility in cleaning agent? Determine solubility at range ph 1-12 Understand solubility at ph of cleaning liquid Understand solubility in cleaning agent liquid 18

19 ph SOLUBILITY PROFILE, ph 1-12 Solubility mg/ml Drug A Drug B ph

20 Amount Dissolved SULFAMETHOXAZOLE ph-solubility Note pka 1 ph 12 20

21 CLEANING MATRIX Determine Worst-Case Soil SOLUBILITY (mg / ml) ph H1 Water ph H12 Alkaline li Cleaning Agent Drug A Drug B Drug C Drug D Drug E Consider acid cleaning agent for drugs D and E 21

22 CLEANABILITY IN DETERMINING MOST DIFFICULT-TO-CLEAN TO CLEAN RESIDUE IN MATRIX PROBLEM: Incomplete evaluation of worst-case residue What factors should be considered to determine worst case residue? Most companies use Solubility (ph?) Toxicity OK for site with simple dosage forms All aqueous solution products (LVP, SVP) 22

23 CLEANABILITY IN DETERMINATING MOST DIFFICULT-TO-CLEAN TO CLEAN RESIDUE IN MATRIX Matrix = Products cleaned by same cleaning procedure Other considerations Solubility in cleaning liquid Toxicity Concentration in dosage form Cleanability Formulation components major effect Cleaning personnel input Dirty hold time Soil-surface interactions (e.g., air-liquid interface) 23

24 CLEANABILITY IN DETERMINATING MOST DIFFICULT-TO-CLEAN TO CLEAN RESIDUE IN MATRIX IR Tablet ER Tablet API API Microcrystalline cellulose Same Lactose Same --- Wax --- Cellulosic polymer Crospovidone --- Talc Same Magnesium stearate Same COMPARE EASE OF CLEANING 24

25 OTHER CONSIDERATIONS Consider flavor and color oils Dyes/lakes may be more difficult to clean than active drug Consider solubility of all components Alcohol explosivity Solvent toxicity 25

26 2. EQUIPMENT PROBLEMS Non-uniform contamination transfer Non-uniform contamination is a worst-case situation and should be addressed. Calculations are demonstrated. Most difficult-to-clean locations in equipment Sites should have an SOP with a defined procedure for identification of most-difficult to clean locations in equipment. These locations are then used in sampling for cleaning validation. 26

27 NON-UNIFORM CONTAMINATION TRANSFER PROBLEM: Non-uniform contamination not considered Cleaning Processes 1. Make product A 2. Clean 3. Make product B. Remaining Product A residue contaminates Product B Equipment categorization Uniform contamination equipment Equipment with all contamination uniformly transferred. Example: Mixing tank Non-uniform contamination equipment Example: Filling needles, compressing machine. 27

28 NON-UNIFORM CONTAMINATION 1. Make 50 L tank of lemonade. 2. Fill 2 L pitcher from tank. 3. Fill cups from pitcher 4. Clean tank and pitcher. 5. Make ice tea in 50 L tank All lemonade residue in tank uniformly transferred to ice tea. 6. Fill 2 L pitcher from tank All lemonade residue in pitcher transferred to ice tea. Fill cups. HIGHEST LEVEL OF CONTAMINATION. 7. Fill same 2 L pitcher from tank Much less lemonade residue left in pitcher transferred to ice tea. Fill cups. 8. Fill same 2 L pitcher from tank Even less lemonade residue in pitcher transferred to ice tea. Fill cups. 9. And so on.. #6, 7, 8, 9.. NON-UNIFORM CONTAMINATION #6 HIGHEST LEVEL 28

29 UNIFORM CONTAMINATION CALCULATION Typical calculation considers total surface area of all shared product contact equipment, and assumes all lot A residue from total t surface area transferred uniformly to all lot B product Residue limit it = Min dose A x Batch size B x Safety factor Max dose B x Surface area References: Fourman and Mullen. Pharmaceutical Technology 17, #4, LeBlanc. Validated Cleaning Technologies for Pharmaceutical Manufacturing. Interpharm/CRC Press,

30 Product A = X Product B = X EQUIPMENT TO BE CLEANED SAMPLING LOCATIONS UNIFORM AND NON-UNIFORM CONTAMINATION Product B flushes filling lines with A residue xxxxxxxxxx x x x x x x x xxxxxxxxxx x xxxxxxxxxx x xxxxxxxxxx x x x x x x x MANUFACTURING TANK 30 PRODUCT

31 NON-UNIFORM CONTAMINATION CALCULATION Residue non-uniformly flushed into initial product units Residue content = Residue level x surface area 5ml Determine how many 5 ml vials to be discarded to be < limit. Reference: LeBlanc. Validated d Cleaning Technologies for Pharmaceutical Manufacturing. Interpharm/CRC Press,

32 NON-UNIFORM CONTAMINATION Contaminated product may be eliminated in set-up. Sites must be prepared to answer questions from auditors based on calculations. 32

33 MOST-DIFFICULT-TO-CLEAN EQUIPMENT LOCATIONS PROBLEM: No rationale for sampling of cleaned equipment. Sampling locations chosen arbitrarily. Easiest-to-clean locations chosen 33

34 MOST DIFFICULT TO CLEAN EQUIPMENT LOCATIONS Equipment Technical Evaluation Deadlegs Corners Undersides Pipe bends Flow velocity Coverage studies Drainability Other considerations (e.g., baseline visual inspection) 34

35 PROCEDURE TO DETERMINE SAMPLING LOCATIONS Specific documented procedure recommended Equipment technical evaluation Observation of equipment after processing Equipment disassembly review Cleaning procedure review Equipment evaluation review Operator interviews SOP describing above Documentation of above for equipment sampling 35

36 SAMPLING PAGES DIGITAL PICTURES One sampling page for each equipment Assemble pages for process train All pages in cleaning validation protocol Arrows for specific sampling locations Random locations unspecified Use for all cleaning validation 36

37 EQUIPMENT SAMPLING INSTRUCTIONS FOR CLEANING VALIDATION EQUIPMENT: IMPACT MILL EQUIPMENT SAMPLING LOCATION PRODUCT CONTACT MATERIAL 1. Rotor Stainless Steel Swab 2. Screen Stainless Steel Swab 3. Discharge Chute Stainless Steel Swab SAMPLE TYPE RATIONALE Maximum residue accumulation. Maximum product contact Maximum residue accumulation. Maximum product contact Maximum residue accumulation Maximum product contact X SAMPLED EQUIPMENT ASSET# EQUIPMENT NAME LOCATION Equipment #XXX Impact Mill Room XXX Equipment #XXX Impact Mill Room XXX Equipment #XXX Impact Mill Room XXX Pictures are representative of all impact mills. SAMPLED BY: DATE: VERIFIED BY: DATE: 37

38 3. CLEANING PROCESS PROBLEMS Manual cleaning qualification Manual cleaning is an inherently high risk activity. Cleaning procedure documentation Cleaning procedure documentation should be equivalent to manufacturing process documentation -- Exact requirements with personnel accountability. Dirty hold time (time to initiate cleaning) At lease one run at worst-case DHT Worst-case DHT is not always longest DHT Campaign length Max number of lots must be controlled Between lot procedure. 38

39 MANUAL CLEANING QUALIFICATION PROBLEM: Manual cleaning process Variation sources Different persons Different motivation Different physical strength Day shift, 2 nd shift, night shift And on and on and on.. 39

40 MANUAL CLEANING Manual cleaning procedures should be monitored and maintained with increased scrutiny compared to non-manual procedures More frequent training of cleaning personnel Increased supervision Periodic (annual?) revalidation batches Manual cleaning is high risk 40

41 MANUAL CLEANING -- Do you really know what is happening? Q to operator: Why is there so much foam in the tub? A: I put in extra soap because the equipment was really dirty. Q to operator: Why is there powder on the (clean) equipment? A: No problem -- We ll get the residue when we set up. Q to operator: Why don t you follow the cleaning procedure? A: The cleaning procedure really doesn t work. Q to operator: You cleaned the gasket with pure soap this is not the procedure? A: That is the only way to get it clean. Q: So why don t you tell someone to change the procedure? A: We don t have time. 41

42 MANUAL CLEANING -- Do you really know what is happening? Q to operator: Why is there powder on the clean equipment? A: It s clean enough. Q to QA (equipment inspection person): Did you approve that the equipment is clean? A: It s clean enough. Q to management: Do you know that your equipment is not clean? A: It s clean enough. Q to management: Did you finish cleaning the equipment? We are here to swab for cleaning validation. A: We cleaned the equipment three times so that we won t have any problems. Q to validation person: Did you know that the manufacturing people always clean the equipment multiple times before it is swabbed? A: Sure, we knew. Q: Why didn t you stop this? A: These people are our friends. We have to work with these people. 42

43 CLEANING PROCEDURE DOCUMENTATION PROBLEM: Exact documentation for process reproducibility Fill volume Amount of cleaning agent = concentration Time Temperature Flow rate (impact) Verification of key steps 43

44 CLEANING PROCEDURE DOCUMENTATION (Cleaning Batch Record) SOP Fill tank half full Add half scoop of soap Scrub as needed Rinse until clean Re-scrub and re-rinse if needed CLEANING PROCEDURE RECORD Fill tank with 500 L water. Sign/date Add 20.0 kg cleaning agent. Sign/date Disassemble Part A. Steps 1,2,3,4,5 Scrub for 20 minutes. Sign/date Disassemble Part B. Steps 1,2,3,4,5 Soak Part B in cleaning liquid for 10 minutes. Sign/date Rinse Part A and Part B with 50 L water. Sign/date Rinse with 50 L Purified Water. Sign/date Dry with compressed air 44

45 CLEANING PROCEDURE DOCUMENTATION (Cleaning Batch Record) Fill tank with 500 L water. Sign/date Add 20.0 kg cleaning agent. Sign/date Disassemble Part A. Steps 1,2,3,4,5 Scrub for 20 minutes. Sign/date Disassemble Part B. Steps 1,2,3,4,5 Soak Part B in cleaning liquid for 10 minutes. Sign/date Rinse Part A and Part B with 50 L water. Sign/date Rinse with 50 L Purified Water. Sign/date Dry with compressed air KEY POINTS Exact concentration of cleaning agent liquid Signature on quantitative steps Grouping non-quantitative steps (e.g., disassembly) 45

46 DIRTY HOLD TIME TIME TO INITIATE CLEANING PROBLEM: No control of dirty hold time Residue changes Drying Chemical changes Physical changes 46

47 DIRTY HOLD TIME What is Dirty Hold Time? 1. Make Product A 2. Clean 3. Make Product B How long between end of #1 and start #2? Is residue same? Does residue change? What can happen to the residue? Hydrolysis, oxidation, photolysis, physical changes, etc. Especially important in wet processes wet residue becomes dry, hardens, cakes, changes? 47

48 LABORATORY STUDY DIRTY HOLD TIME 1. Develop simulated cleaning process Coupon in beaker with stirrer 2. Weigh coupons. Aliquot residue onto coupon surface per time schedule. Allow to air dry. Weigh coupons. 3. Example time schedule: Day Day Day Day Day Day Day 0 4. Perform simulated cleaning. Observe. Air dry. Observe. 5. Weigh dry coupons. Calculate residuals. 48

49 CAMPAIGN LENGTH How many lots in manufacturing campaign before cleaning must be done? What about cleaning between batches? Equipment should be visually clean (FDA) Between lot procedure (not cleaning procedure) 49

50 4. LABORATORY PROBLEMS Residue stability in cleaning residue analysis Analytical methods must measure actual residues that are present. Residue recovery studies Analytical methods must include recovery studies, i.e., proof that process residue may be quantitatively recovered by sampling. Without recovery studies, analysis of cleaning validation samples is questionable Swab sampling technique, reliability, and training Personnel who perform swab sampling must be qualified through training with quantitative performance requirements. Training should utilize worst-case sampling methods and worst-case sampling equipment. 50

51 ANALYTICAL METHOD DEVELOPMENT PROBLEM: Analytical method does not measure actual residues Analytical method must measure actual residue Small molecules API API degraded specific or non-specific method Biotech molecules API degraded non-specific method (e.g., TOC or amino acid) UNDERSTAND RESIDUE CHEMISTRY 51

52 RESIDUE STABILITY IN CLEANING RESIDUE ANALYSIS ACTUAL RESIDUE PRESENT MUST BE MEASURED Solubility Stability Solubility considerations Hydrophilic and hydrophobic molecules Ionization Effect of ph Effect of temperature Stability considerations Hydrolysis, oxidation, photolysis, physical changes What residue is really present? Consider chemistry of residues 52

53 RESIDUE RECOVERY STUDIES PROBLEM: Is residue able to be quantitavely recovered from surfaces? Product contact t materials High % of total surface area identify all areas to be sampled Obtain representative coupons from equipment fabricators Order coupons with new equipment Recovery should be consistent and high (e.g., >50%) Recovery factor used in calculations Multiple approaches Done in lab by lab personnel consideration for future training ANALYSIS IS MEANINGLESS WITHOUT RECOVERY STUDIES 53

54 Case study RESIDUE RECOVERY STUDIES Tablet formulation, stable API, all processing on stainless steel except compressing machine (cast iron) Stainless steel recovery = 100% Audit identified no recovery on cast iron Cast iron recovery = 0% Lab analyst spiked dye tablet with active drug. Dry 5 minutes Swab Recovery = 0% Resolution: Install stainless steel dye table. 54

55 RESIDUE RECOVERY STUDIES Caution with plastics, resins, porous materials. Obtain materials from equipment fabricators Material composition Material porousity Surface roughness Example: % Recovery Neoprene smooth 79.4% Neoprene rough 11.7% Reference: Forsyth. J. Validation Technology, Vol15, #4,

56 RECOVERY STUDIES -- CALCULATION Recovery data = 50% recovery = 0.5 recovery factor Actual residue level = analytical results Recovery factor = 25 mcg/sq. cm 0.5 =50mcg/sq mcg/sq. cm 56

57 SWAB SAMPLING TECHNIQUE, RELIABILITY, AND TRAINING PROBLEM: Swab sampling must recover product residue. Sampling personnel must be trained and qualified. Periodic retraining should be considered. 57

58 ANALYTICAL METHOD DEVELOPMENT Sampling methods Sampling (swab) critical activity Training program Trained sampling personnel Demonstrated acceptable performance Documented training and retraining Worst case compounds / procedures in training Volatile solvents Problem: Solvents evaporate quickly = false negative Worst case sampling equipment Extension poles 58

59 ANALYTICAL METHODOLOGY Case study: Swab sampling with extension pole Interface Biotech tank 59

60 SAMPLING PERSONNEL TRAINING Representative sampling sites Use of auxiliary equipment Representative of most difficult analytical methods Volatile solvents time constraints Retraining considerations Who does sampling? Personnel skills 60

61 SUMMARY Cleaning personnel identified frequent overlooked problems. Residue Equipment Process Analytical 61

62 WHICH ARE MOST IMPORTANT? Risk analysis Type (potency) of drug in facility? Multi-product facility multi use equipment? Matrix? Manual cleaning? SOP cleaning processes how detailed? Signatures? Analytical recovery? Swab sampling by trained personnel? Depending on situation, many of these could be extremely serious issues 62

63 AUDIT QUESTIONS Is residue chemistry considered in developing cleaning procedure? Is ph-solubility profile considered in worst-case matrix analysis? Is residue e cleanability considered in worst-case residue e determination? Is non-uniform contamination considered in residue calculations? Are most difficult-to-clean equipment locations proceduralized? Are manual cleaning personnel qualified and requalified? Are cleaning procedures quantitative and documented? Are dirty hold times controlled? Is residue stability considered in cleaning residue analytical? Have analytical recovery studies been conducted? On representative materials? Are swab sampling personnel trained / qualified? 63

64 FUTURE DEFICIENCY Lifecycle approach requires ongoing monitoring of processes Cleaning processes must be periodically reviewed (~2 years?) Review deviations Review non-conformities Review re-cleans Management awareness Improvement projects 64

65 REFERENCES LeBlanc, Destin A. Validated Cleaning Technologies for Pharmaceutical Manufacturing. Interpharm/CRC Press, Cleaning Validation Practical Compliance Solutions for Pharmaceutical Manufacturing. PDA and DHI Publishing, Cleaning Validation Practical Compliance Solutions for Pharmaceutical Manufacturing, Volume 2. PDA and DHI Publishing, Pluta, Paul L., editor. Cleaning and Cleaning Validation, Volume 1. Basics, Expectations, and Principles. PDA and DHI Publishing, Pluta, Paul L., editor. Cleaning and Cleaning Validation, Volume 2. Application of Basics, and Principles. PDA and DHI Publishing, Kendrick, di Canhuto, and dkreuze. Analysis of fdegradation Products of fbiopharmaceutical lapic Caused by Cleaning Agents and Temperature. Journal of Validation Technology, V15, #3, Summer Cleaning Validation Forum. Coordinated by Jennifer Carlson. Journal of GXP Compliance. New Perspectives on Cleaning: Coordinated by Rizwan Sharnez. Journal of Validation Technology. Pluta and Sharnez. Avoiding Pitfalls in Cleaning Validation. Journal of GXP Compliance, V 14, #3, Summer

66 PAUL L. PLUTA, PhD Editor-in-Chief Journal of Validation Technology Journal of GXP Compliance Advanstar Communications, Iselin, NJ, USA Adjunct Associate Professor University of Illinois at Chicago (UIC) College of Pharmacy Chicago, IL, USA Editor and Chapter Author Cleaning and Cleaning Validation, Volume 1. Basics, Expectations, and Principles, 2009 Cleaning and Cleaning Validation, Volume 2. Application of Basics and Principles, 2013 PDA and Davis Healthcare International (DHI) Publishing Contact: 66