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IMPLEMENTATION OF A CLEANING VALIDATION PROGRAM IN A MUL TI- PRODUCT MANUFACTURING FACILITY

A Thesis

Presented to the Faculty of California State University Dominguez Hills

In Partial Fulfillment of the Requirements for the Degree Master of Science in Quality Assurance

by

HusseinHsu Summer 2000

UMf UMI Microform1399990 Copyright 2000 by Bell & Howell Information and Learning Company. This microform edition is protected against unauthorized copying under Title 17. All rights reserved. United States Code. Bell & Howell Information and Learning Company 300 North Zeeb Road P.UMI Number: 1399990 Copyright 2000 by Hsu.O. MI 48106-1346 . Hussein All rights reserved. Box 1346 Ann Arbor.

Copyright by HUSSEIN HSU Summer 2000 All Rights Reserved .

D.D. Abnmovitch.THESIS: TIlE IMPLEMENT AnON OF A CLEANING VALIDA nON PROGRAM IN A MUL n-PRODUCT MANUFACTURING FACILITY AUTHOR: Hussein Hsu APPROVED: fki ~~ ~S~C7i:::J.tEugene atson. Ph. Ph. Committee Member .

iv . The author also wishes to acknowledge the assistance and advice of professors Rafael Abramovitch and Dan Dunahay in serving on the thesis committee.ACKNOWLEDGMENTS The author wishes to extend his sincere gratitude to professor Eugene Watson for his guidance. patience and support throughout this thesis.

_ _ _ _._. _.._ _ _ _ __ _ _ _ _ __ _. CONCLUSION List of References 5 7 21 26 33 38 41 47 61 64 65 v ._ v _ vi _ vii viii __ _ 2. lNTRODUCTION l ii iii iv _.. US REGULATORY REQUIREMENTS 3. ELEMENTS OF A CLEANING VALIDATION PROGRAM 3 5 Cleaning Goals Cleaning Principles Cleaning Process Strategies Sampling Methods Analytical Methods Acceptance Criteria Calculation of Residual Limits Cleaning Validation Strategies Documentation 4.TABLE OF CONTENTS PAGE Copyright Page Approval Page Acknowledgment Table of Contents List of Tables List of Figures Abstract CHAPTER 1._ _ __ ..

43 53 55 56 57 58 VI . 15 16 17 40 .LIST OF TABLES PAGE TABLE I TABLE 2 TABLE 3 TABLE 4 TABLE 5 TABLE 6 TABLE 7 TABLE 8 TABLE 9 TABLE 10 Selected Residue Characteristics Residual Type Matching Type of Cleaning Method Safety Factors Hypothetical Information Matrix Equipment Utilization Matrix Cleaning Challenge Matrix ToxicitylPotency Matrix Sorted Cleaning Challenge Matrix Sorted ToxicitylPotency Matrix .

LIST OF FIGURES PAGE FIGURE 1 FIGURE 2 FIGURE 3 FIGURE 4 Swab Sampling Swabbing Techniques Rinse Sampling 29 30 32 50 Classification Rationale V1l .

Cleaning validation is the documented proof that a particular pharmaceutical facility can consistently and effectively clean a system or equipment . It is required by the regulations of GMP (Good Manufacturing Practice) and enforced by the U.ABSTRACT The general objective of cleaning and sanitizing of pharmaceutical manufacturing facilities is to ensure that the products manufactured and cleaning agents used do not leave residues behind that will adulterate the quality of the finished product.S. . Every pharmaceutical organization is mandated to put in place a validated cleaning program. It is the intent of this document to increase the awareness of the cleaning validation concept to aU levels of employees so as to facilitate the execution of such a major undertaking.item. This thesis will describe and examine the various key elements of a cleaning validation program by focusing on the fundamentals and strategies of cleaning and presenting a series of mathematical calculations on how to derive cleaning limits. Food and Drug Administration.

The FDA does not publish or recommend any specific methods of carrying out a cleaning validation program. Cross-contamination in the manufacture of pharmaceutical grade oral solid dosage forms can lead to extremely serious consequences if not properly carried out based on established in-house procedures.1 CHAPTER I INTRODUCTION In just the past several years. Simply stated. as wellas of the pharmaceutical industry. Recently proposed amendments to the GMP (Good Manufacturing Practice) clearly define cleaning as a critical process manufacturers requiring validation. cross- contamination of different products running on the same manufacturing line presents a critical concern in the eyes of the FDA. The Food and Drug Administration is the federal agency in the United States which regulates activities of the pharmaceutical industry. they encourage organizations to develop their own approaches as long as the organization can show through scientific evidence and documentation that their cleaning processes can effectively. consistently and adequately remove the contamination (drug and cleaning agent residues) from a previous batch of product to the next. rather. The Food and Drug Administration will enforce these cleaning validation regulations by . cleaning validation has become a practical reality for pharmaceutical manufacturers of oral solid dosage forms. It is extremely important for pharmaceutical and to develop a meaningful cleaning program which will control minimize any potential for cross-contamination.

analytical testing methods. as well as a detailed protocol document designed to prove the equipment soiled under the various manufacturing conditions meet defined justifiable criteria for cleanliness when the cleaning Standard Operating Procedures (SOP) are followed exactly. sampling procedures. A cleaning validation program consists essentially of p-utting in place a system of documentation that descnbes the responsibilities. designed cleaning procedures and strategies. facilities.2 issuing FD 483s observations. which are written violations ofGMP (Good Manufacturing Practice) non-conformances. residue limit justifications and change control procedures. This system of documentation entails a cleaning validation master plan. .

quality or purity of the drug product" (FD~ 1993). These regulations are called current Good Manufacturing Practices and are classified in Title 21. then the work could be for nothing and the final results less than what was intended. and are centered around 2 I CFR § 2 I 1. Part 211 of The Code of Federal Regulations (CFR). identity. The regulations are enforced by the Food and Drug Administration by issuing violation notices called FD-483s.3 CHAPTER II USREGULATORYREQUffirnMlliNT The Food and Drug Administration establishes the regulations and policies relating to pharmaceutical grade products distributed commercially in the United States. maintained and sanitized at appropriate intervals to prevent malfunctions or contamination that would alter the safety. but it is also deceptive. The objective is to ensure that products manufactured and cleaning agents used from a previous batch are not carried over to the next batch causing adulteration of the quality of the next batch of the finished product. The applicable laws at this time are general and somewhat vague. if the amount of analytical work that goes into properly validated cleaning procedures is not carried out with adequate planning and scientific justification. tremendous It sounds simple enough. They are non-conformance warning letters addressed to . strength.67 that states: "Equipment and utensils sball be cleaned. It is important to bear in mind that these regulations were written very broadly and simply so that every manufacturing facility in the United States should have a common goal of establishing a cleaning validation program. For instance.

the manufacturer could be subject to further regulatory action.4 the particular manufacturing organization specifying the correction areas of the system. The FDA warned that that if appropriate corrective steps were not taken. . such as seizures and/or injunctions. In 1998 and part of 1999. The most common GMP deficiencies found focused on the lack of process validation. over 128 warning letters were issued for cleaning problems during FDA routine inspections. the lack of equipment cleaning validation and the lack of laboratory quality control.

When one evaluates the potential risk to the products from all these areas. a basic level of understanding IS necessary. it is clearly understood why cleaning validation is critical (Williams. which remain on the finished . An adequate cleaning program will help minimize the risk of contamination and cross-contamination which may originate from the products or intermediates being processed as well as the cleaning agents. 1994). Cleaning Goals In order to establish a successful cleaning program. such as the tableting and the encapsulating machine. shared and unshared. walls. clarification and goals of a Cleaning Validation Program. The facility includes the floors. ceiling and work surfaces. Cleaning may be defined as the physical or chemical removal of undesirable substances. It begins with the definition. the foUowing is a list of the important elements that the pharmaceutical industry includes in their cleaning validation program. A Cleaning Validation Program should be established to evaluate the ability of the cleaning processes to adequately clean direct drug product contact surfaces. The production equipment includes those that come in direct contact with the actual drug product and cleaning agents. A Cleaning Validation Program is comprised of not only the facility itself but also of all production equipment.5 CHAPTER III ELEMENTS OF A CLEANING VALIDATION PROGRAM Since there is no specific FDA guidance on how to carry out or take an approach on the cleaning validation program. These undesirable substances generally are referred to as contaminants. just to name a few.

In order for cleaning rules to be effective. it will likely become contaminated. product will be contaminated. a contaminant continues to exist until it is removed or reduced to an acceptable level by cleaning or through the actions of another process. The second one states that if one unit of a lot is contaminated.6 product or within processing equipment. ." The first one states that if a product is exposed to a contaminant source. The FDA rules that an organization cannot wait for contamination and other problems to reveal inadequate cleaning procedures. when cleaning agents used in the cleaning process are known to cause residue. a rinse with the best available water. It is well established that the cleaning process necessary to remove the contamination is what must be validated (William. The fifth rule states that once added to a product. Cleaning can be as basic as sweeping an area with a brush or broom. The fourth one states that once added to a product. a contaminant has the opportunity to grow and to react with other materials or contaminants and create new contaminants. There is a set of rules of thumb that the pharmaceutical industry applies to "contarninants. Finally the last rule states that barriers which are intended to keep contamination out will generaJIy keep contamination in as well. the remainder of the lot is probably contaminated. 1994). the organization must check for and reduce those residues to acceptable levels. In addition. The third one states that if processing equipment is contaminated. or scrubbing a floor with a mop. the specific methods chosen must be shown to be effective.

1. In situations where scrubbing or abrasive materials are often used to aid in the removal of contaminants. vacuuming or carrying Cleaning removal of undesirable contaminants out of the manufacturing environment. Cleaning is done utilizing a combination of physical and chemical cleaning. processes in pharmaceutical manufacturing fall into at least four broad groups. 1994). and compressed air can introduce contaminated water and lubricating oils if supply lines are not properly filtered.7 Cleaning Principles Cleaning Process Category The cleaning processes used in the pharmaceutical industry require a degree of sophistication generally not found in any other manufacturing sectors (Robert. such as sweeping. but they are usually less effective at removing inorganic materials and oxides which are formed from base materials. care must be taken to remove these materials foUowing the cleaning process. 2. Sometimes great care must be taken in order to assure the removal of inorganic contaminants resulting from mechanical cleaning. A mechanical cleaning process is often followed by detergent cleaning and rinsing to remove residues. Secondary residues may be introduced by improperly treated water. such as . such as oils. Chemical cleaning: This group includes the majority of detergents and solvents Chemical intended to remove contaminants and leave the base materials intact. Mechanical cleaning: This physical method relies on the manual or mechanical substances. Mechanical cleaning processes may make use of hydraulic or pneumatic pressure and can be combined with heat. cleaning processes are excellent for removing organic materials.

It is basically a mass transfer into a solvent. emulsification. aldehydes. Saponification is the process of using chemically reacting lipids with alkali to convert fatty contaminants into soap. This allows the lifting of the soil off the surface substrate to ensure adequate rinsability. alcohols.8 metal particles or mineral-based polishing media. The effectiveness of the cleaning agent and its effect on the product or processing equipment must be considered when using a disinfectant alone or in combination with other cleaning processes. A reaction takes place when the substrate is somehow functionally altered and dispersed into the cleaning solvent. This chemical method relies on one or more of the following steps: Solubilization. depending on the solubility of each substrate. hypochlorite or hot water. saponification. It involves the use of a solvent in which the substrate is soluble. with no chemical reaction. iodine. phenolics. The disinfectant often contains disinfecting agents such as alcohol. It also involves the dispersion of a certain body substrate by changing its surface chemistry and surface tension. . therefore making the surface wetter than before. quaternary ammonium chlorides. Disinfection: Disinfection is the complete removal of identified microorganisms through the application of a disinfectant. Emulsification is the suspension of contaminants from surfaces to allow either rinsing or wiping them to a satisfactory system to reduce the surface tension of soil interface and soluent. Solubilization is the process of dissolving a contaminant from a surface followed by subsequent rinsing of the contaminant to either an undetectable level or a specified detection. It involves turning the substrate into soap or hydrolyzing the substrate with an alkali into a glycerol and soap 3.

sterilizing gases or exposure to high radiation fields. ultra-violet light or pulsed light to eliminate certain type of radiation sensitive bacteria. by-touch contamination from one's physical body to the product of concern. saturated steam or pressurized liquid (hot water) for steriIization. the use of walls and curtains is to prevent spatial contamination. usually through high heat. Contaminant Residue Type Cleaning processes are constantly designed and improved to reduce the level of contaminants to acceptable levels 0f risk (Anthony. 1994). dry heat. IPA or isopropyl alcohol is used by the industry as a bacteriocidal than a sporocidal. A third mechanism for controlling The use of contamination involves the use of disinfectants and chemical cleaning. hydrogen peroxide. disinfectants is most popular in the pharmaceutical industry and they include isopropyl alcohol. One mechanism involves the use of barriers. Radiation also involves the use of chemicals such as biocidals to remove germicidal growth. (996). Sterilization: This method is the total annihilation and destruction of all microbial forms and spores. involving the use of heat. it has become impractical to use steriIization to clean processing equipment due to its vast surface area (Chesky. In the pharmaceutical industry. the use of gloves and gowns is to avoid tactual. formaldehyde. A second mechanism involves the use of thermal deactivation.9 4. bleach. hot water phenolics. iodine. For instance. Contaminants are viewed as . Another form of deactivation is the use of radiation such as gamma rays. Mechanisms for Contamination Control There are various mechanisms for controlling contamination.

• Drug actives . • Molds . • Dirt . • Excipients and inerts. • Metals and rust. 3. disinfectants. •Cleaning agents. Non-viable (non-living) particles: lubricants. teflon and other gasketing and elastomers . graphite. • Fungus . sterilant residues . .10 foreign particles viable or non-viable. •Gram negative rods . 2. • Gram positive rods .Fiber glass . •Virus. • Water impurities . Non-viable chemical: -Endotoxln . such as the active drug residues or equipment The following is a short list of contamination 1. •Rubber. Viable (living) particles: • Bacteria . cleaning agents or others. residue types : . They may be residues of manufacturing materials. •Biologically active materials .

II Sources of Contamination The effectiveness of a cleaning validation process cannot be validated if the sources of contamination are not understood (Anthony. •Process baths . as they may vary in size. environment surfaces and processing equipment. on the basis of contaminant residue types. 1994). In general. form. •Water treatment systems . Ventilation and Air Conditioning) system. components and the product contact surfaces. •Transport containers. In addition. sources of contamination can be categorized in two types. air circulation. biological contaminants are by far the most difficult contaminants to control. -Compressed air supplies . If tools and equipment are not properly maintained. or for purposes of inspection. •Packaging materials . air circulation. The indirect sources of contamination include workers. smooth movement of product. mobility and the ability to find a home in the production facility. There are also the manufacturing materials that are required in the production process for purposes of equipment lubrication. particles from these surfaces may become attached to the product. .Personnel practices . The direct sources of contamination include personnel. •Room air circulation . •HVAC (Heating. Potential sources of biologic contaminants include: .

• pH adjusted with Sodium Hydroxide or Potassium Hydroxide.12 These potential manufacturing -Equipment • Media . There are also the inadvertent product contacts. . The contamination that may take place due to a variety of other contaminants is unlimited. but some list of aU other possible common sources include: . or phosphoric/organic • Antiscalants. acidic (low pH) classes .C leaning agents -Chemlcal drug active ingredients -Organic solvents -Pest control treatment -Dissolved minerals Cleaning Agents Composition Cleaning agent are composed of the foUowing components: • Buffers or pH adjusters-alkaline (high pH) . • Linings (pipes and vessels) . •Gaskets . • Dyes and oils. • Too I surfaces . materials include: lubrication . acids. • Mold release. neutral.

amylases. These are generally the remaining active and inactive ingredients. 1996). medical equipment. -proteases (breaks up proteins) . aqueous or organic. Cleaning Agent (Chemistry) Selection The key is to have a good understanding of exactly what you are trying to remove as part of the cleaning process (Chesky. -used for biologics. One criteria is by type of chemistry. " . 1996). depending upon the residual materials to be cleaned. dispersants and/or emulsifiers. not phosphates . use temperature surfactant types . Magnesium.no charged ions. The second criteria is by matching to the ""to be cleaned" residual material type.capable of reacting chemically either as an acid or as a base. -pH. Cleaning agents are conventionally selected based on three different criteria (Chesky. goods. -amphoteric . The third one is by "Selected Residues and Characteristics. -cationic.positively charged ions.Builders • Enzymes -lower water hardness-Calcium. -organic chelants (EDT A). they should be fully characterized and controlled by the organizations who use them. -anionic -negatively charged ions. Most cleaning methods rely on residual materials being dissolved using the appropriate solvent system. surfactants. or incorporate detergents. • Surfactants -low foaming.13 . The main guide in selecting a cleaning agent is to have a thorough knowledge of the solubility characteristics of the materials to be removed as part of the cleaning process. Cleaning agents may be a simple solvent. lipases ( breaks up lipids). Whatever cleaning agents are selected. -non-ionic.

• Surfactants .functional. .Solvent . • Acid (low pH). dispersants .14 The "By Type of Chemistry" criteria consists of the following: . • Alkaline (high pH). • Multi. • Chelants/sequestrants/ • Enzymes .

• Note.2 188 76 NA -78 -16 17. Table 1 Selected Residue/Characteristics Criteria Chemical Class Carbohydrates Low Molecular Weight Acids High Molecular Weig!t! Acids Amino aromatic acid Aromatic Bases Epoxies Esters Ketone Alcohols Silicones Study Compound D-glucose Succinic acid Stearic acid 4-aminobenzoic acid 8-hydroxy quinolin bisphenol A+ epichioroh_ydrin Isoamyl Acetate Cyclohexanone Glycerol Silicone Grease Melting Point Deg.• 1995.O .• Lane. J.oC 146 188 71.G .8 NA Water Solubility Very Good Good No Good Slight No Good No Very Good No by Walter. . From "Analytical strategies for cleaning agent residue determination. A." & Herbert.15 The "Selected residue/characteristics" criteria is shown in Table 1.K . K. 136-144. Journal of Validation Technology. 17 (6).

. sections throughout are usually devoted a generic cleaning procedure cleaning techniques is drafted where the first and requirements used to general the procedure. Table 2 Residual Type Matching Criteria Residue Organics ProteinslBiologics Inorganics/Scales OilslFatsIWax Silicones Particulates Chemistry So lvents. Cleaning Process Development In any cleaning procedures.G. From "Analytical strategies for cleaning agent residue determination. Alkaline+Surfactants AlkaIine+Surfactans Acid. K. ." & Herbert.. Lane.O.. Note. 1995.16 The "Residual Type Matching" criteria is shown in Table 2. A. Journal of Validation Technology. CheIants Solvents+Alkaline+Surfactants Solvents+ Alkaline+Surfactants AlkaIine+Surfactants by Walter. 17 (6). 136-144.K. J.

It is not recommended to use multiple water qualities (unless the areas where they are employed are physically separated) due to fear of cross-contamination. 1992. The use of wipes should be specified if they are used for the application of solutions or wiping of surfaces. by Agalloco. Finally. 46 (5)." Journal of Parenteral Science & Technology. . The cleaning solution or solutions. The actual technique used for hand washing and scrubbing of equipment should be detailed to minimize operator to operator variability. From "Points to consider in the validation of equipment cleaning procedures. Required equipment such as soaking tanks. scrub brushes must be listed. such as the detergents. The required water quality. Table 3 Type of Cleaning Method Note. safety precautions must be emphasized. must be specified. such as in manual cleaning. This selection is primarily based on the detergent's ability to remove these contaminant residues. The detergents should be carefully selected based on the expected residues to be removed. such as the degree of purification or potable.17 The various cleaning techniques are listed in Table 3. must be specified with their use dilution and temperature. sinks. 163-168.

Small stainless steel parts should have all surfaces scrubbed and nozzles brushed with pipe cleaners. can be organized into types of equipment based on material types. Equipment used with dry materials should first be vacuumed or wiped. cylinders and plastic parts. small glass beakers. The actual cleaning procedure. The use of compressed air to blow off solids or powders is unacceptable because it can drive residues into comers or difficult to clean places and can generate airborne residue particles. nozzles. Pre-cleaning is done by rinsing away all visible traces of process solution or soaking in an appropriate cleaning solution followed by a rinse.18 The first operational section of a cleaning procedure must describe exactly how soiled equipment is pre-cleaned and then stored prior to actual cleaning. small plastic beakers. cylinders. Knowledge of equipment and feedback from manufacturing personnel can be useful in identifying unexposed surfaces or other areas which are especially difficult to clean. labware. 1992). Cleaning details for the difficult to clean areas should be provided and it may also . Each type of equipment needs specific cleaning instructions to minimize variability. instructions should be detailed to minimize process variability. filter housings. Typical classifications include small stainless steel clamps. flasks. which must be physically separated from the equipment drying and clean storage areas and clearly identified by status tags. medium to large glass carboys and fermentor vessels. Within each classification. after precleaning. Documentation plays a key part of the development of a cleaning procedure because every cleaning activity must be documented in clean log books pertaining to the equipment and cleaning areas (Agalloco. Pre-cleaned equipment should then be stored in a designated soiled equipment storage area. shape or the soil encountered.

in some cases. cleaned equipment should be visua1ly inspected. For larger equipment. it is important that the cleaned equipment be dried to prevent the possible proliferation of microorganisms. the time factor determines the effectiveness of the rinse as a detergent is continually removed from the equipment. It is performed following detergent cleaning. The final step in a cleaning procedure involves the drying of the cleaned wetted equipment. Rinsing plays a crucial aspect in a cleaning procedure. It is essential to train and work with the cleaning operators as the procedure is drafted. Following drying. Rinsing is a dilution process whose effectiveness is controlled by the number and volume of each tank and amount of residual water carry-over between tanks (Cindy. 1994). With this in mind. the standard operating procedure must specify the required rinsing to remove aU residual detergent. it may be impossible to scrub the interior effectively. such as the interior of 20 cubic feet V-shaped blender. pit or leave a residue as long as the alcohol and wipe leave no residue themselves.19 be necessary to define which equipment can be cleaned by cleaning operators and what mechanical items of the particular equipment should be disassembled and cleaned by maintenance personnel. Devices can be constructed to help out and reach these difficult to reach locations. It is recommended to indicate a minimum time spent on rinsing each item. For spray rinsing. Cleaned equipment is now dried in either a validated drying oven or designated drying area An alcohol wipe. the tank number and volume must be specified and operators should be trained to avoid excess carry-over. Regardless of the method used. The use of an acidified initial rinse is most effective for removing alkaline detergent. may be used to eIiminate any remaining water film which may spot. covered or draped to prevent contamination from .

any deficiencies will be easily identified and corrected. discovering its limitations and determining what is achievable during the validation. it is important to conduct an evaluation or pre-validation studies to check the defined cleaning parameter of the procedure such as the cleaning and soaking times. The data obtained from these pre-validation studies are used to fine tune the cleaning procedure. the occurrence of residues left by the detergent. The manufacturing operators should perform these pre-validation studies These studies are used to ensure a robust following the draft cleaning procedure. environmental restriction and the product support and long term reputation of the detergent supplier must be considered (Agalloco. procedure by optimizing the cleaning process. . After a generic cleaning procedure has been developed. The detergent selection should be thoroughly demonstrated during the pre-validation studies aimed at optimizing the cleaning process. 1992). The ease of detergent rinsing. wash and rinse water volumes and to identify the difficult to clean items and soils. detergent selection and concentrations.20 the surrounding environment and then stored in a designated clean storage area All manufacturing personnel should be able to inspect their equipment for cleanliness and understand the importance of doing so. By challenging the process at extremes.

The Food and Drug Administration has always shown concern about the manufacturer's practice of using dedicated equipment to a particular product batch or using the same piece of equipment for multiple product batches in their facilities.21 Cleaning Process Strategies Cleaning validation is the qualification of cleaning procedures used for facilities and equipment in order to reduce the microbial contamination (bioburdens). Multiple Use Versus Dedicated Equipment A major consideration from the FDA viewpoint is whether the facility employs equipment used for multiple products or whether equipment is dedicated to a specific product (FDA. The fourth approach involves the use of a single global cleaning procedure versus a grouped cleaning procedure versus a multiple. thus preventing product contamination. In some cases. The third approach involves the installation of a CIP versus COP cleaning process system. unique cleaning procedures. Validated cleaning ensures that clean equipment is used on each batch of product. One approach involves use of "Dedicated versus Multiple Use" equipment cleaning. 1993). There are generally four different strategic approaches to developing cleaning process strategies. a combination of situations may arise when certain equipment is dedicated . Various organizations have adopted different strategic approaches to creating optimal cleaning processes that are capable of reducing these contamination to acceptable levels. while maintaining the performance capabilities of the manufacturing facilities and its equipment (Harder. The second approach involves the use of "Manual versus Automatic" cleaning. physical contamination and chemical residues to an acceptable level. 1994).

band washing. equipment scrubbing) in which operator to operator variability exists and affects the quality of the cleaning.22 for a single product or steps in a process. Manual cleaning procedures are subject to human error.e. The same person can be following the same cleaning procedure everyday. a well-designed cleaning standard operating procedure is essential to ensure cleaning consistency (Joseph. should work. The procedure. 1993). So. Manual Versus Automatic Cleaning For manual cleaning procedure. whereas equipment in other parts of the facility may be used for multiple products because that particular product or that particular piece of equipment is difficult to clean. the regulatory requirement does not specify how to clean equipment. Manual cleaning involves personnel in the actual manual cleaning operation (i. Some pharmaceutical organizations employs the use of disposable surfaces. 1994). the manual cleaning procedure must be validated. The FDA has made it clear that it does not favor manual cleaning procedures due to concerns over procedural and quality variability introduced by the human factor (FDA. but simply requires validation (proof) that the cleaning process can consistently produce equipment meeting . Anywhere manual cleaning is incorporated. It is a requirement of the FDA that separate facilities be used for the manufacture of antibiotics. this single use surface equipment is discarded and never used again. as long as it is being done in the way that it was validated and intended. Once used. such as penicillin and cephalosporins. but there is no way of assuring that person's performance is exactly the same day in and day out. FDA is concerned with the Multiple Use Cleaning approach due to the issue of cross contamination. the personal hygiene of the operators needs to be taken into account. However.

reliable. The most important element in manual cleaning is the people (Anthony. CIP (Clean-In-Place>Versus COP (Clean-Out-of-Place) The third strategic approach involves installing a CIP (Clean-In-Place) or COP (Clean-Out-of-Place) cleaning process system. The training session has to stress the importance of doing things in the same way all the time. but during inspections it will closely evaluate any manual procedures used and the training and the ability of cleaning technicians/operators to consistently follow those manual procedures. The FDA usually would require a company to employ an automated cleaning system if the manual cleaning procedures were not properly validated. There are no operator to operator . variability issues. The process is automatic. It is very important that these people know the importance of doing things the same way as it was done during the validation studies. and cannot be expected to perform exactly "in the same way" if you do not tell them to do so. assuming there are no mechanical failures. Clean-In-Place system technologies have been applied to many types of pharmaceutical processing system to provide effective. With this in mind. repeatable and validated cleaning of equipment and interconnecting piping. the same way all the time. 1994). the FDA is allowing manual cleaning procedures. In an automated cleaning system. "In the same way" must be understood because human beings are not machines.23 the firm's own specification for cleanliness. the machine will always do the same job. New employees have to be trained thoroughly. The automatic cleaning procedures are not subject to human errors since the person is replaced with the automated machine.

Processing equipment and piping systems which are cleaned in place receive less wear and tear than comparable items which are manually cleaned. interconnecting piping and valves are all CIP cleanable. Typically. Post Rinse. cleaning agent and effluent treatment costs. Alkaline Detergent Wash. These CIP cycles often are comprised of a sequence that includes a Pre-Rinse. 1994). will continue to do so as long as it is properly maintained. Processing tanks and piping systems comprised of pumps. CIP cleaning procedures operate more efficiently when their washing solutions are re-circulated because this minimizes water. the solutions are made up at a remote station. washing and sanitizing solutions are brought into intimate contact with all product-contacting surfaces. for instance. A CIP cleaning system meets that profile. if programmed to function properly. and personnel can avoid contact with these extreme elements. Acidified Wash and Final Rinse. Its cleaning program can be monitored and documented not only by recorder charts but via printed reports. This procedure generally involves the removal of residues by erosion. More aggressive cleaners and higher temperatures can be used than is possible with manual cleaning methods. The success of the application of CIP technology to these processing system has often depended upon the degree to which CIP cleaning has been designed into the equipment and interconnecting piping system that it serves (Seiberling & Hyde. Labor required . The application of CIP technology is commonly characterized by cleaning cycles in which rinsing. A cleaning process controlled in a reproducible way will eliminate the human element and.24 Equipment is cleaned in place by circulating cleaning solutions through the equipment. then pumped to the system being cleaned. using chemical and cleaning agents rather than physical force.

25 for cleaning and maintenance will generally be substantially reduced. rinsing. A COP (Clean-Out-of-Place) cleaning process can be automatic or manual where equipment is disassembled and transported to a remote cleaning station and subjected to a washer for ultrasonic scrubbing. Single "Global" Procedure Versus "Grouped" Procedure Versus Multiple "Unique" Cleaning Procedure Depending on the objectivity of their cleaning processes. This qualification will provide assurance prior to cleaning cycle performance qualification that the CIP systems and process equipment units were installed and operate as they were designed. a fully automated CIP system is expensive. operation and control system of the units involved. rinsing. washing. mopping. and the attitude of operating personnel responsible for cleaning and sanitation will change dramatically. given these products are similar in their chemistries (Gold. personnel safety is also improved through properly designed CIP. The processing system productivity may be increased through a reduction of down-time. Connections are made and cleaning agents are circulated through the system. 1996). include preparation. washing. The cleaning cycles in a typical automated and manual CIP. They become system operators rather than clean-up people. sanitizing and a final rinsing. Most importantly. However. spraying and wiping or pressure spraying. many firms employ the so-called one "Global" procedure where the cleaning procedure is designed to clean out the entire firm's list of products. This approach usually applies to a company that specializes in a single . A CIP system must also be qualified in regards to its installation. pre-cleaning.

1994). 1994). Areas to be swabbed must be .26 product for its survival. the so-called blockbuster drug product. the other is by evaluating rinse samples and the last one is to perform visual inspection. Swab sampling techniques must be unifonn. Selection of either methods is generally based on factors such as equipment design and solubility of residues.g. Sampling Methods Sampling methods are part of the cleaning validation program where the question of how to measure the level of cleanliness arises. The wiper is usually referred to as the swab. Swabs may be used when the residues are relatively insoluble or the equipment is designed in such a manner that there are exceptionally "difficult to clean" sites. solid dosage form. And there are other firms who go to the extent of designing product-specific unique cleaning procedure where every single product manufactured has its own cleaning agenda. Direct Surface Swabbing. Rinse Sampling and Routine Production In-Process Control Monitoring constitute the three recognized methods for cleaning validation sampling (Douglas. parenteral drugs) are grouped into a single group and a group-specific cleaning procedure is designed for cleaning. using a liquid and wiper (Joseph. One is by evaluating swab samples. The FDA has always recommended a combination of rinse and swab samplings because swabbing cannot reach all areas but rinse sampling can cover a larger surface area that swabs cannot. Other firms employ the "Grouped" procedure where similar products (e. Direct Surface Swabbing Surface swabbing is the process of extracting a particular residue from a surface of an equipment.

Contamination of the swab can come from raw materials. thickness and length. Contamination on the swab will reduce its utility for sampling and may contaminate the area being sampled. Swabs are available in many different materials and configurations. Swabbing has the advantages of being direct. The swabbing materials themselves must be characterized and not be a source of subsequent contamination. . thickness and length. usually made by affixing a cotton cloth or foam to the end of a wooden or plastic handle.27 specifically identified by site and size. packaging. • Stick flexibility. shipping and handling. polyester. polyurethane or other materials. the handle material. The swab and solvent must be chosen to be effective in the residue and yet not interfere with the analysis (Douglas. width. 1994). width. and the disadvantages of potential inconsistent results due to the techniques used. the type of bonding of head to the handle. the packaging and any liquid solvent supplied with the swab. The likely residues must also be identified and characterized so that a swabbing material can be found to recover them all in enough quantities to analyze and quantify. The following is a list of swab characteristics that are critical for successful use in cleanroorns: . The head of the swab is available in cotton. relatively inexpensive. Some of the differences among swabs include the head material. The swab is basically an absorptive medium with a handle or shaft. This is often a difficult task as the swab must absorb the residues from the surface and subsequently release it into a diluent without shedding a significant quantity of particles that might interfere with the assay analysis. fabrication.Size .

sampling scheme designed for use in a cleanroom.Retention-water retained . Surface swabbing technique is best done by going from the more clean to the less clean area with parallel and partially overlapping strokes and using a new area of the material to start with each new stroke. Sampling sites must be selected that are representative of the total surface area to be tested.Solvent resistance . Surface swab sampling should be conducted while wearing gloves to minimize contamination of the surface being sampled and of the swab. Figure 1 shows a swab . milligram per head and per gram. The area to be sampled should be clearly delineated and its dimension recorded. • Abrasion resistance . • Absorption-water. minimizing redeposition. • Surface cleaning ability-soluble and insoluble challenges. This technique puts the swab at its cleanest in contact with the surface at its cleanest.28 . thus improving sampling efficiency. . • Particles . • Extractables .

. Cleaning ValidationAn Exclusive Publication. 4. . C.~ Analyzer Sensitivity Figure 1. 1994.29 +- Swab Sampling Swab Extraction ." by Robert. From "Using swabs for cleaning validation. Swab sampling. 74-89.

Swabbing technique. From "Using swabs for cleaning validation. Food and Drug Administration. 1995). the FDA made it clear that the sampling and analysis combination (compatibility with sampling methods) should be challenged to determine what fraction of the target material is actually sampled and detected in order to ensure that the contaminants can be recovered from the equipment surface and at what level (50%. In the FDA's Guide to Inspections (U." by Robert.30 Figure 2. This study must be done because a negative result may indicate a poor sampling technique or a lack of analytical sensitivity. 90% recovery. This brings us to the issue of percent swab recovery efficiency study. Lane & Herbert.S..). During production. 1993). Cleaning ValidationAn Exclusive Publication. the analyte (contaminant) is in close contact with equipment surfaces . Recovery efficiency is the fraction of material originally present on the test surface that is subsequently quantified by the analysis (Walter. 4. 74-89. C. 1994. etc.

Then. Rinsing can deal with a larger surface area and can get to inaccessible areas. the surface would be swabbed. and the quantity thus found is compared with the original known amount. a known amount of material of interest would be deposited on the surface just as it would be in real practice. complete solubility can be achieved. rinse samples provide data for the entire product contact surface. but may not have the required removal efficiency of a swab.31 that usually are composed of stainless steel or glass. Final rinse . If the rinse solvent and contact time is sufficient. Rinse samples are often used when the materials to be cleaned and the cleaning agents are readily soluble in water. Ideally. It is not unusual for the analyte to bind to the surface in such as manner that it is difficult to extract using chemical or physical means. 1994). like water (Joseph. the extract quantified. The solvent system must be fully characterized and controlled. Rinse sampling requires specifications for rinse times and volumes. The third reason is that the residue must be quantifiable at very low levels as the amount of dilution is difficult to control and assess with final rinse water samples. easy and inexpensive. The main disadvantage is that the sample collected may not be representative of the residue levels on the processing equipment due to three problems: One problem is only those residues that are contacted by final rinsing water will appear in the sample. which may be chemically active. The sampling of final rinse water has the advantage of being relatively quick. the swab extracted in the solvent. Theoretically. The second reason is the residues must be water soluble or they will not appear in the sample. Rinse Sampling Rinsing is the process of extraction of a certain residue from a surface using a liquid form.

just as with swab recovery studies. rinse sampling consists of rinsing the entire surface of a given piece of equipment with either an organic solvent like alcohol or water. filter housing and liquid circulation systems. 66-73 . tablet presses and encapsulation equipment. D. granulators. 1994. J. shows the method of rinse extraction technique. powder filling equipment. The equipment design plays a factor in deciding to use rinse samples or not. From "Aspects to consider during cleaning process validation. Ideally. Cleaning Validation-An Exclusive Publication. Figure 3. blenders. Figure 3.32 should be performed with USP complied Purified Water (USP) or Water for Injection (USP).. Rinse recovery studies need to be performed to assure recovery efficiency. milling machines. It is less suitable for fluid bed dryers. 4. Rinse sampling. Rinse sampling applies well to equipment like tanks." by Anthony.

these analytical testing are performed on the samples to identify and quantify the residues recovered. . These analytical methodologies can be sorted out into two general categories: residue non-specific assays and residue-specific assays. The method used must be able to detect residues of manufacturing materials and their degradants. as well as the cleaning materials and rinse materials (Smith. This method is not very sensitive and the results are not easily quantified. visual inspection plays part of the routine production in-process control monitoring. 1994). There is a host of methodologies available ranging from Thin Layer Chromatography to Total Organic Carbon to High Pressure Liquid Chromatography to Gas ChromatographylMass Spectrophotometry. Following sampling. the manufacturer must be able to validate the method and demonstrate that the methodology will produce the desired results to the detection levels necessary. While not as quantitative as final rinse or surface swabbing sampling. It is used to verify that there are no areas within the process equipment systems that contain residues that can be seen with the naked eyes.33 In-Process Monitoring Visual inspection of equipment plays an important part of cleaning validation monitoring. thereby providing a quick and inexpensive assessment of process equipment (Joseph. 1993). Analytical Methods Whichever analytical method is chosen. This can provide a reality check for overall cleaning efficacy.

residuals is that the and relative be determined is required used if in they all comprise information the overall TOe Additional facilities. It is a non-specific relatively (swabbing) effectiveness measurement for oxidizable carbon residues. The detection is measured either by membrane. to the TOe cannot testing direct conductivity identity because further or non-dispersive quantities infrared. such as organic or inorganic. The compounds fundamental contained principles behind TOC is the analyzer oxidizes the orgaruc in the water soluble samples to carbon dioxide and the amount of The internal oxidation process is done either by combustion carbon dioxide is measured. in units of ppb (repeatable results parts per billion-ug/L) and ppm (parts per million-rng/L) and has minimal interference and yields reliable information on the quantity of organic residues present in the final rinse or surface samples. is needed. This method is final rinse water and surface for the assessment sampling easy to use and adaptable testing. TOC or Total Organic Carbon test is commonly used in the detection quantification of carbonaceous residues (e.TOC results are reported as Carbon). or the use of heated persulfate with ultraviolet of the C02 (carbon dioxide) produced light or with titanium oxide. and more and (Smith. cleaning agents) following cleaning. or not. proteinaceous conductive or non-conductive. light absorbing non-proteinaceous. to both TOC is a commonly used method of cleaning as it yields sensitive «I ppb. 1993). The main disadvantage of the carbonaceous number.g. In multi-product TOC is often . drug residue.34 Residue Non-Specific Residue compounds Assays assays are those that detect and quantify groups of or non-specific by general chemical criteria.

HPLC or High Pressure Liquid Chromatography is a commonly used technique . This technique is sensitive but requires that the analyte contains a strong chromophore (UV absorbing group of compounds) to allow detection at trace concentrations. These analytical methods are often the same as those used for in-process manufacturing quality control testing. This assay can be relatively simple and inexpensive. made up of acids and bases. It can be used in conjunction with other methods to provide additional information about potential post-cleaning residues. and has the same disadvantages as other residue non-specific methods.35 conjunction with other residue specific assays. Since these cleaning agents are strongly ionic. It is designed tor aqueous samples. TOC results are reported in units ofppb (J. like HPLC. This technique is useful for items such as cleaning agents or detergents when the composition is unknown and the sample contains one or more ionic species. It is commonly used to detect residues at low levels of rinsate samples.lgIL) and ppm (mgIL) as Carbon. Conductivity is another non-specific analytical method useful in the detection of inorganic or ionic residuals. UVNIS absorbance spectrophotometry is another methodology of choice used in the detection of specific light-absorbing compounds in final rinse water samples. they can be easily detected by conductivity testing. The target residue must often be relatively soluble in water and contain carbon so that the TOC analyzer can detect. Residue Specific Assays Residue-specific assays are those that can detect and quantify specific known compounds by analyzing for unique characteristics of the compound.

and HPLC methods interaction. 1993). accuracy. Endotoxin bacterial is that fragmented can be relatively method product HPLC and labor detect assay is another fragments Endotoxin residue-specific (endotoxin). linearity of response follow the and range. HPLC can be very effective in the detection mo lecules such as detergent phase. according must be validated to established States to demonstrate consistently its limits (Fourman (USP) & Mullen. The main disadvantage or degraded expensive used to to the use of HPLC for cleaning validation residues intensive. Method Validation The analytical methodologies ability to detect residuals Guidelines Conference validation ingredients). of nucleic acids and smaller may include The primary reverse components.36 for cleaning validation studies testing. Typical peptides. The validation of analytical methodology products related to cleaning testing. The linearity and specificity . Bioassay is another analytical method used to determine the biological activity of a given molecule. is usually performed on final rinse water sample. from both the United on Harmonization based on the types Pharmacopeia and the International for method active (ICH) of outline material the necessary being tested tests needed (finished product. size exclusion hydrophobic reproducibility biologically testing assays advantage proteins of HPLC is its specificity. limit of detection and quantitation. may not be detected. accuracy. ion exchange. and quantify cell wall and it is a requirement for the testing ofUSP Water for Injection. and its ability to detect that are basically intact but not may be active. follows the include same principles of those related to finished specificity. precision (repeatability These principles and interim precision). proteins.

Precision is a measure of either the degree of reproducibility or of repeatability of the analytical methods under normal operating conditions. The linearity of an analytical procedure is its ability (within a given range) to obtain test results that are directly proportional to the concentration amount of the analyte in the sample. It is arguably the most important in the assessment of a cleaning analytical method. Method precision is the degree of agreement among individual test results when the method is applied repeatedly to multiple samplings of a homogeneous sample. reproducibility refers to the use of the analytical procedure in different laboratories. In this context. Repeatability is also known as the Intra-assay precision. The range of the method is the concentration range used for the linearity study so long as the lowest level is at least 2x higher than the method of limit of quantitation. as in a collaborative study. The IP is referred by USP as the Ruggedness. The specificity of an analytical procedure is its ability to assess unequivocably the anaIyte in the presence of other components that may be expected to be present.37 precepts of regression analysis. Accuracy and precision can be estimated as offshoots of the data generated for the regression tests. Specificity is merely a linearity in the presence of the product matrix. Repeatability refers to the use of the analytical procedure within a laboratory over a short period of time using the same analyst with the same equipment. The limit of detection (LOD) is the lowest amount of the analyte in a sample that can be . The Intermediate Precision (IP) of the method expresses the within-laboratory variations and is evaluated by having a different analyst carry out the analytical procedure for a solution prepared at the limit concentration only and using different equipment. The method accuracy is the closeness of test results obtained by that method to the true value.

the nature of other products made in the same equipment and the batch size of other products made in the same equipment. NMT 2%.38 detected but not necessarily quantitated as an exact value. one question inevitably arises. solubility of the potential residue. The LOQ is a parameter of quantitative assays for low levels of compounds in sample matrices and is used particularly for the determination of impurities and/or degradation products. Clearly. How clean is clean? The FDA has made it clear it does not intend to establish limits for cleanliness. The limit of quantitation (LOQ) is the lowest amount of the analyte in a sample that can be quantitatively determined with suitable precision and accuracy. difficulty of cleaning. toxicity of the material. The establishment of acceptance criteria for post-cleaning residue limits must be logical and based on the manufacturer's knowledge of the materials involved (Robert. though the industry is expected to set its own limits. These post-cleaning residue limits must be safe. acceptance criteria converts these limits criteria to specific sample results based on factors like recovery studies. assumptions and data calculation. e. Limits are simply combined policies with a set of objectives and assumptions. 1994). The FDA expects the manufacturers to have a documented rationale for the establishment of these limits of cleanliness.g. The actual numerical limit of cleanliness can be based on therapeutic dosage levels. achievable and verifiable. Acceptance Criteria Regardless of the cleaning approach or strategy. practical. There . These limits are then converted to a measurable analytical quantity called acceptance criteria. Documentation must exist and be secured that exp1ains the scientific soundness behind these established residue limits.

The first is that pharmaceuticals are often considered to be non-active at 0. and the limit lower for these cases. The idea behind this method is that. The third is that the cleaning validation program should be robust. .g. will be a smaUer fraction is allowed to carry over). This reasonable degree of risk is different for different dosage form manufacturing. 1993). The second is a safety factor that measures a reasonable degree of risk. The safety factor is adjustable based on different dosage forms as presented in Table 4.001 fraction. This fraction of the smallest therapeutic dose is 1I1000th. for active drug products.1 of their normally prescribed dosage. The risk is usually higher for research compounds because little is known about the toxicity of the material. no more than I/lOOOth of a dose of a given active drug product shall be part of the maximum daily dose of another drug product (carried over to the next product). This is because I/lOOOth is considered to be a "no effect dosage" and thus is acceptable. a greater safety factor is applied. There are three factors of ten in the 0.39 are several approaches manufacturers can choose w hen establishing acceptance criteria (residual limit) using one of the following calculation methods: I) 1I1000th of a dose maximum carryover. (e. The limit is based on allowing not more than a fraction of a therapeutic dose to be present in subsequent products (Fourman & Mullen. Therefore.

000 1/100 to 1110 Note: From "Determining cleaning validation acceptance limits for pharmaceutical manufacturing operations . certain levels of hazardous materials are considered acceptable in animal tissues and poultry products that enter the human food chain.000 1/1..• 1993. 2) 10 ppm maximum carryover The basic idea behind this method is that no more than 10 ppm of a given product shall be part of anyone dose of the next product to be manufactured (Fourman & Mullen.000 to 115. G.) Topical Products Safety Factor 1/100. L. In those regulations.000 1/5.. For detergents. The idea of using a maximum allowable parts per million level has its roots in the regulations that apply to food products. 17 (4) 54-60. the acceptance criteria calculation is based on one one-thousandths (lIlOOOth) of the LDso of the most potent detergent component. This method is popularly replaced by the carryover method. Caplets . Pharmaceutical Technology.40 Table 4 Safety Factors Dosage Form Research Compound Intravenous Products Ophthalmic Products Oral Dosage Forms (Tablets. V.000 1/10. 1993).. & Mullen.000 to 1110. M. i/rooo" of a dose maximum ... by Fourman.

the maximum daily dosage and the product contact surface area of each piece of equipment in the facility. If the quantity of safe residues is visible on GMP equipment. the foUowing information about the facility must be gathered. No quantity of residues may be visible on the equipment after cleaning procedures are performed. To do the necessary calculations. As an example of a simple limit calculation for a given active drug product. the number of dosage units per batch (e.1g 2 x 2 in ( 4 in2 ) swab area per Calculation of Residual Limits The method of calculation is best described by an example. the batch size. the smallest strength manufactured. A list of all the products that are manufactured in the facility is required. Assume that a person has just been given the assignment to determine cleaning validation acceptance limits for hislher pharmaceutical facility. For each product. Spiking (dilution) studies have determined that the active ingredients in most products are visible at approximately 100 J. 1993). Product "B" will be designated as the product that will be manufactured in the same equipment subsequent to the . there is a series of observational guidelines and assumptions to follow. Product "A" will be designated as the product that was manufactured in the equipment prior to the cleaning process. the product that is being cleaned at the moment.41 3) Visual Cleanliness This method is based upon the idea that residues of active drug can be seen on processing equipment surfaces in concentrations as low as 100 micrograml4 in2 (Fourman & Mullen. 2 million tablets). they must be cleaned until no residues are seen.g.

let's say. . All remaining residues of Product "A" on the process equipment surfaces are assumed to be transferred to the next production batch of Product "8" and uniformly dispersed. The assumptions made are that all remaining residues of Product "A" are assumed to be unifonnIy dispersed on the product contact surfaces of the process equipment. the foUowing information is coUected and shown in Table 5. Considering the . the product that is the unintended recipient of residues of Product A.00 1 dose criterion for Product A. Assuming that an individual works in a very small facility that makes only five products and has only five pieces of equipment. a 70 kg adult. the maximum carry-over from Product "A" to Product "B" will be designated as less than one one thousandth (111000) of the normal therapeutic dosage of Product "A" for.42 cleaning process.

.43 Table 5 Hypothetical Infonnation Matrix Product A STD(mg) Max Dosing (units /day) Batch Size (unitsllot) Unit Weight (mg) Batch Size (kg/lot) Product B Product C Product D ProductE 50 1 40000 400 16 15 6 65000 200 13 15 3 90000 400 36 200 4 30000 500 15 1000 8 35000 750 26 Equipment Surface Area (in2 ) Product A Product B Product C x Product D Product E x Sieve Miller Mixer Press Coater Note: 2000 100 3000 1500 2000 x x x x x x x x x x x x x x From "How to solve complex cleaning validation problem. 1994." by Pierre.. Journal of Validation Technology. 4(1) 22-28. R.

STD is the smallest therapeutic (strength) dose of Product "A" in mg. which equates to 1. BS is the batch size of Product "8". is the total product contact surfaces of the process equipment between Product "'A" and "8" . 2 million units of tablets) L WSD is the largest daily dose of Product "8" in units of tablets ( Maximum daily dose of the next product). APR is the Allowable Product "'A" Residual level per in2 of product contact surfaces subsequent SA_total common to the cleaning. that the Product "A" remained "A" residues are uniformly dispersed. the Based on the assumptions allowable "mass" of Product per in2 of surface is calculated from the following equation: APR = (MAC) / SA_total where. A) X (BS-Product B) / (SF) X (L WSD-Product B) MAC is the maximum allowable carryover from Product "'A "to Product ·'B". in # of dosage units (e. SF is the safety factor.481 mg or B. in in unit of irr'.000. one finds the limit for cleaning Product in the production schedule A to be .44 The following of swab area: equation is utilized to calculate the limit of Product A permitted per 4 in2 MAC = (STD-Product where. The total if the next product is Product .g. SA_total will be determined After performing 481 ug/swab the math.

If the schedule calls for product D. This method of calculation is based on the use of animal toxicity. As an example of a simple limit calculation for a given detergent. what if the next product is not product A but product C? The same equation is used again to obtain a limit of .481 mg. This LDso data is widely available on the Material Safety Data Sheets and other references where toxicity data is available.e cleaning detergents). that same equation would be used again to calculate a limit of 333 ug/swab.500 in2 from the press. the EPA was attempting to determine the amount of chemicals which the human body could ingest on a daily basis . The limit for Product "A" = (50 mg/6 units x 1000) x 65. This method is based on the concepts of Acceptable Daily Intake (ADI) and No Observed Environmental Protection Agency (EPA).000 in2 from the mixer and 1.000 unitsl4. the sum of3.500 in2. and the most conservative of the four. This method is particularly suited for determining limits for materials that are not used therapeutically (i. the maximum allowable amount will be cased upon one one-thousandth (1/1000) of the LDso of the most potent detergent component. the limit would be 194 ug/swab.45 equipment surface area found in common between the two products is 4. 194 ug/swab is selected to meet the . However. If it were product E.500 in2) x 4 in2 = . The LDso is defined as the dose in mg/kg body weight of test animal that is lethal to 50% of the test subjects.001 dose criterion for any possible product that could be on the next production schedule. Now that all possible products that could foUow Product A have been considered. Effect Level (NOEL) developed by the Basically.923 mg = 923 ug/swab.

LWSD is the largest daily dose of Product "B" (maximum daily dose of next product). chemical X. intravenous route or oral by mouth route). . The NOEL is calculated from the LDso by the following mathematical relationship: NOEL = LDso X . If it is assumed that the following toxicity. The ADI is calculated once the NOEL is known following this mathematical relationship: ADI = NOEL / SF Where.005 is a constant derived from a large toxicity data base.46 without undue risk and toxicity. SBS is the smallest batch size of Product "B".g. batch size and dosage information is known. consider a fictitious chemical substance. Different LDso values will be used depending on the route of administration of the other product manufactured in the same equipment (e. then the maximum allowable carry-over can be calculated as follows: LDso = 419 mg/Kg . As an example. SF is an appropriate safety factor And finally the Maximum Allowable Carry Over (MAC) can be calculated from this relationship: MAC = ADI x SBSILWSD Where.005 Where. they found that this level of ''Acceptable Daily Intake" could be calculated from the toxicity of the materials expressed as an LDso. In the process.

0005= .147 mg MAC = ADI x BIR = .g. for multiple product facilities in developing cleaning program philosophies for dosage form manufacturing. with one product chosen for cleaning validation applicable to all products in that . Products manufactured in the same equipment can be grouped together. Cleaning Validation Strategies Product Grouping and Worst Case Selection Active Drug Residue The overall cleaning validation strategy employs the utilization of Product Grouping and Worst Case Selection (Gold.665/100 = .000.000mg / 300mg = = 19. NOEL = .665 mg ADI = NOEL / SF using a safety factor of 100 (for the oral route) = 14. parenteral drugs) into a single group and then choose one or more worst case examples to evaluate for cleaning validation purposes.2095 mglkglday For a normal adult of70 kg.147 x 4O. solid dosage form.005 = 419mg/kg x .47 Smallest batch size made in the same equipment of next product B is 40 Kg The largest normal daily dosage is 300 mg. 1996).2095mglkg x 70kg = 14.6 gm. It has been common practice. NOEL = LDso X . to group similar products (e.

There should also be some rationale for selecting the representative example. water solubility. Otherwise. . 1994). This grouping of product material residues can be based on dosage forms (tablets. the cleaning procedures. the matrix approach appears to be the only practical method of choice. A series of logical steps should be designed to generate a matrix from which worst case products can be extrapolated. the first step is to review the existing. if not. Before initiating a cleaning matrix. capsules. and not based on worst cases assuming an out-of-control process. The Matrix Approach In dealing with complex cleaning validation problems. which should typically be the most difficult to clean product. operating parameters. used These cleaning agents can vary from the typical cleaning products in the pharmaceutical industry to typical cleaning products used in our kitchens and bathrooms. liquids. it is feasible and realistic (pierre. pH or molecular weight. Grouping can also be based on a combination of used equipment and cleaning procedures employed. create. Worst-case examples should be selected within the normal cleaning. it would be costly to validate the cleaning for every product residue. Examples of within the operating parameter include the lowest cleaning temperature. as shown in Figure 4. It is a given requirement that the same cleaning process must be used for the products in the same group.41 group. One of the first elements to consider is the cleaning agent. The matrix approach is preferred when cleaning programs cover a wide variety of products manufactured with a broad variety of equipment. cream). There should be some scientific rationale for grouping these products together. the lowest cleaning agent concentration and the most difficult to clean areas (for residue sampling).

. In situations where a product or a piece of equipment is known to be difficult to clean. It is also beneficial to look at the possibility for the operator to decide which cleaning agents should be used depending on the nature of the product or its cleaning difficulty. This change in cleaning agent. after validation. which will require additional validation and revalidation. the dedication of the equipment or a specific validation program should be considered.49 It is preferable to use industrial cleaning products as their contents and technical information are obtainable. can also invalidate the previously established matrix. since any change in the cleaning agent yields a new cleaning procedure. The standardization of the cleaning agents is crucial for the establishment of a matrix approach.

. The location of the cleaning is also a consideration because most firms clean their equipment in different locations. Classification Rationale. • CLASS" •• [ No I~ CLASS III. F. CLASS V.. Note: From "Charting a course for cleaning validation" [on-line] by Bruce. CLASS IV. depending on the equipment and where it is cleaned. For example. Special - Figure 4.comlvalidtn. No or IImlt. the cleaning . depending on the size of the equipment and its usage. CLASS VI.html. This kind of situation often causes significant differences in the cleaning procedures to be used. Available ITP: Hostname: pharmaquality . 1999. A.d I CLASS .so CLASS I CLASS V.

if a cleaning procedure is satisfactory for the removal of traces of the worst case products to acceptable levels. The first worst-case product is based on the difficulty of cleaning and the solubility of ingredients. temperature. are consistently used for each piece of equipment. flow rate should be specified. Some rooms may have access to purified water outlets and others do not. The matrix approach is applicable only if the same cleaning procedures. then the same cleaning procedure will be more than adequate to remove traces of any other products to acceptable levels. pressurized water guns.51 room is often equipped with soaking tanks. Without complete and detailed cleaning procedures. the matrix approach becomes a useless exercise. detergent concentration. The matrix approach takes into consideration the nature of the products manufactured in a firm based on worst-case products for each piece of equipment. Each decision. regardless of the type of product manufactured previously. The procedure should also specify which pieces of equipment should be dismantled for cleaning. That approach is sufficient to cover the entire production. This is essential because the matrix approach is based on the principle that. These situations are compatible with the matrix approach to validation when they are properly addressed. The level of All major critical parameters such as duration. or automated detergent distnbutors that are not present in the manufacturing rooms. taking into account all the issues mentioned earlier. details specified in the cleaning procedures should be reviewed. A crucial aspect of the matrix approach is a clearly documented rationale for each step of the process. selection or consideration leading to the realization of the matrices must be documented in writing. The cleaning sequences should also be addressed. If the cleaning procedure is effective enough to remove traces .

it will be at least as effective for products easier to clean. indicate which equipment For example. In order to determine the two worst-case products for each major piece of equipment. same materials in product contact. The "most difficult to clean" product is established according to two criteria. The first criterion is the cleaning difficulty based on the operator's experience. it will be equally sufficient to remove traces to an acceptable level for products less toxic/potent. An example of a matrix is shown in Table 6. Mixer #1 and Filler #2. the two worst cases determined for each piece of equipment is based on the "most difficult to clean" product with the least soluble ingredient and the most "most toxic/potent" product. The shaded ceUs in Table 6 is used for each product. . Sometimes. two difficult. Operators are usually asked to rate the cleaning difficulty for each product listed in the matrix from one to four. Cream A is manufactured using Reservoir #1. a matrix of all products and equipment used for manufacturing those products needs to be established. ingredients and same functionality. In this case. if the cleaning procedure is efficient enough to remove traces of the most toxic/potent product to an acceptable level. The second worst-case is based on the toxicity or therapeutic potency of a product. after an initial matrix is issued. some equipment may be grouped together because the production personnel have considered certain equipment to be too similar and sharing similar characteristics like having the same shape. similar dimensions. In other words. one being very difficult to clean.52 of the "most difficult to clean" products. three fairly easy and four very easy. same utilization to mix.

53 Table 6. The second criterion is the ingredient solubility. . with one being Totally Water Insoluble. Equipment Utilization Matrix Reservoir #2 Mixer #1 Mixer #2 Filler #1 Filler #2 Cream B Tablet A Tablet B Capsule A Capsule B Note: From "How to solve complex cleaning validation problem. Validation Technology.." by Pierre. In cases where there are more than one ingredient. 1994. R. These two information criteria were added to the matrix now called the Cleaning Challenge Matrix as shown in Table 7. the less soluble is selected. three being as Partially Water Soluble and four being Totally Water Soluble. Journal of 4( 1) 22-28. The solubility criterion is rated from one to four. Products containing one active ingredient are selected as a solubility marker. two being Practically Water Insoluble.

54

The most toxic/potent product is established based on the toxicity or potency of its ingredients. For products containing one active ingredient, the minimum therapeutic dose (MTD) of this ingredient is selected. For products containing more than one active, the most potent ( the one with the lowest MID) is selected. But for products containing no actives, the most concentrated ones are considered based on the lowest LD so value. The MTD and LDso values are then converted to Maximum Allowable Carry-over

(MAC) values in mg. The MAC value corresponds to the maximum quantity of a product ingredient that can be safely transferred to another product. This value is based on the toxicity or minimum therapeutic dose of a chemical through a simple calculation, as shown in Table 7. After the two matrices are established, the "cleaning challenge" matrix (see Table. 7) and the "toxicity/potency" matrix (see Table 8) are both sorted. For the "cleaning

challenge" matrix, the sort is conducted with the primary key as the cleaning difficulty and the secondary key as the solubility index. Both are sorted ascendingly in order to obtain worst-case products, e.g. the most difficult to clean with the least soluble active at the top of the Sorted Cleaning Challenge Matrix (see Table 9). The cleaning difficulty is selected because experience shows it is a better indicator of actual worst-case product than the solubility of the ingredients. The "Toxicity/Potency' matrix (see Table 8) is sorted by ascending MAC in order to obtain the worst case products, e.g. the product with the smallest MAC at the top of the matrix. as shown in the Sorted ToxicitylPotency Matrix (see Table 10).

55 Table 7 Cleaning Challenge Matrix

Cream A Cream B Tablet A Tablet B Capsule A Capsule B Lotion A Lotion B

aaa 2 bbb ccc ddd tlf eee ggg 2

2

3
I

3
2 2

3
2

1

4 4 1

hhh

Note:

From "How to solve complex cleaning validation problem," by Pierre, R., 1994, Journal of
4(1)

Validation Technology,

22-28

Cleaning Challenge (Difficulty)

1. Very difficult to clean
2. Difficult to clean

3. Fairly easy to clean 4. Very easy to clean

Solubility l. Totally water insoluble 2. Practically water insoluble 3. Partially water soluble 4. Totally water soluble

56

Table 8 Toxicin:lPotency Matrix Ingredient Cream A Cream
B

aaa bbb ccc 0.1

Tablet A Tablet
B

7.7 17.5 5.25 2.0 2.0 5.0

ddd
fff eee ggg hhh

Capsule A Capsule
B

Lotion A Lotion
B
Note:
Validation

From "How to solve complex cleaning validation problem," by Pierre, R., 1994. Journal of
Technology.
4(1) 22-28

1994. R. Lotion A represents the worst-case products for equipment Reservoir #1 and Lotion B represents the worst case product for equipment Mixer #2. for the sorted ''Cleaning Challenge" matrix (see Table 9). Sorted "Cleaning Challenge" Matrix Cleaning Capsule B Lotion A Cream B Tablet B Capsule A Lotion B Tablet A Cream A 1 1 2 2 2 2 Ingred Solubility 4 4 Reservoir #1 eee ggg bbb ddd tlf hhh 3 3 2 1 1 2 3 4 ccc aaa Worst case products Note: From "How to solve complex cleaning validation problem." by Pierre.57 Table 9. .. each equipment. it is simple now to identify the worst-case products for cleaning difficulty and toxicity/potency. Journal of Validation Technology. 4(1) 22-28 Using this approach. The worst-case products are listed immediately below For example.

for the sorted "ToxicitylPotency" matrix (see Table 10). .." by Pierre. it is simple now to identifY the worst-case products for cleaning difficulty and toxicity/potency.7 17. 22-28 Using this approach. eachequipment. Cream A represents the worst case products for equipment Reservoir #1 and Capsule B represents the worst case product for equipment Mixer #2.58 Table 10.5 ccc ddd Worst Case Products Note: From "How to solve complex cleaning validation problem.25 7.0 5. The worst-case products are listed immediately below For example. Journal of 4( I) Validation Technology.1 0. Sorted "ToxicitylPotenc~' Matrix Actives Cream A Cream B Capsule B Lotion A Lotion B Capsule A Tablet A Tablet B aaa bbb eee ggg hhh flf MAC(mg) 0.0 2.0 5. 1994. R.1 2.

There must be a rationale for the development of that strategy. One approach is to determine which component of the cleaning agent (other . most cleaning agents do not have a true active component but a combination of components within the formulation. With this focus. For a cleaning agent. This determination is important because if a cleaning agent effectively removes the drug-product residue but leaves behind its own residue. A decision needs to be made regarding which component or components in the cleaning agent residue should be assayed. the first issue that must be addressed is whether to center the analysis on a specific assay for a single component of the cleaning agent or on a "whole-product" analysis (Anthony.59 Product Grouping and Worst Case Selection Cleaning Agent Residues An analytical strategy must be devised to determine the amount of cleaning agent residue left on the surface that has been cleaned. it is to develop an assay for the active ingredient. For a drug product. 1994). and not a drug product. then one type of contamination has been exchanged for another. a cleaning agent. The rationale is that a cleaning agent is just that. the component or components of interest must be identified. The product usually has no definable active component. and the equipment has not been cleaned effectively. When developing an analytical strategy for cleaning agent residue determination. The specific assay for a single component is the strategy that most analysis prefer when determining cleaning agent residues because it is similar to the strategy used for the analysis of drug-product residues. instead the combination of formulation components results in the product's cleaning ability.

Like in liquid chromatography. Another approach is to look for the components easiest to assay. specific method to quantify a particular component at low residue levels. The developmental reasoning behind the single component analysis is further complicated by the low residue levels needed for quantification components and the complex structural interactions of these cleaning If a single component strategy is followed. these in the formulation. It is often difficult to develop an accurate. then a single component analysis approach is not applicable. If a particular compound cannot be experimentally identified as a selective adsorber. Another approach is to look for the most toxic component based upon the LDso or other toxicity data for the components. approach is directed towards determining whether the cleaning agent contains a selective adsorber. None of these approaches really answer the question of "what from the cleaning agent is left on the surface of equipment after cleaning?" A single component analysis chosen To answer this question. the soluble analyte can adsorb onto column packing material due to the surface interactions resulting in adsorption of cleaning agent compounds to the surface being cleaned. interactions would have to be investigated. then it can be assumed that all other cleaning agent components have been removed as well. The rationale behind this approach is that if it can be demonstrated that the selective adsorber has been removed. On the other hand. a "whole-product" analysis approach involves the use of a single assay to determine the presence of cleaning agent components in the residue .60 than water) is present in the greatest amounts and develop an assay for it. It is important to note that selective adsorption is not a solubility issue. the without evaluating this latter question is not justifiable.

Documentation Documentation of the entire cleaning validation program must exist upon FDA inspection of the facility. scope. the document that describes how a particular company will conduct its cleaning validation. A cleaning Master Plan. cleaning validation approach. existing and future products. The FDA expects to see a system of documentation that outlines all aspects of the cleaning validation program. The development of a cleaning validation master plan comprises of a series of sections that include. The program is multiple tasked and requires a series of protocols which need to be organized based on their contingencies and priorities. then it should not only remove the target substance but should also rinse freely.61 without identifying which particular component or components make up the residue. cleaning validation . If the cleaning agent is effective. It is important to remember that these are cleaning agent residues. the objective. specific Protocols and Standard Operating Procedures must be in place for FDA to inspect during a facility audit. The master plan is essential for the implementation of a cleaning validation program. This would support the applicability of a non-specific analytical method to determine whether cleaning agent residue of any kind was left behind. cleaning process. not drug product residues and the whole-product analysis focus may provide the necessary information concerning cleaning agent residue levels without the need for investigation of the cleaning agent's complex formulation component interactions. Cleaning Validation Master Plan Any cleaning validation process must begin with a master plan. background.

The background section explains the reason for initiating a cleaning validation program along with a brief description of the facility and the equipment. Finally. 1999). The cleaning process section entails a brief description of how the cleaning process should be performed throughout the firm based on cleaning standard operating procedures. the individual cleaning standard operating procedures. Cleaning Validation Protocols The validation protocol is the official cleaning validation task for a specific drug product (Bruce. The cleaning validation schedule section is a timetable of the tentative starting and completion deadline per current and future products. cleaning acceptance criteria and recommendations for the handling of deviations that may occur. The existing and future products section lists all current and future potential product projects to be made at this particular facility. the analytical methods. 1999). The approach section discusses the organizational responsibilities. the cleaning agent section lists the cleaning agents of choice and its "how" usage. initiation and guidelines of writing specific protocols. The protocol formats vary among manufacturers. The objective of the validation plan is to provide a road map for the various tasks or protocols that will be needed to complete the program. cleaning sampling plans. The scope section discusses the cleaning policies and the risk assessment approach (grouping approach).62 schedule and the cleaning agents (Bruce. A well-written protocol should be easy to . The purpose of the cleaning validation protocol is to provide documented assurance that following all cleaning procedures consistently results in equipment that is at or below acceptable levels of cleanliness on all product surfaces.

The product information section discusses all relevant technical information about the drug product. lists all bibliographical references like specific regulations. acceptance criteria. The acceptance criteria section discusses the calculation of the acceptable level of cleanliness of both the active ingredient and the cleaning agent. The description of the manufacturing process section can include a simplified chart of the manufacturing process and a table listing the specific cleaning standard operating procedures and SOP numbers for each specific piece of equipment. product information. The deviation section discusses the procedure for handling any deviations from the established protocol procedures. The detergent information section discusses all relevant technical information about the cleaning agents to be used to clean the equipment. The execution section discusses the storage of cleaned equipment. . The scope section addresses the specific equipment used to manufacture the specific drug product and a brief discussion of the actual cleaning procedures to be used on these listed equipment. deviation and attachments.63 follow and must be specific. detergent infonnation and description of the manufacturing process. The objective section addresses the over-all purpose of this cleaning validation in regard to the specific drug product. The attachment section lists all relevant documents that were generated during the execution of the cleaning validation protocol. responsibilities. The validation protocol format should include the objective. scope. documentation during cleaning. references. The reference section The responsibility section to this validation discusses the specific responsibilities of the relevant departments protocol. execution. sampling plan and the analytical methods.

Though not yet backed by the force of regulation.64 CHAPTER V CONCLUSION Cleaning validation is a process to ensure that equipment cleaning procedures are removing residues to predetennined scientific demonstration of levels of acceptability. Incorporating operator the effectiveness variability and assessing possible contamination are important concepts in the cleaning validation program. toxicity and stability. Cleaning validation is a of cleaning. It has become a practical mandate for which plans should be in place for accomplishment in a reasonable period of time. performance. a tremendous challenge. increase in product yield and purity. Benefits of a well designed program can bring to an organization greater consistency and unifonnity between batches. There is no doubt that a pharmaceutical organization cannot avoid the issue of implementing a cleaning validation program. if done properly. although a cleaning validation program presents It is important to understand that. cleaning validation is expected by the FDA. The procedures presented in this thesis can help firms to get into the right direction on starting a cleaning validation program. the rewards will be truly significant. verification of optimum equipment and system performance and increase operator awareness of the impact that cleaning and monitoring have on the product purity. .

REFERENCES .

Cleaning Validation. C. 163-168. (1994).An Exclusive Publication. Manual cleaning procedure design and validation. 55-60. How clean is clean? Cleaning Validation. Anthony. (1994). s. 21-32. 74-89. Agalloco. W. 46 (5).H.66 REFERENCES William. Pharmaceutical Technology. Cleaning Validation. 90-95.An Exclusive Publication. 4-13. 96-100. (1994). Points to consider in the validation of equipment cleaning procedures. J. (1994). (1994). (1994). (1994). Robert. (1992). Harder. (1994). 14-20. C. E. 4.H. C. Cleaning Validation. 4. D. Douglas. D.An Exclusive Publication. R. G. Validation of chemical processes for pharmaceutical chemical processes. Cleaning Validation. Cindy. Cleaning validation programs: How to get started. Cleaning Validation.T. (1996). Robert. what.w. how much. The validation of cleaning procedures. 29-34. PDA Journal of Pharmaceutical Science & Technology. J.An Exclusive Publication. 4. Using swabs for cleaning validation: A review. Determining acceptance criteria for cleaning process validation.An Exclusive Publication. Gold. Validation: why. Joseph.An Exclusive Publication. . Cleaning Validation. Aspects to consider during cleaning process validation. 4. 4. 8 (5). Journal ofParenteraI Science & Technology. when.An Exclusive Publication. 4. 50 (1). 66-73. 4.

comlvalidtn. FDA Guide to Inspections of Validation of Cleaning Processes.. 136-144. K. How to solve complex cleaning validation problem. Title 21. J. A.html. July 1993. Lane. "Current good manufacturing practices for finished pharmaceuticals. Chesky.L. Washington DC. Pierre. 4453. Walter.O. 22-28. revised . R.S.R. M. 88-98. Available FTP: Hostname: pbarmaquality. acceptance limits G. Determining cleaning validation manufacturing operations. [on-line]. Division of Field Investigations. Code of Federal Regulations.~ & Mullen. (1995). 4 (1). F.. Cleaning and disinfection.V. Pharmaceutical Technology. Journal of Validation Technology. FDA Mid-Atlantic Region Inspection Guide on Cleaning Validation. 17 (6). Analytical strategies for cleaning agent residue determination. 1999)." U.67 Fourman. Government Printing Office. Journal of Validation Technology.K.1993. Smith.G. (Sept. 17 (4). Journal of Validation Technology.54-60. J. 4 (I). 17 (6). & Herbert. May 7. Journal of Validation Technology. (1994). for pharmaceutical (1993). Charting a course for cleaning validation. Bruce.M. (1996). Selecting analytical methods to detect residue from cleaning compounds in validated process system. (1993). S.Selection of biodecontamination parameters/materials and their applications. Part 211.

Cleaning Validation.A. Pharmaceutical process design criteria for validatable CIP cleaning.68 USP 231NF 18. (96)." Federal Register 62. Hyde. General Chapter <1225>. (United States Pharmacopeia! Convention. Seirberling. 27463-27467 (1997). 1. 1995). pp. (1994).M. 4.An Exclusive Publication. ""ICH guideline on the validation of analytical procedures: Methodology. D. MD. "Guideline on validation of analytical procedures: Methodology" (November 1996). 1982-1984. Food & Drug Administration. International Conference on Harmonization. Rockville.. . 38-58.

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