A review of current implementation strategies for validation of cleaning processes in the pharmaceutical industry.

ABSTRACT
 The current Good Manufacturing Practice (cGMP) regulations recognize that cleaning is a critical issue to ensure product quality. A wide range of factors influence the potential for cross contamination, and the achievement of robust and effective cleaning operations offers a significant challenge to all product manufacturers. Cleaning method validation is an important element for both qualification and process validation of drug substance and drug product manufacturing. It is the means of confirming the reproducibility and efficiency of a cleaning procedure. The monitoring of microbiological and endotoxin contamination, and steps for their elimination, form part of the cleaning validation. This article discusses the validation methodology, elements, components, cleaning mechanisms, and procedure. A stepwise procedure for the cleaning validation program includes the selection of cleaning method, selecting the scientific basis for the contamination limit, selec!
ting the worst-case related to the equipment, selecting the worst-case related to the product, establishing the storage period after cleaning, selecting the sampling method, selecting the analytical method, and documentation. Inclusion of regulatory reference is also done to emphasize the requirement of different regulatory bodies such as: U.S. Food and Drug Administration (FDA) Part 211 and Medicines Control Agency (MCA). Validation assumes a critical documented step in helping assess the cleaning operations being carried out in the pharmaceutical industry. Various parameters and steps usually adopted for validation of cleaning operations have been identified and are presented in the article.
INTRODUCTION 
 The cleaning of pharmaceutical equipment is an area of increasing regulatory importance within the industry. The cGMP regulations recognize that cleaning is a critical issue to ensure product quality. Virtually every aspect of manufacturing involves cleaning, from the initial stages of bulk production to the final dosage form. A wide range of factors influences the potential for cross contamination of materials, and the achievement of robust and effective cleaning operations offers a significant challenge to all product manufacturers. The validation of cleaning method is an important element for both qualification and process validation of drug substance and drug product manufacturing.
WHY CLEANING VALIDATION?
Effective cleaning is a key to product quality assurance. Cleaning is performed to remove product and non-product contaminating materials. Ineffective cleaning may lead to adulterated product, which may be caused by previous product batches, cleaning agents, or other extraneous materials introduced into, or generated by, the process. Cleaning validation is the means of confirming the reproducibility and efficiency of a cleaning procedure. The cleaning validation program is designed to demonstrate that the quality features built into facility, utilities, and processes ensure that they are fully functional, remain in place, and conform to the relevant regulatory requirements. The monitoring of microbiological and endotoxin contamination, and steps for their elimination, form a part of the cleaning validation.
Objective
The purpose for completing a cleaning validation is to attain documented evidence that provides a high degree of assurance that the cleaning procedure can effectively remove both residues of a product and a cleaning agent from the manufacturing equipment, to a level that does not raise patient safety concerns.
Advantages of Validation
* Reduction of quality costs
* Assurance of quality and safety
* Compliance with government regulations
* Making good business sense
* Less down time
* Fewer batch failures
* Possibly more efficient operation and cleaning
Disadvantages of Validation
* Cost incurred
* People
* Delays
* Inadequate equipment
CLEANING METHODOLOGY
The qualification or optimization of the cleaning process prior to the performance of validation will minimize patient risk and improve process robustness.
Elements or Components of Validation (1)
* Analytical Test Procedure
* Calibration of Instruments
* Operator Qualification
* Equipment Qualification
* Standard Operating Procedures (SOPs)
* Analytical Test Procedure
Any instrumental analytical procedures used to test samples taken during cleaning validation studies need to be specified and sufficiently sensitive to determine the low levels of residues.
* Calibration of Instruments
All the instruments to be used should be calibrated in prior procedures.
* Operator Qualification
Personnel should be fully trained concerning plant operations, process, and methods of cleaning.
* Equipment Qualification
Design qualification (DQ), Installation qualification (IQ), Operational qualification (OQ), should have been completed prior to commencement of Performance qualification (PQ).
* Standard Operating Procedures
SOPs should be written for the following:
** Plant operations
** Product process
** Method of cleaning
** Sampling and testing methods
Cleaning Procedure (3, 6)
The cleaning procedure should specify the following:
* Precautions and safety warnings.
* Cleaning tools and materials with their names, concentrations, their dilution instructions, volume requirements, and storage period requirements.
* Time limitations:
** Time between end of manufacturing and start of cleaning
** Time between final rinse and drying
** Frequency of major cleaning for manufacturing batches of the same product in a campaign
** Time until additional cleaning is performed for unused clean equipment
* Cleaning level:
** Type A: Minor -- Between two batches of the same product or between different strengths of the same product. For minor cleaning, cleaning validation is not required, since cross contamination is not an issue.
** Type B: Major -- Between two products. In this case, validation of the effectiveness of the cleaning procedure in removing residues to the required level is mandatory.
* Critical cleaning parameters such as time, temperature, volume, flow rate etc., should be mentioned. Operators should be trained.
* Drying is very important to prevent microbiological proliferation. Sometimes the final rinse is conducted with hot purified water to facilitate evaporation of the water. In some cases, non-aqueous solvents may be used as the final rinse to facilitate drying and act as a sanitizing agent. Drying time and temperature should be defined.
* Visual inspection:
No traces or particles visible to the naked eye should be observed after the cleaning.
* Cleaned status should be indicated by placing a label or a card on the cleaned equipment to prevent mix-ups with equipment not yet cleaned.
* Storage place of cleaned equipment and utensils with proper wrapping and instructions should be clearly mentioned.
* Cleaning log should be maintained. In some companies, cleaning entries are made in an equipment log book, which also contains preventive maintenance (PM), equipment modification, and calibration entries. It is also common practice to document cleaning by entries in the batch records.
VALIDATION TOOLS
The Cleaning Validation Programme
A stepwise procedure for the cleaning validation program would include the following:
*** Selecting a cleaning method
*** Selecting the scientific basis for the contamination limit
*** Selecting the worst-case related to the equipment
*** Selecting the worst-case related to the product
*** Establishing the storage period after cleaning
*** Selecting the sampling method
*** Selecting the analytical method
*** Documenting the program
Selecting a Cleaning Method (2, 3, 6, 7, 8)
* Clean-In-Place (CIP) Method
The term clean-in-place generally refers to an automated system that consists of a recirculation system that uses various tanks and a return system such as an eductor or return pumps. Cleaning of the equipment is performed in place without disassembly. A system of piping delivers the cleaning solution to the equipment and returns it to a motive or recirculation tank. Cleaning process may be controlled manually or by an automated program. The equipment utilizes spraying devices to provide coverage and physical impingement of the cleaning solution on equipment surfaces. These systems are commonly used to clean large pieces of equipment such as manufacturing tanks, fluid bed dryers, reactors, and fermentation tanks. The CIP system need not have a recirculation system, i.e., it may be a single-pass system, where appropriate.
Bulk pharmaceuticals are typically manufactured within closed systems increasingly equipped with automated or semi-automated CIP equipment. The mechanical qualification of flow rates, pressures, and spray ball patterns must be established. This provides a very consistent and reproducible cleaning method and can be validated readily. Being a closed system, visual inspection of all components is difficult.
* Clean-Out-of-Place (COP) Method
Clean-out-of-place equipment includes such items as wash tanks used to clean small parts or parts removed from large equipment. These systems usually have some sort of automated or programmed control system. One example is a recirculating bath used for cleaning small parts, pump components, gaskets, and other parts removed from larger equipment. Cleaning of disassembled equipment may also be performed in a central washing machine or a dishwasher type cabinet. This type of cleaning is also known as closed system cleaning. The washing machine also requires validation including the temperature, ultrasonic activity, cycle time, cleaning operating sequence, detergent quantity dispensed, etc.
* Manual Cleaning Method
The manual cleaning method is accomplished by scrubbing and/or wiping by the operator. This method is difficult to validate. Most extensive and elaborate cleaning procedures are required. A high quality and extensive training program is required. Some considerations of manual cleaning include:
** "Seeing is Believing"
** Product diversity
** Risk of failure of cleaning equipment
** Validation of automated cleaning equipment
** Trained and experienced working staff
The equipment design and manual cleaning method are taken into consideration for selection of equipment. All equipment is selected while keeping the following cleaning considerations in mind:
** Ease of disassembling contact parts
** Non-reactivity of all contact surfaces to cleaning method
** Dedicated disposable materials where difficult to clean e.g.: Fluid Bed Drier (FBD) bags, filters, disposable bags in transit containers, etc.
It is well known that there is least chance of contamination from equipment non-contact parts e.g.: lubricants, gaskets, drive system, mechanical seals, etc.
The risk involved in manual cleaning processes can be mitigated by the following:
** Proper washroom design with drying, protection, and storage requirements
** Detailed cleaning SOPs
** Training and qualification of cleaning operators
Selecting the Scientific Basis for the Contamination Limit (3, 6, 10)
Different manufacturing and cleaning situations may require different approaches. It is important to factor into the limit calculation the following product to be manufactured in the same equipment. Factors, such as the batch size of the following product, the route of administration, and the largest daily dose of subsequent product that might be administered, are important in the calculation. Residue limits should be practical, achievable, and verifiable, and based on the most deleterious residue. Limits can be established based on the minimum known pharmacological, toxicological, or physiological activity of the active pharmaceutical ingredient (API) or its most deleterious component.
* Limit calculation on the basis of smallest therapeutic dose
The limit is often based on allowing not more than a fraction of a therapeutic dose to be present in a subsequent product. The fraction in this case is called a "Safety Factor." The degree of risk may be different for different dosage forms. Normally accepted safety factors for different dosage forms are given in Figure 2.
Factors such as the batch size of the following product, the route of administration, and the largest daily dose of subsequent product which might be administered, are important in the calculation.
All of the factors mentioned previously are usually summarized in an equation, which may take the following general form:
MAR = [TD x BS x SF]/[LDD]
Where:
MAR = The Maximum Allowable Residue
TD = Smallest Therapeutic Dose amongst all products
BS = Smallest Batch Size amongst the next product to be manufactured in the same equipment
SF = The Safety Factor
LDD = The Largest Daily Dose amongst the next product to be manufactured in the same equipment
Some limits that have been mentioned by industry representatives in the literature or in presentations include: analytical detection levels, such as 10 ppm; biological activity levels, such as 1/1,000 of the normal therapeutic dose; and organoleptic levels, such as no visible residue. (9, 12, 13, 14)
If the calculated value based on the 0.001 daily dose is more than 10 ppm, then a value of less than 10 ppm residue in the subsequent product is the acceptance criteria.
To determine this, the MAR limit in ppm would be = [MAR limit in milligrams]/[Total batch size of subsequent product in kilograms]
If this calculation gives a value more than 10 ppm, equivalent value of 10 ppm in milligram must be calculated. This would be as follows:
[10/[MAR limit in subsequent batch in units of ppm]] X [MAR limit in subsequent batch in units of milligrams]
The value obtained in units of milligrams would be the MAR limit for all shared equipment.
* An example on MAR limit calculation
Following is the relevant data for calculation:

Previous Product : A
Strength of tablet : 100 mg.
Minimum dose per day : 1 tablet

Following or next product : B
Largest daily dose : 800 mg.
Batch size : 10 kg.
SF = Safety factor for solid dosage form = 1/1000
MAR = TD x BS x SF/LDD
MAR = 100 x 10 x 1000 x 1000/ 800 x 1000 = 1250 mg.
(Where: 1000 x 1000 accounts for conversion of unit of weight for batch size of next product (B) from kg into mg)
This is the total limit for all residues on all equipment used to manufacture the product.
* Limit calculation on the basis of equipment surface area
The previous sections calculate the limit for maximum allowable residue on possible manufacturing and packing equipment utilized in the manufacturing process. Once the maximum allowable residue limit is calculated, it is practical and logical to break up the limit for individual equipment train proportionately with reference to the respective equipment surface area.
MAR limit for the total swab area sampled collectively can be calculated as follows:
MAR limit for the sampled surface = [No. of swab samples x swab area]/[Equipment Surface Area] X [Total MAR Limit]
Either the limit can be calculated in terms of the total swabbed area or per swab.
* Limits based on the toxicity of the residue
Using the therapeutic dose as the basis of limits calculations is appropriate for situations where the material is an active ingredient and therapeutic dosage levels are known. There are other situations where the material is not medically used and there are no known therapeutic dose data available. Examples are precursors and intermediates used in chemical synthesis (i.e.: manufacture of APIs, and cleaning agents). These materials have no quantitative therapeutic dosage levels. Yet, they may have a medical or toxic effect in the body. In these cases, it is necessary to base the limits calculation on the toxicity of the material.
The following methodology can be used:
NOEL = L[D.sub.50] x empirical factor
ADI = NOEL x AAW x SF
Where:
NOEL = No Observed Effect Level
L[D.sub.50] = Lethal Dose for 50% of animal population in study
Empirical factor = derived from animal; model developed by Layton, et al. (15)
ADI = Acceptable Daily Intake
AAW = Average Adult Weight
SF = Safety Factor
This equation can be applied to a pharmaceutical cleaning validation study for the purpose of calculating a limit. The result would be as follows:
MAR = [ADI x B]/R
Where:
MAR = the Maximum Allowable Residue
B = Smallest Batch Size of any subsequent product
R = Largest Daily Dose of any product to be manufactured in the same equipment
It is important that the L[D.sub.50] be from the same route of administration as the product for which the limit is calculated. For example, if the product is an oral product, then L[D.sub.50] should be from the oral route of administration.
* Acceptance criterion based on visual inspection
The visual detection limits of most active ingredients are approximately 4[micro]g/cm. (2, 9, 10)
Selecting the Worst-case Related to the Equipment (8)
One may choose to selectively perform cleaning validation studies on representative groups of equipment. Identical, interchangeable pieces of equipment with the same cleaning procedure can be grouped together. Equipment with the same operating principle and the same cleaning procedure, but with different product contact surface areas, can be grouped, if they can be interchanged. The worst-case for a group of equipment is represented by the equipment with the larger product contact surface and the hardest-to clean locations.
* Equipment Database
A tabulation or matrix is prepared for the entire number of equipment in the manufacturing unit used for the production, against the list of products for which they are used. This forms the equipment database.
Selecting the Worst-case Related to the Product (8)
Only one product out of a group of products processed in a piece of equipment is selected for the cleaning validation study, based on the lowest solubility of the active ingredient, potency, toxicity, difficulty to clean, and its therapeutic dose.
* Product Database
A tabulation or matrix is prepared for the entire number of products produced in the manufacturing unit against the potency, daily dosage, batch size, route of administration, solubility in various solvents (especially water), difficulty of cleaning, toxicity, stability, therapeutic use, etc. This forms the product database.
** To arrive at the worst-case equipment and worst-case product we need Equipment Database and Product Database as mentioned above.
Establishing the Storage Period after Cleaning
The objective for establishing a time limit between equipment cleaning and reuse is to ensure that the equipment remains clean until the next use. This requires demonstration that there is no microbial proliferation in cleaned equipment during storage.
This time limit depends upon the:
* Level of protection provided to the equipment after cleaning.
* Environmental control and work practices.
* Nature of the product to be manufactured using the subject equipment.
For establishing the time limit, the equipment should be dried. Initial swab samples of the surface should be taken. Thereafter, the equipment should be protected as prescribed in the SOP and stored in its designated area. Periodic samples of product contact surface for microbiological contamination should be taken. (1st day, 2nd day, 3rd day, etc.) Based on the data generated from the study of these samples, establish the acceptable time limit. (The approach taken by many companies for the acceptance level for surface sampling is 10 cfu / 25 sq [cm.sup.10])
The very first criterion is absence of pathogenic organisms such as E. coli, and Salmonella. Representative colonies of the micro organisms isolated during cleaning validation should be identified in order to build a plant microbial flora baseline with the aim of locating and eliminating potential contamination resources. (10)
Selecting the Sampling Method (2, 3, 4, 5, 8, 12)
The main sampling methods are as follows:
* Swab sampling
* Rinse sampling
* Coupon sampling
* Solvent sampling
* Product sampling
* Placebo sampling
* Direct surface monitoring
* Swab sampling method
This method is based on the physical removal of residue left on a piece of equipment after it has been cleaned and dried. A swab wetted with a solvent is rubbed over a previously determined sample surface area to remove any potential residue, and thereafter extracted into a known volume of solvent in which the contaminant active ingredient residue is soluble. The amount of contaminant per swab is then determined by an analytical method of adequate sensitivity.
* Rinse sampling method
This method is based on the analytical determination of a sample of the last rinsing solvent (generally water) used in the cleaning procedure. The volume of solvent used for the last rinse must be known to allow for the quantitative determination of the contamination. Thus, collection of rinse samples should consider location, timing, and volume.
* Coupon sampling method
In this method, coupons of the same materials of construction as the item to be cleaned can be affixed to the equipment, spiked with the product, subjected to the cleaning procedures, and then submitted to the laboratory for direct analysis and recovery studies.
* Solvent sampling method
This technique uses a solvent not normally employed in the cleaning process to maximize recovery of expected residues. Known volume of solvent is applied to the surface in question. The method can be used in combination with swabbing.
* Product sampling method
This method is similar to placebo sampling except that it uses actual product. It requires examination of the next production batch for trace residuals of the previous batch.
* Placebo sampling method
It can be used to detect residues on equipment through the processing of a placebo batch subsequent to the cleaning process. Placebos are used primarily to demonstrate the lack of carryover to the next product. The placebo should mimic product attributes. The equipment characteristics also impact the choice of the placebo batch size.
* Direct sampling monitoring
This method is used to evaluate surface cleanliness without surface contact, for example: measurement using spectrophotometric probes.
Sampling Locations and Number of Samples
The sample locations are dictated by worst-case conditions. The hard to clean equipment locations are identified based on cleaning experience and the design of equipment. The number of samples should take into consideration the equipment surface area, design, shape, operating principle, and construction material. Since the homogeneity of the contaminant on the equipment product contact surface area can only be assumed, several samples, but not less than three samples per piece of equipment, must be taken including the hardest to clean locations. (10)
Sample Surface Area
Sample surface areas usually vary from 25 sq cm to 100 sq cm and should be large enough to allow the recovery of contamination quantity sufficient to be detected by the analytical method. This small sample surface area is assumed by extrapolation to represent the amount of residual contaminant in the whole equipment surface area. (7, 10)
Swab Recovery Study
A swab recovery study is performed to determine the ability of the swab to quantitatively remove the contaminant from the surface sampled. Generally, companies use special swabs available from suppliers such as: Whatman[R], Texwipe[R], or Coventry[R].
Selecting the Analytical Method (3, 5)
* The Basic Requirements for the Analytical Method
** The sensitivity of the method shall be appropriate to the calculated contamination limit.
** The method shall be practical and rapid, and as much as possible, use instrumentation existing in the company.
** The method shall be validated in accordance with the International Conference on Harmonization (ICH), the United States Pharmacopoeia (USP), and the European Pharmacopoeia (EP) requirements.
** The analytical development shall include a recovery study to challenge the sampling and testing methods.
The method may be specific or non-specific, which includes the analytical methods for cleaning sample analysis shown in Figure 5.
Of the specific methods noted in Figure 5, chromatography methods are the methods of choice, because they separate analytes, are highly specific, highly sensitive, and quantitative; however, the methods are costly and time consuming. For monitoring cleaning procedure, TOC method is used. It offers a moderate cost, and in addition to its rapidity, a detection capability down to the ppb range.
Documenting the Program
Records and reports are maintained for all cleaning operations and shall be readily available for authorized inspection during the retention period at the establishment. Given below is a list of various records that are maintained for cleaning validation: (1, 2, 4)
* Validation Master Plan (VMP).
* Equipment Qualification Reports (DQ/IQ/OQ/PQ).
* Technical Transfer Information (such as solubility of product ingredients, recommended cleaning agent and conc., medical or toxicity data) along with data of contact surface area, batch size, etc., for the preparation of product matrix.
* Equipment Logs.
* Training Records.
* Method Validation of analytical test method.
* Cleaning Validation Protocol.
* Cleaning Validation Reports.
* Validation Master Plan
A VMP is a key document and should consider the following elements:
** Introduction (philosophy, purpose, and objective)
** Scope
** Organization committee (responsibilities of validation organization committee and validation task force)
** Pre-requirement
** Reference to relevant standard operating procedure
** Product and equipment grouping
** Selection of analytical method (specific analytical test method and non-specific analytical test method)
** Selection of cleaning method (clean-in-place method, clean-out-of-place method, and manual cleaning)
** Selection of sampling method (direct surface (swab) sampling and rinse sampling method)
** Establishment of limit and acceptance criteria (limit calculation on the basis of smallest and limit calculation based on toxicity)
** Establishing maximum allowable time limit for the storage of cleaned equipment before use
** Cleaning validation protocol
** Revalidation and verification criteria
** Definitions and abbreviations
** Signed authorization by quality departments, technical expert, and the owner or senior management designee.
* Cleaning Validation Protocol contains:
** Objective of the validation process
** Responsibility for performing and approving validation study
** Description of the equipment to be used
** The interval between the end of the process and the beginning of the cleaning process
** The number of cleaning cycles to be performed consecutively
** Cleaning procedures to be used for each product, each manufacturing system or each piece of equipment
** Sampling procedures
** Sampling location
** Data on recovery studies, where appropriate
** Analytical methods including the limit of detection and limit of quantitation of those methods
** Acceptance criteria
** Revalidation criteria
* Summary Report
** Study performed
** Acceptance criteria
** Results
** Evaluation
** Discussion of any deviations or failures that occurred during the study
** Conclusion and recommendation
** Summary Report approval
REGULATORY REFERENCE (12, 16, 17)
FDA Part 211--Current Good Manufacturing Practice for Finished Pharmaceuticals
Subpart D -- Equipment
Section 211.63 Equipment design, size, and location
Equipment used in the manufacture, processing, packing, or holding of a drug product shall be of appropriate design, adequate size, and suitably located to facilitate operations for its intended use and for its cleaning and maintenance.
Section 211.67 Equipment cleaning and maintenance.
Equipment and utensils shall be cleaned, maintained, and sanitized at appropriate intervals to prevent malfunctions or contamination that would alter the safety, identity, strength, quality, or purity of the drug product beyond the official or other established requirements.
Written procedures shall be established and followed for cleaning and maintenance of equipment, including utensils used in the manufacture, processing, packing, or holding of a drug product.
Subpart J -- Records and Reports
Sec. 211.182 Equipment cleaning and use log.
A written record of major equipment cleaning, maintenance (except routine maintenance such as lubrication and adjustments), and use shall be included in individual equipment logs that show the date, time, product, and lot number of each batch processed. If equipment is dedicated to manufacture of one product, then individual equipment logs are not required, provided that lots or batches of such product follow in numerical order and are manufactured in numerical sequence. In cases where dedicated equipment is employed, the records of cleaning, maintenance, and use shall be part of the batch record. The persons performing and double-checking the cleaning and maintenance shall date and sign or initial the log indicating that the work was performed. Entries in the log shall be in chronological order.
FDA Guide to Inspections of Validation of Cleaning Processes
* FDA expects firms to prepare specific written validation protocols in advance for the studies to be performed on each manufacturing system or piece of equipment which should address such issues as sampling procedures, and analytical methods to be used including the sensitivity of those methods.
* FDA expects firms to conduct the validation studies in accordance with the protocols and to document the results of studies.
* FDA expects a final validation report which is approved by management and which states whether or not the cleaning process is valid. The data should support a conclusion that residues have been reduced to an "acceptable level."
* Examine the design of equipment, particularly in those large systems that may employ semi-automatic or fully automatic clean-in-place (CIP) systems since they represent significant concern. For example, sanitary type piping without ball valves should be used. When such non-sanitary ball valves are used, as is common in the bulk drug industry, the cleaning process is more difficult.
* Examine the detail and specificity of the procedure for the (cleaning) process being validated, and the amount of documentation required.
* When more complex cleaning procedures are required, it is important to document the critical cleaning steps (for example certain bulk drug synthesis processes).
* Determine the specificity and sensitivity of the analytical method used to detect residuals or contaminants.
* Check the manner in which the limits are established.
* When a detergent or soap is used for cleaning, determine and consider the difficulty that may arise when attempting to test for residues.
MCA, Rules and Guidance for Pharmaceutical Manufacturers and Distributors 1997
Part four, "Guide to Good Manufacturing Practice for Medicinal Products," Section 3.36. Manufacturing equipment should be designed so that it can be easily and thoroughly cleaned. It should be cleaned according to detailed and written procedure and stored only under clean and dry conditions.
Annex 2, "Manufacture of Biological Medicinal Products for Human Use," Section 15. The layout and design of production areas and equipment should permit effective cleaning, and decontamination procedures should be validated.
CONCLUSION
Cleaning processes have become regulated and specific with more emphasis on quality and repeatability. Such situations demand a well-documented and systematic approach toward cleaning. Validation assumes a critical step in helping assess the cleaning operations being carried out in the pharmaceutical industry. Various parameters and steps usually adopted for validation of cleaning operations have been identified and presented in this article.
REFERENCES
1. "Cleaning Validation," 1999 Institute of Quality Assurance, Pharmaceutical Group No. 10.
2. Paul Y. McCormick, Leo F. Cullen, "Cleaning Validation," in Pharmaceutical Process Validation, edited by Ira R. Berry, Robert A. Nash, second edition, Marcel Dekker, Inc., New York, pp. 319, 321-326, 335-341.
3. PDA Journal of Pharmaceutical Science and Technology, "Points to Consider for Cleaning Validation," Technical report No. 29, volume 52 no. 6 Nov.-Dec. 1998 supplement.
4. P. P. Sharma, in Practice of Good Manufacturing Practices, third edition, Vandana publications, pp. 99-105, 108-109.
5. ICH, "Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients."
6. Sidney H. Willig, James R. Stoker, in "Equipment (subpart D"), Good Manufacturing Practice for Pharmaceuticals: A Plan for Total Quality Control, Fourth Edition, revised and expanded, Marcel Dekker, Inc., New York, pp. 55-59.
7. David Sherwood, in "Cleaning: Multiuse Facility Issues," Biopharmaceutical Process Validation, edited by Gail Sofer, Dane W. Zabriskie, Marcel Dekker, Inc., New York, pp. 238-241,246.
8. Peter D. Smith, "Domestic and Foreign API Manufacturing Facility Audits and Findings," pp. 148 and William E. Hall, "Cleaning for Active Pharmaceutical Ingredients Manufacturing Facilities," pp. 405-408, in Validation of Active Pharmaceutical Ingredients, edited by Ira R. Berry, Daniel Harpaz, second edition, CRC Press.
9. Destin A. LeBlanc, "Establishing Scientifically Justified Acceptance Criteria for Cleaning Validation of Finished Drug Products", Pharm. Technology, Oct 1998.
10. "Cleaning Validation Policy," pp. 47, 51 and "Special Cleaning Validation Issues," pp. 89-90, in Cleaning Validation: A Practical Approach, edited by Gill Bismuth and Shosh Neumann, Interform Press, Benver Colorado, 2000.
11. Revised Schedule M, "Good Manufacturing Practice and Requirements of Premises, Plant and Equipment for Pharmaceutical Products Part 1A: Environmental Monitoring."
12. FDA, "Guide to Inspections of Validation of Cleaning Processes," Office of Regulatory Affairs, July 1993.
13. Health Products and Food Brach Inspectorate, "Guidance Document: Cleaning Validation Guidelines." 2000-08-01, Canada.
14. Robert A. Nash, "Validation of Pharmaceutical Processes," in Encyclopedia of Pharmaceutical Technology edited by James Swarbrick, James C. Boylan, Volume 16, "Unit Processes in Pharmacy: The Operations to Zeta Potential," Marcel Dekker, Inc., New York, pp.203.
15. D. W. Layton, et al., "Deriving Allowable Daily Intakes for Systemic Toxicants Lacking Chronic Toxicity Data," Regulatory Toxicology and Pharmacology 7, 96-112, 1987.
16. www.fda.gov
17. www.mca.gov
ABOUT THE AUTHORS
Dr. Praful D. Bharadia is a Professor in the Department of Pharmaceutical Technology, S. K. Patel College of Pharmaceutical Education and Research. Dr. Bharadia has many national and international publications to his credit. He has rich experience in parenteral manufacturing and clean room design at Cadila Laboratories, Gujarat, India. Dr. Bharadia may be contacted via email at: pdbharadia@yahoo.com
Ms. Jignyasha A. Bhatt is a research scholar with the Department of Pharmaceutical Technology, S. K. Patel College of Pharmaceutical Education and Research. She has five years experience in Quality Assurance and documentation at Torrent Pharmaceuticals Ltd., Gujarat, India. Ms. Bhatt may be contacted via email at: jignyasha26@rediffmail.com
BY PRAFUL D. BHARADIA, PH.D. AND JIGNYASHA A. BHATT
Article Acronym Listing
<pre>
AAW Average Adult Weight
ADI Acceptable Daily Intake
API Active Pharmaceutical Ingredient
BS Batch Size
CFU Colony Forming Units
cGMP Current Good Manufacturing Practice
CIP Clean-In-Place
COP Clean-Out-of-Place
DQ Design Qualification
EP European Pharmacopoeia
FBD Fluid Bed Drier
FDA Food and Drug Administration
ICH International Conference on Harmonization
IQ Installation Qualification
LD Lethal Dose
LDD Largest Daily Dose
MAR Maximum Allowable Residue
MCA Medicines Control Agency
NOEL No Observed Effect Level
OQ Operational Qualification
PM Preventive Maintenance
PQ Performance Qualification
SF Safety Factor
TD Therapeutic Dose
TOC Total Organic Carbon
USP United States Pharmacopoeia

Figure 1 Cleaning Mechanisms

CLEANING MECHANISMS

Mechanical refers to physical actions such as brushing, scrubbing, and
Action the use of pressurized water to remove particulates
Dissolution involves dissolving residues with a suitable solvent. The
most common and practical solvent is water because of its
advantages: non-toxic, low cost, does not leave residues,
and is environmentally friendly. However, in some cases it
may be preferable to use a non-aqueous solvent or a
combination of both aqueous and non-aqueous solvents due to
the solubility characteristics of the materials and/or the
incompatibility of equipment or process to water.
Alkaline or acidic solvents, for example, can enhance
dissolution of the materials and could be advantageous.
Detergency requires the use of surfactant, usually in an aqueous
system. Detergents act in four different ways: wetting
agents, solubilizers, emulsifiers, and dispersants.
Usually, detergents possess all these properties, which
broaden their action.
Chemical such as oxidation and hydrolysis in which the residues are
reaction chemically changed, e.g.: Sodium Hypochloride.

During cleaning validation, the effectiveness of these mechanisms ought
be challenged and checked as a whole in the cleaning procedure.

Figure 2 Safety Factors for Common Dosage Forms

Dosage Form Safety Factor

Research compound 1/100,000-1/10,000
Parenteral products 1/10,000-1/5,000
Ophthalmic products 1/5,000
Oral dosage forms 1/1,000
(tablets, capsules)
Topical products 1/100-1/10

Figure 3 Surface Limits for Microbial Contamination

Recommended Limits for Microbial Contamination of Surface (Average
Values) (11)

Contact Plates (diameter
Grade 55 mm), cfu / plate

A (Class 100) &lt;1
B (Class 1000) 5
C (Class 10,000) 25
D (Class 100,000) 50

Figure 4 Sampling Methods

Characteristics of Sampling Methods
Method Advantages Disadvantages

Swab ** Direct evaluation of ** An invasive technique that
sampling surface contamination. may introduce fibres.
method ** Insoluble or poorly ** Difficult to implement in
soluble substances may be large-scale manufacturing
physically removed from equipment.
the equipment surfaces. ** Extrapolation of results
** Hard-to-clean but obtained for a small sample
accessible areas are surface area to the whole
easily incorporated into product contact surface
the final evaluation. area.
** Applicable to active, ** Subject to the vagaries of
microbial, and cleaning site selection.
agent residues.
Rinse ** Ease of sampling. ** No physical removal of the
sampling ** Evaluation of entire contaminant.
method product contact surface. ** The rinsing solvent may not
** Accessibility of all reach inaccessible or
equipment parts to the occluded parts of
rinsing solvent. equipment.
** Best fitted to sealed or ** Use of organic solvents for
large scale equipment and water insoluble materials.
equipment that is not ** May be difficult to
easily or routinely accurately define and
disassembled. control the areas sampled;
therefore, usually used for
rinsing an entire piece of
equipment, such as a
vessel.
** Rinse volume is critical to
ensure accurate
interpretation of results.
Coupon ** Allows for direct surface ** Might interfere with the
sampling sampling with an cleaning process.
method analytical method. ** Subject to the vagaries of
** Useful in cleaning site selection.
development. ** Invasive.
** Useful in evaluation of
equipment materials of
construction.
Solvent ** Commonly used in bulk ** May require operator
sampling chemicals facilities protection and other safety
method ** Applicable to active, and environmental
cleaning agents, protection measures.
excipients. ** Reduced physical sampling
** Allows sampling of a of the surface.
large surface area. ** May require removal of
** Maximizes recovery solvent prior to use.
relative to rinse
sampling.
Product ** The next product contacts ** Difficult to determine
sampling the same surfaces as the recovery.
method previous product. ** Lowers analytical
** Applicable for specificity and inhibits
hard-to-clean surfaces. detectability.
** Requires no additional ** Residues may not be
sampling steps. homogeneously distributed.
** No direct measurement of
residues on product contact
surfaces.
Placebo ** Placebo contacts the same ** Difficult to determine
sampling surfaces as the product. recovery.
method ** Applicable to ** Lowers analytical
hard-to-clean surfaces. specificity and inhibits
** Requires no additional ** Takes longer and adds
sampling steps. expense.
** Residues may not be
homogeneously distributed.
** No direct measurement of
residues on product contact
surfaces.
Direct ** Rapid. ** Subjective.
sampling ** Non--invasive. ** Some techniques not widely
monitoring ** Economical. developed or available.

Figure 5 Safety Factors for Common Dosage Forms

Analytical Methods for Cleaning Sample Analysis
Specific Methods Non-Specific Methods