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) <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
Sunday, August 26, 2007
A risk management solution designed to facilitate risk-based qualification, validation
InfoTrac OneFile (R)
Journal of GXP Compliance
, 07/01/2006 10 4
A risk management solution designed to facilitate risk-based qualification, validation, and change control activities within GMP and Pharmaceutical regulatory compliance environments in the EU, Part I: fundamental principles, design criteria, outline of process. O'Donnell, Kevin *~|~*Greene, Anne *~|~*
COPYRIGHT 2006 Advanstar Communications, Inc.
Risk-based Qualification, Validation, and Change Control--Opportunities for Improvement In the European Union (EU), the Good Manufacturing Practice (GMP) requirements place specific obligations on manufacturers of medicinal products to implement risk-based qualification, validation, and change control programmes. (1,2,3)
Annex 15 to the EU Guide to GMP titled, "Qualification and Validation," requires:
a) That a risk assessment approach be used to determine the scope and extent of validation. (Note: Within the EU GMP and others, the term, 'validation,' is generally understood to encompass qualification as well as validation activities.)
b) That risk analysis be employed when assessing the likely impact of changes.
How these GMP requirements are met has been the subject of much discussion between Regulators and Industry in recent years, and as a Regulatory Agency, the Irish Medicines Board has received numerous requests from Industry for guidance in this area.
From the authors' experience as a GMP Inspector, it is evident that risk factors are often taken into account when designing qualification and validation programmes, and when processing change control proposals. However, as mentioned in the International Conference on Harmonization (ICH) Guideline on Quality Risk Management, ICH Q9, (4) the use of risk management in the Pharmaceutical Industry has, to date, been limited, and the full benefits of risk management, as a valuable component within a quality system, have yet to be realised.
Despite ever-increasing qualification and validation costs, as described in publications of the International Society of Pharmaceutical Engineering (ISPE) and others, (5-7) there is evidence that defective and non-compliant medicinal products continue to be manufactured and released. These often result in product recalls being required to protect patients and users of medicinal products. (8,9) As discussed in ISPE's White Paper on Risk-Based Qualification for the 21st Century, (5) current qualification practices, for example, are often document-intensive, expensive, and time-consuming, but do not necessarily add value, or lead to clear patient risk-mitigation strategies or process understanding. Likewise, validation activities sometimes do not adequately address the critical aspects of processes. (10) In the area of change control, proposed changes often involve substantial capital expenditure and large project teams, but sometimes important risks introduced by the change !
are not identified. Therefore, it is likely that the use of more formalised and scientific approaches to risk management may prove beneficial within GMP environments.
A Risk Management Solution for GMP and Regulatory Compliance Environments
There are many formal risk management tools available, such as Fault Tree Analysis, (11) Failure Modes and Effects Analysis (FMEA), (12) and Hazard Analysis and Critical Control Points (HACCP). (13) However, most were not specifically designed for GMP applications, much less as solutions for facilitating risk-based qualification, validation, and change control activities within GMP environments. As a result, a degree of design modification is often required before an existing tool may be used for these activities. Of the tools which are GMP-specific, such as the approaches developed by ISPE (14) and GAMP, (15) their focus tends to be somewhat narrow, being tailored for equipment and systems qualification and computerised systems validation, respectively. As a result, the day-to-day practicalities of how to apply GMP risk management more broadly remain somewhat under-developed.
In addition, few if any, of the available tools were designed as complete, documented, and ready-to-use risk management methodologies that address all of the components of risk management and have been accepted via ICH Q9 as important. These are as follows: risk assessment, risk control, risk communication and risk review. As a result, a further degree of modification is often required before any of the existing risk management tools may be used as a complete risk management solution.
In response to the requests received by the Irish Medicines Board from Industry for guidance in the interpretation of the risk-related requirements of Annex 15 to the EU GMP Guide, and as part of our efforts to better understand how risk management may be used in practice, the Irish Medicines Board has developed a practical risk management methodology, or tool, designed specifically as a means of addressing those Annex 15 requirements. As part of this work, a series of practical case studies have been developed on the use of this tool, in order to show how the tool works in practice. This risk management solution is designed so that it provides a complete and documented means of addressing all of the aforementioned components of risk management.
In this series of papers, in two parts, this risk management methodology is described. In Part I, the principles underlying this approach are given, and the design criteria used for development of the risk management tool are outlined. The tool uses a documented ten-step process, also described in Part I. In Part II, the scope and structure of the risk management tool are described, and some of the limitations of this tool are given. An outline of some of the principle findings made to date with this tool is also given in Part II. (It is emphasised that this work is not intended to place any specific regulatory obligations on manufacturers, nor is the risk management solution presented here being promoted in any way as a tool that should be used by Industry. This work simply demonstrates how GMP risk management may be applied in practice.)
Is this Risk Management Solution Intended to Replace other Available Tools?
It is not the intent of this work to replace other available tools; existing tools are valuable in their own right. The risk management methodology described here was designed for a specific purpose--to facilitate risk-based and patient-focused qualification, validation, and change control activities. This tool focuses on evaluating how GMP controls, both current and proposed, lead to mitigation and control of the risks identified, and on the qualification and validation status of such controls.
Importantly, this work does not seek to "reinvent the wheel," and during the technical development of this risk management solution, some of the useful features and concepts behind other risk management tools and approaches were adopted or taken into account. For example:
* FMEA and FMECA
This risk management solution draws upon some features of FMEA and FMECA, (16) in that it recognises the value in assigning Probability, Severity, and Detection ratings during risk assessment work, and in re-assessing these ratings following risk control strategies. It also recognises the value in breaking down the item under study into manageable components for individual assessment.
However, the approach developed here handles risk detection in a markedly different way. Here, detection controls are considered and evaluated after the risk has been estimated, not before, and significantly, this tool requires a formal and critical evaluation of any detection controls that are in place, in order to determine whether these controls actually give assurance that the risk is adequately controlled and that no further controls are required.
This approach also classifies GMP controls differently, and this impacts upon how risks are generally estimated and controlled. This tool requires one to address qualification and validation issues for current controls as well as for new controls, even when the related risk is deemed acceptable with current controls. Also, this approach does not make use of FMEA's 'Risk Priority Number' concept, and 'Failure Mode' terminology is not used.
* HACCP
This risk management solution draws upon some concepts of HACCP, in that it recognises the value in prevention rather than detection, and the value in determining critical control points, their related limits, and target levels. HACCP also provides a comprehensive and documented approach for practical risk management exercises.
However, HACCP-based applications do not normally offer a clear, formal process for characterising or differentiating (by either qualitative or quantitative means) the risks posed by a potential hazard, and the HACCP requirement to pre-define corrective actions for situations when Critical Control Points (CCP) limits have been exceeded is not used here. Rather, this solution provides a formal means of assessing individual risks, and it focuses on identifying and implementing GMP controls which give assurance, via qualification and validation, that such risks are either reduced to an acceptable level or controlled to an acceptable level.
* The GAMP 4 Risk Assessment Process
This risk management solution draws upon some features of the GAMP 4 Risk Assessment process, in that it recognises the value in estimating risks on the basis of likelihood and severity considerations only, not on detection factors, and the value in using the risk assessment process to help focus validation activities and to assess change control proposals. Also, the GAMP process considers the complexity and degree of customisation of the item under study when determining how much rigor to apply during the risk management process.
However, the approach described here deals with risk detection in a different way, as it does not allow users to automatically assign risk priorities simply on the basis of detection ratings.
* The ISPE Impact Assessment Process
This risk management solution draws upon some features of the ISPE Impact Assessment process, as described in ISPE's Baseline Guide on Commissioning and Validation, in that it recognises the value in using structured and systematic techniques to determine critical components of systems on an "impact" basis, with respect to product quality. It also recognises the value in focusing qualification activities on those critical components.
However, the approach described here addresses additional items, such as the risks presented when equipment and system faults occur, as well as risk control, communication, and review activities.
The Fundamental Principles Underlying this Risk Management Solution
A number of key principles underlie the design of this risk management solution. These were considered fundamental to this application of risk management in GMP and Regulatory Compliance environments, and are shown in Figure 1.
These principles were based primarily upon the guidance of ICH Q9, on the current EU GMP requirements, and on the ISO 14971:2000 Standard, on the application of risk management for medical devices. (17) The authors' own experiences in using other risk management tools, and a broad review of risk management-related publications also provided insight on key issues.
As is evident, the Principles noted in Figure 1 are largely self-explanatory. The following notes provide some background and explanatory information relating to each:
* Principle 1 is based on Annex 15 (Qualification and Validation) to the EU GMP Guide. (1) It implies that, before validation master plans and qualification and validation protocols are finalised, risks associated with the items under study should be considered, resulting in the identification of risk-based critical parameters requiring qualification or validation. This Principle also implies that, before change control proposals are approved, the potential risks presented by the change should be identified and a strategy determined for managing such risks.
* Principles 2, 3, and 4 reflect the guidance presented in ICH Q9 and other publications, such as ISO/IEC Guide No. 73, titled, "Risk Management--Vocabulary--Guidelines for Use in Standards." (18) The inclusion of loss of product availability in the definition of harm is considered important in GMP risk management activities, because the loss of product availability may adversely impact not only business, but also patients and users of medicinal products.
* Principle 5 reflects the author's experience in applying risk management principles and tools to GMP situations--that sometimes, the probability of occurrence of harm, or the severity of that harm, just cannot be reduced to levels that render the risk acceptable with current or realistic resources, but that such risks can be controlled to an acceptable level by means of detection or other risk-control measures.
* Principles 6 and 7 recognise that risk can be difficult to quantify, and that there may be uncertainties in the outcome of any risk management exercise. As discussed in ICH Q9, for example, different stakeholders may perceive different potential harms, or place a different probability on the occurrence of each harm, or assign different severities to each harm, and this can lead to uncertainty. This principle implies that the risk management solution should be able to address such difficulties and uncertainties. (The papers 19-22, detailed in the References section, provide useful information in this regard.)
* Principle 8 requires that the risk management solution should help to formally identify who the stakeholders are for the item under study. This enables the concerns of those stakeholders to be taken into account and for appropriate definitions of severity to then be determined.
* Principle 9 is far reaching, and it renders this solution somewhat different to other risk management tools with respect to dealing with risk detectability. Here, users may not automatically conclude that a high detectability for a negative event or its effects means that a risk is acceptable or adequately controlled. For example, the ability to detect glass in filled and stoppered vials may sometimes be high, but this detection control does not mean that the vial filling and sealing process is under adequate GMP control if the incidence of glass in vials is relatively high.
* Principle 10, also based on ICH Q9, means that the risk management solution must formally be able to identify and manage any new risks that may be introduced as part of Risk Control activities. New risks can be introduced, for example, when a new Process Analytical Technology (PAT)-based sensor is installed in a drying vessel to monitor a parameter such as water content. The material housing the sensor may be incompatible with the contents of the dryer, or it may not be adequately robust, giving rise to a risk of product contamination.
* Principle 11 recognises the benefit of using multi-disciplinary teamwork when performing risk management, and is certainly not a new concept. Well established tools such as HACCP, as outlined by the Codex Alimentarius Commission, (23) require the use of multi-disciplinary teams.
* Finally, Principle 12, again reflecting ICH Q9, recognises that much of what we do within GMP environments is risk-based, even if we do not call it that. This is important, because often, there may be no need to use a formal risk management tool, when existing procedures may be adequate. This principle, in a subtle way, also recognises the fact that risk events can have multiple causes, with multiple associated risks, some less important that others. This can result in formal risk management activities becoming costly and quite labour-intensive exercises, and should, therefore, be targeted at the most complex or critical issues.
Design Criteria for this Risk Management Solution
During the design stage for this risk management solution, it was determined that the tool had to meet certain pre-defined criteria if it was going to serve its intended purpose: to facilitate risk-based qualification, validation, and change control activities.
These pre-defined criteria were as follows:
* That the tool should offer GMP and Regulatory Compliance environments a documented, scientific, practical, systematic, transparent and flexible solution for determining and managing, on a risk basis, the scope and extent of qualification and validation, and the likely impact of changes.
* That the tool should allow for the highest risks to be identified and prioritised for action.
* That the tool should be a readily usable and complete risk management solution, without requiring extensive modification before it may be used to address all of the required elements of risk management.
* That the tool should have wide applicability across GMP and Regulatory Compliance environments.
* That the tool should directly conform to each of the twelve aforementioned principles which were defined as being important for facilitating risk-based qualification, validation, and change control activities within GMP and Regulatory Compliance environments.
With the above design criteria in mind, a structured and systematic risk management process was developed. This comprises of ten discrete process steps, as outlined in Figure 2. A detailed, instructional worksheet has been developed, which facilitates each of the ten steps. This worksheet is used to document the risk management exercise, and to guide users through the actual risk management process. Detailed guidance on carrying out each of these ten steps is available in the Tool's User Manual.
This ten-step process, as outlined above, complements some of the points made in ISPE's White Paper of 2005, (5) which, while focused only on equipment and facility qualification, made a number of very useful recommendations on ways to achieve true risk-based qualification. One was that risk assessments, process development, and experimental design should be used to identify critical features, functions, and critical process parameters, and that qualification efforts should be process-based, and focused on the concept of risk-mitigation for patients. The risk management solution developed here offers a practical means for how this might be achieved.
While this risk management methodology provides a means by which risk management might be of use within GMP environments, at the same time, it was designed to serve as a potential risk management solution for GMP regulators, for use within their own work activities. This is considered important, recognising the significant contribution made by ICH Q9 in promoting the use of risk management principles and tools by both parties. This aspect of the tool is explained in more detail in Part II of this paper.
CONCLUSION
In Part I of this paper, a risk management solution is described that is designed to facilitate risk-based qualification, validation, and change control activities within GMP and regulatory compliance environments in the EU. This solution is based upon a set of pre-defined, fundamental principles and design criteria, which were considered important. It offers a documented and ready-to-use ten-step process for determining and managing, on a risk basis, the scope and extent of qualification and validation, and the likely impact of changes.
This is a formal and rigorous approach to risk management. As such, it is designed so that its use should be commensurate with the complexity and/or criticality of the issue to be addressed. It is not intended for use in all situations, or to address all risk areas or concerns, and in many instances, in line with ICH Q9 principles, a more informal approach to risk management may be more appropriate, and indeed proportionate.
In Part II of this paper, the scope of this risk management solution is presented, and the structure of the tool and some of its key features are described. Some novel aspects relating to this risk management solution are also presented, and a number of limitations associated with this solution are discussed. Finally, an outline of the main findings made to date with using this tool is given.
Overall, this work seeks to demonstrate how risk management principles may be used in practical terms across a broad range of EU GMP and Regulatory Compliance environments. It is hoped that these efforts will serve to build upon the milestone that was ICH Q9, and the work done to date by FDA, ISPE, GAMP and many others in promoting true risk-based qualification, validation and change control activities.
ABOUT THE AUTHORS
Kevin O'Donnell is currently Market Compliance Manager at the Irish Medicines Board (IMB), Dublin, Ireland. He joined the Inspectorate Department of the IMB in 2001; he was appointed a GMP Inspector in 2002, and took up his current position in 2005. His current responsibilities involve managing a number of compliance programmes within the IMB, including IMB's Quality Defect and Recall programme and its Sampling and Analysis Market Surveillance activities.
Kevin has a chemistry background; he obtained his Chemistry Degree from University College Galway, Ireland, in 1991, and his Masters Degree in Pharmaceutical Quality Assurance from the Dublin Institute of Technology, Dublin, in 2002. He spent a number of years working in the Pharmaceutical Industry, both in Ireland and in the United States before joining the IMB. Kevin has an active interest in education, having spent three years as a Mathematics teacher in his native County Donegal, Ireland. He lectures occasionally, in pharmaceutical-related degree courses in Dublin. Kevin can be reached at kod1@eircom.net.
Anne Greene, PhD, is currently a lecturer in Pharmaceutical Technology at the School of Chemical and Pharmaceutical Sciences at the Dublin Institute of Technology in Dublin, Ireland. She is also Course Director for Masters of Sciences studies in Pharmaceutical Quality Assurance and Validation Technology at DIT.
Professor Greene came to academia after serving as Technical Services Chemist at Sterling Winthrop from 1990 through 1992 and as Validation Manager at Wyeth Medica Ireland from 1992 through 1996. She can be reached via email at anne.greene@dit.ie.
REFERENCES
1. The Rules Governing Medicinal Products in the European Community, Volume IV, published by the European Commission, and available at www.pharmacos.eudra.org/F2/eudralex/vol-4/home.htm.
2. European Commission Directive 2003/94/EC of 8 October 2003 laying down the Principles and Guidelines of Good Manufacturing Practice in respect of Medicinal Products for Human Use and Investigational Medicinal Products for Human Use, Official Journal of the European Union L262, 14/10/2003.
3. European Commission Directive 91/412/EEC of 23 July 1991 laying down the Principles and Guidelines of Good Manufacturing Practice for Medicinal Products for Veterinary Use, Official Journal of the European Union L228, 17/08/1991.
4. ICH Q9--Quality Risk Management, at Step 4 of the ICH Process, November 9th, 2005. Available at www.ich.org.
5. 'A White Paper on Risk-Based Qualification for the 21st Century,' ISPE's Qualification Task Team Steering Committee, ISPE 9 March 2005, available at http://www.ispe.org.
6. G. C. Wrigley, 'Strategies for Minimising Validation Costs,' Journal of Validation Technology, Vol. 10, Issue 3, 2004.
7. Proceedings of the conference titled "Reducing Validation Costs," Dublin Institute of Technology, Dublin, Ireland, 9 September, 2004.
8. For information in this regard, see the quality defect and recall sections of the Irish Medicines Board Annual Reports for 2003 and 2004, available from www.imb.ie.
9. For information on recalls which have occurred in the UK over recent years, see the Drug Alerts section of the website of the UK Medicines and Healthcare Products Regulatory Agency, at http://www.mhra.gov.uk.
10. For information in this regard, see the presentations from the Irish Medicines Board Inspectorate Information Days of 27 September 2002 and 15 October 2004, available from the IMB upon request.
11. IEC 61025
--Fault Tree Analysis.
12. IEC 60812
--Analysis Techniques for System Reliability--Procedures for Failure Mode and Effects Analysis (FMEA).
13. WHO Technical Report Series No. 908, 2003, Annex 7, Application of Hazard Analysis and Critical Control Point (HACCP) methodology to pharmaceuticals.
14. ISPE Baseline Pharmaceutical Engineering Guide
, Volume 5, 'Commissioning and Validation
,' March 2001.
15. GAMP 4 Guide, 'Validation of Automated Systems,' December 2001.
16. Military Standard No. MIL-STD-1629A, Procedures for Performing a Failure Mode, Effects, and Criticality Analysis (FMECA), U.S. Department of Defense, Washington, DC, 24 November, 1980.
17. ISO 14971:2000
, 'Medical Devices--Application of Risk Management to Medical Devices,' December 2000.
18. ISO/IEC Guide 73:2002
, 'Risk Management--Vocabulary--Guidelines for Use in Standards.'
19. D. W. Vincent and B. Honeck, Risk Management Analysis Techniques for Validation Programs,' Journal of Validation Technology, Vol. 10, Issue 3, 2004.
20. For example, see EMEA Public Statement of 18 October 2005 on the risk of inhibitor development for Factor VIII recombinant products, available at http://www.emea.eu.int.
21. E. C. Tidswell, 'Risk Profiling Pharmaceutical Manufacturing Processes', European Journal of Parenteral and Pharmaceutical Sciences 2004; 9 (2):49-55.
22. M. G. Morgan, 'Risk Analysis and Management', Scientific American, July 1993.
23. Recommended International Code of Practice: General Principles of Food Hygiene Cac/rcp 1-1969, rev. 3-1997, amd., (1999). [Note: This document is from the Codex Alimentarius Commission and the FAO/WHO Food Standards Programme.]
Article Acronym Listing
<pre>
CCP Critical Control Point
CPP Critical Process Parameter
EU European Union
FDA Food and Drug Administration
FMEA Failure Mode and Effects Analysis
FMECA Failure Mode, Effects and Criticality Analysis
GAMP Good Automated Manufacturing Practice
GMP Good Manufacturing Practice
HACCP Hazard Analysis and Critical Control Points
ICH International Conference on Harmonization
ISO International Organization for Standardization
ISPE International Society of Pharmaceutical Engineering
MA Marketing Authorization
PAT Process Analytical Technology
</pre>
Addendum
Laminated Card for the Risk Management Tool
Risk = P x S
This Card shows the default Probability, Severity, and Detection definitions for the Risk Management Tool. It also shows the Risk Table, with the Risk Acceptability criteria. Important: The definitions shown for each P, S, & D Level are default definitions; they can be modified as required. See Step 3 of the Tool Worksheet for details.
<pre>
Probability of Occurrence Levels for the Negative Event
High The Negative Event is Likely to Occur
Medium The Negative Event May Occur
Low The Negative Event is Unlikely to Occur
Remote The Negative Event is Very Unlikely to Occur, or is Extremely
Unlikely to occur
Severity Levels for the Effects of the Negative Event
Critical The Effects are Severe
* Very Significant GMP/MA Non-Compliance
* Potential Patient Injury
Moderate The Effects are Moderately Severe
* Significant GMP/MA Non-Compliance
* Potential Patient Impact
Minor The Effects are Not Severe
* Minor GMP/MA Non-Compliance
* No Patient Impact
Risk = P x S
Negative
Event Prob: Minor Severity Moderate Severity Critical Severity
High Unacceptable Risk Intolerable Risk Intolerable Risk
Medium Acceptable Risk Unacceptable Risk Intolerable Risk
Low Acceptable Risk Acceptable Risk Unacceptable Risk
Remote Acceptable Risk Acceptable Risk Acceptable Risk </pre>
RISK DEFINITIONS:
Intolerable: Work to eliminate the Negative Event, or build in systems or controls to ensure the effects of the Negative Event are not realised (e.g. via back-up or redundant controls).
Unacceptable: Reduce the risk, or control the risk to an acceptable level.
Acceptable: The risk is acceptable as is. No risk reduction or new controls are required.
Detection Control Ratings:
** High -- the control will likely detect the negative event or its effects
** Medium -- the control may detect the negative event or its effects
** Low -- it is not likely that the control will detect the negative event or its effects
** Zero -- no detection control in place
By Kevin O'Donnell (Corresponding Author) Compliance Department, Irish Medicines Board and Anne Greene, School of Chemistry and Pharmaceutical Sciences, Dublin Institute of Technology
Note: The views expressed in this paper are those of the authors, and should not be taken to represent the views of the Irish Medicines Board.
<pre>
Figure 1 Principles Underlying this Risk Management Solution
NO. PRINCIPLE
1. That the scope and extent of qualification and validation, and the
likely impact of changes, should be determined and managed on a
risk basis.
2. That risk is the combination of the probability of ocurrence of
harm and the severity of that harm, and that harm is considered to
be damage to health, including the damage that can occur from loss
of product quality or availability.
3. That as a minimum, risk management contains the following four
components: risk assessment, risk control, risk communication, and
risk review, as defined and described in ICH Q9.
4. That a consideration of "what might go wrong" is fundamental to the
risk management exercise.
5. That there may be some risks that cannot be eliminated or reduced
to an acceptable level with current or realistic controls or
resources, but that may be controlled to an acceptable level with
improved detection or other measures, as determined on a case-by-
case basis.
6. That risk management is not an exact science and, while a
scientific approach should form the basis of the risk management
process, there may be uncertainties associated with the outcome of
the risk management exercise.
7. That risk may be assessed qualitatively as well as quantitatively,
and that a good qualitative assessment of risk may be more valid
than a poor quantitative assessment.
8. That the main stakeholders associated with the application of risk
management within GMP and Regulatory Compliance environments are
patients and users of medicines, including healthcare
professionals, as well as Industry and Regulators, and that, while
the concerns of all involved stakeholders should be taken into
account in any risk management exercise, protection of the patient
is of prime importance, and therefore, risk management should
ultimately link to the protection of the patient.
9. That, in GMP environments, a high detectability of risk does not
necessarily mean that the risk is eliminated or adequately
controlled.
10. That the implementation of risk control measures could, in itself,
inadvertently introduce new risks, which will need to be managed.
11. That performing risk management exercises can be improved through
the use of multi-disciplinary teams.
12. That a formal risk management process may not always be necessary
or appropriate in all situations, and that the level of effort,
rigor, formality, and documentation associated with the risk
management process should be commensurate with the complexity and/
or criticality of the issue being addressed.
Figure 2 A Ten-Step Risk Management Process
Step 1: Document Specific Information on the Risk Management Exercise
Being Undertaken:
* Identify whether the exercise is a Prospective, Retrospective, or a
Change Control risk management exercise.
* Define the item under study and the scope of the exercise. If
possible, define boundaries for the item under study.
* Provide relevant background information so that the reason for the
risk management exercise is made clear.
* State any pertinent assumptions being made, especially those
relating to qualification and validation, and document any
significant uncertainties associated with the data being used in the
exercise.
Step 2: Who's Who? -- Define the Risk Management Team:
* Identify the risk management team leader and other team members.
* The team should be multi-disciplinary and include persons
knowledgable in the item under study.
* At least one person should have a firm understanding of the risk
management process, principles, and methodology.
* If possible, there should be personnel on the team who have the
necessary authority (or the means) to make key decisions regarding
the implementation and funding of risk mitigation controls.
Step 3: Review the Default Definitions Provided for Negative Event
Probability, Severity, and Detection:
* Review the default Probability, Severity, and Detection definitions
provided in this Risk Management Tool. These are presented on a
laminate card, which accompanies the tool worksheet.
* The team then decides whether the default definitions as provided
are appropriate for the specific risk management exercise at hand.
* This is where new or modified Probability, Severity, and Detection
definitions can be drawn up, if required. For example, the
definitions for Probability of Occurence can be made quantitative,
or the Severity definitions can be altered to better reflect the
concerns of any specific stakeholders.
* A Risk Table (or matrix) is used by this Risk Management Tool, and
this is also shown on the laminate card. (See page 25.)
Step 4: What Might Go Wrong? -- Identify Potential Negative Events:
* Review relevant documentation, records and data, and use
brainstorming techniques to identify potential negative events for
the item under study. (Note: Guidance on brainstorming is provided
in a Questions and Answers document provided with the tool.)
* Of the potential negative events identified, review each, discussing
their potential severities, and select and list those considered to
be the most critical and/or complex negative events, for formal
evaluation in this exercise.
* As this is a formal and rigorous risk management methodology, only
the highest priority or most important potential negative events
should normally be selected for formal evaluation. However, any
number can be selected.
Step 5: Risk Evaluation -- Is the Risk Acceptable, Unacceptable, or
Intolerable?
* For each potential negative event, identify and document the
potential negative consequences.
* Document and critically evaluate any currently in place back-up or
redundancy controls for the potential negative event, and assign a
Severity rating.
* Identify and document the cause(s) of each potential negative event.
* Document and critically evaluate any currently in place preventive
controls for each cause, and assign a Probability of Occurrence
rating to each cause.
* Using the Risk Table provided on the laminated card which
accompanies the tool worksheet, estimate each risk associated with
the potential negative event.
* This results in the classification of each risk as either
Acceptable, Unacceptable, or Intolerable.
* Risks deemed to be Acceptable progress directly to Step 8 of the
worksheet; all other risks progress to Step 6.
Step 6: Risk Evaluation -- Is the Risk Adequately Controlled?
* Document and critically evaluate any detection controls currently in
place for each Unacceptable and Intolerable risk.
* Assign a Detection rating to these controls, and determine whether
these controls give assurance that the risk is adequately
controlled and that no further controls are required.
* Risks that are considered adequately controlled progress directly to
Step 8. All other risks progress to Step 7.
Step 7: Risk Control:
* Identify and critically evaluate any new or improved back-up or
redundancy controls, which may be put in place for Unacceptable and
Intolerable risks.
* With these controls in mind, assign a new Severity rating to the
potential negative event.
* Identify and critically evaluate any new or improved preventive
controls, which may be put in place for the cause(s) of each
Unacceptable and Intolerable risk.
* With these controls in mind, assign a new Probability of Occurrence
rating to each cause.
* Using the Risk Table provided on the laminated card, which
accompanies the tool worksheet, re-estimate each risk.
* This results in the re-classification of each risk as either
Acceptable, Unacceptable, or Intolerable.
* Risks deemed to be Acceptable progress to Step 8 of the worksheet;
all other risks continue through Step 7.
* Identify and critically evaluate any new or improved detection
controls for each Unacceptable and Intolerable risk.
* Assign a Detection rating to these controls, and determine whether
these controls give assurance that the risk is now adequately
controlled and that no further controls are required.
* Risks that are considered adequately controlled progress to Step 8.
* For risks that are still not considered adequately controlled, Step
7 (Risk Control), should be repeated. (A redesign of the item under
study may be necessary in order to eliminate the potential negative
event.)
Step 8: Qualification and Validation:
* For each control listed on Worksheets No. 5, 6, and 7, identify the
items (such as documentation, equipment, facilities, personnel
resources, etc.), which are required for the control to be in place.
* Determine Critical Process Parameters, their limits, and any other
acceptance criteria or required outcomes for each control.
* Determine any training and assessment of training requirements for
each control.
* Determine any Qualification or Validation activities required for
each control, and assign a Qualification and Validation status to
each.
Step 9: Action Items:
* Document any action items arising out of the risk management
exercise, and assign responsibilities for each.
* These could be actions required to implement a control, or they
could be Qualification or Validation exercises.
Step 10: Risk Communication and Continuous Improvement (Periodic Review)
Activities:
* Identify and document any communication activities required for the
risks identified during the exercise.
* Assign responsibilities and timelines for each communication.
* Define when the risk management exercise should be reviewed as part
of continuous improvement, and document any key areas or issues to
be reviewed at that time.
* Close out the risk management exercise. </pre>
InfoTrac OneFile (R)
Journal of GXP Compliance
, 07/01/2006 10 4 A risk management solution designed to facilitate risk-based qualification, validation, and change control activities within GMP and Pharmaceutical regulatory compliance environments in the EU, Part I: fundamental principles, design criteria, outline of process. O'Donnell, Kevin *~|~*Greene, Anne *~|~*
COPYRIGHT 2006 Advanstar Communications, Inc.
Risk-based Qualification, Validation, and Change Control--Opportunities for Improvement In the European Union (EU), the Good Manufacturing Practice (GMP) requirements place specific obligations on manufacturers of medicinal products to implement risk-based qualification, validation, and change control programmes. (1,2,3)
Annex 15 to the EU Guide to GMP titled, "Qualification and Validation," requires:
a) That a risk assessment approach be used to determine the scope and extent of validation. (Note: Within the EU GMP and others, the term, 'validation,' is generally understood to encompass qualification as well as validation activities.)
b) That risk analysis be employed when assessing the likely impact of changes.
How these GMP requirements are met has been the subject of much discussion between Regulators and Industry in recent years, and as a Regulatory Agency, the Irish Medicines Board has received numerous requests from Industry for guidance in this area.
From the authors' experience as a GMP Inspector, it is evident that risk factors are often taken into account when designing qualification and validation programmes, and when processing change control proposals. However, as mentioned in the International Conference on Harmonization (ICH) Guideline on Quality Risk Management, ICH Q9, (4) the use of risk management in the Pharmaceutical Industry has, to date, been limited, and the full benefits of risk management, as a valuable component within a quality system, have yet to be realised.
Despite ever-increasing qualification and validation costs, as described in publications of the International Society of Pharmaceutical Engineering (ISPE) and others, (5-7) there is evidence that defective and non-compliant medicinal products continue to be manufactured and released. These often result in product recalls being required to protect patients and users of medicinal products. (8,9) As discussed in ISPE's White Paper on Risk-Based Qualification for the 21st Century, (5) current qualification practices, for example, are often document-intensive, expensive, and time-consuming, but do not necessarily add value, or lead to clear patient risk-mitigation strategies or process understanding. Likewise, validation activities sometimes do not adequately address the critical aspects of processes. (10) In the area of change control, proposed changes often involve substantial capital expenditure and large project teams, but sometimes important risks introduced by the change !
are not identified. Therefore, it is likely that the use of more formalised and scientific approaches to risk management may prove beneficial within GMP environments.
A Risk Management Solution for GMP and Regulatory Compliance Environments
There are many formal risk management tools available, such as Fault Tree Analysis, (11) Failure Modes and Effects Analysis (FMEA), (12) and Hazard Analysis and Critical Control Points (HACCP). (13) However, most were not specifically designed for GMP applications, much less as solutions for facilitating risk-based qualification, validation, and change control activities within GMP environments. As a result, a degree of design modification is often required before an existing tool may be used for these activities. Of the tools which are GMP-specific, such as the approaches developed by ISPE (14) and GAMP, (15) their focus tends to be somewhat narrow, being tailored for equipment and systems qualification and computerised systems validation, respectively. As a result, the day-to-day practicalities of how to apply GMP risk management more broadly remain somewhat under-developed.
In addition, few if any, of the available tools were designed as complete, documented, and ready-to-use risk management methodologies that address all of the components of risk management and have been accepted via ICH Q9 as important. These are as follows: risk assessment, risk control, risk communication and risk review. As a result, a further degree of modification is often required before any of the existing risk management tools may be used as a complete risk management solution.
In response to the requests received by the Irish Medicines Board from Industry for guidance in the interpretation of the risk-related requirements of Annex 15 to the EU GMP Guide, and as part of our efforts to better understand how risk management may be used in practice, the Irish Medicines Board has developed a practical risk management methodology, or tool, designed specifically as a means of addressing those Annex 15 requirements. As part of this work, a series of practical case studies have been developed on the use of this tool, in order to show how the tool works in practice. This risk management solution is designed so that it provides a complete and documented means of addressing all of the aforementioned components of risk management.
In this series of papers, in two parts, this risk management methodology is described. In Part I, the principles underlying this approach are given, and the design criteria used for development of the risk management tool are outlined. The tool uses a documented ten-step process, also described in Part I. In Part II, the scope and structure of the risk management tool are described, and some of the limitations of this tool are given. An outline of some of the principle findings made to date with this tool is also given in Part II. (It is emphasised that this work is not intended to place any specific regulatory obligations on manufacturers, nor is the risk management solution presented here being promoted in any way as a tool that should be used by Industry. This work simply demonstrates how GMP risk management may be applied in practice.)
Is this Risk Management Solution Intended to Replace other Available Tools?
It is not the intent of this work to replace other available tools; existing tools are valuable in their own right. The risk management methodology described here was designed for a specific purpose--to facilitate risk-based and patient-focused qualification, validation, and change control activities. This tool focuses on evaluating how GMP controls, both current and proposed, lead to mitigation and control of the risks identified, and on the qualification and validation status of such controls.
Importantly, this work does not seek to "reinvent the wheel," and during the technical development of this risk management solution, some of the useful features and concepts behind other risk management tools and approaches were adopted or taken into account. For example:
* FMEA and FMECA
This risk management solution draws upon some features of FMEA and FMECA, (16) in that it recognises the value in assigning Probability, Severity, and Detection ratings during risk assessment work, and in re-assessing these ratings following risk control strategies. It also recognises the value in breaking down the item under study into manageable components for individual assessment.
However, the approach developed here handles risk detection in a markedly different way. Here, detection controls are considered and evaluated after the risk has been estimated, not before, and significantly, this tool requires a formal and critical evaluation of any detection controls that are in place, in order to determine whether these controls actually give assurance that the risk is adequately controlled and that no further controls are required.
This approach also classifies GMP controls differently, and this impacts upon how risks are generally estimated and controlled. This tool requires one to address qualification and validation issues for current controls as well as for new controls, even when the related risk is deemed acceptable with current controls. Also, this approach does not make use of FMEA's 'Risk Priority Number' concept, and 'Failure Mode' terminology is not used.
* HACCP
This risk management solution draws upon some concepts of HACCP, in that it recognises the value in prevention rather than detection, and the value in determining critical control points, their related limits, and target levels. HACCP also provides a comprehensive and documented approach for practical risk management exercises.
However, HACCP-based applications do not normally offer a clear, formal process for characterising or differentiating (by either qualitative or quantitative means) the risks posed by a potential hazard, and the HACCP requirement to pre-define corrective actions for situations when Critical Control Points (CCP) limits have been exceeded is not used here. Rather, this solution provides a formal means of assessing individual risks, and it focuses on identifying and implementing GMP controls which give assurance, via qualification and validation, that such risks are either reduced to an acceptable level or controlled to an acceptable level.
* The GAMP 4 Risk Assessment Process
This risk management solution draws upon some features of the GAMP 4 Risk Assessment process, in that it recognises the value in estimating risks on the basis of likelihood and severity considerations only, not on detection factors, and the value in using the risk assessment process to help focus validation activities and to assess change control proposals. Also, the GAMP process considers the complexity and degree of customisation of the item under study when determining how much rigor to apply during the risk management process.
However, the approach described here deals with risk detection in a different way, as it does not allow users to automatically assign risk priorities simply on the basis of detection ratings.
* The ISPE Impact Assessment Process
This risk management solution draws upon some features of the ISPE Impact Assessment process, as described in ISPE's Baseline Guide on Commissioning and Validation, in that it recognises the value in using structured and systematic techniques to determine critical components of systems on an "impact" basis, with respect to product quality. It also recognises the value in focusing qualification activities on those critical components.
However, the approach described here addresses additional items, such as the risks presented when equipment and system faults occur, as well as risk control, communication, and review activities.
The Fundamental Principles Underlying this Risk Management Solution
A number of key principles underlie the design of this risk management solution. These were considered fundamental to this application of risk management in GMP and Regulatory Compliance environments, and are shown in Figure 1.
These principles were based primarily upon the guidance of ICH Q9, on the current EU GMP requirements, and on the ISO 14971:2000 Standard, on the application of risk management for medical devices. (17) The authors' own experiences in using other risk management tools, and a broad review of risk management-related publications also provided insight on key issues.
As is evident, the Principles noted in Figure 1 are largely self-explanatory. The following notes provide some background and explanatory information relating to each:
* Principle 1 is based on Annex 15 (Qualification and Validation) to the EU GMP Guide. (1) It implies that, before validation master plans and qualification and validation protocols are finalised, risks associated with the items under study should be considered, resulting in the identification of risk-based critical parameters requiring qualification or validation. This Principle also implies that, before change control proposals are approved, the potential risks presented by the change should be identified and a strategy determined for managing such risks.
* Principles 2, 3, and 4 reflect the guidance presented in ICH Q9 and other publications, such as ISO/IEC Guide No. 73, titled, "Risk Management--Vocabulary--Guidelines for Use in Standards." (18) The inclusion of loss of product availability in the definition of harm is considered important in GMP risk management activities, because the loss of product availability may adversely impact not only business, but also patients and users of medicinal products.
* Principle 5 reflects the author's experience in applying risk management principles and tools to GMP situations--that sometimes, the probability of occurrence of harm, or the severity of that harm, just cannot be reduced to levels that render the risk acceptable with current or realistic resources, but that such risks can be controlled to an acceptable level by means of detection or other risk-control measures.
* Principles 6 and 7 recognise that risk can be difficult to quantify, and that there may be uncertainties in the outcome of any risk management exercise. As discussed in ICH Q9, for example, different stakeholders may perceive different potential harms, or place a different probability on the occurrence of each harm, or assign different severities to each harm, and this can lead to uncertainty. This principle implies that the risk management solution should be able to address such difficulties and uncertainties. (The papers 19-22, detailed in the References section, provide useful information in this regard.)
* Principle 8 requires that the risk management solution should help to formally identify who the stakeholders are for the item under study. This enables the concerns of those stakeholders to be taken into account and for appropriate definitions of severity to then be determined.
* Principle 9 is far reaching, and it renders this solution somewhat different to other risk management tools with respect to dealing with risk detectability. Here, users may not automatically conclude that a high detectability for a negative event or its effects means that a risk is acceptable or adequately controlled. For example, the ability to detect glass in filled and stoppered vials may sometimes be high, but this detection control does not mean that the vial filling and sealing process is under adequate GMP control if the incidence of glass in vials is relatively high.
* Principle 10, also based on ICH Q9, means that the risk management solution must formally be able to identify and manage any new risks that may be introduced as part of Risk Control activities. New risks can be introduced, for example, when a new Process Analytical Technology (PAT)-based sensor is installed in a drying vessel to monitor a parameter such as water content. The material housing the sensor may be incompatible with the contents of the dryer, or it may not be adequately robust, giving rise to a risk of product contamination.
* Principle 11 recognises the benefit of using multi-disciplinary teamwork when performing risk management, and is certainly not a new concept. Well established tools such as HACCP, as outlined by the Codex Alimentarius Commission, (23) require the use of multi-disciplinary teams.
* Finally, Principle 12, again reflecting ICH Q9, recognises that much of what we do within GMP environments is risk-based, even if we do not call it that. This is important, because often, there may be no need to use a formal risk management tool, when existing procedures may be adequate. This principle, in a subtle way, also recognises the fact that risk events can have multiple causes, with multiple associated risks, some less important that others. This can result in formal risk management activities becoming costly and quite labour-intensive exercises, and should, therefore, be targeted at the most complex or critical issues.
Design Criteria for this Risk Management Solution
During the design stage for this risk management solution, it was determined that the tool had to meet certain pre-defined criteria if it was going to serve its intended purpose: to facilitate risk-based qualification, validation, and change control activities.
These pre-defined criteria were as follows:
* That the tool should offer GMP and Regulatory Compliance environments a documented, scientific, practical, systematic, transparent and flexible solution for determining and managing, on a risk basis, the scope and extent of qualification and validation, and the likely impact of changes.
* That the tool should allow for the highest risks to be identified and prioritised for action.
* That the tool should be a readily usable and complete risk management solution, without requiring extensive modification before it may be used to address all of the required elements of risk management.
* That the tool should have wide applicability across GMP and Regulatory Compliance environments.
* That the tool should directly conform to each of the twelve aforementioned principles which were defined as being important for facilitating risk-based qualification, validation, and change control activities within GMP and Regulatory Compliance environments.
With the above design criteria in mind, a structured and systematic risk management process was developed. This comprises of ten discrete process steps, as outlined in Figure 2. A detailed, instructional worksheet has been developed, which facilitates each of the ten steps. This worksheet is used to document the risk management exercise, and to guide users through the actual risk management process. Detailed guidance on carrying out each of these ten steps is available in the Tool's User Manual.
This ten-step process, as outlined above, complements some of the points made in ISPE's White Paper of 2005, (5) which, while focused only on equipment and facility qualification, made a number of very useful recommendations on ways to achieve true risk-based qualification. One was that risk assessments, process development, and experimental design should be used to identify critical features, functions, and critical process parameters, and that qualification efforts should be process-based, and focused on the concept of risk-mitigation for patients. The risk management solution developed here offers a practical means for how this might be achieved.
While this risk management methodology provides a means by which risk management might be of use within GMP environments, at the same time, it was designed to serve as a potential risk management solution for GMP regulators, for use within their own work activities. This is considered important, recognising the significant contribution made by ICH Q9 in promoting the use of risk management principles and tools by both parties. This aspect of the tool is explained in more detail in Part II of this paper.
CONCLUSION
In Part I of this paper, a risk management solution is described that is designed to facilitate risk-based qualification, validation, and change control activities within GMP and regulatory compliance environments in the EU. This solution is based upon a set of pre-defined, fundamental principles and design criteria, which were considered important. It offers a documented and ready-to-use ten-step process for determining and managing, on a risk basis, the scope and extent of qualification and validation, and the likely impact of changes.
This is a formal and rigorous approach to risk management. As such, it is designed so that its use should be commensurate with the complexity and/or criticality of the issue to be addressed. It is not intended for use in all situations, or to address all risk areas or concerns, and in many instances, in line with ICH Q9 principles, a more informal approach to risk management may be more appropriate, and indeed proportionate.
In Part II of this paper, the scope of this risk management solution is presented, and the structure of the tool and some of its key features are described. Some novel aspects relating to this risk management solution are also presented, and a number of limitations associated with this solution are discussed. Finally, an outline of the main findings made to date with using this tool is given.
Overall, this work seeks to demonstrate how risk management principles may be used in practical terms across a broad range of EU GMP and Regulatory Compliance environments. It is hoped that these efforts will serve to build upon the milestone that was ICH Q9, and the work done to date by FDA, ISPE, GAMP and many others in promoting true risk-based qualification, validation and change control activities.
ABOUT THE AUTHORS
Kevin O'Donnell is currently Market Compliance Manager at the Irish Medicines Board (IMB), Dublin, Ireland. He joined the Inspectorate Department of the IMB in 2001; he was appointed a GMP Inspector in 2002, and took up his current position in 2005. His current responsibilities involve managing a number of compliance programmes within the IMB, including IMB's Quality Defect and Recall programme and its Sampling and Analysis Market Surveillance activities.
Kevin has a chemistry background; he obtained his Chemistry Degree from University College Galway, Ireland, in 1991, and his Masters Degree in Pharmaceutical Quality Assurance from the Dublin Institute of Technology, Dublin, in 2002. He spent a number of years working in the Pharmaceutical Industry, both in Ireland and in the United States before joining the IMB. Kevin has an active interest in education, having spent three years as a Mathematics teacher in his native County Donegal, Ireland. He lectures occasionally, in pharmaceutical-related degree courses in Dublin. Kevin can be reached at kod1@eircom.net.
Anne Greene, PhD, is currently a lecturer in Pharmaceutical Technology at the School of Chemical and Pharmaceutical Sciences at the Dublin Institute of Technology in Dublin, Ireland. She is also Course Director for Masters of Sciences studies in Pharmaceutical Quality Assurance and Validation Technology at DIT.
Professor Greene came to academia after serving as Technical Services Chemist at Sterling Winthrop from 1990 through 1992 and as Validation Manager at Wyeth Medica Ireland from 1992 through 1996. She can be reached via email at anne.greene@dit.ie.
REFERENCES
1. The Rules Governing Medicinal Products in the European Community, Volume IV, published by the European Commission, and available at www.pharmacos.eudra.org/F2/eudralex/vol-4/home.htm.
2. European Commission Directive 2003/94/EC of 8 October 2003 laying down the Principles and Guidelines of Good Manufacturing Practice in respect of Medicinal Products for Human Use and Investigational Medicinal Products for Human Use, Official Journal of the European Union L262, 14/10/2003.
3. European Commission Directive 91/412/EEC of 23 July 1991 laying down the Principles and Guidelines of Good Manufacturing Practice for Medicinal Products for Veterinary Use, Official Journal of the European Union L228, 17/08/1991.
4. ICH Q9--Quality Risk Management, at Step 4 of the ICH Process, November 9th, 2005. Available at www.ich.org.
5. 'A White Paper on Risk-Based Qualification for the 21st Century,' ISPE's Qualification Task Team Steering Committee, ISPE 9 March 2005, available at http://www.ispe.org.
6. G. C. Wrigley, 'Strategies for Minimising Validation Costs,' Journal of Validation Technology, Vol. 10, Issue 3, 2004.
7. Proceedings of the conference titled "Reducing Validation Costs," Dublin Institute of Technology, Dublin, Ireland, 9 September, 2004.
8. For information in this regard, see the quality defect and recall sections of the Irish Medicines Board Annual Reports for 2003 and 2004, available from www.imb.ie.
9. For information on recalls which have occurred in the UK over recent years, see the Drug Alerts section of the website of the UK Medicines and Healthcare Products Regulatory Agency, at http://www.mhra.gov.uk.
10. For information in this regard, see the presentations from the Irish Medicines Board Inspectorate Information Days of 27 September 2002 and 15 October 2004, available from the IMB upon request.
11. IEC 61025
--Fault Tree Analysis. 12. IEC 60812
--Analysis Techniques for System Reliability--Procedures for Failure Mode and Effects Analysis (FMEA). 13. WHO Technical Report Series No. 908, 2003, Annex 7, Application of Hazard Analysis and Critical Control Point (HACCP) methodology to pharmaceuticals.
14. ISPE Baseline Pharmaceutical Engineering Guide
, Volume 5, 'Commissioning and Validation,' March 2001. 15. GAMP 4 Guide, 'Validation of Automated Systems,' December 2001.
16. Military Standard No. MIL-STD-1629A, Procedures for Performing a Failure Mode, Effects, and Criticality Analysis (FMECA), U.S. Department of Defense, Washington, DC, 24 November, 1980.
17. ISO 14971:2000
, 'Medical Devices--Application of Risk Management to Medical Devices,' December 2000. 18. ISO/IEC Guide 73:2002
, 'Risk Management--Vocabulary--Guidelines for Use in Standards.' 19. D. W. Vincent and B. Honeck, Risk Management Analysis Techniques for Validation Programs,' Journal of Validation Technology, Vol. 10, Issue 3, 2004.
20. For example, see EMEA Public Statement of 18 October 2005 on the risk of inhibitor development for Factor VIII recombinant products, available at http://www.emea.eu.int.
21. E. C. Tidswell, 'Risk Profiling Pharmaceutical Manufacturing Processes', European Journal of Parenteral and Pharmaceutical Sciences 2004; 9 (2):49-55.
22. M. G. Morgan, 'Risk Analysis and Management', Scientific American, July 1993.
23. Recommended International Code of Practice: General Principles of Food Hygiene Cac/rcp 1-1969, rev. 3-1997, amd., (1999). [Note: This document is from the Codex Alimentarius Commission and the FAO/WHO Food Standards Programme.]
Article Acronym Listing
<pre>
CCP Critical Control Point
CPP Critical Process Parameter
EU European Union
FDA Food and Drug Administration
FMEA Failure Mode and Effects Analysis
FMECA Failure Mode, Effects and Criticality Analysis
GAMP Good Automated Manufacturing Practice
GMP Good Manufacturing Practice
HACCP Hazard Analysis and Critical Control Points
ICH International Conference on Harmonization
ISO International Organization for Standardization
ISPE International Society of Pharmaceutical Engineering
MA Marketing Authorization
PAT Process Analytical Technology
</pre>Addendum
Laminated Card for the Risk Management Tool
Risk = P x S
This Card shows the default Probability, Severity, and Detection definitions for the Risk Management Tool. It also shows the Risk Table, with the Risk Acceptability criteria. Important: The definitions shown for each P, S, & D Level are default definitions; they can be modified as required. See Step 3 of the Tool Worksheet for details.
<pre>
Probability of Occurrence Levels for the Negative Event
High The Negative Event is Likely to Occur
Medium The Negative Event May Occur
Low The Negative Event is Unlikely to Occur
Remote The Negative Event is Very Unlikely to Occur, or is Extremely
Unlikely to occur
Severity Levels for the Effects of the Negative Event
Critical The Effects are Severe
* Very Significant GMP/MA Non-Compliance
* Potential Patient Injury
Moderate The Effects are Moderately Severe
* Significant GMP/MA Non-Compliance
* Potential Patient Impact
Minor The Effects are Not Severe
* Minor GMP/MA Non-Compliance
* No Patient Impact
Risk = P x S
Negative
Event Prob: Minor Severity Moderate Severity Critical Severity
High Unacceptable Risk Intolerable Risk Intolerable Risk
Medium Acceptable Risk Unacceptable Risk Intolerable Risk
Low Acceptable Risk Acceptable Risk Unacceptable Risk
Remote Acceptable Risk Acceptable Risk Acceptable Risk </pre>
RISK DEFINITIONS:
Intolerable: Work to eliminate the Negative Event, or build in systems or controls to ensure the effects of the Negative Event are not realised (e.g. via back-up or redundant controls).
Unacceptable: Reduce the risk, or control the risk to an acceptable level.
Acceptable: The risk is acceptable as is. No risk reduction or new controls are required.
Detection Control Ratings:
** High -- the control will likely detect the negative event or its effects
** Medium -- the control may detect the negative event or its effects
** Low -- it is not likely that the control will detect the negative event or its effects
** Zero -- no detection control in place
By Kevin O'Donnell (Corresponding Author) Compliance Department, Irish Medicines Board and Anne Greene, School of Chemistry and Pharmaceutical Sciences, Dublin Institute of Technology
Note: The views expressed in this paper are those of the authors, and should not be taken to represent the views of the Irish Medicines Board.
<pre>
Figure 1 Principles Underlying this Risk Management Solution
NO. PRINCIPLE
1. That the scope and extent of qualification and validation, and the
likely impact of changes, should be determined and managed on a
risk basis.
2. That risk is the combination of the probability of ocurrence of
harm and the severity of that harm, and that harm is considered to
be damage to health, including the damage that can occur from loss
of product quality or availability.
3. That as a minimum, risk management contains the following four
components: risk assessment, risk control, risk communication, and
risk review, as defined and described in ICH Q9.
4. That a consideration of "what might go wrong" is fundamental to the
risk management exercise.
5. That there may be some risks that cannot be eliminated or reduced
to an acceptable level with current or realistic controls or
resources, but that may be controlled to an acceptable level with
improved detection or other measures, as determined on a case-by-
case basis.
6. That risk management is not an exact science and, while a
scientific approach should form the basis of the risk management
process, there may be uncertainties associated with the outcome of
the risk management exercise.
7. That risk may be assessed qualitatively as well as quantitatively,
and that a good qualitative assessment of risk may be more valid
than a poor quantitative assessment.
8. That the main stakeholders associated with the application of risk
management within GMP and Regulatory Compliance environments are
patients and users of medicines, including healthcare
professionals, as well as Industry and Regulators, and that, while
the concerns of all involved stakeholders should be taken into
account in any risk management exercise, protection of the patient
is of prime importance, and therefore, risk management should
ultimately link to the protection of the patient.
9. That, in GMP environments, a high detectability of risk does not
necessarily mean that the risk is eliminated or adequately
controlled.
10. That the implementation of risk control measures could, in itself,
inadvertently introduce new risks, which will need to be managed.
11. That performing risk management exercises can be improved through
the use of multi-disciplinary teams.
12. That a formal risk management process may not always be necessary
or appropriate in all situations, and that the level of effort,
rigor, formality, and documentation associated with the risk
management process should be commensurate with the complexity and/
or criticality of the issue being addressed.
Figure 2 A Ten-Step Risk Management Process
Step 1: Document Specific Information on the Risk Management Exercise
Being Undertaken:
* Identify whether the exercise is a Prospective, Retrospective, or a
Change Control risk management exercise.
* Define the item under study and the scope of the exercise. If
possible, define boundaries for the item under study.
* Provide relevant background information so that the reason for the
risk management exercise is made clear.
* State any pertinent assumptions being made, especially those
relating to qualification and validation, and document any
significant uncertainties associated with the data being used in the
exercise.
Step 2: Who's Who? -- Define the Risk Management Team:
* Identify the risk management team leader and other team members.
* The team should be multi-disciplinary and include persons
knowledgable in the item under study.
* At least one person should have a firm understanding of the risk
management process, principles, and methodology.
* If possible, there should be personnel on the team who have the
necessary authority (or the means) to make key decisions regarding
the implementation and funding of risk mitigation controls.
Step 3: Review the Default Definitions Provided for Negative Event
Probability, Severity, and Detection:
* Review the default Probability, Severity, and Detection definitions
provided in this Risk Management Tool. These are presented on a
laminate card, which accompanies the tool worksheet.
* The team then decides whether the default definitions as provided
are appropriate for the specific risk management exercise at hand.
* This is where new or modified Probability, Severity, and Detection
definitions can be drawn up, if required. For example, the
definitions for Probability of Occurence can be made quantitative,
or the Severity definitions can be altered to better reflect the
concerns of any specific stakeholders.
* A Risk Table (or matrix) is used by this Risk Management Tool, and
this is also shown on the laminate card. (See page 25.)
Step 4: What Might Go Wrong? -- Identify Potential Negative Events:
* Review relevant documentation, records and data, and use
brainstorming techniques to identify potential negative events for
the item under study. (Note: Guidance on brainstorming is provided
in a Questions and Answers document provided with the tool.)
* Of the potential negative events identified, review each, discussing
their potential severities, and select and list those considered to
be the most critical and/or complex negative events, for formal
evaluation in this exercise.
* As this is a formal and rigorous risk management methodology, only
the highest priority or most important potential negative events
should normally be selected for formal evaluation. However, any
number can be selected.
Step 5: Risk Evaluation -- Is the Risk Acceptable, Unacceptable, or
Intolerable?
* For each potential negative event, identify and document the
potential negative consequences.
* Document and critically evaluate any currently in place back-up or
redundancy controls for the potential negative event, and assign a
Severity rating.
* Identify and document the cause(s) of each potential negative event.
* Document and critically evaluate any currently in place preventive
controls for each cause, and assign a Probability of Occurrence
rating to each cause.
* Using the Risk Table provided on the laminated card which
accompanies the tool worksheet, estimate each risk associated with
the potential negative event.
* This results in the classification of each risk as either
Acceptable, Unacceptable, or Intolerable.
* Risks deemed to be Acceptable progress directly to Step 8 of the
worksheet; all other risks progress to Step 6.
Step 6: Risk Evaluation -- Is the Risk Adequately Controlled?
* Document and critically evaluate any detection controls currently in
place for each Unacceptable and Intolerable risk.
* Assign a Detection rating to these controls, and determine whether
these controls give assurance that the risk is adequately
controlled and that no further controls are required.
* Risks that are considered adequately controlled progress directly to
Step 8. All other risks progress to Step 7.
Step 7: Risk Control:
* Identify and critically evaluate any new or improved back-up or
redundancy controls, which may be put in place for Unacceptable and
Intolerable risks.
* With these controls in mind, assign a new Severity rating to the
potential negative event.
* Identify and critically evaluate any new or improved preventive
controls, which may be put in place for the cause(s) of each
Unacceptable and Intolerable risk.
* With these controls in mind, assign a new Probability of Occurrence
rating to each cause.
* Using the Risk Table provided on the laminated card, which
accompanies the tool worksheet, re-estimate each risk.
* This results in the re-classification of each risk as either
Acceptable, Unacceptable, or Intolerable.
* Risks deemed to be Acceptable progress to Step 8 of the worksheet;
all other risks continue through Step 7.
* Identify and critically evaluate any new or improved detection
controls for each Unacceptable and Intolerable risk.
* Assign a Detection rating to these controls, and determine whether
these controls give assurance that the risk is now adequately
controlled and that no further controls are required.
* Risks that are considered adequately controlled progress to Step 8.
* For risks that are still not considered adequately controlled, Step
7 (Risk Control), should be repeated. (A redesign of the item under
study may be necessary in order to eliminate the potential negative
event.)
Step 8: Qualification and Validation:
* For each control listed on Worksheets No. 5, 6, and 7, identify the
items (such as documentation, equipment, facilities, personnel
resources, etc.), which are required for the control to be in place.
* Determine Critical Process Parameters, their limits, and any other
acceptance criteria or required outcomes for each control.
* Determine any training and assessment of training requirements for
each control.
* Determine any Qualification or Validation activities required for
each control, and assign a Qualification and Validation status to
each.
Step 9: Action Items:
* Document any action items arising out of the risk management
exercise, and assign responsibilities for each.
* These could be actions required to implement a control, or they
could be Qualification or Validation exercises.
Step 10: Risk Communication and Continuous Improvement (Periodic Review)
Activities:
* Identify and document any communication activities required for the
risks identified during the exercise.
* Assign responsibilities and timelines for each communication.
* Define when the risk management exercise should be reviewed as part
of continuous improvement, and document any key areas or issues to
be reviewed at that time.
* Close out the risk management exercise. </pre>
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Overview of Pharmaceutical Product Development and Its Associated Quality System Potency Method Validation
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M2 Presswire , 09/21/2006
Overview of Pharmaceutical Product Development and Its Associated Quality System Potency Method Validation.
COPYRIGHT 2006 M2 Communications Ltd.
M2 PRESSWIRE-21 September 2006-Research and Markets: Overview of Pharmaceutical Product Development and Its Associated Quality System Potency Method Validation(C)1994-2006 M2 COMMUNICATIONS LTD RDATE:22092006
Dublin - Research and Markets (http://www.researchandmarkets.com/reports/c42485) has announced the addition of "Analytical Method Validation and Instrument Performance Verification" to their offering.
Validation describes the procedures used to analyze pharmaceutical products so that the data generated will comply with the requirements of regulatory bodies of the US, Canada, Europe and Japan. Calibration of Instruments describes the process of fixing, checking or correcting the graduations of instruments so that they comply with those regulatory bodies. This book provides a thorough explanation of both the fundamental and practical aspects of biopharmaceutical and bioanalytical methods validation.
It teaches the proper procedures for using the tools and analysis methods in a regulated lab setting. Readers will learn the appropriate procedures for calibration of laboratory instrumentation and validation of analytical methods of analysis. These procedures must be executed properly in all regulated laboratories, including pharmaceutical and biopharmaceutical laboratories, clinical testing laboratories (hospitals, medical offices) and in food and cosmetic testing laboratories.
KKey Topics Covered Include:
Method Validation for HPLC Analysis of Related Substances in Pharmaceutical Drug ProductsOverview of Pharmaceutical Product Development and Its Associated Quality SystemPotency Method ValidationDissolution Method ValidationDevelopment and Validation of Automated MethodsAnalysis of Pharmaceutical Inactive IngredientsValidation Study of JP Heavy Metal Limit TestBioanalytical Method ValidationProcurement, Qualification, and Calibration of Laboratory Instruments: An OverviewPerformance Verification of UV-Vis SpectrophotometersPerformance Verification of HPLCOperational Qualification of a Capillary Electrophoresis InstrumentLC-MS Instrument CalibrationKarl Fisher Apparatus and Its Performance VerificationThe pH Meter and Its Performance VerificationQualification of Environmental ChambersEquipment Qualification and Computer System ValidationValidation of Excel Spreadsheet
For more information visit http://www.researchandmarkets.com/reports/c42485
CONTACT: Laura Wood, Senior Manager, Research and MarketsFax: +353 1 4100 980 e-mail: press@researchandmarkets.com
((M2 Communications Ltd disclaims all liability for information provided within M2 PressWIRE. Data prepared by named party/parties. Further information on M2 PressWIRE can be obtained at http://www.presswire.net on the world wide web. Inquiries to info@m2.com)).
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