Qualification, Validation, and Verification 4

"If clearly visible growth of microorganisms is obtained after the incubation, visually comparable to that in the control vessel without product, either the product possesses no antimicrobial activity under the conditions of the test or such activity has been satisfactorily eliminated. The test for sterility may then be carried out without further modification."
It may be advantageous, and more consistent, for the text in Chapter ‹71› to be changed to "Suitability of the Test Method," if not to "Verification of the Test Method." The latter change also may be appropriate for Chapters ‹61› and ‹62›, given that what is being assessed is the verification that the actual test conditions relative to those established during the validation permits the proper functioning of the method. Given the harmonized status of these three chapters, such changes, although possible, would certainly take longer to become official.
The same cautions provided at the end of the section on validation are applicable here. If a method in use previously was derived from a pharmacopeial method but used for a purpose other than satisfying monograph requirements, it is not necessary to adopt a revised method in the pharmacopeia when it becomes official. It is therefore not necessary to reverify the suitability of your test article to the revised method. Likewise, the use of a nonpharmacopeial method for purposes other than satisfying a monograph requirement when a pharmacopeial method exists of potential relevance does not necessitate reverification.
General requirements for validationThere are numerous documents that describe the general approach to a validation process. They describe several characteristics (data elements in Chapter ‹1225›) that may be examined during validation, with specific sets selected based upon the nature of the test method. A brief description of these characteristics is provided herein using the characteristics as outlined in the IC Harmonization Harmonized Tripartite Guideline, Validation of Analytical Procedures: Text and Methodology.
Accuracy is a determination of how close the measured value is (in the case of an analytical method) to the true value. As such, one might define accuracy of method as equal to true value plus error. Error may contain both the systematic error (bias) and imprecision of measurement. With the potential error possible, it is important to include a means of reflecting the "true value" as closely as possible. For many compendial tests, this involves the use of a reference standard. Because a method is expected to be useful over a range of true values, the accuracy should be assessed over the expected range of values to which the method is to be applied. As stated previously, the validation should also state the conditions under which the accuracy was determined. Because it is not possible to determine all possible sets of conditions for which a compendial assay might be applicable, accuracy may need to be verified before use of a validated method. The concept of accuracy is more problematic for microbiological assays.
The precision of a method determined during validation should be representative of the repeatability (reproducibility) of the method. As was the case for the determination of accuracy, it should be determined over the expected range of articles to be measured, and the conditions used during the validation should be clearly stated. As for accuracy, the use of reference standards is common because the goal of the assessment of precision is to determe method repeatability without introducing unknown variance as a result of different test articles or test articles drawn from a heterogeneous source. The latter point also complicates the validation of microbiological assays.
Specificity refers to the ratio of false positives to false negatives. A highly specific method would have a very low ratio, given that it should be able to detect the article of interest present in very low quantities in the presence of much higher quantities of similar but not identical articles. As stated previously, specificity should be determined over the expected range of usage for the method, and conditions used during the validation should be clearly stated.
Linearity, in essence, refers to the existence of a direct relationship between the quantity of article contained in the sample being analyzed and the measured value resulting from the analysis. It is not the purpose of this article to delve into statistical intricacies pertaining to data transformation, the use of linear or nonlinear regression techniques, residual analysis, and so forth. Currently, it is sufficient that an assay purporting to be quantitative in nature must have a demonstrable quantitative relationship between the quantity of material of interest contained in the sample and the measured response.

Qualification, Validation, and Verification 3

By: David A. Porter
Therefore, given the following from FDA's Guide to Inspections of Pharmaceutical Quality Control Laboratories: "Methods appearing in the USP are considered validated and they are considered validated if part of an approved ANDA" (8), the use of Method 3 would be valid if the conditions stated are met in testing the material of interest. The same FDA document states "For compendial methods, firms must demonstrate that the method works under the actual conditions of use," which, for the sake of this article, will be considered verification. Chapter ‹1047› provides several other procedures, all also validated, that could be considered given test material that does not satisfy the conditions for Method 3.
Remember the purpose. It is important to bear in mind the purpose of the method to be validated. If the method is intended to serve as an alternative to a pharmacopeial method, then one must establish its equivalence to the pharmacopeial method in terms of the end result. Remember that the purpose of a method in the pharmacopeia is to determine whether the pharmacopeial article (for which a monograph exists in the pharmacopeia) satisfies the requirements in the monograph. If instead the purpose behind the use of a pharmacopeial method is for a purpose other than demonstrating that the article complies with monograph requirements (for example, imagine that total organic carbon is to be determined using Chapter ‹643› "Total Organic Carbon"), it is not necessary to perform the validation relative to the pharmacopeial results. This means that the validation should be conducted relative to the specific purpose for which it is intended. Also implicit in this is the use of a nonpharmacopeial method to determine something for which a pharmacopeial method exists, but again for purposes unrelated to satisfying a monograph requirement. In such a case, it is unnecessary to consider validating the method relative to that in the pharmacopeia.
Verification
If the use of the term validation is restricted to mean the demonstration of suitability of a method or process for its intended purpose, and the term verification for the demonstration that the previously validated method is suitable for use given specific experimental conditions that may or may not be appropriate given the conditions present during the validation, the terminological situation may be clarified.

Figure 1

These actual conditions include specific ingredients or products, specific laboratory personnel, equipment, and reagents. There are, however, instances in the literature where this distinction is not maintained. Consider the dictionary definition given previously for validation and its use of verification as a synonym for validation. Further muddying of the waters occurs when phrases such as "system suitability tests" (see Figure 1 and the system-suitability section in Chapter ‹621› "Chromatography"). The phrase also appears in the "Suitability of the Counting Method in the Presence of Product" section of Chapter ‹61› "Microbiological Examination of Nonsterile Products: Microbial Enumeration Tests", the "Suitability of the Test Method" section of Chapter ‹62› "Microbiological Examination of Nonsterile Products: Tests for Specified Microorganisms", and the "Validation Test" section of Chapter ‹71› "Sterility Tests." (1). In all cases, the intention is to ensure that the validated method will work under the specific conditions the analyst plans to use. This means that a chromatographic system can deliver resolution and reproducibility on par with the system used during validation. For the two microbiology test chapters for nonsterile products, one must show that microbial growth in the presence of the article to be tested is not hindered. This is because the method depends on unencumbered microbial growth for it to work. In other words, a condition established in validating the method initially was unhindered microbial growth. The use of "validation test" in Chapter ‹71› is unfortunate because the intention was again to demonstrate that microbial growth is not hindered, as indicated in the following text:

Qualification, Validation, and Verification 2

By: David A. Porter
FDA provides a definition of validation in numerous documents. One such document, Guidance for Industry: Analytical Procedures and Methods Validation Chemistry, Manufacturing, and Controls Documentation says "methods validation is the process of demonstrating that analytical procedures are suitable for their intended use" (5). There also are numerous documents defining validation within the context of processes. From FDA's Guideline on General Principles of Process Validation:
"Validation—Establishing documented evidence which provides a high degree of assurance that a specific process will consistently produce a product meeting its predetermined specifications and quality attributes (6)."
The same definition is provided in other FDA documents, such as Guideline on Sterile Drug Products Produced by Aseptic Processing. FDA document Guidance for Industry: Quality Systems Approach to Pharmaceutical Current Good Manufacturing Practice Regulations provides this definition:
"With proper design (see section IV.C.1), and reliable mechanisms to transfer process knowledge from development to commercial production, a manufacturer should be able to validate the manufacturing process. In a quality system, process validation provides initial proof, through commercial batch manufacture, that the design of the process produces the intended product quality (7). "The remainder of the discussion about validation in this article will be restricted to a discussion of method validation.
Does it suit its purpose? The foregoing is clearly not an exhaustive list of the manners in which validation has been defined. It does appear that a recurring theme among the various definitions pertains to demonstrating that the method or process is suitable for its intended use. In this article, consider validation to be the demonstration that a method or process is suitable for its intended purpose. Accepting that, it is imperative that the intended purpose of a method or process is clearly stated at the outset of the validation. An example of the importance of such a statement can be found in Chapter ‹71› "Sterility Tests" (1). It states that "the following procedures are applicable for determining whether a Pharmacopeial article purporting to be sterile complies with the requirements set forth in the individual monograph with respect to the test for sterility." The next paragraph states
"These Pharmacopeial procedures are not by themselves designed to ensure that a batch of product is sterile or has been sterilized. This is accomplished primarily by validation of the sterilization process or of the aseptic processing procedures."
During the years there has been concern that the tests for sterility as provided in Chapter ‹71› are not adequate to prove that a batch of product is sterile. As stated previously, the tests in Chapter ‹71› were intended only to show that a Pharmacopeial article is sterile. Such a demonstration constitutes a necessary but not sufficient condition for sterile pharmacopeial articles. If one were to validate an alternative procedure for that in Chapter ‹71›, it would not be necessary to develop one that is intended to demonstrate sterility of an entire lot of product.
In addition, it is appropriate that the conditions are provided under which the validation was performed. Given that there are essentially countless variations on experimental conditions, product matrix effects, and so forth, a validation cannot reasonably expect to address all such permutations. For example, Method 3 in the section of Chapter ‹1047› "Biotechnology-Derived Articles—Tests", which addresses assays for total protein, indicates in a note:
"[Do not use quartz (silica) spectrophotometer cells: the dye binds to this material. Because different protein species may give different color response intensities, the standard protein and test protein should be the same.] There are relatively few interfering substances, but detergents and ampholytes in the test specimen should be avoided. Highly alkaline specimens may interfere with the acidic reagent (1)."

Qualification, Validation, and Verification 1

By: David A. Porter
The terms qualification, validation, and verification occur numerous times in US Pharmacopeia 29 (1). Qualification is found in Chapters ‹1035› "Biological Indicators for Sterilization," ‹1043› "Ancillary Materials Cell, Gene, and Tissue-Engineered Products," ‹1046› "Cell and Gene Therapy Products," and ‹1119› "Near-Infrared Spectrophotometry," among others. Validation appears in ‹1225› "Validation of Compendial Procedures," ‹1223› "Validation of Alternative Microbiological Methods," ‹1010› "Analytical Data—Interpretation and Treatment," ‹1043› "Ancillary Materials for Cell-, Gene-, and Tissue-Engineered Products," ‹1117› "Microbiological Best Laboratory Practices," ‹1120› "Raman Spectrophotometry," and many others. Verification appears in ‹1010› "Analytical Data—Interpretation and Treatment," ‹1035› "Biological Indicators for Sterilization," ‹1035› "Biological Indicators for Sterilization," ‹85› "Bacterial Endotoxins Test," and others. The terms also are present in documents from the US Food and Drug Administration, the Environmental Protection Agency (EPA), and the International Conference on Harmonization (ICH). Given the numerous definitions for the three terms, this article in part is intended to provide an approach to fostering more consistency in the usage of the terms. A recent issue of the Pharmacopeial Forum (2) had a diagram from a proposed General Chapter ‹1058› "Analytical Instrument Qualification" that was intended to show "...four critical components involved in the generation of reliable and consistent data (quality data)." From most to least critical, the components were quality-control check samples, system suitability tests, analytical methods validation, and analytical instrument qualification. In this article, consider system-suitability tests to be the same as verification. Why this usage should be acceptable will be explained. This article will consider validation and verification in detail. Reference to analytical instrument qualification is made. For further discussion of the top tier, "Quality Control Check Samples," refer to Chapter ‹1058› "Analytical Instrument Qualification" (1).
Qualification
Qualification of analytical instrumentation is essential for accurate and precise measurement of analytical data. If the instrumentation is not qualified, ensuring that the results indicated are trustworthy, all other work based upon the use of that instrumentation is suspect. For the purposes of this article, the assumption will be made that the foundation of validation and verification work to follow is based solidly upon well-qualified instrumentation. Validation
Definitions. Numerous documents provide definitions of validation. A dictionary definition (3) of validation includes "...the process of determining the degree of validity of a measuring device," and for validate: "to make legally valid," with synonyms "verify, substantiate." Clearly, the synonyms do not distinguish between validation and verification, so let us now turn to definitions provided by other sources. USP chapter ‹1225› "Validation of Compendial Procedures" provides the following:
"Validation of an analytical procedure is the process by which it is established, by laboratory studies, that the performance characteristics of the procedure meet the requirements for the intended analytical applications."
From the ICH document Validation of Analytical Procedures: Text and Methodology:
However, it is important to remember that the main objective of validation of an analytical procedure is to demonstrate that the procedure is suitable for its intended purpose

Equipment Hold-Time for Cleaning Validation 3

By: Richard J. Forsyth

Table V: Wet granulation equipment train—clean-hold validation (Acceptable residue limit [ARL] = 100 cfu/swab) An examination of the clean-hold time data supports the more aggressive approach. The data were consistent for both the wet- and dry-granulation equipment. The average bioburden level for the 180 samples taken was 1.1 cfu/swab. There were 128 samples with no detectable bioburden and only nine with a bioburden greater than 10 cfu/swab. Although the majority of samples were taken shortly after cleaning, samples were taken at 1, 2, 5, and 8 mo and at 2 yrs, 5 mo with no discernable increase in bioburden. With a bioburden limit of 100 cfu/swab, clean-hold time is not an issue for cleaned equipment that is dried, covered, and stored appropriately. Table VI: Equipment clean-hold time The dirty-hold-time study needed to answer two questions. Does the soil become harder to clean the longer it sits, and what is the possibility of microbial proliferation on soiled equipment? Soils can be more difficult to clean when they are wet and allowed to dry onto the surface, or when the soil is hygroscopic and transforms into a pasty material or subsequently dries. A high-shear granulator is the only equipment that carries out wet granulation at the conclusion of unit operation. The dirty-hold time for the high-shear granulator (196 h) was lengthy enough to allow any wet material to dry. The controlled humidity of the pilot plant prevented any moisture uptake by residual granulation. All other equipment in the validation studies resulted in a dry granulation at the conclusion of unit operation. Microbial proliferation was not a realistic possibility, which was corroborated by the clean-hold time data. Figure 1. High-shear granulator prepared for cleaning. (FIGURES ARE COURTESY OF THE AUTHOR) Subsequent to the validation studies, the gross cleaning of the equipment, including scraping and vacuuming the equipment was shifted from the equipment-cleaning process to the manufacturing process, which effectively shortened dirty-hold times. Because of environmental considerations for residue disposal, equipment operators scrape and vacuum accumulated residue from equipment surfaces. Operators then wipe equipment surfaces with alcohol to remove as much of the residue as possible to minimize the amount of residue discharge to the municipal sewer system. An example of a typical soiled equipment surface prepared for cleaning is shown in Figures 1 and 2. The steps taken for environmental concerns effectively shorten the dirty-hold time. The alcohol wipe dries within minutes, leaving no wet material to dry and become harder to clean. The dry soiled surfaces do not have sufficient water activity to support microbial proliferation. There is no sufficient residue remaining for hygroscopic residues to be a concern. The dirty-hold time data, which measured cleaning effectiveness out to 9 days, demonstrated a worst-case scenario for the pilot plant facility. The dirty-hold time is not of significant concern for soiled equipment awaiting cleaning. Figure 2. Granulator exit chute prepared for cleaning. Under the operating conditions tested as part of the cleaning validation studies, the clean- and dirty-hold times have little impact on the ongoing operations of the pilot-plant facility. In addition, routine verification of adherence to these parameters adds little value to a firm's ability to produce quality formulations. The risk, therefore, tied to not monitoring hold times should be low for validated cleaning and storage conditions.

Conclusion
If clean- and dirty-equipment hold times are established during validation and maintained under properly defined and controlled conditions, the need to monitor clean- or dirty-hold times is not necessary. Avoiding these steps can result in savings of time and resources as well as potential regulatory exposure.
Richard J. Forsyth is an associate director of worldwide GMP quality with Merck & Co., Inc, WP53C-307, West Point, PA. 19486, tel. 215.652.7462, fax 215.652.7106, richard_forsyth@merck.com
References
1. FDA, Guide to Inspection of Validation of Cleaning Processes, Division of Field Investigations, Office of Regional Operations, Office of Regulatory Affairs (Rockville, MD), July 1993.
2. EU, Annex 15, European Union Guide to Good Manufacturing Practice, Working Party on Control of Medicines and Inspections, European Commission (Brussels, Belgium), July 2001.
3. Health Canada, Cleaning Validation Guidelines (Guide-0028), Drug GMP Inspection Unit (Ottawa, Ontario) May 2000.
4. "Recommendations on Validation Master Plan Installation and Operational Qualification; Non-Sterile Process Validation; and Cleaning Validation," in proceedings of the PIC/S (PIC/S, July 2004).
5. R. J. Forsyth and D. Haynes, "Cleaning Validation in a Pharmaceutical Research Facility," Pharm. Technol. 22 (9), 104–112, 1998.
6. J. A. Morales Sanchez, "Equipment Cleaning Validation Within a Multi-Product Manufacturing Facility," BioPharm Inter. 31 (2), 38– 49, 2006.
7. A. H. Mollah, "Risk-Based Cleaning Validation in Biopharmaceutical API Manufacturing," BioPharm Inter. 30 (11), 54–68, 2005.
8. T. Fugate, "Hold Time Studies: A Lost Parameter for Cleaning Validation," J. Val. Technol. 13 (3), 206–209, 2007.