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The United States Pharmacopeia emphasizes mechanical calibration and a performance test to esnure integrity of the dissolution procedure.
In October 2007, the USFood and Drug Administration released a draft Guidance for Industry: Use of Mechanical Calibration of Dissolution Apparatus 1 and 2—Current Good Manufacturing Practice and called for public comments (1). This article summarizes the basis for the US Pharmacopeia's (USP) request to withdraw the draft guidance, provided in a detailed response to the public docket (2).
The intent of the USP performance verification test (PVT), which is used for nonsolution orally administered drug products, is to ensure continuing equivalence between the clinical trial material on which safety and efficacy conclusions were made and the manufactured article following approval. US regulatory approaches do not require postapproval reconsideration of bioequivalence for drug products, barring postapproval change. Thus, reliance on USP becomes a key if not the sole means of ensuring consistency in a drug product's performance.
USP General Chapters ‹701› Disintegration and ‹711› Dissolution, and other chapters provide general procedures with acceptance criteria that can be adapted by manufacturers to specific products (3, 4). Data arising from the adaptation undergo regulatory review and, if approved, become one of the tests in the private drug product specification.
The dissolution procedure described in ‹711› requires an assembly that allows a kinetic measure of drug release over time. Combining effects from the analyst and analytic procedure, the procedure is usually performed at batch release and also as part of stability studies. The assembly is a complicated mechanical device and includes many factors that can influence results. For this reason, USP, and until recently, FDA have emphasized the importance of a periodic PVT* together with careful mechanical calibration to ensure that the combined experimental study yields consistent results.
FDA's draft guidance argues that only mechanical calibration is needed. Based on substantial research and development efforts, USP maintains instead that both PVT and mechanical calibration are critical to ensure the integrity of the dissolution procedure and that mechanical calibration alone cannot ensure the validity of dissolution results (6–15). The dissolution test system consists of the mechanical apparatus (itself composed of several components), the physical environment in which the apparatus exists, the analytical procedure, and the analyst. Mechanical calibration addresses and controls only some of the components of the apparatus.
Justification for a combined approach
Metrology. Fundamental metrology concerns the establishment of measurement units, the realization of measurement standards, and the transfer of traceability from these standards to users in society. Applied to manufacturing, metrology ensures the suitability of measurement instruments, their calibration, and quality control of measurements. In the legal sense of the term, metrology enables regulatory requirements for measurements and measuring instruments for the protection of health, public safety, and the environment, and supports decisions regarding protection of consumers and fair trade. A core concept in metrology is traceability, defined as "the property of the result of a measurement or the value of a standard whereby it can be related to stated references, usually national or international standards, through an unbroken chain of comparisons, all having stated uncertainties" (16). The level of traceability establishes the level of comparability of the measurement between results in any and all laboratories that conduct the procedure. USP's tests and procedures are developed with this objective in mind and form the basis for the legal recognition of USP's standards of strength, quality, and purity in the adulteration provisions of the Federal Food, Drug, and Cosmetic Act (17). USP thus works to ensure that manufacturers, for commercial purposes, and FDA, for regulatory purposes, have access to procedures that achieve a high degree of assurance in test results without regard to time and space.†
The overarching goal of metrological traceability is the transfer of accuracy (trueness) and precision throughout the measurement "ladder." The two fundamental transfer agents of this ladder are procedures with specified methods and reference materials. USP's monograph procedures are frequently grounded in reference materials (e.g., official USP reference standards), with the understanding that the relationship between the procedure for the measurand (the material being examined) is closely linked to the reference material reflective of that measurand. At times, USP uses informally the terms "vertical standards" for the article under test and "horizontal standards" for the monograph's procedures. A key example of horizontal documentary and reference material standards is the dissolution procedure, described in ‹711›. There is a metrologic aspect to the dissolution procedure because a concentration is determined and can be traced to the base SI units of mass (kilogram). USP, however, notes that the kinetic aspects of the dissolution procedure are not well-grounded in metrology (i.e., there is no absolute number from the kinetic study that can be traced to an SI unit). In this regard, the dissolution procedure has the kinetic character of an enzyme assay that yields results in units per mass rather than in SI units alone. This does not mean that such grounding could not be improved, nor does it mean that the procedure is without value. The complex character of an assembly in fact requires careful consideration of horizontal standards to ensure acceptable results.
USP endorses the concept of mechanical calibration (grounded in metrology), conducted at periodic intervals, to ensure that the mechanical components meet specifications and are in a state of control. These mechanical checks, however, are necessary but not sufficient because they ignore the chemical and kinetic aspects of the dissolution procedure, an oversight that is common in most chemical tests. For example, even the best-calibrated high-performance liquid chromatography equipment still needs systems suitability standards to ensure proper performance within and across laboratories. In one of the most common chemical measurement tests performed, pH, it is not sufficient to ensure only that the electronics of the meter (essentially a voltmeter) are functioning. Rather, there must be assurance that the entire system (the meter, the glass electrode, the counter electrode, and the analyst) is performing adequately through the use of pH buffer standard solutions. Traceability, accuracy, and comparability can then be ensured. USP reference standard tablets used in PVT help ensure that the complex character of a dissolution assembly, coupled with an analyst and analytical procedure, act in concert to yield results within and among laboratories with acceptable accuracy and precision.
USP has established that mechanical calibration of a dissolution assembly does not address adequately all factors (e.g., vessel symmetry) that influence dissolution results (9, 13). Recent USP research also leads to the conclusion that the current tolerances and specifications set for mechanical calibration are inadequate and must be tightened (e.g., 7, 9). Even if mechanical calibration could be brought to complete realization (i.e., control of all possible impacting factors through conformance to specified tolerances), a PVT would still be needed to test the system as a whole and in actual use. Control of each factor individually might be possible, but that would not mean that all elements working in concert would yield reproducible and comparable results.
ISOproficiency. In the terminology of the International Organization for Standardization (ISO), USP's chemical reference standard tablets used in PVT are elements of a proficiency test whereby a laboratory may compare its results to those from other laboratories (18). USP emphasizes the value of these publicly available reference standards that allow PVT within and among laboratories to ensure that all laboratories achieve similar results in the interests of setting a metrologically sound and publicly derived USP performance test in the drug product specification.
GMPs. Ensuring the quality of data generated by analytical equipment includes an overall approach to equipment quality. Pharmaceutical scientists have long accepted that equipment qualification—installation qualification (IQ), operational qualification (OQ), and performance qualification (PQ)—under good manufacturing practices (GMPs) should be executed to verify acceptable quality of output from multicomponent analytical instrumentation. Although practitioners may debate where in the IQ, OQ, and PQ process individual qualification activities should take place, the fundamental principles are indisputable. Each component of the verification process contributes to overall quality of data generated from multicomponent analytical instrumentation, and omission of any component will compromise the quality assurance of data (19). On the basis of its research, USP concludes that mechanical calibration must be coupled with PVT to satisfy GMP requirements for OQ and PQ, respectively.
Quality of USP prednisone RS tablets
FDA has claimed that the USP prednisone RS tablet exhibits poor quality. The first time this claim came to USP's attention was during presentations by FDA staff at USP's 2004 Annual Science Meeting in Iselin, NJ, and again at meetings of the FDA Advisory Committee for Pharmaceutical Science in May and October 2005. USP refutes the claim based on studies conducted over the past several years (6). USP's Lot P prednisone RS tablet exhibits variability that is less than that of commercially marketed therapeutic drug products but is about the same as that of FDA's NCDA #2 tablet lot (20, 21).
In studies cited in this commentary (6–15, 20) and in various internal and external discussions with its Expert Committee members, stakeholders, and others, USP has determined that a PVT performed at periodic intervals, in addition to mechanical calibration, is required to ensure the integrity and reliability of the dissolution procedure when referenced in the USP performance test and in private regulatory drug product specifications. USP believes that additional work is needed to improve its General Chapters that function to ensure the consistency of drug products and expand them to products other than nonsolution orally administered dosage forms. USP also is in accord with an often stated view that new approaches to assess drug product performance in vitro are needed.
In the long term, USP envisions an evolved set of approaches to assess drug product performance for all nonsolution dosage forms over time following regulatory approval. Although the use of a PVT with some kind of physical article will be needed in the short term, these newer approaches could offer better public health protection and ease of use by pharmaceutical manufacturers. It is important not to abandon current approaches that have worked well before new opportunities become available. USP hopes that this work can advance jointly with FDA, industry, and other stakeholders.
* USP General Chapter ‹711› has been revised, replacing the term "apparatus suitability test" with "performance verification test" (5). Although USP reference standard tablets have been referred to as calibrators, this is a misnomer. The tablets are not, and cannot, be used for calibration.
† The argument has been made that a manufacturer can make its own physical artifact (an in-house reference material standard) for a PVT. Although such standards may work locally, this approach is inconsistent with national and international measurement systems, where comparability and consistency across time and space are essential. This approach is also untenable if the goal is to align laboratories among manufacturers and between manufacturers and regulatory laboratories. The task of developing a reliable and useful reference material tablet is not an easy one and would require much duplication of effort.
Thomas Foster, PharmD, is chair of the USP Biopharmaceutics Expert Committee. Darrell R. Abernethy, MD, PhD,* is chief science officer, William F. Koch, PhD, is chief reference materials officer, and Walter W. Hauck, PhD, is senior scientific fellow, all three at USP, 12601 Twinbrook Parkway, Rockville, MD 20852-1790, tel. 301.816.8141, firstname.lastname@example.org
*To whom correspondence should be addressed.
1. FDA, CDER, Guidance for Industry: Use of Mechanical Calibration of Dissolution Apparatus 1 and 2—Current Good Manufacturing Practice, Office of Regulatory Affairs (Rockville, MD), 2007.
2. Public Docket 2007D-0365, available at frwebgate.access.gpo.gov/cgi-bin/getpage.cgi?dbname=2007_register&position=all&page=59298,
accessed Feb. 1, 2008.
3. USP, USP 30–NF 25, Disintegration ‹701›, US Pharmacopeial Convention (Rockville, MD, 2007), pp. 276–277.
4. USP, USP 30-NF 25, Dissolution ‹711›, US Pharmacopeial Convention (Rockville, MD, 2007), pp. 277–284.
5. USP, "Interim Revision Announcement, Dissolution ‹711›," Pharm. Forum 33 (4), 626–630 (2007).
6. G. Deng et al., "The USP Performance Verification Test, Part I: Quality Attributes and Experimental Variables Contributing to Dissolution Variance," Pharm. Res., in press (2008), available at www.springerlink.com/content/j8246315n5404j18/?p+8a0886888caf41b4b69722da48bfd8&pi=0, accessed Jan. 29, 2008.
7. M. Glasgow et al., "The USP Performance Verification Test, Part II: Collaborative Study of USP's Lot P Prednisone Tablets," Pharm. Res., in press (2008), available at www.springerlink.com/content/b3726195727184gl/?p=8a0886888caf41b4b69722da48bfb5d8&pi=1, accessed Jan. 29, 2008.
8. P. Nithyanandan et al., "Evaluation of the Sensitivity of USP Prednisone Tablets to Dissolved Gas in the Dissolution Medium Using USP Apparatus 2," Dissolution Technol. 13 (3), 15–18 (2006).
9. J. Eaton et al., "Perturbation Study of Dissolution Apparatus Variables—A Design of Experiment Approach," Dissolution Technol. 14 (1), 20–26 (2007).
10. M.R. Liddell et al., "Evaluation of Glass Dissolution Vessel Dimensions and Irregularities," Dissolution Technol. 14 (2),
11. W.W. Hauck et al., "Proposed Change to Acceptance Criteria for Dissolution Performance Verification Testing," Pharm. Forum 33 (3), 574–579 (2007). Reprinted in: Dissolution Technol. 14 (3), 8–12 (2007).
12. W.W. Hauck et al., "Reliability and Reproducibility of Vertical Diffusion Cells for Determining Release Rates from Semisolid Dosage Forms," Pharm. Res. 24 (11), 2018–2024 (2007).
13. M. Liddell et al., "Dissolution Testing Variability: Effect of Using Vessels from Different Commercial Sources," Am. Pharm. Rev. 10 (6), 122–128 (2007).
14. R.G. Manning et al., "Dissolution Testing and Metrological Measurement of Quality for Solid Oral Dosage Forms," Pharm. Technol. 31 (5), 68–74 (2007).
15. G. Deng et al., "Frequency-domain Vibration Measurement and Analysis in Dissolution Testing," poster presented at the 2007 Annual AAPSMeeting (San Diego, CA).
16. International Bureau of Weights and Measures et al., International Vocabulary of Basic and General Terms in Metrology, Second Ed., ISO (Geneva, Switzerland, 1993), p. 47.
17. 21 USC 501(b). Federal Food, Drug, and Cosmetic Act.
18. ISO, Standard 5725 Accuracy (Trueness and Precision) of Measurement Methods and Results, Parts 1–6, ISO (Geneva, Switzerland, 1994).
19. FDA, "ORA Laboratory Procedure. Assuring the Quality of Test Results. ORA-Lab.5.9," 2007, available at www.fda. gov/ora/science_ref/lm/vol2/secion/5_09.pdf, accessed Jan. 29, 2008.
20. P. Nithyanandan et al., "Dissolution Variability: Comparison of Commercial Dosage Forms with US Pharmacopeia Lot P Prednisone Reference Standard Tablets," AAPS PharmSciTech., in press (2008).
21. Z. Gao et al., "Gauge Repeatability and Reproducibility for Accessing Variability during Dissolution Testing: A Technical Note," AAPS PharmSciTech. 8 (4), Art. 82 (2007).