QA is determined by top-level policies, procedures, work instructions, and governmental regulations. At the beginning of the validation process, QA can provide guidance for the development of or review of validation protocols and other validation documents. During the analytical stage, QA's job is to ensure that the proper method or procedure is in use and that the quality of the work meets the guidelines and regulations. QA can be thought of as the process that will determine the template and pattern of quality control tasks. As opposed to QC checks, QA reports are more likely to be performed by managers, by corporate level administrators, or third-party auditors through the review of the quality system, reports, archiving, training, and qualification of the staff that performs the work. AMV Guidance
Since the late 1980s, government and other agencies (for example, FDA, International Conference on Harmonization-ICH) have issued guidelines on validating methods. In 1987, the FDA designated the specifications in the current edition of the United States Pharmacopeia (USP) as those legally recognized when determining compliance with the Federal Food, Drug, and Cosmetic Act (3,4). More recently, new information has been published, updating the previous guidelines and providing more detail and harmonization with International Conference on Harmonization (ICH) guidelines (5,6). Guidelines are documents prepared for both regulatory agency personnel and the public that establish policies intended to achieve consistency in the agency's regulatory approach, and to establish inspection and enforcement policies and procedures. For example, the FDA guidance provides recommendations to applicants on submitting analytical procedures, validation data, and samples to support the documentation of the identity, strength, quality, purity, and potency of drug substances and drug products, and it is intended to assist applicants in assembling information, submitting samples, and presenting data to support analytical methodologies. The recommendations apply to drug substances and drug products covered in new drug applications (NDAs), abbreviated new drug applications (ANDAs), biologics license applications (BLAs), product license applications (PLAs), and supplements to these applications.
One final introductory comment: Although for the most part the topic of discussion in most "Validation Viewpoint" columns is HPLC, the guidelines are generic; that is, they apply to any analytical procedure, technique, or technology used in a regulated laboratory (for example, gas chromatography [GC], mass spectrometry [MS], or IR spectroscopy). It also should be noted that the USP publishes official methods, often called compendial methods, which have been accepted by the USP as already validated. However it is common practice to verify these methods, and a separate USP chapter is devoted to this topic (7,8).
The Validation Process
When looking at the guidelines, one observes that AMV is just one part of the overall validation process that encompasses at least four distinct steps: software validation, hardware (instrumentation) validation–qualification, analytical method validation, and system suitability. The overall validation process begins with validated software and a validated–qualified system; then a method is developed and validated using the qualified system. Finally, the whole process is wrapped together using system suitability. Each step is critical to the overall success of the process.
Before undertaking the task of method validation, it is necessary to invest some time and energy up-front to ensure that the analytical system itself is validated, or qualified. Qualification is a subset of the validation process that verifies proper module and system performance before the instrument being placed on-line in a regulated environment. In March, 2003, the American Association of Pharmaceutical Chemists (AAPS), the International Pharmaceutical Federation (FIP), and the International Society for Pharmaceutical Engineering (ISPE) cosponsored a workshop entitled "A Scientific Approach to Analytical Instrument Validation" (13). Among other objectives, the various parties (the event drew a cross-section of attendees; users, quality assurance specialists, regulatory scientists, consultants, and vendors) agreed that processes are "validated" and instruments are "qualified," finally reserving the term validation for processes that include analytical methods–procedures and software development.
The proceedings of the AAPS et al. committee have now become the basis for a new general USP chapter, number 1058, on Analytical Instrument Qualification (AIQ) that originally appeared in the USP's Pharmacopeial Forum (14–16). The chapter details the AIQ process, data quality, roles and responsibilities, software validation, documentation, and instrument categories.
Instruments are qualified according to a stepwise process grouped into four phases: design qualification (DQ), installation qualification (IQ), operational qualification (OQ), and performance qualification (PQ). The DQ phase usually is performed at the vendor's site, where the instrument is developed, designed, and produced in a validated environment according to good laboratory practices (GLP), current good manufacturing practices (cGMP), and ISO 9000 standards.
During the IQ phase, all of the activities associated with properly installing the instrument (new, pre-owned, or existing) at the users' site are documented. After the IQ phase is completed, testing is done to verify that the instrument and instrument modules operate as intended in an OQ phase. First, fixed parameters, for example, length, weight, height, voltage inputs, pressures, and so forth are either verified or measured against vendor-supplied specifications. Because these parameters do not change over the lifetime of the instrument, they usually are measured just once. Next, secure data handling is verified. Finally, instrument function tests are undertaken to verify that the instrument (or instrument modules) meets vendor and user specifications.
Instrument function tests should measure important instrument parameters according to the instruments' intended use and environment. For LC, the following types of tests might be included: n pump flow rate
- detector wavelength accuracy
- gradient linearity
- injector precision, linearity, and accuracy
- detector linearity
- column oven temperature.
In 1998, Furman and colleagues proposed a way to classify allowable adjustments (19). But it was not until 2005 that guidance appeared on the topic (20–22). Although USP guidance on this topic recently was included into USP Chapter 621 on chromatography (17), the FDA Office of Regulatory Affairs (ORA) has had guidance in place for a number of years (20). Table III summarizes the adjustments allowed for various HPLC parameters taken from both the USP and ORA documents. Adjustments outside of the ranges listed in Table III constitute modifications, or changes, which are subject to additional validation. Sound scientific reasoning should be used when determining method adjustment versus method change for a specific method. For example, if robustness studies have shown that the method conditions allow less variability for a parameter than that listed in Table III, or when robustness testing have shown that more variability is allowed, the robustness results (as summarized in the validation report) should prevail.
A few additional comments: Adjustments to chromatographic systems to comply with system-suitability requirements should not be made to compensate for system malfunctions or column failures. To prevent specification "creep," adjustments are made only from the original method parameters each time the method is run and are not subject to continuous adjustment. Adjustments are permitted only when suitable reference standards are available for all compounds used in the suitability test and only when those standards are used to show that the adjustments have improved the quality of the chromatography so as to meet system suitability requirements. The suitability of the method under the new conditions must be verified by assessment of the relevant analytical performance characteristics. Because multiple adjustments can have a cumulative effect in the performance of the system, any adjustments should be considered carefully before implementation.
In today's global market, validation can be a long and costly process, involving regulatory, governmental, and sanctioning bodies from around the world. A well-defined and documented validation process provides regulatory agencies with evidence that the system (instrument, software, method, and controls) is suitable for its intended use. AMV is a critical part of this process, and will be further addressed in detail in Part II of this two-part series.
Michael Swartz "Validation Viewpoint" Co-Editor Michael E. Swartz is Research Director at Synomics Pharmaceutical Services, Wareham, Massachusetts, and a member of LCGC 's editorial advisory board.
Ira S. Krull "Validation Viewpoint" Co-Editor Ira S. Krull is an Associate Professor of chemistry at Northeastern University, Boston, Massachusetts, and a member of LCGC 's editorial advisory board.
The columnists regret that time constraints prevent them from responding to individual reader queries. However, readers are welcome to submit specific questions and problems, which the columnists may address in future columns. Direct correspondence about this column to "Validation Viewpoint," LCGC, Woodbridge Corporate Plaza, 485 Route 1 South, Building F, First Floor, Iselin, NJ 08830, e-mail email@example.com [firstname.lastname@example.org]
(1) United States Food and Drug Administration, Guideline for submitting samples and analytical data for methods validation, February 1997. US Government Printing Office: 1990-281-794:20818, or at www.fda.gov/cder/analyticalmeth.htm
(2) Current Good Manufacturing Practice in Manufacturing, Processing, Packing, or Holding Of Drugs, 21 CFR Part 210, http://www.fda.gov/cder/dmpq/cgmpregs.htm|~http://www.fda.gov/cder/dmpq/cgmpregs.htm
(3) Current Good Manufacturing Practice for Finished Pharmaceuticals, 21 CFR Part 211, http://www.fda.gov/cder/dmpq/cgmpregs.htm|~http://www.fda.gov/cder/dmpq/cgmpregs.htm
(4) USP 32-NF 27, August 2009, Chapter 1225.
(5) Analytical Procedures and Method Validation. Fed. Reg. 65(169), 52,776-52,777, 30 August 2000. See also: www.fda.gov/cder/guidance
(6) International Conference on Harmonization, Harmonized Tripartite Guideline, Validation of Analytical Procedures, Text and Methodology, Q2(R1), November 2005, See www.ICH.org.
(7) USP 32-NF 27, August 2009, Chapter 1226.
(8) M.E. Swartz and I.S. Krull, LCGC 23(10), 1100–1109 (2005).
(9) FDA, General Principles of Software Validation; Guidance for Industry and FDA Staff. See: http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm085371.pdf|~http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm085371.pdf
(10) Guidance for Industry Computerized Systems Used in Clinical Investigations, FDA May 2007. See: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm070266.pdf|~www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm070266.pdf/
(11) FDA, 21 CFR Part 11, "Electronic Records; Electronic Signatures; Final Rule." Federal Register Vol. 62, No. 54, 13429, March 20, 1997.
(12) FDA, Part 11, Electronic Records; Electronic Signatures — Scope and Application, 2003. See: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm072322.pdf|~http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm072322.pdf
(13) Qualification of Analytical Instruments for Use in the Pharmaceutical Industry: A Scientific Approach, AAPS PharmSciTech, 2004, 5(1) Article 22 ( http://www.aapspharmscitech.org|~http://www.aapspharmscitech.org/
(14) Pharmacopeial Forum , 31(5), 1453–1463 (Sept-Oct 2005).
(15) USP 32-NF 27, August 2009, Chapter 1058
(16) M.E. Swartz, Analytical Instrument Qualification, Pharmaceutical Regulatory Guidance Book (Advanstar Communications, July 2006), pp. 12–16.
(17) USP 32-NF 27, August 2009, Chapter 621
(18) Center for Drug Evaluation and Research (CDER), Reviewer Guidance: Validation of Chromatographic Methods, US Government Printing Office, 1994 - 615-023 - 1302/02757.
(19) W.B. Furman, J.G. Dorsey, and L.R. Snyder, Pharm. Technol. 22(6), 58–64 (1998).
(20) FDA ORA Laboratory Procedure, #ORA-LAB.5.4.5, USFDA ( 09/09/2005). See also: http://www.fda.gov/ora/science_ref/lm/vol2/section/5_04_05.pdf|~http://www.fda.gov/ora/science_ref/lm/vol2/section/5_04_05.pdf
(21) Pharmacopeial Forum, 31(3), 825 (May-June 2005).
(22) Pharmacopeial Forum, 31(6) 1681 (Nov.-Dec. 2005).