Current Validation Process and Issues Exemplified by the

Current Validation Process and Issues: Exemplified by the HPLC Instrument Validation Moheb M. Nasr, Ph. D. Division of Pharmaceutical Analysis (FDA, CDER, DPA)

FDA 483 s - Quality and Laboratory Issues

HPLC Validation Issues z Assigned title: “Current Validation Process and Issues: Exemplified by HPLC Instrument Validation” z Today’s Presentation: “Current Issues: Laboratory Method Validation and Instrument Qualification”

Current Issues: Laboratory Method Validation and Instrument Qualification Validation: Processes are validated. Formulation Blending Analytical Methods Qualification: Equipment is qualified. V-Blender HPLC Chromatography System Each activity is to confirm suitability for intended use.

Current Issues: Laboratory Method Validation and Instrument Qualification z Current Method Validation and Instrument Qualification Practices z FDA’s Expectations z FDA 483 s - Quality and Laboratory Issues z Conclusions z Acknowledgments

Current Issues: Laboratory Method Validation and Instrument Qualification The following topics will not be addressed: y. Vendor Validation Support Programs y. Automation of Method Validation y. Laboratory Compliance with FDA’s Part 11

Current Method Validation and Instrument Qualification Practices Extent of validation depends on intended use z. Analytical Methods Validation: y. Analytical Method Attributes y. Instrument Qualification Parameters z. Method Validation Tools: y. FDA Guidance Documents y. ICH Guidelines Documents y. USP Documents

Current Method Validation and Instrument Qualification Practices Method Validation Evaluation of method’s suitability for intended purpose z Method Validation Tools y Spike and recovery (addition of known quantity) y Method comparison (analyze a standard using two different methods) y Standard Reference Materials (SRM, Material of established property to be used for method assessment and/or calibration) y Duplicates and replicates (repeated determinations of same test by same analyst) y Blanks or simulated test materials y Collaborative studies ( > 8, to establish method’s characteristics toward accuracy, precision, sensitivity, range, specificity, LOD, LOQ, selectivity and practicality)

Current Method Validation and Instrument Qualification Practices Methods Attributes and Validation Parameters y Practicality and applicability y Working range and Linearity y LOQ and LOD y Accuracy y Precision (repeatability) to access random error associated with whole process (sample prep to concentration calculation) y Precision (reproducibility) to access random error associated with changing operator, over time y Specificity and selectivity y Sensitivity y Robustness and ruggedness to measure capacity of analytical method to remain unaffected by changes in method parameter

Current Method Validation and Instrument Qualification Practices Laboratory Instrument Qualification: y. Design Qualification (DQ): traditionally vendor driven y. Installation Qualification (IQ): user/vendor driven y. Operational Qualification (OQ): user/vendor driven y. Performance Qualification (PQ): user driven User is responsible for documenting all levels of qualification

Qualification of HPLC Systems z Purpose: To Document continuing suitability of HPLC system for all anticipated applications and to assure it is kept under optimum maintenance and calibration conditions z Qualification Documentation and Protocols y User is responsible for documenting all levels of qualification y Documentation can be prepared by user and/or vendor y GMP vs non-GMP Equipment (contract laboratories) DQ IQ OQ Bedson and Rudd, Accred Qual Assur, 4: 50 -62, 1999 PQ

Qualification of HPLC Systems: Design Qualification (DQ) Instrument Specifications and Selection Criteria y Modular or integrated system, software control, data acquisition, processing and presentation y Sample preparation and introduction (sample injection, autosamplers, injection volume, needle wash, etc. ) y Construction materials y Documentation (manuals, CDs, SOPs) y Maintenance and support (ease of use, cost and availability of parts, service and technical support y Training requirements and training materials y Equipment environment and safety conditions

Qualification of HPLC Systems: Installation Qualification (IQ) Instrument received as specified and properly installed z Utilities z Environment z Establish Calibration Schedule z Establish Preventative Maintenance Protocol z Identify SOPs z Identify Training

Qualification of HPLC Systems: Operational Qualification (OQ) Verification of key performance aspects (modular, not method related) y To assure that main operating parameters (injection volume, flow rate, mobile phase mixing, column temperature control, detection wavelength) are within specified limits y Conducted after initial installation, system maintenance and repair, and repeated periodically y Conducted in-house y Frequency will depend on manufacturer’s recommendations, required performance, degree of use, nature of use and instrument history

Qualification of HPLC Systems: Performance Qualification (PQ) Demonstration of suitability of “entire” HPLC system for routine use y Vendor normally will conduct holistic performance test following initial OQ to verify entire system performance by analyzing a test mixture using a test column under defined conditions y User must conduct further tests, on regular basis, to provide continued evidence of system suitability and satisfactory instrument performance y PQ tests need to be simple, noninvasive, and comprehensive y PQ tests can be built into system suitability tests (SST) to assure evidence of satisfactory precision and linearity over desired range

Qualification of HPLC Systems: Performance Qualification (PQ) Critical HPLC PQ Parameters: x. Injection volume precision (< 1% RSD) x. Injection volume linearity (in some cases) x. Injection carryover (using a blank; method specific) x. Flow rate precision (< 0. 5% RSD RT) x. Column oven temperature (< 0. 5% RSD RT) x. Linearity of detector response (using standards; method specific) x. Signal to noise ratio (using dilute standards and blank; method specific) Individual components tests (Dolan, LC-GC, September 2002)

Qualification of HPLC Systems: System Suitability Specifications (SST) x Essential to assure performance of the chromatographic system x Amount of testing depends on purpose of test x It is recommended that SST be conducted before and during analysis x Peaks of interest should be well resolved from other peaks and void volume x RSD of < 1% for precision (injection repeatability) is desirable x Relative retention is not needed in cases where resolution (R s) is stated x Rs > 2 between peak of interest and closest interfering peak is desirable x Tailing factor (T) of < 2 is desirable x Theoretical plate number (N) depends on elution time x Adjustments vs. Modifications (Furman, Dorsey & Snyder; Pharm. Technol. , June , 1999)

Performance Qualification (PQ) and System Suitability Tests (SST) z Do we need to do both? x. SST may not guarantee error free chromatography (Don Parriott, LC-GC, Feb. 1994) x. Lack of SST in old monographs x. SST may not be comprehensive enough to detect critical HPLC system performance problems x. Undesirable need to adjust method parameters to compensate for chromatographic system problems x. Ensuring independent and objective qualification of critical system components (detector, pump and autosampler) will aid in the development of robust and transferable methods z Modular vs. Holistic Validation (Furman’s paper)

FDA’s Expectations z ICH-Q 2 A Guideline for Industry – Text on Validation of Analytical Procedures z ICH-Q 2 B Guideline for Industry – Validation of Analytical Procedures: Methodology z FDA Guidance for Industry – Analytical Procedures and Methods Validation Chemistry, Manufacturing and Controls Documentation z Reviewer Guidance Validation of Chromatographic Methods Nov. ’ 94 z U. S. Pharmacopeia/National Formulary (Chapters <621> and <1225> )

FDA’s Expectations z Each NDA and ANDA must include the analytical procedures necessary to ensure the identity, strength, quality, purity, and potency of the drug substance and drug product, including bioavailability of the drug product (21 CFR 314. 50(d)(1) and 314. 94(a)(9)(i)). Data must be available to establish that the analytical procedures used in testing meet proper standards of accuracy and reliability (21 CFR 211. 165(e) and 211. 194(a)(2)). z All analytical procedures are of equal importance from a validation perspective. In general, validated analytical procedures should be used, irrespective of whether used they are for in-process, release, acceptance, or stability testing. Each quantitative analytical procedure should be designed to minimize assay variation. z Validation should not be a one-time situation to fulfil agency filing requirement. z Applicants should submit information on the validation characteristics of their proposed analytical procedures (see ICH Q 2 A and ICH Q 2 B). Although not all of the validation characteristics are needed for all types of tests (see section VII. A. 3), typical validation characteristics are: Accuracy, Precision (repeatability and intermediate precision), Specificity, Detection limit, Quantitation limit, Linearity, Range, and Robustness

FDA’s Expectations z All chromatographic analytical procedures should include system suitability testing and criteria. Parameters typically used in system suitability evaluations are defined and discussed in the CDER Reviewer Guidance on Validation of Chromatographic Methods (November 1994). z A listing of all equipment (e. g. , instrument type, detector, column type, dimensions) should be included, as well as a list of equipment parameters (e. g. , flow rate, temperatures, run time, wavelength settings). z VALIDATION OF COMPENDIAL METHODS y Compendial procedures vary from highly exacting analytical determinations to subjective evaluation of attributes y Performance characteristics meet the requirements for the intended analytical applications y Equipment, electronics, analytical operations, and samples to be analyzed constitute an integral system that can be evaluated as such z System suitability tests verify that the resolution and reproducibility of the chromatographic system are adequate for the analysis to be done.

FDA 483 s - Quality and Laboratory Issues

FDA 483 s and Warning Letters Warning Letter A (Drug Product Manufacturer) z Failure to conduct performance qualification on the laboratory instruments (HPLC and GC) that are used to analyze raw materials and finished products. z Failure to validate software programs used to run HPLC equipment. Software used doesn’t secure data from alterations, loss, or erasures and allow for overwriting of original data. Warning Letter B (Drug Product Manufacturer) z Failure to calibrate HPLC used for testing in-process lots. z Performance qualifications didn’t include critical chromatographic specifications z No SOP requiring calibration of laboratory equipment. Warning Letter C (Drug Product Manufacturer) z Failure to establish SOPs or document the performance qualifications and maintenance of analytical equipment used in the testing and release of drug product.

FDA 483 s and Warning Letters Warning Letter D (Drug Product Manufacturer) z Failure to validate the Dissolution Test Method used to test the drug product. z There is no assurance that qualification or maintenance of laboratory equipment can consistently produce valid and accurate analytical results because of numerous instrument malfunction. Warning Letter E (Contract laboratory) z No established procedure for the qualification of analytical instruments for drug testing, when purchased and installed in this laboratory. 483 Observations A (Drug Product Manufacturer) z Several major laboratory instruments (HPLC, AA/AE/GC, etc, . . ) have not been qualified (installational, operational and performance qualification ). z System suitability tests are not performed for several methods.

FDA 483 s and Warning Letters 483 Observations B (Contract Test Laboratory) z Routine calibration, inspection, and checking of equipment is not performed according to a written program designed to assure proper performance. z Major laboratory equipment have not been qualified (installation, operational and performance qualification). 483 Observations C (Contract Test Laboratory) z No performance qualification conducted on several instruments (HPLC, UV/VIS and AA Spectrometer). z GMP vs non-GMP laboratory studies. 483 Observations A (Drug Product Manufacturer) z For HPLC instrumentation used for drug product testing, there was no documentation available which was approved by appropriate personnel showing that HPLC was fully qualified. This includes lack of written and approved installation and operational qualification documentations.

Conclusions z Do your homework prior to method development and instrument’s purchase: Method validation and instrument qualification should focus on suitability for intended use z Installation Qualification should clearly identify calibration, maintenance, SOP and training needs z Operational Qualification should ensure proper function of all system components z Performance Qualification should ensure suitability of “entire” HPLC system z Develop and validate methods using appropriate system suitability tests z SST failures? Go back to PQ (holistic), if necessary OQ (modular)to identify problems, initiate repairs, etc.

Acknowledgments z Nick Buhay (DMPQ, OC) z Rosa Motta (DMPQ, OC) z Nick Westenberger (DPA) z Jack Spencer (DPA) z Hank Drew (DPA) z Cindy Buhse (DPA) z Yuan-yuan Chiu (ONDC) z Ajaz Hussain (OPS)