药物和生物制剂的分析程序和方法验证行业指南

Analytical Procedures and Methods Validation for Drugs and Biologics Guidance for Industry U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER) July 2015 Pharmaceutical Quality/CMC Analytical Procedures and Methods Validation for Drugs and Biologics Guidance for Industry Additional copies are available from: Office of Communications, Division of Drug Information Center for Drug Evaluation and Research Food and Drug Administration 10001 New Hampshire Ave., Hillandale Bldg., 4th Floor Silver Spring, MD 20993 Phone: [phone] or 301-796-3400; Fax: [phone] Email: [e-mail] http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm and/or Office of Communication, Outreach and Development Center for Biologics Evaluation and Research Food and Drug Administration 10903 New Hampshire Ave., Bldg. 71, Room 3128 Silver Spring, MD 20993 Phone: [phone] or 240-402-7800 Email: [e-mail] http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER) July 2015 Pharmaceutical Quality/CMC Contains Nonbinding Recommendations TABLE OF CONTENTS I. INTRODUCTION............................................................................................................. 1 II. BACKGROUND ............................................................................................................... 2 III. ANALYTICAL METHODS DEVELOPMENT............................................................ 3 IV. CONTENT OF ANALYTICAL PROCEDURES.......................................................... 4 A. Principle/Scope...............................................................................................................................4 B. Apparatus/Equipment...................................................................................................................4 C. Operating Parameters...................................................................................................................4 D. Reagents/Standards.......................................................................................................................4 E. Sample Preparation .......................................................................................................................5 F. Standards Control Solution Preparation.....................................................................................5 G. Procedure........................................................................................................................................5 H. System Suitability ..........................................................................................................................5 I. Calculations....................................................................................................................................5 J. Data Reporting...............................................................................................................................6 V. REFERENCE STANDARDS AND MATERIALS........................................................ 6 VI. ANALYTICAL METHOD VALIDATION ................................................................... 7 A. Noncompendial Analytical Procedures........................................................................................7 B. Validation Characteristics.............................................................................................................7 C. Compendial Analytical Procedures..............................................................................................8 VII. STATISTICAL ANALYSIS AND MODELS ................................................................ 8 A. Statistics..........................................................................................................................................8 B. Models.............................................................................................................................................9 VIII. LIFE CYCLE MANAGEMENT OF ANALYTICAL PROCEDURES ........................ 9 A. Revalidation..................................................................................................................................10 B. Analytical Method Comparability Studies................................................................................10 1. Alternative Analytical Procedures.................................................................................................10 2. Analytical Methods Transfer Studies.............................................................................................12 C. Reporting Postmarketing Changes to an Approved NDA, ANDA, or BLA...........................12 IX. FDA METHODS VERIFICATION.............................................................................. 12 X. REFERENCES................................................................................................................ 13 Contains Nonbinding Recommendations 1 1 Analytical Procedures and Methods Validation for Drugs and 2 Biologics Guidance for Industry1 3 4 5 6 This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) on 7 this topic. It does not create any rights for any person and is not binding on FDA or the public. You can 8 use an alternative approach if it satisfies the requirements of the applicable statutes and regulations. To 9 discuss an alternative approach, contact the FDA staff responsible for this guidance as listed on the title 10 page. 11 12 13 14 I. INTRODUCTION 15 16 This guidance supersedes the draft of the same name that published on February 19, 2014 (79 FR 17 9467) and replaces the 2000 draft guidance for industry on Analytical Procedures and Methods Validation 2,3 18 and the 1987 Guidelines for Submitting Samples and Analytical Data for Methods 19 Validation. It provides recommendations on how you, the applicant, can submit analytical procedures4 and methods validation5 20 data to support the documentation of the identity, strength, quality, purity, and potency of drug substances and drug products.6 21 It will help you assemble 22 information and present data to support your analytical methodologies. The recommendations 23 apply to drug substances and drug products covered in new drug applications (NDAs), 24 abbreviated new drug applications (ANDAs), biologics license applications (BLAs), and 25 supplements to these applications. The principles in this guidance also apply to drug substances 26 and drug products covered in Type II drug master files (DMFs). 27 28 This guidance complements the International Conference on Harmonisation (ICH) guidance 29 Q2(R1) Validation of Analytical Procedures: Text and Methodology (Q2(R1)) for developing and 30 validating analytical methods. 31 32 This guidance does not address investigational new drug application (IND) methods validation, 33 but sponsors preparing INDs should consider the recommendations in this guidance. For INDs, 34 sufficient information is required at each phase of an investigation to ensure proper identity, 35 quality, purity, strength, and/or potency. The amount of information on analytical procedures and methods suitability will vary with the phase of the investigation.7 36 For general guidance on 1 This guidance has been prepared by the Office of Pharmaceutical Quality in the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER) at the Food and Drug Administration. 2 Sample submission is described in section IX, FDA Methods Verification. 3 We update guidances periodically. To make sure you have the most recent version of a guidance, check the FDA Drugs guidance Web page at http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm. 4 Analytical procedure is interchangeable with a method or test procedure. 5 Compendial methods are verified rather than validated as described in section VI, C. 6 The terms drug substance and drug product are used in this guidance to refer to both human drugs and biologics. 7 See 21 CFR 312.23(a)(7). Contains Nonbinding Recommendations 2 37 analytical procedures and methods validation information to be submitted for phase one studies, 38 sponsors should refer to the FDA guidance for industry on Content and Format of 39 Investigational New Drug Applications (INDs) for Phase 1 Studies of Drugs, Including 40 Well-Characterized, Therapeutic, Biotechnology-Derived Products. General considerations for 41 analytical procedures and methods validation before conduct of phase two and three studies are 42 discussed in the FDA guidances for industry on INDs for Phase 2 and 3 Studies of Drugs, 43 Including Specified Therapeutic Biotechnology-Derived Products (February 1999) and IND 44 Meetings for Human Drugs and Biologics, Chemistry, Manufacturing, and Controls 45 Information. 46 47 This guidance does not address specific method validation recommendations for biological and 48 immunochemical assays for characterization and quality control of many drug substances and 49 drug products. For example, some bioassays are based on animal challenge models, and 50 immunogenicity assessments or other immunoassays have unique features that should be 51 considered during development and validation. 52 53 Analytical methods required during product and process development activities are discussed in FDA 54 guidance for industry on Process Validation: General Principles and Practices. 55 56 In addition, a risk-based approach on the need for revalidation of existing analytical methods 57 may need to be considered when the manufacturing process changes during the product’s life 58 cycle. For questions on appropriate validation approaches for analytical procedures or 59 submission of information not addressed in this guidance, you should consult with the 60 appropriate FDA quality assessment staff. 61 62 If you choose a different approach than those recommended in this guidance, we encourage you 63 to discuss the matter with the appropriate FDA quality assessment staff before you submit your 64 application. 65 66 In general, FDA’s guidance documents do not establish legally enforceable responsibilities. 67 Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only 68 as recommendations, unless specific regulatory or statutory requirements are cited. The use of 69 the word should in Agency guidances means that something is suggested or recommended, but 70 not required. 71 72 73 II. BACKGROUND 74 75 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.8 76 Each BLA must 77 include a full description of the manufacturing process, including analytical procedures that 78 demonstrate the manufactured product meets prescribed standards of identity, quality, safety, purity, and potency.9 79 Data must be available to establish that the analytical procedures used in 8 See 21 CFR 314.50(d)(1) and 314.94(a)(9)(i). 9 See 21 CFR 601.2(a) and 601.2(c). Contains Nonbinding Recommendations 3 80 testing meet proper standards of accuracy, sensitivity, specificity, and reproducibility and are suitable for their intended purpose.10 81 82 83 Analytical procedures verification or validation data should be submitted in the corresponding 84 sections of the application in the ICH M2 eCTD: Electronic Common Technical Document Specification. 11 85 86 87 When an analytical procedure is approved/licensed as part of the NDA, ANDA, or BLA, it 88 becomes the FDA-approved analytical procedure for the approved product. This analytical 89 procedure may originate from FDA recognized sources (e.g., a compendial procedure from the 90 United States Pharmacopeia/National Formulary (USP/NF)) or a validated procedure you 91 submitted that was determined to be acceptable by FDA. To apply an analytical method to a 92 different drug product, appropriate validation or verification studies for compendial procedures 93 with the matrix of the new product should be considered. 94 95 96 III. ANALYTICAL METHODS DEVELOPMENT 97 98 An analytical procedure is developed to test a defined characteristic of the drug substance or 99 drug product against established acceptance criteria for that characteristic. Early in the 100 development of a new analytical procedure, the choice of analytical instrumentation and 101 methodology should be selected based on the intended purpose and scope of the analytical 102 method. Parameters that may be evaluated during method development are specificity, linearity, 103 limits of detection (LOD) and limits of quantitation (LOQ), range, accuracy, and precision. 104 105 During early stages of method development, the robustness of methods should be evaluated 106 because this characteristic can help you decide which method you will submit for approval. 107 Analytical procedures in the early stages of development are initially developed based on a 108 combination of mechanistic understanding of the basic methodology and prior experience. 109 Experimental data from early procedures can be used to guide further development. You should 110 submit development data within the method validation section if they support the validation of 111 the method. 112 113 To fully understand the effect of changes in method parameters on an analytical procedure, you 114 should adopt a systematic approach for a method robustness study (e.g., a design of experiments 115 with method parameters). You should begin with an initial risk assessment and follow with 116 multivariate experiments. Such approaches allow you to understand factorial parameter effects 117 on method performance. Evaluation of a method’s performance may include analyses of 118 samples obtained from various stages of the manufacturing process from in-process to the 119 finished product. Knowledge gained during these studies on the sources of method variation can 120 help you assess the method performance. 121 122 10 See 21 CFR 211.165(e) and 211.194(a)(2). 11 Sections as applicable in Module 3: 3.2.S and 3.2.P. Contains Nonbinding Recommendations 4 123 IV. CONTENT OF ANALYTICAL PROCEDURES 124 125 You should describe analytical procedures in sufficient detail to allow a competent analyst to 126 reproduce the necessary conditions and obtain results within the proposed acceptance criteria. 127 You should also describe aspects of the analytical procedures that require special attention. An 128 analytical procedure may be referenced from FDA-recognized sources (e.g., USP/NF, Association of Analytical Communities (AOAC) International)12 129 if the referenced analytical 130 procedure is not modified beyond what is allowed in the published method. You should provide 131 in detail procedures from other published sources. The following is a list of essential 132 information you should include for an analytical procedure: 133 134 A. Principle/Scope 135 136 A description of the basic principles of the analytical test/technology (i.e., separation, detection); 137 target analyte(s) and sample(s) type (e.g., drug substance, drug product, impurities or compounds 138 in biological fluids). 139 140 B. Apparatus/Equipment 141 142 All required qualified equipment and components (e.g., instrument type, detector, column type, 143 dimensions, and alternative column, filter type). 144 145 C. Operating Parameters 146 147 Qualified optimal settings and ranges (include allowed adjustments supported by compendial 148 sources or development and/or validation studies) critical to the analysis (e.g., flow rate, 149 components temperatures, run time, detector settings, gradient, head space sampler). A drawing 150 with experimental configuration and integration parameters may be used, as applicable. 151 152 D. Reagents/Standards 153 154 The following should be listed where applicable: 155 156 · Description of reagent or standard 157 · Grade of chemical (e.g., USP/NF, American Chemical Society, High 158 Performance or Pressure Liquid Chromatography, or Gas 159 Chromatography and preservative-free) 160 · Source (e.g., USP reference standard, qualified in-house reference material, 161 WHO International Standard/Reference Material, CBER standard) 162 · Purity (for pure chemicals only), State (e.g., dried, undried), and concentration 163 · Potencies (where required by CFR, USP) 164 · Storage conditions 165 · Directions for safe use (as per current Safety Data Sheet) 166 · Validated or documented shelf life 12 See 21 CFR 211.194(a)(2). Contains Nonbinding Recommendations 5 167 168 New batches of biological reagents, such as monoclonal antibodies, polyclonal antisera, or cells, 169 may need extensive qualification procedures included as part of the analytical procedure. 170 171 E. Sample Preparation 172 173 Procedures (e.g., extraction method, dilution or concentration, desalting procedures and mixing 174 by sonication, shaking or sonication time) for the preparations for individual sample tests. A 175 single preparation for qualitative and replicate preparations for quantitative tests with appropriate 176 units of concentrations for working solutions (e.g., µg/ml or mg/ml) and information on stability 177 of solutions and storage conditions. 178 179 F. Standards Control Solution Preparation 180 181 Procedures for the preparation and use of all standard and control solutions with appropriate 182 units of concentration and information on stability of standards and storage conditions, 183 including calibration standards, internal standards, system suitability standards, etc. 184 185 G. Procedure 186 187 A step-by-step description of the method (e.g., equilibration times, and scan/injection sequence 188 with blanks, placeboes, samples, controls, sensitivity solution (for impurity method) and 189 standards to maintain validity of the system suitability during the span of analysis) and allowable 190 operating ranges and adjustments if applicable. 191 192 H. System Suitability 193 194 Confirmatory test(s) procedures and parameters to ensure that the system (equipment, 195 electronics, and analytical operations and controls to be analyzed) will function correctly as an 196 integrated system at the time of use. The system suitability acceptance criteria applied to 197 standards controls and samples, such as peak tailing, precision and resolution acceptance criteria, 198 may be required as applicable. For system suitability of chromatographic systems, refer to the 199 FDA guidance for industry on Validation of Chromatographic Methods and USP General 200 Chapter <621> Chromatography. 201 202 I. Calculations 203 204 The integration method and representative calculation formulas for data analysis (standards, 205 controls, samples) for tests based on label claim and specification (e.g., assay, specified and 206 unspecified impurities and relative response factors). This includes a description of any 207 mathematical transformations or formulas used in data analysis, along with a scientific 208 justification for any correction factors used. 209 Contains Nonbinding Recommendations 6 210 J. Data Reporting 211 212 A presentation of numeric data that is consistent with instrumental capabilities and acceptance 213 criteria. The method should indicate what format to use to report results (e.g., percentage label 214 claim, weight/weight, and weight/volume) with the specific number of significant figures 215 needed. The American Society for Testing and Materials (ASTM) E29 standard describes a 216 standard practice for using significant digits in test data to determine conformance with 217 specifications. For chromatographic methods, you should include retention times (RTs) for 218 identification with reference standard comparison basis, relative retention times (RRTs) (known 219 and unknown impurities) acceptable ranges and sample results reporting criteria. 220 221 222 V. REFERENCE STANDARDS AND MATERIALS 223 224 Primary and secondary reference standards and materials are defined and discussed in the 225 following ICH guidances: Q6B Specifications: Test Procedures and Acceptance Criteria for 226 Biotechnological/Biological Products, and Q7 Good Manufacturing Practice Guidance for 227 Active Pharmaceutical Ingredients. For all standards, you should ensure the suitability for use. 228 You should strictly follow storage and usage conditions and handling instructions for reference 229 standards to avoid modifications and contaminations, which could result in additional impurities 230 and inaccurate analysis. You should include information supporting any reference standards and 231 materials that you intend to use in the application. Information supporting reference standards 232 and materials should include qualification test reports and certificates of analysis (including 233 stability protocols, reports, and relevant known impurity profile information) as applicable. For 234 biological products under BLAs, qualification of subsequent reference standard lots should be 235 included in annual reports. 236 237 Reference standards can often be obtained from USP and may also be available through the 238 European Pharmacopoeia, Japanese Pharmacopoeia, World Health Organization, or National 239 Institute of Standards and Technology. Reference standards for a number of biological products 240 are also available from CBER. For certain biological products marketed in the U.S., reference standards authorized by CBER must be used before the product can be released to the market. 13 241 242 Reference materials from other sources should be characterized by procedures including routine 243 and beyond routine release testing as described in ICH Q6B. You should consider orthogonal 244 methods for reference material characterization. Additional testing could include attributes to 245 determine the suitability of the reference material not necessarily captured by the drug substance 246 or product release tests (e.g., more extensive structural identity and orthogonal techniques for 247 potency, purity and impurities). 248 249 A new batch of reference standard material (official or in-house) should be qualified/calibrated 250 against the current reference standard. For biological reference standards and materials, we 251 recommend that you follow a two-tiered approach when qualifying new reference standards to 252 prevent drift in the quality attributes. A two-tiered approach involves a comparison of each new 13 See 21 CFR 610.20. Contains Nonbinding Recommendations 7 253 reference standard with a primary reference standard so that it is linked to clinical trial material 254 and the current manufacturing process. 255 256 257 VI. ANALYTICAL METHOD VALIDATION 258 259 A. Noncompendial Analytical Procedures 260 261 Analytical method validation is the process of demonstrating that an analytical procedure is 262 suitable for its intended purpose. The methodology and objective of the analytical procedures 263 should be clearly defined and understood before initiating validation studies. This understanding 264 is obtained from scientifically-based method development and optimization studies. Validation 265 data must be generated under a protocol approved by the sponsor following current good 266 manufacturing practices with the description of methodology of each validation characteristic and predetermined and justified acceptance criteria, using qualified instrumentation. 14 267 Protocols 268 for both drug substance and product analytes or mixture of analytes in respective matrices should 269 be developed and executed. You should include details of the validation studies and results with 270 your application. 271 272 B. Validation Characteristics 273 274 Although not all of the validation characteristics are applicable for all types of tests, typical 275 validation characteristics are: 276 277 · Specificity 278 · Linearity 279 · Accuracy 280 · Precision (repeatability, intermediate precision, and reproducibility) 281 · Range 282 · Quantitation limit 283 · Detection limit 284 285 ICH Q2(R1) is considered the primary reference for recommendations and definitions on 286 validation characteristics for analytical procedures. The FDA guidance for industry on 287 Validation of Chromatographic Methods is available as well. 288 289 If a procedure is a validated quantitative analytical procedure that can detect changes in a quality 290 attribute(s) of the drug substance and drug product during storage, it is considered a stability291 indicating test. To demonstrate specificity of a stability-indicating test, a combination of 292 challenges should be performed. Some challenges include the use of samples spiked with target 293 analytes and all known interferences; samples that have undergone various laboratory stress 294 conditions; and actual product samples (produced by the final manufacturing process) that are 295 either aged or have been stored under accelerated temperature and humidity conditions. 296 14 For drugs see 21 CFR 211.165(e); 21 CFR 314.50 (d), and for biologics see 21 CFR 601.2(a), 601.2(c), and 601.12(a). Contains Nonbinding Recommendations 8 297 As the holder of the NDA, ANDA, or BLA, you must: (1) submit the data used to establish that 298 the analytical procedures used in testing meet proper standards of accuracy and reliability, and 299 (2) notify the FDA about each change in each condition established in an approved application 300 beyond the variations already provided for in the application, including changes to analytical procedures and other established controls.15 301 302 303 The submitted data should include the results from the robustness evaluation of the method, 304 which is typically conducted during method development or as part of a planned validation study.16 305 306 307 C. Compendial Analytical Procedures 308 309 The suitability of an analytical procedure (e.g., USP/NF, the Official Methods of Analysis of 310 AOAC International, or other recognized standard references) should be verified under actual conditions of use.17 311 Information to demonstrate that USP/NF analytical procedures are suitable 312 for the drug product or drug substance should be included in the submission and generated under 313 a verification protocol. 314 315 The verification protocol should include, but is not limited to: (1) compendial methodology to 316 be verified with predetermined acceptance criteria, and (2) details of the methodology (e.g., 317 suitability of reagent(s), equipment, component(s), chromatographic conditions, column, detector 318 type(s), sensitivity of detector signal response, system suitability, sample preparation and 319 stability). The procedure and extent of verification should dictate which validation characteristic 320 tests should be included in the protocol (e.g., specificity, LOD, LOQ, precision, accuracy). 321 Considerations that may influence what characteristic tests should be in the protocol may depend 322 on situations such as whether specification limits are set tighter than compendial acceptance 323 criteria, or RT or RRT profiles are changing in chromatographic methods because of the 324 synthetic route of drug substance or differences in manufacturing process or matrix of drug 325 product. Robustness studies of compendial assays do not need to be included, if methods are 326 followed without deviations. 327 328 329 VII. STATISTICAL ANALYSIS AND MODELS 330 331 A. Statistics 332 333 Statistical analysis of validation data can be used to evaluate validation characteristics against 334 predetermined acceptance criteria. All statistical procedures and parameters used in the analysis 335 of the data should be based on sound principles and appropriate for the intended evaluation. 336 Several statistical methods are useful for assessing validation characteristics, for example, an 337 analysis of variance (ANOVA) to assess regression analysis R (correlation coefficient) and R 15 For drugs see 21 CFR 314.50 (d), 314.70(d), and for biologics see 21 CFR 601.2(a), 601.2(c), and 601.12(a). For a BLA, as discussed, you must obtain prior approval from FDA before implementing a change in analytical methods if those methods are specified in FDA regulations. 16 See section III and ICH Q2(R1). 17 See 21 CFR 211.194(a)(2) and USP General Chapter <1226> Verification of Compendial Procedures. Contains Nonbinding Recommendations 9 338 squared (coefficient of determination) or linear regression to measure linearity. Many statistical 339 methods used for assessing validation characteristics rely on population normality, and it is 340 important to determine whether or not to reject this assumption. There are many techniques, 341 such as histograms, normality tests, and probability plots that can be used to evaluate the 342 observed distribution. It may be appropriate to transform the data to better fit the normal 343 distribution or apply distribution-free (nonparametric) approaches when the observed data are 344 not normally distributed. Appropriate literature or text should be consulted for information on 345 statistical procedures to use when developing new test methods, evaluating existing test methods 346 or evaluating measurement system performance, as well as other general information on the interpretation and treatment of analytical data.18 347 The data analysis should be assured either by 348 using appropriately validated software or independent verification for correctness. 349 350 B. Models 351 352 Some analytical methods might use chemometric and/or multivariate models. When developing 353 these models, the number of samples to provide adequate statistical power and range for model 354 development and validation should be considered. Suitable software should be used for data 355 analysis. Model parameters should be deliberately varied to test model robustness. 356 357 358 VIII. LIFE CYCLE MANAGEMENT OF ANALYTICAL PROCEDURES 359 360 Once an analytical procedure (including compendial methods) is successfully validated (or 361 verified) and implemented, the procedure should be followed during the life cycle of the product 362 to continually assure that it remains fit for its intended purpose. Trend analysis on method 363 performance should be performed at regular intervals to evaluate the need to optimize the 364 analytical procedure or to revalidate all or a part of the analytical procedure. If an analytical 365 procedure can only meet the established system suitability requirements with repeated 366 adjustments to the operating conditions stated in the analytical procedure, the analytical 367 procedure should be reevaluated, revalidated, or amended, as appropriate. 368 369 Over the life cycle of a product, new information and risk assessments (e.g., a better 370 understanding of product CQAs or awareness of a new impurity) may warrant the development 371 and validation of a new or alternative analytical method. New technologies may allow for 372 greater understanding and/or confidence when ensuring product quality. Applicants should 373 periodically evaluate the appropriateness of a product’s analytical methods and consider new or 374 alternative methods. 375 376 In anticipation of life cycle changes in analytics, an appropriate number of retention samples 377 should be maintained to allow for comparative studies. The number should be based on 378 scientific principles and an assessment of risk. For complex products that are sensitive to 379 manufacturing changes, reserve samples can be an important tool to make these comparisons. 18 See References section for examples including USP <1010> Analytical Data – Interpretation and Treatment, ASTM E1488 Standard Guide for Statistical Procedures to Use in Developing and Applying Test Methods and ASTM E2782 Standard Guide for Measurement Systems Analysis. Contains Nonbinding Recommendations 10 380 The retention samples used in comparative studies should include samples that represent 381 marketed product and, when possible, pivotal clinical trial material. 382 383 If a risk-based evaluation or other drivers lead to changes in an analytical procedure or 384 replacement with a new method or if the procedure is transferred to a new testing site; 385 revalidation, a new validation exercise, an analytical method comparability study, or a 386 combination of these exercises should be considered. In some cases, changes to the drug 387 substance or drug product manufacturing process may also warrant analytical procedure 388 revalidation. These additional studies are discussed below. 389 390 A. Revalidation 391 392 Principles described in the validation section (section VI) apply to revalidation. When a change 393 is made to an analytical procedure (e.g., a change in a piece of equipment or reagent or because 394 of a change in manufacturing process or formulation), revalidation of all or part of the analytical 395 procedure should be considered. Analytical method revalidation may also be warranted because 396 of manufacturing process changes, such as an alteration in the drug substance manufacturing 397 process that could impact method performance (e.g., route of synthesis, fermentation) or 398 introduction of a new drug product formulation. 399 400 You should revalidate to ensure that the analytical procedure maintains its critical performance 401 characteristics (e.g., specificity, precision, accuracy). The degree of revalidation depends on the 402 nature of the change. 403 404 B. Analytical Method Comparability Studies 405 406 Analytical method comparability study requests are typically generated when you propose to 407 substitute an FDA-approved analytical procedure with an alternative analytical procedure or 408 when an analytical method is transferred from one laboratory to the other. For information on 409 statistical procedures to use for determining equivalence of two test methods, appropriate literature or text should be consulted. 19 410 These scenarios are discussed below. 411 412 1. Alternative Analytical Procedures 413 414 An alternative analytical procedure is an analytical procedure that you use in place of the FDA415 approved analytical procedure. For an NDA or ANDA, you should include any proposed 416 alternate analytical procedures in the application. You must include a description of the procedure.20 417 After approval, for an NDA or ANDA, or for a procedure approved in a BLA but 418 not included in an FDA regulation, the addition, revision, or deletion of an alternative analytical 419 procedure that provides the same or increased assurance of the identity, strength, quality, purity, 19 See References section for examples including USP General Chapter <1010> Analytical Data – Interpretation and Treatment and ASTM E2935 Standard Practice for Conducting Equivalence Testing in Laboratory Applications. 20 See 21 CFR 314.50. Contains Nonbinding Recommendations 11 420 or potency of the material being tested as the analytical procedure described in the approved application, must be documented in the next annual report.21 421 422 423 For biological products, in rare cases an analytical procedure may be included in an FDA 424 regulation. If the analytical method required is described by a regulation, however, and you want 425 to use an alternate method, you must submit the alternate method for review and approval 426 according to 21 CFR 610.9(a). You must present evidence “…demonstrating that the 427 modification will provide assurances of the safety, purity, potency, and effectiveness of the 428 biological product equal to or greater than the assurances provided by the method or process 429 specified in the general standards or additional standards for the biological product.” 430 Modification of such procedures requires FDA approval during application review or in a postapproval supplement.22 431 432 433 You should identify the use of the alternative analytical procedure (e.g., release, stability testing) 434 and provide a rationale for its inclusion, validation data, and comparative data to the FDA435 approved analytical procedure. You should perform an analytical method comparability study 436 that demonstrates at a minimum that: 437 438 · The new method coupled with any additional control measures is equivalent or 439 superior to the original method for the intended purpose. 440 441 · The new analytical procedure is not more susceptible to matrix effects than the 442 original procedure. 443 444 If new process-related or product-related variants or any new impurities are discovered with the 445 new procedure, testing on retention samples from historical batches should be performed to 446 demonstrate that the variants/impurities detected by the new method are a result of an increase in 447 the sensitivity or selectivity of the new procedure and not a result of a change to process-related 448 impurities. 449 450 If the procedure has stability-indicating properties: 451 452 · Appropriate samples should be included that allow a comparison of the ability of 453 the new and original method to detect relevant product variants and degradation 454 species. 455 · The number of batches analyzed for comparison should provide sufficient 456 statistical power. 457 · Equivalence, non-inferiority, or superiority studies should be performed with 458 appropriate statistical methods to demonstrate that the new or revised methods performance is comparable or better than the original method. 23 459 460 · The statistical analyses performed to compare product testing should be 461 identified. 21 See 21 CFR 314.70(d)(1), (d)(2)(vii). 314.81(b)(2), and 601.12(d)(vii). 22 See 21 CFR 610.9(b). 23 ASTM E2935 – Standard Practice for Conducting Equivalence Testing in Laboratory Applications. Contains Nonbinding Recommendations 12 462 · All bias or differences between analytical procedures seen with comparative 463 results should be discussed with an explanation, as appropriate. 464 465 2. Analytical Methods Transfer Studies 466 467 Analytical method transfer is typically managed under a transfer protocol that details the 468 parameters to be evaluated in addition to the predetermined acceptance criteria that will be 469 applied to the results. Transfer studies usually involve two or more laboratories or sites 470 (originating lab and receiving labs) executing the preapproved transfer protocol. A sufficient 471 number of representative test articles (e.g., same lot(s) of drug substance or drug product) are 472 used by the originating and receiving laboratories. The comparative studies are performed to 473 evaluate accuracy and precision, especially with regard to assessment of interlaboratory 474 variability. In cases where the transferred analytical procedure is also a stability-indicating 475 method, forced degradation samples or samples containing pertinent product-related impurities 476 should be analyzed at both sites. The USP General Chapter <1224> Transfer of Analytical 477 Procedures provides additional guidance on this topic. 478 479 C. Reporting Postmarketing Changes to an Approved NDA, ANDA, or BLA 480 481 Postmarketing changes to analytical procedures must be reported to the FDA in compliance with 21 CFR 314.70 or 21 CFR 601.12.24 482 Additional information on the appropriate reporting 483 category for various kinds of postapproval changes for NDAs and ANDAs is provided in the 484 FDA guidance for industry on Changes to an Approved NDA or ANDA and Changes to an 485 Approved NDA or ANDA; Specifications – Use of Enforcement Discretion for Compendial 486 Changes. Similar information on postapproval changes to BLAs regulated by CDER and CBER 487 is provided in the FDA guidance Changes to an Approved Application for Specified 488 Biotechnology and Specified Synthetic Biological Products. 489 490 491 IX. FDA METHODS VERIFICATION 492 493 Part of the approval process for NDAs and ANDAs may include FDA laboratory assessment to 494 determine whether the analytical procedures are acceptable for quality control and suitable for regulatory purposes.25 495 If a laboratory assessment will be conducted, the FDA laboratory will 496 send you a request that will detail what samples and supplies to send to the FDA laboratory. 497 These could include product samples, standards, critical reagents, material safety data sheets, and 498 supplies. Laboratory results and comments will be forwarded from the FDA laboratory to the 499 product quality reviewer. 500 501 For certain biological products, samples representative of the product for licensure along with 502 summaries of results of tests performed on the lots represented by these samples should be submitted with the BLA.26 503 The FDA laboratory verifies the performance of the methods and the 24 As noted, for a product licensed under a BLA, if the change is to a procedure prescribed in FDA regulations that change must be approved by FDA pursuant to 21 CFR 610.9(b). 25 See 21 CFR 314.50(e). 26 See 21 CFR 601.2(a). Contains Nonbinding Recommendations 13 504 results you submit. During a pre-BLA meeting or after submission of the BLA, the FDA 505 laboratory can send you a request to provide standards, controls, reagents, material safety data 506 sheets, and supplies. 507 508 X. REFERENCES 509 Guidance for Industry27 510 511 512 ANDAs: Impurities in Drug Products (November 2010) 513 514 ANDAs: Impurities in Drug Substances (July 2009) 515 516 Changes to an Approved NDA or ANDA (April 2004) 517 518 Changes to an Approved Application for Specified Biotechnology and Specified Synthetic 519 Biological Products (July 1997) 520 521 Changes to an Approved NDA or ANDA; Specifications – Use of Enforcement Discretion for 522 Compendial Changes (November 2004) 523 524 Content and Format of Investigational New Drug Applications (INDs) for Phase 1 Studies of 525 Drugs, Including Well-Characterized, Therapeutic, Biotechnology-derived Products (November 526 1995) 527 528 IND Meetings for Human Drugs and Biologics, Chemistry Manufacturing and Controls 529 Information (May 2001) 530 531 INDs for Phase 2 and 3 Studies of Drugs, Including Specified Therapeutic Biotechnology532 Derived Products (February 1999) 533 534 Investigating Out of Specification (OOS) Test Results for Pharmaceutical Production (October 535 2006) 536 537 Process Validation: General Principles and Practices (January 2011) 538 539 Reviewer Guidance, Validation of Chromatographic Methods (November 1994) 540 541 Submission of Chemistry, Manufacturing, and Controls Information for Synthetic Peptide 542 Substances (November 1994) 543 27 Draft guidances have been included for completeness only. As draft documents, they are not intended to be implemented until published in final form. We update guidances periodically. To make sure you have the most recent version of a guidance, check the FDA Drugs guidance Web page at http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm. Contains Nonbinding Recommendations 14 544 Guidance for Industry: International Conference on Harmonization 545 546 Q1A(R2) Stability Testing of New Drug Substances and Products (November 2003) 547 548 Q1B Stability Testing: Photostability Testing of New Drug Substances and Products (May 549 1997) 550 551 Q1C Stability Testing for New Dosage Forms (May 1997) 552 553 Q2(R1) Validation of Analytical Procedures: Text and Methodology (March 1995, May 1997) 554 555 Q3A(R2) Impurities in New Drug Substances (June 2008) 556 557 Q3B(R2) Impurities in New Drug Products (August 2006) 558 559 Q3C Impurities: Residual Solvents (December 1997) 560 561 Q3C Tables and List (February 2012) 562 563 Q5C Quality of Biotechnological Products: Stability Testing of Biotechnological/Biological 564 Products (July 1996) 565 566 Q6A Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and 567 New Drug Products: Chemical Substances (December 2000) 568 569 Q6B Specifications: Test Procedures and Acceptance Criteria for Biotechnological/Biological 570 Products (August 1999) 571 572 Q7 Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients 573 (August 2001) 574 575 United States Pharmacopeia/National Formulary 576 577 General Chapter <621> Chromatography 578 579 General Chapter <1010> Analytical Data – Interpretation and Treatment 580 581 General Chapter <1224> Transfer of Analytical Procedures 582 583 General Chapter <1225> Validation of Compendial Procedures 584 585 General Chapter <1226> Verification of Compendial Procedures 586 587 General Notices and Requirements, Applying to Standards, Tests, Assays, and Other 588 Specifications of the United States Pharmacopeia: 7. Test Results 589 Contains Nonbinding Recommendations 15 590 Interpretation and Treatment of Analytical Data; USP Pharmacopeial Forum, United States 591 Pharmacopeial Convention, Inc., Rockville MD: 1994, Volume 24, Number 5, pp. 7051 - 7056 592 593 Other 594 595 ASTM Standard, E29 - 2008 Standard Practice for Using Significant Digits in Test Data to Determine Conformance with Specifications, ASTM International, West Conshohocken, PA, 597 (www.astm.org). 598 599 ASTM E1488 – Standard Guide for Statistical Procedures to use in Developing and Applying 600 Test Methods, ASTM International, West Conshohocken, PA, (www.astm.org). 601 602 ASTM E2782 – Standard Guide for Measurement Systems Analysis (MSA), ASTM 603 International, West Conshohocken, PA, (www.astm.org). 604 605 ASTM Standard, E2935 – 2013 Standard Practice for Conducting Equivalence Testing in 606 Laboratory Applications, ASTM International, West Conshohocken, PA, (www.astm.org). 607 608 J.N. Miller and Miller, J.C., 2010, Statistics and Chemometrics for Analytical Chemistry, 6th 609 edition, Pearson Education Canada. 610 611 Saunders, B.D. and R.G. Trapp, 2004, Basic and Clinical Biostatistics, 4th edition, Lange 612 Medical Books/McGraw Hill.

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