FDA最新指导原则：药物分析程序及方法验证指导原则

Analytical Procedures and Methods Validation for Drugs

and Biologics

DRAFT GUIDANCE

This guidance document is being distributed for comment purposes only. Comments and suggestions regarding this draft document should be submitted within 90 days of publication in the Federal Register of the notice announcing the availability of the draft guidance. Submit electronic comments to https://www.wendangku.net/doc/7a13924693.html,. Submit written comments to the Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. All comments should be identified with the docket number listed in the notice of availability that publishes in the Federal Registe r.

For questions regarding this draft document contact (CDER) Lucinda Buhse 314-539-2134, or (CBER) Office of Communication, Outreach and Development at 800-835-4709 or 301-827-1800.

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)

February 2014

CMC

Analytical Procedures and Methods Validation for Drugs

and Biologics

Additional copies are available from:

Office of Communications

Division of Drug Information, WO51, Room 2201

Center for Drug Evaluation and Research

Food and Drug Administration

10903 New Hampshire Ave., Silver Spring, MD 20993

Phone: 301-796-3400; Fax: 301-847-8714

druginfo@https://www.wendangku.net/doc/7a13924693.html,

https://www.wendangku.net/doc/7a13924693.html,/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm

and/or

Office of Communication, Outreach and

Development, HFM-40

Center for Biologics Evaluation and Research

Food and Drug Administration

1401 Rockville Pike, Rockville, MD 20852-1448

ocod@https://www.wendangku.net/doc/7a13924693.html,

https://www.wendangku.net/doc/7a13924693.html,/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm

(Tel) 800-835-4709 or 301-827-1800

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)

Febr uary 2014

CMC

TABLE OF CONTENTS

I.INTRODUCTION (1)

II.BACKGROUND (2)

III.ANALYTICAL METHODS DEVELOPMENT (3)

IV.CONTENT OF ANALYTICAL PROCEDURES (3)

A.Principle/Scope (4)

B.Apparatus/Equipment (4)

C.Operating Parameters (4)

D.Reagents/Standards (4)

E.Sample Preparation (4)

F.Standards Control Solution Preparation (5)

G.Procedure (5)

H.System Suitability (5)

I.Calculations (5)

J.Data Reporting (5)

V.REFERENCE STANDARDS AND MATERIALS (6)

VI.ANALYTICAL METHOD VALIDATION FOR NDA, ANDAs, BLAs, AND DMFs (6)

A.Noncompendial Analytical Procedures (6)

B.Validation Characteristics (7)

https://www.wendangku.net/doc/7a13924693.html,pendial Analytical Procedures (8)

VII.STATISTICAL ANALYSIS AND MODELS (8)

A.Statistics (8)

B.Models (8)

VIII.LIFE CYCLE MANAGEMENT OF ANALYTICAL PROCEDURES (9)

A.Revalidation (9)

B.Analytical Method Comparability Studies (10)

1.Alternative Analytical Procedures (10)

2.Analytical Methods Transfer Studies (11)

C.Reporting Postmarketing Changes to an Approved NDA, ANDA, or BLA (11)

IX.FDA METHODS VERIFICATION (12)

X.REFERENCES (12)

Guidance for Industry1

1

Analytical Procedures and Methods Validation for Drugs and

2

Biologics

3

4

5

This draft guidance, when finalized, will represent the Food and Drug Administration’s (FDA’s) current 6

thinking on this topic. It does not create or confer any rights for or on any person and does not operate to 7

bind FDA or the public. You can use an alternative approach if the approach satisfies the requirements of 8

the applicable statutes and regulations. If you want to discuss an alternative approach, contact the FDA

9

staff responsible for implementing this guidance. If you cannot identify the appropriate FDA staff, call 10

the appropriate number listed on the title page of this guidance.

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12

13

14

I. INTRODUCTION

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16

This revised draft guidance supersedes the 2000 draft guidance for industry on Analytical

17

Procedures and Methods Validation2,3 and, when finalized, will also replace the 1987 FDA

18

guidance for industry on Submitting Samples and Analytical Data for Methods Validation. It

19

provides recommendations on how you, the applicant, can submit analytical procedures4 and

20

methods validation data to support the documentation of the identity, strength, quality, purity,

21

and potency of drug substances and drug products.5It will help you assemble information and 22

present data to support your analytical methodologies. The recommendations apply to drug

23

substances and drug products covered in new drug applications (NDAs), abbreviated new drug 24

applications (ANDAs), biologics license applications (BLAs), and supplements to these

25

applications. The principles in this revised draft guidance also apply to drug substances and drug 26

products covered in Type II drug master files (DMFs).

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This revised draft guidance complements the International Conference on Harmonisation (ICH) 29

guidance Q2(R1)Validation of Analytical Procedures: Text and Methodology(Q2(R1)) for

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developing and validating analytical methods.

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This revised draft guidance does not address investigational new drug application (IND) methods 33

validation, but sponsors preparing INDs should consider the recommendations in this guidance.

34

For INDs, sufficient information is required at each phase of an investigation to ensure proper

35

identity, quality, purity, strength, and/or potency. The amount of information on analytical

36

procedures and methods validation will vary with the phase of the investigation.6 For general

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1 This guidance has been prepared by the Office of Pharmaceutical Science, 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

https://www.wendangku.net/doc/7a13924693.html,/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.

4Analytical procedure is interchangeable with a method or test procedure.

5The terms drug substance and drug product, as used in this guidance, refer to human drugs and biologics.

6 See 21 CFR 312.23(a)(7).

guidance on analytical procedures and methods validation information to be submitted for phase 38

one studies, 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 method validation (e.g., bioassay) before conduct of phase three

42

studies are discussed in the FDA guidance for industry on IND Meetings for Human Drugs and 43

Biologics, Chemistry, Manufacturing, and Controls Information.

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This revised draft guidance does not address specific method validation recommendations for

46

biological and immunochemical assays for characterization and quality control of many drug

47

substances and drug products. For example, some bioassays are based on animal challenge

48

models, and immunogenicity assessments or other immunoassays have unique features that

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should be considered during development and validation.

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In addition, the need for revalidation of existing analytical methods may need to be considered 52

when the manufacturing process changes during the product’s life cycle. For questions on

53

appropriate validation approaches for analytical procedures or submission of information not

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addressed in this guidance, you should consult with the appropriate FDA product quality review 55

staff.

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If you choose a different approach than those recommended in this revised draft guidance, we

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encourage you to discuss the matter with the appropriate FDA product quality review staff before 59

you submit your application.

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FDA’s guidance documents, including this guidance, do not establish legally enforceable

62

responsibilities. Instead, guidances describe the Agency’s current thinking on a topic and should 63

be viewed only as recommendations, unless specific regulatory or statutory requirements are

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cited. The use of the word should in Agency guidances means that something is suggested or

65

recommended, but not required.

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II.BACKGROUND

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Each NDA and ANDA must include the analytical procedures necessary to ensure the identity, 71

strength, quality, purity, and potency of the drug substance and drug product.7 Each BLA must 72

include a full description of the manufacturing methods, including analytical procedures that

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demonstrate the manufactured product meets prescribed standards of identity, quality, safety,

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purity, and potency.8 Data must be available to establish that the analytical procedures used in 75

testing meet proper standards of accuracy and reliability and are suitable for their intended

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purpose.9 For BLAs and their supplements, the analytical procedures and their validation are

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submitted as part of license applications or supplements and are evaluated by FDA quality

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review groups.

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7 See 21 CFR 314.50(d)(1) and 314.94(a)(9)(i).

8 See 21 CFR 601.2(a) and 601.2(c).

9 See 21 CFR 211.165(e) and 211.194(a)(2).

Analytical procedures and validation data should be submitted in the corresponding sections of 81

the application in the ICH M2 eCTD: Electronic Common Technical Document Specification.10

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When an analytical procedure is approved/licensed as part of the NDA, ANDA, or BLA, it

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becomes the FDA approved analytical procedure for the approved product. This analytical

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procedure may originate from FDA recognized sources (e.g., a compendial procedure from the 86

United States Pharmacopeia/National Formulary (USP/NF)) or a validated procedure you

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submitted that was determined to be acceptable by FDA. To apply an analytical method to a

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different product, appropriate validation studies with the matrix of the new product should be

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considered.

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III.ANALYTICAL METHODS DEVELOPMENT

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An analytical procedure is developed to test a defined characteristic of the drug substance or

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drug product against established acceptance criteria for that characteristic. Early in the

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development of a new analytical procedure, the choice of analytical instrumentation and

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methodology should be selected based on the intended purpose and scope of the analytical

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method. Parameters that may be evaluated during method development are specificity, linearity, 99

limits of detection (LOD) and quantitation limits (LOQ), range, accuracy, and precision.

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During early stages of method development, the robustness of methods should be evaluated

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because this characteristic can help you decide which method you will submit for approval.

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Analytical procedures in the early stages of development are initially developed based on a

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combination of mechanistic understanding of the basic methodology and prior experience.

105

Experimental data from early procedures can be used to guide further development. You should 106

submit development data within the method validation section if they support the validation of 107

the method.

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To fully understand the effect of changes in method parameters on an analytical procedure, you 110

should adopt a systematic approach for method robustness study (e.g., a design of experiments 111

with method parameters). You should begin with an initial risk assessment and follow with

112

multivariate experiments. Such approaches allow you to understand factorial parameter effects 113

on method performance. Evaluation of a method’s performance may include analyses of

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samples obtained from in-process manufacturing stages to the finished product. Knowledge

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gained during these studies on the sources of method variation can help you assess the method 116

performance.

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IV.CONTENT OF ANALYTICAL PROCEDURES

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You should describe analytical procedures in sufficient detail to allow a competent analyst to 122

reproduce the necessary conditions and obtain results within the proposed acceptance criteria. 123

You should also describe aspects of the analytical procedures that require special attention. An 124

analytical procedure may be referenced from FDA recognized sources (e.g., USP/NF,

125

10 See sections 3.2.S.4 Control of Drug Substance, 3.2.P.4 Control of Excipients, and 3.2.P.5 Control of Drug

Product.

Association of Analytical Communities (AOAC) International)11 if the referenced analytical

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procedure is not modified beyond what is allowed in the published method. You should provide 127

in detail the procedures from other published sources. The following is a list of essential

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information you should include for an analytical procedure:

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A.Principle/Scope

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A description of the basic principles of the analytical test/technology (separation, detection, etc.); 133

target analyte(s) and sample(s) type (e.g., drug substance, drug product, impurities or compounds 134

in biological fluids, etc.).

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B.Apparatus/Equipment

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All required qualified equipment and components (e.g., instrument type, detector, column type, 139

dimensions, and alternative column, filter type, etc.).

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C.Operating Parameters

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Qualified optimal settings and ranges (allowed adjustments) critical to the analysis (e.g., flow

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rate, components temperatures, run time, detector settings, gradient, head space sampler). A

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drawing with experimental configuration and integration parameters may be used, as applicable. 146

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D.Reagents/Standards

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The following should be listed:

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?Grade of chemical (e.g., USP/NF, American Chemical Society, High

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Performance or Pressure Liquid Chromatography, or Gas

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Chromatography and preservative free).

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?Source (e.g., USP reference standard or qualified in-house reference material). 155

?State (e.g., dried, undried, etc.) and concentration.

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?Standard potencies (purity correction factors).

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?Storage controls.

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?Directions for safe use (as per current Safety Data Sheet).

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?Validated or useable shelf life.

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New batches of biological reagents, such as monoclonal antibodies, polyclonal antisera, or cells, 162

may need extensive qualification procedures included as part of the analytical procedure.

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E.Sample Preparation

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Procedures (e.g., extraction method, dilution or concentration, desalting procedures and mixing 167

by sonication, shaking or sonication time, etc.) for the preparations for individual sample tests. 168

A single preparation for qualitative and replicate preparations for quantitative tests with

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11 See 21 CFR 211.194(a)(2).

appropriate units of concentrations for working solutions (e.g., μg/ml or mg/ml) and information 170

on stability of solutions and storage conditions.

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F.Standards Control Solution Preparation

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Procedures for the preparation and use of all standard and control solutions with appropriate

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units of concentration and information on stability of standards and storage conditions,

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including calibration standards, internal standards, system suitability standards, etc.

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G.Procedure

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A step-by-step description of the method (e.g., equilibration times, and scan/injection sequence 181

with blanks, placeboes, samples, controls, sensitivity solution (for impurity method) and

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standards to maintain validity of the system suitability during the span of analysis) and allowable 183

operating ranges and adjustments if applicable.

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H.System Suitability

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Confirmatory test(s) procedures and parameters to ensure that the system (equipment,

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electronics, and analytical operations and controls to be analyzed) will function correctly as an 189

integrated system at the time of use. The system suitability acceptance criteria applied to

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standards and controls, such as peak tailing, precision and resolution acceptance criteria, may be 191

required as applicable. For system suitability of chromatographic systems, refer to CDER

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reviewer guidance on Validation of Chromatographic Methods and USP General Chapter <621> 193

Chromatography.

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I.Calculations

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The integration method and representative calculation formulas for data analysis (standards,

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controls, samples) for tests based on label claim and specification (e.g., assay, specified and

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unspecified impurities and relative response factors). This includes a description of any

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mathematical transformations or formulas used in data analysis, along with a scientific

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justification for any correction factors used.

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J.Data Reporting

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A presentation of numeric data that is consistent with instrumental capabilities and acceptance 206

criteria. The method should indicate what format to use to report results (e.g., percentage label 207

claim, weight/weight, and weight/volume etc.) with the specific number of significant figures 208

needed. The American Society for Testing and Materials (ASTM) E29 describes a standard

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practice for using significant digits in test data to determine conformance with specifications. For 210

chromatographic methods, you should include retention times (RTs) for identification with

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reference standard comparison basis, relative retention times (RRTs) (known and unknown

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impurities) acceptable ranges and sample results reporting criteria.

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V.REFERENCE STANDARDS AND MATERIALS

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Primary and secondary reference standards and materials are defined and discussed in the

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following ICH guidances: Q6A Specifications: Test Procedures and Acceptance Criteria for 219

New Drug Substances and New Drug Products: Chemical Substances (ICH Q6A), Q6B

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Specifications: Test Procedures and Acceptance Criteria for Biotechnological/Biological

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Products, and Q7 Good Manufacturing Practice Guidance for Active Pharmaceutical

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Ingredients. For all standards, you should ensure the suitability for use. Reference standards for 223

drug substances are particularly critical in validating specificity for an identity test. You should 224

strictly follow storage, usage conditions, and handling instructions for reference standards to

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avoid added impurities and inaccurate analysis. For biological products, you should include

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information supporting any reference standards and materials that you intend to use in the BLA 227

and in subsequent annual reports for subsequent reference standard qualifications. Information 228

supporting reference standards and materials include qualification test protocols, reports, and 229

certificates of analysis (including stability protocols and relevant known impurity profile

230

information, as applicable).

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Reference standards can often be obtained from USP and may also be available through the

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European Pharmacopoeia, Japanese Pharmacopoeia, World Health Organization, or National 234

Institute of Standards and Technology. Reference standards for a number of biological products 235

are also available from CBER. For certain biological products marketed in the U.S., reference 236

standards authorized by CBER must be used before the product can be released to the market.12 237

Reference materials from other sources should be characterized by procedures including routine 238

and beyond routine release testing as described in ICH Q6A. You should consider orthogonal 239

methods. Additional testing could include attributes to determine the suitability of the reference 240

material not necessarily captured by the drug substance or product release tests (e.g., more

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extensive structural identity and orthogonal techniques for purity and impurities, biological

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activity).

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For biological reference standards and materials, we recommend that you follow a two-tiered 245

approach when qualifying new reference standards to help prevent drift in the quality attributes 246

and provide a long-term link to clinical trial material. A two-tiered approach involves a

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comparison of each new working reference standard with a primary reference standard so that it 248

is linked to clinical trial material and the current manufacturing process.

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VI.ANALYTICAL METHOD VALIDATION FOR NDA, ANDAs, BLAs, AND 252

DMFs

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A.Noncompendial Analytical Procedures

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Analytical method validation is the process of demonstrating that an analytical procedure is

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suitable for its intended purpose. The methodology and objective of the analytical procedures 258

should be clearly defined and understood before initiating validation studies. This understanding 259

12 See 21 CFR 610.20.

is obtained from scientifically-based method development and optimization studies. Validation 260

data must be generated under an protocol approved by the sponsor following current good

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manufacturing practices with the description of methodology of each characteristic test and

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predetermined and justified acceptance criteria, using qualified instrumentation operated under 263

current good manufacturing practices conditions.13 Protocols for both drug substance and

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product analytes or mixture of analytes in respective matrices should be developed and executed. 265

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ICH Q2(R1) is considered the primary reference for recommendations and definitions on

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validation characteristics for analytical procedures. The FDA Reviewer Guidance: Validation of 268

Chromatographic Methods is available as well.

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B.Validation Characteristics

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Although not all of the validation characteristics are applicable for all types of tests, typical

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validation characteristics are:

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?Specificity

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?Linearity

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?Accuracy

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?Precision (repeatability, intermediate precision, and reproducibility)

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?Range

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?Quantitation limit

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?Detection limit

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If a procedure is a validated quantitative analytical procedure that can detect changes in a quality 284

attribute(s) of the drug substance and drug product during storage, it is considered a stability

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indicating assay. To demonstrate specificity of a stability-indicating assay, a combination of

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challenges should be performed. Some challenges include the use of samples spiked with target 287

analytes and all known interferences; samples that have undergone various laboratory stress

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conditions; and actual product samples (produced by the final manufacturing process) that are

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either aged or have been stored under accelerated temperature and humidity conditions.

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As the holder of the NDA, ANDA, or BLA, you must:14 (1) submit the data used to establish

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that the analytical procedures used in testing meet proper standards of accuracy and reliability, 293

and (2) notify the FDA about each change in each condition established in an approved

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application beyond the variations already provided for in the application, including changes to 295

analytical procedures and other established controls.

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The submitted data should include the results from the robustness evaluation of the method,

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which is typically conducted during method development or as part of a planned validation

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study.15

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13 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).

14 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 below, you must obtain prior approval from FDA before implementing a change in analytical

methods if those methods are specified in FDA regulations

15 See section III and ICH Q2(R1).

https://www.wendangku.net/doc/7a13924693.html,pendial Analytical Procedures

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The suitability of an analytical procedure (e.g., USP/NF, the AOAC International Book of

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Methods, or other recognized standard references) should be verified under actual conditions of 305

use.16 Compendial general chapters, which are complex and mention multiple steps and/or

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address multiple techniques, should be rationalized for the intended use and verified. Information 307

to demonstrate that USP/NF analytical procedures are suitable for the drug product or drug

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substance should be included in the submission and generated under a verification protocol.

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The verification protocol should include, but is not limited to: (1) compendial methodology to 311

be verified with predetermined acceptance criteria, and (2) details of the methodology (e.g.,

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suitability of reagent(s), equipment, component(s), chromatographic conditions, column, detector 313

type(s), sensitivity of detector signal response, system suitability, sample preparation and

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stability). The procedure and extent of verification should dictate which validation characteristic 315

tests should be included in the protocol (e.g., specificity, LOD, LOQ, precision, accuracy, etc.). 316

Considerations that may influence what characteristic tests should be in the protocol may depend 317

on situations such as whether specification limits are set tighter than compendial acceptance

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criteria, or RT or RRT profiles are changing in chromatographic methods because of the

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synthetic route of drug substance or differences in manufacturing process or matrix of drug

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product. Robustness studies of compendial assays do not need to be included, if methods are 321

followed without deviations.

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VII.STATISTICAL ANALYSIS AND MODELS

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A.Statistics

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Statistical analysis of validation data can be used to evaluate validation characteristics against 329

predetermined acceptance criteria. All statistical procedures and parameters used in the analysis 330

of the data should be based on sound principles and appropriate for the intended evaluation.

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Reportable statistics of linear regression analysis R (correlation coefficient), R square

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(coefficient of determination), slope, least square, analysis of variance (ANOVA), confidence 333

intervals, etc., should be provided with justification.For information on statistical techniques 334

used in making comparisons, as well as other general information on the interpretation and

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treatment of analytical data, appropriate literature or texts should be consulted.17

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B.Models

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Some analytical methods might use chemometric and/or multivariate models. When developing 340

these models, you should include a statistically adequate number and range of samples for model 341

development and comparable samples for model validation. Suitable software should be used for 342

data analysis. Model parameters should be deliberately varied to test model robustness.

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16 See 21 CFR 211.194(a)(2) and USP General Chapter <1226> Verification of Compendial Procedures.

17 See References section for examples including USP <1010> Analytical Data – Interpretation and Treatment.

VIII.LIFE CYCLE MANAGEMENT OF ANALYTICAL PROCEDURES

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Once an analytical procedure (including compendial methods) is successfully validated and

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implemented, the procedure will be followed during the life cycle of the product. Trend analysis 349

on method performance should be performed at regular intervals to evaluate the need to optimize 350

the analytical procedure or to revalidate all or a part of the analytical procedure. If an analytical 351

procedure can only meet the established system suitability requirements with repeated

352

adjustments to the operating conditions stated in the analytical procedure, the analytical

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procedure should be reevaluated, revalidated, or amended, as appropriate.

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Over the life cycle of a product, new information (e.g., a better understanding of product CQAs 356

or awareness of a new impurity) may warrant the development and validation of a new or

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alternative analytical method. New technologies may allow for greater understanding and/or 358

confidence when ensuring product quality. Applicants should periodically evaluate the

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appropriateness of a product’s analytical methods and consider new or alternative methods.

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In anticipation of life cycle changes in analytics, an appropriate number of samples should be 362

archived to allow for comparative studies. The number should be based on scientific principles 363

and an assessment of risk. For complex products that are sensitive to manufacturing changes, 364

archived samples can be an important tool to make these comparisons. The archived samples 365

used in comparative studies should include samples that represent pivotal clinical trial material 366

and marketed product.

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If a risk-based evaluation or other drivers lead to changes in an analytical procedure or

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replacement with a new method or if the procedure is transferred to a new testing site;

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revalidation, a new validation exercise, an analytical method comparability study, or a

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combination of these exercises should be considered. In some cases, changes to the drug

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substance or drug product manufacturing process may also warrant analytical procedure

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revalidation. These additional studies are discussed below.

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A.Revalidation

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Principles described in the validation section (section VI) apply to revalidation. When a change 378

is made to an analytical procedure (e.g., a change in a piece of equipment or reagent or because 379

of a change in manufacturing process or formulation), revalidation of all or part of the analytical 380

procedure should be considered. Analytical method revalidation may also be warranted because 381

of manufacturing process changes, such as an alteration in the drug substance manufacturing

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process that could impact method performance (e.g., route of synthesis, fermentation) or

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introduction of a new drug product formulation.

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You should revalidate to ensure that the analytical procedure maintains its critical performance 386

characteristics (e.g., specificity, precision, accuracy, etc). The degree of revalidation depends on 387

the nature of the change.

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B.Analytical Method Comparability Studies

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Analytical method comparability study requests are typically generated when you propose to

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substitute an FDA approved analytical procedure with an alternative analytical procedure or

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when an analytical method is transferred from one laboratory to the other. These scenarios are 394

discussed below.

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1.Alternative Analytical Procedures

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An alternative analytical procedure is an analytical procedure that you use in place of the FDA 399

approved analytical procedure. For an NDA or ANDA, you should include any proposed

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alternate analytical procedures in the application. You must include a description of the

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procedure.18 After approval, for an NDA or ANDA, or for a procedure approved in a BLA but 402

not included in an FDA regulation, the addition, revision, or deletion of an alternative analytical 403

procedure that provides the same or increased assurance of the identity, strength, quality, purity, 404

or potency of the material being tested as the analytical procedure described in the approved

405

application, must be documented in the next annual report.19 Additions or revisions of analytical 406

procedures in BLAs may require submission as a supplement. FDA recommends discussion with 407

the appropriate review group to determine the appropriate reporting category

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For biological products, rarely an analytical procedure may be included in an FDA regulation. 410

When that occurs, alternative analytical procedures are submitted following 21 CFR 610.9(a). It 411

states that the applicant will present evidence “…demonstrating that the modification will

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provide assurances of the safety, purity, potency, and effectiveness of the biological product

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equal to or greater than the assurances provided by the method or process specified in the general 414

standards or additional standards for the biological product.” Modification of such procedures 415

requires FDA approval during application review or in a postapproval supplement.20

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You should identify the use of the alternative analytical procedure (e.g., release, stability testing) 418

and provide a rationale for its inclusion, validation data, and comparative data to the FDA

419

approved analytical procedure. You should perform a comparability study that demonstrates at a 420

minimum that:

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?The new method coupled with any additional control measures is equal or

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superior for the original method for the intended purpose.

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?The new analytical procedure is not more susceptible to matrix effects than the 426

original procedure.

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If new process or product related variants or any new impurities are discovered with the new

429

procedure, testing on archived samples from historical batches should be performed to

430

demonstrate that the variants/impurities detected by the new method are a result of an increase in 431

18 See 21 CFR 314.50.

19 See 21 CFR 314.70(d)(1), (d)(2)(vii). 314.81(b)(2), and 601.12(d)(vii).

20 See 21 CFR 610.9(b).

the sensitivity or selectivity of the new procedure and not a result of a change to process related 432

impurities.

433

434

If the procedure has stability indicating properties:

435

436

?Appropriate samples should be included that allow a comparison of the ability of 437

the new and original method to detect relevant product variants and degradation 438

species.

439

?The number of batches analyzed for comparison should be statistically relevant 440

and justified for a pre-established confidence interval.

441

?Equivalence, non-inferiority, or superiority studies should be performed with

442

appropriate statistical methods to demonstrate that the new or revised method

443

performance is comparable or better than the original method.

444

?The statistical analyses performed to compare product testing should be

445

identified.

446

?All bias seen with comparative results should be discussed with an explanation, as 447

appropriate.

448

449

2.Analytical Methods Transfer Studies

450

451

Analytical method transfer is typically managed under an internal transfer protocol that details 452

the parameters to be evaluated in addition to the predetermined acceptance criteria that will be 453

applied to the results. Transfer studies usually involve two or more laboratories or sites

454

(originating lab and receiving labs) executing the preapproved transfer protocol. A sufficient 455

number of representative test articles (e.g., same lot(s) of drug substance or drug product) are 456

used by the originating and receiving laboratories. The comparative s tudies are performed to 457

evaluate accuracy and precision, especially with regard to assessment of interlaboratory

458

variability. In cases where the transferred analytical procedure is also a stability indicating

459

method, forced degradation samples or samples containing pertinent product-related impurities 460

should be analyzed at both sites. The USP General Chapter <1224> Transfer of Analytical

461

Procedures provides additional guidance on this topic.

462

463

C.Reporting Postmarketing Changes to an Approved NDA, ANDA, or BLA 464

465

Postmarketing changes to analytical procedures must be reported to the FDA in compliance with 466

21 CFR 314.70 or 21 CFR 601.12.21 Additional information on the appropriate reporting

467

category for various kinds of postapproval changes for NDAs and ANDAs is provided in the

468

FDA guidance for industry on Changes to an Approved NDA or ANDA and Changes to an

469

Approved NDA or ANDA; Specifications – Use of Enforcement Discretion for Compendial

470

Changes. Similar information on postapproval changes to BLAs regulated by CDER and CBER 471

is provided in the FDA guidance Changes to an Approved Application for Specified

472

Biotechnology and Specified Synthetic Biological Products.

473

474

475

21 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).

IX.FDA METHODS VERIFICATION

476

477

Part of the approval process for NDAs and ANDAs may include FDA laboratory assessment to 478

determine whether the analytical procedures are acceptable for quality control and suitable for 479

regulatory purposes.22 If a laboratory assessment will be conducted, the FDA laboratory will 480

send you a request that will detail what samples and supplies to send to the FDA laboratory.

481

These could include product samples, standards, critical reagents, material safety data sheets, and 482

supplies. Laboratory results and comments will be forwarded from the FDA laboratory to the 483

product quality reviewer.

484

485

For certain biological products, samples representative of the product for licensure along with 486

summaries of results of tests performed on the lots represented by these samples should be

487

submitted with the BLA.23 The FDA laboratory verifies the performance of the methods and the 488

results you submit. During the pre-BLA meeting or after submission of the BLA, the FDA

489

laboratory can send you a request to provide standards, controls, reagents, material safety data 490

sheets, and supplies.

491

492

493

X.REFERENCES

494

495

Guidance for Industry24

496

497

ANDAs: Impurities in Drug Products (November 2010)

498

499

ANDAs: Impurities in Drug Substances (July 2009)

500

501

Changes to an Approved NDA or ANDA (April 2004)

502

503

Changes to an Approved Application for Specified Biotechnology and Specified Synthetic

504

Biological Products (July 1997)

505

506

Changes to an Approved NDA or ANDA; Specifications – Use of Enforcement Discretion for 507

Compendial Changes (November 2004)

508

509

Content and Format of Investigational New Drug Applications (INDs) for Phase 1 Studies of 510

Drugs, Including Well-Characterized, Therapeutic, Biotechnology-derived Products (November 511

1995)

512

513

INDs for Phase 2 and 3 Studies of Drugs, Including Specified Therapeutic Biotechnology-

514

Derived Products (February 1999)

515

516

22 See 21 CFR 314.50(e).

23 See 21 CFR 601.2(a).

24 Draft guidances have been included for completeness only. As draft documents, they are not intended to be

implemented until published in final form.

Investigating Out of Specification (OOS) Test Results for Pharmaceutical Production (October 517

2006)

518

519

Submission of Chemistry, Manufacturing, and Controls Information for Synthetic Peptide

520

Substances (November 1994)

521

522

Guidance for Industry: International Conference on Harmonization

523

524

Q1A(R2) Stability Testing of New Drug Substances and Products (November 2003)

525

526

Q1B Stability Testing: Photostability Testing of New Drug Substances and Products (May 527

1997)

528

529

Q1C Stability Testing for New Dosage Forms (May 1997)

530

531

Q2(R1) Validation of Analytical Procedures: Text and Methodology (March 1995, May 1997) 532

533

Q3A(R2) Impurities in New Drug Substances (June 2008)

534

535

Q3B(R2) Impurities in New Drug Products (August 2006)

536

537

Q3C Impurities: Residual Solvents (December1997)

538

539

Q3C Tables and List (February 2012)

540

541

Q5C Quality of Biotechnological Products: Stability Testing of Biotechnological/Biological 542

Products (July 1996)

543

544

Q6A Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and 545

New Drug Products: Chemical Substances (December 2000)

546

547

Q6B Specifications: Test Procedures and Acceptance Criteria for Biotechnological/Biological 548

Products (August 1999)

549

550

Q7 Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients

551

(August 2001)

552

553

Reviewer Guidance

554

555

Validation of Chromatographic Methods (November 1994)

556

557

United States Pharmacopeia/National Formulary

558

559

General Chapter <621> Chromatography

560

561

General Chapter <1010> Analytical Data – Interpretation and Treatment

562

563

General Chapter <1224> Transfer of Analytical Procedures

564

565

General Chapter <1225> Validation of Compendial Procedures

566

567

General Chapter <1226> Verification of Compendial Procedures

568

569

General Notices and Requirements, Applying to Standards, Tests, Assays, and Other

570

Specifications of the United States Pharmacopeia: 7. Test Results

571

572

Interpretation and Treatment of Analytical Data; USP Pharmacopeial Forum, United States

573

Pharmacopeial Convention, Inc., Rockville MD: 1994, Volume 24, Number 5, pp. 7051 - 7056 574

575

Other

576

577

ASTM Standard, E29 - 2008 Standard Practice for Using Significant Digits in Test Data to

578

Determine Conformance with Specifications, ASTM International, West Conshohocken, PA, 579

(https://www.wendangku.net/doc/7a13924693.html,).

580

581

Miller, J.C., J.N. Miller, and E. Horwood, Statistics for Analytical Chemistry, 3rd edition,

582

Prentice

583

Hall, 1993.

584

585

Saunders, B.D., and R.G. Trapp,Basic and Clinical Biostatistics, 2nd edition, Appleton and 586

Lange,

587

1994.

588

589

590

591

20.化学药物质量控制分析方法验证技术指导原则 2005年颁布

指导原则编号： 【H】G P H 5-1 化学药物质量控制分析方法验证 技术指导原则 二○○五年三月

目 录 一、概述 (1) 二、方法验证的一般原则 (2) 三、方法验证涉及到的三个主要方面 (2) （一）需要验证的检测项目 (2) （二）分析方法 (3) （三）验证内容 (3) 四、方法验证的具体内容 (3) （一）专属性 (3) 1、鉴别反应 (4) 2、杂质检查 (4) 3、含量测定 (4) （二）线性 (5) （三）范围 (5) 1、含量测定 (6) 2、制剂含量均匀度 (6) 3、溶出度或释放度 (6) 4、杂质 (6) （四）准确度 (6) 1、含量测定 (7) 2、杂质定量试验 (7) （五）精密度 (7) 1、重复性 (8) 2、中间精密度 (8) 3、重现性 (8)

（六）检测限 (8) 1、直观法 (8) 2、信噪比法 (9) （七）定量限 (9) 1、直观法 (9) 2、信噪比法 (9) （八）耐用性 (10) （九）系统适用性试验 (10) 五、方法再验证 (11) 六、方法验证的评价 (12) （一）有关方法验证评价的一般考虑 (12) （二）方法验证的整体性和系统性 (12) 七、参考文献 (13) 八、著者 (13)

化学药物质量控制分析方法验证技术指导原则 一、概述 保证药品安全、有效、质量可控是药品研发和评价应遵循的基本原则，其中，对药品进行质量控制是保证药品安全有效的基础和前提。为达到控制质量的目的，需要多角度、多层面来控制药品质量，也就是说要对药物进行多个项目测试，来全面考察药品质量。一般地，每一测试项目可选用不同的分析方法，为使测试结果准确、可靠，必须对所采用的分析方法的科学性、准确性和可行性进行验证，以充分表明分析方法符合测试项目的目的和要求，这就是通常所说的对方法进行验证。 方法验证的目的是判断采用的分析方法是否科学、合理，是否能有效控制药品的内在质量。从本质上讲，方法验证就是根据检测项目的要求，预先设置一定的验证内容，并通过设计合理的试验来验证所采用的分析方法能否符合检测项目的要求。 方法验证在分析方法建立过程中具有重要的作用，并成为质量研究和质量控制的组成部分。只有经过验证的分析方法才能用于控制药品质量，因此方法验证是制订质量标准的基础。方法验证是药物研究过程中的重要内容。 本指导原则重点探讨方法验证的本质，将分析方法验证的要求与所要达到的目的结合起来进行系统和规律性的阐述，重点阐述如何科学合理地进行论证方案的设计。 本指导原则主要包括方法验证的一般原则、方法验证涉及的三个主要方

药品微生物检验替代方法验证指导原则

药品微生物检验替代方法验证指导原则 本指导原则是为所采用的试验方法能否替代药典规定的方法用于药品微生物的检验提供指导。 随着微生物学的迅速发展，制药领域不断引入了一些新的微生物检验技术，大体可分为三类：（1)基于微生物生长信息的检验技术，如生物发光技术、电化学技术、比浊法等；(2)直接测定被测介质中活微生物的检验技术，如固相细胞技术法、流式细胞计数法等；（3)基于微生物细胞所含有特定组成成分的分析技术，如脂肪酸测定技术、核酸扩增技术、基因指纹分析技术等。这些方法与传统检查方法比较，或简便快速，或具有实时或近实时监控的潜力，使生产早期采取纠正措施及监控和指导优良生产成为可能，同时新技术的使用也促进了生产成本降低及检验水平的提高。 在控制药品微生物质量中，微生物实验室出于各种原因如成本、生产量、快速简便及提高药品质量等需要而采用非药典规定的检验方法（即替代方法）时，应进行替代方法的验证，确认其应用效果优于或等同于药典的方法。 微生物检验的类型及验证参数 药品微生物检验方法主要分两种类型：定性试验和定量试验。定性试验就是测定样品中是否存在活的微生物，如无菌检查及控制菌检査。定量试验就是测定样品中存在的微生物数量，如菌落计数试验。 由于生物试验的特殊性，如微生物检验方法中的抽样误差、稀释误差、操作误差、培养误差和计数误差都会对检验结果造成影响，因此，药品质量标准分析方法验证指导原则（附录XIX A)不完全适宜于微生物替代方法的验证。药品微生物检验替代方法的验证参数见表1。 表1 不同微生物检验类型验证参数 注： 尽管替代方法的验证参数与药品质量标准分析方法验证参数有相似之处，但是其具体的内容是依据微生物检验特点而设立的。替代方法验证的实验结果需进行统计分析，当替代方法属于定性检验时，一般采用非参数的统计技术；当替代方法属于定量检验时，需要采用参数统计技术。 进行微生物替代方法的验证时，若替代方法只是针对药典方法中的某一环节进行技术修改，此时，需要验证的对象仅是该项替代技术而不是整个检验方法。如无菌试验若改为使用含培养基的过滤器，然后通过适宜的技术确认活的微生物存在，那么，验证时仅需验证所用的微生物回收系统而不是整个无菌试验方法。 替代方法验证的一般要求 在开展替代方法对样品检验的适用性验证前，有必要对替代方法有一个全面的了解。首先，所选用的替代方法应具备必要的方法适用性证据，表明在不含样品的情况下，替代方法

生物样品定量分析方法验证指导原则

9012 生物样品定量分析方法验证指导原则
1. 范围
准确测定生物基质（如全血、血清、血浆、尿）中的药物浓度，对于药物和 制剂研发非常重要。这些数据可被用于支持药品的安全性和有效性，或根据毒动 学、药动学和生物等效性试验的结果做出关键性决定。因此，必须完整地验证和 记录应用的生物分析方法，以获得可靠的结果。
本指导原则提供生物分析方法验证的要求，也涉及非临床或临床试验样品实 际分析的基本要求，以及何时可以使用部分验证或交叉验证，来替代完整验证。
生物样品定量分析方法验证和试验样品分析应符合本指导原则的技术要求。 应该在相应的生物样品分析中遵守 GLP 原则或 GCP 原则。
2. 生物分析方法验证
2.1 分析方法的完整验证
分析方法验证的主要目的是，证明特定方法对于测定在某种生物基质中分析 物浓度的可靠性。此外，方法验证应采用与试验样品相同的抗凝剂。一般应对每 个物种和每种基质进行完整验证。当难于获得相同的基质时，可以采用适当基质 替代，但要说明理由。
一个生物分析方法的主要特征包括：选择性、定量下限、响应函数和校正范 围（标准曲线性能）、准确度、精密度、基质效应、分析物在生物基质以及溶液 中储存和处理全过程中的稳定性。
有时可能需要测定多个分析物。这可能涉及两种不同的药物，也可能涉及一 个母体药物及其代谢物，或一个药物的对映体或异构体。在这些情况下，验证和 分析的原则适用于所有涉及的分析物。
对照标准物质 在方法验证中，含有分析物对照标准物质的溶液将被加入到空白生物基质 中。此外，色谱方法通常使用适当的内标。 应该从可追溯的来源获得对照标准物质。应该科学论证对照标准物质的适用 性。分析证书应该确认对照标准物质的纯度，并提供储存条件、失效日期和批号。 对于内标，只要能证明其适用性即可，例如显示该物质本身或其相关的任何杂质 不产生干扰。 当在生物分析方法中使用质谱检测时，推荐尽可能使用稳定同位素标记的内 标。它们必须具有足够高的同位素纯度，并且不发生同位素交换反应，以避免结 果的偏差。
1

药物非临床药代动力学研究技术指导原则

附件5 药物非临床药代动力学研究技术指导原则 一、概述 非临床药代动力学研究是通过体外和动物体内的研究方法，揭示药物在体内的动态变化规律，获得药物的基本药代动力学参数，阐明药物的吸收、分布、代谢和排泄（Absorption, Distribution, Metabolism, Excretion, 简称ADME）的过程和特征。 非临床药代动力学研究在新药研究开发的评价过程中起着重要 作用。在药物制剂学研究中，非临床药代动力学研究结果是评价药物制剂特性和质量的重要依据。在药效学和毒理学评价中，药代动力学特征可进一步深入阐明药物作用机制，同时也是药效和毒理研究动物选择的依据之一；药物或活性代谢产物浓度数据及其相关药代动力学参数是产生、决定或阐明药效或毒性大小的基础，可提供药物对靶器官效应（药效或毒性）的依据。在临床试验中，非临床药代动力学研究结果能为设计和优化临床试验给药方案提供有关参考信息。 本指导原则是供中药、天然药物和化学药物新药的非临床药代动力学研究的参考。研究者可根据不同药物的特点，参考本指导原则，科学合理地进行试验设计，并对试验结果进行综合评价。 本指导原则的主要内容包括进行药物非临床药代动力学研究的 基本原则、试验设计的总体要求、生物样品的测定方法、研究项目（血

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