FDA指南 混合均匀性接受标准

Powder Blends and Finished Dosage Units — Stratified In-Process Dosage Unit Sampling and Assessment

DRAFT GUIDANCE

This guidance document is being distributed for comment purposes only. Comments and suggestions regarding this draft document should be submitted within 60 days of publication in the Federal Register of the notice announcing the availability of the draft guidance. Submit comments to Dockets Management Branch (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 Register.

For questions regarding this draft document contact Jon E. Clark, 301-594-5613 or Mike Gavini, 301-827-9053.

U.S. Department of Health and Human Services

Food and Drug Administration

Center for Drug Evaluation and Research (CDER)

October 2003

Pharmaceutical CGMPs

Powder Blends and Finished Dosage Units — Stratified In-Process Dosage Unit Sampling and Assessment

Additional copies are available from:

Office of Training and Communication

Division of Drug Information, HFD-240

Center for Drug Evaluation and Research

Food and Drug Administration

5600 Fishers Lane

Rockville, MD 20857

(Tel) 301-827-4573

https://www.wendangku.net/doc/687891266.html,/cder/guidance/index.htm

U.S. Department of Health and Human Services

Food and Drug Administration

Center for Drug Evaluation and Research (CDER)

Office of Pharmaceutical Science (OPS)

Office of Compliance (OC)

October 2003

Pharmaceutical CGMPs

Draft — Not for Implementation

TABLE OF CONTENTS

I.INTRODUCTION (1)

II.BACKGROUND (1)

III.SCOPE (2)

IV.CORRELATION OF IN-PROCESS STRATIFIED SAMPLING WITH POWDER MIX AND FINISHED PRODUCT (4)

A.Assessment of Powder Mix Uniformity (4)

B.Correlation of Powder Mix Uniformity with Stratified In-Process Dosage Unit Data (5)

C.Correlation of Stratified In-Process Samples with the Finished Product (6)

V.EXHIBIT/VALIDATATION BATCH POWDER MIX HOMOGENEITY (6)

VI.VERIFICATION OF MANUFACTURING CRITERIA (7)

A.In-Process Dosage Unit Sampling and Analysis (7)

B.Criteria to Meet the Readily Pass Classification (8)

C.Criteria to Meet the Marginally Pass Classification (8)

D.Sample Locations for Routine Manufacturing (9)

VII. ROUTINE MANUFACTURING BATCH TESTING METHODS (9)

A.Standard Criteria Method (SCM) (9)

1.Stage 1 Test (10)

2.Stage 2 Test (10)

B.Marginal Criteria Method (MCM) (10)

C.Switching to Standard Test Method from Marginal Test Method (11)

VIII.REPORTING THE USE OF STRATIFIED SAMPLING (11)

A.Applications Not Yet Approved (11)

B.Postapproval Change (12)

GLOSSARY (13)

ATTACHMENT 1: VERIFICATION OF MANUFACTURING CRITERIA (14)

ATTACHMENT 2: ROUTINE MANUFACTURING BATCH TESTING (15)

Guidance for Industry1

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Powder Blends and Finished Dosage Units — Stratified In-Process 3

Dosage Unit Sampling and Assessment

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This draft guidance, when finalized, will represent the Food and Drug Administration's (FDA's) current 8

thinking on this topic. It does not create or confer any rights for or on any person and does not operate to 9

bind FDA or the public. You can use an alternative approach if the approach satisfies the requirements of 10

the applicable statutes and regulations. If you want to discuss an alternative approach, contact the FDA 11

staff responsible for implementing this guidance. If you cannot identify the appropriate FDA staff, call 12

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

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I.INTRODUCTION

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This guidance is intended to assist manufacturers of human drug products in meeting the

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requirements of 21 CFR 211.110 for demonstrating the adequacy of mixing to ensure uniformity of in-process powder blends and finished dosage units. This guidance describes the procedures 20

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for assessing powder mix adequacy, correlating in-process dosage unit test results with powder 22

mix test results, and establishing the initial criteria for control procedures used in routine

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manufacturing.

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

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responsibilities. Instead, guidances describe the Agency's current thinking on a topic and should 27

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 29

recommended, but not required.

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II.BACKGROUND

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This guidance is the result of an Agency effort to achieve a science-based policy and regulatory enforcement. Experts from industry, academia, and the FDA developed the principles

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underlying this guidance after extensive public discussion. A brief history of the evolution of 37

this guidance is provided in the following paragraphs.

1 This guidance has been prepared by the Office of Pharmaceutical Science and the Office of Compliance in the

Center for Drug Evaluation and Research (CDER) at the Food and Drug Administration in cooperation with the Product Quality Research Institute (PQRI) (see footnote 3). This guidance document represents the Agency's

current thinking on assessment of the uniformity of powder blends and finished dosage units in the absence of new technology development or implementation.

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In response to industry concerns regarding regulations for demonstrating the adequacy of in-

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process powder mixing, the FDA published a draft guidance for industry on blend uniformity 41

analysis in August 1999.2 Comments submitted to the docket resulted in the formation of the 42

Blend Uniformity Working Group (BUWG) by the Product Quality Research Institute (PQRI).3 43

The PQRI BUWG conducted a public meeting, PQRI Workshop on Blend Uniformity, on

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September 7 and 8, 2000.

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Using the consensus reached by participants in this workshop, the BUWG developed a draft

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recommendation, The Use of Stratified Sampling of Blend and Dosage Units to Demonstrate

Adequacy of Mix for Powder Blends. The draft recommendation received examination and peer 48

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review in multiple scientific and public venues. In addition, the Advisory Committee for

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Pharmaceutical Science (ACPS) reviewed the draft recommendation and received public

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comment during scheduled meetings of the committee.4 The draft recommendation was revised 52

to incorporate the results of peer review and public comment and was presented to CDER's

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Center Director in final form on December 30, 2002. The recommendation was subsequently 54

published in the PDA Journal of Pharmaceutical Science and Technology.5 This draft guidance 55

reflects CDER's effort to incorporate the draft recommendation into regulatory policy.

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III.SCOPE

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Stratified sampling is the process of sampling dosage units at predefined intervals and collecting representative samples from specifically targeted locations in the compression/filling operation 61

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that have the greatest potential to yield extreme highs and lows in test results. These test results 63

are used to monitor the manufacturing process output that is most responsible for causing

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finished product variability. The test results can be used to develop a single control procedure to 65

ensure adequate powder mix and uniform content in finished products.

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The methods described in this guidance are not intended to be the only methods for meeting

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Agency requirements to demonstrate the adequacy of powder mix. Traditional powder blend 69

sampling and testing, in conjunction with testing for uniformity of content in the finished

product, can be used to comply with current good manufacturing practice requirements

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2 The FDA withdrew the guidance for industry ANDAs: Blend Uniformity Analysis o n May 17, 2002.

3 PQRI is a collaborative body involving FDA's Center for Drug Evaluation and Research (CDER), industry, and

academia. Since its inception in January 1996, the mission of PQRI has been to generate scientific information in support of regulatory policies through research. Additional information about PQRI is available at https://www.wendangku.net/doc/687891266.html,.

4 The PQRI BUWG recommendation appeared on the public ACPS agenda on November 28, 2001 (introduction),

May 8, 2002 (distribution and comment), and October 22, 2002 (final comment).

5 G Boehm, J Clark, J Dietrick, L Foust, T Garcia, M Gavini, L Gelber, J Geoffry, J Hoblitzell, P Jimenez, G

Mergen, F Muzzio, J Planchard, J Prescott, J Timmermens, and N Takiar, "The Use of Stratefied Sampling of Blend and Dosage Units to Demonstrate Adequacy of Mix for Powder Blends, PDA J. Pharm. Sci Technol,. 57:59-74, 2003.

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(CGMPs). Use of at-, in-, or on-line measurement systems can also be appropriate and are

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described in other guidance documents.6

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This guidance provides recommendations on how to:

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?Conduct powder blend sampling and analyses.

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?Establish initial criteria for stratified sampling of in-process dosage units7 and evaluation 78

of test results.

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?Analyze the stratified samples and evaluate data.

?Correlate the stratified sample data with the powder blend data.

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?Assess powder mix uniformity.

?Correlate the stratified sample data with the finished dosage unit data and assess

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uniformity of content.

?Test exhibit and validation batches for adequacy of powder mix.

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?Test and evaluate routine manufacturing batches.

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?Report the use of stratified sampling in the application.

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The methods described in this guidance can be used to monitor active ingredient homogeneity of 89

powder blends and to ensure uniform content of the finished product for solid oral drug products. 90

These methods are only one way to satisfy the CGMP and application review requirements for 91

in-process testing to demonstrate adequacy of powder mix and uniform content of the finished 92

product. The method assumes appropriate monitoring of all manufacturing steps as required by 93

the regulations or application commitments. This guidance does not discuss the assessment of the potency and other attributes that can affect the finished dosage units, or the homogeneity of 94

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inactive ingredients. Formulations with extremely low dose and/or high potency may call for

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more rigorous sampling than that described in this guidance to assess the uniformity of powder 97

blends or the uniformity of content of the finished dosage units.

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When using the methods described in this guidance, certain data or trends may be observed. We 100

recommend that manufacturers scientifically evaluate these types of research data to determine if they affect the quality of a product and, if so, how. The FDA does not intend to inspect research 101

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data collected on an existing product for the purpose of evaluating the suitability of proposed

methods. Any FDA decision to inspect research data would be based on exceptional situations 103

6 In August 2003, the Agency issued the draft guidance for industry PAT – A Framework for Innovative

Pharmaceutical Manufacturing and Quality Assurance. Once finalized, it will represent the Agency's perspective on this issue.

7 The in-process dosage unit is a capsule or tablet as it is formed in the manufacturing process before it is coated or

packaged.

similar to those outlined in Compliance Policy Guide Sec. 130.300.8 Those data used to support 104

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validation or regulatory submissions will be subject to inspection in the usual manner.

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IV.CORRELATION OF IN-PROCESS STRATIFIED SAMPLING WITH POWDER 109

MIX AND FINISHED PRODUCT

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If you plan to follow the procedures described in this guidance document, we recommend that 112

you first complete the process development procedures described in this section before using the methods described in sections V, VI, VII. The subsections below describe how to assess the 113

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adequacy of powder mix, uniformity of content of the in-process and finished dosage units

through correlation and assessment of data from development, validation and manufacturing 115

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batches. These procedures can reveal deficiencies in the blending operation that may not have 117

been previously detected. We recommend that manufacturers correct deficiencies in the

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blending operation before implementing the routine manufacturing control methods described in 119

this guidance.

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A.Assessment of Powder Mix Uniformity

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We recommend the assessment of powder mix uniformity using the following procedures:

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?Conduct blend analysis on batches by extensively sampling the mix in the blender and/or 125

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intermediate bulk containers (IBCs).

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?Identify appropriate blending time and speed ranges, dead spots in blenders, and locations 128

of segregation in IBCs. Determine sampling errors.

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?Define the effects of sample size (e.g., 1-10X dosage unit range) while developing a

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technique capable of measuring the true uniformity of the blend. Sample quantities larger 131

than 3X can be used with adequate scientific justification. Appropriate blend sampling 132

techniques and procedures should be developed for each product with consideration to 133

various designs of blend powder sampling and the physical and chemical properties of 134

the blend components.

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?Design blend-sampling plans and evaluate them using appropriate statistical analyses. 136

?Quantitatively measure any variability that is present among the samples. Attribute the 137

sample variability to either lack of uniformity of the blend or sampling error. Significant 138

within-location variance in the blend data can be an indication of one factor or a

combination of factors such as inadequacy of blend mix, sampling error9 or

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8 FDA/ORA Compliance Policy Guide, Sec. 130.300, FDA Access to Results of Quality Assurance Program Audits

and Inspections (CPG7151.02)

9 If blend sampling error is detected, more sophisticated, statistical analyses should be applied to assess the situation,

such as the use of methods described in J Berman, DE Elinski, CR Gonzales, JD Hofer, PJ Jimenez, JA Planchard, RJ Tlachac, PF Vogel, “Blend Uniformity Analysis: Validation and In-Process Testing.” Technical Report No. 25, PDA J Pharm. Sci. Technol. 51(Suppl 3i-iii), S1-99, 1997.

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agglomeration.10, 11 Significant between-location variance in the blend data can indicate

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that the blending operation is inadequate.

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B.Correlation of Powder Mix Uniformity with Stratified In-Process Dosage 144

Unit Data

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We recommend the following steps for correlation:

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?Conduct periodic sampling and testing of the in-process dosage units by sampling them at 148

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defined intervals and locations throughout the compression or filling process. Use a

minimum of 20 appropriately spaced in-process dosage unit sampling points. There

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should be at least 7 samples taken from each of these locations for a total minimum of at

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least 140 samples.

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?Take 7 samples from each additional location to further assess each significant event,12 154

such as filling or emptying of hoppers and IBCs, start and end of the compression or

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filling process and equipment shutdown. This may be accomplished by using process

development batches, validation batches, or by using routine manufacturing batches for 156

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approved products.

?Significant events may also include observations or changes from one batch to another 158

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(e.g., batch scale-up and observations of undesirable trends in previous batch data).

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? Prepare a summary of the data and analysis used to correlate the stratified sampling

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locations with significant events in the blending process. We recommend you submit this

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summary with the application as described in section VIII of this guidance.

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?Compare the powder mix uniformity with the in-process dosage-unit data described above.

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?Investigate any discrepancies observed between powder mix and dosage-unit data and establish root causes. At least one trouble-shooting guide is available that may be helpful 166

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with this task.13 Possible corrections may range from going back to formulation

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development to improve powder characteristics to process optimization. Sampling

10OS Sudah, PE Arratia, D. Coffin-Beach, FJ Muzzio, "Mixing of Cohesive Pharmaceutical Formulations in Tote (Bin)-Blenders,” Drug Dev. Ind. Pharm, 28(8): 905-918, 2002.

11V Swaminathan, DO Kildsig, “Polydisperse powder mixtures: effect of particle size and shape on mixture

stability,” Drug Dev. Ind. Pharm., 28(1):41-48, 2002.

12 A s ignificant event is any operation during the solid dosage production process that can affect the integrity of the

in-process materials – see section IX Glossary.

13 JK Prescott, TJ Garcia, "A Solid Dosage and Blend Content Uniformity Troubleshooting Diagram," Pharm.

Technol., 25 (3):68-88, 2001.

problems may also be negated by use of alternate state-of-the-art methods of in situ real-169

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time sampling and analysis.

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C.Correlation of Stratified In-Process Samples with the Finished Product

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We recommend the following steps:

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?Conduct testing for uniform content of the finished product using an appropriate

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procedure or as specified in the Abbreviated New Drug Application (ANDA) or the New

Drug Application (NDA) for approved products.

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?Compare the results of stratified in-process dosage unit analysis with uniform content of the finished dosage units from the previous step. This analysis should be done without 180

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weight correction.14

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?Prepare a summary of the data and analysis used to conclude that the stratified in-process 183

sampling provides assurance of uniform content of the finished product. We recommend

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you submit this summary with the application as described in section VIII of this

guidance.

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V.EXHIBIT/VALIDATATION BATCH POWDER MIX HOMOGENEITY

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This section describes sampling and testing the powder mix of exhibit and process validation 190

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batches used to support implementing the stratified sampling method described in this guidance.

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We recommend that during the manufacture of exhibit and process validation batches, you assess

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the uniformity of the powder blend, the in-process dosage units, and the finished product

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independently. We recommend you use the following steps to identify sampling locations and

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acceptance criteria prior to the manufacture of the exhibit and/or validation batches.15

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1.Carefully identify at least 10 sampling locations in the blender to represent potential areas

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of poor blending. For example, in tumbling blenders (such as V-blenders, double cones,

or drum mixers), samples should be selected from at least two depths along the axis of 201

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the blender. For convective blenders (such as a ribbon blender), a special effort should

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be made to implement uniform volumetric sampling to include the corners and discharge

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area (at least 20 locations are recommended to adequately validate convective blenders).

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2.Collect at least 3 replicate samples from each location. Samples should meet the

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following criteria:

14 Weight correction is a mathematical correction to eliminate the effect of potentially variable tablet weight on

measurement of mix adequacy—see Glossary, Section IX.

15 This is described in Section IV of this guidance.

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?Assay one sample per location (number of samples (n) ≥ 10)

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(n = 20 for ribbon blender).

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?RSD (relative standard deviation) of all individual results ≤ 5.0 percent.

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?All individual results are within 10.0 percent (absolute) of the mean of the results. 215

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If samples do not meet these criteria, we recommend that you investigate the failure according to 217

the flow chart in Attachment 1. We also recommend that you not proceed any further with 218

implementation of the methods described in this guidance until the criteria are met.

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Sampling errors may occur in some powder blends, sampling devices, and techniques that make 221

it impractical to evaluate adequacy of mix using only the blend data. In such cases, we

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recommend that you use in-process dosage unit data in conjunction with blend sample data to 223

evaluate blend uniformity.

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Some powder blends may present unacceptable safety risk when directly sampled. The safety 226

risk, once described, may justify an alternate procedure. In such cases, process knowledge and 227

data from indirect sampling combined with additional in-process dosage unit data may be

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adequate to demonstrate the adequacy of the powder mix. Data analysis used to justify using 229

these alternate procedures should be described in a summary report that is maintained at the 230

manufacturing facility.

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As an alternative, you can substitute the procedures described in the PDA Technical Report No. 233

25, (see reference in footnote 8) to ensure that the blend is uniform and that the method meets or 234

exceeds the criteria described above.

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VI.VERIFICATION OF MANUFACTURING CRITERIA

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You should complete the assessment of powder mix uniformity and correlation of stratified in-240

process dosage unit sampling development procedures before establishing the criteria and

controls for routine manufacturing. We also recommend that you assess the normality and

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determine RSD from the results of stratified in-process dosage unit sampling and testing that 243

were developed. The RSD value should be used to classify the testing results as either readily 244

pass (RSD ≤ 4.0%), marginally pass (RSD ≤ 6.0%) or inappropriate for demonstration of batch 245

homogeneity (RSD > 6.0%). The procedures are discussed in the following sections:

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A.In-Process Dosage Unit Sampling and Analysis

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We recommend the following steps:

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?Carefully identify locations throughout the compression or filling operation to sample in-251

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process dosage units. The sampling locations should also include significant process

events such as hopper changeover, filling or machine shutdown and the beginning and 253

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end of the compression or filling operation.16 There should be at least 20 locations with 7 255

samples each for a minimum total of 140 samples. These include periodic sampling

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locations and significant event locations.

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?Sample at least 7 in-process dosage units from each sampling location.

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?Assay at least 3 of the 7 and weight correct each result. (The number of samples should 259

be specified and justified for a given product and process.)

?Conduct an analysis of the dosage unit stratified sampling data to demonstrate that the 260

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batch has a normal distribution of active ingredient. Indications of trends, bimodal

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distributions, or other forms of a distribution other than normal should be investigated. If 263

these occurrences significantly affect your ability to ensure batch homogeneity, they

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should be corrected.

?Prepare a summary of this analysis. Potential investigation results along with a

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description of batch normality should be included in the summary. Submit this summary 266

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with the application as described in section VIII of this guidance.

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In addition to this analysis of batch normality, we recommend that you classify the test results as 269

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readily pass or marginally pass according to the following procedure:

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B.Criteria to Meet the Readily Pass Classification

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For each separate batch, compare the test results to the following criteria:

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?For all individual results (for each batch n ≥ 60) the RSD ≤ 4.0 percent.

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?Each location mean is within 90.0 percent to110.0 percent of target strength.

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?All individual results are within the range of 75.0 percent to 125.0 percent of target strength.

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If your test results meet these criteria, they are classified as readily pass and you can start routine 284

batch testing using the Standard Verification Method (SVM) described in section VII. If your 285

test results fail to meet these criteria, we recommend that you compare the results with the

marginally pass criteria described below.

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C.Criteria to Meet the Marginally Pass Classification

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If your dosage unit test results fail to meet the criteria for the r eadily pass classification, you 291

should assay the remaining dosage units (all 7 units per location) and compare the test results to 292

the following criteria:

16 The beginning and end samples are taken from dosage units that would normally be included in the batch.

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?For all individual results (for one batch n ≥ 140) the RSD ≤ 6.0 percent.

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?Each location mean is within 90.0 percent to 110.0 percent of target strength.

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?All individual results are within the range of 75.0 percent to 125.0 percent of target

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strength.

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If your test results meet these criteria, results can be classified as marginally pass. If your

samples do not meet these criteria, we recommend that you investigate the failure, find justified 302

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and assignable cause(s), correct the deficiencies, and repeat the powder mix homogeneity

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assessment, in-process dosage unit sampling correlation, and initial criteria establishment

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procedures. The disposition of batches that have failed the m arginally pass criteria is outside the 306

scope of this guidance.

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D.Sample Locations for Routine Manufacturing

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We recommend that you prepare a summary of the data analysis from the powder mix

assessment and stratified sample testing. From the data analysis, you should establish the

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stratified sample locations for routine manufacturing, taking into account significant process 313

events and their effect on in-process dosage unit and finished dosage unit quality attributes. You should identify at least 10 sampling locations during capsule filling or tablet compression to 314

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represent the entire routine manufacturing batch.

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VII. ROUTINE MANUFACTURING BATCH TESTING METHODS

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We recommend that you evaluate the routine manufacturing batches against the following

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criteria after completing the procedures described above to assess the adequacy of the powder 322

mix and uniform content in finished dosage form.

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These routine manufacturing batch-testing methods include the Standard Criteria Method (SCM) 325

and the Marginal Criteria Method (MCM). The SCM consists of two stages, each with the same accept/reject criteria. The second of the two stages recommends using a larger sample size to 326

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meet these criteria. The MCM uses accept/reject criteria that are different from the SCM.

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If the batch data fail to conform to the SCM criteria, we recommend continued sampling and 330

testing to intensified criteria (MCM). Both verification methods and the procedures for

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switching from one to the other are detailed below and in the flow chart in Attachment 2.

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A.Standard Criteria Method (SCM)

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We recommend using the SCM verification method when either of the following conditions is 336

met:

?Results of establishing initial criteria are classified as readily pass.

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?Results of testing to the MCM pass the criteria for switching to the SCM (see section C 340

below).

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The SCM should meet the same criteria using a different number of sample test results as

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described below:

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1.Stage 1 Test

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To perform the stage 1 test, we recommend that you (1) collect at least 3 dosage units from each 348

sampling location, (2) assay 1 dosage unit from each location, (3) weight correct the results, and 349

(4) compare the results with the following criteria:

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?RSD of all individual results (n ≥ 10) ≤ 5.0 percent.

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?Mean of all results is 90.0 percent to 110.0 percent of target assay.

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If the results pass these criteria and the adequacy of mix and uniformity of dosage unit content 355

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for the batch are adequate, you can use the SCM for the next batch. If test results fail stage 1 357

criteria, you should conduct extended testing to stage 2 acceptance criteria.

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2.Stage 2 Test

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To perform the stage 2 test, we recommend that you assay the remaining two dosage units (from 362

stage 1) for each sampling location and compute the mean and RSD of data combined from both 363

stage 1 and stage 2. Compare the results with the following criteria:

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?For all individual results (n ≥ 30) the RSD ≤ 5.0 percent.

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?Mean of all results is 90.0 percent to 110.0 percent of target assay.

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If your results pass these criteria, the adequacy of mix and uniformity of content for the batch are 369

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adequate and you can use stage 1 of SCM for the next batch. If test results fail the criteria, use 371

the MCM described in the next section.

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B.Marginal Criteria Method (MCM)

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After powder mix assessment, in-process dosage unit stratified sampling correlation and initial 375

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criteria establishment, we recommend that you use the MCM when either of the following

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conditions is met:

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?Results of initial criteria establishment qualified as marginally pass.

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?Results of initial criteria establishment qualified as readily pass or a batch was tested 381

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according to SCM and the test results failed both stage 1 and stage 2 criteria.

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Then, we recommend you use the weight-corrected results from the stage 2 SCM analysis and 385

compare this with the MVM criteria:

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?For all individual results (n ≥ 30) the RSD ≤ 6.0 percent.

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?Mean of all results is 90.0 percent to 110.0 percent of target assay.

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We recommend that all results from analysis of any remaining location samples be computed 391

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with the stage 2 SCM data. No test results should be removed from the analysis. If the test

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results pass these criteria, the adequacy of mix and uniformity of content for the batch are

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adequate. We recommend that you continue to test routine manufacturing batches with MCM 395

criteria. If the test results fail the criteria, you should no longer use the verification testing

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methods to ensure adequacy of mixing or uniformity of content until you investigate the failure 397

(per 21 CFR 211.192) to establish justified assignable cause(s), take necessary corrective actions 398

and repeat the powder mix assessment, stratified sample correlation, and initial criteria

establishment procedures.

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C.Switching to Standard Test Method from Marginal Test Method

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It is appropriate to switch to the SCM when the following criterion is met:

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?Five consecutive batches pass the MCM criteria and result in RSD ≤ 5.0 percent

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VIII.REPORTING THE USE OF STRATIFIED SAMPLING

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A.Applications Not Yet Approved

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This section refers to the scientific data analysis and other information that should be submitted 413

to an NDA or ANDA. Information submitted in the application should include summary reports and scientific analyses or statements about the method being used. The raw data collected to 414

support using this method should be maintained at the manufacturing site.

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We recommend that you provide the following information in the Manufacturing Process and 417

Process Controls section of the application (CTD17 3.2.P.3.3).

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?Statement that the methods in this guidance are being used to demonstrate the adequacy 420

of powder mix or a description of alternative methods that demonstrate the adequacy of

the powder mix

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?Summary of data analysis from the powder mix assessment and from stratified sample 423

testing

17 M4Q: The CTD – Quality, one in a series of guidances that provide recommendations for applicants preparing the

Common Technical Document for the Registration of Pharmaceuticals for Human Use (CTD) for submission to the FDA.

?Summary of the in-process dosage unit stratified sampling data analysis demonstrating a 424

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normal distribution of active ingredient in the batch

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?Summary of the powder mix sampling data analysis demonstrating that it met the minimum criteria for validation and establishing initial criteria

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We recommend that you provide the following information in the Drug Product Specification 429

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section of the application (CTD 3.2.P.4.1):

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?Statement in the product specification stating that the methods in this guidance are being 433

used to demonstrate finished product uniformity of content or a description of alternative

methods used to demonstrate finished product uniformity of content

434

435

436

We also recommend that you provide the following information in the Pharmaceutical

437

Development Information section of the application (CTD 3.2.P.2.2):

438

439

?Summary of data analysis for correlation of in-process dosage unit stratified sampling 440

with finished product uniformity of content

441

?Summary of data analysis for correlation of powder mix uniformity with in-process

442

443

dosage unit stratified sampling

444

445

B.Postapproval Change

446

447

If you plan on changing the existing controls for adequacy of mix and uniformity of content to

448

the methods described in this guidance, the change should be considered a minor change as

449

described in the postapproval changes guidance.18 We recommend you provide a notice of the

change in the next annual report along with the information indicated in section A, above. The 450

451

raw data collected to support changes can be maintained at the manufacturing site.

18 FDA's guidance for industry on Changes to an Approved NDA or ANDA.

452

453

GLOSSARY

454

Absolute as used to define the acceptable range (+/- 10%) in which individual blend sample 455

456

values must fall and which is independent of the value of the mean. For example, if the mean of 457

all blend samples is 95.0%, the absolute range is 85.0% to105.0%, (not 95.0% +/- 9.5%).

458

Exhibit Batches refer to any batch submitted in support of an NDA or ANDA. This includes 459

460

bioequivalence, test, and commercial production batches of a drug product.

461

462

In-process dosage unit is a capsule or tablet as it is formed in the manufacturing process before it is coated or packaged.

463

464

465

RSD is relative standard deviation; RSD = [(standard deviation)/(mean)] x 100%.

466

467

Significant event is any operation during solid dosage production process that can affect the 468

integrity of the in-process materials and, hence, their quality attributes. Transferring powder 469

from a blender to a bin or from the bin to a hopper are two examples of significant events in the blending and compression process.

470

471

472

Stratified sampling is the process of collecting a representative sample by selecting units

473

deliberately from various identified locations within a lot or batch, or from various phases or 474

periods of a process to obtain a sample dosage unit that specifically targets locations throughout 475

the compression/filling operation that have a higher risk of producing failing results in the

476

finished product uniformity of content.

477

478

Target assay is the intended strength or intended amount of active ingredient in the dosage unit. 479

480

Validation batch is a batch manufactured and tested to verify the proposed routine

481

manufacturing process controls are adequate.

482

483

Weight correct is a mathematical correction to eliminate the effect of potentially variable tablet weight on measurement of mix adequacy. For example, a tablet with a strength of 19.4 mg and 484

485

weight of 98 mg = 19.4 ÷ 98 = 0.198 mg/mg. Label claim is 20 mg per each 100 mg tablet, so 486

the weight corrected result is 0.198 ÷ 0.20 * 100 = 99% of target blend assay.

ATTACHMENT 1: VERIFICATION OF MANUFACTURING CRITERIA

487488489490491492493494495496497498499500501502503504505506507508509510511512513514515516517

5185195205215221

Examples of “mean +/- 10% (absolute)” are: If the mean strength = 95%, then the interval is 95% +/- 10%; thus, all individuals must fall within 52385.0% to 105.0%. If the mean strength = 103.0%, then the interval is 103.0% +/- 10.0%; thus all individuals must fall within 93.0% to 113.0%.524525 2

When comparing individual dosage units to 75.0% - 125.0% of target strength, use the as is results (not corrected for weight).

526

ATTACHMENT 2: ROUTINE MANUFACTURING BATCH TESTING

527

528

529

Before using this chart to demonstrate adequacy of mix and content uniformity during routine

530

manufacture conduct assess the powder mix, stratified sample correlation and establishes initial criteria. 531

Identify at least 10 sampling locations during filling or compression to represent the entire batch. Remove 532

3 or more dosage units at each sampling location.

533 Array 534

535

536

1.生物等效性研究的统计学指导原则 2018年第103号 2018-10-17

附件1 生物等效性研究的统计学指导原则 一、概述 生物等效性（Bioequivalence, BE）研究是比较受试制剂（T）与参比制剂（R）的吸收速度和吸收程度差异是否在可接受范围内的研究，可用于化学药物仿制药的上市申请，也可用于已上市药物的变更（如新增规格、新增剂型、新的给药途径）申请。 目前生物等效性研究通常推荐使用平均生物等效性（Average Bioequivalence, ABE）方法。平均生物等效性方法只比较药代动力学参数的平均水平，未考虑个体内变异及个体与制剂的交互作用引起的变异。在某些情况下，可能需要考虑其他分析方法。例如气雾剂的体外BE研究可采用群体生物等效性（Population Bioequivalence，PBE）方法，以评价制剂间药代动力学参数的平均水平及个体内变异是否等效。 本指导原则旨在为以药代动力学参数为终点评价指标的生物等效性研究的研究设计、数据分析和结果报告提供技术指导，是对生物等效性研究数据资料进行统计分析的一般原则。在开展生物等效性研究时，除参考本指导原则的内容外，尚应综合参考《以药动学参数为终点评价指标的化学药物仿制药人体生物等效性研究技术指导原则》和《药物临床试验的生物统计学指导原则》等相关指导原则。 二、研究设计 （一）总体设计考虑 生物等效性研究可采用交叉设计或者平行组设计。 —1 —

1.交叉设计 生物等效性研究一般建议采用交叉设计的方法。交叉设计的优势包括：可以有效减少个体间变异给试验评价带来的偏倚；在样本量相等的情况下，使用交叉设计比平行组设计具有更高的检验效能。 两制剂、两周期、两序列交叉设计是一种常见的交叉设计，见表1。 表1 两制剂、两周期、两序列交叉设计 序列 周期 1 2 1 T R 2 R T 如果需要准确估计某一制剂的个体内变异，可采用重复交叉设计。重复交叉设计包括部分重复（如两制剂、三周期、三序列）或者完全重复（如两制剂、四周期、两序列），见表2和表3。 表2 两制剂、三周期、三序列重复交叉设计 序列 周期 1 2 3 1 T R R 2 R T R 3 R R T —2 —

总局关于发布人体生物等效性试验豁免指导原则的通告(2016

总局关于发布人体生物等效性试验豁免指导原则的通告（2016 年第87号） 2016年05月19日发布为规范仿制药质量和疗效一致性评价工作，根据《国务院办公厅关于开展仿制药质量和疗效一致性评价的意见》（国办发〔2016〕8号）的有关要求，国家食品药品监督管理总局组织制定了《人体生物等效性试验豁免指导原则》，现予发布。 特此通告。 附件：人体生物等效性试验豁免指导原则 食品药品监管总局 2016年5月18日附件 人体生物等效性试验豁免指导原则 本指导原则适用于仿制药质量和疗效一致性评价中口服固体常释制剂申请生物等效性（Bioequivalence）豁免。该指导原则是基于国际公认的生物药剂学分类系统（Biopharmaceutics Classification System，以下简称BCS）起草。

一、药物BCS分类 BCS系统是按照药物的水溶性和肠道渗透性对其进行分类的一个科学架构。当涉及到口服固体常释制剂中活性药物成分（Active Pharmaceutical Ingredient，以下简称API）在体内吸收速度和程度时，BCS系统主要考虑以下三个关键因素，即：药物溶解性（Solubility）、肠道渗透性（Intestinal permeability）和制剂溶出度（Dissolution）。 （一）溶解性 溶解性分类根据申请生物等效豁免制剂的最高剂量而界定。当单次给药的最高剂量对应的API在体积为250ml（或更少）、pH值在1.0—6.8范围内的水溶性介质中完全溶解，则可认为该药物为高溶解性。250ml的量来源于标准的生物等效性研究中受试者用于服药的一杯水的量。 （二）渗透性 渗透性分类与API在人体内的吸收程度间接相关（指吸收剂量的分数，而不是全身的生物利用度），与API在人体肠道膜间质量转移速率直接相关，或者也可以考虑其他可以用来预测药物在体内吸收程度的非人体系统（如使用原位动物、体外上皮细胞培养等方法）对渗透性进行分类。当一个口服药物采用质量平衡测定的结果或是相对于静脉注射的参照剂量，显示在体内的吸收程度≥85%以上（并且有证据证明药物在胃肠道稳定性良好），则可说明该药物具有高渗透性。 （三）溶出度

emea生物利用度和生物等效性研究指导原则问答

e m e a生物利用度和生物等效性研究指导原则问答 This model paper was revised by the Standardization Office on December 10, 2020

审评四部审评七室陈俊春高晨燕 EMEA自2002年对《生物利用度和生物等效性研究指导原则》（以下简称EMEA指导原则）修订后，于2006年7月发布了《生物利用度和生物等效性研究指导原则问答》（以下简称EMEA指导原则问答）对该原则的一些重要部分作出解释。以下就其问答全文结合我国的《化学人体生物利用度和生物等效性研究技术指导原则》（以下简称我国指导原则）与EMEA指导原则做一简介。 1.、生物等效判定时对Cmax的要求 EMEA指导原则的生物利用度等效评价要求Cmax比值的90％置信区间在–范围内。特殊情况下，如药物治疗窗窄，则可接受的区间范围应更窄。仅在特定情况下，才可接受更宽的区间范围，如－；而且该区间应事先确定，即在试验设计时应考虑到接受大于常规区间范围的情况，事后扩大原方案中确定的可接受区间的做法不可取；并应证明该范围对于病人更换时在安全和有效性方面的合理性。 EMEA指导原则在此提及的增加Cmax比值（非AUC）可接受区间范围的情况并不多见，并且仅扩大了一点，仍窄于我国指导原则中规定的范围－。扩大时仅限于以下情况：1）该药物安全性和有效性的PK/PD相关性资料足以显示Cmax可接受区间的扩大不会显着影响其临床药效。 2）如PK/PD资料不充分，临床安全性和有效性资料可以作为替代，但这些资料仅限于该研究药物。 3）药物在个体内的生物利用度具有高变异性。EMEA和我国的指导原则都对高变异性药物做了定义（即：个体内变异系数大于30%），但是要评价其个体内变异性需要设计重复试验。

人体生物等效性研究技术经验指导原则

精心整理附件3 以药动学参数为终点评价指标的 化学药物仿制药人体生物等效性研究 技术指导原则 体循环的过程，通常将受试制剂在机体内的暴露情况与参比制剂进行比较。 在上述定义的基础上，以药动学参数为终点评价指标的生物等效性研究又可表述为：通过测定可获得的生物基质（如血液、血浆、血清）中的药物浓度，取得药代动力学参数作为终点指标，藉此反映药物释放并被吸

收进入循环系统的速度和程度。通常采用药代动力学终点指标C max和AUC 进行评价。 如果血液、血浆、血清等生物基质中的目标物质难以测定，也可通过测定尿液中的药物浓度进行生物等效性研究。 药效动力学研究： 2）两 每位受试者依照随机顺序接受受试制剂和参比制剂。对于半衰期较长的药物，可选择第2种试验设计，即每个制剂分别在具有相似人口学特征的两组受试者中进行试验。第3种试验设计（重复试验设计）是前两种的备选方案，是指将同一制剂重复给予同一受试者，可设计为部分重复（单制剂重复，即三周期）或完全重复（两制剂均重复，即四周期）。重复试验设

计适用于部分高变异药物（个体内变异≥30%），优势在于可以入选较少数量的受试者进行试验。 对于高变异药物，可根据参比制剂的个体内变异，将等效性评价标准作适当比例的调整，但调整应有充分的依据。 （二）受试者选择 18 60岁 通常推荐采用单次给药药代动力学研究方法评价生物等效性，因为单次给药在评价药物释放的速度和程度方面比多次给药稳态药代研究的方法更敏感，更易发现制剂释药行为的差异。 （五）稳态研究 若出于安全性考虑，需入选正在进行药物治疗，且治疗不可间断的患

者时，可在多次给药达稳态后进行生物等效性研究。 （六）餐后生物等效性研究 食物与药物同服，可能影响药物的生物利用度，因此通常需进行餐后生物等效性研究来评价进食对受试制剂和参比制剂生物利用度影响的差异。 2小 推荐采用实测药物峰浓度C max评价吸收速度。药物浓度达峰时间T max 也是评价吸收速度的重要参考信息。 2.吸收程度/总暴露量 对于单次给药研究，建议采用如下两个参数评价吸收程度： （1）从0时到最后一个浓度可准确测定的样品采集时间t的药物浓

生物等效性样品的管理指导原则

1、简介： 本指导原则用于指导临床研究主办单位、药物生产商、CRO公司、现场管理组织、临床监察机构和第三方独立组织管理生物利用度试验和生物等效性试验的样品。本指导原则的重点内容有：⑴BE和BA试验的测试样品和对照品是如何分发给试验机构的。⑵试验机构如何随机挑选测试样品和预留样品。⑶预留样品如何保管。（本指南参考法规21CFR 320.38 and 320.63，320.38 and 320.63） 2、背景： 由于80年代的通用药物丑闻，FDA在1990年11月8号发布了临时法规限制BE和BA样品的保存。颁布这项临时法规的目的是制止实验赞助商或药品生产机构在临床实验中进行可能的欺骗行为。1993年4月28日正式法规颁布。 在法规的序言中说明研究赞助商或药物生产机构不能在将产品分发到实验机构之前分出测试样品和对照品的保存样品。这样是为了保证保留样品能够代表申报批产品。生产商应该多寄几批测试样品和对照样品，以便研究机构可以随机挑选试验样品和保留样品。产品应该保存在生产商提供的包装内。 在法规的序言中还提到，对保留样品的保存是进行临床试验的组织的责任。目的是避免生产商将样品替换以欺骗FDA。 FDA的科学调查部门和ORA的领域研究者为生产商提供检查临床 试验地点和分析样品场所的服务。这些检察人员经常发现临床试验机构中保留样品的缺失。在很多案件中，检察人员发现临床机构将样品

退回生产商。在其他的案件中，生产商指定实验样品和对照品阻止研究机构从生产商从提供的样品中进行随机选样。检察人员还发现在等效性实验中临床端点经常与临床安全性研究和功效性研究相混淆。药效学或临床的等效性研究的端点通常很多，由内科医生或临床监察员使用它们的诊所或办公地点根据合同进行盲目的研究。更过分的事，一些临床研究者相信他们不是CRO公司所以不用保存样品。本原则明确了保留样品的责任方。 3、保留样品的技术： 我们要求临床试验机构从生产商提供的多批样品中随机挑选实验样品和对照品以保证样品具有代表性并且样品要存放在生产商提供的包装内。因为生产商可能会提供多个包装规格。FDA对于这个样品的代表性问题有着灵活的观点。例如，以下任何一种样品的保管技术都可以被研究机构应用。 单包装——如果生产商只提供了样品和对照品的单个包装，研究机构应该取出足够进行实验的样品和对照品，剩余的在原来的包装内进行保留。 多包装——如果生产商提供了样品和对照品的多个包装，研究机构可以随机挑选出足够进行实验的样品和对照品的包装形式，剩余的在原来的包装内进行保留。 一般来说，不赞同打开很多包装。我们希望研究机构限制作为研究留样的打开包装的数量。 剂量单位——如果生产商按照剂量单位提供了样品和对照品，研究机

生物利用度和生物等效性试验用药品的处理和保存 要求技术指导原则(征求意见稿)

生物利用度和生物等效性试验用药品的处理和保存要求技术指导原则 （初稿） 药品审评中心

2012年10月

目录 一、引言 (1) 二、背景 (1) 三、抽样方法 (1) 四、多个研究和多次提供情况下的样品留存 (2) 五、留存样品的数量 (3) 六、研究承担机构的职责 (3) （一）在试验机构进行的临床研究 (4) （二）SMO参与的研究 (4) （三）在SMO中进行的盲法药效学或临床终点研究 (5) 七、吸入制剂的例外情况 (6) 精选

生物利用度和生物等效性试验用药品的处理和保存要求 技术指导原则 一、引言 本指导原则旨在向药品注册申请人、合同研究组织（CRO）、研究机构管理组织（SMO）、临床试验机构和独立的第三方机构提供生物利用度（BA）和生物等效性（BE）试验用药品处理和保存方法的建议。本指导原则重点讨论以下内容：（1）用于BA和BE研究的试验用药品（包括受试制剂和参比制剂，下同）提供至药品临床试验机构（以下简称试验机构）的方法；（2）试验机构随机抽取用于临床研究的试验用药品和用于留存的试验用药品的方法；（3）留存试验用药品的保存方法。 二、背景 在以前的BA和BE试验中，存在的常见问题是实施研究的试验机构未对试验用药品进行留样保存，在多数情况下，试验机构将试验剩余样品全部返回给注册申请人。这种情况难以确保试验样品的真实性及可溯源性。为了保证试验样品的真实性及可溯源性，有必要规定试验机构在BA和BE试验中应当对试验样品进行留存。本指导原则对各方在试验用药品提供及留存样品保存方面所承担的职责进行了明确的阐述。 注册申请人在将试验用药品提供至试验机构之前，不得从试验用药品中分出留存样品，以确保留存样品是注册申请人提供给试验机构用于临床试验的同批产品。试验机构应从注册申请人提供的全部试验用样品中随机抽取进行临床试验药品和用于留存的样品。 本指导原则规定留存试验用药品是实施BA或BE的试验机构的职责，是为了消除注册申请人擅自更换留存样品的可能性。 三、抽样方法 注册申请人应将提供至试验机构的试验用药品（同批产品）进行适当包装，以便使试验机构可随机抽取用于临床研究的药品和留存样品，进而确保留存样品

符合性声明模板

符合性声明 产品名称：XXXXX（符合性声明对象的产品名称） 产品材质：XXXX（根据相关产品标准标要求标识产品材质，对于复合、组合材料及制品 可以列表的形式体现各层材料或部件的材质） 生产商：XXXXXX 联系方式（适用时）：XXXXXX 声明方：XXXXXX 联系方式（适用时）：XXXXXX 产品使用条件a)：可以或不可以接触的食品/食品类型、与食品接触的使用条件限制（接触时 间和接触温度）、最大面积体积比（或最小容量）和重复使用情况等。 符合法规：产品符合GB 4806.1-2016《食品安全国家标准食品接触材料及制品通用安 全要求》、GB 9685-2016《食品安全国家标准食品接触材料及制品用添加 剂使用标准》和GB 4806.6《食品安全国家标准食品接触材料及制品用塑料 树脂》、GB 4806.7-2016《食品安全国家标准食品接触用塑料材料及制品》 适用于本产品的相关要求。产品生产过程符合GB 31603-2015《食品安全国 家标准食品接触材料及制品生产通用卫生规范》要求。 法规符合性说明：产品对上述法规技术指标的符合情况见附件。 责任声明：我司对所提供产品试样、产品信息、测试报告的真实性及配方的变更负法律 责任。产品使用者对正确使用该产品负有法律责任。 a)对于终产品，其符合性声明中必须说明产品的安全使用条件，其说明信息包括但不限于以上 内容。当不做任何说明时，则意味着产品可在任何条件下使用。 签名： 日期：

附件：产品技术指标法规限量要求及其符合性一、基础理化指标符合性 二、有限制物质限量指标的符合性 1.特定迁移量指标的符合性 2.残留量指标的符合性

人体生物等效性研究技术指导原则

附件3 以药动学参数为终点评价指标的 化学药物仿制药人体生物等效性研究 技术指导原则 一、概述 本指导原则主要阐述以药动学参数为终点评价指标的化学药物仿制药人体生物等效性试验的一般原则，适用于体内药物浓度能够准确测定并可用于生物等效性评价的口服及部分非口服给药制剂（如透皮吸收制剂、部分直肠给药和鼻腔给药的制剂等）。进行生物等效性试验时，除本指导原则外，尚应综合参考生物样品定量分析方法验证指导原则等相关指导原则开展试验。 生物等效性定义如下：在相似的试验条件下单次或多次给予相同剂量的试验药物后，受试制剂中药物的吸收速度和吸收程度与参比制剂的差异在可接受范围内。生物等效性研究方法按照研究方法评价效力，其优先顺序为药代动力学研究、药效动力学研究、临床研究和体外研究。 药代动力学（药动学）研究： 对于大多数药物而言，生物等效性研究着重考察药物自制剂释放进入体循环的过程，通常将受试制剂在机体内的暴露情况与参比制剂进行比较。 在上述定义的基础上，以药动学参数为终点评价指标的生物等

效性研究又可表述为：通过测定可获得的生物基质（如血液、血浆、血清）中的药物浓度，取得药代动力学参数作为终点指标，藉此反映药物释放并被吸收进入循环系统的速度和程度。通常采用药代动力学终点指标C max和AUC进行评价。 如果血液、血浆、血清等生物基质中的目标物质难以测定，也可通过测定尿液中的药物浓度进行生物等效性研究。 药效动力学研究： 在药动学研究方法不适用的情况下，可采用经过验证的药效动力学研究方法进行生物等效性研究。 临床研究： 当上述方法均不适用时，可采用以患者临床疗效为终点评价指标的临床研究方法验证等效性。 体外研究： 体外研究仅适用于特殊情况，例如在肠道内结合胆汁酸的药物等。对于进入循环系统起效的药物，不推荐采用体外研究的方法评价等效性。 二、基本要求 （一）研究总体设计 根据药物特点，可选用1）两制剂、单次给药、交叉试验设计；2）两制剂、单次给药、平行试验设计；3）重复试验设计。 对于一般药物，推荐选用第1种试验设计，纳入健康志愿者参与研究，每位受试者依照随机顺序接受受试制剂和参比制剂。对于

TUV符合性声明样稿(中英文)

Declaration of Conformity Manufacturer: ABC Medical Devices Co., Ltd. No.107, Super Road, Sanya, 530012, China European ZYX Regulatory Affair Service Co., Ltd. Representative: Str. UbRtse, Berlin, D-09856, Germany Product Name: Patient Monitor Model Number: P20, P22 and P24 (Start from S/N 04100001) UMDNS Code: 16484 Classification (MDD, Annex IX): IIb, rule 10 Conformity Assessment Route: Annex II.3 We herewith declare that the above mentioned products meet the transposition into national law, the provisions of the following EC Council Directives and Standards. All supporting documentations are retained under the premises of the manufacturer. 符合性声明 制造商：XX医疗器械公司 XX地址 欧盟代表：XX 地址 产品名称：XX 产品编号：XX 欧盟通用医疗器械编号（UMDNS Code:）：XX 分级（按照MDD的分级）：XX 符合性评估依据：XX 我们宣告以上提到的医疗器械符合国际法律法规，欧盟的医疗器械指令和标准。所有的文档都以制造商为前提进行保存。 DIRECTIVES General applicable directives: Medical Device Directive: COUNCIL DIRECTIVE 93/42/EEC of 14 June 1993 concerning medical devices (MDD 93/42/EEC). Amended by DIRECTIVE 2007/47/EC of 5 September 2007 Standard Applied: EN980:2008 EN1041:2008 EN ISO 13485:2003/AC:2007 EN ISO 14971:2007 EN 60601-1:1990+A1+A2 EN 60601-1-1:2001 EN 60601-1-2:2001 EN 60601-2-49:2001 EN 60601-1-6:2004 指令 主要适用标准： 医疗器械指令：1993年6月14日有关医疗器械的指令，标准委员会93/42/EEC 2007年9月5日修订2007/47/EEC 引用标准： EN980:2008 医疗器械标签中使用的图形符号 EN1041:2008医疗器械厂商提供的信息

药物制剂人体生物利用度和生物等效性试验指导原则word版本

药物制剂人体生物利用度和生物等效性试验指导原则

附录三药物制剂人体生物利用度和生物等效性试验指导原则生物利用度是指剂型中的药物被吸进入血液的速率和程度。生物等效性是指一种药物的不同制剂在相同的试验条件下，给以相同的剂量，反映其吸收速率和程度的主要动力学参数没有明显的统计学差异。 口服或其他非脉管内给药的制剂，其活性成分的吸收受多种因素的影响，包括制剂工艺、药物粒径、晶型或多晶型，处方中的赋形剂、黏合剂、崩解剂、润滑剂、包衣材料、溶剂、助悬剂等。生物利用度是保证药品内在质量的重要指标，而生物等效性则是保证含同一药物的不同制剂质量一致性的主要依据。生物利用度与生物等效性概念虽不完全相同，但试验方法基本一致。为了控制药品质量，保证药品的有效性和安全性，特制定本指导原则。何种药物制剂需要进行生物等效性或生物利用度试验，可根据有关部门颁布的法规要求进行。 进行药物制剂人体生物利用度和生物等效性试验的临床实验室和分析实验室，应提供机构名称以及医学、科学或分析负责人的姓名、职称和简历。 一、生物样品分析方法的基本要求 生物样品中药物及其代谢产物定量分析方法的专属性和灵敏度，是生物利用度和生物等效性试验成功的关键。首选色谱法，如HPLC、GC以及GC-MS、LC-MS、LC-MS-MS联用技术，一般应采用内标法定量。必要时也可采用生物学方法或生物化学方法。

由于生物样品取样量少、药物浓度低、内源性物质（如无机盐、脂质、蛋白质、代谢物）及个体差异等多种因素影响生物样品测定，所以必须根据待测物的结构、生物介质和预期的浓度范围，建立适宜的生物样品分析方法，并对方法进行验证。 1．专属性必须证明所测定的物质是原形药物或特定的活性代谢物，内源性物质和相应的代谢物不得干扰样品的测定。对于色谱法至少要提供空白生物样品色谱图、空白生物样品外加对照物质色谱图（注明浓度）及用药后的生物样品色谱图。对于复方制剂应特别加强专属性研究，以排除可能的干扰。对于LC-MS和LC-MS-MS方法，应着重考察基质效应。 2．标准曲线与线性范围根据所测定物质的浓度与响应的相关性，用回归分析方法获得标准曲线。标准曲线高低浓度范围为线性范围，在线性范围内浓度测定结果应达到试验要求的精密度和准确度。 必须用至少6个浓度建立标准曲线，应使用与待测样品相同的生物介质，线性范围要能覆盖全部待测浓度，不允许将线性范围外推求算未知样品的浓度。标准曲线不包括零点。 3．精密度与准确度要求选择3个浓度的质控样品同时进行方法的精密度和准确度考察。低浓度选择接近定量下限（LLOQ），在LLOQ的3倍以内；高浓度接近于标准曲线的上限；中间选一个浓度。每一浓度至少测定5个样品。 精密度用质控样品的日内和日间相对标准差（RSD）表示，RSD一般应小于15%，在LLOQ附近RSD应小于20%。 准确度是指用特定方法测得的生物样品浓度与真实浓度的接近程度，一般应在85%～115%范围内，在LLOQ附近应在80%～120%范围内。

生物等效性研究指导原则 英文版

Technique Guideline for Human Bioavailability and Bioequivalence Studies on Chemical Drug Products Contents (Ⅰ) Establishment and Validation for Biological Sample Analysis Methods (2) 1. Common Analysis Methods (2) 2. Method Validation (2) 2.1 Specificity (2) 2.2 Calibration Curve and Quantitative Scale (3) 2.3 Lower Limit of Quantitation (LLOQ) (3) 2.4 Precision and Accuracy (4) 2.5 Sample Stability (4) 2.6 Percent recovery of Extraction (4) 2.7 Method Validation with microbiology and immunology (4) 3. Methodology Quality Control (5) (Ⅱ) Design and Conduct of Studies (5) 1. Cross-over Design (5) 2. Selection of Subjects (6) 2.1 Inclusion Criteria of Subjects: (6) 2.2 Cases of Subjects (7) 2.3 Division into Groups of the Subjects (7) 3. Test and Reference Product, T and R (8) 4. Sampling (8) (Ⅲ) Result Evaluation (9) (Ⅳ) Submission of the Contents of Clinical Study Reports (9)

仿制药生物等效性试验指导原则(日本)

药食审发第1124004号文 2006年11月24日尊敬的各省市县医药卫生主管部门领导 厚生劳动省医药品食品卫生管理局管理科科长签发有关仿制药生物等效性试验等指导原则的一系列制订与修订事宜 在药品申报时、对于所应交付的仿制药生物等效性试验资料要求，曾在1997年12月22日医药审发第487号文“仿制药生物等效性试验指导原则”、2000年2月14日医药审发第64号文“含量规格不同的口服固体制剂生物等效性试验指导原则”、2000年2月14日医药审发第67号文“口服固体制剂更改处方后生物等效性试验指导原则”、2001年5月31日医药审发第786号文“仿制药生物等效性试验等一系列指导原则的修订事宜（即增补版）”及2003年7月7日药食审发第0707001号文“局部皮肤用药的仿制药生物等效性试验指导原则”等一系列文件中公布出来。此次对以上各指导原则再次进行了修订，详见附件-1、2、3和4。其中所附事项，请各相关单位敬请留意并遵照执行。 序 1．此次变更的指导原则 (1) 仿制药生物等效性试验指导原则 (2) 含量规格不同的口服固体制剂生物等效性试验指导原则 (3) 口服固体制剂更改处方后生物等效性试验指导原则 (4) 局部皮肤用药的仿制药生物等效性试验指导原则 2．以上各指导原则的执行时间 自2006年11月24日起执行。但原指导原则仍可并行使用至2007年11月24日。

附件-1 《仿制药生物等效性试验指导原则》 目录 第1章序言 第2章专业用语 第3章试验部分 A．口服普通制剂与肠溶制剂 I. 参比制剂与仿制制剂 II. 生物等效性试验 1．试验方法 1）试验计划 2）试验例数 3）受试者 4）给药条件 a. 给药量 b. 给药方法 ①单次给药 ②多次给药 5）测定 a. 体液采集 b. 采集次数与时间 c. 检测组分 d．分析方法 6）停止给药时间 2．评价方法 1）等效性评价指标 2）生物学同等性判定范围 3）统计学分析 4）同等性判定 III. 药力学试验

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