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)

Technique Guideline for Human Bioavailability and Bioequivalence

Studies on Chemical Drug Products

Specific Requirements for BA and BE Studies

(Ⅰ) Establishment and Validation for Biological Sample Analysis Methods

Biological samples generally come from the whole blood, serum, plasma, urine or other tissues. These samples have the characteristics such as little quantity for sampling, low drug concentration, much interference from endogenous substances, and great discrepancies between individuals. Therefore, according to the structure, biological medium and prospective concentration scale of the analytes, it is necessary to establish the proper quantitative assay methods for biological samples and to validate such methods.

1. Common Analysis Methods

Commonly used analysis methods at present are as follows: (1) Chromatography: Gas Chromatography(GS), High Performance Liquid Chromatography (HPLC), Chromatography－mass Spectrometry (LC-MS, LC-MS-MS, GC-MS, GC-MS-MS), and so on. All the methods above can be used in detecting most of drugs; (2) Immunology methods: radiate immune analysis, enzyme immune analysis, fluorescent immune analysis and so on, all these can detect protein and polypeptide; (3) Microbiological methods: used in detecting antibiotic drug.

Feasible and sensitive methods should be selected for biologic sample analysis as far as possible.

2. Method Validation

Establishment of reliable and reproducible quantitative assay methods is one of the keys to bioequivalence study. In order to ensure the method reliable, it is necessary to validate the method entirely and the following aspects should be generally inspected:

2.1 Specificity

It is the ability that the analysis method has to detect the analytes exactly and exclusively, when interference ingredient exists in the sample. Evidences should be provided that the analytes are the primary forms or specific active metabolites of the test drugs. Endogenous instances, the relevant metabolites and degradation products in biologic samples should not interfere with the detection of samples. If there are several analytes, each should be ensured not to be interfered, and the optimal detecting conditions of the analysis method should be maintained. As for chromatography, at least 6 samples from different subjects, which include chromatogram of blank biological samples, chromatogram of blank biologic samples added control substance (concentration labeled) and chromatogram of biologic samples after the administration should be