国家药品标准物质制备指导原则-en

Guideline for Preparation of National Pharmaceutical Reference Standards This guideline is indicated for normalizing and guiding preparation of national pharmaceutical reference standards and ensuring implementation of national drug standards. I. Establishment of varieties of national pharmaceutical reference standards

Varieties of reference standards to be prepared should be established according to use requirements (varieties, purpose) put forward in setup and revision of national drug standards. II. Selection of candidate materials for reference standards

1. For selection of materials, the principles of suitability, representation and availability should be followed, and the quantity needed should be satisfied.

2. Properties of materials should comply with the use requirements.

3. Quantity value spectra of homogeneity, stability and other relevant properties of material should be suitable for purposes of the corresponding reference standards.

III. Preparation of candidate reference standards

1. Select rational preparation procedures and crafts according to physicochemical properties of candidate reference standards and prevent contamination and value changes of corresponding properties.

2. For candidate reference standards the corresponding property values of which cannot be homogenized easily, not only necessary homogenizing measures should be taken in the process of preparation, but also preliminary homogeneity test should be carried out.

3. Where values of corresponding properties of a candidate reference standard show the trend to be unstable, factors affecting its stability should be paid attention to in the process of preparation and necessary measures should be taken to improve its stability, and a suitable environment should be selected for storage.

4. When the prepared amount of a candidate reference standard is large, graded subpackaging may be applied for convenient storage.

5. Suppliers of candidate reference standards should have favorable experimental conditions and capacity and provide the following data:

1) Completed data including test methods, values, number of repeated times of tests, necessary spectra and chromatograms;

(2) Storage conditions (temperature, humidity and light irradiation) complying with stability requirements;

(3) Hygroscopicity study results or hydroscopicity description of candidate reference standards;

(4) Results of accelerated stability study;

(5) Specific data about identification and percentages of related substances, relative response factors of principal ingredients in national drug standards;

(5) Latest safety data related to health risks.

IV. Standardization of candidate national drug reference standards

Candidate reference standards are standardized as per the following requirements. Conditions permitting, comparison with international reference standards or pharmacopoeial reference standards of advanced countries and regions such as Europe and America should be performed:

1. Characterization of chemical structures or components

1) As for validation of a compound with known structure, necessary physicochemical parameters and spectral data as well as relevant literatures and comparison data should be provided. Where no literature report is available, complete structure elucidation should be provided.

2) For reference standards the structures of which cannot be characterized using contemporary physicochemical methods, suitable methods should be carried out to identify their components.

2. Examination of physicochemical properties

Test items of physicochemical properties should be established depending on properties of the reference standards and the specific conditions, e.g. description, melting point, specific optical rotation, crystal form, loss on drying and hydroscopicity.

3. Test for impurity and related substances

Test items for impurity and related substances should be established according to use requirements of reference standards, e.g. reaction intermediates, byproducts, etc.

4. Homogeneity test

Candidate reference standards prepared in batches and subpackaged into minimum packaging units must be subjected to homogeneity test. Candidate reference standards of graded subpackaging, homogeneity test must be carried out when they are subpackaged from large packages to minimum packaging units.

5. Evaluation

Evaluation can be performed after the above requirements are met.

The evaluation method should be one proving to be accurate and reliable in both theory and practice. Inherent systematic errors and random errors from the measurement method, the measurement process and the sample treatment process, e.g. contamination and loss of the sample in dissolution and separation operations, should be first investigated; measurement equipment should be calibrated periodically; traceable reference substances should be used; a feasible quality assurance system should be available to ensure traceability of measurement results.

1) Principle of evaluation

In the assay of a candidate chemical standard substance/reference substance, the sum of determination results of water, organic solvents, inorganic impurities and organic impurities is 100%.

2) Use the following methods for evaluation of candidate reference standards

(1) Use a high-accuracy absolute or authoritative measurement method for evaluation

In the measurement, more than two analyzers should carry out the operation independently on different experimental instruments.

(2) Use more than two reliable methods of different principles with known accuracy for evaluation

Precision of measurement methods of different principles should be investigated to estimate the systematic errors of the methods, and necessary measures should be taken to validate accuracy of the methods.