IV. REFERENCE STANDARDS
A. Types of Standards A reference standard (i.e., primary standard) may be obtained from the USP/NF or other official sources (e.g., CBER, 21 CFR 610.20). If there are questions on whether a source of a standard would be considered by FDA to be an official source, applicants should contact the appropriate chemistry review staff. When there is no official source, a reference standard should be of the highest possible purity and be fully characterized.
IV 标准品
A.标准品的类型
可以从USP/NF处或其它官方(比如说,CBER,21CFR 610.20)获得标准品 (也就是一级对照品)。如果不能确定一标准品的来源是否会被FDA认为是官方来源,申请者应当要向适当的化学评审人员咨询。如果没有官方来源,则被用来作标准品的物质应当要有尽可能高的纯度,并得到充分界定。
A working standard (i.e., in-house or secondary standard) is a standard that is qualified against and used instead of the reference standard.
工作对照品 (也就是内部标准品或二级标准品)是根据一级对照品标定的,并用来代替一级对照品的。
B. Certificate of Analysis
A certificate of analysis (COA) for reference standards from non-official sources should be submitted in the section of the application on analytical procedures and controls. For standards from official sources, the user should ensure the suitability of the reference standard. The standard should be stored correctly and used within the established use interval.
B.分析报告单
对于非官方标准品,在申请的分析方法和控制章节中应当要提供该标准品的分析报告单。对于从官方获得的标准品,用户应当要确保标准品的适用性。应当正确储存标准品并在已确定的时间段内使用该标准品。
C. Characterization of a Reference Standard
Reference standards from USP/NF and other official sources do not require further characterization. A reference standard that is not obtained from an official source should be of the highest purity that can be obtained by reasonable effort, and it should be thoroughly characterized to ensure its identity, strength, quality, purity, and potency.
C.标准品的界定
从USP/NF及其它官方来源获得的标准品是不需要进一步界定的。非官方对照品要有尽可能高的纯度,并进行充分地界定以确保其结构,剂量,质量,纯度和效力。
The qualitative and quantitative analytical procedures used to characterize a reference standard are expected to be different from, and more extensive than, those used to control the identity, strength, quality, purity, and potency of the drug substance or the drug product. Analytical procedures used to Draft — Not for Implementation characterize a reference standard should not rely solely on comparison testing to a previously designated reference standard.
用于界定标准品的定性和定量分析方法应当要不同于用于控制原料药或制剂的结构,剂量,质量,纯度和效力的分析方法,要比它们更深入。用于标准品界定的分析方法不应仅仅是和先前的指定标准品进行比较实验。
Generally, this characterization information should include:
A brief description of the manufacture of the reference standard, if the manufacturing process differs from that of the drug substance. Any additional purification procedures used in the preparation of the reference standard should be described.
一般来说,界定资料应当要包括:
标准品的简单工艺描述,如果其生产工艺是否于其相应的原料药的话。应当要叙述制备标准品时所用的补充精制过程。
Legible reproductions of the relevant spectra, chromatograms, thin-layer chromatogram (TLC) photographs or reproductions, and other appropriate instrumental recordings. Data establishing purity. The data should be obtained by using appropriate tests, such as TLC, gas chromatography (GC), high-pressure liquid chromatography (HPLC), phase solubility analysis, appropriate thermometric analytical procedures, and others as necessary.
相关光谱图,色谱图,TLC照片及其它仪器输出的清晰复印件。建立纯度的资料。应当要应用适当的检测方法来获得这些资料,比如说TLC,GC,HPLC,相溶解分析,适当的热分析方法及其它必要的分析方法。
Appropriate chemical attribute information, such as structural formula, empirical formula, and molecular weight. Information to substantiate the proof of structure should include appropriate analytical tests, such as elemental analysis, infrared spectrophotometry (IR), ultraviolet spectrophotometry (UV), nuclear magnetic resonance spectroscopy (NMR), and mass spectrometry (MS), as well as applicable functional group analysis. Detailed interpretation of the test data in support of the claimed structure should be provided.
适当的化学性质资料,比如结构式,经验式和分子量等。结构确证资料应当要包括适当的分析测试,比如元素分析,IR,UV,NMR和MS,及适用的官能团分析。还应当要提供具体的结构解析资料。
A physical description of the material, including its color and physical form. Appropriate physical constants such as melting range, boiling range, refractive index, dissociation constants (pK values), and optical rotation. A detailed description of the analytical procedures used to characterize the reference standard.
物理性质的描述,包括颜色和物理形态。 适当的物理常数,比如说熔程,沸程,折射率,离解常数(pK值)和旋光度。用于界定标准品的分析程序的详细叙述。
For biotechnological/biological product reference standards, the recommendations on characterization information above may apply and should be considered. However, additional and/or different tests would be important to assess physicochemical characteristics, structural characteristics, biological activity, and/or immunochemical activity.
至于生物技术/生物产品的标准品,应当要考虑上述建议,可能可以应用。然而,其它确定物理化学性质,结构特性,生物活性和/或免疫化学活性的补充检测和/或其它检测将是非常重要的。
Physicochemical determinations may include isoform, electrophoretic, and liquid chromatographic patterns, as well as spectroscopic profiles. Structural characterization may include a determination of amino acid sequence, amino acid composition, peptide map, and carbohydrate structure. Biological and/or immunochemical activity should be assessed using the same analytical procedures used to determine product potency.
物理化学性质包括异构体,电泳和
液相色谱行为及光谱性质等。结构界定可能包括氨基酸序列,氨基酸组成,缩氨酸图和碳水结构。确定生物和/或免疫化学活性的分析方法应当要和用来确定产品效力的分析方法一样。
These can include animal-based, cell culture-based, biochemical, or ligand/receptor-binding assays. While these tests may be needed for complete characterization of certain reference standards, specific recommendations for validation of biological and immunochemical tests are not contained in this guidance document.
这些分析方法可以包括基于动物的,细胞培养的,生物化学的或配位体/接受体螯合的分析方法。如果这些检测需用于某些标准品的界定,生物和免疫化学检测的分析方法验证方面的特殊建议并不在本指南的范围之内。