Review of Current Regulatory Guidance and Industry Publications
| Reference standards and reagents | Reference standard | Metabolite | Internal standard |
|---|---|---|---|
| FDA (7–9) | ·Authenticated reference standard of known identity and purity ·Identical to analyte or established chemical form (free base or acid, salt, or ester) ·Source ·Lot number ·Expiration date ·CoA (or evidence of identity and purity provided) Types of reference standards: (1) certified reference standards, (2) commercially supplied reference standards, and (3) other materials of documented purity in report Large molecule: ·Reference standards should be characterized appropriately and stored under defined conditions | ·Cross-reactivity should be evaluated individually and in combination with analyte ·Document evidence of purity and identity | ·Document evidence of purity and identity |
| EMA (10) | ·Authentic and traceable source ·Important that quality (purity) is ensured ·CoA (to include purity, storage conditions, expiration date, and batch number) Suitable reference standards: (1) certified standards, (2) commercially available standards, and (3) sufficiently characterized standards Document: origin, batch number, CoA, stability, and storage conditions Large molecule: ·Reference should be well characterized and documented, e.g., CoA and origin Purest reference available at the time should be used and should be from the same batch as dosing material for nonclinical and clinical studies. For batch change, analytical characterization and bioanalytical evaluation should be carried out to ensure performance characteristics of the method are not altered Commercial kits: Need to be re-evaluated to ensure LLOQ and QC samples perform accurately and precisely | · Investigate interference caused by metabolites · Evaluate possibility of back conversation of metabolite into parent and evaluate impact to study results | ·Certified standard not needed as long as suitability of use is shown ·CoA is not required. ·Demonstrate lack of analytical interference for substance and any impurities ·A stable isotope-labeled IS is recommended for MS detection. Labeled standard should be of highest purity and without isotope exchange |
| ANVISA (11) | Must use certified reference standards. RDC-27/12: use preferably pharmacopeic. For characterized chemical substances, submit the manufacturer documentation with the following data: name, CAS number, formula, molecular weight, shape, properties, impurity profiling care and maintenance and storage, identity, and content validity or retest date | Not addressed specifically. The current understanding based on discussions with ANVISA in 2012 is that they follow the requirements of characterized chemical substances | Not addressed specifically. Current understanding is it is preferable to use the IS labeled with stable isotope. Its use is dispensed if technically justified |
| MHLW (12) | ·Chemical structure from an authenticated source ·CoA (to include lot number, expiration date, content (purity), storage conditions, and batch number) | Not addressed specifically | ·CoA is not required ·Demonstrate lack of analytical interference with the analyte |
| ICH (13) | ·Well-characterized reference material, with documented purity. Recommend testing for impurities of product vs impurities of assay | Not addressed specifically | Not addressed specifically |
| White papers (14–17) | ·CoA (to include purity and stability of analyte) ·Record of receipt and storage Document: ·Lot numbers (manufacturer), purity, storage, stability, and handling and supporting documents ·Stability at time of use Large molecule: ·Reference standards are often heterogenous and may present unique comparability and stability considerations Biomarker kits: Typically not well characterized and prone to lot-to-lot variability. It is desirable to use reference from a single lot if possible throughout a study; alternatively, appropriate bridging procedures are to be followed | ·CoA if available, if not, at least documented purity information | ·No CoA is required, but lack of interference between IS and analyte should be established |
FDA Food and Drug Administration, CoA certificate of analysis, EMA European Medicines Agency, LLOQ lower limit of quantitation, QC quality control, IS internal standard, MS mass spectrometry, ANVISA Agência Nacional de Vigilância Sanitária, CAS Chemical Abstracts Service, MHLW Ministry of Health, Labour and Welfare, ICH International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use
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