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Temple University School of Pharmacy QA/RA Graduate Program Test Methods and Specifications for Drug Substances (API), Excipients and Dosage Forms Frank Diana
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Drug Substance (API) Release/Reassay/Stability Drug Product Release/Reassay/Stability In-process Samples Raw Material (Excipient) Release/Reassay Packaging Components Release Equipment Cleaning Samples Complaint Samples
Method Transfer Samples Method Validation Testing Qualification of Standards Instrument Calibration Investigational Samples
Description/Appearance Assay versus a qualified reference standard (unless a nonspecific assay is employed, i.e. titration) Impurity Profile Identification Tests Residual Solvents, OVIs Water Determination
Compendial tests, i.e., heavy metals, ROI, clarity of solution, chloride, etc. Physical Tests, i.e., particle size, bulk and tap density, surface area, polymorphic forms Microbiological tests particularly for APIs to be used in parenteral formulations Chiral purity, specific rotation (as appropriate)
Description/Appearance Assay versus a qualified reference standard Degradation Product Profile (vs API impurity profile) Identification Test(s) Dissolution or Drug Release Uniformity of Dosage Units pH
Moisture Determination Clarity/Particulate Matter Preservative or Anti-oxidant Physical tests such as hardness or disintegration Micro tests such as Bacterial Endotoxins or sterility or antimicrobial preservative effectiveness
USP28/NF23 contains about 4000 monographs and over 160 general chapters General Chapters <1> - <999>: include general requirements for tests and assays General Chapters <1000>-<1999> are informational Pharmacopeial Forum (PF) is the working document of the USP Committee of Revision Legal Status of the USP/NF
Significant Figures and Limits USP References Standards Foreign Substances and Impurities Volumetric Apparatus <31> - Use of Class A All solutions in tests/assays are to be prepared with purified water Light-Resistant, Well-Closed, Tight Containers Controlled Room Temperature Definition Beyond use date for dispensing
Every compendial article in commerce must meet monograph requirements, when (if) tested Automated vs Manual methods Use of Alternative Methods Equivalent or superior methods In the event of dispute, procedure in USP/NF is conclusive
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USP/NF Monographs
USP drug substances and dosage forms NF Excipients; if therapeutic agent and an excipient, included in USP with cross-reference in NF Excipient Any component other than the active substance(s), intentionally added to the formulation of a dosage form
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General Chapters
Injections<1> Reference Standards <11> Micro tests, <51>, <61> and <71> Chemical Tests and Assays Physical Tests and Determinations
<621> Chromatography <711> Dissolution <724> Drug Release <905> Uniformity of Dosage Units
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<1078> Principles of GMPs for Bulk Pharmaceutical Excipients <1086> Impurities in Official Articles <1088 In Vitro/In Vivo Evaluation of Dosage Forms <1111> Microbiological Attributes of Nonsterile Pharmaceutical Products <1151> Pharmaceutical Dosage Forms <1225> Validation of Compendial Methods <1227> Validation of Microbial Recovery From Pharm. Articles <1231> Water for Pharmaceutical Purposes
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Sampling procedures should ensure sample integrity and prevent contamination Less stringent in-process controls may be appropriate in early processing steps whereas tighter controls should be applied to later synthesis, isolation and purification steps
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Written procedures should be established to monitor the progress and control the performance of those manufacturing processes that may cause variability in the quality characteristics of APIs and intermediates.
Example chiral purity of API is assured by control/testing of intermediate and subsequent analysis of the precursor. Example testing of the 4 isolated intermediates in the API synthesis for purity. In particular the purity of the final two intermediates has the most impact on the quality of the final drug substance.
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Assay vs a reference standard Impurity profile by HPLC or GC (typically area%) Identification Water/residual solvents, as appropriate
Method Validation for assay/purity of key raw materials, intermediates and in-process tests is expected and varies according to the usage of the method Results are documented in the batch record Transfer of testing to manufacturer (R&D to vendor, if necessary)
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Written sampling procedures based on valid data and scientifically sound sampling practices Specs should be established based on data obtained for batches tested as well as safety qualification levels Reserve samples, at least 2X quantity needed for testing Reprocessing/reworking of APIs Except for compendial tests, all methods should be appropriately validated.
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Blend Uniformity Analysis (In-process test) (BUA) In-process controls are required The in-process testing requirement for adequacy of mixing to ensure uniformity and homogeneity is established in 21CFR211.110(a)(3). Normally performed during development and on validation batches, however for ANDAs it has become a release requirement for some products. FDA Guidance issued 10/2003 indicates that assessment should occur during development and establish criteria for routine manufacturing
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Typically 1 to 3 tablet weights (taken with sampling thief) Sample larger than 3X with adequate justication 10 locations for tumbling blenders (i.e. v-blender), 20 locations may be required for ribbon blenders Acceptance Criteria individual results within 10% of the mean, RSD of no more than 5.0%
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