Presentacion Universidad USP

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Pharmaceutical Lab Quality Systems and Operations (PH489)

Temple University School of PharmacyQA/RA Graduate Program

Test Methods and Specifications for Drug Substances (API), Excipients and Dosage Forms

Frank Diana

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Analytical Testing in the Pharm. Lab– 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

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Analytical Testing in the Pharm. Lab– Method Transfer Samples– Method Validation Testing– Qualification of Standards– Instrument Calibration– Investigational Samples

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Drug Substance Release - Tests to Consider:– 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

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Drug Substance Release - Tests to consider:– 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)

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Drug Product Release – Tests to consider:– 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

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Drug product release –Tests to Consider:– 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

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US Pharmacopeia & National Formulary (www.usp.org)– 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

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USP/NF General Notices– 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

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USP/NF General Notices– 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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General Information Chapters– <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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In-Process Testing during API Synthesis– 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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In-Process Testing during API Synthesis– “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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In-process/intermediate testing is usually limited to:– 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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Release Testing of Drug Substances (API)– 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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Blend Uniformity Analysis– 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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Tote Bin Blender

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PQRI Blend Uniformity Working Group & FDA Guidance– Stratified Sampling of in-process dosage units and

correlation with blend uniformity data– 20 locations during compression, 7 units from each

- Sampling/Acceptance Criteria during Development, Validation, Routine Manufacturing

– Follow Flow Diagrams (Attachment 1 & 2)

Documents

Presentacion Universidad USP