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Pharmaceutical Issues

Pharmaceutical Issues. Rao Vishnuvajjala, Ph.D Chief, Pharmaceutical Resources Branch (PRB). Requirements. Chemical Substance to Human Drug Standardize Processes to Assure Safety & Consistency Identity Quality Purity Strength. Operational Areas. Bulk Drug Synthesis

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Pharmaceutical Issues

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  1. Pharmaceutical Issues Rao Vishnuvajjala, Ph.D Chief, Pharmaceutical Resources Branch (PRB)

  2. Requirements Chemical Substance to Human Drug • Standardize Processes to Assure Safety & Consistency • Identity • Quality • Purity • Strength

  3. Operational Areas • Bulk Drug Synthesis • Analytical Development & Validation • Formulation Research & Development • Clinical Dosage Form Manufacture • Shelf Life Monitoring

  4. Research Contracts • Solicitation - RFP Process • Select Organizations With Expertise • Selected by Open Competition • Contracts Awarded for Five Year Periods

  5. Bulk Drugs ASI, Starks, Alchem Analytical MRI, RTI, SRI Formulations Arizona, Kansas, Utah Manufacture Ben Venue Labs, Iowa Shelf Life US Bio/Medimmune Contractors

  6. Recompetitions • Shelf Life Contract • Analytical Contracts • Formulation R& D Contracts • Dosage Form Manufacture Contracts • http://rcb.nci.nih.gov/appl/rfp/

  7. PRB Staff • Shanker Gupta, Ph.D. • Paul Liu, Ph.D. • Ken Snader, Ph. D. • Vacant (Pharmaceutical Chemist) • http://reports.cit.nih.gov/jobsnih/advacsearch.asp

  8. Bulk Drug Synthesis • Develop Synthetic Route • Purification Process • Scale Up of Reactions • Improve Purification Process & Optimize Yield • Develop GMP Procedures • Prepare Large Batches & Provide Documentation • Prepare Reference Standard

  9. Synthetic Projects SarCNU DB-67 CDDO RH-1

  10. Synthetic Projects Phortress CAI 9-Nitropaullone XK-469R

  11. Synthetic Projects PT-523 5-Azacytidine BPU 17-AAG

  12. Analytical Chemistry (General) • Identity of Molecular Structure • IR, NMR, MS, EA, etc… • Develop Purity Tests • HPLC, GC, TLC, etc… • Test for Other Impurities • Moisture (K-F), Residual Solvents (GC) • ROI, Heavy Metals

  13. Analytical Chemistry (Batches) • Confirm Identity • Determine Purity & Potency (Assay) • Levels of Other Impurities • Methods Validation • Establish Release Specifications • Stability of Bulk Drug Substance

  14. Typical Specifications • Bulk Drug Substance • Purity: > 98% • Impurities: NMT 2% Total; 0.5% Single • Residual Solvents: NMT 0.1 to 0.2% • Residue on Ignition: NMT 0.1%

  15. Formulation Research (Goals) Provide Solution of Active Drug for iv Use. Solution Components Should Be: • Compatible with Blood • Non-Toxic to Blood Components and Host • Should be Free of Particulates • Isotonic • Suitable for Sterilization • Approved, USP/NF, Where Possible • Proven Safety Record

  16. Solubility Options • Salt Formation • Co-solvents: DMSO, EtOH, PG, PEG,etc. • Surfactants: Cremophor EL, Tween, etc. • Emulsions: O/W, EPL, Pluronics, Etc.. • Complexes: HPCD, SBE-4. • Pro-drugs • Liposomes

  17. Stability Options • Hydrolysis pH adjustment, Lyophilization • Oxidation Anti-oxidants • Photochemical Amber Vials, Boxes • Thermal Storage Temp.

  18. Formulation Research • Defines • Components & Composition • Type of Dosage Form • Container/Closure System • Storage Conditions • Reconstitution Vehicles (Lyo products) • Useable Periods • Stability and Compatibility with Devices

  19. Drug Product Manufacturing • Manufacture of Pilot Batches • Accelerated Stability Testing • Raw Material Qualifications • Bio-load Determination • Microbial Validations • Preparation of PIP • Preparation of Master Batch Record • Design and Printing of Labels

  20. Drug Product Manufacturing • Follow SOPs, GMP and QC Procedures • Prepare Drug Product, In-process Testing • Sterilize and Lyophilize, as applicable • Quality Control, Including Chemical & Microbial Testing • Establish Product Release Specifications • QC Release, Labeling, and Packaging

  21. Drug Product Manufacturing • QC/QA Review of Procedures and Batch Record • Send Clinical Batches to NCI Repository • Provide Documentation for IND • Special Studies: • Solution Stability and Compatibility with Infusion Solutions and Devices ( pumps, bags, iv sets, etc…)

  22. Shelf Life Monitoring • Develop Storage & Stability Testing Protocols • Monitor Stability on Established Time Schedule • Promptly Recall Batches that fall Outside Established Specifications • Each Clinical Lot is Monitored for Stability

  23. Our next speaker is: Dr. Joseph Tomaszewski Toxicology & Pharmacology Branch Developmental Therapeutics Program

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