Pharmaceutical Issues

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Pharmaceutical Issues

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

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Requirements

• Chemical Substance to Human Drug
• Standardize Processes to Assure Safety
  Consistency
• Identity
• Quality
• Purity
• Strength

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Operational Areas

• Bulk Drug Synthesis
• Analytical Development Validation
• Formulation Research Development
• Clinical Dosage Form Manufacture
• Shelf Life Monitoring

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Research Contracts

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

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Contractors

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

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Recompetitions

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

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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
  

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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

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Synthetic Projects
SarCNU
DB-67
CDDO
RH-1
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Synthetic Projects
Phortress
CAI
9-Nitropaullone
XK-469R
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Synthetic Projects
PT-523
5-Azacytidine
BPU
17-AAG
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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

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Analytical Chemistry (Batches)

• Confirm Identity
• Determine Purity Potency (Assay)
• Levels of Other Impurities
• Methods Validation
• Establish Release Specifications
• Stability of Bulk Drug Substance

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Typical Specifications

• Bulk Drug Substance
• Purity gt 98
• Impurities NMT 2 Total 0.5 Single
• Residual Solvents NMT 0.1 to 0.2
• Residue on Ignition NMT 0.1

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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

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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

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Stability Options

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

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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

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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

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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

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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)

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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

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