Pharmaceutical Issues

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Pharmaceutical Issues

• Shanker Gupta, Ph.D
• Pharmaceutical Resources Branch (PRB)

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Requirements

• Chemical Substance to Human Drug
• Standardize Processes to Establish
• 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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PRB Staff

• Rao Vishnuvajjala, Ph. D., Chief
• Shanker Gupta, Ph.D.
• Sung Kim, Ph. D.
• Paul Liu, Ph.D.
• Ken Snader, Ph. D.

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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
RH-1
CDDO
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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.
• SurfactantsCremophor EL, Tweens, etc.
• Emulsions O/W, EPL, Pluronics, Etc..
• ComplexesHPCD, SBE-4, Counter Ionic.
• Pro-drugs
• Liposome

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Stability Options

• Hydrolysis Lyophilize
• 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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Liposomal Formulation of DB-67

• A liposomal formulation was proposed containing
  DMPC, DMPG and the drug in a molar ratio of 130,
  druglipid.
• The formulation procedure used organic solvents
  which had to be evaporated with the film
  suspended in phosphate buffer containing sucrose.
• The resulting suspension was fairly coarse with
  relatively large particle size. The particle
  size was reduced by extruding the suspension
  through a polycarbonate membrane.

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Scale Up Considerations

• It was not possible to use certain organic
  solvents due to safety considerations.
• The drug is fairly lipophilic and was lost in the
  polycarbonate membrane owing to adsorption.
• It is not possible to use polycarbonate membranes
  readily in a large scale process.
• The suspension at the end of extrusion was not
  reproducibly reduced in particle size such that
  it can be sterilized by membrane filtration.
• It is obvious that this process cannot be
  validated for GMP production of a human phase I
  clinical batch without modifications.

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Refined Process

• The procedure was modified by eliminating the
  extrusion step in favor of microfluidization.
  This procedure reduces particle size by applying
  high energy shear forces to the suspension.
• This also resulted in avoiding drug losses due to
  adsorption to the polycarbonate membrane.
• The particle size at the end of homogenization
  step was reproducibly less than 0.22 microns such
  that the product can be sterilized by membrane
  filtration.

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Refined Process for Clinical Batch

• At the end of sterilization, the drug suspension
  was filled in vials and lyophilized.
• A conservative lyophilization cycle was used. The
  suspension was frozen, and lyophilization in a
  multi-step drying process such that the resulting
  film (next slide) could be easily rehydrated
  using 2 mL of WFI yielding 1 mg/mL of drug
  suspension suitable for injection.

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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 GMP and QC Procedures
• Follow all SOPs
• Prepare Drug Product, Sterilize and Lyophilize,
  as applicable
• Quality Control testing, 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
• Ship 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. Adaline
Smith Toxicology Pharmacology
Branch Developmental Therapeutics Program