Generic drug development process of solid dosage (tablet) form include following major stages: 

  • Literature Search
  • API Sourcing
  • API Evaluation and Procurement
  • Pre-formulation Study
  • Feasibility Batches
  • Manufacturing Process Development
  • Container Closure System  (Packaging material) Development 
  • Pilot Batch Scale Up
  • Process Optimization 
  • Process Validation

Literature Search

  • Literature: USP, BP, JP, EP, Merck, Florey etc.
  • FDA-FOIA: Summary Basis of Approval
  • On-line search of FDA/CDER info: Data Base guidelines for test methods, dissolution, impurities, Bio-study  parameters. etc.
  • Patent Evaluation: Orange Guide + FDA/CDER www.patent consultant

API Sourcing

  • Sourcing of Active Pharmaceutical Ingredient (API); Drug Substance: US & International Suppliers from (Europe, Asia, etc.).
  • Have Potential Supplier lists: Request Technical Binder & DMF Information.
  • US agent for API: Request samples & CoA and Specifications, At least two suppliers for full evaluation.

API Evaluation and Procurement

  • At least 2-3 potential API supplier
  • DMF availability & Status
  • Compliance with USP monograph
  • Impurity profile and stability
  • Potential polymorphic forms
  • Commitment for physical specification (micronized, crystal)
  • Statement of non-patent infringement 
  • In g/kg quantities for method development & pre- formulation study

Pre-formulation Study

Drug Substance: Physico-chemical evaluation for: Moisture sorption/ desorption, Flowability, Particle size, B/T Density and Compactability study, Drug-Excipient Compatibility study.

Innovator Product (RLD): At least 3 different lots in smallest and largest pack size, Evaluation of physical parameters (Shape, Size, Dimension, Score, Color, Embossing for Logo), Container/Closure system (packaging materials, dunnage: cotton, polyester, rayon; desiccant; odor absorbent, oxygen scavenger etc.). Physical testing for: Weight, Thickness, Hardness, LOD, Friability, Disintegration etc. For MR Tablets: Evaluation of tablet’s  disintegration behavior: Erosion Vs Congealing characteristics.

Microscopic observation:  By slight crushing of tablet with a mortar & pestle and observing under microscope for: Particles Vs granules for particle size, crystal shape & habit. Differentiation on the presence specific excipients can be verified from  microscopic observation. e.g., Lactose  modified Vs Anhydrous Lactose, Cross-linked cellulose, Starch and Avicel have a specific shapes and morphology and may be detected.

Dissolution Profile: USP monograph and FDA method - (where present) Dissolution; 12 unit Dissolution Profile. In case of Modified Release Tablet: In Water, 0.1N HCl, pH 4.5 Buffer, and pH 6.8 Buffer.

Feasibility Batches

  • Drug-Excipient compatibility using DSC methods and stability assessment
  • Accelerated Stability: 40°C/75% RH ; Time points 0 up to 3 months
  • Stress Stability: 60°C up to 3 weeks
  • Qualitative and Quantitative Composition
  • Matching dissolution with RLD.
  • All excipients within IIG limits.
  • Process and Equipment Train Identified.
  • Container/Closure with either accelerated or stress stability established.
  • IVIVC or BE by Pilot Bio.

Manufacturing Process Development

Process suitability study: Wet granulation (aqueous or non-aqueous) high shear mixing / low shear mixing, FBD spray procedure), or Dry mixing, dry granulation and/'or Slugging.

Granulation parameter/ check point: Determination of order of mixing, Determination of pre-mixing (in Granulator), Determination of fluid addition (if relevant), Determination of granulation time, Determination of torque end-point value, Determination of Drying parameters, Determination of LOD limits, Determination of testing temperature for checking LOD limits.

Container Closure System Development

Selection of container and closure system for pharmaceutical products include: 
  • Material composition,
  • Type of thermoplastic resin and resin pigments,
  • Manufacturers and suppliers,
  • Liners and seals used by closure manufacturer,
  • Dunnage : (cotton, polyester, rayon), odor absorbent and desiccants.
  • Manufacturer's DMF numbers for all component parts.

Pilot Batch Scale Up

  • Scale-up batch prepared if larger batch size scale up problems anticipated.
  • Process optimization batch and Scale-up batch may be evaluated as a single batch.

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