Definition - Active Pharmaceutical Ingredient
• Any substance or mix of substances intended to be used in the manufacture of a drug (medicinal) product and that, when used in the production of a drug, becomes an active ingredient of the drug product.
Drug Nomenclature
- Trade/Brand Name
- Generice Name
- Dosage Form Description
API Physical Forms
- Crystalline solids
- Amorphous solids
- Gases, liquids
- Solutions
Types and Sources of APIs
Small Molecules
• Inorganic salts (potassium chloride)
• Isolated from natural sources (morphine) or fermentation of naturally occurring microbes (penicillin, lovastatin)
• Chemical modification of natural product (hydrocodone, simvastatin)
• Chemical synthesis (acetaminophen, atorvastatin)
Macromolecules
• Microbial fermentation (insulin, plasmid DNA)
• Animal or human cell culture (adalimumab, adenovirus)
• In vitro enzymatic synthesis (mRNA)
API Manufacturing Processes
- Highly diverse in complexity, process and scale
- All API manufacturing processes are validated to control SISPQ
- Process details are confidential
- Generic APIs are commodity chemicals, and comply with compendial requirements
- Process details and controls are filed with regulators, and manufacturing is subject to regular inspection by authorities
- Vehicle for regulatory filing is a New Drug Application (NDA) for proprietary new drugs, or a Drug Master File (DMF) for generics
- Impurity profiles and physical properties can differ among manufacturers of the same generic API
API Storage and Stability
- Stability studies are conducted according to ICH guidelines, and include stressful storage conditions (temperature, light, humidity) to identify conditions that will impact SISPQ + characterize degradation products
- Storage containers are impermeable, compatible, suitable for shipment, and offer light protection when warranted
- APIs are generally stored under conditions that do not result in significant degradation over time
- Rather than an expiration dating period as for drug products, a retest interval is established
- Regulatory limitations on repeated retesting for commercial products
API Impurities
• This category includes:
– synthetic impurities and by-products, such as enantiomeric impurities
– process impurities (unreacted reagents, residual solvents, elemental impurities)
– degradation products that might be produced during storage or handling.
How do you pick an API?
• Develop a model/target for the therapeutic indication
• Develop API candidate library
• Screen for therapeutic window (potency versus toxicity)
– Filter in on-target effects (potency)
– Filter out off-target effects (toxicity)
• Iterate, using successively refined models
– Literature/IP -> in silico -> in vitro assays - > in vivo studies -> clinical trials
– At later iterations, consider effects on manufacturing, impurities, and stability
