Lecture 2

Question 1

Definition - Active Pharmaceutical Ingredient

Answer 1

• 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.

Question 2

Drug Nomenclature

Answer 2

• Trade/Brand Name
• Generice Name
• Dosage Form Description

Question 3

API Physical Forms

Answer 3

• Crystalline solids
• Amorphous solids
• Gases, liquids
• Solutions

Question 4

Types and Sources of APIs

Answer 4

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)

Question 5

API Manufacturing Processes

Answer 5

• 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

Question 6

API Storage and Stability

Answer 6

• 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

Question 7

API Impurities

Answer 7

• 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.

Question 8

How do you pick an API?

Answer 8

• 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