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Drug Product Development

Active pharmaceutical ingredient (API): component that produces pharmacological activity (drug substance). May
be produced by chemical synthesis, from natural product, enzymatic reaction, recombinant DNA, fermentation, etc.
New chemical entity (NCE): drug substance with unknown clinical, toxicological, physical, chemical properties.
According to the FDA, NCE is an unapproved API.
Drug product: finished dosage form containing API and excipients.
Generic drug products: after patent expiration of brand drug. Therapeutically equivalent to the brand and has the
same drug amount in the same dosage form. Must be bioequivalent (same rate and extent of absorption) same
clinical results. May differ from brand in excipients (tablets only unless safety studies are done) or physical
Abbreviated New Drug Application (ANDA): submitted to the FDA for approval of generic drugs. Preclinical safety
and efficacy studies are not required. Human bioequivalence is needed (on healthy human volunteers). Chemistry,
manufacturing and controls for generics are similar to the brand.
Specialty drug products: existing products developed for new delivery system or new therapeutic indication. Safety
and efficacy studies are not required. Example nitroglycerin transdermal patch after sublignual tablets.
New drug approval
Preclinical (animal safety / pharma) IND Phase I (healthy human safety) Phase II (# patients) Phase III
(# patients) NDA FDA green light for marketing Phase IV (scale up) Phase V (continuous
Preclinical stage: animal pharmacology and toxicology to determine safety and efficacy. Formulation is not final.
Phase I: Submit an Investigational New Drug (IND) clinical studies on healthy volunteers to determine toxicity
and tolerance. For oral drugs simple hard gelatin capsule.
Phase II: small number of patients under close supervision. Dose-response studies to determine optimum dosage
for treatment. Determine the therapeutic index (toxic dose/effective dose). Develop final drug formulation
(bioequivalent to that used in initial clinical studies). Start chronic toxicity studies for 2 years in 2 species.
Phase III: large-scale multicenter clinical studies with final dosage form (from phase II) to determine safety and
efficacy in patients. Watch for new, rare, toxic or side effects.
NDA submission: FDA satisfaction with safety and efficacy for marketing.
Phase IV: scale-up in preparation for marketing. Only minor modifications on the formulation are allowed.
Phase V: continuous drug product improvements after marketing.
Product development
New chemical entities
Physical and chemical characterization of the drug and dosage form during preclinical phase. Includes general
properties (particle size / shape, polymorphism, crystalline structure, density, surface area, hygroscopicity), solubility
(dissolution, pH-solubility profile, various solvents), chemical properties (surface energy, pH stability profile, pKa,
temperature stability, excipient interactions), stability analytical methods.
Formulation development: continuing process.
Injections: final formulation is developed in preclinical phase, stability in solution is critical, few excipients allowed, no
bioavailability for IV.
Topicals / local: final formulation developed in phase I, study release in in vitro diffusion cell models, local irritation
and systemic absorption are the issues.
Topicals / systemic: drug delivery through skin / mucosa / rectum, final formulation in phase III.
Oral drugs: final formulation in phase II.
Final product considerations: size, shape, color, taste, skin feel, viscosity, physical appearance, production
equipment / site.
Product line extensions:
Dosage forms with change in physical form or strength but not use or indication. Usually occurs during Phases III, IV,
Regulatory approval: based on stability, analytical / manufacturing controls, bioequivalence studies, clinical trials
Solid products:
Different strength in a tablet or capsule form only bioequivalence required (simplest case). Easier if in vitro
dissolution / in vivo bioavailability correlation exists.
Modified release: clinical trials required.
If new indication new NDA and new efficacy studies.
Liquid products:
If an extension of a liquid same as above for solids

If an extension of a solid if big difference in extent / rate of absorption new clinical trials.
Preapproval inspections
Manufacturing facility is inspected prior to NDA / ANDA approval or after a major reported change to NDA / ANDA.
Includes: general cGMP inspection, reviews documentation, verifies traceability of information to documentation,
consults the chemistry / manfucaturing / control (CMC) section of NDA / ANDA, make a final recommendation.
Scale-up and post-approval changes (SUPAC)
Guidelines to # of manufacutring changes that require preapproval by the FDA.
Examples: minor formulation changes, change site of manufacture, batch size or , change manufacturing process
/ equipment.
1. Very minor changes not requiring approval are reported in an annual report. Examples: compliance with
guidance, label description, deletion of colorant, expiration date extension, container / closure type (not size),
analytical method
2. Changes being effected supplement: minor changes but require some validation, documentation. A supplement
but no pre-approval is required. Examples: new specs, label changes on clinical info, different cGMP manufacturing
facility but same process.
3. Preapproval supplement: major changes require specific preapproval. Examples: adding or deleting an
ingredient, relaxing specs, deleting a spec or method, method of manufacture, in-process controls.
Therapeutic and Bio-equivalence: must be shown for any change. Minor change comparable dissolution
profiles. Major change in vivo bioequivalence study.
Minimum requirements for manufacturing, processing, packing, or holding drugs. Include criteria for personnel,
facilities, processes to ensure final product has the correct identity, strength, quality, purity.
Quality Control (QC): department responsible for establishing process and product specifications. The QC dept test
the product and verifies specs are met. This includes acceptance / rejection of incoming raw materials, packaging
components, water, drug products, environmental conditions.
Quality Assurance (QA): a department that determines that the systems and facilities are adequate and that written
procedures are followed.