Product development

New chemical entities Preformulation:  Preformulation is defined as a developmental stage during which the physicochemical...

New chemical entities

Preformulation: 

Preformulation is defined as a developmental stage during which the physicochemical properties of the drug substance is characterized and established. A thorough knowledge of therapeutic and physicochemical properties of the drug allows the determination of its method of preparation and proper delivery.

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.  

Importance of Pre Formulation

It describes the process of optimizing drug delivery via determination of physical, chemical properties of new drug molecule that affect the performance of drugs and the development of a stable dosage form.

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, V.

Regulatory approval: based on stability, analytical / manufacturing controls, bioequivalence studies, clinical trials

Solid products:

Different strength in a tablet or capsule form à only bioequivalence required (simplest case).  Easier if in vitro dissolution / in vivo bioavailability correlation exists.

Modified release: clinical trials required.

If new indication à new NDA and new efficacy studies.

Liquid products:

If an extension of a liquid à same as above for solids

If an extension of a solid à if big difference in extent / rate of absorption à 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 à comparable dissolution profiles.  Major change à in vivo bioequivalence study.

GMPs

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.