PREFORMULATION Important stages where Preformulation, Biopharmaceutics and Formulation plays a key role are – Candidate drug selection Various stages of product development Objective of Pharmaceutical R&D “converting ideas into candidate drugs for development.” Objective of Product Development “converting candidate drugs into products for registration and sale.”

PREFORMULATION Dr. Dinesh M. Biyani, M. Pharm. Ph.D. DBM, DIRPM, Dip TD Associate Professor, SKB College of Pharmacy, Kamptee dineshbiyani10@gmail.com

Major Hurdles to Successful Product Registration and Sale S. No. Activity Requirements 1. Research Novel compounds(patentable), Novel biological mechanism (patentable) Unmet medical needs, Potent and selective 2. Safety High margin of safety, Non toxic (Carcinogenicity, Teratogenicity, Mutagenicity) 3. Clinical Tolerable side effects profile, Efficacious, Acceptable duration of action 4. Drug process Bulk drug can be synthesized/ scaled up 5. Pharmaceutical Acceptable formulation/ pack (meets customer needs), Drug delivery/ product performance acceptable, Stable/ acceptable shelf life, Clinical trial process robust and can be scaled up 6. Regulatory Quality of data/ documentation 7. Manufacturing Manufacturability, Able to pass pre-approval inspection 8. Marketing/ Commercial Competitive, Meets customer needs, Value for money, Commercial return

1 in 5000 to 10000 compounds screened in research reach the market (Tucker 1984) Failure rate - 1 in 5 to 10 compounds achieve registration and reach market place of those that are nominated for development Significant commercial risk from those that are marketed; only 3 out of 10 are likely to achieve a fair ROI POOR ROI IS RESULT OF Either, poor candidate drug selection (compound doesn’t have desired properties of safety, selectivity, efficacy, potency or duration) And/ or, poor product development (development program doesn’t establish the value of product)

Product Life Cycle Strategic Research Exploratory Marketing & Research Further market/ medical needs – new indications Sales & profit Based on co.strategy Exploratory Research Marketing & Commercial Further market/ medical needs – product line ext. Launch Reg. submission Candidate Selection Full Development Candidate drug selected Exploratory Development Safety & efficacy demonstrated Proof of concept demonstrated

Some figures Block buster - Reaching sales of > 1billion US $ per year A product that is 6 months late to market will miss out on 1/3rd of potential profit over the product's life time Development cost overspend of 50% would reduce profits by just 3.5 % and, A 9% overspend in production costs reduced profits by 22% -Mc Kinsey & Co. 1991

Product Life Cycle Management Cash flow COMPETITOR & GENERIC PRODUCTS PEAK SALES MARKET SHARE HELD WITH LINE EXT. R E S A C H + LAUNCH MARKET PENETRATION DEV NO LINE EXT. TIME (IN YRS.) 5 10 15 20 25 30 DEV COST MFG.&LAUNCH COST - Primary patent expires

Current Trends in Pharmaceutical Ind. Increasing competition & threat with respect to maintaining continued sales growth & income It requires volume growth which requires new products to be introduced in market BUT, DDD cost increasing and no easy targets left, also increased cost of goods sold S0, M&A to acquire new leads, share cost, reduced time to license and to maintain growth BUT, M&A result in streamlining & job losses which at the same time increases efficiency and reduce overhead cost

Changing trend in Nature of Candidate Drug Molecular weight (low to macro) Biotechnological products (USFDA & EMEA approved products for anaemia, cystic fibrosis, growth deficiency, hepatitis & transplant rejection) SO, Major challenge – DEVELOP self administered formulations to deliver macromolecules by oral/ inhalation route…NDDS Pressures on pharmaceutical industry which affect the way products are developed. E.g. More comprehensive documentation to demonstrate compliance with cGMP and GLP & to demonstrate that systems & procedures have been validated “RIGHT FIRST TIME” Other pressures – political/ economical or environmental nature

Framework for Product Development Planning / documentation Candidate drug Biopharmaceutics Preformulation Characterize drug Prod. design Product profile – critical quality parameters Prod. Optimization Quantitative formula Raw mat./ component specification Process design Process outline, equipment/ facility definition Process optimization. In process control Product specification Process validation Scale up for comm. prodn Mfg. Launch stock Scale up for CT NDA sub. Phase I Phase II Phase III Regulatory review launch Phase IV

Aiding Candidate Drug Selection Stages of Drug Discovery & Development process Strategic research – Feasibility studies - company’s inherent research competence and expertise - therapeutic areas of unmet clinical need - market potential / commercial viability Exploratory research - investigation of biological mechanism & identification of a chemical lead that interferes with it…….Combinatorial Chemistry and HTS…. Rational drug design and QSAR….. Genomics Candidate drug selection Chemical lead specific chemical compound i.e. one or more candidate drug nominated for development (Criteria – optimal desired characteristics like potency, specificity, duration, safety and pharmaceutical aspects.) Two criteria – Pharmacology and Pharmaceutical

Preferred drug synthesis & Pharmaceutical properties for compounds intended for oral solid dosage form development Drug Synthesis Factors Formulation/ Drug Delivery Factors Least complex structure (none/ few chiral centers) Exists as a stable polymorphic form Few synthesis steps as possible Non hygroscopic High yields as possible Crystalline Non explosive routes / safety issues Acceptable solid-state stability of candidate drug Commercial availability of building blocks & contract manufacturers Acceptable oral bioavailability Low cost of goods compared to overall cost of product on market Not highly colored/ strong odor (to ensure batch reproducibility & reduce problems with blinding in clinical studies) No predictable problems in scale up Compatible with key excipients

4. Exploratory development To gauge how candidate drug is absorbed and metabolized in healthy volunteers before studying effects on patients (Phase I) 5. Full development Phase II (Dose ranging) and phase III(Commercial formulation)