1. 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.”

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

3. 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

4. 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)

5. 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

6. 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

7. 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

8. 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

9. 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

10. 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

11. 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

12. 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

13. 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)