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1. Discovery and development timeline
Cristian Rocha-Roa etal. Frontiers in Cellular and Infection Microbiology. 2018.8. 360
IND NDA
or
BLA

2. Comments on previous slide
• Pharmacophore is the 3D orientationof the functional
groups of a molecule that interacts with target protein
• Druggability is a term used in drug discovery to
describe a biological target that is known to or is
predicted to bind with high affinity to a drug.
Furthermore,by definition, the binding of the drug to a
druggable target must alter the function of the target
with a therapeutic benefit to the patient.

3. CMC (Chemistry Manufacturing & Controls) componentsof NDA
(New Drug Application)

4. Process chemistry
• Process development begins with drug discovery
• Discovery chemists
– Prepares many compounds from a common intermediate.
– convenient routes to preparesimilar compounds
• Development chemists
– Develops and optimizes the processes to prepareone
compound with minimum impurities

5. Formulation development
• Understanding physicochemical
properties of a compound is essential in
rational formulation and process
development.
– Permeability
– Ionization Constant (pKa)
– Solubility
– Stability (hydrolytic, oxidative,
photolytic)
– Solid-state properties

6. Formulation Development - Challenges
• Approaches to overcome
solubility/dissolution-limited bioavailability
 Chemical modification (Salt or prodrug)
 Particle size reduction (micronizationand nanonization)
 Incorporation of surfactants
 Solid dispersions
 Complexation (β-CD)

7. Solid-State Form and Particle Size
Salt Screen
Compound that can be ionized
– Solubility/Dissolution Rate
– Stability (chemical and physical)
– Processing
– Bioavailability/ProductPerformance
Form and Polymorph Screen
To identify and characterizedifferent forms
– To mitigate risks associatedwith form definition, such as variable product performance,
regulatoryissues and manufacturing.
– Stability (chemical and physical)
– Solubility/Dissolution Rate
– Processing
– Bioavailability/ProductPerformance.
Particle Size
– Drug particle size may impact dissolution rate, bioavailability, content uniformity, stability,flow
characteristics.
– Establishing impact of particle size on dissolution and PK performance is essential, especially
for BCS class II and IV.

8. Preclinical studies
• Use animals and/or cells or tissues.
• Give informationabout candidate’s
– Pharmacodynamics
– Pharmacokinetics
– Toxicology
• Information from non-clinical testing
is used in planning clinical trials in
humans
– startingdose should be
– range of does to be tested
– clinicalsigns of expected side effects

9. Clinical Trials
• Clinical trials of drugs provide information
about:
 Whether the drug has the effect it is supposed to have.
 How much of the drug to give to a patient and how often.
 What side effects are associated with the drug and how
they can best be managed.
 How a drug is broken down in the body, and how long it
stays in the body.
 Which foods, drinks, or other drugs can be used at the
same time or should be avoided.
 Clinical trial results allow the FDA to make decisions about
whether or not a drug should be approved for marketing.
Courtesyof David Kiere ( Acting Laboratory Chief, Branch I of the CDER of the US FDA)

10. Phase 1
• Healthy volunteers.
• The goal here is to determine what the drug's
most frequentside effects(DRUG SAFETY)are
and, often, how the drug is metabolized and
excreted.
• The number of subjects typicallyranges from 20
to 80
• Are there any unacceptabletoxicities?
• Takes months
• ~70 % move on to phase 2.

11. Phase 2
• Is the drug effective?
• Does the drug safely work in people who have a
certain disease or condition.
• Could be few dozen to about 300 patients.
• Months- years
• ~33 % move on to phase 3

12. Phase 3
• More information about safety and efficacy
– different populations?
– different dosages?
– combinations with other drugs?
• The number of subjects usually ranges from
several hundred to about 3,000 people.
• Usually double-blind
• Years to decades
• ~25-30 % move on to the market

13. Common Problems-clinical trials
• Safety issues or failure to demonstrate a
drug's effectiveness.
– A sponsor may need to conduct additional
studies-perhaps studies of more people, different
types of people or for a longer period of time.
• Scale up problems: the drug made for clinical
testing is not the same as the final
manufactured drug.

14. Cont’d
• Manufacturing issues are also among the
reasons that approval may be delayed or
denied.
– Drugs must be manufactured in accordance with
standards called GMP
– FDA inspects manufacturing facilities before a
drug can be approved.
– If a facility isn't ready for inspection, approval can
be delayed. Any manufacturing deficiencies found
need to be corrected before approval.

15. Cost of development
2
1
 The calculations were based on 63 drugs developed by publicly traded U.S.-based
biopharma companies.

16. 16
Considerations in the design of drug product
A. Biopharmaceutic Considerations
The essential elements of the biopharmaceutical
considerations in drug product design include:
• (1) studies done to decide the physicochemical nature of
the drug to be used, for example, salt and particle size;
• (2) the timing of these studies in relation to the preclinical
studies with the drug;
• (3) the determination of the solubility and dissolution
characteristics;
• (4) the evaluation of drug absorption and physiological
disposition studies; and
• (5) the design and evaluation of the final drug formulation.

17. 17
Goal and barriers
• Goal: The drug product must effectivelydeliver
the active drug at an appropriate rate and
amount to the target receptorsite so that the
intendedtherapeuticeffectis achieved.
• Barriers: To achieve this goal, the drug
– must traverse the requiredbiologicalmembrane
barriers,
– escape widespreaddistributionto unwantedareas,
– endure metabolicattack,and
– cause an alterationof cellular function.

18. Reaching a middle ground
• The finished drug product is a compromise of various factors, including
– therapeuticobjectives,
– pharmacokinetics,
– physicaland chemical properties,
– manufacturingcost,and
– patient acceptance.
• Mostimportant, the finished drug productshould meet the therapeutic
objective by delivering the drug with maximum bioavailability and
minimum adverse effects
18

19. 19
B. Pharmacodynamic Considerations
Pharmacodynamics is the study of the effect of a drug in the
body and its mechanism of action
• An oral drug used to treat an acute illness is generally
formulated to release the drug rapidly, allowing for quick
absorption and rapid onset.
• If more rapid drug absorption is desired, then an injectable
drug formulation might be formulated.

20. • In the case of nitroglycerin, which is highly
metabolized if swallowed, a sublingual tablet
formulation allows for rapid absorption of the
drug from the buccal area!! (sublingual area)
of the mouth for the treatment of angina
pectoris.
20

21. • For the treatment of certain diseases, such as
hypertension, chronic pain, etc, an extended- or
controlled-release dosage form is preferred.
• The extended-release dosage form releases the drug
slowly, thereby controlling the rate of drug
absorption and allowing for more constant plasma
drug concentrations.
21

22. • In some cases, an immediate-drug-release
component is included in the extended-release
dosage form to allow for both rapid onset followed
by a slower sustained release of the drug, for
example, zolpidem tartrate extended-release tablets
(Ambien® CR tablets).
28
Qiang Fu. et al. PowderTechnology,Volume 301,2016

23. C. Drug Substance Considerations
• Physicochemicalproperties of DS discussed in table 15-1 are
major factors that are controlled or modified by the
formulator.
• Many approaches are used to address these properties
23

24. D. Pharmacokinetics of the Drug
• Clinical failures of about 50% of the InvestigationalNew Drug
(IND) filings are attributed to their inadequate ADME
attributes.
• Therefore, pharmaceutical industry is searching for ever more
effective means to minimize this problem.
• Approaches to solve the above problem?
• Role of polymorphism. Which polymorphism? Genetic
polymorphism.(will be covered)
24

25. 25
E. Bioavailability of the Drug
• pharmacologic response is generally related to the
concentration of drug at its site of action,
• the availability of a drug from a dosage form is a critical
element of a drug product’s clinical efficacy.
• However, most bioavailabilitystudies involve the
determination of drug concentration mainly in the plasma
since it is rather difficult to measure the concentration at the
site of action.
• Need to consider stability in GIT and presystemicelimination

26. 26
F. Dose Considerations
• Some patients experience unique differences from the regular
adult population in pharmacokinetic parameters due to
– differences in metabolic background,
– renal clearance,
– weight,
– volume of distribution,
– age, and
– disease stage (eg, liver impairment, renal impairment),
• Consequently,require individualized dosing.
• Therefore, the drug product must usually be available in
several dose strengths to allow for individualized dosing and
possibly dose titration.
• Some tablets are also scored for breaking, to potentially allow
the administration of fractional tablet doses.

27. • The size and the shape of a solid oral drug
product are designed for easy swallowing.
• For oral dosage forms, if the recommended
dose is large (1 g or more), then the patient
may have difficulty in swallowing the drug
product.
• many patients may find a capsule-shaped
tablet (caplet) easier to swallow than a large
round tablet
27

28. 28
G. Patient Considerations
• The drug product and therapeutic regimen must be
acceptable to the patient.
• Poor patient compliance may result from poor
product attributes, such as
– difficulty in swallowing,
– disagreeable odor,
– bitter medicine taste, or
– frequent and/or unusual dosage requirements.