overview analytical chemistry in drug development...

Overview Analytical Chemistry in Drug Development

Lecture 1Jan 14, 2009

Rosario LoBrutto,

Key Responsibilities

Develop safe, efficient,

high quality dru

g

substancem

anufacturing processes

Develop high quality manufacturing

processes and control methods for handover

to Production

Plan & supply drug substance, drug

products and packaged clinical supplies

Develop specialized, stable, state-of-the-art

drug products, devices and packaging

Develop accurate, reproducible, and

validated analytical methods

Provide

Chemistr

y,

Manufac

turing

&

Control

documen

tation fo

r

registr

ation

QA

QA

QAPR

Form

Research

Form

3 Presentation Title / Name / Date

Global Research and Development

RD plays a key rolespanning the entire drug development process

From receipt of a new chemical or biological entity from Research or an outside firm

to the transfer of fully developed drug substances and drug products to Production at the time of dossier filing for registration

Interactions of Analytical Chemists

Analytical Chemists:DS and DP

Organic Chemists

Chemical Engineers

Formulators GMPAuditors

Manufacturing

Toxicology

Discovery Research Phase I Phase II Phase III Phase IV

Pre-clinical (Proof of Concept & Tox studies)

Clinical Trials

Safety Trials

Efficacy Trials Long term Safety and Efficacy Trials

LeadSelection

andoptimization

Target Selections

Developabilityof Lead

Full development• Confirmation of Dosage

Form• Route of Administration

PostMarketing

Development

pKaLog PLog DIntrinsic SolubilityRamanXray

HPLCMSMS/MSNMR

Integrated Drug Development Continuum

API Development Activities

Excipient Compatibility Studies

Optimization of synthesis and yield

Early Development Full Development

Figure 1 : Drug Development and Method Transfer Continuum for Pharmaceutical Active Ingredients (API)

Launchto

Market

Early DS synthesis

Extensive Stability Studies

Production ScaleSynthesis

Tier 1 HPLC Method

Tier 3 HPLC Method Registration

Method

Transfer Methods

Tier 2 HPLC Method

Research &

DiscoveryPhase I Phase IIa/b Phase III

Registration \Phase IV

Regulatory ReviewApproval & Launch

Finalized DSSynthesis

Pharmaceutical Dosage Form Development

Production scaleof Final marketImage

Excipient Compatibility Studies

Optimize Formulation. and Processing conditions and scale up: Market Formulation to Final Market Image

Early Development Full Development

Figure 2 : Drug Development and Method Transfer Continuum for Pharmaceutical Dosage Forms-

Launchto

Market

Prototype Formulation

Extensive Stability Studies

Tier 1 HPLC Method

Tier 3 HPLC Method

Registration Method

Transfer Methods

Tier 2 HPLC Method

Research &

DiscoveryPhase I Phase IIa/b Phase III

Registration \Phase IV

Regulatory ReviewApproval & Launch

Questions?

How do I develop a chromatographic method? What type of analyses are needed to monitor a reaction? What does it mean that my peaks are spectrally homogenous?

Why can’t I use titration instead of HPLC for weight percent calculation?

What is a key raw material and what analyses are needed?How do I address analyzing compounds with no UV absorbance?

What is mass balance?How much organic chemistry does an analytical chemist have to know to make sound decisions?

•HPLC*•LC/MS Ion trap/ Triple quadrupoles•GC/HS-GC/GC-MS •CE•NMR/ LC-NMR •Karl Fischer•ICP/MS•FTIR spectroscopy •Microscopy /Image analysis•TGA•DSC and micro calorimetery•X-ray Powder diffraction and crystallography•Automation- Multi dose and TPWII stations

Analytical Technologies Applied

* At least 80% of analysis are carried out with this technique

Where is HPLC used?Drug SubstanceAnalysis of key raw materialsReaction MonitoringSolution and solid state stability (shelf life determination)Drug substance purity

Drug Product (Preformulation and Formulation)Binary Blend studiesExcipient CompatibilitySolubilityDrug product assay and purityContent UniformityDissolutionDrug Product stability (shelf life determination)Reference technique for NIR and other spectroscopic methods (PAT)

Method optimization• Extraction issues• Challenging separations• Speed of separation • Sensitivity and detection issues • Specialized forms of chromatography

Processing and stability issues• Mass balance issues• Packaging optimization• Degradation characterization and Pathway

elucidation • Degradation Isolation• Physical chemical characterization

ARD Technical Challenges

UV spectroscopy

nm200 225 250 275 300 325 350 375

Anorm

0

20

40

60

80

Abs

.

Wavelength (nm)

Optimal wavelength for analysis

Not a good wavelength for analysis

nm200 225 250 275 300 325 350 375

Anorm

0

20

40

60

80

Abs

.

Wavelength (nm)

Optimal wavelength for analysis

Not a good wavelength for analysis

•Used to determine optimal wavelength for detection•Why is this important?•Peak Homonogenity

Overlay of DS and 6 impurities UV spectra

UV absorbance as a function of pH

•Understanding the effect of pH on anlayte ionization is important for HPLC•How does this relate to chromatographic response?

N

H H

:

+

H

H

HN

0

5

10

15

20

25

0 1 2 3 4 5 6 7

pH of aqueous phase

Ab

sorb

ance

, 23

2 n

m

30% AcN

pKa = 4.0

-10

40

90

140

190

240

290

340

210 230 250 270 290 310

Wavelength (nm)

Ab

s.

pH=2

pH=4

pH=8

• Determine the pKa of target compound and impurities if possible. (Literature values, titration, HPLC, ACD software)

• Determine if analytes are acidic or basic.Group on Aromatic pKaLinear alcohol >12 (acid)Carboxylic acid, -COOH 4-5 (Acid)Thiol, -SH 6-7 (Acid)Phenol, -OH 10-12 (Acid)alkyl amine (pri, sec, tert) >9 (base)aromatic Amine, -NH2, -NR2 4-6 (base)Pyridine 5-7 (Base)

• addition of R(methyl, ethyl,etc) group on aromatic ring or on NR2 will cause an increase of compound pKa due to electron donating effects from methyl groups.

• substitution in general of halogens on aromatic ring will decrease compound pKa, Ex. o-chloroaniline pKa=2.6, aniline pKa=4.6

pKa of Analytes: Know your basic organic chemistry

Dependencies of Analyte Ionization on the pH of the Mobile Phase

Aniline: pKa=4.6

Ionization HPLC

pH

k

[C6H5NH2]

[C6H5NH3+]

[C6H5NH3+]

pKb=9.4

[C6H5NH2]

0

10

20

30

40

50

60

70

80

90

100

0 2 4 6 8 10 12 14

%Io

niz

ed

pH

Effect of pH on Basic Analyte Retention

N

pyridinepKa = 5.17

N

CH2CH3

4-ethylpyridinepKa = 5.87

NH3C

CH3

2,4-lutidinepKa = 6.74

N CH3

CH3

CH3

NH2

2,3-dimethylanilinepKa = 4.70

CH3

NH2

phenylethylaminepKa=9.83

2-picolinepKa=5.96

EA

A

pH=2.04

B C

D

E F

pH=3.05

A+BC

D

E F

pH=4.04

B+C

A

D

EF

pH=5.08

B+C C

D

F

pH=6.03

E

A

B

C

D

F

pH=7.04

A

E

B

C

D

F

pH=8.04

A

E

B

C

D

F

C

A: Pyridine, pK=5.17B: 2-Picoline, pK=5.96C: 2,4Lutidine, pK=6.74D: 4-ethylpyridine pK=5.87E: Phenylethylamine pK=9.83F: 2,3dimethylaniline pK=4.7

a

a

a

a

a

a

Chromatographic ConditionsColumn: 15 cm x 0.46 cm ZorbaxEclipse XDB-C18Eluent: 90% Aqueous / 10% MeCNBuffer: 10 mM Na2 HPO4•7H2 O + xH3PO4Flow rate: 1 ml/minTemp: 25o C

Time (min.)

WorkshopEffect of pH on the retention of acidic and

zwitterionic components

Topics for discussion:Effect of mobile phase pH on the analyte ionizationRelative retention of ionic and neutral analyte forms

Example Chromatogram: pH 2

pH=2Name tr (min) k'

4-Aminobenzoic acid 2.23 0.72Phenylacetic acid 5.94 3.57

o-Toluic acid 9.05 5.96m-Toluic acid 9.84 6.57

Pindolol 1.68 0.29

Example Chromatogram: pH 8

pH=8Name tr (min) k'

4-Aminobenzoic acid 1.328 0.02154Phenylacetic acid +o-Toluic acid 1.461 0.12385

m-Toluic acid 1.568 0.20615Pindolol 3.406 1.62

Retention factor vs. pH

•Plotting data•Discuss inflection points•Discuss dependencies of pH on analyte retention

Questions for Lab• What was the optimal pH estimated for the analysis of

the analytes just by looking at the analyte pKas at 30% acetonitrile mobile phase composition?

• Looking at the chromatograms which mobile phase pH provides the optimal selectivity for all components in the acid mix and how does this compare to estimated optimal pH?

• Why did the retention time of the acid components decrease with an increase of the mobile phase pH?

• What would happen to elution time of the components at a mobile phase pH lower than pH 2.0?

• What is the cause of the strange retention behavior of 4-aminobenzoic acid?

• Draw the ionization state of 4-aminobenzoic acid at pH=1 and at pH=6.

Putting it all together

Synthetic Process

J.E.Hoover in : Remingtons’s Pharmaceutical Sciences, 15th ed., Mack Printing, Easton PA, 1974, p. 1158

HPLC GC

Reaction Monitoring

DS A

Impurities in Key Raw Material

Gary J. Lehr, Thomas L. Barry, Glenn Petzinger, George M . Hanna, S. William Zito, J. Pharmaceutical and Biomedical Analysis, 19 (1999), 373 – 389, Isolation and identification of process impurities in trimethoprim drug substance by high-performance liquid chromatography, atmospheric pressure chemical ionization liquid chromatography/mass spectrometry and nuclear magnetic resonance spectroscopy.

2,4-diamino-5-(-4-ethoxy-3,5-dimethoxybenzyl) pyrimidine and 2,4-diamino-5-(3-Bromo-4,5-dimethoxybenzyl) pyrimidine

Impurity 1

Impurity 2

•These impurities may react in the downstream chemistry.

Purity of the Drug Substance

Impurity 1 and Impurity IIreact with next intermediateto form synthetic by-productsin the downstream chemistry

Different lots from different vendorsare evaluated and/or specificationsare set for level of impurity in keyRaw materials.

J.E.Hoover in : Remingtons’s Pharmaceutical Sciences, 15th ed., Mack Printing, Easton PA, 1974, p. 1158

Reaction Monitoring: Drug Substance

0.0 1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0 9.0 10.0 11.0 12.0 13.0 14.0

Starting material

Intermediate

Starting material

Time: 60 min

•Is Reaction complete?•Are synthetic by products formed?•What is relative response factor?•What is the acceptance criteria?

0

20

40

60

80

100

0 20 40 60 80 100 120

Time (min.)

Are

a%

Starting material

Intermediate

Define an experiment to monitora reaction.What data can be extracted?

pH solubility profile- TAE 226 Free Base

-0.2

0.8

1.8

2.8

3.8

4.8

5.8

6.8

7.8

8.8

9.8

0 1 2 3 4 5 6 7 8

pH

solu

bili

ty

(g/L

)Preformulation: Determining the Solubility of a free base using HPLC

This could be demonstrated by using saturated solutions of commerciallyavailable compound made at different pHs and analyzing the supernatant•UV or HPLC•Reference std needs to be available.

Determining Spectral Purity

nm2 5 0 . 0 0 3 0 0 . 0 0 3 5 0 . 0 0

2 1 0 . 8

2 6 5 . 0

3 3 1 . 5

2 1 3 . 2

2 8 1 . 62 8 0 . 4

-5% and apex

+5%-5%, rise of peak

Apex

+5%, fall of peak

A

B

C

m/z

% Area = 94.9%

-5% +5%

apex

Time (min.)

Moving from offline UV to online diode arrayMoving from offline UV to online diode array

Time

Time (min)

Time(min)

2.31

6mAU

150

250

350400 1

41 5 63 7 8 92

1000

0

50

100

150

200

250

300

350

400

1

Norm.Norm.Spectrum of 1 (2.9 min)

200 225250275300325350375

Spectrum of 1 (2.3 min)

Synthetic process 2

•diode array •spectral homogeneity

2: 2.9 min

2

Understanding UV absorption of aromatic substances

Compound MolecularFormula

E2 Band B Band

λmax (nm) ε max λmax (nm) ε max

Benzene C6H6 204 7900 256 200Naphthalene C10H8 286 9300 312 289

Toluene C6H5CH3 207 7000 261 300Chlorobenzene C6H5Cl 210 7600 265 240

Phenol C6H5OH 211 6200 270 1450Phenolate ion C6H5O - 235 9400 287 2600Thiophenol C6H5SH 236 10000 269 700

Aniline C6H5NH2 230 8600 280 1430Anilinium ion C6H5NH3+ 203 7500 254 160

What are some UV experiments that can be performed?•Run Toluene at different pHs•Run Aniline at different pHs

*Skoog and Leary

-5

0

5

10

15

20

25

30

210 230 250 270 290 310

Wavelength (nm)

Ab

s.pH = 2.0, 30% MeCN

pH = 4.0, 30% MeCN

pH=8.0, 30% MeCN

Effect of pH on the analyte UV absorbance

CH3

Toluene

Analytical Techniques in Stability Experiments

• Shelf Life determination (DS and DP)• Formulation Development- Excipient

Compatibility, Solution stability• Package Considerations• Manufacturing / Processing

parameters

•Enhanced sensitivity is obtained by analyzing aniline in its neutral state•An HPLC experiment can be performed to show the effect of pH on:

• UV response at a particular wavelength •Analyte Retention

Effect of pH on Aniline Retention and UV response (220 nm)

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19

Det

ecto

r R

espo

nse

(µV

)

wwpH 2

wwpH 4

wwpH 5

wwpH 6

wwpH 9

Time (min.)

Chromatographic ConditionsColumn: 15 cm x 0.46 cm Luna C18(2)Eluent: 90% Aqueous: 10% MeCN

Aqueous: 15 mM K2 HPO4•7H2 O adj. to wwpH 1.5 - 9 with H3PO4Flow rate: 1 ml/minTemp: 25o C

0

0.2

0.4

0.6

0.8

1

1.2

1.4

1.6

1.8

2

DS

Avicel P

H 101

A-TAB

Di-TAB

Lacto

se Anh

ydrou

sMan

nitol

HPCHP

MC PVP

Ac-Di-S

ol

Na CMC

Na Star

ch G

lycola

te

Starch

1500

Cutina

Mag. S

tearat

e

Cab-O

-Sil

Binary Blend

% d

egra

datio

n co

mpa

red

to in

itial

50/75_2wk

50/75_4wk

50D_2wk

50D_4wk

Preformulation: Binary Blend Compatibility: Project X

H2O CH3NH2HN

HN

O

DS

RHN

HO

OR

Carboxylic acid ImpurityMajor Degradation product

•Basic organic chemistry needs to be known•Reactions of acids and bases•Hydrolysis of esters

pH Solution Stability

•Calibration of pH meters•Mass Balance (Area normalization versus assay)•What compounds are prone to hydrolysis?

pH-stability at 37°C, aqueous solution

82

84

86

88

90

92

94

96

98

100

0 5 10 15 20 25 30 35

Time (h)

Per

cent R

emai

nin

g (%

)

pH 1.0

pH 2.0

pH 3.0

pH 4.0, 5.0, 6.5, 7.4

Are

a P

erce

ntA

rea

%AU

0 . 0 0

0 . 1 0

0 . 2 0

0 . 3 0

0 . 4 0

0 . 5 0

0 . 6 0

0 . 7 0

0 . 8 0

0 . 9 0

M i n u t e s

2 . 0 0 4 . 0 0 6 . 0 0 8 . 0 0 1 0 . 0 0 1 2 . 0 0 1 4 . 0 0 1 6 . 0 0 1 8 . 0 0 2 0 . 0 0 2 2 . 0 0 2 4 . 0 0 2 6 . 0 0 2 8 . 0 0 3 0 . 0 01 h

30 h

AU

0 . 0 0

0 . 0 2

0 . 0 4

0 . 0 6

0 . 0 8

0 . 1 0

0 . 1 2

0 . 1 4

0 . 1 6

0 . 1 8

0 . 2 0

M i n u t e s3 . 0 0 4 . 0 0 5 . 0 0 6 . 0 0 7 . 0 0 8 . 0 0 9 . 0 0 1 0 . 0 0 1 1 . 0 0 1 2 . 0 0 1 3 . 0 0 1 4 . 0 0 1 5 . 0 0

AU

0 . 0 0

0 . 0 5

0 . 1 0

0 . 1 5

0 . 2 0

M i n u t e s3 . 0 0 4 . 0 0 5 . 0 0 6 . 0 0 7 . 0 0 8 . 0 0 9 . 0 0 1 0 . 0 0 1 1 . 0 0 1 2 . 0 0 1 3 . 0 0 1 4 . 0 0 1 5 . 0 0

AU

0 . 0 0

0 . 0 2

0 . 0 4

0 . 0 6

0 . 0 8

0 . 1 0

0 . 1 2

M i n u t e s3 . 0 0 4 . 0 0 5 . 0 0 6 . 0 0 7 . 0 0 8 . 0 0 9 . 0 0 1 0 . 0 0 1 1 . 0 0 1 2 . 0 0 1 3 . 0 0 1 4 . 0 0 1 5 . 0 0

Forced Degradation Study: H2O2 stress study, 1mg/ml in 3% H2O2 solution

0.748282810.52

98.181104412410.20

0.76850809.37

0.32362978.28

%AAreaR.T.

0.709192210.52

97.591289388710.20

0.44576849.37

1.281691318.28

%AAreaR.T.

0.514013410.52

83.00655358810.20

9.077158589.37

7.425860938.28

%AAreaR.T.

Initial

72 hrs, 5C

72 hrs, RT

•What compounds are prone to oxidation? Why is it important?

0

0.1

0.2

0.3

0.4

0.5

0.6

0.79 0.94 1.59 1.6 1.64 1.71 1.78 2.08 2.12 2.15RRT

% A

rea

Initial

2wks,5C

6wks,5C

3m,5C

Drug Product Stability Studies (Long Term and Accelerated)

How do we define stability of the drug product?Why is it important?What is RRT?

00.10.20.30.40.50.6

0.79 0.94 1.59 1.6 1.64 1.71 1.78 2.08 2.12 2.15

RRT

%A

rea

Initial

2wks, 40C/75RH

6wks, 40C/75RH

3m,40C/75RH

0

0.1

0.2

0.3

0.4

0.5

0.6

0.79 0.94 1.59 1.60 1.64 1.71 1.78 2.08 2.12 2.15RRT

% A

rea

Initial

2wks, 25C/60RH

6wks, 25C/60RH

3m,25C/60RH

Defining Storage Conditions

What is next?-Impurity identification

Conclusion-•Product must be stable at acceleratedCondition (+15C) to get 4x shelf life at proposed storage condition.

•In this case 5C would be the storage conditionand 25/60 RH was ouraccelerated condition

Types of Drug Product Stability Testingv Long-Term Testing

Formal stability studies under normal storage conditions(typically 25 °C/60% RH) shelf-life determination, part of formal stability program

v Accelerated Testing“Studies designed to increase the rate of chemical degradation orphysical change of an active drug substance or drug product using exaggerated storage conditions as part of the formal, definitive, storage program”(40 °C/75% RH for RT stored products) ICH Stability guideline (Q1Ar), 2002 shelf-life prediction, part of formal stability program

v Stress Testing“Studies undertaken to elucidate the intrinsic stability of the drug substance. Such testing is part of the development strategy and is normally carried out under more severe conditions than those used for accelerated testing.”ICH Stability guideline (Q1Ar), 2002, not part of formal stability program

Jan. 21, 2009Lecture 2


Why are identification of impurities in DP important?



Can the LOQ be greater than the Reporting Threshold?Is their anything else we should consider about the impurities relative to API?

0.5%= 250 ug =(50*1000)*0.005Therefore 200 ug is used for Qual. Threshold

0.2%=(50)*0.002= 0.1mgTherefore 0.1 mg is <2 mg and is used for identification threshold


Why are identification of impurities in API important?

Acceptable limit of the impurities in drug substances is dependent upon:

Maximum daily dose and the qualification threshold

Lower thresholds can be appropriate if the impurity is known to be unusually potent or to produce toxic or unexpected pharmacological effects either thru genetoxicity studies, general toxcicty studies and/or in-silico assessment.

*ICH, Guidance for the Industry: Q3A: Impurities in new drug substances, 2003.

Drug Development Overview

Drug development process consists of four distinct stages

1. Drug discovery2. Preclinical development3. Clinical development4. Manufacturing

Each stage culminates with a specific milestone

1. Identifying a lead candidate2. IND (Investigational New Drug substance)3. NDA (New Drug Application)4. Sales

Source: Based on PhRMA 2001-2002 analysis, updated for data per Tufts Center for the Study of Drug Development (CSDD) database and www.fda.org.

Discovery and Development of a Successful Drug

YEARS

3,000 - 10,0003,000 - 10,000

10 - 2010 - 20

5 - 105 - 10

22

11POST-MARKETING SURVEILLANCEPOST-MARKETING SURVEILLANCE

PRECLINICAL TEST (ANIMALS)PRECLINICAL TEST (ANIMALS)

DEVELOPMENT 2 - 52 - 5

NUMBER OF CANDIDATES

00112233445566778899

101011111212131314141515

MARKET LAUNCH

RESEARCH

CLINICAL TEST (HUMANS)

BASIC

•Only 5 in 5,000 drugs that pharmaceutical companies test on animals reach human clinical trials, and on average•Only one of those five drugs reaches the market (New York Times, 12/1).

Screen, identify and Optimize lead compounds

For example, of 100 drugs for which INDS are submitted to FDA•about 70 will successfully complete phase 1 trials and go on to phase 2•about 33 of the original 100 will complete phase 2 and go to phase 3; •25 to 30 of the original 100 will clear phase 3 •On average, about 20 of the original 100 will ultimately be approved for marketing).

25-30 percentSafety, dosage, effectiveness

1-4 years

Several hundred to several thousand

Phase 3

33 percentSome short-term safety but mainly effectiveness

Several months to 2 years

Up to several hundred

Phase 2

70 percentMainly safetySeveral months

20-100Phase 1

Percent of Drugs Successfully Tested*

PurposeLengthNumber of Patients

Testing in Humans

http://www.fda.gov/fdac/special/newdrug/testtabl.html

Clinical Studies

http://www.fda.gov/fdac/graphics/newdrugspecial/drugchart.pdf

•The Tufts analysis found that improving clinical approval success rates fromone in five to one in three will reduce total costs by approximately 30%.

IND

Drug Discovery/Pre Clinical Development

• HTS and combinatorial chemistry methodologies have been developed in the past two decades.

• Advances in-silico and in vitro strategies have also emerged to screen these compounds and assess their potential to become leadcandidates.

• Compounds emerging as hits from these screening procedures are characterized further and tested in vivo for safety and efficacy.

• Compounds need to be formulated into a dosage form that can be used to administer the drug.

• Rapid formulation screening and identification of an appropriateformulation is crucial for accurate assessment of compounds in adrug discovery setting.

Before clinical testing begins, researchers analyze the drug's main physical and chemical properties in the laboratory and study itspharmacologic and toxic effects in laboratory animals.

If the laboratory and animal study results show promise, the sponsor can apply to FDA to begin testing in people.

Once FDA has seen the sponsor's plans and a local institutional review board--a panel of scientists, ethicists, and non-scientists that oversees clinical research at medical centers throughout the country--approves the protocol for clinical trials, experienced clinical investigators give the drug to a small number of healthy volunteers or patients.

Preclinical Testing

IND• Regulatory Review: Investigational New Drug (IND)

Application• - An application filed with the U.S. FDA prior to human

testing. • The IND application is a compilation of all known

information about the compound. • It also includes a description of the clinical research plan

for the product and the specific protocol for phase I study.

• Unless the FDA says no, the IND is automatically approved after 30 days and clinical tests can begin.

Clinical TrialsPhase I Clinical Evaluation

The first testing of a new compound in human subjects, for the purpose of :• establishing the tolerance of healthy human subjects at different doses • Defining its pharmacologic effects at anticipated therapeutic levels• Studying its absorption, distribution, metabolism, and excretion patterns in

humans.

• These phase 1 studies assess the most common acute adverse effects and examine the size of doses that patients can take safely without a high incidence of side effects.

• Initial clinical studies also begin to clarify what happens to a drug in the human body--whether it's changed (metabolized), how much of it (or a metabolite) gets into the blood and various organs, how long it stays in the body, and how the body gets rid of the drug and its effects.

• If phase 1 studies don't reveal major problems, such as unacceptable toxicity, the next step is to conduct a clinical study in which the drug is given to patients who have the condition it's intended to treat.

• Researchers then assess whether the drug has a favorable effect on the condition.

Clinical TrialsPhase II Clinical Evaluation• Controlled clinical trials of a compound's potential usefulness

and short term risks. • A relatively small number of patients, usually no more than

several hundred subjects, enrolled in phase II studies.

Phase III Clinical Evaluation• - Controlled and uncontrolled clinical trials of a drug's safety and

effectiveness in hospital and outpatient settings. • Phase III studies gather precise information on the drug's

effectiveness for specific indications, determine whether the drug produces a broader range of adverse effects than those exhibitedin the small study populations of phase I and II studies, and identify the best way of administering and using the drug for the purpose intended.

• If the drug is approved, this information forms the basis for deciding the content of the product label.

• Phase III studies can involve several hundred to several thousand subjects.

NDA

• Regulatory Review: New Drug Application (NDA)

• - An application to the FDA for approval to market a new drug.

• All information about the drug gathered during the drug discovery and development process is assembled in the NDA.

• During the review period, the FDA may ask the company for additional information about the product or seek clarification of the data contained in the application.

Tech Transfer and Manufacturing

• The key to a successful transfer from research and development to production hinges on the existence of validated methods, finalized API synthetic schemes/routes and optimized formulations of the pharmaceutical active ingredient.

• HPLC analysis and in-process controls provide the crucial means by which the assessment is made of the existence of a validated process that yields a reproducible API or robust pharmaceutical dosage form that can be commercialized.

• This assessment is made by comparing data generated using HPLC and other analytical techniques against a set of pre-determined acceptance criteria.

• Once NDA approved, analysis are focused on specifications to provide regulatory compliance and to ensure quality during manufacturing

Bioavailability• Bioavailability Studies• - The use of healthy volunteers to document the rate of absorption

and excretion from the body of a compound's active ingredients.

• Companies conduct bioavailability studies both at the beginning of human testing and just prior to marketing to show that the formulation used to demonstrate safety and efficacy in clinical trials is equivalent to the product that will be distributed for sale.

• Companies also conduct bioavailability studies on marketed products whenever they change the method used to administer the drug (e.g., from injection or oral dose form), the composition of the drug, the concentration of the active ingredient, or the manufacturing process to produce a drug.

0

10

20

30

40

50

60

70

80

1997 1998 1999 2000 2001

Year

% M

edic

ines

Dro

pped

Preclinical

phase I

Phase II

Phase III

PreRegistration

[Source: SCRIP Magazine, February 2002, page 72 (data from Pharmaprojects)]

Why do so many drugs fail in Development?

•Failures are often for multiple reasons but can be broadly classified on the basis of:

•safety concerns•lack of efficacy •poor bioavailability properties.

The most high profile failures are often due to safety and efficacy but in reality bioavailability is the 'silent assassin'.

Attrition Rates from 1997 – 2001

0

20

40

60

80

100

120

140

1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004

# o

f N

ew M

edic

ines

, Vac

cin

es, a

nd

Bio

log

ics

Ap

pro

ved

by

the

FD

A

Total NDA approved

NCE

http://www.fda.gov/cder/rdmt/NDAapps93-03.htmhttp://www.phrma.org/publications/publications//2004-03-31.937.pdf

•Number of NMEs has not varied much over the past 9 years, although there has been a downward trend over the past few years.•2 to 3 times as many new drug application (NDA) approvals as NME approvals•Difference between the approved NDAs and NMEs is mainly attributable to reformulations and new indications of existing compounds. •30% of R&D spending is devoted to bringing line extensions to market compared to about 18% in 1999.(Pharma 2001).

NDAs and NMEs from 1993 – Sept. 2004

•Decrease in the number of NMEs approved and the smaller proportion of NME to NDA approvals indicate that among the drugs coming to market few are innovative.

•This reflects the recent focus of the industry on creating formulations and finding new indications of already approved drugs.

•These drugs are less new than the typical NCE, however often account for substantial sales and offer therapeutic advantages in terms of efficacy, administration and patient compliance.

Why the Gap (NDAs and NME)?

1991

19931997

1999

2001

2005?

0

200

400

600

800

1000

1200

1400

1600

1800

1

Year

$ m

illio

n

Estimated full cost of bringing NMEs to market ($ million)

•http://csdd.tufts.edu/NewsEvents/RecentNews.asp?newsid=6•http://www.fda.gov/cder/reports/rtn/2003/rtn2003-1.HTM#Statistics•Lehman Brothers 2001

•Increased cost of human clinical trials has led to "much of the increase" in drug development costs (Pear, New York Times, 12/1).

•The study found that total research costs increased only 7.4% per year during the 1990s, but the cost of human clinical trials rose 12% per year (Harris, Wall Street Journal, 12/3).

•http://csdd.tufts.edu/NewsEvents/RecentNews.asp?newsid=6•http://www.fda.gov/cder/reports/rtn/2003/rtn2003-1.HTM#Statistics•Lehman Brothers 2001

•Rapidly rising drug R&D spending in the US is helping usher in a new R&D paradigm, shortening development times while improving clinical success rates. •Economic pressures in pharmaceutical markets are growing, thus compelling firms to improve the efficiency of the drug development process.

R & D Spending in the Pharma Industry

overview analytical chemistry in drug development...

Documents