Drug Development Process

1

Tuotekehityksen vaiheet

Luennot helmikuu 2006 Helsingin Yliopisto, Farmasian tiedekunta, teknologia, lääkevalmisteblokki.

FaT Marja Ritala

M. Ritala 2006


Mitä on tuotekehitys? A definition

Product development?Drug development?Technical development?Pharmaceutical development?Drug delivery technology?Chemistry and manufacturing?

M. Ritala 2006


Drug Development Process

DISCOVERY PRE-CLINICAL

CLINICAL PHASE I

CLINICAL PHASE II

CLINICAL PHASE III PHASE IV

NDA MA, LAUNCH

PHARMACEUTICAL DEVELOPMENT

PRODUCT LIFE CYCLE MANAGEMENT

IND

MAINTENANCE

PROOF OFCONCEPT

SAFETY ANDEFFICACY

M. Ritala 2006


Contents (1)DefinitionsTrends in the pharmaceutical industryProcessesPreformulationFormulationAnalytical developmentSpecifications, qualityChoice of manufactureStability

M. Ritala 2006


Contents (2)

BiostudiesNew chemical entitiesLife cycle management of productsGeneric drug substances and productsMarketing authorisation applications Case studies of formulation and life cycle management Skilled people neededPharmaceutical development in the future

Trends in the Pharmaceutical Industry

2

M. Ritala 2006


Trends in the Pharmaceutical Industry (1)

Market growthMega mergersConsolidationNetworking (emerging technologies)Biotechnology in addition to chemistryCost containment of healthcareR&D productivity challenge

M. Ritala 2006


Trends in the PharmaceuticalIndustry (2)

Fully integrated pharmaceutical companiesVirtually integrated pharmaceutical companiesOutsourcing

strategic partnershipscontract services

NetworkingSpin-offsIntensive life-cycle management

Processes

M. Ritala 2006




CLINICAL PHASE I

CLINICAL PHASE II

CLINICAL PHASE III PHASE IV

NDA MA, LAUNCH

PHARMACEUTICAL DEVELOPMENT

PRODUCT LIFE CYCLE MANAGEMENT

IND

MAINTENANCE

PROOF OFCONCEPT

SAFETY ANDEFFICACY

M. Ritala 2006


STABILITY PRIMARYSTABILITY

ANALYTICAL DEVELOPMENT

DRUG SUBSTANCE



PHASE I P II PHASE III PHASE IV

FORMULATION

INDUSTRI-ALISATIONMFR PROCESS DEVELOPMENT

NDA MA, LAUNCH

PRODUCTMAINTENANCE

FOLLOW-UP STAB.

Phar

mce

utic

al d

evel

opm

ent

IND

M. Ritala 2006


Development data brings new information to the pharmaceutical development

LIFE CYCLEMANAGEMENT AND

BRAND DEVELOPMENT


PHASE I P II PHASE IV

MOLECULARPROPERTIES

PRE-CLINICALADME,

PHARMACOLOGYTOX PROFILE

PHARMACO-KINETICS

IN HUMANSAND DOSING

COMMERCIALPRODUCT

STRENGTH(S)

TO BE USED FOR:- DRUG SUBSTANCE DEVELOPMENT- ANALYTICAL DEVELOPMENT- ADMINISTRATION ROUTE SELECTION - DOSAGE FORM SELECTION AND DESIGN- UNIT DOSES AND DOSING- ETC.

PHASE III

3

M. Ritala 2006


Main Processes in Pharmaceutical Development

Drug substance developmentPreformulationFormulationDevelopment of SpecificationsAnalytical methods developmentStability studies

Manufacturing process developmentIndustrialisationProcess validationDocumentation of dataProject planning and management

Drug substance development

M. Ritala 2006


Drug substance development

A robust synthesis process with consistent batch-to-batch qualitySelection of saltAnalytical methodologyMastering the physical properties like particle size and polymorphismStabilityScaling up and technlogy transferDocumentation

Preformulation

M. Ritala 2006


PreformulationSolubility (aqueous, pKa, log P, log D)Molecular optimization (salt, hydrate, solvate, new analogs,…)Crystal Engineering (polymorph, habit, size, surface characteristics…)Crystal structure determinationBiopharmaceutical classification (BCS) (solubility, dissolution, absorption) Drug stability evaluation (physical, chemical, solution phase, solid phase, …)Compatibility analyses (drug substance, excipient, packaging materials)

Formulation

4

M. Ritala 2006


FormulationComposition + process = formulationProduct designFormulation determines how the drug is deliveredA good composition

is simple, but innovativeness may be neededutilises standard compendial excipientseasy to manufacturegood stabilityfacilitates straightforward analyticsprotects the product against generic competition

Formulation work is based on information gained through preformulation and biostudiesLaboratory scale workThe guidelines of authorities give a roadmap

M. Ritala 2006


Characteristics of a soundinnovation

Underpinning science must be soundUniqueness

it solves a problemcan be patentedcreates cost advantagecan be used as an asset when

forming exclusive partnershipsTechnology can be validated

M. Ritala 2006


Prerequisites of a successful formulation :

Formulation work is based on sciencemolecule propertiesphysiology, biologydelivery technology

The consumer needs are identifiedTarget product profile is definedThere is a clear view of the indication and target populationThere is an understanding of administration route, dose and dosage form

M. Ritala 2006


Commercialised drug delivery technologies today

Oral controlled release $$$$$$Transdermal $$$$$Implants $$$$Quick dissolve $$$Single isomers $$Liposomes $

M. Ritala 2006


Drug delivery companies and technologies

Oral controlled releaseBiovail, Elan, Alza (JJ), Skye Pharma, Cardinal Health...

Transdermal deliveryAltea, Alza (JJ), 3M...

Respiratory deliveryNectar (Inhale), Biovail, Elan, Skye Pharma...

M. Ritala 2006


The largest drug delivery products of the 1990’s

Schering Plough600 Mill.$KeyNitro Dur

Novartis800 Mill.$Several developers

Nicotine Patch

Hoechst1,000 Mill.$ElanCardizem SR/CD

TAP1,100 Mill.$TapLupron

Johnson & Johnson

1,200 Mill.$AlzaDuragesic

Pfizer1,250 Mill.$AlzaProcardia XL

MarketerPeak salesDeveloperDrug

5

M. Ritala 2006


Procardia XL: A pharmaceutical company's dream scenario

Instead of suffering a monumental loss when an important drug goes off patent, the company launches a new, vastly improved version that eclipses both the original drug and its generic competition. That's exactly what Pfizer did when it partnered with ALZA to develop Procardia XL®, which incorporates ALZA's OROS® osmotic technology.

ALZA's technology gave Procardia XL® several major advantages over Pfizer's original product, Procardia®, and generic nifedipine. As a result, the label indication for Procardia XL® was expanded to include treatment of both angina and hypertension. In Finland marketed under name Adalat Oros

M. Ritala 2006


Technology selection criteriaScientific understandingSimilarity of compounds or problems addressedRealistic assessment of successStage of developmentFreedom to operate (drug type, therapeutic area)Manufacturing capabilityScope for intellectual propertyDevelopment timescaleCostsPredicted sales and profitability

Analytical development

M. Ritala 2006


Why analyse products during development?

Formulations are often fine-tuned after analysing concentrations of the drug and it’s metabolites in blood or target organ

Stability study results determine the shelf-life

Validated analysis methods are used tocontrol and assure the quality of the drug

M. Ritala 2006


Analytical developmentHPLC, TLC, IR, NIR, UV, GC, MS, CE... are the methods to analyse

Assay of drug substanceDegradation profileIdentificationContent uniformityDissolutionOrganic volatile impurities

The methods are validated in regard to accuracy, sensitivity, robustness, selectivity...

according to ICH

Specifications and quality

6

M. Ritala 2006


A typical specification for a tablet formulation (1)

Appearance: White film coated tablet, scored on both sides, engraving MR1 on one sideIdentification: HPLC: same as active standard solution TLC: same spot and Rf as active standard solutionMean weight: target mg±5%. Uniformity of mass: 90% of tablets between mean weight found ±5%. 100% of tablets between mean weight found±10%.Water content (KF): ≤2%Disintegration: water, <30 minutesHardness: 140-160 N

M. Ritala 2006


A typical specification for a tablet formulation (2)

Dissolution: 30 min Q>80%Assay (HPLC): Active substance 95-105%Chromatographic purity:

Known individual impurity ≤0,3%Unknown individual impurities ≤0,1%Total impurities ≤1%

Microbiological quality*: total aerobic bacteria≤10² moulds per gram or ml. Absence of E. Coli

*) the parameter is controlled once every 10 batches or at least once a year

Choice of manufacture

M. Ritala 2006


Choise of manufacture

Make, byu or outsource?Europe, U.S., China or India?Investment on new buildings, new machinery?Calculations on volumes and costs

batch sizes?cost of goods?sourcing strategy?

M. Ritala 2006


Manufacturing process development in different scales

•Screening studies for identification of critical control parameters (CCPs)

• FMEA

• Use of database

•Quality team meetings

ProcessValidation

&Commercial manufacture

Laboratory scale

Pre-pilot scale

Pilot scale

Production scale

Producteval. mtg

1

Producteval. mtg

2

Producteval. mtg

3

Producteval. mtg

4

•Update of CCPs

• Optimisation study

• Update of FMEA

• Use of database

•Quality team meetings

Producteval. mtg

5

M. Ritala 2006


Process development/Deliverables

Quality targets and metrics specified for the product and manufacturing processLimits set for critical process control parameters Risk analyses (FMEA, statistical predictions)Process database system established to be used during commercial manufactureFinalised master formulaFine tuning of product specifications

7

M. Ritala 2006


Common Tools for Successful Drug Development Work

Portfolio managementProject managementScientific networksKnowledge managementInformation mgmt systemsWell described processesBalanced Scorecard

Target Product Profile Drug Product ConceptStatistical methodsOptimisation methodsRisk assessment and managementFailure modes and effects analysisSix sigma

Stability

M. Ritala 2006


Shelf-life of a product

Shelf-life is the period during which drug product conforms to a given set of specificationsBased on the results of stability studiesProposed and justified in regulatory documentation12 month data from three batches required at the time of submission (NCE’s)6 month data from two batches required for generic productsStorage conditions to be studied:

25˚C, 60% RH40˚C, 75% RH30˚C, 60% RH

Usually enough data gathered at the time of approval for a shelf-life of 24 months

Biostudies

M. Ritala 2006


Biostudies

Give important feedback for the formulators of

dosage form selection and designselection of strengthsin vivo-in vitro correlationbioequivalence of generic products

M. Ritala 2006


Bioanalytics and pharmacokinetics

Analysis of the drug andits metabolites from body fluids, tissues andexcretions.

ADME:A = absorptionD = distributionM = metabolismE = excretion

Drug concentration in plasma

0.01

0,1

1

10

100

0 1 3 6Time, h

Con

cent

ratio

n, µ

g/m

l 0.25 mg/kg/day

2.5 mg/kg/day

2.5 mg/kg/day

8

New chemical entities

M. Ritala 2006


STABILITY PRIMARYSTABILITY

ANALYTICAL DEVELOPMENT

DRUG SUBSTANCE



PHASE I P II PHASE III PHASE IV

FORMULATION

INDUSTRI-ALISATIONMFR PROCESS DEVELOPMENT

NDA LAUNCH

PRODUCTMAINTENANCE

FOLLOW-UP STAB.

Phar

mce

utic

al d

evel

opm

ent

M. Ritala 2006


New chemical entities

how long from discovery to market?what does it cost? Who is financing it?is there a medical need?indications?target population?...and risks?

M. Ritala 2006


Keys to success with NCE’s in the pharmaceutical industry

High quality basic and biomedical researchSufficient R&D fundingExperience in drug development resulting in proprietary medicinesSufficient number of skilled peopleNetworking and collaborationBecoming international, global strategies

Generic drug substances and drug products

M. Ritala 2006


Generic drug substances and drug products

patents expiringhow fast and how cheap can one do it?life cycle managementusing technological innovationsKeys to success:

be fast, be there when the patent expireshave several products on the market and under development

9

Marketing authorisation applications

M. Ritala 2006


Marketing authorisation applications

FDA: NDA and ANDA EU: centralised and mutual regocnition proceduresJAPANApplications are written in CTD-formats

M. Ritala 2006


Case 1: Development and life cycle management of Clarityn® (1)

Clarityn from Schering Plough Inc. Originator of loratadin The largest allergy product?First pass metabolism over 50%Generic competition begun in 2001-02well before that Schering Plough made an agreement with a drug delivery company R.P. Scherer (now Cardinal Health) of developing a new formulatoin which could be patented.

M. Ritala 2006


Case 1: Life cycle management of Clarityn® (2)

Clarityn-S® (Claritin Reditabs) was developedFreeze-drying technology, called Zydis ®, was used in Clarityn-S ®Zydis ® technology is wery well protected by patents owned by Cardinal Health Ltd, UK.readily dissolving in the mouthcan be taken without water”speed of melting does not affect speed of relief”.is generic to Clarityn

M. Ritala 2006



Clarityn-S was registred in Finland already 1995generic, but in Finland not exchengeable, because of different dosage form

M. Ritala 2006



Composition of Clarityn 10 mg tablet

LoratadineLactoseMaize starchMagnesium stearate

Stability 3 years

Composition of Clarityn-S 10 mg tablet, freeze dried

LoratadinGelatinCitric acidMannitolPeppermint aroma

Stability 2y, after opening the foil: 6 months

10

M. Ritala 2006



Generic competition in Finland, prices 1.2.2006 and 1.1.2004 (10 mg, 30 tabs)

Loratadin Durascan 3.97 € (4.26 €) Geklimon Gea not mark. (4.58 €)Loratadin Alpharma 4.75 € (4.58 €)Loratadin Generics 4.98 € (4.68 €)Tuulix, Verman 4.74 € (4.98 €)Loratadin ratiopharm 5.88 € (6.37 €)Loratadin Biochemie not mark. (7.34 €)Loratadin Copyfarm 5.89 € not mark.Loratadin Hexal 5.89 € not mark.Clarityn, Schering Plough not mark. (15.17 €)Clarityn-S 16.65 €

M. Ritala 2006



The next step in life cycle management was desloratadine

Desloratadine is the active metabolite of loratadineAerius® tablet containing 5 mg of desloratadine was approved by EMEA in January 2001Well absorbed, no first pass metabolismSuspects of hepatic toxicity have been reported

M. Ritala 2006



Composition of Aerius 5 mg tablet, film-coatedDesloratadinGelatinMannitolAspartamePolacrilin potassiumDye Opatint Red (red iron oxide, hypromellose)Flavour Tutti-FruttiCitric acid

Stability 2years

M. Ritala 2006


Case 2: development of a generic product, simvastatin (1)

Originator MSD, ZOCOR 10mg and 20mg tabletsMolecule patent expired in 2003Price in Jan. 06: 46.61 € (20 mg, 98 tabl)

Price in Jan. 04 : 163.54 €

First generic approvals in Finland 200112 generic products on the market in Finland in Jan. 06Cheapest generic price 9.90 €

21.42 € in Jan. 0545.89 € in Jan. 04

M. Ritala 2006


Case 2: development of a generic product, simvastatin (2)

Composition of Zocor 20 mgSimvastatin*Butylhydroxyanisol*Ascorbic acid*Citric acid*Microcrystalline cellulose*Pregelatinised starch*Lactose*Magnesium stearate*Hypromellose*HPMCTitanium dioxide*, Yellow and Red iron oxide

Composition of Simvastatin Alternova 20 mg

all ingredients marked *and Propylene glycol

Marketing authorisation in 2003Their application probably consisted of a few trial batches in pilot scale, stability studies and a biostudy, where the bioequivalence criteria with Zocor was met.

M. Ritala 2006


Generic competition...

11

M. Ritala 2006


Case 3: Concerta depottablets (1)

Concerta® (methylphenidate HCl) CII once-daily extended-release tablet for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in patients age six and older.Concerta® uses an advanced OROS® patterned-release delivery system to achieve the desired improvement in symptoms, eliminating the need for in-school and after-school dosing.

M. Ritala 2006


Oros-technology from Alza

M. Ritala 2006


Methylphenidate plasma concentrations

M. Ritala 2006


Case 3: Concerta depottablets (2)

CompositionMethylphenidate HClButylhydroxytoluen Cellulose acetate HypromellosePhosphoric acid Poloxamer Polyethylenoxide Povidone Sodium chloride

Stearic acid Black and yellow iron oxide Lactose Titanium oxide Carnauba wax Macrogol 400 Isopropyl alcohol Propylene glycol Purified water

M. Ritala 2006


M. Ritala 2006


12

M. Ritala 2006


Case 4: life cycle management of Comtess (entacapone) (1)

Originator Orion PharmaApproved 1997-8 by FDA and EMEACOMT-inhibitorTo be used together with levodopa-carbidopa medication (Sinemet)dose of entacapone is always 200 mg, dose of levo-carbi varies depending on the severity of the disease

M. Ritala 2006


Case 4: life cycle management of Comtess (entacapone) (2)

The dose is adjusted individually and taken 2-8 times/dayStalevo from Orion Pharma contains entacapone, levodopa and carbidopa in one tablet

Three strengths of Stalevo allow individual adjustment and makes the dosing simpleEasy to swallow due to small sizeStalevo was approved by EMEA and FDA in 2003The formulation is patented

M. Ritala 2006


Case 4: life cycle management of Comtess (entacapone) (3)Composition of Comtess

EntacaponeMicrocrystalline celluloseMannitol*Croscarmellose sodium*Hydrogenated vegetable oilHypromellose*Polysorbate 80*Glycerol*Sucrose*Magnesium stearate*Red and yellow iron oxide*Titanium oxide*

Composition of StalevoEntacaponeLevodopaCarbidopaMaize starchPovidone K30and ingredients marked * in composition of Comtess

M. Ritala 2006


Case 4: life cycle management of Comtess (entacapone) (4)Comtess 200 mg

stability 3 yearsprice for 100 tablets 123.20 €*price for Sinemet 100 tablets 100/25 mg (Paranova) 34.57 €*

originator MSD does not market their Sinemet in Finland anymoreSinemet does not have any generic competitors.Extensive formulation patents!

Stalevo 100/25/200 mgstability 3 yearsprice for 100 tablets 155.34 €*

* price 01.02.2006 in Finland

Skilled people are needed...

M. Ritala 2006


The products are developed by people

Continuous support for personal development and scientific trainingContinuous training of leadershipProvide up-to-date tools and facilitiesNurture the human resource

Pharmaceutical development relies heavily

on individual expertise!

13

M. Ritala 2006


Prerequisites for successful team work

Shared company valuesShared goalsClear roles and responsibilitiesCo-operationCommitmentEmpowermentCommunication

Quality of workProfessional skillsLeadershipPlanning and schedulingFeedbackControl and reporting

M. Ritala 2006


To run drug development nice and smoothly (1):

decision making: kill bad projects early enough (bad projects are notnecessarily the painful ones) listen to the scientistsdo not spend too much time trying to find concensuskill a few comittees and meetings

escape unnecessary regulationsopen, honest, professionel relationship with the authoritiesdo not overdevelop

M. Ritala 2006


To run drug development niceand smoothly (2):

do POC properly, but be fastphase I and II a can give invaluable informationuse miniaturisation and micro dosing where ever you can

maximise the moleculedo life cycle management early enoughremember the dosage forms patiens –consumers- like: -transdermal, eye, oromucosaluse the opportunities to develop polymorphs, enantiomersand controlled release formulations

watch the NIH syndrome!

Pharmaceutical development in the future

M. Ritala 2006


Opportunities for formulators to aid flow of new products through smart drug delivery

Increased emphasis on life cycle managementnew, improved products and indicationsproduct differentiation

Growing biopharmaceutical marketsimple parenterals will not satisfy the market

More new drugs (molecules!) with sub-optimal properties

high throughput screening and synthesisdecreased compound attrition

Increased specificity of delivery systemscellular targeting and programmed releaseindividualised therapies (... but who can afford them?)

Environmental considerationsM. Ritala 2006


14

M. Ritala 2006


Important future technologies in drug delivery

Oralcontrolled releaseimproved solubilityrapid absorption

Site specific implantsNon-invasive protein/peptide delivery

oralinhalation (insulin!)

Improved macromoleculessustained release injectable

M. Ritala 2006


Inhaled insulin, Exubera

Fast acting powder formulation of human insulin inhaled by a simple deviceDeveloped by Pfizer (and Aventis) and Nektar Therapeuticsapproved by FDA and EMEA in January 2006long term pulmonary safety was a concern that delayed the approval for several years

M. Ritala 2006


M. Ritala 2006


The challenges of drug developmenthave continued to grow

Global strategiesVirtually integrated companiesIncreasing R&D expenses and timelines

poor productivity?true value creation?

Expanding number of technologieschallenging the traditional approaches

Increasing need to deliver return to investors, partners and customers

M. Ritala 2006


Have a look at... www.

nam.fiemea.eu.intfda.govduodecim.fiorionpharma.comapteekit.net controlledrelease.orgiirusa.com/drugdeliverypartnerships

alza.comcardinal.combdpharma.comnektar.compharmaprofiles.co.ukltslohmann.com

Documents

Drug Development Process