Tuotekehityksen vaiheet

Mitä on tuotekehitys?
A definition
„ Product development?
Tuotekehityksen vaiheet „ Drug development?
„ Technical development?
Luennot helmikuu 2006 Helsingin „ Pharmaceutical development?
Yliopisto, Farmasian tiedekunta, „ Drug delivery technology?
teknologia, lääkevalmisteblokki.
FaT Marja Ritala „ Chemistry and manufacturing?

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Drug Development Process Contents (1)

PROOF OF SAFETY AND
CONCEPT EFFICACY „ Definitions
„ Trends in the pharmaceutical industry
Processes
DISCOVERY PRE-CLINICAL
„
„ Preformulation
CLINICAL CLINICAL CLINICAL
PHASE I PHASE II PHASE III
PHASE IV
„ Formulation
„ Analytical development
PHARMACEUTICAL DEVELOPMENT MAINTENANCE „ Specifications, quality
„ Choice of manufacture
„ Stability
IND NDA MA, LAUNCH
PRODUCT LIFE CYCLE MANAGEMENT
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Contents (2)
„ Biostudies
Trends in the Pharmaceutical
„ New chemical entities Industry
„ Life cycle management of products
„ Generic drug substances and products
„ Marketing authorisation applications
„ Case studies of formulation and life cycle
management
„ Skilled people needed
„ Pharmaceutical development in the future

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Trends in the Pharmaceutical Trends in the Pharmaceutical

Industry (1) Industry (2)
„ Fully integrated pharmaceutical companies
„ Market growth „ Virtually integrated pharmaceutical companies
„ Mega mergers „ Outsourcing
„ Consolidation „ strategic partnerships
„ Networking (emerging technologies) „ contract services
„ Biotechnology in addition to chemistry
„ Networking
„ Cost containment of healthcare
„ R&D productivity challenge „ Spin-offs
„ Intensive life-cycle management

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Drug Development Process

PROOF OF SAFETY AND
CONCEPT EFFICACY

Processes DISCOVERY PRE-CLINICAL

CLINICAL CLINICAL CLINICAL

PHASE IV
PHASE I PHASE II PHASE III

PHARMACEUTICAL DEVELOPMENT MAINTENANCE

IND NDA MA, LAUNCH

PRODUCT LIFE CYCLE MANAGEMENT
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Development data brings new information to

Drug Development Process the pharmaceutical development

DISCOVERY PRE-CLINICAL
DISCOVERY PRE-CLINICAL
PHASE I P II PHASE III PHASE IV
PHASE I P II PHASE III PHASE IV

LIFE CYCLE
Pharmceutical development

IND COMMERCIAL MANAGEMENT AND

DRUG SUBSTANCE PRODUCT BRAND DEVELOPMENT
PHARMACO- STRENGTH(S)
FORMULATION NDA MA, LAUNCH KINETICS
IN HUMANS
INDUSTRI- PRODUCT AND DOSING
MFR PROCESS DEVELOPMENT ALISATION MAINTENANCE PRE-CLINICAL TO BE USED FOR:
ADME, - DRUG SUBSTANCE DEVELOPMENT
ANALYTICAL DEVELOPMENT PHARMACOLOGY - ANALYTICAL DEVELOPMENT
TOX PROFILE - ADMINISTRATION ROUTE SELECTION
PRIMARY FOLLOW-
STABILITY MOLECULAR - DOSAGE FORM SELECTION AND DESIGN
STABILITY UP STAB.
PROPERTIES - UNIT DOSES AND DOSING
- ETC.
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Main Processes in
Pharmaceutical Development

„ Drug substance „ Manufacturing

development process development
Drug substance development
„ Preformulation „ Industrialisation
„ Formulation „ Process validation
„ Development of „ Documentation of
Specifications data
„ Analytical methods „ Project planning and
development management
„ Stability studies
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Drug substance development

„ A robust synthesis process with consistent
batch-to-batch quality
„ Selection of salt
Preformulation
„ Analytical methodology
„ Mastering the physical properties like particle
size and polymorphism
„ Stability
„ Scaling up and technlogy transfer
„ Documentation
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Preformulation
„ Solubility (aqueous, pKa, log P, log D)
Molecular optimization (salt, hydrate, solvate, new
Formulation
„
analogs,…)
„ Crystal Engineering (polymorph, habit, size, surface
characteristics…)
„ Crystal structure determination
„ Biopharmaceutical classification (BCS) (solubility,
dissolution, absorption)
„ Drug stability evaluation (physical, chemical, solution
phase, solid phase, …)
„ Compatibility analyses (drug substance, excipient,
packaging materials)

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Characteristics of a sound
Formulation innovation
„ Composition + process = formulation
„ Product design
„ Formulation determines how the drug is delivered ƒUnderpinning science must be sound
„ A good composition ƒUniqueness
„ is simple, but innovativeness may be needed ƒit solves a problem
utilises standard compendial excipients
ƒcan be patented
„

„ easy to manufacture
„ good stability ƒcreates cost advantage
„ facilitates straightforward analytics ƒcan be used as an asset when
protects the product against generic competition
forming exclusive partnerships
„

„ Formulation work is based on information gained through

preformulation and biostudies ƒTechnology can be validated
„ Laboratory scale work
„ The guidelines of authorities give a roadmap

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Prerequisites of a successful Commercialised drug delivery

formulation : technologies today
„ Formulation work is based on science „ Oral controlled release $$$$$$
„ molecule properties
„ physiology, biology „ Transdermal $$$$$
delivery technology
„
„ Implants $$$$
„ The consumer needs are identified
„ Target product profile is defined „ Quick dissolve $$$
„ There is a clear view of the indication and „ Single isomers $$
target population
„ There is an understanding of administration „ Liposomes $
route, dose and dosage form

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Drug delivery companies and The largest drug delivery

technologies products of the 1990’s
„ Oral controlled release Drug
„ Developer Peak sales Marketer
„ Biovail, Elan, Alza (JJ), Skye Pharma, Procardia XL Alza 1,250 Mill.$ Pfizer
Cardinal Health...
Duragesic Alza 1,200 Mill.$ Johnson &
„ Transdermal delivery Johnson
„ Altea, Alza (JJ), 3M... Lupron Tap 1,100 Mill.$ TAP

„ Respiratory delivery Cardizem SR/CD Elan 1,000 Mill.$ Hoechst

„ Nectar (Inhale), Biovail, Elan, Skye Nicotine Patch Several 800 Mill.$ Novartis
Pharma... developers
Nitro Dur Key 600 Mill.$ Schering Plough

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Procardia XL: A pharmaceutical

company's dream scenario Technology selection criteria
„ Instead of suffering a monumental loss when an „ Scientific understanding
important drug goes off patent, the company „ Similarity of compounds or problems addressed
launches a new, vastly improved version that eclipses
both the original drug and its generic competition. „ Realistic assessment of success
That's exactly what Pfizer did when it partnered with „ Stage of development
ALZA to develop Procardia XL®, which incorporates
ALZA's OROS® osmotic technology. „ Freedom to operate (drug type, therapeutic area)
„ Manufacturing capability
„ ALZA's technology gave Procardia XL® several „ Scope for intellectual property
major advantages over Pfizer's original product, „ Development timescale
Procardia®, and generic nifedipine. As a result, the
label indication for Procardia XL® was expanded to „ Costs
include treatment of both angina and hypertension. „ Predicted sales and profitability
„ In Finland marketed under name Adalat Oros
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Why analyse products

during development?
Formulations are often fine-tuned after
Analytical development
„
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 to
control and assure the quality of the drug

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Analytical development
„ HPLC, TLC, IR, NIR, UV, GC, MS, CE... are the
methods to analyse
„ Assay of drug substance Specifications and quality
„ Degradation profile
„ Identification
„ Content uniformity
„ Dissolution
„ Organic volatile impurities
„ The methods are validated in regard to
accuracy, sensitivity, robustness, selectivity...
„ according to ICH
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A typical specification for a A typical specification for a

tablet formulation (1) tablet formulation (2)
„ Appearance: White film coated tablet, scored on both „ Dissolution: 30 min Q>80%
sides, engraving MR1 on one side „ Assay (HPLC): Active substance 95-105%
„ Identification: HPLC: same as active standard
solution TLC: same spot and Rf as active standard „ Chromatographic purity:
solution „ Known individual impurity ≤0,3%
„ Mean weight: target mg±5%. „ Unknown individual impurities ≤0,1%
„ Uniformity of mass: 90% of tablets between mean „ Total impurities ≤1%
weight found ±5%. 100% of tablets between mean „ Microbiological quality*: total aerobic bacteria≤10²
weight found±10%. moulds per gram or ml. Absence of E. Coli
„ Water content (KF): ≤2% „ *) the parameter is controlled once every 10 batches or at
„ Disintegration: water, <30 minutes least once a year
„ Hardness: 140-160 N

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Choise of manufacture
„ Make, byu or outsource?
Choice of manufacture „ Europe, U.S., China or India?
„ Investment on new buildings, new
machinery?
„ Calculations on volumes and costs
„ batch sizes?
„ cost of goods?
„ sourcing strategy?

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Manufacturing process
Process development/Deliverables
development in different scales
•Screening studies for •Update of CCPs
identification of critical
control parameters
• Optimisation study „ Quality targets and metrics specified for the product and
(CCPs) • Update of FMEA manufacturing process
• FMEA • Use of database
Process „ Limits set for critical process control parameters
Risk analyses (FMEA, statistical predictions)
• Use of database •Quality team meetings Validation „
•Quality team meetings &
Laboratory Pre-pilot Pilot Production Commercial „ Process database system established to be used during
scale scale scale scale manufacture commercial manufacture
„ Finalised master formula
Product Product Product Product Product „ Fine tuning of product specifications
eval. mtg eval. mtg eval. mtg eval. mtg eval. mtg
1 2 3 4 5

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Common Tools for Successful Drug

Development Work

„ Portfolio management „ Target Product Profile

„ Project management „ Drug Product Concept Stability
„ Scientific networks „ Statistical methods
„ Knowledge „ Optimisation methods
management „ Risk assessment and
„ Information mgmt management
systems „ Failure modes and
„ Well described effects analysis
processes „ Six sigma
„ Balanced Scorecard
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Shelf-life of a product
„ Shelf-life is the period during which drug product conforms to a
given set of specifications
„
„
Based on the results of stability studies
Proposed and justified in regulatory documentation
Biostudies
„ 12 month data from three batches required at the time of
submission (NCE’s)
„ 6 month data from two batches required for generic products
„ Storage conditions to be studied:
„ 25˚C, 60% RH
„ 40˚C, 75% RH
„ 30˚C, 60% RH
„ Usually enough data gathered at the time of approval for a
shelf-life of 24 months

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Biostudies Bioanalytics and pharmacokinetics

„ Give important feedback for the Analysis of the drug and

formulators of its metabolites from body
fluids, tissues and
Drug concentration in plasma

100
dosage form selection and design
0.25 mg/kg/day
Concentration, µg/ml

„ excretions. 2.5 mg/kg/day

10 2.5 mg/kg/day

„ selection of strengths 1
„ in vivo-in vitro correlation ADME: 0,1

„ bioequivalence of generic products A = absorption

0.01
D = distribution 0 1 3 6
Time, h
M = metabolism
E = excretion
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Drug Development Process

DISCOVERY PRE-CLINICAL

New chemical entities PHASE I P II PHASE III PHASE IV

Pharmceutical development
DRUG SUBSTANCE

FORMULATION NDA LAUNCH

INDUSTRI- PRODUCT
MFR PROCESS DEVELOPMENT
ALISATION MAINTENANCE

ANALYTICAL DEVELOPMENT

PRIMARY FOLLOW-
STABILITY
STABILITY UP STAB.

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Keys to success with NCE’s in the

New chemical entities pharmaceutical industry

„ how long from discovery to market? „ High quality basic and biomedical research
Sufficient R&D funding
„ what does it cost? Who is financing it? „

„ Experience in drug development resulting in

„ is there a medical need? proprietary medicines
„ indications? „ Sufficient number of skilled people
„ Networking and collaboration
„ target population? „ Becoming international, global strategies
„ ...and risks?

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Generic drug substances and

drug products
Generic drug substances and „ patents expiring
drug products „ how fast and how cheap can one do it?
„ life cycle management
„ using technological innovations
„ Keys to success:
„ be fast, be there when the patent expires
„ have several products on the market and
under development

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Marketing authorisation
applications
Marketing authorisation „ FDA: NDA and ANDA
applications „ EU: centralised and mutual regocnition
procedures
„ JAPAN
„ Applications are written in CTD-formats

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Case 1: Development and life cycle Case 1: 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 2001-02
„ well before that Schering Plough made an
agreement with a drug delivery company R.P.
management of Clarityn® (2)
„ Clarityn-S® (Claritin Reditabs) was developed
„ Freeze-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 mouth
can be taken without water
„

”speed of melting does not affect speed of relief”.

Scherer (now Cardinal Health) of developing „

a new formulatoin which could be patented. „ is generic to Clarityn

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Case 1: Life cycle Case 1: Life cycle

management of Clarityn® (3) management of Clarityn® (4)
„ Clarityn-S was registred in Finland „ Composition of Clarityn „ Composition of Clarityn-
10 mg tablet S 10 mg tablet,
already 1995 „ Loratadine freeze dried
Lactose Loratadin
„ generic, but in Finland not „

„ Maize starch
„

„ Gelatin
exchengeable, because of different „ Magnesium stearate „ Citric acid
Stability 3 years Mannitol
dosage form „ „

„ Peppermint aroma
„ Stability 2y, after
opening the foil:
6 months

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Case 1: Life cycle
management of Clarityn® (5)
„ Generic competition in Finland, prices 1.2.2006 and
1.1.2004 (10 mg, 30 tabs)
„ Loratadin Durascan
„ Geklimon Gea
„ Loratadin Alpharma
„ Loratadin Generics
„ Tuulix, Verman
„ Loratadin ratiopharm
„ Loratadin Biochemie
„ Loratadin Copyfarm
„ Loratadin Hexal
„ Clarityn, Schering Plough
„ Clarityn-S
M. Ritala 2006
Case 1: Life cycle
management of Clarityn® (7)
„ Composition of Aerius 5 mg tablet, film-coated
„ Desloratadin
Gelatin
„
„ Mannitol
„ Aspartame
„ Polacrilin potassium
„ Dye Opatint Red (red iron oxide, hypromellose)
„ Flavour Tutti-Frutti
„ Citric acid
„ Stability 2years
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Case 2: development of a generic
product, simvastatin (2)
„ Composition of Zocor 20 mg
„ Simvastatin*
„ Butylhydroxyanisol*
„ Ascorbic acid*
„ Citric acid*
„ Microcrystalline cellulose*
„ Pregelatinised starch*
„ Lactose*
„ Magnesium stearate*
„ Hypromellose*
„ HPMC
Titanium dioxide*, Yellow
„
and Red iron oxide
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Case 1: Life cycle
management of Clarityn® (6)
„ The next step in life cycle management was
3.97 € (4.26 €) desloratadine
not mark. (4.58 €) „ Desloratadine is the active metabolite of loratadine
4.75 € (4.58 €)
4.98 € (4.68 €) „ Aerius® tablet containing 5 mg of desloratadine
4.74 € (4.98 €) was approved by EMEA in January 2001
5.88 € (6.37 €) „ Well absorbed, no first pass metabolism
not mark. (7.34 €)
5.89 € not mark. „ Suspects of hepatic toxicity have been reported
5.89 € not mark.
not mark. (15.17 €)
16.65 €
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Case 2: development of a generic
product, simvastatin (1)
„ Originator MSD, ZOCOR 10mg „ First generic approvals
and 20mg tablets in Finland 2001
Molecule patent expired in 12 generic products on
„ „
2003 the market in Finland in
„ Price in Jan. 06: 46.61 € Jan. 06
(20 mg, 98 tabl) „ Cheapest generic price
„ Price in Jan. 04 : 163.54 € 9.90 €
„ 21.42 € in Jan. 05
„ 45.89 € in Jan. 04
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Generic competition...
„ Composition of Simvastatin
Alternova 20 mg
„ all ingredients marked *
„ and Propylene glycol
„ Marketing authorisation in
2003
„ Their application probably
consisted of a few trial
batches in pilot scale,
stability studies and a
biostudy, where the
bioequivalence criteria with
Zocor was met.
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Case 3: Concerta depottablets

(1) Oros-technology from Alza
„ 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.
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Methylphenidate plasma Case 3: Concerta depottablets

concentrations (2)
„ Composition „ Stearic acid
„ Methylphenidate HCl „ Black and yellow iron
„ Butylhydroxytoluen oxide
„ Cellulose acetate „ Lactose
„ Hypromellose „ Titanium oxide
„ Phosphoric acid „ Carnauba wax
„ Poloxamer „ Macrogol 400
„ Polyethylenoxide „ Isopropyl alcohol
„ Povidone „ Propylene glycol
„ Sodium chloride „ Purified water

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Case 4: life cycle management Case 4: life cycle management

of Comtess (entacapone) (1) of Comtess (entacapone) (2)
„ Originator Orion Pharma „ The dose is adjusted individually and taken 2-
8 times/day
„ Approved 1997-8 by FDA and EMEA
„ Stalevo from Orion Pharma contains
„ COMT-inhibitor entacapone, levodopa and carbidopa in one
„ To be used together with levodopa- tablet
carbidopa medication (Sinemet) „ Three strengths of Stalevo allow individual
adjustment and makes the dosing simple
„ dose of entacapone is always 200 mg, „ Easy to swallow due to small size
dose of levo-carbi varies depending on „ Stalevo was approved by EMEA and FDA in 2003
the severity of the disease „ The formulation is patented

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Case 4: life cycle management Case 4: life cycle management

of Comtess (entacapone) (3)
„ Composition of Comtess
„ Entacapone
„ Microcrystalline cellulose
Mannitol*
„ „
Croscarmellose sodium*
„ „
„ Hydrogenated vegetable oil
„ Hypromellose*
„ Polysorbate 80*
„ Glycerol*
„ Sucrose*
„ Magnesium stearate*
Red and yellow iron oxide*
„
„ Titanium oxide*
of Comtess (entacapone) (4)
„ Composition of Stalevo „ Comtess 200 mg „ Stalevo 100/25/200 mg
„ Entacapone stability 3 years
„ „ stability 3 years
„ Levodopa price for 100 tablets
Carbidopa
„
„ price for 100 tablets
123.20 €*
Maize starch 155.34 €*
„ price for Sinemet 100
„ Povidone K30 tablets 100/25 mg
„ and ingredients marked * in (Paranova) 34.57 €*
composition of Comtess „ originator MSD does not
market their Sinemet in
Finland anymore
„ Sinemet does not have
any generic competitors.
„ Extensive formulation
patents!

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* price 01.02.2006 in Finland

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The products are developed by people

Pharmaceutical development
Skilled people are needed... relies heavily
on individual expertise!

„ Continuous support for personal development and

scientific training
„ Continuous training of leadership
„ Provide up-to-date tools and facilities
„ Nurture the human resource

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To run drug development nice and

Prerequisites for successful team work smoothly (1):
„ Shared company „ Quality of work „ decision making:
values „ Professional skills „ kill bad projects early enough (bad projects are not
„ Shared goals „ Leadership necessarily the painful ones)
Clear roles and listen to the scientists
„ „ Planning and scheduling „

responsibilities
„ Co-operation
„ Commitment
„ Empowerment
„ Communication
„ Feedback
„ do not spend too much time trying to find concensus
„ kill a few comittees and meetings
„ Control and reporting
„ escape unnecessary regulations
„ open, honest, professionel relationship with the authorities
„ do not overdevelop

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To run drug development nice

and smoothly (2):

„ do POC properly, but be fast Pharmaceutical development

„

„
phase I and II a can give invaluable information
use miniaturisation and micro dosing where ever you can
in the future
„ maximise the molecule
„ do life cycle management early enough
„ remember the dosage forms patiens –consumers- like:
-transdermal, eye, oromucosal
„ use the opportunities to develop polymorphs, enantiomers
and controlled release formulations
„ watch the NIH syndrome!

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Opportunities for formulators to aid flow of new

products through smart drug delivery

„ Increased emphasis on life cycle management

„ new, improved products and indications
„ product differentiation
„ Growing biopharmaceutical market
„ simple parenterals will not satisfy the market
„ More new drugs (molecules!) with sub-optimal
properties
„ high throughput screening and synthesis
„ decreased compound attrition
„ Increased specificity of delivery systems
„ cellular targeting and programmed release
„ individualised therapies (... but who can afford them?)
„ Environmental considerations
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Important future technologies in

drug delivery Inhaled insulin, Exubera
„ Oral „ Fast acting powder formulation of human
„ controlled release insulin inhaled by a simple device
„ improved solubility
„ rapid absorption „ Developed by Pfizer (and Aventis) and Nektar
„ Site specific implants Therapeutics
„ Non-invasive protein/peptide delivery „ approved by FDA and EMEA in January 2006
„ oral „ long term pulmonary safety was a concern
inhalation (insulin!)
that delayed the approval for several years
„

„ Improved macromolecules
„ sustained release injectable

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The challenges of drug development

have continued to grow

ƒGlobal strategies
ƒVirtually integrated companies
ƒIncreasing R&D expenses and timelines
ƒpoor productivity?
ƒtrue value creation?
ƒExpanding number of technologies
ƒchallenging the traditional approaches
ƒIncreasing need to deliver return to
ƒinvestors,
ƒpartners and
ƒcustomers
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Have a look at... www.

„ nam.fi „ alza.com
„ emea.eu.int „ cardinal.com
„ fda.gov „ bdpharma.com
„ duodecim.fi „ nektar.com
„ orionpharma.com „ pharmaprofiles.co.uk
„ apteekit.net „ ltslohmann.com
„ controlledrelease.org
„ iirusa.com/drugdelivery
partnerships
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