Project Management on
API Manufacturing
Cortona
September 19th, 2010
Develop an Efficient Control Strategy and
Andrea Castellin PhD Implementation
FIS worldwide
New Ways of Partnership in the Fine Chemicals Global Development
FIS US Office
PHF Pharmaceutical Holding FIS F.I.S. – Montecchio (VI)
65 Harristown Road, Glen
Lugano - Switzerland Montecchio Maggiore (VI) - Italy
Rock
NJ 07452 - USA
F.I.S. – Termoli (CB) FIS CHINA Office
Termoli (CB) - Italy Shanghai - China
A team committed to develop, produce and deliver high quality substances: active
ingredients, key intermediates and building blocks for the pharmaceutical industry worldwide.
Interactions
FACT&FIGURES
2 manufacturing area
PMDA 8 plants
Japan 1700 m3 reactor capacity
620 employees
All of them located in Italy
SFDA
China
KFDA
South Korea
AIFA
Italy
FDA
USA
Foreign IPRs
authorities
What we learn in doing this job…
• Develop a process is not only matter to
deliver product to customer
• Have a customer doesn’t justify meanings in
front a patent or a regulatory body
• Built-in quality it is not only matter to
respect a guidelines
• Do research to introduce innovation it is not
only to make up your budget of investments
Rather is …
What we do
Make just in time
What they want
In the smoothest way
And
Eventually get to your stakeholder
A perception of quality that meet their expectations
Project management flow: planning a proposal
Technical Evaluation:
Complexity of chemistry, stoichometry process
Outward examination of the performance, raw material consumption, technology
chemistry and technology fitting, therapeutic equivalence and plant suitability,
Activities
Collect general information toxicological profile…
Financial and commercial data
Technical package analysis from the Economical Evaluation:
customer if available Raw material supply chain investigation, lab and Kilolab,
Pilot operation, Validation and commercial scale costs
evaluation, investments and budgeting
Pre-Evaluation Phase Evaluation Phase
Duration
Best track: 5 working days Best track: 11 working days
Deliverables
Formal communication to the Customer will be receive from Commercial Area Manager:
customer of entry to next level of - Detailed Project plan
examination - Technical Presentation
- Quotation
Project handling on R&D phase
At the project kick-off meeting R&D generate a consolidate version of the project plan, re-defining
activities, and the project charter, a tool intended to handle the different activities progression together
with the customer. Basically the project charter collect the following flow of activities:
Other Process R&D Process Phase Deliverable
contribution Contents
DEFINITION R&D
OBJECTIVES
Bibliographic search
PROJECT CHARTER
SHEET IPRs analysis report
QC PROCESS Preliminary cost evaluation sheet
PROJECT MILESTONES
DEFINITION OF ANALYTICAL DEVELOPMENT
LOGISTIC DEFINITION OF SUPPLIER RAW MATERIALS
PROCESS & BUILDING BLOCKS
Project handling on R&D phase
Other Process Deliverable
contribution Contents
R&D Process Phase •Lab and Klab procedures/process
description
•Lab and Klab work order
•Personnel instruction
•Data experimental collection
PROJECT CHARTER
SHEET •Analytical method developments for
IPC and target product
QC PROCESS
•Process safety analysis
Process familiarization, research •Definition of critical RSM and RMs
and development •Definition of plant scheme
Analtical development activities •Lab and Klab samples
LOGISTIC •Post production and waste treatment
Supply chain definition
PROCESS methods
•Hold point definition
•Solvents recovery
•RMs and intermediates impurity carry
over
•Cleaning procedures
•QbD and Risk assessment
Analyzing a specific case: Olopatadine HCl
AIFA PMDA
Italy Japan
Analyzing a specific case: Olopatadine HCl
Olopatadine HCl: chemistry background
“Grignard reagent” approach
Some of the described innovator’s pathway
O N
O Thionyl Chloride O
OH . O
H2N
CH2 Cl2
+ OH Toluene
O Ethyl Acetate
O
N
N
O N
O HO
Magnesium
+ Cl N . O
THF
O CH2 Cl2
NH4OH O
HCl
N NaOH N
N O
HO
O p-Toluen-Sulphonic Acid OH
Final API
Salt formation
Ethanol
O
O
Wittig reagent approach: FIS’ pathway
Some key project milestones
1. April 2008, a bibliographic and patent analysis were carried out
2. June 13th 2008, FIS received from supplier the two key raw
materials
3. July 31st 2008, samples of the API were dispatched to Japan
4. February 2009 after in deep patent analysis, research &
development, the process reaches a definitive configuration
5. June 2009 a “DEMO Batch” of Olopatadine HCl was produced
6. After the synthesis of the DEMO Batch some synthetic
parameters were revised and minor process changes were
introduced. Changes were applied in several Lab trials and as
result overall yield of the process was increased.
7. December 2009: Validation Campaign was performed
Project management: plan assumptions
Basic requirements
3 stages chemsitry
2 main chemical transformations and other expertise required
o Ester formation
o Wittig/Ilide addition
o Salt break up
o Crystal abit, polymorphism control
o Psd control
2 isolated intermediates/final product
Micronization required
Process development and front run Kilolab sample required by the
customer
Qualification batches
Validation batches
DMF filing
Project management: actuation plan
Project kick-off
meeting activities
Deliverable
Duration
IPRs analysis
6 wd Deliverable
Definition of technical requirements
Supplier Qualification
Competitive intelligence analysis
Duration Deliverable
Supply Chain RMs
38 wd Raw material - Comparison test and specifications
Analytical development
Technology transfer/Method validation
Duration Stability studies (second stage)
32 wd Analytical Dept. activities
(analytical dev.)
Deliverable
Familiarization studies
Duration Process safety evaluation
Process Development Front run sample from lab to Klab
46 wd
Project reporting (weekly and TCs)
Solvent recovery studies and other economical impact evaluation
Duration QbD analysis
Plant Setup
20 wd
Deliverable
Duration Qualification batch MBRs
40 wd Pilot plant Project reporting (weekly and TCs)
Campaign report
Next stage
Quality Assurance activities
wd: working days
Project management: actuation plan
Previous stage
Deliverable
Qualification batch MBRs
Pilot plant Project reporting (weekly update)
Duration Campaign report
40 wd
Deliverable
Duration
Validation Campaign MBRs
62 wd
Commercial plant Validation report
Link to QA activities
Duration Quality Assurance activities
245 wd
Deliverable
cGMP customer audits on site
Batch releases
Validation summary report
DMF preparation and submission to Italian Health Authority (AIFA)
Entering the phase of review period by AIFA (120-180 days)
Total Duration
300 working days, from the kick-off meeting
wd: working days Dispatch of validation batches
Define a strategy
Risk assessment table
Steps that do not influence the purity of final API
Steps that could influence the purity of final API but can be easily controlled
Steps that can impact the purity of final API
Ishikawa diagram of the process
Raw Materials Reactions work-up Concentrations
Purity of Isoxepac Butylester Amount of Solvents Temperature
Purity of Wittig Salt Charcoal amount
Olopatadine HCl
Purity
Dilution
Re
Reaction Temperature
Reaction Temperature Reaction Tem
Reaction Time
NaH Equivalents D
NaH equivalents
Kf of Methyl THF KOH Equivale
Wittig Salt Equuivalents
Ilide Formation Wittig Reaction
Ishikawa diagram of the process
Concentrations Seeding HCl Salt Formation
ture Amount Required Water Amount
KF of Free Base
HCl Equivalents
Addition rate
Final API
Reaction time
Reaction Temperature
Dilution Drying Time
KOH Equivalents Dilution Temperature
Hydrolysis Crystallization as Free Base Drying
Set up a DoE study
A road map for the investigation
Critical Parameter Identified for the syhthesis of Olopatadine HCl
Ilide formation Wittig Reaction Hydrolysis Crystallization as Free Base HCl Salt Formation
NaH Equivalents Posphonium Salt Equivalents KOH Equivalents Seeding Purity Acetone Amoount
Reaction Temperature Temperature Water Amount
Dilution Dilution HCl Equivalents
DoE as a tool
Parameter investigated_1
Proposed Critical Process Parameters
Proposed Design Space Proposed Control Space
Variable
Min. Max. Min. Max.
Ilide Formation
NaH Equivalents (referred to Isoxepac Butylester) 2,1 eq. 3,3 eq. 2,5 eq. 2,7 eq.
Wittig Reaction
Phosphonium Salt Equivalents 1,1 eq. 1,5 eq. 1,2 eq. 1,3 eq.
Reaction Temperature 10,0 °C 50,0 °C 38,0 °C 42,0 °C
Total solvent Amount 6,0 V 12,0 V 7,0 V 9,0 V
Hydrolysis
KOH Equivalents (Referred to Isoxepac Butylester) 0,7 eq. 1,1 eq. 0,8 eq. 0,9 eq.
Dilution (Methanol Water = 1.8 : 1) 18,0 V 26,0 V 19,0 V 23,0 V
Reaction Temperature 20,0 °C 75,0 °C 60,0 °C 70,0 °C
Purification of Free Base
Total solvent Amount 3,0 V 6,0 V 3,5 V 4,5 V
Filtration Temperature -15,0 °C 20,0 °C 0,0 °C 5,0 °C
Olopatadine HCl Formation / Crystallization
Acetone Total Amount (dilution in Volumes referred to Olopatadine Free Base) 15,0 V 25,0 V 17,0 V 20,0 V
Water Amount (dilution in Volumes referred to Olopatadine Free Base) 0,0 V 1,5 V 0,5 V 0,8 V
HCl Amount 1,0 eq. 2,0 eq. 1,4 eq. 1,6 eq.
Parameter investigated_2
Other Process parameter ranges for the process
Proposed Design Space Proposed Control Space
Variable
Min. Max. Min. Max.
Ilide Formation
Reaction temperature 75,0 °C 79,0 °C 75,0 °C 79,0 °C
Methyl THF amount (in Volumes referred to Isoxepac Butylester) 5,0 V 6,5 V 5,7 V 5,9 V
Reaction Time 3,0 Hrs 8,0 Hrs 4,0 Hrs 6,0 Hrs
Wittig Reaction
Reaction time 2,0 Hrs 10,0 Hrs 3,0 Hrs 5,0 Hrs
Wittig Reaction Work-up
Water Amount 3,0 eq. 6,0 eq. 4,0 eq. 4,5 eq.
Phases separations Temperature 15,0 °C 30,0 °C 20,0 °C 25,0 °C
Maximum Concentration Temperature 60,0 °C 50,0 °C
Hydrolysis
Methanol Amount 12,0 V 20,0 V 14,0 V 16,0 V
Water Amount 5,0 V 10,0 V 7,0 V 9,0 V
Reaction Time 2,0 Hrs 8,0 Hrs 2,0 Hrs 4,0 Hrs
Hydrolysis Work-up
Maximum Concentration Temperature after hydrolysis 60,0 °C 50,0 °C
Phases separations Temperature 15,0 °C 30,0 °C 20,0 °C 25,0 °C
Maximum Concentration Temperature after Toluenic phases separations 70,0 °C 50,0 °C
Crystallization of Free Base
Seeding Amount / Quality 0,005 W 0,050 W 0,005 W 0,010 W
Seeding temperature 15,0 °C 30,0 °C 20,0 °C 25,0 °C
Olopatadine HCl Formation / Crystallization
Filtration Temperature 0,0 °C 25,0 °C 0,0 °C 5,0 °C
Drying Temperature 25,0 °C 60,0 °C 40,0 °C 50,0 °C
Conclusions
≈ Structural approach to gain process
knowledge
≈ Developing robust manufacturing control
strategy
≈ Give space to innovation to fulfill the
robustness
Acknowledgement
Old wood and science
Clark Ferrari, Project Leader, Olopatadine HCl
Marco Galvagni, Divisional Director R&D
Thank you!
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