Presentation Patheon Symposium IMA ok

High Containment
perforated coater:
from lab scale to
production
May 2016
CONFIDENTIAL ©2015 PATHEON®
Patheon
Overview
CONFIDENTIAL ©2015 PATHEON®
Patheon is a leading provider of contract development and
commercial manufacturing services to the pharmaceutical &
biotechnology sectors.
We offer the broadest set of solutions to clients including
development and commercial manufacturing services for both large
and small molecule drug substance and drug product in a wide range
of dosage forms.
3
Confidential
Inspire & Simplify.
Appointed James C. Mullen
as Chief Executive Officer
and to Board of Directors
2011
Legacy Patheon
business had a strong
PDS and DPS offering
2012
DPx was formed as a part
of a $2.7 billion transaction
between JLL Partners and
Royal DSM
2013
Acquisition of Banner
Pharmacaps, a market leader
in soft gelatin capsule
technology, adding a new
proprietary products and
technology business
Acquisition of IRIX
added North
American API
services
2014
2015
Acquisition of Gallus
BioPharmaceuticals, adding
North American capabilities to
its existing biologics operations
in Groningen, Netherlands and
Brisbane, Australia
PharmSource Report cites Patheon winning
the greatest % of NMEs and non-NMEs
over the last 10 years
Acquisition of Agere
added low solubility
May 25, 2016 | 4
CONFIDENTIAL ©2015 PATHEON®
Single Source Provider, End-to-End
Drug Substance Services
Process Development
and production of active
pharmaceutical ingredients for small
molecule drugs and biologic drug
substances for preclinical studies
through commercialization
May 25, 2016 | 5
CONFIDENTIAL ©2015 PATHEON®
Single Source Provider, End-to-End
Pharmaceutical
Development
Services
Full spectrum of advanced scientific services from discovery to
regulatory approval. Services include formulation development
across approx. 40 dosage forms, analytical services, and life cycle
management.
May 25, 2016 | 6
CONFIDENTIAL ©2015 PATHEON®
Single Source Provider, End-to-End
Drug
Product
Services
Commercial manufacturing, packaging and other support
for marketing prescription, OTC and nutritional products in
a wide range of dosage forms
May 25, 2016 | 7
CONFIDENTIAL ©2015 PATHEON®
Patheon is a Global Service Provider
More than 25 locations across
North America, Europe, Latin America & Australia
Whitby, Canada
Toronto, Canada
Cincinnati, OH USA
Boston, MA USA
Durham, NC USA
High Point, NC USA
Greenville, NC USA
Princeton, NJ USA
St. Louis, MO USA
Bend, OR USA
Florence, SC USA
Greenville SC, USA
Manatí, Puerto Rico
Capua, Italy
Monza, Italy
Ferentino, Italy
Milton Park, UK
Swindon, UK
Bourgoin, France
Groningen, Netherlands
Utrecht, Netherlands
Tilburg, Netherlands
Linz, Austria
Regensburg, Germany
Small Molecule Drug Substance
Large Molecule Drug Substance
Drug Product
As of April 2015
May 25, 2016 | 8
CONFIDENTIAL ©2015 PATHEON®
Tokyo, Japan
Shanghai, China
Brisbane, Australia
Patheon Bourgoin Overview
Pharmaceutical site since 1960’
PATHEON site since1999
May 25, 2016 | 9
Manufacturing Area: 25 250 m2
Employees: 262 (Commercial) + 50 (Development Services)
CONFIDENTIAL ©2015 PATHEON®
Bourgoin Overview
Site authorized and focused on High-potent compounds (up to Cat3B)
PDS (Development) co-located with commercial plant (DPS).
Solid oral dosage forms manufacturing
Compatible processes to allow smooth scale up of solid dose manufacturing
processes from
clinical batches and small commercial batches (1 – 150 kg) to
larger commercial (150 – 750kg) process scales
EU Center of Excellence Packaging: blisters, bottling, sachets
May 25, 2016 | 10
CONFIDENTIAL ©2015 PATHEON®
High Potent Oral Solid Dose Center Of Excellence
Seamless contained development and manufacturing service
- Safely APIs process with a minimum OEB 4 / OELs >10 ng/m3 (Cat 3b)
-Contained processing design concept to minimise the need for PPE (personal protective equipment) for routine
operations. Compliant with Big Pharma HiPo Health-Security-Environment internal rules
- Design-for-manufacture approach enabling reproducibility from development scale (1kg) to commercial scale
EOB 5
EOB 4
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CONFIDENTIAL ©2015 PATHEON®
What is Containment?
Material
Personnel
Containment
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CONFIDENTIAL ©2015 PATHEON®
Environment
Patheon Bourgoin
Filmcoating
Equipments
CONFIDENTIAL ©2015 PATHEON®
October 2015
Contained Film Coating Pan – IMA Perfima LAB (2012)
Interchangeable drums 10L & 70L
Perforated pan
Aqueous or organic solvent coating
1 or 2 spray guns
Glove port for containment
Loading in flexible glove box
Batch size from 2.5 Kg up to 60 Kg
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CONFIDENTIAL ©2015 PATHEON®
Contained Film Coating Pan – IMA Perfima 500 (2015)
Perforated pan
Aqueous coating
6 spray guns
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Glove port for containment
Loading with contained stainless steel tote
Batch size from 200 Kg up to 500 Kg
CONFIDENTIAL ©2015 PATHEON®
Knowledge acquisition with Perfima 500
• May 2015: Delivery of the equipment
• June- July 2015: Qualification QI&QO, QP with existing products
• July 2015, 15th: New High Potent tablet Scale-up start
• July - August2015: 12 Technical batches
• August 2015: 3 Proven acceptable range batches
• September 2015: Pre-validation batch
• October 2015: 2 Technical batches
• December 2015: Second Pre-validation batch
• February 2016: 3 validation batches
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CONFIDENTIAL ©2015 PATHEON®
Hipo Tablet
Process
overview
CONFIDENTIAL ©2015 PATHEON®
Hipo Product Data
• Core tablet:
• 1.1 g weight
• 18 Kp Hardness
• Embossed on 2 sides
• 45% insoluble API
• OEL 1µg/m3
• Coating system:
• Opadry 85F purple and yellow
• Coating amount 3% of tablet weight
• Suspension 20% dry material
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CONFIDENTIAL ©2015 PATHEON®
Scale-up strategy : From Perfima Lab to Perfima 500
The Product Quality on lab scale was perfect in a proven acceptable range defined for
the Perfima Lab 70 liters drum
• Keep thermodynamic conditions (Environmental Equivalency Factor) consistant with
lab scale
• Keep peripheral speed consistant with lab scale
• Keep tablet core temperature consistant with lab scale
• Target spray rate 110 g / min / gun
May 25, 2016 | 19
CONFIDENTIAL ©2015 PATHEON®
Process Parameters for scale-up
Process
Parameters
Inlet Air
67°C
64 °C
61°C
69°C
72°C
66°C
Temperature
Product core
49°C
44°C
39°C
44°C
49°C
39°C
T°C Target
Inlet Air Flow
1050 m³/h 1000 m³/h 950 m³/h 5200 m³/h 4900 m³/h 4600 m³/h
Rate
Nozzle diam. 1,2 mm 1,2 mm 1,2 mm 1.5 mm 1.5 mm 1.5 mm
Atomizing Air
1.6 bar
1,5 bar
1.4 bar
1.9 bar
2.0 bar
1.8 bar
Pressure
Pattern Air
Spraying
1.6 bar
1,5 bar
1.4 bar
1.9 bar
2.0 bar
1.8 bar
Flow Pressure
Suspension
100 g/min 120 g/min 140 g/min 550 g/min 660 g/min 770 g/min
Spray Rate
Suspension
6 kg
6 kg
6 kg
50 kg
50 kg
50 kg
calculated (kg)
Overage
16%
16%
16%
tbd
tbd
tbd
sprayed (%)
Pan Speed
13 rpm
12 rpm
11 rpm
8 rpm
9 rpm
7 rpm
Time
71 min
58 min
50 min
76 min
91 min
66 min
EEF
4,302
3,192
2,422
4,272
3,154
2,382
EEF
Texh. Calculated 56.8 °C
51.3 °C
45.6 °C
61.3 °C
54.6 °C
48.2 °C
Process Step
F
i
l
m
C
o
a
t
i
n
g
Perfima 500HC 650L Perfima 70L - pilot scale
commercial scale
Pan load (tablet cores) : 40kg Pan load (tablet cores) : 335kg
Dry
Target
Wet
Dry
Target
Wet
conditions conditions conditions conditions conditions conditions
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CONFIDENTIAL ©2015 PATHEON®
Batch size Perfima Lab: 40 Kg (Pan load 82%)
Batch size Perfima 500: 335 Kg (Pan load 74%)
Production runs in containment mode:
-No stop during spraying
-No sampling during spraying for Perfima lab
-Sampling with specifically designed tool for
Perfima 500
2.5 bar
Technical batches in Perfima 500
Unexpected coating issue with a high proportion of
appearance defect:
-
Film peeling
-
Chipped core
-
Chipped edge
Nozzle
Coating Coating
diamete Product
color
conditions r (mm)
T° probe
AQL
(number
of
Atomizing Pattern
air
air
Spray
defects
pressure
pressure Pan speed Air flow rate
in 1250
(bar)
(bar)
(spraying) (m3/h) (g/min) tablets)
Type
# Run
Pan
load
(kg)
Active
1
300kg
purple
target
1.5
yes
2.4
2.0
7-8
4900
660
81
Active
2
223kg
purple
wet
1.5
yes
2.3
1.9
7-8
4600
770
108
Active
3
231kg
purple
dry
1.5
yes
2.6
2.1
7-8
5200
550
150
Active
3 bis
234kg
yellow
target
1.5
yes
2.4
2.0
7-8-6
4900
660
Not
tested
Active
4
241kg
purple
target
1.5
no
2.4
2.0
7-8
4900
660
failed
Active
4 bis
241kg
yellow
target
1.2
no
3.5
3.0
7-8
4900
660
failed
Active
5
257kg
purple
target
1.2
no
3.5
3.0
7-8
5500
500
failed
183
19
Active
5 bis
257kg
yellow
target
1.2
no
3.5 - 2.5
3.0 - 2.5
7-6
5500
500 650
Active
6
331kg
yellow
target
1.2
no
2.5
2.5
6
5500
660
May 25, 2016 | 21
CONFIDENTIAL ©2015 PATHEON®
With IMA
And
Colorcon
What’s the problem ?
• The tablet design is poor, as there are 2 preferential
contact points on each side of the tablet
• The peeling appearance defect can be generated
either by abrasion (dry condition) or film removal
during knock on metalic surface(wet condition)
• The chipped tablet is mainly due to a low thickness of
film on the edge (dry condition) and an high speed of
the pan
SCALE EFFECT ISSUE
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CONFIDENTIAL ©2015 PATHEON®
Tablet Bed Temperature Probe: Exagerated Focus
• Change probe depth
NO MEASURABLE
IMPROVEMENT
• Add partial silicone protection
• Add complete silicone protection
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CONFIDENTIAL ©2015 PATHEON®
Inspect Surface of the Pan
• Same design as Perfima Lab
• Several inspections
NO DEFECT ON PAN SURFACE
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CONFIDENTIAL ©2015 PATHEON®
Return to basics
• Find best spray pattern: Test on bench different pressures
• Adapt ramp distance to tablet bed: Check on bench the overlapping (25 cm)
• Balance liquid spray rate per nozzle: Collect liquid per nozzle
• Check generation of foam in preparation tank: Adapt excess of solution
• Perform an appropriate calibration of the pump: Follow IMA SOP
Calibration Perfima 500 / Opadry II 85F 20%
• Minimize abrasion during loading & preheating
800
750
y = 19,827x + 41,99
R² = 0,9998
Amount sprayed per nozzle (g/min)
Liquid
Pressure
(bar)
0,5
0,5
0,7
0,6
0,6
Pump
speed
(rpm)
25
30
35
31,2
31,2
1
89
106
122
110
109
2
88
104
121
108
108
3
90
108
124
111
111
4
89
106
122
110
109
5
90
106
122
110
110
May 25, 2016 | 25
6
91
108
124
111
111
Total spray
rate
(g/min)
537
638
735
660
658
Total spray rate
(g/min)
700
650
600
Total spray rate
(g/min)
550
Lineare (Total spray rate
(g/min))
500
450
400
CONFIDENTIAL ©2015 PATHEON®
20
22
24
26
28
30
Pump speed
(rpm)
32
34
36
Proven acceptable range batches
May 25, 2016 | 26
CONFIDENTIAL ©2015 PATHEON®
First pre-validation batch
• Pre-validation batch pass all specifications
• Is 4% of defective tablets for a validation an
appropriate acceptance quality level ? NO
• How to deal with an 1.5% AQL, with all
thermodynamic parameters allready filed ?
May 25, 2016 | 27
CONFIDENTIAL ©2015 PATHEON®
New technical batches - Second pre-validation batch
CHANGE THE PARADIGM: GOOD PROCESS KNOWLEDGE BEFORE PERFECT CONTAINMENT
•
•
•
•
Shunt the door to able sampling and observation during spraying
Measure all along the process the distance between nozzles and tablet bed
Work as close as possible to cover correctly the tablet (20 - 21 cm)
Correct the process by adapting the distance: Film removal -> +2 cm
BRING THE CHANCE ON YOUR SIDE
• Call IMA and Colorcon for assistance
• Define quick decision process during trials to
correct promptly even if the asistance is important
in the process room (12 people)
May 25, 2016 | 28
CONFIDENTIAL ©2015 PATHEON®
Validation Batches – key parameters
• Pan speed at 5rpm to decrease chipped tablets
• Distance to tablet bed 21 cm during first 45 min
• Distance to tablet bed 23 cm after 45 min
• Spray theoritical amount of coating close to 3.5%
VALIDATION WAS SUCCESFULL WITH NEW APPEARANCE AQL
May 25, 2016 | 29
CONFIDENTIAL ©2015 PATHEON®
Lessons learned
• Scale-up in coating can generate unexpected surprise
• Don’t forget the basics of coating
• IMA and Colorcon experience and expertise are valuable
• Process Knowledge first then work on good containment conditions
• Get QA position sooner
• Don’t file process parameters when the process is still not reliable
May 25, 2016 | 30
CONFIDENTIAL ©2015 PATHEON®