Packaging of Biotech Drug Products: Challenges and Innovative Solutions Annalisa Delnevo – Research Pharma Odra Pinato – SG Lab Analytics Milan, October 25th 2017
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Packaging of Biotech Drug Products: Challenges and Innovative Solutions
Annalisa Delnevo – Research Pharma Odra Pinato – SG Lab Analytics
Milan, October 25th 2017
2 | Strictly Confidential
STEVANATO GROUP
Stevanato is a worldwide producer of high
quality cGMP manufactured solutions for
the healthcare industry.
• Privately held multi-national
conglomerate (HQ Padova, Italy)
• Vertically integrated manufacturer
• Supports primary & secondary pharma
packaging and offers fully integrated
turnkey device solutions.
3 | Strictly Confidential
STEVANATO GROUP: THE STRUCTURE
PHARMACEUTICAL SYSTEMS
ENGINEERING SYSTEMS
GLASS PROCESSING
PHARMA INSPECTION
SYSTEMS
ASSEMBLY & PACKAGING
GLASS PRIMARY
PACKAGING
SPECIALTY PLASTICS &
DELIVERY DEVICES
4 | 2015 | Strictly Confidential
STEVANATO GROUP: MAIN MILESTONES
STEVANATO GROUP
OMPI Foundation
1949
SPAMI Foundation
EZ-FILL VIALS & CARTRIDGES New Sterile Department
1971 BRATISLAVA PLANT Medical Glass Acquisition
LATINA PLANT Alfamatic Acquisition
OPTREL Acquisition
EZ-FILL SYRINGE Sterile Department
MONTERREY PLANT Opening
MONTERREY PLANT Doubling
ZHANGJIAGANG PLANT Foundation stone
INNOSCAN Acquisition
SVM Acquisition
EZ-FILL SYRINGES New Sterile Department
SETE LAGOAS PLANT Foundation Stone
2012 2014 2010 1993
2016
2007
2011 2005 2008 2013
BALDA Acquisition
5
STEVANATO GROUP TODAY
Brabrand
Monterrey
Bratislava
Zhangjiagang
Piombino Dese
Latina
Piombino Dese
Piombino Dese
Newtown, PA | Sales Office
Piombino Dese | Headquarters
Zhangjiagang | Sales Office
Sete Lagoas | Sales Office (plant under construction)
Silkeborg
Bad Oeynhausen
Oceanside Ontario Anaheim
Timisoara
6
OMPI PRODUCT PORTFOLIO
Glass Primary Packaging Supplier & Engineering Systems and Services
One-stop solutions for Drug-Delivery-Systems
YESTERDAY TODAY AND TOMORROW
7 Fully automatic control machine
1. GLASS TUBE
LOADER 2. GLASS
PROCESSING
3. AFTERFORMING
LINE
4. ANNEALING OVEN
6. FINAL PACKING 5. COSMETIC CONTROL
PRODUCTION LINE
8
BIOPHARMACEUTICALS: UN-CONVENTIONAL DRUGS
Acetylsalicylic acid mAb !!!
SMALL MOLECULE DRUGS BIOLOGICAL DRUGS
SIZE • Small (single molecule) Low molecular weight
Large (mixture of related molecules) High molecular weight
STRUCTURE Simple, well defined, independent of manufacturing process
Complex (heterogeneous), defined by the exact manufacturing process
MODIFICATION Well defined Many options
MANUFACTURING • Produced by chemical synthesis • Predictable chemical process • Identical copy can be made
• Produced in living cell culture; • Difficult to control from starting material to final
API; • Impossible to ensure identical copy
CHARACTERISATION Easy to characterize Cannot be characterized completely the molecular composition and heterogeneity
STABILITY Stable Unstable, sensitive to external conditions
IMMUNOGENICITY Mostly non-immunogenic Immunogenic
9
BIOPHARMACEUTICALS: UN-CONVENTIONAL DRUGS
Ø Protein Structure–Activity relationship is a milestone of biopharmaceutics;
Ø Needs to ensure and maintain the stability of these complex molecules:
Ø Exposition to a variety of interfaces throughout the DP life cycle à during transportation and storage, up to the delivery to the patients;
Ø Primary packaging is definitely considered one of the interface systems that deeply contributes to the biopharmaceutical stability, safety and efficacy.
10
As noted by FDA's Container Closure Systems guidance: Every packaging system should be shown to be suitable for its intended use: 1. .Protect the dosage form; 2. .Compatible with the dosage form; 3. .Be composed of materials that are considered safe for use and the route of
administration; 4. .If the packaging system has a performance feature in addition to containing the
product, the assembled container closure system should be shown to function properly.
CONTAINER CLOSURE SYSTEM SUITABILITY ASSESSMENT
11
OUR GLASS PRODUCT PORTFOLIO
Vials Syringes Cartridges Ampoules Special product
Ready to Use Vials
Ready to Use
Syringes
Ready to Use
Cartridges
Non sterile Container
Different complexity rate of the container closure system
12
CONTAINER CLOSURE SYSTEM: VIALS VS SYRINGES
13
CCS & BIOPHARMACEUTICALS: LITERATURE
14
PROTEIN STABILITY ENEMIES IN CONTAINER CLOSURE SYSTEM
Bee J., et al. Effects of surfaces and leachables on the stability of biopharmaceuticals. J pharm Sci. 2011. 100, 4158-4170.
Absorption at Contact Surfaces: Liquid/Solid & Liquid/Air
Reaction/binding with Leachables from CCS components
à Chemical modification (oxidation, deamidation)
à Physical modification (agggregation, precipitation, particles, etc)
à Loss/reduction of potency
à Immunogenicity
Stability, Safety and Efficacy are not guaranteed!
15
Mechanisms of protein aggregation, particles formation and protein damage:
q Leaching of Silicone oil droplets;
q Leachables from CCS components (glass, plastic, rubber, stainless steel, tungsten, adhesive etc.)
LEACHABLES FROM CCS COMPONENTS
Reaction/binding with Leachables from CCS components
LEACHABLES DO migrate in the DP: Organic & Inorganic chemical entities that migrate from packaging system into a DP under normal condition of storage and use or during accelerated stability studies
EXTRACTABLES CAN migrate in the DP: Organic & Inorganic chemical entities that can be released from packaging system into a DP under laboratory condition may accelerate or exaggerate the normal condition of storage and use.
Ex
L
16
LEACHING OF SILICONE OIL DROPLETS: CCS VS. PROTEIN INCOMPATIBILITY
q Syringe and Cartridge barrels are coated with silicone oil: q to facilitate smooth movement of plunger;
q Silicone oil treatment can lead to droplets of silicone oil suspended in DP;
q Protein adsorption to wall and droplet can result in particles with aggregated protein.
17
SILICONE OIL-INDUCED VISIBLE PARTICULATE FORMATION
0 hr 72 hr
High Silicone Oil Concentration
Low Silicone Oil Concentration
High Silicone Oil Concentration
Low Silicone Oil Concentration
Lysozyme Formulations (pH 7.5, phosphate buffer) à Spiked with Silicone Oil
18
EPREX: HOW LEACHABLES CAN AFFECT BIOPHARMACEUTICAL SAFETY AND EFFICACY
q During the period of 1998 to 2002, there was an increase in the incidence of antibody-positive pure red cell aplasia (PRCA) in patients receiving subcutaneous administration of EPREX (epoietin alfa).
q The aqueous formulation containing polysorbate 80, introduced in 1998, facilitated the leaching of small-molecule, aromatic compounds from the uncoated rubber syringe plunger.
q Interaction between the extractables from the elastomeric syringe plunger and the drug product formulation caused the adverse event of pure red cell aplasia in certain patients.
q The resolution for this issue was a move to a barrier-coated plunger to minimize migration of extractables into the drug product.
19 | 2015 | Strictly Confidential
CONTAINER CLOSURE SYSTEM: OUR APPROACH
CONTAINER QUALITY
MONITORING
Set analytical methods to measure what is critical
for container functionality
MANUFACTURING
Transform needs in product with the right process: i.e. low-Tungsten, Silicone, EZ-Fill, …
360° DESIGN THE RIGHT CONTAINER
Take care about biotech drug & Pharma needs
HELP CUSTOMER
to understand containers interaction with drug
20 | 2015 | Strictly Confidential
CONTAINER CLOSURE SYSTEM: OUR APPROACH
QUALITY MONITORING
Measure and check the critical to quality
parameters
MANUFACTURING
Transform needs in product with the complete set of competences available in Stevanato Group
360° DESIGN THE RIGHT DRUG DELIVERY
SYSTEM
Take care about delivery system specifications
HELP CUSTOMER
to improve a drug delivery device
21
OUR CONTRIBUTION TODAY …
NEW COATING GOALS: q Particles reduction
q Reduced E&L
22
0
20000
40000
60000
80000
100000
120000
140000
Std Syringes HQ Syringes ALBA syringes
1-2 µm
2-5 µm
5-10 µm
10-25 µm
25-50 µm
• All the three Types of
syringes are inside the USP788 requirements
• Significant particles reduction for the Alba syringes
• Alba solution answers to the requirements of low particles making the syringe compliant with USP789
2243
1205
122 26 5
0
500
1000
1500
2000
2500 1-2 µm
2-5 µm
5-10 µm
10-25 µm
25-50 µm
1. Fill the syringes with 1,3mL of filtered (0,22µm) and distilled water
2. Cap the syringes with aluminum foil
3. Put the syringes inside the autoclave (1h at 121°C)
4. Analyze the extracts with the MFI 5200 series
Methodology Description*
Comments
Con
cent
ratio
n (#
/mL)
Con
cent
ratio
n (#
/mL)
Ompi Alba | Syringes
*Test method development and analysis by SGlab
10
ALBA SYRINGES – PARTICLES RESULTS
23
homogeneous coating distribution for Alba syringes
1. Empty the syringes 2. Analyze the syringes by Rap-id
Layer Explorer
Methodology Description*
Comments
15
Alba syringes Syringes siliconized with
a not optimized process
Col
orim
etric
sca
le (n
m)
Biotech syringes
*Analysis by SGlab
ALBA SYRINGES - COATING LAYER AND DISTRIBUTION
24
homogeneous coating distribution for Alba syringes
guaranteeing the same thickness along the entire
surface
1. Empty the syringes 2. Analyze the syringes by Rap-id
Layer Explorer
Methodology Description*
Comments
16
Thic
knes
s (n
m)
Length (mm)
Syringes siliconized with a not optimized process – Silicone profile
0
100
200
300
400
0 10 20 30 40 50 0
100 200 300 400 500 600 700 800
0 10 20 30 40 50
Thic
knes
s (n
m)
Length (mm)
Biotech syringes – Silicone profile
0 100 200 300 400 500 600 700 800
0 10 20 30 40 50
ALBA syringes – Coating profile
Length (mm) Th
ickn
ess
(nm
) *Analysis by SGlab
ALBA SYRINGES - COATING LAYER AND DISTRIBUTION
25
TAKE HOME MESSAGES
Drug primary packaging is not a background decision to take just before the market launch:
the rationalized selection of the proper container
closures system can make the difference in terms of drug stability, safety and efficacy.
Drug delivery is fundamental feature to take care:
the best drug with poor delivery will result, in the best case, in inefficacy of therapy.
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