Packaging of Biotech Drug Products: Challenges and Innovative Solutions. Annalisa Delnevo Research Pharma Odra Pinato SG Lab Analytics

Transcription

1 Packaging of Biotech Drug Products: Challenges and Innovative Solutions Annalisa Delnevo Research Pharma Odra Pinato SG Lab Analytics Milan, October 25th 2017

2 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. Strictly Confidential 2

3 STEVANATO GROUP: THE STRUCTURE PHARMACEUTICAL SYSTEMS ENGINEERING SYSTEMS GLASS PRIMARY PACKAGING SPECIALTY PLASTICS & DELIVERY DEVICES GLASS PROCESSING PHARMA INSPECTION SYSTEMS ASSEMBLY & PACKAGING Strictly Confidential 3

4 STEVANATO GROUP: MAIN MILESTONES SPAMI Foundation BRATISLAVA PLANT Medical Glass Acquisition MONTERREY PLANT Opening MONTERREY PLANT Doubling INNOSCAN Acquisition SVM Acquisition SETE LAGOAS PLANT Foundation Stone BALDA Acquisition STEVANATO GROUP LATINA PLANT Alfamatic Acquisition OPTREL Acquisition EZ-FILL VIALS & CARTRIDGES New Sterile Department ZHANGJIAGANG PLANT Foundation stone EZ-FILL SYRINGES New Sterile Department OMPI Foundation EZ-FILL SYRINGE Sterile Department 2015 Strictly Confidential 4

5 STEVANATO GROUP TODAY Bad Oeynhausen Newtown, PA Sales Office Brabrand Bratislava Oceanside Ontario Anaheim Silkeborg Timisoara Piombino Dese Piombino Dese Monterrey Zhangjiagang Piombino Dese Latina Zhangjiagang Sales Office Sete Lagoas Sales Office (plant under construction) Piombino Dese Headquarters 5

6 OMPI PRODUCT PORTFOLIO YESTERDAY TODAY AND TOMORROW Glass Primary Packaging Supplier & Engineering Systems and Services One-stop solutions for Drug-Delivery- Systems 6

7 PRODUCTION LINE 5. COSMETIC CONTROL 6. FINAL PACKING 1. GLASS TUBE LOADER 2. GLASS PROCESSING 4. ANNEALING OVEN 3. AFTERFORMING LINE Fully automatic control machine 7

8 BIOPHARMACEUTICALS: UN-CONVENTIONAL DRUGS SIZE STRUCTURE SMALL MOLECULE DRUGS Small (single molecule) Low molecular weight Simple, well defined, independent of manufacturing process BIOLOGICAL DRUGS Large (mixture of related molecules) High molecular weight Complex (heterogeneous), defined by the exact manufacturing process MODIFICATION Well defined Many options MANUFACTURING CHARACTERISATION Produced by chemical synthesis Predictable chemical process Identical copy can be made Easy to characterize Produced in living cell culture; Difficult to control from starting material to final API; Impossible to ensure identical copy Cannot be characterized completely the molecular composition and heterogeneity STABILITY Stable Unstable, sensitive to external conditions IMMUNOGENICITY Mostly non-immunogenic Immunogenic Acetylsalicylic acid!!! mab 8

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. 9

10 CONTAINER CLOSURE SYSTEM SUITABILITY ASSESSMENT 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. 10

11 OUR GLASS PRODUCT PORTFOLIO Non sterile Container Ampoules Vials Syringes Cartridges Special product Ready to Use Vials Ready to Use Syringes Ready to Use Cartridges Different complexity rate of the container closure system 11

12 CONTAINER CLOSURE SYSTEM: VIALS VS SYRINGES 12

13 CCS & BIOPHARMACEUTICALS: LITERATURE 13

14 PROTEIN STABILITY ENEMIES IN CONTAINER CLOSURE SYSTEM 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! Bee J., et al. Effects of surfaces and leachables on the stability of biopharmaceuticals. J pharm Sci ,

15 LEACHABLES FROM CCS COMPONENTS 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 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 Mechanisms of protein aggregation, particles formation and protein damage: q q Reaction/binding with Leachables from CCS components Leaching of Silicone oil droplets; Leachables from CCS components (glass, plastic, rubber, stainless steel, tungsten, adhesive etc.) 15

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. 16

17 SILICONE OIL-INDUCED VISIBLE PARTICULATE FORMATION Lysozyme Formulations (ph 7.5, phosphate buffer) à Spiked with Silicone Oil High Silicone Oil Concentration Low Silicone Oil Concentration High Silicone Oil Concentration Low Silicone Oil Concentration 0 hr 72 hr 17

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 antibodypositive 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. 18

19 CONTAINER CLOSURE SYSTEM: OUR APPROACH HELP CUSTOMER to understand containers interaction with drug CONTAINER QUALITY MONITORING Set analytical methods to measure what is critical for container functionality 360 DESIGN THE RIGHT CONTAINER Take care about biotech drug & Pharma needs 2015 Strictly Confidential MANUFACTURING Transform needs in product with the right process: i.e. low-tungsten, Silicone, EZ-Fill, 19

20 CONTAINER CLOSURE SYSTEM: OUR APPROACH HELP CUSTOMER to improve a drug delivery device QUALITY MONITORING Measure and check the critical to quality parameters 360 DESIGN THE RIGHT DRUG DELIVERY SYSTEM Take care about delivery system specifications 2015 Strictly Confidential MANUFACTURING Transform needs in product with the complete set of competences available in Stevanato Group 20

21 OUR CONTRIBUTION TODAY NEW COATING GOALS: q Particles reduction q Reduced E&L 21

22 ALBA SYRINGES PARTICLES RESULTS Ompi Alba Syringes Methodology Description* 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 Comments Concentration (#/ml) µm 2-5 µm 5-10 µm µm µm Concentration (#/ml) µm 2-5 µm 5-10 µm µm 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 0 Std Syringes HQ Syringes ALBA syringes *Test method development and analysis by SGlab 22 10

23 ALBA SYRINGES - COATING LAYER AND DISTRIBUTION Methodology Description* Syringes siliconized with a not optimized process Biotech syringes Alba syringes 1. Empty the syringes 2. Analyze the syringes by Rap-id Layer Explorer Comments Colorimetric scale (nm) homogeneous coating distribution for Alba syringes *Analysis by SGlab 23 15

24 ALBA SYRINGES - COATING LAYER AND DISTRIBUTION Methodology Description* 1. Empty the syringes 2. Analyze the syringes by Rap-id Layer Explorer Thickness (nm) Syringes siliconized with a not optimized process Silicone profile Length (mm) Thickness (nm) Biotech syringes Silicone profile Length (mm) Comments homogeneous coating distribution for Alba syringes guaranteeing the same thickness along the entire surface *Analysis by SGlab Thickness (nm) ALBA syringes Coating profile Length (mm) 24 16

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. 25

26 Thanks for your attention