Delivering Biotherapeutics to Patients

Delivering Biotherapeutics to Patients UK-PharmSci 2010 - "The Science of Medicines" East Midland Conference Centre, Nottingham Kevin King 1 September 2010

Overview Points to consider in dosage form development of a biotherapeutic Alternative delivery to differentiate a medicine Case study: pre-filled syringe development for a monoclonal antibody

Overview Points to consider in dosage form development of a biotherapeutic Alternative delivery to differentiate a medicine Case study: pre-filled syringe development for a monoclonal antibody

Points to Consider in BioTx Formulation Clinical and therapeutic needs/requirements Dose, mode/site/duration of action, route of delivery Safe and efficacious Ease of manufacture Molecular Properties Molecular type, Physiochemical properties, PK Stable with suitable shelf life Regulatory requirements Guidelines, specifications, justifications Fileable Marketing Wants! Patent considerations Differentiation, attractiveness Marketable

Overview Points to consider in dosage form development of a biotherapeutic Alternative delivery to differentiate a medicine Case study: pre-filled syringe development for a monoclonal antibody

Industry Trends Driving Alternative Delivery R&D productivity: life cycle management External pressure for value based healthcare: improved compliance with medicines Emerging markets: multiple, culturally diverse markets Personalised medicines: meeting the needs of specific groups Complex diseases: reduced dosing frequency Rise in biotherapeutics: options to IV/IM/SQ

Listening to the Patient. Historically, biologics have been administered parenterally as intravenous or subcutaneous injections, typically in a physician s office or hospital setting Technological innovations have spurred the development of novel delivery approaches (i.e. needle-free, transdermal, inhaled, etc.) Less/non-invasive delivery is an important consideration

Formulation, Dosage and Usage Guides the Device Choices BD HyPak Pre-filled syringes Formulation and Primary Packaging Liquid vs. lyophilized Viscosity Existing vs. new Primary Packaging Dosing Route of administration Frequency Volume Fixed vs. variable Home or Clinic Usage Ease of use Patient compliance Genotropin delivery systems http://www.bd.com/pharmaceuticals/products/bd_hypak.pdf Pre-Filled Syringe Pens/Auto-injectors Reconstitution Aids (Lyo vial) Genotropin delivery systems http://www.genotropin.com/ BioJect Recon Adapters www.bioject.com/products.html

Overview Points to consider in dosage form development of a biotherapeutic Alternative delivery to differentiate a medicine Case study: pre-filled syringe development for a monoclonal antibody

A Few Monoclonal Facts Monoclonal antibodies (mabs) are relatively stable macromolecules mabs are typically administered at high doses Challenging to develop high concentration formulations for mabs to allow for a more patientfriendly route of administration Challenging, but not impossible Need to accommodate in timeline and $ s 10

A Few Monoclonal Facts (continued) SC dosing has lower injection volume requirements Higher the total dose, more challenging it is Ceiling of injection volume means higher protein concentration: potential solubility issues Example: Total dose 100mg, volume 1mL =100mg/ml Doses >/=2-3mg/Kg: new approaches When dose is administered SC need to account for BA Typically 50-80% of IV PD modeling could impact dose Arena for alternate delivery routes is still fairly new and upcoming 11

Challenges Formulation and Stability Concentration dependent degradation route of aggregation is the greatest challenge In addition to the potential for non-native protein aggregation and particulate formation, reversible selfassociation may occur Impact to properties such as Viscosity and Delivery by injection Analytical Chromatographic and electrophoretic assays may not be accurate at high protein concentration Sample dilution may result in non-native matrix effect as well as analytical errors 12

Challenges (continued) Manufacturing Processes to achieve high concentrations at lab-scale may not be scalable for manufacturing Scale-dependant stress factors play an important role Higher viscosity also complicates manufacturing of high protein concentrations by filtration approaches Another important challenge is lack of large quantities of material to conduct adequate screening and formulation development studies Solution? 13

Biologics in Prefilled Syringes Worldwide PFS market size ~1.8 billion units US market growth ~20% per year European market growth ~10% per year Biologics portfolio in prefilled syringes is increasing industrywide Customer Benefits Minimized microbial contamination Reduced medication dosing errors Enhanced convenience and ease of use Market Benefits Reduced therapy and injection costs 2% overfill vs. 23% typical of single does vials Optimized numbers of doses from existing supply 20% API savings vs. vial filling Increased market preference Reference:_http://www.baxterbiopharmasolutions.com/contract_manuf acturing/fill_finish/prefilled_syringes.html

Development Approach Formulation Development Component Selection Analytical Method Development Manufacture/ Supply Chain Liquid formulation developed for vial presentation Need to optimize for syringes Syringe barrel Needle-type Tip-cap Plunger Analytical methods available for formulation. Syringe-specific methods needed to be developed Type of filling Plunger placement Shipping of supplies

Syringe Selection Approach Assortment of PFS components to choose from Barrels: Staked-in needle (SN) vs. Luer tip/lock (LL) Standard vs. Long format Varying volumes Tip-cap/Needle Shield Varying designs Tamper-evident designs Plungers Coated vs. non-coated Packaging format Nested vs. rondo trays

Watch-outs Silicone Necessary for syringe functionality Known to have particulate issues with proteins Tungsten Needed to bore the cavity at syringe tip Residual tungsten could lead to stability issues with biologic molecules Glue In case of SN, needed to hold needle in place Could lead to stability issues with formulation

PFS Selection Workflow Stage 1: Define needs/wants Stage 2. Gather information from vendors Step 3: Compare options by real-time studies Step 4: Ensure communication between vendor and manufacturer

PFS Wish List Minimal to zero silicone on syringe or rubber Baked-on silicone preferred over sprayed-on LL available Staked needle available when silicone is baked on syringe Practically inert stopper to reduce sorptive losses and/or decrease E/L from stopper Compatibility with Tween 20/80 Coated stoppers? When using a staked needle autoclaving is still possible and E/L work is not complicated No particulates or particulate generating syringe system Maintains CCI throughout stability and use period Is simple and easy to fill/process

Answers Requested from Vendors Set of syringes that would meet the typical variety of a large clinical portfolio A set of rubber solutions to cover the typical variety of syringe applications Information on how supplier s offers measure up against our wish-list Other emerging technologies or offerings we may have missed on our wish-list Other reasons why we should select the vendors offerings for our standard solution set Technical & Sales Service Level Expectations If Selected

Vendor comparisons Component Attribute Silicone-free option Vendor A Yes Vendor B No Vendor C No Baked-on silicone (luer tip only) Yes Yes No Sprayed-on silicone Yes Yes Yes Staked-on needle + Baked-on silicone No No Yes All tip-cap options available Yes Yes Yes Coated plungers available Yes Yes Yes Desired packaging format available No Yes Yes Willingness to work with us/manufacturing site to optimize silicone levels for product Yes Yes Yes Prior manufacturing experience at site with vendor(s) Yes Yes No

Plungers and Tip Caps If data in vials available, then see if vendor offers plunger that is comparable to stopper Preservatives in the formulation can Adsorb to the elastomer surface, or Enhance leaching from plunger Many biologic formulations contain surfactants Several examples in literature where surfactants have shown to increase E/L from uncoated rubber stoppers Inert coating may help reduce absorptive losses and/or decrease E/L from the stopper In case where product requires stoppering under special gaseous environment, need to assess permeability of tip-cap for gases

Appropriate Sizing of the Container System Large ratio of available rubber surface area : liquid makes E/L from the elastomers a significant concern Relatively low fill volumes may enhance concentration of E/L in solution

Molecule Considerations PFS presentation has injection volume restrictions What is the efficacious dose(s)? Is the molecule stable at high concentration? Sensitivity to silicone/tungsten/glue? Tendency to form subvisible and visible particulates? Is any special head-space needed? Syringeability considerations?

Formulation Efforts Formulation development for vial presentation was available Goal was to stay with same formulation if possible Injection volume of 1 ml or less was preferred Concentration of vial formulation was sufficient to deliver desired dose in 1 ml Check for container-closure-specific matters: Impact to quality attributes that are specific to the new container closure Difference in process during manufacturing that impact the product attributes Identify process parameters that can be controlled to result in comparable product

Silicone: Friend or Foe? Work with vendor to get average silicone levels per barrel (LT & SN) The dispersion of free silicone can be observed by coating the glass surface with silicon carbide powder The sprayed syringe has greater amounts of free silicone Silicone oil droplets are visible in formulations extracted from syringes using light microscopy. Silicone extraction can also be performed

Silicone Spiking Studies Use worse-case scenario to define 1x levels Silicone Spiking study: Formulations in vials spiked with 1x, 2x and 3x amount of silicone present in SN barrel 4 Visual appearance results 3 2 1 0 1 X Silicone Level 2 X Silicone Level 3 X Silicone Level 1 3 6 9 12 1 3 6 9 12 Also conducted a shaking stress study at the silicone spiking levels 300 rpm on orbital shaker No particle formation seen at 5 o C or 25 o C for up to 5 days Months at 5 o C Months at 25 o C

Stability Data from Formulation in PFS Majority of product quality attributes remain unchanged between vial and PFS Only differences seen in particulate matter Visible Sub-visible How to ensure that you are seeing the full picture? Reference:http://www.learningpage.com/i mages/clipart/zoo_animals/images/lp_za_f f_img02_elephant.gif

Silicone Oil and Sub-Visible Particles Sub-visible particulate matter data obtained after formulations in PFS were subjected to shaking stress 35 Cummulative Particles Cummulative Particles 30 25 20 15 10 5 450 0 400 350 300 250 200 150 10 0 50 Baked-on Si: 1 ml f ill Baked-on Si: 0.5 ml fill Sprayed-on Si: 1 ml fill Sprayed-on Si: 0.5 ml fill Baked-on Si: Placebo Particles < 25µm Sprayed-on Si: Placebo Particles < 10µm T0 24hr 168hr USP Criteria: <6000 10um particles/container <600 25um particles/container T0 24hr 168hr 0 Baked-on Si: 1 ml fill Baked-on Si: 0.5 ml fill Sprayed-on Si: 1 ml fill Sprayed-on Si: 0.5 ml fill Baked-on Si: Placebo Sprayed-on Si: Placebo PFS-type & Fill volume No significant trends or differences between formulations for SN and LL PFS

Silicone oil and Sub-visible Particles (contd.) Sub-visible particulate matter data obtained after formulations in PFS were subjected to real time stability study at 5 and 25 o C 25C data indicates particles that are TNTC even at the 3 month time-point HIAC Measurements for SN PFS Formulation at 2-8 o C Cumulative Counts per ml 16000 14000 12000 10000 8000 6000 4000 2000 0 T= 0 T=3M T=6M 1.5 2 5 8 10 25 Particle Size Channel (µm)

Visualization of Particles by Light Microscopy Few samples were examined by light microscopy to determine: Nature of the particles causing opalescence Cause of HIAC sensor saturation 100x magnification 100x magnification Too many silicone oil droplets Single amorphous particle (protein?) Oil droplets range from 1 20 µm in diameter

Selection of Tip Cap/Needle Shield Although tip cap/needle shield materials are less prone to product contact, it is important to choose the appropriate material. Accelerated stability for the product in contact with material can enhance the understanding and can help to choose the appropriate component % Oxidation 9 7 5 3 Data at 25 C 0 1 2 3 4 5 6 7 Time (months) Tip Cap 3 was chosen for the product. Control Tip cap 1 Tip cap 2 Tip cap 3 In addition, cracking of tip cap formulation should be evaluated under normal environmental conditions

Plunger Movement Concerns for PFS Filled syringes are transported to labeling/packaging sites, clinics, distribution centers, pharmacies, etc Due to a silicone coating in the barrel, there is less friction and the stopper is able to move Plungers can move in pre-filled syringes due to external/internal pressure changes and pressure changes can occur during Air shipment of syringes Travel through high elevation regions Temperature changes Product sterility could be affected if the plunger moves past the second rib of the stopper* (> 5 mm) Product contact 2 nd Rib Barrel Plunger Rod Stopper Tip Cap Reference: Stopper (plunger) movement in syringe systems by Jerome Olivas in PDA conference 2006

Challenges to be Addressed As part of product development in syringes, a systematic study was designed to address following questions: Does the plunger move during air transport? How much does the plunger move? Will the plunger come out of the barrel? What is the impact of sterility as well as container closure integrity of a PFS system? What is the effect of the stoppering method (gap)? Is there a difference between sprayed vs. baked on silicone? Staked in needle vs. luer cone syringes Is the movement consistent between various fill volumes? Do we need to design a packaging system which can minimize plunger movement? 5 mm

Transportation and Pressure Effects Cargo aircraft Used in most situations Regulated to the same altitude and temperature as commercial aircraft 7,500-8,000 ft and 20-23 C Cargo Aircraft Feeder aircraft Feeder Aircraft May not be pressurized if cabin has oxygen Maximum flying altitude of 20,000 ft Altitude Above Sea Level (feet) 7,000 10,000 15,000 20,000 25,000 30,000 35,000 40,000 Absolute Atmospheric Pressure (Torr) 586 522 429 350 282 226 179 141 Max altitude (20,000 ft) = 350 Torr = Worst Case Pressure

Effect of Stoppering Methods on Air Gap Mechanical stopper placement through insertion tube Stopper is compressed in a narrow tube and placed at a predetermined distance through the use of mechanical plungers Typically results in larger gap Vacuum Stoppering Filled syringes are placed into a unit where a vacuum is applied to place the plungers Results in minimal gap of < 1 mm Vacuum Mechanical Gap 0-1 mm

Development of a Lab Scale Model LyoStar II (FTS Smart Lyophilizer) used as a pressure & temperature chamber to simulate various environments Syringes placed in an upright position near a metric ruler Photographs taken to document movement Pressure cycle simulates 2 flights Variables Fill volume 0.4 ml and 1 ml Temperature 5 C and 25 C Pressure ATM (760 Torr) ~300 Torr ATM (760 Torr) Hold Time N/A 18 hours 8 hours Syringe type ~300 Torr 18 hours LC and SN ATM (760 Torr) Minimum of 2 hours Gap 0-1 mm, 1-2 mm, 3-4 mm, and 5-6 mm

Development of a Lab Scale Model Feasibility of the use of powder coatings to detect plunger movement Initial positions At 2 Torr Carbon Black Si Carbide Gold Carbon Black Si Carbide Gold Final positions Carbon Black Si Carbide Gold

Effect of Air Gap Amount LC PFS with 1 ml fill (4 gaps) 540 Torr: movement begins 415 Torr: some PFS with 5-6 mm gaps have moved past the 2nd rib 320 Torr: PFS with gaps >3 mm have moved past the 2nd rib 760 Torr: stoppers return to initial position

Impact of Air Gap on Plunger Movement The linear relationship between gap and plunger movement at various pressures tested can be used to estimate movement 7 Air Gap vs. Plunger Movement Agerage Plunger Movement (mm) 6 5 4 3 2 1 540 Torr 415 Torr 320 Torr y = 1.0764x + 0.1745 y = 0.5382x + 0.0873 y = 0.3527x - 0.0509 Movement past the 2 nd rib of stopper 0 0 1 2 3 4 5 6 Average Air Gap (mm)

Key Take-Away Messages Choice of container closure can impact quality attributes of product Define user requirements early in the program Work with Procurement and Manufacturing to narrow down on component vendors Vendors are in the R&D business as well, and are looking at ways to offer products with better fit You d be surprised at their willingness to work with you! Remember Less is more and Keep it Simple If re-formulating a vial product to PFS, need to minimize changes to the formulation

Key Take-Away Messages Increasing number of contact materials increases risks Staked-on needle vs. Luer tip barrel Silicone is required for syringe functionality Some vendors offer silicone-free options Optimize silicone levels to balance product quality vs. functionality Consider sub-visible particulate analysis as a key assay for selection Monitor the lower size ranges (less than 2, 5, 8 µm) Early discussions with Commercial group helps define user requirements Assessment needed to balance needs vs. risks

Key Take-Away Messages Work with Supply Chain and Packaging group to identify transport routes Verify container closure integrity during transportation Theoretical equations and models available to calculate plunger movement Experimental approaches are not too difficult to setup in a typical formulation laboratory

Road Map of Available Drug Delivery Technologies: 10 yr Outlook Based on Current Information Low MW (<5kDa) Medium MW (5 50kDa) High MW (>50kDa) Delivery Modality Low Dose (<10 mg) Medium Dose (10-30mg) Low Dose (<10mg) Medium Dose (10-30mg) Low Dose (<10mg) Medium Dose (10-30mg) IV/SC (Immediate Release) Now Now Now Now Now Now Depot Injection Now Now Now Now Now 3-5 years Pulmonary Now 3-5 years 2-3 years 3-5 years 3-5 years Unlikely Transdermal 2-3 years Unlikely 2-3 years Unlikely 2-3 years Unlikely Transmucosal 2-3 years >5 years 2-3 years >5 years 3-5 years Unlikely Oral >5 years >5 years >5 years >10 years >5 years >10 years Technology available, but some not optimized Significant technology development required Existing technology options unlikely to delivery

Alternate Delivery Modalities What will future BioTx drug products look like? 45

Overview Points to consider in dosage form development of a biotherapeutic Alternative delivery to differentiate a medicine Case study: pre-filled syringe development for a monoclonal antibody

Acknowledgements Advait Badkar Leigh Bohack Tapan Das Sambit Kar Parag Kolhe Sandeep Nema Vinay Radhakrishnan Amanda Wolf