Enablement of Accurate Dose Administration for a Pre-Filled Syringe Drug Product Pooja Arora, Jennifer Johns, Samantha Citron

and Rajesh Gandhi Drug Product Science and Technology Bristol Myers Squibb, New Brunswick, NJ

Objective, Challenges and Strategy

Objective: To enable a clinical presentation of a single use glass PFS with acceptable accuracy for dose delivery Challenges Achieving acceptable accuracy for delivering low dose (g range) Lack of precedence in Biopharma industry to ensure required level of suitability for the graduation of glass PFS delivery device Establish acceptable specifications based upon drugs safety and efficacy profile Implementation Strategy Determine the fill volume based upon label claim dose and end user instructions Identify the factors that result in dose variability, and ways to mitigate Develop, validate and verify a robust and reproducible method for precision labeling to ensure reliable dose delivery

4. Evaluate Precision Labeling for Placing Graduation Lines

1. Determined specifications for label placement on glass barrel 2. Identified a reliable reference point in the syringe 3. Determined an allowed variation in label placement based upon factors listed in Section 3 4. Developed a method for evaluating placement of graduation lines on barrel
A B C D

Identification of New Reference Point

1. 2. 3. 4. 5. Reference point identified as bottom of the barrel Syringes were prepared by expelling air bubble Distance measured between the Reference point and stopper front edge (h) Solution expelled and weighed to determine delivered volume Determine the correlation between distance and delivered volume 6. Ensured that Reference point can be accurately and reproducibly identified during the labeling operation
h

5. Identification of Reference Point

1. Initially selected point on the shoulder where the tangent of the radius of the shoulder meets the syringe body 2. 3. Based upon input from the syringe manufacturer Distance determined between stopper front edge and Reference Point for known delivered solution volume 4. Excellent correlation between theoretical and experimental data

6. Method Development for Label Placement

1. Fill Volume Determination for the PFS Presentation

(1) Determine the amount of product lost during bubble expulsion using a user study with representative subjects (2) Evaluate hold up volume in syringe based upon comparison of solution added and expelled from the syringe (3) Determine filler variability for the target fill volume Final target fill volume = label claim dose + (1) + (2) + (3)

Excellent linear correlation between delivered volume and distance Used to back-calculate the distances for clinical label claim delivered doses

2. Identify Variables Impacting Dose Delivered Variability

Protein Concentration Variation in label printing and placement Syringe Dimensions/Geometry ID, solution column height, shoulder variability, etc. adjustment Cumulative variability was compared to the maximum allowed variation based upon products safety and efficacy profile Syringe preparation by the end user that requires bubble expulsion and dose

7. Confirmation of Acceptable Precision Labeling

100% inspection of the labeled syringes ensured acceptable specifications Cross-validation of labeled syringes Using proper instructions, labeled syringes were prepared by multiple users for all target doses Less than 5% difference between experimental and target delivered volumes

Conclusions Challenges Associated with Selected Reference Point

Enabled design and implementation of a clinical presentation with acceptable dose delivery specifications 1. Significant variability based upon syringe geometry 2. Cannot be reliably detected for multiple syringe lots 3. Necessitated identification of a new reference point Via precision labeling to place graduation lines on syringe barrel to be used as a reference point during dose adjustment procedure for the end users Developed an innovative method to enable accurate dose administration for a variable dose prefilled syringe product Method and specifications were successfully developed, transferred, and validated collective successful outcome Collaboration with several internal and external functional areas is the key for a

3. Implement Strategies to Minimize Variability Factors

1. Utilized tighter internal analytical specifications for protein concentration 2. Collaborated with Clinical Supply and Co-packer to develop a method for minimization of label printing variability 3. Changed container closure to result in tighter dimensional controls 4. Based upon outcomes and observation from the user study, developed detailed IFU and training video
Note: The data in linear plots have been numerically scaled by a constant factor