Liraglutide Injectable Device-Drug Case Study

Edition 1 / March 2020

Author
Umberto Romeo
R&D Manager, CordenPharma Caponago

Liraglutide Injectable Drug-Device Combination Product: A Case Study

Analytical Chemist performs analytical method development on a UPLC in CordenPharma Caponago’s new R&D Lab, which supports the CMC development of a broad range of molecule types (small molecules, mABs, fABs, peptides, oligos etc.) from early clinical stage to commercialization.

At CordenPharma, we believe that our vertically-integrated supply chain model provides development and manufacturing expertise spanning the complete GMP supply chain. Our extensive infrastructure expands the supply chain with cGMP starting materials, API manufacturing, commercial-scale Drug Products (including Finished Dosage Formulation), and Pharma Packaging & Logistics. This model benefits customers in terms of reduced development and manufacturing time and cost. As a demonstration of our fully-integrated supply chain expertise, we would like to highlight a recent case study developed in our CordenPharma Caponago facility on the Injectable Drug-Device Combination Product Liraglutide.

Liraglutide, sold under the brand name Victoza^® among others, is a medication used to treat diabetes mellitus type 2 and obesity. It is a fragment (see Figure 1) of the naturally occurring human glucagon-like peptide-1 sequence position 7-37, with 97% homology and a lipophilic substituent for the prolongation of half-life. It is a modified polypeptide of 31 amino acid residues with a covalent linkage at the γ-position of N-palmitoylglutamic acid to the ε-amino group of Lys.

Liraglutide reduces meal-related hyperglycemia (for 24 hours after administration) by increasing insulin secretion (only) when required by the increase of glucose levels, thus delaying gastric emptying, and suppressing prandial glucagon secretion. It is a multi-dose parenteral drug-device combination product, filled in a 3 mL glass cartridge, and assembled into an Auto-Injector.

Specifically, Liraglutide makes for an excellent example of our capabilities to provide an integrated supply solution, where the API is manufactured under our Peptides, Lipids & Carbohydrates Platform (CordenPharma Brussels & CordenPharma Colorado), while the Drug Product is ideally suited for our Injectables Platform (CordenPharma Caponago).

CordenPharma Caponago’s Injectable manufacturing capacity covers both Terminal Sterilization and Aseptic Filling Technologies for Pre-filled Syringes (PFS), vials, ampoules and lyophilized vials, with a wide range of filling volumes (Aseptic from 0.5 to 10 ml fill volume; Terminally Sterilized from 5 to 100 ml). With multiple process and filling lines, and an overall annual capacity of ~100 million units, the Injectable Platform offers the flexibility to support multiple programs and customers (> 100 markets) in parallel, at any scale and stage of drug development & commercialization.

In this case study, we will focus on the Drug Product component of the project and in particular, the CMC development of this drug.

Liraglutide Injectable Drug Product Case Study

The drug product development project started with an initial risk assessment to identify all the development-associated risk factors, along with potential mitigation strategies. In the laboratory, initial work began on the development of appropriate stability, indicating analytical methods that would enable the assessment of the formulation trials. As would be expected, these drug product methods used the API methods as a starting point, but were then further refined and developed to engineer appropriate robust drug product methods. The final stage of the development scoping activities was to obtain the Reference Listed Drug (RLD) of Victoza^® and conduct a de-formulation exercise to create the target profile for the development studies.

The formulation strategy was based on the evaluation of the formulation robustness. According to the International Conference on Harmonization Q8 (R2), critical formulation attributes and process parameters are generally identified through an assessment of the extent to which their variation can impact the quality of the drug product, which can then inform the need to assess the robustness of a formulation. A multivariate formulation robustness study was performed to demonstrate acceptable quality at the target composition, as well as at the edges of the allowable composition ranges.

• >> In this case study the edges of allowable composition ranges were determined by referencing the FDA’s Q1/Q2 requirements (21 CFR 314.94 (a)(9)(iii) – i.e. inactive ingredient changes permitted in drug products intended for parenteral use) for generic parenteral drug products.
• >> In fact, a generic drug product intended for parenteral use must contain the same inactive ingredients (Q1) and in the same concentration (Q2) as the RLD. According to some FDA assessors’ recommendations, the difference in the quantitative composition between the RLD and the generic drug should not exceed 5%.
• >> CordenPharma designed a robustness study based on a Design of Experiment (DoE) approach. Design of experiments is a systematic approach to understand how material attributes, process, & product parameters affect process outcomes with a limited number of experiments, using statistic tools.
• >> Through the support of the statistical software Minitab 17, a Full Factorial DoE with 1 block, 1 replicate for each run, and 3 center point replicates was created as shown in Figure 2:

• >> This design can estimate only linear effects (no square effects), with no confounding, meaning all linear main effects & interactions.
• >> Figure 3 reports a summary of all the formulation prepared to support the DoE. For confidentiality reasons, the actual values and final results of the study won’t be reported.

• >> All 19 formulations were put through stability studies for 6 months at two conditions (storage and accelerated stability).
• >> The data collected supported the selection of the target formulation we submitted to industrialization for scale-up to the commercial manufacturing line.
• >> Because CordenPharma Caponago’s cartridge & Pre-Filled Syringe filling line is based on Nest & Tub ready-to-fill technology, three technical (engineering batches) batches were manufactured, enabling the identification of the Critical & Key process parameters, along with the process NORs (Normal Operating Ranges) and PARs (Proven Acceptable Ranges). This confirmed the final commercial manufacturing process.
• >> In conclusion, the identified process will be used to manufacture the registration batches required for the ANDA submission of the generic Liraglutide.