2024-11-05 19:50:00
Wyost (denosumab, also known as GP2411) was developed as a biosimilar to Xgeva (denosumab), the reference biologic drug. The weight of evidence for similarity between a biosimilar and the reference biological drug is provided by structural and functional studies. Biosimilar drugs are manufactured under the same regulatory standards as other biologic drugs. In addition to a typical set of chemistry and manufacturing data submitted for a new standardized biologic drug, biosimilar drug submissions include comprehensive data demonstrating similarities to the reference biologic drug.
Comparative structural and functional studies
The drug substance, denosumab (GP2411), was developed as a biosimilar to the reference denosumab marketed by Amgen Canada Inc. as two drug products that differ only in denosumab concentration, container closure and indications: Prolia (denosumab 60 mg/ml supplied in a pre-filled syringe) and Xgeva (denosumab 120 mg/1.7 ml [70 mg/ml] supplied in a single-use bottle). Sandoz Canada Inc. has submitted to Health Canada the New Drug Submission (NDS) for Wyost, a biosimilar intended for Xgeva, in conjunction with the NDS for Jubbonti (control number 271806), a biosimilar intended for Prolia.
The sponsor carried out comprehensive biosimilarity assessment studies using a range of comparative structural analyzes and functional assays to demonstrate the analytical and functional biosimilarity between GP2411 and reference biological products approved in the Union (referred to here as Prolia-EU and Xgeva-EU) and the United States (referred to here as Prolia-US and Xgeva-US) Prolia-US . and Xgeva-US. were considered suitable substitutes for Prolia and Xgeva authorized in Canada because they met the requirements for a non-Canadian reference biological drug set out in the Guidance Document: Information and Submission Requirements for Biosimilar Biological Drugs. The comparative analytical and functional evaluations of GP2411, Prolia-EU, Prolia-US, Xgeva-EU and Xgeva-US, together with the results of the three-way pharmacokinetic and pharmacodynamic comparisons of GP2411, from Xgeva-USA. and Xgeva-EU in healthy adult men helped establish a scientific link between Prolia-US. and Prolia-EU, as well as between Xgeva-US. and Xgeva-EU.
The results of biosimilarity studies demonstrate that GP2411 and Prolia/Xgeva are identical with respect to primary structure and very similar with respect to higher order structure, purity and impurities, biological activities and attributes related to the drug product. Additionally, the data demonstrate that GP2411 and Prolia/Xgeva bind specifically and selectively to the target, receptor activator of nuclear factor kappa-B (RANKL) ligand, and confirm that GP2411 and Prolia/Xgeva do not induce no antibody-dependent cell-mediated cytotoxicity, antibody-dependent cell-mediated phagocytosis, or complement-dependent cytotoxicity. Slight differences between GP2411 and Prolia/Xgeva were observed in immunoglobulin G2A (IgG2A) isoforms, charge variants, deamidation and glycation. However, these analytical differences have no impact on the biological activity of denosumab and are unlikely to have clinical significance. Slightly higher levels of high-mannose glycans were observed in GP2411 compared to reference products, but the differences are not expected to be of clinical significance. Comparative forced degradation studies performed under different stress conditions generated very similar degradation profiles for GP2411 and Prolia/Xgeva, further confirming the similarity of the products. Collectively, the results suggest that GP2411 is very similar to Prolia/Xgeva and supports the quality requirements for GP2411 to be considered a biosimilar to Prolia/Xgeva.
Characterization of the drug substance
Denosumab (GP2411), the medicinal ingredient in Wyost, is a fully human IgG2 monoclonal antibody with affinity and specificity for RANKL. The monoclonal antibody consists of two heavy chains of the gamma 2 subclass (containing 447 amino acids per chain) and two light chains of the kappa subclass (containing 215 amino acids per chain). Its approximate molecular weight is 145 kDa.
Detailed characterization studies were performed to ensure that denosumab consistently exhibits the desired characteristic structure and biological activity.
The results of the process validation studies indicate that the methods used make it possible to adequately control the quantities of impurities linked to the product and the process. The impurities that were reported and characterized did not exceed established and acceptable limits.
Process for manufacturing the drug substance and drug product and process controls
Wyost’s drug substance is produced using a Chinese hamster ovary cell line that is genetically engineered to express the protein.
A single vial of the working cell bank is thawed and used as the starting inoculum. After a series of expansion steps, the cells are transferred into the production bioreactor. The bulk harvest is clarified by centrifugation and deep filtration. Subsequently, the drug substance is purified from the clarified harvest through a series of chromatography, viral inactivation and viral filtration steps. These are followed by an ultrafiltration or diafiltration step aimed at concentrating the protein to the target value and transferring the protein solution into the buffer solution. After final filtration and filling into containers, the drug substance is stored at or below -60°C.
The drug product manufacturing process includes thawing the drug substance, manufacturing the excipient dilution solution, manufacturing the bulk drug product solution (including preparation and microbial filtration), followed by sterile filtration, aseptic filling, assembly, visual inspection, labeling, secondary packaging and storage at 2°C to 8°C. None of the nonmedicinal ingredients (excipients) present in Wyost are prohibited for use in drug products by the Food and Drug Regulations. The compatibility of the medicinal ingredient with the excipients is confirmed by the stability data provided.
Controls for critical process steps in the manufacturing of drug substances and drug products were established during manufacturing development and were based on risk assessment and process characterization. Process validation, performed at the intended commercial scale, demonstrated that the manufacturing processes are capable of consistently producing the drug substance and drug product that meet predefined specifications and quality attributes.
Control of the drug substance and drug product
Release and stability specifications for the drug substance and drug product have been established and appropriately justified. The analytical procedures used for release and stability testing of the drug substance and drug product have been appropriately validated in accordance with the relevant guidelines of the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use. The compendial methods complied with the relevant Pharmacopoeia standards.
A risk assessment relating to the potential presence of nitrosamine impurities has been carried out in accordance with the requirements set out in the Health Canada Guidance on Nitrosamine Impurities in Drugs. No risks have been identified from the formation or introduction of nitrosamines during the manufacturing processes of drug substances and drug products. Therefore, no confirmatory testing is required.
Wyost is a Schedule D drug (biological products) and is therefore subject to Health Canada’s Lot Release Program before being sold in accordance with the Guideline for promoters: Program for Authorization for the Release of Batches of Drugs Listed in Annex D (Biological Products).
Stability of the drug substance and drug product
Based on the stability data presented, the proposed shelf life and storage conditions for the drug substance and drug product have been adequately supported and found to be satisfactory. The proposed shelf life of 36 months at 2°C to 8°C for the drug product, when protected from light, is considered acceptable.
Compatibility of the drug product with the container-closure system has been demonstrated through stability studies and studies of extractables and leachables.
Facilities and equipment
Based on the risk assessment score determined by Health Canada, an on-site assessment of the pharmaceutical manufacturing facility was not deemed necessary. During the review, in lieu of the recommended on-site assessment of the drug substance manufacturing facility, Health Canada considered inspection observations from the United States Food and Drug Administration (FDA) ( mentioned in Form FDA 483) as well as the corresponding corrective and preventive measures.
The layout, operation and control mechanisms of the facilities and equipment used in production are considered acceptable for the activities and products produced. Both facilities involved in production comply with good manufacturing practices.
Safety Assessment of Adventive Agents
The drug substance manufacturing process uses adequate control measures to prevent contamination and maintain microbial control. In-process testing is performed to monitor bioburden, endotoxins, mycoplasma and viruses. Purification process steps designed to inactivate and remove any potential viral contaminants from the cell culture process are adequately validated.
No raw materials of animal or human origin are used in the manufacturing process of the medicinal substance. Other materials used comply with the Explanatory Note concerning the reduction of the risk of transmission of animal spongiform encephalopathy agents by medicinal products for human and veterinary use (EMEA/410/01, Rev.3). The risk of contamination of the drug product with bovine spongiform encephalopathy and transmissible spongiform encephalopathy agents is considered to be negligible.
The excipients used in the formulation of the medicinal product are not of animal or human origin.
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GMP guidelines in Pharma industry PDF
Canada, the facilities and equipment used in the manufacturing of Wyost were found to meet the necessary regulatory standards for the production of biological products. The manufacturing sites are equipped with appropriate technologies and systems that ensure consistent quality and compliance with good manufacturing practices (GMP).
The facilities are designed to minimize contamination risks, with controlled environments for both the production and filling processes. Routine monitoring of environmental conditions within the manufacturing areas is conducted to ensure that parameters such as temperature, humidity, and particulate contamination remain within acceptable limits.
The equipment used throughout the manufacturing process, including bioreactors, chromatography systems, and filtration equipment, has undergone rigorous qualification and validation. This ensures that the equipment operates correctly and consistently within established specifications. Regular maintenance and calibration schedules are in place to uphold the integrity of the processes.
the facilities and equipment associated with the manufacturing of Wyost demonstrate a high level of compliance with regulatory expectations, ensuring that the drug substance and drug product can be manufactured safely and effectively. The quality management system employed is designed to manage risks throughout the production process, thereby supporting the overall quality of the final product.
### Conclusion
Wyost (GP2411), as a biosimilar to Prolia and Xgeva, has undergone comprehensive characterization and evaluation to confirm its biosimilarity to the reference biologics. The manufacturing processes have been well-defined and validated, ensuring that both the drug substance and drug product are consistent, safe, and effective. Stability data supports the proposed shelf life and storage conditions, while the facilities and equipment meet stringent regulatory standards. The absence of concerns regarding nitrosamine impurities and the commitment to Health Canada’s Lot Release Program further reinforce the overall quality and safety of Wyost for patient use.