Zusammenfassung der Merkmale des Arzneimittels - Bortezomib Onko 3,5 mg Pulver zur Herstellung einer Injektionslösung
Decentralised Procedure
Bortezomib Onko 3,5 mg Pulver zur Herstellung einer Injektionslösung
Procedure-Number: DE/H/7098/001/DC
Active Substance:
Bortezomib
Dosage Form:
Powder for solution for injection
Marketing Authorisation Holder in the RMS, Germany:
Onko Pharmaceuticals Bulgaria Ltd EOOD
Publication:
13.06.2022
This module reflects the scientific discussion for the approval of Bortezomib Onko 3,5 mg Pulver zur Herstellung einer Injektionslösung. The procedure was finalised on 01.04.2022.
II.4 G eneral comments on compliance with GMP, GLP, GCP and agreed ethical
| Proposed name of the medicinal product in the RMS | Bortezomib Onko 3,5mg Pulver zur Herstellung einer Injektionslösung |
| Name of the drug substance (INN name): | Bortezomib |
| Pharmaco-therapeutic group (ATC Code): | L01XG01 |
| Pharmaceutical form(s) and strength(s): | Powder for solution for injection |
| Reference Number(s) for the Decentralised Procedure | DE/H/7098/001/DC |
| Reference Member State: | DE |
| Concerned Member States: | LU |
| Legal basis of application: | Generic Art 10.1 Dir 2001/83/EC |
| Marketing Authorisation Holder (name and address) | Onko Pharmaceuticals Bulgaria Ltd EOOD Ul.gramada 18 1680 Sofia Bulgaria |
| Names and addresses of all proposed manufacturer(s) responsible for batch release in the EEA | Wessling GmbH Johann-Krane-Weg 42 48149 Muenster Germany Wessling Hungary Kft. Anonymus u. 6 1045 Budapest Hungary |
Based on the review of the data on quality, safety and efficacy, the RMS considers that the application for Bortezomid Onko 3,5mg Pulver zur Herstellung einer Injektionslösung, indicated
– as monotherapy or in combination with pegylated liposomal doxorubicin or dexamethasone for the treatment of adult patients with progressive multiple myeloma who have received at least 1 prior therapy and who have already undergone or are unsuitable for haematopoietic stem cell transplantation.
– in combination with melphalan and prednisone for the treatment of adult patients with previously untreated multiple myeloma who are not eligible for high-dose chemotherapy with haematopoietic stem cell transplantation.
– in combination with dexamethasone, or with dexamethasone and thalidomide, for the induction treatment of adult patients with previously untreated multiple myeloma who are eligible for highdose chemotherapy with haematopoietic stem cell transplantation.
– in combination with rituximab, cyclophosphamide, doxorubicin and prednisone for the treatment of adult patients with previously untreated mantle cell lymphoma who are unsuitable for haematopoietic stem cell transplantation,
is approved.
No inspection action is needed.
II.1 Problem statement
Not applicable, this is a generic application.
II.2 About the product
Bortezomib is a highly selective proteasome inhibitor. It is specifically designed to inhibit the chymotrypsin-like activity of the 26S proteasome in mammalian cells. The 26S proteasome is a large protein complex that degrades ubiquitinated proteins. The ubiquitin-proteasome pathway plays an essential role in regulating the turnover of specific proteins, thereby maintaining homeostasis within cells. Inhibition of the 26S proteasome prevents this targeted proteolysis and affects multiple signalling cascades within the cell, ultimately resulting in cancer cell death.
Pharmacotherapeutic group: Antineoplastic agent
ATC code: L01XG01
Proposed indicationsBortezomid Onko 3,5mg Pulver zur Herstellung einer Injektionslösung as monotherapy or in combination with pegylated liposomal doxorubicin or dexamethasone is indicated for the treatment of adult patients with progressive multiple myeloma who have received at least 1 prior therapy and who have already undergone or are unsuitable for haematopoietic stem cell transplantation.
Bortezomid Onko 3,5mg Pulver zur Herstellung einer Injektionslösung in combination with melphalan and prednisone is indicated for the treatment of adult patients with previously untreated multiple myeloma who are not eligible for high-dose chemotherapy with haematopoietic stem cell transplantation.
Bortezomid Onko 3,5mg Pulver zur Herstellung einer Injektionslösung in combination with dexamethasone, or with dexamethasone and thalidomide, is indicated for the induction treatment of adult patients with previously untreated multiple myeloma who are eligible for high-dose chemotherapy with haematopoietic stem cell transplantation.
Bortezomid Onko 3,5mg Pulver zur Herstellung einer Injektionslösung in combination with rituximab, cyclophosphamide, doxorubicin and prednisone is indicated for the treatment of adult patients with previously untreated mantle cell lymphoma who are unsuitable for haematopoietic stem cell transplantation.
Proposed posology and methods of administration are in accordance with the originator reference product Velcade 3.5 mg, powder for solution for injection by Janssen-Cilag International NV.
II.3 General comments on the submitted dossier
This decentralised application concerns a generic version of bortezomib, under trade name “Bortezomib Onko 3,5mg Pulver zur Herstellung eine Injektionslösung” In this Assessment Report, the name Bortezomib Onko is used.
The originator product is Velcade (3,5mg powder for solution for injection) by Janssen-Cilag International NV, approved throughout the EU on 26 April 2004.
With DE as the Reference Member State in this Decentralized Procedure, Onko Pharmaceuticals Bulgaria Ltd EOOD applied for the Marketing Authorisations for Bortezomib Onko in LU.
No bioequivalence study was submitted to support the application.
According to Appendix II to the Guideline on the Investigation of Bioequivalence (CPMP/EWP/QWP/1401/98 Rev.1/ Corr**), bioequivalence studies are generally not required if the test product is to be administered as an aqueous intravenous solution containing the same active substance as the currently approved product and the excipients do not interact with the drug substance.
According to the application form and a check of the Community Register of orphan medicinal products the following medicinal products has/have been designated as orphan medicinal products, but not yet been granted a marketing authorisation in the EU:
EU/3/21/2424 EU/3/20/2331 EU/3/20/2277 EU/3/20/2252 EU/3/19/2204 EU/3/18/2078 EU/3/18/1918 EU/3/17/1863 EU/3/16/1767 EU/3/11/881
EU/3/08/600
EU/3/05/286 EU/3/04/248
EU/3/04/245 EU/3/21/2450
EU/3/20/2373 EU/3/17/1954 EU/3/16/1625 EU/3/15/1552 EU/3/10/831 EU/3/04/250
The applicant should monitor these products during the entire procedure to check if a marketing authorisation has been granted. In case a marketing authorisation is granted, the applicant should update the report on similarity and, if applicable, submit the data to support derogation from orphan market exclusivity.
The applicant has provided a similarity report due to potential similarity with authorised orphan medicinal products under market exclusivity. The detailed RMS assessment of similarity is presented in the attached RMS Similarity AR.
Conclusion
Having considered the arguments presented by the applicant and with reference to Article 8 of Regulation (EC) No 141/2000, Bortezomib Onko is considered not similar (as defined in Article 3 of Commission Regulation (EC) No. 847/2000) to Imnovid (pomalidomide), Farydak (panobinostat), Kyprolis (carfilzomib), Ninalaro (ixazomib), Darzalex (daratumumab), Blenrep (belantamab mafodotin), Abecma and Tecartus. Therefore, with reference to Article 8 of Regulation (EC) No. 141/2000, the existence of any market exclusivity for Imnovid (pomalidomide), Farydak (panobinostat), Kyprolis (carfilzomib), Ninalaro (ixazomib), Darzalex (daratumumab), Abecma and Blenrep (belantamab mafodotin) for the treatment of multiple myeloma and Tecartus for the treatment of mantle cell lymphoma, does not prevent the granting of the marketing authorisation of Bortezomib Onko. This finding is without prejudice to the outcome of the scientific assessment of the marketing authorisation application.
II.4 General comments on compliance with GMP, GLP, GCP and agreed ethical principles.
The RMS has been assured that acceptable standards of GMP are in place for these product types at all sites responsible for the manufacture and assembly of this product.
For manufacturing sites within the Community, the RMS has accepted copies of current manufacturer authorisations issued by inspection services of the competent authorities as certification that acceptable standards of GMP are in place at those sites.
For manufacturing sites outside the Community, the RMS has accepted copies of current GMP Certificates of satisfactory inspection summary reports, ‘close-out letters’ or ‘exchange of information’ issued by the inspection services of the competent authorities (or those countries with which the EEA has a Mutual Recognition Agreement for their own territories) as certification that acceptable standards of GMP are in place at those non-Community sites.
GMP active substance
Regarding the statement on GMP for the active substance a statement/declaration is provided from the manufacturer(s) responsible for manufacture of the finished product and batch release situated in the EU.
III.1 Quality aspects
Drug Substance (additional data provided by the applicant only)Overall, the data provided for the drug substance is sufficient. Batch analysis data has been presented for the two batches used for manufacturing of the finished product.
Specifications are in line with the specifications of the drug substance manufacturer. The same analytical procedures as used by the drug substance manufacturer have been applied. Appropriate validation data has been provided in the applicant’s part of the ASMF. Reference standards are indicated and acceptable.
Drug Substance (applicant’s part of the ASMF)In general, sufficient information have been provided to describe the physical and chemical properties of the API.
The manufacturing process is sufficiently described.
Suitable analytical procedures have been applied to characterize the structure of bortezomib in its trimeric boroxine form.
The impurity profile of bortezomib has been discussed in sufficient detail. Carry-over studies have been performed for all possible reagents and starting materials.
Analytical procedures have been sufficiently described for the determination of reagents.
The test procedures and acceptance criteria for Bortezomib drug substance have been appropriately established. For the impurity the limit of 0.30% is considered acceptable based on the qualification report provided. The limits of residual solvents are set according to ICHQ3C and based on toxicological data. Forced degradation studies have been performed and confirmed the stability indicating nature of the analytical procedures for related substances and assay.
The data provided for reference standards and materials is in general acceptable but some discrepancies need to be clarified.
Bortezomib typical packaging configuration is a borosilicate brown glass bottle with a screw cap complete with a PTFE seal. The data provided for primary, secondary and tertiary packaging materials is accepted.
Stability data has been provided for three commercial scale batches manufactured in 2018 for up to 6 months accelerated (5 °C ± 3°C) and 24 months long term storage at 20°C ± 5 °C. Out of specification results for any individual impurities were observed for all three batches under accelerated conditions. The OOS results obtained during accelerated stability studies have been identified as peroxyamides and the structure has been elucidated by HPLC-MS/MS. The origin of the peroxyamide and the high variability of any unspecified impurities in the batches manufactured from 2018 has been discussed. The applicant applies a reduced stability specification, which has been sufficiently justified.
All three batches complied to specifications upon long term storage for 24 months. The retest period of 24 months is acceptable.
Photo stability studies have been performed in line with ICH Q1B. Forced degradation studies have been sufficiently conducted.
Drug ProductBortezomib 3.5 mg Powder for Solution for Injection is a white or whitish lyophilized powder or cake in a transparent glass vial. The composition of the finished drug product has been sufficiently described. Trimeric boroxine is used and the conversion factor is indicated.
The formulation development was based on the quality attributes of the reference medicinal product Velcade®. Since a parenteral product has been developed no bioequivalence studies have been conducted. A Quality by Design has been applied for formulation development.
An aseptic process comprising of compounding, sterile filtration, filling and lyophilisation has been developed. PES filters have been used for sterile filtration. Compatibility to PES filters has been appropriately confirmed. The overfill of 0.05 ml is applied for filling and acceptable. The bulk solution was stable for 24 hours.
The aseptic manufacturing process has been described in sufficient detail. Appropriate specifications have been provided for all In-process controls. A maximum holding time of 24 h has been defined for the bulk solution before and after filtration.
The aseptic manufacturing process has been sufficiently validated based on three commercial scale validation batches. Aseptic simulations have been appropriately performed by media fills. 0.22 µm PES test filters with a smaller filtration area have been validated for a contact time of 24 hours.
The excipients Mannitol, sterile water for injections, and nitrogen are of compendial grade. In-house specifications of tert-butanol have been provided. The validation of the in-house chromatographic procedure for 2-butanol content has been appropriately conducted.
Specifications have been provided for the final drug product and comprise all relevant tests for parenteral products. Higher stability specification limits for bortezomib amide and Hydroxyamid have been proposed and are appropriately justified based on ICHQ3B.
There are no additional impurities in the finished drug product compared to the drug substance. A risk assessment of elemental impurities has been sufficiently conducted. A nitrosamine risk assessment has been conducted and no risk of presence of nitrosamines has been identified.
Reference standards are indicated and CoA have been provided.
The container closure system has been sufficiently described. The suitability of the container closure system is supported by stability data, and extractable studies have been performed for glass vials and rubber stoppers.
Stability studies have been appropriately conducted for three validation batches. 6 months accelerated (40°C±5°C/75% ±5% RH) and up to 24 months long-term stability studies (at 25°C ± 2°C/60% RH ± 5% RH) have been performed. The proposed shelf-life of 30 months is acceptable. In-use stability studies confirmed stability for 8 hours. Bortezomib was found to be photo-labile and an appropriate statement for storage protected from light has been included in the SmPC. Freeze/thaw stability studies confirmed stability of Bortezomib finished product against changes in temperatures.
III.2 Non clinical aspects
Pharmacodynamic, pharmacokinetic and toxicological properties of bortezomib are well known. As bortezomib is a widely used, well-known active substance, the applicant has not provided additional studies and further studies are not required. Overview based on literature review is, thus, appropriate.
Environmental Risk Assessment (ERA)
Since Bortezomib Onko 3,5 mg Pulver zur Herstellung einer Injektionslösung is intended for generic substitution, this will not lead to an increased exposure to the environment. An environmental risk assessment is therefore not deemed necessary.
III.3 Clinical aspects
The applicant claims essential similarity of its applied medicinal product with the reference product Velcade 3,5mg, powder for solution for injection, manufactured/marketed by Janssen Pharmaceutica NV, Belgium / Janssen-Cilag GmbH, Deutschland.
The indications sought for Bortezomib for Injection are the same as those for Velcade® (bortezomib) Powder for Injection. As this is a generic application claiming essential similarity to a currently marketed product, no clinical studies have been undertaken to support the application.
The formulation of applicant’s Bortezomib 3,5 mg Powder for Solution for Injection has been developed as the generic equivalent of Velcade®. The test formulation having the same qualitative and
quantitative composition in terms of active substance and excipients as the reference product and also is of the same pharmaceutical form as the reference product
According to Appendix II to the Guideline on the Investigation of Bioequivalence (CPMP/EWP/QWP/1401/98 Rev. 1), the Applicant is not required to submit a bioequivalence study if the product is to be administered as an aqueous solution containing the same active substance in the same concentration as the currently authorized reference product and excipients do not interact and/or otherwise affect the disposition of the drug substance. The same applies for subcutaneous administration when the test product is of the same type of solution, contains the same concentration of the same active substance and the same excipients in similar amounts as the medicinal product currently approved.
All these conditions are fulfilled in the present application, as the formulation contains the same active substance in the same concentration and the same excipients in similar amounts as the reference product. Furthermore, the proposed product Bortezomib Onko has the same indication, pharmaceutical form, strengths and route of administration as the reference medicinal product.
The data to support the claimed essential similarity has been assessed in Quality assessment report.
PharmacokineticsNo new data have been submitted. None is required for this type of generic applications.
The pharmacokinetic claims in the SmPC are consistent with the reference product.
PharmacodynamicsNo new data have been submitted. None is required for this type of generic applications. The pharmacodynamics claims in the SmPC are consistent with the reference product.
Clinical efficacyNo new data has been submitted. None is required for this type of generic applications. The clinical efficacy of bortezomib is known, and the proposed indications for Bortezomib Onko are consistent with the reference product.
Clinical safetyThe clinical safety of bortezomib, used in the approved indications, is known. There is no new clinical information regarding safety submitted with this application.
Summary Pharmacovigilance systemThe Applicant has submitted a signed Summary of the Applicant's Pharmacovigilance System. Provided, that the Pharmacovigilance System Master File fully complies with the new legal requirements as set out in the Commission Implementing Regulation and as detailed in the GVP module, the RMS considers the Summary acceptable.
Risk Management PlanThe MAH has submitted a risk management plan, in accordance with the requirements of Directive 2001/83/EC as amended, describing the pharmacovigilance activities and interventions designed to identify, characterise, prevent or minimise risks relating to the medicinal product(s) applied for authorisation.
Safety specification
According to the Applicant the safety specification is in full accordance with the current safety specification agreed and published for a similar product which is acceptable.
Pharmacovigilance Plan
Routine pharmacovigilance is suggested and no additional pharmacovigilance activities are proposed by the applicant, which is endorsed.
Risk minimisation measures
Routine risk minimisation is suggested and no additional risk minimisation activities are proposed by the applicant, which is endorsed.
Summary of the RMP
The submitted Risk Management Plan is considered acceptable.
The MAH shall perform the required pharmacovigilance activities and interventions detailed in the agreed RMP presented in the dossier of the Marketing Authorisation and any agreed subsequent updates of the RMP.
An updated RMP should be submitted:
– At the request of the RMS;
– Whenever the risk management system is modified, especially as the result of new information being received that may lead to a significant change to the benefit/risk profile or as the result of an important (pharmacovigilance or risk minimisation) milestone being reached.
If the dates for submission of a PSUR and the update of a RMP coincide, they can be submitted at the same time, but via different procedures.
Periodic Safety Update Report (PSUR)With regard to PSUR submission, the MAH should take the following into account:
PSURs shall be submitted in accordance with the requirements set out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and published on the European medicines web-portal. Marketing authorisation holders shall continuously check the European medicines web-portal for the DLP and frequency of submission of the next PSUR. For medicinal products authorized under the legal basis of Article 10(1) or Article 10a of Directive 2001/83/EC, no routine PSURs need to be submitted, unless otherwise specified in the EURD list. For medicinal products that do not fall within the categories waived of the obligation to submit routine PSURs by the revised pharmacovigilance legislation, the MAH should follow the DLP according to the EURD list.Common renewal dateThe common renewal date is 01.04.2027.
Legal StatusMedicinal product subject to medical prescription.
User TestingThe results of the submitted user test of Bortezomib Onko 3.5mg powder for solution for injection demonstrate that the proposed PIL is suitable according to the recommendations of the GUIDELINE ON THE READABILITY OF THE LABEL AND PACKAGE LEAFLET OF MEDICINAL PRODUCTS FOR HUMAN USE” (Revision January 2009) Update of Directive 2001/83/EC as amended by Directive 2004/27/EC).