Zusammenfassung der Merkmale des Arzneimittels - Bortezomib Novumgen 3,5 mg Pulver zur Herstellung einer Injektionslösung
National Authorisation in accordance with § 21 et seq AMG
Bortezomib 3,5 mg Pulver zur Herstellung einer Injektionslösung
ENR: 7011810
Active Substance:
Bortezomib
Dosage Form:
Pulver zur Herstellung einer Injektionslösung
Applicant:
NOVUMGEN LIMITED
Publication:
01.02.2024
This module reflects the scientific discussion for the approval of the above mentioned procedure. The procedure was finalised on 16.01.2024.
II.4 G eneral comments on compliance with GMP, GLP, GCP and agreed ethical
| Proposed name of the medicinal product in the RMS | Bortezomib 3,5 mg 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): | Pulver zur Herstellung einer Injektionslösug 3,5 mg |
| ENR | 7011810 |
| Legal basis of application: | Art. 10 Abs. 1 der RiL 2001/83/EC NOVUMGEN LIMITED Office 2, 12 A Lower Main Street |
| Applicant (name and address) | K78 X5P8 LUCAN, DUBLIN Ireland |
| Names and addresses of all manufacturer(s) responsible for batch release in the EEA | SIA “UNIFARMA” Vangazu street 23 Riga, LV-1024, Latvia |
Based on the review of the data on quality, safety and efficacy, the DE considers that the national application for Bortezomib 3,5 mg 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.
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, Other Antineoplastic agent
ATC code: L01XG01
Proposed indicationsBortezomib 3,5 mg 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.
Bortezomib 3,5 mg 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.
Bortezomib 3,5 mg 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.
Bortezomib 3,5 mg 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.
II.3 General comments on the submitted dossier
This national application concerns generic version of bortezomib, under the tradename Bortezomib 3.5 mg Pulver zur Herstellung einer Injektionslösung. In this Assessment Report the name Bortezomib Novumgen is used.
The active substance, bortezomib, is not considered a new active substance.
European Reference Product (ERP)A European Reference Product is used in DE: Velcade 3.5 mg, powder for solution for injection by Janssen-Cilag International NV (EU/1/04/274/001), registered in 2004.
Bortezomib 3,5 mg Pulver zur Herstellung einer Injektionslösung is applied as generic medicinal product of Velcade 3.5 mg, powder for solution for injection according to Article 10(1) of Directive 2001/83/EC. The applicant is NOVUMGEN LIMITED.
Assessment of similarity with authorised orphan medicinal product(s) under market exclusivityAccording to the application form and a check of the Community Register of orphan medicinal products the medicinal products have been designated as orphan medicinal products, but not yet been granted a marketing authorisation in the EU.
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 product(s) 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 3,5 mg Pulver zur Herstellung einer Injektionslösung is considered not similar (as defined in Article 3 of Commission Regulation (EC) No. 847/2000) to Farydak, Ninlaro, Kyprolis, Blenrep, Abecma, Carvykti, Talvey and Tecartus.
Therefore, with reference to Article 8 of Regulation (EC) No. 141/2000, the existence of any market exclusivity for Farydak, Ninlaro, Kyprolis, Blenrep, Abecma, Carvykti and Tavey in the treatment of multiple myeloma and Tecartus in the treatment of mantle cell lymphoma does not prevent the granting of the marketing authorisation of Bortezomib 3,5 mg Pulver zur Herstellung einer Injektionslösung. 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 substanceAn ASMF with the current Applicant’s part and Restricted part has been provided.
Drug substance (additional data provided by the applicant only)The finished product manufacturer controls the drug substance with the same specifications and analytical procedures as the DSM. Analytical procedures are sufficiently described. Validation reports for chromatographic procedures, microbial enumeration tests and bacterial endotoxins are presented. Not all parameters have been validated by the finished product manufacturer. However, based on complete validation reports of the drug substance manufacturer, this is considered acceptable.
The current reference standards used for drug substance and specified impurities by the finished drug product manufacturer have been provided and sufficiently characterized.
Drug ProductThe finished product is presented as lyophilised powder in clear glass vials. The composition of bulk solution and filled vial prior lyophilisation has been sufficiently described.
The development of the proposed finished product was based on the physico-chemical properties of the reference product VELCADE. The QTPP and CQAs have been provided.
The composition of reference and test product and impurity profiles have been compared and are considered similar.
The excipients of the proposed product are qualitatively the same as those of the reference product Velcade.
No overage is applied but an excess fill volume of 0.05 mL, which is considered acceptable.
From a quality point of view, the reference and test product are considered similar and the proposed biowaiver can be granted.
The manufacturing process development has been described in detail. The finished product is manufactured by aseptic processing, sterile filtration, and subsequent lyophilisation.. Process parameters have also been optimised. Sterile PVDF filters are used. Compatibility studies confirmed the suitability of filters, silicone tubing and stainless steel vessels. The lyophilisation cycle development has been described.
Compatibility studies confirmed the suitability of the proposed container closure system. Extractable and leachable testing has been conducted for the finished product.
Appropriate reconstitution studies have been conducted in 0.9% sodium chloride solution. Stability of reconstituted drug product has been demonstrated for 1 mg/mL and 2.5 mg/mL solutions in vials and syringes for up to 8 hours.
The batch formula for commercial batch size has been provided.
A list of equipment has been provided.
An acceptable process flow chart including in-process controls and input materials has been provided. The manufacturing process has been described in sufficient detail. Pre-and post-integrity testing is performed.
Sufficient in-process controls are presented and analytical procedures have been described in detail. The manufacturing process has been sufficiently validated for three full-scale batches. The critical process parameters and recommendations have been provided.
The product specifications cover appropriate parameters for this dosage form. Analytical procedures have been sufficiently described. Validation data is presented for all chromatographic procedures and in principle acceptable.
Forced degradation testing has been conducted to confirm the stability indicating nature of the procedures for related substances and assay. A mass balance table is presented.
Elemental impurity and nitrosamine risk assessment has been sufficiently conducted. No risk of presence of nitrosamine impurities has been identified. The risk evaluation outcome has been included in the dossier.
Appropriate information on reference standard and working standard used for bortezomib API have been presented. Impurity reference standards are given for all specified impurities.
The finished product is packed in clear glass vials and stoppered with rubber stoppers, sealed with flip-off seals. Appropriate specifications, drawings and quality compliance certificates have been provided.
Stability studies have been sufficiently conducted for three commercial scale process validation batches. Accelerated stability studies have been conducted at 40°C/75% RH and 6 months data are available. All specifications were met. Long-term stability studies have been conducted at 25°C/60% RH. The finished product was found stable in the proposed marketing pack. The proposed shelf life of 36 months is considered acceptable based on extrapolation.
Photostability studies have been sufficiently performed. The finished product was sensitive to light and the proposed storage condition: “Keep the vial in the outer carton in order to protect from light” is endorsed.
Thermal cycling studies and an additional extreme temperature excursion study demonstrated stability of the finished product to short-term excursions during shipping.
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. The non-clinical overview on the pre-clinical pharmacology, pharmacokinetics and toxicology is adequate.
The non-clinical sections of the SmPC are generally in line with the originator product Velcade.
Environmental Risk Assessment (ERA)Since Bortezomib Novumgen 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 has not conducted any clinical studies with bortezomib and all the relevant clinical information provided is literature based.
The clinical overview is dated 10th November 2022 and refers 95 publications up to year 2021.
The clinical overview on clinical pharmacology, efficacy and safety is adequate.
The applicant claims essential similarity of its applied medicinal product with the reference product Velcade 3.5 mg, powder for solution for injection. Test product Bortezomib 3.5 mg Powder for Solution for Injection contains same active substance Bortezomib and same pharmaceutical form similar to reference product Velcade 3.5 mg powder for solution for injection, which is authorised/manufactured by Janssen-Cilag International NV, Belgium.
No bioequivalence study was submitted. The applicant justifies waiving of clinical studies by referring to the guideline on the investigation of bioequivalence (CPMP/EWP/QWP/1401/98 Rev. 1/Corr**), appendix II – parenteral solutions. According to the Guideline, 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 (see Table below). Furthermore, the proposed product Bortezomib Novumgen has the same indications, pharmaceutical form, strengths and route of administration as the reference medicinal product.
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 efficacy data have been submitted and none are required for this application.
Clinical safety
No new safety data have been submitted and none are required for this application.
Summary Pharmacovigilance systemThe Applicant has submitted a signed Summary of the Applicant's and/or Proposed Future MAH'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.
* applicable in case the future MAH in RMS/CMSs will be different from the applicant
Risk Management PlanThe MAA 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/similar products 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.
After approval, 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 date5 years after finalisation of the procedure.
Legal StatusMedicinal product subject to medical prescription.
User TestingThe bridging report and the justification for not conducting a full User Testing provided by the applicant are considered adequate. For more information, see the appendix ‘QRD Guidance and Checklist for the Review of User Testing Results’