Zusammenfassung der Merkmale des Arzneimittels - Bortezomib Koanaa 2,5 mg/ml Injektionslösung
Decentralised Procedure
Bortezomib Koanaa 2,5 mg/ml Injektionslösung
Procedure-Number: DE/H/7493/001/DC
Active Substance:
Bortezomib
Dosage Form:
Solution for injection
Applicant:
Koanaa Healthcare Spain S.L.
Publication 05.10.2023
This module reflects the scientific discussion for the non-approval of the above-mentioned procedures. The procedures was withdrawn by the applicant and finalised at 14.09.2023
II.4 G eneral comments on compliance with GMP, GLP, GCP and agreed ethical
| Proposed name of the medicinal product in the RMS | Bortezomib Koanaa 2,5 mg/ml Injektionslösung |
| Name of the drug substance (INN name): | Bortezomib |
| Pharmaco-therapeutic group (ATC Code): | L01XG01 |
| Pharmaceutical form(s) and strength(s): | 2,5mg/ml solution for injection |
| Reference Number(s) for the Decentralised Procedure | DE/H/7493/001/DC |
| Reference Member State: | DE |
| Concerned Member States: | ES |
| Legal basis of application: | Other Generic application Art 10.3 Dir 2001/83/EC |
| Applicant (name and address) | Koanaa Healthcare Spain S.L. Cami De Can Camps 17–19 Piso 2 H 08174 Barcelona Spain |
| Names and addresses of all manufacturer(s) responsible for batch release in the EEA | APIS Labor GmbH Resslstraβe 9 9065 Ebenthal in Kärnten, Austria |
Based on the review of the data on quality, safety and efficacy, the RMS considers that the application for Bortezomib Koanaa 2,5 mg/ml 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 high-dose 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
N/A
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
The indications applied for are:
Bortezomib Koanaa 2,5 mg/ml 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 Koanaa 2,5 mg/ml Injektionslösung 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 Koanaa 2,5 mg/ml Injektionslösung 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 Koanaa 2,5 mg/ml Injektionslösung 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.
Posology and method of administration
Depending on the indication different treatments schedules are applied (refer to the SmPC for details). The product is administered via intravenous or subcutaneous injection at recommended doses of 1.3 mg/m2 body surface area or reduced doses of 1.0 mg/m2 or 0.7 mg/m2 body surface. At least 72 hours should elapse between consecutive doses.
Absorption
Following intravenous bolus administration of a 1.0 mg/m2 and 1.3 mg/m2 dose to 11 patients with multiple myeloma and creatinine clearance values greater than 50 ml/min, the mean first-dose maximum plasma concentrations of bortezomib were 57 and 112 ng/ml, respectively. In subsequent doses, mean maximum observed plasma concentrations ranged from 67 to 106 ng/ml for the 1.0 mg/m2 dose and 89 to 120 ng/ml for the 1.3 mg/m2 dose.
Following an intravenous bolus or subcutaneous injection of a 1.3 mg/m2 dose to patients with multiple myeloma (n=14 in the intravenous group, n=17 in the subcutaneous group), the total systemic exposure after repeat dose administration (AUClast) was equivalent for subcutaneous and intravenous administrations. The Cmax after subcutaneous administration
(20.4 ng/ml) was lower than intravenous (223 ng/ml). The AUC last geometric mean ratio was 0.99 and 90% confidence intervals were 80.18%-122.80%.
Distribution
The mean distribution volume (Vd) of bortezomib ranged from 1,659 l to 3,294 l following single- or repeated-dose intravenous administration of 1.0 mg/m2 or 1.3 mg/m2 to patients with multiple myeloma. This suggests that bortezomib distributes widely to peripheral tissues. Over a bortezomib concentration range of 0.01 to 1.0 μg/ml, the in vitro protein binding averaged 82.9% in human plasma. The fraction of bortezomib bound to plasma proteins was not concentration-dependent.
Metabolism
In vitro studies with human liver microsomes and human cDNA-expressed cytochrome P450 isozymes indicate that bortezomib is primarily oxidatively metabolised via cytochrome P450 enzymes, 3A4, 2C19, and 1A2. The major metabolic pathway is deboronation to form two deboronated metabolites that subsequently undergo hydroxylation to several metabolites. Deboronated-bortezomib metabolites are inactive as 26S proteasome inhibitors.
Excretion
The mean elimination half-life (t1/2) of bortezomib upon multiple dosing ranged from 40–193 hours. Bortezomib is eliminated more rapidly following the first dose compared to subsequent doses. Mean total body clearances were 102 and 112 l/h following the first dose for doses of 1.0 mg/m2 and 1.3 mg/m2, respectively, and ranged from 15 to 32 l/h and 18 to 32 l/h following subsequent doses for doses of 1.0 mg/m2 and 1.3 mg/m2, respectively.
II.3 General comments on the submitted dossier
This decentralised application concerns a generic version of bortezomib. It was submitted as a hybrid application according to article 10(3) of Directive 2001/83/EC, referring to Velcade 3.5 mg (powder for solution for injection) by Janssen-Cilag International NV, as reference product. Velcade has been registered in the EU since 26th of April 2004. The current product concerns a solution for injection, whereas the reference product is a powder for solution for injection, therefore article 10(3) is considered to be appropriate as legal basis.
With DE as the Reference Member State in this Decentralized Procedure, Koanaa Healthcare Spain S.L. applied for the Marketing Authorisations for Bortezomib Koanaa in ES.
European Reference Product (ERP)A European Reference Product is used in RMS DE and CMS ES: Velcade 3.5 mg (powder for solution for injection) by Janssen-Cilag International NV registered in 2004 (EU/1/04/274/001).
Assessment of similarity with authorised orphan medicinal product(s) under market exclusivity Potential similarity with orphan medicinal productsAccording to the application form and a check of the Community Register of orphan medicinal products there are medicinal products that 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 products under market exclusivity.
Conclusion
Having considered the arguments presented by the applicant and with reference to Article 8 of Regulation (EC) No 141/2000, Bortezomib Koanaa is considered not similar (as defined in Article 3 of Commission Regulation (EC) No. 847/2000) to Farydak, Ninlaro, Imnovid, Kyprolis, Darzalex, Blenrep, Abecma, Carvykti and Tecartus.
Therefore, with reference to Article 8 of Regulation (EC) No. 141/2000, the existence of any market exclusivity for Farydak, Ninlaro, Imnovid, Kyprolis, Darzalex, Blenrep, Abecma and Carvykti 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 Koanaa. This finding is without prejudice to the outcome of the scientific assessment of the marketing authorisation application.
A risk management plan is submitted with this application.
No scientific advice has been given.
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
The quality of the drug substance Bortezomib is documented in an EU/ASMF/00558. The ASMF of the drug substance manufacturer is acceptable. The ASMF version Letters of access to current version have been provided.
Drug Substance (related to additional data provided by applicant only)
The finished product manufacturer and drug substance manufacturer are the same. The same drug substance specification is used. Method transfer reports are provided. Some minor issues on reference standards of impurities need to be resolved.
Drug Product
The finished product is presented as solution for injection in clear glass vials containing 2.5 mg/mL equivalent to the total content of 3.5 mg/1.4 mL bortezomib. The amount per vial and labelled concentration is indicated.
The development of the proposed generic drug product was based on the reference product VELCADE® (Bortezomib for Injection) 3.5 mg. In contrast to the reference product (powder for solution for injection) the finished product was developed as solution for injection.
Comparison of formulations of 3.5 mg/1.4 mL strengths with reference product has been provided. The impurity profiles of reconstituted reference product and batches of generic drug product are comparable. As the finished product is indicated for parenteral use, no BE study has been conducted.
A biowaiver is requested for the proposed finished product based on same qualitative and quantitative composition of test product and reconstituted reference product. The physicochemical similarity has been determined by NMR and is considered acceptable from a quality point of view.
The development of an aseptic manufacturing process has been described. No overage is applied but an overfill of max. 2 % (0.13 mL) is used. The dilution volume for intravenous injection has been appropriately adapted in the SmPC. The container closure system has been selected based on the information available for the reference product.
The batch formula for the process validation and commercial batch size have been presented.
Holding times have been established. In-process controls and analytical procedures have been presented. Container closure integrity testing is not performed as in-process control but has been sufficiently validated by microbial ingress.
The manufacturing process has been sufficiently validated for commercial scale process validation batches. Validation results are presented and accepted. Media fills have been conducted and confirmed the appropriate aseptic processing. Filter validation data comprising relevant filter validation studies have been presented.
Release and shelf life specifications are presented. Relevant parameters for the control of a parenteral solution for injection have been included. The analytical procedures have been appropriately described and validated.
Forced degradation studies have been conducted. The finished product was most sensitive to oxidative, photolytic, and thermal degradation. Batch analyses results have been presented and indicate consistency. Specified impurities are presented in the dossier including respective source and mechanism. Elemental impurity risk assessment has been sufficiently conducted. No risk of presence of nitrosamine impurities has been identified.
Reference and working standards of bortezomib and specified impurities have been provided for API bortezomib and relevant impurities.
The finished product is primarily packed in type I clear glass vials and stoppered with bromobutyl coated rubber stoppers. An aluminium plastic cap is used for sealing.
Stability studies have been sufficiently conducted in line with the requirements of ICHQ1A(R2). The commercial scale process validation batches have been placed on accelerated stability studies and longterm studies at 2°C-8°C.
6 months accelerated stability data in inverted orientation have been provided for all batches. Significant changes were observed after three to six months storage at room temperature in particular for one specified impurity.
Up to 18 months long term stability data are available for all batches. No significant changes were observed. Based on the results of stability studies the storage conditions (‘Store in a refrigerator at 2°C to 8°C. Keep the vial in the outer carton in order to protect from light.’) are endorsed.
The proposed shelf life of 18 months can be granted.
Photo stability studies have been conducted and the drug product was sensitive to light.
In-use compatibility studies have been conducted for diluted solution (1.0 mg/mL) in vials and polypropylene syringes. Diluent compatibility studies confirmed stability of solutions in vials and syringes for 36 days at 2–8°C protected from light, 8 days at 25°C protected from light or 24 hours at 25°C in normal indoor lighting conditions.
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 submitted non-clinical overview on the pre-clinical pharmacology, pharmacokinetics and toxicology is adequate.
The non-clinical sections of the SmPC are in line with the originator product Velcade.
Environmental Risk Assessment (ERA)Since Bortezomib Koanaa 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
To support the application, the applicant did not submit any clinical trial reports, bioequivalence studies or therapeutic equivalence studies.
The application is supported by reference to the published literature which is consistent with the SmPC of the reference product.
The clinical overview is dated 15.04.2022 and refers 77 publications up to year 2022.
The applicant’s product Bortezomib Koanaa 2,5 mg/ml Injektionslösung is of the same indication and route of administration as that of the reference medicinal product VELCADE 3.5 mg powder for solution for injection.
The applicant has referred to the chapter 5.1.6 of the “Note for guidance on the investigation of bioavailability and bioequivalence” (CPMP/EWP/QWP/1401/98) as to why the submission of a bioequivalence study is not necessary. Please note that the newer version of this guideline is currently in use and in line with the it i.e. EMA Guideline on the Investigation of Bioequivalence – (CPMP/EWP/QWP/1401/98 Rev. 1/ Corr **, January 2010), the bioequivalence study is 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 excipients do not interact with the drug substance (e.g. complex formation), or otherwise affect the disposition of the drug substance.
In the case of other parenteral routes, e.g. intramuscular or subcutaneous, and when the test product is of the same type of solution (aqueous or oily), contains the same concentration of the same active substance and the same excipients in similar amounts as the medicinal product currently approved, bioequivalence studies are not required. Moreover, a bioequivalence study is not required for an
aqueous parenteral solution with comparable excipients in similar amounts, if it can be demonstrated that the excipients have no impact on the viscosity.
In this current application, the proposed ready to use solution of Bortezomib Koanaa 2,5 mg/ml Injektionslösung has the same qualitative and quantitative composition in active substance (bortezomib) as the reconstituted reference medicinal product (VELCADE) and the excipients present in proposed formulation are qualitatively and quantitatively proportional to excipients present in reference product. Further, the proposed formulation is an aqueous solution meant for intravenous and subcutaneous administration, same as reference product. Therefore, a biowaiver can be accepted.
Pharmacokinetics
As mentioned, no bioequivalence study has been submitted to support this application. The pharmacokinetic claims in the SmPC are consistent with the reference product.
Pharmacodynamics
No new data have been submitted. None is required for this type of generic applications. The pharmacodynamic claims in the SmPC are consistent with the reference product.
Clinical efficacy
No new data has been submitted. None is required for this type of generic (hybid) applications. The clinical efficacy of bortezomib is known, and the proposed indications for Bortezomib 2.5 mg/ml solution are consistent with the reference product.
Clinical safety
The 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/Proposed Future MAH has submitted a signed Summary of the Applicant's/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/Rapporteur 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 Bortezomib Koanaa Healthcare.
Safety specification
| Summary of Safety Concerns | |
| Important identified risks | None |
| Important potential risks | None |
| Missing information | None |
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. In case the active substance will be removed in the future from the EURD list because the MAs have been withdrawn in all but one MS, the MAH shall contact that MS and propose DLP and frequency for further PSUR submissions together with a justification.Common Renewal DateThe common renewal date is 14.09.2028.
Legal StatusMedicinal product subject to medical prescription.
User TestingThe bridging report is acceptable.