PUBLIC ASSESSMENT REPORT

Decentralised Procedure

Fraxiparine 0.3 2,850 I.U. anti-Xa/ 0.3 ml; Fraxiparine 0.4 3,800 I.U. anti-Xa/ 0.4 ml; Fraxiparine 0.6 5,700 I.U. anti-Xa/ 0.6 ml; Fraxiparine 0.8 7,600 I.U. anti-Xa/ 0.8 ml Procedure Number: DE/H/4762/002-005/DC

Fraxodi 19000 UL / ml; 0.6 ml Fraxodi 19000 UL / ml; 0.8 ml Fraxodi 19000 UL / ml; 1.0 ml Procedure Number: DE/H/4763/001-003/DC

Fraxiparine Multi 9,500 anti-Xa IU/ 1.0 ml Fraxiparine Multi 9,500 anti-Xa IU/ 1.0 ml Procedure Number: DE/H/4770/001-002/DC

Active Substance: Nadroparin-Calcium

Dosage Form: Solution for injection

Marketing Authorisation Holder in the RMS, Germany: Aspen Pharma Trading Limited

Publication: 19.11.2018 TABLE OF CONTENTS

I. RECOMMENDATION ...... 4 II. EXECUTIVE SUMMARY ...... 4 II.1 Problem statement ...... 4 II.2 About the product ...... 4 II.3 General comments on the submitted dossier ...... 4 II.4 General comments on compliance with GMP, GLP, GCP and agreed ethical principles. . 5 III. SCIENTIFIC OVERVIEW AND DISCUSSION ...... 5 III.1 Quality aspects ...... 5 III.2 Non-clinical aspects ...... 9 III.3 Clinical aspects ...... 9 IV. BENEFIT RISK ASSESSMENT ...... 12

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ADMINISTRATIVE INFORMATION

Fraxiparine 0.3 2,850 I.U. anti-Xa/ 0.3 ml; 0.4 3,800 I.U. Proposed name of the medicinal anti-Xa/ 0.4 ml; 0.6 5,700 I.U. anti-Xa/ 0.6 ml; 0.8 7,600 product(s) in the RMS I.U. anti-Xa/ 0.8 ml; DE/H/4762/002-005/DC

Fraxodi 19,000 I.U. / ml; DE/H/4763/01-03/DC

Fraxiparine Multi 9,500 anti-Xa I.U./ 1.0 ml DE/H/4770/01-02/DC Name of the drug substance (INN Nadroparin-Calcium name): Pharmaco-therapeutic group B01AD06 (ATC Code): Pharmaceutical form(s) and Solution for injection strength(s): Reference Number(s) for the DE/H/4762/02-05/DC Decentralised Procedure DE/H/4763/01-03/DC DE/H/4770/01-02/DC Reference Member State: DE Member States concerned: IE Legal basis of application: Generic Art 10.1 and 10.2 Dir 2001/83/EC Marketing Authorisation Holder Aspen Pharma Trading Limited (name and address) 3016 Lake Drive, Citywest Business Campus DUBLIN 24 Ireland Names and addresses of all Aspen Notre Dame de Bondeville manufacturer(s) responsible for 1, rue de l’Abbaye batch release in the EEA 76960 Notre Dame de Bondeville France

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I. RECOMMENDATION

Based on the review of the data and the Applicant’s response to the questions raised by RMS and CMSs on quality, safety and efficacy, the RMS considers that the application for Fraxiparine (9,500 I.U. anti-Xa / 1.0 ml solution, pre-filled syringe) in the prophylaxis and/or treatment of deep venous thrombosis, is approved.

II. EXECUTIVE SUMMARY

II.1 Problem statement

For generic application this section is not applicable.

II.2 About the product

The Originator product Fraxiparine ® was first authorised in Germany in 1997 and is indicated as follows:- - Perioperative thrombosis prophylaxis: o Peri- and postoperative primary prophylaxis of deep vein thrombosis in patients with low, moderate or high thromboembolic risk. o Peri- and postoperative primary prophylaxis of deep vein thrombosis in patients undergoing larger orthopedic surgeries (e.g. elective hip surgeries) - Treatment of deep vein thrombosis. - Thrombosis prophylaxis and anticoagulation with extracorporeal circulation during hemodialysis and hemofiltration. Fraxiparine has a pharmacotherapeutic group: antithrombotic ATC code: B01 AB06 The active substance of Fraxiparine is Nadroparin Calcium. Nadroparin calcium is a low molecular weight heparin (LMWH). This LMWH is prepared by depolymerisation of unfractionated porcine heparin sodium (UFH) by means of nitrous acid, followed by extraction/purification, then conversion to the calcium salt. Nadroparin calcium consists of fragments of the glycosaminoglycan, heparin, in which the relative molecular mass of the major species is between 4000 and 5000 Da. The degree of sulphation is approximately 2 per disaccharide unit. Most of the constituents have a 2-O-sulpho-δ-L- idopyranosuronic acid structure at the non-reducing end, and a 6-O-sulpho-2,5-anhydro-D-mannitol structure at the reducing end of the chains.

II.3 General comments on the submitted dossier

The application concerns a Marketing Authorisation Application under the Decentralised Procedure in accordance with Article 10(1) of Directive 2001/83/EC (abridged, “generic” application) with Fraxiparine ® as the reference medicinal product (RMP). The applicant, Aspen, is also the current MAH for Fraxiparine 0.3 2,850 I.U. anti-Xa/ 0.3 ml, Fraxiparine 0.4 3,800 I.U. anti-Xa/ 0.4 ml, Fraxiparine 0.6 5,700 I.U. anti-Xa/ 0.6 ml and Fraxiparine 0.8 7,600 I.U. anti-Xa/ 0.8 ml.

The use of the “generic” Article 10(1) basis rather than biosimilar10(4) for the current application was chosen by the Applicant on the basis that Fraxiparine (i.e. Fraxiparine 0.3 2,850 I.U. anti-Xa/ 0.3 ml, Fraxiparine 0.4 3,800 I.U. anti-Xa/ 0.4 ml, Fraxiparine 0.6 5,700 I.U. anti-Xa/ 0.6 ml and Fraxiparine 0.8 7,600 I.U. anti-Xa/ 0.8 ml) is identical to Fraxiparine ® in all but invented name and packaging. An application according to Article 10(1) (abridged, “generic” application) is based on the information provided by the Applicant, i.e. the identical qualitative and quantitative composition in drug substance and excipients and the same pharmaceutical forms and strengths between the two products and that for DE/H/4762/002-005/DC ; Fraxiparine DE/H/4763/001-003/DC ; Fraxodi DE/H/4770/001-002/DC ; Fraxiparine Multi Public Assessment Report Page 4/12 both, there would be no change in the manufacturing process, manufacturer or manufacturing site that could lead to differences regarding safety or efficacy compared to Fraxiparine ®. The MAH needs to ensure that the new product is kept updated to reflect any changes to the reference medicinal product, including changes concerning quality of the medicinal product, throughout the life cycle of the two products. This application contains no new clinical or preclinical data, other than supporting literature where necessary.

II.4 General comments on compliance with GMP, GLP, GCP and agreed ethical principles.

All relevant sites have valid manufacturing authorizations or valid GMP certificates as appropriate. Hence, no GMP inspections are deemed necessary at this stage within the scope of this MAA evaluation procedure.

GLP, GCP and agreed ethical principles: N/A as no clinical studies are submitted.

III. SCIENTIFIC OVERVIEW AND DISCUSSION

III.1 Quality aspects

Drug substance

Nadroparin calcium is the calcium salt of a low molecular-mass heparin prepared by nitrous acid fragmentation of heparin obtained from porcine intestinal mucosa. Nadroparin calcium is manufactured and released by Aspen Notre Dame de Bondeville, 1, rue de l’Abbaye, 76960 Notre Dame de Bondeville, France.

Manufacturing Process and Process Controls In the manufacturing process description for nadroparin calcium a reference is now included that refers to the heparin sodium manufacturing process starting from pooled porcine mucosa. This is in accordance with the classification of pooled porcine intestinal mucosa as starting material for heparin and heparin derivatives (EMA/CHMPBWP/429241/2013).

The conversion of heparin sodium to nadroparin calcium is performed by controlled depolymerisation of porcine heparin sodium by means of nitrous acid. The solution is then purified and converted to the calcium salt. The product is filtered, precipitated and washed with ethanol, and finally dried.

The depolymerisation process is guided by pH, sodium nitrite concentration, temperature and time. Critical parameter and tests have been defined and included in the application.

The depolymerisation product is purified at various operations to comply with predefined quality attributes, in particular presence of reducing groups and molecular weight distribution. Reprocessing is restricted to performed in exceptional circumstances, e.g. in case of technical failure. This is considered appropriate.

The batch size of a nadroparin calcium batch derived from heparin sodium is approximately 80kg.

Control of Materials Materials used in the manufacturing process are either controlled by compendial standards, standards adapted to a compendial monograph or by in-house specifications. For sodium heparin from the intended suppliers respective CoAs have been provided. Furthermore, a reference is included as pooled porcine mucosa is to be classified as starting material.

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Control of Critical Steps and Intermediates Critical steps have been described and process controls are in place to deliver product within predefined acceptance criteria. There are no process intermediates.

Process Validation Retrospective re-validation has been performed using three validation batches. The process validation data demonstrate that the proposed manufacturing process provides a product with a regular molecular distribution and low impurity content complying with the specifications. Furthermore, following the introduction of an alternative process for the calcium exchange step, a new validation exercise was performed. Related to the new process validation, presence of two different batches named “0001” is noted. However, clarification has been provided with regard to batch nomenclature.

Manufacturing process development No information has been provided on manufacturing development as the process is well established and subject to a Ph.Eur. Monograph. This is considered acceptable.

Characterisation The provided characterisation data are considered appropriate including physico-chemical properties of nadroparin calcium such as molecular weight distribution, UV- and IR spectra, 1H and 13C nuclear magnetic resonance spectra, molecular ratio of sulfate to carboxylate ions, uronic acid and glucosamine content. Nadroparin calcium is characterised by the presence of a specific sugar, 2,5 anhydro-D-mannitol, at the reducing end of polysaccharide chains resulting from the depolymerisation process. Nadroparin calcium ATIII binding activity has been demonstrated using affinity chromatography.

Process- and product- related impurities have been sufficiently addressed for evaluation of the impurity profile. Stress studies have been performed (and presented in Module 3.2.S.7) to identify stability-indicating analytical methods. All potential impurities are controlled by respective limits included in the DS specification.

Specification The proposed DS specification combines all tests required in the EP Monographs “Nadroparin calcium” and “Low molecular mass heparins” and additional specifications for microbial contamination. For all of the tests included in the proposed DS specification the respective acceptance criteria are those of the EP Monographs or tighter. Compendial and in-house analytical methods used for nadroparin specification are clearly indicated.

The methods used to test Nadroparin Calcium are pharmacopoeial methods except the sodium content method for which appropriate description and method validation data have been reported.

Analytical data for three commercial batches using the manufacturing stage 3.1. and three pilot batches manufactured using the alternative manufacturing stage 3.2. of nadroparin calcium have been provided to demonstrate compliance with the DS specification.

EP reference standards are used for manufacture of nadroparin calcium beside internal working standards. For the current in-house working standard sufficient information has been provided.

Stability Nadroparin calcium DS is stored in a transparent polyethylene double bag sealed with a band, placed with a desiccating sachet in a polyethylene container, itself sealed with a polyethylene cap. For the proposed container closure system respective material specification and CoA has been provided.

Stability data are provided for three commercial scale batches manufactured using the stage 3.1 process and stored for 24 months at long-term conditions (25°C/60% RH) and 6 months at accelerated conditions (40°C/75% RH). Three pilot-scale batches of Nadroparin Calcium manufactured using the alternative stage 3.2 process were also placed on stability. 12 months data for storage at 25°C/60% RH and six months data for storage at 40°C/75% RH are currently available.

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Based on the stability data it is considered acceptable to claim 24 months stability for storage at 25°C/60% RH.

Drug Product

Description of the product and Pharmaceutical Development Nadroparin Calcium 9500 IU AXa/ml subcutaneous injection is filled in a single dose prefilled syringe in four presentations: 0.3 0.4, 0.6 and 0.8 mL. Syringe barrel is a type I glass cylinder of 1 mL capacity, which is graduated for the 0.6 mL and 0.8 mL presentations. The barrel is stoppered with chlorobutyl plunger stoppers. A stainless steel needle is secured to the syringe body by means of a single component adhesive polymerisable under UV light. The needle is covered by a needle shield. The excipients are water for injections as solvent and calcium hydroxide or hydrochloric acid as pH adjusters.

No development has been performed. The reference product for the proposed drug product is “Fraxiparine 9500 anti-Xa IU/mL solution for injection” marketed by Aspen Pharma Trading Limited with the marketing authorisation number of 40533.00-05.00 since 1997. The composition of both products (generic and reference product) is identical.

The manufacturing process of the proposed drug product consists of dissolution of the components, sterile filtration and aseptic filling. Sterilisation by filtration is chosen since by applying steam sterilisation at 121 °C for 20 minutes, an increase in pH and a decrease of free sulphates concentration was observed which is evident for product degradation.

In order to demonstrate the suitability of the proposed container closure systems different studies were conducted. Compatibility studies of the plunger stopper and the drug product solution have been performed. The studies are adequately described. The results obtained demonstrate compatibility of the drug product solution and the plunger stoppers. The content of silicone deposited on the internal surfaces of the syringe was identified by using the analytical method as described in Ph.Eur. monograph for sterile single-use syringes. The results meet the Ph.Eur. specification.

Nadroparin Calcium 9500 IU AXa/ml prefilled syringes are graduated for the 0.6 mL and 0.8 mL presentations. With respect to accuracy and precision of the graduation of the syringes the graduation is tested by weighing of a volume of water corresponding to three graduations: 0.6 mL, 0.8 mL and 1.0 mL. The results demonstrate accuracy and precision.

A risk assessment for metal impurities in accordance with ICHQ3D was provided. The finished product analysis demonstrated that the impurity levels for the applicable elements are less than 30 % of the PDEs. Hence, a test on elemental impurities in the drug product specifications is not necessary.

Manufacture of the product and process controls Two manufacturing sites are responsible for manufacture, control and primary packaging of Nadroparin Calcium 9500 IU AXa/mL, pre-filled syringes, solution for injection. Valid manufacturing authorisations for these facilities are presented. In addition, Aspen Notre Dame de Bondeville, France is also responsible for secondary packaging and batch release.

The manufacturing process consists of dissolution of Nadroparin calcium, pH adjustment, sterile filtration, filling, stoppering, inspection, labelling and packaging and is in general similar for both manufacturers.

Description of the manufacturing process and controls of critical steps of both manufacturers is sufficient.

For process validation at the first manufacturer nine commercial bulk solution batches resulting in three pre-filled syringe batches of the fill volumes 0.3, 0.4, 0.6 mL, 0.8 mL and 1.0 mL have been DE/H/4762/002-005/DC ; Fraxiparine DE/H/4763/001-003/DC ; Fraxodi DE/H/4770/001-002/DC ; Fraxiparine Multi Public Assessment Report Page 7/12 manufactured. Different fill volumes have partly been filled from a common bulk solution. This is accepted. All process parameters were within the operational ranges and all batch analysis data met specifications for all tests.

Filter validation has been provided for the manufacturing process comprising microbial retention study, chemical compatibility study, extractables evaluation and adsorption test.

Hold time studies have been performed for bulk solution after pre-filtration and for filling process time. The hold times of < 21 days for bulk solution hold and < 9 days for filling process time are based on media fill runs.

For process validation at the second manufacturer three commercial bulk solution batches resulting in three pre-filled syringe batches of the fill volumes 0.2, 0.3, 0.8 mL and 1.0 mL have been manufactured. Different fill volumes have been filled from a common bulk solution. This is accepted.

The hold time between end of filtration and end of filling has been validated.

Validation of the filters used for the manufacturing process comprising microbial retention study, chemical compatibility study, extractables evaluation and adsorption test is available.

Product specification The drug product release and shelf-life specifications have been amended as requested. The identification sections in the release and shelf-life specification were harmonised and the test on appearance was amended with the specification that the solution is practically free from particles as requested. The explanations to omit the identification test on molecular distribution and the tests on break loose and glide force are accepted.

The tests methods are sufficiently described and validated.

Batch analysis data are provided confirming consistency and uniformity of the drug product manufactured at both sites.

Container Closure System Nadroparin Calcium 9500 IU AXa/mL pre-filled syringes consist of a single dose prefilled syringe. Each pre-filled syringe consists of a barrel with a needle, needle shield and a plunger stopper and is equipped with a safety device. Sufficient information on the container closure system for the drug product is provided.

Stability of the product

Stability studies have been carried out on six commercial scale batches of the drug product, i.e. on one batch of the different fill volumes of 0.2 ml, 0.3 ml, 0.4 mL, 0.6 mL, 0.8 ml and 1.0 ml. It is stated that the same compounding solution (bulk solution) is filled in identical primary packaging material to yield different strengths per volume of the finished product and that it therefore was not deemed necessary to generate stability data on 3 batches per strength of the finished product. Considering that all batches show in principle the same characteristics over time this is accepted.

36 months stability data are available for samples stored at 25°C/60%RH and 30°C/65%RH. All stability data at 25°C/60%RH and 30°C/65%RH are within the pre-defined specification limits with no obvious trends except for a decrease of pH associated with the increase of free sulphates.

Based on the stability data presented, the proposed shelf-life of 36 months when stored below 30°C in the SPC, PL and labeling is accepted.

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Sufficient stability data have been provided for both manufacturers. Photo stability testing data have been provided. No significant changes between protected and exposed samples were found. Thus, the drug products are considered photo stable and no special storage conditions with respect to light protection are necessary.

Adventitious Agents

The virus safety of Nadroparin is depending on the quality of starting material porcine mucosa as well as on the virus clearance capacity of the manufacturing processes for heparin sodium and Nadroparin calcium. As regards TSE-safety, freedom from ruminant contamination and identification of porcine origin of the mucosa is considered to be of importance and is controlled by qPCRs performed on the crude heparin. Selected steps of the manufacturing processes of heparin sodium by the first manufacturing site (KMnO4, H2O2 treatment) and the second manufacturing site (Heat, KMnO4 treatment, methanol precipitation) have been validated for their virus inactivating/removal capacity. The viral clearance capacity of the heparin sodium manufacturing processes was found to range from 9.9 to 11.26 log10 for the first manufacturing site and 13.8 to 21.3 log10 for the second manufacturing site. The viral clearance capacity of the Nadroparin calcium manufacturing process has also been validated at the steps depolymerization at acidic pH, reduction at basic pH, UV treatment and was found to be range from 6.83 to 16.76 log10. This adds up to an overall virus reduction factor for the whole manufacturing process from porcine mucosa to Nadroparin of at least 16 log10 and ranges from 16.6 to 24 log10 (first manufacturer) and 19.5 to 27 log10 (second manufacturer). In conclusion, the virus clearance capacity of the Nadroparin calcium manufacturing process comprising also heparin sodium manufacture is considered adequate to ensure the virus safety of the product.

Overall conclusion on quality

The applicant has provided satisfactory responses to the requests for supplementary information with respect to the drug substance and the drug product. The application is approvable from a quality perspective.

III.2 Non-clinical aspects

Pharmacodynamic, pharmacokinetic and toxicological properties of nadroparin are well known. As nadroparin 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 has been dated June 2016. Report refers 33 publications up to year 2015. The non-clinical overview on the pre-clinical pharmacology, pharmacokinetics and toxicology is adequate.

Environmental Risk Assessment (ERA) Since Fraxiparine 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 clinical overview refers 129 publications up to year 2014.

The clinical overview on the clinical pharmacology, efficacy and safety is adequate.

The applicant confirms that the product to be registered has the same active substance, and the same concentration as the reference product. He confirms that the product is produced in the same manufacturing process and in the same manufacturing sites(s) as the reference medicinal product. The product is in fact identical (as it is the same product and the same dossier for the currently approved

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Therefore, no bioequivalence study was performed. The RMS is of the opinion that this approach can be considered acceptable for a 10(1) application.

Summary Pharmacovigilance system The 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 considers the Summary acceptable.

Risk Management Plan

The Applicant has submitted a revised RMP (version: 1.3-dcp; data lock point: 25 April 2016, date of final sign off: 5 January 2018), 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 following medicinal products:

Pre-filled syringes (9,500 I.U. anti-Xa/ ml):  Nadroparine calcium Aspen 2,850 I.U. anti-Xa/ 0.3 ml solution for injection  Nadroparine calcium Aspen 3,800 I.U. anti-Xa/ 0.4 ml solution for injection  Nadroparine calcium Aspen 5,700 I.U. anti-Xa/ 0.6 ml solution for injection  Nadroparine calcium Aspen 7,600 I.U. anti-Xa/ 0.8 ml solution for injection

Multi Dose Vials (9,500 I.U. anti-Xa/ ml):  Nadroparine calcium Aspen multi 9,500 I.U. anti-Xa/ 1.0 ml solution for injection

Pre-filled syringes (19,000 I.U. anti-Xa/ ml):  Nadroparine calcium Aspen 19.000 I.U. anti-Xa/ ml solution for injection

Proposed summary of safety concerns:

Proposed pharmacovigilance activities:

- Routine pharmacovigilance.

Proposed risk minimisation measures:

- Routine risk minimisation.

Conclusion

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The summary of safety concerns is endorsed. Routine pharmacovigilance activities are considered sufficient. Medicinal products containing LMWHs are generally well-known. The risks connected to LMWH use are considered adequately controlled by routine risk minimisation measures. The RMP is considered overall acceptable. Taking into account the fact that nadroparin will be introduced for the first time on the Irish market with the generic medicinal products under review, a national communication (outside the RMP) might be required in Ireland in order to minimise the potential risk of medication errors. As requested, the Applicant has provided a commitment that the need for such a national communication will be addressed with the HPRA in Ireland prior to launch. The Applicant has placed said commitment on an Applicant’s commitment tracker (#1056).

The MAH shall perform the required pharmacovigilance activities and interventions detailed in the agreed RMP 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 date 5 years after the finalisation of the procedure.

Legal status Medicinal product subject to medical prescription.

User Testing The Readability test was performed for the leaflet Fraxiparine® 0.3.

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The Fraxiparine 0.3 leaflet satisfies the readability testing criteria established in the current legislation. Bridging reports were provided for: Fraxiparine 0.4, Fraxiparine 0.6, Fraxiparine 0.8, Fraxodi, Fraxiparine Multi, which was accepted.

IV. BENEFIT RISK ASSESSMENT

The B/R profile of the active substance nadroparin as well as of the generic product Fraxiparine is well known since it is identical to the originator product which is marketed since 1997.

The application is approved. For intermediate amendments see current product information.

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