17 December 2015
`EMA/32587/2016
`Committee for Medicinal Products for Human Use (CHMP)
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`Assessment report
`
`Caspofungin Accord
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`International non-proprietary name: caspofungin
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`Procedure No. EMEA/H/C/004134/0000
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`Note
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`Assessment report as adopted by the CHMP with all information of a commercially confidential nature
`deleted.
`
`30 Churchill Place ● Canary Wharf ● London E14 5EU ● United Kingdom
`Telephone +44 (0)20 3660 6000 Facsimile +44 (0)20 3660 5520
`Send a question via our website www.ema.europa.eu/contact
`
`
`
`An agency of the European Union
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`AMNEAL EX. 1015
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`Table of contents
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`
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`1. Background information on the procedure .............................................. 4
`1.1. Submission of the dossier ..................................................................................... 4
`1.2. Steps taken for the assessment of the product ........................................................ 5
`
`2. Scientific discussion ................................................................................ 6
`2.1. Introduction ........................................................................................................ 6
`2.2. Quality aspects .................................................................................................... 6
`2.2.1. Introduction...................................................................................................... 6
`2.2.2. Active substance ............................................................................................... 6
`2.2.3. Finished medicinal product ................................................................................. 9
`2.2.4. Discussion on chemical, and pharmaceutical aspects ........................................... 11
`2.2.5. Conclusions on the chemical, pharmaceutical and biological aspects ...................... 11
`2.2.6. Recommendation(s) for future quality development ............................................. 11
`2.3. Non-clinical aspects ............................................................................................ 12
`2.3.1. Introduction.................................................................................................... 12
`2.3.2. Ecotoxicity/environmental risk assessment ......................................................... 12
`2.3.3. Toxicology ...................................................................................................... 12
`2.3.4. Discussion on non-clinical aspects ..................................................................... 13
`2.3.5. Conclusion on the non-clinical aspects ............................................................... 13
`2.4. Clinical aspects .................................................................................................. 13
`2.4.1. Introduction.................................................................................................... 13
`2.4.2. Pharmacokinetics ............................................................................................ 14
`2.4.3. Pharmacodynamics .......................................................................................... 14
`2.4.4. Post marketing experience ............................................................................... 14
`2.4.5. Discussion on clinical aspects ............................................................................ 14
`2.4.6. Conclusions on clinical aspects .......................................................................... 15
`2.5. Risk management plan ....................................................................................... 15
`2.6. PSUR submission ............................................................................................... 17
`2.7. Pharmacovigilance ............................................................................................. 17
`2.8. Product information ............................................................................................ 17
`2.8.1. User consultation ............................................................................................ 17
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`3. Benefit-risk balance .............................................................................. 17
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`4. Recommendation .................................................................................. 18
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`List of abbreviations
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`
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`ASMF
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`Active Substance Master File
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`CHMP
`
`Committee for Medicinal Products for Human use
`
`cfu
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`CQA
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`EC
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`GC
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`
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`
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`Colony Forming Units
`
`Critical Quality Attribute
`
`European Commission
`
`Gas Chromatography
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`HPLC
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`High performance liquid chromatography
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`ICH
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`International Conference on Harmonisation of Technical Requirements for Registration of
`
`Pharmaceuticals for Human Use
`
`IPC
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`
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`In-process control
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`ICP-MS
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`Inductively coupled plasma mass spectrometry
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`IR
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`IV
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`KF
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`Infrared
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`Intra-venous
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`Karl Fischer titration
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`LCMS
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`Liquid chromatography mass spectrometry
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`MAH
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`MS
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`NMR
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`NMT
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`Marketing Authorisation holder
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`Mass Spectrometry
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`Nuclear Magnetic Resonance
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`Not more than
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`Ph. Eur.
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`European Pharmacopoeia
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`ppm
`
`
`
`parts per million
`
`QTPP
`
`Quality target product profile
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`RRT
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`
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`Relative retention time
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`SmPC
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`Summary of Product Characteristics
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`USP
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`UV
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`WCB
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`
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`United States Pharmacopoeia
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`Ultraviolet
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`Working Cell Bank
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`1. Background information on the procedure
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`1.1. Submission of the dossier
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`The applicant Accord Healthcare Ltd submitted on 6 March 2015 an application for Marketing Authorisation to
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`the European Medicines Agency (EMA) for Caspofungin Accord, through the centralised procedure under
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`Article 3(3) of Regulation (EC) No. 726/2004– ‘Generic of a Centrally authorised product’. The eligibility to
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`the centralised procedure was agreed upon by the EMA/CHMP on 18 December 2014.
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`The application concerns a generic medicinal product as defined in Article 10(2)(b) of Directive 2001/83/EC
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`and refers to a reference product for which a Marketing Authorisation is or has been granted in in the Union
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`on the basis of a complete dossier in accordance with Article 8(3) of Directive 2001/83/EC.
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`The applicant applied for the following indications:
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`- Treatment of invasive candidiasis in adult patients;
`
`- Treatment of invasive aspergillosis in adult patients who are refractory to or intolerant of amphotericin B,
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`lipid formulations of amphotericin B and/or itraconazole. Refractoriness is defined as progression of infection
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`or failure to improve after a minimum of 7 days of prior therapeutic doses of effective antifungal therapy;
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`- Empirical therapy for presumed fungal infections (such as Candida or Aspergillus) in febrile, neutropaenic
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`adult patients.
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`The legal basis for this application refers to:
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`Generic application (Article 10(1) of Directive No 2001/83/EC).
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`The chosen reference product is:
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`
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`
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`
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`
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`■ Medicinal product which is or has been authorised in accordance with Community provisions in accordance
`with Community provisions in force for not less than 6/10 years in the EEA:
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`Product name, strength, pharmaceutical form: CANCIDAS, 50 mg and 70 mg, powder for concentrate
`for solution for infusion
`
`Marketing authorisation holder: Merck Sharp & Dohme Ltd, United Kingdom
`
`Date of authorisation: 24-10-2001
`
`
`
`Marketing authorisation granted by:
`
` Community
`Community Marketing authorisation number: EU/1/01/196/001 (50 mg); EU/1/01/196/003 (70 mg)
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`■ Medicinal product authorised in the Community/Members State where the application is made or
`European reference medicinal product:
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`Product name, strength, pharmaceutical form: CANCIDAS, 50 mg and 70 mg, powder for concentrate
`for solution for infusion
`
`Marketing authorisation holder: Merck Sharp & Dohme Ltd, United Kingdom
`
`Date of authorisation: 24-10-2001
`
`
`
`Marketing authorisation granted by:
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` Community
`Community Marketing authorisation number: EU/1/01/196/001 (50 mg); EU/1/01/196/003 (70 mg)
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`■ Medicinal product which is or has been authorised in accordance with Community provisions in force and
`to which bioequivalence has been demonstrated by appropriate bioavailability studies:
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`N/A (this medicinal product is a parenteral preparation. Therefore a bioequivalence study is not applicable
`
`according to CPMP/EWP/QWP/1401/98 Rev.1)
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`Information on paediatric requirements
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`Not applicable
`
`Licensing status
`
`The product was not licensed in any country at the time of submission of the application.
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`1.2. Steps taken for the assessment of the product
`
`The Rapporteur appointed by the CHMP was:
`
`Rapporteur:
`
`Karsten Bruins Slot
`
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`•
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`•
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`•
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`•
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`•
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`The application was received by the EMA on 6 March 2015.
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`The procedure started on 26 March 2015.
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`The Rapporteur's first Assessment Report was circulated to all CHMP members on 12 June 2015.
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`PRAC RMP Advice and assessment overview, adopted by PRAC on 9 July 2015.
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`During the meeting on 23 July 2015, the CHMP agreed on the consolidated List of Questions to be
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`sent to the applicant. The final consolidated List of Questions was sent to the applicant on
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`27 July 2015.
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`The applicant submitted the responses to the CHMP consolidated List of Questions on
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`21 August 2015.
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`The Rapporteur circulated the Assessment Report on the applicant’s responses to the List of
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`Questions to all CHMP members on 25 September 2015.
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`PRAC RMP Advice and assessment overview, adopted by PRAC on 8 October 2015.
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`During the CHMP meeting on 22 October 2015, the CHMP agreed on a list of outstanding issues to be
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`addressed in writing by the applicant.
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`The applicant submitted the responses to the CHMP consolidated List of Outstanding Issues on
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`17 November 2015.
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`Rapporteur assessment report on the responses provided by the applicant, dated 1 December 2015.
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`PRAC RMP Advice and assessment overview, adopted by PRAC on 3 December 2015.
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`During the meeting on 17 December 2015, the CHMP, in the light of the overall data submitted and
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`the scientific discussion within the Committee, issued a positive opinion for granting a Marketing
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`Authorisation to Caspofungin Accord.
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`2. Scientific discussion
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`2.1. Introduction
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`Caspofugin acetate is a semi-synthetic lipopeptide that belongs to the relatively new class of antifungal
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`agents called the echinocandin family. Caspofungin blocks, through non-competitive inhibition of the enzyme
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`β(1,3)-D-glucan synthase, the synthesis of the fungal cell wall component β(1,3)-D-glucan which is essential
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`for the cell wall synthesis of numerous fungal species and yeasts, but is absent in mammalian cells.
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`The reference product Cancidas (EU approval 24 October 2001) is marketed worldwide and is indicated for
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`various fungal infections, in Europe for the:
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`
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`
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`Treatment of invasive candidiasis in adult or paediatric patients,
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`Treatment of invasive aspergillosis in adult or paediatric patients who are refractory to or intolerant of
`
`amphotericin B (AmB), lipid formulations of AmB and/or itraconazole, and
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` Empirical therapy for presumed fungal infections (e.g. Candida or Aspergillus) in febrile, neutropenic
`
`adult or paediatric patients.
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`Accordingly, the safety and efficacy of caspofungin have been shown in several clinical trials in these
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`indications for the reference medicinal product. Additionally, there is a long-term post-marketing experience
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`contributing to the knowledge of the clinical use of this active substance.
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`Both the Caspofungin Accord and the originator product Cancidas are intended for intravenous use and must
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`be reconstituted and further diluted prior to use.
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`Caspofungin Accord should be given as a single daily infusion administered as slow intravenous infusion over
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`approximately 1 hour.
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`2.2. Quality aspects
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`2.2.1. Introduction
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`The finished product is presented as powder for concentrate for solution for infusion containing 50 or 70 mg
`
`of caspofungin (as diacetate salt) as active substance.
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`Other ingredients are sucrose, mannitol, succinic acid and sodium hydroxide.
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`The product is available in type I clear glass vials with bromobutyl rubber stoppers and red or orange
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`aluminium seals with transparent plastic flip off buttons as described in section 6.5 of the SmPC.
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`2.2.2. Active substance
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`General information
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`The information on caspofungin acetate is provided according to the Active Substance Master File (ASMF)
`
`procedure.
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`The chemical name of caspofungin acetate is 1-[(4R,5S)-5[(2-aminoethyl)amino]-N2-(10,12-dimethyl-1-
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`oxotetradecyl)-4-hydroxy-L-ornithine]-5-[(3R)-3-hydroxy-L-ornithine]pneumocandin Bo diacetate or
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`(4R,5S)-5-((2-aminoethyl)amino)-N(2)-(10,12-dimethyltetradecanoyl)-4-hydroxy-L-ornithyl-L-threonyl-
`
`trans-4-hydroxy-L-prolyl-(S)-4-hydroxy-4-(p-hydroxyphenyl)-L-threonyl-threo-3-hydroxy-L-ornithyl-trans-3-
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`hydroxy-L-proline cyclic (6-1)-peptide. It has the molecular formula C56H96N10O19 corresponding to a relative
`molecular mass of 1213.42 g/mol and it has the following structure:
`
`
`
`The structure of caspofungin acetate was elucidated by a combination of 1D and 2D 1H and 13C NMR
`spectroscopy, IR spectroscopy, UV spectroscopy, LCMS/MS and elemental analysis. Comparison of IR, UV and
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`HPLC spectra with those of the reference product provided further proof of structure.
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`Caspofungin acetate is a white to off-white hygroscopic amorphous powder and is freely soluble in water. It is
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`sensitive to humidity and heat but is not photosensitive. The finished product is a lyophilised powder which is
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`produced under conditions which minimise degradation.
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`Caspofungin acetate contains 16 chiral centres. Of these, 15 are controlled in the constituent amino acids and
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`by the fermentation process. The final centre is introduced selectively in the final step of the synthetic
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`process. Only two of the chiral centres are at all chemically labile which would result in diastereomers,
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`detectable by HPLC. A test for specific optical rotation is included in the active substance specifications.
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`Polymorphism has not been observed for caspofungin acetate and it is only known in the amorphous form.
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`Manufacture, characterisation and process controls
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`Detailed information on the manufacturing process of the active substance has been provided in the
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`restricted part of the ASMF and it was considered satisfactory.
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`Three manufacturers are involved in the production of Caspofungin. The first two carry out a fermentation
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`with different processes and on different scales to produce an intermediate. The third manufacturer then
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`converts the intermediate into the active substance, the quality of which is equivalent, irrespective of which
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`fermentation process is used. The starting materials were re-defined during the procedure at the request of
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`CHMP in order to ensure the quality of the active substance throughout the product lifecycle.
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`A series of purification steps are carried out to remove impurities and ensure the purity of the active
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`substance. Stereochemistry originates in the raw material inputs and is controlled by the organism during
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`fermentation. Stereochemistry at the aminal centre is maintained during the final substitution reaction under
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`substrate control.
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`Adequate in-process controls are applied during the synthesis. The specifications and control methods for
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`intermediate products, starting materials and reagents have been presented and considered satisfactory.
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`Potential and actual impurities were well discussed with regards to their origin and characterised. The purge
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`of catalyst residues is ensured by the heavy metals and elemental impurities tests in the active substance
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`specification. Adequate purge of reagents and their by-products has been demonstrated.
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`The active substance is packaged in a laminated aluminium bag, sealed by heat welding, and stored inside a
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`second identical bag. The materials comply with EC directive 2002/72/EC and EC 10/2011 as amended.
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`Specification
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`The active substance specification includes tests for appearance, identity (IR, HPLC-UV (caspofungin and
`
`acetate), specific optical rotation), sulphated ash (Ph. Eur.), heavy metals (Ph. Eur.), elemental impurities
`
`(ICP-MS), pH (Ph. Eur.), residual solvents (GC), related substances (HPLC), water content (KF), acetate
`
`content (HPLC-UV), assay (HPLC) and microbiological quality (Ph. Eur.).
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`Impurities present at higher than the qualification threshold according to ICH Q3A were either set at levels
`
`equivalent to the originator active substance or qualified by toxicological studies and appropriate
`
`specifications have been set. Acceptance criteria for heavy metals elemental impurities ensure adequate
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`purge of metal catalysts and appropriate levels have also been set for residual solvents used in the synthetic
`
`process.
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`The analytical methods used have been adequately described and non-compendial methods appropriately
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`validated in accordance with the ICH guidelines. Satisfactory information regarding the reference standards
`
`used for assay and impurities testing has been presented.
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`Batch analysis data on three production scale batches of active substance made with intermediate from both
`
`sources was provided. The results were within the specifications and consistent from batch to batch.
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`Stability
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`Stability data on three production scale batches of caspofungin acetate from the proposed manufacturer
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`stored in the intended commercial package for up to 24 months under long term conditions (-80 ± 10 °C)
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`and for up to 6 months under accelerated conditions (-20 ± 5 °C) according to the ICH guidelines were
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`provided. The following parameters were tested: appearance, water content, related substances and assay.
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`The analytical methods used were the same as for release and were stability indicating. All tested parameters
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`were well within specification at all time-points and no significant trends were observed.
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`Forced degradation studies were carried out in solution and in the solid state. Solid caspofungin acetate is
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`very sensitive to heat and humidity whilst in solution, degrading under both acidic and basic conditions.
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`Photostability testing following the ICH guideline Q1B was also performed on one batch and the active
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`substance shown not to be photosensitive.
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`A further study on one batch stored at 5 ± 3 oC showed that the active substance is stable at this
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`temperature for up to one month. Thus, short term temperature excursions during shipping should not affect
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`the quality of caspofungin acetate.
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`The stability results indicate that the active substance manufactured by the proposed supplier is sufficiently
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`stable. The stability results justify the proposed retest period of 24 months stored in the proposed container
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`at -80 ± 10 °C.
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`2.2.3. Finished medicinal product
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`Description of the product and Pharmaceutical development
`
`The aim of development was to develop a finished product equivalent to that of the reference medicinal
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`product, Cancidas. Accordingly, the quality target product profile (QTPP) was defined following analysis of
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`Cancidas as a lyophilised powder for concentrate for solution for IV infusion with the same active substance
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`and excipient content, appearance and container that meets compendial and other relevant quality standards
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`for assay, purity, microbial quality and is stable over a suitable shelf-life. Critical quality attributes (CQAs)
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`identified were sterility, appearance and reconstitution characteristics, assay, purity and stability.
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`Caspofungin acetate is highly soluble in aqueous media but sensitive to heat, oxygen and extremes of pH.
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`Optimum stability is achieved between pH 5 and 7. In order to ensure stability during compounding and
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`reconstitution, as well as suitable osmolarity, a series of buffers was examined. Succinic acid was chosen
`
`since, out of those investigated, it has the best buffering capacity between pH 5.5 and 6.5, results in less
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`degradation, and produces a reconstituted solution of suitable osmolarity for infusion. It also enables
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`production of a satisfactory cake following lyophilisation.
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`Other than the buffering agent, the composition is quantitatively and qualitatively identical to that of
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`Cancidas. All excipients are well known pharmaceutical ingredients and their quality is compliant with Ph. Eur.
`
`or other relevant standards. There are no novel excipients used in the finished product formulation. The list
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`of excipients is included in section 6.1 of the SmPC and in paragraph 2.1.1 of this report.
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`During manufacture, compounding is carried out at 2-8 oC under an argon atmosphere with the exclusion of
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`oxygen to minimise degradation. Stirrer speed is limited to prevent foaming. The unrefrigerated holding time
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`between compounding and lyophilisation is appropriately controlled. Excipients are dissolved first and pH
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`adjusted to 5.5-5.7 which minimises the compounding time of the active substance and results in a final bulk
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`solution of pH 5.9-6.1. Each vial is over-filled in order to enable extraction of 10 ml of reconstituted solution
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`containing the required (5.2 or 7.2 mg/ml depending on the strength/dose) concentration. Limits for the
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`filling process have been set based on the equipment capability and assay limits of the finished product.
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`Appropriate limits have also been set for compounding, filling and overall processing times in order to
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`minimise degradation.
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`Temperature and pressure at various stages of the lyophilisation process were optimised in order to ensure
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`an adequate cake appearance, prevent collapse, and minimise the formation of degradants.
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`The entire process is carried out aseptically since the finished product is both heat and oxygen sensitive and
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`thus not compatible with terminal sterilisation. Seal integrity was demonstrated, thus preventing oxygen or
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`moisture ingress throughout shelf-life.
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`The primary packaging is a type I clear glass vial with bromobutyl rubber stopper and aluminium seal with
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`transparent plastic flip off button. The materials comply with Ph. Eur. and EC requirements. The container
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`closure system chosen is similar to that of the reference medicinal product. Compatibility with the materials
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`has been demonstrated, in particular, with the rubber stopper. The choice of the container closure system
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`has been validated by stability data and is adequate for the intended use of the product.
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`Manufacture of the product and process controls
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`The manufacturing process consists of five main steps carried out aseptically: compounding; sterile filtration;
`
`filling; lyophilisation; sealing. The compounding is carried out under a continuous flow or argon with checks
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`for dissolved oxygen and pH before addition of the active substance. The process is considered to be a non-
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`standard manufacturing process.
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`The applicant originally proposed to manufacture the product on two separate scales. The process has been
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`validated on three consecutive batches of each strength at the smaller scale. However, the larger scale
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`process has not yet validated and being a non-standard process, this is not considered acceptable. Therefore,
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`only the smaller scale can be used commercially until full validation on the larger scale has been performed.
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`The larger proposed manufacturing scales will need to be applied for post-authorisation.
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`It has been demonstrated that the smaller scale manufacturing processes are capable of producing the
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`finished product of intended quality in a reproducible manner. The in-process controls are adequate for this
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`aseptic process, given the sensitivity of the active substance.
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`Product specification
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`The finished product release specifications are appropriate for this kind of dosage form and include tests for
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`appearance, identification (IR, HPLC), pH of solution (Ph. Eur.), completeness, clarity and colour of solution
`
`(Ph. Eur. or in-house methods), water content (KF), assay (HPLC), related substances (HPLC), deliverable
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`volume (Ph. Eur.), particulate contamination (Ph. Eur.), uniformity of dosage units (Ph. Eur.), sterility (Ph.
`
`Eur.) and bacterial endotoxins (Ph. Eur.). Several degradation products and water content increase during
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`storage and therefore, limits are different for release and during shelf-life. Nonetheless, these limits are
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`appropriate since the impurities are either known in vivo metabolites or toxicologically qualified.
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`Separate in-use shelf life specifications have been provided with wider limits for impurities given that these
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`parameters were outside of specification following reconstitution (see stability section for details).
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`The analytical methods used have been adequately described and appropriately validated in accordance with
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`the ICH guidelines. Satisfactory information regarding the reference standards used for assay and impurities
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`testing has been presented.
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`Batch analysis results are provided for three production scale batches of each strength confirming the
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`consistency of the manufacturing process and its ability to manufacture to the intended product specification.
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`Stability of the product
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`Stability data on three production scale batches of each strength stored for up to 18 months (50 mg) or for
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`up to 24 months (70 mg) under long term conditions (5 ± 3 °C) and for up to 6 months under accelerated
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`conditions (25 °C / 60% RH) in line with the ICH guidelines was provided. The batches of finished product are
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`identical to and packed in the same primary packaging as those proposed for marketing and were stored
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`either upright or inverted. Samples were tested for appearance, pH of solution, completeness, clarity and
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`colour of solution, water content, assay, related substances, particulate contamination, sterility and bacterial
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`endotoxins. A trend of increasing impurities was observed for both strengths although the levels were well
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`within the specifications at the latest time-point. Water content appears to increase initially but is then stable
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`or decreases. Therefore, the wider limits for impurities, assay, and water content in the shelf-life
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`specifications are justified.
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`In addition, one batch of the 70 mg presentation was exposed to light as defined in the ICH Guideline on
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`Photostability Testing of New Drug Substances and Products. No differences were observed between the
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`exposed sample and a control sample stored in the dark. Thus, Caspofungin Accord is not photosensitive.
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`Forced degradation studies were carried out in the solid state (exposure to heat) and in solution (exposed to
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`acid, base, oxidant and heat). Significant degradation was seen under all conditions via different pathways.
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`In-use stability studies were carried out on the 70 mg vial as this was shown to be the worst case scenario in
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`terms of degradation. The product was treated according to the administration instructions in the SmPC
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`(section 4.2). Following reconstitution as a concentrate with either 0.9% saline solution or lactated Ringer’s
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`solution, two impurities increase over time. One is a hydrolysis product and in vivo metabolite, the other a
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`dimer. On subsequent dilution into infusion bags, the amount of hydrolysis product continues to increase
`
`whilst the amount of dimer decreases. The levels of impurities are higher than stated in the release and
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`shelf-life specifications. Therefore, separate in-use shelf life specifications have been provided with wider
`limits for impurities. This is considered acceptable and an in-use shelf-life of 24 hours at 25 oC for the
`concentrate and 24 hours at 25 oC or 48 hours refrigerated for the diluted solution is acceptable,
`
`notwithstanding microbiological recommendations as stated in the SmPC (section 6.3).
`
`Based on available stability data, the proposed shelf-life 2 years stored in a refrigerator at 5 ± 3 °C as stated
`
`in the SmPC (sections 6.3 and 6.4) is acceptable.
`
`Adventitious agents
`
`No excipients derived from animal or human origin have been used.
`
`2.2.4. Discussion on chemical, and pharmaceutical aspects
`
`Information on development, manufacture and control of the active substance and finished product has been
`
`presented in a satisfactory manner. The results of tests carried out indicate consistency and uniformity of
`
`important product quality characteristics, and these in turn lead to the conclusion that the product should
`
`have a satisfactory and uniform performance in clinical use. Due to the inherent instability of the active
`
`substance, precautions have been taken in terms of storage conditions, and in-use stability specifications
`
`have been provided.
`
`2.2.5. Conclusions on the chemical, pharmaceutical and biological aspects
`
`The quality of this product is considered to be acceptable when used in accordance with the conditions
`
`defined in the SmPC. Physicochemical and biological aspects relevant to the uniform clinical performance of
`
`the product have been investigated and are controlled in a satisfactory way.
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`2.2.6. Recommendations for future quality development
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`Not applicable.
`
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`Assessment report
`EMA/32587/2016
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`Page 11/18
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`AMNEAL EX. 1015
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`2.3. Non-clinical aspects
`
`2.3.1. Introduction
`
`A non-clinical overview on the pharmacology, pharmacokinetics and toxicology has been provided, which is
`
`based on up-to-date and adequate scientific literature. The overview justifies why there is no need to
`
`generate additional non-clinical pharmacology, pharmacokinetics and toxicology data. The non-clinical
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`aspects of the SmPC are in line with the SmPC of the reference product. The impurity profile has been
`
`discussed and was considered acceptable.
`
`Therefore, the CHMP agreed that no further non-clinical studies are required.
`
`2.3.2. Ecotoxicity/environmental risk assessment
`
`No Environmental Risk Assessment was submitted. This was justified by the applicant as the introduction of
`
`Caspofungin Accord manufactured by Accord Healthcare Ltd. is considered unlikely to result in any significant
`
`increase in the combined sales volumes for all caspofungin containing products and the exposure of the
`
`environment to the active substance. CHMP agreed that the risk for the environment is not expected to be
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`increased.
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`
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`2.3.3. Toxicology
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`Excipients
`
`The excipients used in Caspofungin Accord are commonly used in oral products. With exception of the
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`buffering agent succinic acid, the excipients are the same as for the originator Cancidas (MSD). Thus, no
`
`toxicological qualification is considered necessary.
`
`Impurities
`
`Compared to the reference product Cancidas (MSD), higher levels for identified drug product impurities have
`
`been proposed.
`
`Impurity B is the primary degradation product of caspofungin, but also the major systemic human
`
`metabolite. Consequently, this impurity can be accepted at levels exceeding specifications for Cancidas
`
`without any further toxicological qualification.
`
`Impurity C is a degradation product of caspofungin formed by reaction of two caspofungin molecules with
`
`each other. The Applicant has performed a safety assessment based on results from non-clinical studies
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`conducted previously with the reference product Cancidas (MSD) in order to justify the proposed limits. This
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`was considered acceptable by CHMP.
`
`A genotoxicity evaluation of caspofungin acetate impurities and raw materials did not identify any alerting
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`structures.
`
`Impurity at RRT 1.23 is a degradation product formed only in solid state and only in lyophilized product when
`
`it is exposed to heat. This impurity is controlled according to ICH Q3B (R2), although fermentation products
`
`are not covered by the scope of Q3B. This was considered acceptable by CHMP.
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`Assessment report
`EMA/32587/2016
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`Page 12/18
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`AMNEAL