14 September 2017
`EMA/CHMP/690823/2017
`Committee for Medicinal Products for Human Use (CHMP)
`
`Assessment report
`
`Nyxoid
`
`International non-proprietary name: naloxone
`
`Procedure No. EMEA/H/C/004325/0000
`
`Note
`
`Assessment report as adopted by the CHMP with all information of a commercially confidential nature
`deleted.
`
`Opiant Exhibit 2089
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00688
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`Administrative information
`
`Name of the medicinal product:
`
`Nyxoid
`
`Applicant:
`
`Mundipharma Corporation Limited
`Milton Road
`Cambridge Science Park
`Cambridge
`CB4 0AB
`UNITED KINGDOM
`
`Active substance:
`
`NALOXONE HYDROCHLORIDE DIHYDRATE
`
`International Non-proprietary Name/Common
`Name:
`
`naloxone
`
`Pharmaco-therapeutic group
`(ATC Code):
`
`Therapeutic indication(s):
`
`all other therapeutic products, antidotes
`(V03AB15)
`
`Nyxoid is intended for immediate
`administration as emergency therapy for
`known or suspected opioid overdose as
`manifested by respiratory and/or central
`nervous system depression in both
`non-medical and healthcare settings.
`
`Nyxoid is indicated in adults and adolescents
`aged 14 years and over.
`
`Nyxoid is not a substitute for emergency
`medical care.
`
`Pharmaceutical form(s):
`
`Nasal spray, solution in single-dose container
`
`Strength(s):
`
`Route(s) of administration:
`
`1.8 mg
`
`Nasal use
`
`Packaging:
`
`Package size(s):
`
`single dose spray container
`
`2 spray containers
`
`Opiant Exhibit 2089
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00688
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`
`
`Table of contents
`
`1. Background information on the procedure .............................................. 7
`1.1. Submission of the dossier ..................................................................................... 7
`1.2. Steps taken for the assessment of the product ........................................................ 9
`2. Scientific discussion .............................................................................. 10
`Problem statement ................................................................................................... 10
`2.1. Quality aspects .................................................................................................. 11
`2.1.1. Introduction.................................................................................................... 11
`2.1.2. Active Substance ............................................................................................. 11
`2.1.3. Finished Medicinal Product ................................................................................ 12
`2.1.4. Discussion on chemical, pharmaceutical and biological aspects.............................. 16
`2.1.5. Conclusions on the chemical, pharmaceutical and biological aspects ...................... 16
`2.1.6. Recommendations for future quality development ............................................... 16
`2.2. Non-clinical aspects ............................................................................................ 16
`2.2.1. Introduction.................................................................................................... 16
`2.2.2. Pharmacology ................................................................................................. 17
`2.2.3. Pharmacokinetics ............................................................................................ 17
`2.2.4. Toxicology ...................................................................................................... 17
`2.2.5. Ecotoxicity/environmental risk assessment ......................................................... 18
`2.2.6. Discussion on non-clinical aspects ..................................................................... 20
`2.2.7. Conclusion on the non-clinical aspects ............................................................... 20
`2.3. Clinical aspects .................................................................................................. 20
`2.3.1. Introduction.................................................................................................... 20
`2.3.2. Pharmacokinetics ............................................................................................ 21
`2.3.3. Pharmacodynamics .......................................................................................... 26
`2.3.4. Discussion on clinical pharmacology ................................................................... 27
`2.3.5. Conclusions on clinical pharmacology ................................................................. 28
`2.4. Clinical efficacy .................................................................................................. 28
`2.4.1. Discussion on clinical efficacy ............................................................................ 43
`2.4.2. Conclusions on the clinical efficacy .................................................................... 44
`2.5. Clinical safety .................................................................................................... 44
`2.5.1. Discussion on clinical safety .............................................................................. 50
`2.5.2. Conclusions on the clinical safety ...................................................................... 50
`2.6. Risk Management Plan ........................................................................................ 51
`2.7. Pharmacovigilance ............................................................................................. 52
`2.8. Product information ............................................................................................ 53
`2.8.1. User consultation ............................................................................................ 53
`3. Benefit-Risk Balance ............................................................................. 53
`3.1. Therapeutic Context ........................................................................................... 53
`
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`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00688
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`3.1.1. Disease or condition ........................................................................................ 53
`3.1.2. Available therapies and unmet medical need ....................................................... 53
`3.1.3. Main clinical studies ......................................................................................... 54
`3.2. Favourable effects .............................................................................................. 54
`3.3. Uncertainties and limitations about favourable effects ............................................. 55
`3.4. Unfavourable effects ........................................................................................... 55
`3.5. Uncertainties and limitations about unfavourable effects ......................................... 55
`3.6. Benefit-risk assessment and discussion ................................................................. 55
`3.6.1. Importance of favourable and unfavourable effects .............................................. 55
`3.6.2. Balance of benefits and risks ............................................................................ 56
`3.7. Conclusions ....................................................................................................... 56
`4. Recommendations ................................................................................. 57
`
`
`
`
`Opiant Exhibit 2089
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00688
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`List of abbreviations
`
`
`
`BDP
`
`CEP
`
`CFU
`
`Bulk drug product
`
`Certificate of Suitability
`
`Colony Forming Units
`
`CHMP
`
`Committee for Medicinal Products for Human use
`
`CPP
`
`CU
`
`DDU
`
`DSC
`
`CQA
`
`GMP
`
`EC
`
`Critical process parameters
`
`Content uniformity
`
`Delivered dose uniformity
`
`Differential Scanning Calorimetry
`
`Critical quality attributes
`
`Good manufacturing practices
`
`European Commission
`
`EDQM
`
`European Directorate for the Quality of Medicines & Healthcare
`
`ERA
`
`FAO
`
`Extended risk assessment
`
`Food and Agriculture Organization of the United Nations
`
`HDPE
`
`High Density Polyethylene
`
`HLRA
`
`High level risk assessment
`
`HPLC
`
`High performance liquid chromatography
`
`IPC
`
`In-process control
`
`IRMP
`
`Integrated risk mitigation plan
`
`MV
`
`mass variation
`
`NMT
`
`Not more than
`
`Ph.Eur. European Pharmacopoeia
`
`PRA
`
`QbD
`
`QP
`
`q.s.
`
`Process risk assessment
`
`Quality by design
`
`Qualified person
`
`quantum satis (the amount which is sufficient)
`
`QTPP
`
`Quality target product profile
`
`SCFM
`
`Standard cubic feet of gas per minute
`
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`SmPC
`
`Summary of Product Characteristics
`
`TAMC
`
`Total aerobic microbial count
`
`TGA
`
`Thermo-Gravimetric Analysis
`
`TYMC
`
`Total yeasts/moulds count
`
`TSE
`
`UDS
`
`Transmissible spongiform encephalopathy
`
`Unit dose
`
`UDVs
`
`Unit dose vials
`
`UV
`
`Ultraviolet
`
`WHO World Health Organisation
`
`
`
`Opiant Exhibit 2089
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00688
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`1. Background information on the procedure
`
`1.1. Submission of the dossier
`
`The applicant Mundipharma Corporation Limited submitted on 1 November 2016 an application for marketing
`authorisation to the European Medicines Agency (EMA) for Nyxoid, through the centralised procedure under
`Article 3 (2) (b) of Regulation (EC) No 726/2004. The eligibility to the centralised procedure was agreed upon
`by the EMA/CHMP on 19 November 2015. The eligibility to the centralised procedure under Article 3(2)(b) of
`Regulation (EC) No 726/2004 was based on demonstration of interest of patients at Community level.
`
`The application concerns a hybrid medicinal product as defined in Article 10(3) of Directive 2001/83/EC and
`refers to a reference product, as defined in Article 10 (2)(a) of Directive 2001/83/EC, for which a marketing
`authorisation is or has been granted in a Member State on the basis of a complete dossier in accordance
`with Article 10a of Directive 2001/83/EC.
`
`
`
`The applicant applied for the following indication:
`
`Nyxoid is intended for emergency use for known or suspected opioid overdose as manifested by respiratory
`and/or central nervous system depression in:
`
`the home or other non-medical setting
`
`a health facility setting
`
`•
`
`•
`
`
`
`For this reason, Nyxoid should be carried by persons at risk of, or likely to witness such events.
`
`Nyxoid is indicated in adults and children.
`
`
`
`The legal basis for this application refers to:
`
`Hybrid application (Article 10(3) of Directive No 2001/83/EC).
`
`The application submitted is
`
`composed of administrative information, complete quality data, a bioequivalence study with the reference
`medicinal product Naloxon HCl B. Braun and appropriate non-clinical and clinical data
`
`The chosen reference product is:
`
`Medicinal product which is or has been authorised in accordance with Community provisions in force for not
`less than 6/10 years in the EEA:
`
`•
`
`Product name, strength, pharmaceutical form: Naloxon HCl B. Braun 0.4mg/ml, solution for injection
`
`• Marketing authorisation holder: B.Braun Melsungen AG
`
`• Date of authorisation: 22-08-2006
`
`
`
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`• Marketing authorisation granted by:
`− Member State (EEA) : Netherlands
`MRP
`
`−
`
`• Marketing authorisation number: RVG 33994
`
`Medicinal product authorised in the Community/Member State where the application is made or European
`reference medicinal product:
`
`•
`
`Product name, strength, pharmaceutical form: Naloxon HCl B. Braun 0.4mg/ml, solution for injection
`
`• Marketing authorisation holder: B.Braun Melsungen AG
`
`• Date of authorisation: 16-07-2007
`
`• Marketing authorisation granted by:
`− Member State (EEA): Germany
`MRP
`
`−
`
`• Marketing authorisation number: 67923.00.00
`
`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:
`
`•
`
`Product name, strength, pharmaceutical form: Naloxon HCl B. Braun 0.4mg/ml, solution for injection
`
`• Marketing authorisation holder: B.Braun Melsungen AG
`
`• Date of authorisation: 16-07-2007
`
`
`
`• Marketing authorisation granted by:
`− Member State (EEA): Germany
`MRP
`
`−
`
`• Marketing authorisation number(s): 67923.00.00
`
`
`
`• Bioavailability study number(s): 2015-004493-15
`
`Information on Paediatric requirements
`
`Not applicable.
`
`Information relating to orphan market exclusivity
`
`Similarity
`
`Pursuant to Article 8 of Regulation (EC) No. 141/2000 and Article 3 of Commission Regulation (EC) No
`847/2000, the applicant did not submit a critical report addressing the possible similarity with authorised
`
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`orphan medicinal products because there is no authorised orphan medicinal product for a condition related to
`the proposed indication.
`
`
`Applicant’s request(s) for consideration
`
`Accelerated assessment
`
`The applicant requested accelerated assessment in accordance to Article 14 (9) of Regulation (EC) No
`726/2004.
`
`Scientific Advice
`
`The applicant received Scientific Advice from the CHMP on 19 November 2015. The Scientific Advice
`pertained to non-clinical and clinical aspects of the dossier.
`
`1.2. Steps taken for the assessment of the product
`
`The Rapporteur and Co-Rapporteur appointed by the CHMP were:
`
`Rapporteur: Bruno Sepodes
`
`Co-Rapporteur: Juris Pokrotnieks
`
`• The application was received by the EMA on 1 November 2016.
`
`• The procedure started on 24 November 2016.
`
`• The Rapporteur's first Assessment Report was circulated to all CHMP members on 20 February 2017.
`The Co-Rapporteur's first Assessment Report was circulated to all CHMP members on 15 February 2017.
`The PRAC Rapporteur's first Assessment Report was circulated to all PRAC members on 28 February
`2017.
`
`• During the meeting on 23 March 2017, the CHMP agreed on the consolidated List of Questions to be
`sent to the applicant.
`
`• The applicant submitted the responses to the CHMP consolidated List of Questions on 18 May 2017.
`
`• The following GMP inspection(s) were requested by the CHMP and their outcome taken into
`consideration as part of the Quality/Safety/Efficacy assessment of the product:
`
`A GMP inspection at one site responsible for manufacture of the finished product located in USA
`performed at 19 June 2017. The outcome of the inspection carried out was issued on 04 September
`2017.
`
`• The Rapporteurs circulated the Joint Assessment Report on the applicant’s responses to the List of
`Questions to all CHMP members on 30 June 2017.
`
`•
`
`During the PRAC meeting on 06 July 2017, the PRAC agreed on the PRAC Assessment Overview and
`Advice to CHMP.
`
`• During the CHMP meeting on 20 July 2017, the CHMP agreed on a list of outstanding issues to be sent
`to the applicant.
`
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`• The applicant submitted the responses to the CHMP List of Outstanding Issues on 15 August 2017.
`
`• The Rapporteurs circulated the Joint Assessment Report on the applicant’s responses to the List of
`Outstanding Issues to all CHMP members on 31 August 2017.
`
`• During the meeting on 14 September 2017, the CHMP, in the light of the overall data submitted and the
`scientific discussion within the Committee, issued a positive opinion for granting a marketing
`authorisation to Nyxoid on 14 September 2017.
`
`2. Scientific discussion
`
`Problem statement
`
`Naloxone is a widely accepted opioid antagonist used to reverse respiratory depression caused by opioid
`overdose. It has been used in emergency medicine since the 1970s. Naloxone is listed by World Health
`Organisation (WHO) as an “essential medicine” and is traditionally available in injectable forms. Parenteral
`(IV, IM or SC) naloxone is commonly used in the treatment of reversing opioid overdose with a dose range
`from 0.4 mg to 2 mg.
`
`Naloxone is a µ-opioid competitive antagonist with affinity for µ-opioid receptor (and partly at the δ-opioid
`receptor) that competes with other drugs for this receptor thereby controlling this specific opioid receptor.
`Due to this property, naloxone is able to reverse the effects of opioids such as heroin by preventing their
`metabolites to influence the receptor’s normal function. This reversal effect is very rapid.
`
`About the product
`
`Naloxone 1.8 mg nasal spray, solution is intended for immediate administration as emergency therapy for
`known or suspected opioid overdose as manifested by respiratory and/or central nervous system depression.
`
`The nasal spray has the potential to remove the psychological and policy barriers which can prevent
`availability of existing injectable forms of naloxone for emergency administration in the first minutes
`following an opioid overdose.
`
`The rationale for the development of intranasal naloxone builds on the background of take home naloxone
`(THN) programmes and improves on current improvised IN naloxone use.
`
`Type of Application and aspects on development
`
`The CHMP did not agree to the applicant’s request for an accelerated assessment as the product was not
`considered to be of major public health interest. This was based on the fact that the Applicant did not
`demonstrate the unmet medical need.
`
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`2.1. Quality aspects
`
`2.1.1. Introduction
`
`The finished product is presented as nasal spray, solution in a single dose container containing 1.8 mg of
`naloxone (as hydrochloride dihydrate) as active substance.
`
`Other ingredients are: trisodium citrate dihydrate, sodium chloride, hydrochloric acid, sodium hydroxide and
`purified water.
`
`The product is available in a type I glass vial with siliconised chlorobutyl stopper containing 0.1 ml solution.
`The secondary packaging (actuator) is comprised of polypropylene and stainless steel, as described in section
`6.5 of the SmPC.
`
`2.1.2. Active Substance
`
`General information
`
`The chemical name of naloxone hydrochloride dihydrate is (5R,9R,13S,14S)-17-(prop-2-enyl)-3,14-
`dihydroxy-4,5-epoxymorphinan-6-one hydrochloride corresponding to the molecular formula
`C19H22ClNO4·2H2O. It has a relative molecular mass of 399.9 and the following structure:
`
`Figure 1 – Structural formula of naloxone hydrochloride dihydrate
`
`
`
`The active substance is a white or almost white, hygroscopic, crystalline powder, freely soluble in water,
`soluble in ethanol (96 per cent) and practically insoluble in toluene.
`
`The structure of the molecule and its hydrate form have been characterised using common analytical
`techniques. Analysis has confirmed that naloxone hydrochloride used to manufacture Nyxoid is present in the
`dihydrate form.
`
`The finished product contains the active substance in the form of a solution and consequently properties such
`as particle size distribution and polymorphism of the active substance of are of no relevance when it comes to
`clinical performance of the product.
`
`Naloxone exhibits stereoisomerism due to the presence of four chiral centres; this is controlled routinely
`using standard techniques.
`
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`As there is a monograph of naloxone hydrochloride dihydrate in the European Pharmacopoeia, the
`manufacturer of the active substance has been granted a Certificate of Suitability of the European
`Pharmacopoeia (CEP) for naloxone hydrochloride dihydrate which has been provided within the current
`Marketing Authorisation Application.
`
`The relevant information regarding proof of structure studies and physicochemical characterisation has been
`assessed by the EDQM before issuing the Certificate of Suitability.
`
`Manufacture, characterisation and process controls
`
`The relevant information has been assessed by the EDQM before issuing the Certificate of Suitability.
`
`Specification
`
`The active substance specification includes tests for: appearance (visual), identity (IR), identity of chlorides
`(Ph. Eur.), appearance of solution (Ph. Eur.), acidity or alkalinity (Ph. Eur.), specific optical rotation (Ph.
`Eur.), related substances (HPLC), water (Ph. Eur.), sulfated ash (Ph. Eur.), assay (Ph. Eur.) and residual
`solvents (GC).
`
`The analytical methods used have been adequately described and non-compendial methods appropriately
`validated in accordance with the ICH guidelines. Satisfactory information regarding the reference standards
`used for assay and impurities testing has been presented.
`
`The control tests were carried out to comply with the specifications and test methods of the Ph. Eur.
`monograph.
`
`Batch analysis data (n=3, commercial scale) of the active substance are provided. The results are within the
`specifications and consistent from batch to batch.
`
`Stability
`
`The relevant information has been assessed by the EDQM before issuing the Certificate of Suitability. The re-
`test period of the active substance as stated in the Certificate of Suitability is 36 months if stored in two
`polyethylene bags placed in an opaque container.
`
`Comparability exercise for Active Substance
`
`Not applicable.
`
`2.1.3. Finished Medicinal Product
`
`Description of the product and pharmaceutical development
`
`The finished product is presented as a nasal spray, solution in a single dose container containing 1.8 mg of
`naloxone (as hydrochloride dihydrate) as active substance. The solution is contained in a Type I clear glass
`vial, sealed with a chlorobutyl elastomer stopper/plunger that is fitted into a non-reusable, Unit Dose System
`
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`(UDS) nasal spray which delivers 100 μl of solution as a single dose. The finished product is comprised of two
`individually blister-packaged units of naloxone 1.8mg nasal spray contained in a single cardboard carton.
`
`The aim of the pharmaceutical development was to develop a naloxone hydrochloride solution suitable for
`nasal administration.
`
`The pharmaceutical development of the finished product contains Quality by Design (QbD) elements.
`
`A process risk assessment was performed to identify any areas that require risk mitigation or further
`development activities prior to process validation and commercialization. This was made by identifying the
`product CQAs and the critical process parameters (CPP) with respect to the operations and activities of
`component supply, manufacturing process and packaging process. The methodology used for this purpose
`comprised a high-level and extended risk assessment leading to an integrated risk mitigation plan. None of
`the risks identified were assigned as high. The medium risks identified in the risk assessment were further
`assessed in an extended risk assessment and corresponding integrated risk mitigation plans were
`recommended.
`
`Naloxone hydrochloride dihydrate is freely soluble in water and therefore is appropriate for delivery in an
`aqueous solution. As mentioned above, the particle size of active substance is not relevant for the
`performance of the nasal solution.
`
`All excipients are well known pharmaceutical ingredients and their quality is compliant with Ph. Eur
`standards. There are no novel excipients used in the finished product formulation. The list of excipients is
`included in section 6.1 of the SmPC and in paragraph 2.1.1 of this report.
`
`Compatibility of the active substance and the excipients was confirmed in the stability studies.
`
`The pH of formulation is important in order to avoid irritation of the nasal mucosa and the pH of the solution
`has an impact on the product stability. Therefore, a buffer is included in the formulation to control the
`product pH.
`
`The original indication claimed by the applicant included children of all ages including new-borns. However,
`the pharmaceutical development section of the dossier lacked a discussion on the suitability of the proposed
`product for the paediatric population, including a discussion on suitability of the tip of the nasal spray device
`(diameter of 1 cm) for the size of the nostrils/nasal cavity of the target age group(s). This constituted a
`major objection. In recognition of the lack of available data to support the original proposed indication
`including children, the applicant decided to revise the indication at the request of the CHMP to include adults
`and adolescents aged 14 and above only.
`
`The nasal spray produces a fine mist of droplets. The spray is formed by the liquid exiting the device spray
`orifice and was characterised. Pump delivery, spray content uniformity and droplet size distribution were also
`measured and limits included in the finished product specification.
`
`During pharmaceutical development of the finished product, the applicant assessed the impact of angle of
`orientation on the performance of the nasal spray, and submitted data concerning the effect of angle of
`orientation on pump delivery and droplet size distribution. The angle of actuation was found to have no
`impact on the volume of spray delivered (pump delivery). Droplet size distribution was measured by laser
`diffraction. Results showed d10, d50 and d90 were very similar with all angle orientations tested. These data
`confirmed that the spray characteristics and doses delivered were consistent and comparable for upright or
`angled spray delivery, and that the device performance was orientation independent.
`
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`The effect of dropping, vibration and shaking on device performance was also studied. Extractables and
`leachables from the primary container (vial, stopper/plunger and actuator) were also assessed. A discussion
`on potential delamination of glass vials was provided, being supported by long-term stability data.
`
`Prior to use, the drug product solution is in contact with the vial and plunger. During use the drug product
`passes through the actuator with momentary contact. The tip of the nasal actuator temporarily comes in
`contact with the patient during use. Studies were performed to determine the potential extractables from
`each component with patient and product contact.
`
`Controlled extraction studies targeting organic and inorganic compounds were performed on the
`polypropylene actuator, chlorobutyl elastomer stopper/plunger and Type I glass vial to determine the
`compounds which could potentially leach into the finished product from each component.
`
`One lot of finished product was placed on stability for 36 months and will be monitored for the presence of
`organic and inorganic leachables using the same analytical procedures used for the extraction studies.
`
`The finished product is supplied as a unit dose delivery system. The formulation contains no antimicrobial
`preservatives.
`
`The container closure system is comprised of primary and secondary packaging. The primary packaging is a
`type I glass vial with siliconised chlorobutyl stopper containing 0.1 ml solution. The material complies with
`Ph. Eur. and EC requirements. The secondary packaging comprises a container holder, into which the primary
`container is seated, which is subsequently assembled with an actuator to form the secondary packaging. The
`finished product is individually packaged in a blister pack with peel-off backing. The blister is not intended to
`enhance the stability of the product and is used as protective package for storage and labelling purposes.
`Two individual blister packs are packaged in a cardboard outer carton to form the patient pack, in line with
`posology. The choice of the container closure system has been validated by stability data and is adequate for
`the intended use of the product.
`
`Manufacture of the product and process controls
`
`The manufacturing process consists of five main steps: component preparation, formulation, filling and
`bioburden reduction step, inspection and assembly, and packaging.
`
`Major steps of the manufacturing process have been validated by a number of studies. The process is a
`standard manufacturing process, and the manufacturer is experienced in manufacturing nasal spray unit dose
`devices and its components.
`
`It has been demonstrated that the manufacturing process is capable of producing the finished product of
`intended quality in a reproducible manner. The in-process controls are adequate for this type of
`manufacturing process and pharmaceutical form.
`
`Product specification
`
`The finished product release specifications include appropriate tests for this kind of dosage form: description
`of product (visual), description of container (visual), pH (potentiometric, Ph. Eur.), identification (HPLC, UV),
`assay (HPLC), specified degradation products (HPLC), unspecified degradation products (HPLC), total
`degradation products (HPLC), spray content uniformity (HPLC), uniformity of dosage units (HPLC), microbial
`
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`limits (enumeration, Ph. Eur.), osmolality (osmometer, Ph. Eur.), pump delivery (weight), droplet size
`distribution (laser diffraction).
`
`The analytical methods used have been adequately described and appropriately validated in accordance with
`the ICH guidelines. Satisfactory information regarding the reference standards used for assay and impurities
`testing has been presented.
`
`Batch analysis results are provided for 3 commercial scale batches confirming the consistency of the
`manufacturing process and its ability to manufacture to the intended product specification.
`
`The finished product is released on the market based on the release specifications, through traditional final
`product release testing.
`
`Stability of the product
`
`Stability data from 3 commercial scale batches of finished product stored for up to 12 months under long
`term conditions (25 ºC / 60% RH), for up to 12 months under intermediate (30 ºC / 75% RH) and for up to 6
`months under accelerated conditions (40 ºC / 75% RH) according to the ICH guidelines were provided. The
`batches of medicinal product are identical to those proposed for marketing and were packed in the primary
`packaging proposed for marketing.
`
`Samples were tested for description of product, description of container, pH, identification, assay, specified
`degradation products, unspecified degradation products, total degradation products, spray content
`uniformity, uniformity of dosage units, microbial limits, osmolality, pump delivery, and droplet size
`distribution. The analytical procedures used are stability indicating. No significant changes were observed at
`any of the conditions tested
`
`Forced degradation studies were performed using stressed conditions: heat, acid, base, oxidation and light. It
`was shown that the product is sensitive to oxidation and basic conditions.
`
`In addition, a single batch was exposed to light as defined in the ICH Guideline on Photostability Testing of
`New Drug Substances and Products. Samples of the finished product solution were exposed to light in their
`primary container closure (vial and plunger stopper) and in their secondary container closure (container
`holder and actuator).
`
`A study was performed according to Ph. Eur. 2.2.18 to determine the freezing point of the finished product
`solution. The freezing point was determined, which was the basis for assigning a special storage condition ‘do
`not freeze’.
`
`Based on available stability data, the proposed shelf-life of 24 months and the storage precaution ‘do not
`freeze’ as stated in the SmPC (section 6.3) are acceptable.
`
`Comparability exercise for finished medicinal drug product
`
`Not applicable.
`
`Adventitious agents
`
`No excipients derived from animal or human origin have been used.
`
`Opiant Exhibit 2089
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00688
`Page 15
`
`

`

`GMO
`
`Not applicable.
`
`2.1.4. Discussion on chemical, pharmaceutical and biological aspects
`
`Information on development, manufacture and control of the active substance and finished product has been
`presented in a satisfactory manne