PLAINTIFFS'
`TRIAL EXHIBIT
`PTX0141 e
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`xhibitsticker.com
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`1
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`CIP2173
`Argentum Pharmaceuticals v. Cipla Ltd.
`IPR2017-00807
`
`

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`Investigation report: Dymista 6.4 g Nasal
`Spray Stability results
`
`Code:
`CQA'UB'0039/01
`
`Table of Contents
`
`1. Description of Incident ......................................................................................................... 3
`
`2. General Overview of the product and its processes ........................................................... 6
`
`3. Composition of the Product .................................................................................................... 7
`
`4. Manufacturing Flow .................................................................................................................. 8
`
`5. Investigation ............................................................................................................................ 10
`
`5.1
`
`Batch documentation ...................................................................................................... 10
`
`5.2 Analytical testing .............................................................................................................. 10
`
`5.3
`
`Investigation in production / packaging ........................................................................ 11
`
`6. Root Cause Analysis ............................................................................................................. 12
`
`7. Risk Assessment .................................................................................................................... 14
`
`8. CAPA........................................................................................................................................ 14
`
`9. Distribution of product ............................................................................................................ 14
`
`10. Conclusion ............................................................................................................................ 14
`
`File: CQA-UB-0039_01 Investigation RepOIt_Dymista.docx
`
`Page 2 of 14
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`CQA—U B-0039/O1
`
`Investigation report: Dymista 6.4 g Nasal
`Spray Stability results
`
`Code:
`
`1.
`
`Description of Incident
`
`Observations during stability studies:
`
`
`
`Specifications of parameters, where 003 results have been observed:
`
`
`Parameter
`Specification
`
`
`release and shelf-life
`
`
` shelf—life
`
`release and shelf-life
`
`
`
`
`
`Assay Azelastine HCI
`
`Assay Fluticasonpropionate
`
`Assay Benzalkonium chloride
`
`Assay Phenylethylalcohol
`
`Assay Disodium EDTA
`
`
`
`shelf-life
`
`
`release and shelf-life
`
`
`Delivered Dose Uniformity
`
`release and shelf-life
`
`
`
`
`
`
`
`shelf—life
`Weight loss
`
`
`All imported batches are undergoing EU—testing and all batches met the release specification
`and were released to the market.
`
`After the first 008 report forthe validation batches has been received, batch release for this
`product and manufacturing has been put on hold.
`
`A shelf life of 36 months is registered for the 6.49 and the 239 form as well.
`
`File: CQA-UB—003 9_01 Investigation Report_Dymista.docx
`
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`Investigation report: Dymista 6.4 g Nasal
`Spray Stability results
`
`Code:
`CQt’rUB-OOE‘29/01
`
`
`Product: Dymista Nasal Spray 6.4g
`
`
`
`F02100 06/2012
`F02100
`
`
`F02102 07/2012
`F02102
`
`
`F02106 07/2012
`
`F02106
`
`FC3188 05/2013
`
`F03188
`F03192
`FC3297
`
`FC3458
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`F04001 01/2014
`
`FC4001
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`Table 1: Finished product of Dymista 6.4g preparations with running stability studies
`
`File: CQA—UB—0039_01 Investigation Report_Dymista.docx
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`Investigation report: Dymista 6.4 g Nasal
`Spray Stability results
`
`Coder
`CQA'UB'OO39/01
`
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`()smolnli
`Dolivemd dose uniformity
`Weight
`Batch
`Comlmon/
`loss M ax.
`AS“),
`lJIdlYll‘Illtll—‘EIIUOS
`1y
`Orientation
`, 0%
`73—123‘m
`mosmol/
`-.
`,
`kg
`
`Alclnstine (‘r’d
`Flnticasono (‘1?)
`BAC (’32)
`PEA ("2)
`EDTA (’7)
`Azolnslinu
`Flutimwmm
`
`95.0 405.0“;
`95.0 405.0%
`80.0 405.01}
`70.0 - 105.05?
`90.0 - 110.0%
`
`
`
`
`FC 2100
`25”C/60%RH/
`
`
`upright
`FC 3100
`15“CIGD%RH/
`
`
`horimnlal
`
`
`25°C/60‘I’0RH/
`FC3103
`
`upright
`FC 2102
`Eff/60501111]
`horizontal
`FC 2 I06
`25°C/60%RH/
`
`upright
`
`FClIOE-
`25"CI60%RH/
`
`
`horizontal
`
`
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`
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`
`
`SOT/75%RHI
`FC 2100
`
`upright
`30“CflS%Rl—ll
`FCZIOO
`
`
`horizontal
`
`
`FC 2102
`30”Cfl5%RHI
`
`upright
`30“Cl75%RH/
`FC 2 [02
`
`horizontal
`30”C/75%RH/
`FC 2 I06
`upright
`FC 2I06
`30“U75%RH/
`horizontal
`
`
`
`Table 2: Summary of results of batches FCZ100, FC2102 and FC2106 after 24 months 25°C/
`60% r.h. and 30°C / 75% r.h.
`
`is stored in u ri ht and horizontal osition.
`
`
`
`Attachment 1: Complete stability tables of batches FCZ100, FCZ102 and FCZ106 at 25°C, 60%
`r.h. up to 24 months
`
`
`Batch
`Condition
`Weight
`Assay
`Assay
`Assay
`Delivered Dose
`loss Limit Azelastine
`Fluticasone
`Benzalkoniu
`Uniformity
`NMT
`Limit 95.0 —
`Limit 95.0 —
`mchloride
`Fluticasone Not more
`2.0%
`105.0%
`105.0%
`Limit 80.0 —
`than20ut0f20
`105.0%
`determinations are
`outside 80 - 120% of
`label claim, none is
`outside 75 — 125% of
`label claim for
`Azelastine HCl and
`Fluticason ro ionate
`
`
`
`
`
`
`FC3188
`
`25°C/
`60%r.h.
`
`Upright 18
`months
`
`
`
`Table 3: Summary of 003 results of batch FC3188 (18 months storage)
`
`
`
`File: CQA-UB-OO39*01 Investigation Report_Dymista.docx
`
`Page 5 of 14
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`Investigation report: Dymista 6.4 g Nasal
`Spray Stability results
`
`Code:
`CQA~Ul3-0039/01
`
`
`Condition
`months
`
`
`
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`Batch
`
`FC4001
`
`Assay Fluticasone Limit
`950 — 105.0%
`
`25°C/
`60%r.h.
`
`Upright 9
`
`
`
`Table 4: Summary of 003 results of batch FC4001 (9 months storage)
`
`2. General Overview of the product and its processes
`
`Dymista is a nasal spray with the two active pharmaceutical ingredients Azelastine HCI and
`Fluticasonepropionate. This fixed combination product was registered in the EU via a DCP
`submission and approved in January 2013 in EU. The product is marketed in two pack sizes.
`Vials with 6.49 (number of actuations >=28) and vials with 239 (number of actuations >= 120).
`The product is also registered in several Non—EU countries.
`The product manufacturing was first established at Cipla in Goal India in 2007 and transferred
`in 2012 to another Cipla manufacturing site of Cipla lndore/ India.
`
`The following sites are involved in the manufacturing process:
`
`
`
`All imported batches are undergoing EU-testing and all batches met the release specification
`and were released to the market.
`
`File: CQA-UB-0039_01 Investigation Rep01t_Dymista.docx
`
`Page 6 of 14
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`CQA—UB-OO39/O1
`
`Investigation report: Dymista 6.4 g Nasal
`Spray Stability results
`
`Code:
`
`3. Composition of the Product
`
`
`Function
`
`Amount % W/W
`
`mg/spray
`
`mg/g
`
`Quality
`component
`standard 1
`
`Azelastine
`
`hydrochloride
`Ph' Eur.
`
`Fluticasone propionate Ph. Eur.
`.
`.
`Ph. Eur./
`
`DISOdlulIl edetate
`L SP-NF
`Ph. Eur./
`
`Glycerol
`L SP—NF
`
`Ph. Eur./
`Miprpcrystalihne
`ce u ose an
`.
`2
`L SP—NF
`
`cannellose sodluIn
`
`Ph. Eur./
`
`Polysorbate 80
`L SP-NF
`Benzalkonium
`Ph. Eur/USP-
`
`chloride 3
`1\ F
`
`
`
`
`
`
`Phenylethyl alcohol
`USP-NF
`
`
`.
`Water, purified
`
`Ph. Eur./
`USP—NF
`
`4
`
`Ph. Eur./
`.
`L SP-NF
`Nitrogen
`
`Total
`
`] The quality complies with the re uirements of the monograph in its current version.
`2 Apparent viscosity
`3 Added as benzalkonium chloride solution
`4 Optionally, nitrogen may be used during compounding and as a processing aid during filling/pump application.
`
`Primary packaging components:
`
`Bottles:
`
`Dymista Nasal Spray 6.4g, Suspension is filled into Ph. Eur. Type I amber glass bottles. Each
`bottle is fitted with a spray pump and a nasal applicator (actuator) assembled with a dust cap.
`The spray pump is crimped to the glass bottle and cannot be taken apart.
`
`information on the bottle can be found in the following table.
`
`
`Pack size
`
`Component Material
`
`Bottle size
`
` Ph. Eur. Type | amber glass 10 mL (13.5 mL fill capacity)
`
`
`
`6.4g
`
`Bottle
`
`File: CQA-UB-0039a01 Investigation Report_Dymista.docx
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`Investigation report: Dymista 6.4 g Nasal
`Spray Stability results
`
`Code:
`CQA'UB'0039/01
`
`
`
`Spray pump:
`
`A VP3/14O CSZO nasal spray pump with a nominal delivery volume of 140 pL is used for the
`dosing of Dymista Nasal Spray. A brief summary of the components of the spray pump and the
`materials employed is provided in the following table.
`
`
`
`Floating gasket
`
`Spring support
`
`
`
`
`Component
`‘ Material
`Body
`Polypropylene blend
`
`
`
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`Spring cap
`
`Return spring
`Stainless steel
`
`
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`Stem
`Piston
`
`Stem spring
`
`
`Polyoxymethylene (POM)
`
`Stainless steel
`
`
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`Nitrile rubber
`
`Aluminum
`
`Ethylene vinyl acetate (EVA)
`
`Low density polyethylene
`
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`Stem gasket
`Ferrule
`
`Neck gasket
`
`Dip tube
`
`
`
`
`
`
`
`Nasal applicator:
`
`An actuator with cap CB18 NAC/3/B + BZ5/A is used for the nasal application of Dymista Nasal
`Spray. A brief summary of the components of the nasal applicator and the materials employed
`is provided in the following table.
`
`
`
`Component
`Material
`Head
`Polypropylene blend
`
`Polypropylene
`Polypropylene
`
`l Cap
`
`i
`
`I
`
` Captive insert
`
`4. Manufacturing Flow
`
`Diagram 1: Manufacturing flow chart of Dymista Nasal Spray (250kg batch size)
`
`File: CQA—UB-0039_01 Investigation Report_Dymista,docx
`
`Page 8 of 14
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`

`

`Investigation report: Dymista 6.4 g Nasal
`Spray Stability results
`
`Code:
`CQA'UB‘OO39/01
`
`
`
`File: CQA-UB-0039A01 Investigation Repofi_Dymista.docx
`
`Page 9 of 14
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`Investigation report: Dymista 6.4 g Nasal
`Spray Stability results
`
`Code:
`CQA-UB-0039/01
`
`
`
`
`
`Assay
`Benzalkonium
`chloride Limit
`80.0 —105.0%
`
`Condition
`
`Assay Azelastine
`Limit 950 —105.0%
`
`Assay Fluticasone
`Limit 95.0 — 105.0%
`
`
`FCZ‘IOO
`23°C
`
`I_
`~ 34 months
`
`~ 34 months
`F02106
`23°C
`
`~ 34 months
`F03188
`23°C
`
`~ 22 months
`FC4001
`23°C
`
`~ 14 months
`FC4127
`23°C
`~ 11 months
`
`
`
`
`
`Table 6: Results of reference samples tested at Cipla Indore
`
`Compared to the initial release results all stability results confirm the behaviour of the product
`during storage showing assay increase.
`
`
`
`File: CQA—UB-003 9_01 Investigation Rep01t_Dymista.docx
`
`Page 10 of 14
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`Investigation report: Dymista 6.4 g Nasal
`Spray Stability results
`
`Code:
`CQA'UB'0039/01
`
`Impact of starting Materials
`
`Pump
`
`all batches manufactured have been supplied by the qualified
`
`The spray pumps for
`manufacturer Aptar/USA.
`The length of the dip tubes, diameter of ferrule and ferrule height has been checked as possible
`influence on the closing system for batches FCZ100, F02102 and FCZ106. All results comply
`with the specification.
`
`Vials
`
`The bottles for all batches manufactured have been supplied by the qualified manufacturer
`Nuova Ompi, Italy.
`No impact ofthe glass could be detected.
`
`Nasal Applicator
`
`The nasal applicators for all batches manufactured have been supplied by the qualified
`manufacturer Aptar/USA.
`No impact of the nasal applicator could be detected.
`
`Active Pharmaceutical Ingredients
`
`The Active ingredients have been supplied by the qualified manufacturers Cipla, Kurkumbh,
`India and Evonik, Hanau, Germany. No impact of the API batches used could be detected.
`
`Excipients
`
`All excipients have been supplied by qualified manufacturers. No impact of the excipient could
`be detected.
`
`5.3
`
`Investigation in production I packaging
`
`No deviations were reported in the respective packaging records.
`
`Since 2012, when the manufacturing of the product was transferred from Cipla Goa to Cipla
`Indore and the process was validated, no changes in equipment and premises were done. The
`procedures remained unchanged.
`
`The difference between the former manufacturing site in Goa and the new manufacturer in
`Indore is the mechanism of closing of the vials, machine speed and filling process.
`
`No significant difference could be seen for the stability data for both sites.
`
`File: CQA—UB-0039_01 Investigation Report_Dy1nista.docx
`
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`Investigation report: Dymista 6.4 g Nasal
`Spray Stability results
`
`Code:
`CQA'UB'0039/01
`
`
`
`File: CQA-UB-0039_01 Investigation Rep01t_Dymista.docx
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`

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`Investigation report: Dymista 6.4 g Nasal
`Spray Stability results
`
`Code:
`CQA-UB-0039/01
`
`
`
`File: CQA—UB-0039_01 Investigation Repofi_Dymista.docx
`
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`Investigation report: Dymista 6.4 g Nasal
`Spray Stability results
`
`Code:
`CQA-UB-0039/01
`
`7. Risk Assessment
`
`A clinical assessment of API assay levels up to 125% was performed (attachment 2). The
`increase is considered as not clinically relevant with no risk for the patient.
`
`8. CAPA
`
`After _became available, manufacture and release of 6.4 9 pack size was put on
`hold.
`
`As CAPA the primary packaging material and sealing technology including increase of
`compression force is under evaluation.
`
`Actual registered glass manufacturer had supplied vials for trials to support hypothesis.
`Trials have been executed, gasket compression is higher and weight loss results are lower
`compared to standard vials.
`Those results show that the sealing bead improves the tightness of the closing system.
`
`A variation to reduce the shelf-life for 6.4g pack size to 18 months will be done in addition.
`
`9. Distribution of product
`
`A list of all Dymista 6.4g batches,
`attachment 3.
`
`that have been released since 03/2013 is available in
`
`10. Conclusion
`
`The— results have been confirmed on all batches that are currently part of
`stability studies. Deviation is not a batch specific issue.
`The clinical evaluation confirms that there is no risk to patient health and safety.
`CAPA will be established before manufacturing of new commercial batches.
`
`List of attachments:
`
`Attachment 1: Compiled stability data for ICH validation batches F02100, FC2102 and F02106
`at 25°C, 60% r.h. up to 24 months
`Attachment 2: Clinical Expert Statement
`Attachment 3: Distribution list of Dymista 6.49
`
`File: CQA-UB-003 9_01 Investigation Report_Dymista.docx
`
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`CQA—UB—OO39/01
`
`Investigation report: Dymista 6.4 g Nasal
`Spray Stability results
`
`Code:
`
`Change Index
`
`
`Valid from Registration, assessment and
`Version Reason for update
`release in the framework of a
`
`Change Control Procedure
` no
`yes year/current No.
`
`'X'
`0%?“ 201?)”
`C 7
`I hfw Ecflf‘wi
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`File: CQA-UB-0039_01 Investigation Report_Dymista.docx
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`17
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`
`19
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`20
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`MEDA APTX02129741
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`HIGHLY CONFIDENTIAL-
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`32
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`SUBJECT TO STIPULATED PROTECTIVE ORDER
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`MEDA APTX02129749
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`32
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`mm
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`53moham.3
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`552.0m2552
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`mgcm£832
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`EiqofimNago8mamm< 925.53E38503a93:85;is3830m:33he«3.E33a:£8?
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`85:5vamo33¢“
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`298%“;“onu<2
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`33
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`33
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`