Confidential

Causative Factor(s) of Agglomeration Observed for Lots of Lorcaserin Hydrochloride Hemihydrate Stored at

40°C/75%RH Are Not Relevant to Storage Under Less Severe Conditions (≤ 30°C/65%RH)

7 December, 2015

Belviq® API Molecular Formula & Structure

2

NHCl

HCl0.5 H2O

Lorcaserin HCl Hemihydrate(Form III)

C11H16Cl2NO0.5

241.16 g/mol

Belviq® is Arena’s NDA approved drug product for weight management, containing the active pharmaceutical ingredient (API), lorcaserin HCl hemihydrate (Form III), which was observed to agglomerate during 40°C/75%RH accelerated stability testing at ≥ 3 months, prior to NDA submission. Since agglomeration of an API presents potential challenges to drug product manufacturing, it was necessary to investigate the causative factors(s) resulting in agglomeration of lorcaserin HCl hemihydrate.

Agglomerated versus Typical API

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Lorcaserin HCl hemihydrate is a white to off-white powder, cohesive in nature, and capable of forming soft aggregates, which easily crumble with light pressure or agitation. In contrast, agglomerated API is hard and brittle.

Agglomerated API Post-6 Months at 40°C/75%RH Typical API Appearance

Agglomerate conformed toshape of container

Possible Causative Factors

• API Hygroscopicity• API Deliquesce Point Depression• Low API Melting Point• API Melting Point Depression, due to Contamination• Hygroscopic Impurity Contamination of API• Polymorphic Form Conversion• Presence of Amorphous Content• Capillary Condensation• Surface Area/Particle-size Differences between API Lots

Release and Particle-Size Data

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There were no correlations derivable between agglomeration at 40°C/75%RH and API impurity profile, residual solvent content, or water content. Also, in the case of particle size, API lots were observed to agglomerate independently of particle size or milling.

Attribute Screened MilledAPI Lot A B C D E F

Agglomerated at 40°C/75%RH No No Yes Yes Yes Yes

Particle size (Dv50) (µm) 79 81 38 175 78 34

Appearance Conforms Conforms Conforms Conforms Conforms Conforms

Identity by FTIR Conforms Conforms Conforms Conforms Conforms Conforms

Assay (%w/w) 99.8 100.2 99.5 100.7 100.3 100.2

Related substances by achiral HPLC (%area)—Total impurities

0.2 0.1 0.2 0.2 0.2 0.1

Enantiomeric purity (%ee) 99.7 99.8 99.7 99.6 99.7 99.8

Residual solvents (ppm)Acetone

< 20 (QL) < 20 (QL) < 20 (QL) < 20 (QL) < 20 (QL) < 20 (QL)

Residual solvents (ppm)Cyclohexane

< 20 (QL) < 20 (QL) < 20 (QL) < 20 (QL) < 20 (QL) < 20 (QL)

Residual solvents (ppm)Ethyl acetate

256 223 207 257 467 223

Residual solvents (ppm)1,2‑Dichlorobenzene

< 20 (QL) < 20 (QL) < 20 (QL) < 20 (QL) < 20 (QL) < 20 (QL)

Chloride content (%) 14.7 14.6 15.0 14.7 14.6 14.6

Water content(%w/w) 3.8 3.8 3.8 3.6 3.6 3.8

Residue‑on‑ignition (%) 0.1 0.0 0.0 0.0 0.0 0.0

Heavy metals (ppm) < 20 < 20 < 20 < 20 < 20 < 20

DL = detection limit; ee = enantiomeric excess; FTIR = Fourier transform infrared; NA = not available; ND = not detected; QL = quantitation limit

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Polymorphic Form Contamination

All six API lots exhibited identical powder X-ray diffraction (PXRD) patterns, consistent with the calculated PXRD pattern for lorcaserin HCl hemihydrate Form III, as derived from single-crystal X-ray data for Form III. Additionally, no evidence of amorphous halo was observed for any of the six API lots.

Typical API PXRD patternCalculated PXRD pattern

Deliquescence Point Suppression and Amorphous Form Contamination

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The deliquescing relative humidity (DRH) of lorcaserin HCl hemihydrate at 25°C and 40°C was determined to be ca. 91% and 84%RH, respectively, with no evidence of deliquescence point suppression or amorphous form contamination observed during dynamic moisture balance analysis of the six API lots.

Lot 06P0148 Adsorption/Desorption Isotherm @ 25°C

0

2

4

6

8

10

12

14

0 20 40 60 80 100

%RH

Wei

ght (

% c

hang

e)

Adsorption

Desorption

No Water UptakeBelow 85%RH

Typical API Hygroscopicity Profile

Capillary Condensation

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Agglomeration was observed independently of low-angle laser light-scattering (LALLS) particle size and Brunauer, Emmett and Teller (BET) surface area. Additionally, all six API lots exhibited similar average micro-pore diameters, suggesting capillary condensation was not a likely causative factor.

Lot Agglomerated @ 40°C/75%RH

Processing

LALLS Dv50 (mm)

Surface Area (m2/g)a Average Pore Diameter (nm)a

A No Screened 79 0.089, 0.084 1.03

B 81 0.102, 0.079 1.04

C Yes 38 0.152, 0.136 1.09

D 175 0.040, 0.042 0.85

E Milled 78 0.209, 0.142 0.95

F 34 0.292, 0.209, 0.251 0.94, 1.06

aAll available data reported to provide information regarding measurement reproducibility

Crystal Surface Dissolution Observed Post-6 Months at 40°C/75%RH

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Microphotographs (taken at a fixed magnification) of lorcaserin HCl hemihydrate 6-month stability samples show clear, visual evidence (loss of crystal edge definition) of crystal surface dissolution and re-crystallization at 40°C/75%RH, but not 25°C/60%RH, suggesting the API momentarily exceeded the lorcaserin HCl hemihydrate DRH.

25°C/60%RH 40°C/75%RH

25°C/60%RH 40°C/75%RH

Effect of Temperature Upon the Amount of Water Vapor Air Can Hold

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Relative humidity is defined as the ratio of the partial pressure of water vapor in an air/water mixture to the saturated partial pressure of water at the temperature of the water. Relative humidity can be expressed as

RH =(H2O)

*(H2O)X 100%

where• RH is defined as the relative

humidity of the water‑air mixture• (H2O) is the partial pressure of

water vapor in the water‑air mixture• *(H2O) is the saturated vapor

pressure of water in air at the temperature of the water‑air mixture

Relative Humidity Varies As a Function of

Temperature

Agglomeration Primary Causative Factor

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Interior of drum initially at 25.4°C and 57%RH.

Upon warming to 40°C, internal %RH should have dropped to 32%, but only dropped to 40%, consistent with %RH penetrating the drum.

Drum interior reaches 62%RH within 2 days.

Drum interior reaches 65%RH within 17 days, just before drum is removed from the 40°C/75%RH chamber. Dew point for 40°C/65%RH is 29°C.

Drum interior reaches maximum of 87±4%RH at 25°C, while the deliquesce point of lorcaserin HClHH at 25°C is ca. 91%RH.

Interior of drum initially at 25.4°C and 57%RH.

Upon warming to 40°C, internal %RH should have dropped to 32%, but only dropped to 40%, consistent with %RH penetrating the drum.

Drum interior reaches 62%RH within 2 days.

Drum interior reaches 65%RH within 17 days, just before drum is removed from the 40°C/75%RH chamber. Dew point for 40°C/65%RH is 29°C.

Drum interior reaches maximum of 87±4%RH at 25°C, while the deliquesce point of lorcaserin HClHH at 25°C is ca. 91%RH.

Removal of 1-L HDPE drums, used for API stability testing, from a 40°C/75%RH chamber results in momentary %RH spikes, potentially reaching the API DRH and causing crystal surface dissolution. As HDPE drums exhibit some permeability to water vapor, the interior %RH eventually drops below the API DRH, resulting in recrystallization and bonding together of individual crystals.

RH Correlation Pre-/Post-Removal of 1-L HDPE Drum from 40°C/75%RH

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Correlating the %RH spike to the drum interior %RH immediately before removal from the stability chamber shows a linear correlation. Therefore, the drum interior must reach ca. 68%RH, and ambient laboratory temperature must be ca. 15°C below the stability condition temperature for the %RH spike to reach the API DRH upon cooling.

y = 1.111x + 14.945R2 = 0.9967

70

75

80

85

90

95

50 55 60 65 70

%RH in Drum Immediately Before Removal

Peak

%R

H

Regression results assume 40°C 25°C

Conclusions

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The primary causative factor resulting in agglomeration of lorcaserin HCl hemihydrate during accelerated stability testing has been determined to be the result of %RH spikes occurring inside the 1-L HDPE drums, as they are cooled from 40°C to ambient temperature. It was further determined that the drum internal %RH would have to be ≥ 68%, followed by a rapid ≥ 15°C drop in temperature to reach the deliquescence point (DRH) of lorcaserin HCl hemihydrate. Therefore, these results not only explain the reason for agglomeration at 40°C/75%RH, but provide a mechanistic understanding of why agglomeration has not been observed at 30°C/65%RH or 25°C/60%RH and why agglomeration is not an issue for long-term lorcaserin HCl hemihydrate storage.

Acknowledgements

• Anthony C. Blackburn• Scott Peterson

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