Influence of aggressive screening conditions and glass composition on the extractables and leachables from glass containers

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1 Extractabes & Leachabes 2013 December 2013 London Infuence of aggressive screening conditions and gass composition on the extractabes and eachabes from gass containers Christophe Wagner Gass Surface Technoogy Christophe Wagner In partnership with SGD

2 Agenda Background: Overview of pharma gass packaging options Comparison study between moded gass and tubing gass Extractabes evauation from USP <1660> Chapter Leachabes Concusion Extractabes and Leachabes Europe

3 Gass Surface Technoogy & SGD Gass Surface Technoogy Technica Expertise in gass packaging and technoogy to sove packaging chaenges Design and anaysis of acceerated aging tests and extractions Design of soutions and coatings to improve inner durabiity and product contact SGD Independent Gass Producer (formery Saint-Gobain Desjonquères) Dedicated Pharmaceutica gass operations in France and Germany R&D ab is ocated in Mers-Les-Bains Faciity, France, where Type I gass is produced Extractabes and Leachabes Europe

5 Tubing Gass 2 step process: Cane manufacturing Converting Capabiities: Vias Cartridges Syringes Extractabes and Leachabes Europe

6 Moded Gass 1 step process SGD Capabiities: Vias and IV bottes from 3 m to 1 L. Neck finish 20 mm and higher Can aso produce non round vias and bottes Extractabes and Leachabes Europe

8 Mass Composition Anaysis Method: X-Ray Fuorescence Spectrometry Vias are cut in pieces Sampes fattened at 750 C Surface is poished X-Ray Fuorescence on 34mm diameter sampes FX S8 TIGER BRUKER Extractabes and Leachabes Europe

9 Type I gass composition NEUTRAL GLASS is an akaine borosiicate gass with main components of (typica mouded gass composition): Network Formers : SiO2+A2O3-73% B2O3-12% Network Modifiers: Na2O;K2O - 10% CaO;BaO;ZnO 5% NEUTRAL GLASS may be composed of 2 primary phases Siica-rich phase with ow akaine content Boron-rich phase with most akaine eements of the gass; it may be separated into micro-dropets within the siica rich matrix, depending on the composition Extractabes and Leachabes Europe

10 Composition by X-Ray Fuorescence Spectrometry (%) Moded Tubing 1 Tubing 2 Network Formers Network Modifiers Stronger network for buk tubing gass, ess modifiers Network modifiers needed to soften the gass to shape the vias for moded gass Extractabes and Leachabes Europe

11 Surface Composition Anaysis SIMS Surface SIMS anaysis by Time-of-Fight Secondary Ion Mass Spectrometry (ToF-SIMS) 4 gass via sampes : 2 moded and 2 tubing vias ToF SIMS Profie by aternating anaysis and abrasion cyces Anaysis: Primary Ions Bi1+ 25 kev, I =1pA Surface anayzed 100 x 100 µm², 128x128pixe Positive Secondary Ions anayzed Abrasion: Primary Ions O2+ 500eV, I = 100nA Surface : 300 x 300 µm² Cyce Anaysis : acquisition of 1 scan (time of max fight = 100 µs) Abrasion : 1.6s, Pause : 1s Extractabes and Leachabes Europe

12 Gass Composition : from interna surface to inside the gass (SIMS) Extractabes and Leachabes Europe

13 Surface Composition differences A sampes show a different composition at the surface from the buk Sma and curved sampes may expain different buk compositions between the bottom and the side wa More surface composition differences between side wa and bottom for tubing vias Sodium depetion at surface on the via bottom for tubing, Boron-rich at the surface on side wa from Via Forming Sodium depetion during forming for Asovex Type I gass, both on bottom and on side was (bowing effect) Extractabes and Leachabes Europe

14 Hydroytic Resistance Testing Standard test for Pharma Gass - Hydroytic stabiity, expressed by the resistance to the reease of soube minera substances into water under the prescribed conditions of contact between : the inner surface of the container (Test A, surface test according to European Pharmacopeia, 3.2.1) gass grains (Test B, gass grain test according to European Pharmacopeia, 3.2.1) The hydroytic resistance is evauated by titrating reeased akai. The gass grain test is performed on crushed gass pieces, so represents the chemica resistance of the buk gass Extractabes and Leachabes Europe

15 Hydroytic Resistance Comparison in (m) HC N/100 Grain Hydroytic Resistance (m) Type I Moded Tubing T Better grain resistance for Tubing than moded because more network formers and ess modifiers, Type I Limit 1 m Type I Moded M-5 Tubing T-5 Type I Moded M-10 Tubing T-10 Vo 90% (m) Type I Limit Surface Hydroytic Resistance (m) More critica for product interaction A vias are ower than type I surface imit, as required Better surface Hydroytic resistance for moded vias 15

16 Extractabes evauation Autocave soution anaysis with ICP Soution Preparation Deionized water ph (18 MΩ.cm resistivity) adjusted : with HC for acid ph with NaOH for base ph Vias Extraction fied at nomina capacity with the soution Vias in autocave at 121 C for 1h, Eur. Pharma. HR cyce, 3 to 5 for each ph ICP Preparation Acidification HNO3 Suprapur 2% before ICP measurement Equipment Caibration with certified PE mutieements soution and acidification HNO3 Suprapur 2% Resuts Equipment : Emission Spectrometry ICP (Perkin Emer Optima 7300 DV) The bank soution is anayzed and subtracted from the autocaved soutions. Extractabes and Leachabes Europe

17 Via comparison : Tota Extractabes by ICP after 1h at 121 C 5 &10m Less eements extracted with Moded vias, for a ph Higher ph (10 or more) causes higher extractions Less extraction in voume for bigger vias, surface/voume ratio ower Extractabes and Leachabes Europe

18 Extractabes Anaysis by eement 5m No visibe attack of the gass, no fake (methyene bue test shows nothing) Different oca / surface gass compositions with tubing may cause higher extractions ICP detection imit on the bank soution 3σ<4µg/L (σ cacuated on 10 measurements of the bank soution), Via to via variation +/- 10% Extractabes and Leachabes Europe

19 Comments on Extractabes Tubing : more Na and Ca extracted, but aso A, Si and B which are the gass network formers Moded : more K (not in the tubing 10m gass composition) and Ba (traces in the tubing gass composition), which are mainy gass modifiers and ess impacting the gass chemica robustness Buk hydroytic resistance is good for tubing, but surface resistance is not at the same eve Loca changes in gass compositions (processing effect) may expain some of the increased extraction Extractabes and Leachabes Europe

21 Testing Pan 3 Soutions for New USP 1660 Chapter to evauate gass containers - KC 0.9% ph 8.0 Autocave for 2H at 121 C (2 1h autocave cyces) - 3% Citric Acid at ph 8.0 for 24h at 80 C - 20 mm (1.5g/L) Gycine at ph 10.0 for 24h at 50 C NaOH (contains K) added to bring ph to the right eve, so Na and K not measured in extracted soutions Autocave sampes cosed with borosiicate ab gass, Other vias cosed with auminum foi Gass Sampes : 100m Type I mouded vias from different gass makers ICP Preparation Acidification HNO3 Suprapur 2% before ICP-OES measurement Equipment Caibration with certified PE mutieements soution and acidification HNO3 Suprapur 2% Resuts Equipment : Emission Spectrometry ICP (Perkin Emer Optima 7300 DV) The bank soution is anayzed and subtracted from the autocaved soutions Extractabes and Leachabes Europe

22 Resuts with Fint Gass SGD Type I Citric acid extraction is quite extensive : modifiers and network formers The 3 soutions are more agressive than water 1h 121 C testing extracts more with Citric acid and Gycin than 24H at 80 and 50 C Extractabes and Leachabes Europe

23 Resuts Citric Acid at ph 8 is more agressive than the other soutions A Fint Gass are simiar with same chemica soution and testing procedure Extractions depend on : soution, gass composition and extraction conditions Extractabes and Leachabes Europe

24 Resuts A gass are type I gass (Hydroytic Resistance better than imit) Composition differences (Fint vs. Amber) may impact chemica resistance 8/26/13 Extractabes and Leachabes Europe

25 Agenda Background: Overview of pharma gass packaging options Comparison study between moded gass and tubing gass Extractabes evauation from USP <1660> Chapter Leachabes Evauation Concusion Extractabes and Leachabes Europe

26 Testing Conditions Same 1660 Soutions as previous part, with ph adjusted 2 ways - Demineraized water at ph 5.6-3% Citric Acid at ph 8.0, ph adjusted with NaOH - 3% Citric Acid at ph 8.0, ph adjusted with KOH - 20 mm (1.5g/L) Gycine at ph 10.0, ph adjusted with NaOH - 20 mm (1.5g/L) Gycine at ph 10.0, ph adjusted with KOH Gass Sampes : 100m Type I mouded Fint SGD vias A containers cosed with Omnifex Hevoet stoppers 21 days aging at 50 C Extractabes and Leachabes Europe

27 Resuts A resuts with Citric Acid are simiar, higher than Gycine and water Adjusting the ph with KOH or NaOH gives simiar resuts Extractabes and Leachabes Europe

28 Agenda Background: Overview of pharma gass packaging options Comparison study between moded gass and tubing gass Extractabes evauation from USP <1660> Chapter Leachabes Evauation Concusion Extractabes and Leachabes Europe

29 Concusions Choice of a via is a compete decision depending on severa parameters, incuding Extractabes and Leachabes and chemica resistance : Product interaction with the via depends on 1) composition 2) how it was formed Process difference: 1 step forming process of moded vias seems to extract ess gass formers than 2 step tubing process Tubing gass starts off better at cane stage but chemica robustness is impacted by converting step, which can differ from 1 suppier to another Due to its chemica robustness, moded can be considered as an aternative in aggressive extraction conditions Not a vias are equa for chemica resistance : it depends on process, gass and soution composition, as we as storage conditions Extractabes and Leachabes Europe

30 Acknowedgements Work done by SGD ab in Mers-es-Bains, France Caroine Brasme Didier Pichard Joe Bourjot Sébastien Dussardier SIMS profies done by Biophy Research Extractabes and Leachabes Europe