EDQM Glass containers for pharmaceutical use

Transcription

1 EDQM Glass containers for pharmaceutical use European Pharmacopoiea 8.3 Ongoing revision of Chapter : an overview on hydrolytic resistance and delamination risk Emanuel Guadagnino Past Chairman of ICG/TC 2 Chemical Durability and Analysis Webinar, Strasbourg,

2 Borosilicate glass structure

3 Glass Containers for Pharmaceutical Use Chemical Composition of Type I Glasses Oxides Weight % Pyrex Type A Neutral Type B Average chemical composition of Type I tubing glass containers SiO₂ 80,0 73,0 B₂O₃ 13,0 11,0 Al₂O₃ 2,0 6,0 Na₂O + K₂O 5.0 8,0 CaO + BaO - 2,0 Exp.coeff

4 Glass / water interactions The first stage of the reactions between a glass surface and a liquid phase (water or water vapor e.g. humidity) is always an ion-exchange ruled out by interdiffusion between the alkaline ions in the glass and the hydrogen ion H + (nh 2 O) + Na + SiO - (glass) Na + + SiOH (nh 2 O) (1) There is another mechanism based on the diffusion of water into the glass and its adsorption at the NBO sites nh 2 O+ Na + SiO - (glass) Na + + OH - (soln)+sioh (nh 2 O) (2) Reactions (1) e (2) are leaching reactions and produce: a) hydration of the glass surface; b) formation of an alkali-depleted layer; c) deposits of alkaline species on the top surface, especially in humid environments or in minimum extraction volumes

5 Water Corrosion Mechanism Stage 1: Leaching Stage 2: total dissolution

6 Si and H Enrichment Profiles Exchange with H+ ions increases the concentration of surface OH 2 Relative concentration/depth Modifiers depletion causes Si surface enrichment Conc. relativa di Si e H 1,8 1,6 1,4 1,2 Si H The silica enriched layer behaves as a barrier to further leaching 1 0 0,2 0,4 0,6 0,8 1 1,2 Profondità, µm dalla superficie

7 Surface alkalinity of tubing glass containers The vast majority of injectable preparations is distributed in tubing glass containers To test surface alkalinity, EP prescribes a water extraction at 121 C for 1h and the titration of the following extract solution The test simulates roughly a storage time of 2-3 years at room temperature and gives an information about possible ph changes over the years Under these conditions only a minor release of sodium and boron is expected due to the nature of the glass itself The conversion of the tubing glass canes into finished containers affects the morphology of inner surface and has a strong inluence on alkalis release

8 Production of Tubing Glass Containers for Canes Loading and distribution Left turret Right turret Central turret

9 Production of Tubing Glass Containers Pre-heating and cutting stage Pre-heating Pre-heating Cutting

10 Production of Tubing Glass Containers Flame drilling to open the mouth Flame Drilling

11 Production of Tubing Glass Containers Bottom Forming and Polishing Bottom Forming F. Nicoletti Do not reproduce without permission

12 Variability of the Surface State The exposure to flames has a strong impact on the surface state of the finished container Extensive surface flaming causes evaporation and re-deposition of borate salts wich results in local silica enrichment Bottom and shoulder are in a vial the most exposed area and local compositions are different from the wall The within-sample variabilty will affect the between- samples variability of any single lot The reproducibility of the forming conditions at the conversion plant is the key factor to obtain a low alkali release and to reduce surface alterations A strict control over flame temperatures and exposure times will contribute to reduce delamination propensity as well

13 Sodium Surface Analysis of Container Bottom And Wall The surface chemical composition of tubing vials is different in different zones: sodium decreases at the bottom, due to evaporation during forming (the hottest region), and increases where condensation takes place, in the coldest regions. From Schott Newsletters No. 14, April 2011

14 Other Sources of Variability The endogenous alkali contribution of the base glass Within-batches variability of the inner surface of the raw cane Small, uncontrolled fluctuations of high temperature flames Significant differences in containers of the same base glass produced by different vendors Quality of the raw material : small dimensional variations along the length of the cane require flame adjustments to re-distribute the glass around the most critical points All these factors contributes to increase the alkali release, to cause phase separation and surface pitting and to make the glass surface more exposed to delamination risk

15 Minimization of Alkalinity Measurements Uncertainty Sodium release is a measure of the variability of the surface, hence of the quality of the entire process Any improvement in its measurement contributes to minimize the total process uncertainty and to freeze disputes between parties In the 90 s collaborative tests were carried out by ICG/TC2 in connection with the EU Research Centre in Geel to improve data quality About 10 experienced labs belonging to the glass industry and academic institutions participated in the project

16 Laboratory Intercomparison Soda-lime containers Extraction at 121 C for 1h Obvious outliers, spread, errors in autoclaving (lab No3,10), errors in FAAS (lab 6)

17 Main Sources of Errors Some autoclaves could not be programmed to reproduce the thermal cycle, manual operation was required The real temperature in the containers was not known by most labs Different temperatures inside/outside containers, the thermal cycle was not followed correctly Heating ramp from 100 to 121 C not strictly followed Variations in heating rate resulted in a sensible difference in final temperatures (up to 3 C) 1 C corresponds to about 10% difference in Na release

18 Analytical Protocol The temperature was measured with a calibrated thermocouple inserted in one container Participants were requested to monitor and record the entire cycle, also manually if necessary Tests carried out under conditions of strict repeatability, 6 replicate measurements in different days A detailed testing protocol was distributed, significant improvements were achieved The reference material IRMM 435 was certified The testing protocol, with minor changes, was enforced in the ISO 4802 norm

19 Improvement of Data Quality Borosilicate Glass Containers - Titration Results Lab Nr. Replicate measurements / ml mean / ml s / ml mean (n=5) and s s rel / % 3.7 Mean values + std. dev.

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21 EUROPEAN COMMISSION JOINT RESEARCH CENTRE Institute for Reference Materials and Measurements CERTIFIED REFERENCE MATERIAL IRMM 435 CERTIFICATE OF ANALYSIS PHARMACEUTICAL GLASS CONTAINERS Volume of titration solution 0.01 mol/l HCl per 50 ml of leachate Alkali leaching and release Certified value 1) [ml] Uncertainty 2) [ml] Certified value 1) [mg/l] Uncertainty 2) [mg/l] Sodium release per volume of leachate Release of Na 2 O per volume of leachate ) Unweighted mean of 5 accepted mean values, independently obtained by 5 laboratories. The value is traceable to the adapted method for alkali release based on the European Pharmacopoeia method and ISO 4802, and to the International System of Units (SI) as far as gravimetrically prepared brants are concerned. 2) Expanded uncertainty with a coverage factor k = 2, corresponding to a level of confidence of about 95 %.

22 EP 8.3 Chapter Autoclaving process current requirements Insert a calibrated thermocouple in a container Raise temperature to 100 C within 30 mins Freesteaming for10 mins Raise temperature to 121 C at 1 C/min Hold temp. at 121 C for 60 +/- 1 min Cool down to 100 C at 0.5 C/min Adjust temperature curve acc. to thermocouple readings Automatic recording temperature vs time

23 Time/Temperature Plot

24 Classic Autoclave with Heating Coils

25 Insertion of Calibrated Thermocouple

26 Calibrated Thermocouple (Yellow) and Autoclave Resistance Thermometer (Purple)

27 Steam autoclave and boiler

28 Autoclave Resistance Thermometer and Housing for Calibrated Thermocouples

29 Temperature Measuring Device and Draining Pipe

30 Temperature Distribution in the Autoclave Chamber

31 Autoclaving process ongoing revision Better focus on the reference thermal curve Separation of autoclave calibration stage from routine analysis Distinction between classic old model and steam autoclaves where freesteaming is not always possible Notes to clarify reasons for more accurate measurements and highlight potential sources of errors Calibration frequence to be set by the user on the basis of sound QC criteria Files record to give evidence of compliance

32 Glass Delamination Separation of thin glass layers (lamellae) that appear as shiny, needle shaped particles floating in the contact liquid The formation of a silica-rich layer poorly bonded to the substrate is the first stage of an extended delamination Glass-liquid interactions are responsible for the formation of an altered layer Long time storing of a solution with a high ionic strength (NaCl, KCl) and/or sterilization cycles may favor the delamination mechanism

33 Typical Flakes Aspect

34 Delamination of Pharmaceutical Glass The first stage is always the formation of an altered layer When vials are filled with the liquid preparation, this layer is subject to a strong re-hydration and swelling

35 Delamination of Tubing Glass Containers OH - Glass flakes Some preparations may favour delamination Alkaline solutions strongly affect the dissolution of the silica layer. SiO 2 concentration in the extraction liquid increases steeply Flakes appearance, by increasing ph some particles redissolve

36 SEM Micrographs of Silica Enriched Corroded Surfaces EDS analysis showed flakes were mostly made of silica and alumina Exp. 51, vial bottom - Initial crizzling - Signs of incipient corrosion Exp.33, sulphur treated vial, bottom - Extensive corrosion - Scales detachment

37 Phase Separation with Interconnected Morphology in Borosilicate Glasses B.Wheaton and A Clare, J.Non-cryst.Solids, 2007,Vo.53,

38 Scales Detachment and Pitting in Droplets Pitting (borate-rich phase dispersed on a silica-rich phase) is observed on the detaching layer and the residual surface From Wen et al., J.Pharma.Sci., 2012, 101,

39 Factors Affecting Delamination of Pharma Glasses Sulfur Treatment Siliconization Coating Surface treatments Speed of the Transformation Process Burners Flame Temperature Improper Annealing Stage, Tensile Stresses Type of Glass Conversion process Chemistry of the Buffer Supporting the Active Principle ph & Ionic Strength of the Drug Solution Organic Acids Sterilization Process Storage Conditions Drug formulation & post-treatments

40 Open Questions How can delamination be predicted? What parameters can be used to investigate delamination propensity?! Are EP values still a good indicator of delamination resistance? Which glass Type is more suitable to which preparation? What are typical weak areas in a vial?

41 Extraction in Neutral Aqueous Solution Correlation With EP Values ,9% KCl ph 121 C, 1h FLAKES Glass type E.P. titration values Exp Exp 51/b Exp 51/a 0.63 SIO 2 ppm FLAKES Extraction number Exp 51/b Pyrex Exp 51/a Sulphur treated E51S sulfur treated 0.51 No flakes observed for treated/untreated Exp51 vials Flakes obseved after the first extraction in Exp33 vials Strong increase of soluble silica in solution in connection with flakes appearance No correlation with EP value

42 Extractions with Slightly Alkaline Solutions Glass type E.P. titration values Exp51/b 0.92 Exp 51 Exp51/a 0.63 Exp 51 Sulfur treated 0.51 Exp51 vials : SiO2 increases with increasing extraction number, Flakes recoverd after 2 extraction Sulphur treated vials produced flakes since the 1 extraction, even if EP allkalinity is excellent and SiO2 in solution is very low

43 Extractions with 3% Citric Acid 3% Citric acid ph 80 C 350,00 300,00 250,00 Visual inspection indicated early flaking. SiO 2 ppm 200,00 150,00 Exp51/a Exp51/b Sulfur treated Exp33 In Exp33 and Exp51 sulfur treated vials flakes appear after the first 2 hours 100,00 50,00 0, t (h)

44 Organic Acids Extractions Glass Treatment 3% Glutaric Acid + 1 % KCl ph=8.0 3% Citric Acid + 1% KCl ph=8.0 SiO 2 ph SiO 2 ph Exp 51/A Exp 51/B Sulf. treated 1 h121 C F F h121 C F F h121 C F F h121 C F F h121 C F F h121 C F F 7.97 Exp 33 1 h121 C F F h121 C F F 8.42

45 EARLY PREDICTION BY METHYLENE BLUE COLORIMETRIC TESTING Sulfur Treated EXP 33 Vials Methylene blue testing 1 autoclave cycle Samples as received Flakes (+++) SiO 2 50 ppm

46 Delamination of Tubing Glass And Preventive Indicators The use of high burners flames in the formation of bottom and shoulder of Type I tubing glass vials alters the surface state exposing areas with a silica-rich surface Phase separation and pitting are other phenomena In principle, neutral solutions do not cause scales detachment but flakes are observed at semi neutral ph, for low SiO2 values Slightly alkaline solutions affect the dissolution of the silica layer, especially in Exp.33 glass vials. The formation of flakes is possible also at moderately alkaline ph With increasingly alkaline solutions the concentration of SiO2 in the extraction liquid increases steeply When SiO2 solubility limits are exceeded, suspended particles shall appear SiO2 concentration is a risk parameter, no strict correlation with EP alkalinity values

47 Conclusions EP Version Production The propensity to delamination of glass containers from different sources can be assessed and ranked by exposing the container to accelerated degradation testing, carried out at specified temperatures for a short time and using the solutions associated with the actual pharmaceutical preparation as extractants. Accelerated degradation testing can be used as a predictive tool to select the most appropriate container for the intended preparation, but the full compatibility of the active substance with the glass leachate can only be assessed by a stability test under normal conditions of use.

48 Thank You for Your Attention! Emanuel Guadagnino 2014 EDQM, Council of Europe. All rights reserved. 48