Risk factors associated with delamination of glass vialsMatthew M. Hall, Associate Professor of Biomaterials & Glass ScienceKazuo Inamori School of Engineering at Alfred UniversityE-mail: firstname.lastname@example.org
Glass delamination is a coupling of chemical alteration and mechanical fracture of the vial surface D. Haines (SCHOTT North America), Image taken from presentation at the 2011 PDA Glass Quality Conference/Rx-360 Special Symposium on Glass Delamination• Delamination flakes are produced by the localized fracture of the interior vial surface• Fracture requires two components – a flaw and a stress acting to propagate the flaw• Time for delamination to occur is variable depending on condition – could range from hours to years
Glass delamination is receiving increased attention due to a series of high profile voluntary recalls 25 21 100,000,000 + # of Recalled Units 20# of Recallls 15 10 5 4 3 395,000 1,600,000 + 0 1996-2000 2001-2005 2006-2011 1996-2000 2001-2005 2006-2011 Year Range Year Range Assuming an average product value of $10/vial, the recalls between 2006 to 2011 represent more than $1 billion in lost revenues.
Altered surface layer fractures to produce glassdelamination particles • This scanning electron microscopy image 10 μm represents an extreme case of what can happen to glass surfaces that are heavily corroded • The corroded surface has cracked during drying of the surface. Under appropriate conditions, the surface can flake or peel away from the bulk • Note that the nominal composition of this glass is 50Na2O-50SiO2 (mol%), which places it on a completely opposite end ofNa2O-SiO2 Glass the chemical durability spectrum relative D.E. Clark et al., (1976). J. Am. to Type I to III glasses used for parenteral Ceram. Soc., Vol. 59, pp. 62-65. packaging
Altered surface layer fractures to produce glassdelamination particles • Surface of Type I borosilicate glass vial after exposure to glutaric acid solution (2 sterilization cycles and 2 weeks storage at 40°C) • This image is more characteristic of typical delamination in that a thin, corroded surface layer giving rise to high aspect ratio flakes is observed • With that said, we have generally observed that no two cases of delamination observed in the field are identical • Can any sort of universal framework be applied to the problem?R.G. Iacocca et al. (2010). Factors affecting the chemical durability of glassused in the pharmaceutical industry. AAPS PharmSciTech, 11: 1340-1349.
Theoretical framework for considering risk factorsassociated with glass delamination Intrinsic “Flaw” Extrinsic Surface Fracture Intrinsic Stress Extrinsic• Stress acts on one or more flaws to produce a fracture resulting in glass delamination• Stresses and flaws can both have intrinsic and extrinsic origins• Intrinsic Arising from factors primarily linked to decisions made by the vial manufacturer• Extrinsic Arising from factors primarily linked to decisions made by the vial user
Flaws may have chemical and mechanical origins Intrinsic Extrinsic Glass type pH Electrolyte Phase separation Active ingredient Forming Autoclaving? Post-forming treatments Handling? “Glass type” is an intrinsic source of flaws insomuch as it drives other factors such as phase separation and forming requirements
Type I glasses exhibit phase separation Droplet in Matrix Interconnected Morphology Morphology B. Wheaton and A. Clare (2007). J. Non-Cryst. Solids, Vol. 353, pp. 4767-4778.• Depending upon composition, glasses may exhibit phase separation – i.e., the glass “unmixes” into two (and possibly more) chemically distinct phases• Two basic phase separation morphologies are observed, as shown in the false color images above that were obtained using atomic force microscopy• 33 expansion glasses are known to exhibit droplet in matrix morphology; 51 expansion glasses are also likely phase separated, although the morphology has not been positively characterized our knowledge; SLS glass (Type III) is not expected to be phase separated
Type I glasses exhibit phase separation • Phase separation potentially matters since the properties of the chemically distinct phases within the glass will be different • For example, a 33 expansion glass nominally consists of sodium- and boron-rich droplets dispersed within a continuous silica-rich matrix • The droplet phase will be more prone to corrosion, thereby creating a potential flaw HOWEVER… • The phase separation issue is also likely linked to forming-related factors • The SEM image shown here is taken from the heel region of a Type IA vial exposed to WFI• The shape of the pitting is reminiscent of a droplet in matrix phase separation morphology in which a non-durable droplet phase has been selectively corroded (note: the oblique view of the image is the cause of the elliptical appearance of the circular pits)• The size of the pits shown in the SEM image are much, much larger than the size of the droplets typically expected in a Type IA borosilicate glass (on the order of tens of nanometers)• Hypothesized sources of the enlarged droplets include: • Modification of the glass surface chemistry (perhaps through a condensation process), thereby modifying the scale of phase separation • Coalescence of phase separated droplets due to holding glass at elevated temperature in appropriate range• The full impact of phase separation has yet to be truly addressed and represents an important area for future research
Forming processes can alter the glass surface Finish forming Flame cutting Bottom fire Next cycle Heat Heat Lehr Heat Tooling Illustration provided by Gerresheimer Glass• Continuous tubing is converted to vials by a multi-step sequence• Tubing conversion process require the application of heat and tooling to impart an appropriate geometry• Specific processing parameters depend upon the manufacturer, glass type, tubing diameter, machine type, etc.
Forming processes can alter the glass surface Image taken from Stevanato Group web site Condensation Volatilization DiffusionIntense, localized heating during the conversion process can lead to modifications of the glass vialsurface through a combination of possible mechanisms, including mass transport driven by thermalgradients, evaporation of volatile species, and condensation of vapors on the interior surface.Glass vials produced from converted tubing experience the greatest heating in the heel and shoulder.The altered surface chemistry of these regions can potentially impact properties, including chemicalstability.
Forming processes can alter the glass surface Blistering of interior surface in the heel region of a Type I glass vial (a defect that is rarely observed in our experience)
Forming processes can alter the glass surface Methylene blue stain • Methlyene blue is a cationic dye molecule that is known to bind to negatively charged surfaces such as silicate glasses at near-neutral pH values • The intensely stained region is likely due to sub-visible porosity in the surface of the heel region that concentrates the dye • Methylene blue staining can serve as a qualitative indicator of regions that are potentially more susceptible to corrosion
Post-forming treatments alter the glass surface Alkali-depleted Sodium sulfate deposits produced by surface treatment surface “Bulk Glass”• Sulfate treatments were originally developed for improving the chemical durability of SLS glass (Type III), not borosilicate glass (Type I)• Evidence has been found that sulfate treatments of Type I glass can produce irreversible surface damage to the interior of glass vials• A conclusive link between sulfate treatments and delamination has yet to be established, but we would generally recommend avoiding sulfate treatment in the interest of being conservative• No one to our knowledge has reported on the possibility of using alternative treatments for removing surface alkali – e.g., why not rinse with a dilute mineral acid such as HNO3?
Parenteral formulations can effect glass dissolution behavior ~100 C ~60 C -7 8 pH 12.7 1. Pyrex (Type I glass) 2. SLS (Type III glass) mg SiO2/g Glass Powder pH 4 7 log Dissolution Rate (cm/s) pH 11.9 pH 7 -8 6 pH 10.4 pH 9 5 pH 9.5 pH 8.7 -9 4 3 -10 2 1 -11 0 2 2.2 2.4 2.6 2.8 3 3.2 0 50 100 150 1000/T (1/K) Time (min) Increasing Temperature 1. G.W. Perera and R.H. Doremus (1991). J. Am. Ceram. Soc., Vol. 74, pp. 1554-8. 2. R.W. Douglas and T.M.M. El-Shamy (1967). J. Am. Ceram. Soc. Vol. 50, pp. 1-8.• The above examples are taken from fundamental literature on glass corrosion that were not specifically focused on chemical stability within the context of parenteral packaging – results are nonetheless applicable• The left-hand figure demonstrates that the dissolution of a Type I glass (as measured by surface removal) can be significantly influenced by temperature and pH. As expected, dissolution increases with increasing temperature and increasing pH• The right-hand figure demonstrates that the dissolution rate of a Type III glass (as measured by extraction of SiO 2) is also significantly influenced by pH. In general, we expect Type III glass to be less durable than Type I glass with increasing pH.
Parenteral formulations can effect glass dissolutionbehavior 3.0 0.1M NaCl 2.5 Dissolution Rate (g/m2-d) 2.5M NaCl 2.0 SLS glass (Type III glass) 1.5 1.0 0.5 0.0 0 5 10 15 Number of semi-weekly interval C.L.Wickert et al. (1999). Phys. Chem. Glasses. Vol. 40, pp. 157-170.• This is another example taken from the fundamental literature on glass corrosion• The results show the effect of changing electrolyte concentration (in this case NaCl) on the dissolution rate of a Type III glass as measured by weight loss over time
Parenteral formulations can effect glass dissolutionbehavior • Phosphate solutions appear to be a special case in which the silicate network is attacked • The SEM image shows the heel region of a Type I glass vial exposed to a concentrated phosphate solution (the dendritic structure in the upper right-hand region is likely a salt deposit)
Parenteral formulations can effect glass dissolution behavior 14 Glass Attack Rate (a.u.) 0.2% EDTA SLS glass (Type III) 12 0.2% EDTA + 0.4% Catechol 10 0.5M Sodium Acetate 8 6 4 2 0 8 10 12 14 pH F.M. Ernsberger (1959). J. Am. Ceram. Soc., Vol.42, pp. 373-5.• Chelating compounds can accelerate the dissolution of silicate glasses• Effect of chelating agents is linked to a reduction in the solution-phase thermodynamic activity of the complexed ion, thereby driving continued extraction from the glass• Common species used in parenteral formulations that chelate cations relevant to glass include acetate anions, citrate anions, and EDTA; larger biomolecules may also contain chelating groups
Parenteral formulations can effect glass dissolution behavior…an interesting counter-example 70 • In this study, the dissolution behavior of Borosilicate borosilicate glass fibers (not equivalent 60 glass fibers to Type I glass) was evaluated in theDissolved Silica (mg/L) 50 presence of pre-dissolved silica • The extent of glass fiber dissolution 40 generally decreased with increasing concentration of pre-dissolved silica 30 0 ppm • These observations raise an interesting conjecture – could formulations be 50 ppm 20 “spiked” with dissolved inorganic 75 ppm species such as silicon to suppress 10 corrosion? 100 ppm • While this an academically interesting 0 question, it clearly raises a number of 0 5 10 15 20 25 30 regulatory issues Time (days) P. Baillif et al. (2000). J. Mater. Sci., Vol. 35, pp. 967-973
Stresses can also be produced by intrinsic andextrinsic mechanisms Endogenous Exogenous Glass corrosion Hydration/Dehydration Forming induced stress Depyrogenation? Handling? Nominally erased by proper annealing procedures, although thin surface layers of modified glass within heel region are likely under tensile stress
Reactions associated with glass corrosion cangenerate stress in the glass surface H3O+ H2O ≡Si-OH + HO-Si ≡ ≡Si-O-Si ≡ Surface Na+ ≡Si-O-Si ≡ + H2O ≡Si-OH + HO-Si ≡ Bulk Ion Exchange Network Hydrolysis RepolymerizationVarious reactions associated with glass corrosion can lead to masstransport and structural arrangement within the surface layer. Thiscan in turn cause volumetric changes that lead to stress generation.
Reactions associated with glass corrosion cangenerate stress in the glass surface 30 20 Surface Stress (MPa) Compressive Tensile 10 0 -10 -20 SLS Glass 0.5M HCl -30 (Type III Glass) 5M HCl -40 0 2 4 6 8 Time (hr) T.A. Michalske et al., (1990). J. Non-Cryst. Solids, Vol. 120, pp. 126-137.
Hydration/dehydration cycles can generate stressin corroded glass surfaces This is extreme example of how a glass with poor chemical durability can undergo failure when subjected to fluctuations in humidity. This phenomenon, also called “glass disease” or “crizzling”, occurs as the corroded glass surface swells and shrinks in response to humidity changes. It should be noted that no one has openly identified storage conditions as a contributing factor towards the propensity for glass delamination. Furthermore, there is no reason to necessarily predict that Type I glass vials would be particularly sensitive to this issue. Nevertheless, it begs the question – how are your vials being stored? Crizzling and the Preservation of Glass, Corning Museum of Glass, http://www.cmog.org/dynamic.aspx?id=5678#.Tx7Wu28V1Cg
Does the depyrogenation process matter?• The potential influence of depyrogenation is still an open issue• There is anecdotal evidence that depyrogenation of “wet” vials can increase the propensity for delamination• Assuming that the glass surface (particularly within the heel region) has a porous, silica-rich gel layer that retains liquid, one could hypothesize that a rapid depyrogenation process might further weaken the surface due to rapid expansion of steam • Could be regarded as an extreme example of crizzling • Similar behavior is seen bulk porous glass that contains liquid and is rapidly heated; the glass fractures by decrepitation• This issue could clearly benefit from further study; parameters of interest include: • What is the impact of retained water versus dry vials? • What is the impact of time/temperature profiles associated with the depyrogenation process?
Does handling matter?• For example, would mechanical impact of vials increase the propensity for delamination?• It is unlikely that handling-induced stress is a significant factor• It is however possible to consider a situation in which vibration, shock, etc. may help to dislodge a surface layer that is already prone to delamination • In this case, avoiding mechanical trauma is not a cure • The surface is already compromised, and delamination is almost certain at some point in the future• These comments are based on educated guesses – further study of handling-induced effects are justified but perhaps not as urgent as the depyrogenation issue
Summary • Delamination in pharmaceutical glass vials is a combination of chemical ateration and mechanical fracture of the vial surface • Intrinsic and extrinsic factors can give rise to both factors leading to delamination • Forming processes are known to alter the glass surface, particularly in the heel region of the vial that is subject to the most intense heating • Heel region is more susceptible to corrosion and most likely to undergo detectable delamination • Delamination is not a new problem and may never fully go away since any vial can be made to fail if subjected to inappropriate usage conditions • Vial compatibility must be evaluated on a case by case basis and by close collaboration between the suppliers and users of packaging productsMatthew M. Hall, Associate Professor of Biomaterials & Glass ScienceKazuo Inamori School of Engineering at Alfred UniversityE-mail: email@example.com