Glass Delamination – USP 1660

Pharmaceutical glass containers may be susceptible to glass delamination or the appearance of thin lamellae or thin flexible flakes of glass, which can be subvisible and less than 50 micrometers to visible and greater than 200 micrometers.  Glass delamination is a very serious quality issue and may lead to a product’s recall.  The presence of glass delamination is a strong indication of drug product interaction with the interior surface of the glass container.  Several factors that may influence the inner surface and durability of a glass container are outlined in Table 1.  A proactive approach to ensure compliance with cGMP practices, it is recommended for drug manufacturing companies to undergo stability studies and glass delamination testing; testing the drug product for the presence of lamellae and testing the interior surface of the glass container for evidence of glass delamination or pitting.

Background on Glass Manufacture, USP 1660

Glass may be defined as, “the inorganic product of fusion which has cooled to a rigid condition without crystallizing” (ASTM C162-05, 2010) or an amorphous solid completely lacking in long range, periodic atomic structure, and exhibiting a region of glass transformation behavior.

Glass containers are prepared by either a mold process or by processing glass tubes.  Molded glass containers are manufactured where a molten glass is cut into a glob that subsequently inters into a mold where air or tooling is used to shape the container of the mold.  Tubular glass of a specified size is processed into containers where gas flames are used to melt the glass to form the base of a vial or ampul, and soften the glass to form the neck.  Following container formation, the glass container is annealed to remove residual stress in the glass.  During the annealing process the glass is placed within a lehr that heats the container to approximately 20 – 30 degrees above the transformation (transition) temperature, Tg, of the glass formulation and then gradually cooled.  This process is crucial to the durability of inner glass surface and its susceptibility to glass delamination.

Glass containers for pharmaceutical uses are either borosilicate (Type I) or soda-lime-silica glass (Types II, III).  The Type of glass is determined by its chemical composition and its propensity to hydrolytic resistance under guidance of USP 660.  Hydrolytic stability of glass containers for pharmaceutical uses is expressed by the resistance to the release of soluble elements into water under a set of prescribed conditions of contact between the inner surface of the container glass with water.  Type I glass has a high hydrolytic resistance due to the chemical composition of the glass itself, whereas Type II glass exhibits a higher hydrolytic resistance than Type III due to a surface treatment, and Type III glass has a moderate hydrolytic resistance.  Type I glass containers are suitable for most pharmaceutical preparations.  Type II glass containers are suitable for most acidic and neutral, aqueous pharmaceutical preparations.  Type III glass containers are suitable for non-aqueous preparations, for powders (excluding lyophilized or freeze-dried preparations) and for preparations that are not for parenteral administration.  Common glass manufacture batch raw materials is presented in Table 2, the classification of common components may be found in Table 3, and physical properties of a select few types of glass is presented in Table 4.  These hydrolytic resistance tests are typically completed prior to performed prior to the evaluation of the inner surface durability of glass containers under guidance of USP  1660.
 
Table 2: Common Raw Materials Used in the Manufacture of Glass.
 

Glass Delamination Studies According to USP 1660

The recommended approach is to evaluate the potential of a drug product to cause formation of glass particles (precipitated glass which was dissolved vie etching of glass from the inner surface of the glass container) and delamination of the inner surface of the inner surface of the container.

Glass delamination may be defined as the appearance of thin flexible flakes of glass (lamellae or platy) with typical size ranges between less than 50 µm to 200 µm in a drug product solution.  Glass delamination is potentially a serious quality issue and may result in the recall of a product by the FDA.  The presence of glass lamellae is an indication of a strong interaction between the drug product in solution and the inner surface of the glass container, see Figures 1 and 2.

Screening studies may comprise a number of analytical techniques to examine three key parameters, Table 5, visual examination and chemical profiles of the inner surface layer, the amount and identity of extracted elements in the drug product solution, and the number of visible and subvisible particles in solution.

The evaluation of the inner surface of glass containers begins with the Surface Glass Test under guidance of USP or EP, in which water is used as the extracting medium, followed by a series of analytical techniques to screen for the inner surface of the container for evidence of glass delamination, pitting, and glass precipitation or glass particulates.

Figure 1:  Defect on Interior Surface of Glass Vial