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Reducing the risk of delamination: why it happens and ways to solve the problem.

Approximately 100 million filled pharmaceutical vials were recalled by the pharmaceutical industry in the United States due to glass flakes found in the medicine between 2006 and 2011. These flakes--delamination--detach from the inner surface of the vial due to interactions between the medicine and its packaging, which has resulted in the FDA requiring that companies exercise stricter risk management to prevent delamination from occurring, even though there are still no reports that indicate that glass flakes in injections could actually cause harm to patients.

It's impossible to rule out the possibility of intravenous injections causing embolisms, thrombosis, or venous inflammations. Also, with subcutaneous injections, there is a chance that foreign body granulomas could form, or the immune system could be activated unintentionally (1). The toll these recalls take on pharmaceutical companies comes in the form of lost revenue and damaged reputations. If we assume that an average product is worth $10 for each recalled filled vial, this would mean that American drug makers lost $1 billion in revenue (2). Additional costs can result if filling lines stand still. In some cases, companies attempt to prevent delamination by significantly shortening the storage periods they recommend for their pharmaceuticals (3).

The list of drug recalls (4) and, even more importantly, the enforcement reports (5) of the FDA show that recalls still take place today due to glass flakes in products. In fact, if we take a look at the FDA's list of drug recalls and enforcement reports, we will see that the number of recalls due to delamination is on the rise. Pharmaceutical companies and packaging manufacturers are faced with the challenge of solving this problem, and as a result, the pharmaceutical industry is increasingly demanding approaches that minimize the risk of glass flakes. Oftentimes companies turn to packaging manufacturers to learn more about appropriate measures or to request that they be taken.

Delamination typically takes place with drugs that have been stored for longer periods of time. Using vials that have been proven to have a lower risk of experiencing delamination can offer an alternative. In fact, these types of vials are already available on the market. These products are constantly being monitored for delamination by performing a quick test procedure while they are being manufactured. These vials can replace the conventional products that are being used with approved pharmaceuticals, and there is no need to have them registered again. While pharmaceutical companies still need to perform warehouse studies to determine the risk of delamination in specific cases, SCHOTT delamination controlled (DC) vials minimize the risk of delamination, and a new test can pinpoint the potential for delamination based on threshold values.

COMPLEX INTERACTIONS BETWEEN GLASS AND DRUGS

The complex processes that take place when a pharmaceutical formulation reacts with the inner glass surface of the vial basically depend on the composition of the glass. Here, the pharmaceutical formulation itself is also extremely important. Quick and reliable screening methods can be used to analyze the specific interactions between drugs and packaging materials. As such, a few general statements can be made. For example, hydroxyl ions attack silicon-oxygen compounds in alkaline solutions--in other words the structure of the glass. On the other hand, in acidic solutions, an exchange of ions takes place between hydrated protons and sodium or other alkaline ions in the glass (leaching). An even attack on the inner surface by the pharmaceutical formulation is referred to as corrosion and has nothing in common with the phenomenon of delamination.

A local attack on the inner surface of the wall zone at the bottom of the container takes place when delamination occurs. This chemically less stable position can be visualized using a variety of different techniques during manufacturing of the vial. Delamination occurs once glass flakes become selectively detached. This section is normally low on sodium and boron. Buffer substances in the pharmaceutical formulation can also react selectively with the ingredients of glass and thus contribute to the peeling of glass flakes.

Chapter <660> of the U.S. Pharmacopeial Convention (USP) describes the requirements for glass containers used to store medications. However, it only refers to the need for resistance, not to the tendency of the inner glass surface to experience delamination. In March 2011, however, the FDA wrote a letter (1) to inform the pharmaceutical industry of the problem and listed factors that can increase the risk of delamination. Then, in April 2012, the USP presented the first draft of a new chapter in which it described techniques with which the stability of the inner glass surface can be predicted more accurately and monitored more effectively (6).

SOLVING THE PROBLEM THROUGH COATING

Manufacturers can reduce the tendency of a vial to release sodium during interaction with a formula by treating it with ammonium sulfate. Ammonium sulfate forms highly soluble sodium sulfate when it meets up with the sodium, found just a few angstroms beneath the glass surface. The sodium concentration of the inner glass surface can thus be lowered considerably. Nevertheless, this does not lower the probability of delamination occurring. In fact, this type of treatment can even increase it (6).

However, pharmaceutical packaging manufacturers can lower the risk of delamination by applying a thin quartz-like coating to the inner surface of the glass. This forms an extremely homogeneous and effective barrier between the glass and the medication. It largely prevents ions from the glass from diffusing into the drug. These types of coated vials ensure high safety and stability of proteins produced biotechnologically, as well as other sensitive drugs. SCHOTT's Type I plus vials follow this process, and their resistance to delamination has been documented by performing warehouse studies using standard buffer systems (phosphate, citrate, and acetate buffers).

CONTROLLED PRODUCTION PROCESS

Vials for injectable pharmaceutical formulations are made of Class 1 borosilicate glass (USP <660>, EP 3.2.1, ASTM E438), and are therefore extremely resistant to hydrolysis. They can be manufactured in two completely different ways: molded glass vials are manufactured using a single high-temperature process step in which the molten glass is blown or pressed into shape. With tubular glass vials, the glass tubing is produced first and then, in a second step, shaped into vials at high temperatures. Molded glass vials generally contain a higher share of alkali and earth-alkaline elements than tubular glass vials, and a lower share of silicon. This higher share of alkali and alkaline-earth elements allows manufacturers to use a lower processing temperature.

Generally speaking, tubing glass is considered to be more chemical-resistant than molded glass. Nevertheless, the tendency of delamination to occur with a pharmaceutical vial made of tubular glass strongly depends on how the process is controlled during forming. Volatile components like boron and sodium evaporate while the bottom of the glass is being formed. As the production process continues, these substances produce inhomogeneous spots on the glass surface near the bottom that are generally more susceptible to delamination. Active control of this process is possible if the quality of the glass surface and its tendency to experience delamination are monitored during production. This marked the starting point for a new way to test the risk of delamination.

DELAMINATION QUICKTEST

SCHOTT developed a test that allows packaging manufacturers to determine the risk of delamination within only a few hours by applying threshold values. During the first part of the test, the glass surface is gradually attacked locally. Vials are removed from production and subjected to stress inside an autoclave, in a steam environment, at a temperature of 121[degrees]C. In the past, vials were subjected to visual inspections with a stereomicroscope after autoclaving in steam. Inhomogeneous spots on the inner glass surface or a distinct cloudy ring and/ or colorful interference ring can then be seen on the wall of the vial toward the bottom using stereomicroscopy. This method has been replaced as an indicator of the future probability of delamination occurring by atomic absorption spectroscopy, a method that can be performed much more easily during everyday production operations.

The test works as follows: the vials are filled with water so that the zone in which delamination normally occurs is slightly covered. Then sodium is extracted inside an autoclave at a temperature of 121[degrees]C. Next, the amount of sodium that has been extracted is determined using atomic absorption spectroscopy. This correlates with the probability that the vial being inspected will experience delamination at some point in time. SCHOTT's patented Delamination Quicktest continues to monitor whether a defined threshold value for the amount of sodium that has been extracted is observed during manufacturing. The probability of delamination occurring in the vials manufactured can thus be constantly monitored.

VIALS DC

Extremely high-quality HOLAX tubing marks the starting point for manufacturing vials that have a lower risk of experiencing delamination. The forming process achieves an inner surface more homogeneous than that of conventional vials, resulting in higher chemical resistance and a lower tendency to experience delamination. This was confirmed by performing comparative warehouse studies on formulations that had caused recalls due to delamination in the past. Filled with 15% potassium chloride solution or 10% sodium thiosulfate solution, DC vials remained stable even after being exposed to a temperature of 60[degrees]C for 12 weeks. Neither glass flakes nor a reactive zone could be seen while conventional vials showed clear signs that delamination had set in. These tests were performed using high resolution SEM-EDX and ICP-OES.

SCHOTT manufactures Vials DC with the help of an optimized forming process, and using the Delamination Quicktest, and have been available since the beginning of 2014. The company provides product samples, as well as its analytical expertise, to help customers perform the warehouse tests necessary before a new pharmaceutical product can be introduced to the market.

Because delamination usually occurs after only several months or even years later, these tests must be capable of speeding up the delamination process without changing the basic attack mechanisms on the glass. Complementary analysis methods are also needed in order to be able to reliably determine signs of delamination early on (7).

While coated vials are one solution to minimizing the costly and potentially dangerous phenomenon of delamination, there is now a unique new packaging alternative for pharmaceutical companies to use: uncoated vials that reliably lower the risk of delamination. In addition, the creation of the Delamination Quicktest allows manufacturers to test, for the first time, the likelihood of delamination during the manufacturing process. Based on threshold values, the test can be used to monitor the vials and ultimately reduce the possibility that delamination will occur.

As a result of these new techniques, pharmaceutical manufacturers can not only better ensure that medicines achieve their intended outcome for patients, but also comply with FDA requirements, avoid costly recalls, and better maintain their reputations.

References

(1.) FDA, Drugs Advisory to Drug Manufacturers: Formation of Glass Lamellae in Certain Injectable Drugs, 25.3.2011, http://mmv.fda.gov/drugs/ drugsafety/ucm248490.htm

(2.) Hall, M.; Risk Factors Associated with Delamination of Glass Vials, Presentation, http://de.slideshare.net/matthewmicahhall/risk-factors-associated-with-glass-delamination

(3.) Swift, R.; Amgen presentations, PDA April 2011 San Antonio; PDA/FDA Glass Quality Conference May 2011

(4.) http://www.fda.gov/Drugs/Drugsafety/DrugRecalls/default.htm

(5.) http://www.fda.gov/Safety/Recalls/EnforcementReports/default.htm

(6.) USP <1660> Evaluation of the Inner Surface Durability of Glass Containers, http://www.usp.org/sites/default/files/usp_pdf/EN/USPNF/revisions/cl660.pdf

(7.) Haines, Dan; Scheumann, V.; Rothaar, U.; Contract Pharma, June 2013, S.92, http://www.contractpharma.com/issues/2013-06/view_features/glass-flakes/

Dr. Bernhard Hladik

SCHOTT Pharmaceutical Systems
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Author:Hladik, Bernhard
Publication:Contract Pharma
Date:Apr 1, 2014
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