Glass breakage in pharmaceutical packaging

Glass breakage in pharmaceutical packaging – highly welcome or utmost feared?

Author: Dr.-Ing. Carina Bronnbauer (Product Manager of SCHOTT Pharmaceutical and Technical Tubing)

Thanks to low extractable/leachable profiles, small diffusion coefficients, and high transparency still set glass as the undisputed material of choice for parenteral packaging. Its inherent breakage risk was long-time believed to be the major drawback of glass, but today´s increasingly emotional discussion about breakage encourages reconsidering this aspect. 

In the pharmaceutical packaging industry, discussions about glass breakage can be traced back to two main areas of context: Fill and finish (F&F) line performance and container closure integrity (CCI). Related to F&F line performance, the questions is asked, whether breaking containers on the line cause less disruption and yield loss than breaking machine components due to highly break resistant containers. Related to container closure integrity and therewith patient safety, the question is raised whether immediate and reliable container failure on the F&F line could possibly prevent unrecognized crack formation and thus container leakage or ingress to be channeled into the market. 

Regarding both areas of interest three questions should be addressed consequently:
  1. What is the right level of container strength and how can it be achieved?
  2. At which step of the value chain should the strength and the integrity of the container be investigated? 
  3. What is the appropriate test scenario regarding container strength and integrity to make container performance predictable?
Figure 1: Schematic representation of fracture toughness of glass. Left: glass with large defects that breaks upon little applied tensile stress. Right: glass with small defects that breaks upon large applied tensile stress.

Based on the tremendous negative impact of surface flaws on mechanical stability of the final product, there are two common approaches to control the mechanical strength of glass: (i) Minimize the generation of surface flaws along the full value chain, e.g. via F&F line optimization or special glass coatings at the outside of the container. (ii) Lower the destructive impact of existing surface flaws via post-processing, e.g. via chemically toughening. Within this process, intended built-in stress profiles are generated through systematic ion exchange. 

The good news is, there is no need for a special glass type for either of these approaches. All common silicate glasses, such as e.g. soda-lime, aluminosilicate and borosilicate glass, are suitable candidates. Especially for the second approach, the bad news is, that manipulations of the mechanical strength via chemically toughening do not only affect the breakage resistance, but may also influence the fracturing behavior, the glass chemistry of the inner surface and thus the E&L profile of the pharmaceutical container 2). The last aspect has to be taken into account when it comes to regulatory container approvals and drug shelf life-studies. Especially for drugs that are already on the market significant costs for the repetition of shelf-life studies and other regulatory requirements have to be taken into account. Furthermore, since chemically toughening requires additional post-processing steps, increased purchasing costs for the container itself and additional manufacturing costs due to line adaption and a modified flow of goods have to be considered, too. When it comes to variations in the fracturing behavior, it is the crack formation risk, or CCI, respectively, as well as F&F line performance that needs to be reinvestigated.

For demonstration of possible ambiguous fracturing behaviors, chemically strengthened and non-strengthened containers were either clamped between two metal plates while the mechanical load was continuously increased along the vertical axis until breakage occurred, or sawn with a diamond plate to depict the containers’ fracturing behavior upon crack formation. The results are displayed in Figure 2 and 3. A chemically strengthened container can withstand high mechanical load if clamped between two metal plates and bursts apart into predominantly superfine particles upon breakage. Conversely, if the same type of container is scratched by a sharp and strongly stiff material, it suddenly breaks apart into rather large cullets. In contrast, non-strengthened glass containers withstand less mechanical load if clamped between two metal plates, resulting in much larger fragment sizes compared to a strengthened container. When in contact with a sharp and stiff material, cracks will not necessarily lead to breakage. Here, even deep furrows can be easily sawn into such containers without leading to full destruction. 
Figure 2: Breakage behavior of a non-strengthened (left) and chemically strengthened (right) glass container upon axial compression acc. to DIN EN ISO 8113 (Glass containers - Resistance to vertical load -- Test method ISO 8113:2004)
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Figure 3: Sawing of a non-chemically strengthened (left) and chemically strengthened glass (right) glass container with a diamond-cutting disc 

The differences in fracturing characteristics between both types of containers can cause different scenarios during container utilization on e.g. the filling machines. The first assumption, that strengthened containers allow a higher production yield because of less glass breakage proves to be incorrect. Since strengthened glass can show even higher mechanical strength than certain machine parts, it is not only breakage of glass that needs to be considered, but also the destruction of machine components due to too strong clamped containers. Thus, an increase of Total Cost of Ownership (TCO) might be the result, due to longer machine downtimes as well as a reduction in machine throughput. Taking this into account, an outer coating of non-strengthened containers that minimizes glass-to-glass contact might be the better alternative if aiming for a good production yield. 

However, in theory but still without statistical evidence, strengthened containers might at least lower the risk of jeopardizing patients’ health through imperceptible ingress of impurities into the aseptic drug, since crack formation at strengthened containers result in immediate breakage.

Accordingly, today’s questions on the right container strength cannot be sufficiently answered yet. It is rather a question of defining the perfect match between container properties and the optimum processing as well as supply chain environment. How small the risk of crack or breakage actually is, can be exemplified by looking at some statistical numbers: Projections estimate 20 billion vials for filling injectable drugs are processed on an annual basis, while only 6 recalls related to “crack” and “breakage” were announced within the last six years for borosilicate glass containers 3). Already starting from a very low risk potential, of course the primary goal is to lower it even further in order to finally achieve “zero defect”. Thus, what happens if crack formation will become fully negligible in the future through line optimization and if no crack remains undetected?
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When to measure glass strength and crack formation?

This brings us directly to the next question: “At which step of the value chain should the strength and the crack formation risk of the container be investigated?” In general, if the glass surface is not regenerated via additional processing steps, like e.g. fire-polishing or via etching with harsh chemicals, products made of glass will have a non-erasable memory regarding surface defects. Meaning, surface flaws on the container accumulate throughout the entire process chain and continuously lead to a reduction of the container strength. Hence, considering the entire value chain, starting from the glass melt all the way to the end user, it is more than obvious that there cannot be one single test scenario for glass breakage or crack formation risk, respectively, that models all numerous processing steps. 

Similar to the recommendation acc. to United States Pharmacopeia <1207>, three test stations along the full value chain seem to be reasonable (a) right before, (b) during, and (c) after containers are passing through the F&F line, see Figure 4. Of course, if shelf life stability tests are included, additional studies have to be conducted, too. Conversely, investigations that are supposed to characterize the mechanical stability of glass tubing or freshly converted vials (no coatings, no chemically strengthening etc.) are rather less informative. For both product categories, there is still a long way to go before the product reaches the end user. Here, it is much more important to focus on the intactness of the glass by detecting any existing surface flaws.
Figure 4: Along the value chain of pharmaceutical containers. (a), (b) and (c) indicate potential testing stations. The respective test setups at each station are listed in Table 1.

Tests right before the containers enter the fill and finish line (a) are relevant not only for sorting pre-damaged containers but also to allow a general differentiation between container categories, like e.g. strengthened containers, non-strengthened containers, bulk containers, ready-to-use containers etc.. Next, in-line monitoring of containers passing through the fill and finish line (b) can help to identify high-risk areas causing surface flaws on the container. Investigations of the vials directly after the fill and finish line (c) with respect to mechanical stability and leakage due to crack formation are most relevant when it comes to patients’ health since this reflects the end user container stability the most. Since each test station aims to answer a different question of container strength and CCI, each station has to be equipped with a different experimental setup. 
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How to measure glass strength and crack formation?

Table 1 summarizes potential experimental methods, that can be applied at the three given stations. Moreover, it also clarifies whether the measurement is either destructive or non-destructive. Taking into account that container strength tests only allow statistical statements due to the destructive nature of such tests, there can never be a 100% guarantee in terms of container strength. In contrast, tests intending to detect cracks can be both, destructive or non-destructive. Cracks are either detectable directly via camera inspection units or indirectly via CCI analysis methods. Hence, opening up the opportunity for fully in-line integrated crack inspection systems that analyzes every single container before being finally packed and sent to the customer. 

Picture 1

Picture 2

Picture 3

Picture 4

(a) Before F&F (b) During F&F (c) After F&F
Test Resembles Test Test Resembles
Picture 1 Vertical compression* e.g. crimping Visual inspection units** Headspace analysis** Ingress through crack / CCI
Picture 2 Slide compression* e.g. back pressure/Clamping during on line transportation Smart Skin Drone Systems** Vacuum decay** Ingress through crack / CCI
Picture 3 Pendulum* e.g. punctual pressure through metal edges   High voltage** Imgress through crack / CCI
Picture 4 Burst pressure* e.g. internal presure variations during lyophilisation   Repeat all tests listed in column (a)* Impact of F&F line on final container strength
Table 1: Possible test methods to investigate either the mechanical strength or the CCI of a container.
*destructive test, **nondestructive test
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As previously mentioned, tests at position (a) mainly focus on the investigation of mechanical strength to reflect e.g. progress in product development of new container systems. Since the mechanical strength cannot directly be implemented into the filling line due to its destructive nature, lab test need to be developed that try to resemble the numerous mechanical loads to which a container is exposed to on a F&F line. Possible test scenarios could be: vertical compression (resembling e.g. the crimping process), side compression (resembling e.g. back pressure during container transport in depyrogenation tunnel), pendulum (resembling e.g. punctual impact through metal edges), and burst pressure (resembling e.g. pressure differences within a closed container during lyophilisation).  All respective test scenarios are schematically shown in Table 1. After completing the various mechanical tests, one should not stop with the investigations. Here, subsequent fractographic analysis can be a promising tool to identify the origin of the breakage and thus might even allow to ascertain the weakness of the analyzed container 4). 

It is important to conduct not just one mechanical stability experiment, but rather several different tests. Latest in-house studies indicate, that each type of the container (other glass type, other surface treatment, other converter etc.) has its own finger print when it comes to the correlation between the different mechanical strength tests. Meaning, by conducting e.g. burst pressure stability tests, the outcome for axial compression is not predictable.

Nowadays, visual camera inspection systems are well established on F&F lines (b), and can be even considered as standard features. However, also in this field of application, new technologies are explosively evolving since the last few years. For example, mathematical algorithms based on neural network programming, might soon facilitate fast-learning and adaptive on-line inspection units for even small lot sizes with fast changing container dimensions.

On top of this, another new technology has been recently launched on the market. Here, a drone container is passing through the complete F&F line together with regular glass containers, detecting: pressure, spin, tilting and shock 5). With that approach, it is now possible to optimize production lines with respect to any potential mechanical stress that may cause surface flaw generation and thus CCI issues. Once identified, high risk areas within production are often easy to eliminate. Since smoothly running lines go hand in hand with low production losses, this new method may reduce the TCO, too 6).

Coming to station (c), and thus to the most crucial indicator for ensuring patients’ health, non-destructive test methods to ensure API policy for CCI investigations should be indispensable for future pharmaceutical packaging. So far, however, regulatory bodies only prescribe “100% integrity testing” for fused containers like glass ampoules 7). For other type of containers, like syringes, vials or cartridges, such tests still remain a recommendation only 8). Nonetheless, on-line fully integrated CCI inspection units like high voltage leak detection modules, vacuum and pressure decay technologies, or laser-based headspace analysis are already available and well established on the market. Machine outputs of up to 600 containers/min are becoming more and more common. Hence, there is no longer a limitation regarding the technical feasibility of 100% on-line inspection systems.  Despite CCI evaluation, it is also the mechanical strength of the container that has to be examined critically. By repeating the statistical strength analysis as described for position (a), potential weaknesses of the F&F line might be identified. Moreover, only at this stage, the “real” mechanical stability of a utilized container can be evaluated.

To conclude, all types of containers – strengthened/non-strengthened, coated/non-coated, fire polished/non-fire polished, borosilicate/aluminosilicate/soda-lime – have their own specific advantages or disadvantages regarding crack formation risk and processability. So far it is sure, that none of all given solutions will ever enable us to fully control the inherent statistical nature of glass breakage. However, well positioned measurement setups in combination with new technology can help to make it more assessable. Most likely, the propagated methods of analysis to detect cracks and to investigate the mechanical strength of glass containers, see Table 1, is not complete yet and may open up the discussion whether these test scenarios are really the most relevant to perform. So, let’s discuss and tackle the question about the next generation containers because a strong container right before entering the F&F line, but a weak container if utilized at the patient, is the most risky scenario to look at! 

References

1) Introduction to Glass Science and Technology, J. E. Shelby, Royal Society of Chemistry, 2015
2) C. Heinl, Glass along the Value Chain: Certain Treatments and their Impact on Extractables for Borosilicate and Aluminosilicate Glass. PDA Letter (2018)
3) U.S. Food and Drug Administration Recall Information Search on 06/20/2018, excluding cracked caps /capsules/tablets / foil of blister packs
4) D. Haines, F. Maurer, U. Rothaar Why do Pharmaceutical Glass Containers Break: The Underestimated power of Strength Testing and Fractography, IPI 2016 8 (1), 88-92
5) SMARTSKIN, https://smartskintech.com/en/products/packaging-pressure-monitoring, 16.08.2018
6) L. Eberle, H. Sugiyama, S. Papadokonstantakis, A. Graser, R. Schmidt, K. Hungerbühler, Data-driven tiered procedure for enhancing yield in drug product manufactuaring 2016 87, 82-94
7) EU GMP Annex 1 – Manufacture of Sterile Medicinal Products 117 
8) USP <1207> Sterile Product Packaging- Integrity Evaluation
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Tubing PDA Glass Breakage Carina Bronnbauer

About the Author:

Carina Bronnbauer, PhD
is responsable for product magement for technical and pharmaceutical tubing at SCHOTT.
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Copyright

PDA: Licensed to Schott AG
Republished with permission of PDA
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