Pharma glass defects - Part 36. Broken detached bottom

Hello everyone – welcome to Part 36 of an ongoing series focused on defects that may be observed in pharma glass vials.? I briefly touched on the “Broken General ” defect all the way back in Part 20, but it turns out we’re not done talking about glass breakage yet.? There are specific mechanical failure modes that get a special call out in the PDA TR 43 lexicon, including the “Broken Detached Bottom” (BDB) defect, also referred to as the “Lensed” defect.? A BDB defect is a case where the bottom of a glass vial completely separates from the vial body, as shown in Figure 1 (see Footnote 1).? An important characteristic of the BDB defect is the circular fracture surface that is confined to the heel region of the vial.? This distinguishes the BDB defect from the “Broken Ring Off” defect that we’ll cover in a future post.

No special considerations are needed in classifying a BDB – it is always considered a Major A defect that renders the glass container unusable.? Instead, I’d like to focus on the implications of the BDB defect relative to where the defect is detected – i.e., is the defect detected with empty vials at incoming inspection (see Footnote 2) or after the vial has gone through some/all of the fill-finish process.?

Let’s start by recalling that glass breaks when a sufficiently large tensile stress activates a sufficiently large flaw (see Footnote 3).? The operative questions then become: 1) How and where in the vial life cycle was the critical flaw created? and 2) How and where in the vial life cycle was the tensile stress applied to activate the flaw?? The two events can occur at essentially the same time.? In other cases, the critical flaw is introduced first and the stress leading to breakage happens at a later time.? Irrespective of when it is detected, observing a BDB defect means that the critical flaw was introduced into the heel region of the vial.? If the BDB is detected at incoming inspection, it further suggests that: 1) the flaw was created during the initial vial manufacturing process or possibly during shipping to the end user and 2) the tensile stress leading to breakage occurred during shipping.? Detecting the BDB during or after the fill-finish process is more complicated.? The critical flaw could still have been introduced during vial manufacturing or shipping, but that fill-finish process itself is now an additional potential root cause.? For example, transition points between different modules of filling lines can cause “heel strikes” that create glass surface damage leading to BDB’s later in the process.? Additionally, a BDB defect found during/after the fill-finish process implies that the activating tensile stress occurred at the site of the end user.

A classic cause of lensing breaks during the fill-finish process is stress created during lyophilization.? A common source (but not the only potential source) of stress is crystallization of solutes such as sodium dibasic phosphate and mannitol from an amorphous matrix created during the initial freezing process.? The crystallization event results in a volumetric expansion of the drug product that imparts stress to the glass vial.? In some cases, this stress can activate critical flaws in the heel region of the vial, leading to a lensing break (see Footnote 4).? I particularly like the 2023 study from Sahni et al. demonstrating the use of strain gauges to monitor vials throughout various lyophilization cycles (see Footnote 5).? The authors demonstrate what I think is an important point.? Vial breakage rates can vary considerably between the initial R&D/clinical phases and tech transfer/commercial phases of a drug product.? The R&D/clinical phases are more likely to involve manual vial filling or robotic filling of RTU vials with minimal glass-to-glass contact, resulting in fewer opportunities to introduce strength-limiting defects.? Once the process is transferred to a bulk filling line, additional damage can be introduced to the vials that unexpectedly result in increased breakage during lyophilization.

?

Footnotes

1.?????? The circular shape of the bottom fragment gives rise to the alternate Lensed defect terminology.? On a relate note, you might also hear this referred to as a “lensing” breakage event.

2.?????? Just to be clear – my use of the phrase “incoming inspection” refers to a visual inspection of ?empty vials performed by the end user.? The incoming inspection is performed to verify that the vials meet the quality standards expected from the vial supplier.

3.?????? Refer to my prior post on the strength of pharma glass vials for a refresher.

4.?????? This situation can be further exacerbated by the geometry.? A vial with a smaller heel radius can amplify the stress caused by solute crystallization.

5.?????? Reference: Sahni EK, Searles JA, Nachtigall M, Owen E, Lyne D (2023).? Vial breakage in lyophilization – Case studies from commercial manufacturing and laboratory studies.? Journal of Pharmaceutical Sciences, 112: 1151-1159.