Pharma glass defects – 8. Changes in Critical defect classification

Hello everyone – this is part 8 in my ongoing series that takes a look at pharma glass defects with a focus on tubular glass vials.? I’ve previously noted that this series will prioritize defects that can be potentially be classified as Critical, meaning “a nonconformity that is likely to result in personal injury or potential hazard”. (see Footnote 1)? I was recently checking up on my progress through the list of 12 possible Critical defects, and I was reminded of all the changes that had occurred between the 2013 and 2023 version of PDA TR 43.? I touched on this briefly in my post on “Residual Stress” – i.e., a nonconformance that was previously classified as Critical but was actually removed entirely from the defect lexicon.? However, this is by no means the only change to Critical defect classifications in going to the new 2023 revision (see Footnote 2).

I created a list of all the Critical defects from both the 2013 and 2023 versions and attempted to classify them by assigning a change in status.? The terminology I used in making these assignments are purely my invention – they’re not official to the defect lexicon in any way.? My analysis indicates that the Critical defects appearing in the 2013 version went through one of seven possible changes in status:

1.???? Unchanged – as the name suggests, there was no change in the definition or classification of the defect.? Note that I am not counting the clarifications (e.g., Method, Source, etc.) that were holistically applied to all defect types within the lexicon.? These clarifications are highly useful, but they don’t fundamentally change anything.

2.???? Removed – a defect type that was entirely removed from the lexicon.

3.???? Upgraded Criticality – a defect type appearing in the 2013 version that had a maximum classification lower than Critical and was upgraded to potentially being Critical in the 2023 version

4.???? Downgraded Criticality – a defect type appearing in the 2013 version that had a potential classification of Critical and was downgraded to a lower maximum classification.

5.???? Disaggregated – a Critical defect appearing in the 2013 version that was sub-divided into multiple defects to presumably provide more granularity in classification.

6.???? Aggregated – multiple Critical defects that were grouped together into a single defect type to presumably simplify classification.

7.???? Revised – defects that retained their essential character between the 2013 and 2023 versions but experienced one or more revisions.

Figure 1 maps all of the aforementioned status changes onto the Critical defects present (or potentially absent) in the 2013 and 2023 versions.? Let’s walk through each one of these point by point:?

• It’s not necessarily surprising that the “Crack” defect is the only one that is unchanged.? There’s not a lot of room for negotiation here.? The location or size of a Crack is irrelevant in terms of classification – it obviously meets the definition of a Critical defect.
• The “Residual Stress” defect also experienced a singular change in status – i.e., Removed (see Footnote 3).?
• The “Knot” and “Stone” defects were upgraded in criticality after recognizing their potential to compromise container-closure integrity (CCI), particularly if located on the sealing surface of the vial flange.
• Four defects were downgraded in criticality, meaning that they still appear in the 2023 version but do not have the potential to be considered a Critical defect.? The “Spiticule” defect is perhaps the stand out for me.? In brief, a Spiticule is a bead or string of glass created during the vial converting process that adheres to the interior of the glass.? It’s maximum classification was reduced to Major A, which is consistent with the Major A classification applied to the “Adhered Glass” defect.? One could debate the potential risk of loose particle formation from a thin string of adherent glass versus an adhered glass fragment, but I digress…it’s a reasonable change.
• The “Contamination” defect from the 2013 version was disaggregated into four new defects: “Alkali or Glass Powder Spots”, “Contamination (Bulk Unwashed)”, “Contamination (Ready-to-Use)”, and “Haze”.? I haven’t done a post on Haze yet, and so here’s a sneak peek – it has the same root cause as Alkali or Glass Powder Spots, but a distinct visual appearance (see Footnote 4).? The disaggregation of these defects from the other “Contamination” defects importantly recognizes that there are many possible sources of contaminants.? For example, the material source of the Haze defect is entirely intrinsic.? The “Contamination” defects in the 2023 version have been redefined to focus on extrinsic sources of contamination, including oil lubricants, plastic packaging materials, etc. (see Footnote 5).
• A multitude of converting-related defects were aggregated together into “Malformed Finish”, which by itself was another defect within the 2013 version.? While the specific root causes can vary for the unique converting defects identified in the 2013 version, they’re not necessarily so different relative to the factors that presumably led to the disaggregation of the “Contamination” defect, as discussed in the prior point.? The ultimate goal is to identify converting-related issues with the finish that can impact CCI, and so this seems like a reasonable approach to me.? Note that the “Unfilled Finish” defect is still a unique type.? I’m assuming this is meant to distinguish between having too much/not enough gathered glass versus not properly converting a sufficient quantity of glass.
• Last but not least, four potentially Critical defects were revised.? In my parlance, a revision can mean that multiple aspects of the definition and/or classification have changed between the 2013 and 2023 versions.? In particular:
• Wavy Top – additional flexibility was provided if the waviness did not compromise CCI and was within specifications
• Unfilled Finish – similar changes as Wavy Top
• Chip – new quantitative specifications were defined, irrespective of whether CCI is compromised or not
• Adhered Glass – additional clarification was provided on Adhered Glass on the interior versus the exterior of the glass vial.

I want to emphasize that all of these nonconformances have the potential of being a Critical defect.? With the exception of the “Crack” defect, lower level classifications may be applied depending on location, size, and/or impact on container(-closure) performance (see Footnote 6). ?Table 1 summarizes all of the potential classifications that may be applied to nonconformances within the 2023 revision that can possibly be classified as Critical defects.? I find it interesting that all of the defects with a status change of “Upgraded Criticality” or “Disaggregated” include the possibility of being classified as a Critical or Minor defect.? I interpret this as an increased recognition that location of the defect is important.

You may be saying “That’s great, Matt – so what?”? The takeaway is that a diverse group of pharma companies and glass suppliers got together to review the classification of defects in pharma glass containers.? A majority of the entries for potentially Critical defects were modified in some way between the 2013 and 2023 versions.? If you’re a pharma company, I would recommend taking a look at these changes and deciding if they’re significant for your drug product.

Got questions? – please leave them in the comments below or contact me directly.

Footnotes

1. ?PDA Technical Report 43 (Revised 2023). Identification and Classification of Nonconformities in Moulded and Tubular Glass Containers for Pharmaceutical Manufacturing. Available at https://www.pda.org/bookstore/product-detail/7320-tr-43-molded-and-tubular-glass-containers

2.? Changes in the Critical defect classifications are the subject of the post, but there are numerous changes to other categories.? I’m focusing on Critical defects because of their relative importance and for the sake of brevity.

3.? Residual stress is gone from PDA TR 43 but not forgotten.? ISO 8362-1 still contains a specification for maximum allowable residual stress in tubular glass vials.

4.? The root cause is evaporation of material from the molten region created during the vial converting process.?

5.? I have yet to discuss “Bulk” versus “Ready-to-Use” (RTU) vials.? I’ll eventually get around to it.? For now, it’s only important to know that the presence of removable interior contamination in RTU vials is still a problem because they are specifically designed to not be washed at the fill-finish site prior to use.

6. Let’s explain this somewhat odd “container(-closure) performance” terminology.? One aspect of defining defect criticality may only rely on the container – i.e., the glass vial.? For example, classification of the “Alkali or Glass Powder Spots” defect considers whether or not the containers comply with the Hydrolytic Resistance Test.? This has nothing to do with the elastomer closure. ?Other cases rely on the container-closure combination, such as classifying a “Knot” or “Stone” defect.