Pharma glass defects – Part 43. Contamination

Hello everyone – welcome back to Part 43 of my ongoing series devoted to defects that may be observed in pharma glass vials.? The subject of today’s post is the “Contamination” defect.? At a very high level, Contamination is extraneous matter that is removable or non-removable.? “Extraneous matter” is a broad term -- it can encompass any number of possible contaminants of synthetic or biological origin, including fibers, particles, deposits, or even whole organisms (see Footnote 1).? A detailed discussion of the various types of Contamination is beyond the scope of this post (see Footnote 2).? Instead, I’ll try to focus on general features of the Contamination defect.

I think one of the most important aspects of Contamination is the potential complexity of upfront identification – in other words, is what you’re seeing truly a Contamination defect?? For example, a strand of hair inside of a vial is definitely Contamination, but it’s not always so obvious. ?Figure 1 provides an example of what I’m talking about here.? The brownish, circular deposits seen through my trusty eye loupe are present on the exterior surface of the vial shoulder region.? However, PDA TR 43 lists six other wholly distinct defect types that are related to Contamination: 1) Adhered Glass, 2) Alkali or Glass Powder Spots, 3) Knot, 4) Loose Glass, 5) Stone, and 6) Water Spot (see Footnote 3).? Recall that Contamination is based on extraneous material – each of these alternate defects instead involves material that is in some way intrinsic to the original glass container material. ?In this case, I would say that a conclusive determination of whether Figure 1 is an actual Contamination defect requires that we perform a chemical analysis of the deposits using appropriate analytical techniques such as electron microscopy in conjunction with energy dispersive X-ray analysis, optical microscopy in conjunction with vibrational spectroscopy methods (infrared or Raman), etc. ?

Let’s assume that we have used appropriate methods to positively identify a defect as Contamination – what’s next?? We now have to classify the Contamination into an appropriate risk level – i.e., Critical, Major, etc.? The “Classification” entry for the Contamination defect is the lengthiest amongst all of the defects for tubular glass vials listed in PDA TR 43. ?A series of up to four additional questions still have to be answered to properly classify the defect, including:

1.?????? Is the Contamination defect on the interior or exterior surface of the vial? (see Footnote 4) The answer to this question has clear implications for a risk-based classification of the defect.? Contamination on a interior surface is obviously a much greater concern due to both direct and indirect risks to the patient.? In this case, a “direct” risk means the contamination has the potential to harm the patient, perhaps because its chemical composition presents a toxicological risk.? An “indirect” risk means that the Contamination can interact with the drug product in a way that compromises its safety or efficacy.

2.?????? Is the Contamination defect removable or non-removable? Per PDA TR 43, “removable” means that the contaminant is easily removed with the swipe of a gloved hand, water flush, air flush, water flush, or a soft probe – i.e., we would expect the Contamination defect to be generally removed from the container with a typical washing process.

3.?????? Is the Contamination defect fully embedded within the wall of the container? A fully embedded contaminant is presumably isolated from the environment.? The question of whether it’s embedded or not is relevant for both the interior and exterior surfaces of the container.? The importance of the internal surface is more obvious.? However, exposed extraneous matter on the exterior surface is still important since it can potentially migrate to contaminate the internal surface of the container and/or other areas of the filling line.

4.?????? What is the size of the Contamination defect? Contamination defects are classified on the basis of area using a calibrated measuring device such as a microscope.

Once we have answered these questions, we’re almost ready to fully classify the Contamination defect.? There’s just one additional point that needs to be covered.? Contamination in PDA TR 43 is officially divided into two related defect types: 1) Contamination (Bulk, Unwashed) and 2) Contamination (Ready-to-use).? The process for answering the question “Is it Contamination?” does not depend on whether the vial is in a bulk, unwashed form or a ready to use (RTU) form.? However, the defect classification process does vary slightly for a bulk versus a RTU presentation.? We assume that answering the question “Is it removable or non-removable?” is irrelevant for a RTU vial.? The RTU vial has already gone through a washing process, and so any observed Contamination defect should by definition be non-removable.

With that out of the way, let’s finally cover the classification scheme for a Contamination defect.? I’ll be organizing this based on whether we’re considering a bulk vail or RTU vial and whether the Contamination is on the interior or exterior surface

·?????? Contamination on the interior surface of a bulk vial is: 1) a Critical defect if non-removable AND ≥0.1 mm2 in size, 2) a Major A defect if exposed, partially embedded, OR adhered, non-removable, AND ≥0.3 mm2, or 3) a Minor defect if removable AND ≥0.5 mm2.

·?????? Contamination on the exterior surface of a bulk vial is: 1) a Minor defect if fully embedded OR non-removable AND ≥0.5 mm2 or 2) otherwise an Acceptable Imperfection.

·?????? Contamination on the interior surface of a RTU vial is: 1) a Critical defect if ≥0.1 mm2, 2) a Major A defect if exposed, partially embedded OR adhered AND ≥0.3 mm2, or 3) otherwise an Acceptable Imperfection.

·?????? Contamination on the exterior surface of a RTU vial is: 1) a Minor defect if fully embedded AND ≥0.5 mm2 or 2) otherwise an Acceptable Imperfection.

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The primary point that I hope you take from this post is that the identification and classification of a Contamination defect can potentially be a complicated process. ?Furthermore, the analytical resources needed to fully characterize Contamination can be non-trivial.? As a result, I always encourage end users to communicate directly with their glass suppliers in the case of Contamination defects (particularly the less obvious ones).? Knowledge sharing and possible access to additional analytical tools can hopefully help avoid confusion and decrease the time needed to properly identify and classify the defect.

Questions or comments? – please leave a comment below or feel free to directly contact me.

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Footnotes

1.?????? Yes – even whole organisms.? The example I’m familiar with is insects that manage to find their way into a container.? I’ve seen it happen a couple times with bulk, unwashed vials in my ~5 year career in the pharma packaging industry.

2.?????? I have just one comment on the different types of Contamination that I think is worth noting in the Footnotes section.? The detectability of the various types of Contamination is known to vary based on factors such as aspect ratio (e.g., long, thin fibers versus a roughly circular deposit) and optical properties (e.g., clear versus opaque) of the contaminant.? This comment could also be generalized in some respects to the entirety of PDA TR 43, which primarily classifies defects based on risks to the drug product and the patient.? With that said, I’m also not suggesting that PDA TR 43 should be explicitly consider detectability, although the document will sometimes note that a given defect can be obscured by other packaging components.? For example, Tooling Marks present on the flange of a vial will be covered by an aluminum crimp seal at the end of the fill-finish process.? The probability of detection of a particular defect for a given product or process can be strongly case dependent.?

3.?????? In the interest of being complete, PDA TR 43 also lists “Contamination (Ready-to-use)” as a related defect, but I’m treating this differently for the purpose of this discussion.? Read on within the post for further clarification.

4.?????? PDA TR 43 only mentions extraneous matter on the exterior surface of the container in the “Definition” column for the Contamination (Bulk, Unwashed) defect.? In contrast, the Contamination (Ready-to-Use) defect only mentions extraneous matter on the interior surface. ?However, entries for both defect types in “Classification” column include consideration of the interior and exterior container, and so I have to assume the definitions contain typos that accidentally omit interior (in the case of bulk) or exterior (in the case of RTU) surfaces.