The Importance of Preventing Particulate Matter in Injectable Drug Products

Particulate matter, as defined by the USP, refers to the presence of mobile undissolved particles in solutions, excluding gas bubbles. It is a critical aspect to consider for those involved in packaging injectable drug products, requiring a thorough understanding, mitigation, and adherence to regulatory standards. During this first post in our series, P.E.R.F.E.C.T.-ing the Pharmaceutical Packaging Selection Process, we will delve into the fundamental aspects of categorizing, considering, and mitigating particulate matter.

An Introduction to Particulate in Injectable Drugs

Particulate is an important area of consideration for those using elastomeric packaging components for their injectable drug products. Particulate matter (a term used interchangeably with “particulate” or “particle” in the pharmaceutical industry) is defined by the United States Pharmacopoeia (USP) as “mobile undissolved particles, other than gas bubbles, unintentionally present in the solutions”. This can include anything from manufacturing lubricants to hairs or follicles floating in drug product. Particulate is often associated with the “cleanliness” of a product, or freedom from uninvited specks and flecks. 

The Impact of Particulate Matter on Drug Efficacy and Patient Safety

In general, drug manufacturers seek to limit particulate for the safety of the end-user. Particulate can decrease faith in the brand, harm patients, or in the worst circumstances, even cause death. This is because particulate can be injected into the patient during the administration of the drug product, making its way down veins, venules, and capillaries until it lodges itself in a too-small vessel and prevents blood flow to the area. In fact, the smaller the particulate, the further along the blood vessel system it may fit, causing damage in unexpected ways down the line. In contrast, large particles may be more likely to be noticed by the administer of the drug product, resulting in the disposal of the product before it is injected. This is positive in that it can prevent harm, but negative in that there may be a bad association with the brand responsible for the particulate-containing drug product. 

When particulate is not noticed before it is injected, the best-case scenario is that it causes very little harm and does not affect any major bodily functions. In the worst-case scenarios, the particulate may make its way to vital organs – the heart, brain, lungs – and disrupt the flow of oxygen. This can cause a stroke or heart attack, which is particularly dangerous for the vulnerable patients most likely to receive drug injections. 

Consider, for example, a patient undergoing open-heart surgery who receives heparin to help prevent blood clotting. In a truly disastrous situation, excess particulate from the heparin injection could potentially become stuck in a blood vessel during or after the surgery, resulting in poor outcomes or death despite the performance of the surgeon and medical team. 

Though scary to contemplate, these risks must be examined by those in a position to impact change. High-quality products can help prevent such episodes from occurring. In this way, Datwyler is committed to educating the pharmaceutical industry about the risks of particulate. As the provider of the lowest-particulate elastomeric solutions on the market, Datwyler is dedicated also to providing solutions that can help.

Particulate risks can be different with different applications. Most commonly, injections come in three forms: Intravenous (IV), Intramuscular (IM), Subcutaneous (SC). One less-common route of administration is Intraocular (IO), also called Ophthalmic Injections. These highly specific injection routes present their own unique risks associated with particulate. As the eye is a very small, sensitive part of the human body, particulate must be especially limited. USP <789> addresses this explicitly, saying that “ophthalmic solutions should be essentially free from particles that can be observed on visual inspection” and recommending the Light Obscuration Particle Count Test or Microscopic Particle Count Test. 

Categorization of Particulate Matter in Injectable Drug Products

Particulate is generally categorized in two different ways: by size and by origin. 

Size can be considered in a variety of ways. The simplest is to break particulate into two groups: visible and subvisible particles. Visible particles, as the name suggests, can be seen with the naked eye. Subvisible particles, on the contrary, are too small to be seen without magnifying technology. 

A particle is measured by its longest dimension. Therefore, an oval-shaped particle with a length of 5 µm and a height of 2 µm would be considered a 5 µm particle. Though there is not one uniform standard for the designation of “visible” particulate across all regulatory standards, a good rule of thumb is 25 µm. Anything smaller than this would typically be considered subvisible, and anything larger would be considered visible particulate.  

Many companies break size into even more precise groupings. Datwyler assesses the following size ranges:

• > 100 µm
• 50-100 µm
• 25-50 µm
• 10-25 µm
• 5-10 µm
• 2-5 µm

As is common in pharmaceutical packaging, larger particle sizes are allowed fewer particles per surface area. This means that if 1,000 particles of the smallest size are allowed, perhaps only 10 of the largest size will be allowed. 
If you would like to know the specifications of any individual products or product lines, please contact your Datwyler Technical & Scientific Services representative.

Particulate can also be categorized based on origin. This relates to the question: “Where did the particle come from?” 

• If the answer is “It is present due to the nature of the product itself” then the particle may be considered “inherent”. This might be something like silicone oil, added intentionally to facilitate machinability but not part of the stopper formulation or the drug product.
• If the answer is “Likely within the process of creating the elastomeric component” then the particle is considered “intrinsic”. This might be something like a drop of processing agent, or a chunk of dried rubber from a previous run.
• If the answer to the question of origin is “Likely from outside of the process of creating the component”, then the particle is considered “extrinsic”. An example may be a hair or fiber from the clothing of an operator.

“Looseness” can also contribute to potential risk of the particle. Embedded particles may be less likely to harm a patient, as they are less likely to be accidentally injected alongside the drug product. Loose particles, as they float in the pharmaceutical, are sometimes more likely to be injected into the patient and potentially cause damage. 

Detecting Particulate Matter in Elastomeric Components

USP <788> defines two methods for the determination of particulate matter: Light Obscuration and Microscopic Particle Count Test. For sub-visible particles, Light Obscuration is preferred. 

Light Obscuration involves passing a sample through a controlled light source; the amount of light blocked or obscured by particulate matter is measured using a Particle Counter instrument. This method is sensitive to both visible and sub-visible particles.

Microscopic Particle Count Testing involves visually inspecting a sample using a microscope to detect and quantify particulate matter. It is generally used for larger particles that may not be effective measured by Light Obscuration. 

Environmental Factors for Controlling Particulate Matter in Injectable Drug Products

As pharmaceutical packaging components must be limited in the amount of particulate they introduce to a container closure system, so must the environments in which they are used. ISO 14644-1 defines Cleanroom Standards for various levels of manufacturing environments, including the number of particles that may be present:

Relevant Compendia for Monitoring Particulate

The most important compendium for particulate is ISO 8871-3 “Elastomeric parts for parenterals and for devices for pharmaceutical use – Determination of released-particle count”. This details how one should determine visible and subvisible particle counts, including principles, classifications, apparatuses, materials, and testing.  

It is not dissimilar to other compendia in this space, including:

• USP <788> “Particulate Matter in Injections”
• USP <790> “Visible Particulates in Injections”
• EP 2.9.19 “Particulate contamination: sub-visible particles”
• EP 2.9.20 “Particulate contamination: visible particles”
• JP 6.06 “Foreign Insoluble Matter Test for Injections”

Additionally consider:

• ISO 14644-1 “Cleanroom Standards”
• FED STD 209E Cleanroom Standards

Conclusions

Overall, Particulate is a crucial consideration when choosing an elastomeric closure for a pharmaceutical injectable. Low levels of particulate can help to prevent harm to patients, preserve the reputation of a drug company, and promote quality and cleanliness. In the creation of life-saving drugs, life-threatening risks must be mitigated. Though choosing appropriate elastomeric components can be difficult, Datwyler is available to help guide our clients through the selection process.

Look for the next post in the P.E.R.F.E.C.T.-ing the Pharmaceutical Packaging Selection Process series, in which Extractables & Leachables will be addressed.

Sources

https://www.futuremarketinsights.com/reports/injectable-drugs-market