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The presence of particulate matter (PM) in parenteral drug products is a well-known challenge for pharmaceutical companies due to the potential quality and safety risks involved. In biotherapeutics, critical attributes related to efficacy, potency, clinical safety, and immunogenicity can be affected by PM.1-3
PM is defined as extraneous mobile undissolved particles (excluding gas bubbles) that are unintentionally present in solutions.4
Several USP chapters describe the measurement of PM, namely:
In this article, the scopes of <787> and <788> will be discussed since both chapters address injections and have the same regulatory requirements according to their nominal volumes for subvisible PM.
As compared to visible PM, subvisible PM is unnoticeable without a microscope and is harder to detect. Subvisible particulates present a greater challenge for detection and higher risks that they might go undetected due to their smaller size. As a result, establishing PM profiles for subvisible particulates is highly demanding, and made more so by instrumental limitations and sample handling challenges (to be discussed further in the article).
The occurrence of subvisible PM can stem from several different sources. Particularly, the subvisible particulates found in sterile drug products originating from packaging components and delivery systems are a major concern for drug manufacturers, with potential sources attributed to material components, process aids used to assemble the system, secondary packaging, insufficient washing, and contamination during fill-finish process.5 Therefore, understanding the method of determination and enumeration are critical.
What are Subvisible Particulates and Their Sources?
Subvisible particulates are particles < 100 µm in size and are not visible to the naked eye.6 A related chapter in USP <1787> Measurement of subvisible particulate matter in therapeutic protein injections categorizes this undesired PM as intrinsic, extrinsic, or inherent.
Intrinsic PM arises from sources related to formulation ingredients, packaging, manufacturing processes and equipment. This may also stem from the poor selection or cleaning of components and systems. An example is silicone oil, which is an important manufacturing and product constituent that may ultimately affect PM count.
Environmental factors, that is, materials that are not part of the formulation, package, or assembly process, are the main sources of extrinsic PM. The production environment, including personnel gowning and behaviours can contribute extrinsic PM to the filled product.
Additionally, some products contain a small level of unintended PM that is inherent to the product and therefore, are considered potentially acceptable characteristics of the product. Proteinaceous aggregates are examples of inherent PM found in therapeutic protein drugs, formed by interactions of the protein with itself or with other formulation ingredients. Heterogeneous particulates consisting of more than one chemical entity may also result from protein aggregation. They can be classified as extrinsic or intrinsic based on the nonproteinaceous component that the protein combines with to form the aggregate.
Intrinsic and extrinsic particulates account for the majority of the PM originating from elastomeric closure components and their manufacturing process. Different types of PM have diverse effects on safety and product stability. It is critical to perform PM evaluations and concentration measurements to understand the nature of the particulates involved. Thereafter, the amount of PM can then be minimized in the final drug product upon PM identification and ascertaining their sources.
Determination of PM
USP <787> and <788> describe two procedures for measuring subvisible PM in parenteral products by direct testing of the drug product itself: light obscuration (LO) particle count test and microscopic particle count test.
USP <1788> suggests the use of Flow Imaging (FI) method, not only to complement the above methods, but also allows particles to be characterized into categories of intrinsic, extrinsic and inherent, in the case of biologics for the purpose of risk assessment and continuous improvement. For the simplicity of this article, FI will not be discussed.
LO Particle Count Test vs Microscopic Particle Count Test
An LO particle count test is based on the principle of light scattering that enables automatic determination of particles size and the number of particles according to size. A laser beam that is shone through the liquid sample as it is drawn though an optical flow cell, will be scattered or absorbed by any particles, air bubbles or liquid droplets, thus reducing the total transmitted light. The scattering pattern or “shadow” produced on the light-sensitive detector can then be translated to information on particle size and quantity.
A microscopic particle count test is an alternative technique to LO for subvisible particle analysis. It involves the use of a suitable binocular microscope, a filter assembly for the retention of particulate matter, and a membrane filter for examination. The liquid sample is filtered and inspected through the microscope, followed by manual counting of particles above the size threshold. However, liquid droplets and aggregated proteins that can pass through or absorb onto the filter are not reliably counted by this method.
As a fully automated method, LO can analyze large volumes of samples quickly and easily, with high resolution, minimal operator errors, and without requiring interpretation of data. Therefore, LO is generally the preferred method and the microscopic particle count test is applied only when the former is not applicable. For example, drug products (i.e., emulsions, colloids and liposomal preparations) with high viscosity and/or high opacity are not suitable for LO method. Products that generate air or gas bubbles upon drawing into the sensor are also more appropriate for microscopic particle count testing. This is because these bubbles might be detected as a particle, resulting in false positive data.
As for the microscopic particle count test, complete sample measurement is performed by filtering through the entire sample. The PM retained on the membrane can be used for characterization and identification, if desired (LO method does not allow sample to be reused for further characterization after the count test has been conducted). However, this process requires analyst expertise and experience.
Due to the inherent limitations in particle count techniques, it may be beneficial to utilize both test methods to accurately quantify the number of particles present.
Regulatory Requirements according to USP <787> and <788>
With the different test methods there are different sets of specifications for parenteral infusion or solutions for injection supplied in containers according to volume. The acceptance criteria are illustrated in Table 1 based on each method and the nominal volume of contents within the containers supplied.
West as a Scientific Destination
Understanding of the relevant particle count technology, method capability, and the particle source is critical in mitigating the risks associated with subvisible PM. To achieve accurate and reliable data on subvisible particle count, West can provide comprehensive guidance on the use of analytical methods described in USP <787> and <788>, as well as additional particle characterization methods described in USP <1787> by orthogonal techniques. West’s Analytical Laboratory is capable of performing characterization and identification of particles and this can be performed as part of the development phase, root cause analysis for nonconformance investigations, stability study, and risk assessment.
Information and data obtained from these testing methodologies will aid in the selection of proper components suitable for each application. West is equipped with the appropriate experience, knowledge, and facilities to perform evaluations according to the standards cited and offers testing through its Integrated Solution platform. `
References
The development of a drug product is an arduous and intricate process. Besides ensuring the sterility and effectiveness of the final product, it should also be as free of particles as possible. In protein-based pharmaceuticals, aggregates may form over time and are mostly detrimental to product quality, as they can affect the efficacy, potency, clinical safety, and immunogenicity of the product.<sup>1-3</sup> Protein aggregates are considered a type of particulate matter (PM), and it is important to minimize their occurrence, as well as to quantify the PM for ensuring the quality and safety of the drug products.
Regulatory and market expectations constantly increase. Novel drug products such as cell and gene therapies have a very high value and therefore each dose is precious. With that, drug product manufacturers face increased pressure to minimize rejects of finished drug products. One aspect of this is controlling particulate matter. Particulate matter in finished drug products can come from a number of sources, including the ingredients in the drug product, manufacturing equipment and environment, or the components of the container closure system. This blog describes approaches to control and measure particulate matter.
Particles in an injectable drug product represent a huge risk not only to patient safety – but also to a drug company’s reputation and bottom line. Presence of visible or sub-visible particles has been one of the most common reasons for recalls. According to the <em>FDA Recalls, Market Withdrawals, & Safety Alerts</em> database, 23 of 59 (39%) recalls, market withdrawals, and safety alerts between 2018 and 2020 were due to particulate contamination<sup>1</sup>.
Recently, there has been increased scrutiny from regulatory authorities to quantify and qualify subvisible particles in biopharmaceutical products. Such particles, which can cause a protein to denature, are of concern to pharmaceutical manufacturers since they can affect the efficacy of the drug product. As regulatory bodies continue to raise the bar on quality, industry is looking for “zero defect” and particle free components as well as a way to minimize quality variation.
The level of particles in parenteral pharmaceutical formulations is a critical quality attribute. This is no surprise; the clinical consequence of their presence can be very severe, including fatality. In the major pharmacopeia, from the US, Europe, and Japan, there is a specified limit for particles in the final parenteral formulation. Moreover, these pharmacopeia specify two methods for measurement – light obscuration (LO) and microscopic particle count (MPC).
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