We apologize your item could not be found. Not all items are listed on our website. Please contact your account manager for details regarding your searched item.
Material number (eg: xxxxxxxxxxx) no space or hyphen needed.
No Results Found
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.
Injectable drug products have rigorous requirements for the presence of both visible and subvisible particulates. Current guidance on analytical methods and particulate matter limits in injectable drug products are published in national and regional pharmacopeias. Requirements include being essentially free of visible particulates. Particulates, if present, can interact with the injectable drug product and change the chemical consistency. If injected, they can cause inflammation, tissue damage, or allergic or immunogenic reactions.
United States Pharmacopeia (USP) Chapter <1> Injections and Implanted Drug Products (Parenterals)—Product Quality Tests states that injectable drug preparations should be designed to exclude particulate matter as defined in USP Chapters <787> Subvisible Particulate Matter in Therapeutic Protein Injections, <788> Particulate Matter in Injections, and <789> Particulate Matter in Ophthalmic Solutions. Each final container should be inspected for particulate matter, as defined in Chapter <790> Visible Particulates in Injections. Containers that show the presence of visible particulates must be rejected.
Per USP Chapter <790>, all products must be visually inspected for the presence of particulate matter. The initial 100% inspection can be automated, manual, or semi-automated. The subsequent acceptable quality level (AQL) inspection must be performed manually. The lower limit of the visible range is assumed to be 100 µm, but varies depending on product container, nature of the drug product, and particulate matter properties (color, shape, refractive index).
Informational USP Chapter <1790> Visual Inspection of Injections addresses the topic of prevention of particulates, including packaging components. Common sources of particulates in packaging components are extractables and leachables, silicone oil, and glass delamination. It is recommended that each step of the washing and rinsing processes for container and elastomeric components are evaluated for particulate matter reduction opportunities. The methods of light obscuration (LO), membrane microscopy, or other automated particulate counting method, may be used to demonstrate reduction of subvisible and visible particulates during washing. Finally, siliconization processes should be evaluated to minimize excess silicone levels.
USP Chapters <787>, <788>, and <790> provide guidance on subvisible particulates. USP Chapter <788> provides two methods for the determination of particulate matter: Method 1 (LO Particle Count Test) and Method 2 (Microscopic Particle Count Test). Method 1 is preferred. However, if the test sample has issues resultant from low clarity or high viscosity (e.g., emulsions, colloids, and liposomal preparations), or produces air or gas bubbles, Method 1 is unsuitable and Method 2 should be used. If the viscosity of the test sample is too high for either method, a quantitative dilution may be made to decrease viscosity. The particulate level limits for Methods 1 and 2 are described below:
| Method 1 | |||
| Particle equivalent diameter | > 10 µm | > 25 µm | |
| Container > 100 mL: | < 25 per mL | < 3 per mL | |
| Container < 100 mL: | < 6,000 per container | < 600 per container | |
| Method 2 | |||
| Particle equivalent diameter | > 10 µm | > 25 µm | |
| Container > 100 mL: | < 12 per mL | < 2 per mL | |
| Container < 100 mL: | < 3,000 per container | < 300 per container | |
USP Chapter <787> is an alternative chapter to USP Chapter <788>. It was developed with therapeutic protein injections in mind and provides two methods for detection (as does USP Chapter <788>). This Chapter provides the following particulate matter classifications: extrinsic (foreign contamination), intrinsic (resulting from insufficient cleaning or formulation instability), and inherent (formulation components). The particulate level limits for Methods 1 and 2 according to Chapter <787> are described below:
| Method 1 | |||
| Particle equivalent diameter | > 10 µm | > 25 µm | |
| Container > 100 mL: | < 25 per mL | < 3 per mL | |
| < 6,000 per container | < 600 per container | ||
| Container < 100 mL: | < 6,000 per container | < 600 per container | |
| Method 2 | |||
| Particle equivalent diameter | > 10 µm | > 25 µm | |
| Container > 100 mL: | < 12 per mL | < 2 per mL | |
| Container < 100 mL: | < 3,000 per container | < 300 per container | |
Ophthalmic drug products should be essentially free from particulates that can be observed on visual inspection. The test procedures follow Chapter <788> guidance. Particulate matter limits as set in USP Chapter <789>, specifically for ophthalmic drug products, are described below:
| Method 1 and 2 | ||||
| Particle equivalent diameter | > 10 µm | > 25 µm | > 50 µm | |
| Number of Particles | <50 per mL | <5 per mL | < 2 per mL | |
While particulate matter in drug products is regulated as described, there is no regulatory guidance on either particulate matter limits for primary packaging components or measurement. Instead, specifications are established between suppliers and customers. It is expected however that the packaging components are handled to prevent contamination. The journey towards zero visible particulates in injectable drug products can start with a thorough evaluation of both the pharmaceutical and packaging manufacturing processes for sources of particulates. Pharmaceutical manufacturers can collaborate with packaging suppliers to reduce particulate matter in finished drug products – in particular, through use of components with minimized levels of loose, embedded, and adhered particulates.
West is committed to the continuous improvement of its products and services. As such many approaches to minimize particulate levels of components are employed:
West offers a variety of products with particulate specifications. These products are tested for number of particulates on release, compared with acceptable values, and results are reported.
Finally, West offers 100% visually inspected components: Daikyo RSV, Daikyo RUV and Daikyo D Sigma components, as well as West Envision® verification process and NovaPure components. NovaPure components were developed under the principles of Quality by Design (QbD). West developed these components using a comprehensive quality target product profile that includes industry leading visible and subvisible particulate specifications as part of the component critical quality attributes.
The use of packaging components designed to meet high-quality standards can aid in reducing the risk of rejected drug products. For more on how West can help to address particulate matter concerns visit our website or contact West’s Technical Support.
The Knowledge Center contains a wealth of information on particulate. To learn the basics of particles, take a look at our introductory course in the Learning Center called Particle 101: Introduction to Particles for the Parenteral Drug Packaging and Delivery Industry; for an in-depth look at the results from the PDA sponsored Stopper Analytical Test Method Qualification Strategy sub-team, see this presentation from 2020 PDA Europe in Basel, Switzerland: Quantifying Loose Particles on Elastomeric Components. Please note that you must be logged into Westpharma.com to open these documents.
Westar, Envision, and NovaPure are registered trademarks of West Pharmaceutical Services, Inc., in the United States and other jurisdictions.
Daikyo RSV, Daikyo RUV and Daikyo D Sigma are trademarks of Daikyo Seiko, Ltd.
Sources:
USP 43 – NF 38. General Chapters: <1> Injections and Implanted Drug Products (Parenterals)—Product Quality Tests (2020), US Pharmacopeia/National Formulary
USP 43 – NF 38. General Chapters: USP <790> Visible Particulates in Injections (2016), US Pharmacopeia/National Formulary
USP 43 – NF 38. General Chapters: <788> Particulate Matter in Injections (2013), US Pharmacopeia/National Formulary
USP 43 – NF 38. General Chapters: <787> Subvisible Particulate Matter in Therapeutic Protein Injections (2021), US Pharmacopeia/National Formulary
USP 43 – NF 38. General Chapters: <789> Particulate Matter in Ophthalmic Solutions (2015), US Pharmacopeia/National Formulary
USP 43 – NF 38. General Chapters: <1790> Visual Inspection of Injections (2021), US Pharmacopeia/National Formulary
21CFR211.Current Good Manufacturing Practice for Finished Pharmaceuticals. Subpart E - Control of Components and Drug Product Containers and Closures
As regulatory expectations increase, drug product manufacturers face increased pressure to produce products free of defects and minimize rejects of finished drug products. Particulate matter in finished pharmaceuticals can come from a number of sources, including the ingredients in the drug product, manufacturing equipment or the container closure system.
<em>Summary of FDA’s recent Inspection for visible particles draft guidance “Inspection of Injectable Products for Visible Particulates” and how it applies to components</em><br />The visual inspection of injectable drug product has been a regulatory requirement since 1936<sup>1</sup>, however, successful implementation of the standard has been challenging for many organizations. The number of recall notices issued by the U.S. Food and Drug Administration (FDA) from 2010 through 2019 for injectable products due to visible particulate have reduced since 2014 but at the current trend, will be some time before it approaches zero<sup>2</sup>. Between 2009 and 2019, the presence of visible particles in parenteral product was the second leading cause for product recalls.<sup>3</sup> Patient safety is the main driver for requiring injectable products to meet the criteria of “essentially free of visible particulates.”<sup>4</sup>
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.<sup>1-3 </sup><br />PM is defined as extraneous mobile undissolved particles (excluding gas bubbles) that are unintentionally present in solutions.<sup>4</sup><br />Several USP chapters describe the measurement of PM, namely:
West’s Peg Frandolig and Lynn Lundy share how vision inspection systems can help drug product manufacturers and packaging suppliers work together to regulate foreign and particulate matter in finished drug products in the December/January issue of <em>Pharmaceutical Formulation & Quality</em>.
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.
English
Chinese
