Olga Laskina

Manager, Technical Product Development

November 17, 2021

Regulatory guidance on particulate matter in injectable drugs

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.

Particle Analysis

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:

  • Use of viewing corridors in manufacturing spaces. This allows management of visitors and auditors in a more controlled manner.
  • Controlled entry into cleanrooms through gown rooms.
  • Designated gowning areas and gowning requirements.
  • Rigorous air filtration
  • Point of use filters on process contact utilities
  • Use of building monitoring systems to ensure positive cascading pressure between cleanrooms and adjacent manufacturing areas.
  • Minimization of paper, labels, and tools in manufacturing areas.
  • Optimized raw materials preparation and mixing.
  • Optimized cleaning procedures for molding equipment.
  • Optimized trim processes to reduce amounts of rubber particulates.
  • Improved cart designs to ease cleaning and materials of construction that minimize shedding of particulates.
  • Optimized washing processes in a certified cleanroom, with packaging performed in a Zone 5 environment.
  • Use of high-quality bags for product packaging.
  • Incoming inspection of packaging for particulates.

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.

  • Westar® and Westar® Select elastomers on particulates bigger than 25 µm;
  • NovaPure® elastomers on particulates bigger than 5 µm;
  • Daikyo RSV® and Daikyo RUV® and Daikyo D Sigma® elastomers on particulates bigger than 2 µm;
  • Aluminum CCS seals on particulates bigger than 25 µm;

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