Particulates in Parenteral Products and the Search for the Holy Grail

Particulates in parenteral products as well as other pharmaceuticals have gained increased attention from regulatory agencies and from pharmaceutical firms who desire to be in the forefront of patient safety and effectiveness in the products they supply for patients.  Foreign particulates in parenteral products come from multiple sources and can vary widely in type, size and significance depending on the nature of the drug product and its formulation, the manufacturing process, and the particular materials and circumstances of primary packaging.  The original standards of USP <788>[1] have been tightened by the requirements set forth in USP <790>[2].  This standard stated as “essentially free of particulates” has set the industry on the quest for the Holy Grail of no particulates in any of its parenteral product containers.

The sources of extrinsic foreign material (unexpected foreign material, such as cellulose) are many and mostly come from the environmental conditions during the fill-finish operations and from the handing of materials prior to use in final formulation.  These sources would include human contamination by cells, hair, etc., trace material from cleaning equipment such as wipes and mops, extraneous material from the facility such as particles from facility or equipment repair.  These sources can be reduced by more stringent cleaning at any stage of production that could contribute particulates and not just fill-finish.  Also by trending and tracking defects and rejects more closely.

Intrinsic sources of particulates (“intrinsic” resulting from addition or by insufficient cleaning during manufacturing, such as tank metals or gaskets, lubricants, filling hardware, or resulting from instability) can come from any of the equipment used in the process of drug substance or drug product formation.  These are present due to the normal ware that takes place as equipment is used in production. The breakdown of seals and gaskets, metal parts and any other material that is part of the production assembly needs to become an issue of preventative maintenance rather than reactive response.

Intrinsic particulates can be the result of incomplete washing of vials prior to use in filling.  Glass vials are often obtained from suppliers and washed, dried and depyrogenated on site.  Appropriate validation and revalidation of these processes is essential to reduce particulates from the vials themselves.

The particulates that are derived from the inherent components in the formulation can arise from the products and chemicals used to produce the drug product.  In this case the materials and processes used to produce the drug product need to be considered for particulate content or generation as part of the drug product development process.  This is also essential for the elimination of sub-visible particulates.

For examination of vials for particulates per USP <790>, the initial screen of 100 percent of the lot is performed by light scatter/obfuscation detection during manufacture.  This eliminates as many vials as possible with particulate and other obvious vial issues.  The lot is then sampled for individual inspection by random sampling of vials and examination by the methods listed in USP <790> for detection of particulates by inspectors using black and white backgrounds using specified light intensity.

InQuest Science's  Identifier Software is the missing piece to the life-cycle approach. It will help accomplish this goal consistently, a holistic approach to determine particulate sources throughout the production process to which all points must be undertaken.

Read the full article, published on January 3, 2019 written by Jon H. Hunt from Laboratory Validation Specialists

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