Particulates in Parenteral Products and the Search for the Holy Grail

October 30, 2018

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.  Like the search for the Grail, the path to find that goal of essentially no particulates is full of trial and cost to those who would take on the quest. 

USP <787>[3] lists the sources of particulates in the following excerpt and is referenced in USP <788> as the source for explanation of the sources: 

The particles may be (a) truly foreign, or “extrinsic”, e.g., unexpected foreign material, such as cellulose; (b) “intrinsic” resulting from addition or by insufficient cleaning during manufacturing, such as tank metals or gaskets, lubricants, filling hardware, or resulting from instability, e.g., changes over time, such as insoluble drug salt forms or package degradation; and (c) “inherent”, such as particles of the protein or formulation components. 

The sources of extrinsic foreign material 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.  This precaution will add to costs but will reduce the potential for addition of foreign material to the environment that is used to create the product. 

Intrinsic sources of particulates 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 presence of these materials in parenteral products implicates the cleaning that has been performed but also could indicate the maintenance performed on the equipment has not been as rigorous as it needs to be.  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.  Lack of understanding of the breakdown process of seals or the rouging process of tanks can contribute to the inevitable breakdown of both and allow the production of particulates.  The replacement of seals and the reconditioning of metal surfaces would need to be performed on a risk based schedule based on known features of the materials used in the equipment.  In some cases, the materials used in production equipment and how the equipment is designed may need to be reconsidered. 

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.  Intrinsic particulates can also develop due to changes in stability of the formulation over time or from interaction of the components of the formulation with the primary packaging.  Particulate formation over time can be caused by generation of salt precipitates or other aggregations of formulation components.  In some instances, the formulation has been found to interact with the vials used for primary packaging resulting in delamination of the glass and glass particulates in the vials.  The FDA issued a specific Advisory in 2011[4] on the problem and noted an increase in lamellae formation with use of tubing glass to generate vials, use of high pH buffers in the formulation and long times of product storage at room temperature.  The advisory suggested the use of non-alkaline earth borosilicate glass vials and re-examination of supplier quality management programs as ways to address the problems.  Alternatively, plastic polymer vials are available that can be manufactured without the potential for particulates and delivered for use in a sterile state[5].  Various types of plastic polymer vials are available as an alternative to glass if a formulation is incompatible with standard glass vials.  These materials may have their own issues with leachables and extractables to consider.  If interaction with the primary packaging is determined during development or stability studies, packaging alternatives or formulation changes would need to be implemented.  These changes would be simpler and less costly than making changes to fix the problem after the product is on the market.

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 backgounds using specified light intensity.  The stated requirement for essentially no particulates is defined in USP <790> as specified by the methods in ISO 2859-1, Sampling Procedures for Inspection by Attributes[6], for an AQL-(Acceptance Quality Limit) of 0.65.  For batches of 35001 to 500000 units with samples of 500-800 vials this translates to no more than a total of 7 to 10 vials out of the sample to be found positive for visible particulates for the batch to be acceptable.  With this AQL the batch is acceptable if no more than slightly more than 1% of the vials from the sample are found to have particulates. 

To accomplish this goal consistently, a holistic approach to determine particulate sources throughout the production process at all points must be undertaken.  All possible sources of particulates must be examined, the mechanism they use to enter the production stream defined and solutions to eliminate them be implemented.  This process like the search for the Holy Grail will be arduous and sometimes costly but it is a necessary quest to provide compliant, safe and effective parenteral solutions to the medical community and to the patient. 

[1] USP 39 Chapter <788> Particulate Matter in Injections

[2] USP 39 Chapter <790> Visible Particulates in Injections

[3] USP 39 Chapter <787> Sub visible Particulate Matter In Therapeutic Protein

Injections

[4] Advisory to Drug Manufacturers: Formation of Glass Lamellae in Certain Injectable Drugs, (http//www.fda.gov/Drugs/Drug Safety/ucm248490.htm)

[5] Trisha Gladd, Editor Pharmaceutical Online, https://www.pharmaceuticalonline.com/doc/getting-particular-about-particulates-how-can-you-avoid-becoming-the-next-recall-0001

[6] ISO 2859-1, Sampling Procedures for Inspection by Attributes