FDA addresses establishment of inspection programs for injectables

Regulatory NewsRegulatory News | 16 December 2021 |  By 

The US Food and Drug Administration (FDA) on Thursday issued a draft guidance to help manufacturers set up inspection testing programs to ensure that their injectable drugs are free of visible particles.
The 18-page draft guidance "addresses the development and implementation of a holistic, risk-based approach to visible particulate control that incorporates product development, manufacturing controls, visual inpsection techniques, particulate identification, investigational and corrective actions designed to assess, correct, and prevent the risk of visible particulate contamination," said FDA’s announcement.  
The draft guidance "also clarifies that meeting an applicable U.S. Pharmacopoeia (USP) compendial standard alone is not generally sufficient for meeting the current good manufacturing practice (CGMP) requirements for the manufacture of injectable products.” The document does not address subvisible particles or physical defects such as container integrity flaws or fill volume.
The guidance stems from FDA’s concerns that "visible particulates can jeopardize patient safety." FDA cites published case reports involving "serious adverse events” with visible particle contamination. These adverse events have included infection and venous and arterial emboli as well as  microemboli, abscesses, and granulomas within visceral organs. At injection sites, patients have experienced phlebitis, granulomas and localized infections.
The agency defines particulates as "mobile undissolved particles other than gas bubbles that are unintentionally present in an injectable product.”
Although particulates can be comprised of a variety of substances such as metal, glass, dust, fiber, rubber, polymer, mold, or degradant precipitant, FDA explains that all fall into one of three categories. Inherent particulates are innate to the product itself; intrinsic particulates come from outside the product, but within the manufacturing and fill-finish systems or the product formulation; and extrinsic particulates come from the larger manufacturing environment, but not from the manufacturing process itself.
Numerous recalls, warning letters stemming from particles
Numerous recalls have been announced stemming from particle contamination of injectable products: In December, Gilead announced a voluntary nationwide recall of two lots of Veklury (remdesivr) due to the presence of glass particles. Mylan, Merck, and Teva have all also issued recent recalls of injectable products because of particulate contamination. 
Other enforcement actions, such as warning letters, have followed from inadequate investigation of particles in injectable drugs. In August, FDA issued a warning letter to Toyoba, a company in Japan, for inadequate microbiological controls and lax investigation of particles; black and white particles and “stain” like particles of various colors were found in drug products. (RELATED: FDA warns Japanese firm for particle contamination, takes mask maker to task- again, Regulatory Focus 26 August 2021)
Three types of inspections
Each unit of an injectable product should undergo visual inspection in the final container, but before labeling. Inspections can either be conducted using manual, semi-automated or automated testing techniques. For manual inspections, the guidance specifies that the inspection station "should have a backdrop of one or more solid colors (e.g., black and white) to provide adequate contrast and to allow maximum visibility of product content. The light intensity of the inspection station is also critical to achieving maximim visibility. Manufacturers should consider container color, size, and shape as well as product characteritics when determining the ideal intensity."

Semi-automated inspections involve a machine that rotates the product past a trained inspector’s field of vision, and rejected products are removed either mechanically or by hand.
Automated inspection technology can either replace manual inspections or be used as an additional testing measure. Such technology "can use different wavelengths and sensors to detect hard-to-see particulates in sterile powder, suspensions, or light-protected injection products for which visual inspection is not completely effective."
Statistical sampling plans
Following an inspection, manufacturers should use “statistically sound sampling plans.” These plans must be consistent with the USP’s General Chapter 1,“Injections and Implanted Drug Products (Parenteral) Product Quality Tests” and Chapter 790,  “Visible Particulates in Injections.” Yet, FDA specifies that "more stringent sampling plans and acceptance criteria may be appropriate for higher-risk products."
USP has proposed a new chapter on visually testing injectable drugs for particles that would address current testing gaps and would be developed with input from the European Pharmacopeia and the Japanese Pharmacopoeia (RELATED: Pharmaceutical officials propose new USP harmonized chapter on visual inspections, Regulatory Focus, 7 June 2021)
The guidance further specifies that "only certified inspectors and qualified equipment" should be used to inspect these products for visible particles and stressed the need for formal training and qualification programs to “help minimize variability among different inspectors or machines.”
The deadline for commenting is 14 February.
FDA draft guidance


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