Industry wants FDA to align visible particle classifications and inspections with USP

Regulatory NewsRegulatory News | 16 February 2022 |  By 

Drugmakers and pharmaceutical industry groups urged the US Food and Drug Administration (FDA) to align its classification categories for visible particles with the US Pharmacopoeia’s (USP) Chapter 1790 in comments on the agency’s recent draft guidance on inspection of injectable products for visible particulates.
 
One international group asserted that “different definitions lead to different interpretations,” while a European organization complained that the guidance does not incorporate any text of the soon-to-be published EU Annex 1 on good manufacturing practices (GMPs) for sterile drug manufacturing.
 
The comments were in response to FDA’s draft guidance for manufacturers on developing and implementing particle control programs for injectable products. (RELATED: FDA addresses establishment of inspection programs for injectables, Regulatory Focus 16 December 2021)
 
The guidance follows numerous recalls stemming from particulate contamination of injectable products and was issued to address FDA’s concern that visible particulates can jeopardize patient safety.
 
FDA should align with USP
 
Numerous companies, including the International Society for Pharmaceutical Engineering (ISPE), Boehringer Ingelheim, and Novartis, suggested that FDA align the guidance with USP’s Chapter 1790, specifically the classification categories and language governing visual inspections.
 
USP’s Chapter 1790 “General Chapter Visible Particulates in Injections” describes inspection procedures used to demonstrate that injectable products are essentially free from particulates.
 
FDA’s guidance defines inherent particles as those that are an innate to the product; and defines intrinsic particulates as derived from the manufacturing equipment, product formulation or container systems; and extrinsic particulates originating from the manufacturing environment and foreign to the manufacturing process.
 
Boehringer Ingelheim wrote that “the definition of particle categories does not completely match with USP (1788 and 1790).” The company also added that FDA’s definitions of intrinsic and extrinsic particulates “appear to be contradictory” and that it also differs from the USP and the Ph. Eur. categories.
 
The International Society for Pharmaceutical Engineering (ISPE) similarly urged FDA to align their terminology with USP’s. The group wrote the “definition of the different kinds of particles should be aligned with the USP definition in chapter <1790> Section 4.1. Different definitions lead to different interpretations.”
 
Novartis also weighed in, writing to “please align definitions with USP 1790.”
 
ISPE also suggested that FDA’s language on manual visual inspections be aligned with USP’s Chapter 790. The draft states that “the light intensity of the inspection station is also central to achieving maximum visibility. Manufacturers should consider container color, size, and shape as well as product characteristics when determining the ideal intensity.” This chapter defines when injectable products are “essentially free” of objectionable organisms.
 
ISPE noted that “light intensity is defined in the USP. A uniform approach is needed. We suggest staying with the content of the monograph pharmacopoeia.”
 
No mention of Annex 1
 
The European Compliance Academy’s (ECA) Visual Inspection Group pointed out that the draft guidance does not incorporate language on the contamination control strategy in the soon-to-be released Annex 1 on GMPs for sterile drug products. The annex is expected to be released by the EU, in collaboration with the Pharmaceutical Inspection Cooperation Scheme (PIC/S) and the World Health Organization.
 
ECA writes that “FDA, being a member of PIC/S was fully included in the consultation process. It is irritating that the draft FDA guidelines does not at all include any of the adopted wording and considerations laid down in the Annex to implement a contamination control strategy intended not only to control and limit microorganisms and pyrogens but also particles, based on current product and process understanding. The Annex is very descriptive in its requirements for such a control strategy.”
 
ECA said that a targeted stakeholder consultation on Annex 1 has ended, and a final version to be published “within the next months.”
 
Why inspect good product?
 
Boehringer Ingelheim also questioned why manufacturers should visually inspect good and defective units containing visible particles. The company wrote “the added value of using a mixture of good and defective units (instead of only defective units) for the validation of an automated inspection systems is unclear. Unlike qualification sets for human operators, there is no need to add good units to an AVI validation set to prevent inspection bias.”
 
Delete shape in threshold studies
 
ISPE also suggested deleting shape estimations in threshold studies used to determine the characteristics of visible particles. The guidance called for manufacturers to assess the size, shape and color of visible particles that can be detected by trained personnel in threshold studies.
 
“Not every type of shape can be quantified or described sufficiently to allow detection by a trained operators by an instrument,” said ISPE. “Therefore, the word shape should be deleted.”
 
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