Pharmaceutical industry officials have proposed the United States Pharmacopeia (USP) develop a new harmonized chapter on visual inspections of parenteral drugs that would address current testing gaps. This chapter would be developed with input from the European Pharmacopeia and the Japanese Pharmacopeia.
Such a chapter would allow for more robust detection of visible particles in these drugs, which is a common reason for reason for recalls and warning letters in the US, said a recent stimuli article that appeared in the Pharmacopeial Forum on 3 May. The chapter would fill current “pharmacopeial gaps” and would “result in a universal, consistent definition of visible particles and the method by which they are analyzed,” wrote lead author Linda Nahri of Genentech and her coauthors, who included other members of industry and from the National Institute of Standards and Technology (NIST).
“The presence of visible particles that are not anticipated to be present in drug products is one of the most common cause of recalls and warning letters,” noted the authors. The presence of these particles, considered a critical quality attribute, is typically found during visual inspections.
The USP, the European Pharmacopeia, and the Japanese Pharmacopoeia, all have chapters addressing visual inspections that describe the amount of light used to illuminate the sample and recommend the inspection of the drug product container and its contents against a white background and a black background, wrote the stimuli article authors. The chapters also recommend tests to measure the visual acuity of inspectors.
Yet the authors assert that “many parameters and operational conditions are left to the discretion of individuals, manufacturers and end-users.” These include the size of the particles detected and defined as visible, the training of inspectors and the interpretation of results.
The authors also “observe variability among organizations in the stringency of the method and the limits applied, as well as inconsistency between sites, contract manufacturing organizations (CMOs), and products within a single organization.”
They recommend a harmonized compendial chapter which includes use of “universally available standards” to train inspectors, qualify the methods, and validate the results.
In addition to the standard, commercially available polystyrene spherical particles that are currently available to train inspectors and ensure assay uniformity, the authors recommend adding other types of particles to standard sets. The spherical particles “do not look like typical particles routinely observed during visual inspection,” they noted. Intrinsic and extrinsic particles such as fibers from gowning and packaging, rubber and glass lamellae would be more representative of particle types likely to be encountered in visual inspections.
The authors also recommend that inspectors be certified “according to the percentage of particles detected when analyzing different types of particles in the standard training set,” assuring a uniform certification process for all visual inspectors.
The article also calls for consensus on “a harmonized definition of visible particles based on size and particle type,” an effort which NIST is supporting by leading a cooperative effort to evaluate these standards.
Risk assessment considerations for varying types of particles could be supported by creating a particle library that that would include analytical results and, preferably, “videos of the particles in motion after swirling,” wrote the authors.
The proposed chapter should also lay out more specific guidance related to acceptance criteria that are phase-appropriate, and set specifications for visible particles that are based on both the type of particle and phase of development for the product, wrote Nahri and her coauthors.
Using these methods “would go a long way towards increasing the assay consistency and the ability to compare results and analytical capabilities across departments, and analytical capabilities across products, departments, and the organization.”
Comments are being accepted until 31 July 2021.
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