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Summary of FDA’s recent Inspection for visible particles draft guidance “Inspection of Injectable Products for Visible Particulates” and how it applies to components
The visual inspection of injectable drug product has been a regulatory requirement since 19361, however, successful implementation of the standard has been challenging for many organizations. The number of recall notices issued by the U.S. Food and Drug Administration (FDA) from 2010 through 2019 for injectable products due to visible particulate have reduced since 2014 but at the current trend, will be some time before it approaches zero2. Between 2009 and 2019, the presence of visible particles in parenteral product was the second leading cause for product recalls.3 Patient safety is the main driver for requiring injectable products to meet the criteria of “essentially free of visible particulates.”4
The FDA Draft Guidance: “Inspection of Injectable Products for Visible Particulates”
Adverse events can be associated with the injection of visible particulate and are dependent on the route of administration and patient population, among other things, and can result in infection, emboli, granulomas, phlebitis and more.5 Control of visible particle is essential under section 501 of the Federal Food, Drug, and Cosmetic Act (FD&C Act), in order to prevent a drug product from becoming adulterated. The draft guidance is titled “Inspection of Injectable Products for Visible Particulates” (hereafter referred to as the draft guidance) to clarify the various areas where controls must be in place in order to have a successful particle control strategy that meets the regulatory expectations set forth in USP <790>4 and the associated cGMP regulations.
The draft guidance outlines several important visual inspection considerations, which are divided into the following five categories: 100% inspections, Statistical sampling, Training and Qualification, Quality Assurance through a Life-Cycle Approach, and Actions to Address Non-Conformance. This section of the guidance should make considerable progress in demystifying some aspects of how to implement the visual inspection programs specified in USP <790>.
The draft guidance also clarifies what is needed for a risk-based approach to a visual inspection program. The approach is multi-faceted and starts with product development. The guidance also stresses the importance of a particle-control program which includes operator training and qualification. Test kits which contain representative particle types and sizes should be used for operator training and qualification. A 100% visual inspection (either manual, semi-automated, or fully automated) must be followed by statistical sampling, such as acceptance quality limit (AQL) testing. Another point stressed is that a visual inspection program alone is not enough to ensure compliance with cGMP standards. A holistic life-cycle approach to particle control is needed which includes sourcing, development, and commercial manufacturing environment.2
Inherent, Intrinsic and Extrinsic particulates
The type of particles observed in the finished product must be considered when formulating the quality risk assessment. Inherent (or formulation-related) particulates do not necessitate product reaction if they are a property of the product. Intrinsic particles, or particles related to the manufacturing process, must be controlled through component selection. They can also be related to the formulation or stability in the case of particles such as glass delamination or particles from silicone oil-protein interaction. The draft guidance highlights that “a robust product design achieved through formulation optimization and container closure screening during development is critical to reduce the formation of product-related intrinsic particles.”
Extrinsic particulates are particles that are not related to the formulation, its components, or the manufacturing process contact surfaces. These particles indicate a lack of control in the manufacturing facility and “could indicate possible microbial contamination or another CGMP issue.” The draft guidance also states that “manufactures should not rely on downstream adjustments during manufacturing to justify a poorly designed product or process. Instead, quality should be built into the manufacturing process, starting with the development phase and continuing during scale-up, process qualification studies, and commercial manufacturing.” The draft guidance reiterates that applying acceptance criteria outlined in USP <790> is not enough to be in full compliance with cGMP requirements. There is a need to prepare injectable products in a manner designed to exclude visible particulates which starts in development and continues through careful selection, evaluation and continuous improvement of materials, and processes up to and including commercial manufacturing. The guidance also states, “Depending on the clinical risk profile associated with a specific product, FDA may expect that product to comply with stricter standards than those set forth in the compendia.”
Overcome the challenges of particulates
To be able to meet the holistic expectations set forth in the draft guidance, manufacturers of injectable drug products should choose components that lower the risk of the presence of visible particulate and particulate formation. The guidance states that components and closure systems are a contributing source of visible particulate. As such, the draft guidance states that “manufacturers must have written procedures for the receipt, identification, storage, handling, sampling, testing and approval or rejection of components and product containers.” Based on two Parenteral Drug Association (PDA) conducted surveys related to visual inspection,6,7 the major contribution of particulate from the manufacturing process is from primary packaging components.
West offers NovaPure® components, which reduce the presence of visible particulate using Quality by Design (QBD) principles. The product is washed, sterilized, camera-inspected, and packaged using cellulose-free packaging materials. The product also has barrier film to limit drug-closure interactions. NovaPure® products are designed to meet vial, cartridge, and pre-filled syringe packaging needs and have the highest levels of manufacturing process controls around reduction of particulate in the West portfolio.
Continuous improvement is also a factor separating NovaPure® components from standard offerings. The NovaPure® component platform has a dedicated particulate task force focused on identifying and implementing improvements and has annual quality and operations product reviews. Continuous improvement is achieved through implementing best practices across the West network through the process of define, measure, analyze, improve, and control (DMAIC). By selecting NovaPure® product line for vial, syringe or cartridge containment systems, the risk of product rejections due to the presence of visible particulate originating from elastomeric components can be reduced.
NovaPure® Components and the Customer experience
As an example, a major biotech company approached West while looking for a vendor to help build quality into their process. The biotech company was using a QBD approach in the development of a life-altering treatment to treat a chronic disease in older patients. The company recognized that the NovaPure® component offering, which was also developed with a QBD approach, was a perfect fit for their product and the biotech company adopted a platform approach with the NovaPure® product line.
In addition to limiting the risk of visible particulate through product selection, drug product manufacturers can monitor incoming components such as stoppers and plungers for the presence of particulate. PDA Technical Report (TR) 858 “Enhanced Test Methods for Visible Particle Detection and Enumeration on Elastomeric Closures and Glass Containers” provides parenteral manufacturers with a background on the control of visible particle control in components. The TR also describes an analytical method that can be utilized to monitor the presence of visible particles and fibers on elastomeric components as well as a visual inspection method for glass containers. Tools for method training and method qualification are also described in Appendix A of the TR.
West Analytical Laboratory Services
The Analytical Laboratory Services group at West can assist parenteral manufacturers with testing associated with product development. Additionally, West’s Technical Customer Support group can help drug product manufacturers select the best packaging system for particle-sensitive products including West’s NovaPure® product line.
Webinar: Understanding & Applying the Updated FDA Guidance: Inspection of Injectable Products for Visible Particulate
For those that would like to learn more about the topics discussed in this blog, West hosted a webinar titled Understanding & Applying the Updated FDA Guidance: Inspection of Injectable Products for Visible Particulate on August 16, 2022. Click here to view the recording.
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Prepared by: John Rech, Manager, Particle Tech, NA Laboratory
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