By Mark Durivage, Quality Systems Compliance LLC
The FDA’s Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER), and Center for Veterinary Medicine (CVM) recently released draft guidance — Inspection of Injectable Products for Visible Particulates for the purpose of public comment.
This FDA guidance addresses the development and implementation of a holistic, risk-based approach to visible particulate control incorporating product development, manufacturing controls, visual inspection, particulate identification, investigation, and corrective actions designed to assess, correct, and prevent the risk of visible particulate contamination.
The FDA clarifies “that meeting an applicable United States Pharmacopeia (USP) compendial standard alone is not generally sufficient for meeting the current good manufacturing practice (CGMP) requirements for the manufacture of injectable products.”
Injectable products generally refer to injectable human drugs or animal drugs and include drug or biological product as a constituent part of a combination product, such as a drug or biological product prefilled into a syringe.
Particulates refer to mobile, undissolved particles (metal, glass, dust, fiber, rubber, polymer, mold, degradant precipitate) other than gas bubbles that are unintentionally present in an injectable product. Particulates can be divided into three categories: inherent particulates are particulates that are an innate product characteristic; intrinsic particulates are particulates that are derived from the manufacturing equipment, product formulation, or container system: and extrinsic particulates are particulates that originate from the manufacturing environment and are foreign to the manufacturing process.
Adverse events caused by particulate contamination depend on the route of administration, the nature of the patient population, and the nature of the particulates themselves. Serious adverse events involving injectable products contaminated with visible particulates include infection and venous and arterial emboli; microscopic emboli, abscesses, and granulomas in visceral organs; and phlebitis, inflammatory reactions, granulomas, and infections at injection sites.
The FDA suggests that manufacturers should consider clinical risk factors including patient age, personal or family history of thrombophilia, major surgery, cancer, trauma, underlying infection, autoimmune disease, diabetes-associated late-stage vasculitis, obesity, and smoking when developing quality target product profiles and in establishing an appropriate control strategy and acceptance criteria for visible particulates.
A risk assessment during product development should be conducted to limit clinical risk. During this risk assessment, manufacturers should identify the types and sources of visible particulates that could contaminate the injectable product as well as identify appropriate analytical methods to monitor them and mitigation strategies to prevent their presence in the final product.
The FDA emphasizes the importance of building quality into the manufacturing process (prevention), starting with the development phase and continuing during scale-up, process qualification studies, and commercial manufacturing and not relying on downstream adjustments and inspection during manufacturing to detect particulate contamination. Continuous process monitoring to ensure the process is in control is also essential to prevent particulate contamination.
Manufacturers should define and document procedures for the inspection process, including how to perform product inspections, statistical sampling plan(s), acceptance and rejection criteria, and for evaluating inspection results. These procedures should be evaluated as part of the change control process when the batch size changes, there is a change to the manufacturing process, or conditions change, including raw materials and packaging configurations. Additionally, a robust competency-based training program should be established to ensure the inspectors can properly distinguish between contaminated and non-contaminated products.
The FDA requires manufacturers to perform 100% inspection “during the stage at which there is the greatest likelihood that visible particulates will be detected in the final container” and “ensure that the equipment used and the physical environment where visual inspection is performed are designed to minimize variability and maximize detectability in the inspection process.”
Inspections can be conducted manually or by using a range of automated inspection techniques.
For manual inspections, the inspection station should be ergonomically designed for inspector comfort, have a backdrop of one or more solid colors such as black and white to provide adequate contrast, and allow maximum visibility of product contents. Manufacturers should consider container color, size, and shape as well as product characteristics when determining the ideal light intensity (lumens). The vision requirements of the inspector should be documented as 20-20 vision or corrected to 20-20 vision to ensure consistency of the inspection process. Manual inspection programs should be supported by gage studies to ensure the consistency of the inspection process.
Semi-automated inspections utilize a machine that rotates the product at a constant rate past an inspector’s field of vision at a specified distance and speed. Rejected products are removed mechanically or by hand. Semi-automated inspection equipment should be properly calibrated and qualified at a specific vial-spin and belt speed. Lighting should also be qualified to allow for accurate human detection of defective products. Semi-automated inspection systems should be supported by gage studies to ensure the consistency of the inspection process.
Automated inspection technology (high-speed industrial camera, visible diode array, X-ray, near-field radar, ultraviolet and near infrared spectroscopy) utilizes various wavelengths of light and sensors to detect particulates in suspension in injection products for which visual inspection is not completely effective. Automated inspection technology may also be more capable of detecting particulates in opaque products and containers. Automated inspection systems should be qualified/validated to ensure they are suitable for their intended use and to determine the lower limit of detectability of particulates. Additionally, automated inspection systems should be periodically challenged to ensure they are operating properly, using known “boundary” samples.
Following 100% inspection, manufacturers should employ statistically valid sampling plans, validated inspection methods, and appropriate acceptance criteria to ensure that each batch meets preestablished criteria.
Quality Assurance And Nonconformances
Process performance, continuous process monitoring, and product quality results should provide information to identify issues and ensure control of the process. Trending particulate contamination, identification of new types of particulates, or particulates that exceed alert or action limits may indicate a flaw in product or process design. Additionally, post-market surveillance data can be used to assess process performance and control.
Manufacturers are required to investigate quality discrepancies identified through the inspection process, quality testing, complaints, and batch failures. Investigations should identify the particulates and categorize them (intrinsic or extrinsic), because the presence of certain categories of particulates could indicate GMP issues or sterility failures. Investigations may result in tightened sampling plans (increased inspection), examination of particles to understand their origin, and evaluation of batch release impact. Investigations should determine the sources of the variation and identify appropriate corrective actions and preventive actions.
This guidance does a good job of laying out expectations and linking the expectations to the regulatory requirements. Public comment on the guidance document will be accepted through Feb. 15, 2022.
About the Author:
Mark Allen Durivage has worked as a practitioner, educator, consultant, and author. He is managing principal consultant at Quality Systems Compliance LLC, an ASQ Fellow and SRE Fellow. He earned a BAS in computer aided machining from Siena Heights University and an MS in quality management from Eastern Michigan University. He holds several certifications, including CRE, CQE, CQA, CSQP, CSSBB, RAC (Global), and CTBS. He has written several books available through ASQ Quality Press, published articles in Quality Progress, and is a frequent contributor to Life Science Connect. Durivage resides in Lambertville, Michigan. Please feel free to email him with any questions or comments.