Abstract
Visible particulate matter contamination is responsible for the rejection or recall of numerous batches of injectable product each year. The result is wasted time, effort, money, product and the limited availability of medically necessary drug and biologic products. Recently published compendial standards have alleviated some of the confusion surrounding suitable test methods and acceptance criteria for visible particulates; however, the complexities of visual inspection methods across a wide range of injectable product types packaged in diverse and sometimes complex container systems has complicated the approach to visible particulate control in injectable products. The solution is a life-cycle approach to visible particulate contamination control that addresses the prevention, inspection, identification, and remediation of visible particulate contamination. More importantly, the life-cycle approach to visible particulate control is aligned with current United States Food and Drug Administration's good manufacturing practices and can serve as an effective tool for demonstrating regulatory compliance for inspections, audits, and regulatory submissions.
Introduction
In her 2004 article titled “The Concept of Pharmaceutical Quality”, Janet Woodcock of the United States Food and Drug Administration's (FDA's) Center for Drug Evaluation and Research wrote that “the FDA considers high-quality drug products to be those that consistently and reliably deliver the clinical performance and other characteristics stated in the label, are not contaminated, and are available” (1). Though sometimes overlooked, the issue of product availability is of critical importance as even the most pure and efficacious products are useless if they're not accessible to the patient.
Injectable drug products should be free from chemical, microbiological, and physical contaminants. This includes visible particulate matter that could either have a direct effect on patient safety or indicate manufacturing issues that could impact the safety, quality, purity, or potency of the product (2). The failure to prevent and/or detect visible particulate contamination can adversely affect product availability because of the potential for rejected and/or recalled product batches.
Cost of Visible Particulate Contamination
Injectable products are expected to be “essentially free” (3), “practically free” (4), or “free from readily detectable” (5) visible particulate matter that can affect product quality and patient safety. In 2014, the United States Pharmacopeia (USP) published General Chapter <790> Visible Particulates in Injections (6), which provides a test method (based upon European Pharmacopoeia Chapter 2.9.20) and a minimum acceptance criterion for a production lot of drug product to be considered “essentially free” of visible particulate matter. USP <790> also provides the industry with a compendial reference for visible particulate inspection that can be used for internal inspection procedures or included in a finished product specification. In 2017, the USP published General Chapter <1790> Visual Inspection of Injections, which provides additional information on the overall visual inspection program for injectable drug products. Despite the publication of these chapters, factors such as the probabilistic nature of visible particulate detection, complex patient risk assessments, difficult to inspect products, and the current good manufacturing practice (CGMP) implications of certain types of visible particulate matter contamination pose significant challenges to the implementation and execution of a robust visible particulate prevention and detection program. Between 2009 and 2019, the presence of foreign particulate matter ranked second only to the lack of sterility assurance as the reason for injectable product recalls in the U.S. (7). In 2011, particulate contamination ranked second only to super or subpotent formulations as the reason for all class 1 drug product recalls (8). Additionally, a 2015 Parenteral Drug Association survey of manufacturers that produced difficult-to-inspect parenteral products revealed the following four points:
43% of the respondents had reinspected between one and five product batches in the previous year because of particulate matter, and 18% had reinspected more than 10 batches in the previous year.
50% of the respondents had rejected batches of product in the previous year; 32% had one to three batches rejected and the remaining percentage had more than three batches rejected.
26% of the respondents reported having received observations from regulators related to particulate control.
9% of the respondents reported having one or more batches recalled for particulate matter in a finished product in the past year (9).
The result of particulate matter contamination is wasted time, effort, material, resources, money, product and the potential for drug shortages because of unreleasable or recalled product.
Life-Cycle Approach to Visible Particulate Control
Visible particulate contamination of injectable products can be addressed by implementing a life-cycle approach to visible particulate control that covers the entire product development, manufacturing, and inspection process (9⇓–11). This holistic approach to visible particulate control should be used in conjunction with a quality risk management program that focuses on the prevention, detection, and remediation of visible particulate matter contamination. This approach is consistent with the philosophy that quality cannot be tested into products but should rather be built into the product by design (1, 12⇓⇓⇓⇓–17).
One model for the life-cycle approach to visible particulate control is provided in Figure 1. The prevention of visible particulate contamination begins during product development with the evaluation of product attributes, container closure system characteristics, and stability limitations. The life-cycle approach also requires the control of the manufacturing environment, container/closure system processing, product components, and manufacturing equipment. Adequate inspectional method development, training, and qualification are required to validate and execute the visual inspection process. The information gained through the inspection process is then evaluated and used to prevent future excursions. A manufacturer's overall quality risk management program should consider the sources of visible particulate contamination to enhance the development of inspection methods ensuring that each lot of finished product is essentially free of visible particulates (3). A sample fishbone diagram to identify and control visible particulate contamination is provided in Figure 2. The quality risk management exercise can be tailored to address a specific pain-point regarding visible particulate control (e.g., specification development, inspector training, or container component control) or design/improve the overall life-cycle approach to visible particulate control. The result will be a sustainable and defensible approach that allows manufacturers to avoid visible particulate issues during product development and react quickly to visible particulate excursions during tech transfer or production. Information on particle characteristics and source(s) gained during the prevention, inspection, and identification process can then be used to improve the manufacturing process and prevent future visible particulate excursions.
A life-cycle model for visible particulate control.
A sample fishbone diagram for visible particulate control.
FDA Regulations and the Life-Cycle Approach
The life-cycle approach to visible particulate control is consistent with the FDA's CGMP regulations designed to prevent, detect, and remediate manufacturing issues such as visible particulate contamination (Figure 3). Although this article does not contain an exhaustive list of FDA regulations that may apply to visible particulate control, it is intended to show how CGMP compliance goes hand in hand with a holistic approach to visible particulate control in injectable products.
FDA regulatory references pertaining to each step of the visible particulate life cycle.
Prevention of Particulate Contamination
The prevention of visible particulate contamination begins during product development and continues with the management of components, equipment, and the manufacturing environment. Developmental studies should characterize any inherent visible particulates (innate or innocuous characteristics of some products), such as liposomes, suspensions, or proteinaceous aggregates, that may be present in the drug product. Inherent particulates should be described in the regulatory submission and may warrant inclusion in the finished product specification as a characteristic of the product's appearance. The early identification and characterization of inherent particulate matter also allows for the implementation of manual or automated visual inspection techniques and training methods that differentiate inherent particulates from foreign matter (e.g., the differentiation of “ropey” inherent proteinaceous particulates from extrinsic fibers). Developmental studies can also address the likelihood of intrinsic particulate (those derived from the product, process, or container system) formation, such as glass lamellae or precipitates resulting from the reaction between glass containers and the drug product. Such reactions can often be predicted based upon drug product characteristics, such as pH, ionic strength, buffer system, and method of sterilization. Since these reactions are also time- and temperature-dependent, studies conducted according to the labeled storage conditions and/or the use of containers that eliminate glass-based particulate formation when stored according to the product label may be necessary (21 CFR (§)211.94(a), §600.11(h), §211.166) (18).
The manufacturing process should also be designed to minimize the risk of visible particle contamination during production. Manufacturing facilities, equipment, and components must be suitable for preventing visible particulate contamination while allowing for adequate maintenance, cleaning, and operation (§211.42, §211.56, §211.63, §211.65, §211.67, §211.113, §600.11). For example, airborne contaminants in aseptic processing areas are controlled though the use of high-efficiency particulate air filters, cleaning, wall and ceiling maintenance, good gowning practices, and operator training to prevent microorganism-carrying particulates from entering product containers. Similarly, the contribution of metal or glass particulates because of events such as impeller grinding, filling needle strikes, or glass breakage should be minimized through proper facility design and manufacturing equipment maintenance. Manufacturing facilities must be clean and free of infestation and vermin (e.g., insects, rodents, birds) that can contribute to the visible particulate load and written procedures must be established for cleaning and sanitization practices designed to prevent visible particulate contamination (§211.56, and §600.11). A drug may be deemed adulterated if it is prepared, packed, or held under conditions where it may have been contaminated with filth or the manufacturing methods or facilities do not conform to CGMPs ensuring the safety and quality of the product (Food Drug and Cosmetic Act section 501(a)(1)) (19). Thus, if the identity of the visible particulate is indicative of a filthy manufacturing environment or a violation of CGMPs, the contaminated product could be considered adulterated. Written procedures must be established for the receipt, identification, storage, handling, examination, quarantine, sampling, testing, prevention of contamination, and approval/rejection of drug product components and container closure materials (e.g., in the case of a package of glass vials contains broken containers or packages received with breaches to the outside environment, §211.80 and §211.82). Statistically suitable sampling procedures and test methods are used to ensure that components and containers/closures meet appropriate written specifications for identity, strength, quality, and purity. Drug product components and container/closure components that are susceptible to contamination with filth (e.g., flexible plastic container systems that can be contaminated with insects, hair, and/or facility debris) or other visible particulate matter must be sampled, tested, or examined as per established specifications for those types of contaminants (§211.84).
Inspection Process Development
When developing a visual inspection process for parenteral products, one should consider the product characteristics, container type, inspection method, and the type of defect the method is intended to detect. The visible particulate inspection process, whether it uses a fully manual, semiautomated, or automated system, may be integrated into the overall visual inspection process for other defect classes (e.g., cracks, leaks, unseated stoppers, lyo cake defects, and so forth) and should be fully validated for its intended use. In addition, threshold studies should be conducted to determine the limit of detection for different classes of visible particulates (e.g., glass, fibers, rubber, and so forth) in representative product and container systems. Difficult to inspect parenterals, such as lyophilized products, flexible bags with overwraps, or those packaged in opaque or semiopaque containers, cannot fully rely on 100% visual inspection to identify containers with visible particulates and may require supplemental destructive testing to meet compendial requirements (3, 6). Automated and semiautomated inspection processes may offer advantages in terms of increased throughput, reduced manual labor, and the use of artificial intelligence/deep learning to improve the inspection process. However, the process and equipment for detecting each defect class should be fit for purpose and multiple systems may be necessary to ensure adequate 100% visual inspection of the product lot. Equipment used for automated or semiautomated inspection should perform its intended function satisfactorily as per a written program and written records of routine equipment calibration checks and performance verification should be maintained (§211.68). Personnel involved in the manufacture and inspection process must have the appropriate training, education, and experience to perform their assigned functions (§211.25, §600.10). This should be applied to both the training required to prevent visible particulate contamination of product (e.g., gowning, aseptic technique, equipment maintenance, and so forth) and the inspection of finished product for particulate contamination (e.g., routine eye exams, visual inspection requalification, and so forth). This training occurs on a continuous basis and there should be an adequate number of personnel dedicated to each task to complete the job. Likewise, supervisors must have the training, education, and experience necessary to perform their assigned functions.
100% Inspection
USP <1> Injections and Implanted Drug Products (Parenterals) Product Quality Tests (3) states that:
Each final container of all parenteral preparations should be inspected to the extent possible for the presence of observable foreign and particulate matter (hereafter termed visible particulates) in its contents.
Qualification of the inspection process should be performed with reference to particulates in the visible range and those particulates that might emanate from the manufacturing or filling process.
Every container in which the contents show evidence of visible particulates must be rejected.
The inspection process should be designed and qualified to ensure that every lot of all parenteral preparations is essentially free from visible particulates, as defined in Visible Particulates in Injections <790>.
Any drug product labeled as “USP”, having a name that is recognized by the USP, or referencing USP <1> or USP <790> in its finished product specification, should have validated procedures for ensuring compliance with the compendial standards for visual inspection (Food Drug and Cosmetic Act section 501(b), §211.165). Because USP <1> refers to 100% inspection and USP <790> is dependent upon the 100% inspection process to remove any defective units before the acceptance quality limit (AQL) test, the qualification of personnel and/or equipment involved in the 100% inspection is imperative. As noted in §211.100, the appropriate organizational quality unit should implement written procedures for production and process control designed to ensure product quality. These include procedures for the prevention of particulate contamination before and during the manufacturing process as well as procedures to inspect finished product.
Valid in-process specifications for visible particulate contamination rates are established based upon historical data and should be consistent with the final drug product specifications (§211.110). The results of in-process and laboratory testing for visible particulates are recorded in the batch record (§211.188, §600.12).
Manufacturers should establish acceptance limits for critical, major, and minor defects associated with visible particulate contamination and other visible defects. Critical defects are generally considered to be those that could cause serious adverse events to the patient when administered as directed in the product label. Defects such as cracks, leaks, or the presence of visible particulates that could indicate a lack of product sterility would fall into this category. Major defects such as the presence of certain intrinsic particulates that are unrelated to CGMP violations and are not indicative of sterility assurance failures generally carry a remote possibility of adverse events when used as directed but should still result in the rejection of the product unit. However, factors such as the intended patient population, route of administration, and dosing frequency should be considered when making this determination. Minor defects such as container blemishes or other cosmetic defects do not impact patient safety but may be cause for unit rejection. Trending of these defects ensures batch quality and uniformity by allowing the early detection of process control issues.
Acceptance Sampling and Testing
Acceptance sampling and testing are used to confirm that preventative measures and the 100% inspection process are adequate to control visible particulate contamination in the lot of drug product prior to release. USP <790> Visible Particulates in Injections (15) states that acceptance sampling and testing (AQL testing) should be conducted “at batch release” but not as a condition for batch release. However, if USP <1> or <790> are referenced in the approved product specification as the methodology and/or acceptance criteria for visible particulate inspection, then each batch of drug product should have an appropriate laboratory determination of satisfactory conformance to visible particulate testing as stated in the final specification (§211.165). This includes written procedures for sampling and testing of each batch and the number of samples tested. Manufacturers must validate and document the accuracy, sensitivity, specificity, and reproducibility of the test method under actual conditions of use (§211.194(a)(2)) and batches failing to meet the specification should be rejected. Reinspection of lots that fail initial AQL testing may be permissible with appropriate scientific justification, procedures and quality unit approval (11). Additional information regarding the sampling plans, test methods, and conformance to written specifications regarding visible particulate testing is found in §211.160. Although USP <790> provides a minimum AQL (manufacturer's risk) acceptance criteria, it is also important to consider the unacceptable quality limit (UQL) (customer's risk) when making the decision to accept or reject each batch of product (11).
To assure batch uniformity, written procedures are established for in-process controls, tests, or examinations conducted on samples from each batch to monitor output and validate manufacturing process performance (§211.110). This is important when drawing samples from a batch for quality sampling to confirm the prevention of visible particulate contamination in production batches and when assessing the suitability of the 100% inspection process. Laboratory records should include complete data from the tests required to assure compliance with established specifications for visible particulate matter (§211.194).
Retention, Investigation, and Remediation
Units containing visible particulates that are rejected during the 100% or AQL inspection process should be analyzed and trended for the type, source, and criticality of particulate matter contamination. Production and control records associated with visible particulate testing should be reviewed to ensure compliance with approved written procedures before batch release and distribution. Any unexplained discrepancies or failure of the batch or components (e.g., stoppers, containers, raw materials) should be investigated, even if the batch has been distributed. This investigation may extend to other affected batches that may be associated with a specific failure or discrepancy and a written record of the investigation and conclusion should be completed (§211.192). Manufacturers must establish written procedures for handling oral and written complaints related to visible particulate matter contamination and maintain written records of all complaints (§211.198). Written procedures must also be established for the review of complaints, recalls, returned samples, and a representative number of product batches to determine if any changes to the established specifications, manufacturing, or control processes should be made. The information obtained from the 100% inspection, the AQL inspection, consumer complaints, and stability samples can be used to identify sources of visible particulate contamination and opportunities for manufacturing process improvement. Analysis of the particulates in these rejected containers can provide valuable information regarding the type and frequency of visible particulate defects found within a given manufacturing environment. This information can be used to remediate visible particulate issues or enhance the manual or automated inspection methods. For example, increased incidence of fibrous visible particle contamination could be because of a change in wipes used to sanitize manufacturing areas, which can shed and contaminate product, a change in the source of rubber stoppers, which can serve as a carrier of fibrous particles, or stability issues with proteinaceous products leading to the misidentification of protein agglomerates as fibrous particulates. Analysis and trending can also help differentiate random contamination events from single source particulate contamination, which could be indicative of equipment wear or malfunction.
Summary
The application of a life-cycle approach to visible particulate matter control should be tailored to the individual manufacturing process, product, container system, and regulatory requirements. The implementation of a visible particulate control strategy that begins during product development, incorporates CGMP into preventative strategies and test method validation, and uses the information gained to foster continuous improvement will reduce waste because of product rejection or recall, enhance product quality, and improve product availability. This benefits manufactures, regulators, and patients by ensuring the availability of high-quality safe and effective injectable products.
Conflict of Interest Declaration
The author declares that he has no competing interests.
- © PDA, Inc. 2020
