Particulate matter refers to mobile, undissolved particles other than gas bubbles that are unintentionally present in pharmaceuticals or vaccines injected into the human body. Particulate matter in parenteral drugs / vaccines has been recognized as a risk to patients. Particulates can come from the environment, primary packaging materials, formulation ingredients, interactions between the formulation and the product packaging, or during drug processing.
Three categories
1.Inherent particulates are an innate product characteristic.
2.Intrinsic particulates are derived from the manufacturing equipment, product formulation, or container system.
3.Extrinsic particulates are from the manufacturing environment and are foreign to the manufacturing process.
Types of particulates
Visible particulates– Observed through naked eye. Generally human eye can observe particles more than 50 micron in size. Limit- Essentially free from particulates.
Sub visible particulates-Cannot be seen by naked eye and can be counted through instruments. Limits- In Pharmacopoeia.
Control of visible particulate – product development, manufacturing controls, visual inspection techniques, particulate identification, investigation, and corrective actions designed to assess, correct, and prevent the risk of visible particulate contamination.
Injectable products should be prepared in a manner designed to exclude visible particulates, and the inspection process should be designed and qualified to ensure that the products are essentially free of visible particulates. Each final container must be inspected [100% inspection] using a qualified method to detect particles within the visible size range, and all units that are found to contain visible particulates must be rejected.
Clinical risk of visible particulates
The clinical manifestations of adverse events caused by particulate contamination vary and may depend on the route of administration [e.g., intravascular, intravisceral, intramuscular], patient population, and nature or class of the particulates themselves [e.g., physical size or shape, quantity, chemical reactivity to certain cells or tissues, immunogenicity, infectivity, carcinogenicity].
Particulates in intravascular or intravisceral injections generally can cause more adverse events than those in subcutaneous or intramuscular injections
Venous and arterial emboli [thrombotic or non-thrombotic]
Microscopic emboli, abscesses, and granulomas in visceral organs.
Phlebitis, inflammatory reactions, granulomas, and infections at injection sites.
Quality Risk Assessment
To ensure product quality and to limit clinical risk, a risk assessment should be conducted during product development. The typical visible particulates that could contaminate the injectable product, their size ranges, quantity, composition, risks for each type should be identified. Visual description [e.g., photographs or drawings of typical defects] to be used for training purposes. Potential sources of particulates, appropriate analytical methods to monitor, mitigation strategies to prevent their presence in the final product should be identified.
Inherent particulates are associated with specific products or their formulations-such as proteinaceous particulates, liposomes, or agglomerates and are considered part of the quality target product profile. Their presence should not be cause for rejection of individual units or product batches if they are a property of the approved product and product release specifications are met. Time-dependent changes during stability testing that may lead to increases in size or number beyond the approved acceptance criteria should be monitored.
Intrinsic particulates can be related to the manufacturing process. Such particulates could come from components, containers and closures [e.g., glass vials, rubber stoppers] and product contact processing equipment [e.g., tubing, filters, gaskets]. Such particulates should be controlled before the actual manufacturing process through careful selection and quality control of components, containers and closures, packaging materials, and manufacturing equipment. Studies should be conducted to determine whether their manufacturing processes generate particulates. The impact of handling, washing and sterilization processes on manufacturing equipment that could lead to particulate generation over time should be studied. Such process development studies can minimize intrinsic particulates by informing selection of the appropriate handling, washing, and sterilization procedures and establishing equipment life spans. Trends in reject data at designated manufacturing facilities should be evaluated.
This type of intrinsic particulate forming under accelerated or stressed conditions in the product development phase to determine particulate characteristics and any time-dependent particulate formation or growth that can occur should be studied.
Extrinsic particulates arise from sources other than the formulation’s components, the containers and closures, or the manufacturing equipment’s product contact surfaces. These particulates, derived from materials not intended to be in contact with the injectable product. Their presence in the final product can occur because of poor conditions in the manufacturing facility [e.g., poor environmental control; equipment design, age, and maintenance; facility location, construction, and maintenance; material and personnel flows].
Visual Inspection program
Visual inspection program is to ensure that injectable products are essentially free of visible particulates. During product development, product inspection procedures, statistical sampling plan(s), acceptance/rejection criteria should be established.
Visible inspection program should include the training and qualification of operators. Trained and qualified personnel, automated inspection technology, or a combination of both should be used to inspect each unit of injectable product for visible particulates [100% inspection]. In addition, the quality unit should sample each batch for acceptance quality limit [AQL] testing. Acceptance quality limit refers to ASTM E456, Standard Terminology Relating to Quality and Statistics.
A visual inspection program should ensure that any visible particulates present in the batch at the time of release are only those that have a low probability of detection because they are of a size approaching the visible detection limit.
Factors to consider
Components and Container Closure Systems
Written procedures should be in place for the receipt, identification, storage, handling, sampling, testing, and approval or rejection of components and product containers before use in manufacturing.
Facility and Equipment
Manufacturing facilities must be designed, constructed, and outfitted with equipment to prevent injectable products from being contaminated with particulates
Manual / automated Inspections
For manual inspections, the inspection station should have a backdrop of one or more solid colors [e.g., black and white] to provide adequate contrast and to allow maximum visibility of product contents. The light intensity of the inspection station is also critical to achieving maximum visibility. The inspection environment should be free from distractions and extraneous light, ergonomically designed for inspector comfort and the inspection rate should be qualified. Inspection feasibility studies for visible particulate detectability, unit inspection duration, illumination, and fatigue time frame should be established. Light intensity selected for manual inspection stations should be qualified.
Procedures should cover handling of the units [e.g., swirling, inversion, distance from light], maximum length of the inspection period without a rest break, and disposition and documentation of products that were rejected based on the results of the visual inspection.
Semi-automated inspections
A machine rotates the product at a constant rate past a trained inspector’s field of vision. Rejected products are removed mechanically or by hand. Automated inspection technology can be used as part of an investigation in the inspection process as a replacement for manual inspection, or as an additional quality assurance step. Automated inspection technology can use different wavelengths and sensors to detect hard-to-see particulates in sterile powder, suspensions or light-protected injection products for which visual inspection is not completely effective. Routine calibration of specific vial-spin, lighting and belt speed should be established.
Among the automated inspection technologies currently in use [e.g., high-speed industrial camera, visible diode array, X-ray, near-field radar, ultraviolet and near infrared spectroscopy], each has its advantages and disadvantages but, if properly implemented, all can substantially improve the accuracy of visual inspection.
Special Injectable Product Considerations
LVP- Large volume Parenterals should undergo the same level of 100% inspection as small volume injectable products. Supplemental destructive testing may also be warranted to ensure these products are essentially free of visible particulates if the packaging does not allow for the identification of particulates within the accepted visible size range.
Opaque products and containers [e.g., lyophilized powders, suspension products, tinted vials] present obvious challenges to visual inspection. Using advanced technologies e.g., X-ray spectroscopy can help, as can supplemental destructive testing after the 100% inspection, which provides additional assurance.
Statistical Sampling
Following 100% inspection, statistically sound sampling plans, validated inspection methods, and appropriate acceptance criteria to ensure that each product batch meets a pre-established AQL for visible particulate contamination should be established. An adequate sampling plan with an acceptable AQL for nondestructive/destructive testing could follow ASTM E2234 equivalent to the ANSI/ASQ Z1.4 standards.
Training and qualification
Only certified inspectors and qualified equipment should be used to inspect injectable products for visible particulates. Personnel conducting inspections [100% inspection and AQL inspection] must be adequately trained.
The program can include a combination of training materials, standard operating procedures [SOPs], on-the-job training, and testing. Inspector candidates should be trained in the relevant CGMP requirements and should have normal near visual acuity [with or without the use of corrective lenses] and no impairment of color vision.
Visual inspection qualification kit
For personnel qualification and automated inspection systems validation, a mixture of good injectable product units and defective units containing visible particulates should be used. This test set should be prepared and approved by QA. Libraries of defective units from samples collected throughout the product life cycle, samples created to simulate production defects, or samples purchased to be representative of the types of particulates likely to occur for the drug product and its manufacturing process. QA should review the library of defective samples and compare the samples to established standards for classification. The library should contain examples from the lower limits of visual detection determined in the threshold studies. If a new particulate matter defect is identified, it should be analyzed to determine its source and added to the training library.
The percentage of defective units in a test set should not exceed 10-20 percent. Trained inspectors should review defective units before they are included in the test set to determine if the visible particulates in them can be detected under normal conditions, and the identity of defective units should be masked to test subjects. QA should control the test sets to ensure that qualification tests are not manipulated or biased.
Quality Assurance through a life cycle approach
Product quality indicators [e.g., stability test results, complaints, returned product] can help determine whether particulate matter in the product caused an event. Similarly, field alert reports and adverse event reports could reveal possible particulates-related quality issues. This information should be used to evaluate the effectiveness of visible particulate control strategies.
Trends of increased 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. For example, inconsistent product quality could be caused by any one or a combination of these factors:
Inadequate controls of components, containers, or closures.
A product formulation that is not stable.
Uncontrolled changes to the manufacturing process.
Equipment and facilities that are not suitable for their intended use.
Personnel practices that generate particles.
Investigation of quality discrepancies identified through the inspection process, QC testing, complaints, or as a result of a batch failure should be extended to other batches that may be affected. Investigations of manufacturing inspection outcomes should be conducted in situations such as the following:
Individual or total defect limits are exceeded.
A batch fails to meet AQL limits.
Atypical trends.
Reinspection of product batches may be permissible with appropriate scientific justification and should be conducted according to approved SOPs with tightened acceptance criteria. FDA does not recommend more than one reinspection in an attempt to release a batch with atypical defect levels. Samples failing the AQL reinspection should be counted along with rejects from any other inspection of the product (e.g., such as 100% inspection and the original AQL visual inspection) in calculations to account for and reconcile all units of final product in the batch. Corrective actions, such as reinspection, should be justified based on risk and have quality unit oversight and must be documented consistent with applicable written procedures.
Conclusion
To control visible particulate in product/s, risk-based approach should be followed that include use of a robust visual inspection program along with the implementation of other relevant CGMP measures to help ensure that injectable products are not adulterated and are essentially free of visible particulates.
References
Inspection of Injectable Products for Visible Particulates, Guidance for Industry, USFDA Dec 2021.
USP <790> Visible Particulates in Injections, inspection procedures used to demonstrate that injectable products are essentially free from particulates.
USP <1790> recommendations on inspection programs for visible particulates.
USP <1> Injections and Implanted Drug Products (Parenterals)-Product Quality Tests.
Note-The images given for representation in this blog are taken from Google Images. Many thanks for Google.
Very good insight of the subject matter.
Thank you Rao