Understanding Regulatory Expectations for Manual Visible Particle Detection, Human Advantages and Disadvantages, and Inspector Qualifications

Do you visually inspect each sterile injectable after it's been compounded under suitable and controlled conditions?

The presence of foreign particulate matter in injectable parenteral drugs is one of the most common reasons for recalls in the pharmaceutical industry. Notably, from 2008 to 2012, Steven Lynn of the FDA office of Manufacturing and Product Quality showed in a report in 2013 that 22% of sterile injectable drug recalls during this period were due to the presence of visible particles.

As the FDA begins to inspect more compounding pharmacies and hospitals, there has been a rise in observations with inadequate visual inspection procedures. In order to understand how and what to do for the manual visible particle detection process, this article explains the regulatory expectations, patient impact of particulate contaminants in injectable drugs, human inspection advantages and disadvantages, and inspector training & qualifications.

Regulatory Expectations

Hospitals, 503A pharmacies, and 503B outsourcing facilities must comply with USP Chapter 790, which states that injectable drug products must be essentially free of visible particulates. Particles can be carriers of microbiological contamination; and both large and small particles can pose a threat to blood vessels by blocking them. As such, there's essentially zero tolerance for the presence of particulates in injectable drugs.

Regulatory expectations include:

Injectable drug products must be essentially free of visible particles
Parenteral products are inspected individually for extraneous contamination and other defects
Inspections are performed under suitable and controlled conditions of illumination and background
Qualified inspectors, test methods, and equipment are required to detect defects in a reproducible and controlled manner
Results must be documented
Investigate out of specification results

USP 790 describes all parenteral drug products must be visually inspected individually for extraneous contamination and other defects. Whether one unit is compounded and dispensed to a patient or 1,000 units are mass produced and distributed to hospitals, each unit of each lot must be visually inspected for defects, including the presence of visible particles.

Entities are expected to perform the visual inspection under suitable and controlled conditions of illumination and background. Organizations that prepare sterile compounds must use qualified visual inspectors, visual inspection, test methods, and equipment to detect defects of each unit in a reproducible and controlled manner. Results in the visual inspection must be documented if it was performed and the compound or batch met specifications. Anything not meeting the acceptance criteria must be investigated for out-of-specification results.

Patient Impact

Dispensing compounded sterile injectable drug preparations that contain particulates can have serious patient safety implications. While there is a lack of controlled human studies to demonstrate the clinical concerns that particles can be carriers for microbiological contamination, they have been shown to potentially block blood vessels. Anecdotal studies found that foreign body emboli and granulomas are the most common result of particulate matter present in intravenous solutions. For example, pulmonary emboli and granulomas were observed in intravenous drug abusers who injected non-sterile slurries of ground tablets. The route of administration of a drug preparation (whether it's injected intramuscularly, subcutaneously, intravenously, etc.) also affects the risk of such adverse events. The propensity for a particle to cause problems may be higher given intravenously over other routes of administration. Given the potential for granulomas and emboli to form when particles are injected intravenously, the goal is to eliminate or greatly reduce the risk of this occurrence.

100% Visual Inspection Methods are Not 100% Effective

The problem with the visual inspection test is that it is not 100% effective. John Shabushnig reported in 1995 at a Parenteral Drug Association meeting that human inspection performance has about a 70% probability of detection (POD) of a particle size of 150 microns and increases with increasing size. In other words, if a person were to inspect 100 units of a batch where each unit is contaminated with a 150-micron particle, the person would only be able to find 70 of the 100 defects, and 30 would be sent out to the public. The smaller the particle, the harder it is to find, and the lower the probability of detection. Conversely, the larger the particle, the easier it is to detect, and the higher the probability of detection.

For manual visual inspection methods, the probability of detection is 70% corresponding to a particle diameter of 150 microns. For perspective, sub-visible particles are between 0 and 100 microns in length as per USP <788>. Shabushnig reported the probability of detection approaches 100% at a diameter of about 200 microns. The probability of detection of particles can also change depending on the characteristics of the particle (color, shape, refractive index), product container, and nature of the drug product. For example, colored particles are easier to detect against a white background and may be visible at 50 microns in diameter. In addition to these findings, the Visual Inspection Working Group of the European Compliance Academy published a good practice paper in 2014, stating particles 150-microns in length are readily visible.

Human Advantages and Disadvantages

There are several advantages of human manual visual inspection methods over automated machine inspection methods. First, humans are flexible in inspecting new products and packages. They can readily pick up a syringe, vial, or bag and begin the inspection. Automatic or semi-automatic inspection machines, however, require tools to handle different containers. Humans are also quicker in their response to detecting new defect types. If, for example, a new compounding process is instilled or new raw materials are used, causing an increase in plastic or fiber particles, humans can adapt more readily and quickly through the appropriate detection, training, and competency tests. Conversely, a machine would have to be studied to ensure the new particles can be detected consistently and reliably. People are also more cost-effective for individual compounds or small-batch inspections, proficient at inspecting many different preparation types, and have a low initial start-up cost, while visual inspection machines are expensive.

The downside of manual visual inspection methods over automation is that human inspectors are not validatable. Inspectors can be qualified to provide reliable performance, but there can be variability between inspectors and even within a single inspector. For example, one inspector may inspect an IV antibiotic and detect a particulate, however, a second inspector may be unable to confirm the defect. In another example, one inspector can inspect a batch of 100 units and not detect a single defect, but may detect three defects upon re-inspection of the same batch at a later time.

To minimize variability among and within inspectors:

Require inspectors to have 20/20 vision and the absence of color-blindness.
Provide a robust training and competency program.
Employ detailed standard operating procedures.
Control the inspection conditions with the use of calibrated lighting and a black and white background.
Define the duration of inspection allowed per unit and provide a timing device to keep the appropriate cadence.

Inspector Prerequisites

Inspector candidates should be properly qualified to ensure they have the physical capability to detect particles reproducibly and reliably. The confirmation of 20/20 visual acuity, either unaided or corrected, provides objective evidence that an individual is able to detect particles at the micron level. The potential inspector cannot have color blindness so that all particles of varying colors can be adequately detected. An eye exam can be performed by a licensed optometrist, ophthalmologist, or other practitioner licensed to perform such an assessment. The inspector candidate must also engage in robust visual inspection training, reflective of the organization’s procedures and historical defects. They must pass an objective visual inspection challenge test to demonstrate competency. For initial qualifications, passing a challenge test in triplicate provides confidence and scientific justification that the individual is qualified for the task. Then, re-qualification tests can be repeated annually.

Training Program

A robust training program details the procedures and training materials, specifies the frequency of training required, depicts the performance evaluation process, requires appropriate documentation, and provides a remediation plan if performance is lacking. Visual inspector candidates confirmed to be physically able to perform an inspection with a passing vision test, can be admitted to the training program. Such a program will likely require the individual to first read and understand the related procedure(s), next shadow a designated expert performing the visual inspection procedure, then perform the inspection with units explicitly designated for training repeatedly under the supervision of the expert, and finally take and pass a visual inspection challenge test.

The Training Set

Units designated for training may originate from an organization’s library of past actual compound defects. This type of training set can be ideal for candidates to better recognize defects they may actually encounter in the future. Other firms may purchase standardized training sets. Regardless of origin, it is important that the training set include each container type (e.g., vial, bag, syringe) and provide each type of defect category (e.g., particulate, precipitate, turbidity) encountered at a practice site. Training sets should also incorporate acceptable units. Additionally, some firms may choose to define the minimum quantity of units of a particular container, closure, and product family that a candidate must inspect. Repetition with hands-on training gives a candidate more experience and confidence to pass the challenge test.

The Challenge Test

The challenge test must be designed very carefully to demonstrate a candidate's competency. A challenge test may be made up of 100 units or more, so the inspector has enough repetitions statistically to demonstrate their competency. The test set may contain 10 to 20% rejects (the closer to 10% rejects, the better). Test sets that contain more than this percentage can cause a Hawthorne effect, where there is positive reinforcement for finding a defect. The units present in a test set should appropriately represent the container types, sizes, and fill volumes produced at the organization. To ensure test integrity, it's advised to retain at least three versions of a challenge test set. Alternatively, coded validated test units of a challenge test may be chosen to customize a test set for an individual. Recall that manual visual inspection methods aren't 100% effective. Detection is probable for every length of particle. Particle defects that are too small to be considered visible, could be too difficult to detect the defect consistently. Certified challenge tests comprised of particle defects that are able to be consistently detected can be utilized. Given the probability of detection for a particle and the fact that experienced human inspectors may not detect 100% defects, the industry expectation for passing the challenge test is ≥80%.

Inspection Equipment

As per USP <790>, dedicated inspection areas or booths must be equipped with black and white backgrounds. A vertical non-glare white panel is placed next to a vertical matte black panel. White fibers or plastic particles are very difficult to detect against light-colored backgrounds. Dark particulates are hard to detect against dark backgrounds, so having both color backgrounds are essential. The booth must also be equipped with a calibrated lighting device suitable to detect foreign matter. There are different colors, focuses, and intensities of lights available. USP <790> requires a minimum light intensity between 2,000 and 3,750 lux be illuminated at the inspection point for an injectable drug packaged in a clear container. Lux is a measurement term for light intensity as perceived by the human eye of light that hits or passes through a surface. Translucent or amber packaged compounds require higher light intensities, at least 8,000 lux. To ensure the inspector inspects each unit for the appropriate duration, the booth can be outfitted with a calibrated timing device. As with compounding areas and equipment, the inspection area and equipment should be routinely maintained in a preventative maintenance program.

Inspection Preparation

To prepare for the visual inspection procedure, the immediate area should first be observed and documented for line clearance (e.g., there should not be any other compounds or lots present at the station as this could cause mix-ups). The container's lot number or prescription number must be checked that it matches the production batch record or formula worksheet. A pair of gloves should be donned before handling the unlabeled compound. It is necessary to check that the outside surface of the container is clean. If, for example, there is preparation residue adhered to the outside of the container, it must be wiped down with an isopropyl alcohol-soaked cloth to the appropriate cleanliness required.

Manual Inspection Method

It is not appropriate to hold a compounded injectable drug up to a light in the room to check for particulates. As per USP <790>, 100% of the containers must be inspected under appropriate lit conditions. Using a calibrated light will provide consistency in the inspection. The unit shall be gently inverted or swirled. Biologicals and protein products are exempt from inverting and swirling, which could denature their structure. Each unit shall be inspected for five seconds against a black background and then five seconds against a white background. Exceeding the qualified inspection rate could cause false rejects. As such, a calibrated timing device is suggested to be used during the inspection to keep the appropriate cadence and prevent variability of results. To prevent false negatives, it is recommended that an inspector take a five to ten minute break at least every hour if visual inspection is the only function being performed for an extended period of time.

Does your facility produce quality preparations?

If you’re ready to bring quality to the center of your compounding operations, consultants at Restore Health Consulting LLC can help you design a robust quality management system to promote patient safety and regulatory compliance.

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References

Steven Lynn, FDA Office of Manufacturing and Product Quality, March,14, 2013
Foreign Particle Embolism in Drug Addicts: Respiratory Pathophysiology, FG Douglas, et al, Annals Int. Med. 75, pgs 865-872 (1971)
Shabushnig, Melchore, Geiger, Chrai and Gerger. PDA Annual Meeting 1995 Published in the PDA Survey Summaries.
USP 43 – NF 38. General Chapters: <1> Injections and Implanted Drug Products (Parenterals)—Product Quality Tests (2020), US Pharmacopeia/National Formulary
USP 43 – NF 38. General Chapters: USP <790> Visible Particulates in Injections (2016), US Pharmacopeia/National Formulary
USP 43 – NF 38. General Chapters: <788> Particulate Matter in Injections (2013), US Pharmacopeia/National Formulary
USP 43 – NF 38. General Chapters: <1790> Visual Inspection of Injections (2021), US Pharmacopeia/National Formulary
Generalized Methodology for Evaluation of Parenteral Inspection Procedures, JZ Knapp and HR Kushner, J. Parent. Sci & Techn. 34 (1), pgs. 14-61 (1980)
Implementation and Automation of a Particle Detection System for Parenteral Products, JZ Knapp and HR Kushner, J. Parent. Sci & Techn. 34 (5), pgs. 369-393 (1980)
Particulate Matter in Injectable Drug Products, Stephen E. Langille, PDA J Pharm Sci and Technol, 67 (3) pgs. 186-200 (2013)
Considerations for Design and Use of Container Challenge Sets for Qualification and Validation of Visible Particulate Inspection, James A. Melchore and Dan Berdovich, PDA J Pharm Sci and Technol, 66 (3) pgs. 273-284 (2012)
Visual Inspection and Particulate Control, D. Scott Aldrich, Roy T. Cherris and John G. Shabushnig, DHI Press ©2016, PDA Bookstore

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Amy SummersApril 8, 2022