Visual inspection ranks as an essential operation in parenteral drug production to ensure the safety of the drug product in its container, such as a vial or syringe. The industry is seeing an increased emphasis by regulators on having a well-characterized and robust inspection process, especially with regard to particulates, says John Shabushnig, PhD, principal consultant at Insight Pharma Consulting. Pharmaceutical Technology spoke with Shabushnig, who is also the group leader for the Parenteral Drug Association (PDA) Visual Inspection of Parenterals Interest Group and a member of the United States Pharmacopeial Convention (USP) Visual Inspection Expert Panel, about available technologies, current trends, best practices, and work at industry associations that aims to improve understanding and define guidelines.
PharmTech: What flaws are typically identified by visual inspection?
Shabushnig: Visual inspection identifies crucial container integrity defects such as cracks, missing or misapplied stoppers and seals, foreign material such as particulate matter, precipitation or discoloration of the product, over- or under-filled containers, and cosmetic defects such as scratches or dirt on the outside of the container. Specific defects will vary by product and container type.
However, when discussing inspection and rejection of defective units, it is just as important to consider defect prevention. The data obtained from the visual inspection program should not only ensure removal of defective units, but also provide information for process improvement to reduce and prevent such defects in the future.
PharmTech: Have the number of recalls associated with visual flaws increased or decreased in the past five years? To what do you attribute this change?
Shabushnig: There has been an increase in recalls due to visual defects. This is driven by recalls for particles, especially glass particles. I believe this was influenced by a renewed concern about the risk of glass delamination or the formation of glass lamellae due to interaction of the liquid product with the interior surface of the glass container. This has expanded to a broader concern with other types of hard particles including metallic particles as well as glass. Increased regulatory activity is pushing an upward spiral with companies taking increasingly conservative actions and recalling batches that would have been acceptable in the past. In the absence of good clinical studies on the risk posed to patients by small numbers of visible particles, we must base any risk assessment on anecdotal reports. I believe this lack of quantifiable data has led to the very conservative regulatory and industry position we see today. It also has led to a wide range of differing practices within the industry, often based on a company’s recent regulatory experience. Through education and guidance developed by PDA and USP, I hope we will see more consistency in this area and ultimately reduce the number of recalls associated with visual defects.
Comparing manual and automated inspection
PharmTech: Can human inspectors work as effectively as automated equipment? If so, what tools and practices are essential to inspector success?
Shabushnig: Both humans and machines can provide effective inspection of parenteral products. Originally, automated systems were limited to detecting particulate matter in solutions, but current systems can also detect container and seal defects. Although human inspectors and automated systems can achieve similar levels of sensitivity, each has different strengths and weaknesses.
Human manual inspection, however, is still the reference standard for visual inspection and is the method stated in the European Pharmacopoeia of the Council of Europe (Ph. Eur.) and the pending USP <790> (1, 2). Human inspectors are flexible and can respond to something they have never seen before or something that ‘doesn’t look right.’ They can also more easily tolerate normal variation in containers, especially those formed by molding, reducing the number of falsely rejected good product. However, people are more limited in the rate of inspection (i.e., the number of containers per minute or hour that they can inspect). They also suffer fatigue and require frequent breaks to maintain a high performance level. These limitations all lead to greater variation in manual inspection results, but this variation can be minimized through good training and operating procedures.
Machines have the advantage of speed, and some are capable of inspecting 600 units/minute. Equipment is validated to provide consistent performance at any time and on any day or shift. But machines are not very flexible and generally unsuited to products in molded containers. In addition, the high cost of automated systems may be unjustifiable if product volumes are low or there is a mix of many different products. Automated systems are best suited to high volumes of a limited number of products. These considerations are similar to those encountered in other forms of automation.
PharmTech: What are the most common visual inspection technologies in use today? How do they overcome inspection challenges?
Shabushnig: The most common inspection technologies use machine vision, the combination of video and computer technologies, to capture and quickly analyze images of product. Today’s automated inspection systems use several cameras to inspect specific regions of a vial or syringe in detail. These inspection stations include specialized lighting to highlight specific types of defects.
There are also semiautomatic inspection systems in use. Available for a number of years, these systems rely on a human inspector to inspect the product and make the quality decision, but automate the material handling, transporting, and rotating of the container under controlled lighting in front of the inspector.
PharmTech: What new visual inspection technologies look promising?
Shabushnig: For manual inspection, more inspection stations are being equipped with light sources based on light-emitting diode (LED) technology. LED lighting offers a cool, stable, and long-lived source of illumination.
There has always been a desire to see inside difficult-to-inspect products and packages such as freeze-dried powders, suspensions, and darkly colored solutions as well as translucent or opaque containers. X-ray technology is being investigated for this purpose, and recent advances in X-ray sources and detectors are bringing this technology closer to routine use. The deployment of this technology must be coupled with an understanding of how the exposure to very low X-ray doses affects the stability of a specific product.
PharmTech: Are combination systems (e.g., visual inspection/leak detection systems) gaining ground?
Shabushnig: Yes, the availability and usage of combination systems is growing. Combination systems are a good example of the synergy possible when different technologies work together with each performing the task(s) they do best. For example, when compared to machine or human visual inspection, leak detection systems, whether based on high voltage, vacuum decay or headspace analysis, offer greater sensitivity when confirming container integrity. This sensitivity level also is achieved with lower false-reject rates. When using vision alone, it is often necessary to tune the system to such a high sensitivity to detect small cracks that high false-reject rates result. By combining technologies, it is possible to reduce the sensitivity of the visual inspection and false-reject rate while maintaining sufficient sensitivity to catch visual defects. In combination systems, higher overall sensitivity with lower false rejection can be achieved. Such combinations can be expensive, and thus, a high volume of a limited number of products is necessary to support purchase, validation, and operation of these systems.
PharmTech: What regulatory activities are influencing visual inspection?
Shabushnig: The increased emphasis on the inspection process by regulatory inspectors has certainly focused attention on visual inspection. The upward trend in recalls also has brought visual inspection concerns to the forefront. USP and PDA have worked to bring a better understanding of the inspection process to the industry and help set practical guidelines for routine inspection.
PharmTech: What is the status of USP’s draft chapter <790> Visible Particulate Matter in Injections? If approved, how will it update current practices?
Shabushnig: The development of USP General Chapter <790> was initiated in 2009 with the publication of a stimuli article (3). A Stakeholders Forum was held in 2010, and subsequent drafts were published for public comments in 2012. The chapter has been approved, is scheduled for publication in April 2014 in the first supplement to USP 37, and should become official in August 2014.
This chapter will offer important guidance on inspection method and acceptance criteria. It defines critical parameters (e.g., illumination intensity, inspection time, backgrounds, and movement) for a reference inspection method. These parameters are harmonized with the method currently found in Ph. Eur. In addition, a sampling plan and acceptance criteria are provided to better define the current expectation that ‘every lot of parenteral preparation is essentially free from visible particulates’ (4). These acceptance criteria recognize the serious concern regarding particles in injectable products but also current process capabilities with contemporary manufacturing and filling equipment and packaging materials.
A companion Information Chapter <1790> Visual Inspection of Injectable Products is also currently under development. This chapter is expected to provide guidance on good practice for visual inspection. A draft is expected to be published in USP Pharmacopeial Forum in 2014.
PharmTech: What best practices have been identified by PDA’s Visual Inspection of Parenterals Interest Group?
Shabushnig: There are many opportunities for improvement of the inspection process in the pharmaceutical industry. We have learned much about these processes through benchmarking surveys conducted through PDA. The most recent was in 2008, and we are planning to update this survey in 2014.
Best practices include a detailed list of defects with a risk assessment to support the risk category chosen (e.g., critical, major, or minor). This list supports training of human inspectors, validation of automated inspection equipment, and lot assessment through acceptance sampling (i.e., acceptable quality-level inspection).
Training of inspectors should be confirmed with a robust challenge with a set of good containers seeded with known defects. A well-characterized test set is needed for this purpose. This test set also should establish the detection probability of a range of typical defects. During routine inspection, the illumination intensity of the inspection station should be measured regularly to confirm operation within the compendial range, and inspectors should take frequent breaks to avoid lower performance due to fatigue.
For automated systems, a comprehensive validation should include a challenge with a broad range of defect samples to document the detection probability. In routine use, a small set of both good and defective product should be used to challenge the system to assure performance at the level observed during validation.
Upgrading visual inspection of parenteral products
PharmTech: What are the three most important considerations when updating or upgrading visual inspection of parenteral products?
Shabushnig: When updating or upgrading visual inspection of parenteral products, a thorough understanding of expected defects and unique product characteristics is needed. This knowledge can be obtained from production history, complaints, review of similar products, and ‘what-if’ discussions. Inspection is made more difficult by high viscosity, foaming (i.e., forming bubbles), highly colored, suspensions, powders, and molded, colored, or opaque containers. These more challenging to inspect products will likely result in a higher false reject rate with automated inspection.
Secondly, successful implementation of visual inspection depends on a realistic assessment of product mix and production volume to identify the optimum technology (manual, semiautomatic, or automated).
Finally, successful visual inspection requires sufficient expertise and resources to evaluate and support the inspection process and technology chosen.
1. EurPh, 8.0, 2.9.20, “Particulate Contamination: Visible Particles” (EDQM, Strasbourg, France, 2013) p. 323.
2. USP In-Process Revision: <790> “Visible Particulates in Injections [New],” Pharmacopeial Forum 38 (6) (2012).
3. R. Madsen, R. Cherris, J. Shabushnig, and D. Hunt, USP PF 35 (5) 1383-1387 (2009).
4. USP General Chapter <1>, “Injections, Foreign and Particulate Matter” (US Pharmacopeial Convention, Rockville, MD, 2013).