Visual inspection of parenterals is critical for ensuring that these drug products meet ever-increasing quality specifications. At the same time, faster production speeds and more complex production processes are presenting challenges. Peter Spinelli, sales director in North America for Bosch Inspection Technology, Emanuele Cudiferro, service manager with Brevetti, and independent consultant John G. Shabushnig, previously a team leader in Pfizer’s Global Quality Operations group, spoke with Cynthia Challener, editor of the Pharmaceutical Sciences, Manufacturing & Marketplace Report, about how advances in technologies for both manual and automated inspection methods are helping address this need in parenteral manufacturing.
Demand for higher quality
Pharmaceutical Sciences, Manufacturing and Marketplace Report: What are the key attributes of good visual inspection systems for parenterals manufacturing? What performance requirements are needed for the parenteral formulations that are being developed today and why?
Cudiferro (Brevetti): Parenteral manufacturers are facing increasingly strict quality standards that require them to produce products free of visible particles, reduce process/product variation, and minimize rejects. At the same time, current methodology based on the quality-by- design (QbD) philosophy requires a deep knowledge of the product and its manufacturing process. As a result, automated inspection systems are playing a key role in parenteral manufacturing processes. Efficiency, considered as the reduction of false rejects, and detailed information regarding the cause of rejection are the key attributes that enable improvement of performance.
Spinelli (Bosch): Good visual inspection systems for parenterals must adhere to increasingly strict safety regulations all over the world. These regulations require the highest product quality to protect patients from contaminated medicines, which must be achieved at a time of growing parenteral production capacities, greater complexity of manufacturing processes, and higher production speeds.
Parenteral products are typically injected and go directly into the bloodstream, where they might cause adverse reaction due to contamination or the presence of undesired particles. Inspection systems must be able to detect contaminated APIs or foreign matter within the product, as well as cosmetic container defects, such as cracks in syringe flanges or defects in the sealing integrity of ampoules.
Shabushnig (Consultant): Consistent quality is achieved by good control of critical manufacturing and inspection parameters. For human manual inspection, the method referenced by all of the pharmacopeias, it is important to control the light intensity, contrast (through the use of black and white backgrounds), the speed or pace of the inspection, and the presentation of the container being inspected. This last point involves a swirl or inversion to get particulates in motion to increase their visibility. These same points apply to semi-automated or automated inspection systems as well. Additional requirements for machine inspections are that the resolution of the sensor or camera and the algorithms that are used are appropriate and enable quality decisions based on analysis of images of containers and products.
New light sources, improved analytical tools, and flexibility
Pharmaceutical Sciences, Manufacturing and Marketplace Report: What recent advances in automated inspection systems have been made and what need(s) in the marketplace led to their development?
Shabushnig (Consultant): For manual inspection, new light sources, such as florescent lamps with high-frequency ballasts or light-emitting diodes (LEDs), have been introduced and offer several advantages, including stable, flicker-free viewing, which reduces inspector fatigue and variation in light intensity, reduced heat output, and better energy conservation when compared to incandescent lamps.
For automated inspection systems, sensor and camera resolution continue to increase along with image processing speed. These improvements follow the same trend seen in consumer electronics with cell phones, digital cameras, and laptops. For inspection systems, such advances provide the ability to resolve greater detail and “see” smaller defects or inspect a larger area of the container in a single view.
There is also continuing development of commercial X-ray-based imaging systems that permit the detection of denser particles inside opaque containers or products such as suspensions or lyophilized powders.
Cudiferro (Brevetti): Organization of the images acquired during the automatic visual inspection process into digital libraries currently is helping pharmaceutical manufacturers to meet various process requirements. Remote Parametrization & Validation (RPV), recently developed by Brevetti, creates the basis for a deep analysis of the inspection results and makes it possible to reduce the false rejection rate and highlight any possible improvements in the manufacturing process. Importantly, this type of analysis can be easily performed off line without impacting the online productivity.
Spinelli (Bosch): Flexibility and high output rates are important for new technologies. In addition, compared to manual inspection systems, semi-automated systems are able to perform visual inspection at higher rates while minimizing operator fatigue. As a result, it is possible to achieve optimized inspection of particulates in liquid parenteral products and specks on lyophilized products, as well as the detection of cosmetic container defects.
That is why Bosch Inspection Technology recently launched a computer-bound visual tabletop unit for the inspection of filled or empty pharmaceutical containers such as vials, ampuls syringes, and cartridges. A camera transmits the results directly to the computer, which allows for an especially fast evaluation. It is suitable for containers with diameters from eight to 50 millimeters and is primarily used for research purposes and small batch applications, such as verification of product rejects, particle and defect analyses, and stability surveys. That makes it the ideal starter instrument for companies that plan to switch to fully automated machines in the near future.
Pushing the limits
Pharmaceutical Sciences, Manufacturing and Marketplace Report: What are some of the current issues/limitations that still remain that must be addressed to improve automated inspection systems for parenteral manufacturing?
Spinelli (Bosch): Due to the growing number of parenterals, and particularly generic products, manufacturers require ever-faster machines for larger production quantities. Here, manual inspection is quickly stretched to its limits. Even the best-trained human inspector cannot keep up with the high speeds of all production types. Yet, manual and semi-automated visual inspection systems remain very important for inspecting parenterals.
Depending on the size and type of the pharmaceutical product and container, a combination of automated and visual inspection is sure to be the most reliable approach. As an example, during the validation process for fully automated inspection machines, challenge set samples are critical for ensuring that inspection machines maintain their validated state under dynamic conditions. Manual and semi-automated visual inspection tools are particularly well-suited for the inspection of these important samples.
Shabushnig (Consultant): Inspection by human or machine is still a probabilistic process, thus 100% inspection does not detect all defects. Generally, detectability is size-dependent, with the smallest particles or container defects having the lowest detection probability, and current manufacturing processes and packaging materials do not yield products free of visual defects. A trained inspector using a controlled inspection process or a validated inspection machine can, however, give good sensitivity, delivering safe, high-quality products.
With respect to automated systems, though, it has been difficult to reach an agreement regarding acceptance specifications for inspector qualification of machine validation.
Cudiferro (Brevetti): Taking into consideration that leak detection is one of the standard requirements for the industry, the possibility of combining automated visual inspection with the most advanced leak detection technologies represents one of the current challenges for equipment manufacturers.
Pharmaceutical Sciences, Manufacturing and Marketplace Report: What is being done to address these issues? Are there any new technologies under development that could have an impact in the near future?
Cudiferro (Brevetti): To maximize the performance of our visual inspection systems, we recently made available as optional features a high voltage module for the leak detection of liquids and a headspace gas analyzer (HGA) device for the leak detection of freeze-dried products. Importantly, the new modules can be fully integrated into our compact, automatic visual inspection system.
Shabushnig (Consultant): Machine builders continue to advance inspection technology, offering higher levels of performance. This process is generally an evolutionary one, but there have been significant improvements since these technologies were first introduced over 30 years ago.
The Parenteral Drug Association (PDA) has been offering forums to discuss and advance these issues for many years. There is a Visual Inspection Interest Group that meets in the US and Europe. There is also an annual Visual Inspection Forum dedicated to this topic. In addition, the PDA Training and Research Institute offers training on visual inspection to help the industry achieve consistent inspection results.
In addition, the Expert Panel at USP has published a draft general chapter to better define the conditions for inspection and the acceptance criteria for meeting the current requirement that each lot of injectable product be “essentially free” of visible particles. Draft chapter has been published for comment and continues to advance through the USP review and publication process.
Any future efforts should balance the need for good inspection practices with prevention. Prevention is certainly preferred for both product quality and process yield. The path forward will rely on both continuous process improvement for the prevention of defects as well as better methods for detecting and rejecting them.