Hallie Forcinio is BioPharm International's packaging editor, editorhal@sbcglobal.net

Hallie B Forcinio

If the COVID-19 pandemic has a theme, it’s shortages. At times, there hasn’t been enough personal protective equipment for front-line workers and caregivers or ventilators for the sickest victims. In addition, limitations related to testing, lab capacity, and contact tracing continue to make it difficult to identify those exposed to the virus in a timely manner.

When a vaccine becomes available, will the packaging supply chain be better prepared? Suppliers are working hard to prevent shortages and bottlenecks. Because many organizations are developing vaccine candidates that look promising, there is a possibility more than one vaccine will be commercialized. If these vaccines rely on different administration routes (e.g., inhaled, oral, transdermal, and injectable), then demand for primary packaging can be extended across multiple packaging formats. Relying on a combination of blow-fill-seal syringes, glass-coated plastic vials and syringes, fused-quartz vials, microneedle array patches, prefilled glass or plastic syringes, traditional glass vials or syringes, bottles for solid dosage forms, or metered-dose inhalers may be needed to quickly deliver the billions of COVID-19 vaccine doses that will be required.

Another shortage-mitigation factor is that packaging suppliers and fill/finish operations were investing heavily to meet rising demand before the pandemic started and have accelerated efforts in recent months to ensure they will be ready to address the skyrocketing need generated by the approval of COVID-19 vaccines and treatments (1). “We are confident that there will be enough primary packaging containers available globally to deliver one or more vaccines safely and fast to the people,” says Stefan Marc Schmidt, vice-president of global sales and marketing at SCHOTT Pharmaceutical Systems.

Borosilicate glass is the most widely used material to package vaccines and has been used for more than a century. Approximately 50 billion borosilicate glass containers are made annually worldwide for use with a wide variety of vaccines and treatments (2). With well-established infrastructure and long-term fill/finish experience, most COVID-19 vaccines will likely use this packaging format. In fact, SCHOTT, which operates a global validated production network with 20 plants and more than 600 production lines for pharma glass and packaging, already has delivered millions of glass vials to SARS-CoV-2 programs including supplying three out of every four COVID-19 vaccine projects undergoing Phase I, II, and III testing (3).

Schmidt believes demand for glass vials generated by the approval of one or more COVID-19 vaccines can be met without causing shortages for non-COVID-related vaccines, treatments, and diagnostics. He reports, “We are closely monitoring the demand for vials. The supply process for pharmaceutical vials itself has not changed and is based on standardized procedures. As a packaging supplier, we know with several months lead time how many vials to deliver and when to deliver them. This [lead time] gives us enough room to prioritize our production. Since we produce the pharmaceutical glass tubing for the packaging ourselves, we are also able to adjust the capacities for glass production in advance, which also benefits packaging manufacturers who do not have their own glass production facilities.”

SCHOTT and other producers of borosilicate glass containers, such as Stevanato Group, Gerresheimer, Corning, and DWK Life Sciences, have been working to boost capacity and quality for some time (2, 4). SCHOTT announced in 2019 it would invest approximately $1 billion. “We are on track to increasing tubing capacity by roughly 40,000 tons by the end of 2021,” says Fabian Stöcker, vice-president of strategy and innovation at SCHOTT Pharmaceutical Systems. “That equals roughly seven billion pharma packaging containers,” he explains. The investment program enables rapid ramp-up of production. “Since our sites are already validated by the authorities and by major pharma companies, our expansion is happening at a very fast pace,” reports Stöcker.

DWK Life Sciences has more than doubled production capacity for borosilicate glass vials at its ISO 9001-certified plant in Rockwood, TN. Specific upgrades include the addition of automated tube loaders with vertical loading capabilities; automated, touchless manufacturing processes; and Class 8 certified cleanroom robotic packing. “By converting to state-of-the-art lines, complete with dimensional and cosmetic vision inspection equipment, we’ve increased productivity in the plant and are delivering industry-leading quality for glass vials,” said Rick Schwartz, senior vice-president of marketing and sales at DWK Life Sciences (4). 

Corning produces both borosilicate glass tubing and coated aluminosilicate Valor Glass vials. For Valor Glass vials, an ion-exchange process helps minimize breakage, cracks, and particulate contamination, while the coating lowers the coefficient of friction and eliminates cosmetic flaws. Despite eliminating boron and adjusting the ratios of other ingredients, Valor Glass meets the current United States Pharmacopeia (USP) Type I hydrolytic criteria and has low extractable concentrations (5).

Valor Glass vials can enable drug/vaccine manufacturing fill lines to run at much higher speeds while maintaining high operational efficiency (80+%) and improved yields compared to conventional containers, reports Corning. “Increased speed improves capacity for producing COVID-19 countermeasures,” notes Brendan Mosher, vice-president and general manager of Corning Pharmaceutical Technologies. He continues, “We . . . believe that both [borosilicate and Valor Glass] can play an important role in the supply chain for COVID-19 pharmaceutical products.”

In mid-October 2020, Corning projected it would ship tens of millions of vials in the coming weeks to multiple Operation Warp Speed vaccine developers. Mosher reports, “We’ve quadrupled capacity at our Big Flats manufacturing facility in New York and will be able to ship enough vials to support hundreds of millions of COVID-19 vaccine doses next year. We will continue to scale manufacturing to meet increasing customer demand over the next three years and beyond.”

A new glass furnace installed at its Vineland, NJ facility was scheduled to begin serving customers in November 2020. Mosher says, “With the US government’s investment that we announced in June, we will be able to scale manufacturing to meet increasing customer demand. This will result in a three- to four-fold capacity increase by the end of this year, and a 10-fold increase by the end of next year as our Durham, NC, manufacturing footprint comes online in the second half of 2021. Per the agreement ... with BARDA [Biomedical Advanced Research and Development Authority, part of the US Department of Health and Human Services’ Office of the Assistant Secretary for Preparedness and Response], Corning will provide priority access to designated BARDA vaccine and drug development partners.”

Glassmakers also have focused on preventing supply chain problems. At SCHOTT, Schmidt says, “When the pandemic started, we knew that we needed to make sure that our products were getting to customers without delay.” Incoming supplies were secured and authorities were alerted to ensure the products would be regarded as essential and shipments would not be stalled in transit.

Andrea Zambon, marketing and product management director at Stevanato Group, reports, “Since the outbreak of COVID-19, we’ve been securing supplies. We’ve increased our staff in production and redesigned shifts [so they could continue] to produce without any stop and deliver our products while preserving our staff’s health and safety. We’ve proactively invested by adding significant capacity as much as we could in our worldwide operations for the production of bulk and ready-to-use vials. We’ve been able to act fast, installing the latest generation of our glass converting lines, which we produce in-house through our company Spami.”

Stevanato Group also is collaborating to supply Pur Q fused-quartz vials from Momentive Technologies in Stevanato’s EZ-fill packaging format, which provides ready-to-use containers for aseptic fill/finish operations. The EZ-fill configuration gives pharma companies clean, sterilized, and depyrogenated ready-to-fill containers with a high level of machinability and compatibility with existing fill/finish technology. “Pur Q vials conform to the ISO vial dimensional requirements, which ensure their compatibility with all the leading stopper/closure systems ... used on these vials, in the pharmaceutical industry today,” explains Robert Koch, global commercial director at Momentive Technologies.

Made from 99.995% pure silicon dioxide (SiO2), the fused-quartz vials have an exceptionally inert, nonreactive surface that virtually eliminates any risk of interaction with packaged drug formulations (6). Koch reports, “The raw materials are very tightly controlled and then subjected to a number of refining steps that result in the consistent, industry-leading purity. Each batch of raw material undergoes a trace elemental screen using ICP-OES [inductively coupled plasma-optical emission spectrometry] before it is released for production,” he adds.

In comparison, Koch says, “Conventional Type I vials in use today are typically 75–80% SiO2 with the remaining components comprised of additives, particularly from the boron, alkali, and alkaline earth groups. While borosilicate Type I glass vials are an effective packaging material for many of the pharmaceutical drugs on the market today, Pur Q vials are ideal for sensitive drugs where interaction with even trace elements could be detrimental.”

EZ-fill secondary packaging stores vials safely in a tray or nest-and-tub configuration for efficient filling, while minimizing glass-to-glass contact and the chance of breakage, cosmetic defects, or particulate generation during fill/finish operations. The ready-to-use format allows drug makers to screen early-stage drug formulations and scale up to full production, without changing the container or filling process (6). “Being a ready-to-fill solution, SG EZ-fill can speed up the time to market,” explains Fabio Bertacchini, director of product management at Stevanato Group.

In addition, a low (near zero) coefficient of thermal expansion makes the Pur Q fused-quartz vials extremely resistant to thermal shock and therefore compatible with any storage temperature. “As an example, in other industrial applications, fused-quartz tubing is regularly exposed to temperatures of -196 °C,” says Koch, noting that storage temperatures for drug products in fused-quartz vials are more likely to be limited by stopper and closure system limitations.

Many of the vaccine candidates rely on a vial format, which requires stoppers and seals. To prevent shortages of these components and bottlenecks in vaccine distribution, West Pharmaceutical Services, a supplier of stoppers and flip-off seals with 25 plants worldwide, is taking steps to ensure adequate supplies.

“We are working with our suppliers so we will have the raw materials needed to meet these huge demands, and we are investing in capacity and flexibility to quickly meet market needs,” reports Whitney Winters, senior director, strategic marketing, Biologics at West Pharmaceutical Services. “In some cases, we are talking with suppliers and customers daily,” she reports.

In addition, she says, “We are spending a lot of time in scenario planning for next year to ensure we’ll be able to meet the needs of COVID-19 vaccines, treatments, and diagnostics while still supporting makers of non-COVID-19 vaccines, treatments, and diagnostics.” As a result, West Pharmaceutical Services is scaling up both equipment and labor. Winters notes, “In-shoring is one of our top priorities. We’re adding production lines and team members to cover additional shifts and capacity ramp-up. Some plants already run 24/7, others are adding shifts. We have two priorities—to ensure the health and safety of team members and to supply the market for COVID-19 and non-COVID-19 products without interruption.”

One West product, the FluroTec stopper, is designed for sensitive biologics. A fluoropolymer barrier film, applied to the elastomer, provides a protective layer that separates the product from the stopper. The stoppers can be autoclaved by West and provided as a sterile component or sterilized at the fill/finish location. Seals also can be delivered as a sterile component after gamma sterilization by a third-party provider. 

Sterilization of primary packaging, an essential step in delivering a safe, beneficial vaccine, ranks as a critical factor in the timely distribution of a COVID-19 vaccine. Options include gamma radiation, e-beam, ethylene oxide (EtO), and x-rays, among other technologies. Greater adoption of the e-beam sterilization process could help prevent bottlenecks associated with sterilization constraints.

www.pharmtech.com/view/e-beam-process-could-offset-sterilization-constraints

The proven FluroTec technology and the company’s well-established NovaPure brand of stoppers provide vaccine makers with a high level of confidence the packaging will pass container/closure integrity and stability tests, says Winters. “Right now, vaccine makers need tried-and-true packaging,” she says. To help save time, West’s Analytical Services Lab can assist with container/closure integrity testing.

Although many of the vaccine candidates are parenteral dosage forms, oral vaccines are under development by Vaxart and Merck (7, 8). If successful, these vaccines would likely rely on conventional high-density polyethylene or multilayer barrier bottles or blister packaging commonly used for solid dosage forms. “SARS-CoV-2, the coronavirus that causes COVID-19, is primarily transmitted by viral particles that enter through the mucosa—nose, mouth, or eyes—strongly suggesting that mucosal immunity could serve as the first line of defense. In addition, our vaccine is a room temperature-stable tablet, an enormous logistical advantage in large vaccination campaigns,” stated Andrei Floroiu, CEO of Vaxart (7). A self-administered solid-dose vaccine eliminates the need for sterile fill/finish operations and temperature-controlled handling and also offers sustainability benefits because it would eliminate the need to dispose of administration supplies, such as vials, syringes, needles, gloves, masks, and cotton balls (9). 

SCHOTT, “Answering the Hard Questions about Packaging Supply,” 

SCHOTT, Stevanato Group, Gerresheimer, “Leading Pharma Packaging Companies Commit to Supply for COVID-19 Fight,” Press Release, June 16, 2020.

SCHOTT, “Three Out of Every Four COVID-19 Vaccine Projects across the Globe Rely on SCHOTT Vials, Press Release, Sept. 8, 2020.

DWK Life Sciences, “DWK Life Sciences Increases Glass Vial Production Capacity to Meet Increased Market Demand,” Press Release, Sept. 1, 2020.

Stevanato Group, Momentive Technologies, “Momentive Technologies and Stevanato Group Collaborate to Offer Pur Q Fused Quartz Vials in EZ-fill Configuration,” Press Release, October 13, 2020.

Vaxart, “Vaxart’s COVID-19 Vaccine Selected for the U.S. Government’s Operation Warp Speed,” Press Release, June 26, 2020.

PharmTech, “Merck Announces Acquisition, Collaborations for Developing COVID-19 Vaccines and Therapies, 

Vaxart, “The Pill against Pandemics, a Disruptive Oral Vaccine Platform,” Corporate Presentation, July 2020.

Hallie Forcinio is packaging editor for 

Vol. 44, No. 12
December 2020
Pages: 47–50

When referring to this article, please cite it as H. Forcinio, “Is the Packaging Supply Chain Ready?” 

Articles

Packaging suppliers prepare to meet the demand unleashed by COVID-19 vaccines and treatments. 

Is the Packaging Supply Chain Ready?

As efforts to develop COVID-19 vaccines continue, the advent of non-traditional dosage forms and packaging formats expands options for vaccine packaging. Two plastic-based formats, a blow-fill-seal (BFS) syringe and glass-coated plastic vials/syringes, offer the potential for fast scale-up and good economics.

Still, the challenge is formidable. If more than one dose is needed to confer immunity, approximately 650 million doses of COVID-19 vaccine will be needed for the US population alone, reports Jay Walker, chairman and CEO of ApiJect, a supplier of the patented BFS syringe.

ApiJect was awarded a contract from the US Department of Health and Human Services (HHS) and the Department of Defense (DoD), under the Defense Production Act, that is valued up to $138 million in May 2020 to accelerate the building of a US-based, high-speed, population-scale emergency drug injection capability with prefilled syringes from its subsidiary RAPID (Rapid Aseptic Packaging of Injectable Drugs) USA. The public/private effort, dubbed Project Jumpstart, is expected to supply 100 million prefilled syringes by the end of 2020 (1).

BFS technology is widely used for containers for ophthalmic products; the BFS syringe adds a needle hub. The prefilled syringe, made of pharmaceutical-grade low-density polyethylene, is under stability testing for several products. “We are racing forward at full speed and retrofitting current ophthalmic lines to [biosafety level] BSL-2 requirements,” says Walker. The next step is to build three, 350,000-ft2 greenfield facilities for vaccines to BSL-2 and current good manufacturing practices (CGMP), and add cold-chain requirements capable of producing 4 billion syringes/year. Together, the plants will house 30 BFS machines from Rommelag, each fitted with a needle-hub application module and integrated with an inline wrapper that applies foil-based outer wrap to provide barrier properties and protect product shelf life. Walker says, “We effectively need 20 machines to hit US population-scale capacity each month; the 30 lines provide redundancy,” he explains. He adds the lines should be operational by the third quarter of 2021 and “will work with the widest possible range of products . . . and be able to extremely quickly fill and finish almost any vaccine.” Because the lines have been designed to be flexible, it will be easy to switch from filling a BSL-2 product to a CGMP product.

“There’s a need for an ultra-low-cost, prefilled syringe,” says Walker, noting glass syringes are a 165-year-old technology. He adds, “Our goal is to provide vaccines in prefilled syringes and replace multi-dose vials. Ultimately, the RAPID facilities in the US will have enough capacity to serve needs beyond the US. But we also anticipate building plants outside the US once domestic facilities are completed.” 

Another promising non-traditional primary package with impressive scale-up potential is a patented glass-coated plastic container from SiO2 Materials Science, which has received a $143 million contract from the US government to scale up capacity to support the development of COVID-19 vaccines and therapeutics (2). Lawrence Ganti, chief business officer at SiO2 Materials Science, reports, “We have 16 pharma companies using our packaging platform. This includes three companies that have a COVID-19 vaccine candidate in development.” Moderna is testing mRNA-1273

 its COVID-19 vaccine candidate, in the glass-coated containers

The vaccine is given in two doses, a month apart, and Phase III trials began at the end of July 2020 (3).

In the production process for the containers, after medical-grade cyclic olefin copolymer or cyclic olefin polymer is injection stretch blowmolded, a thin (nanometers thick), glass-like barrier is applied via plasma-enhanced chemical vapor deposition (PECVD). “The SiO2 vials solve significant challenges in the commercialization of vaccines and biological drugs that presently cannot be solved by glass or plastic vials,” said Dr. Glenn Fredrickson, a materials scientist who helped develop the product (2). 

In the cleanroom manufacturing process, “We apply the PECVD right after the vials come out of the molding machine and … pass through our first automated inspection system,” explains Ganti. Since the coating is covalently bonded, it cannot delaminate. “The PECVD process creates a new hybrid material,” he explains. Testing internally and by outside labs has confirmed there is no separation.

The container technology was cleared by FDA in a 510k filing in 2016 and has been confirmed as equivalent to glass. The containers have passed 

 tests for glass equivalency tests for hydrolytic stability, surface durability, and container durability. “In addition, we are collecting troves of data,” says Ganti. “We capture more than 50 individual data points on each vial or syringe. We have also shared exhaustive stability data from many of our customers with FDA and have an outlined pathway for rapid regulatory filing.”

Efforts are already underway to triple production. “We have [capacity for] more than 40 million vials (any combination of sizes) and will have [capacity for] 120 million by the end of November [2020],” he reports. Turnaround time for new production lines is relatively short. He notes, “We need two months of lead time to get a new system built, validated, and online. Each system can make 40 million units.”

To maximize output, Moderna has augmented its fill/finish capabilities via partnerships with Lonza and Catalent for domestic production and ROVI for international needs. These partnerships could make it possible to deliver approximately 500 million doses in 2020 and up to 1 billion/year beginning in 2021 (3).

1. ApiJect, “ApiJect Awarded HHS-DOD Title 3, Defense Production Act (DPA) Contract,” Press Release, May 12, 2020.

2. SiO2 Materials Science, “SiO2 Materials Science Receives $143 Million Contract from US Government to Accelerate Capacity Scale-Up of Advanced Primary Packaging Platform for COVID-19 Vaccines and Therapeutics,” Press Release, June 8, 2020.

3. Moderna, “Moderna Announces Publication in The New England Journal of Medicine of Interim Results From Phase 1 Study of Its mRNA Vaccine Against COVID-19 (mRNA-1273),” Press Release, July 14, 2020.

Plastic primary packaging could help prevent supply chain shortages associated with high demand for COVID-19 vaccines.

Expanding Options for Vaccine Packaging 

Parenteral product quality is improving. Since 2014, when 

<790> “Visible Particulates in Injections” (1) became official, particle-related recalls of injectable products have dropped significantly (see 

	However, “I want to be cautious and not give all of the credit to 

 <790>,” says John G. Shabushnig, PhD, owner and principal consultant at Insight Pharma Consulting and leader of the Parenteral Drug Association’s (PDA’s) Visual Inspection Interest Group. “There was a lot going on during this period including significant recalls from compounding pharmacies; however, I do think having clear guidance on inspection and acceptance criteria was a contributor to this drop.”

<1790> “Visual Inspection of Injections” (2) is another positive influence. Shabushnig says, “

 <1790> provides a more complete picture of good practices when implementing and operating a visual inspection program. It also clearly discusses a lifecycle approach to inspection, with an emphasis on continuous process improvement and using inspection data to drive that process. Defect prevention should always be the primary goal.”

	In addition, there continues to be a shift toward lower acceptable quality limit (AQL) values for acceptance sampling after 100% inspection, according to a benchmarking survey (3) performed in 2014 by PDA. Shabushnig says, “This trend is especially true for critical defects, having moved from 0.10% to 0.065%. More firms are classifying particles as critical defects despite an implied classification as a major defect, which would have a mean AQL of 0.65%, in 

 <790>. The subsequent PDA benchmarking survey for difficult-to-inspect products also showed that many firms have not adopted the supplemental (destructive) testing specified for these products in 

<790>. Examples include reconstitution of lyophilized or powder products or dilution or filtration of opaque or strongly colored solutions.”

	Wider adoption of automated inspection ranks as another positive force on product quality. This effort begins with container production. “Aiming for zero defects in our pharmaceutical packaging production, we employ an automated inspection system (AIS),” reports Michael Feldhaus, director of Technology at Schott Pharmaceutical Systems. “This 100% visual inspection technology examines all key surfaces of our vials and cartridges and merges cutting-edge machine vision technology with our decades-long glass-forming expertise.”

	Feldhaus explains, “Camera inspection allows for inline process control. The sensitivity and reliability of the system enable us to perform 100% cosmetic inspection for vials and pen cartridges, resulting in high-quality pharmaceutical containers. In addition, the data help us optimize process control.”

	With quality control demands escalating continuously, both the software and hardware used for cosmetic inspection have improved significantly. “For example,” Feldhaus says, “we have further developed our AIS software, which creates a 3D image of the container based on visual material from multiple cameras with different light settings. This process allows the container surface to be analyzed in a more comprehensive way. Moreover, machine learning technology helps detect patterns and improve the process further. On the hardware side, higher processing power and improved illumination enable systems to provide more data and sharper images. In addition to using improved machinery, our employees regularly take part in training to strengthen their overall quality awareness and ensure our products meet high quality demands.”

	Makers of parenteral packaging components such as closures and stoppers also rely on automated inspection. Datwyler Pharma Packaging Division uses advanced 100% camera inspection technologies and improved lighting sources to ensure product quality throughout its manufacturing process. Increased processing power permits use of more powerful detection algorithms, which improve detection capabilities and minimize false rejects. As a result, “some of the most critical production defects have been brought to the lowest level ever recorded,” reports Dirk Vander Mierde, Datwyler’s site director in Alken, Belgium. Potential defects caught by the system include the presence of foreign matter, deformation, or damaged coating. In addition, any rejects undergo additional inspection to help identify ways to improve the process.

	On parenteral packaging lines, automated inspection tends to be limited to high-volume operations due to capital and validation costs. As a result, manual inspection continues to dominate with approximately 50% of firms relying on it, according to the 2014 PDA benchmarking survey (3). Shabushnig reports, “Approximately 30% use automated inspection with the remaining 20% using semi-automated systems.” He notes, “This is actually a drop in the response rate for automated inspection since the 2008 survey (3). This does not, however, mean that fewer companies are using automated inspection; rather, there are differences in which companies respond to the survey each year. More importantly, the survey is structured so that each company/site has a single ‘vote.’ That vote counts the same if the company/site is making 10,000 or 100,000,000 units each year. If the results were normalized for units produced, I believe we would see more units inspected by automated systems. We should also note that manual inspection continues to be the reference visual inspection method in all of the pharmacopeias and that smaller-volume operations will continue to use manual inspection for the foreseeable future. Automated inspection does not ensure greater detection ability, and a well-run manual inspection process is very capable of delivering a high degree of security.”

	Meanwhile, automated inspection continues to evolve and protect product quality with enhanced lighting, flexibility, container handling, and speed.

	“LED lighting has provided a great improvement to our automatic inspection machine (AIM) in several ways,” reports Jose Zanardi, head of Vision Technology Engineering at Bosch Packaging Technology. LED lighting reduces downtime due to less frequent bulb changes and post-change verification. It also provides a consistent light level, eliminating the need for the inspection machine to compensate for light degradation. Compared to the halogen lighting it replaces, LED illumination generates less heat, eliminating concerns about product exposure to potentially damaging temperatures and the need for time-out programming for lamps.

	“LED lights offer both precision and flexibility,” says Christopher Nerreau, area sales manager at Laetus US, which introduced LED lighting for machine vision in 1994. Combining low cost and easy implementation, options address virtually any application with bicolored, ultraviolet, or standard LED illumination.

	Higher resolution cameras and customizable software also enhance flexibility. For example, Bosch’s Halcon vision system in its flagship AIM 8 series provides a standard vision tool that can be customized to maximize identification of visual defects. Zanardi notes customized inspection algorithms are essential to protect the quality of parenteral products. He explains, “Most of the medicines produced today pose challenges for inspection due to product clarity, viscosity, and fill volume, as well as container challenges such as dual chamber design, increased use of plastic, and influence of siliconized components, which attract both product and foreign particles.”

	Other new features on equipment from Bosch include a patented, dynamic puck material handling system. It eliminates glass-to-glass or glass-to-hard-surface contact and minimizes size changeover time via a semiautomatic puck exchange system. Finally, Bosch has developed a fourth-generation static division unit. The SD4 module inspects particles in motion and offers the highest reliability for solutions and light suspensions with easy-to-develop recipes and validation.

	Despite advancements in software, off-line image storage and analysis, and inspection speed, automated inspection systems using machine vision still pose challenges related to tuning and validation complexity. “Machines also have difficulty in managing the ‘normal’ variation found in many container closure systems,” says Shabushnig. “This difficulty is especially true for molded vials, which results in a high false reject rate (i.e., acceptable units that the machine rejects to assure that true rejects are detected with sufficient sensitivity and certainty).”

	In addition, challenges remain with line integration and interpreting inspection results. Shabushnig explains, “In most cases, a scratch and a crack look the same to a machine yet have differing risks to patients (critical vs. minor). This limitation makes analyzing reported inspection results difficult and often requires a reinspection of rejected units to assess the type of defects found in the batch.”

	For optimum line performance, automated inspection must integrate with equipment before and after filling. Nerreau notes, “There is a wide variety of parenteral products requiring vision solutions. Some examples include: using color identification to recognize color-coded needles, pattern matching to identify missing products in the package, optical character recognition to identify expiration dates on vials, and serialization for security.” Each application poses challenges for machine integration. 

	Prior to filling, inspection equipment typically connects to exterior washing or capping machines. After filling, the typical connection is to container closure integrity testing equipment using high voltage or laser headspace or vacuum technology, or to a re-nester/re-trayer for syringe applications. “Ensuring proper container transfer with sensors to manage product flow is essential to the integration process,” says Zanardi. In projects where glass-to-glass contact must be eliminated, precise design engineering is necessary to assure that container handling and machine starts and stops do not damage the product or the machine.

	“To perform complex image processing tasks in quality control environments, it is essential that the camera and lighting systems are tailored to the specific application,” says Nerreau, adding, “It is imperative for any machine integration to include extensive discussions and intensive consultations early on, along with a personal survey of the production environment.”

	With the industry focused on quality improvement, visual inspection continues to be a hot area, reports Shabushnig. A project at PDA is addressing visible particles in injectable products, with a current focus on improvements to the primary packaging materials. It seeks to better understand the risks as well as methods to detect and control particles in these components. This project is supported by both pharmaceutical manufacturers through the Pharmaceutical Manufacturers Forum and a number of primary packaging component manufacturers.

	PDA’s Visual Inspection Interest Group was to meet in April 2018 in the United States and in Europe to discuss the draft revision of Annex 1 (4). “Changes included significant expansion of sections associated with visual inspection and container integrity,” says Shabushnig. In addition, PDA continues to provide hands-on training in the area of visual inspection in the US, Europe, and Brazil. 

	Meanwhile USP continues to review comments and Â­suggestions for 

 <790> and <1790>. “Current topics of interest include the selection and use of sampling plans for 

 <790> and using risk-based methods to set alternative acceptance criteria for particles,” reports Shabushnig. “The Expert Panel responsible for these chapters is always interested in feedback to improve the understanding and use of these chapters,” he concludes.

	1. USP, USP General Chapter <790>, “Visible Particulates in Injections” (US Pharmacopeial Convention, Rockville, MD, 2014).
	2. USP, USP General Chapter <1790>, “Visual Inspection of Injections” (US Pharmacopeial Convention, Rockville, MD, 2017).
	3.  J. Shabushnig, “PDA Survey: 2014 Visual Inspection”  (Parenteral Drug Association, 2015).
	4.  EC, Consultation Document for Revision to EudraLex Volume 4: Good Manufacturing Practice Guidelines, “

Annex 1, Manufacture of Sterile Medicinal Products


	Vol. 42, No. 5
	May 2018
	Pages: 52–54

	When referring to this article, please cite it as H. Forcinio, "Improving Visual Inspection," 

Updated guidelines and new technologies aid visual inspection of parenteral products and packaging.