	Glass has long served as the traditional primary package for parenteral products. Unfortunately, glass breaks relatively easily and has been known to cause particulate contamination, to delaminate, and to interact with the drug product. 

	“Current issues with borosilicate glass containers such as breakage, cracks, and particles can lead to patient harm due to contamination, decreased drug efficacy, and drug shortages, as a result of recalls and manufacturing inefficiencies,” says John Tobin, vice-president of Commercial Operations at Corning. 

	He notes, “Current glass packaging has not innovated at the same or even a comparable pace to the scientific breakthroughs in biologic medicines and vaccines throughout the industry. Corning first became aware of glass quality issues with current pharmaceutical packaging for injectable drugs when a major pharmaceutical company and long-time customer asked us to develop a substantially more robust glass solution that also eliminates delamination and reduces particles. At the time, the United States Food and Drug Administration (FDA) had recently issued an advisory regarding the formation of glass lamellae in certain injectable drug containers. It became very clear to Corning that the industry needed a 21st-century glass package that provides the enhanced quality required to protect 21st-century drugs and, more importantly, provide more reliable access to vital medicines for patients around the world.” 

	To target the problems encountered with Type I borosilicate glass, Corning’s glass experts worked in collaboration with Merck and Pfizer to develop Valor Glass, an aluminosilicate glass, which is now commercially available. As a drop-in replacement for borosilicate glass, the new glass type is compatible with existing stoppers, caps, labels, and fill/finish lines.

	Corning used glass chemistry and an ion-exchange process, and lowered the coefficient of friction of the surface to produce a glass that is inherently strong and damage resistant (see 

). Traditional borosilicate Type I glass contains a significant amount of boron. However, Tobin says, “When introduced to heat, such as during the converting process, the boron in the glass network becomes volatile and evaporates out of the glass, creating surface heterogeneities (regions of non-uniform glass composition) on the interior drug-contacting surface of the package. Corning intentionally removed boron from the Valor Glass composition because of its volatility, which can cause delamination. The other glass components are the same but the ratios are slightly altered to enable a high degree of chemical durability. As a result, Valor Glass has a pristine, chemically durable drug-contacting surface both before and after the converting process, effectively eliminating the root cause of delamination.” 

	An ion-exchange process also minimizes issues such as breakage, cracks, and particulate contamination. Despite the difference in chemistry, Valor Glass meets the current 

Type I hydrolytic criteria and has low extractable concentrations. Work is underway at 

 to broaden the definition for Type I glass to include Valor Glass. 

	A protective coating on Valor Glass lowers its coefficient of friction and eliminates cosmetic flaws. Eliminating high-friction vial-to-vial contact protects the surface of the containers, results in a more uniform container flow, and enhances machinability. As a result, vials and cartridges run smoothly on fill/finish machines. Incidents with downed vials, jams, and broken containers are virtually eliminated, and throughput increases. For drug manufacturers, fewer line interventions mean less downtime and a decreased risk of contamination and quality defects. Trials on commercial filling lines have confirmed performance and shown a 96% reduction in peak particle counts, according to Corning.  

	Valor Glass has drawn the attention of more than 40 pharmaceutical companies. Tobin reports, “We initially thought interest would be for pipeline products, but it’s being looked at for marketed drugs as well. Corning has filed a drug master file for Valor Glass with FDA and will continue to work closely with pharmaceutical manufacturers to provide supporting information to facilitate adoption.” 

	Merck has announced plans to convert several products to Valor Glass pending regulatory approvals. At a press conference on July 20, 2017, Kenneth C. Frazier, Merck’s chairman and CEO, said, “Biologics today are on the leading edge of scientific innovation, and Valor Glass represents a similar advancement in materials science: glass that is purpose-built for medicines and vaccines.” At the same press conference, Valor Glass was described as a potential game changer. “Our initial trial results with Valor Glass show promise, and we are working with Corning to assess the full potential of this glass solution on products at several of our manufacturing sites,” said Ian C. Read, chairman and CEO at Pfizer (1). 

	As the designer of the composition, technology, and manufacturing platform, Corning manufactures and sells Valor Glass and oversees all purchases of it. In addition, established partners, such as Gerresheimer and Stevanato Group, are providing converting and related expertise to speed delivery to the industry and patients. 

	With usage of prefilled syringes continuing to rise, Schott has doubled polymer syringe production at its syringe competence centre in St. Gallen, Switzerland. The new capacity started up in June 2017 and builds on a previous expansion. Additional capacity is being installed and will be operational in 2018 (2).  

	“Schott has optimized singular process steps based on our existing quality and production experience,” says Tom van Ginnecken, global product manager, Polymer Syringes at Schott. He notes, “Typical improvements involve the state-of-the-art technologies for transportation and handling to further reduce the risk of cosmetic defects. In addition, Schott is getting prepared for future pharma requirements in automation and data exchange.”

	He explains, “We see a growing trend toward customized delivery systems. The first reason for this trend is the focus of pharmaceutical companies on orphan diseases. With a highly individualized injection solution, the pharmaceutical companies try to increase patient comfort and increase drug adherence by offering a tailor-made solution that is compliant with the patient group’s impairments and abilities. Another driver for more customized delivery systems is the need for product differentiation. More pharmaceutical companies use the injection device as a way to differentiate their drug in the market. In a fiercely fought market space with a lot of competition, such as generic drugs; this method of differentiation could mean the success or the failure of a drug. Also, the injection molding process of a polymer syringe inherently offers a broad range of customization possibilities.” 

	Polymer syringes offer advantages beyond customization and differentiation. The material maintains glass-like transparency, resists breakage, and offers excellent barrier properties to keep the medication stable throughout its shelf life. Schott polymer syringes are available in 1–50-mL sizes and delivered ready-to-fill in a nest-and-tub configuration. For more sensitive applications, Schott TopPac SD syringes feature a reduced extractable and leachable profile that ensures high drug stability (2). 

	Glass ampoules remain widely used to package injectable drugs, and demand is actually growing in emerging markets. Although typically used for high-volume, mainly small-molecule drugs, ampoules “could be interesting for biopharma products as well,” notes Neus Ferré, global product manager, Ampoules at Schott. 

	Schott’s glass ampoules combine dimensional stability with 100% inspection to suit either end of the spectrum: long runs at high speeds or flexible fill/finish systems for small batches. “At Schott, we are following a zero defect philosophy, resulting in ampoules of high and stable dimensional quality,” reports Ferré. She explains, “On the one hand, this is achieved by an excellent raw material-Fiolax Type I borosilicate glass-combined with a precise manufacturing process. On the other hand, we have invested in intelligent camera inspection systems that help to improve both cosmetic and dimensional quality even further.” 

	The DualFusion vial from Wheaton, now DWK Life Sciences, combines the best properties of both plastic and glass into one container. Using plasma-enhanced chemical vapour deposition, an organosilicate protective layer is fused with a silicon dioxide barrier layer that is fused to a cyclic olefin polymer (COP) shell to form a robust, covalently bonded material. The outer COP shell provides mechanical strength, protects against breakage, and can withstand temperatures from -196 °C to 121 °C without cracking. The inner barrier layer prevents permeation of oxygen, water vapour, and other gases, protects against delamination, and eliminates concerns over leaching of metal ions, which can compromise the integrity of vial contents (3). 

	Each ready-to-use, ready-to-sterilize DualFusion vial has a unique barcode for traceability and authentication. Applications include highly toxic drugs and biologics (4). More recently, there’s been interest for freeze-drying applications. The vial has a completely flat bottom that allows efficient temperature transfer from the lyophilizer to the drug product, and the vial’s barrier layer allows extended storage time, says Jeffrey Reid, strategic markets manager, DWK Life Sciences. 

	The increase in personalized medicine is driving growth in small batch fills. “Therefore,” says Reid, “pharmaceutical companies require smaller packouts of ready-to-use (RTU) packaging components.” To address this need, DWK Life Sciences will begin supplying RTU packaging components such as vials, rubber stoppers, and seals grouped together in one box with an average packout of 200 pieces per component. “This will allow our customers to shift to smaller fill runs and not have to worry about a large scrap rate of packaging components,” concludes Reid. 

	1. Corning, “Merck and Pfizer Collaborate with Corning to Modernize Pharmaceutical Glass Packaging,” News Release, July 20, 2017.
	2. Schott, “In Light of Growing Demand, Schott Again Increases Its Polymer Syringe Production,” News Release, July 26, 2017. 
	3. Wheaton, “The New DualFusion Vial Is First Vial that Combines the Benefits of a Strong, Protective Plastic Outer Layer and the High-Performance Barrier Properties of an Inner Silica Layer, News Release, July 31, 2016. 
	4. H. Forcinio, 

	When referring to this article, please cite it as H. Forcinio, "Improved Materials Enhance Parenteral Packaging," 

Articles

Feature

Manufacturers introduce innovations in glass and plastic packaging for injectables.

Improved Materials Enhance Parenteral Packaging

	Pure water is essential for pharmaceutical manufacturing. The 

) and other global pharmacopeias require pharma manufacturers to begin with drinking water and purify it further to standards depending on the use, such as purified water or water for injection (WFI).

	Modern purified water systems are well designed and generally do not have any problems meeting pharmacopeial requirements, says Nissan Cohen, principal scientist for High Purity Water Systems at Commissioning Agents, Inc., a US consultancy. Systems typically include pretreatment followed by purification, which can include reverse osmosis, deionization, distillation, ozone, and ultraviolet sterilization. Cohen sees two major issues, however, that pharma manufacturers must deal with soon or be faced with increased operational costs: drinking water shortages and inefficient legacy laboratory-based testing.

	Drinking water-the source for purified water for pharma-is a limited resource. The World Health Organization (WHO) predicts that by 2025, half of the world’s population will “be living in water-stressed areas.” (1). Although numbers vary regarding the severity of this complex problem, the Water Resources Group predicts that, if nothing is done to improve efficiency, global water demand would be 40% more than accessible, reliable supply by 2030 (2).

	Industrial use represents a significant part of this demand, says Nik Krpan, president of Cheme Engineering, a Canadian consultancy focused on water systems for the bio/pharma industry. “The pharma industry needs to think about how to use water more efficiently, because the cost is going up,” says Krpan.

	Zero liquid discharge, a concept that is new to the pharma industry, is a potential solution to the water-shortage problem that involves recycling or reusing process water.  

	“There are many uses for water; the key is how to reuse what is being sent to the drain-maybe in the process itself, or in cooling towers or building sanitation systems,” says Cohen. “For example, you could take water draining from the clean-in-place system and retreat it or use it for tertiary systems in the building. As another example, water from flushing studies (in which water is run for 30 seconds before microbial sampling) could be reused.” 

	“Water reuse must be carefully implemented so that you don’t affect quality, but it can be done,” notes Krpan.

	At the International Society for Pharmaceutical Engineering (ISPE) annual meeting, on Oct. 30, 2017, Krpan, Cohen, and others will discuss these concepts and the technologies used in zero liquid discharge in more detail.

	Compendial tests required for water for pharma manufacturing are total organic carbon (TOC), conductivity, bioburden (i.e., microbial content), and, for WFI, endotoxin. It is common practice for manufacturers to use online process analytical technology (PAT) for testing TOC and conductivity for process control.

	“More companies are relying on the integrity of data from online PAT instruments to increase their process understanding,” says Luke Swanson, Life Science applications engineer for GE’s Analytical Instruments, now part of Suez, which acquired GE Water & Process Technologies on Oct. 2, 2017. “A best practice is to have at least one online instrument at the end of the high purity water loop. Some companies also have one at the front end of the loop and do occasional grab samples, tested in the laboratory, in the middle of the loop as checks.”

	There is a trend toward real-time release (RTR) of process water using PAT. “RTR requires the manufacturer to do instrument qualification, method validation, and process validation,” Swanson explains. “The principle behind RTR is driving cost efficiency while not compromising product integrity or traceability of release testing.”

	Laboratory TOC testing, however, is still widely used for release of process water, and one of the challenges is that laboratory and online tests can have different TOC results because “carbon is everywhere, and intermediate handling steps can contaminate the sample,” explains Swanson.

	Online rapid microbial testing is available, but at this point typically needs discrete sampling to verify results, says Cohen, who notes that endotoxin testing is also not yet automated.

	Treating manufacturing effluents, particularly from API manufacturing, is also a concern that is increasingly being recognized by manufacturers.  

	“In Europe, this [need for improved effluent treatment] very much depends on the Integrated Pollution Prevention and Control (IPPC) Directive, which is now part of the Industrial Emission Directive,” notes Bjarne Sandberg, Managing Director, Cambrex Karlskoga. The company is currently constructing a new wastewater treatment plant at its facility in Karlskoga, Sweden to support the expansion of cGMP capacity for small-molecule APIs, the company announced on Sept. 26, 2017. When completed, the wastewater facility will reduce the emission of nitrogen, total organic compounds, and suspended material, improving the site’s environmental footprint (3).

	“The original wastewater treatment plant at our facility in Karlskoga, Sweden was built in 2000, and this recent investment is to increase the capacity of the plant for both existing and future needs. The investment will also help improve our environmental footprint at the Karlskoga site,” explains Sandberg. Cambrex also recently completed an upgrade of wastewater handling capabilities at its Milan, Italy manufacturing facility, he reports.

	1. WHO, “Drinking-Water: Fact Sheet updated July 2017,” 

www.who.int/mediacentre/factsheets/fs391/en/

	2. 2030 Water Resources Group, “Charting Our Water Future” (2009).

	3. Cambrex, “Cambrex Opens API manufacturing Facility and Invests in Supporting Waste Water Treatment Plant at its Karlskoga, Sweden Site,” Press Release, Sept. 26, 2017.

Water shortages, testing expenses, and effluent treatment are important issues for pharma manufacturers.

Equipment and Processing Report-10-18-2017

Improved Materials Enhance Parenteral Packaging

Considering Water Use in Pharma Manufacturing