Packaging / Aseptic Processing / Drug Delivery

Clash of the Titans

Super-rivals glass and plastic square off for patient safety

By Steven Kuehn Editor in Chief

 

CoverOct1Specifying the best material to serve the primary packaging requirements for a given pharmaceutical used to be pretty easy, considering there was virtually only one champion to call on: Glass. Glass was Pharma’s packaging Superman, a hero with well known virtues; strength, purity and transparency. For millennia there were few materials out there that could rival glass’s dominance and reputation.

Glass as a material has been around for a long time, but it wasn’t until about the 1st century BC, that glass blowing was discovered in the Middle East. This advancement created the industry. Glass vessels could now be mass produced, and more economically than pottery vessels.

And the rest is history as they say. During the ensuing millennia, glass as a packaging material came to dominate the world’s food, beverage and pharmaceutical industries; there simply were few or no alternatives. That is, until scientists started uncovering the attributes of organic polymers found first in naturally occurring substances like gum and shellac, then later developing chemically modified materials like galvanized rubber and nitrocellulose. By 1900 the first synthetic plastic Bakelite was developed by Belgian chemist Leo Baekeland. Advances came quickly after that with the likes of BASF, ICI and Dow bringing commercial/industrial ready polymers to market beginning in the ’20s.

As we reach the midpoint of this century’s second decade, material scientists continue to hyper-refine plastics and glass to enhance positive attributes and mitigate less-than-desired attributes relative to Pharma application and commercial/industrial scale economies. The market for pharmaceutical packaging has become immense and is showing no signs of slowing down; leading market research firms predict demand in the U.S. will grow about 5 percent a year and reach ~ $22 billion by 2018, representing about a third of the global market which Freedonia Group pegs at $66 billion by 2017 and growing at 6.4 percent annually.

Indeed, glass and plastic have become Pharma packaging’s superheroes — both working tirelessly to safely deliver medicines to a world plagued by evil-doing disease. But as our heroes pursue this common cause, packaging’s dynamic duo have also become super rivals. However, as far as superhero-to-superhero conflicts are concerned, this one only goes so deep. Suppliers and users understand that any packaging decision is led by the formulation of the drug and ultimately patient safety.

GLASS, THE PROVEN DEFENDER

 In an extensive American Pharmaceutical Review blog titled “Pharmaceutical Glass Containers: Proven Solution for Primary Parenteral Packaging” Gerresheimer Glass Inc.’s technical and quality managers noted that in 2012, market share for primary packaging of injectables was approximately 98 percent, representing 23 billion primary containers for parenterals. According to Gerresheimer, for the storage of parenterals, borosilicate Type I glass is the material of choice. Borosilicate glass was developed to have superior chemical and temperature properties compared to soda-lime glass; it has a stable matrix that reduces thermal expansion and resists chemical attack. It is inert, chemically stable and nonporous.

SCHOTT Pharmaceutical Packaging, the industry’s leading glass supplier, says it delivers 9 billion containers per year and that includes ampoules, vials, cartridges and both glass and polymer syringes. “We are working in the pharma industry, so we abide with all regulations,” says Anil Busimi, head of global product management syringe business at SCHOTT, “which our customers — like the Pharma companies — have to ensure that their products are produced as per specifications and GMP. We fulfill all the regulatory requirements.” At the same time, says Busimi, SCHOTT ensures Pharma quality standards are met by its suppliers. “SCHOTT is a major producer of glass tubing, [a pre-fabrication form] which is used for [Pharma’s] primary packaging containers.

The use of glass pharmaceutical containers remains pervasive, especially for the thousands of well-known, broadly administered and increasingly generic injectable drugs. Materials and production systems are well understood, and in the context of large commercial drug manufacturing operations, there are hundreds of GMP compliant and validated fill-and-finish lines operating out there and a host of reliable glass container suppliers with established supply chains. Data on compatibility and drug/material interactions are both plentiful and accessible to all drug developers and Drug Master Files are kept by regulators. SCHOTT notes that having the technological expertise to support current products when problems come up helps sustain the company and glass’s dominance in the category. SCHOTT’s scientific advisor Dan Haines explains that, “because most of our products are components within other systems, there can be interface problems. Sometimes there are drug interaction problems. So having the technical expertise to help … is very important.” SCHOTT provides this support through its pharma services group as does Gerresheimer and other glass container manufacturers. “In the pharmaceutical industry, it’s a [relatively] slow evolution from one drug platform to the next, says Haines, “so there’s quite long lead time, which is good. But on the other hand, you pretty much have to have rock-solid solutions when going from the current generation to the next generation.”

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DELAMINATION, GLASS' KRYPTONITE
For the most part, and over the last century or so, glass remained impervious to most issues having to do with compatibility. Most formulators took it almost for granted. Most compounds were just fine being contained by glass, but as newer drugs, including biologics with aggressive chemistries introduced, manufacturers were confronted with quality issues stemming from chemical reactions between the glass surface and the drug chemistry known as delamination. According to SCHOTT, between 2006 and 2011 some 100 million pharmaceutical vials were recalled due to glass delamination issues. Delamination became Glass’s kryptonite, exposing its (seemingly) one true vulnerability. At its likely nadir, 2010, glass flakes were discovered in nine different drug products resulting in immediate recalls; 30 million vials in one case. Although the phenomenon was recognized as far back as the ’50s, the dramatic uptick in recalls forced the industry to react. Unfortunately, recalls continue, with several announced just this year.

The problem with glass delamination, say SCHOTT, Gerresheimer and others is that it may take years to manifest itself. The chemistry behind glass attack by water-based liquids is mainly driven by ion exchange and dissolution.

Gerresheimer says glass delamination is a well-known phenomenon, recognizing that even “upscale” Type I containers are prone to delamination under certain circumstances. Regardless, glass pharmaceutical container manufacturers, as well as industry associations (PDA for example), and regulators all have been galvanized to act and address this serious problem. Over the last several years a number of extensive, thorough studies have been conducted to understand the root causes of delamination and to find ways to eliminate the problem. In its 2011 “Advisory to Drug Manufacturers: Formation of Glass Lamellae in Certain Injectable Drugs,” the FDA published that the following conditions were associated with delamination:

• Glass vials manufactured by the tubing process (and thus manufactured under higher heat).
• Drug solutions formulated at high pH (alkaline) and with certain buffers (citrate and tartrate).
• Length of time the drug remains exposed to the inner surface of the container.
• Drug products with room temperature storage requirements.
• Terminal sterilization has a significant effect on glass stability.

The tendency of delamination to occur with a pharmaceutical vial made of tubular glass strongly depends, says SCHOTT, on how the process is controlled during forming. Volatile components like boron and sodium evaporate while the bottom of the glass is being formed. As the production process continues, these substances produce inhomogeneous spots on the glass surface near the bottom that are generally more susceptible to delamination. Active control of this process is possible if the quality of the glass surface and its tendency to experience delamination are monitored during production. According to SCHOTT, this marked the starting point for a new way to test the risk of delamination.

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FIND IT OUT FASTER
SCHOTT’s analysts developed a test that allows pharma glass packaging manufacturers to determine delamination risk within a few hours by applying threshold values. To start the test, the glass surface is gradually attacked locally. Vials removed from the line are stressed inside an autoclave at a temperature of 121 C. In the past, vials were subjected to visual inspections with a stereomicroscope after autoclaving in steam. This method, says SCHOTT, has been replaced by more efficient and effective atomic absorption spectroscopy, a far easier method that can be performed during routine production operations. SCHOTT has received a patent for its in-process Delamination Quicktest, which monitors a threshold value of sodium during manufacturing. To conduct the test, the subject vials are filled with water so the zone where delamination normally occurs is covered slightly. Sodium is extracted inside the autoclave and the amount is determined through atomic absorption spectroscopy. This level correlates with the probability that the vial being inspected will experience delamination eventually.

The bottom line is that SCHOTT and its glass container-making peers, in association with drug makers have worked extra hard to eliminate this issue. Whether through enhanced and refined manufacturing techniques, coatings or better controlled preparation, fill-and-finish operations, delamination of glass containers is becoming less of a threat to operations and supply.

BETTER EARLIER THAN LATER
Tony Pidgeon, applied technology director for finished dose at Patheon explains that from a contract manufacturers’ standpoint, their role is to guide primary packaging choices so that regardless of material choices, all aspects of packaging risk are managed to foster all desired outcomes. “The first thing we do is determine what our client’s product profile is, in other words ‘what are they trying to do’ with their product,” says Pidgeon, explaining that for many customers, the main motivation is to get the product into its trial in a predetermined time frame, so speed is essential. Often, he says, that means trying to piggyback on existing technologies.

For the drug owner, the decision is based on the fact that glass vials are readily available and for the most part a no-brainer. “People know how to use them,” says Pidgeon. “There’s an awful lot of data out there about them; people tend to [choose] a Type I glass — they take that as being considerable quality and assume that from a compatibility point of view that that will be fine. Extractable and leachables — to be honest, even delamination isn’t really considered at the earliest stage. I must say personally I do, but it depends on the formulations they are coming to us with.”

In talking about delamination, says Pidgeon “the general rule of thumb that I tend to follow is that as long as you don’t have extremes of pH, then you’re normally going to be okay.” Regardless of drug formulation, at the beginning stages of the packaging discussion Pidgeon recommends doing comprehensive risk assessment from the very beginning. “That risk assessment will then dictate — or certainly guide — the direction in which you need to go. In other words, do you need to do the standard or get involved with the suppliers of the components themselves?” Pidgeon cautions that just because it’s been done before, the chemistry is similar, etc., doesn’t mean one’s risk associated with packaging is mitigated. “You need to put that risk assessment in place. I suggest you need to do at least some work there, which is obviously unique to your own product,” says Pidgeon. “But if it’s a generic, for example, and there’s something very similar out there, your risk assessment may well suggest that your other data is sufficient. Personally, I would probably be a little bit cautious of this part. I would probably want to have at least some complementary data there, but I would let the risk assessment guide me.”

Pidgeon explains that early packaging risk assessment may prompt deeper inquiry — and involvement of packaging suppliers so customer’s needs can be better met — in the name of patient safety. “We would speak to West, for example,” says Pidgeon, “tell them that our plant is using this product with this kind of formulation and then we would work together to get the client the best service possible.”

No surprise that West agrees. “Our core business relates to helping pharmaceutical and biotech companies select the appropriate packaging materials for injectable drugs,” says West’s vice president of marketing and innovation, Graham Reynolds. “We are currently participating in some way with all the top 35 biologics. We work closely with customers at all levels.”

West is also very concerned with all issues that affect drug safety and efficacy. “This area of extractables and leachables has probably become more critical in the last two years as regulatory agencies look for more information on that subject,” says Reynolds. West says they work with customers to make sure they have the appropriate container solutions period.

To get there, says Reynolds, “the first phase [includes] some element of prescreening work … to select the appropriate materials. That can be done either by us in our laboratories — we have a pretty extensive laboratory in-house where we can do that testing on behalf of customers,” notes Reynolds, adding that many of West’s customers have that capability internally. “It really depends on the sophistication and the capabilities of the drug company that we are working with.” Reynolds explains that this prescreening exercise narrows down the choices, which may include a glass solution and a plastic solution using West’s Daikyo Crystal Zenith cyclic olefin polymer: “Often companies will test a CZ solution and a glass solution.”

Other fundamentals, like how the product will be filled and handled, need to be considered, says Reynolds. “Is it in a vial or prefilled syringe? For instance, if a prefilled syringe is going to go into a mechanical autoinjector, you want to make sure to take into account the viscosity of the drug. What forces are going to be necessary? What speed of injection is needed? At that stage, you need to really be considering not only the extractable, leachables and compatibility, but what is the optimal containment system to give the best result for the final drug delivery? That opens up a whole new world of — do I want glass? Do I want CZ? Do I want break resistance? Am I concerned about particles?”

Who gets involved in these discussions? “At that stage, there might be multiple people involved, depending on the complexity of the customer and their approach,” says Reynolds. “Typically formulation scientists would be involved to select the materials. You may have packaging development people there saying ‘I want it in a vial or syringe or a cartridge,’ and what the dose volume would be, for instance. What we’re finding now is that even at that early stage, the device people are involved.” Kevin Cancelliere, West’s marketing director adds, “there are a number of key stakeholders involved in our discussions. We are also seeing considerable interest from marketing. A lot of brand managers are very much interested in the type of primary containers to see if it can get them a competitive advantage in the marketplace.”

For West, both Reynolds and Cancelliere say they are seeing a stronger trend toward plastic, prefilled syringes. “It’s no doubt that the gold standard legacy is glass containers, but we are seeing a dramatic increase [in the specification of plastic] because of the emergence of the new biologics and the costs associated with them,” says Cancelliere. “Drug companies are very concerned with that expensive biologic and how it interacts with primary containers and components. We are seeing an uptick and we really think that these trends are going to continue to grow over time.” Part of the challenge, says Cancelliere, is overcoming people’s comfort level with glass. “Plastic containers are still relatively new. I think as people become more comfortable with them and see the benefits of plastic, we’re likely to see an increase in demand.”

Prefilled syringes represent one of the fastest-growing packaging and drug delivery segments in Pharma. According to a report published by Transparency Market Research “Prefilled Syringes Market (Glass and Plastic) — Global Industry Analysis, Size, Volume, Share, Growth, Trends and Forecast, 2013-2019,” the demand is being fueled by the advantages associated with prefilled syringes, including eased administration, reduced risk of cross contamination, less opportunity for overfill, simplified handling and ultimately better patient outcomes. In 2012, the global prefilled syringes market, says Transparency Market Research, was valued at $2.09 billion and is expected to grow at 13.3 percent from 2013 to 2019, reaching an estimated value of $4.98 billion in 2019.

“We’ve actually been manufacturing pre-filled syringes for many years,” says Patheon’s Pidgeon. “This year we are validating a brand-new state-of-the-art, pre-filled syringe line at our site in Monza, Italy. It’s a big investment for the company and that’s where plastics are going to be coming in.” Pidgeon explains that while he’s aware that glass is still the most popular amongst Patheon’s clients, plastics and co-polymers are moving up fast.

SCHOTT’s Busimi says his company is working hard to meet the needs of this market. “Definitely we see growth in the prefilled syringe markets,” says Busimi. “Having both products in our portfolio with glass and polymer allows us to understand our customer needs and requirements, and then help them try to find the right solution in our portfolio.”

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PLASTIC IS FANTASTIC
CoverOct2For parenteral, sterile injectables in vials and syringes, glass remains dominant, but advanced plastic materials like West’s CZ are making real headway; SCHOTT’s move to supply advanced polymer syringes is their hedge. One market research firm noted that market growth for plastic prefilled syringe technologies will be double that of glass from 2013 to 2019. But, as far as the pharmaceutical packaging’s universe goes, plastic has clearly become the material of choice across the vast majority of general pharmaceutical container forms. Think about it; most solid dose drugs in quantities of 50 or more come in plastic bottles with those annoying but necessary child-proof caps. Most sterile liquids, saline, water for infusion, etc., come in plastic bags or bottles, not to mention the bulk supplies of the same.

SUPER INNOVATION
Drug innovation is driving packaging innovation and this is most apparent in the area of dispensing/dosing accuracy, patient compliance and other drug delivery technologies. Whether it’s a prefilled multi-dose insulin injector or a dose-metering and counting COPD therapy inhaler, plastics are truly the only choice for designers and engineers fabricating these devices. What’s interesting to note is that for some of these devices the medicine is contained in a cartridge — a market niche that both plastic and glass are vying for, but a category where there’s a good chance a relative newcomer to the scene, plastic Blow/Fill/Seal (BFS), may soon come to dominate.

In 1963, Gerhard Hansen invented and built the first BFS machine; by May of 1964 he founded rommelag in Switzerland and began to sell his products internationally. The innovation was profound. In a single automatic process, BFS creates containers from thermoplastic granules which are blown into a mold, then inserts the liquid contents (fill) and then closes and seals the container.

Among its biggest advantages, BFS technology does not require the cleaning and sterilization processes that are essential in other kinds of container production and fill-and-finish operations. To provide maximum security in the aseptic packaging of sterile liquids, creams, ointments and vaccines, BFS machines can be equipped with additional modules for quality assurance and monitoring as well as aseptic systems for automatic cleaning and sterilization of lines that come into contact with products.

Customers throughout the world, say rommelag, quickly recognized the advantages of plastic containers, and other enterprising entrepreneurs recognized it as well, including Weiler Engineering who licensed the technology and brought it to the U.S. in the ’70s. Its origins may soon be legend because BFS has the potential to truly dominate; not only across most sterile liquids, but for most parenteral injectables as well. Tim Kram, general manager for rommelag USA noted that worldwide interest in the technology is growing, fueled by drug shortage fears that everyone knows are mitigated by high-performing quality management and risk regimes as well as process excellence — something that BFS sterile, class 100 containment brings to fill-and-finish lines.

Describing its rising popularity, Kram points out that in U.S. markets inhalation drugs account for more than 2 billion units, ophthalmic drugs account for 1 billion units and IV solution bottles (worldwide) account for 2.5 billion units. According to Chuck Reed, marketing director for Weiler Engineering, Weiler has machines in over 35 countries producing a wide range of pharmaceutical products which include “everything from generic medicines to vaccines to oral, respiratory therapy, ophthalmic, nasal, otic and nutraceutical applications,” says Reed. The market, he says, is growing in every sector due to (among other things) the increasing interest in the sustainability of the BFS process. Citing its low carbon footprint, recyclable base material, high utility efficiency, Reed notes all of these contribute to the success of BFS, not to mention a large movement away from glass, “which continues to be a driver,” he says.

For rommelag, Kram says, customers break out this way: 40 percent branded, 35 percent CMO and 25 percent Generic, a spread that may indicate that certain segments are more compelled to adopt the technology’s cost and quality efficiencies than others, especially those developing sterile, liquid medicines. Reed notes that “the BFS process provides a significant cost advantage over glass. A complete BFS container is typically less than 1/3 the cost of a similar glass format.” Due to the flexibility in container design, Reed explains, “BFS is becoming a preferred format for many combination products due to the changes in device designs. Additionally, BFS can simplify the manufacturing steps to make the end device more cost effective.”

Purveyors of our other super packaging hero, Glass, say their customers stay with glass because their processes are validated and for anything new, there are tons of data to draw from to support compliance and risk-management regimes. “The risks and costs associated with validating a new product [with glass],” says Kram, “are better known in the U.S. than with BFS technology.” It is understandable, he concedes, that people want to stay with the process that they know. “Thus we try to get onto the packaging option list for new products. We have an extensive knowledge about compatibility that we can offer to new customers, along with test containers made from a selection of plastic resins. Once past compatibility (not guaranteed), the process for validation is similar.” There is no difference in validating plastic resins in the same application, says Kram, “the difference stems from the different product regulatory requirements, that is, non-aseptic (preserved) products, aseptic products and terminally sterilized products.”

Pharmaceutical manufacturers are embracing the technology. For example, says Kram, Nephron Pharmaceuticals in Columbia, South Carolina, is expanding into injectable drugs with a BFS ampoule. An early adopter was AstraZeneca, which began integrating the BFS process into its nose-drop production environment, installing a rommelag machine in the 1980s. By the 1990s the company ramped up BFS operations in Westborough to support the commercialization of its Pulmicort asthma medication, delivered via an ampoule inserted in a nebulizing device.

Both rommelag and Weiler’s marketing and BFS technology development spawned companies that at first demonstrated the technology to potential clients, but over time evolved to provide BFS contract manufacturing services. Catalent (formerly ALP with a shared history with Weiler) offers its customers extensive aseptic, glass-free BFS filling-solution capabilities and capacity with experience providing development through commercial scale manufacturing support covering single- and multi-dose solutions across complex emulsions and suspensions. Since its inception, the company’s owners have continuously invested in the facility; currently the 500,000 sq. ft. plant encompasses a total of 38 BFS lines. Catalent says it’s made significant capital enhancements in recent years and is about to embark on its next wave of investment to further expand and improve operations over the next three years. In September, Ritedose, formerly rommelag’s sister business Holopack, announced a $110 million expansion to its Columbia, South Carolina, facility, planning to add another 80,000 sq. ft. to support enough capacity to meet growing demand, says the company.

Yes, glass and plastic are Pharma packaging’s superheroes, but while they are rivals, they continue to develop their respective technical and material attributes to cope with the ever-changing pharmaceutical manufacturing landscape in an effort to win the hearts and minds of drug makers and help fight the battle for patient safety.