Hallie Forcinio is packing editor for Pharmaceutical Technology and Pharmaceutical Technology Europe, editorhal@sbcglobal.net.

Hallie Forcinio

The intense pressure to develop vaccines and treatments for COVID-19 has helped spur strong growth in the pre-filled syringe market and innovations in syringes and syringe fill/finish operations. “Pre-filled syringes reduce the number of steps for injection, lower the risk of injury and cross-contamination, and offer higher dose accuracy,” explains Silvia Gallina, Syringes Platform Product Management at Stevanato Group.

“Pre-filled syringes are now a widely accepted part of the drug life-cycle and are often considered as early as Phase II in the drug development process,” reports Michelle Deutsch, head of Global Product Management at SCHOTT Pharmaceutical Systems. She adds, “The need for differentiation and the move to homecare continue to be critical drivers of this evolution. New drugs enabling technologies at different stages of development are also beginning to open up new possibilities for pre-filled syringes as it becomes possible to deliver higher fill volumes and higher viscosity drugs as subcutaneous injections.”

As the market for pre-filled syringes expands, attention is being devoted to glass improvements, reducing glass-to-glass and glass-to-metal contact, using cameras and other inspection tools to maximize syringe quality, designing products applicable to autoinjectors, and addressing the needs of sensitive biologics.

“Biologics tend to have high chemical sensitivity, low stability, and high viscosity,” says Gallina. For biologics, control of silicone and tungsten levels is key to minimizing or eliminating particulates, extractables, and leachables. Stevanato Group offers two product lines for biologics, the SG Alba and SG Nexa platforms, and is organizing production so it can provide these syringes anywhere in the world. Both product lines have been developed to reduce risks when a sensitive drug product contacts the containers. “SG Nexa platform features an optimized silicone layer, maximum cosmetic quality, tight dimensional tolerances, and compatibility with autoinjectors on the market,” reports Enrico Barichello,Alba Platform product manager at Stevanato Group. “SG Alba platform offers similar characteristics but has been designed for improved integrity of the lubricant layer, reducing subvisible particles and providing a better functionality when integrated in a device, particularly for drugs that may be very sensitive to silicone oil.”

SCHOTT’s syriQ BioPure prefillable syringes offer minimum levels of tungsten and low or no silicone. “While most approaches to managing this risk are based on immobilizing the silicone layer, syriQ BioPure silicone-free offers an alternative system that uses no silicone, relying instead on tight dimensional specifications and superior hydrolytic resistance,” says Deutsch. Available in 1- and 2.25-mL sizes, the syriQ BioPure syringes meet dimensional tolerances that exceed ISO requirements.

Another glass syringe innovation, a flat-shoulder syringe from Gerresheimer, minimizes or eliminates residual volume, an important characteristic for extremely costly drugs. As storage temperatures have dropped, the bar has risen for glass pre-filled syringes. Deutsch explains, “[Messenger RNA] mRNA—at least for now—has changed the game. Some vaccines had required transport at -4 °C, but today, many customers want to see proof of much deeper cold temperature performance. These requirements are shaping a new kind of pre-filled syringe demand. In some cases, pre-filled syringes made of cyclic olefin copolymer (COC) are a suitable alternative to glass pre-filled syringes.”

Break-resistant and lightweight, COC offers a glass-like appearance and performance and better product stability and shelf-life. One company that has begun to adopt COC syringes is Nephron Pharmaceuticals. The 503B outsourcing operation and producer of generic products has introduced a 50-mL COC syringe, which is filled on automated equipment and is compatible with highly viscous drugs. A disconnected plunger simplifies storage. The first Nephron product to use the COC syringe is 8.4% sodium bicarbonate injection (USP 4.2 mg/50 mL) (1). Sodium bicarbonate is used in emergencies to regulate or increase a patient’s pH levels, and the COC syringe gives it a 365-day beyond-use date. Nephron plans to offer a variety of products in the COC syringe with the next launch scheduled to be 50% dextrose injection. Eventually, the 50-mL COC syringe will be joined by 5 mL, 10 mL, and other sizes.

For biologics that need an autoinjector, BD Medical–Pharma Systems has been developing an addition to its Intevia product line. The Intevia 2.25-mL disposable autoinjector is designed to dose accurately, operate easily and consistently, and minimize injection pain. The two-step, push-on-skin device integrates an autoinjector with a Neopak XtraFlow 2.25-mL glass pre-fillable syringe (2). To accommodate viscosities up to 40 cP and a range of injection volumes, the syringe may be equipped with a 29G Thin Wall, 27G Special Thin Wall, or 27G Ultra Thin Wall needle, which is hidden and protected. When in use, a large inspection window and plunger rod show injection progression. The unit also provides visual and audible feedback indicators (3).

Non-traditional pre-filled syringe options

As the demand for injectables grows, non-traditional options are evolving such as pre-filled blow-fill-seal (BFS) syringes based on technology from ApiJect Systems. To support use of the technology, ApiJect has established a Technology Development Center near Orlando, FL. Plans call for doubling the footprint of the facility to 32,000 square feet and adding two BFS machines by mid-2023 (4). “This new facility is devoted to working with pharmaceutical and biotech companies to design, engineer and test how to fill and finish their injectable drug products in a new type of scalable, single-dose, pre-filled injector that is made using the ApiJect Platform,” reports Jay Walker, chairman and CEO at ApiJect. He explains, “By bringing together the high-speed, high-volume BFS manufacturing process with attachable components, including needle hubs, the ApiJect Platform is designed to make it possible for more injectable medicines and vaccines to efficiently be filled and delivered to patients in a pre-filled injection device. This facility provides capabilities to shorten supply chains and bring the development of critical injection device technologies back to the United States.”

Prevention of needlestick injuries and misdosing is another area of concern and development activity. The Innosafe syringe from Gerresheimer features an integrated safety device and is supplied in a standard tub and nest configuration, so it can run on existing filling lines without any significant line adaptations.

Nemera has expanded its Safe’n’Sound pre-filled syringe accessory lineup with the addition of a 2.25-mL size. Originally introduced for 1-mL, the passive Safe’n’Sound device prevents needlestick injuries. Compatible with low fill volumes and high viscosities, a large thumb pad enhances usage, and a rounded shape offers a larger labeling surface. Clear tip visibility simplifies drug inspection (5). The safety syringes can be assembled on Harro Höfliger Assembly Lab equipment. The semiautomatic machine quickly switches between 1- and 2-mL sizes and can be changed over in a few minutes to handle other devices such as pens or autoinjectors (6).

Protecting patients against painful or incorrectly performed injections is the goal behind the Luer Adapter Fixation concept from Schreiner MediPharm. It reduces the risk of incorrect or incomplete hypodermic needle screw-ins during a syringe’s insertion with a luer adapter (7). It’s particularly well-suited for medicines administered in emergency settings where hectic situations might cause application errors. “In the case of cosmetic medicine, the new adapter concept can help avoid needle pop-off—especially when injecting highly viscous hyaluronic acid, which requires higher exertion of force and pressure,” reports Gene Dul, president of Schreiner MediPharm US.

Developed specifically for glass syringes, the Luer Adaptor Fixation device and label are applied to the syringe during the secondary packaging process. “The plastic ring would be pushed onto the luer adapter of the pre-filled syringe and interlocked with it to equalize the different radii of the adapter and syringe body. The plastic ring and syringe body would then be connected by means of a label to fix the luer adapter in place,” explains Dul. The extended label area offers ample space for additional product information. The design is customized for each application (syringe size, etc.) and the user’s packaging process is evaluated to ensure there’s no impact on container/closure integrity (7). The Luer Adapter Fixation concept can replace shrink labels and avoid heat exposure to temperature-sensitive biotech drugs.

Another pre-filled syringe innovation from Schreiner MediPharm, the Cap-Lock security concept, combines a cap adapter and label. The label wraps around the syringe body and cap adapter. An integrated perforation provides irreversible tamper evidence. “This helps ensure the integrity of the container and prevents its undetected opening,” says Dul. This gives “pharmaceutical manufacturers ... a customized and validated full-service solution for equipping luer-lock syringes with reliable tamper evidence,” says Dul.

Better inventory management is the goal behind syringes equipped with radio frequency identification (RFID) tag-equipped labels. Kit Check technology from Fagron Sterile Services embeds a microchip in the label of ready-to-administer operating room syringes, enables accurate tracking and inventory records, and ensures the right drugs are available when needed (8).

With rising demand from oral, injectable, and veterinary products, the market for syringe fill/finish equipment has expanded significantly since 2019. Deborah Smook, vice-president of Marketing and Business Development for TurboFil Packaging Machines, attributes this growth to the ease of use and dosing accuracy the format can provide. She explains, “Precision dosing is increasingly important as some solutions require exact amounts to be optimally effective. Pre-filled syringes limit point of administration dosing errors either by healthcare personnel or patients themselves.”

She adds, “More specific to the syringes sector, though, are issues regarding regulatory foresight. By this, we mean that the pathway to final product approval isn’t always immediately evident. This is largely because the [equipment] solutions we provide are highly customized and therefore might require individualized guidelines.”

Equipment is becoming more automated and flexible. The push toward automation is driven by manpower shortages and labor costs, and flexibility is demonstrated by a syringe barrel feed system from Shibuya Hoppmann. It can handle six barrel sizes and two tip styles. Feeding and orienting occur at 80 parts/min.

Flexibility is built into benchtop machines capable of handling syringes, cartridges, or vials. Designed to address lab, clinical trial, personalized medicine, and other low-volume needs, the four Labworx machines from Groninger fill with a peristaltic pump, fill with a rotary piston pump, stopper, or crimp. The semiautomatic units feature a laminar-
flow-friendly design, two-button operation, wireless control via tablet or smartphone, and automated batch records (9).

To ensure parenteral products are safe, quality control is essential in product development and production and highly regulated. Data integrity also is required and an area of weakness that often prompts warnings from regulators. A growing role is being played by robotics, which can provide the material handling needed to perform 100% inspection.

Interest in 100% inspection has been given impetus by United States Pharmacopeia (USP) <1207> Package Integrity Evaluation–Sterile Products (10). While USP <1207> is not a requirement, Oliver Stauffer, president of PTI–Packaging Technologies & Inspection, says, “USP <1207> uses strong language and lays out very fundamental principles for container/closure integrity testing (CCIT) … [and] makes a clear case for adopting deterministic methods.” As a result, parenteral packaging operations are shifting to more accurate and reliable CCIT methods. “For pre-filled syringes,” he says, “operations are using methods like helium tracer gas to determine container component seal performance in the design phase, deploying high-voltage leak detection in the production setting, and using vacuum decay to qualify assembled autoinjectors.”

To prevent future regulatory complications, regulatory filings must focus on the science of the test methodology rather than the technology. Stauffer explains, “If a regulatory filing properly identifies scientific reasoning behind the application and lays a foundation for the method deployed, the science and the method are what shall remain constant within the filing. If a filing does not focus on the science and applies a stronger focus on the technology or even the equipment used, the filing is not adaptable to the changing technology landscape. … The scientific fundamentals of a method provide quality, while technology is simply the tool to achieve it.”

With supply chain issues a constant concern, all suppliers of syringes and fill/finish equipment are taking action to prevent delays and shortages. Machine builders have expanded inventories, particularly for electronic components. At TurboFil, “Warehousing certain electronic components, including programmable logic controllers … has limited the adverse impact,” reports Smook.

On the syringe side, Stefan Verheyden, global vice-president Gerresheimer Biological Solutions, reports, “We have done everything needed to secure tubing and component supply while in parallel, we have been, and still are, investing heavily in ready-to-fill capacity expansion on a global level.”

Stevanato Group has taken steps to mitigate supply chain issues and is working closely with suppliers and customers, increasing capacity in its plants and continuing to expand operations. A new plant in Indiana is expected to start production in 2023, and a new plant in China is planned.

Like its counterparts, SCHOTT is boosting operations worldwide with an expansion in St. Gallen and a new facility in Hungary. As a vertically integrated company, SCHOTT produces its own glass tubing but must source other materials and components. To improve sourcing security for components such as syriQ Rigid Cap closures and needles, the company has implemented continuous improvement programs that couple design improvements with supply risk mitigation. Other steps being taken to prevent supply chain snafus include “identifying areas where we can become more self-reliant, standardizing components, and broadening our sources of supply,” says Deutsch. Another tactic, the FastTrack program, maintains minimum stocks in inventory. “With this program, we target a two-week order-to-shipping lead time window,” concludes Deutsch.

SCHOTT also recently announced a substantial investment in a new manufacturing facility in Müllheim, Germany, which will produce prefillable COC syringes. “Our validated polymer syringe systems meet the demanding requirements of new drug categories, including ultra-low temperature storage applications needed for mRNA-based applications,” said Mario Haas, vice-president for the Polymer Solutions division of SCHOTT’s Pharma business unit (11).

Nephron Pharmaceuticals, “Nephron Launches New Syringe Presentation,” Press Release, Jan. 26, 2022.

K. Yadi and L. Maritan, “Innovating in the Viscosity Design Space for Handheld Combination Products: A New 2.25 mL Autoinjector Platform,” ONdrugDelivery 117 pp 40-44 (March 2021).

BD, “BD Solutions for Enabling Delivery of Complex Biologics BD Intevia 2.25 mL Disposable Autoinjector,” Product Sheet, 2021.

ApiJect Systems, “ApiJect Systems Announces the Opening of the ApiJect Technology Development Center in Greater Orlando, FL,” Press Release, April 13, 2022.

Nemera, “Safe’n’Sound 2.25 mL,” Safe’n’Sound 2.25 ml | Passive safety systems for PFS | Nemera, accessed May 4, 2022.

Nemera, Harro Höfliger, “Premium Passive Safety Device,” reference_sheet_nemera_HH.pdf, accessed May 4, 2022.

Schreiner MediPharm, “Schreiner MediPharm Develops Fixation Aid for Ease and Safety of Luer Adapter Handling,” Press Release, Nov. 30, 2021.

Fagron Sterile Services US, “Product Innovation at Fagron Sterile Services US Drives Job Growth and Investment,” Press Release, Mar. 15, 2022.

Groninger, “Labworx Series, Benchtop Machine Portfolio,” Brochure, 2021.

The United States Pharmacopeial Convention, “United States Pharmacopeia <1207> Package Integrity Evaluation–Sterile Products.”

SCHOTT, “Boost for Drug Delivery Systems: SCHOTT Inaugurates Plant for Prefillable Polymer Syringes at New Facility in Germany,” Press Release, May 6, 2022.

Hallie Forcinio is a contributing editor to BioPharm International.

When referring to this article, please cite it as. H. Forcinio, “Pre-filled Syringes Show Strong Growth,” 

Articles

Demand spurs innovations in syringes and syringe fill/finish operations. 

Pre-filled Syringes Show Strong Growth

From a business perspective, solid-dose manufacturers are outsourcing more production to contract development and manufacturing organization (CDMOs). Industry stakeholders also are coping with dramatic increases in the costs of raw materials and overcoming supply-chain constraints.

Rising costs, tight supplies, and long lead times are not uncommon today for both product ingredients and packaging materials. “The COVID-19 pandemic has wreaked havoc in the manufacturing of solid-dose bulk [drugs],” reports Pat Elvin, president of Reed-Lane, a privately held company specializing in pharmaceutical contract packaging. He explains, “This shortage of supply is due to an inability to obtain all ingredients and the lack of employees to operate these facilities at this time.” Paperboard and paper stock for labeling have been in particularly short supply. “Therefore,” he says, “when we look at the private-label market, we are seeing that companies are holding their supply-chain inventory extremely tight, and packaging operators are seeing more line changeovers to accommodate smaller and shorter packaging runs.” An agile supply-chain approach and production schedule are needed.

PCI Pharma Services is focusing on supply-chain tools to improve its ability to respond to changes in the market. Its goal is to enhance productivity and provide instant feedback to all stakeholders by better resource management and material allocation. The CDMO, which offers packaging and clinical trial services, uses the pci | bridge digital platform to share real-time insights, customizable reports, and digitized workflows to ensure all factors are included in a connected digital supply chain. “We also leverage digital tools within our manufacturing environment to make client supply chains more agile and create supply-chain efficiencies, optimized inventories, and predictive analytics,” says Justin Schroeder, global vice-president, Product Development and Commercialization, PCI Pharma Services.

To meet sustainability, serialization, and supply-chain issues, CDMOs are expanding packaging material options; adding or upgrading equipment, lines, and technologies; and optimizing operations and supply chains. Adare Pharma Solutions, for example, has added capacity and is completing validation of a high-speed blister packaging line with integrated cartoning and palletizing. Expected to be operational this year, the line will handle traditional solid-dose formats as well as orally dissolving tablets. Other improvements at Adare Pharma Solutions include an expanded vault for products restricted by the US Drug Enforcement Administration and the startup of high-speed stick-pack equipment for filling powders and granules. The company also is on schedule to implement full-scale aggregation capability before the end of 2022, well ahead of the November 2023 DSCSA deadline.

On the materials side, innovations include new materials, barrier substrates, and more sustainable substrates. ACG Films and Foils, for example, has developed high-barrier polyvinylidene chloride (PVDC) films, more sustainable alternatives to PVC, and a five-layer cold-form foil.

Another alternative to PVC is the AmSkythermoformblistersystem from Amcor. Based on polyethylene (PE), the printable material contains no vinyl or aluminum foil and is compatible with PE recycling streams. Barrier properties are said to be equivalent to a 120-gram coating of PVDC. Processability is equivalent to existing materials, and structures can be child-resistant (1).

SÜDPACK Medica also has developed a more sustainable blister film that is a coextruded polypropylene (PP) designed to replace PVC/PVDC blister materials. “PP as a raw substance basis naturally provides an outstanding steam barrier,” noted Michael Hermann, head of Research & Development at SÜDPACK Medica, in a press release statement. The coextrusion technology offers the potential for enhanced barrier properties and closed-loop material management (2).

With counterfeiting an ever-present concern, Holographyx is working with Hazen Paper and Uhlmann Packaging to develop, test, and launch its Holo-Blister technology. Recently granted patents in both the US and Europe, the Holo-Blister technology enables conventional heat-seal blister packaging equipment to cost-effectively apply custom holograms to the back of blister packs. Holo-Blister holograms are designed to only be visible behind each pill/capsule cavity on the back of each blister pack, providing instant verification of authenticity, while leaving space around the recess to print dosage and marketing information (3).

1. Amcor, “AmSky Thermoform Blister System,” 

AmSky Thermoform Blister System | Flexible Packaging | Amcor

2. SÜDPACK Medica, “SÜDPACK Medica Presents PP Films,” Press Release, Oct. 28, 2021.

3. Holographyx, “Holo-Blister Is a New Anti-Counterfeiting System for Pharmaceutical Blister Packs that Has Just Been Awarded Patents in Both the US and Europe,” Press Release, Feb. 23, 2022.

Innovations address sustainability, serialization, and supply-chain issues.

Supply-Chain Challenges and Innovations in Pharma Packaging

Serialization, quality control, and aseptic filling continue to be major themes in pharmaceutical packaging. Attendees at INTERPHEX 2022 (May 24–26, 2022, at Javits Center in New York, NY) will be able to view the latest innovations in all three areas as the annual show returns to its usual spring-time dates after being canceled and delayed by the pandemic for two years.

Addressing serialization and quality control needs, Wipotec-OCS will display its TQS HC-A checkweigher and serialization unit. The flexible system handles a wide range of carton sizes, shapes, and formats. Short for “Traceable Quality System,” the TQS HC-A system integrates the company’s TQS-SP track-and-trace unit with a precise checkweighing station to deliver quality control and traceability for a broad array of products. Electromagnetic force restoration weigh cells ensure accurate weighing. Flexibility is enhanced by ConfigureFast software, which expedites setup and changeover with control of all system components including camera, printer, and transport system. With ConfigureFast software, identical print data are sent directly to both the printer and the camera’s print imager.

In operation, the TQS HC-A system receives folding cartons via a synchronized, adjustable top belt, which provides smooth transport and seamless spacing for the coding and checkweighing processes. Products with out-of-specification codes are discharged into a separate, lockable container for manual examination, while those with out-of-tolerance weight are segregated through a separate rejection system. At the end of the line, a fully automated grouping table arranges serialized and checkweighed cartons into rows for packing or next-level aggregation (1).

In another serialization innovation, Mettler-Toledo Product Inspection plans to introduce its PCE T16 system. The manual multi-aggregation unit aggregates serialized packages to a case in one click. It also can aggregate packages to pallet. An integrated high-resolution camera verifies product codes and label artwork. The company also plans to demonstrate its X34C x-ray inspection system and C 35 checkweigher with FlashCell load cell (2).

Quality control also is the focus at PTI Packaging Technologies & Inspection. Its VeriPac 465 sub-micron leak detector, introduced in October 2021 at INTERPHEX 2021, is a deterministic micro leak tester for container/closure integrity testing for parenteral products and rigid containers that require precise measurement. Perma-Vac vacuum leak detection technology controls the test system volume and maximizes the signal-to-noise ratio between good and defective samples. The non-destructive test requires no sample preparation and can detect leaks as small as 0.005 cubic centimeter. The unit comes with PTI Ethos 21 

 Part 11 software and also can detect leaks in flexible and semi-flexible packaging formats (3,4).

AST plans to show semiautomatic, benchtop aseptic filling equipment including the Genisys lab container filling system for filling syringes and cartridges or filling and stoppering vials and bottles. A second benchtop unit, the Genisys lab closing system, closes syringes or cartridges using both vacuum and vent-tube methods and handles a wide range of container sizes quickly and easily. A third system, the Genisys lab vial sealing system, applies aluminum caps and accommodates a wide range of vial sizes and finishes. Targeted to small batches, all three systems offer precise control and compatibility with cleanrooms, bio-safety cabinets, laminar airflow hoods, and aseptic isolators (5).

Datwyler Pharma Packaging USA intends to feature its array of elastomeric components and its StarterPack for small quantity component needs. Produced in partnership with Schott, each StarterPack contains compatible components for a low-volume run: Schott’s adaptiQ vials plus Datwyler’s OmniFlex stoppers and Prime caps. All components are ready to use and stability verified (6, 7).

1. Wipotec-OCS, “At INTERPHEX NYC, Wipotec–OCS to Showcase Format-Agnostic Checkweigher & Serialization Unit,” Press Release, March 23, 2022.

2. INTERPHEX, Mettler Toledo Product Inspection, 

METTLER TOLEDO Product Inspection - Exhibitor Details (interphex.com)

3. INTERPHEX, PTI Packaging Technologies & Inspection, 

PTI Packaging Technologies & Inspection - Exhibitor Details (interphex.com)

4. PTI Packaging Technologies & Inspection, “PTI Launches New VeriPac 465 Micro Leak Detection System at INTERPHEX Achieving Sub-Micron Leak Detection,” Press Release, Oct. 8, 2021.

6. INTERPHEX, Datwyler Pharma Packaging USA Inc., 

Datwyler Pharma Packaging USA Inc - Exhibitor Details (interphex.com)

7. PharmTech, “Packaging Components for Parenteral Drug Development,” 

Exhibitors display primary packaging, secondary packaging, and machine innovations at this year’s INTERPHEX. 

INTERPHEX 2022 Moves Back to Spring-time Schedule

Solid-dosage forms continue to play an essential role in the pharmaceutical marketplace despite the attention the COVID-19 pandemic has focused on parenteral products. Factors spurring demand for solid-dose products include the development of new chemical entities, especially in oncology; more complex formulations and formats; and the adoption of technologies such as microencapsulation, taste masking, and mini-tabs.

The solid-dose market also benefits from “the growth and continual rise in generic pharmaceutical companies and their impact on the accessibility and affordability of healthcare,” says Guy Calcagno, vice-president Global Sales, Films & Foils, ACG, a supplier of barrier packaging substrates.

Perhaps most importantly, consumers like the solid-dose format. “Many consumers still prefer [solid-dose] products because of their convenience for ease of dosing and portability,” explains Justin Schroeder, global vice-president, Product Development and Commercialization, PCI Pharma Services, a contract development and manufacturing organization (CDMO), which offers packaging and clinical trial services.

“Oral solid-dose products are … the easiest format to increase patient regimen compliance,” adds Francois Bidet, vice-president of Business Development EMEA for Aptar CSP Technologies, a supplier of drug delivery, consumer product dispensing, and active packaging products.

Demand for solid-dose products is more intense outside North America. “We are seeing strong growth in developing markets, such as the Middle East, Southeast Asia, India, and Latin America,” reports Calcagno.

Schroeder agrees, noting, “The pharmaceutical industry has capitalized on the opportunity to provide rest-of-world nations with more medicines and therapies, bringing life-saving treatments to new patient populations.” Delivering solid-dose products to isolated markets is much simpler than handling biologics, which require cold-chain storage.

Although bottles still account for the largest share of solid-dose packaging, the blister packaging format is showing strong growth worldwide. One forecast predicts pharmaceutical blister packaging will experience a 5.1% compound annual growth rate to reach $8.9 billion by 2031 (1). Unit-of-use blister packaging dominates in developing markets due to price-point advantages that make medication more affordable and barrier structures that can protect the shelf-life of sensitive drugs, even those destined for sale in markets with extremely hot and/or humid weather.

To protect product shelf life in these areas and expedite time-to-market, pharmaceutical manufacturers, contract packagers, and material suppliers devote considerable attention to selecting packaging with optimized barrier properties. “Given the increasing pressure to accelerate the timeline through the clinical phases and to commercialization, schedules for traditional drug formulation activities are often compressed, resulting in medicines that are sensitive to environmental degradants such as oxygen or moisture,” explains Schroeder. As a result, PCI Pharma Services offers a range of packaging options so drawbacks and benefits can be assessed for each material. With that information, the best match of product requirements and package structure can be made for the destination market, thereby enabling a seamless transition from clinical to commercial production. “This means … making our best recommendation to meet ... timeline, budget, and current global supply-chain conditions,” says Schroeder.

In addition to emphasis on barrier structures, Calcagno says, “There is a move away from polyvinyl chloride (PVC) to more sustainable packaging solutions.” Serialization is also top-of-mind with a desire to meet US Drug Supply Chain Security Act (DSCSA) requirements (including aggregation) ahead of the Nov. 27, 2023 deadline for data exchange and product verification.

Other solid-dose trends include a strong interest in patient-centric packaging. Patient-centric packaging provides intuitive design and support that helps consumers take the medication as prescribed, maximizes adherence, and ensures positive outcomes. It can also be a market differentiator for the product. A patient-centric package developed by PCI Pharma Services for a daily-dose preventative therapy, for example, combines intuitive instructions and labeling, ease-of-use, and portability while balancing child-resistant features and consumer-friendly access.

From a business perspective, solid-dose manufacturers are outsourcing more production to CDMOs. Industry stakeholders also are coping with dramatic increases in the costs of raw materials and overcoming supply-chain constraints.

PCI Pharma Services is focusing on supply-chain tools to improve its ability to respond to changes in the market. Its goal is to enhance productivity and provide instant feedback to all stakeholders by better resource management and material allocation. The CDMO’s pci | bridge digital platform shares real-time insights, customizable reports, and digitized workflows to ensure all factors are included in a connected digital supply chain. Schroeder notes, “We also leverage digital tools within our manufacturing environment to make client supply chains more agile and create supply-chain efficiencies, optimized inventories, and predictive analytics.”

To meet sustainability, serialization, and supply-chain issues, CDMOs are expanding packaging material options; adding or upgrading equipment, lines, and technologies; and optimizing operations and supply chains. Adare Pharma Solutions, for example, has added capacity and is completing validation of a high-speed blister packaging line with integrated cartoning and palletizing. Expected to be operational this year, the line will handle traditional solid-dose formats as well as orally dissolving tablets. Other improvements at Adare Pharma Solutions include an expanded vault for products restricted by the US Drug Enforcement Administration and the startup of high-speed stick-pack equipment for filling powders and granules. The company also is on schedule to implement full-scale aggregation capability before the end of 2022, well ahead of the November 2023 DSCSA deadline.

Another alternative to PVC is the AmSky thermoform blister system from Amcor. Based on polyethylene (PE), the printable material contains no vinyl or aluminum foil and is compatible with PE recycling streams. Barrier properties are said to be equivalent to a 120-gram coating of PVDC. Processability is equivalent to existing materials, and structures can be child-resistant (2).

SÜDPACK Medica also has developed a more sustainable blister film that is a coextruded polypropylene (PP) designed to replace PVC/PVDC blister materials. “PP as a raw substance basis naturally provides an outstanding steam barrier,” noted Michael Hermann, head of Research & Development at SÜDPACK Medica, in a press release statement. The coextrusion technology offers the potential for enhanced barrier properties and closed-loop material management (3).

To prevent API degradation, enhance product stability, and extend shelf-life, Aptar CSP continues to develop its Activ-Blister technology. The Activ-Blister structure adds an engineering polymer film to lidstock to control moisture and oxygen levels in the headspace of each blister cavity. “Activ-Blister also helps avoid complex and lengthy reformulations for oral-solid-dose products to withstand harsh climate conditions, such as International Conference on Harmonisation (ICH)3 (hot and dry) and ICH4 (hot and humid) zones,” reports Bidet.

With counterfeiting an ever-present concern, Holographyx is working with Hazen Paper and Uhlmann Packaging to develop, test, and launch its Holo-Blister technology. Recently granted patents in both the US and Europe, the Holo-Blister technology enables conventional heat-seal blister packaging equipment to cost-effectively apply custom holograms to the back of blister packs. Holo-Blister holograms are designed to only be visible behind each pill/capsule cavity on the back of each blister pack, providing instant verification of authenticity, while leaving space around the recess to print dosage and marketing information (4).

Future developments will center on serialization, active packaging, and sustainability, as well as the flexibility to efficiently accommodate shorter runs and frequent changeovers. For example, more efficient serialization equipment is needed, says Renard Jackson, vice-president of North American Contract Service Operations at Adare Pharma Solutions.

Active packaging will make it possible to tailor containers and substrates to the specific sensitivities of various APIs. As a result, Bidet says, “New chemical entities will be more stable and can be launched on a worldwide scale more efficiently and effectively.” Time to market will accelerate.

Sustainability is top-of-mind for everyone. “There’s currently a significant push in the pharmaceutical industry to consider sustainability and eco-friendliness when designing packages,” reports Schroeder. “Pharma companies will need to consider lifecycle assessments of various oral solid-dose products; [this] holistic perspective includes manufacturing, packaging, and transport,” adds Bidet.

“Many traditional high-barrier films are not easily separated for traditional recycling streams,” notes Schroeder. So, film manufacturers are working on materials that are easier to recycle. Thus, Calcagno says, “I believe we will see a huge influx of more cost-effective alternatives to PVC-based films.” Bidet predicts, “Monomaterial or compatible recycling stream material will be preferred.”

“With the introduction of these new materials, equipment will continue to evolve to properly accommodate them,” says Schroeder. He concludes, “By 2025, we’re going to continue to see the evolution of packages, with a continued focus on creating more patient-centric delivery to ensure successful health outcomes while also introducing a more sustainable approach for cradle-to-grave packaging lifecycles.”

Transparency Market Research, “Blister Packaging Market for Pharmaceutical Industry to Reach Valuation of US$ 8.9 Bn By 2031: Transparency Market Research,” Press Release, May 27, 2021.

Amcor, “AmSky Thermoform Blister System,” AmSky Thermoform Blister System | Flexible Packaging | Amcor, accessed Feb. 11, 2022.

SÜDPACK Medica, “SÜDPACK Medica Presents PP Films,” Press Release, Oct. 28, 2021.

Holographyx, “Holo-Blister Is a New Anti-Counterfeiting System for Pharmaceutical Blister Packs that Has Just Been Awarded Patents in Both the US and Europe,” Press Release, Feb. 23, 2022. 


Vol. 46, No. 4
April 2022
Pages: 36–37,53

When referring to this article, please cite it as H. Forcinio, “Meeting Challenges in Solid-Dose Packaging,” 

Innovations address supply-chain constraints, serialization, and new requirements for sustainable and patient-centric designs. 

Meeting Challenges in Solid-Dose Packaging

“Oral solid-dose products are … the easiest format to increase patient regimen compliance,” adds Francois Bidet, vice-president of Business Development EMEA for Aptar CSP Technologies, a supplier of drug delivery, consumer product dispensing, and active packaging products.

To protect product shelf life in these areas and expedite time-to-market, pharmaceutical manufacturers, contract packagers, and material suppliers devote considerable attention to selecting packaging with optimized barrier properties. “Given the increasing pressure to accelerate the timeline through the clinical phases and to commercialization, schedules for traditional drug formulation activities are often compressed, resulting in medicines that are sensitive to environmental degradants such as oxygen or moisture,” explains Schroeder. As a result, PCI Pharma Services offers a range of packaging options so drawbacks and benefits can be assessed for each material. With that information, the best match of product requirements and package structure can be made for the destination market, thereby enabling a seamless transition from clinical to commercial production. “This means … making our best recommendation to meet ... timeline, budget, and current global supply-chain conditions,” says Schroeder. 

In addition to emphasis on barrier structures, Calcagno says, “There is a move away from polyvinyl chloride (PVC) to more sustainable packaging solutions.” Serialization also is top-of-mind with a desire to meet US Drug Supply Chain Security Act (DSCSA) requirements (including aggregation) ahead of the Nov. 27, 2023 deadline for data exchange and product verification.

Other solid-dose trends include a strong interest in patient-centric packaging. Patient-centric packaging provides intuitive design and support that helps consumers take the medication as prescribed, maximize adherence, and ensure positive outcomes. It also can be a market differentiator for the product. A patient-centric package developed by PCI Pharma Services for a daily-dose preventative therapy, for example, combines intuitive instructions and labeling, ease-of-use, and portability while balancing child-resistant features and consumer-friendly access.

To prevent API degradation, enhance product stability, and extend shelf-life, Aptar CSP continues to develop its Activ-Blister technology. The Activ-Blister structure adds an engineering polymer film to lidstock to control moisture and oxygen levels in the headspace of each blister cavity. “Activ-Blister also helps avoid complex and lengthy reformulations for oral-solid-dose products to withstand harsh climate conditions, such as ICH3 (hot and dry) and ICH4 (hot and humid) zones,” reports Bidet.

1. Transparency Market Research, “Blister Packaging Market for Pharmaceutical Industry to Reach Valuation of US$ 8.9 Bn By 2031: Transparency Market Research,” Press Release, May 27, 2021.

Innovations address sustainable and patient-centric designs. 

Trends in Solid-Dose Packaging

Line clearance is part of every changeover on the pharmaceutical packaging line. It’s a time-consuming, manual process that depends on human decision-making as operators physically inspect each work area, packaging line, and machine to ensure it is clean and free from any products, materials, or documents from the previous batch that are not required for the upcoming batch.

FDA requires performance and documentation of a line clearance in its current good manufacturing practices (CGMPs) (1). In Europe, the 

Volume 4 GMP Guidelines refer to line clearance in Part 1 Chapter 5.50 (2). Other than stipulating use of a checklist, neither document provides guidance on how to perform these line clearance activities

So, a checklist is followed, and at the end of the process, there’s a signoff. “These work instructions are typically lengthy documents (50+ pages) which explain the step-by-step process for clearing and changing over a line,” says Dave Taylor, product manager at CXV Global, an engineering solutions and resourcing organization. “Due to historic failures, this process is often then duplicated by another [operator] who will ‘buddy check’ to ensure that the first operator did not miss anything,” adds Taylor. Some companies split the line into zones for inspection; others use two operators. One operator starts at the beginning of the line, and the other starts at the end. After meeting in the middle, each operator continues, checking the work of their partner.

Unfortunately, a completed checklist and signoff do not provide evidence the line clearance has been completed satisfactorily. “It just shows the paperwork has been done,” explains Taylor. Some companies video the line clearance inspection, but this results in hours of footage to review and store. In addition, a video may not show the location or the responsible party if a line clearance omission occurs. “Video doesn’t stop errors from happening,” notes Taylor.

Ergonomics also is an issue. “Operators must bend and stretch and reach under machines,” he explains. It’s not uncommon for operators to climb ladders and perform “blind” checks of an area by feel because a visual inspection is not possible.

With batch sizes shrinking and changeovers becoming more frequent, overall equipment effectiveness (OEE) suffers. The impact of line clearance time is demonstrated in the following example. Taylor explains, “If I can run a line for two days to produce a million units, and then I have a six-hour downtime to change over, then this is okay. However, if I only need to produce 50,000 units for a specific market, then this may only take the machine three hours to run. If I then perform a six-hour changeover, the productivity and efficiency of the line are massively impacted.”

Manual line clearance takes far too long to complete, is physically arduous and not 100% repeatable, exhibits periodic deviations due to the variability of many factors, and generates a large amount of paper for each time it’s performed. “Additionally,” says Elliot Abreu, senior vice president, Xyntek, the US division of CXV Global, “the quality process . . . often remedies specific line clearance failures by adding new checks in the areas where items were previously discovered. Over time, this increases the complexity and length of the work instruction, which has a direct impact on the efficiency of the line or factory.”

Like many other formerly manual processes, line clearance can now be automated. Automated line clearance offers benefits in efficiency, quality, and health and safety. With automated line clearance, CXV says that pharmaceutical manufacturers:

Realize an 85% reduction in line clearance time

Minimize changeover downtime and labor requirements

Experience a double-digit improvement in machine/line efficiency

Eliminate errors caused by overlooked rogue components on the line

Remove the dependency on human decision making for line clearance

Improve operator ergonomics by limiting the need to crawl under machines, stretch to check difficult-to-reach spaces, or scale ladders to times when an anomaly is detected

Prevent equipment damage by stray components

Create a repository of evidence about the state of the line at the time the clearance was performed

Document evidence of the actions performed by the operator and the outcomes of those actions in the audit record.

The CXV Global LineClearance Assistant system, developed in partnership with life-science corporations, consists of industrial-grade cameras mounted at strategic locations inside, above, and below the machine/line along with cables, processing units, operator interface, software, and a full suite of validation documents for quick qualification.

The LineClearance Assistant system can connect to the programmable logic controller (PLC) for the line. The system alerts operators of areas to check for stray product or components and rechecks the area after the operator takes action. Before and after images, which are date- and time-stamped and audit-logged, provide concrete evidence the line was cleared properly. If desired, the system can be set up so the line cannot be restarted until the PLC receives the “ready” signal, indicating the line clearance process has been completed successfully.

The system can integrate into CXV Global’s SmartFactory line management solution, which controls and manages the batch data being sent to the line devices. It also includes an OpenApi-compatible application programming interface, so it can share information with electronic batch record, enterprise resource planning, and manufacturing execution systems. “This digital integration across the factory enables an unparalleled level of control across the line with full end-to-end traceability while increasing the [overall equipment efficiency] of the line,” says Abreu. Once validated, the system is acceptable to regulators in the United States and the European Union. It also meets regulatory requirements for electronic signature requirements such as US 21

Compatible with primary and secondary packaging operations for solid dose, oral health, and tubed products, the CXV Global LineClearance Assistant technology also has potential for cleanroom applications. “We would just need to put the cameras in the right kind of enclosure,” explains Taylor. Several proof-of-concept systems are in place; trials are being run; and several major pharmaceutical companies have begun the installation process.

Alongside the line clearance implementations, CXV Global hosts the Pharma Line Clearance Forum, an industry group dedicated to line clearance, which has operated in various guises for more than three years and currently includes more than 100 collaborators who meet on a quarterly basis.

EC, EudraLexVolume 4: Good manufacturing practice Guidelines, “Part 1: Basic Requirements for Medicinal Products, Chapter 5: Production,” (Brussels, 2014).

EC, EudraLex Volume 4: Good manufacturing practice Guidelines, “Annex 11: Computerised Systems,” (Brussels, 2011).

Digital technology streamlines the line changeover process. 