F. J. Quinn

Maintaining product quality and meeting regulatory specifications is a daily challenge for pharma manufacturers, but recent events have shown that the quality requirements do not end as pills or vials come off the production line—they must be extended through all packaging steps, and the packaging itself can be subjected to a comparable level of quality assurance. Recent product recalls show cases of the wrong dosage strength in containers (or, conversely, the wrong labels being applied) mispackaged product, or problems with the cleanliness of the packaging components. The increasing number of outsourcing arrangements between brand owners and contract packagers only add another level of complexity to the communication and coordination required. Vendors say they are taking a hard look at systems controls to ensure their products and all components are protected from contamination and other hazards.

“Companies dedicated to ensuring the quality of their products and packaging are taking steps to ensure such quality, investing in complete quality solutions that include quality planning, quality control, quality assurance and quality improvement,” observes Patricia Santos-Serrao, senior product manager at Master Control (Salt Lake City), a provider of process and document management software. “Implementing a proven quality management system that enforces standards and practices for quality assurance will help improve quality and minimize risk.” 

Drug packaging is taking center stage as several high-profile drug recalls in 2011 were directly linked to this key component in the manufacturing process. One look no further than Johnson & Johnson (J&J; New Brunswick, NJ), which in the past two years issued more than 25 recalls and led to a high-level management reorganization. Several recalls were packaging related, drawing attention to the importance of designing quality into manufacturing processes. 

In September, Qualitest Pharmaceutical had to recall multiple lots of oral contraceptives because the pills—which have a specific 28-day cycle&mdash;were rotated within their blister cards, altering the weekly regimen if followed. Last March, Pfizer’s Greenstone generics subsidiary had to recall a production lot where the wrong labels were attached, switching a an antidepressant with a prostate hyperplasia treatment. A year ago, RiteDose Corp. had to recall albuterol vials that had the wrong concentration listed on their labels. 

The J&J situation served as a reminder about the suitability of drug packaging materials and structures is a integral part of the drug approval process. FDA requires assurance that drugs will be protected against contamination, tampering, spoilage, and physical damage that could impact is characteristics, and makes a review of drug packaging part of the information it examines. 

“One of the biggest issues that has occurred in the last 18 months — and even earlier – is the failure of companies to report quality-related issues and customer complaints to the FDA in an efficient manner, whether they have occurred in the pre- or post-market,” says K.R. Karu, industry principal, Sparta Systems (Holmdel, NJ), a provider of enterprise quality and compliance management solutions. “This has caused the agency to tighten its oversight of the industry, enforcing stricter regulations for reporting of quality issues and requiring more extensive collection of data related to these issues.” 

	Quality assurance is an important part of any complete quality management strategy. These programs can comprise hundreds of different components, including deviation management, supplier quality management, corrective and preventative actions (CAPAs), investigations, and change management. “Each of these functions is critical, and many of the most forward-thinking companies in pharma have taken to automating them within electronic quality management systems,” Karu says. “In most cases, these records are related, so having them in one system instead of silos creates needed transparency.” 

According to industry members, drug makers are making a concerted effort to enhance quality standards for their manufacturing process, rather than simply reacting to manufacturing incidents. “This is the spirit of Quality by Design initiatives, through which companies design processes to consistently deliver better outcomes,” says Randy Tatlock, customer development manager, Aegis Analytical, a provider of manufacturing and process intelligence software. “Other critical quality components include understanding a process better over time and monitoring process data to improve process understanding.” 

In order to verify quality, one must understand the expectation for a product, whether it is safety, durability, or performance. “One must ask, ‘what is expected from this product in order for it to ‘perform as expected,’” notes Master Control’s Santos-Serrao. “The second component is ensuring that those responsible for assuring that the standards have been met are trained in what to look for when determining that a product meets those standards.” 

One of the most important steps being taken to improve quality assurance is centralizing management of an organization’s quality processes, ensuring standards are enforced across global operations and geographical boundaries. The tendency in pharma companies is to have different locations working in their own unique silos, with disparate processes and ways of managing these processes. “From a quality perspective, this can be, at best, cumbersome and, at worst, devastating when a major issue arises, as they inevitably do,” Sparta Systems’ Karu says. “More and more companies have awoken to the fact that processes should be harmonized across the organization, and managed from a central location, so that issues can be quickly identified and resolved.” 

Several pharma companies outsource the packaging process, which experts say makes it even more important to work closely with contract partners’ quality teams to capture and share the entire quality review information flow in a collaborative environment. “This helps quality and manufacturing teams gain access to all of the precise and timely quality review information that they need to keep current production on track, or to quickly investigate potential issues uncovered in the quality review process,” explains Brian Daleiden, vice president of marketing at TraceLink (Woburn, MA), developer of the TraceLink Network, an industry-wide supply collaboration network. 

As the level of outsourced production grows, pharma companies are seeking to maintain the same level of transparency and coordination in external quality review processes as they have within internal production. TraceLink offers a Quality Review service, part of the cloud-based TraceLink Network collaborative supply network platform, which helps pharma companies and their external supply partners connect the virtual quality team into a collaborative environment. 

“As a result, pharma quality leaders can reduce quality review cycle times by over 20% through improved visibility and tracking from initial review submission to final review closure,” Daleiden says, “reduce manual labor and data entry by over 25% throughout the process, reduce the risk of misinterpretation and misalignment between internal and external quality team members, and provide real-time visibility into quality review KPIs for all external supply relationships.”Anderson Packaging (Rockford, IL) operates a Lean Six Sigma program which enables it to work collaboratively with customers to develop solutions to new problems, optimize systems and continuously improve its processes, according to Justin Schroeder, senior director, marketing and development services. “We also work collaboratively with industry organizations to actively stay ahead of future challenges, including participating and leading ‘think tanks’ and round table opportunities.” 

FIG. 2. VISION SYSTEM OUTPUTS AT ANDERSON PACKAGING

By gaining a better understanding of their processes, industry members say pharma companies can build quality into manufacturing and prevent unwanted outcomes, rather than always reacting to something that has gone wrong. This has led to an increasing number of life sciences manufacturers initiating and expanding QbD programs, Aegis Analytical’s Tatlock says. “There also is increased collaboration between quality and manufacturing teams in the name of preventing and solving quality assurance problems,” he adds. “While these departments often serve as a check-and-balance for one another, sharing more information and working together can have positive impacts on quality.” 

Howell Packaging (Elmira, NY) utilizes FMEA (Failure Mode Effects Analysis) in order to properly plan and ensure clients’ contract packaging programs will be error free and conform to specifications. “We are able to produce packaging components such as folding cartons, rigid boxes, and thermoform plastics,” notes Joe Lally, sales manager, pharmaceutical packaging. “In addition, we can conduct final packaging operations of product and provide storage and distribution from our Howell Marketing Services operation.” 

Sharp Corp. (Allentown, PA), a contract packaging services provider, deploys a comprehensive validation program coupled with failure mode analysis to develop and improve processes. “Electronic systems that perform 100% inspections are used during packaging to verify critical attributes,” explains Daniel Stehn, director of biotechnology packaging. “Having a well trained staff that oversees activities on a continuous basis during production helps ensure that any errors are minimized, either during production and prior to release of any products.” 

	Observers concur that drug companies are realizing it’s important to have a system in place for quickly identifying the root cause of incidents that arise in manufacturing. There are a number of solutions which are said to help pharma companies comply with good manufacturing practices and FDA-regulated production and packaging environments.

	For example, Sparta Systems claims its TrackWise quality management software system is designed to help companies streamline quality processes within their manufacturing organizations, collect the necessary data associated with these processes, and report it to regulatory authorities in a timely and efficient manner. The software offers companies a centralized and configurable solution that speaks to their quality-related business needs. 

“The ROI benefits of TrackWise include, but are not limited to, significant cost savings associated with minimizing quality-related risk, transparency and accountability for the processes that govern the overall delivery of safe and effective products to market, and the assurance of brand reputation,” Karu says. 

MasterControl offers an integrated quality management solution that includes the management of documents, processes such as CAPAs and Deviations, training, supplier management, bill of materials, audits, and risk. “Our solutions suite is highly configurable and can be leveraged not only in quality, but in R&D as well,” Santos-Serrao says. 

Sharp utilizes Document Management and Corrective/Preventive Action software systems which enable concurrent routing of documents for approval (reducing cycle time), tracking and trending capabilities (which identify the most important critical items and facilitate continuous improvement), and integration of activities that allows improved efficiency from existing resources. Anderson utilizes software tools for a similar reason; it enables the firm to document and analyze complaints and defects, optimizing response time and reporting. “We employ real time Overall Equipment Effectiveness (OEE) software that is integrated into our equipment at the line level,” Schroeder says. ”This software provides real-time data driven analysis of our systems, including rejects and downtime.” 

This real-time data capture and analysis provides agility in Anderson’s decision making and efficient resolution of manufacturing challenges. “In addition, we collect and monitor metrics across our business, including our ERP system,” Schroeder says, “enabling us to make calculated and informed decisions, trend data, and continuously improve our business.” 

Howell utilizes a program called Cartons-on-Demand that integrates with its clients’ planning function. “It permits us to establish re-order points, consolidate runs, reduce costs, and provide a true just-in-time program,” Lally explains. Howell also uses new technology with respect to vision systems, bar-code readers, and check weighers in both its contract packaging and packaging component production operations. 

AstraZeneca recently selected Aegis’ Discoverant process intelligence solution for gathering, monitoring and reporting process and quality data. Discoverant is designed to help manage pharmaceutical and biopharmaceutical manufacturing processes. According to Aegis, the first deployment of the process intelligence system will be at AstraZeneca’s Gärtuna facility in Södertälje, Sweden. 

“Leading life sciences manufacturers want to operate robust processes within well characterized design spaces,” states Mark Isaacs, vice president sales, Aegis. “To deliver this, they want a single, proven data management platform for aggregating, accessing and analyzing process and quality data.” 

Manufacturing may have a quality system in place, but when the product moves to the packaging department or to a contract packager, there may not be a quality system in place, or it is disconnected from the company system. “This lack of control and visibility often causes issues that are discovered only after the product has made it through the supply chain and to the consumer,” Sparta’s Karu says. “Having a closed-loop system from suppliers through shipment will help minimize problems that are created outside of the traditional manufacturing process. This can be accomplished by having a single system, or having well-defined integration points between separate systems.” 

Pharmaceutical companies have implemented both document management systems and Enterprise Quality Management Systems (EQMS). The difference is that a document management system manages content and changes within controlled documents while an EQMS creates an electronic record that follows a predefined workflow and manages process, not content. “This means that events are recorded, and a process that includes investigations, root cause analysis, actions taken, and related CAPA and Change Control are managed and effectiveness checks are performed,” Karu points out. “This facilitates events being completed without parts of the process falling between the cracks, or thrown over the wall into another silo without visibility.” These are measurable problems that, when solved, ensure a safe product delivered to consumers and positively impact the company’s bottom line. 

Despite making strides in improving quality across the supply chain, pharma companies still face innumerable challenges in ensuring and maintaining product quality. By improving upon their quality assurance, experts say drug makers can reduce risk, improve compliance and avoid the brand liabilities that can negatively impact business growth and tarnish their reputations in the marketplace. PC 

Articles

Recalls Stimulate Scrutiny of Quality Assurance in Drug Packaging

Most pharmaceuticals are packaged in bulk bottles for delivery to pharmacies, or as dose-specific packages that are in turn packed in cartons and pallets. But nearly any pharmaceutical in the market also has a varied list of special packaging requirements, such as sample packages, combined drug and delivery components (such as syringes), along with promotional materials, medication guides and the like. The clinical trial world brings an order-of-magnitude increase in testing and component combinations. For these and other applications, a kit-assembly process, or “kitting” is the order of the day. And rather than adding to labor- and equipment-intensive processes, manufacturers are increasingly relying on contractors—primarily contract packagers and third-party logistics (3PLs) providers&mdash;to supply kitting services more efficiently. 

“Utilizing logistics providers like ourselves is essentially one-stop shopping for our customers,” declares Jeff Luthman, VP, life sciences solutions at MD Logistics (Plainfield, IN). “Our service offerings improve repackaging cycle time and reduce overall costs.”

	Kitting is said to offer drugmakers a convenient and cost-effective way to deliver products to market while making drug administration easier. Instead of receiving individual components from multiple suppliers required for a given therapy, caregivers receive a self-contained package offering all the necessary components for drug administration.

“Clinical trials are a huge market for kitting,” notes Jim Saponaro, VP for the life sciences and healthcare industry, Exel Logistics (Westerville, OH). “In this instance, several components are bundled together into one package—such as medication, supplies and directions&mdash;and then shipped to patients involved in the trial.” 

FIG. 1. INJECTABLES KIT ON THE ASSEMBLY LINE AT ANDERSON PACKAGING

Components found in kits may include items such as a syringe, vials, swab, delivery devices, and product literature, which are automatically, semi-automatically, or manually sealed into kit units. “It varies, depending on the drug indication, delivery form, and whether it is intended for home use or administered in a clinical setting,” says Justin Schroeder, senior director, marketing and development services, Anderson Packaging (Rockford, IL). “Manufacturers look to us in assembling the kitted components because we offer a turnkey solution, being able to source many of the components, as well as the sophisticated inspection systems we employ to ensure a high level of quality.” 

Determining what gets bundled with the Rx drug often depends on the type of medication. For example, kits that treat chronic illnesses such as MS, diabetes and rheumatoid arthritis, contain product, delivery devices, alcohol swabs and instructions. Many parenteral delivery forms, such as injectable drugs and transdermals, involve a cross section of components necessary to complete unit treatment. “It’s common to see complex, high-cost therapy programs that require ancillary components to support the delivery system utilizing kit presentations,” says Daniel Stehn, director of biotechnology packaging, Sharp Corp. (Allentown, PA). “Home-administered products are also common candidates for kit applications.” 

Kitting provides a real benefit in connecting the physician and patient by providing educational, practice-related and compliance-oriented materials. Kitting of patient starter kits for oral-solid delivery forms often include a compliance prompting package, compliance and adherence supporting materials, rebate or discount cards, and literature to facilitate patient education. “The intent is to maximize the first-time patient experience with the drug,” Anderson’s Schroeder points out. “We have even been asked to assemble promotional marketing kits designed for demonstration purposes only, by virtue of our ability to consistently and reliably ensure every piece is present and in the correct location.” 

“Customers can receive information on new products or discounts for current products by attaching these to kits,” says Denise Odenkirk, VP, O&M HealthCare Logistics, a division of Owens & Minor (Mechanicsville, VA). “Pharmaceutical companies can extend their reach and enhance sales through the simple step of including another piece to the kit.”

FIG. 2. WHERE KITTING HAPPENS AT O&M HEALTHCARE LOGISTICS 

Packages utilized for bundling drugs and relevant components together range from plastic trays and bags to corrugated boxes and totes. Packaging for temperature-controlled pharmaceuticals may also include insulation to maintain temperature standards. 

	Kitting solutions providers say they are well positioned to sourcing the necessary medical components and delivering them in a suitable package for end users. They represent a valuable resource for clients to outsource traditional in-house activities, or companies who have a limited packaging and distribution infrastructure. “Our ability to handle the kitting process efficiently and effectively is a way to leverage our variety of products and services into what we call our ‘value multiplier effect,’” explains Joe Lally, sales manager, pharmaceutical packaging, Howell Packaging (Elmira, NY). “We gain a significant competitive advantage when we bundle our products and services.” Howell offers project management and supply chain specialists who are utilized for projects that require coordination of the many complex elements in kitting production, assembly, storage and distribution. 

Pharma companies often tap into kitting services offered by third-party sources because the planning and logistics of all required materials can be quite an undertaking, observers say. The labor-intensive process involves, among other things, sourcing and assembling various components and coordinating scheduling with multiple manufacturers. 3PLs claim to offer scale and expertise for kitting that drive down costs for pharmaceutical manufacturers compared to in-house options. 

“Kitting can also be an equipment- and labor-intensive endeavor, so 3PLs take on this capital investment and also have the expertise to scale up or scale down labor with demand and provide much-needed flexibility,” Exel’s Saponaro says. “As pharmaceutical companies concentrate more and more on their core business, 3PLs like Exel can offer value in their supply chain expertise and provide synergies between kitting and other supply chain activities.” 

There are various factors impacting whether a pharma company would outsource kitting services, experts say, with cost and efficiency among the most logical. Packaging postponement strategies, product sample creation, and unit of use deployment are additional drivers. “Additionally, shipping larger bulk quantities to the distribution center is more cost-effective and allows for just-in-time (JIT) production,” MD Logistics’ Luthman says. “We are then able to repackage product into the appropriate sizes for the customer.” 

The process can vary widely, depending on the package and run volume. Small runs could be very manual, whereas larger runs could involve automation and elaborate filling systems. “But regardless of size, our processes feature extensive inspection systems throughout,” Anderson’s Schroeder says. “These are critical for ensuring the proper contents for every pack produced. We also provide value in being able to source the many components, leveraging our purchasing power to reduce costs with turnkey supply.” 

“Whenever possible, the ability to position components in their sequence of use can provide advantages, and designing cavities for each component can also provide a quick visual aid to ensure all materials are enclosed,” says Sharp’s Stehn. 

By comparison, 3PLs offer a wide range of supply chain activities — from analysis to execution &mdash; and are often able to identify and provide synergies between kitting and the supply chain. For pharma companies, this can mean shared warehouses, labor and systems, as well as less shipping, handling and damage. “By leveraging these existing assets, a 3PL is closer to the customer and gives the pharmaceutical customer both one point of contact for all supply chain activities,” Exel’s Saponaro says. A trend toward “postponement”&mdash;the practice of sending partially assembled kits to various depots around the world, and then finishing them with country-specific documentation, provides cost efficiencies and supply chain flexibility, since one depot can serve multiple countries in a region, and can help moderate inventory swings among different national markets. 

UPS Healthcare Logistics (Atlanta) operates a packaging group in Louisville, KY, which manages planning and logistics of purchasing and distribution/utilization of packaging for many of its customers. “We are able to add value to these customers by consolidating or aggregating their requirements and leveraging our purchasing power,” notes Alan Amling, director, global logistics and distribution. “The knowledge we gather on customer utilization of packaging and working closely with the customer allows for efficient planning and execution.” 

MD Logistics manages the kitting process by providing a value-added turnkey solution within the four walls of its facility. It regularly has its customers’ products and collateral material in-house, as well as any required packaging components, enabling the firm to schedule production with a JIT mindset. “This provides immediate savings in transportation and handling costs for our customers,” Luthman says. “By providing kitting services in-house, we can mitigate security and product monitoring concerns by utilizing a streamlined process that allows products to remain in our custody and at our facility throughout the supply chain.” 

Kit assembly shares many of the same warehousing and packaging processes of conventional distribution, so there are efficiencies when the service provider has these processes and equipment already in place. “Our skill set allows us to perform kitting through picking, packing, and shipping a variety of products either built to specification or through customization for each order,” O&M’s Odenkirk says. “We are able to assemble kits based on drawings or instructions from clients for standard medical procedures, or alter a kit based on what a surgeon needs for a given patient.” 

As 3PLs move into value-add services like kitting, contract packagers are expanding their logistics and fulfillment capabilities. Some companies, such as Sharp, offer primary and secondary packaging as well as 3PL standard services. “By combining these services, we can partner with our customers and assist them with minimizing their working capital requirements, as well as assist them in fulfilling customer demand requirements,” Stehn says. “By providing these combined services, we streamline their supply chain.” 

Contract packagers and 3PLs say they maintain close ties with suppliers of various components and products for kitting. In some cases, pharma companies may designate or specify suppliers they have audited and approved, experts say. “Pharmaceutical companies are very disciplined about sourcing and often provide all components to 3PLs, or tell us exactly who to buy them from,” Exel’s Saponaro says. “The ability to plan effectively really comes down to the accuracy of the forecast and being able to predict demand, while taking seasonality and other factors into account.” 

In other situations, third-party service providers are given complete latitude to source components. “We typically work with suppliers that our customers already have in place, or we provide turnkey solutions using our own qualified vendors,” MD Logistics’ Luthman says. “In order to uphold the integrity of the kitting process, we prefer to coordinate the ordering and delivery of components to ensure we are time-sensitive and cost-effective.” When ordering materials, MD Logistics utilizes an in-house MRP (materials resource planning) system to manage its processes. 

Howell Packaging implements a program which qualifies and measures the performance for all of its outside sources, Lally says. Supply chain specialists utilize custom software to plan and manage the logistics of all required materials. These specialists are also capable of electronically connecting with customers and collecting their orders. “This allows us to assemble to the market instead of assembling to a forecast,” Lally explains. “This streamlined mode enables tighter response and achieves ultimate ‘postponement’ of final product assembly.” 

	During the sample-build process, assembly or special instructions are created. Once the client has approved the sample and assembly instructions have been approved, production of the kit can begin. There are controls built into the process to handle the intricacies of kitting services while distributing within FDA and DEA guidelines, industry members say. For example, maintaining a master device record of the components placed in the kit and supporting documentation is a necessary control. “Device specifications, production methods, quality assurance procedures, and packaging and labeling requirements may be contained in the device record,” OM HealthCare Logistics’ Odenkirk says. 

Another key component specific to a kitting operation is strict control over the labels, product inserts and similar material. “This would include inventory control, secure storage, and end-of-line clearance and accountability of all items,” UPS’ Amling says. “This process helps ensure that all units created or kitted are done so in accordance with the work instructions and with the original master record.” Kitting of DEA-controlled substances requires another level of security and accountability requirements mandated by the DEA for reporting and inventory control as well. 

In addition to maintaining necessary quality certifications and licenses, the requirements to perform a function such as kitting are the same cGMP type of guidelines followed for the warehousing and distribution of finished goods in healthcare, industry members say. All such activity must be done under the guidance of a compliant quality system that would include general inventory-control aspects such as cycle counting, traceability and product identification. 

FIG. 3. A MULTI-COMPONENT KIT FROM ANDERSON PACKAGING

“Packaging needs to be performed in a cGMP environment with appropriate technologies to ensure the safety of the drug supply,” Anderson’s Schroeder says. “Mistakes can have serious implications for the patient and the drug company.” Anderson says its packaging operations, systems, and facilities are audited by governmental agencies. 

Frequent training is also a control maintained to keep employees aware and

	well-informed of the proper precautions and procedures for processing kits. “All employees should be trained on the specific work instructions for the jobs they will be performing,” Amling says. “General requirements such as sanitation, pest control, change control, and vendor qualification all apply to a kitting operation, the same as with handling finished goods.” 

A key area of expertise third-party service providers can bring is regulatory and compliance knowledge. For an operation such as kitting, regulations mandate strict double checks of the process to ensure accuracy of the finished goods to the approved master record. “This would include random inspections and spot checks along the assembly line, as well as random inspections of the finished items themselves,” Amling says. “This ensures all products were kitted as outlined in the work instructions and that all product, lot and other specific information is accurately maintained and traceable.” 

Expiration dates of all components are tracked, so no product is placed in a kit that is outside of the allowable shipping window, or has already passed expiration. “As part of our batch record process, we work closely with our clients to ensure that the dating of the drug drives the expiration date for the kit presentation and that FIFO is used,” Stehn says, noting that due to the nature of its client base, Sharp sees a range of international regulatory inspections from MHRA, EMEA, and ANVISA. “It is not uncommon to exhaust one lot of a particular component and introduce a second lot when packaging a kit presentation.” 

Compliance with pedigree standards relative to the process of kitting and supply chain management is a major challenge, experts say. This pertains to being able to trace individual components of a kit in the event of a recall, as well as meeting state agency requirements to show the origin and chain of possession of each component in an effort to prevent adulteration and counterfeiting. The tracking of pharmaceuticals through pedigree is still in the early stages of development and thus, not all of the rules have been defined yet. 

“This presents a challenge in the interim of ensuring conformity with current legislation,” OM HealthCare Logistics’ Odenkirk says. “As pedigree rules evolve, 3PLs will take the proper steps to incorporate standards while managing the chain of custody of products within a kit.” PC 

When pharma deliveries involve a multicomponent kit, contractors offer dedicated services

Contract Packagers, 3PLs Vie for Pharma 'Kitting' Services

Historically, one of the barriers for patient acceptance of injectable drugs is a simple but practically unavoidable one: fear of needles. Today, however, the increasing shift from inpatient hospital care to outpatient services and home care is driving innovation in self-administered drug-delivery systems. 

Even after overcoming patient fears, additional obstacles are ensuring safe, accurate drug administration, and meeting the needs of such patients as those suffering from rheumatoid arthritis, which can make manipulating a syringe difficult. All these concerns collectively are driving increased innovation in syringe designs, added safety and dosage features, and protection against contamination from syringe components. The fact that many of the newest, high-value biotech products are injectables only adds further incentives for manufacturers to design syringes and injectors more carefully. 

“Injection devices are rapidly becoming an important strategy in the life-cycle management of diseases to treat chronic conditions, whether it is migraine or rheumatoid arthritis (RA),” notes Sheila Dell, PhD, a VP at Catalent Pharma Solutions (Somerset, NJ). “The increase in the aging population will affect the rising demand for these treatments going forward as well.” 

Proper injectable practices are a challenge for healthcare providers themselves, let alone patients self-administering drugs. This is evidenced by the launch of the Safe Injection Practices Coalition (oneandonlyca mpaign.org) to raise awareness that syringes and other administration devices should be used only once to prevent cross-contamination. The Coalition brings together several provider professional groups, CDC and FDA, and manufacturers including Becton Dickinson, Hospira and Covidien. The One & Only Campaign is aimed at promoting safe injection practices across healthcare settings to protect all patients. A study by Premier Inc., the Charlotte, NC, GPO, showed that 6% of providers sometimes use the same vial to administer injectables to multiple patients; and that 1% sometimes reuse syringes (thinking that merely replacing the needle is sufficient to prevent infection). Premier, also a Coalition member, published the study in the December issue of the Am. J. of Infection Control. 

SCHREINER MEDIPHARM'S NEEDLE COVER PREVENTS ACCIDENTAL STICKS

According to published reports, a lack of understanding exists about current

	regulations and guidelines governing basic safe injection practices and infection control protocols. This is despite the fact that FDA mandates Rx drug labels containing information for administration. “There are usually fairly explicit details with pictures about how to inject,” notes Karen Mahoney, an FDA spokesperson. “FDA evaluates labels and labeling prior to marketing for their potential for medication errors.” 

The frequency of patient-administered therapies is being driven, in part, by increased incidence of diabetes and chronic diseases like multiple sclerosis (MS) and RA, plus an increasing number of new biotech-based therapies and vaccines. Many injectable therapies require regular injections, often performed by the patient or caregiver in the home, which can be difficult. 

Ease of use is therefore of increasing importance, which means that the preferred application form are PFS (prefillable syringes),” says Claudia Petersen, director of business development at Gerresheimer Bünde (Düsseldorf, Germany). “This is one of the reasons why the PFS market still shows a sound growth rate.” Gerresheimer is a manufacturer of high-quality specialty products made of glass and plastic for the global pharma and healthcare industry. 

	Prefillable syringes are projected to post the fastest market growth among all primary parenteral packaging based on infection prevention and response time advantages in the delivery of emergency and critical care medication, according to the Freedonia Group (Cleveland), a market researcher. Many of the latest delivery systems and accessories are touted as being safer to use because they help prevent needle-stick injuries. 

For example, the Gerresheimer TELC from features a Luer Lock closure which combines the standard function of a conventional Luer Lock syringe plus tip cap with an additional tamper-evident function. Unilife Medical Solutions offers a ready-to-fill syringe featuring a retraction mechanism integrated into its barrel component. After drug delivery, the mechanism activates automatically and retracts the needle into the barrel. 

Catalent has forged strategic partnerships with companies such as Innovate, a move which led to the development of the Protector Safety Shield System. This provides a platform of technologies designed for needle stick protection, Dell says. “Catalent can combine these safety devices with its complete line of prefilled syringes, providing patients with improved safety and enhanced product performance.” 

Another example comes from Schreiner MediPharm (Blauvelt, NY), which has been marketing the Needle-Trap system for the past two years. Needle-Trap combines a multi-function label (label conversion being Schreiner’s main business) with a plastic cap-type component that allows needles, once used, to be enclosed, thus preventing needle sticks. More recently, the company introduced a multi-function label for auto-injectors that combines patient information with tamper evidence. 

In addition to safety, advances are being made in providing more user-friendly delivery systems, industry watchers say. In developing Cimzia, the only approved PEGylated anti-TNF, UCB (Brussels) reports it set out to design a prefilled syringe that would be easy for people with RA to hold and comfortable for them to use. Designed by the biopharma company in partnership with OXO Good Grips and created with input from people living with RA, Cimzia enables someone with RA to use and control the syringe with either one or two hands, depending on grip strength and control. 

Freedonia Group reports one of the most popular devices for self-administering insulin and other injectable medication with frequent dosing requirements is pen injectors. Innovations in prefilled insulin pen injectors have led to the commercialization of new automated dosing devices that provide for greater drug administration accuracy. One such device on the market is Novo Nordisk’s (Denmark) Innolet, a hand-held configuration featuring an oversized dial attached to a cylinder-shaped barrel that contains a prefilled cartridge of insulin. The needle tip is placed on the skin and a large activator button on the top of the device is pressured to administer the insulin. 

Eli Lilly (Indianapolis) offers four different insulin formulations in its prefilled pen injectors: Humalog, Humalog Mix 75/25, Humulin, and Humulin 70/30. The dosage dial moves backward and forward, allowing for the easy correction of entry errors. A magnifying window built into the pen’s body enables the user to confirm the number of insulin units prior to injection. 

While pen injectors and multi-dose cartridges can be used for those who have frequent needs, these systems are limited to specific therapies such as diabetes and growth hormones, which often require weighed dosages or dose titration. “They are not ideal for chronic users of fixed-dose medications,” notes Graham Reynolds, a VP at West Pharmaceutical Services (Cincinnati). “Easy-to-use auto-injector systems, which are based on prefillable syringes, are a more convenient method for delivering drug products, especially for patients who may have dexterity or needle phobia issues.” 

West, a manufacturer of components and systems for injectable drug delivery, offers the ConfiDose auto-injector system which allows the patient to have full visibility of the drug content while a single push-button activation enables automatic insertion, delivery and retraction of the needle. “The three-step operation has audible, tactile and visual indicators that function to assure the patient that the full dose has been given,” Reynolds explains. “A hidden needle is fully protected before and after injection, which make the system safe to use and easy to handle.” 

Biotech Drugs Influence Use of Packaging Materials

	The conversion of vials to prefilled syringes in various therapeutic categories, most notably vaccines and biotech drugs, is considered one of the most prominent changes in parenteral drug packaging in the past decade. But changing the primary packaging for a parenteral is typically a challenging project, industry members say, with extensive commitments both in terms of people and capital. Pre-filled, single-dose syringes face a number of challenges, such as compatibility with syringe components due to prolonged contact with the drug, as well as sterility assurance from pressure differential during air shipping. 

What’s more, new, sensitive biopharmaceuticals are forcing the industry to deal with packaging and delivery systems much earlier in the process. “Protein therapeutics are partly much more sensitive regarding potential interactions with leachables from the syringe system compared to chemical entities,” Gerresheimer’s Petersen says. “Syringe suppliers are addressing this problem by continuously improving their processes to minimize/eliminate the leachable source and increase product quality also with regard to cosmetic and dimensional aspects.” 

Suppliers say they are making progress in addressing these areas. For instance, Schott offers a syringe specifically designed for sensitive biotech drugs that makes injections less painful for patients. The InJentle syringe employs a “pinch seal” closure which ensures the drug is not in contact with the metal needle or adhesive of the syringe during storage, preventing contamination. The novel system was developed by Schott’s Pharmaceutical Packaging division in Switzerland with input from Cambridge Consultants (Cambridge, MA). 

SAFETY SYRINGE'S ULTRASAFE DESIGN INCORPORATES SCHOTT'S 'INJENTLE' TECHNOLOGY

“The InJentle syringe has a built-in ‘valve’ system between the barrel and needle to avoid leachables such as tungsten,” explains Alexander Jaksch, director of business development and marketing, Safety Syringes (Carlsbad, CA). The company markets UltraSafe Needle Guards for prefilled pharmaceutical glass syringes used for vaccines, low molecular weight heparins, and other medicines. 

Most prefillable syringes are based on glass, which may cause safety issues such as breakage and delamination. Newer drugs, including those with high viscosity or the need to be administered in high volume, have the potential to interact in a negative fashion with glass containers. “For instance, in a vial format, glass delamination is a potential issue,” West’s Reynolds says. “In staked-needle syringe systems, there are considerations such as adhesives, tungsten and silicone oil that can cause interactions.” 

The consideration of alternative packaging materials, although typically priced higher than glass, mitigates many of these issues and allows for more rapid development. The availability of cost-effective pre-fillable plastic syringes based on high-barrier COC resins provide the strong chemical resistance and high clarity needed for packaging parenteral drugs. It also enables companies to create easy-to-use, safe devices and systems without having to conform to the traditional container closure systems, such as vials or prefillable syringes, experts say. 

Biopharmaceutical and pharmaceutical companies, with the help of delivery systems companies such as West, are introducing break-resistant COCs for pre-fillable syringes, such as Daikyo Crystal Zenith, and unique designs that allow for easier and safer injection. “These systems are not only manufactured from a novel plastic material that reduces the risks of breakage,” Reynolds explains, “but the dimensional tolerances, quality standards, and freedom from materials such as silicone oil, tungsten or adhesives ensure that the systems provide the combined benefits of a plastic with the features necessary to contain a sensitive biopharmaceutical.” 

As the industry moves toward being more patient-centric, experts say product development will enable pharma companies to produce unique, safe and easy-to-use devices or delivery systems. Working closely with a knowledgeable manufacturer can help any company create a delivery system that provides excellent containment, safe administration and full-dosage delivery while mitigating risk. 

Patient-Administered Therapies Drive New Delivery System Designs

For years now, contract packagers (or repackagers) who have been waging a hearts-and-minds battle with pharma brand managers to make the investment in unit-dose packaging (UDP; comprising blister cards, wallets, foil and pouches). Lately—with a view toward the shift in healthcare from the next new blockbuster to improved outcomes&mdash;they have been reinforcing the good story they have to tell on medication adherence. The Healthcare Compliance Packaging Council’s (Bon Air, VA) upcoming national meeting has been renamed “RxAdherence 2011,” and its members are involved with a new study on the subject with M.D. Anderson Cancer Center (Houston). The UDP-adherence connection is also being promoted by new studies form the Agency for Healthcare Quality and Research (AHRQ) of HHS. 

On the plus side, UDP proponents have solid data that demonstrate that this form of packaging maintains better compliance with treatment regiments; that it affords numerous branding and patient-interaction pathways; and that it meshes well with workflows in patient settings like hospitals (so much so that many hospitals repackage pharmaceuticals delivered in bottles into UDP formats). On the negative side, it has a higher cost, usually, than pills in bottles, and in most parts of the retail pharmacy environment, pharmacists prefer to count pills over delivering a blister card or strip of foil-encased pills. UDP also has a harder time navigating the safety strictures of the Consumer Products Safety Commission (CPSC), which pushes manufacturers to provide both “child-resistant” and “senior-friendly” packaging, and has testing protocols for both. UDP designers have produced a steady stream of innovations to meet these requirements. 

UDP is widely used for sample packages as an important brand-communication experience and is a near-necessity for drugs with different titrations over the course of a therapy, notably birth-control pills. But the game has been to expand UDP into more of the conventional multiday-dose regimens that are dominated by pharmacists’ pill bottles.

	“Clearly, there are many reasons why people do not take their medication as directed,” says Walt Berghahn, executive director, Healthcare Compliance Packaging Council (HCPC; Bon Air, VA). “But the result is always the same; they don’t receive the health benefits of the medication that their health care practitioners have prescribed for them.” 

HCPC attributes an estimated $100 billion in lost drug sales and more than 300 deaths daily to patients failing to take their medications in the proper dosage, or on time. Industry studies indicate the top reasons cited for non-compliance are forgetfulness, lack of education and lack of product knowledge. “This means packaging can affect over half of the reasons (for non-compliance) by providing compliance prompting features and educational materials,” reasons Joe Lally, marketing manager, Howell Packaging (Elmira, NY). 

The non-adherence to medication issue has gained traction in the past year and is on the radar of more trade groups and health related associations. A case in point is the National Consumers League (NCL; Washington), which recently announced the development of a national education campaign on the importance of taking medications as prescribed. The three-year program—with planning funds from the AHRQ&mdash;aims to raise consumer awareness on the subject. 

“A significant way that UDP assists in patient non-adherence is by providing a visual cue to act as a reminder in two different fashions,” notes Bill Hartzel, product manager, Catalent Pharma Solutions (Somerset, NJ). “The first being a reminder if the patient took the medicine as prescribed and the second is the indication of the number of doses remaining to remind the patient when the prescription needs refilling.” 

	With a greater focus on patient outcomes, and with an aging, more-prescribed patient population, UDP proponents hope the trends are leaning their way. The high cost of poor patience adherence, and pressures on drugmakers’ and retailers’ supply chains, means the healthcare industry cannot afford to use the same old packaging. The most aggressive research and development of compliance packaging has focused primarily on consumer-based concepts. The challenge has always been related to enabling two critical functions in the packaging arena: consumer acceptance and child resistance. 

“With the advancements in packaging technology focused on achieving child-resistant levels of F=1 in CPSC testing through the ‘outer’ package, rather than the primary, there have been great advancements in the packaging field,” observes Kevin Carter, director of new business development at McKesson Pharmaceutical Packaging (San Francisco). “Simple calendarization is proving to be a great success in patient compliance relative to the ‘premium’ typically associated with compliance packaging.” 

Some of the latest UDP feature a variety of F=1 designs, such as IntuiDose, IntuiPac, CIAB, DuraPac, and AssuraDose from AmerisourceBergen Packaging Group. “We have always maintained that compliance-prompting packaging plays a vital role in driving compliance through calendarization, convenience, and as a platform for patient education,” explains Justin Schroeder, senior director, marketing and development services, at Anderson Packaging, a business unit of AmerisourceBergen. “What’s interesting is that you are finally seeing all the other tools being integrated into more comprehensive approaches, with pharmacist and nurse counseling, enrollment programs, and other tools being combined with compliance-prompting packaging in a very robust approach.” 

An example of this is the Pfizer Toviaz Physician Sample, recognized by HCPC as the 2009 Compliance Package of the Year. The package, developed for the treatment of overactive bladder, utilizes the IntuiDose child-resistant, compliance-prompting design. The design has passed CPSC Child Resistant/Senior Friendly unit dose testing and received favorable scores for senior dispensability. 

Achieving the appropriate child resistance level by dexterity and overcoming cognitive barriers to accessing the actual blister card are said to be among the biggest benefits of new compliance packaging solutions. Another benefit is it leaves the blister opening feature as a simple push through aluminum structure, such as the Burgopak solutions McKesson has brought to market. “We provide a full range of innovative adherence programs such as unique pharmacist-to-patient coaching services, financial assistance programs, applied behavioral expertise and insights, and call center reminders that help pharmaceutical manufacturers effectively reach and engage patients,” Carter says. “The combination of our packaging technologies and adherence programs for physician sampling provides a natural transition from a Burgopak sample to a Burgopak trade package, providing brand loyalty and recognition with patients.” 

Driving dosage compliance through a patented unit dose design is a key benefit of a topical delivery system from Catalent called the DelPouch package. “Convenient and easy to apply, the DelPouch package allows patients to release contents directly onto the treatment area,” Hartzel explains. “The affected area is not touched by anything but the foam pad, with package discarded after one use, so the patient does not come into contact with either the product or the treatment area, providing a safe, sanitary means of application.” This technology is being explored by prescription Rx, OTC, cosmetics, and beauty products. 

	While such innovative designs provide significant value to the patient and differentiation for the brand, further developments center on incorporating more information space and utility into the blister packaging. This allows pharma companies to provide patient-education materials and clear instructions on the dosage regiment, and, most recently, event technology-based cues to serve as reminders/prompters for truly interactive solutions. The expansion of the message is powerful, experts say, in how one gains the ability to convey information about the dosing instruction, potential side effects, and drug interaction information. 

“Graphic real estate is necessary to carry the educational messages pertinent to the product and therapeutic category,” Howell’s Lally says. 

Products such as MeadWestvaco’s (MWV; New York) Dosepak Express and Shellpak are calendared UDPs that provide a visual record of when the patient last took their medication. The MWV formats incorporate educational materials and dosing instructions into the packaging so it stays with patients wherever they go, and are said to provide pharma and retailers with better branding and bill-boarding space. 

Bristol-Myers Squibb’s Onglyza Physician Sample - submitted by Anderson Packaging and the First Runner Up in HCPC’s 2009 Compliance Package of the Year - features a two-panel Physician Sample folder design which utilizes a coldformed “foil-foil” unit dose blister design sealed into a carded blister. Indicated for the treatment of type-2 diabetes, patient prescribing information is integrated into the package. A pocket is included in the design to facilitate compliance supporting literature, allowing for placement of a wallet reminder card that directs patients to the drug website or toll-free number for further information about treatment and potential savings when filling their script. 

By incorporating features to drive patients to relevant therapeutic category support Web sites, the packaging can encourage a relationship between the pharmaceutical company and patient directly. Catalent offers new technology for the healthcare industry which connects the patient with online resources through a smartphone application, right from the package and without taking up valuable real estate. Leveraging imperceptible watermarks, Media Enhanced Packaging technology can be incorporated into packages to provide real-time content management, product-specific messaging, serve up instructional videos in multiple languages, or deliver special offers and coupons directly to the customer. 

“Catalent’s Media Enhanced Packaging technology increases patient engagement and improves overall outcomes,” Hartzel declares. 

The fact that unit dose formats can be designed with such compliance-prompting features is reportedly helping physician’s samples get a leg up on setting compliance behavior for the eventual therapy. The mainstay for samples is blister packaging, especially when the requirements for the sample are to provide several oral-dose pills, and when promotional and safety information are a key component of the package. “Clients are interested in differentiating their products by providing support materials along with the samples/starter kits and having the packaging assure, through compliance features, that the medication is taken properly,” Howell’s Lally said. “Titration of a pharmaceutical regimen may be indicated and specialized compliance packaging can be a key element in the product’s efficacy.” 

While product development is occurring against a backdrop of sample distribution changing to more of an online-request service rather than sales reps delivering samples, the overall purpose and utility of the samples and starter kits remain the same. “Physicians are treating their starter pack or experience kit as way to interact with the patient, informing them about the product itself, ways to understand the disease state and successful management, ways to enroll in support programs, tools for the patient-doctor relationship, and generally providing an ‘experience’ rather than a pocket full of free product that may or may not conclude in the filling of their script,” Anderson’s Schroeder observes. “It’s an investment in creating a lasting relationship and driving medication adherence for healthier outcomes.” 

While there has been a downward trend in the volume of sample packs being produced, this has not minimized the importance of samples. Catalent reports having conducted third-party market research with brand management and found that more targeted sample programs are taking place. “Even with the increasing pressures of generics ‘shelf visibility,’ the first patient engagement is vital in obtaining new scripts,” Hartzel says. 

	Industry studies show markedly improved patient outcomes and drug refill sales when patients receive their Rx drugs in daily-dose blister packs. A new study embarked on by MD Anderson Cancer Center (Houston) is meant to evaluate the impact of bottles and UDP on compliance. According to HCPC, the program will measure the results of compliance-prompting packaging for blood pressure, cholesterol lowering, and diabetes medications, plus aspirin. 

An electronic chip embedded into the unit-dose packaging will record each time a patient dispenses a dose. Similarly, the bottle caps on conventional vials will have embedded electronics to record when a patient opens it. “The captured package data needs to be read in the pharmacy, therefore, the patients are being paid to bring back the package to the pharmacy,” HCPC’s Berghahn explains. “The blister packs are from multiple suppliers, which is intended to neutralize the concern that one unit dose pack or another may influence adherence more readily than others. 

Healthcare providers at MD Anderson will track measurable health indicators such as blood pressure, A1c (blood glucose) and cholesterol and compare these outcomes with the measured differences in adherence by patients using the unit dose packages or bottles. In this way, the study does not simply measure adherence but also the associated impact on health outcomes linked to better compliance. 

MD Anderson operates a CERT (Center for Evaluation and Research on Therapeutics) for the Agency for Healthcare Research and Quality (AHRQ). MD Anderson’s CERT is focused on patient education and adherence,” Berghahn explains. 

While such new developments are promising, several hurdles stand in the way of greater adoption of compliance packaging. One of the biggest relates to cost, as production, shipping and storage expenses may be viewed as unnecessary. And there remains resistance in the pharmacy community, observers say, which is reluctant to change the way it does things. 

Packaging solutions providers say they are investing heavily in technology platforms to support commercialization of new unit dose formats. They offer flexibility and an ability to respond to what is working with respect to adherence features on a specific UDP, and adjust to improve other features that proved to have less utility than expected. “Having the cutting edge equipment in-house and readily available allows our customers to avoid significant capital investments, a particularly sensitive area in this economy,” Anderson’s Schroeder says. “We also offer the experience and expertise in launching pharmaceutical products, navigating the challenges of CR testing, successful qualification, and easing the general challenges and uncertainties in bringing new products to market.” 

Contract packagers say their ability to offer cost-effective compliance packaging solutions is critical to the success of the brands they package for customers. They claim to configure production lines much more rapidly than pharmaceutical clients can in their own in-house operations. “Contract packagers have the opportunity to aggregate more volume from multiple projects to develop their own ROI (return on investment) for further investment in equipment and technology, thus ultimately reducing the barrier to entry for manufacturers,” McKesson’s Carter says. 

An ongoing challenge for the UDP industry is weighing the ROI for investing in their format, which is reportedly a more expensive packaging option. But when costs are factored in over a long period of time, industry members say the economic benefits are huge if it results in lower overall healthcare costs, more patients taking their meds as prescribed, and refilling on time. 

McKesson reports it is setting up a second pilot study in the next 12 months with its Health Mart pharmacies to determine how the Burgopak package stacks up against Rx drug bottles relative to refill and adherence behaviors. The results from the first pilot, which are expected to include qualitative and quantitative data, will only measure the impact of compliance packaging and are expected to be released this year. This data is considered crucial for vendors in gauging whether to switch their packaging vehicle from a bottle or vial. 

Data is viewed as the key driver in convincing brand management to utilize patient adherence packaging, experts say. There are several different studies, such as from Ohio State University, or the Federal Study of Adherence to Medication in the Elderly (FAME), which indicate packaging is a major contributor to increasing patient adherence. “However, most studies incorporate multiple adherence drivers, so it has been difficult to obtain isolated data on just the packaging,” Catalent’s Hartzel says. 

In a recent development, Catalent, through a third-party data collection agency, reports it was able to obtain patient level data comparing the same drug in a conventional package vs. a unit dose adherence package. The information revealed a significant increase in refill rates and the brand teams were able to easily convert this into projected revenue. However, providing the initial data is just the start of the conversation. 

‘We do not believe ‘one size fits all’ for patient adherence packaging solutions,” Hartzel says. “We believe to improve patient adherence the package needs to incorporate multiple adherence drivers that are tailored to the needs of specific therapeutic areas.” The different types of drivers being addressed with Catalent packages are the inclusion of co-pay cards, increased billboard space, configuration for titrations, and sleek designs for portability and discretion. 

Looking ahead, industry members say they remain focused on offering designs that enable packaging that is both functional and serves as a vehicle of communication between pharma companies and patients. Says Hartzel: “We believe that packaging has a unique opportunity to convey a message to patients at the point of use to improve their engagement.” PC 

UDP proponents have solid data that demonstrate that this form of packaging maintains better compliance with treatment regimens