Andreas Graf

The pharmaceutical and medical product industries will witness a converging of trends in the next decade. For example, the global population is projected to rise from 6.5 billion in 2007 to 7.6 billion by 2020.

  Furthermore, the percentage of elderly people is rapidly increasing — predictions suggest the elderly population will increase from today's 7% to approximately 9% by 2020.

  A stronger focus on therapies rather than cures is set to continue, as is the growing need for anti-infectives as resistant strains continue to evolve. Additionally, there will be a greater need for antivirals as the world seeks to prevent the occurrence of pandemics. Some of these trends will present significant opportunities while others will pose new challenges.  

However, all of these opportunities could be negated by the lack of laboratory productivity as nearly a third less drugs are being developed than 10 years ago. 

Although the pharmaceutical industry will have to address this lack of laboratory productivity in the long term, packaging is a vital link to serving an expanded market with an ever shrinking pool of new drugs.   

Pharmaceuticals and medical device manufacturing blur the lines between packaging and product more than any other market. Packaging impacts the safety and usability of a drug or medical device, and often serves as the primary interface with the patient or medical professional.  

Trends in drug delivery, pharmaceuticals, nutraceuticals, biopharmaceuticals and vaccine development, coupled with cost pressures worldwide, have positioned packaging as an integrated process whereby automation and engineering partnerships are a necessity for medical and pharmaceutical device companies to compete effectively. This type of partnership can increase overall usability while increasing efficiency and reducing costs. Looking at some of the key trends in the medical and pharmaceutical industries, and outlining the role of packaging in each can help to better integrate packaging technology to improve profitability. 

The lack of innovation in the laboratory has forced pharmaceutical companies to differentiate themselves in other ways; for example, through packaging. The decrease in the number of new medications, the rise in worldwide population and changing dynamics in the marketplace all affect how packaging is implemented and integrated into the global development, production and marketing of pharmaceuticals. 

Convenience in the medical products market is determined by whether a product is easy to use and whether it encourages patient compliance (correct dosages, correct combinations of dosages, and the elimination of sterilization and verification).  

Single-use medical products are one growing area that illustrates the merger between packaging and product; for example, the move toward prefilled syringes for vaccines, heparin, cardiovascular products and new biotech drugs demonstrates how processing and packaging have merged into one seamless solution. Presterilized syringes are delivered in sealed plastic containers or tubs direct to the filling and packaging operation. The increasing numbers of suppliers of presterilized, readytofill syringes have given this segment stronger market shares compared with bulk syringes, which must be sterilized prior to filling.  

During the years, syringe manufacturing technology has evolved, providing higher capacity and integrating several components into one system. For example, the Bosch FXS 5100 can fill and seal up to 36000 syringes/h, and has a fully automatic inline check weigher and an optional integrated isolator unit.  

The demand for application and dosage control have led to a market growth of inhalers and needlefree injectors. These technologies rely on extremely fine powder that can be challenging to package and control. In addition, these devices are often tailored to administer only certain drugs or brands or drugs. Creating a system that can fill and assemble these devices, and seamlessly integrate them with primary and secondary packaging, helps increase the overall accuracy and efficiency of a packaging/manufacturing system. 

Convenience is inextricably linked with patient compliance, which can have a significant impact on larger health trends. Convenient packaging, such as integrated instruction leaflet, timemarked blisters and easytocarry shapes and sizes, can improve patient compliance. This is particularly relevant given that the overthecounter market is set to grow as governments loosen regulations on pharmaceuticals that pose little threat if the incorrect dose is taken. 

One example of convenient packaging is stick packs, which are conveniently sized and allow powdered healthcare products to be ingested directly by patients: a method favoured by many as it is easier and more pleasant than ingesting a product that has to be dissolved in water. Additionally, pharmaceutical wallets are a packaging style that combine the aforementioned aspects into one package, and are ideal for improving patient compliance. Another example of packaging that is both convenient and boosts patient compliance is Burgopak. This portable product provides integrated patient instructions, easy-to-open and close features and anticounterfeiting measures.  

Safety is a key driver in most industries and is the primary goal in healthcare. Part of safety lies in patient compliance. However, processing medical products safely and accurately is also crucial to the safety of patients, as well as for those working in these manufacturing environments.  

To increase accuracy, safety and efficiency, many packaging and processing applications integrate PAT. This FDA risk-based approach enables high efficiency and quality assurance in pharmaceutical manufacturing by introducing inspection and controlling systems throughout the entire process. This is known as closed loop control — nothing advances to the next step unless a problem is either fixed or a faulty element is rejected from the system.  

PAT is important for ensuring product safety, but further automation and safety technologies, such as advanced isolation and automated cleaning technologies, are required to protect processing workers from harmful exposure to volatile substances such as oncology drugs, biopharmaceuticals and vaccines. These volatile substances are also rapidly growing markets; there are currently 245 pure vaccines and 11 combination vaccines in development. With fears of worldwide pandemics and large foundations funding vaccines on a global scale, this market is set to accelerate production.  

The demand for barrier technology for aseptic filling lines, isolators and containments will also follow suit. These barrier technologies have been gaining wider acceptance in an effort to meet these growing trends for safety and compliance, and because FDA guidelines for aseptic manufacturing strongly recommend the use of such technologies. Although isolators and restricted access barrier systems (RABS) are not new technologies, the industry is rapidly adopting them as a result of improved validation experience.  

Isolators are ideal for new integrated installations while RABS are more suited to preexisting installations. Both, however, offer greater safety for personnel working in the pharmaceutical industry and better quality control for the production of pharmaceuticals, biopharmaceuticals, and vaccines.  

Integration in this area can be key. An integrated isolator and filler offers some advantages compared with two components from two suppliers; for example, in an integrated system, controls are integrated as is the knowledge base behind the system. If the system has to be serviced or changed, the integration of the two components is more easily understood and resolved. 

An increasing trend in the pharmaceutical and medical device markets is product diversity. For scientific and social reasons, such as a movement toward more potent and toxic treatments as well as a demand for greater convenience, discretion and mobility on the part of the patient, these markets have presented more complex and diverse pharmaceutical and medical product solutions. The packaging supply chain is following suit. For example, some medicines, such as cytotoxic agents and hormones, require minimal doses because they are highly potent. These drugs have a higher risk of crosscontamination from harmful dust exposure and powders can vary slightly in density. These factors have led to a rising trend in liquidfilled capsules.  

From a packaging/processing standpoint, technological evolution to meet this product diversity trend is vital, and new innovations have streamlined production and increased quality; for example, liquid encapsulation micro spray (LEMS) has simplified closure of hard gelatin capsules by spraying a solution of ethanol and water on the body and cap overlap, eliminating the need for banding. Degassing is another development that prevents bursting after the closing procedure. This process divides the closing into two steps allowing positive pressure to escape before the final closing occurs. 

Anticounterfeiting is also an important element of safety. The market for pharmaceuticals in E7 developing nations is set to grow from $518 billion (€416.2 billion) in 2006 to more than $800 billion (€642.7 billion) in 2020,

  but counterfeits could threaten this growth. The many anticounterfeiting measures available through packaging technology are a wise investment to maximize growth in this sector. 

Cost pressures on the marketplace are a result of greater competition from low-cost overseas suppliers, higher material prices, and increasing demands for more features and greater convenience. In addition, many government initiatives to drive down costs are on the horizon in Europe and in the US. Administrative costs account for the highest single cost in most healthcare systems — as high as 30% in the US while prescription drugs account for only 10%. Be that as it may, Big Pharma remains a major target in the mindset of political leadership and the public, and cost-cutting measures are likely. 

The packaging industry can reduce costs through efficiency. Greater automation and integration of packaging lines for medical and healthcare products is a direct, yet effective, way of reducing the total cost of operations while maintaining quality and innovation. For example, Sigpack's stick pack solution can be linked directly to a cartoning machine from the same manufacturer. The entire system can pack stick packs in one or two lanes up to 1000/min. Various resources are available to ensure this type of entire-line integration — filling and processing, to primary packaging (e.g., cartons and blisters), all the way to secondary and third degrees of packaging (e.g., cartoners and case loaders) — is expertly integrated from a single source responsible for the entire line's efficient operation. 

Working with a single supplier is a good way to seamlessly integrate a line. The resources of a single supplier allow companies to leverage the collective knowledge of the organization and create solutions that are focused on end results; not on the operation of a single machine. In addition, other resources within the company may be available that can streamline automation.  

Another component of efficiency is in material savings. Reducing use of materials is key to lower costs and has the added benefit of having a positive impact on the environment. Packaging technology plays a large part in saving materials; for example, stick packs can save 20–40% material if used instead of the traditional packet. 

Other packaging technologies can be adapted to use less material or alternative materials. Furthermore, packaging suppliers can often engineer solutions tailored to certain applications that can lead to more efficient uses of materials. An early partnership with packaging machinery manufacturers can help convey a better understanding of end-user needs and material reduction demands. Creating technology to accommodate these factors is more likely with an early partnership in place. 

Integration key — partnership essential

Packaging will play a more important role in differentiating medical products in the market as competition among existing products increases. Because of greater diversity in the marketplace, higher demands for safety and convenience, and greater cost pressures from both the market and competition in lowcost countries, companies will increasingly need packaging partnerships that enhance product performance and reduce the total cost of production. 

To do this effectively, medical device manufacturers and drug producers must bring packaging technology into product development earlier to maximize its impact. Doing this can enhance overall product effectiveness, streamline processes and speed timetomarket. 

The global market for medical products is growing as populations age, emphasis on therapies grow and emerging economies invest more in healthcare. However, an integrated approach to the entire supply chain can ensure that growth is possible safely and economically.  

is Product Management, Sigpack Systems (Switzerland). 			

is Vice President Packaging Systems, Business Unit Robotics and Secondary Packaging Product Lines. 

is Head of Industry Management Pharma, Medical & Healthcare, Sigpack Systems (Switzerland).			

is Director Product Management and Marketing, Bosch — Pharma USA (Minneapolis, USA).			

is Vice President, Moeller & Devicon (Denmark).			

is Head of Product Management, Bosch — Pharma Liquid (Germany).			

Pharma 2020: The vision; Which path will you take

Addressing patient compliance: Targeted marketing driving a shift in focus from acquisition to retention

3. "Non-compliance costs drug industry dear", 

4. Prescription Medicine Compliance, A Review of the Baseline of Knowledge — A Report of the National Council on Patient Information and Education (1995). 

Articles

Creating better pharmaceutical and medical products with packaging partnerships.

The packaging connection

Twenty years ago it was commonplace for pills, tablets and capsules to come in small, plastic or even glass bottles. Syrups were a much more common galenic solution than today, and individual dosages of injectables were only offered in glass vials and ampoules. 

While it is observable that trends vary regionally — in Europe, blister packs have all but displaced glass or plastic bottles, while in the US bottled pills remain popular — there are many global trends that have emerged during the past two decades. Where once galenics were largely confined to pills, tablets and gel capsules; syrups; injectables; and suppositories, there are now several new methods that are becoming more popular, including individually dosed powders, inhalables and pens. All of these developments, along with increasing competitive pressures and the patient's need for convenience, have influenced packaging design, styles and manufacturing. 

Sigpack Systems continuously surveys pharmaceutical market leaders, mainly across the US and Europe, about the industry's requirements for packaging. It also remains abreast of legislative and regulatory trends. In this article, some of the results of recent observations are considered along with predictions about developments in the pharmaceutical sector and their implications for packaging machinery. 

The pharmaceutical packaging market is constantly advancing and has experienced annual growth of at least 5% per annum during the past few years with single applications showing double-digit growth. The market is now estimated to be worth more than $21 billion (€14.5 billion) a year. Figure 1, which provides a breakdown of the current packaging industry, illustrates how the variety of packages have moved inexorably toward blisters and strips, but also how much accessories and closures (indicative of convenience packaging) accounts for in the total value. Blister packs, plastic bottles and primary containers each account for $4 billion (€2.7 billion); pouches and strips account for a further $2 billion (€1.4 billion); while accessories and closures now make up one third of the packaging value at $7 billion (€4.8 billion). 

 Figure 1 A breakdown of the current pharmaceutical packaging market. 

As with most other packaged goods, pharmaceuticals need reliable and speedy packaging solutions that combine product protection, quality, tamper evidence, patient comfort and security needs. Constant innovations in the pharmaceuticals themselves (e.g., prefilled syringes, blow-fill-seal (BFS) vials and powder applications) have also directly impacted on the packaging.  

Traditionally, more than 50% of all medicines have been oral tablets or capsules, packed in blister packs (very common in Europe and Asia) or fed into plastic pharmaceutical bottles (especially in the US). Powders, pastilles and liquids also make up part of the oral medicine intake. However, other methods for taking medicines are now becoming more widely used. These include parenteral or intravenous (~29%), inhalation (~17%) and transdermal (~3%) methods. Oral tablets are now available in a wide range of shapes and sizes. 

These changes have had a big impact on the packaging industry. There is also an increasing need to provide tailored, individual packaging solutions that guarantees the effectiveness of medicines. Degradation as a result of environmental factors, such as light and humidity, often indicates a direct link between packaging and a remedy's effectiveness. 

The packaging of oral medicines generally conforms to requirements for easy dispensing, child resistance and senior-friendliness, but packs must also be identifiable, functional and, very often, hermetically sealed. Some innovations provide added benefits in one area, but may not conform to the expected standards governing another. For instance, blister packs provide convenience and ensure hygiene. They are ideal for our fast-paced lifestyles and the need to take medication on the go and, as a result, there has been a large increase in their use. Indeed, blister packaging has provided the best worldwide growth among all pharmaceutical packaging products. The average demand increases 6.2% annually and reached more than $4 billion (€2.7 billion) in 2006.  

However, alongside increased hygiene and convenience, the medicine still has to be child resistant and identifiable. Few blister packs are child resistant, and this goes against recent government proposals to ensure that medicines containing aspirin, paracetamol and iron are supplied in child-resistant packaging to reduce the occurrence of accidental poisonings. The proposed legislation particularly targets blister packs. 

Advances in packaging machines have included incorporating precise filling mechanisms, as the wrong dosage of a medicine could be life threatening. Gentle handling is also essential and packs should be hermetically sealed for higher product safety. A solution to achieve hermetically sealed packs for blister, blow-fill-seal pouches, vials and other products is to overwrap them into a horizontal flow wrap. These flow wraps consist of a foil laminate that is able to increase the shelf life of the product, as well as ensure 100% moisture and air tightness.  

Some packaging requirements are not driven by the need for hygiene, safety or traceability. The increased focus on the marketing of pharmaceutical products will become even more important in the future, and will influence factors such as the need for flexibility in various pack types and sizes. Other needs are driven by expenses as pharmaceutical manufacturers face increased cost pressures throughout the entire production and packaging process. As a result, packaging machines must become more efficient and user friendly, offering flexibility, easy operation, robustness, intelligence and protection from interference. The challenge is to be able to cover all aspects at once. 

The ongoing globalization trend —with extended competitive landscape in the pharmaceutical industry — will lead to smaller batch sizes as no one company is likely to dominate the market with high-volume blockbuster drugs. Using existing packaging equipment will have a negative effect on productivity because older machines were generally not designed for quick changeovers and flexibility. New packaging lines will have to offer high flexibility while maintaining production levels.  

Availability is an absolute must in the pharmaceutical industry, which necessitates the highest possible packaging speeds combined with minimal waste and high flexibility. High-speed lines can produce the requested small batch sizes within a few hours, but then resetting formats requires additional hours, which negatively impacts the overall efficiency of the packaging line. Format changes and line clearance should be performed within a few minutes. To cope with this, the whole packaging process, including all modules and machines used in the entire system, must be completely harmonized. It is of no use if the majority of machines can be changed to handle a new batch within 15 min if it then takes more than 2 h to do the line clearance because some areas suffer from poor accessibility. 

To accommodate quick changeover times robotic toploading solutions, which are partly replacing sideloader technology in the packaging of cartons, are increasingly being used. With smaller batch sizes — in some cases, very small batch sizes are already a reality — toploaders increase the overall efficiency of the line. When compared with sideloading, toploading significantly reduces the format change time, sometimes from 1–2 h to less than 30 min, and offers greater flexibility for use with various pack types and packing patterns. 

To meet validation requirements, pharmaceutical companies increasingly demand that machinery is modularized and standardized. This includes a standardized operating interface and control systems for all components. Such systems also have monitoring systems for maximum production safety. With standardization and modularity, profitability can also be increased because the lines have to provide rapid changeover times to cater for different dosages of the same medicine in different pack types. The increased profitability is additionally supported by lower maintenance costs.  

It takes more than technology and its standardization to produce high efficiencies — the entire packaging process needs to be harmonized, which offers huge optimization potential. Within the pharmaceutical production and packaging process, many operations and interfaces between process steps are still performed manually.

In the future, many of these tasks will be taken over by flexible robotics technology or smart mechanical solutions. For example, the entire feeding process of products coming from batch production to the packaging line is, predominantly, still a manual process, which will be automated within the next few years. Already, many automated robotic solutions are available to handle blister packs, drug delivery devices, medical devices, intravenous bags,

blow-fill-seal bottles, tubes and other products. 

Until recently, pharmaceutical packaging had to fulfil three main objectives:  

While these criteria still apply — indeed, more than ever in some regions — there is a further dimension that has emerged: packaging ergonomics and design. 

While blister packs for tablets and gel capsules remain dominant, the packaging of loose powders and liquids has undergone some radical developments that packaging systems companies have been required to address as partners to the drug manufacturers. For example, vials produced using BFS technology are gradually replacing glass-filled ampoules for dosages of injectible, ophthalmic or inhalation treatments. BFS will dominate because the process enables very high-speed, low-cost automation, greater resilience and cheaper packaging materials. 

One application for BFS vials is at Dey Laboratories (CA, USA), which produced cards

of five BFS vials. Single overwrapped vials were needed for hospitals, but Dey had never packaged these. The company needed an experienced packaging partner to integrate an entire high-speed line (HSL). The new packaging would also need to satisfy FDA requirements without compromising throughput. 

The challenge was to separate the vials without cutting or breaking them and causing a leak. They also had to be sealed and hermetically wrapped at 600/min. This required two of our HSL

wrappers, which can wrap 300 products/min.  

Sigpack has also supplied a major Japanese manufacturer of prefilled glass and plastic syringes with an automatic flow wrapping system. Starting at a discharge unit from a buffering system, we had to integrate this with the flow wrapping process and an optional oxygen absorber supply. A high sophisticated product handling solution was also needed.  

A rotary disk feeder, combined with a linear screw feeding unit, was selected. As a special packaging option, the sealing of customized Tyvek (Du Pont, DE, USA) material was also used for complete sterilization procedures after the flow wrapping process. 

The integrated flow wrapping system produces up to 250 packages/min, while retaining compliance with the strict quality standards demanded by the Japanese market. The horizontal form fill-seal-technology enables higher productivity, shorter change over times for existing formats and a significant reduction in material costs. 

However, it's not just packaging demands that lead to innovation. Sometimes the packaging itself aids a product's commercial success. For example, the stick pack, which has been popular for years for sugar and beverage packaging, provides a high-speed and inexpensive method of packaging accurately measured doses of pharmaceuticals. This simple style of packaging is growing quickly within certain sectors, such as digestive remedies. Growth was 30% during 2007. 

Working with Warner-Chilcott (NJ, USA) to design packaging for birth control pills, we developed a customized blister packaging system to handle the new pack style. With a production speed in excess of 170 packs/min, contraceptive pill blisters are hermetically sealed using an aluminium foil. The flow-wrapped package includes the plastic wallet to hold the blister envelope, a desiccant and a folded patient information leaflet.  

The HBL is a long dwell seal machine that produces pillow-type packaging with hermatic sealing, and includes reciprocating cross sealing jaws to guarantee perfect airtight seams, which this makes it highly practical for pharmaceutical blisters and hygroscopic products.  

Warner-Chilcott now has a holistic system solution that manages the blister, wallet holder, patient information and desiccant with highest production efficiencies. 

Most markets evolve, but few have seen the radical shifts that have occurred in the pharmaceutical sector. There is no sign of this abating during the coming years because legislative, as well as commercial and galenic, developments create a continuous need to match change with similar packaging transformation.

 is head of industry management for pharma, medical and healthcare business at Bosch Sigpack Systems AG (Switzerland). During Sigpack's 2004 merger with Bosch, he was product manager for flow wrapping systems. Originally trained as an engineer, Andreas has worked within the pharmaceutical industry in a variety of roles for more than 10 years. He is currently studying at Zurich's Graduate School of Business Administration in Switzerland on a global MBA programme in partnership with the Robert H. Smith School of Business (MD, USA).

Twenty years ago it was commonplace for pills, tablets and capsules to come in small, plastic or even glass bottles. Syrups were a much more common galenic solution than today, and individual dosages of injectables were only offered in glass vials and ampoules.

20th Anniversary Special Feature: Two decades of packaging development

The diversity of the pharmaceutical industry, ongoing globalization trends and the growing importance of product differentiation have presented new demands for efficiency and flexibility in the packaging process. Packaging must now be regarded as integral to the rest of the manufacturing process as it plays a vital role, not only in maintaining the competitiveness of over-the-counter (OTC) treatments, but also for the stability and, increasingly, the traceability of all pharmaceutical products.  

Packaging must now guarantee product stability within specified time frames as well as ensure safe and secure storage of the product until final use. Furthermore, in many countries there are requirements for child resistance, tamper evidence, protection against counterfeiting and, simultaneously, maximum patient convenience. 

This changing role for pharmaceutical packaging has created the requirement for innovative yet economical design concepts for integrated lines. The real challenge is to combine product and system flexibility with maximum efficiency of the packaging lines. The era of blockbuster products being manufactured in huge quantities during many years with massive stocks held in warehouses to guarantee product supply at short notice has passed. This scenario put no requirement on packing equipment to be flexible as the packages rarely, if ever, changed.  

Now, products must be shipped from manufacturers without delay, often in several pack variants. Data, such as region-specific leaflets, country codes and languages must be implemented in the packaging process as late as possible. Technological innovations in on-line printing, labelling and even re-engineering of the process itself have had to support these needs. 

With the increased importance of safe and secure supply chains in the global pharma market, PAT has been implemented under various regulations to ensure product and process quality. New technologies to aid traceability and fight counterfeiting, such as RFID tagging, are being driven by the likes of FDA as well as global commercial enterprises such as Wal-Mart. 

All of this has placed a greater imperative on contract packers and co-packers, for the simple reason that increasing numbers of manufacturers are driven towards outsourcing packaging. Apart from relieving themselves of the issues relating to coding, validation and so forth, principals can introduce greater controls over timing, delivery, volume and call-off. Of course, the contractor has to equip itself to cope with these demands — including fluctuations in call-off of product. 

One of the problems faced by contract packaging companies and co-packers is the complexity of modern flexible packaging systems. The prospect of linking conveyor, in-feeds, feed placement systems, wrappers, cartoners, labellers along with quality control measures such as vision systems, check weighers and barcoders, is daunting. The option is to source individual machines and equipment, and then orchestrate mechanical linkages, electronic communications and software. Specialist integrators — especially in the UK and Northern Europe — frequently handle the line set-up and implementation.  

The sourcing of packaging solutions from single vendors has grown in appeal as the need for sophistication and flexibility has increased. The concept of taking equipment from a variety of disparate manufacturers poses problems of integration, but also of subsequent validation. For this reason there has been a marked rise in the using of specialist packaging system integrators. While integrators may do a professional job, they are often largely confined to dealing with software issues relating to the integration of control systems and data capture. Single vendor packaging machine companies can also address hardware compatibility, overall system efficiency and aid the validation process of the entire system.  

Taking the central responsibility for the system engineering, project management and line installation enables the time-to-market to be reduced and the risk of system failure to be minimized. Moreover, the time for line qualification and validation at the end-user's side can be shortened significantly. 

The validation and qualification issue is a thorny one for contract manufacturers and anything that aids rapid qualification is important. With the validation process usually taking anything up to 18 months, it has the potential to cause costly delays in the installation of new packaging equipment. This is a considerably more daunting prospect where several equipment vendors are concerned with the same line. 

Such turnkey supply of packaging systems also provides the sometimes underestimated benefit of common control and quality assurance concepts. Apart from again simplifying the validation process, this factor also:  

provides greater assurance of continuation of after-market support.

For the operators, there are long-term benefits in sustainable system reliability and simplified life cycle management, including after sales services for spare parts, service level agreements, modernization upgrades and field services. 

These changes have made a big impact on the packaging industry and there is an increasing need to provide tailored, individual packaging solutions that guarantee the effectiveness of medicines. Because of degradation from environmental factors, such as light and humidity, there is often a direct link between packaging and a remedy's effectiveness. 

Today, 51% of medicine is taken orally, in tablets, capsules, powders, pastilles and liquids. The introduction of new laws concerning the supply of medicines has had a serious impact on packaging for these oral medicines; for example, Regulation (EC) No. 726/2004 (replacing Regulation 2309/93) and Directive 2004/27/EC (amending Directive 2001/83/EC on human medicines). Both of these are governed under Regulation (EC) No. 658/2007, which covers failure to comply. Legislation ensures that packages are:  

The standard packaging forms of oral medicines generally conform to these requirements, but some innovations that provide added benefits in one area may not conform to the expected standards governing another. For instance, in taking account of our fast-paced lifestyles and the need to take medication on the go, there has been an increase in blister packs, which provide convenience and ensure the hygiene of the tablets. Indeed, blister packaging provides the best worldwide growth prospects among all pharmaceutical packaging products, with demand increasing 6.2% annually to US$4 billion by 2007. In the US, clear flexible packaging is expected to reach $6.2 billion by 2010, of which blister packs are expected to contribute $2.7 billion. However, alongside increased hygiene and convenience, the medicine still must be child resistant and identifiable.  

Not many blister packs are child resistant and this goes against proposals to ensure that medicines containing aspirin, paracetamol and iron are supplied in child resistant packaging to cut the number of accidental poisonings.  

Identifiable packaging is also now being given more attention than in the past. The advantages of being able to trace a tablet, pill or capsule back to the time, day and factory where it was produced have obvious implications such as being able to verify whether products have been tampered with or have substandard ingredients, recipes or processes in their manufacture. Many health and safety organizations propose that the packaging of all medicines should carry information in a standard format, or "number plate", to allow patients and health care professionals to check drug and dosage details quickly.  

Another requirement is that the packaging and labelling of medicines should be redesigned so that products are more clearly identifiable. For this reason pharmaceutical companies must undertake consumer testing of labelling to ensure it is comprehensible. 

Advances in the packaging machines themselves has seen the incorporation of precise filling mechanisms, as the wrong dosage of a medicine could be life threatening. Gentle handling is also essential, and packs have to be hermetically sealed. Linked to this is the increasing trend to substitute OTC medicine for prescription-only medications. As retail medicines do not carry the benefit of a doctor's advice at the point of prescribing, the labelling, patient information and safety precautions take on an even greater imperative". 

To ensure product quality and consistency, it is crucial that all the machinery uses proven technologies and control standards. This includes a standardized operating interface and control system for all components. Such units now incorporate sophisticated monitoring systems for maximum production safety. With standardization and modularity, profitability is increased as the packaging lines now allow rapid changeover times to provide different dosages of the same medicine in different pack types. There is also a growing trend for companies to supply not only the packaging hardware, but also the software to accompany the machines. Some packaging companies offer on-going training to ensure that strict packaging regulations are met.  

It is rare that contract packers can afford the luxury of simply closing down operations while a new line is installed. One of the serious considerations, therefore, is how new equipment can be phased into the existing plant. Apart from the frequently encountered real estate issues of inadequate space, there are also other logistical considerations such as provision of power and so forth.  

Sometimes lines can be upgraded with the incorporation of new equipment — for example, where an existing line that had fixed automation for wrapping is being upgraded to incorporate new, more flexible wrapping systems. In these cases, the expertise and experience of the machine supplier or integrator is at its most essential. 

Another example of packaging line integration comes from the emerging requirement for packing prefilled syringes. As well as providing enhanced safety and accuracy, further benefits lie in prefilled syringes' ease-of-use and timesaving. Indeed, surveys within the industry have predicted increasing demand for this type of product during the next few years. 

The North American Medical Device Packaging Market

 (analyst of the study: Urmila Kishore) — a survey conducted by Frost & Sullivan, shows that the market earned revenues of $569 million in 2006, with that number predicted to rise to $918.8 million by 2013. Another survey conducted by David S. Enterline MD in the US found that the majority of medical workers favour prefilled syringes. There have also been numerous surveys conducted by pharmaceuticals companies and the internet is peppered with positive findings for this relatively new gallenic delivery solution.

The most common pack styles for prefilled syringes are carton trays or thermoformed packages. However, manufacturers under pressure to increase productivity have sought packing systems with higher efficiencies. One solution is to use horizontal form-fill-seal (HFFS) technology, which is well-established in fast-moving consumer goods markets such as foods, confectionery and snacks. Such equipment offers a significant reduction in production costs by the fully automatic flow wrapping of the prefilled syringes. 

A major Japanese manufacturer of prefilled syringes has installed a fully automatic flow wrapping system. The interface within the manufacturer's production process was the discharge unit from a buffering system. This had to be integrated with the flow wrapping process, as well as with an oxygen absorber supply. A new product handling solution was also needed.  

After testing different handling techniques, a rotary disk feeder, in combination with a linear screw-feeding unit, was selected. This produced excellent results in relation to both reliability and product security. As a special packaging option, the sealing of customized Tyvec material was also implemented to enable sterilization procedures to be completed directly after the flow wrapping process. 

The resultant integrated flow wrapping system for prefilled syringes outputs over 200 packages/min, while retaining compliance with the strict quality standards demanded within the Japanese market. The HFFS technology has allowed the customer to benefit from higher productivity, shorter changeover times for existing formats and a significant reduction in material costs. 

The integration of complicated packaging lines from a single vendor source can be clearly identified from design to installation. However, there are further benefits during the lifetime of the equipment, including maximizing its uptime and efficiency. Commonly, the planned maintenance and support for plant and equipment is referred to as asset efficiency optimization. For contract manufacturers, downtime is anathema and hence, being able to rely on continuously running packaging lines is vital. 

Pharmaceutical manufacturers are under increasing pressure to shorten time-to-market, produce treatments with unpredictable product lifetimes, provide greater flexibility and, at the same time, comply with ever more stringent quality, validation, stability and traceability constraints. While this is encouraging for the contract manufacturing sector, it creates the need for even greater manufacturing flexibility.

Packaged solutions for flexible production

Blow-fill-seal (BFS) products are rapidly gaining ground as the preferred delivery method for many oral and ophthalmic treatments in the pharmaceutical industry. The adoption of BFS has, however, created new requirements for product packaging systems. This article examines these requirements and discusses how they can best be addressed. 

Reducing time-to-market, optimizing the efficiency of asset usage and maximizing yields are all key concerns for today's pharmaceutical companies. Yet the processes of qualification and validation are becoming ever more stringent; a development that has the potential to create costly delays in the implementation and commissioning of new systems. An attractive and effective solution to this conundrum is to consider the installation of complete production lines, sourced from a single supplier, rather than obtaining the various elements that make up the line from a variety of different sources. As many pharmaceutical suppliers are currently involved in the installation or specification of packaging lines for BFS products, let us examine how this holistic approach might operate in a typical application of this type. 

The example we will consider handles the complete packaging process from BFS cards in to packed cartons out. To provide this functionality, the line will be made up of a flow wrapper together with deloading facilities for bulk packaging and bowl feeders for product separation. Robots will be used to place the BFS cards into the feeding chain of the flow wrapping. 

Secondary packaging equipment will comprise a carton former, a top-loading platform, a tray closer and a case packer — all located at the end of the packaging line. To further reflect the reality of modern installations, the line will be configured to handle several BFS card formats as single or multiple packs, as well as various sizes of tray. 

Clearly, for applications in the pharmaceutical industry, verification of printed data, such as lot numbers and expiry dates, is an essential requirement. Fortunately, this can readily be achieved in this packaging line using vision systems. 

Modern vision systems are easy to set up and use, as well as being surprisingly inexpensive. They can check all printed data with ease, and can keep an electronic log of the results. It is also relatively easy to arrange for packs with incorrect printed data to be rejected automatically, ensuring that they never reach the final packaging process stages. 

In many pharmaceutical manufacturing plants, cards of BFS vials are blown, formed, filled and sealed in a process that is separate from the packaging line. Typically, the cards are made up of four or five vials containing the portioned pharmaceutical infusion liquid. After manufacture, these cards are bulk stored with random orientation. 

The first stage of the packaging process is, therefore, to deload the cards by placing them on a transport conveyor that moves them to a bowl feeder; automatically stopping and starting the conveyor system can readily prevent overloading. 

While centrifugal bowl feeders find frequent application in pharmaceutical manufacturing, their use with BFS packs imposes special requirements. In particular, guiding spirals designed specifically for this application are essential if continuous feeding is to be achieved, and additional positioning controls may be needed at the feeder exit. 

When the BFS cards leave the bowl feeder, they must then be placed and stacked precisely ready for flow wrapping. The high throughput needed in today's installations means that a robot-based solution with picking rates of at least 100 products/min is virtually essential. 

Let us not forget however, that the orientation of the BFS cards at this stage is still not uniform. A vision system is, therefore, needed to capture an image of each product and determine its orientation. With this information, the robot system can work at maximum efficiency and with the minimum risk of product damage. 

Conveniently, the same vision system can be used to verify key product parameters and initiate the rejection of any products that fail to meet the required specifications. A separate image is captured for each and every product, which means that the product profile can be accurately verified by comparing it with a stored reference shape. 

A log of rejected profiles can also be maintained and the reject rate calculated in real-time. Should this rate exceed a preset value, arrangements will usually be in place to halt the operation of the machine so that the source of the problems can be determined and addressed. 

The type of robot used for placing and stacking the BFS cards is important. Conventional multi-axes designs have limited flexibility, often combined with high inertia that limits operating speeds. An alternative design however, uses a structure based on jointed arms suspended below the operating mechanism. The arms meet at the gripper device, giving the robot an overall appearance somewhat similar to a spider with its legs joined at their tips. 

This arrangement allows arms with low mass to be used, so it has inherently low inertia, which means that high operating speeds can be achieved with ease. It also provides the versatility needed to allow the system to handle multiple pack sizes and product stacking patterns. 

BFS products are most frequently supplied in hermetically sealed packaging; making use of materials with low permeability for oxygen and water vapour and additional functions such as light protection. 

Flow wrappers are readily available, but not all can provide an extended dwell time for the sealing cycle while maintaining the necessary high throughput. Extended dwell time is highly desirable, if not essential, in pharmaceutical applications with the highest requirements for sealing integrity and tightness. 

Further features appropriate to the pharmaceutical industry that are provided by industry-orientated flow wrapping machines include water-cooled cover plates for the longitudinal sealing section to protect the product, and gas flushing to facilitate the use of modified and controlled atmosphere packaging. Cross-seal gusseting for multipacks is also useful, as is online verification of sealing parameters to control process reliability. Finally, in our example application, which involves the use of multiple packaging formats, a fully servo-driven machine will offer the benefit of fast, easy recipe changes. 

Flow-packed BFS products are invariably supplied in cartons. Typically, in the pharmaceutical industry, these are designed with a front flap closure that is tucked in, with dust flaps to each side. Carton forming is a relatively straightforward process, but 100% inspection is recommended to ensure that the cartons are glued perfectly every time. Facilities for inserting user information leaflets can also be provided at this stage. 

Loading the flow-packed products into the cartons is another process where robots provide an optimum solution. In this case, robots of relatively conventional design can be used, but there are still a number of special features that aid productivity and flexibility. 

For example, the ability of the loading system to stack the flow packs vertically or horizontally is invaluable, as is product-specific handling design to place the flow packs very tightly within the carton, thereby minimizing the size of carton needed for a particular product. 

After being filled by the robot loading systems, the cartons require closing. An essential element of this process is precise carton control to ensure that the dust flaps are folded inside, before the top flap is closed and the front flap is tucked in. With most packs, no glue is required, and facilities for changing the pack size without having to change machine parts are highly desirable. In many cases, this is also a convenient stage to mark the cartons with final production data by laser coding, printing or labelling. 

The last operation to be performed by our integrated packaging line is the packing of the individual cartons into cases for shipping. A similar robot system to that used for carton filling can conveniently be used for this process, complemented by a case closer that folds the case flaps and seals them with tape. 

In the pharmaceutical industry, there are clear demands for good manufacturing practice (GMP) and machine qualification procedures. Extensions to FDA regulations, including 21 CRF Part 11, have also placed greater emphasis on validation and product traceability. Purchasers of packaging lines can address all of these requirements by drawing up detailed specifications but, in some cases, there may be a faster, easier and more cost-effective approach. 

This is to make full use of the application adjusted standard documentation supplied by the system vendor, adding to it only where necessary. This procedure is considerably simplified when, as suggested in this article, the whole of the packaging installation is sourced from a single supplier.  

Naturally, relying on vendor documentation is only an option when the system purchaser can be totally confident that this is dependable and comprehensive. 

The most enlightened suppliers to the pharmaceutical industry have addressed these issues by, for example, developing basic standard documents for functional design specification and design qualification, as well as installation qualification (IQ) and operational qualification (OQ) plans based on customer end-user requirement specifications (URS). In this process, adherence to the V-model commonly used in the pharmaceutical industry is an advantage. 

Another development that suppliers of packaging machinery to the pharmaceutical industry have had to accept in recent years is the pressing need of their customers to bring new products to market quickly. This demand is not only addressed by shortened delivery times, but also by achieving full productivity as soon as possible after installation. 

Careful design of the installation plays a significant role in this by ensuring that the system is easy to install and commission. Comprehensive pretesting and prequalification at the vendor's premises is another important element, but there is a further key factor, which is easily overlooked. This is the quality and unification of the operator interface. 

A well-designed operator interface, based on modern graphical display and touchscreen technologies, greatly reduces the need for operator training and the risk of errors during the early stages of operation. Similarly, the use of a common control technology for all sections of the packaging process such as feeding, handling, flow-wrapping and secondary packaging ensures a consistent look and feel that further reduces the need for training. These are important ingredients in putting the installation to productive use in the shortest possible time. 

BFS packaging creates its own special demands. Attention to detail at each stage of the packaging process, following the guidelines discussed in this article, provides a solid foundation for satisfying these demands. Overall, however, the best solution is to adopt a holistic approach to the specification, design and purchasing of the whole packaging system. 

Such an approach not only guarantees that the line components will function optimally with each other, but also simplifies and speeds both commissioning and operator training. Finally, providing that a supplier is selected who is aware of and responsive to the particular needs of the pharmaceutical industry, the holistic approach can do much to reduce the cost and effort involved in meeting the industry's stringent technical requirements. 

The economies in the system approach described are not only suitable for packing blockbuster products with high volumes involved, but are also realizable for smaller production by leveraging system and product flexibility in the engineering phase. Such an approach brings about time-to-market reductions, which is vital for both big pharma, small pharma and subcontract manufacturers. The use of packaging systems, rather than discrete standalone equipment, reduces the validation process since the vendor can share the responsibility for validating its system.  Partnering with a large a reputable supplier also underwrites this approach because there is assurance of continuity of identical spare parts and again a responsibility for the entire system.  

 is product manager pharma, medical and healthcare at Bosch Packaging, Germany.

The type of robot used for placing and stacking the BFS cards is important. Conventional multi-axes designs have limited flexibility, often combined with high inertia that limits operating speeds.