Brianne Harrison

Interphex2007, New    York, NY (Apr. 26)-

As  focus shifts away from “one-size-fits-all” medicines and begins centering on  personalized medicines, many companies begin to wonder how they can manufacture  such drugs economically. Mark Hirschel, chief scientific officer of 

), addressed that issue in  his presentation, “A Bioreactor System Designed for Production of Personalized  Therapeutics,” at Interphex on Thursday. 

According to Hirschel, some of the challenges facing  personalized medicines include:

Manufacturing:       Assessing what capacity is available for the production of personalized medications,       and how to tailor current technology to increase capacity?

Ethical:       how does one explain to a patient that what worked for someone else       probably won’t work for them?

Economic:       personalized medicines do not follow the blockbuster model and are very       expensive to produce, which raises the question of who should pay? 

To illustrate the resolution of these issues, Hirschel  explained how BioVest developed an autologous vaccine for non-Hodgkin’s  lymphoma. Autologous vaccines are based on a particular patient’s tissues,  which are collected, in some cases treated, and then reintroduced into the  body. Autologous treatments in current use include skin grafts and bone-marrow  transplants.

BioVest was faced with the difficulty of manufacturing a  personalized medicine. The process is labor intensive and needs to be modified  for each patient, and it is very difficult to design and operate a facility  that processes thousands of patient-specific cells. The company settled on  manufacturing the vaccine using mammalian cell cultures in a hollow fiber  bioreactor (HFBRx). HFBRx technology, which very recently gained acceptance in  the therapeutic arena, is disposable, easy to scale, and very small.  It automates the process of producing cells,  thus cutting down on labor and minimizing technician interaction, and it also  is a closed system.

BioVest created its own HFBRx, “AutovaxID,” to produce the  non-Hodgkin’s lymphoma vaccine.  The  machine is small enough to fit on a tabletop, thus eliminating the need for  tissue-culture incubators. It is a closed system with secure access and online  data collection.  As the machines are  small, the cost of a facility to house them, according to Hirschel, is $35–40  million, compared with $66–73 million for a classical manufacturing facility.

Hirschel closed by looking to the future.  He believes there will be a move toward  applying technology to autologous or other cellular therapies and toward  further automating the process to ensure reproducibility.

Articles

Interphex2007, New York, NY (Apr. 26)-As focus shifts away from "one-size-fits-all" medicines and begins centering on personalized medicines, many companies begin to wonder how they can manufacture such drugs economically. Mark Hirschel, chief scientific officer of BioVest International, addressed that issue in his presentation, "A Bioreactor System Designed for Production of Personalized Therapeutics," at Interphex on Thursday.

Evaluating Impact of Personalized Medicines on Pharmaceutical Manufacturing

Counterfeit  medicines are of increasing concern to the pharmaceutical industry, both  because of the potential health risks to patients and because of the effects on  pharmaceutical companies’ businesses. While technology such as e-pedigree and radio  frequency identification (RFID) represent solutions to secure the  supply chain, there are challenges. Implementing an e-pedigree program  can be difficult, and strategies for addressing those difficulties were shared  by Sanjay Ahuja president of 

),  in his presentation, “Security and Integrity  in Chain-of-Custody Hand-off Related to Drug or E-pedigree,” at Interphex on  Thursday. 

Counterfeiting cost European manufacturers about EUR 1.55  billion (approx. $2.1 billion) in 2000, according to data presented by Ahuja. The 

)  estimates that fake drugs make up about 10% of the global market  with annual revenues of about $32 billion. To  combat this problem, FDA is investigating new methods of securing the supply  chain by implementing RFID and e-pedigree.   In 2006, an FDA Task Force recommended the implementation of RFID and  instructed stakeholders in the pharmaceutical supply chain to explore the use  of RFID.

Ahuja outlined the process for e-pedigree. The drug  manufacturer first adds a unique package identification and product barcode and  transfers information from the package into a database. The database holds  information on genuine and fraudulent transactions, allowing for easy tracking  of the drug along the supply chain.  Barcodes  are most commonly used, although they are not specific to a single package. RFID  tags are specific to a single package, and Ahuja projects that RFID use will  spread rapidly.  “In eight years, we will  have a very mature environment with RFID,” said Ahuja, who likened the adoption  of RFID to the growth of wireless technology in the mid-1990s.  Implementing an e-pedigree program could help  reduce thefts of goods, as it would allow for more effective tracking of packages.

There are, however, some obstacles to the widespread  adoption of RFID. Several different companies produce RFID tags, but there are  no standards for the production of those tags. Many companies were concerned  about privacy and the ownership of business transaction data. Ahuja believes that the entire supply chain must be examined and an integrated network created to  provide visibility into the pharmaceutical supply chain.  This integrated network should cover all  aspects of the supply chain, from the manufacturer to the seller, and the information  on the main database should include all information pertinent to the drug.  This includes its name, manufacturer, and  expiration date as well as information regarding any transactions it has  undergone and its path of travel since leaving the production line.

Interphex2007, New York, NY (Apr. 26)-Counterfeit medicines are of increasing concern to the pharmaceutical industry, both because of the potential health risks to patients and because of the effects on pharmaceutical companies' businesses. While technology such as e-pedigree and radio frequency identification (RFID) represent solutions to secure the supply chain, there are challenges.

Securing the Chain of Custody in the Pharmaceutical Supply Chain

Interphex2007,   New York, NY (Apr.  24)-

Radio-frequency identification (RFID) technology is an increasingly  important tool in the pharmaceutical supply chain. Paul Rudolph of Arent Fox  PLLC gave the first of several talks on RFID and e-pedigree at Interphex today  in his presentation, “Pedigrees: Update on Federal and State Regulation and  Effect on RFID Tagging of Products.”

RFID and e-pedigree are subjects of increasing interest in  the pharmaceutical industry, as states begin enacting requirements for e-pedigree  tracking of pharma ingredients and devices.  

According to Rudolph, the federal government has not yet  been able to implement a requirement for pedigrees to go back to the  manufacturer-the proposed requirement has been enjoined and US Food and Drug  Administration (Rockville, MD) is appealing to the US Court of Appeals.  FDA, however, has issued a guidance on several issues, including returns and  requirements for third-party logistics providers. .

The bulk of e-pedigree activity has been at the state level.  Nevada, Arizona,  Colorado, Indiana,  Oregon, and Florida had e-pedigree requirements as of  2006. In the first few months of 2007, Idaho, Wyoming, Maryland, and  North and South Dakota  enacted similar requirements. California, Iowa, Kansas, Mississippi, Nebraska, New Mexico, Texas, and Vermont have all  proposed legislation or planned a timeline for enacting e-pedigree.

Most e-pedigree requirements apply to products that leave  the normal distribution channel by passing from the manufacturer to two or more  wholesalers.  This requirement is  becoming more uniform from state to state. It does not, however, apply to  manufacturers, and, as Rudolph pointed out, the definition of manufacturer  varies from state to state, which can make matters complicated, as suppliers  sending goods to other states will have to comply with different states’ different  requirements.

Although some state laws have been drafted with the  Prescription Drug Marketing Act and FDA’s regulatory guidance in mind, many  state pedigree requirements are not consistent with federal pedigree  requirements. For instance, current federal requirements state that  nonauthorized distributors (nonADRs) must pass pedigree, and authorized  distributors (ADRs) are encouraged to pass pedigree-related information on to  nonADRs. The concept of ADRs is not common in state law, and it is not parallel  to the “normal chain” concept used on the state level.

Looking to the future, Rudolph anticipates the lifting of  the injunction on the federal requirement, more enforcement of the federal  requirements, and further guidance on outstanding issues. Manufacturers  probably will not be required to use RFID tags in the near future, at least  until the benefits definitely outweigh the costs. More states will begin  requiring e-pedigree, Rudolph predicts, and the state-by-state requirements  will become more uniform over time, dispensing with varying definitions that  add to confusion and lead to compliance problems.

Rudolph closed by exhorting companies to look to the future,  when e-pedigree will be required in all states, and to establish internal teams  to devise a strategy for adopting e-pedigree.

Interphex, New York, NY (Apr. 24)-Radio-frequency identification (RFID) technology is an increasingly important tool in the pharmaceutical supply chain. Paul Rudolph of Arent Fox PLLC gave the first of several talks on RFID and e-pedigree at Interphex today in his presentation, "Pedigrees: Update on Federal and State Regulation and Effect on RFID Tagging of Products."

E-pedigree Federal and State Requirements Presented

Like all consumers, patients and healthcare providers want products that will make their lives easier, and any product that makes administering or taking an injection easier is bound to be popular. It's no wonder, then, that the vast majority of pharmaceutical companies are noting the advantages of prefilled syringes and scrambling to include them in their portfolios. 

Prefilled syringes are not a new technology by any means. They debuted during World War II to accommodate the need for on-the-spot, sterile medications in battlefield hospitals. The next big push into the market came when Becton Dickinson and Company  (BD, Franklin Lakes, NJ) began supplying glass prefillable syringes to support Dr. Jonas Salks' poliomyelitis vaccination program in the early 1950s. Prefilled syringes continued to be used mostly for delivering insulin or human growth hormone. In the past five years, however, they have really come into their own,  becoming not just a desirable product but almost a required product for parenteral makers to offer. 

"If you're going to launch a new product with an already competitive indication, it should be filled in a prefilled syringe for success on the market," says Jörg Zimmermann, head of production at Vetter Pharma-Fertigung GmbH & Co.  "Most innovative new products, if they're liquid, are going to be in a syringe, when appropriate." 

The numbers attest to this: a study conducted by BD and IMS Health shows that the market for prefilled syringes is expected to grow by 12.8% per year. In 2006, about 1.4 billion prefilled syringes were sold, and by 2010 the quantity is expected to top 2.4 billion. 

The sudden and intense interest in prefilled syringes can be attributed to several changes in the industry.  

 The market has seen an increase in the number of biotechnology therapies and drug candidates that can only be administered by injection. These new treatments target a wide range of areas such as multiple sclerosis, fertility, osteoperosis, hepatitis, rheumatoid arthritis, cancer, anemia, and hemophilia. 

Some biotech-based drugs require frequent injections to be administered by the patients themselves, and it's these patients, according to Michael N. Eakins, principal consultant with Eakins & Associates (West Windsor, NJ), who stand to benefit the most from the ease of use a prefilled syringe offers. 

"A prefilled syringe takes out a series of operations, which makes it quicker and easier," notes Eakins. "It's a great advantage from the patient point of view in ease, safety, and training to have a dose all ready to go in a prefilled syringe." 

It's patients who are the true driving force behind the demand for prefilled syringes. Measuring out a dose from a vial into a syringe may be time-consuming and pose a risk for error for those with little training. Moreover, diseases such as rheumatoid arthritis often make it difficult or even impossible for patients to hold a vial and withdraw an accurate dose. Pharmaceutical products that started out as a lyophilized formulations have been changed to liquid formulations to be packaged in prefilled syringes. Berlex's (Wayne, NJ) "Betaseron" multiple sclerosis treatment, and the human growth hormones "Norditropin" (Novo Nordisk, Princeton, NJ), and "Nutropin" (Genentech, San Francisco, CA) all have been reformulated from lyophilized to liquid and are now offered in prefilled syringes. 

 Syringe component suppliers have stepped up to meet  the rising demand in ready-to-use units. Stelmi's (Paris, France) ready-to-use plungers and BD's "Hypak SCF" prefillable syringes eliminate the need for washing, depyrogenation, and sterilization at the filling site. Ready-to-use components are washed, EtO or gamma sterilized, and validated for direct use. 

 One of the greatest benefits is the significant reduction in the amount of product needed to overfill the container. "By using a prefilled syringe, 10, 15, sometimes even 20% of the API can be saved," Zimmerman notes. "With this all-in-one solution, there is no substance loss through refilling. We've had customers that converted from vial to prefilled syringe that were able to scale down their API process because they didn't need as much," Zimmerman continues.  

Overfill for a prefilled syringe is significantly less—in the single digits, according to Cory Lewis, director of new business development with Baxter BioPharma Solutions (Bloomington, IN). "When you're talking about bulk drug API that's in the thousands of dollars per gram, there is a true economic savings that companies can yield," he says. A BD study indicated a potential for up to 23% more product dose yield in a prefill compared with a vial, as less product is lost in the transfer from a vial to a syringe.  

 Although plastic prefilled syringes are gaining in popularity in Europe, glass barrels are still preferred in the United States: 99% of the prefillable syringes sold in the US by BD are its Hypak prefillable glass syringe. Glass is heavily favored, primarily because it has been part of the industry for a long period of time.  

"The real problem with the plastic is that it is less well known and less well characterized. Glass has been around as a container for drugs since the Egyptian empire," Michael Eakins points out.  

Glass prefilled syringes are made of Type I borosilicate glass, the same type that has been used for vials for a long time. The downside to using glass, however, also is well known: Glass contains alkali ions, which can lead to a surface reaction that forms a small amount of sodium hydroxide. After years of observing this effect in glass vials, most pharma companies know what to expect and have devised ways to get around the problem.  

Until recently, plastics were not as clear as glass, making it difficult for companies to visually inspect their products for particulates. But recently, more companies have taken an interest in plastics, mainly owing to recent advances in their design and makeup. Original plastic syringes, which were introduced in the early 1990s, were made from polypropylene. Several companies now offer syringe barrels made of cyclic olefin polymer or cyclic olefin copolymer, which is as clear as glass but less heavy and less likely to break. Cyclic olefin plastics also are more resistant than polypropylene to water transmission, which may help lengthen the shelf life of the drug product. 

BD, West Pharmaceuticals, and Baxter BioPharma are all developing plastics for prefillable syringes. In 2000, BD launched a plastic prefillable syringe system known as "BD Sterifill SCF," which is transparent, resistant to breakage, and lightweight. Sterifill is composed of BD's "Crystal Clear Polymer," an amorphous, high-performance polycycloolefin. The company also has released its "BD Uniject" single-use, auto-disable prefill injection device, which contains a small, blister reservoir filled with the drug attached to the needle. Squeezing the reservoir releases the drug. 

West's Resin Crystal Zenith (CZ) silicone-free syringe system is made of cyclic polyolefin and has high heat resistance and low temperature characteristics. It is also break-resistant and clear. 

Awaiting approval is Baxter's most recent development, "Clearshot," which, like Sterifill and CZ, is break resistant, lightweight, and offers high clarity. The process used to produce Clearshot is somewhat unique: the syringe is formed, processed, and sterilized inline. "We start off with a resin pellet and at the end of the line comes a syringe with the drug product, stoppered," says Cory Lewis. 

Plastics have a ways to go before they're widely accepted in the pharmaceutical industry, but as more companies produce purer, more glass-like plastics, plastic syringes begin to gain ground. "There has been much more interest in plastics," notes Eakins. "It's quite clear the interest is increasing." 

Vetter produces a dual-chamber syringe in which one chamber is filled with lyophilized product and the other is filled with diluent. When the plunger is pressed, the diluent and lyo products mix and can then be injected. The dual-chamber syringe can also be used with powder and liquid or two liquid products. The latter is, as Vetter's Zimmerman says, a niche market, but it can be used for a multi-dose application that requires a preservative but might not be compatible with the protein for storage.  

 A necessary component of the prefilled syringes is the rubber stopper or plunger, which carries with it its own challenges. Because stoppers are in prolonged contact with the drug, the primary concern is with leachables from the rubber interacting with the drug.  

One example is the case of the antianemic "Eprex." Produced by a subsidiary of Johnson & Johnson (New Brunswick, NJ), Eprex was reformulated to eliminate human serum albumin for the European market and then packaged in a prefilled syringe that replaced the uncoated stopper that had been used before with a coated one. The new formulation of the drug interacted with leachables from the stopper and was later linked to pure red cell aphasia (PRCA) in certain patients, leading to severe anemia.  

To combat the problems that may arise from interactions between drugs and rubber stoppers, Stelmi has developed high-purity formulations with a low level of extractables for their rubber components. In the late 1990s, Stelmi launched its "UltraPure 6901" formulation adapted to prolonged contact with water for injection. In 2004, as prefilled syringes continued to gain in popularity, the company began producing elastomer-based formulations 6955 from a new elastomer known as BIMS, which is exempt from oligomers and, thus, less prone to leaching into the drug.  

Meanwhile, West Pharmaceutical Services (Lionville, PA) is taking a different tack. Rather than retooling the rubber formulation, the company has begun molding a laminate known as "FluroTec" film onto its stoppers. The film acts as a barrier between the stopper and the drug, reducing the amount of leachables going from the rubber stopper to the drug in the syringe. 

Concern over extractables and leachables is growing. At a recent AAPS conference, extractables and leachables came third in a list of the Ten Hot Topics of 2007, whereas a mere seven years ago, they didn't even make the list. Whether made of glass or plastic, prefilled syringes deserve special attention when it comes to controlling extractables and leachables.  

When it began moving one of its protein drugs to a prefilled syringe, Amgen, Inc. (Thousand Oaks, CA) was surprised to notice that the protein was aggregating. After much investigation (and cooperation between Amgen and BD, the manufacturer and supplier of the syringes), the culprit was found to be tungsten, which is used to hold open the fluid channel at the base of the syringe during the manufacture of the glass. The heat used during the molding process vaporized some of the tungsten, which then settled in the glass at the base of the needle. Prolonged exposure of the drug to the tungsten resulted in visible particles in the solution. BD now has the ability to produce a tungsten-free prefilled syringe. 

Some drug makers are concerned that plastics pose a greater risk of extractables and leachables. Plastics and resins are composed of many different components and the formulations can easily change, so there is more uncertainty and potential for extractables. When working with plastics, "you have to take more chemicals into consideration, and therefore there are more unknowns because the plastic vendors will not tell you ... the exact formulation because it is proprietary," says Eakins. The uncertainty means that more testing is often necessary when packaging in plastics, and, according to Eakins, "the last thing you want to do is a lot of research on your packaging, it makes the risks even higher."  

One method of cutting down on the amount of testing is to improve communication between pharmaceutical manufacturers and the companies supplying them with prefilled syringe components. Most components manufacturers will provide their clients with lists of possible extractables and leachables, thus allowing the pharmaceutical manufacturers to narrow the field when testing their drugs. Robert Swift, principal engineer of Amgen, hopes that the increased communication between suppliers and the biopharmaceutical industry will "allow [pharma] companies to identify and mitigate formulation-container interactions very early in development." 

Silicone, however, is one ingredient that's proving very difficult to eliminate. Silicone is used to coat the inside of syringe barrels. Although silicone poses no threat to some drugs, others have exhibited adverse reactions caused by prolonged exposure to it. West Pharmaceutical Services will soon be introducing its resin CZ system, which eliminates the need for silicone. The plunger is coated with FluroTec, which protects the drug from leachables from the rubber and provides the lubrication needed to allow the plunger to move. Other companies are baking on the silicone, and still others are working to reduce the amount of silicone in the barrels to the least amount possible to still allow the plunger to move.  

Besides testing for leachables, pharma companies also must test for break-loose and gliding forces for drugs of various viscosities. For those forces to remain low, there must be some sort of lubricant present. Thus, eliminating or reducing the amount of silicone is challenging. 

Figure 1: Glass syringes are currently preferred, and innovations in automation and robotics have increased the efficiency and consistency of handling glass prefilled syringes on the processing line. The photo shows automated heat-tunnel unloading of prefilled syringes (courtesy of Vetter Pharma-Fertigung GmbH & Co. KG).			

Increasing interest in prefilled syringes has lead to innovative solutions in filling and stoppering technologies, barrier designs, automated processing and transfer systems, and robotic handling.  

 Filling and stoppering syringes present a unique set of challenges than those encountered when processing vials.  

"The method you choose to fill and stopper a syringe can influence the stability of the drug product, the movement of the product inside the syringe during shipping, and, in some cases, the sterility assurance of the product," says Shawn Kinney, president at Hyaluron Contract Manufacturing (HCM, Burlington, MA).

Vacuum stoppering technology has been available for several years, but vacuum filling is relatively new. Vacuum stoppering has, until recently, only been performed offline, away from the fill line in a vacuum box. Recently, syringe manufacturers have developed vacuum filling and stoppering capabilities online, primarily for viscous products.  

Pulling a vacuum through very thin solutions such as water for injection or buffered solutions causes the liquid to boil and splatter. If splattering occurs during the stoppering process, the liquid product may be entrapped in the ribs of the stopper, posing a potential sterility issue.  

Successfully removing air from thin solutions does have several advantages, including increased product stability, lack of stopper movement during shipment and post-sterilization processing, and even potentially enhanced sterility assurance of the solution. Hyaluron has patented a bubble-free filling process that eliminates the air inside the syringe. Bubble-free filling is especially beneficial for oxygen-sensitive pharmaceuticals and proteins that are sensitive to a gas-liquid interphase that appears on small gas bubbles inside the syringe.  

"Some proteins tend to rearrange themselves such that the hydrophobic groups point up into the gas phase and the hydrophilic amino acids point down into the liquid phase, which causes more rapid degradation, says Kinney. "The presence of a gas bubble, in conjunction with the silicone coating, will further exacerbate protein aggregation."  

Other companies are reportedly working on closed-filling systems similar to those used for vials (1).

 The challenges in handling the shape and composition of syringes also are leading to new barrier system designs, specifically isolators and restricted access barrier systems (RABS). 

"Traditional cleanrooms are being phased out in exchange for operations within RABS or isolators," says Eric A. Isberg, product manager, Pharmaceutical Operations, Robert Bosch Packaging Technology (Brooklyn Park, MN).  

Whereas vials can easily sit on a track and be directed along their sides with relatively simple belts and conveyors, syringes require direct handling (see Figure 2). Syringes are unstable because of their high center of gravity and therefore require specialized transport systems to reduce the risk of breaking or scratching. The finger flange of the syringe can be the most vulnerable, so the handling system must allow space between each unit.  

Figure 2: Automated filling lines provide the necessary direct and individual handling of syringes (photo courtesy of Baxter BioPharma Solutions).			

 Syringes can be transported using pucks constructed of thermoresistant plastic or stainless steel. The pucks hold the syringes upright as they move them through heat tunnels. Specially designed trays transport the syringes into autoclaves. Traditional lines are designed to hold syringes by the flange, but some experts believe this system poses a risk to breakage.  

"We are seeing more systems that have either pucks or systems that hold the syringe throughout the transport systems using vacuums on the starwheel. This allows the syringes to be elevated as needed without being supported on the bottom or by the finger flange" says Isberg. 

Many companies are coming up with innovative materials and manufacturing methods to feed the growing demand for prefilled syringes.