	
	A carton with a video screen, filling and closing equipment for parenteral products, and a flexible desiccant inserter represent just a few of the innovations that will be on display at Interphex (April 21-23, 2015, at the Javits Convention Center in New York City).


	To maximize interaction with consumers or caregivers, Rondo-Pak equips cartons with a thin, lightweight HD video screen-complete with sound. Multimedia cartons help introduce products, educate patients, train physicians, and support clinical trials and sales demonstrations. Acting as an engaging high-tech insert, the screen can present instructions for use, information on complementary therapies, customer support options, and answers to frequently asked questions. Alternate languages are another possibility. The carton also can include a digital watermark that can be scanned by a smartphone to deliver additional product information or special offers at point of purchase or use (1).


	New filling/closing systems for parenteral products will be on display. Optima pharma will feature the Optima H4 filling and closing system, with a modular design that combines simple operation, accessibility, and reliability with a compact footprint. The flexible system handles nested vials, syringes, or cartridges and can be equipped with rotary piston, peristaltic or time-pressure pumps and a variety of isolator options. A robot in the filling area also can open tubs and remove Tyvek papers, if required. Semiautomatic systems integrate easily, and retrofits boost output from 400 to 600 units per minute and upgrade in-process controls for vacuum filling and vacuum-stopper insertion (2).

	PennTech plans to introduce its FSC-1R vial filling/stoppering/capping machine. The compact rotary unit handles vials sizes from 2 to 100cc at up to 50 vials per minute. Peristaltic pump filling technology relies on driven rollers with statistical or net-weigh in-process control options (3).

	PennTech also intends to exhibit EVW-Series exterior vial washers. These in-line decontamination systems neutralize and wash vials while protecting the caps from moisture. The wash process minimizes rejects during subsequent inspection and eliminates drug residue that could pose a hazard to operators or consumers. The EVW-60 model handles vials ranging from 2 to 100 mL at rates up to 200 vials/min and can be integrated into the filling line or serve as a standalone unit. The faster EVW-100 model accommodates a broader range of vial sizes (2 to 500 mL) and cleans up to 450 vials/min. No change parts are needed to switch between 13-mm and 20-mm caps. Container size changes require a five-minute, tool-less swap of infeed and outfeed timing screws (3).

					The Type 529 semiautomatic filling and closing machine from Bausch Advanced Technology Group handles a range of intravenous bag sizes. Image courtesy of Bausch Advanced Technology Group.

	For aseptic packaging of infusions, parenteral drugs, and other pharmaceutical and biotech fluids, the second generation Type 529 semiautomatic IV [intravenous] bag filling and closing machine from Bausch Advanced Technology Group handles bags made of any material and volumes from 10 mL to 10 L at up to 26 bags/min. Higher speeds can be achieved by adding semiautomatic filling/closing stations. The basic machine accommodates up to four filling/closing stations without altering its footprint, electronics, in-process control, or operator interface. The updated design offers a clear laminar air-flow path to the open bag and is well-suited for isolators or restricted access barrier systems. The flexible unit also is compatible with a variety of filling technologies including mass flow, peristaltic pump, servo-operated pinched valve, and rotary piston pump. The automated closing system can be adapted to many closure types (for hard ports or flexible tubing) and sealing technologies (e.g., high-frequency, ultrasonic, heat). For highly sensitive products, the Type 529 machine can be equipped with an air evacuating and pre- and/or post-gassing system. Other options include an integrated clean- or sterilize-in-place system. Type 529 machines can be combined with semiautomatic IV bag inspection machines as well as checkweighers and leak testers (4).


	For solid dosage forms, BellatRx is displaying its Rx-Desiccant Plus automatic desiccant inserting machine. Capable of handling either precut pouches or canisters, the unit reaches speeds up to 140 containers/min (5).

	Other intriguing innovations expected to be on display at Interphex include Schreiner MediPharm’s tamper-evident Flexi-Cap. The label/cap combination clearly indicates if a container has been opened, discouraging illegal reuse (6).

		Rondo-Pak, “Rondo-Pak Introduces Multi-media Carton with HD Video Screen for Pharma & Personal Care Products,” Press Release, Sep. 24, 2014.	

		Interphex, Reed Exhibitions, “Optima pharma to Premier H4 at Interphex 2015,” Press Release, Mar. 24, 2015.	

		Interphex, Reed Exhibitions, “PennTech to Launch New Technologies at Interphex,” Press Release, Mar. 19, 2015.	

		Bausch Advanced Technology Group, “Bausch Advanced Technology Group Introduces New Generation of IV Bag Filling and Closing System,” Press Release, Jan. 14, 2015.	

		BellatRx, “Equipment Running at Interphex,” Email, Mar. 24, 2015.	

		Schreiner MediPharm, " Schreiner MediPharm Develops Label + Cap Combination Providing Protection from Counterfeiting for Vials and Bottles," Press Release, June 5, 2014.

Articles

Packaging

Innovations include multimedia packaging and improved filling systems.

Packaging Innovations on Display at Interphex

 	In a typical freeze-drying cycle, a product is placed in vials and dried on a shelf in a freeze dryer by first lowering the temperature sufficiently to ensure that the product is completely frozen. In the subsequent primary drying phase, the chamber pressure is reduced to induce sublimation of the frozen solvent (see 

). A secondary drying phase is performed to achieve the required dryness. 	 	The key characteristics of a freeze-drying cycle are the temperature and pressure gradients. The behavior of a product as it dries, however, is affected by many additional factors, such as vial size, condenser volume, product purity, batch size, and equipment specifications. The following aspects should be considered when designing a freeze-drying cycle and choosing freeze-drying equipment.	 	

	There are three main factors to consider when optimizing the freezing stage of the cycle: the product must be fully frozen; the ice crystal structure should be open to aid sublimation; and complete freezing should be achieved at as high a temperature as possible to save time and energy. Annealing and controlled nucleation can help create optimal freezing conditions. 	 	

Freeze dryers can be programmed to incorporate multiple ramp and hold functions to achieve the required frozen structure. Some programs use an annealing process, which is a technique of raising and lowering the temperature over a range of a few degrees to control the freezing.	 	

 Studies have shown that with uncontrolled nucleation, the drying time for the last vial to nucleate could be almost 20% longer than the first vial and 45% longer than a vial made to freeze close to its thermodynamic freezing point by controlled nucleation (1). Controlled nucleation techniques (e.g., ControLyo by Praxair) make it possible to induce freezing at the maximum safe temperature for the product. For every 1°C increase in the nucleation temperature, primary drying time can be reduced by as much as 3-4%, and the overall time to freeze the product can be reduced (1).	 	

Supercooling is a phenomenon in which the product is cooled below its freezing temperature without ice forming, resulting in unpredictable freezing behavior that may be several tens of degrees below the measured thermodynamic freezing temperature. Because ice crystals require a nucleating point in order to form, supercooling is likely to occur in ultra-filtered pharmaceutical formulations. Controlled nucleation is a useful method for controlling this behavior.	 	

	Most common laboratory pumps, such as single-stage pumps, diaphragm pumps and central vacuum systems, are powerful enough for freeze-drying applications. Most freeze dryers require a pump with an achievable vacuum of the order of <1 Mtorr, measured directly at the pump, according to pump manufacturer data. This vacuum will provide close to 100% of the pumping-speed performance across the typical working range of freeze-drying vacuum requirements. If the freeze-drying system is specified correctly, then the condenser will trap all condensable vapors, and the pump will provide initial pulldown and maintain set vacuum. Vacuum-pump maintenance is often overlooked, but it is one of the more important day-to-day tasks that users can complete simply and easily to ensure the long-term performance of the freeze dryer.	 	 	


		The sublimation of ice crystals during the primary drying phase occurs due to the combination of vacuum pressure and temperature (see 

). The system must achieve a vacuum lower than the vapor pressure of the frozen product temperature to begin the sublimation process. Getting the balance right is the key to achieving the fastest possible rates of sublimation. A common misconception about the drying phase is that the vacuum sucks the moisture out of the sample. If this were the case, then a lower pressure (i.e., a higher vacuum) could speed the process. In freeze drying, however, the purpose of the vacuum is to achieve sublimation of the frozen solvent. Increasing the vacuum further does not speed up this process; in fact, it actually slows it down, because fewer air molecules are available to provide heat to drive sublimation.

	The temperature of the condenser isn’t as important as trapping rate. To condense and freeze the solvent, the condenser needs only to be colder than the product in the chamber. Trapping rates are related to the design (i.e., size and shape) of the condenser. As the ice builds up, the temperature on the surface of the ice will not be as cold as on the condenser surface, and trapping rate might fall. If the deposition rate is exceeded, the risk is that vapor will bypass the condenser and potentially contaminate the vacuum pump, thus reducing its useful lifespan and increasing maintenance. A common misconception is that a colder condenser will improve freeze drying and ‘suck the water out faster,’ whereas specifying colder condensers for straightforward applications will simply increase the cost and complexity of the equipment. Colder condensers are best employed when processing solvents other than water that may have lower freezing points.	 	The actual rate at which drying can progress is far more influenced by the product itself and is highly dependent on the formulation’s parameters, the type of container (e.g., bulk trays or vials), and the fill depth per container. All of these data are used to calculate the total shelf area required to accommodate that load and the optimum choice of freeze-dryer design. On larger production dryers, it is increasingly common to employ automated loading and unloading systems, and shelf spacing also needs to accommodate mechanisms of such equipment.	 	

	A cycle that has been prepared and adopted for a 10-mL vial with a particular fill depth will not necessarily be suitable for a differently sized vial, even with the same fill volume of the same product. Clearly, changing the vial size changes the product depth. This change may result in the product drying more quickly, therefore, requiring additional thermal energy from the shelf to counteract sublimation cooling, or more slowly, requiring less heat energy and extended primary drying. A small change in fill volume could also increase the overall vapor load of the batch, thus decreasing the drying rate or even overloading the condenser. 	Different vial dimensions will affect the rate at which vapor can leave the product, which affects the speed of drying. This characteristic can be useful. For example, a cycle time can be decreased by choosing a larger vial with a shallower fill depth, but conversely the maximum number of vials per batch will also be reduced. It is important to find the right balance between vial size, batch size, and cycle duration. 	 	

	Different formulations of product will freeze dry differently. Concentration alone can significantly affect the processing characteristics of a product, which will consequently affect drying time and batch parameters. Different excipients have different thermal characteristics, so alterations to a formulation’s make-up can affect the freeze-drying cycle. Even small changes in formulation, batch parameters, and equipment can all have an impact on the process requirements. It is therefore not advisable to re-use an existing freeze-drying cycle for a reformulated product.	 	It is essential to know the critical freeze-drying parameters of a formulation, particularly when submitting for regulatory approval. Formulations for freeze drying often exhibit complex and unpredictable behavior, and detailed knowledge of this behavior is vital for effective cycle development. Significant thermal events include collapse, glass transitions, eutectic melting, and crystallizations. The most important critical temperature is the point below which the formulation must be cooled for complete solidification and maintained during primary drying to prevent processing defects. A variety of analytical techniques, including differential scanning calorimetry, differential thermal analysis, impedance analysis, and freeze-drying microscopy, can be used to identify freeze-drying parameters. It is advisable to use several analyses to ensure that a complete and accurate picture is formed. 	 	When changing a formulation, for whatever reason, the product’s changing characteristics should be kept in mind. Not only will this prevent unexpected process failures later down the line, it may be possible to reformulate to provide a more favorable thermal profile and improve efficiency. 	 	

	1. J.A. Searles, T. Carpenter, and T.W. Randolph, 

	Katriona Scoffin is a freelance science writer working for Biopharma Technology Ltd (BTL), a CDMO with expertise in freeze drying; 

 When referring to this article, please cite it as K. Scoffin, “Designing Trouble-Free Freeze-Drying Processes,” 

Troubleshooting

Efficient freeze-drying processes result in time and energy savings, reduced failure rates, and improved batch consistency.

Trouble-Free Lyophilization

	Interphex 2015 (April 21-23) will showcase some of the latest bio/pharmaceutical manufacturing and development technology. An increasingly important segment of that technology will be second-hand equipment. As a growing number of pharmaceutical manufacturers are learning, second-hand doesn't have to mean out-of-date. Like pre-owned late-model cars or electronic devices, late-model drug manufacturing equipment is increasingly available.  Some of it is less than a year old, says Randy Small, vice-president of operations for the Americas at Liquidity Services. In some cases, equipment was purchased but never used, adds Ben Potenza, vice-president of marketing at EquipNet (exhibiting at booth #3359).

	Buying used equipment is a win/win for both buyer and seller. Buyers save money and shorten delivery time, notes Matt Hicks, COO and counsel at Federal Equipment Company (exhibiting at booth #1742). Sellers, who may have closed a facility or who no longer need a piece of equipment, can recoup some of their investment and improve their return on investment. 

 asked these experts what pharmaceutical companies should consider when exploring buying or selling used assets.

 What are the primary reasons a company might want to consider purchasing used equipment?

 One of the top reasons for purchasing second-hand equipment is the lower starting cost. Start-up companies often take this route because they want to get 'in the black' sooner, and there are a lot of start-ups around the world right now. We are also seeing an increasing number of Fortune 500 companies looking at the second-hand market as a sustainable, cost-efficient way to obtain equipment, and we are doing business with more of these large companies this year than last year or the year before. We are selling 47 out of 52 weeks of the year, with 300–500 pieces of bio/pharmaceutical equipment each week.

 The ability to save between 50-75% of the cost of new is an attractive factor. Budgets can be stretched and cash saved for additional purchases. In addition, pre-owned equipment is generally available immediately. Delivery can be made as soon as a purchase is completed, which is not always guaranteed when ordering a new system.

What types of pharmaceutical equipment are typically purchased in the second-hand market? 

 Laboratory R&D assets make up most of the pharmaceutical equipment in the second-hand market today.  Examples include liquid chromatography and mass spectrometry instruments and smaller benchtop assets, because the turnover rate is inherently higher in R&D. About 20% of assets in the market overall are manufacturing assets, typically from Fortune 500 companies, which ensures that they are well maintained and calibrated. The majority are sold in their natural environment, rather than a warehouse.

 All manner of equipment categories are sold in the pre-owned market, including laboratory instrumentation, pilot-scale and formulation machinery, packaging equipment, and plant utility assets. Solid-dose facilities purchase many fluid-bed dryers, encapsulation machines, tablet presses, and blending equipment, for example. Sterile locations might need vial-filling lines, bioreactors, autoclaves, and water-purification equipment.  Tanks are always in demand.

 For our pharmaceutical customers, we focus on processing and primary packaging equipment for all types of solid-dose and liquid pharmaceutical products, including aseptic fill-and-finish. Late-model, quality equipment is always in demand and does not last long in our inventory.

 How old is 'late-model' equipment, and what cost savings can be obtained?

 In general, we consider less than five years old to be late model, with most of it three to five years old. This equipment is desirable because it is well maintained and still current. Startup companies have a high turnover rate, so equipment from them may be one to three years old, or occasionally less than one year. For equipment in the five to eight-year range, you need to do your homework to be sure that the technology is current and that the asset will do what you need.

	The savings compared to purchasing new is typically 30-50% for the less-than-one-year-old range and 40-75% for two-to-three years old. For equipment older than three years, depending on supply, the savings can be in the 50-80% range. Buyers are finding savings a little higher than they did a year or two ago, which is partly due to an expanding marketplace with more sellers.

 The answer here really depends upon the equipment, the original equipment manufacturer (OEM), and the maintenance program. Many types of equipment can have long, productive lifespans-the year of manufacture should not always determine whether a machine is still worthy of use in production. Obsolescence for pharmaceutical process equipment, as a general rule, is when that machine is no longer fit for use in a cGMP environment or there is no support network for the equipment through in-house knowledge, the OEM, or a reliable third party provider. 

	We acquire our inventory from the top names in pharmaceutical manufacturing-companies that purchase higher quality equipment from the start, engineer it to last, and have robust fixed asset management and preventative maintenance programs supporting that equipment. This equipment is more likely to be of a higher quality and in better shape so that OEMs can provide the bulk of the support. The buyer can thus trust each purchase, and have that equipment installed and ready for production as soon as possible. Our inventory can be delivered in weeks or even days, compared with months for built-to-order equipment. 

 Ironically, 'used equipment' is often a misnomer. Many times our clients have built facilities in anticipation of a ramp-up in production that never materializes. In these cases, we are often selling equipment that has never been used but is still 'pre-owned.'  For those items that are used, their value obviously has a direct relation to their age and the state of the current new technology compared to the machine that is for sale. Most buyers that are shopping in the second-hand pharmaceutical market are looking for equipment that is 10 years and younger if there is technology involved.  However, stainless steel tanks can be much older if they are in excellent condition.

 What options would you recommend that a company consider for equipment they no longer need?

 A company should first consider redeployment within sister divisions or other locations. If the equipment is not needed inside their own company, they should consider selling the equipment. This route brings income and avoids the cost of disassembling and relocating the asset, because, typically, the buyer is responsible for moving the asset.

	The market for used equipment is booming. Sellers should find a reputable company with an online marketplace and global market of buyers to ensure they will maximize their return on the assets they want to sell.

 Redeployment should always be the first consideration for a company with surplus equipment.  Clearly, relocating an asset that you already own ensures the highest return on investment for that asset. Beyond redeployment, a facility needs to factor in the amount of time that they have to sell the item. If there is not an immediate deadline for a high-value item, selling it in a negotiated sales platform will yield the next highest level of return.  If it's more of a commodity piece or the owner's priority is quick liquidation instead of highest return, then an online auction event is the preferred channel.

 We specialize in acquiring used equipment in many different ways. Sellers can choose to sell equipment individually, item-by-item, or as a lot through a bidding process.  There are auction and consignment options available. If the equipment is needed internally, we offer an in-network redeployment program when there is a good fit. The key is to understand that the solution for surplus equipment is not 'one-size-fits-all', but to focus on how to maximize the seller’s return in combination with many different factors, including project deadlines, site constraints, removal costs and methods, and conducting the project with minimal disruptions to ongoing operations or other stresses on the facility.

 When should a company consider redeploying surplus equipment?

 Redeployment of existing equipment makes a great deal of sense because it maximizes the potential return for that idle equipment.  Redeployment puts that equipment in a place where it can produce saleable product rather than just being sold for the equipment’s own value. Additionally, the equipment history is completely transparent and records can be easily transferred without too many intellectual property concerns. 

	With that said, a redeployment program will only work if there are multiple sites in the company’s network with similar equipment requirements. There must also be a financial strategy that makes redeployments attractive to the receiving site. This strategy mainly concerns the valuation of the equipment for the receiving site (e.g., net book value or fair market value) in addition to the removal and shipping costs.

	Finally, there should be some strategic review of the transfer against a capital expenditure budget or some other identified objective.  If a transfer cannot be justified against a capital budget or, for example, as a risk mitigation strategy, these would-be assets may just go from storage in one facility to storage in another facility, where they sit inside a crate in a warehouse or take up valuable manufacturing floor space without ever making anyone any money, which is why they were made available in the first place.

Production Trends

Experts discuss some of the latest trends in buying and selling used pharmaceutical equipment assets.

Equipment and Processing Report-04-15-2015

Packaging Innovations on Display at Interphex

Trouble-Free Lyophilization

What's Old is New Again: Wresting Value from Second-Hand Equipment