On June 25, 2012, Daiichi Sankyo Inc. received U.S. Food and Drug Administration approval to package product at its first U.S.-based packaging facility located in Bethlehem, PA.
This marks the beginning of the pharmaceutical company's strategic shift from outsourcing exclusively for the North American market to in-house packaging for its cardiovascular and metabolic drugs, including treatments for hypertension and heart disease, diabetes, thrombosis and other ailments.
The company has invested more than $20 million to acquire and renovate the site, refurbish existing equipment, buy new equipment, and hire and train employees.
Jeff Lane, vp, supply chain and technical operations, says, "From facility and process design to quality control and personnel flow, we incorporated leading-edge technology in the design and development of the Bethlehem facility. The commissioning of this facility is a major milestone for our U.S. organization and augments our ability to manufacture and distribute quality medicines."
Ensuring a stable supply
With headquarters in Parsippany, NJ, and nearly 3,000 employees, Daiichi Sankyo is the U.S. subsidiary of Daiichi Sankyo Co. Ltd., a global pharmaceutical maker with about 30,000 employees in 56 countries. Long-term plans involve having internal operations in all its major markets. "That's part of our ‘creating stable supply' objective for the global corporation," Lane says.
North America was the only market not yet served that way. Until now, packaging operations have been entirely outsourced at contract packagers in Philadelphia, Chicago, Georgia and Ontario. "Product is still being packaged in those sites until we fully execute our transition plan," Lane says. "But given the importance of this market to the longevity of the company—the revenue and profit streams—we felt we needed to make this investment now to support the long-term growth objectives of the company."
The shift to in-house packaging will ensure full operational control of Good Manufacturing Practices to make certain the final product meets the company's highest quality standards. "That's not to say that we didn't produce quality product at our contractor locations. We've always imposed our quality standards on those operations," Lane explains. "However, if it's your brick and mortar, and your resources, you can control those GMP operations a lot more closely than if you're working through a third party. Gaining control over those operations and gaining the flexibility that comes with that control is an important aspect for us."
Operational control also ensures a more secure business. "When you subscribe to an exclusively outsourced model, you have to bear some of the risks that go along with that," Lane says. "What I've seen happening in the contract arena over the past few years was a lot of mergers and acquisitions. You see a lot of those contract manufacturing organizations being gobbled up by private equity and other contractors. I saw that as potentially disruptive to our business because the change in ownership and management sometimes creates changes that are felt at the operational level. They could be potentially disruptive to product flow, product supply, quality."
Daiichi Sankyo began putting this business plan into action in 2011 with the site acquisition, which culminated with the FDA approval in late June and official plant opening in mid-July 2012.
Quick ‘up' time
Four decisions contributed to the successful on-time startup of the company's U.S. packaging operations:
1. Daiichi Sankyo chose to renovate an existing facility instead of building a new plant. In Feb. 2011, it bought the Bethlehem facility from Amcor, who had used it mainly for pharmaceutical contract packaging.
Lane pinpoints the benefits of buying an existing building: "[Time to start up] could be shortened significantly, depending on the overall condition of the facility, utilities and the equipment contained within it," Lane says. "Total cost of ownership is usually lower. And the overall risk profile—whether that risk be related to construction, regulatory, hiring—is generally more attractive when you buy vs build."
But there are downsides, too, that could be limiting. "You potentially forego some design preferences or efficiencies—what I mean by that is workflow—that are typically addressed when developing a greenfield site," Lane says of the tradeoffs. "Similarly, the location, labor pool, economic development climate may not be optimal. Finally, regardless of any engineering effort you put into due diligence, you can still be surprised by unexpected or unidentified issues once you assume title and begin your renovations. It's kind of the ‘peeling back the onion' syndrome. We did encounter a few of those, but it wasn't the case where any drove the budget over the top. It was in the noise, as we say."
2. The Bethlehem location was a good fit for two reasons. First, Pennsylvania was on the short list due to a qualified labor pool (the Northeast is a pharmaceutical hub) and its proximity to Daiichi Sankyo's Parsippany headquarters. Second, Daiichi Sankyo was already familiar with the facility. "This was as much opportunistic as it was strategic: We had qualified one of our products in the former Amcor facility, when it was owned by Alcan at the time," Lane says. "We realized it was perfect for what we were trying to accomplish. When we learned it was on the market, we pursued it pretty aggressively."
3. Daiichi Sankyo was able to use a lot of packaging machinery already in the plant when the company bought it. Two thirds of the equipment on Bottle Line 1, for example, is existing machines brought up to today's standards. When new machines were needed, they were duplicated on both bottle lines and sourced from leading OEMs.
Standardizing on equipment like this helps Daiichi Sankyo realize savings in spare-parts inventory and simplify operator training—as well as gain consistency in operations. "For quality reasons, GMPs dictate that operations are repeatable," Lane says. "The more operators and mechanics understand the operating principles of the equipment, the more likely we are to not only maximize our throughput, but also to maximize our quality."
4. Daiichi Sankyo used an integrated approach to commissioning, qualification and validation, which saved time by eliminating repeat testing. For example, if testing completed during commissioning met a preapproved acceptance criteria, and the machines were not modified, the testing was referenced instead of repeated in qualification.
During renovations, Daiichi Sankyo reconstructed, resurfaced and repurposed the 146,000-sq-ft site to fit its needs. Two bottling lines and two blister packaging lines will handle the bulk of the company's products sold in North America. The company plans to package 360 batches—all solid-oral-dose drugs for now—on these four lines in the next year.
All four packaging operations are set up in a straight-line configuration, with the warehouse at the end of the lines and a transition hallway at the top of them. Materials are pre-staged in this transition zone for each production run. "The linear flow allows for better utilization of material and personnel flow," Lane says. "There is less wasted movement and the operators have a line of sight to the entire operation, allowing for quicker restarts when issues arise."
Bottle Line 1 started up in February 2012, building up inventory as the company awaited FDA approval. Once Daiichi Sankyo received that, it began releasing product to its finished goods distribution center in Tennessee. Its first self-packed products will ship to retail and mail-order pharmacies once inventories already in the supply chain are depleted.
Bottle Line 2 became operational on May 17 when it began validation of its first commercial lot.
Blister Line 1 will be operational in the third quarter of 2012; Blister Line 2 is expected to be running before the end of the year.
The plant's output will be approximately 85 percent bottles, 15 percent blisters. Bottles sizes are 30, 60 and 300cc. The 30cc bottle contains counts that range from 7 to 90; the 60cc bottle holds between 18 to 90 pills; and the 300cc bottle is a 180-count size. Blisters will be thermoformed or cold-formed vinyl/foil in sleeves, cartons and wallet packs.
Once fully operational, the site will employ 82 people, 36 of whom will work on the packaging lines in two shifts. Multi-functional line operators are being cross-trained to work on either bottling or blister lines in primary and secondary packaging.
For the two bottle lines, Daiichi Sankyo hired NJM Packaging to do the line integration, including conveyors and sensors, because of its expertise in pharmaceutical bottling lines. Also, much of the equipment on Bottle Line 1 is NJM equipment, which Daiichi Sankyo planned to use anyway.
To help keep the packaging operations simple and easy to troubleshoot, Daiichi Sankyo chose to delink the line. Each machine has its own upstream and downstream sensors, and a bottle spacing device to automatically start and stop when bottles are backed up. This allows the machine to continuously operate at a consistent level based on bottle supply. Where possible, each machine has its own conveyor, and controls the speed and operation of this conveyor, which provides mini buffers up and down the line.
An accumulation table between primary and secondary packaging keeps track of how many bottles are on the table and will stop spacing wheels to pause all upstream machines to that point to prevent the table from becoming full. Then, when the bottle's minimum number is reached, the accumulator restarts the spacing wheel and upstream equipment automatically starts.
A walk down Bottle Line 1
On the day of Packaging Digest's visit, Bottle Line 1 was filling 300cc bottles of Welchol, a medicine to treat high cholesterol and diabetes. Filling speed for the 300cc 180-count bottle is about 30 bottles per minute. This line can also run 60cc bottles at about 90 bpm (30-count).
Product is currently manufactured in Germany and Canada and shipped to Bethlehem in bulk containers. Round, white HDPE bottles are supplied by Drug Plastics & Glass. A hopper outside the filling suite feeds bottles through the wall to an Omega 4D-SLCX215-CDF unscrambler, controlled with an Allen Bradley Panel View 600 HMI from Rockwell Automation. Bottles are oriented, turned upside down to clean them with an air blast and uprighted for single-file transfer to the filler.
An integrated desiccant placer inserts canisters from Sud Chemie for products that contain moisture-sensitive active pharmaceutical ingredients (API). Welchol does not require a desiccant, so bottles simply bypass this step. Photoelectric sensors from Banner Engineering check the bottle orientation and desiccant presence (when required), and kick out any faults at a bottle reject station.
Here the line splits into two lanes as bottles index into the CF1220 electronic filler from Cremer, where two bottles are filled at a time. An Aylward tablet elevator feeds product from the product hopper to vibratory plates that transport pills to detection channels. While free-falling through these channels, tablets are scanned and counted, before dropping into bottles on the conveyor below.
As bottles exit the filler, they merge back to single file. An NJM CL110 cottoner inserts synthetic (PE) cotton for products that require protection from breakage throughout the supply chain. Welchol tablets are hard-compressed and don't need cotton, so bottles bypass this step. However, photo eyes inspect for cotton presence, when required, and eject any bottles missing the filler.
The straight line continues on to an NJM Unicap 150 disc capper, where push-down-and-turn child-resistant, tamper-evident, continuous-thread closures from Drug Plastics & Glass are applied. A metal detector checks for the presence of the foil liner in the cap. If the foil liner is not there, it rejects the bottle.
An Enercon Super Seal induction sealer activates the foil liner, sealing it to the bottle to provide required tamper evidency. From there, bottles pass through another hole in the wall, leaving the primary packaging suite and continuing on to secondary packaging. NJM accumulation provides from three to five minutes of buffer between the front and back ends of the line.
An NJM retorquer applies the proper torque on the cap after induction sealing before bottles enter labeling. Prior to label application, a Videojet thermal coder prints lot numbers and expiration dates on the labels.
The Weiler RL-1000R-S10 pressure-sensitive labeler is a 10-turret rotating labeler with one label head and the ability to add a side insert placer in the future. It has two roll stations for quick change of labels when a roll is depleted.
Bottles exit the labeler and move down to an MGS Machine Topserter II machine that applies folded product information leaflets using a rotary vacuum wheel. Hot melt fugitive glue holds the paper outserts securely in place, but allows them to be removed without damaging them. A Cognex Dataman scanner checks the bar code prior to outsert application.
Two photoelectric sensors from SICK verify outsert presence by looking for the difference in bottle height (with or without top outsert). Bottles missing outserts are ejected from the line.
Some products are bundled with clear film at this point on an SL18 bundler from Omega. It produces 12-count packs in an easy-to-grasp 3x4 configuration. Welchol is not bundled, so bottles bypass the unit and are manually packed into cases in counts of 12. The RSC cases are manually erected, packed, and then top-and-bottom sealed on a 3M case taper before being manually palletized.
The same...only different
Bottle Line 2 is identical to Bottle Line 1 as far as layout and equipment goes, except for four changes:
1. Bottle Line 2 is dedicated to the 30cc bottle because of the volume of business for this size.
2. Daiichi Sankyo invested in a new Aylward 810 dual-lane electronic filler to reach higher throughput and overall capacity on the line (speed is specified at up to 250 bpm for a 7-count bottle). This model was also selected because it was immediately available and had been used at one of Daiichi Sankyo's contract packagers.
3. The cottoner is an existing DT Lakso system (now owned by IMA).
4. The NJM capper is a different model: a Beltorque.
Daiichi Sankyo has already identified the equipment for its two blister lines. The centerpiece of Blister Line 1, slated to run at 300 blisters per minute, is an existing Uhlmann UPS4 MT thermoforming system, also capable of cold forming, completely rebuilt by Pharma Works with upgraded vision and controls.
The Uhlmann is outfitted with a Wolke coder and will connect with a Pharma Works sleeve-loading system.
Equipment for Blister Line 2 will be an existing Klockner CP3 thermoforming machine, a new MGS wallet machine and a new MGS Eclipse cartoner.
All this activity is just a start, though. The Bethlehem site layout was selected and designed to accommodate future growth, with space for another bottle line and...possibly product manufacturing. "We're in throes of developing a three to five year site plan for U.S. and global needs," Lane says. "We certainly could begin manufacturing in this time frame. Or it could even be sooner."
3M Industrial Adhesives and Tapes Div., 800-362-3550. www.3M.com/packaging
Aylward Enterprises, 252-633-5757. www.aylward-usa.com
Banner Engineering, 763-544-3164. www.bannerengineering.com
Cognex, 508-650-3000. www.cognex.com
Cremer, +44 1276 35053. www.cremer.com
Drug Plastics & Glass, 610-367-5000. www.drugplastics.com
Enercon Industries, 262-255-6070. www.enerconind.com
IMA North America, 800-851-1518. www.ima-na.com
MGS Machine Corp., 800-790-0627. www.mgsmachine.com
NJM Packaging, 603-448-0300. www.njmpackaging.com
Omega Design Corp., 800-346-0191. www.omegadesign.com
Pharma Works, 727-232-8200. www.pharmaworks.com
Rockwell Automation, 414-382-2000. www.rockwellautomation.com
SICK Inc., 800-325-7425. www.sick.com
Süd-Chemie, 502-634-7200. www.sud-chemie.com
Uhlmann Packaging Systems L.P., 973-402-8855. www.uhlmann.de
Videojet Technologies Inc., 800-843-3610. www.videojet.com
Weiler Labeling Systems, 856-273-3377. www.weilerls.com
Wolke (via Videojet Technologies Inc.), 630-860-7300. www.wolke.com