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■ CONTRACT MANUFACTURING, PACKAGING & NEW EQUIPMENT TECHNOLOGY FOR THE BIOPHARM/PHARMACEUTICAL INDUSTRY

OFFICIAL MEDIA SPONSOR OF

W W W. P H A R M P R O . C O M • V O L U M E 3 0 , N U M B E R 6 • J U LY / A U G U S T 2 0 1 5

INSIDE THIS ISSUE:

SETTING THE STAGE Grand River Aseptic Manufacturing’s expanded focus has produced growth and new opportunities for the company and its customers.

■ EMERGING MARKETS Softgel formulation and delivery challenges The latest medical marijuana developments ■ VALIDATION Raw material testing to ensure supply chain security ■ CLINICAL TRIALS The impact of wearable devices Implementing lean practices ■ PRODUCTION Risk assessment’s role in dosage formulation Recruiting and retaining skilled workers Drug shortage impacts

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■ IN THIS ISSUE

10 Grand Scheme of Things

Official Media Sponsor of the INTERPHEX Show

Grand River Aseptic Manufacturing continues to grow its later stage contract manufacturing business.

GENERAL MANAGER, MANUFACTURING GROUP TOM LYNCH, 973-920-7782 tom.lynch@advantagemedia.com EDITORIAL DIRECTOR JEFF REINKE jeff.reinke@advantagemedia.com

14 The Softer Side

EDITOR JASON LOMBERG jason.lomberg@advantagemedia.com

of Things A closer look at the softgels market.

EDITORIAL ADVISORY BOARD Michael J. Beier, Senior Vice President of Operations TITAN PHARMACEUTICALS, INC.

16 U.S. Drug Shortage An interesting look at the dynamics of the drug shortages hitting many prominent sectors.

Dr. James V. Blackwell, PhD, Consultant BIOPROCESS TECHNOLOGY CONSULTANTS, INC. Ronald C. Branning, Vice President Global Quality GENENTECH INC.

18 Validation & Beyond

Robert F. Dream, Vice President H.D.R. COMPANY LTD.

How high-quality validation processes help insulate and improve pharmaceutical supply chains.

20 What to Wear

Johanna Carmel Egan, VGP Project Management ELI LILLY Girish Malhotra, President EPCOT INTERNATIONAL

page 15

How wearable devices are improving clinical trials.

Susan Polizzotto, Manager, R&D QA GMP Compliance US SANOFI PASTEUR

22 Risk Assessment

Carlos Villalobos, Sr. Dir. Global Engineering BRISTOL-MYERS SQUIBB

for Effective Phase I Dosage A closer look at how early stage API characteristics impact formulation, process development and manufacturing.

Richard G. Whitfield, Senior Director PFIZER Patrick Wong, Director of Global Engineering BRISTOL-MYERS SQUIBB (BMS)

page 19

24 Hiring in Biopharma Rapid growth in some markets has created a troubling production bottleneck that stems from a lack of qualified personnel.

32 Medical Marijuana Update A look at the latest developments impacting legal marijuana usage and products.

page 21

■ D E PA RT ME NT S 4 From the Editor 6 What’s Hot Product Section 28 Facility Product Spotlight 30 Worker Safety Products ■2

Allan F. Pfitzenmaier, President VECTECH PHARMA CONSULTANTS INC.

JULY/AUGUST 2015 | PHARMACEUTICAL PROCESSING

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As the eponymous rapscallion Austin Powers once said, allow myself to introduce … myself. I’m Jason Lomberg, the new Editor with Pharmaceutical Processing. You may have caught my biting columns and insightful (not to mention, humble) commentary over at sister publication, Electronic Component News, but given the drastically different markets, you’d be forgiven if this is the first you’ve heard of me. I’ve got a BA in English (yes, you read that correctly – an employed Liberal Arts major), and for the last 7 years, I’ve been writing blogs, editing prose in various degrees of coherence, and travelling the world on behalf of ECN. Hey, no one said the job was boring. Before that, I was in the Army Reserve (that and ECN actually overlapped for awhile) and spent 11 years in the wonderful world of retail. About a month ago, I joined Pharm Pro as its new Editor, and I couldn’t be more excited to dive into such a dynamic industry and explore everything from contract manufacturing to single-use, generics, biosimilars, and much more. I have a naturally inquisitive mind (thank you, Liberal Arts degree!), and I love to learn. And I’ll be doing a lot of that. For over 30 years, Pharmaceutical Processing has provided industry professionals with news and information on cutting-edge technologies and services for the pharmaceutical, biopharmaceutical and nutraceutical markets, and I’m thrilled to climb aboard. I’m a lifelong writer, and I like putting pen to paper (or fingers to keyboard) whenever possible, but what I like best about this job is the opportunity to engage our readers, whether that’s online, vicariously through our print edition, or in-person at a lab, factory, or trade show. I’m an extremely passionate person (again, blame the degree), and I’ve come to expect the same from those I interact with and serve – that would be you, the readers. I love passion and energy. I hate apathy. So get off the sidelines and get involved! Join the conversation on pharmpro.com, send me an email at jason.lomberg@ advantagemedia.com, or say hi if you see me poking my head into your booth. An engaged audience is a loyal one, and it’s my goal to perpetuate Pharm Pro’s 30-year history of excellence while expanding our online focus and leading the conversation. Let us know how we’re doing, how we can improve, and what you’d like to see. We like to consider ourselves “in the know” (three decades of proud service will do that), but you’re the ones on the front lines.

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W H AT ' S H O T

Energy Efficient Ductless Fume Hoods Air Science has introduced its Purair ECO line of Energy-Saving Ductless Fume Hoods in response to an increasing demand for containment cabinets that minimize stress on facility HVAC systems. The Purair ECO is available with a choice of controllers, including the company’s new ECOair™ touchpad control with color display interface. An optional BACnet network interface connects all cabinet control, monitoring and alarm functions to an open-source facility monitoring system. The Purair ECO is available in five standard sizes from 30" wide to 69" wide. ■ www.airscience.com

WHAT’S HOT Induction, Wetting & Dispersing The Ystral Conti-TDS, distributed by Powder Technologies, Inc., offers powder induction, wetting and dispersing of an agglomerate-free liquid with one machine. Additional features include: • 3-A Sanitary Standards, Inc. certified. • Based on an inline dispersing machine with a rotor stator system transporting and dispersing liquid with high-shear energy up to 100 ft./sec. with shear gradient 50,000 sec.-1. • Liquid flows through the dispersing chamber that builds up a high induction vacuum with rates up to 800 lbs./min. This vacuum in turn inducts powder with no agglomeration, without emitting dust or leaving any powder in the bottom of its container, thereby eliminating product waste and environmental hazards. • Can be attached to several vessels or mobilized to work in different production areas. • Features clean-in-place without disassembly. ■ www.powdertechnologyinc.com

More Material, More Efficiency Hapman’s Screw Feeder is designed to measure ingredients and consistently deliver material to the process. This feeder is available with either volumetric or gravimetric controls with a range of measurement options in covering varying applications. The trough is available in 304 or 316 stainless steel, carbon steel, or special alloy material, and can be customized for specific application needs. ■ www.hapman.com

Inline Vial Management System The Intelligent Vial Rejection Module (IVRM) is an Inline Manipulation System designed for detection and treatment of vials during the freeze-drying process. Developed by Telstar, it is a compact inline quality control unit that can be fully integrated in automatic loading and unloading systems in order to automatically manage the paths of vials during the loading and/or the unloading of freeze dryers. ■ www.telstar.com ■6

JULY/AUGUST 2015 | PHARMACEUTICAL PROCESSING

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Pneumatic Bulk Bag Discharging System Material Transfer offers their Material Master Bulk bag discharging system with features that include: • A fork-lift loaded bulk bag lifting frame with a pneumatic bulk bag elongation system to assist with product discharge. • Unit framework constructed from 304 stainless steel structural tube, capped ends, continuously TIG welded. • A stainless steel heavy-duty Flo-Master bulk bag massaging system, a Seal-Master bag spout access chamber, a Sure-Seal bag spout clamping system for dust-tight discharge, and a 316 stainless steel discharge transition with access hatch. • A loss-in-weight 304 stainless steel load cell package with digital weight indicator specifies the amount of product being discharged from unit. ■ www.materialtransfer.com

Microbial Air Samplers EMD Millipore now offers the MAS-100 Iso MH and MAS-100 Iso NT systems for use in isolators to enable sampling at critical control points. The distinguishing feature of the MAS-100 Iso MH system is its four sampling heads, which allow for increased monitoring capacity compared to single-head systems. The MAS-100 Iso NT system features a fully validated air sampler with a double valve that integrates the sampling head into the decontamination process of the isolator. The MAS-100 Iso MH air sampler offers all the benefits of the MAS-100 Iso NT and allows for the installation of up to four sampling heads at all critical control points to increase capacity and costs less than four equivalent single-head systems. The units comply with the guidelines as specified in the new ISO 14698 part 1 and part 2 standards. ■ www.emdmillipore.com

WHAT’S HOT

Corner-Over-Corner Tumblers

Advanced Weighing Terminal

The Morse 309 Series Drum Tumblers are designed to receive an upright steel, plastic or fiber drum and rotate the drum corner-over-corner. Capabilities include: • The ability to agitate drum contents without opening it. • Can incorporate settled ingredients, homogenize valuable products and eliminate sediment at the bottom of a drum. • The option of using a separate drum for each batch and avoid the use of a container to purge between batches. • Measurements from 29" to 37" tall and 18" to 23.5" in diameter. • Explosion-proof speeds of 12 and 14 RPM. • Capacities from 400 to 800 lbs. ■ www.morsedrum.com

Mettler Toledo offers their IND570 as an advanced industrial weighing terminal with broad applications. The terminal's flexibility in connectivity and control options combine with advances in performance verification, efficiency and secure access to critical process data to satisfy greater traceability. ■ www.mt.com

PHARMACEUTICAL PROCESSING | JULY/AUGUST 2015

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Mobile Clean Room Design Walker Barrier Systems has introduced an extended-width mobile clean room with 1,350 square feet of workable space. All Walker rooms include doors with windows, door closers, interlocks, adjustable sweeps, airlocks, cascading pressure operation between rooms and dry chemical fire suppression systems. ■ http://walkerbarrier.com

WHAT’S HOT WHAT’S HOT Aseptic Syringe Filling & Plugging

NJM Packaging introduces the Dara SFL Syringe Filling and Plugging machine, an aseptic filling and plugging system for syringes or vials in a nest or tray. Dara can equip the modular Dara SFL with an isolation barrier or restricted access barrier (RAB) and a peristaltic pump or valve-less rotary piston pump. With its servo motion controls and high quality engineering, the Dara SFL offers filling and plunger insertion, faster changeovers, less maintenance and the flexibility to add package and tray formats. This aseptic manufacturing system fills and closes up to 35 units per minute if equipped with one filling head and one closing head and up to 80 units per minute with two heads. It accommodates glass and plastic syringes with fill volumes from 0.5 to 20 ml and vials with fills volumes from 0.5 to 50 ml. ■ www.njmpackaging.com ■8

Centrifugal Impact Mill

A new pharmaceutical-grade Pin Mill, model CIM18-S316 from Munson Machinery, grinds friable powders, flakes and granules into controlled particle sizes ranging from coarse to fine. The outer and inner discs can swing away from the unit on cantilevered arms, providing full access to both sides of both discs and the mill housing. High-speed rotation of the inner disc creates centrifugal force that accelerates bulk material entering the central inlet of the opposing stationary disc. As material travels from the center to the periphery of the discs at high speed, it passes through a path of five intermeshing rows of precision-machined rotating and stationary impactor pins, with the desired tight particle size distribution obtained by controlling the rotor speed. Constructed of #316 stainless steel, the unit features a sanitary butterfly valve on the air intake, sanitary fittings at the material intake and discharge and a wash-down-duty motor. ■ www.munsonmachinery.com

Mammalian Culture Single-Use System Sartorius Stedim Biotech has introduced Sartoclear Dynamics, a clarification system featuring new single-use technology for harvesting mammalian cell cultures with high cell densities. Higher cell line concentrations place growing challenges on the purification process, and as body feed filtration has proved to be the best solution to solve similar challenges in related industries, Sartorius Stedim Biotech has now developed technology for biotech applications. Specially designed for cGMP processing, Sartoclear Dynamics consists of prefilled single-use bags containing ultrapure diatomaceous earth (DE) in a choice of 0.5 kg to 10 kg. With a new quick-connect adapter for dust-free powder transfer, DE can be directly mixed into the cell culture fluid. This porous filter aid prevents filter blockage. ■ www.sartorius.com JULY/AUGUST 2015 | PHARMACEUTICAL PROCESSING

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■ W H AT ' S H O T

Sanitary Modular Belt Conveyors QC Industries recently launched their HydroClean Sanitary conveyors, the first modular belt conveyors that can be disassembled without tools for quicker turnover. A unique series of pull-pins, sides and guides allow for breaking down and cleaning without a single tool. They are built on a single-piece, 304 stainless steel frame to NSF standards. To minimize opportunities for bacteria growth, they feature a self-draining frame, minimal horizontal surfaces, no exposed threads, and hex head fasteners. Their sealed ball bearings are filled with NSF-approved solid lubricant and covered for protection during in-place cleaning operations. ■ http://qcconveyors.com/hydroclean/video

The One Solution For Contained Product Transfer Volkmann high quality, vacuum conveying systems not only contain your product during transfer, they meet cGMP cleanliness standards and are explosion-proof, all while giving you dense phase vacuum conveying free of segregation, damage or abrasion.

High Speed Disperser The new Ross HSM-100LH-3 Vacuum High Speed Disperser is designed for mixing batches up to five gallons. It can be supplied with a vacuum-rated mix vessel including a heating/cooling jacket and mixer cover with sight/charge ports. Interchangeable sawtooth disperser blades are available (2", 3", 3.5" and 4" diameter), and suitable for variable speed operation up to 4,800 RPM. All wetted parts are stainless steel type 316 and driven by a 3HP VFD-rated motor. Additional features include safety limit switches and a mixing head raised by an air/oil hydraulic lift with pushbutton controls. ■ www.mixers.com

iSeries Deduster Pharma Technology Inc. (PTI) offers its PharmaFlex iSeries Deduster with upgrades that include: • An enlarged tablet inlet and outlet ports for higher output (>1 million/h with 12mm tablets). • An enlarged circumferential dust extraction channel for improved dedusting efficiency. • A self-regulating vibratory base with accelerometer, making it unnecessary to adjust gaps of springs on the unit’s base when changing the deduster’s tower height, or when transitioning from one product to another. • Clear spiral segments for the complete tower, providing direct sightlines to tablets throughout the process. • The unit’s spiral tower can be excahanged and replaced by a clean tower (or a tower of a different height). • Each segment can be removed individually for easier cleaning and changeover. This stackable system also allows for adjustable height gain and shaft extension. • Dust-tight, silicone-sealed tablet press chute connection. • Digital control of all systems, including metal detection, via touchscreen HMI. ■ www.pharmatec.be PHARMACEUTICAL PROCESSING | JULY/AUGUST 2015

Simply the best vacuum conveyor.

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STORY

Setting the Stage A redefined focus and smart investment strategies have elevated performance levels and capabilities at Grand River Aseptic Manufacturing. n By Jeff Reinke, editorial director

riven by an abundance of high-quality lumber and access to the Grand River for transporting huge quantities of the nature resource, Grand Rapids, MI was the epicenter of U.S. furniture manufacturing in the late 1800s. Over time the city transitioned, and now boasts high-tech manufacturing prominence in the aerospace, automotive and healthcare fields. This type of evolution is driven by the ability to recognize and embrace new technologies, as well as their corresponding opportunities. Illustrating this dynamic as well as any company

in the region is Grand Rapids Aseptic Manufacturing. The company was originally founded in 2004 as a joint venture between Grand Valley University and the Van Andel Institute, serving as a pharmaceutical packaging company. The university provided the land while VAI, a bioscience R&D incubator of sorts, established the business. In 2011, a private equity group acquired the company and transitioned it to the contract manufacturer currently known as Grand River Aseptic Manufacturing, or GRAM. Today, the company has more than 70 employees working in two locations

with approximately 40,000 square feet of cGMP space. Capabilities encompass all stages of clinical development and commercial manufacturing, inspection and packaging. Specific contract production services include liquid and lyophilized vial filling, syringe filling, terminal sterilization, labeling, packaging and kitting. A new, recent addition to GRAM is used for finishing work, while filling and development is still handled at the companyâ&#x20AC;&#x2122;s initial location. In addition to bringing a transition from packaging to production, the 2011 acquisition included the investment interests of Tom Ross. An initial

Clean room and filling investments have played a key role in GRAM's growth.

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TOM ROSS, CEO, GRAND RIVER ASEPTIC MANUFACTURING

Validation and testing capabilities have helped GRAM maintain its reputation for quality.

financial supporter of GRAM, Ross gradually became involved in some day-to-day operations in 2013 before taking on the role of president. He was appointed CEO last year. Ross’ elevation coincides with some the most significant decisions GRAM has made in its brief history, as well as some of its most interesting challenges. LATE STAGE DEVELOPMENTS Initially, GRAM focused on smallbatch, clinical manufacturing covering phases 1-3 in taking customers up to the commercialization stages. “Our focus on quality made us very attractive to those wanting to commercialize but weren’t there yet,” offers Val Dittrich, who is part of the business development group at GRAM. A slow-down in early-stage business ignited GRAM to pursue opportunities in the commercialization stages. “As we began targeting potential customers and worked the sales pipeline, the need for immediately available, small-run CMO capabilities became clear,” states Ross. “With the consolidation in the CMO market and the acquisition of various manufacturing facilities by big pharma, many customers needed an immediate solution. We had many of these things in place and moved quickly to scale up production capacities.” “In order to enable growth and attract customers, we had to invest heavily in the facility, equipment, and people,” offers GRAM chief operating

office Connie Degen. “This was driven by the long lead times and required validation activities for facility upgrades and equipment, as well as the technical training required for certain staff. Had we not made the up-front investments, it would have proven difficult to attract new business opportunities and build a solid customer base,” she adds. Accompanying these investments was a slew of implementation challenges focused on handling the increases in production scale. “In early 2014, we doubled the size of our formulation room, expanded our aseptic processing area and added additional WFI capacity to keep up with the demand for larger batch sizes,” recalls Degen. “Since then, we have also gone to three shifts of fill production and are adding automation to our finishing lines,” she states. Degen places the state-of-the-art clean room and the aseptic filling line that supports projects through all phases of development as some of the most critical investments. “As the client base grew and projects moved toward commercial production, we were then able to invest in areas that better supported growth in these areas,” she states. This included increased lab capabilities (chemistry and microbiology), labeling, packaging, inspection and new warehousing space. The later came in the form of the company’s second Grand Rapids facility, which opened

PHARMACEUTICAL PROCESSING | JULY/AUGUST 2015

What are your thoughts on some of the trends impacting CMOs right now? • Serialization regulations: “With the trend of increased regulatory compliance, serialization makes sense as it helps to ensure the safety and security of the supply chain. However, implementation of a new process will be challenging as there is no established ‘standard’ or specific instruction from the regulatory agencies. Each CMO must evaluate the best method, which will depend on their own technology, sourcing and relationships.” • Big Pharma’s interest in acquiring CMOs: “It is not a big surprise to see this trend continue, as Big Pharma is looking to secure capacity, control the process, and bolster their R&D pipelines.” • An increased desire from drug developers for ‘one-stop shops’: “Given all of the stages in drug development, the ability to locate a ‘onestop shop’ would shorten the timeline and reduce the risk in transitioning from one organization to another. For these reasons, drug developers desire this type of service organization. It is GRAM’s goal is to become a ‘onestop shop’ and continue to increase its appeal in the marketplace.” • The increased demand for generics: “The healthcare industry has seen a lot of change over the last few years, specifically with pressures on pricing (services, drugs, etc.). The desire for a low-cost alternative to name-brand drugs will continue to rise, which forces CMO’s to consider an increasing number of generic products. With a lower retail cost than the name-brand alternatives, generics require CMOs to evaluate efficiencies and manufacturing processes to bring costs down. Name-brand drugs will still be a critical part of the pipeline, but generic products are becoming more prevalent.” 11 n

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values and we know what will and will not work. That’s what keeps customers coming back. Based on our history customers know their product is safe here,” she continues. The company has also invested in improving their processes to mesh with expansion, which led to GRAM becoming DEA-licensed for production and storage of schedule 3-5 controlled substances. This competitive advantage was realized after urging from a customer that wanted to grow their business relationship with GRAM.

Adding stage 4 and 5 manufacturing capabilities entailed a great deal of internal investment.

late last year. “However, the single most important investment GRAM has made is in its people,” states Degen. “GRAM’s successes and pivotal moments over the years are a direct result of the talent and expertise of each individual employee and the culture that has been developed. GRAM has invested in talented people and worked to create a strong team environment, which results in each employee’s willingness to step outside their functional areas and help other team members. This investment is what drives company and customer successes.” Currently, GRAM inspects, labels

and packages as many as 20,000 vials per day. The labeling and packaging capacity is expected to increase significantly as GRAM increases automation investments. “We never expected to be doing these types of quantities, but the investments and Tom’s leadership has led to our commercial clientele doubling in the last two years,” states Dittrich. She goes on to say that GRAM’s reputation for quality and customer service has led to referrals from larger CMOs who don’t want to handle smaller runs. GRAM is also experiencing return business from current customers with new products. “We know their company, we know their

The shift in manufacturing scale was a significant challenge as GRAM added commercialization services.

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ROLLING ON THE RIVER “We currently have no clients in Michigan,” offers Dittrich. “We’re one of the few CMOs in the Midwest, with most of our competitors being located on the East or West coasts. It just proves that you don’t have to be in a traditional hub to grow and attract new business.” Looking forward, Ross will rely on a number of key strategies to help GRAM continue bringing new contract manufacturing work to Grand Rapids. “Managing growth in a fast-growing company is challenging,” offers Ross. “Anticipating resource needs and finding highly skilled talent to help achieve aggressive growth targets remain a key focus.” Degen adds, “We are routinely reviewing operations in relation to individual projects with a focus on continuous improvement.” This continuous improvement approach, and the elements of quality inherent to it, also pertain to the way GRAM is growing its workforce. “Dedication to quality begins at the interview process,” states Degen. “Prospective hires are evaluated for their work ethic and understanding of the critical nature of our manufacturing. During the on-boarding process, there is significant emphasis placed on all aspects of quality, including documentation and good manufacturing practices. “For the aseptic manufacturing group, training is interactive and frequent. Every employee is instructed on the importance of their role to the overall quality of the product, and learns to see each unit produced as

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QUALITY BY DESIGN AT GRAND RIVER ASEPTIC MANUFACTURING – CONNIE DEGEN, COO If requested by the CLIENT, GRAM will utilize Quality by Design (QbD) to capture all development activities through full cGMP manufacturing. QbD is defined by GRAM as a systematic approach to development that begins with pre-defined objectives and emphasizes product and process understanding and process control, based on sound science and quality risk management. The activities that will be applied to the formulation and process development by GRAM will follow the QbD approach. This approach will encompass six phases of activities including: 1) Product and Process Design and Development 2) Risk Management 3) Determination of Critical Quality Attributes and Critical Process Parameters 4) Laboratory Scale Formulation and Design of Experiments 5) Process Validation (To be completed before commercial manufacturing) 6) Continuous Monitoring and Improvement (Ongoing during commercial manufacturing) one that may be injected into a loved one. Company management maintains and reinforces this commitment to quality as the most important aspect of our work,” she adds. In continuing with GRAM’s ongoing commitment to both quality and growth, Ross points to the following as potential opportunities and areas of investment: • The price and time paybacks of single-use systems for commercial production. • Capitalizing on growth in markets such as injectables, personal dosage, pre-filled syringes and kitting for finished product. • Possibly adding another clean room to increase production quantities.

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• Merger and acquisition activity has led to some bigger companies eliminating offerings that are not as profitable. Some of these could be opportunities for GRAM. “Over the next few years the goal is to maintain a trend of sustained, profitable growth while continuing to round out our capabilities and service offerings,” states

STORY

Ross. “Before considering expansion into new sectors, we want to continue to solidify our reputation and track record.” Just as the city it calls home, GRAM seems poised to continue evolving and preparing for the next phase of growth. n

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Meeting formulation and delivery challenges for macromolecular drugs How lipid-based drug delivery systems can meet complex formulation, solubility and bioavailability challenges, including specific issues in improving the delivery of peptide and biologic therapeutics. n By Julien Meissonnier, Catalent Pharma Solutions

he biotech market reached revenues of $172 billion in 2014, which accounts for 23 percent of global pharmaceutical drug revenues, and it is expected to grow to 27 percent by 20201. In a recent drug delivery landscape survey2, oral delivery of macromolecules was voted as the top trend set to influence drug development over the next five years. Lipid-based drug delivery systems (LBDDS) incorporated into softgel technologies are frequently used to improve the bioavailability of poorly soluble compounds, and have been used successfully to bring more than 50 poorly soluble molecules to market. Softgel technology enables improved delivery of low-solubility BCS Class II and IV drugs and also provides benefits in modulating membrane permeability for drugs where solubility is not the only biopharmaceutical hurdle to overcome. By modulation of the membrane’s permeability, this technology can be applied to enable the delivery of macromolecular BCS Class III drugs. LBDDS: A VERSATILE TECHNOLOGY The basic principles of LBDDS technology, which has proven to be one of the most successful advanced drug delivery methods applied to BCS Class II drugs, ensure that drug substances are delivered in a solution form that is maintained within biological fluids before the API reaches the intestinal membrane. In addition to the solubility issue, some poorly soluble drug candidates pose further challenges to attain the desired target product profile. LBDDSs have the versatility to offer a broad range of formulation possibilities. For example, some poorly soluble drugs display excessive inter/intra individual variability which may not be compatible with the desired therapeutic effect. There are several strategies specifically designed to reduce such variability,

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including the self-micro emulsifying drug delivery system (SMEDDS), a lipid-based ‘pre-concentrate’ of solubilized drug, composed of lipid excipients, surfactants and co-surfactants, and co-solvents. Dilution of these formulations with gastrointestinal fluids results in the formation of a stable microemulsion, whereby the drug stays in solution and precipitation does not occur. Several new drugs formulated in this way have been commercialized. Other strategies that have been applied to optimize formulations beyond solubility enhancement include the limitation of serum peak concentrations, thus reducing the Cmax/Cmin ratio. To achieve this, semi-solid formulations combining solubility enhancement properties with a modulated release rate have been developed. The technology upon which this formulation is based enables the encapsulation of various LBDDSs at higher temperatures. DELIVERY SYSTEMS FOR MACROMOLECULAR DRUGS Currently there are 200+ therapeutic macromolecules in the market and several have entered clinical trials3. The best known, and most widely administered, is insulin, which accounts for a $25 Billion market worldwide4, followed by monoclonal antibodies. The traditional approach to deliver these macromolecules has been through subcutaneous or intravenous injection, due to absorption, distribution, metabolism, and elimination (ADME) challenges associated with them. However, these dosage forms suffer from short plasma halflives, necessitating frequent administration and ultimately, the risk of poor patient compliance in chronic conditions. Oral drug delivery has always been the ultimate goal for any new therapy, not only because oral forms are so much more convenient and less invasive for patients, but also because clinical development of an orally delivered form is usually more straightforward, and clinical development JULY/AUGUST 2015 | PHARMACEUTICAL PROCESSING

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costs are less than for an injectable formulation. Therefore, development of targeted and efficient oral formulations of macromolecules represents an unmet need. To cater to this need, Catalent initiated research into the application of LBDDS technology for the non-invasive delivery of biologic drugs back in 2007. This has resulted in the development of OptiGelâ&#x201E;˘ Bio technology, a lipid-based formulation that incorporates enteric coating and targeted permeation enhancement to increase the bioavailability of macromolecules, therefore enabling oral delivery of macromolecules. The OptiGelBio technology combines various mechanisms in an effort to counter the challenges faced by macromolecules such as poor stability in the harsh conditions of GI tract, and poor permeability through the intestine cell wall, and therefore, poor bioavailability. When macromolecular peptide or protein drugs are delivered to the stomach, the molecule degrades or denatures when exposed to the acidic environment (pH 1-3) and proteolytic enzymes. The enteric coating applied to OptiGel Bio softgel formulations is intended to enable macromolecules to pass through the stomach and deliver active APIs to the intestine, thus potentially allowing for targeted delivery. In the small intestine, the macromolecules cannot permeate through tight junctions of the intestinal cell wall because of multiple factors, including molecular size and steric hindrance effects, and are vulnerable to further enzymatic and hydrolytic degradation. OptiGel Bio technology dissolves the macromolecule in a Generally Recognized as Safe (GRAS) lipid-based formulation within a softgel. Overcoming the mucus layer, the coated softgel capsule dissolves only after reaching the intestine wall and the lipid formulation evolves under normal biological conditions to release locally high concentrations of permeation enhancers along with the macromolecular API. The permeation enhancers open up the tight junctions, allowing the mac-

EMERGING MARKETS

romolecules to pass through into the bloodstream. After a short period the tight junctions close again, preventing absorption of any toxic molecules. Furthermore, Catalent has created standard pre-formulation and formulation screening models in order to quickly evaluate whether OptiGel Bio technology can assist in the delivery of candidate macromolecules, including peptides. These models enable the determination of potential structural changes to the peptides that could maximize the ability to cross the enterocyte along with the permeation-enhancing system when formulated. Biologics hold great promise with their low immunogenicity and targeted mechanism of action while offering their marketers better brand differentiation. A delivery technology that can enable a convenient administration method, such as the oral route, for these macromolecules could potentially change the landscape of the biopharmaceutical industry. OptiGel Bio technology combines a GRAS lipid-based formulation and enteric coating to offer targeted permeation enhancement and macromolecule protection. The technology offers the potential to increase the bioavailability of macromolecules without absorbing unwanted toxic molecules, and may therefore enable oral delivery of macromolecules. It also has unique design features to reduce intra/inter individual dose variability. These characteristics set it apart from alternative technologies. OptiGel Bio technology is applicable to various classes of macromolecules, including oligosaccharides as well as peptides and proteins. Catalent is conducting further research. REFERENCES 1. Evaluate Pharma, June 2014 2. The 3rd annual drug delivery landscape survey was sponsored by Catalent Applied Drug Delivery Institute. For more information, visit www.drugdeliveryinstitute.com 3. Advanced Drug Delivery Review, July 2013, Ezan E, Pharmacokinetic studies of protein drugs: past, present and future 4. IMS data, 2013

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CASE STUDY: OPTIGELBIO TECHNOLOGY ENABLES IV-TOORAL THERAPY CONVERSION An early-stage biotechnology company had developed a novel macromolecularintravenous (IV) therapy for a thrombolytic post-surgical indication, and approached Catalent to enable conversion of the dose form to oral delivery. The aim was to enable this drug unique safety/efficacy profile to be applied to longer-term indications. The macromolecule was soluble, but it had a high molecular weight (>2500 Da), a strong negative charge and a rigid, inflexible geometry which challenged the desired delivery across the walls of the small intestine into the blood. Catalentâ&#x20AC;&#x2122;s formulation expertize and OptiGel Bio technology achieved an optimized oral therapy which combined both the permeability enhancement and targeted delivery desired. A stepwise screening approach utilizing both in-vitro and in-vivo models was adopted to evaluate formulation candidates and so to overcome the permeability challenge of the macromolecule. These studies demonstrated that lipid formulations, made of GRAS ingredients, releasing under normal biological permeation enhancers showed superior performance to formulations evolving into nanoparticulate systems. Those formulations have proven a superior permeability enhancement. Despite the improvements in bioavailability, the pharmacokinetic (PK) variability highlighted the need for dose form optimization. The final dose form design was optimized. 15 n

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A C C U P D AT E

Pharma Playing Key Role in Economic, Chemical Growth

s its name would suggest, the American Chemistry Council (ACCs) works with and represents the interests of companies engaged in the global, $812 billion business of chemistry. Many of the businesses housed in the chemical fraternity are obviously aligned with the pharmaceutical marketplace. One of the services/on-going projects of the ACC is their weekly Chemical Activity Barometer, an economic report which highlights and ana-

lyzes the ongoing strengths and weaknesses of the chemical marketplace. Recent postings have seen fluctuating, but generally positive economic conditions for the chemical marketplace as a whole, with year-over-year increases in production and pricing levels. Recent ACC reports also indicated that market productivity is accelerating at a pace that hasn’t been seen since the first quarter of 2011. One of the dynamics surrounding this economic push has been gains in the pharmaceutical marketplace.

Overall economic indicators feeding growth in this and other sectors include lower energy prices, steady inflation rates, rising consumer confidence, improving pay levels and lower unemployment rates. An example of how these factors are encouraging growth in the pharmaceutical sector include year-over-year production increases for the month of May. Additionally, imported pharmaceutical product prices have been flat, while exported product pricing has increased, meshing with overall price increases.

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Pharmaceutical Validation & Beyond: Creating a Trusted Supply Chain The ability to track raw material sources before they hit the manufacturing line adds a critical layer of supply chain security. After all, no one wants sawdust turning up in baby powder. n By Jim Lee, Vice President of Product Management, Systech

hat is the difference between validation and qualification? Very often, the terms are intermingled. To help clear the confusion, “things” are qualified, while the ways they are “used” (processes) are validated. Validation aims to solve a single problem: accelerating approval from regulatory bodies in order to bring a product to market. Validation by definition is the action of proving -- in accordance with the principles of GMP -- that any procedure, process, or activity will consistently produce a product that meets specifications within set quality guidelines. Qualification is an inherent part of validation and is the action of proving -- in accordance with the principles of GMP -- that any equipment, material, facility or system is able to achieve the expected results. As an example, the FDA defines process validation as the collection and evaluation of data, from the process design stage through commercial production, which establishes scientific evidence that a process is capable of consistently delivering quality product. Process validation involves a series of activities taking place over the lifecycle of the product and process with the goal of identifying potential hazards, failures and contamination. In short, validation is an integral part of quality assurance. However, it doesn’t necessarily secure the supply chain by collecting the necessary data points that provide visibility from

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the origination of raw materials to their final destination. Systech sees the future of validation going far beyond this finite definition as it relates to quality assurance. As we migrate toward a better, more effective means of validation, manufacturers will seek documentation to help ensure that systems, facilities and processes deliver uniform batches, which will meet required specifications and subsequent approvals. In addition, it is Systech’s view that it is becoming ever more important to focus on the origins of raw materials so they can be traced back through the supply chain prior to manufacture –including being able to validate authenticity to address questions like: Is this a real shipment? Was our supply chain contaminated or infiltrated? THE RISKS In order to bring a drug to market, procedures for each step in a drug’s creation and how it will be consistently, repetitively produced -- backed by scientific evidence -- is validated. However, as the product moves and scales into the manufacturing cycle, the risks associated with producing multiple batches in a variety of locations introduce a myriad of pitfalls, specifically around contamination. This is becoming more apparent with the steady growth of counterfeiting, which is fueled by the general demand on firms to do more with less (increase profits). The use of lower-cost materials combined with an increase in outsourced manufacturing in a rush to meet evolving compliance guidelines can be a recipe for disaster. At this point, the risks start to scale exponentially as contaminants begin to enter the supply chain at various stages in the process, from the sourcing of raw materials all the way to packaging, before they even enter the distribution chain. The consequences often lead to: • Inferior quality products. • Bulk recalls. • Quarantined product. JULY/AUGUST 2015 | PHARMACEUTICAL PROCESSING

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• Loss of revenue and market valuation. • Brand and reputation damage. The way quality control for validation is handled today is typically through the manual sampling of raw materials. However, most QC departments simply don’t have adequate manpower to do this. Moreover, even if they did, it doesn’t necessarily provide enough data to identify the actual source issue or the specific goods impacted. This leads to large recalls as only the batch can be identified, which can potentially be millions of units. WHAT NEEDS TO BE DONE The supply chain needs to be secured from end to end. Serialization has gone a long way to provide a form of identification for packaged items; typically at a batch level, enabling manufactures to issue recalls on a wide scale. Combined with track-and-trace technologies, the post-production supply chain can potentially be secured when all partners in the process leverage a common automated system. Unfortunately, when it comes to raw materials, serialization is not currently applied, nor is it legislated. However, due to the issues previously discussed, it’s no doubt just a matter of time. If you look to non-pharma industries such as consumer electronics, most major brands have implemented process, procedures and systems to secure their supply chains to such an extent that it has become commonplace for them to be able to issue recalls against individual products for specific faulty components. Pharma and life sciences can learn from the consumer product companies and reap critical benefits such as: 1. Ensuring consistent quality. 2. Reducing costs associated with recalls. 3. Continuously building brand trust. 4. Controlling counterfeiting. 5. Real-time authentication. 6. Developing consumer engagement channels (consumer/ retailer). PHARMACEUTICAL PROCESSING | JULY/AUGUST 2015

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HOW? Take a page out of the anti-counterfeiting book and combine it with serialization and track-and-trace to create the ultimate secured supply chain. 1. Serialize the product and packaging lines (required for compliance). 2. Implement track-and-trace, extending it upstream to shipping and distribution utilizing Internet-enabled technologies. 3. Implement track-and-trace technologies with raw goods/material providers. 4. Integrate with QMS to support validation. 5. Deploy anti-counterfeiting and authentication solutions. From the creation and packaging of raw materials, through shipping and into production and upwards through the supply chain, it now becomes possible to pinpoint a specific product at any point in its lifecycle, providing not only supply chain security, but also business intelligence and insight. By building an ecosystem of suppliers, CMOs and CPOs that leverage these technologies to build a secured supply chain, manufacturers make validation simpler and quicker; while at the same time increase their flexibility. This level of visibility allows manufactures to know, in real time, where the core ingredients originated and where those ingredients are, by product, location, stock levels, etc. This gives them a competitive advantage in controlling and reporting on supply chain diversion, infiltration and gray markets.

Taking it one step further, this technology can enable consumer engagement by encouraging consumers to ‘scan’ their medication when they take it, providing a feedback loop to deliver drug information on interactions, etc. and enable automatic re-ordering. Most importantly, it can quickly and efficiently notify end-users of a recall! The possibilities are endless and a game changer for the pharma industry as a whole. n 19 n

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Could Wearables Turn Traditional Trial Design on Its Head? Could it bring us closer to patient-centered R&D? n By Thaddeus Wolfram and Jon Lange

he planning and execution of clinical trials is a complex and deliberate process that must account for multiple factors in order to successfully enable the desired scientific outcome. Tactical coordination of finance, operations, IT and quality are necessary and important components in the process, but the core protocol design has always been the key driver that directly impacts study success. Over the years, protocol design has become a fairly standard procedure across the industry, shaped and constrained by the fundamental concept that a protocol very prescriptively specifies patient profile and related data to be collected and analyzed as part of the study. The advent of wearable technologies and their application in clinical trials could mean a rethinking of this concept and a fundamental change to the way clinical trial design and protocols are approached. While trial endpoints still need to be defined and proven, the mechanism for achieving these objectives through collection and analysis of patient data can now be executed in a very different way. Wearables could turn the current norm associated with trial design and data collection on its head, where, going forward, perhaps only 20 percent of the data needed for the study has to be collected through tradi-

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tional means. Under this concept, the other 80 percent of data could be harvested directly from the universe of patient data that wearables and other channels, such as electronic medical records, can now realistically enable access to. This will require, during a trial, close collabora- tion among sponsors, inves-

tigators and patients to navigate and control this pool of data for the desired purpose. It will be vital to have flexible means for analyzing and utilizing what is determined to be critical information, with advanced analytics and data integration capabilities becoming the key tools to leveraging this data and making sense of it. Additionally, the incremental study data which make up the information that is unique to your trial design and mandatory for the study endpoints will need to be collected and integrated in a streamlined fashion as well. Through this inverted trial design concept, wearables are a catalyst for value as one of the tools that underpin a forward-thinking R&D shift more targeted to the patient. Applying this concept, we could expect improved and more targeted safety and efficacy data, and gain more, relevant understanding and articulation of the value of a therapy by analyzing a real-world set of data specific to each and every trial participant. Therein lies the importance of the conceptual shift from specifying almost all of the data to be collected in a clinical trial, to specifying only a unique portion of it. But what can be stated so simply in reality poses a myriad of challenges and required changes that will result from the downstream effects of this fundamental shift.

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REDUCING SITE VISITS The remote real-time collection of study data afforded through wearables and other channels won’t eliminate the need for study participants to visit brick-and-mortar clinical sites; however, it will break some of the physical constraints that exist today. Alternative means for interacting with the investigator will evolve and the availability of electronic data will facilitate a virtual model for patient screening/enrollment, “study visits,” and the collection and monitoring of study data. This dynamic means study designs and the supporting operational processes will need to account for potential challenges to data consistency, such as patient adherence to study protocol if left to their own accountability, wearable technological glitches, or end-user error. Where previously the clinical site and site-based monitoring activities provided a stronger degree of control over data collection and timelines, going forward, protocol design will need to be more flexible/adaptive to enable compliance and data consistency within the specified study timeline.

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CONTROLLING STATISTICAL POWER REQUIRES INCREASED ATTENTION Under the concept of this wearable-enabled protocol design model, the volume of data will increase substantially — but the key will be to verify the quality of that data will still be acceptable. Foresight is required to proactively address potential shortcomings that could impact the power of the study results. Efforts will also need to be made to clarify what results will be accepted by health authorities and what will be needed for acceptance of a primary or secondary endpoint. It will be critical to design the trial to best limit the number of possible significant deviations from the protocol during the study and to provide ways that investigators can be made

FLEXIBILITY FOR DESIGN CHANGES BECOMES THE NORM With a large percent of study data being pulled from the available universe of data that is associated with a patient, it will be more likely during the process that insights coming out of the trial might dictate the need/value for an in-flight change to the study design. Investigators will need to plan as best as possible to be able to adapt based on the real-time insights gained. But with this challenge comes opportunity, as this model could potentially enable more effective adaptive trial design and execution given real-time access to this new set of data, helping to better inform the next stages of the trial. PHARMACEUTICAL PROCESSING | JULY/AUGUST 2015

aware when deviations do occur. For example, technology alerts could be instituted as part of the overarching element of maintaining control over the variables that can affect the power of the study results. The emerging use of wearables in clinical trials is an exciting opportunity for the industry and one that should lead to the development of better therapies for more targeted patient populations. Some participants in the industry will dive headfirst into this new model and others will take a more cautious and measured approach. Varying levels of success are expected in the near term, with the greatest overall success coming to those leaders who are able to iron out the wrinkles in this new trial design concept first. In either case, it appears that the incorporation of wearables into the clinical trials process is inevitable, and an event that will dramatically change the traditional approach to designing clinical trials for the better. The views expressed herein are those of the authors and do not necessarily reflect the views of Ernst & Young LLP. n

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API MANUFACTURING

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API Properties – Risk Assessment for Effective Phase I Dosage form Development Decisions n Anil Kane, Ph.D., Executive Director, Global Head of Formulations, Pharmaceutical Development Services, Patheon

haracterizing the physicochemical properties of an active pharmaceutical ingredient (API) in a solid state is extremely important in early-stage product development. Understanding these characteristics impacts the choice and design of the formulation, process development and manufacturing, and the performance of the dosage form. A robust solid-state characterization of the API at an early stage helps drug developers better understand the properties of the API and the effect they have on drug behavior, especially on uniform particle size and distribution, solubility, stability, in-vitro dissolution and bioavailability. A complete knowledge of the relevant physicochemical properties is essential for effective formulation development decisions.

PHASE I DOSAGE FORM DEVELOPMENT AND CRITICAL CONSIDERATIONS The most commonly developed solid oral dosage forms for a Phase I clinical study are: • Neat API in a capsule. • Blend in a capsule. • Powder in a bottle. • Liquid-filled hard shell capsule/softgel if it is a lipid-based delivery. Only in special cases is a tablet dosage form developed for an early Phase I clinical study. At this early stage, it is essential to develop a dosage form that brings speed and flexibility in dosing for a quick proof of concept as API is available in very small quantities and there is seldom an opportunity to perform elaborate development work to optimize a formulation and process. In addition, since the duration of the clinical study is often short, the stability of the dosage form required should be enough to cover the clinical program and justify the suitability of the clinical material. The physical properties of the API critical in developing the above-described “Quick to Clinic™” dosage forms are – particle size, bulk and tapped density and, to a certain extent, flow, cohesiveness and static behavior.

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Since the API is not handled in large quantities and Phase I dosage form requirement is typically a couple of thousand dosage units, clinical supplies can be manufactured using bench-top, small-scale equipment that uses manual or semi-automated process. Depending on the API dosage and drug loading, these parameters may or may not be critical to manufacturing. From a chemical standpoint, we need to understand the choice of the right and stable polymorph, its chemical stability, hygroscopicity and forced degradation profile. The dose range of the API is a critical parameter in consideration of the choice of the dosage form that can be developed. CAPSULES The dose of the API, the particle size, density and flow are critical in successfully filling the accurate amount of API in a capsule. Larger doses with a low bulk density and poor flow characteristics could pose a challenge as the capsule-filling mechanism may not be able to densify, tamp or pack a low bulk density powder in the capsule. When API is blended with a minimum number of excipients such as fillers and flow aids, the blend is better handled by equipment designed for capsule filling of a better flowing material. Capsule fillers that use a plate of 50, 100 or 300 capsules could be a better choice for filling a blend of API with excipients such as fillers, disintegrants and flow-aids as this mechanism cannot fill partial capsules. Another advantage of adding fillers is that tamping helps to densify and pack the low-density blend into the volume of the capsule. These types of capsule fillers are popular as the small number of capsules required for a short clinical study can be speedily manufactured. Several thousands of unit dose capsules can be manufactured using these types of encapsulators with a reasonable weight variation. POWDER IN A BOTTLE The process commonly referred to as powder for reconstitution is another approach for a quick manufacture JULY/AUGUST 2015 | PHARMACEUTICAL PROCESSING

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of clinical supplies for a Phase I study. This format is suitable for API that require larger doses and that can be reconstituted with water or other vehicles to form a solution/suspension as a multi-dose preparation. The API needs to have a sufficient physical and chemical stability in a vehicle until it is dosed, and dose uniformity needs to be ensured as a two-phase suspension is being administered. This format can also be used for a pediatric clinical study because of the ease of administration. LIQUID-FILLED HARD SHELL CAPSULES OR SOFTGELS Poorly soluble compounds from BCS Class II and IV may be formulated using a lipid delivery system utilizing lipidic vehicles and filling either a two-piece hard shell or softgel capsules. API properties such as the log P, octonal-water coefficient, solubility and stability in non-polar vehicles, surfactants, self-emulsifying agents and bio/permeation enhancers will determine the suitability of this capsule format for a quick Phase I clinical study. API properties such as particle size distribution, static charge, cohesive and sticky behavior, density and flow problems that can pose a significant challenge for the abovementioned formats can be easily managed in a liquid-filled hard/soft capsule format. It may be challenging to formulate large API doses that are sometimes required to be administered in a dose-finding study with an ascending dose. If a large dose is required to be administered in this presentation, the only way is to administer multiple unit doses/capsules for a Phase I controlled study as the volume of the hard capsule or the size of the softgel can accommodate only a certain volume of dissolved or suspended active in a vehicle. A risk assessment tool that considers the API properties previously discussed in the selection of the dosage form that can be developed for Phase I clinical study and classifies the risk as â&#x20AC;&#x201C; low, medium or high helps decision-making. This tool allows evaluation of the impact of changing the properties of the API to determine if the risk of developing a dosage form can be reduced from high to low. This in-house developed risk assessment tool helps in systematic evaluation and understanding of the API properties and justification of the choice of a dosage form for a speedy Phase 1 clinical study. It allows the user to choose the API properties and change the parameters within the tool to assess the risk of individual APIs. An example of this tool is shown in the attached Fig. 1. In addition, a similar risk assessment tool has been Figure 1 developed in-house for selection of a Phase II dosage form such as tablets, capsules, etc. and also for select- compression, roller compaction or wet granulation for solid oral ing the platform manufacturing process such as direct dosage forms based on critical API properties. n PHARMACEUTICAL PROCESSING | JULY/AUGUST 2015

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Hiring in Biopharma: Rapid Industry Growth is Creating Bottlenecks Downstream process development positions are becoming more difficult to fill, and are an especially problematic hiring area in the U.S. Hiring budgets are increasing, but the industry is also outsourcing more process development jobs to cut costs. n By Eric S. Langer, president and managing partner at BioPlan Associates

chronic inability to hire and retain the right staff. According to BioPlan Associates’ latest industry study, the 12th Annual Report and Survey of Biopharmaceutical Manufacturing Capacity and Production [1], not nearly enough is being done to alleviate the trained staffing shortages that have plagued FLOW − THERMAL − STRESS − EMAG this segment for at ELECTROCHEMISTRY − CASTING − OPTIMIZATION least a decade. And REACTING CHEMISTRY − VIBRO-ACOUSTICS as the report’s results MULTIDISCIPLINARY CO-SIMULATION show, even those hired will not be easy to retain. Each year, we examine hiring and training trends as part of our study, as this industry – which is highly technical in nature –depends on the skills and expertise of the people within it. In recent years, we have observed important changes in the types of job functions the industry is having info@cd-adapco.com trouble filling, likely www.cd-adapco.com reflecting wider industry shifts. he consistent, rapid growth in the biopharma industry has its downsides that most other industries would envy:

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The study asks respondents to indicate which job positions they are finding it difficult to fill at their facilities. This year, we find that process development – upstream and downstream – staff are clearly the most challenging to hire for, cited by 38.5 percent and 37.2 percent of respondents, respectively. This likely reflects the industry’s greater focus on process efficiency. But while challenges hiring upstream process development staff have stabilized in recent years, difficulties hiring downstream PD staff have continued. This may well be related to the increasing attention paid to downstream processing, which has failed to match recent upstream improvements. In fact, this appears to be a more acute problem in the U.S., where it is the position considered most difficult to fill overall, by 45.8 percent of respondents (compared to 33.3 percent in Western Europe). Meanwhile, other positions the industry is having trouble filling include: • Quality assurance (24.4 percent) • Process engineers (23.1 percent) • Downstream operations staff (21.8 percent) • Validation (21.8 percent) Beyond the focus on process and downstream, the challenges hiring quality assurance staff are likely a reflection of the wider penetration of

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quantitative-based quality-assurance and validation methods, such as PAT and QbD. As the industry moves towards continuous bioprocessing, staff expertise levels will generally need to be higher, and some worry that filling positions will be more difficult if staff are needed around-the-clock to run and monitor continuous bioprocessing. Still, increasingly automated areas of biomanufacturing that aim to take human error out of the equation might ease the burden. Broadly speaking, the difficulties with hiring in these and other important areas aren’t likely to be alleviated in coming years. With the first wave of bioprocessing professionals on the cusp of retirement, there may well be a shortage of skilled senior staff in the near-term, as sophisticated expertise in these areas can take years to accumulate.

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Fig. 1: Some Selected Areas Where Hiring Difficulties Exist in Biopharmaceutical Operations

increase their budgets for hiring new operations staff by 4.9 percent this year, up from a 1.9 percent projected increase last year and the highest level going back at least five years. Budgets allocated to hiring new scientific staff are also set to grow significantly since last year. As with other

BUDGETING FOR HIRING This staffing crunch may result in greater competition – and salaries – for highly qualified staff, and respondents to our survey indeed are budgeting significant increases in funding for staff. According to our study, respondents are expecting to

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areas of biomanufacturing, hiring budgets have certainly rebounded since the recession. Perhaps as a result of the particularly difficult situation with respect to process development (and potential increase in related salaries), we see this year a significant increase in the percentage of respondents who report having outsourced jobs in process development in order to cut costs. More than one in six respondents said their facility had done so in the past year, up from roughly one in eight over the past four years. SKILLED STAFF SHORTAGE CREATING BOTTLENECKS Beyond the obvious problems associated with difficulties filling key positions, our study results show just how important a qualified and experienced staff is to facilities. When we asked respondents to indicate the factors that might lead to a capacity bottleneck at their facility over the

next 5 years, staffing concerns occupied four of the top seven positions: • Inability to retain experienced technical and production staff (29 percent) • Inability to hire new, experienced technical and production staff (28 percent) • Inability to hire new, experienced scientific staff (28 percent) • Inability to retain experienced scientific staff (22 percent) More worrisomely, concerns over these hiring problems have increased over the past few years. This is most evident when it comes to the inability to retain experienced technical and production staff, cited by almost three in 10 respondents, up from 20 percent in 2008-2009. Clearly the industry is aware that staffing difficulties are increasing, with the shortage of talent leading to more poaching. An experienced staff is needed to avoid bottlenecks – and likewise to improve performance. Separately in our report, a small majority indicated that better operations staff training had led to “significant” or “some” improvements at their facility over the past year. Looking back over the past few years, we see that the impact of better training has gradually risen, from 47 percent reporting improvements in 2011. Even so, operations staff training has led to improvements for fewer respondents in the U.S. (47 percent) than in Western Europe (58 percent) and the rest of the world (72 percent), a finding potentially tied to the greater difficulties U.S. respondents are having in hiring upstream and

downstream operations staff. Perhaps U.S. staff also simply aren’t receiving as much training, with our data indicating that the industry is less likely to be giving longer-term training to new staff than in years past. All told, the concerns with hiring – particularly of process development and operations staff – are deepening. Faced with rising hiring problems in years to come, arresting this problem may require stronger measures including collaborations between employers, training organizations, and leading universities. REFERENCES: 1. 12th Annual Report and Survey of Biopharmaceutical Manufacturing Capacity and Production, BioPlan Associates, Inc. Rockville, MD., April 2015,

About the Author: Eric S. Langer has been the editor of numerous studies, including Biopharmaceutical Technology in China, Advances in Large-scale Biopharmaceutical Manufacturing, and many other industry reports. He can be reached at elanger@bioplanassociates. com 301-921-5979; www.bioplanassociates.com Survey Methodology: The 2015 Twelfth Annual Report and Survey of Biopharmaceutical Manufacturing Capacity and Production yields a composite view and trend analysis from biopharmaceutical manufacturers and contract manufacturing organizations. The methodology also included suppliers of materials, services and equipment. This year's study covers new product needs, facility budget changes, current capacity, future capacity constraints, expansions, disposables, downstream purification, quality management, hiring and employment. The trend analysis provides details and comparisons of production by biotherapeutic developers and CMOs. It also assesses differences in the world's major markets. n

JULY/AUGUST 2015 | PHARMACEUTICAL PROCESSING

PHARMA EXPO IN VEGAS DRAWING CLOSER Follow PMMI on Twitter (@PMMIorg) to stay up-to-date with show happenings. The latest manufacturing advances for the pharmaceutical, biopharmaceutical, nutraceutical and medical device industries arrive in Las Vegas this fall at Pharma EXPO, co-located with PACK EXPO Las Vegas (Sept. 28–30, 2015; Las Vegas Convention Center). Pharma EXPO is produced in partnership by PACK EXPO owner and organizer PMMI, The Association for Packaging and Processing Technologies, and the International Society for Pharmaceutical Engineering (ISPE). Together, the two shows will provide access to 2,000 processing and packaging solutions providers and 30,000 attendees. Pharma EXPO is expected to feature more than 160 solutions providers addressing the entire pharmaceutical supply chain. The full exhibitor list is available at Pharmaexpo.com, where visitors can search for the specific technologies that best meet their needs. In addition to the variety of new technologies that will be on display, Pharma EXPO will provide educational opportunities to help industry professionals stay ahead of game-changing market trends and regulations. Examples include: • The Innovation Stage (Booth #N-559) will offer free half-hour educational sessions from industry experts, highlighting new technologies and ideas for pharmaceutical and medical device manufacturing. • ISPE’s conference program, with tracks concentrating on manufacturing operations (Monday, Sept. 28), compliance trends (Tuesday, Sept. 29) and pharmaceutical packaging (Wednesday, Sept. 30). Schedules for the Pharma EXPO Conference Program and the Innovation Stages at Pharma EXPO and PACK EXPO can be found online at Pharmaexpo.com. Session tickets are available individually and in one and three-day packages. • A number of vendors will also be providing in-booth educational sessions, including All-Fill, Dir Technologies, Gramatech, JLS Automation and MULTI-FILL.

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FAC I L I T Y M A I N T E N A N C E P R O D U C T S

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Flow Meters Combine Intelligence and Convenience Aalborg Instruments’ ZFM Mass Flow Meters are designed for multi-range functionality up to eight bar (currently six gases) and standard accuracy of ± (0.5% RD + 0.2% FS) based on actual calibration. By connecting the instrument to the RS232/RS485 port of a PC or laptop and running free ZFM Configuration Utility software, the user can select different gas types and flow ranges within a few minutes without removing the instrument from the installation. ■ www.aalborg.com

Microprocessor-Based Gas Monitor The GSM-60 is a microprocessor-based gas monitor that, can be custom-configured with both internal and external sensors for monitoring a combination of gas parameters, including VOCs, dew point, oxygen and CO, or a number of other target gases including O3, HF, HCl and Cl2. As an option, the monitor can also be connected to a wide range of remote 4-20 mA toxic or combustible gas sensor/ transmitters. ■ www.enmet.com

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Safer Blowdown Valves Clampseal blowdown valves are fully serviceable in-line using standard Conval tools. The valves feature a uniform one-piece gland, which eliminates the potential for stem damage from gland cocking. With leak-proof bonnet, the cartridge-style packing chamber allows rapid access to valve trim for inspection and maintenance. The pressure seal fixed backseat provides valve integrity by ensuring a positive internal stop for the valve and stem and disc assembly. ■ www.Conval.com

Non-Contact Voltage Tester Klein Tools offers its NCVT-3 Non-Contact Voltage Tester with Flashlight. It identifies AC voltage in cables, cords, circuit breakers, outlets, wires, thermostats, low-voltage lighting systems and more. Features include: • The ability to detect the full range of 12 – 1,000 VAC. • An integrated flashlight works independent of the tester and is practical enough to use as a standalone tool. • CAT IV 1,000-volt safety rating and drop protection of up to 6.6 ft. • Simultaneous visual and audible voltage indicators. • Auto Power-Off conserves and extends battery life. • Screw-thread battery cap with o-ring ensures dustproof and waterproof ingress protection. ■ www.kleintools.com

JULY/AUGUST 2015 | PHARMACEUTICAL PROCESSING

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FAC I L I T Y M A I N T E N A N C E P R O D U C T S

Ultrasonic Leak Detector

Vibration Sensor App

Omega offers their ultrasonic leak detector to pinpoint exact locations of the leak point. Leaking air or gas is generally considered to be viscous flow and as the flow velocity increases, the frequency of the ultrasonic sound emitted will become higher. The HHLT1R amplifies and converts these sounds to frequencies and levels that the human ear can hear. ■ www.omega.com

Density Analysis Meter The VIDA 80H by PAC is a fully automated reliable density analysis meter that works on an advanced osciallating stainless steel u-tube technology in obtaining density measurements. Fully automated, the tool offers a simplified, push-button solution powered by smart software that automates every step of the test sequence. The meter features a patented auto injection and bubble detection technology that delivers density measurements on a wide range of fluids. It is in compliance with ASTM D4052, ASTM D5002, ASTM D5931, ISO 12185, ISO 15212-1, DIN 51757 and JIS K2249-1 international standards. ■ www.paclp.com

SKF offers Enlight, which combines a mobile app with a special Bluetooth-enabled vibration sensor to allow non-expert staff to gather critical machinery data, effectively turning a standard mobile device into a data-collection device. In the event of a parameter warning or alert, the user can then request an “On Demand Diagnostic,” whereby the data is sent wirelessly to the SKF Remote Diagnostic Center (RDC) network for analysis and reporting. ■ www.skfusa.com

Broad-Beam UV Leak Detection The Spectroline TRITAN 365 is a multi-LED, broad-beam UV leak detection lamp used to pinpoint fluid leaks in a wide range of processing systems. Features include: • Three ultra-hi-flux UV LEDs for fluorescent leak detection. • A white light LED for general component inspection in dimly lit areas. • A 45” inch coverage area at a 20’distance. • A compact head for accessing tight spaces. ■ www.spectroline.com

PHARMACEUTICAL PROCESSING | JULY/AUGUST 2015

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SAFET Y PRODUCTS

Push For Safety

FasTrax For Safety

ASI offers their ISO13850 Platinum Series Emergency Stop pushbuttons that are UL-approved and IP69K-compliant. Available styles include Latch/Pull-to-Release, Latch/Turn-to-Release and Latch/Key-toRelease. The 40 mm mushroom heads emergency stop switches have a 22 mm base, and up to six auxiliary contacts can be connected to the mounting adapter. ■ www.asi-ez.com

Rite-Hite offers their FasTrax Doors to help reduce maintenance costs and increase safety by offering their “soft edge” technology and other features that include: • Designed to match any interior, exterior, wash down, high wind, cooler or freezer application. • The ability to be stored in multiple track configuration. • Through-beam photo eyes and optional motion detection. • Operating speeds up to 100" per second. ■ www.ritehite.com

Emergency Decon Booth

Low-Profile Explosion Proof LED

HEMCO Emergency Shower/Decontamination Booths are fully assembled and ready for installation to water supply and waste systems. The shower is molded in one-piece, chemical-resistant fiberglass and is equipped with a pull rod-activated shower and push handle eye/face wash. The shower is also equipped with frosted front strip curtains, interior grab bars, raised deck grating and bottom or rear drain outlet. It’s also compliant with A.N.S.I. and O.S.H.A. requirements. ■ www.HEMCOcorp.com

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Larson Electronics offers their 104-watt explosion proof low profile LED light fixture that provides operators with a powerful and energy efficient alternative to traditional hazardous location luminaries. The EPL-LP-48-LED is a Class 1 Division 1 & 2, Class 2 Division 1 & 2 fixture that provides 13,520 lumens of high-quality light. Instead of using diffused glass, optics or reflectors to distribute the light, it uses boards within the fixture to provide a wide area light. Two offset LED assemblies within the fixture allow this lamp to provide a 100-degree horizontal beam spread and 140-degree vertical beam spread. Additional features include a tempered borosilicate glass tube protected by an aluminum wire guard and a copper-free aluminum alloy body that is powder-coated for added durability. ■ www.larsonelectronics.com

JULY/AUGUST 2015 | PHARMACEUTICAL PROCESSING

■PHARMPRO.COM

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More Accurate Dust Monitor

New Star Environmental introduces its Kanomax Dust Monitor focused on ensuring accurate dust measurements via an intuitive interface. Features and capabilities include: • Particles can be measured in concentrations of PM 10. • Particle sizes range from 0.1 to 10µm. • Measuring range is 0.001 to 10mg/m3. • Data logging up to 100,000 measurements and USB interface for data transfer. • This compact and light-weight (2.9 lbs.) unit has more than 24-hour run time with Li-ion battery. • Capable of analog and digital output. • Comes with a tripod mount, rubber protector and shoulder strap. ■ www.newstarenvironmental.com/product/dust-monitor

SAFET Y PRODUCTS

Omni-Directional Alarm Module Patlite introduces the LU7-LB – a loud, multi-sound module capable of producing sound pressure up to 100 dB and easily heard over ambient noise. It features four preset alarm sound patterns with various frequencies, selectable from a DIP switch, to maximize the effectiveness of the alert/notification process in almost any situation. The LU7-LB sound module can be used even when a five-light configuration is used and the alarm can be triggered to sound with any of the five LED modules and connects with LED unit for simultaneous control. ■ www.newstarenvironmental.com/ product/dust-monitor

Keeping Employees Safe

Preventing Pipe and Dust Fires The ValvEx is designed to prevent flame and pressure propagation through pipes, ducts or conveying lines to interconnected process equipment or operating locations. It consists of a heavy-duty coated steel body containing a high-strength, formed stainless steel flap. Air flow will open the flap to allow normal process conveyance conditions. When an explosion occurs in the adjacent vessel, the flow will reverse, causing the flap to close onto its field-replaceable seal, stopping explosion pressure and flame propagation. Additional features include ATEX certification and NFPA 69 compliance. ■ www.fike.com

PHARMACEUTICAL PROCESSING | JULY/AUGUST 2015

Rite-Hite offers the GateKeeper Mezzanine Safety Gate, a reciprocating barrier that creates a controlled access area in which workers can safely load and unload from the edge of a mezzanine or elevated work platform. The GateKeeper is designed with a dual reciprocating gate that is interconnected and can’t be open at the same time. It is installed on the edge of a mezzanine, pick module or elevated platform where pallet loads from the floor level are regularly deposited for pick-up. When the outer gate opens to allow pallets to enter the mezzanine level, the inner gate automatically closes. After the pallet is received, the mezzanine-level workers open the inner gate to remove the material from the work zone. The GateKeeper’s exclusive link bar design ensures that both gates always work in unison, and a Saf-T-Latch prevents a worker from raising the outer gate while inside the work zone. ■ www.ritehite.com 31 ■

n MEDICAL

nPHARMPRO.COM

MARIJUANA

The Latest on Medical Marijuana n By Meagan Parrish and Andy Szal

MEDICAL MARIJUANA DOESN’T LEAD TO RISE IN TEEN TOKING In the ongoing war over whether or not America’s most popular weed should be legal in any capacity, one often-cited argument against it is how its use will send the wrong message to teenagers. Teen drug use is a concern for a host of reasons including the fact that studies have found that teens who toke heavily can often have cognitive difficulties later in life. Meagan Parrish, But a comprehensive study has shown Editor, Chem.info that there is no strong correlation between medical marijuana use and an increased rate of teen pot smoking. The report published by The Lancet Psychiatry was based on surveys of more than a million adolescents in 48 states between 1991 and 2014. The research found that teen pot use was already higher in states that had adopted medical marijuana laws, and it didn’t spike after those laws were passed. Their bottom line? Though teen marijuana use has been increasing, medical marijuana laws don’t appear to be the reason.

TEXAS APPROVES MEDICAL MARIJUANA… SORT OF Texas is considered one of the strictest states when it comes to marijuana laws. But early in June, it seemed a bit of change was coming when Gov. Greg Abbott signed the state’s first-ever medical marijuana law. Thing is, patients in the state still aren’t likely to have access to the treatment. Texas’ law only allows patients to use Andy Szal, cannabis-based oil that contains small Digital Reporter, traces of THC, but doesn’t allow patients Pharmaceutical Processing to purchase marijuana in plant form. It is also only available to patients with intractable epilepsy. But what negates the law even more, several analysts have mentioned, is that it is written so that doctors must “prescribe” medical marijuana instead of “recommend” it. The distinction is important because it’s illegal for doctors to prescribe a Schedule 1 substance without a DEA license — turning it into a risky prescription doctors aren’t likely to make.

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Pharmaceutical Vacuum Receivers for Fine Powders VAC-U-MAX pharmaceutical receivers are designed to convey free to nonfree flowing powders for use in many applications including loading tablet press machines, blenders, mix tanks, and loss-in-weight feeder refill. Units are USDA accepted and constructed of stainless steel, with convey rates from 500 to 5000 pounds per hour and beyond. Variety of discharge valve types and finishes are available, including bead blast, satin or mirror polish. VAC-U-MAX www.vac-u-max.com info@vac-u-max.com

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Bioprocessing fluid path solutions Watson Marlow Fluid Technology Group provides highly accurate peristaltic pumps, Flexicon aseptic filling systems, Biopharmaceutical grade tubing, BioPure single-use bio-processing flow components and ASEPCO high purity aseptic valves. Our products offer many benefits, including filling validation, sterile processes, traceability, superior flow rates and metering accuracy, scalable solutions and reliable dispensing performance.

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