INTERPHEX never disappoints. Whatever packaging solution is needed can be found on the show floor. Highlights of the 2012 event, which took place 1–3 May at New York City's Javits Center, included a container-making alternative to injection moulding, versatile vial fillers and other equipment for the packaging line, expanded service offerings, new carton and label concepts, cold-chain support, integrated serialization systems, and quality control innovations.

A hybrid forming technology has advantages over traditional injection moulding. The marriage of compression forming and blow moulding generates less waste, shortens cycle time and requires less energy and heat, largely because no manifold is needed to distribute molten resin to individual cavities. A 12-station, rotary machine extrudes and cuts molten high-density polyethylene and transfers the shot into a compression cavity for a subsequent two-stage blowing process. Container sizes range from 60–300 mL. Eliminating station-to-station indexing shortens cycle time. The absence of a manifold for melt distribution prevents temperature variations and lessens chances of flaws from resin burn and degradation. An extremely consistent wall thickness offers the potential for lightweighting. The machine also integrates three levels of quality control: leak detection, infrared inspection for surface and embedded particulates, and plasma surface treatment to improve label adhesion. A 20-station machine, currently under development, will require only minor adjustments to change from high-density polyethylene to polystyrene, polypropylene, or polyethylene terephthalate (Compression blow-formed containers, Amcor Rigid Plastics; compression blow-forming machines, Sacmi Group).  

Chemical tempering after the forming process strengthens glass cartridges used in autoinjectors and pen systems. A molten potassium nitrate bath replaces sodium ions in the glass with larger potassium ions and results in a denser surface. It also increases the surface compression and reduces stress created by miniscule flaws in the tubular glass, which cannot be seen by the naked eye but are always present (tempered glass cartridges, Gerresheimer AG).  

With requirements for Braille labelling likely to expand, a fourth-generation, family-owned carton converter was on display that is prepared to emboss and verify the tactile code on its folding cartons. A high-speed camera system checks the depth and accuracy of each embossed dot at production speeds and rejects any faulty cartons. The Braille embosser and inspection system are installed on the folder-gluer and are an alternative to a more complex system and expensive die-cutter-mounted system (AccuBraille embossing system from Bobst and BrailleChek system from Valco Melton, installed at Ingersoll Paper Box Co.). 

Digital, flexographic, and offset printing address low, medium and high-volume folding carton runs with virtually no variation in print quality. The printer also offers services to reduce carton costs by consolidating sizes and stock-keeping units (SKU Consolidation and Right-Sizing services, Innomark Packaging Solutions).  

New label concepts include a design to impart child resistance to blister cards. The multilayer, pressuresensitive label provides six barriers to entry—three logical and three physical. In use, the first step is to peel off the top layer to reveal a series of pictograms, which provide instructions for access (CRSF label, Faubel Pharma Services).  

Gerresheimer’s glass-tempering technology strengthens glass cartridges. 

A 48-page booklet label marries insert and primary label to cut costs and simplify inventory, ordering, quality control and packaging-line changeover. Also available in a ribbon style, the insert/label combo is integrated as the label is flexographically printed. Barcodes on each component prevent mix-ups (booklet label, Platinum Press).  

Bosch Packaging’s fully integrated FXS line fills presterilised syringes.  

Special adhesive and die cutting produce a pressure-sensitive label that applies smoothly to the narrow circumference of autoinjectors. Options include embossed bumps that could carry a Braille message, but are primarily intended to prevent the pen from slipping during use. Labels also may incorporate colourshifting ink for anticounterfeiting protection or thermochromic ink that shows when a product has reached the correct dispensing temperature. In pens designed for multiple doses, multiply structures permit reverse printing that preserves the readability of any messages or instructions despite repeated handling. A peelable layer allows users to check product level through a window, but otherwise blocks transmission of ultraviolet light (Pen Label, Schreiner MediPharm).  

Contract manufacturers and packagers are investing in their operations to meet rising demand. Several firms have added capacity for filling solid dosage forms in bottles (A+ Secure Packaging, Almac, Pharma Packaging Solutions, Reed-Lane). 

Contact manufacturers have also invested in new lines dedicated to blister packaging. One blister line integrates blister foil printing, checkweighing and vision inspection. The 200-per-minute line handles a range of materials, including polyvinyl chloride (PVC), PVC/polyvinylidene chloride, Aclar, and aluminum/aluminum (UPS 4 blister line from Uhlmann, installed at Almac).  

A UK-based specialist in clinical trials and small batches has installed an aseptic vial line for small-volume parenterals. The line primarily fills volumes ranging from 2–20 mL, but could handle vials up to 100 mL (SCM Pharma).  

A year-old stick-packaging line forms, fills and seals 400 mg to 3 g of moisture-sensitive pharmaceuticals and probiotics in narrow, foillaminate packs. Especially wellsuited to products for paediatric and geriatric populations that are intended to be mixed with food, the fully integrated line operates in a humidity- and temperature-controlled environment. Rated at 1000 packs per minute, the line doses 10 packs at a time and loads finished packs into 7-, 14-, 28- or 56-count cartons (Stick-pack contract packaging service, Ropack).  

An on-site, visual inspection service provides equipment, certified technicians and service without the capital investment, integration, maintenance and training issues associated with purchasing equipment. With several models available, equipment can be matched to the application and installed in line or as a standalone unit. Scalable contracts adjust to changes in usage (contract inspection service utilising Viswill (formerly Kanebo) equipment, Visionspect Division of Daiichi Jitsugyo Viswill). 

A fully integrated filling line for presterilised syringes starts with automatic bag and tub openers and features an integrated checkweigher. A combi-filling station accommodates traditional or single-use product paths as well as rolling diaphragm or peristaltic pumps (FXS line, Bosch Packaging, shown running syringes from Schott North America and stoppers from West Pharmaceutical Services). 

A servo-driven, double-tool, rotary filler/capper indexes two containers at a time to handle up to 70 containers per min. Container size changes require removal and installation of the appropriate dedicated starwheel. Height adjustment is automated. The machine is typically integrated with a rotary table at the infeed and a label applicator and accumulation table at the outfeed (3020 DT monoblock, M&O Perry Industries).  

A compact system designed for Class 100 cleanrooms features a peristaltic pump and single-use product path. Available with two, four, six or eight filling heads, the servodriven unit automates both container height and nozzle stroke adjustments. The filler handles container diameters ranging from 16 to 76 mm (⅝ to 3 in) at up to 30 cycles per min. Maximum container height is 203mm (8 in) (VR2PP series liquid filling machine, Cozzoli Machine Co.).  

Peristaltic and rotary piston pump options are available on a higherspeed filling/stoppering machine capable of handling 100 vials per min. Tool-less changeover adjusts the unit for vial sizes from 2–100 mL. The system integrates with vial washing, sterilising/depyrogenation tunnel, capping and tray-loading equipment, as well as a Class A restricted access barrier system. Options include pre- and post-fill gas flushing, in-line process control, automatic fill adjustment and automatic vial reject (FS-22 Filling/Stopper Inserting Machine, PennTech Machinery Corp.).  

A vial filler/capper provides feedback statistics on machine performance including applied torque. The serialisation-ready system tares bottles before filling, checkweighs and applies stoppers and caps. Pumps are matched to product characteristics (Bambino vial filler, Capmatic).  

Cozzoli’s VR2PP aseptic filler with single-use product path is designed for Class 100 cleanrooms. 

A servo-driven benchtop system, equipped with a peristaltic pump and single-use product path or rotary piston pump, fills and applies stoppers to presterilised nested vials (2–20 mL) or Hypac syringes (0.5–20 mL). Bottom-up filling with vacuum seal prevents air bubbles in the product. The stoppering function also depends on vacuum. Programmable logic controller automates all operations except placement and removal of the nest of containers (FSM modular syringe and vial filling system, Colanar) 

QS Systems bowl feeders from Service Engineering feature quick-connect latches and simple lift-off components. 

Another tabletop system fills infusion bags. The semiautomatic machine requires manual feeding of the bags and sealing caps and is capable of filling about eight, 500-mL bags per min. Other bag sizes include 50, 100, 250 and 1000 mL (Plümatex-BFM 007-SFC Filling and Sealing Machine, Plümat North America).  

A variety of bag structures are available for infusions and other intravenous products. Three-layer coextruded polypropylene bags with a highly inert, weldable inner layer protect sensitive products and can be produced in a variety of single- and multichamber styles with various ports and connectors (Inerta bags, Technoflex). For products that must be frozen or for cryogenic stem cell preservation, bags, tubing and connectors are made of a material capable of withstanding temperatures from -10 to -196 °C (Ethylene vinyl acetate bag, tubing, and connectors, Technoflex).  

A three-dimensional (3D) video based on CAD drawings of equipment provides a virtual look at how various fillers and integrated machines work. Although currently used as a marketing tool to showcase turnkey line capabilities, the 3D technology has potential as a training aid (interactive 3D virtual tour, Optima pharma).  

A versatile, servo-driven blister packager thermoforms or coldforms blisters up to 40 mm deep and features tool-less changeover. An integrated print station prints on the top or bottom of the lidstock depending on how the material is threaded. An autolift mechanism protects heat-sensitive products by raising the seal station if the machine stops (BP540 blister machine, Pentapack NA). 

Bowl feeders for stoppers and other small parts change over without tools, thus reducing downtime from 10–30 min to less than 1 min. Patent-pending units simply unlatch and lift off; the unlatching/latching mechanism can be automated (QS Systems bowl feeders, Service Engineering).  

Dots of an instant-bonding, pressure-sensitive adhesive are dispensed from a paper carrier web to provide a competitively priced alternative to hot melt for sealing folding cartons or attaching inserts/outserts to packaging. Eliminating hot melt reduces waste, clean-up tasks, warm-up time and burn hazards. Once adhered, the FDA-compliant pressure-sensitive adhesive peels cleanly with no fibre tear or residual staining, thus making it wellsuited for use with inserts or other materials where print must remain undamaged. A video trial programme allows prospective purchasers to see how the automated applicator works for their application before they buy a system (SD-900 applicator for Glue Dots brand adhesive, Glue Dots International).  

A lab-scale unit punches and seals lidstock to unit-dose containers. The tabletop, servo-driven machine monitors force, time and temperature and handles either peelable or nonpeelable lidstock (RD 06 punching and sealing machine, Rychiger US).  

Packagers who need containment or an aseptic filling environment can retrofit a flexible isolator with clear polyurethane or PVC walls that allow operators more freedom of movement than rigid counterparts. Systems are compatible with negative air pressure or nitrogen atmospheres. Single-use systems eliminate much of the cleaning and validation required with conventional rigid isolators (Ace flexible wall isolators, Telstar North America).  

An inkjet printer handles print widths from 108 to 540 mm (4.26 to 21.26 in.) at speeds of up to 100 m (328 ft) per min. Ultraviolet ink dries instantly and doesn't absorb or bleed to produce crisp alphanumeric characters as small as 4-point. Designed for mounting on horizontal form-fill-seal, blister and flow pack machines, the digital coder also reproduces serialized numbers, one and two-dimensional barcodes, and graphics at a resolution of 600 dpi (InteliJet HD inkjet printer, Bell-Mark Corp.).  

INTERPHEX returns to New York's Javits Center April 23–25, 2013. 

Articles

Packaging Forum

Our Packaging Forum editor reports on the infamous US trade show, INTERPHEX. Highlights included the latest in pharmaceutical packaging equipment, containers and labels, as well as new capabilities among contract service providers.

New Technologies Displayed at INTERPHEX

The biopharmaceutical industry has a voracious appetite for new technologies that increase productivity and improve performance, a point confirmed by BioPlan Associates' annual survey on bioprocessing trends and innovation (1). 

When asked about average budget changes from 2009–2012, those surveyed reported the highest budget increases were for new technologies to improve efficiencies and costs for downstream production (an average 6.4% increase) and for upstream production (an average 6.0% increase). For new products, the largest portion of respondents cited disposable bags and connectors (40.0%), followed by probes and sensors, (36.1%), chromatography products (32.2%), bioreactors (31.7%) and purification products (28.9%) (see 

). Much of the interest in improved sensors, bioreactor, purification and other equipment involves single-use applications. Only 10% of respondents wanted new stainless steel equipment. In services, upstream process development services topped the list. 

Figure 1: Select new product and service areas of interest, 2010â2012. 			

The survey showed that a common cause for dissatisfaction with current  single-use bioreactors, liners and other equipment that is not robust enough. Single-use equipment is still not adaptable to the more extreme mixing, heat and other conditions involved with most microbial systems (e.g., 

When asked to rate the factors responsible for creating bioprocessing improvements in the last 12 months, the largest portion (72.6%) cited "overall better control of processes," followed by "improved downstream production operations," and "use of disposable/single-use devices."   

To evaluate how well vendors' R&D match industry needs, the BioPlan survey asked about budget changes in 2012. Vendor respondents reported an average 1.9% increase in basic R&D for product development, a 2.4% increase for hiring new staff, a 4.3% gain in sales budgets and a 3.4% uptick in capital-equipment purchases. Survey data show vendors concentrating much of their R&D on improved and new single-use equipment (see 

Figure 2: The top six new technologies being worked on by vendors, 2010 â 2012. 			

The largest portion (46.2%) report working on bioprocess development/optimisation services and bioprocess modeling, followed by disposable/single-use bioreactors and consumables, single-use bags and films, filtration and chromatography products. Other examples of vendor R&D include: animal-free media components; bioreactor control; chromatography alternatives to Protein A; cell- line optimisation; sensors and probes; culture-media optimisation services; alternative mammalian-cell  expression systems; monitoring systems; culture-media supplements; controller systems; impurities detection; bacterial expression systems; lyophilisation; testing/assay services (e.g., raw materials, glycosylation, viral clearance, cell lines); and packaging materials. 

Several major trends have contributed to improved bioprocessing in the past decade. Legacy expression systems from the 1980–1990s, such as Chinese hamster ovary systems, yeasts and 

, have shown improvements in process yield (2). Mammaliancell culture yields over 10 g/L are expected and mammalian expression systems thoroughly dominate as classic microbial, including 

and yeast systems, are being displaced for in-house systems. Cell-line engineering and product-specific expression optimisation are rather common in supporting higher yields and better product quality, particularly as off-patent high-yield cell lines go off patent and become more widely available. 

Preclinical, clinical, and other precommercial manufacturing is dominated by single-use/disposable equipment. Single-use equipment is on the verge of being adopted for commercial manufacture (3). 

Major advances in sensors, automation and process control have been made for improving quality control, such as single-use sensors and sensors for new analytes. Also, manufacturing systems can now be modelled, which facilitates process and facilities design and removes bottlenecks. 

is president of BioPlan Associates and a periodic contributor to Outsourcing Review. 

9th Annual Report and Survey of Biopharmaceutical Manufacturers 

Outsourcing Review

The industry wants more innovation, but can suppliers meet customers' needs?

Biomanufacturing Innovation

As a drug type, peptides offer certain benefits, such as specificity and potency, but they also present challenges, such as poor stability and short halflife. Recent partnerships among large pharmaceutical companies and specialised companies, as well as advances from academia, are seeking to resolve these problems.  

Peptides and proteins have the size and functionality to effectively modulate intracellular protein–protein interactions, but they often do not permeate cells and, therefore, are used to modulate extracellular targets such as receptors (1, 2). According to a recent analysis of the peptide drug pipeline by the Peptide Therapeutics Foundation (3), the majority of peptide candidates target extracellular molecules with less than 10% binding to intracellular targets. The most common extracellular targets were G-protein coupled receptors (GPCR), which include nearly 1000 transmembrane proteins that activate cellular response. During 2000–2008, 60% of peptides entering clinical development targeted GPCRs and most had agonist activity (3). 

Although making up only a small portion of total drug candidates, the number of peptide drugs entering clinical development has increased during the past several decades. The Peptide Therapeutics Foundation analysis, which excluded insulins, found that the average number of new peptide candidates entering clinical development in the 1970s was 1.2 per year, rising to 4.6 per year in the 1980s, 9.7 per year in the 1990s and 16.8 per year through 2000–2008 (3). During 2000–2008, peptides entering clinical study were most frequently treatments for cancer and metabolic disorders (including diabetes and obesity), respectively, representing 18% and 17% of peptide drug development. Decreases were observed for peptides studied as therapies for treating allergies, immunological disorders and cardiovascular diseases. 

On a commercial level, several peptide-based therapeutics have reached blockbuster status, defined as having sales of $1 billion or more, or near blockbuster status (3). These drugs, using 2011 global sales figures from company annual financial reports, include:   

Teva Pharmaceutical's Copaxone (glatiramer acetate), an L-glutamic acid polymer with L-alanine, L-lysine and L-tyrosine; (2011 global sales of $3.6 billion).

Abbott's Lupron (leuprolide acetate), a synthetic nonapeptide analogue of the naturally occurring gonadotropin-releasing hormone (GnRH or luteinising hormone-releasing hormone [LHRH]); (2011 global sales of $810 million).

AstraZeneca's Zoladex (goserelin acetate), a decadpeptide and GnRH agonist and synthetic analogue of a naturally occurring LHRH); (2011 global sales of $1.1 billion),

Novartis' Sandostatin (octreotide acetate), a cyclic octapeptide with pharmacologic actions mimicking those of the natural hormone somatostatin; (2011 global sales of $1.4 billion).

Eli Lilly/Amylin Pharmaceuticals' Byetta (exenatide), a 39-amino acid peptide amide; (2011 global sales, Eli Lilly, $423 million, Amylin, $518 million).

Forteo (teriparatide recombinant), which contains recombinant human parathyroid hormone (1-34), is also called rhPTH (1-34). It has an identical sequence to the 34 

terminal amino acid (the biologically active region) of the 84-amino acid human parathyroid hormone; (2011 global sales of $951 million) (4–9).

. One important collaboration in peptide drug development is between the biopharmaceutical company Aileron Therapeutics and Roche. In November 2011, Aileron expanded its collaboration with Roche for the discovery, development and commercialisation of stapledpeptide drugs. The potential $1.1billion drug development collaboration, launched in August 2010, encompasses up to five programmes with the initial two programmes focusing on oncology, and a third programme being launched to focus on inflammatory diseases. 

Stapled peptides use peptide-stabilisation technology to enhance potency and cell permeability of a drug to address pharmacological limitations of small molecules and existing biologics in intracellular protein–protein interactions. Although small molecules can penetrate cells, the large binding surfaces for intracellular protein–protein interactions often make small-molecule modulators ineffective. As cited previously, peptides cannot permeate cells so act extracellularly (1, 10). Stapled peptides seek to resolve this problem. Because many undruggable therapeutic targets include those protein–protein interactions, in which alpha-helices are required in lock-and-key-type mechanisms, an approach is to design alpha-helical peptides that have structural and functional properties that enable them to penetrate into the cell, bind to the therapeutic target and modulate the biological pathway (1, 10). Aileron stabilises peptides by "stapling" them with hydrocarbon bonds into an alpha-helix. Once constrained in the alpha-helix structure, the peptides are protected from degradation by proteases. The stabilised alphahelical peptides can penetrate cells by energy-dependent active transport and typically have a higher affinity to large protein surfaces (1, 2, 10). 

Publicâprivate partnerships in biomanufacturing  

Researchers at the New York Structural Biology Centre recently reported on high-resolution solution nuclear magnetic resonance techniques with dynamic lightscattering to characterise a family of hydrocarbon-stapled peptides with known inhibitory activity against HIV-1 capsid assembly to evaluate the various factors that modulate activity. The researchers reported that helical peptides share a common binding motif, but differ in charge, the length and position of the staple. The research showed that the peptides share a propensity to self associate into organised polymeric structures mediated predominantly by hydrophobic interactions between the olefinic chain and the aromatic side-chains from the peptide. The researchers also detailed the structural significance of the length and position of the staple and of olefinic bond isomerisation in stabilising the helical conformation of the peptides as potential factors influencing polymerisation (11).  

. In April 2012, researchers at Carnegie Mellon University (Pennsylvania, USA) reported on their manufacturing method for producing a synthetic form of a cyclic peptide. Macrocyclic peptides with multiple disulphide crosslinkages, such as those produced by plants and those found in nonhuman primates, hold potential as drugs because of their broad biological activities and high chemical, thermal and enzymatic stability (12). Because of their intricate spatial arrangement and elaborate interstrand crosslinkages, some macrocyclic peptides are difficult to prepare in large quantities and high purity because of the nonselective nature of disulphide-bond formation (12).  

In the current study, the Carnegie Mellon researchers focused on RTD-1, a cyclic peptide held together by three disulphide bonds. RTD-1 has a broad range of antibacterial, antifungal and antiviral capabilities, and has been shown to inhibit HIV from entering cells. The researchers created a mimic of RTD-1. While the outside of the mimic peptide maintained the same amino acids as the original, the researchers replaced the disulphide bonds at its centre with noncovalent Watson–Crick hydrogen bonds without significantly affecting the biological activity of the peptide. The researchers say the work provides a general strategy for engineering conformationally rigid, cyclic peptides without the need for disulphide-bond reinforcement (12). 

They tested the efficacy of the mimic RTD-1 by mixing the peptide with 

— bacteria that RTD-1 typically protects against. The mimic proved to be effective in killing each of the types of bacteria tested by the researchers, which included both gram-positive and gram-negative bacterial strains. Furthermore, the mimic peptide worked by binding to the bacteria's cell membrane, not its DNA or RNA, decreasing the probability that the bacteria could develop resistance to the peptide. The researchers plan to see if the mimic RTD-1 is effective against other types of pathogens, including antibiotic-resistant bacteria. They also plan to apply their method to manufacture mimics of other cyclic peptides. 

. In 2011, the biopharmaceutical company Sutro Biopharma formed a multiyear collaboration with Pfizer for the research, development and commercialisation of novel peptidebased therapeutics. The partnership gives Pfizer access to peptides that have been difficult to produce using conventional technologies using  a biochemical protein synthesis technology platform developed by Sutro. In 2008, Pfizer acquired CovX, a biopharmaceutical company with a technology platform that links therapeutic peptides to an antibody scaffold. The peptide targets the disease while the antibody scaffold allows the peptide to remain in the body long enough to achieve therapeutic benefit. The technology thereby allows for better half-life extension and bioavailability to support optimal dosing regimens for peptide therapeutics. 

Development Trends for Peptide Therapeutics Report

(Feb. 27, 2009), Drugs@FDA, accessed May 15, 2012. 

 (Mar. 28, 2012), Drugs@FDA, accessed May 15, 2012. 

 (Jan. 14, 2011), Drugs@FDA, accessed May 15, 2012. 

 (Mar. 23, 2012), Drugs@FDA, accessed May 15, 2012. 

 (Oct. 19, 2011), Drugs@FDA, accessed May 15, 2012. 

 (July 26, 2009), Drugs@FDA, accessed May 15, 2012. 

Ingredients

Although representing a small part of overall drug development, peptides and related technologies to improve their production are making inroads.

Peptides Gain Traction in Drug Development

Establishing adequate stability of a preclinical dose-formulation is a crucial component of drug development because it ensures that the test system receives the appropriate amount of test article based on protocol specifications. Considerations for designing adequate stability protocols must include assessment of formulation, storage, and dosing conditions.  

Determination of dose-formulation stability is required for all preclinical regulated studies used to assess the safety of drugs. Stability assessments are completed by the analytical testing laboratory. These assessments, however, cannot be completed in isolation of the analytical laboratory because formulation, storage, and dosing conditions must all be considered to adequately support data collected for preclinical studies.  

Analytical methods for assessing concentrations of preclinical dose-formulation analysis are typically less rigorous and are validated using less stringent criteria than those for drug substances or drug products. Methods for preclinical dose formulations are developed for assay potency at concentrations appropriate for dosing 

 studies. Moreover, the scope of validation used to support these methods is dependent upon the phase of preclinical drug development. Traditional impurity and related substance assays, which focus on quantitative analysis of impurity and degradant products, are not typically used because of long analysis run times and the resources that would be required to develop and validate these types of methods. Forced-degradation studies, which are used in the development of standard impurity and related substance assays, are not required for preclinical dose-formulation methods. 

Assessment of stability for preclinical dose formulations is completed by comparing a potency value obtained at time-zero (or a nominal concentration) with a potency value obtained following a specified amount of time and corresponding storage conditions. The observed difference is then compared to predetermined specifications to assess the stability of the formulated dosing material. For example, a formulation is validated using acceptable accuracy criteria of 100 ± 10% of nominal concentration. When the formulation was subsequently evaluated for stability, the results shown in 

Based on the specifications for stability being 100 ± 10% of nominal concentration, the 1.0 mg/mL formulation at six hours is acceptable for dosing while the same formulation at 24 hours would not. The data indicate that considerations would need to be made to ensure that dosing of the formulation was completed within six hours of preparation.  

While the primary analyte peak is generally used to assess stability, known degradant peaks may be included in the assessment. Known degradant peaks are generally included with the potency value and may be quantitated as a percentage of total observed peak response. In the example previously cited, if a known degradant peak is being monitored along with the primary analyte peak, one would expect the degradant peak to increase inversely relative to the primary analyte peak as a function of time. The specifications may include a requirement that the degradant peak area remains below a specific percentage of the primary analyte peak area. For materials that are well characterised, this provides more stringent information on dose formulation stability. As is often the case  during the early stages of drug development, analyte degradants are not well characterised and the comparison of concentrations determined from the primary analyte peak is sufficient and fit for purpose. 

Stability assessments may not be performed at all dose levels, which is in contrast to a finished pharmaceutical product (i.e., drug product) whereby stability is assessed at each dose level. Typically, stability assessments are performed using low and high concentrations that encompass the range of possible dosing concentrations.  

Stability assessments of preclinical dosing formulations need to consider conditions that are representative of the formulation process used for preparing the dose preparation. Specifically, preparations manufactured in an analytical laboratory to evaluate method performance may not be representative of the process used in the formulation laboratory and, therefore, may not be appropriate for use in assessing stability. Differences in scale, equipment, and mixing methods may need to be considered. For example, heat generated from the use of high speed mixers in a dosing batch may not have been apparent during the preparation of a small-scale batch. As such, direct heating of the dosing batch may be required. Extended or overnight mixing times also may be required for a dosing batch where they may not be required for a small-scale validation batch. These variables need to be considered when establishing an appropriate stability protocol to ensure stability batches are representative of dosing batches.  

Stability data need to cover the conditions encountered during dosing in the 

 studies. Related to dosing, physical stability becomes just as crucial as chemical stability. Questions related to maintaining a viable suspension or homogeneous mixture during the dosing period may need to be considered and addressed. In situations where dosing formulations have known stability issues, either chemical or physical adjustments may be needed for dosing. Conditions such as preparing the dose formulation under yellow light, temperature control, continuous stirring and timed dosing are all strategies that may be used to ensure that the integrity of the dosing formulation material remains intact. For example, a dose-formulation was found to be chemically stable for 48 hours at ambient temperature and observed recoveries were near 100% of the time-zero value. An optimal dosing viscosity, however, could not be maintained at ambient temperature and the material required heating before and during dosing. As a consequence, heating was incorporated into the original stability assessment. 

Consistent with stability assessment for drug products, storage of preclinical dose formulations needs to be considered when evaluating stability. This evaluation may range from a simple assessment of material at ambient or refrigerated conditions or for material being used over multiple dosing days and include evaluation of freeze/thaw cycles. Extensive stability programmes, comparable to those designed for drug substances and drug products, are not required as storage and use are tightly controlled.  

Stability studies on dose formulations are required to support preclinical regulated studies. While stability protocols for preclinical dose formulations are not as comprehensive as their subsequent drug-substance and drug-product programmes, the information they provide to support an 

 study is critical. Development of stability studies requires consideration of formulation, dosing, and storage to ensure the stability data collected are directly relevant to the 

 is director of analytical laboratory operations and 

 is analytical manager, both with MPI Research; headquarters located at 54943 North Main Street, Mattawan, MI 49071			

 Part 58 Good Laboratory Practice Regulations Final Rule (Rockville, MD, 1987). 

Stability Testing of New Drug Substances and Products 

Validation of Analytical Procedures: Text and Methodology.

Analytical

A number of factors need to be considered when evaluating preclinical dose-formulation stability. The authors discuss formulation, storage and dosing conditions.

Preclinical Dose-Formulation Stability

It is with real pleasure that I join the 

 (PTE) team. I am honoured to be the Editor of this magazine, especially at such an exciting time. This year celebrates the 35th anniversary of the Pharmaceutical Technology brand, an event that will be celebrated with special feature articles that evaluate the last three and a half decades of developments in the pharmaceutical industry (be sure to check out 

 in July for the celebratory retrospectives). 

Given the current economic climate, none of us can foresee what the future holds for the industry, but our editorial team will endeavour to continue bringing you relevant, topical and unbiased information. As Editor, I will undertake providing you with engaging, enjoyable content that you will find both interesting and beneficial.  

I look forward to meeting some of you at industry events in the coming months and hearing your views on what we can do to make your job easier. We welcome your feedback and participation in our online PharmTechGroup communities on LinkedIn and Twitter.  

This month also sees the next ACHEMA event. In current economic times such shows can seem a financial burden, but the chance to meet people face-to-face is becoming less frequent, and to have such large numbers from the industry all under one roof is a compelling enough reason to attend. This year, the majority of the PTE team will be attending the show in Frankfurt. Visit us in hall 3.1, stand J25. You are more than welcome to visit us to let us know what's happening in your corner of the market, or to tell us about something exciting you've seen. 

I would like to thank you, European Pharmaceutical Technologists, for your continued support of PTE over the years. With your constant input we will go on making PTE the successful magazine that it is. 

It is with real pleasure that I join the Pharmaceutical Technology Europe (PTE) team.

Welcome!

What is at stake in the proposed Patent Box legislation that has been unveiled in the UK?

Currently, companies in the UK must pay a corporate tax of 25% on taxable profits. The UK's new Patent Box legislation, however, will reduce the tax on patent profits to 10%. Although the government is still consulting on the finer details of the legislation, this change will give companies the chance to evaluate how best to apply the new tax rate to all profits attributable to qualifying patents, whether these are paid separately as royalties or embedded in the price of products. 

The new tax regime will take effect in April 2013 and aims to encourage innovation across all high-growth industries in the UK, including the pharmaceutical industry, that rely heavily on cutting-edge research and development. It should provide an incentive for companies to retain and commercialise existing UK patents by making the UK more competitive with foreign regimes that already offer similar tax reliefs.  

Unlike other tax regimes elsewhere in Europe, such as in Ireland, Switzerland and Luxembourg, the UK system will not apply to copyright or brands because the UK government does not consider these forms of intellectual property (IP) to be strongly linked to the high-growth, R&D heavy activities that it wishes to encourage. Companies will need to analyse the pros and cons of all of the available tax relief schemes in Europe to identify the best geographical location for their patents to be held.  

It is not only UK companies that can benefit from the Patent Box—the legislation applies to patents granted not only by the UK's Intellectual Property Office, but also by the European Patent Office and some other EU national patent offices that have similar patentability criteria to the UK. Again, the government hopes that more international pharmaceutical companies will commercialise their patents in the UK to take advantage of the tax relief.  

The new legislation will encourage UK competition with other European countries, some of which have had similar tax-reduction systems in place for years. Previously, patent-rich UK businesses faced a higher overall effective tax rate compared with similar companies abroad, resulting in the emigration of intellectual property and its exploitation overseas rather than in the UK. Luxembourg, for instance, has had a Patent Box in place since 2008 that exempts 80% of royalties, damages and capital gains realised on certain intellectual property rights, creating an effective tax rate of around 5%, while Belgium offers a maximum effective tax rate of 6.8%. 

Whilst the UK's existing system of R&D tax credits, which offers a tax deduction based on R&D spending in the UK, has provided relief for certain expenditure, there is no similar incentive for businesses to retain intellectual property in the UK once it has been created. At a time when low R&D productivity is a major challenge for the entire global pharmaceutical industry, the UK government hopes that the Patent Box will reestablish the country as a leader in patented technologies. 

How effective is the Patent Box likely to be?

Although the tax relief will be welcomed, it may not be enough to help life-sciences companies in the UK. Even once the regime is in place, the UK's overall effective tax rate of 10% will still be higher than those of other European countries, such as Belgium and Luxembourg. In addition, the legislation will not apply to patents granted to UK companies in other major R&D centres, such as the US and Japan. What's more, because the scheme will be phased in over time, the full effect of the relief will not come into play until the financial year 2017–2018. 

There are also anomalies in the legislation. In particular, for many companies, the Patent Box will not necessarily provide an optimal tax position because it is a 'one size fits all' model that has been designed to accommodate all sectors and industries in the UK.  

In the pharmaceutical technology, patents are business critical and can be numerous. For medical devices, for example, there can be thousands of components that each have their own patent, but the number of patents embedded in a product is not directly taken into account when calculating Patent Box tax relief. In fact, without careful internal legal and tax controls, implementation of the Patent Box could be an extremely convoluted exercise as the calculations of tax relief become increasingly complicated. In Luxembourg, by contrast, tax relief is much easier to compute by applying a deduction from net positive intellectual property income.  

The global pharma industry landscape is undergoing substantial change. E-health and medical devices are particularly huge areas of growth and development that require a convergence of technology with traditional pharma. Medical devices often gain market share based not on attractive design and brands, but on software, user interface and other functionality that are not necessarily protected by patents. Countries like Luxembourg that permit the inclusion of such nonpatent IP may therefore prove more attractive to companies planning for the long-term.  

How can pharmaceutical technology companies maximise profits under the new tax regime? 

To maximise the effect of the new tax regime, pharmaceutical technology companies— particularly those with international footprint or sales and those that have a choice of location for the development and commercialisation of intellectual property—will need to develop more sophisticated tax and transfer pricing structures. And they need to act now. It can take months to implement new structures, particularly as board-level decisions and legal input may be required. With the new legislation coming into force on April 1, 2013, little more than a year away, this should be a high priority for pharmaceutical executives in 2012. 

Ask the Expert

Nick Beckett from the UK law firm CMS Cameron McKenna explains how the UK government's proposed Patent Box legislation may impact the pharmaceutical sector.

Bolstering UK Pharma with a Patent Box

Many pharmaceutical companies use social media platforms, such as Facebook and Twitter, as channels to distribute press releases and other company announcements. Is the industry exploiting the full potential of these public platforms? 

The majority of Internet users actively use social media. Social networks have transformed the way we communicate and, more importantly, they offer a platform that is one of the biggest, most diverse and probably the most powerful medium of communication observed to date. 

For the pharmaceutical industry, social media can bridge the gap between companies and drug end users. As a direct consequence, approximately 74% of pharmaceutical companies have adopted social media platforms (

www.cognizant.com/InsightsWhitepapers/Adaptive-Social-Media-in-Life-Sciences.pdf

). However, social media is only one key component in a communication strategy, and not a complete replacement. The level of adoption and maturity in implementation of social media is relatively low and inadequate in the pharmaceutical industry because of various factors. In particular, the regulatory environment in which the industry operates is a challenge. 

Despite the challenges, many pharmaceutical companies are broadening the way they use social media. For instance, as well as using platforms like Twitter and Facebook for distributing press releases and other company announcements, companies are also using them to promote awareness of health issues and diseases, manage corporate affairs, share corporate social responsibility initiatives and engage with customers while providing them with efficient service in real-time.  

enhance a company’s reputation by demonstrating chronic disease leadership

mitigate the reputation vulnerability of research transparency with a commitment to product safety, transparency and pricing

collect data providing insight into customer preferences and behaviours aligned with the data-driven approaches adopted through the business models of pharmaceutical companies to remain agile and customer-centric

collect information on patient needs and physician treatment habits

cast a wide net for data collection and analysis that can then be focused on specific clinical, attitudinal, geographic or set of financial topics.

The pharmaceutical industry is heavily regulated so it is no surprise that strict regulatory and compliance demands are a fundamental inhibitor to the adoption of social media. Currently these demands do not explicitly recognise the potential use of social media platforms and fall into two broad areas:

. As an example, in the US, pharmaceutical companies are bound to adhere to the guidelines of the FDA’s Division of Drug Marketing, Advertising, and Communications (DDMAC), which aims to ensure that prescription drug information is truthfully conveyed to the public. While the communication guidelines for print and broadcast media are explicit, the guidelines fail to adequately balance the management of advantages and risks arising from use of new and fast evolving social media channels, in terms of supporting innovation, educating and engaging with patients versus the risk of non-compliance and antipathy.  While waiting for clear, revised guidance from regulatory bodies, most pharmaceutical companies have been attempting to adopt use of social media within existing DTC rules. Though social media involves direct interactions, most companies treat social media as a channel equivalent to television or radio.

 The German drug maker, Boehringer Ingelheim, provides an example of an innovative way in which companies can adhere to regulations and still reach out to the drug end user. The company’s Twitter feed is filled with articles and retweets about more than just prescription drugs with some high profile celebrity tweeters, such as Lance Armstrong and Stephen Fry. The content ranges from studies, articles, blogs and video interviews on YouTube promoted in twitter. It has more than 10,000 followers. In Europe, in general, however, direct-to-consumer advertising is more heavily regulated.  

Regulatory demand for accurate and timely adverse event(s) and off label reporting.

 Manufacturers, packers and distributors are required to submit all known reports of adverse drug side effects to regulatory bodies. Use of social media presents a risk of non-compliance because it is hard to identify the authenticity of the patient and the situation of the occurrence. 

There is a legitimate concern that regulations will always be chasing the latest technology and communication medium and that by the time regulations catch up with existing social media activities, they may already be outdated. Proactive measures that may help the pharmaceutical industry to mitigate risks of regulatory non-compliance are:

Develop clear social media and ethics policies about the purpose of engaging in the social media.

Be sure you understand current legal restrictions. Stay in communication with legal team and keep an eye on the news for any regulatory changes

Encourage regulatory bodies to actively engage in social media with the industry to support and guide them to research and resolve issues through this evolving process. 

Are there any other concerns that the pharma industry has with regards to social media? 

Listening is tracking what customers are saying about pharmaceutical companies across social media channels rather than engaging customers in conversation. Listening to social media regarding mature products offers many opportunities to collect information on patient needs, physician treatment habits, product positioning and competitive intelligence. These products typically have narrower datasets and analytical objectives, aiming to glean customer feedback on specific products. This approach provides baseline sentiment and analysis for brands that are already on the market. This requires more planning and resources to ensure that adverse events and off-label information are appropriately handled. 

Completeness of data by Therapeutic Area.

 Social media user engagement can vary depending on type and stage of illness. For example, evidence suggests that breast cancer patients are more engaged than diabetes patients, as diabetes may be considered more manageable and less life threatening than cancer or HIV/AIDS. Using social media to collect data about diabetes patients is difficult and could provide insufficient results and inconclusive analysis. This is something that pharmaceutical companies should bear in mind when collecting data through social media channels.

 Another substantial concern of pharmaceutical companies focuses on their liability for inappropriate communication with patients through social media and the importance of not providing biased, incomplete or misleading information.

 Pharmaceutical companies have no control over antipathy in social media by public or various groups with vested interests and their ability to balance the “bad” or misleading information in public domain is another area where Pharmaceuticals have major reservations.

What are the limitations of popular social media platforms when it comes to using them in a commercial or professional context? 

One of the biggest limitations of social media is the inability to moderate uncontrolled comments, which can be inappropriate and may not always be factually correct. In 2011, for example, many pharmaceutical companies were forced to shut down their Facebook pages—particularly those devoted to certain drugs—after Facebook stopped offering the companies an option to moderate public comments on the respective pages. All social media brand pages leave companies open and vulnerable to negative comments from disappointed customers and activists, which can be damaging to a brand's reputation.  

What do you think is the next step in the evolution of social media platforms and technology in the pharmaceutical industry? How can pharma companies transfer their current experience with social media into more measurable data and results?

Today, social media provides potential components of an overall communication and marketing strategy. Currently the way in which it is being used demonstrates interest, but little overall harmonised use across therapeutic areas and geographies. The pharmaceutical industry is using social media mostly for the following:

Managing perception and informing the public about CSR initiatives 

In future, it is Cognizant’s view that social media will be a significant component within global sales and marketing efforts targeted at healthcare professionals, as well as end users, and that consistently supports brand re-enforcement/reputation management and effective two-way product communication. 

Pharma companies are also working towards benefiting from social media in the areas of:

Attracting and retaining talent; prospective employees may feel more inclined to apply for jobs at pharmaceutical companies that are using social media in a creative and innovative way 

Crowd sourcing (innovation); Boehringer Ingelheim partnering with Kaggle, the platform that uses gamification to solve complex scientific problems, to create a new model relating to molecular development.

Cross industry collaboration, through tools that enable employees to interact in real-time, boosting efficiency and productivity  

Creating online communities where customers can interact to discuss their experiences of pharmaceutical brands and social customer relationship management (CRM)  - Social CRM also allows customers to interact with brands in real-time without the burden of email or customer service calls. In turn, organisations can better understand customer preferences and who influences those preferences online.

Can you give an example of a company that has used social media successfully? 

In terms of widely-known social networks, Pfizer has the best kudos for its customer engagement on Facebook and Twitter. Pfizer has the most followers on Twitter and is the third most 'liked' pharma company on Facebook.  

Meanwhile, Johnson and Johnson has created an active social presence that utilises a blog focused on stories of employees, wellness information, and corporate content. The blog contains robust content and is supplemented with YouTube and Facebook pages on corporate social responsibility initiatives and its involvement in social causes. 

How important is it for companies to harness social media? 

Most companies understand that social media is important, but the challenge is in making it work for the business. The majority of companies have established Twitter feeds and branded Facebook pages, but few have a complete grasp on exactly how to use social media to interact with consumers, improve products, services and brand recognition and, ultimately, drive sales and profitability. 

The potential of social media is unlimited due to the diverse nature of available platforms, and with their experience in data collection and applied analytics, pharmaceutical companies are well placed to address the challenges of social media. However, pharmaceutical companies need to continue to invest in social media and exploit its use in new areas.  

Pharmaceutical companies already have the experience required to manage data collection, applied analytics and generate businesses insights.  Furthermore, new, flexible processes such as adaptive design provide frameworks that can be applied to other business areas, as well as enable more cost-efficient and decision-oriented ways of operating.

However, like other new technologies social media tools need to be managed into the workplace to release the process innovation potential and new ways of working within Regulatory constraints. The new ‘millennial’ workforce represents a generation of employees that are accustomed to using social media applications on an everyday basis, and by giving them the right tools to replicate their digital lives in the workplace, it can truly improve an organisation’s overall performance if coordinated. The main point is to identify those business processes that will benefit from a social application or improved social interaction, so they can operate more efficiently and effectively.

Pharmaceutical companies have always depended on technology partners for innovation and consulting capability to ensure coherence of new ways of working:

Partners and suppliers are making strategic investments to bring value to the ecosystem in social media and analytics. An example is Sanofi Aventis funding of ginger.io, a behaviour analytics firm, who developed an innovative approach aligned to crowdsourcing. It works whereby a big pharmaceutical companies is asks patients, physicians, and any other stakeholders what they think matters most and that pharmaceutical company funds external developers to come up with ideas to address the problem as the crowd would like to see it addressed. 

Cognizant has been working with pharmaceutical customers for the last decade, and has invested heavily in adopting social media technologies as part of key business processes and IT environments.

is vice president and head of life sciences, Europe, Cognizant. 

Interview

With social media receiving increased focus as the pharma industry strives to make the most of new communication technologies, we speak with Cognizant's Bhaskar Sambasivan to find out where pharma is when it comes to social media implementation and what more should be being done.

Is Pharma Getting the Best out of Social Media?

Recently there have been many announcements about the pharmaceutical industry's positive influence in developing countries, and this progress looks set to continue thanks to initiatives being launched by the World Health Organisation (WHO) and the European Commission (EC).			

The WHO recently launched a new plan that aims to completely eliminate measles and rubella. Key to the success of the plan will be vaccination. According to the WHO, measles deaths have reduced by 74% between 2000 and 2010 thanks to vaccines. Now, the WHO wants to go a step further by introducing rubella vaccines too. By 2015, the plan intends to cut deaths by 95% compared with 2000 levels, and to completely eliminate measles and rubella in at least five WHO regions by 2020. 

The initiative, named Measles & Rubella Initiative, has received strong support from the GAVI Alliance, which obtains vaccines from the pharma industry at subsidized prices for use in vaccination campaigns in developing countries. 

 Renaud Visage/Digital Vision/GettyImages			

Meanwhile, the European Commission has offered a €2-million inducement prize to encourage researchers to overcome one of the main barriers to using vaccines in developing countries: the need to keep them stable at any ambient temperature. 

Vaccines used in tropical and developing countries are often rendered ineffective by temperature variations during transport and storage long before they reach their intended patients. Vaccine delivery from manufacturers to recipients can take 18 months and often requires an unbroken cold chain, but such a system can be difficult to implement in developing countries. In a statement, the EC quotes the World Health Organisation's claim that half of all supplied vaccine doses are wasted — mainly by an inadequate cold-chain. 

According to the EC, solving the challenge of vaccine stability could go far in aiding the vaccine efforts of developing countries and an inducement prize could be just what's needed given that innovations such as tinned food, transatlantic flights and navigation at sea were all encouraged via competitions and prizes. 

Of course, it's all very well for the WHO and the EC to launch these initiatives but support from the pharmaceutical industry is vital. Fortunately, many pharma companies are already on the case. 

The Pharmaceutical Research and Manufacturers of America (PhRMA) recently announced that more than 300 vaccines were currently in development in the US. As well therapeutics of interest to the west, such as cancer vaccines, the list also includes a vaccine for protecting infants against meningococcal disease, a leading cause of meningitis and a recombinant vaccine to prevent malaria. 

Big Pharma names have also been in the headlines for their efforts in developing countries. At the end of last month, for instance, Christopher A. Viehbacher, CEO of Sanofi, took a trip to Africa to see the work the company is conducting to support the fight against neglected tropical diseases, such as sleeping sickness. According to a press statement, Sanofi and its partners are on track to eliminate this disease by 2020. 

Other big-name companies are also pursuing projects in the developing world. For example, in March, the UK's University of Dundee announced that it had received more than £10 million from the Wellcome Trust to work with GlaxoSmithKline on treatments for tropical diseases, including Chagas disease, leishmaniasis and sleeping sickness. The aim is to deliver at least one treatment against one of these diseases in the next five years. 

In January, a huge coordinated push to fight neglected tropical diseases was launched by several global health organisations and pharmaceutical companies. No doubt we will be hearing more about pharma and neglected diseases in the future. 

The UK's National Health System has cut the cost of treating wet age-related macular degeneration (AMD) by prescribing a cheaper drug over a more expensive one. The controversial element is that the cheaper drug isn't licensed for wet AMD, which has prompted anger from Novartis.  

Merck KGaA has revealed further details about its restructuring programme, including plans to eliminate around 580 jobs. A further 750 positions will be transferred from Switzerland to alternative sites mainly in Germany, the US and China. Among other actions, the company will close its Merck Serono headquarters in Geneva. 

The UK's Medicines and Healthcare products Regulatory Agency (MHRA) has launched a new anticounterfeiting strategy with the aim of curbing the occurrence of falsified medicines in the county's supply chain. The strategy will focus on prevention, incident management, and investigation of all reports of falsified medicines in the UK. 

Pharmaceutical Technology Europe-06-01-2012