SUPPLEMENT TO THE AUGUST 2018 ISSUE OF 2018

APIs, Excipients, & Manufacturing

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2018 Planning Guide

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APIs, Excipients, & Manufacturing 2018 API IN CAPSULE PharmTech Europe Contributing Editor Editor Cynthia A. Challener, PhD s4 Application of API-in-Capsule Adeline Siew, PhD Global Correspondent [email protected] Sean Milmo Best Practices to Accelerate Drug (Europe, [email protected]) PharmTech Group Editorial Director Art Director Product Development Dan Ward Rita Peters [email protected] Publisher Jeff Williamson Michael Tracey Senior Editor [email protected] Agnes Shanley HPAPI CLASSIFICATION Sales Manager [email protected] Linda Hewitt Managing Editor Tel. +44 (0) 151 353 3520 s9 Classifying Potent and Susan Haigney [email protected] [email protected] Senior Sales Executive Highly Potent Molecules Stephen Cleland Manufacturing Editor Tel. +44 (0) 151 353 3647 Jennifer Markarian [email protected] Jeff Pavlovich [email protected] Science Editor Sales Operations Executive EXCIPIENTS Barbara Williams Feliza Mirasol [email protected] [email protected] s12 Paving the Way for Modernized Drug- Associate Editor C.A.S.T. Data and List Information Amber Lowry Michael Kushner [email protected] Product Manufacturing Through Excipients [email protected] Amina Faham, Kathryn Hewlett, and True Rogers Published by EVP & Managing Director, UBM UBM Medica Hinderton Point Georgiann DeCenzo Lloyd Drive s16 Selecting Excipients for Liquid- Filled Cheshire Oaks VP & Managing Director, Cheshire CH65 9HQ, United Kingdom Pharm/Science Group Hard Capsules Tel. +44 151 353 3500 Dave Esola Fax +44 151 353 3601 VP & Managing Director, CBI/IVT Milind K. Biyani Johanna Morse UBM Americas: VP, Marketing & Audience Chief Executive Offi cer ANTIBODYDRUG CONJUGATES Scott Schulman Development Joy Puzzo Chief Operating Offi cer Brian Field UBM PLC: s20 Tackling Aggregation Challenges Head of Legal Chief Executive Offi cer Michael Bernstein Tim Cobbold in ADC Production Chief Financial Offi cer EVP & Senior Managing Director, Marina Wyatt Adeline Siew Life Sciences Group Thomas W. Ehardt ASEPTIC FILLING Senior VP, Finance Tom Mahon s23 Robotics Solve Aseptic Filling Challenges Jennifer Markarian

TOPICALS s26 A Perspective on the Topical Delivery Editorial: All submissions will be handled with reasonable care, but the publisher assumes no responsibility for of Macromolecules safety of artwork, photographs, or manuscripts. Every precaution is taken to ensure accuracy, but the publisher cannot accept responsibility for the accuracy of information supplied herein or for any opinion expressed. Subscriptions: Marc Brown and Jon Lenn Pharmaceutical Technology Europe is free to qualifi ed subscribers in Europe. To apply for a free subscription, or to change your name or address, go to Pharm- Tech.com, click on Subscribe, & follow the prompts. To cancel your subscription or to order back issues, please email your re- quest to magazines@superfi ll.com, putting PTE in the subject line. s31 Testing Topicals: Analytical Strategies for Please quote your subscription number if you have it. List Rental: Contact Sarah Darcy; Tel. +44 1244 629 326 Fax +44 1244 659 321 the In Vitro Demonstration of Bioequivalence Reprints: Reprints of all articles in this issue and past issues are available (500 minimum). Licensing and Reuse of Content: Contact our offi cial partner, Wright’s Media, about available usages, li- cense fees, and award seal artwork at [email protected] for more information. Please note that Paul Kippax, Jennifer Burt, and Carolyn O’Grady Wright’s Media is the only authorized company that we’ve partnered with for Advanstar UBM materials.

Copyright 2018 UBM (UK) all rights reserved. s36 Ad Index Copyright 2018 UBM (UK) all rights reserved. No part of the publication may be reproduced in any material form (including photocopying or storing it in any medium by electronic means and whether or not transient- ly or incidentally to some other use of this publication) without the written permission of the copyright owner except in accordance with the provisions of the Copyright Designs & Patents Act (UK) 1988 or under the terms SPECIAL SECTION of the license issued by the Copyright License Agency’s 90 Tottenham Court Road, Lindon W1P 0LP, UK.

Applications for the copyright owner’s permission to reproduce any part of this publication outside of the Copyright Designs & Patents Act (UK) 1988 CPhI 1-14 CPhI Worldwide Planning Guide provisions, should be forwarded in writing to Permission Dept. fax +1 732-647-1104 or email: [email protected]. Warning: the doing of an unauthorized act in relation to a copyright work may result in both a civil claim for damages and criminal prosecution. 10% Post Consumer Waste On the Cover: Elisanth/Shutterstock.com; Dan Ward Preformulation: Setting the tone for drug products Drug substance manufacturers have an exhaustive list of challenges in synthesizing new compounds to bring forth the purest, most stable candidate. Addressing issues such as “lot-to-lot variability” and “scale factor” can be a daunting task for product development teams as they start down the path of evaluating and advancing candidate compounds. Although mitigated by experimental designs, APIs may gain more defined physical risk factors, such as changes in particle size and flow properties, as they progress through Application of API-in- the development process, which can have a profound effect on how the dosage form will be developed. Capsule Best Practices A significant number of steps go into both API synthesis and to Accelerate Drug drug product development, and a full understanding of the API characterization is a crucial Product Development starting point. It is never too early to investigate physicochemical properties of new compounds, and API-in-capsule approaches enable pharmaceutical companies to quickly assess the data from initial screening is new drug candidates with reduced API consumption and to increase speed to clinic. the source for a number of debates between synthesis chemists and drug product development teams. Jeff Williamson harmaceutical companies are faced with the routine challenge These initial discussions and data is director of Product Pof screening and advancing their active pharmaceutical should take into consideration the Development at Lonza. ingredients (APIs) through a drug product lifecycle. Early dosing range, potency, hygroscopicity, investments in the APIs are often costly. Identifying viable solubility, flow properties, moisture/ candidates for clinical dosage early and eliminating less viable or light/oxygen sensitivity, and other non-viable candidates are, therefore, crucial in meeting aggressive physicochemical assessments that project timelines. These new APIs have key risk areas that can affect drug product design dictate understanding of physicochemical properties when the and development. Preformulation synthesis process is in early stages. Physical and environmental typically entails x-ray powder effects can define these compounds as “challenging” as they diffraction to detect polymorphs, pH move from drug substance manufacturing into drug product solubility profiling, understanding of development, and therefore, they require additional processing hygroscopicity through vapor sorption steps or control measures to promote the API into a viable analyses, and particle morphology dosage form. Environmental effects such as hygroscopicity, light by scanning electron microscopy sensitivity, and the need for containment can pose some initial and sizing through laser diffraction, risks as the API is introduced into the development pathway. allowing design teams to determine Specific processing steps, specialized capsules, and micro- if the API is crystalline or amorphous dosing encapsulation techniques are available to address with good or poor flow characteristics. and mitigate environmental and physicochemical challenges, At this stage, product development streamline development processes, and accelerate clinical teams have more information to timelines. Precision powder micro-dosing systems facilitate the define the initial target product profile rapid manufacture of API-in-capsule (AIC) drug products that and are challenged with defining an can be expediently dosed in oral or pulmonary administration expedient path to a final dosage form. routes. These AIC dosage form presentations can reduce API To expedite the programme, the API consumption and early-stage evaluation time (Phase I and II) could potentially be introduced into an by eliminating the need for specific formulation steps, such accelerated pathway by dispensing it as excipient compatibility testing. AIC studies have become solely into a capsule for dosing while a beneficial evaluation technique for highly potent, low-dose other conventional development

applications where accurate micro-dosing is required. action steps are in planning stages. tin/Shutterstock.com

s4 Pharmaceutical Technology Europe APIs, EXCIPIENTS, & MANUFACTURING 2018 PharmTech.com Medical Solutions

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The system accurately controls Figure 1: Xcelodose design principle. capsule dosing by continuously monitoring the net weight being Solenoid Tapper Arm dispensed in real-time and automatically adjusting the tapping rate during dispensing. As the weight approaches the target value, the rate of powder delivery is reduced and then eventually stopped when in the fill weight range. Once the Computer dispensing operation is complete, the systems have the ability to Capsule recognize and reject units that are under or over weight based on the predetermined fill weight range. These systems also provide comprehensive documentation for the filling operation, Balance including individual weights of each capsule produced in the run.

Micro-dosing: API in capsule: Micro-dosing may be required in a development Capsule selection systems and approach programme for dose ranging studies. Once the initial preformulation Micro-dosing can prove essential Depending on the physical properties assessments of the API have for accelerating drug product of the powder blends, micro-dosing been performed, and the route development and quickly introducing may be used to provide multiple of administration is confirmed, a dosage form into various clinical strengths using the same formulation. decisions can be made for the phases. Micro-dosing is essentially the The neat API or a powder blend capsule composition and size. Most precision weighing and dispensing of can be encapsulated, used for of the capsule presentations used powders into capsules using various analytical assessments, and even for micro-dosing range from Size 4 equipment platforms or techniques. placed on stability studies while up to Size 00. Particle size, powder Micro-dosing has become more other approaches of drug product densities, and any necessary salt prevalent with the rising number of development are conducted in correction factors further define the highly potent candidate compounds parallel or in sequence to support size of capsules, while hygroscopicity, for oncology and other indications. a particular programme. More chemical structure, and stability APIs (or blends and other importantly, if the programme requires of the compounds may define the formulations) may be directly multiple strengths for preclinical capsule composition. There are a encapsulated to accelerate the or clinical dosing, an AIC approach wide range of capsule presentations identification of viable prototypes provides the ability to dispense the available for use in micro-dosing, and move them expediently into powders using exactly the same geared to accelerating drug product clinical studies. Depending on the precision weighing process. development. The conventional material physical attributes, API Xcelodose Precision Powder Micro- approach has been using gelatin doses as low as 100 micrograms Dosing Systems (Lonza) have been capsule shells; however, there are can be encapsulated with minimal widely adopted for early phase AIC other encapsulation options when variance in weight. In a typical studies. Figure 1 depicts the operating formulators are faced with challenges, drug product project plan, there principles for this technology where such as moisture-sensitive APIs are demands on API quantities for powder is dispensed through a mesh or having to encapsulate or store analytical method development screen at the base of a dispense under lower humidity conditions. efforts, excipient compatibility studies, head based on precise tapping Alternative polymers have been and initial experimental evaluations technology. Powder is released introduced into capsules for several of formulation and process. API through the screen by the tapping technical and market reasons, for availability can be quite limited in action of a solenoid on the dispense example, to better avoid unwanted these early stages of evaluation arm that cradles the dispense head. impurities due to moisture ingress and screening, so an efficient AIC Parameters defining the tapping with hygroscopic APIs and to avoid approach can prove crucial in process can be tightly controlled and brittleness from conventional gelatin providing a “jump start” to dosage include dispense head type, mesh capsule shells. Hypromellose and form development, eliminating the hole size, number of holes, tapping hydroxypropylmethylcellulose need for excipient compatibility frequency, and desired dispense (HPMC) capsules (e.g., Capsugel studies, and minimizing the usage rate. These parameters are selected VCaps Plus) have evolved to give of APIs. For blends and other based on the physical characteristics drug product formulators more

formulations, some adjustments of the material and desired dose. flexibility and stability beyond gelatin Figures are courtesy of the author. s6 Pharmaceutical Technology Europe APIs, EXCIPIENTS, & MANUFACTURING 2018 PharmTech.com SMA MicroParticle ICS Non-Viable Particle Counters

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Figure 2: Multiple dosing fill weight ranges using micro-dosing in dry powder inhaler (DPI) formulations.

presentations—they contain less Case studies of mechanics and gravity fill can water, eliminate moisture-driven micro-dosing applications introduce blend segregation, leaving impurity concerns from the shells, High-potency API (HPAPI). In a analytical teams chasing a content and can withstand lower humidity representative case study, the uniformity issue during testing. In conditions for encapsulation. challenge presented was an HPAPI, a representative case study, the Capsules have been used as part of low-dose application for initial clinical challenge presented was to provide pulmonary delivery devices, which presentation on an aggressive a paediatric dose of 5 mg using a have specific requirements that timeline. The target dose for the current formulated capsule of 30 influence product design, especially clinical programme was 0.1-mg fill mg strength with a lower fill weight because very small amounts of weight into a size 1 capsule. Several initially. Once again, the timeline APIs or blends are introduced into fill evaluations were performed challenges of this “one-time” batch them. HPMC capsules are, therefore, under containment to determine the did not warrant reformulation and typically the preferred capsule for dry appropriate dispensing head, tapping additional stability studies. Using powder inhalation (DPI) applications frequency, and other parameters Xcelodose technology, the capsules due to efficient capsule clearance for a reasonable yield. Through were produced and tested to ensure upon actuation in DPI devices. early experimental evaluations, uniformity of dosage unit to meet the Not all APIs are intended for the parameters were identified to clinical delivery date. The additional immediate release for performance produce capsules on the small-scale reformulated paediatric capsule reasons, such as likely instability in Xcelodose 120S and transferred to development timeline was reduced acidic conditions or projection of the higher capacity Xcelodose 600S by an estimated four to six months. improved absorption rate further in the for GMP production. The yield for In an additional and more gastrointestinal tract. Early formulation this operation was only 46%, which challenging “API blend” case study, and process development of enteric was expected as the fill weight a comparator study was to be delivery or delayed release dosage was exceptionally low, though conducted with a commercially forms can add significant development overage was produced to meet the available immediate release tablet time due to the required coating desired quantity with minimal loss versus a new API. The problem was steps to achieve this functionality. of API. The clinical delivery date (i.e., that the tablets were a much higher Capsules have been engineered overall programme from preliminary strength than what was needed. To with suitable enteric polymers (e.g., evaluations to clinical release dosage address the need, tablets were Vcaps Enteric) in the actual shell form in three months) was met. actually milled to create a powder composition, allowing delayed release Blends. Micro-dosing is not only blend and filled using an Xcelodose or enteric protection of the contents geared toward neat API, though this system to the desired strength. The without having to employ time- is certainly the primary application. capsules met acceptance criteria for consuming coating processes. These The technique is also used to assay and content uniformity and intrinsically enteric capsules can be introduce blends into capsules when progressed to the clinical dosing. readily used in AIC approaches for necessary. Using this approach preclinical and clinical assessments. can be tricky because the tapping Contin. on page s15 s8 Pharmaceutical Technology Europe APIs, EXCIPIENTS, & MANUFACTURING 2018 PharmTech.com to be highly potent, one assessed 37 of the 38 to be highly potent, and the third fell somewhere between the two extremes. The subjective nature of these results highlights that any CMO managing a facility to manufacture multiple APIs that may, or may not, be highly potent should consider each project on a case- by-case basis. A flexible approach allows manufacturing techniques, equipment, and containment options Classifying to be tailored to the molecule’s properties, and the requirements of each individual step of the synthesis. Potent The result should be increased safety, lower costs, and enhanced capacity and Highly for the manufacturing of HPAPIs. Risk determination Potent When determining risk, the starting point is the OEL and other safety- related properties of the molecule Molecules determined as part of the drug development process. Once an Determining how much containment is needed investigational drug reaches the for API handling requires evaluation of multiple factors. large-scale manufacturing stage, extensive safety data will have been compiled, including results from preclinical toxicology assessments, animal studies, and early-stage Jeff Pavlovich is senior ighly potent drugs represent a growing proportion of medicines, clinical trials. process safety engineer at Hincluding therapies in development and those commercially These data on potential hazards Cambrex. available. As older products reach patent expiry, generic-drug and dose–response effects are companies are also moving into this space, creating an increasing used as a basis by experts in risk demand for capability and capacity to manufacture highly potent APIs assessment to generate OELs and (HPAPIs), particularly for contract manufacturing organizations (CMOs). occupational exposure bands (OEBs) A significant proportion of HPAPIs are in the oncology field, and as that allow informed decisions to be approximately one-third of all new drug approvals are currently cancer made about engineering strategies medicines, this represents a substantial market opportunity. Other and industrial hygiene requirements. therapeutic areas where drugs may be highly potent include asthma Appropriate containment and and pain management. personal protective equipment should The chemistry to make these molecules is not necessarily difficult; be supplemented by comprehensive however, the greater challenge is in the handling and containment of training to ensure their proper use. them to ensure operator and environmental safety. It is vital that a There is an important caveat. careful assessment is made of the hazards posed by each individual Although toxicological data offer product, reagent, and intermediate involved in the synthesis ahead a useful starting point, there is a of manufacture. If the risks are underestimated, people within difference between potency and and around the plant will be in danger. Conversely, if the risks are toxicity. Potency is a measure of overestimated, the result will be excessive amounts of money spent how much of the API is required to on containment and an increase in project costs. have a therapeutic effect; toxicity is A compound is deemed to be potent in pharmaceutical terms if a measure of its adverse effects. A it has an eight-hour, time-weighted average occupational exposure cytotoxic drug to treat cancer may limit (OEL) of 10 μg/m3 or less. There is, however, no formally be extremely toxic but its potency agreed definition of the OEL level that constitutes a “highly potent” might be low, and therefore, side- compound. To add to the confusion, the same compound might be effects are likely. Conversely, for classified differently by individual risk assessors. This variability in some drugs that only require very classification is exemplified by a study carried out by Cambrex in small doses to have a medical which a panel of 38 molecules was sent to three risk assessors. Three benefit, the dose that causes side-

Orawan Pattarawimonchai/Shutterstock.com Orawan different results were provided: one assessor deemed five of the 38 effects may be substantially larger.

Pharmaceutical Technology Europe APIs, EXCIPIENTS, & MANUFACTURING 2018 s9 HPAPI Classification

in this context, and the inadvertent Figure 1: Points of departure. NOEL is no-observed-effect level; inhalation of dust in a manufacturing NOAEL is no-adverse-event level; LOEL is low-effect level; LOAEL facility; there is no direct correlation is low-adverse-effect level; MTD is maximum tolerated dose; between these clinical trial data and BMDL is benchmark dose level; LD50 is median lethal dose; the safe exposure level for operators. ED50 is median effective dose; and TD50 is median toxic dose. The data will, however, provide indications to issues that might occur with acute exposure. If they highlight issues such as respiratory problems, lachrymatory issues, adrenergic concerns, or somnolence, for example, acute problems might be anticipated in manufacture. There may be indicators toward chronic exposure issues, also, if there are indications that the compound might be carcinogenic, mutagenic, a sensitizer, or a clastogen. With this information in hand, the next step is to identify any critical effects that exposure might have, such as target organ toxicity or pharmacological effect, and the dose-response curve. However, inter- person variation makes it difficult to Table I: Contributors to uncertainty. make a definitive risk assessment. At the lower end of the dose– Uncertainty Area of uncertainty response curve (Figure 1) is factors no-observed-effect level (NOEL), Intraspecies variation 10 where the chemical causes no effect Interspecies variability 2–12 at all. The next point moving up the curve is the no-adverse-event level Study duration 3–10 (NOAEL), which is commonly cited in Low-effect level (LOEL) to low-adverse-effect level (LOAEL) 10 risk assessments. Next, there are the Database sufficiency 1–10 analogous low-effect level (LOEL) and Severity of effect 1–10 low-adverse-effect level (LOAEL), and then doses that are well tolerated, Bioavailability 1–10 followed by the maximum tolerated Bioaccumulation 1–10 dose (MTD). Past this point, the APIs Pharmacokinetics 3–10 are likely to be hazardous. In animal Route-to-route 3–10 tests, at the ED50 point, half of the animals will experience an effect; at the TD50 point, half will experience Modifying factors toxicity; and at the LD50 point, half Slope of dose-response curve the study animals will die at that level Choice of critical effect of exposure. The OEL equation (Equation 1) Susceptible subpopulations includes uncertainty factors (Table I) Clinical significance of critical effect that compensate for unknowns. Reversibility of critical effect The numerator comprises factors Relevance of critical effect on workers that will increase occupational Read-across similarity exposure, while the denominator includes those that will reduce it, Lack of independence for uncertainty factors including uncertainty factors. Those components that can contribute The handling requirements in the application to OELs, either. The to uncertainty include variation manufacturing plant will be very aim of an early-phase clinical study between species and between different for the two. is to determine optimal doses, subjects, the duration of the Toxicology data gleaned from balancing therapeutic benefit and study, the severity of the effect, preclinical research or clinical what patients can tolerate. There is bioavailability and bioaccumulation,

trials are not designed for direct a huge difference between exposure and pharmacokinetics. AUTHOR THE OF COURTESY FIGURE s10 Pharmaceutical Technology Europe APIs, EXCIPIENTS, & MANUFACTURING 2018 PharmTech.com HPAPI Classification

process will take longer. How containment strategy is appropriate PoD x BW necessary is it that the API is treated and working successfully before the OEL (μg/m3) = UFc X MF x V [Eq. 1] as so much more hazardous? And hazardous material is introduced. what about the intermediates OEB4 APIs are more highly potent Where: involved in its production? It is less and toxic, and special handling OEL is occupational exposure limit likely that there will be a calculated and careful containment will be PoD is point of departure for OEL for those intermediates. required. An additional band, OEB4+, extrapolation (mg/kg-bw/day) It is important to carefully encompasses compounds that are BW is body weight (kg) consider exposure modifiers. Is the so potent that their OEL falls below UFc is composite uncertainty factor process likely to generate dust? 0.1 μg/m3. For OEB4 and OEB4+ MF is modifying factor If so, the likelihood of airborne compounds, the opportunity for V is volume of air breathed during hazard is far greater. How long customization is limited, and the work shift (m3) will the operator be exposed to process must be designed around the material? Theoretical OELs the containment, and not the other Modifying factors are also are based on an eight-hour way around. Dedicated isolators will considered by some risk assessors, exposure; however, the time of most likely be employed, and rapid including the slope of the dose– potential exposure may be only transfer ports for APIs deemed to be response curve, and the choice a few minutes. A case-by-case OEB4+. of critical effect and its clinical assessment of the actual facility, This type of complete containment significance, its reversibility, and its process, and procedures will give is extremely expensive, and while relevance to workers. Susceptible a far more realistic picture of the conservative approach would subpopulations and read-across the hazard. There may be limits be to use such containment for all similarity may also be considered, on how long people can work on highly potent compounds, in reality as may a lack of independence for individual projects because of the it may be overkill for OEB3 APIs. uncertainty factors. potential for chronic effects. If an Instead, it may be more realistic to This uncertainty is at the root of API is a known teratogen, it may be start out with the assumption that the variability in risk assessments. advisable for pregnant women to full containment is required, but then Depending on the magnitude of keep well away. relax the handling requirements as uncertainty values that are applied, further data become available, if and whether modifying factors are Determining OEBs the data suggest this will be safe. given weight, there is the potential Occupational exposure bands are This level of flexibility will allow a for as much as eight orders of a useful tool for matching a hazard CMO to offer its customers a more magnitude of difference in the OEL with containment requirements. cost-effective solution, and faster determined by individual assessors. APIs that fall into OEB1 are non-toxic, timelines. PTE Reconciling this variability in the and a standard exposure level of 500 final risk assessment is a major μg/m3 will suffice. OEB2 compounds challenge. will have special hazards, such as Catalent and Cambrex The solution lies, at least in part, carcinogenicity, and the OEL will Announce Acquisitions in applying real-world context to need to be lower. the uncertainty factors. Perhaps the At OEB3, where the hazards Catalent announced on 3 July 2018 that it has agreed to ac- most important is the acceptable are greater but not extreme, exposure risk for an individual the opportunity to customize quire Juniper Pharmaceuticals, Inc., including its Nottingham, operator, and even for the most handling to account for real-world UK-based Juniper Pharma Services division, expanding the conservative risk assessor, a one-in- situations is greater; this is where company’s formulation development, bioavailability, and clin- one-thousand risk may well be more the greatest cost and time savings ical-scale oral dose manufacturing services. Juniper provides realistic than the one-in-one-million might be anticipated. Here, the bioavailability enhancement for poorly soluble compounds, risk to be an appropriate likelihood containment could—and should— including nano-milling, spray drying, hot-melt extrusion, lip- of an exposure happening. The one- be designed around the process id-based drug delivery, as well as cGMP clinical manufacturing in-one-thousand risk is not without itself. The existing plant may suffice; for potent and controlled substances. context: it is commonly cited as alternatively, safety requirements On 23 July 2018, Cambrex announced it has entered into an the chance of a severe injury in a might be met by introducing high- agreement to acquire dosage form contract development and hazardous work environment. efficiency particulate air (HEPA) manufacturing organization (CDMO) Halo Pharma, brining Three orders of magnitude filters or soft-sided isolators, a more difference in acceptable exposure conservative approach than simply Cambrex into the finished dosage form CDMO market. Halo risk can represent a major difference using personal protective equipment. provides drug product development and commercial manu- in cost. If an API is placed in a The risk assessment should also facturing services, for oral solids, liquids, creams, and sterile higher OEB in the absence of data consider the solvents and whether and non-sterile ointments, specializing in highly complex and and with a large weight placed on they can degrade processing difficult-to-produce formulations, products for paediatric indi- uncertainty factors, then far more or containment equipment. A cations, and controlled substances. costly containment will have to be programme of surrogate testing —The editors of Pharmaceutical Technology Europe employed, and the manufacturing is required to prove that the

Pharmaceutical Technology Europe APIs, EXCIPIENTS, & MANUFACTURING 2018 s11 allow them to focus on other life-saving innovations. The push for a more sustainable planet has also gained continuous manufacturing popularity as companies become increasingly conscious to have a smaller environmental footprint. For the drug- product manufacturer, continuous manufacturing offers the additional benefits of implementing process analytical technology, consequently improving process control and enabling real-time release. It offers the additional benefit of smaller, more flexible manufacturing footprints that are more easily transferrable across Paving the Way for manufacturing sites. Continuous manufacturing can Modernized Drug-Product significantly save time and energy associated with wet granulation and thus reduce the environmental impact Manufacturing Through of drug-product manufacturing. Table II reflects the amount of energy and water used in wet-granulation Excipients operations. For high-volume drug products (roughly 400 million tablets Commonly referred to as the future of advanced pharmaceutical manufacturing, per year), nearly 50 metric tons of continuous manufacturing has gained major traction in the past 10 years to enable water and 31 megawatt hours of significant improvements in efficiency, safety, cost, and speed to market. energy per year could be saved through direct compression. Companies that move away from Amina Faham atient safety is a top priority at each stage of the manufacturing batch-by-batch processing to create is global associate director, Pprocess and requires an increased attention to detail. There more reliable and affordable drug Pharma Application are a number of hurdles to clear when implementing any new products at a faster rate are at a Development & Innovation; initiatives or process changes. Historically, these challenges mean the significant competitive advantage. Kathryn Hewlett pharmaceutical industry is slower to innovate and hesitant to adopt The need for drug products to be is an Application new strategies that could improve manufacturing productivity. more readily available to patients will Development & Continuous manufacturing has garnered global attention in its ability only continue to rise. One facet of Innovation scientist; and to alleviate costs, while simultaneously increasing productivity and this demand increase is driven by the True Rogers is R&D quality. Thus far, the full potential it offers remains relatively untapped rise in aging population. Predictions Technologies leader—all as only two continuous-processed drug products have been submitted indicate that in 2050, the number at The Dow Chemical and approved. Despite slow adoption, the benefits of continuous of people aged 80 years or over will Company. manufacturing are clear to manufacturers, and the industry seems reach 434 million globally, having more optimistic based on drug-product development using continuous than tripled in number since 2015 (2). manufacturing. As the concept matures and both innovative and generic- As people are living longer, it will be drug companies express interest, the question to implement continuous vital for drug products to be more processes will continue to transition from a question of “why” to “how.” accessible to ensure quality of life in the aging population. Understanding the “why” Lower pharmaceutical manufacturing costs mean drug products will Understanding the “how” be more globally accessible and available to patients who need them. Companies want to find a way to Direct-compression tabletting is a form of continuous manufacturing incorporate new processes without that can eliminate expensive and energy-intensive granulation steps hindering productivity and disrupting to offer a cost-effective solution. In addition, using less process steps processes that have been in place for removes potential sources of variability in the final drug product. decades. For many manufacturers, As demonstrated in Table I, switching to continuous processes that the answer to this challenge is to enable direct-compression tabletting can help reduce total operating incorporate excipients in formulations costs by up to 60% and cut time by more than 50% to streamline for improved flowability and manufacturing and gain efficiencies (1). Shortened development time and processability. lowered manufacturing costs offer both short- and long-term benefits Dow Pharma Solutions has

for drug-product manufacturers as the freed-up resources and time will responded to the industry-wide trend Grycaj/Shutterstock.com s12 Pharmaceutical Technology Europe APIs, EXCIPIENTS, & MANUFACTURING 2018 PharmTech.com the next highly potent compound... Let’s develop it together.

Specialty expertise in highly potent APIs We also offer particle engineering (particle Visit pharma.lonza.com size reduction and spray drying) under isolation USA +1 201 316 9200 Identifying a collaboration partner that as well as specialized dosage forms designed Japan +81 (0)3 6264 0600 can meet the aggressive timelines often for highly potent, low dose applications. We Rest of world +41 61 316 81 11 associated with highly potent drug candidates have more than 20 years’ track record in HPAPI Email [email protected] is critical. At Lonza Pharma & Biotech, we manufacturing and compressed scale-up © 2018 Lonza. All rights reserved. offer the necessary development, upscaling timelines. and manufacturing capabilities under full containment that support API handling to A partner that you can count on for all aspects exposure levels to 1ng/m3. of your drug program – Lonza. Excipients

Table I: High-shear wet granulation vs. direct compression—operating costs estimates. High-shear wet granulation Direct compression Cost/hour hours hours Equipment preparation US$150 3 1 Material dispensing US$120 3 3 Excipient blend US$160 1 1 Lubrication blend US$160 0.5 0.5 High-shear granulation US$240 1 0 Drying the granulation US$240 1 0 Granulation sizing US$120 1 0 Clean-up costs US$120 5 1 Total hours 15.5 6.5 Operating costs/1 mm—tablet batch €1918 (US$2250) €742 (US$870) Savings ~60%*

Table II: Reduction in environmental impact of wet granulation for a single formulation. Wet-granulation operations Manufacturing capacity Water consumption Drying energy (106 tablets/year) (metric tons/year) (megawatt hour/year) 30 4 2 50 6 4 100 13 8 200 25 15 400 50 31 Assumptions: 500 mg tablets, 0.25 g Water/ 1 g dry powder, drying to 2% water content, ΔHVAPOR = 2257 kJ/kg water.

in switching from batch production to By choosing the right technologies transitioning to continuous processing continuous processing with Methocel and suppliers that have the expertise as well as for customization or DC2 hydroxypropyl methylcellulose and experience needed, drug product creation of new excipients to better (HPMC). The technology is engineered manufacturers are equipped with the fit their evolving formulation and to improve dry-powder flow for tools necessary to tackle the “how.” manufacturing needs. streamlined matrix-tablet manufacture The new concept “designed for and improved drug content uniformity. Uptick of excipients purpose” has gained popularity This also helps shorten development in drug formulations amongst drug-product manufacturers time and reduce manufacturing costs There has been an increased focus and reflects the need for individualized by up to 60%. on excipients as drug makers solutions to optimize each When choosing excipients, drug- continue to explore new ways to take manufacturer’s processes. Currently, product manufacturers should pharmaceutical manufacturing to the drug makers are hesitant to use consider additional attributes of next level. Formulations will require novel excipients. Therefore, industry excipients such as particle size, new excipients to support evolving leaders and regulatory bodies are particle morphology, density in continuous-manufacturing processes, working together to explore regulatory relation to impact on powder and thus it is imperative for drug- pathways that would enable the use flowability, compactibility, and the product manufacturers to have better of novel excipients and ensure new critical quality attributes of excipients understanding of excipient properties and modified excipients can more impacting performance of the final and variability. readily move through approvals. drug product. To successfully do this, The dependence on excipients Knowledgeable suppliers can assist in drug manufacturers must partner with has prompted drug manufacturers overcoming this hurdle by developing suppliers who have rigorously tested to work with their suppliers more novel excipients within existing their excipients against industry closely than ever before to ensure pharmacopoeia standards as well as standards and have available data. their current supply of excipients is innovating completely new-to-the- Drug-product manufacturers who consistent and quality is being upheld world functional polymers. partner with trusted suppliers will to control variability. Drug-product These factors have the potential to have the support needed to ensure manufacturers must partner with impact current regulatory standards they are choosing the strongest fit for trusted suppliers to ensure current and pave the way for a new approval their formulation. excipients are still applicable when process for novel excipients. s14 Pharmaceutical Technology Europe APIs, EXCIPIENTS, & MANUFACTURING 2018 PharmTech.com Excipients

Roadblocks in of current approval processes will The collaboration between industry continuous manufacturing allow drug-product manufacturers leaders and regulatory agencies will The pharmaceutical industry transition to enjoy a more connected industry play a vital role in pharmaceutical to continuous manufacturing will be landscape. These efforts will advancement. challenging and time-consuming, but revamp industry infrastructure and The nature of continuous the long-term benefits will outweigh alleviate some of the challenges manufacturing is an example of the time and money invested. associated with adopting continuous the opportunity to thrive with the The first hurdle drug-product technologies. combination of business- and science- manufacturers must clear is the initial driven approaches. Manufacturers startup cost. This cost can include Lasting legacies of continuous will become increasingly business old batch equipment retirement, manufacturing savvy to maintain a competitive edge. new technology purchases, new The implementation of continuous Continuous manufacturing will help processes implementations that manufacturing will bring about many satisfy both sides of the spectrum adhere to quality-by-design principles, changes that will likely have lasting by improving the overall product and staff retraining. To justify the positive effects on the pharmaceutical for formulation ease, patient safety, large expenditure, drug-product industry. Recognizing change at manufacturing flexibility, while also manufacturers must focus on the this scale can be time-consuming reducing costs and mitigating risks. long-term benefits of this investment but manufacturers recognize the and how continuous manufacturing positive impact it could have on their References will eventually be imperative to business. Many collaborations will 1. Dow Pharma & Food Solutions, maintain a competitive edge. be formed between drug-product “Methocel DC2 Premium Excipients”, Lengthy approval times and manufacturers and suppliers to help pg. 4, accessed 12 May 2018. inconsistent regulatory requirements navigate the complexity of continuous 2. United Nations, Department of across borders create the need for manufacturing. Economic and Social Affairs, Population increased collaboration between Regulatory agencies are actively Division (2015), “World Population manufacturer and supplier. The drive engaged in the modernization of drug Ageing 2015,” pg. viii, accessed 12 May for harmonized regulatory standards manufacturing to better facilitate 2018. PTE across country lines and the updating implementation of new technology.

API in Capsule — contin. from page s12 DPI applications. Micro-dosing produce much larger quantities to on the technology and powder can be used for DPI programmes support late-stage clinical and even properties. Not only is application as well, as previously mentioned. potential commercial endeavours. The speed increased, the quality of the Particle sizing is typically key for a equipment has a different approach micro-dosing is maintained by a DPI delivery system, and specialized than the Xcelodose gravity-fed 100% in-line fill mass monitoring DPI capsules are often employed to system but can be readily scaled and rejection, thus facilitating an provide optimized capsule clearance. from Xcelodose-based Phase I–II overall rapid commercialization Particle engineering is typically studies. Such systems allow for rapid- for AIC applications. required for DPI applications to to-market approaches leveraging ensure an average particle size in precision micro-dosing technology Summary the 2.5–3 micron range and a tight for encapsulated API or blends. Using AIC approaches, particle size distribution. Spray drying Harro fully automated devices can pharmaceutical companies have is increasingly being used to achieve micro-dose powders using dosators the ability to increase speed to the required particle size distribution and vacuum drums depending on clinic, quickly assess their new and morphology for effective DPI the fill weight of the capsules. The assets, and remain cost conscious therapeutic effect. Employing dosator change parts dispense to investments in development of encapsulation of spray-dried API using powders from 5 mg or more into formulated dosage forms. AIC studies micro-dosing can rapidly advance capsule shells, while vacuum and start with API characterization, dosage form development, using membrane presentations can from which an understanding of the same filling principles across dispense powders into capsules as the API morphology, solubility, and multiple dosing ranges (see Figure 2). low as 0.5mmg/unit. Specifically, other key attributes define the drug Scale-up considerations. the Harro Modu-C MS drum filler product design and decision flow A number of technological uses custom designed drums with diagram. Choosing the right capsule advancements have been made precision drilled holes and vacuum composition and size, employing with micro-dosing applications at systems to produce low-impact micro-dosing encapsulation commercial scale, which facilitate forces and powders to introduce techniques, and leveraging scale-up efficient late-stage clinical and/or them into capsules at high rates of best practices can help progress commercial scale up. Harro Höfliger, speed. These advancements have these new APIs quickly from for example, has developed high- resulted in the ability to produce up concept to the later stage clinical/ speed capabilities that are able to to 72,000 capsules per hour based commercial drug products. PTE

Pharmaceutical Technology Europe APIs, EXCIPIENTS, & MANUFACTURING 2018 s15 with accuracy and precision so that coefficient of variation (CV) of fill- weight values less than 1% are often achieved. Single components such as dietary supplements (e.g., evening primrose oil) or a two-component formulation where the bioactive substance dissolves in the excipient should fill satisfactorily at ambient temperature. Capsules need sealing if the liquid is flowable at ambient temperatures. Capsule sealing machines have been improved over the years to avoid leakages (2).

The dose of the drug substance and the quantity of an excipient that can be filled are Selecting limited by the capsule size.

Excipients for Liquid- Cross-linking potential. Another consideration is the potential for crosslinking. A low concentration Filled Hard Capsules of aldehydes may be present in or produced during storage by some Thixotropic gels, thermosoftened systems, and of the excipients used in liquid-fill self-emulsifying systems have expanded the range of potential excipients. formulations and may cause cross linking of gelatin, which consequently affects dissolution. To check this interaction, filled capsules are stored Milind K. Biyani, PhD iquid-filled hard capsules (LFHCs) are typically composed of a shell at 40 ºC and 75% RH for six months. (Tech.) is R&D consultant Lof gelatin or hydroxypropyl methylcellulose (HPMC) and filled with The capsules are emptied, cleaned, at Aspire Advisors Pvt. Ltd., compatible liquids or compositions that can flow below 70 ºC. LFHC and then filled with acetaminophen Mumbai, India, drmilind@ technology offers several advantages over other solid dosage forms as the dissolution reference aspire-advisors.net. (1). It is crucial, however, to select excipients that are compatible with material. Comparison of dissolution capsule shell integrity and suitable for the purpose of a formulation. data for acetaminophen from the stored and reference capsules can Excipient considerations provide evidence for interactions Capsule shell integrity. Hard-gelatin capsules contain 13–16% between the investigated fill moisture. Hygroscopic vehicles such as glycerin, propylene glycol, material and the gelatin capsule. If and liquid polyethylene glycols (PEGs), however, cannot be used on this interaction is the problem, it their own because they will cause gelatin capsule shell brittleness can be overcome by the use of and fracture. If the moisture content of a filled capsule does not HPMC capsules that do not undergo change more than 2% at 65% relative humidity (RH) and 25 ºC these cross-linking reactions (3). for six months, then the gelatin capsule will retain its integrity. PEG 400 and 600 can also distort HPMC capsules slightly due to Excipient types swelling of shell walls caused by PEG diffusion. PEG 900 does not Excipients that have been found to cause this problem. HPMC capsules (moisture content 3–8%) may be incompatible with hard-gelatin be useful for moisture-sensitive and hygroscopic products and capsules include ethanol, glycerol, whenever capsules of vegetable source need to be used (2). glycofurol 75, medium-chain Sizes of capsules. The dose of the drug substance and monoglycerides (e.g., Alkoline MCM, the quantity of an excipient that can be filled are limited by Capmul MCM, Inwitor 308), PEG with the capsule size. Commonly available hard capsule sizes a molecular weight (MW) less than for liquid filling along with their filling capacity are listed in 4000, Pharmasolve (N-methyl-2- Table I. Normally, only 90% of the available volume is used for pyrolidone), propylene glycol, Span ensuring proper filling of liquids and sealing of the capsules. 80, and Transcutol P (diethylene Viscosity. The viscosity of the filled material should be in the glycol monoethyl ether) (4). It may

range of 0.1–25 Pa•s (100–25000 cps), and filling can be achieved be possible, however, to incorporate kkkawpunnn/Shutterstock.com

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thermosoftening process, provided Table I: Hard-capsule sizes and their liquid-filling capacity. that aging does not adversely Size000123 affect drug-release properties (2). Volume (mL) 0.91 0.68 0.5 0.37 0.30 Drug release from the SSM formulation could be altered by changing the hydrophilic-lipophilic small amounts of these excipients was dispersed in Miglyol 829/Aerosil balance of PEG stearate, the type into liquid-fill formulations. The 200 thixotropic gels. The drug and concentration of polymer, and maximum tolerable concentration of release rate was dependent upon the drug loading. This work led an excipient should be determined the silicon dioxide concentration. to a patent for Opticaps (10). experimentally. Formulations An increase in Aerosil percentage Self-emulsifying systems. This for hard-gelatin capsules that increased apparent viscosity of the type of formulation is designed use mixtures containing PEG triglyceride gel, causing a reduction to self-emulsify in contact with 200 have been published (5). in drug diffusion from the SSM (8). aqueous media to form a fine The numerous excipients that dispersion. In each case, the basis are compatible with hard-gelatin The scope of liquid filling of the formulation is a mixture of oil, capsules are classified in three main has been increased by the a surfactant, and a co-surfactant, categories by Cole (4) as follows: use of thixotropic gels, which can lead to improved drug 1. Lipophilic liquids (e.g., refined delivery and bioavailability. A thermosoftened systems, oils, triglycerides, and esters) self-emulsifying drug delivery 2. Semi-solid lipophilics and viscosity and self-emulsifying system (SEDDS) was formulated for modifiers (e.g., hydrogenated oils, systems. Coenzyme Q10 using Myvacet 9-45 cetostearyl/cetyl/stearyl alcohols, (diacetylated monoglyceride) (40% glyceryl esters, and Aerosil Thermosoftened systems. w/w) as oil, Lebrasol (50%) w/w) [fumed silica] for thixotropic gels) Thermosoftened formulations are as surfactant, and lauroglycol 10% 3. Solubilizers, surfactants, prepared at an elevated temperature w/w as co-surfactant. It showed a emulsifiers, absorption enhancers to produce a formulation that is two-fold increase in bioavailability (e.g., PEGs with MW more than sufficiently mobile for satisfactory compared to a powder formulation, 900 for HPMC capsules and more filling. A typical formulation may be when tested in dogs. A self- than 4000 for gelatin capsules, based on a solid excipient (e.g., PEG nanoemulsified system (SNEDDS) Tween 80, poloxamers). or poloxamer that will melt below based on a mixture of an essential 70 ºC) in which the active substance oil, polyoxol 35 castor oil (Cremophor Liquid filling in hard capsules will melt, dissolve, or disperse. When EL), and a medium-chain mono- The scope of liquid filling has been cooled to ambient temperature, it will and diglyceride mixture (Capmul increased by the use of thixotropic be a solid or semi-solid dispersion MCM-C8) overcame some of the gels, thermosoftened systems, and in the capsule. The filling process problems, such as low solubility self-emulsifying systems. In these temperature is usually limited up and irreversible precipitation semi-solid matrices (SSMs), the to a maximum of 70 ºC to avoid of active drug, associated with active substance is present as thermal damage to the capsule the SEDDS formulations (11). a particulate disperse phase. shell and to reduce operational Thixotropic gels. A thixotropic hazards (2). As an example, Merck’s Applications of LFHC for gel undergoes shear thinning during Entereg capsule, which was particular drug formulations filling followed by gel restructuring approved in the US in 2008, contains Hygroscopic drugs. Vancomycin with an increase in its apparent alvimopan suspended in PEG 3350. HCl is a highly hygroscopic drug, and viscosity in the filled capsule, which As another example, a study it was first available only as a dry reduces tendency to leak from the showed that ibuprofen, which powder in sealed ampoules. The capsule. For example, Miglyol 95% has melting point 75 ºC, formed problem of hygroscopicity was solved w/w and silicon dioxide (Aerosil clear solutions at 70 ºC with PEG using an SSM formulation (12). The 200) 5% w/w mixture and a liquid 6000, 10000, poloxamer, and SSM formulation was prepared by paraffin 95% w/wo hydrogenated Dynafill (a palmitic acid derivative of a thermosoftening technique with castor oil (Thixcin R) 3% w/w and polyoxyethylenepolyoxypropylene PEG 6000 that protected the drug Aerosil 200 2% mixture were both block copolymer) (9). from moisture uptake and produced filled satisfactorily with a CV of fill PEGs and poloxamers are stable a stable and effective preparation in weight of 2.8% and 2%, respectively for several hours at temperatures a liquid-filled hard-gelatin capsule. A (6). The particulate active substance between 60 and 70 ºC that are similar approach was used to solve is dispersed uniformly in the gel. commonly used for liquid-filling a problem with the hygroscopic and Poloxamer/silicon dioxide gels thermosoftened SSMs. PEGs of MW very unpalatable drug mercaptamine have been also studied (7). 4000–10000 and poloxamers have hydrochloride (13). An SSM In another example, a highly water- ideal physical properties for liquid- formulation with PEG 6000 protected soluble drug, propantheline bromide, filling into hard capsules by the the drug from moisture uptake

s18 Pharmaceutical Technology Europe APIs, EXCIPIENTS, & MANUFACTURING 2018 PharmTech.com Excipients

and masked the taste and smell of 1000 and Gelucire 44/14; it was References mercaptamine hydrochloride, which lower with PEG 1500 and lowest 1. M. Biyani, Pharm. Tech. resulted in excellent compliance with PEG 6000 and PEG 4000 (18). 41 (10) 36-41 (2017). and the successful treatment of Bioavailability enhancement. 2. G. Rowley, “Filling of Liquids and cystinosis in the children (2). Biphenyl dimethyl dicarboxylate Semi-solids into Two Piece Hard Sustained release. Sustained- dissolved in a concentrate prepared Capsules,” in Pharmaceutical release formulations have been from Tween 80, Neobee M-5, Capsules, F. Podczeck, B. Jones, prepared by using excipients and triacetin provided improved Eds. (Pharmaceutical Press, that influence the hydrophilic- bioavailability (19). Isotretinoin in 2nd Ed., 2004), pp. 169-194. lipophilic balance of the SSM (2). sorbitan monooleate, soyabean 3. S. Nagata et al., AAPS PharmSci. Phenylpropanolamine was formulated oil, and stearoylpolyoxyl 3 (3) Poster (2001). as an SSM of arachis oil, beeswax, glycerides is approved as 505(b) 4. E. T. Cole, Pharm. Tech. and silicon dioxide (14), and captopril (2) product against a softgel Internat. 1 (8) 29-33 (1989). is an SSM consisting of soybean oil product (20). Another marketed 5. W. Lahr, Pharm. Ztg. 131 and glycerol monostearate (15). product contains hydrogenated (15) 88-91 (1986). soyabean oil, polysorbate 80, 6. S. E. Walker et al., J. Pharm. Micronization of the soyabean oil, and white wax. Pharmaco. 32, 389-393 (1980). drugs in oil and filling Avoiding hepatic metabolic 7. T. Saeed, G. Rowley, and P. A.Walters, the suspension in oil will pathway for higher bioavailability. Proceedings Pharmaceutical minimize exposure to the The undecanoate ester of Technology Conference (Athens) testosterone exhibits much lower 16 (2) 217-224 (1997). potent drug. aqueous solubility than the native 8. P. A. Walters et al., Drug Dev. Ind. form, yet demonstrates higher Pharm. 18, 1613-1631 (1992). Propranolol capsules contained a oral bioavailability due to a greater 9. A. R. Hawley et al., Drug Dev. Ind. rapid-release phase of propranolol lipophilicity and a greater propensity Pharm. 18 (16) 1719-1739 (1992). in oleic acid and a sustained-release to enter the systemic circulation 10. Mepha Ltd, Aesch/BL, “Medicament phase of an erodible matrix of via the lymph, particularly when with a delayed release of active ingre- the same drug. The mixing of two formulated as a lipid solution dient,” US patent 4795643, Jan. 1989. phases was prevented by either (Andriol Testocaps). It is dissolved 11. S. Nazzal et al., Int. J. Pharm inserting a hydrophilic Gelucire in castor oil and propylene glycol 235, 247-265 (2002). barrier between the two phases or monolaurate and filled as a soft- 12. W. J. Bowtle, H. J. Barker, by adding a hydrophobic Gelucire gelatin capsule (21) or LFHC. and J. Wodhams, Pharm. to the rapid-release phase to Formulating drug compounds Tech. 12 (6) 86-91 (1988). solidify it at temperatures less than in liquid or semi-solid excipients 13. F. K. Dixon et al., Proceedings 37 ºC (16). For example, isosorbide is used to target lymphatic Pharmaceutical Technology dinitrate retard capsules (Tillotts transport (22) or to circumvent Conference (Strasbourg) Pharma) contain 40% lactose and the impact of transporters (23) 13 (1) 260-270 (1982). 60% Gelucire 50/02 as excipients. and metabolizing enzymes (24) 14. D. Francois et al., Pharm. Potent drugs. Micronization in the gastrointestinal tract. Ind. 44, 86-89 (1982). of the drugs in oil and filling the Abuse-resistant formulations. 15. Y. Seta, Int. J. Pharm. 41, suspension in oil will minimize Liquid and semisolid filled capsules 263-269 (1988). exposure to the potent drug. by their nature are resistant to 16. S. J.Burns, Int. J. Pharm. Agglomeration results in reduced crushing and powdering, and a 134, 223-230 (1996). solubility and hence reduced drug is difficult to extract from 17. W. T. Ebert, Pharm. Tech. 1, 44-50 (1977). bioavailability, but filling the waxes. For example, Oradur (Durect) 18. Dordunoo, et al., Drug Dev. and Ind. oily suspension instead of uses a high-viscosity base matrix Pharmacy 17 (12) 1685-1713 (1991). powder reduce the chances of of sucrose acetate isobutrate. 19. K. Chong-Kook, C.Yeon-Ju, agglomeration. Triamterene dosed and J. Zhong-Gao, Control. at 20 mcg in a PEG mixture as Conclusion Release 70, 149-155 (2001). a semi-solid filled in capsules Large varieties of excipients 20. G.F. Webster, J.J. Leyden, and shows a standard variation at 1.8%, are available for use in LFHCs J.A. Gross. J. of the Am. Acad. of compared to 3.1% for powder-fill based on the purpose of the Dermatology 69, 762-767 (2013). capsules. The main reason for the formulation. Compatibility with the 21. E. Nieschlag et al., Acta improved standard deviation lies capsule shell and viscosity at the Endocrinologica 79, 366-374 (1975). in volumetric filling, which does temperature of filling up to 70 ºC 22. Griffin and O’Driscoll, J. Pharm. not show differences in density are most important considerations. Pharmacol. 58, 917-925 (2006). and homogeneity for semi-solids With the advancements in 23. Martin-Facklam, et al., Br. J. Clin. as it does for powders (17). The machinery for sealing of hard Pharmacol. 53, 576-581 (2002). highest in-vitro dissolution was capsules, more products could 24. Gao and Morozowich, Expert Opin. when it was formulated with PEG be developed as LFHCs. Drug Deliv. 3 (1) 97-110 (2006). PTE

Pharmaceutical Technology Europe APIs, EXCIPIENTS, & MANUFACTURING 2018 s19 However, the most significant issue that increases the propensity of antibodies to aggregate is the modification of their surfaces through chemical conjugation to hydrophobic payload linkers. Once the payloads are conjugated to the antibody, they present hydrophobic patches that attract hydrophobic areas on other antibodies, thus initiating the aggregation process. Once formed, these low molecular weight aggregates form nuclei sites where further aggregation can occur, eventually leading to high molecular weight aggregates and ultimately Tackling Aggregation precipitation from solution.

Challenges in “The most significant issue that increases the propensity of ADC Production antibodies to aggregate is the modification of Immobilizing the antibodies on a solid-phase support, such as a resin, their surfaces through and carrying out the conjugation of the payload-linker while the antibodies chemical conjugation are bound to that support will prevent aggregation at its source. to hydrophobic payload linkers.”—Johnson

Adeline Siew, PhD ntibody-drug conjugates (ADCs) are targeted therapies that Conventional techniques Acombine a specific antibody or antibody fragment linked to a PTE: What are the limitations drug. ADCs have revolutionized the treatment of a number of diseases of conventional manufacturing by enabling more specific drug targeting with fewer side effects. techniques used in ADC Despite the growing ADC pipeline, Charlie Johnson, CEO of ADC Bio, production and why do they fail notes that many promising ADCs are being overlooked because of in preventing aggregation? critical aggregation control problems. Pharmaceutical Technology Johnson: Conventional conjugation Europe spoke to Johnson about the limitations of conventional of ADCs occurs in dilute aqueous manufacturing techniques used in the production of ADCs and buffered solutions. The buffer why preventing aggregation at its source is the best solution. conditions and pH are adjusted to suit the chemical conjugation conditions Causes of aggregation for attachment of the payload-linker PTE: What are the causes of aggregation in ADCs? to the antibody. Historically, ADCs Johnson: Aggregation of biomolecules can occur for a have been prepared by conjugation variety of reasons. Some antibodies are inherently prone to of either naturally occurring aggregation, especially when they are maintained in solution lysine or cysteine residues on the under conditions that promote aggregation, for example: antibody, although more recent • Unfavourable buffer conditions where either the salt type and/or developments see the use of ‘site- salt concentration is too low or too high can cause aggregation. specific’ residues, some of which • Aggregation can occur if the system is held at a pH that coincides focus on engineered-in residues (e.g., with the isoelectric point of the antibody (this is the point where thiomabs) or through modification the biomolecule carries no net charge and represents the point of naturally occurring sites on the of least aqueous solubility). This pH may be required, for example, antibody (e.g., glycan modification). when a particular conjugation chemistry requires a specific pH. What is common to all conventional • It is often the case during conjugation that solvents are conjugations is that eventually the required to solubilize otherwise poorly soluble payload- antibody or modified antibody will linkers, in particular highly hydrophobic ones. Some be exposed to a payload-linker

solvents are known to promote aggregation. to produce the ADC, and that is molekuul_be/Shutterstock.com

s20 Pharmaceutical Technology Europe APIs, EXCIPIENTS, & MANUFACTURING 2018 PharmTech.com

Antibody-Drug Conjugates

commonly the most unstable point of the antibodies on a solid-phase process equipment and hence the in the process for the antibody, support, such as a resin, and carry manufacturing footprint required because conditions such as buffer out the conjugation of the payload- depending on the process developed. composition, concentration, pH, and linker while the antibodies are addition of co-solvents are selected bound to that support. ADC Bio’s Locking mechanism to optimize the conjugation chemistry, Lock-Release technology uses this PTE: Can you tell us more about not the stability of the antibody. approach and can be performed the locking mechanism? Johnson: Lock-Release at its most basic level is a conceptual way of “The best solution to the aggregation problems constructing ADCs on solid supports, prevalent with conventional conjugation methodology designed to improve both the quality is to prevent aggregation at its source.”—Johnson of ADCs, the yield, and as a result, the economics of production. ADC Bio has patented multiple methods A degree of aggregation is, in either batch or flow mode. It is of Lock-Release. The favoured therefore, always expected, although easily scalable in the same way that technique to date is based on affinity the degree to which the antibodies other chromatography methods are. capture, using mimetic resins. The aggregate is mainly determined by The initial step is antibody specific resins used depend on the the inherent hydrophobicity of the capture onto the resin, which is process in question and, to some payload itself. Efforts have been made analogous to the protein A capture extent, where on the antibody the to reduce hydrophobicity of payloads step in downstream processing conjugation of the payload-linker either through modification with of antibody manufacture. Once is required. As with most affinity solubilizing linkers or modification immobilized, the antibodies are capture methods, the release of the payload structure, but these sequentially exposed to process method relies on varying pH and salt efforts have not fully solved the reagents and the payload-linker to concentration. The demonstrated problems of aggregation. Aggregation produce the ADC, with intermediary capacity of our Lock-Release resins of ADCs is not simply an issue of yield washing steps to remove excess is in the range 5 to 50 mg per mL inefficiencies and costs, although reagents. At the end of the process, of resin, but we expect that this these issues can be severe and lead the immobilized ADC is released range can be enhanced further. to the unviability of a product. Aggregates and, in particular, soluble high molecular weight “Lock-Release processing provides a unique way aggregate must be removed as of preventing aggregation of ADCs at source they are immunogenic and can while ensuring that the ADCs produced are free cause severe allergic reactions of contaminants (e.g., free payload linkers and if administered. Historically, solvents)…”—Johnson aggregates are removed from ADCs via application of chromatographic methods such as size exclusion or from the resin into a stabilized A significant advantage of hydrophobic interaction separation buffer matrix that prevents any using affinity-based capture techniques. These approaches subsequent aggregation. techniques is that the resin add further processing time and Lock-Release processing provides can be re-used over multiple cost, and it reduces the yield a unique way of preventing batches, and that the quality of of the system, which all adds to aggregation of ADCs at source product is extremely high and the cost of producing an ADC. while ensuring that the ADCs consistent over multiple batches. produced are free of contaminants Lock-Release can be run in either Preventing aggregation (e.g., free payload-linkers and stirred batch or column (flow- PTE: What’s the solution to solvents) that can interfere with mode). For manufacturing purposes, such aggregation problems? in-vitro and in-vivo read-outs and flow mode is preferred because it Johnson: The best solution to also lead to enhanced toxicity offers predictable linear scale-up the aggregation problems prevalent when administered to patients. as with other chromatography- with conventional conjugation ADC manufacturing using Lock- based techniques. As such, the methodology is to prevent Release is significantly simplified required manufacturing footprint aggregation at its source. If antibodies compared to conventional and equipment train remain are held physically separate from manufacturing, because the similar for all Lock-Release-based each other during the ‘unfavourable’ process equipment train used processes, which offers significant conditions of conjugation, they is the same irrespective of the productivity and capital cost cannot aggregate in the first place. ADC being made. Conventional advantages over conventional An obvious way to prevent this manufacturing, in contrast, will have manufacturing techniques at aggregation is through immobilization different requirements in terms of commercial manufacturing scale. PTE

s22 Pharmaceutical Technology Europe APIs, EXCIPIENTS, & MANUFACTURING 2018 PharmTech.com A potential drawback to robotic systems is running speed. “These systems aren’t yet designed to run 500,000 unit batches or produce 100 million units a year. But that’s not where the demand is anyway, and conventional systems weren’t meeting the need for small batch flexibility,” says Procyshyn. “If a company is making high-value drugs into multiple formats or sizes, they want a robust, repeatable process that reduces risk. That happens best with a closed robotic filling system.” “Traditional aseptic systems Robotics are proving to not be well suited to address these personalized therapeutic products because they Solve Aseptic lack the ability to efficiently produce low-volume, high-mix batches,” agrees Russell. “However, robotic Filling Challenges systems that have recipe-driven operation and the ability to process syringes, vials, and cartridges on a Automated robotic arms manipulate nested single platform are an ideal solution.” trays and containers inside closed aseptic filling systems. In addition, more companies are finding that robotic systems give them the flexibility, ease of use, and sterility assurance they need to replace manual filling of clinical batches. “From a staffing standpoint, automating these tedious and Jennifer Markarian n aseptic and sterile drug fill/finish and inspection, automation repetitive processes reduces Ican reduce or eliminate operator intervention, which reduces the risk associated with precise contamination potential and improves efficiency. Traditional, one-axis dosing and employee fatigue, and automation works well for high-speed processes, but multi-axis robotic automation can reduce scrap and arms offer repeatability with the flexibility to easily change the process re-work [compared to manual or the type of container being filled. Technology advances have made methods],” adds Walter Langosch, robotic systems suited for aseptic processing and easy to operate. Global Business Development While the pharma industry may be more familiar with robotics director at ESS Technologies. For used in packaging operations, advances in technology, such as “near example, the company’s TaskMate zero particle generating designs and complete tolerance to in-situ robotic syringe filler/capper, which biodecontamination cycles with gaseous hydrogen peroxide” have was introduced in December 2016, made robotics compatible with aseptic manufacturing, explains Josh replaces manual methods and can fill Russell, director of business development and technical sales at AST. and cap up to 15 syringes per minute. Today’s robotic systems are also easily reprogrammed for changes “We clearly see a high demand after the system is set up, without requiring a programming specialist for robotics in aseptic filling,” says on staff, say suppliers. Some platforms, such as those from AST Sebastien Schmitt, Robotics division and Vanrx Pharmasystems, are recipe-driven, and an operator manager, North America, at Stäubli. inputs the recipe information—such as the type of container and One growing use is in automated volume to be dispensed—through a touchscreen interface. compounding pharmacies in hospitals, in which robots can be Flexibility for small batches programmed flexibly to produce Flexible and repeatable filling are becoming more crucial due to drugs on demand, adds Schmitt. changes in the biopharma industry, notes Chris Procyshyn, CEO at Robotics provide consistent Vanrx Pharmasystems. “The focus on targeted therapies for smaller performance, with less equipment patient populations creates a challenge for companies to produce a inside an isolator, hence, reducing higher number of smaller batches into different container formats. risk and facilitating maintenance. Biologics, plus new modalities such as cell and gene therapies, Steriline Robotics, a spin-off are more complex and process intensive. The use of robotics is company created by Steriline

Bork/Shutterstock.com growing in response to these changes,” explains Procyshyn. with Milan Polytechnic, produces

Pharmaceutical Technology Europe APIs, EXCIPIENTS, & MANUFACTURING 2018 s23 Aseptic Filling

aseptic filling machines primarily aseptic tasks without violating basic isolators or RABs,” adds Procyshyn. used in hospitals and in pharmacy “first air” principles. In addition, the The workcells are entirely closed to the compounding. “The machine robotic system enables a real-time outside environment, and they also use we developed uses two robots fill-weight check. AST’s machine uses single-use product-contact materials. cooperating to help pharmacies in an in-process feedback loop to the Contract development and targeted drug reconstitution for each filling pump for closed-loop control. manufacturing organization (CDMO) patient, according to their specific In addition to the commercial-scale FUJIFILM Diosynth Biotechnologies prescription,” notes Federico Fumagalli, ASEPTiCell i100 line, a laboratory- announced in a 23 May 2018 press chief commercial officer at Steriline. scale line GENiSYS was introduced release that it was investing in the Steriline is focused on “zero-loss” in October 2017 for small-scale SA25 Aseptic Filling Workcell gloveless aseptic filling systems that aim filling for R&D (e.g., stability studies), isolator technology as it expanded to increase production efficiency for clinical production, and also for its gene therapy and viral vaccine fill/ and reduce the waste associated small-scale commercial production, finish capabilities to provide services with rejects using traditional such as cell and gene therapy. in support of late-phase candidates automation. Their robotic system and commercial supply (1). Fujifilm can, for example, identify a filled vial Gloveless isolator highlighted the advantages of that is missing a stopper and send A common use of robots in aseptic automated environmental monitoring it to be stoppered during a second processing is to use a robot to and no glass-to-glass contact. cycle, preventing the loss of that vial, replace certain operations, such as Vanrx Pharmasystems recently says Fumagalli. Steriline’s systems removing the cover from a nested introduced a smaller-scale gloveless run faster than some other robotic container tub. Entirely rethinking isolator system, the Microcell vial systems due to their artificial-vision the aseptic filling process, however, filler, designed for rapid scale-out of system, reaching a filling speed of allows manufacturers to take full personalized medicines, such as cell almost 100 vials/min, he says. advantage of robotics. Procyshyn and gene therapies and immuno- explains, “First, robots provide a oncology products, from clinical Solution for nested vials highly repeatable production process. through commercial manufacturing. Nested vials have been available Using recipe-driven processes, they The system replaces manual filling for more than five years, and the are able to produce multiple drug and small-volume filling machines technology to optimally handle vials products at equally high quality levels in biosafety cabinets, RABS, or in this format is now catching up, into different containers. Second, isolators, says the company (2). The says Russell. In AST’s ASEPTiCell robotic systems are agile and change Microcell can fill 2R-50R nested and GENiSYS aseptic filling and quickly between vial, syringe, and vials with toolless changeover and closing machines, six-axis articulated cartridge formats. Robots can handle decontamination in 15 minutes. robots perform all the critical aseptic every type of container the same operations, including removing way if the containers and closures Cobots the tub from its sterile overbag, are nested, so there are limited Stäubli’s TX Stericlean series was the opening the tub, and denesting change parts. Without traditional first robot introduced in 2008 for aseptic the containers (i.e., vials, syringes, electro-mechanical components production areas, says the company, or cartridges). After filling, the complicating the machine’s interior, which reports that its new TX2 line of robot closes the containers almost decontamination cycles are much collaborative robots (i.e., cobots) are also immediately, resulting in less time shorter too. Third, robots allow a first for aseptic processing. The use of that the sterile drug product is the design of gloveless isolators. A cobots allows glove boxes to be located exposed to the aseptic environment. gloveless isolator can run much next to the robot, so that the operator “The system is completely closed. cleaner than a conventional isolator can intervene in the isolator without It eliminates operator intervention and be completely closed. [There are] stopping the production process. The and allows a completely aseptic fill,” no mouse holes, conveyors, glass- TX2 robots are Industry 4.0-compatible, says Russell. Depending upon the to-glass contact, or sortation bowls, in that they can collect production data application requirements, the system which all create risks to the batch.” and are capable of communicating with can be used inside a restricted Procyshyn notes that Vanrx each other, reports the company. access barrier system (RABS), Pharmasystems SA25 Aseptic Filling isolator, or laminar airflow hood. Workcell gloveless isolator technology References The robotic system allows a is based on a standard design, which 1. Fujifilm USA, “Fujifilm Announces streamlined deck that is easier to allows filling operations to be built the Expansion of Its Fill Finish clean than traditional automation, faster than before (with lead times Services to Include Late Phase and explains Russell. Another advantage of less than a year) and in less space. Commercial Production of Gene over fixed automation is that the The workcell design provides agility, Therapies and Viral Vaccines to robot has various pre-programmed with the ability for one machine to Become an End-to-End Solutions “maintenance positions” where it is fill multiple container formats with Provider,” Press Release, 23 May 2018. ergonomically positioned for operators minimal changeover times. “Gloveless 2. Vanrx, “Vanrx Microcell Wins to access the disposable fluid path isolator technology provides better INTERPHEX ‘Best in Show’ Award,” and to perform other necessary aseptic assurance than conventional Press Release, 18 April 2018. PTE s24 Pharmaceutical Technology Europe APIs, EXCIPIENTS, & MANUFACTURING 2018 PharmTech.com Grifols guides pharmaceutical companies through the process of switching from concentrated formula to pre-mixed solution in ready-to-use flexible bags

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model or testing system that mimics the in-vivo condition. This task is even more challenging when the size of the compounds exceeds 1000 Da because many of the analytical tools used to detect and quantify small molecules are problematic for larger molecular weight compounds. Many researchers have used animal models, such as rodents and/or minipigs, either in vitro or in vivo, to assess the passive delivery of large molecules. It can be argued that these models have yet to show good correlation to the clinical situation as A Perspective on the proven by the lack of products on the market. In fact, many of these studies have been shown to be Topical Delivery of misleading as a result of inappropriate experimental design or a lack of contextualization of this limitation in Macromolecules the study conclusions.

The authors review the potential of delivering aptamers to the skin, At present, there is with evidence that therapeutically relevant levels can be reached no approved topical in both the epidermis and dermis. formulation containing a drug with a molecular weight of more than 1000 Da.

Marc Brown, PhD, is he human skin protects the body from physical, mechanical, and There have been, nonetheless, chief scientific officer and Tchemical insults while preventing endogenous water loss. This some glimmers of hope when co-founder of MedPharm; function is predominantly achieved by a thin (10–30 μm) cornified polysaccharides, proteins, and and Jon Lenn, PhD, is outermost layer—the stratum corneum (SC)—generated through oligonucleotides are explored. senior vice-president for terminal differentiation of the basal epidermal keratinocytes. The Hyaluronic acid (HA), a naturally MedPharm’s US operations. stratum corneum protects the human body, but also severely limits occurring polyanionic polysaccharide drug delivery into and across the skin. The historical and theoretical up to 1000 kDa, is found in the skin understanding of the type of compound that will permeate the skin is and has been shown to be a key based on the “500-dalton rule” (1, 2), where it is assumed that most molecule involved in skin moisture compounds permeating the SC have a relatively small molecular due to its capacity to retain water (4). weight (<500 Da) and are moderately lipophilic (log P 1–3.5) (3). There have been many publications Such an understanding was, however, based on the assumption of investigating the topical delivery of transdermal delivery across healthy skin with an intact barrier. Yet, HA. One of the earliest and most according to the data from Citeline’s Pipeline database, 7% of topical comprehensive studies examined medicines for the treatment of skin disease contain drugs with the topical delivery of HA following molecular weights from 600–1000 Da. Tacrolimus and pimecrolimus application to the human forearm in (804 Da and 810 Da, respectively), for example, are the two most well- situ (5). Tritiated HA was detected in known compounds that appear to contradict the “500-dalton rule.” the dermis just below the epidermis, Nevertheless, at present, there is no approved topical formulation and the authors took many steps containing a drug with a molecular weight of more than 1000 Da. to eliminate artifacts to ensure the observations were real and valid. Topical delivery of macromolecules Since publication in 1999, the group The literature consists of publications claiming topical delivery did not report further findings on of macromolecules. Why the discrepancy? Critical evaluation of HA. However, there have been many this literature suggests that some of the methodologies can be other studies claiming to have shown misleading and may contain artifacts that make translating to a HA permeation through human skin, clinical significance difficult. One of the challenges when attempting yet the topical delivery HA continues

to understand passive topical delivery of compounds is establishing a to be taken with scepticism (6–11). Tefi/Shutterstock.com

s26 Pharmaceutical Technology Europe APIs, EXCIPIENTS, & MANUFACTURING 2018 PharmTech.com Topical Delivery

Figure 1: Topical application of IL-23 aptamer shows penetration into the human skin and into the keratinocytes. (a) Penetration of IL-23 Cy3 labelled aptamer (orange) into intact human abdominal skin after zero (wash control), 6 and 24 hours post dosing. (b) Uptake of IL-23 aptamer into skin keratinocytes (dashed lines indicating the epidermal junction). (c) Intracellular uptake of aptamer (green) with nuclear DAPI stain (blue) used for cellular orientation. Scale bar = 50 μm.

In addition, latex proteins One of the challenges expression in psoriatic skin (15). This have been proposed to cause when attempting to technology will be interesting to hypersensitivity allergen-based understand passive topical watch because it appears there are reactions (12). Latex proteins are delivery of compounds several similar compounds in early larger molecular weight compounds is establishing a model development. (14–52 kDa); hence, it is interesting or testing system that how these proteins can produce Topical delivery of aptamers mimics the in-vivo allergic responses in the skin. It is Aptamers are a subclass of large condition. presumed that the proteins are able molecules that have been shown to cross the skin barrier to elicit the to have high binding affinity and response. In fact, there are studies Phase I/II (14) but despite the clinically selectivity with the ability to disrupt that show latex proteins were able positive data, it does not seem to protein–protein interactions. to penetrate excised human skin, have progressed further. Some of the Currently, it is not possible to disrupt and that exposure induced an IgG1 constraints related to modifications these protein–protein interactions response in vivo (13). of antisense molecules and their fixed with traditional small molecules. There have been several intriguing structural nature may explain this Aptamers, therefore, represent a new studies exploring the topical delivery lack of progression. More recently, class of molecules that could have of oligonucleotides within the past topical application of a tumor antibody-like binding affinity with the decade. Experimental studies using necrosis factor (TNF)-α suppressing possibility of topical delivery. Evidence a nuclear factor kappa B decoy antisense spherical nucleic acid from the literature supports their oligonucleotide (13 kDa) showed showed that treatment with the rapid clearance from the systemic initial promise as a potential topical highest dose resulted in a statistically circulation, thus limiting unwanted treatment for atopic dermatitis. The significant decrease in TNF systemic side effects and restricting

Figures are courtesy of the authors. product progressed as Avrina into messenger ribonucleic acid (mRNA) the biologic effects of topically

Pharmaceutical Technology Europe APIs, EXCIPIENTS, & MANUFACTURING 2018 s27 Topical Delivery

Figure 2: Topical application of IL-23 aptamer inhibits Th17- and IL 22-derived cytokines in human skin. Freshly excised human abdominal skin was mounted and clamped in place using static cells containing growth media and stimulated 24 hours later to induce a Th17 response. The skin was treated topically twice with 8 μL of IL-23 aptamer (210 μg/cm2) in an aqueous vehicle before and concurrent with Th17 stimulation. IL-23 aptamer (10 μM) and a ROR gamma inverse agonist (10 μM; small molecule) was included in the media as systemic controls. Twenty-four hours post stimulation, skin was harvested and relative transcript levels of Th17-type cytokines, IL-17f (a), IL-22 (b), and IL-23 (c) were determined by quantitative polymerase chain reaction (qPCR). Bars represent the mean percent of maximum stimulation (set to 100%) from three different skin donors (n=3).

administered aptamers to the skin In a recent publication, researchers human interleukin (IL)-23 cytokine, (16). Interestingly, aptamers offer at GlaxoSmithKline, University permeated intact human skin to significant conformational plasticity of Reading, and MedPharm therapeutically relevant levels in and flexibility. Moreover, their showed, for the first time, that a both the epidermis and dermis (19). structure can be modified without the 62-nucleotide (20,395 Da) RNA- This observation was particularly loss of significant activity (17, 18). based aptamer, highly specific to the surprising considering the compound

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was 40 times larger than what is production (see Figure 2) following skin in vitro. The final and perhaps commonly accepted as possible for topical application. Interestingly, most crucial step is to ensure passive topical delivery in the skin. there may be some structural the macromolecule is tested for commonalities between HAs, latex biological activity ideally using ex-vivo Aptamers are a subclass allergens, oligonucleotides, and skin to assess target engagement of large molecules that aptamers, which potentially explain from a topical application. Given the have been shown to have the positive observations for topical counterintuitive challenge of proving high binding affinity and delivery; however, this hypothesis topical delivery with macromolecules, selectivity with the ability requires further investigation. study designs tend to include a to disrupt protein–protein Nevertheless, if this in-vitro work majority of controls (both negative interactions. were to be confirmed clinically, and positive) to ensure an unbiased, this result could present a major non-artifact, and robust result. In the study, the authors used breakthrough in dermatology and multiple approaches to demonstrate topical drug delivery as it could open References the topical delivery of the aptamers, new areas of research and potentially 1. G.L. Flynn in Principles of Route- including fluorescently labelled targets that are not accessible using to-Route Extrapolation for Risk aptamer, confocal microscopy, and traditional small molecules. Assessment (Eds T. R. Gerrity, C.J. a novel dual hybridization assay that Henry) 93-127 (Elsevier, 1990). used capture and detection probes A development strategy 2. R.O. Potts and R.H. Guy, Pharm Res 9 with oligonucleotide precipitation to for macromolecules (5) 663-669 (1992). be able to quantify the aptamer at There are several critical 3. A. Williams, Transdermal and Topical picomolar levels. They showed the experimental parameters required Drug Delivery: from Theory to Clinical IL-23 aptamer delivered into the skin to ensure robust, artifact-free Practice (Pharmaceutical Press, 2003). was significantly above the cellular results to allow for improved 4. E. Papakonstantinou, M. Roth, and G.

IC50 values (119,000-fold > IC50 in the translation to clinical situations. Karakiulakis, Dermato-endocrinology 4

epidermis; 3400-fold > IC50 in the Some of these experimental (3) 253-258 (2012). dermis) when treated topically using parameters are the use of 5. T.J. Brown, D. Alcorn, and J.R. Fraser, J a simple cream formulation. This human skin with an intact or Invest Dermatol 113 (5) 740-746 (1999). portion of the study used freshly uncompromised barrier, clinically 6. A. Torrent et al., Osteoarthritis and excised human skin and a diffusion relevant dosing volumes, a validated Cartilage 18 (Supp 2) S229 (2010). cell commonly referred to in-vitro highly sensitive analytical method 7. B. Birkenfeld et al., Pol. J Vet. Sci. 14 (4) penetration/permeation (IVPT) and for extraction and quantitation of 621-627 (2011). is considered the “gold standard” for the compound, and potentially, 8. M. Farwick et al., Skin Pharmacol. assessing topical delivery for both confirmation of biological activity Physiol 24 (4) 210-217 (2011). biopharmaceutical companies and and structure using human skin. 9. J.A. Yang et al., Biomaterials 33 (25) regulatory agencies. To confirm the 5947-5954 (2012). IVPT delivery and to help visualize this Aptamers represent a 10. H.J. Lim et al., Colloids and Surfaces delivery, confocal microscopy was new class of molecules A: Physicochemical and Engineering introduced on sections from the IVPT that could have antibody- Aspects 402, 80-87 (2012). study, and this aptamer appeared like binding affinity with 11. M. Kong et al. Carbohydr. Polym. 94 (1) to localize to the intracellular and the possibility of topical 634-641 (2013). extracellular compartments within delivery. 12. E. Proksch, A. Schnuch, and W. Uter, the viable epidermis (see Figure 1). It J Eur. Acad. Dermatol Venereol. 23 (4) was interesting that this observation The first step is to develop an 388-393 (2009). was noted to confirm a previous analytical method to ensure the 13. B.B. Hayes et al., Toxicol. Sci. 56 (2) publication, showing the uptake of detection, analysis, and quantitation 262-270 (2000). a different aptamer into primary of the macromolecule is fit for 14. M. Dajee et al., J Invest Dermatol 126 human keratinocytes (20). From this purpose and free from interference. (8) 1792-1803 (2006). independent observation, it could be Having duplicate analytical methods 15. KT. Lewandowski et al., J Invest extrapolated that intracellular and using alternate techniques is an ideal Dermatol 137 (9) 2027-2030 (2017). extracellular targets are possible with approach to further confirm that the 16. A.D. Keefe, S. Pai, and A. Ellington, Nat. this technology. observations are valid. As with any Rev. Drug Discov. 9, 537-550 (2010). To ensure the delivery observed topical programme, it is imperative 17. Y.S. Kim and M.B. Gu, Adv Biochem Eng with the other techniques was at that proper preformulation studies Biotechnol. 140, 29-67 (2014). therapeutic levels and the aptamer occur to establish compound and 18. Y.I.A. Nakamura and S. Miyakawa, was bioavailable, the authors formulation stability both from a Genes Cells 17 (5) 344-364 (2012). developed a Th17 mediated biological chemical and biological activity 19. J.D. Lenn et al., J Invest Dermatol, 138 model using ex vivo human skin and sense. The next step is to screen (2) 282-290 (2017). showed the IL-23 aptamer was able compounds and formulations for 20. R. Doble et al., J Invest Dermatol 134 (3) to suppress IL-17 and IL-22 mRNA passive topical delivery using human 852-855, (2014). PTE

s30 Pharmaceutical Technology Europe APIs, EXCIPIENTS, & MANUFACTURING 2018 PharmTech.com creams and explores some of the analytical techniques necessary.

Complex generics and the regulatory landscape A whitepaper (3) arising from a 2016 conference at the New York Academy of Sciences (4) divides complex drugs into two categories, based on the challenges involved in proving their pharmaceutical equivalence (PE) and BE. The first Testing Topicals: category includes those products with complex active ingredients and/ or complex formulations, for which Analytical Strategies the demonstration of both PE and BE is difficult. The second category includes products for which delivery for the In Vitro routes, dosage forms, or drug-device combinations are complex, and Demonstration of the establishment of either PE or BE is challenging. Because of their delivery route and the difficulties of Bioequivalence assessing BE, locally acting topical drugs fall into this second group. As discussed, for topical, locally Taking acyclovir as an illustration, this article acting drugs, systemic PK testing examines IVBE testing requirements for topical is not always relevant or easily creams and explores some of the analytical techniques necessary. conducted. Therefore, most require clinical endpoint studies to determine BE. However, these studies are costly, time-intensive, and require Paul Kippax is director opical pharmaceutical products usually take the form of lotions, high patient numbers, creating a of Product Management– Tcreams, gels, ointments, or pastes and are used to deliver locally- barrier to entry for development of Morphology Group; acting drugs to their sites of action. Local anesthetics, dermatological generic formulations. Innovators Jennifer Burt is treatments for eczema and dermatitis, and antiviral preparations needing to demonstrate batch-to- applications specialist; and for cold sores are just some of the medications delivered using batch equivalence for post-approval Carolyn O’Grady is UK formulations applied directly to the skin. As many locally acting drugs changes or scale-up face a similar applications manager, are deemed to have complex delivery routes, they fall within the challenge (5). In recognition of this, all at Malvern Panalytical. growing pharmaceutical category of complex drug products. Complex FDA has issued various product- drug products include drugs with complex active ingredients or specific guidance documents for formulations and those such as inhalers and nasal sprays, which rely complex drug products, including on specific drug-device combinations. The generic versions of complex some locally- acting drugs such as drug products are in high demand (1), and pressure is mounting cyclosporine ophthalmic emulsions to develop these alternatives more quickly and more efficiently. (6) and acyclovir ointments (7). One challenge in developing a generic version of a locally acting These guidance documents include drug lies in demonstrating its bioequivalence (BE) to its reference- simplified product-specific BE listed drug (RLD) counterpart. For solid oral-dose formulations recommendations and are published intended for systemic delivery, this is an established process involving on a case-by-case basis. Importantly, human pharmacokinetic (PK) studies supported by in-vitro dissolution they include the use of in-vitro testing. PK studies based on the systemic in vivo attainment of a methods to assess bioequivalence, therapeutically active drug concentration, however, have limited thereby linking the physical and Editor’s Note: This article relevance for locally acting substances. Measuring directly at chemical properties of a drug is an abbreviated version of the site of action also presents challenges, given the potential with its efficacy. For locally acting the original article, which variability of factors such as exposure time and size of application topical drugs, IVBE is restricted to was published online 22 area. Alternative approaches are, therefore, being explored and are formulations that have qualitative (Q1) Feb. 2018 and can be found exemplified in US Food and Drug Administration (FDA) guidance on and quantitative (Q2) equivalence to at: www.pharmtech.com/ establishing bioequivalence for acyclovir (2), the API in the topical the RLD. The availability of suitable testing-topicals-analytical- cold sore treatment Zovirax (GlaxoSmithKline). In-vitro bioequivalence analytical techniques, a thorough strategies-vitro-demonstration- (IVBE) testing is one of the options proposed. Taking acyclovir as an evaluation and understanding of the

Sisacorn/Shutterstock.com bioequivalence. illustration, this article examines IVBE testing requirements for topical reference drug, and identification

Pharmaceutical Technology Europe APIs, EXCIPIENTS, & MANUFACTURING 2018 s31 Testing Topicals

of the critical process parameters and risk involved in developing of acyclovir cream, and discuss are all necessary precursors to a complex generic product. the insight they offer. Specifically, successful implementation of this these case studies look at a approach for the development of Acyclovir and FDA guidance comparison of an innovator generics and the reduction of the for the development product and a generic version. need for clinical endpoint studies. of generic versions Acyclovir was the world’s first Case study: Particle size Deformulation and successful antiviral drug and has and shape of the generic bioequivalence been available in topical form and innovator products Applying physicochemical since the early 1980s, with oral Many drug substances exist in characterization methods to the and intravenous preparations more than one crystal form. Such development of pharmaceutical also prescribed for systemic use. polymorphism can affect a drug’s generics is not a new concept, and Although marketed originally and chemical and physical properties the now-familiar deformulation still available as Zovirax since its and influence its processing or workflow for solid-dosage forms patent expiration in the 1990s, manufacture. These variations can was first published in 2005 acyclovir has been available under also affect drug product stability, (8). Fundamental to this is the many brand names worldwide. The dissolution, and bioavailability, with concept that having quantitative drug treats viruses of the herpes consequences for quality, safety, and qualitative information about family, most notably herpes simplex and efficacy. It is, therefore, vital key RLD ingredients simplifies (HSV) Types 1 and 2 (cold sores and to characterize and understand the optimization of prototype genital herpes) and Varicella-zoster polymorphs in terms of their particle formulations, reducing both virus (chickenpox and shingles). The size, shape, and chemistry. In the number of experiments topical formulation is marketed topical formulations, the particle needed and the risks along the primarily as a cold sore treatment. size and crystal habit of the API developmental pathway. FDA guidance covering topical will, for example, influence the This application of physicochemical acyclovir (2) defines the criteria that speed at which it permeates the methods to deformulation can also must be met for formulations to skin. In-vitro permeation data be used directly in the development qualify as suitable for IVBE studies. indicate that for acyclovir, small size of complex generic drugs. FDA sets Key among these is that the “test rectangular crystals are more rapidly out three levels of equivalence and RLD products are physically absorbed than large oval ones (11). requirements. Q1 equivalence asks and structurally similar based MDRS can be used to determine if there is qualitative similarity upon an acceptable comparative the polymorphic form of the API between the RLD and test (generic) physicochemical characterization” in a formulation, its particle size, drug product: do they have the same (2). More specifically, testing and its crystal habit, enabling active ingredient and excipients? Q2 should include the following: direct comparison between test equivalence asks if the active and • Assessment of appearance products and the RLD. This technique excipient ingredients are present in • Analysis of the acyclovir combines automated static particle the same amounts in both products. polymorphic form in imaging with Raman spectroscopy Q3 equivalence examines whether the drug product to measure particle size and shape both the RLD and the test product • Analysis of particle size and provide chemical identification have the same physicochemical distribution and crystal habit of individual particles, enabling the attributes or microstructure. with representative microscopic generation of component-specific Similarity at the Q3 level delivers images at multiple magnifications size and shape distributions. the opportunity to move to in-vitro • Analysis of the rheological Figure 1 shows how bioequivalence testing and provides behaviour, which may Morphologically-Directed Raman the possibility of approval without be characterized using a Spectroscopy (MDRS) (Morphologi clinical endpoint studies (9). Not rheometer that is appropriate 4-ID, Malvern Panalytical) can be used only does this offer considerable for monitoring the non- to determine the polymorphic form cost savings, but potentially a Newtonian flow behaviour of of API particles. The instrument first faster time to market. Different Q3 semi-solid dosage forms conducts automated morphological parameters being considered in • Analysis of specific gravity, analysis for all particles in the product-specific guidance documents water activity, pH, and any acyclovir sample, establishing include: appearance, pH, globule size other potentially relevant particle size and shape distributions. distribution, rheological behaviour, physical and structural The instrument then returns to a drug release profile, drug particle size similarity characterizations. selected subset of the total particle distribution, drug polymorphic form, The following case studies illustrate population to obtain Raman spectra and specific gravity (10). Choosing the use of morphological imaging, to identify which particles are API the correct analytical techniques including Morphologically-Directed (the acyclovir 3:2 hydrate form). to measure these parameters Raman Spectroscopy (MDRS) and Once particle classes have been and applying them effectively can rheological measurements in the established, MDRS can be used significantly reduce the time, cost, physicochemical characterization to determine the particle size s32 Pharmaceutical Technology Europe APIs, EXCIPIENTS, & MANUFACTURING 2018 PharmTech.com Testing Topicals

Figure 1: Using Morphologically-Directed Raman Spectroscopy (MDRS) to determine API polymorphic form in acyclovir cream.

1. Automated morphological analysis 2. Chemically identify API polymorphic form - Size and shape parameters for every particle

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0 100 200 300 400 500 600 700 800 900 1000 1100 1200 1300 1400 1500 1600 1700 1800 1900 Raman Shift (cm-1) Confirm acyclovir 3:2 hydrate form

3. Automatically create class of particles with acyclovir 3:2 hydrate form

www.malvern.com

distribution (PSD) specifically for the API (Figure 2). In this case, comparing PSDs for the API in the innovator (blue) and generic (red) preparations shows that the API particles in the generic formulation are smaller than those in the innovator. This would be expected to have a significant impact on the solubility rate of the API and, therefore, its bioavailability. Figure 3 shows a comparison of particle shape distributions, using both circularity (left) and elongation (right) parameters. The API present in the generic (red) is more circular and less elongated than that in the innovator (blue), which contains more-rectangular API particles. This difference may suggest that, although both formulations contain a similar polymorph, the processing of the generic formulation has led to particle attrition (crystal breakage). This may also explain the differences in particle size.

Case study: Rheological parameters As a complex formulation, acyclovir cream typically consists of a base comprising an oil-wax phase (e.g., liquid paraffin, white soft paraffin, and silicone oils), stabilizers, and thickening agents, into which go the API and preservatives, together with additives to improve sensory or functional behaviour. Formulation, composition, and processing of the cream all impact its underlying microstructure (droplet volume and size and lamellar structure), in turn influencing the final product’s rheological behaviour, evident in such characteristics as flow and deformation. Understanding the rheology of a product is essential in controlling and optimizing the physical properties that deliver the appropriate stability, texture, delivery, and appearance. Rheology is therefore a crucial link between formulation, processing, and final product performance, and measuring a range of rheological parameters provides the information needed to engineer a product’s microstructure toward the desired end-product properties. FDA guidance on Q3 testing of acyclovir topical creams recommends the following in respect of rheological measurements (2): • A complete flow curve of shear stress (or viscosity) vs. shear rate should consist of multiple data points across the range of attainable shear rates, until low- or high-shear plateaus are identified • Yield stress values should be reported if the

Figures are courtesy of the authors material tested exhibits plastic flow behaviour

Pharmaceutical Technology Europe APIs, EXCIPIENTS, & MANUFACTURING 2018 s33 Testing Topicals

Figure 2: Using Morphologically-Directed Raman Spectroscopy (MDRS) to determine API particle size in acyclovir cream (generic formulation shown in red, and innovator in blue). A. B. C.

D[v, 10] μm: 3.26 D[v, 50] μm: 7.55 D[v, 90] μm: 13.33 0.8 D[v, 10] μm: 8.07 D[v, 50] μm: 17.19 D[v, 90] μm: 31.81

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Record 1: Generic Record 2: Innovator

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viscosity and elasticity and provide Figure 3: Using Morphologically-Directed Raman Spectroscopy (MDRS) to information about the viscoelastic determine API crystal habit in acyclovir cream (generic formulation shown in properties, or springiness/stiffness of red, and innovator in blue). the material. The generic formulation was found to have a more elastic 100 100 90 90 character, compared to the much 80 80 10.18 10.17 10.17 higher G* value of the innovator, 70 70 10.27 10.27 10.25 60 60 which will deform less with a given

50

% 50 10.14 10.13 10.12 % amount of force and will feel stiffer to 40 40 10.20 10.20 10.20 the touch. This corresponds with the 30 30

20 10.10 10.09 10.08 20 yield stress results, because a stiffer 10 10 10.17 10.16 10.15 structure will require more stress to 0 0 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Elongation rupture. Again, the stiffer structure HS Circularity

Record 3: Generic Record 4: Innovator of the innovator product may aid Record 3: Generic Record 4: Innovator patients in applying the formulation. Viscosity versus shear • The linear viscoelastic response of the sample starts to decrease. rate. Figure 5 shows viscosity (storage and loss modulus Figure 4 shows measurements as a function of shear rate for the vs. frequency) should be for the innovator (blue) and a innovator (red line in Figure 5) measured and reported. generic (green) acyclovir product, and generic (blue line in Figure Examples for both an innovator showing that the innovator has a 5) products. Both are shear- and a generic product, with much higher yield stress than the thinning, so viscosity decreases as measurements made on a generic product in this case. This shear rate increases, the result of rotational rheometer (Kinexus, structure may make the innovator microstructural reorganization. The Malvern Panalytical), are product easier to apply to the innovator has a higher viscosity discussed in the following: area of skin requiring treatment. across all shear rates than the Yield stress. Many emulsions Linear viscoelastic response. generic and is likely to flow less behave like solids at rest, because Viscoelastic properties are readily and spread less easily in emulsion droplets flocculate to representative of the underlying use. It will also feel thicker on form a floc network. The stress that microstructure of a material before it rubbing because of its high viscosity must be applied to break down this yields, and provide information on its at high shear rates, and is likely structure and cause the material stiffness and elasticity. Measurement to more readily hold its structure to flow is known as the yield stress. involves oscillatory testing on a on application and stay in place Generally, the higher the yield stress, rotational rheometer, whereby the for longer, potentially providing the more solid-like the structure. A sample is sheared back and forth more effective treatment. cream with a higher yield stress will using small forces and displacement need more force to be squeezed so as not to disturb the structure. In Conclusion from a tube but will better retain its this case, an oscillation frequency In-vitro bioequivalence is of structure when applied to the skin, of 1 Hz, generally representative of significant interest across the allowing a greater amount to stay textural processes (touching), was generic-drug industry and is at the desired location. The cream used to test the generic and innovator especially welcomed by those will also appear and feel thicker. products. G*, the complex shear working with complex generic Measuring yield stress using a modulus, which is a measure of total products, where traditional BE testing rotational rheometer involves linear stiffness (from elasticity and viscosity may not yield the most appropriate ramping of shear stress over time combined) and the phase angle (δ), results. FDA bioequivalence and identifying when the viscosity can be considered as a ratio between guidance documents are now s34 Pharmaceutical Technology Europe APIs, EXCIPIENTS, & MANUFACTURING 2018 PharmTech.com PDA Europe Conference, Exhibition, Education Outsourcing & Supply Chain – A 360° View

6-7 November 2018 Register by 23 Sept 2018 Seville | Spain and SAVE! Testing Topicals

RegulatoryInformation/ Figure 4: Measuring yield stress in topical acyclovir creams Guidances/UCM428195.pdf (generic formulation shown in green, and innovator in blue). 3. L. Hussaarts, et al., Annals of the New York Academy of Sciences, Vol. 1407,

Yield stress results 39–49, DOI 10.1111/nyas.13347 (26 5 10 Innovator Apr. 2017), http://onlinelibrary.wiley. Generic com/doi/10.1111/nyas.13347/full

104 4. The New York Academy of Sciences, Equivalence of Complex Drug 80 Pa 103 Products: Scientific and Regulatory Challenges, Academy eBriefings, 2016, www.nyas.org/ComplexDrugs16-eB 102 5. S. Bhoopathy, et al., AAPS News Shear vlscostly (Pa s) Magazine 18 (2) (February 2015), 101 www.nxtbook.com/nxtbooks/ 8 Pa aaps/newsmagazine_201502/ 0 10 index.php?startid=16#/12 10-2 10-1 100 101 102 103 Shear stress (Pa) 6. FDA, Draft Guidance on Cyclosporine (FDA, October 2016), www.fda.gov/downloads/ Drugs/GuidanceCompliance Figure 5: Viscosity vs shear rate for acyclovir creams. RegulatoryInformation/ Guidances/UCM358114.pdf Viscosity vs Shear rate 7. FDA , Draft Guidance on Acyclovir (FDA, 103 March 2012), www.fda.gov/down- loads/Drugs/GuidanceCompliance RegulatoryInformation/ 102 Guidances/UCM296733.pdf Innovator 8. A. Bansal and V. Koradia,

101 Pharmaceutical Technology (Pa s)

η 9 (8) (August 2005). Generic 9. Martinez and Fahmy, The AAPS 100 Journal, 17 (2) (March 2015). 10. R. Lionberger, “Pharmaceutical Science of Generic Drugs: The 10-1 Science of Equivalence,” NIPTE 100 101 102 103 Y. (s -1) Research Conference, 30 April 2015. 11. R. Lionberger, “FDA, GDUFA Regulatory Science Update,” GDUFA Regulatory Science Public available for a range of complex drug type of information required to Meeting 20 May 2016. PTE products, including various topical compare the properties of innovator formulations. These documents set and generic forms and demonstrate out in detail the Q3 physicochemical the power of these techniques in analysis required for a product to providing real insight into topical Ad Index be considered for approval on the products and their behaviours. COMPANY PAGE basis of IVBE testing, in place of Between these two technologies, it clinical endpoint testing. Selecting is possible to answer to three of the Abitec Corp ...... 21 the most appropriate analytical five criteria from the FDA guidance for Butterworth Laboratories ...... 17 techniques for physicochemical the physicochemical (Q3) IVBE testing Catalent characterization will ensure a more of generic acyclovir products (2). Pharma Solutions ...... Back Cover complete understanding of the Grifols International SA ...... 25 product at both the deformulation References Hermes Arzneimittel GmbH ...... 33 stage of generic development, 1. R. Lionberger, “Developing New Lonza Biologics Inc ...... 13 through to manufacture, quality Bioequivalence Approaches for Nolato AB ...... 5 control, and post-approval testing. Complex Products,” Presentation Novasep Synthesis - Finorga ...... 2 Taking acyclovir cream as an delivered at GPhA Fall Technical Novo Nordisk example, this article presents Meeting, 29 Oct. 2014. Pharmatech A/S . . . Inside Back Cover data generated using two key 2. FDA, Draft Guidance on Acyclovir (FDA, Orientation Marketing ...... 29 technologies: MDRS and rotational December 2016), www.fda.gov/down- PDA ...... 35 rheometry. The data illustrate the loads/Drugs/GuidanceCompliance Veltek Associates ...... 7 s36 Pharmaceutical Technology Europe APIs, EXCIPIENTS, & MANUFACTURING 2018 PharmTech.com The editors of Pharmaceutical Technology Europe are pleased to present this special planning guide for the 2018 CPhI Worldwide trade show, which will be held 9–11 October in Madrid, Spain. This section highlights the exhibition, conference, and networking activities of this leading industry event.

CPhI 2 ...... Highlights

CPhI 4 ...... Introducing bioLIVE 2018 CPhI 6 ...... Exhibition Overview CPhI 7 ...... Exhibition Floor Plan

PLANNING CPhI 8 ...... Featured Exhibitors GUIDE CPhI 9 ...... Education Sessions CPhI 13 ...... CPhI Pharma Awards

CPhI 14 ...... Registration and Travel

Pharmaceutical Technology Europe and CPhI are brands of UBM, a part of Informa PLC.

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Pharmaceutical Technology Europe CPHI WORLDWIDE PLANNING GUIDE 2018 CPhI 1 CPhI EVENTS AND HIGHLIGHTS

CPhI Worldwide 2018 Highlights

CPhI Worldwide hosts its 2018 trade show from 9–11 October with a new bioprocessing event—bioLIVE—joining five other pharma industry exhibitions. Conferences, awards, and networking opportunities fill the programme.

Comprehensive Exhibition Big Data & Machine Learning Pharma Summit Tuesday, 9 October 2018: 9:30–17:30 Wednesday, 10 October 2018: 9:30–17:30 In collaboration with Innovation Enterprise Thursday, 11 October 2018: 9:30–16:00 Wednesday 10 October, 9:30–17:30 IFEMA, Feria de Madrid, Spain Room N101, North Convention Centre, CPhI Worldwide is home to more than 2500 exhibitors in IFEMA, Feria de Madrid dedicated zones covering ingredients, APIs, excipients, finished Machine Learning and the advanced analytics are positioned dosage, contract services, packaging, machinery, and more to solve some pharmaceutical supply chain challenges for small-molecule and biologics drugs. Visitors can meet with and inefficiencies that lead to drug shortages, missed suppliers of fine chemicals and intermediates, biologic drug sales, and higher prices. At this one-day summit—held in development products, drug delivery and devices, supply conjunction with the Innovation Enterprise—researchers, chain solutions, laboratory equipment and instruments, and data scientists, and engineers will discuss how machine contract services. See pages CPhI 6–8 for more information. learning and artificial learning can streamline process, increase efficiency, and better understand patients and Educational Sessions outcomes. The agenda will include big data and analytics Tuesday, 9 October–Thursday, 11 October 2018 in drug development and discovery, application of machine Visitors to CPhI Worldwide can learn about the latest learning in counterfeit drug detection, pre-clinical discovery, trends, opportunities, and developments in Pharma at demand planning, and big data in supply chain. free educational sessions located in the exhibit halls. To register, visit: www.theinnovationenterprise.com/ Pharma Insight Keynotes are a series of educational summits/big-data-and-machine-learning-summit-europe-2018. sessions offering in-depth information on ingredients, outsourcing, packaging, drug pricing, partnerships, and more—presented by bio/pharma industry experts. In a second roundtable, representatives from During the Pharma Insight Briefings programme, company Country Pavilion partners will discuss key challenges representatives explain the latest trends and technologies regarding import and export strategy, globalization, the for API development, excipients, drug development, and regulatory environment, and emerging markets. manufacturing, packaging, drug delivery, contract services, and more. The Pharma Insight Keynotes and Pharma Insight Briefings are free to attend. See CPhI pages 9–12 for details.

Recognising Innovation: CPhI Pharma Awards Gala Tuesday, 9 October 2018, 18:00–22:30 Eurostars Madrid Tower, Madrid, Spain The CPhI Pharma Awards honour innovation and excellence in 17 categories. Winners will be announced at the CPhI Pharma Awards Gala on 9 October. For additional information, see page CPhI 13 or visit awards.cphi.com.

Industry Roundtable Discussions CPhI Worldwide will host two invitation-only roundtable discussions. The C-Suite Roundtable, held in partnership with SCI, will bring together CEOs and executive leaders from across Pharma to come together to discuss key challenges regarding policy,

regulation, industry growth, new markets, and global challenges. BRKART/SHUTTERSTOCK.COM IMAGES: TOP/BOTTOM R.CLASSEN/SHUTTERSTOCK.COM

CPhI 2 Pharmaceutical Technology Europe CPHI WORLDWIDE PLANNING GUIDE 2018 PharmTech.com TOP/BOTTOM IMAGES: BRKART/SHUTTERSTOCK.COM Begins at 18:30 CPhI Pharma Awards Gala Eurostars Madrid Tower, Coaches depart IFEMA at 17:30. at IFEMA depart Tower, Coaches Madrid Eurostars Location 6 5and Halls between Avenida the Forum, Madrid de Pharma Feria IFEMA, Madrid de Feria IFEMA, Centre, Convention North S100E Room Madrid, de Feria IFEMA, Theatre—9C80 CPhI only) Gala (invitation Awards Pharma CPhI Roundtable Pavillion Country 18:30 at Begins Workshops Insight Pharma 14:00–17:30 10:30–11:40 Briefings Insight Pharma and Keynotes Insight Pharma Open Exhibition Activity only) 10:30–17:00 (invitation Roundtable C-Suite 9:30–17:30 8:30–11:00 Time 2018 9October Tuesday, 10:30–11:40 Pharma Insight Workshops Pharma Forum, the Avenida between Halls 5 and 6 5and Halls between Avenida the Forum, Madrid Pharma de Feria IFEMA, Madrid de Feria IFEMA, Theatre—9C80 CPhI Workshops Insight Pharma Madrid de Feria IFEMA, Centre, Convention North N106, Room 10:30–11:40 Briefings Insight Pharma and Keynotes Insight Pharma Open Exhibition Madrid de Feria IFEMA, Centre, 10:30–15:40 Convention N101, Room North Theatre—9C80 CPhI 9:30–16:00 2018 11 October Thursday, 13:10–13:40 10:30–11:40 Briefings Insight Pharma and Keynotes Insight Pharma Open Exhibition Summit Pharma 10:30–17:00 Learning &Machine Data Big 9:30–17:30 Forum Leadership in Women 9:30–17:30 8:30–11:30 2018 10 October Wednesday, Representative from DuPont Chair the from Welcome 8:30–08:35 &Networking Breakfast 8:00–08:30 Agenda development. career for strategies assess and losses, and wins share workplace, the in diversity to meet peers, hear from senior executives on promoting environments. work bias-free toward working and recruitment, ethical responsibly, talent place and source to ways about discussions open will and acquisition talent happen? this make to colleagues and peers their with work they can how and women for mean this does what level, entry to level board from organisations their in diversity increase to programmes creating are leaders company While Madrid de Feria IFEMA, Centre, Convention N106, North Room 8:00–11:30 10 October, Wednesday, byDuPont Sponsored Pharma in Women Empowering Forum inLeadership Women CPhI Worldwide 2018 CPhI Worldwide Schedule This event provides participants with an opportunity opportunity an with participants provides event This on focuses Forum Leadership in Women annual fifth The Pharma Insight Workshops Pharma Forum, the Avenida between Halls 5 and 6 5and Halls between Avenida the Forum, Pharma Workshops Insight Pharma (As of 27 July 2018)—View www.cphi.com/europe for schedule updates Pharmaceutical Technology Europe visit: cphi.com/europe/women-leadership-forum-cphi-worldwide speakers and agenda updated an For required. is Pre-registration 11:00–11:30: Coach Leadership Authentic Demuynck, Helena Moderator: Discussions Group and Networking Café World 10:10–11:00 Laboratories Dr. Reddy’s Officer, Resources Human Chief Bhaskar, Archana NEMERA sales, global VP Johnston, Denise DuPont from Representative Panellists: coach Penner, business Zarmina Moderator: leadership senior in Diversity • Pharma in talent female of apipeline sustaining and Creating • progression, career recruitment, impacts M&A How • Q&A: and discussion Panel Pharma in Talent Female Retaining and Sourcing 9:05–10:10 Representative from DuPont Speaker Keynote 8:35–09:05 and retention talent C Innopack/P-MEC Theatre—4F121Innopack/P-MEC ICSE Theatre—1G90 Innopack/P-MEC Theatre—4F121Innopack/P-MEC ICSE Theatre—1G90 Theatre—4F121Innopack/P-MEC ICSE Theatre—1G90 P h Coffee andCoffee Networking EVENT I

CPHI WORLDWIDE GUIDE PLANNING 2018 S

N HI AND G HLI G CPhI 3 HT

S CPhI PLANNING GUIDE

Welcome to bioLIVE Launched in 2018 and co-located with CPhI Worldwide, bioLIVE is an exhibition and conference for biopharmaceutical development and manufacturing.

he newest event at CPhI Worldwide, bioLIVE focuses on www.bio.live Tlarge-molecule biopharma manufacturing and processing within the industry. The exhibition and conference offer Tuesday, 9 October 2018: 9:30–17:30 trade show exhibits, conferences, commercial presentations, Wednesday, 10 October 2018: 9:30–17:30 and networking opportunities in a unique environment. Thursday, 11 October 2018: 9:30–16:00 Hall 12, IFEMA, Feria de Madrid, Spain Technologies and services featured at bioLIVE: • Processing equipment • Analytical instruments • Continuous processing systems • Separation and purification systems • Quality and analytical services • Cell line, cell culture, and fermentation • Cell therapy production • Gene therapy production • Automation systems and software • Formulation services • Freeze-drying • Process control, smart lab design, cleanrooms • Biopharma ingredients • Contract services and R&D • Commercialised products, vaccines, and biosimilars.

The bioLIVE exhibition will feature products and services used in the development of biopharmaceuticals. For updates, see www.bio.live.

bioLIVE exhibiting companies, as of 18 July 2018. Company Country Stand 73100 Portugal 12A20 Abzena United States 12A26 Admescope Finland 12A24 BIOCOM AG Germany 12A36 BIOTECHPHARMA UAB Liechtenstein 12B31 BSP Pharmaceuticals S.p.a Italy 12B14 c-LEcta GmbH Germany 12A30 China Chamber of Commerce of Medicines & Health Products China 12A32 Dow Europe GmbH Switzerland 12C31 Frontier Biotechnologies Inc. Switzerland 12B11 GeneScience Pharmaceuticals Co., Ltd. China 12A33 HORIBA United Kingdom 12B30 Luina Bio Pty Ldt Australia 12C30 M J Biotech Private Limited India 12B10 MabPlex International United States 12C12 Nanogen Pharmaceutical Biotechnology JSC Vietnam 12D20 Prestige BioPharma Pte. Ltd. Singapore 12A22 Rousselot Netherlands Netherlands 12B13 Samsung Biologics South Korea 12C14 Sekisui United Kingdom 12C10 SINOVAC BIOTECH CO., LTD. China 12D24 TOP/BOTTOM IMAGES: BRKART/SHUTTERSTOCK.COM IMAGES: TOP/BOTTOM PLA2NA/SHUTTERSTOCK.COM

CPhI 4 Pharmaceutical Technology Europe CPHI WORLDWIDE PLANNING GUIDE 2018 PharmTech.com CPhI PLANNING GUIDE

bioLIVE Conference Programming Building a Skilled Bioprocessing Workforce bioLIVE offers free, comprehensive content programmes Discussion and Real-World Training Sessions addressing key trends in bioprocessing and manufacturing. Rapid growth of the biopharma sector, combined with the shortage High-level commercial and technical content sessions are of skilled workers, mean effective hiring and retention strategies open to registered visitors and are free to attend. are essential for any biopharma company to ensure continued The Content Dome will host keynotes, panel discussions, growth. This session, led by National Institute for Bioprocessing and fireside chats on key topics in the following focus areas. Research and Training (NIBRT), will address the biggest challenge the industry is facing—a lack of a skilled workforce. Accelerating Bioprocessing Innovation: The Intersection of Business and Science Additional features at bioLIVE Bioprocessing business and scientific leaders discuss the future bioLIVE Insights Theatre of the bioprocessing market, highlighting current thinking Hear about the latest products, solutions, and innovations around how different industry innovations will transform from bioLIVE exhibitors. the bioprocessing market for the year 2024 and beyond. Start-Up Hub Cell Therapies and Gene Therapies Learn about the latest innovations emerging from start-up Cell therapies and gene therapies present an exciting and innovative companies that are developing the solutions of tomorrow. area of biopharmaceutical development; however, sophisticated manufacturing technologies and processes are needed to bring Introduction to Bioprocessing Breakfast Meeting these new products to market. This module will focus on the Small-molecule drug companies looking to enter biologics can latest strategies for overcoming these manufacturing challenges. gather insights on how to break into the biologics sector.

Artificial Intelligence and the Future of Visit bio.live/content-programme for updates. Biomanufacturing: Identifying Fact from Fiction The interest in artificial intelligence (AI)-driven solutions Registration for early-stage drug discovery is growing steadily with a A Visitor’s pass to bioLIVE provides access to all projected market volume reaching US$10 billion by 2024 for CPhI events. See page CPhI 14 for details. AI-based medical imaging, diagnostics, personal AI assistants, drug discovery, and genomics. Industry visionaries will review the latest developments in AI as well as practical case study applications in the biopharma space. bioLIVE Speakers

Confirmed speakers, as of 31 July 2018, include: • Lucy Foley, director of biologics, The Center for Process Innovation • Maria Agustina Duguine, owner, Global Regulatory Affairs and Consulting and professor BA Chemistry, UB University Argentina • Dawn Ecker, consultant and bioTRAK database manager, BioProcess Technology Consultants • Alan Moore, vice-president and commercial chief for advanced therapies, WuXi Advanced Therapies • Killian O’Driscoll, director of projects, NIBRT • John Milne, training director, NIBRT • Ronald Kompier, managing director, Biotech Training Facility • Ronald Kander, dean, Kanbar College and associate provost for applied research, Jefferson University • Amy Peck, founder and CEO, EndeavorVR • Samet Yildirim, technology innovation manager, Boehringer Ingelheim • Philip Ridley Smith, sales and marketing director, Cobra Biologics • Paul Thorning, CEO, Crystec Pharma TOP/BOTTOM IMAGES: BRKART/SHUTTERSTOCK.COM IMAGES: TOP/BOTTOM VLADKOL/SHUTTERSTOCK.COM

Pharmaceutical Technology Europe CPHI WORLDWIDE PLANNING GUIDE 2018 CPhI 5 EXHIBITI CPhI 6 M manufacturing. and development biopharmaceutical for event adjacent an bioLIVE, of addition the with markets biologic-drug and small-molecule the cover events co-located its and CPhI CPhI Expands to Six Events pharmaceutical drugs. pharmaceutical for equipment and machinery features P-MEC 4, Hall in Located P-MEC suppliers. system drug-delivery as well as industries, packaging tertiary and secondary, primary, for services and products zone, alabelling features 4, 2and Halls in located InnoPack, Systems Delivery andDrug Packaging Pharmaceutical InnoPack: 3. 1and Halls Exhibit in exhibition ICSE the in showcased are services logistics and packaging, services, analytical IT, biotech, manufacturing, contract research, contract trials, clinical offer that providers solution Outsourcing Services ICSE: Contract 5 Hall Extracts: Natural 7, Halls Pharma: 9 Integrated 10 Hall Intermediates: and Chemicals Fine 8 Hall Excipients: 10 Hall Manufacturing: Custom 3,5,6,7, Halls APIs: 8,10 zones: category product in arranged are exhibits Worldwide CPhI CPhI Worldwide P-MEC, FDF, and InnoPack—with one exhibition pass. exhibition one FDF, InnoPack—with P-MEC, and see https://ubm.cphi.com/europe/exhibit/floor_plan/. exhibitors, of location and hall exhibit each of plans floor detailed For event. the of site Madrid, de Feria IFEMA, of opportunities. networking and sessions, educational exhibits, through manufacturing and development drug biologic in drugs. biologic-based and small-molecule of manufacture and development the services—for contract and products, dosage finished packaging, equipment, excipients, APIs, services—including 2018. 9–11 from October Worldwide CPhI InnoPack—at and FDF, P-MEC, bioLIVE, ICSE, events—CPhI, co-located six the Visitors can attend all co-located events—CPhI, ICSE, bioLIVE, bioLIVE, ICSE, events—CPhI, co-located all attend can Visitors overview an 7provides CPhI page on floorplan facility The advances on focus will event bioLIVE 2018, in the Launching and products their showcase will vendors 2500 than More 150 countries will converge on Madrid, Spain to explore explore to Spain Madrid, on converge will 150 countries from professionals bio/pharmaceutical 45,000 than ore Pharmaceutical Technology Europe O N

O V E R V I E W CPHI WORLDWIDE PLANNING GUIDE 2018 GUIDE PLANNING WORLDWIDE CPHI

Finished Dosage Formulation (FDF) Formulation Dosage Finished biologic-based drugs. See pages CPhI 4–5 for details. for 4–5 CPhI pages See drugs. biologic-based for processes manufacturing and development drug to dedicated is 12. Hall bioLIVe in located be and Worldwide CPhI to adjacent run will 2018, bioLIVE for event A new bioLIVE represented. are forms suppository and sublingual, nasal, inhalation, creams, patches, vials, drugs, parenteral gels, capsules, tablets, including forms sterile and sprays, liquids, semi-solid, dose, Solid companies. generic-drug and distributors, product end specialists, out-licensing manufacturing, contract pharma, including chain supply 12, formulation 14.1 14.0, Halls the in and FDF targets Thursday, 11 October 2018: 9:30–16:00 11 October Thursday, 2018: 9:30–17:30 10 October Wednesday, 2018: 9:30–17:30 Tuesday, 9October Hours Exhibition CPhI CPhI/FDF, ICSE, and InnoPack. Admission is free to all visitors. all to free is Admission InnoPack. and CPhI/FDF, ICSE, spanning galleries three in packaging and services, contract in pharmaceutical ingredients, finished dosage formulation, innovative view can Visitors Worldwide. CPhI at introduced products new for ashowcase is Gallery Innovation The Gallery Innovation live-pharma-connect-match-meet-service. www.cphi.com/europe/ at online more Learn stand. exhibitor’s the at or area &Meet Match Connect Pharma Live dedicated the in place take can meetings databases to find business connections. Face-to-face search manually to need the eliminates service the system, matching automated an Using meetings. onsite arrange to portal online Connect Pharma Live the use can events co-located and CPhI at exhibitors and Visitors Live Pharma Connect Special Activities PharmTech.com

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P CPhI 7 FEAT CPhI 8 Stand #4C30 Stand www.gerresheimer.com Gerresheimer Stand # 3F30 Stand www.lonza.com Lonza Abitec Corporation Worldwide. CPhI at exhibiting companies following the visit to sure Be Exhibitors Featured Stand #8A20 Stand www.novonordiskpharmatech.com Novo Nordisk Pharmatech A/S Novo Nordisk #8F70 Stand www.colorcon.com Colorcon #8A110SSPStand www.abiteccorp.com U Pharmaceutical Technology Europe E E RED

X H I B I T O R S CPHI WORLDWIDE PLANNING GUIDE 2018 GUIDE PLANNING WORLDWIDE CPHI Stand # 4D22 Stand www.nolato.com Nolato #3F102 Stand www.partnershipgrifols.com SA International Grifols Stand #7F30 Stand www.cordenpharma.com Corden Pharma #8F90 Stand www.galeniq.com Beneo GmbH Stand #8B101 Stand www.itwreagents.com AppliChemPanreac

PharmTech.com Stand # 10C82 Stand www.novasep.com Novasep #1G41 Stand www.hermes-pharma.com Hermes Pharma Stand #3D10 Stand www.catalent.com Catalent Pharma Solutions Stand #9A70 Stand www.pitdc.org.tw Taiwan Alliance Pharmaceutical #7B80 Stand www.lohmann4minerals.com Dr Paul Lohmann

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Sessions Explore Bio/Pharma Topics

CPhI Worldwide visitors can stay current on technologies, ingredients, manufacturing and packaging practices, and business strategies by attending Pharma Insight Briefings.

t CPhI Worldwide, visitors can learn from experts who Pharma Insight Briefings Ashare insights, opinions, and technical updates in Pharma Insight Briefings. The 30-minute sessions are held in open- Tuesday, 9 October 2018: 10:30–17:00 plan theatres on the show floor. The keynote sessions offer Wednesday, 10 October 2018: 10:30–17:00 in-depth information by industry experts. Briefings cover Thursday, 11 October 2018: 10:30–15:40 the latest technologies, serivces, and product offerings. Free to attend. Seating is limited. All sessions are free to attend. Session and speaker information is as of 31 July 2018. For updates visit cphi.com/europe/agenda.

CPhI: APIs, Excipients, and Drug Delivery KEYNOTE SESSIONS Location: CPhI Theatre—9C80

Tuesday, 9 October 2018, 10:30–11:00 Addressing an Unmet Need: How Pharmaceutical Industry Professionals Can Extract Value from Data Routinely Collected on Products and Processes Mike Tobyn, research fellow, Bristol-Myers Squibb

Tuesday, 9 October 2018, 11:10–11:40 Quality by Design Amina Faham, executive board member, International Pharmaceutical Excipients Council Europe

Wednesday, 10 October 2018, 10:30–11:00 Tuesday, 9 October 2018, 12:30–13:00 Current Trends in Generics Portfolio Strategies A Novel Method for Delivering Hygroscopic Pharmaceutical Drugs Brandon Boyd, segment lead – generics, Clarivate Analytics Susana Ecenarro Probst, director of scientific business development, Qualicaps Wednesday, 10 October 2018, 11:10–11:40 Brexit: The Wider Implications for the Pharmaceutical Sector Tuesday, 9 October 2018, 13:50–14:20 In Partnership with SCI Shaken Not Stirred? How Will USP <661.1> and ICH Q3D Impact Your Packaging Materials Cocktail? Thursday, 11 October 2018, 10:30–11:00 Dan-Ola Svensson, technical manager, Clariant Plastics & Coatings The Future is Digital and What This Means for Pharma Speaker to be announced Tuesday, 9 October 2018, 15:10–15:40 Biological Assays: Responding to Increasing Thursday, 11 October 2018, 11:10–11:40 Demands in the Release of Peptide-Based APIs Logistics: A Point of View from Outside Pharma Michael Postlethwaite, business development manager, Bachem Speaker to be announced Wednesday, 10 October 2018, 11:50–12:20 CPhI: APIs, Excipients, and Drug Delivery Champagne Taste for Beer Price? Metabolomic and Isotopic PHARMA INSIGHT BRIEFINGS Fingerprint of Commercial Saw Palmetto Extracts Location: CPhI Theatre—9C80 Roberto Pace, vice corporate quality director, Indena

Tuesday, 9 October 2018, 11:50–12:20 Wednesday, 10 October 2018, 12:30–13:00 Innovative Gelatine Product to Manufacture Capsule-Based Dry Powder Inhalation: Enteric Soft Capsules in One Step Opportunities, Trends, and Solutions

TOP/BOTTOM IMAGES: BRKART/SHUTTERSTOCK.COM IMAGES: TOP/BOTTOM ESB PROFESSIONAL/SHUTTERSTOCK.COM Martin Junginger, product manager pharma gelatine, Gelita Fernando Diez, scientific business development manager, ACG Associated Capsules

Pharmaceutical Technology Europe CPHI WORLDWIDE PLANNING GUIDE 2018 CPhI 9 HRAIN PHARMA CPhI 10 Lonza API, for development ofcommercial head director, senior Janssen, Maurits Manufacturing and Development (HPAPI) API Potent Highly for Practices Best 2018, 13:10–13:40 10 October Wednesday, Fresenius Kabi SwissBioSim GmbH GmbH SwissBioSim Kabi Fresenius pharmacovigilance, and safety ofclinical head Gudat, Uwe and Biosimilars? Products Biological for Scenario New the What´s 2018, 11:10–11:40 11Thursday, October India Sanofi generics, head–global Bansal, Amit China: Entering the Arena of European Generics 2018, 10:30–11:00 11 October Thursday, Republic Czech ofthe Industry ofChemical Association association ofthe director Soucek, Ivan Republic Czech the in Specialties Chemical of Production 2018, 13:10–13:40 10 October Wednesday, Pharmaceutical Manufacturers Russian ofthe withAssociation Partnership In Russia: Market Outlook 2018, 11:10–11:40 10 October Wednesday, R&D, BIOCAD Ivanov, Vice-President, Roman Diseases Autoimmune and Oncology of Treatment State-of-the-Art the to Access on Biologics Class of and Biosimilars, Impact Generics, Next-In- 2018, 10:30–11:00 10 October Wednesday, (TBC) Ingelheim Boehringer compliance, quality and assurance quality affairs, ofregulatory head Önol, Bostanci Melek GmbH Mylan Europe, – access market and policy of head Mendonça, Lino Victor Europe for director, Medicines access market Baelen, van Maarten Moderator: Market aSustainable Creating Affordability: and Pricing Discussion: Panel 2018, 10:30–11:40 Tuesday, 9October 6 5 and Halls between Avenida Forum, Pharma Theatre, Insight Pharma Workshops Insight Pharma Pharmaceutical Technology Europe

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Christos Varsakelis, senior manager process modelling, GSK modelling, process manager senior Varsakelis, Christos SANOFI leader, project ITS Morlec, Raphael Quality Manufacturing Optimise and Time, Minimise Agility, Improve to Plan Your of Manufacturing Part as Strategy 4.0 Industry an Creating Panel: Discussion 2018, 10:30–11:40 11Thursday, October AG Partners Kurmann partner, managing Bieri, Christoph supply, Pfizer global development Kent,business vp Tim AB Recipharm development, corporate EVP Quick, Mark Services Pharmaceutical Avara &CEO, Tyson,Tim chairman Sanofi affairs, –industrial development business and investments planning, director, strategic Bellettre, Gérard International Results partner, Kevin Bottomley, Moderator: Pharma for Outlook M&A Discussion: Panel 2018, 10:30–11:40 10 October Wednesday, bybioLIVE Powered Drug Manufacturers from Large-Molecule Learn Can Manufacturers Drug Small-Molecule What Overlap: Bioprocessing 2018, 11:10–11:40Tuesday, 9October PharmSource of president Miller, former Jim Plan 5-year the in Ifs” “What Outlook: CDMO Chat: Fireside 2018, 10:30–11:00 Tuesday, 9October Theatre—1G90 ICSE Location: KEYNOTE SESSIONS andManufacturing Formulation ICSE: Outsourcing Reiner Christensen, CEO, Chameleon Pharma Chameleon CEO, Christensen, Reiner Players Pharma and OTC for Markets Emerging the in Opportunities Vast The 2018, 11:50–12:20Tuesday, 9October Theatre—1G90 ICSE Location: BRIEFINGS INSIGHT PHARMA andManufacturing Formulation ICSE: Outsourcing Andreas Berg Storsve, director R&D, Aker Biomarine R&D, Aker director Storsve, Berg Andreas Adults in Elasticity and Hydration Skin Improves Supplementation Oil Krill Superba 2018, 15:50–16:20 10 October Wednesday, KG GmbH Dr. Lohmann Paul biopharma, manager Kuhz, project Henning Salts Iron on Data Scientific Novel Salt: Innovative with Your Bioprocesses Improve 2018, 13:50–14:20 10 October Wednesday, PharmTech.com

TOP/BOTTOM IMAGES: BRKART/SHUTTERSTOCK.COM PHARMA INSIGHT BRIEFINGS

Tuesday, 9 October 2018, 12:30–13:00 Wednesday, 10 October 2018, 13:50–14:20 The Journey of Revealing Unknowns and ALCOA Data Integrity Assessment Impurities by Material Knowledge Francesco Amarosi, vice-president business development, PQE Lise Vanderkelen, department head of microbiology and pharmaceutical services, Nelson Labs Wednesday, 10 October 2018, 15:10–15:40 Specialty Containers: PVC-free Freeflex Bags and Tuesday, 9 October 2018, 13:10–13:40 Pre-filled Syringes for Sterile Drug Products Is Your Product Sterile or Sterilized? Comparison between Gabriele Pfaffenthaler, key accounts and business Aseptic Processing and Terminal Sterilization development manager product partnering sterile Annick Gillet, Sterigenics pharmaceuticals Central Europe, Fresenius KABI

Tuesday, 9 October 2018, 14:30–15:00 Wednesday, 10 October 2018, 15:50–16:20 What´s Next for Sterile Contract Managing the Pharmaceutical Supply Chain Manufacturing in Emerging Markets? Lynne Byers, executive director, pharma biotech, NSF International Laura Pandolfi, business development manager product partnering sterile pharmaceuticals, Europe, Wednesday, 10 October 2018, 16:30–17:00 LAM, Africa and Asia, Fresenius Kabi Accessing the European Market Alberto Carazo Fornieles, pharmaceutical Tuesday, 9 October 2018, 15:10–15:40 scientific advisory director, Azierta Technology Selection Methodologies for Addressing Bioavailability Challenges Thursday, 11 October 2018, 12:30–13:00 Caroline Bauer, pharmaceutical development CIS Market: Regulatory Strategies in Dynamic Convergence manager, Lonza Ploermel Polina Dombure, member of the board, Inpharmatis, SIA

Tuesday, 9 October 2018, 15:50–16:20 Thursday, 11 October 2018, 13:50–14:20 Recipharm Pathway to Clinic–From Formulation to Clinical Trial Third-Party Voluntary Evaluation of APIs and Intermediates Mikael Bisra, development and technology sales director, Recipharm Codema Pharma

Wednesday, 10 October 2018, 11:50–12:20 Innopack/P-MEC: Packaging and Manufacturing Compaction Simulation as a Powerful Quality-by-Design Tool: KEYNOTE SESSIONS How We Optimize Prototyping, Scale-up, and Even Production Innopack/P-MEC Theatre—4F121 Equipment Workload of Complex Oral Solid Dosage Forms. Aline Moulin, senior project manager– Tuesday, 9 October 2018, 10:30–11:00 pharmaceutical development, Skyepharma Latest Consumer Trends in Packaging: Pharma Perspective TOP/BOTTOM IMAGES: BRKART/SHUTTERSTOCK.COM IMAGES: TOP/BOTTOM KASTELIC/SHUTTERSTOCK.COMMATEJ

Pharmaceutical Technology Europe CPHI WORLDWIDE PLANNING GUIDE 2018 CPhI 11 HRAIN PHARMA CPhI 12 OMPI EZ-Fill, Systems Pharmaceutical OMPI Largoni, Martina Challenges Biodrug for Choice Syringe Prefillable Glass The Nexa: Ompi 2018, 14:30–15:00 Tuesday, 9October Inc. Chemical and Gas Mitsubishi researcher, Usuda, Kenichiro Biologics for Syringe and Vial Plastic Best The 2018, 13:50–14:20 Tuesday, 9October Systems Pharmaceutical SCHOTT development, of business head Bauert, Dominique Injectors Wearable for Solutions Packaging Primary 2018, 13:10–13:40Tuesday, 9October Pharma Aptar development, business Nadler, director Guenter Platforms Technology New Exploring Tract: Your Respiratory for Care Portable 2018, 12:30–13:00 Tuesday, 9October Breath Next president, Suman, Julie Gamma vs. Steam of Study A Migration Sterilization: Gamma of Myths Leachable the Debunking 2018, 11:50–12:20Tuesday, 9October Theatre—4F121 Innopack/P-MEC BRIEFINGS INSIGHT PHARMA andManufacturing Packaging Innopack/P-MEC: Consultants Stewardship &Product Packaging Environmental EPI-Global president, Bell, Victor Packaging in Pharmaceutical Sustainability of Future The Workshop: 2018, 10:30–11:0 11 October Thursday, announced tobe Speaker Transportation Packaging and Stability API in Excellence for Strategies New 2018, 11:10–11:40 10 October Wednesday, GSK activities, pre-competitive PTS head Badman, Clive Industrialisation to Science Fundamental from Collaboration Innovations: Packaging Pharmaceutical 2018, 10:30–11:00 10 October Wednesday, IDIPAC director, managing Waterhouse, Christopher Solutions Personalised to Volumes Large from Shifting Packaging: Pharma to Approach A Personal 2018, 11:10–11:40Tuesday, 9October Organisation Packaging World Ambassador, Global AVPS, Chakravarthi Pharmaceutical Technology Europe

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medical systems, Gerresheimer systems, medical support technical manager Zeiss, Bernd Germany in Made Syringe -aCOP ClearJect RTF Gx 2018, 16:30–17:00 10 October Wednesday, GmbH Stoelzle-Oberglas medical, and pharma CSO Luccarda, Jan Feature Anti-Counterfeiting with Packaging Primary on Tracking 2018, 15:50–16:20 10 October Wednesday, Pharma SGD officer, commercial Zuber, chief Laurent VAL-U director, Advisory managing Jailloux, Frédéric FEVE manager, affairs public Judson, Jean-Paul Moderator: OTC and Biotechs Supporting is Glass Moulded How Future? the Moulding 2018, 15:10–15:40 10 October Wednesday, Instruments House Light Line, Product Director Duncan, Derek Products Pharmaceutical Sterile of Testing Integrity Closure Container 2018, 14:30–15:00 10 October Wednesday, Aptar devices, connected for director development Shankar, business Sai Medicines Digital for Eco-System Devices aConnected Building 2018, 13:50–14:20 10 October Wednesday, Agilent manager, Taylor, marketing Lester pharma QC Pharma to Approaches Modern 2018, 13:10–13:40 10 October Wednesday, Tek B&W development, business Diz, Lozano Enrique Analysis QA/QC Pharma for Method Preferred into Raman of Evolution 2018, 12:30–13:00 10 October Wednesday, Pylote SAS CEO, Marchin, Loic Patients Protect Better and Preservatives Replace to Products Pharmaceutical to Application Power: Matter’s bythe Protection Antimicrobial 2018, 11:50–12:20 10 October Wednesday, development, Mitsui Chemicals Inc. business director, overseas Sugasawa, Hiroaki Inc. Chemicals Mitsui Bilcare technology, new and R&D vice-president, Kulkarni, Sanjeev Packaging Blister Pharmaceutical for Coating Heat-Seal Solvent-free, High-Performance, 2018, 16:30–17:00 Tuesday, 9October Europe Systech sales, of Taylor,Alastair vice-president Consumers to Threat aSerious Pose Fake Drugs 2018, 15:50–16:20 Tuesday, 9October PharmTech.com

TOP/BOTTOM IMAGES: BRKART/SHUTTERSTOCK.COM TOP/BOTTOM IMAGES: BRKART/SHUTTERSTOCK.COM AWARDS IMAGE: COURTESY OF CPhI/KATE MILLER network, receive recognition, and boost their company’s profile. company’s their boost and recognition, receive network, setting, acelebratory in leaders industry 500 than more with connect can Participants entertainment. and champagne, wines, meal, athree-course awards—includes the for nominated teams of Tower Hotel. Madrid Eurostars the of Ballroom Barcelona Grand the at held be will ceremony The Spain. Madrid, in Worldwide CPhI 2018 during 9October on Ceremony Awards well-being. patient promote to efforts industry and advance bio/pharmaceutical development, manufacturing, to strategies and technologies, approaches, new developed Contract Services andOutsourcing Services Contract Excellence in Pharma: andDistribution Logistics, Chain, Supply Excellence in Pharma: Excellence in Pharma: Packaging Devices Delivery Drug inPharma: Excellence andCompliance Procedures Regulatory Excellence in Pharma: Control andQuality Testing, Analysis, Excellence in Pharma: &Manufacturing Bioprocessing Excellence in Pharma: andEquipment Technology Manufacturing Excellence in Pharma: Excellence in Pharma: Excipients Excellence in Pharma: Formulation Development API inPharma: Excellence world. the around patients to therapies drug effective deliver to services and processes, technologies, innovative developed have who experts of achievements the recognize Awards Pharma CPhI Awards Pharma Innovation Celebrate Awards are offered in the following categories: following the in offered are Awards success the celebrate to opportunity ceremony—an awards The aGala at recognized be will 17 in categories Winners 18 20 bio/pharma that have community global the from companies innovator N Pharma Awards recognize top top recognize Awards Pharma 15th CPhI year, its in ow the Pharmaceutical Technology Europe IT, &Digitilisation mHealth Excellence in Pharma: Patient Centricity Excellence in Pharma: Excellence in Pharma: OTC Year the of Company Pharma Excellence in Pharma: Year the CEOof inPharma: Excellence Social Responsibility Corporate Excellence in Pharma: andCompliance Procedures Regulatory Excellence in Pharma: seats. For more information, visit awards.cphi.com/gala visit information, more For seats. individual and tables for available are gala the for Tickets For information: awards.cphi.com/gala Spain Madrid, Tower Hotel, Madrid Eurostars Ballroom Barcelona Grand 2018 9 October 2018 CPhI Pharma Awards Gala Recognize Excellence in Pharma 2018 CPhI Pharma Awards 2 8 S 008C 1 8

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2018 CPhI Registration and Travel

Madrid, Spain is host to the 2018 CPhI Worldwide event. The following location, transportation, registration, and travel information can assist visitors in planning their time at CPhI.

Exhibition Hours whose exit is at the South Entrance The Exclusive VIP package includes 9 October 2018: 9:30–17:30 of the complex. Line 8 also connects the basic and VIP offerings, plus reserved 10 October 2018: 9:30–17:30 the exhibition complexes terminals seating for Pharma Insight Briefings and 11 October 2018: 9:30–16:00 of Barajas International Airport. Women in Leadership Forum, a dedicated cloakroom, a video interview, and entrace Location By bus to the CPhI Pharma Awards Gala. IFEMA-Feria de Madrid is located at A bus network provides access to Feria de Visit https://www.cphi.com/europe/ Avda. del Partenón, 5, 28042 Madrid, Madrid from different points in the city: visit/packages-and-prices for details. Spain, a 10-minute ride from the • Route 112-Feria de Madrid-Bº Aeropuerto. No one under 18 years of Barajas International Airport and 15 • Route 122-Avda. de América- age will be admitted. kilometers from the city center. Feria de Madrid. The facility is accessible by taxi, • Route 828-Universidad Autónoma- Travel Arrangements automobile, Metro, and bus. Visit Alcobendas-Canillejas-Feria de Madrid. Hotels www.ifema.es for details. b network, the official accommodation agency for CPhI in 2018, has secured By taxi Registration accommodations at different Accessible at each entrance to the Registration provides access to CPhI and price points and can assist with exhibition complex, more than 15,000 taxis co-located exhibitions ICSE, P-MEC, accommodation bookings at more are available to visitors to Feria de Madrid. FDF, InnoPack, and bioLIVE, as than 100 properties in Madrid. well as prearranged meetings with By car exhibitors at exhibitors’ stands or Air Travel Feria de Madrid is linked by road to Madrid’s the Live Pharma Connect Stand. SkyTeam is the Official Alliance Network major access routes and ring roads: the Visitor registration is free of charge when for air travel to CPhI, offers travel savings M11 (Exits 5 and 7), the M40 (Exits 5, 6, and registered online until 9 September 2018. up to 15% and no fees for online bookings. 7) and the A2 (Exit 7). The South, North, and A fee of €50 is charged from East Entrances to the exhibition complex 10–23 September 2018. Visas provide direct access to parking areas. A fee €140 is applicable on or CPhI can provide Visa application after 24 September 2018. assistance to all visitors who require it. By Metro The upgraded VIP package includes See www.cphi.com/europe/registration- Feria de Madrid can be accessed via access to VIP lounges, fast track visa for travel information and details. the Feria de Madrid station on Line 8, entry, and access to Happy Hours. TOP/BOTTOM IMAGES: BRKART/SHUTTERSTOCK.COM IMAGES: TOP/BOTTOM JOYFULL/SHUTTERSTOCK.COM

CPhI 14 Pharmaceutical Technology Europe CPHI WORLDWIDE PLANNING GUIDE 2018 PharmTech.com Quality. Proven

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