DECEMBER 2017 Volume 29 Number 12

Ingredients for Bio/Pharma Career Advancement 2017 Employment Survey

API SYNTHESIS FACILITIES FORMULATION Hazardous Chemistry Sustainable Facilities Softgels Versus Hardgels When it comes to mops, Contec cleans up!

At Contec we have our own cleanrooms which is why we understand the importance of the correct mopping equipment for encouraging compliance and maintaining environmental results. Our continuous innovation has led to the introduction of sealed edge mops with very low particulates, special tools for curtain cleaning, small tools for RABS & isolators and cost effective options for all sizes of facility. For more information or to request a trial please contact Contec at [email protected] or by calling +33 (0) 2 97 43 76 98. December 2017 Pharmaceutical Technology Europe is the authoritative Advancing Development & Manufacturing source of peer-reviewed research and expert analyses for scientists, engineers, and managers engaged in process PharmTech.com development, manufacturing, formulation and drug delivery, API synthesis, analytical technology and testing, packaging, IT, outsourcing, and regulatory compliance Cover: Sergey Nivens/ in the pharmaceutical and biotechnology industries. Shutterstock.com Art direction: Dan Ward

24 3614 38

PharmTech.com

Features Peer-Reviewed COVER STORY 14 What are the Ingredients for 30 Methods for Identifying Out-of-Trend Data in Bio/Pharma Career Advancement? Analysis of Stability Measurements—Part II: Amid business and regulatory uncertainty, bio/pharma By-Time-Point and Multivariate Control Chart experts reveal opinions on salary, recognition, and training. The by-time-point method and the multivariate control chart method are investigated and improved FORMULATION AND MANUFACTURING approaches are suggested. The method is illustrated 19 Opportunities with Softgels using real data sets. Softgel capsules are a popular dosage form among patients but they also provide a number of manufacturing benefits over liquid-filled hardgel capsules. Columns and Regulars 22 Critical Parameters in Transdermal Patch Manufacturing 6 Product Spotlight A QbD approach can address manufacturing complexities. 8 European Regulatory Watch Disputes Over Manufacturing Waiver API SYNTHESIS AND MANUFACTURING and Other SPC Exemptions 24 Hazardous Chemistry: Choosing Batch or Flow For many processes involving hazardous chemistry, 12 Outsourcing Review running in flow mode has safety and economic Outsourcing: A Year in Review advantages. 41 Corporate Profiles LYOPHILIZATION 28 Modernizing Lyophilization 49 Ask the Expert A technology roadmap aims to drive and What’s in Your SOP? consolidate improvements in a process that has remained unchanged for more than 70 years. 50 Ad Index

FACILITY DESIGN AND OPERATIONS 36 Designing Sustainable Pharma Facilities Innovative methods for water and Join PTE’s community energy conservation can reduce carbon footprint. Join the Pharmaceutical Technology Europe group on LinkedIn™* and start discussing the issues that matter to you with your peers. GOOD DISTRIBUTION PRACTICES Go to PharmTech.com/linkedin 38 Reliability Rooms and the Move *The linkedIn logo is a registered trademark of LinkedIn Corporation to Proactive Supply Chain Management and its affi liates in the United States and/or other countries Cross-functional reliability rooms identify risk and planning metrics, provide insights for production forecasts, and predict trends and areas for improvement.

Pharmaceutical Technology Europe DECEMBER 2017 3 EDITORIAL ADVISORY BOARD

PharmTech Europe Contributing Editor Editor Cynthia A. Challener, PhD Reinhard Baumfalk Luigi G. Martini Adeline Siew, PhD Global Correspondent Vice-President, R&D Chair of Pharmaceutical [email protected] Sean Milmo Instrumentation & Control (Europe, [email protected]) Innovation PharmTech Group Sartorius AG King’s College London Editorial Director Art Director Dan Ward Rita Peters Rafael Beerbohm Thomas Menzel [email protected] Publisher Director of Quality Systems Menzel Fluid Solutions AG Michael Tracey Boehringer Ingelheim GmbH Senior Editor [email protected] Jim Miller Agnes Shanley Sales Manager Phil Borman [email protected] President,PharmSource Linda Hewitt Director, Product Managing Editor Tel. +44 (0) 151 353 3520 Information Services [email protected] Quality & Compliance Susan Haigney GlaxoSmithKline Colin Minchom Senior Sales Executive [email protected] Senior Director Stephen Cleland Evonne Brennan Manufacturing Editor Tel. +44 (0) 151 353 3647 Pharmaceutical Sciences Jennifer Markarian European Technical Product [email protected] Shire Pharmaceuticals [email protected] Manager, Pharmaceutical Science Editor Sales Operations Executive Division, IMCD Ireland Clifford S. Mintz Barbara Williams Feliza Mirasol [email protected] Rory Budihandojo President and Founder [email protected] BioInsights Director, Quality and EHS Audit Associate Editor C.A.S.T. Data and List Information Tim Peterson Amber Lowry Michael Kushner Boehringer-Ingelheim [email protected] [email protected] Christopher Burgess Transdermal Product Managing Director Development Leader, Drug Published by VP & Managing Director, Burgess Analytical Consultancy Delivery Systems Division, 3M UBM Pharm/Science Group Hinderton Point Dave Esola Ryan F. Donnelly John Pritchard Lloyd Drive Technical Director Cheshire Oaks VP & Managing Director, CBI/IVT Professor Cheshire CH65 9HQ, United Kingdom Johanna Morse Queens University Belfast Philips Respironics Tel. +44 151 353 3500 VP & Managing Director, Thomas Rades Fax +44 151 353 3601 Veterinary Group Tim Freeman Becky Turner Chapman Managing Director Professor, Research Chair in UBM Americas: Formulation Desgin and Drug De- Chief Executive Offi cer VP, Marketing & Audience Freeman Technology Scott Schulman Development livery, University of Copenhagen Joy Puzzo Filipe Gaspar Chief Operating Offi cer Rodolfo Romañach VP, Media Operations Vice-President, R&D Brian Field Professor of Chemistry Francis Heid Hovione Head of Legal University of Puerto Rico, Michael Bernstein Director, Human Resources Sharon Grimster Jamie Scott Durling Puerto Rico ReNeuron EVP & Senior Managing Director, UBM PLC: Siegfried Schmitt Life Sciences Group Anne Marie Healy Tom Ehardt Chief Executive Offi cer Principal Consultant Tim Cobbold Professor in Pharmaceutics and Senior VP, Finance PAREXEL Group Operations Director Pharmaceutical Technology Tom Mahon Stane Srcic Andrew Crow Trinity College Dublin, Ireland EVP & Managing Director, Professor UBM Medica Chief Financial Offi cer Deirdre Hurley Marina Wyatt University of Ljubljana, Slovenia Georgiann DeCenzo Senior Director, Plant EVP, Strategy & Business Chairman Griet Van Vaerenbergh Dame Helen Alexander Helsinn Birex Development GEA Process Engineering Mike Alic Pharmaceuticals Ltd. Makarand Jawadekar Benoît Verjans Independent Consultant CEO Arlenda Editorial: All submissions will be handled with reasonable care, but the publisher assumes no responsibility for safety of Henrik Johanning artwork, photographs, or manuscripts. Every precaution is taken to ensure accuracy, but the publisher cannot accept Tony Wright responsibility for the accuracy of information supplied herein or for any opinion expressed. CEO, Senior Consultant, Managing Director Subscriptions: Genau & More A/S 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 PharmTech.com, click on Subscribe, & follow Exelsius the prompts. Marina Levina To cancel your subscription or to order back issues, please email your request to magazines@superfi ll.com, putting PTE Product Owner-OSD, TTC- in the subject line. Please quote your subscription number if you have it. Tablets Technology Cell, GMS List Rental: Contact Sarah Darcy; Tel. +44 1244 629 326 Fax +44 1244 659 321 GlaxoSmithKline Reprints: Reprints of all articles in this issue and past issues are available (500 minimum). Contact Brian Kolb at Wright’s Media, 2407 Timberloch Place, The Woodlands, TX 77380. Telephone: 877-652-5295 ext. 121. Email: [email protected].

Copyright 2017. Advanstar Communications (UK) Ltd. All rights reserved. No part of this publication may be reproduced in any material form (including photocopying or storing it in any medium by electronic means and whether or not transiently 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 & Above is a partial list of the Pharmaceutical Technology brand editorial advisory mem- Patents Act (UK) 1988 or under the terms of a licence issued by the Copyright Licensing Agency, 90 Tottenham Court Road, London W1P 0LP, UK. bers. The full board, which includes advisory members of Pharmaceutical Technology North America, can be found online at www.PharmTech.com/pharmtech-editorial- Applications for the copyright owner’s permission to reproduce any part advisory-board. Pharmaceutical Technology publishes contributed technical articles of this publication should be forwarded in writing to Permissions Dept, Honeycomb West, Chester Business Park, Wrexham Road, Chester, CH4 9QH. that undergo a rigorous, double-blind peer-review process involving members of our Warning: The doing of an unauthorized act in relation to a copyright work distinguished Editorial Advisory Board. Manuscripts for editorial consideration should may result in both a civil claim for damages and criminal prosecution. 10% Post Consumer be sent directly to Susan Haigney, managing editor, [email protected]. Waste

4 Pharmaceutical Technology Europe DECEMBER 2017 PharmTech.com Blaze a Trail with Continuous Processing Optimize your oral solid dosage production with state-of-the-art technology from GEA

With 10 years of inspiration, 67 installed lines and the If your process equipment supplier hasn’t won a CPhI Pharma first ever FDA-approved breakthrough therapy developed Award for Equipment Excellence and an ISPE Facility of the and manufactured using the ConsiGma™ platform, no Year Award, you’re not working with GEA. We’ve got a lot to other company has done more to pioneer continuous talk about. Contact gea.com/contact for more information manufacturing for the pharmaceutical industry. and learn about our award-winning solutions. PRODUCT SPOTLIGHT

Telemanipulator for Oven Autosampler for Remote-Handling Systems Automated KF Titration The VERSA Telemanipulator from The InMotion Karl Fischer (KF) Oven Central Research Laboratories Autosampler from Mettler Toledo (CRL), a Destaco company, is is suited for KF titration and comes suited for remote-handling in two models: InMotion Flex and applications that involve spe- InMotion Pro. Features include a cific customization require- vial with a one-piece screw cap ments. The device is available for sample preparation safety, an sealed or unsealed and offers automatic gas flow meter for gas medium-duty (MD) and heavy- flow control, and a temperature scan function that can determine duty (HD) models with lifting a substance’s ideal heating temperature in one run containing up capacities of 20 lbs (9.0 kg) and 50 lbs (22.7 kg), respectively. Device to 120 samples without stopping, according to the company. features include a three-piece design, a manual Command Arm The instrument allows up to 26 samples to be analyzed on a Z Indexing for operator height adjustment, removable/change- 25-centimeter platform. The Pro model offers three platforms able wrist joints, a remote-mounted drive system, an adaptable and vial size, with customizable sizes available. The procedure seal tube for interchangeable use with MD or HD models. calibrates both the oven temperature and the gas flow rate to the Additionally, according to the company, the device titration cell, complying with current Official Medicines Control uses the VR8 Handle System, which provides adjustability Laboratory (OMCL) guidelines (Qualification of Automatic Titrators, and heel to prevent slippage, long handle length, a quick- 2016). Details are documented with certificates, and the company release clamp for efficient and tool-free changeouts, and provides service and support throughout the product’s entire user-friendly tang/hilt, base, and activation buttons. lifecycle. Additionally, both models connect to the latest versions of the company’s Volumetric (V30S) and Coulometric (C30S) KF Central Research Laboratories Titrators, as well as to the modular T7 and T9 Excellence Titrators. www.destaco.com Mettler Toledo www.mt.com Gas Analyzer for TGA/TA Analytics CIP-Ready Ultra- The Hiden ExQ quantitative gas High Shear Mixer analyzer is a mass spectrometer system providing continuous The Ross, Charles & Son Ross on-line analysis of dynamic gas X-Series is a clean-in-place (CIP) streams at pressures from sub- ready ultra-high shear mixer for atmospheric up to 30 bar. The system inline emulsification, particle size has a range of process interface reduction, and homogenization. The options that enable adaptation device features a patented rotor/ of the system for direct connection to the majority of standard stator that runs at speeds more thermogravimetric analysis and thermal analysis instruments. than 11,000 ft/min, and forces The system monitors gaseous species through the mass range product through concentric rows of intermeshing teeth. The to 300 amu. Minor species composition is measurable down to combination of high fluid velocity and close tolerances 100 part-per-billion. External process data, sample temperature, or between interlocking channels in the rotor/stator subjects the sample mass change can be imported for combined integration product to mechanical and hydraulic shear in a single pass. and presentation with the mass spectral data. An optional carbon CIP-ready models are driven by a washdown-duty motor. All monoxide analyzer monitors low levels of carbon monoxide. wetted parts are type 316 stainless steel machined to 32 Ra finish. The inlet system operates at up to 200 °C with response times The mix chamber, rated for 150 psig at 250 °F, includes tri-clamp less than 300 milliseconds. The fully integrated system is config- inlet/outlet connections and can be supplied with a heating/cooling urable both for benchtop and for rack-mounting operation and jacket. It is designed for thorough cleaning and disinfection, with is mountable as standard up to 2m from the sampling point. no dead zones where product can collect. The X-Series is equipped with a heavy-duty bearing assembly that comprises an oil sump Hiden Analytical with cooler and circulation pump for use in continuous operations. www.hidenanalytical.com Ross, Charles & Son www.mixers.com

6 Pharmaceutical Technology Europe DECEMBER 2017 PharmTech.com ELIMINATE PARTICULATES & FIBERS IN THE CORE.

SYNTHETIC WRITING SUBSTRATE CUSTOM DOCUMENTATION HEPA FILTERED PRINTING SYSTEM

§ Low particulate § Logbooks, ID tags, § Print wirelessly into cleanrooms and non-shedding Forms and Labels § Use with pre-sterilized § Exceptionally durable § Constructed using CLEANPRINT 10 § Abrasion and CLEANPRINT 10 § 316L Stainless Steel chemical resistant § Customized specifically Construction, can be § Easy to write on per customer completely disinfected § § § Double bagged Individual unique HEPA Filter cabinet packaged sterile numbering § Sheet fed, high speed and integrity features digital printer using § RFID Technology available chemical resistant ink

15 Lee Boulevard Malvern, PA 19355-1234 USA (610) 644-8335

www.sterile.com EUROPEAN Sean Milmo REGULATORY WATCH is a freelance writer based in Essex, UK, [email protected].

Disputes Over Manufacturing Waiver and Other SPC Exemptions

The European Commission’s effort to relax supplementary protection certificates to help generic-drug makers and biosimilars producers has sparked strong opposition from the research-based pharmaceutical sector.

he European Commission, the Brussels-based European intellectual property rights. Rather than strengthening the TUnion executive, mentioned in a strategy document (1) in European pharmaceutical sector, it would undermine its R&D 2015 possible changes in the system under which research- capabilities. “[We] believe that the introduction of an SPC based pharmaceutical companies have been able to extend manufacturing exemption would be detrimental to medical their patents on their new medicines through the granting innovation and Europe’s knowledge-based economy,” a of five-year supplementary protection certificates (SPCs). spokesman for the European Federation of Pharmaceutical Among the alterations to the SPC rules suggested by the Industries and Associations (EFPIA), representing the research- commission was one that would provide a waiver for generic based sector, told Pharmaceutical Technology Europe. and other drug producers to allow them to make, but not SPCs were first introduced in Europe in the early 1990s as market, medicines covered by the extended patents. The a means of compensating drug originators for the lengthy commission, however, in October 2017, put forward for public testing and clinical trials that their products needed to gain consultation a list of proposed SPC improvements, including marketing authorizations. Because of stricter regulatory a manufacturing waiver. After the consultation ends early requirements, the 20-year protection period for drugs was

REGULATION & COMPLIANCE REGULATION next year, the commission has indicated that it would then effectively being reduced to 10 years or less. By 2015, the start work on drawing up firm proposals to include possible number of SPCs issued in Europe had reached 20,000, a figure amendments to existing EU legislation. that the European Commission said showed how important “The commission has been a little bit slow in doing they were to medicine developers. something about this issue, but now the process for making Generic-drug and biosimilar producers and small medium- changes has started,” says Adrian van den Hoven, director sized enterprise (SME) innovators, particularly small biotech general of Medicines for Europe, a lobby group representing companies, have long complained that the rules on SPCs have generic drug and biosimilar medicine manufacturers. “We are restricted the quantities of SPC drugs they can manufacture hoping that if everything goes smoothly, the changes will come during the five-year protection period. Bolar exemptions first into force in one and half to two years, with the manufacturing introduced in the EU legislation (3) in 2001 allow manufacturing waiver being the priority for us.” The organization wants of SPC-covered drugs for research or testing purposes to new rules that will enable large quantities of a drug to be provide data for marketing and other regulatory approvals. But manufactured during its SPC protection period to take like SPCs themselves, the Bolar exemptions are granted on advantage of the expiry or non-existence of the protection a national basis by the 28 EU member states, which has led certificates in non-EU markets. The waiver should also be to variations in their scope. Some only apply to development applicable in the EU itself so that generic-drug or biosimilar work for national or EU marketing authorizations and others for producers can launch their products immediately in European approvals outside Europe and anywhere in the world. markets as soon as the certificates expire. The generic-drug and biosimilar producers in Europe are “There is a relatively large number of blockbuster drugs, focusing on achieving legislative changes that will enable them many of them biopharmaceuticals, whose SPCs are expiring to manufacture sufficient quantities of a drug during the SPC in Europe over the next few years,” van der Hoven told period to supply markets that do not have SPC regulations or Pharmaceutical Technology Europe. “That is an opportunity we where the certificate on a medicine has expired. Their major want to take full advantage of.” Furthermore, manufacturing target is the right to stockpile a medicine so that they can waivers would help to make the European generic drugs and immediately launch it on the EU market as soon as its SPC biosimilars sector more competitive internationally, attract expires. The commission’s eventual proposals for alterations investment in EU drug manufacturing capacity, and help create to the SPC system in the EU may fall short of what the generic- thousands of new jobs in the industry, according to Medicines drugs and biosimilars sector wants. for Europe (2). Impact of the SPC manufacturing Opposition from drug innovators waiver and a broadened Bolar exemption Manufacturing waivers for bulk production of medicines The proposals (4) listed by the commission for the public during the SPC period is, however, being opposed by many consultation include, among three options, one of no change.

drug innovators on the grounds that it is weakening their The other two are the use of non-legislative instruments IMAGES RF/GETTY ZOONAR GLOBE:

8 Pharmaceutical Technology Europe DECEMBER 2017 PharmTech.com EUROPEAN REGULATORY WATCH to improve the implementation of existing rules and the Also, the opportunities for exporting European generic drugs introduction of amendments to existing EU legislation to to non-European markets prior to an SPC expiry had been allow manufacturing waivers for stockpiling purposes. At the exaggerated. Often, SPC extensions in Europe during which same time, as it launched the consultation, the commission generic-drug companies could be entitled to a manufacturing published a study (5) by the UK-based consultancy Charles waiver, expire earlier or only a little later than the intellectual REGULATION COMPLIANCE & River Associates (CRA) on the economic impact of the SPC property rights for medicines in other non-EU markets, manufacturing waiver and a broadening of the Bolar research according to EFPIA. exemptions. The study, which was funded by the commission, In a report (6) on the impact of the introduction of SPC was completed in 2016. exemptions on the biopharmaceuticals sector, Pugatch The CRA report (5) concludes that the manufacturing waiver Consilium, a consultancy in Bicester, England, points out would pose minor threats to the innovative sector while boosting that many non-EU generic-drug and biosimilar markets have sales, investment, and jobs in the generic-drugs and biosimilars erected trade barriers to restrict imports from areas such segment. Among the main benefits would be more investment as Europe. “Why would India and Brazil or other emerging in pharmaceutical R&D and in manufacturing, €9.5 billion (US$11 markets favour European generic [-drug] manufacturers billion) additional net sales for the EU pharmaceutical industry, as opposed to their own domestic ones?” asked David and the creation of 25,000 direct jobs and 100,000 indirect ones. Torstensson, partner at Pugatch and author of the report (6). “In many cases, they already have a policy framework in place that actively discriminates against foreign competitors,” By 2015, the number of he continued. “Such localization policies often include price preferences in government tenders; import bans and SPCs issued in Europe had increased taxation on foreign products; and local affiliation and/or production requirements. As a result, locally-produced reached 20,000. generic drugs can take as much as 90% of the local generic- drug market in many emerging markets.” For the EU generic-drug makers and biosimilar producers, EFPIA has urged that in areas where improvements to the biggest gain would be from an exemption on their the SPC system are considered to be necessary, a non- manufacturing SPC drugs for export to third, mainly non- legislative approach should be taken. Without legislation, European, countries where SPC protection had expired or there would be no manufacturing waiver, which would be a does not exist. Export generic-drug sales would go up by an major disappointment to the generic-drugs and biosimilars additional €7.6 billion while sales of branded medicines are sector. It will also reinforce the view within the European expected to fall by only up to €278 million. The net sales rise pharmaceuticals sector that it needs to act together on key would be equivalent to an increase in EU pharmaceutical issues like patents and patent exemptions. exports of up to 18%, according to CRA. Biosimilar export sales “The manufacturing waiver is something which helps the would increase by nearly €3 billion. European pharmaceutical industry as a whole,” says van den A significant bonus from the broadening of the Bolar Hoven. “The research-based sector knows it is a good step exemption would be the likely benefit to EU-based suppliers for the generic drugs and biosimilars sector. If there was of APIs at a time when the vast majority of APIs in the something being considered which was good for them, we European market are being imported from Asia. The CRA study would not try to block it.” At the moment, a united front within estimated that sales by third-party European generic-API the industry on matters such as the manufacturing waiver and producers could increase by up to 29%, equivalent to an even other SPC exemptions seems a long way away. additional €180 million in annual sales by 2030. References Disputes from EFPIA and other consultancies 1. European Commission, Upgrading the Single Market: More The combined effects of the SPC export waiver and the Opportunities for People and Business, COM (2015) 550 final extension of the Bolar exemption could result in additional (Brussels, 28 Oct. 2015). EU API sales of €254 million by the end of the next decade. 2. Medicines for Europe, SPC Manufacturing Waiver Note However, the figures and conclusions of the CRA report are (Brussels, October 2017). being disputed by other consultancies as well as originator 3. European Union Directive, Community Code Relating to Medicinal Products for Human Use, 2001/83/EC (Brussels, 28 representatives such as EFPIA. Nov. 2001). “The potential negative impact of the adoption of an SPC 4. European Commission, Public Consultation on Supplementary manufacturing waiver on the R&D-based pharmaceutical Protection Certificates (SPCs) and Patent Research Exemptions industry has been underestimated,” says the EFPIA (Brussels, October 2017). spokesman. “Recent studies find that the adoption of such 5. Charles River Associates (CRA), “Assessing the Economic a measure would lead to the loss of between 4500–7700 Impacts of Changing Exemption Provisions During Patent direct jobs in the [research-based] industry with an additional and SPC Protection in Europe” (February 2016). 19,000–32,000 indirect job losses. It would also result into a 6. Pugatch Consilium, “To SPC or not to SPC…” (Bicester, decrease of between €215–€364 million in R&D investment.” England, October 2017). PTE

Pharmaceutical Technology Europe DECEMBER 2017 9 The People and Science Behind Patheon OneSource™ for Small & Emerging Pharma

LECUL MO E scientists ready 2400+ for your challenge The Drug Substance Molecule Team collaborates with the Drug Product Team to ensure that your molecule becomes a formulation-ready API. The integrated Molecule Team is a key driver of the Patheon OneSource™ time savings. Andreas Stolle, Ph.D., joined us in 2015 Vice President, API Process Development Services SUBSTA UG NC T R E development EAMS D 560+ programs in 2016 Whether you are working with a large molecule or a small molecule, your Drug Substance Project Manager proactively works to ensure your molecule has its best shot at success by maintaining timelines and minimizing potential rework during development. Angela Colarusso, joined us in 2007 Sr. Director, Biologics Program and Proposals Management P R R O E JE AG CT AN M ™ e rc Pr ou og S ra ne m O M RC n a OU ING o n S e a Smart sourcing th g e Procurement experts assist a P r with sourcing generic API and raw materials to ensure availability and reliable supply. T EAM

ISTR IN AT I M O D N

A

Simplified administration If it works better for your business, we can establish one Master Service Agreement, one Drug Substance/Drug Product Contract and one Quality Agreement. This also means one taxation and regulatory structure, one currency and one invoicing process.

© 2017 Patheon Inc. All rights reserved. Faster Drug Development

NDA approvals ICAL TR 112 in 10 years IN IA We develop 75% L L More than 2x any other CDMO of all dosage forms C For both large and small molecules, the For large and small molecules, close collaboration Patheon OneSource™ methodology with the Drug Substance Molecule Team allows M minimizes failures due to foreseeable events the application of right-fit science for formulation, A G N I N and maximizes your molecule’s chances of U R process development, tech transfer and scale-up FACT U out-licensing or making it to market. to ensure a smoother transition to market. Anil Kane, Ph.D., MBA, joined us in 2000 Executive Director, Global Head of Technical & Scientific Affairs G PRODU RU CT D

Stability and scalability By collaborating with the Drug Substance Project Manager, the Drug Product Project Manager ensures your trial-level drug product is also suitable for scale-up. Nicky Arvanitis, MBA, joined us in 1997 Director, PDS Project Management

P R R O E JE AG CT MAN L PAC A KA IC G N I I N Securely packaged for on-time distribution

L G

C Combining best-in-class robust primary and secondary clinical packaging and secure on-time distribution to meet A N N quality standards and patient compliance. D IO D T IST RIBU

ACK-UP B We always have a back-up plan To ensure your molecule never goes Save an average of P off track, every team includes a

R R

O E Back-up Program Manager ready to G G R A step in any time life gets in the way. N 14 Weeks AM A M & $44.7M1 Something needs to be done about the high cost of drug development. By combining drug substance, drug product, clinical manufacturing and clinical packaging into a single process, Patheon OneSource™ accelerates your Speed through communication molecule like nobody else can. The Program Manager is the architect of your drug development program. This single point of contact both within Patheon, and with you, simplifies every interaction and manages your molecule’s critical path to ™ deliver unmatched time and cost savings. OneSource

Aaron Williams, PMP, joined us in 2011 Program Manager, www.patheon.com/onesource Patheon OneSource™ 1. Assessing the Financial Benefits of Faster Development Times: The Case of Single-Source vs. Multi-Vendor Outsourced Manufacturing, Tufts Center for the Study of Drug Development, 2017 OUTSOURCING REVIEW Outsourcing: A Year in Review

In a productive year, 2017 was filled with acquisitions, facility expansions, and new biopharma technology.

Susan Haigney utsourcing in the bio/pharmaceutical industry packaging services provider, in October. Millmount Ohad a productive 2017. A flurry of acquisitions, provides services in blister packaging, bottling, and tub an expansion of biotechnology needs, and a growth filling, as well as in late-stage customization and cold in new facilities and services offered were seen. The chain packaging services. The acquisition supports following are some of the highlights. PCI’s efforts to expand its clinical trial service offerings. The addition of Millmount, based near Dublin, Ireland, Mergers and acquisitions will be PCI’s fourth acquisition outside of the United Acquisitions were robust in 2017, with more than States in four years (5). 25 companies making moves to gain new facilities and services. The following are some of the notable Partnerships mergers and acquisitions of 2017. Sanofi and Lonza announced on 27 Feb. 2017 that they Recipharm completed the acquisition of Kemwell’s have entered into a strategic partnership to build and pharmaceutical businesses located in Bengaluru, operate a large-scale mammalian cell culture facility for India in February 2017. As part of the transaction, monoclonal antibody production in Visp, Switzerland. Recipharm also has a right of first negotiation to The strategic partnership enables Sanofi to react acquire Kemwell’s Indian biopharma business, which quickly to fluctuations in demand in a short timeframe, was not included in the transaction and will continue reinforcing their capability to launch biologic medicines to be retained by the sellers. and ensure consistent access for patients. It also The acquired business, Recipharm Pharmaservices provides Lonza with needed capacities to respond Private Ltd, offers development services and commercial to growing manufacturing demands for large-scale manufacturing of solid, semi-solid, liquid, and topical mammalian cell culture-based therapeutic proteins (6). products. The development business provides Vetter and medical-device company Microdermics formulation development, small-scale manufacturing for entered into a strategic cooperation agreement to clinical trials, and analytical services (1). develop innovative microneedle drug-delivery systems In April 2017, Sartorius Stedim Biotech (SSB) in May 2017. The companies have joined forces to acquired Umetrics, a specialized provider of data enable the progress of the microneedle technology analytics software for development and manufacturing to late-stage process development and device processes headquartered in Malmö, Sweden. SSB has manufacture on a commercial scale. Vetter’s primary been a cooperation partner of Umetrics since the end role will be in the fill/finish aspect, but the it will also of 2012, distributing and co-marketing their software jointly conduct proof-of-concept studies on selected to players in the biopharmaceutical industry. Umetrics’ drugs and drug classes. Vetter will jointly design software has applications in critical process steps of devices for testing, including how to integrate the biopharmaceutical manufacture and development, microneedle technology into injection devices (7). including cell culture processes and specific In June 2017, Rentschler Biotechnologie GmbH and purification steps (2). Rentschler Fill Solutions GmbH announced a strategic Lonza announced in August 2017 that it acquired partnership to provide new fill/finish facilities and Micro-Macinazione (Switzerland), a contract solutions for biopharmaceutical products. Under the manufacturer providing micronization of active terms of the agreement, Rentschler Fill Solutions will ingredients for the pharmaceutical and fine chemical serve as the exclusive partner for the fill/finish services industries, from Cross Equity, a Swiss private equity of Rentschler Biotechnologie’s manufacturing projects. firm. The acquisition boosts Lonza’s micronization Rentschler Fill Solutions is owned by the Rentschler services at its existing micronization clinical and family and will begin operations in mid-2018. In addition commercial manufacturing site in Quakertown, PA, to servicing Rentschler Biotechnologie’s clients, which Lonza gained through its previous US$5.5-billion Rentschler Fill Solutions will offer its fill/finish services acquisition of Capsugel (US) in early July 2017 (3). on a clinical as well as commercial scale to its own In September 2017, Roquette completed its client base. The company will employ advanced aseptic acquisition of Itacel, an excipient division of Blanver, filling technology at the Rentschler Fill Solutions facility a Brazilian multinational company specializing in the in Austria (8). development, manufacture, and commercialization Recipharm announced on 20 Sep. 2017 a long-term of raw materials and drugs. The acquisition is part of manufacturing pact with Roche. The pact will add a series of investments made by Roquette to position €35 million to Recipharm’s annual sales, matching itself globally, according to the company (4). more than 6% of the company’s current sales. Under PCI Pharma Services (PCI) acquired Millmount the agreement, Recipharm will acquire a manufacturing Healthcare, a pharmaceutical and healthcare contract facility located in Leganés, Spain, from Roche. The (Spotlight image) Stockbyte/GettyImages image) (Spotlight

12 Pharmaceutical Technology Europe DECEMBER 2017 PharmTech.com Outsourcing Review

pact will also extend a collaborative 10-L to 400-L vessels to support both Macinazione to Create the Global opportunity to Recipharm’s nearby clinical and commercial manufacturing Leader in Micronization Capacity and facility in Parets, Spain (9). of antibody-drug conjugates. The Capabilities,” Press Release, 4 Aug. 2017. In September 2017, Recipharm also stand-alone facility is purpose-built 4. Roquette, “Roquette Completes the signed a contract with Kancera for and offers R&D services, quality Acquisition of Itacel and Reinforces the development and manufacture of control, and scale-up laboratories (14). its Ambition of Being a Leader in drug candidate KAND567 as a capsule Eurofins Scientific announced on Pharmaceutical Excipients,” Press formulation for oral administration. 20 Mar. 2017 that it will be establishing Release, 1 Sept. 2017. Recipharm will develop the preparation a pharmaceutical chemistry and 5. PCI Pharma Services, “Acquisition of required for effective release of microbiology facility in Livingston, Millmount Heathcare,” Press Release, 2 KAND567 from the capsules, as well Scotland. The announcement Oct. 2017. as manufacturing the pharmaceutical follows Eurofins’ acquisition of 6. Lonza, “Sanofi and Lonza Enter into product. The work will be performed Exova’s pharmaceutical, food, and a Strategic Partnership to Establish at Recipharm’s development facility in water testing business in the United a Large-Scale Biologics Production Solna, Sweden (10). Kingdom and Ireland in July 2016, Facility,” Press Release, 27 Feb. 2017. SGS announced on 12 Oct. 2017 and the subsequent purchase of ILS’s 7. Vetter, “Vetter and Microdermics Enter that it has entered into a collaboration pharmaceutical business in October into a Strategic Cooperation Agreement,” with biotech company Bavarian Nordic 2016 (15). Press Rlease, 31 May 2017. A/S to develop a new respiratory FUJIFILM Diosynth Biotechnologies 8. Rentschler Biotechnolgie, “Rentschler syncytial virus (RSV) challenge strain. announced in September 2017 Biotechnolgie and Rentschler Fill The collaboration will assist with the the opening of its new 10,000-ft2 Solutions Announce Strategic advancement of a universal vaccine cell culture Process Development Partnership for One-Stop Solutions with candidate designed to induce protective Laboratories in Wilton Centre, New State-of-the-Art Fill and Finish immune responses against both Teesside in the United Kingdom. The Facilities,” Press Release, 13 June 2017. subtypes (A and B) of RSV. The project laboratories were built through a 9. Recipharm, “Recipharm Signs Long-Term will build upon the results of Phase II JPY 1-billion (US$9-million) investment, Manufacturing Agreement with Major trials conducted by Bavarian Nordic, part of a greater JPY 14-billion New Customer and Acquires Facility in and will include a human challenge (US$130-million) expansion. The new Spain,” Press Release, 20 Sept. 2017. study, which will be carried out at laboratories will be dedicated to 10. Recipharm, “Recipharm and Kancera the SGS Clinical Pharmacology Unit in supporting activities in the Saturn mAb Collaborate to Manufacture Clinical Trial Antwerp, Belgium, using the new RSV Platform (16). Supply,” Press Release, 14 Sept. 2017. challenge strain, once it has been fully Sartorius announced on 13 Sept. 11. SGS, “SGS and Bavarian Nordic to developed and validated (11). 2017 the official opening of its Develop a Novel and Differentiated new facility for the manufacture of Challenge Model for RSV,” Press Release, New facilities laboratory instruments in the Sartorius 12 Oct. 2017. MilliporeSigma announced in January Campus in the industrial zone of Grone 12. MilliporeSigma, “MilliporeSigma Opens 2017 the opening of a facility in in Goettingen, Germany. Approximately Production Facility Exclusively for Mollet des Vallès, Spain dedicated €42 million has been invested into Meglumine in Spain,” Press Release, 17 to the manufacture of meglumine, the 25,000-m2 building, representing Jan 2017. a US Food and Drug Administration the largest single investment of the 13. Almac, “Almac Group Announces Further (FDA)-approved excipient for Sartorius Campus (17). Global Expansion as it Secures New pharmaceuticals and a component Sartorius Stedim Cellca is building Premises in Republic of Ireland,” Press of medical imaging contrast media. a new €30-million Cell Culture Release, 26 Jan. 2017. The FDA-validated facility in Spain is Technology Centre at Science Park III in 14. Novasep, “Novasep Opens €11M solely dedicated to the production of Eselsberg, situated at the northwestern New Antibody-Drug Conjugate (ADC) meglumine, an amino sugar derived scientific hub in Ulm, Germany, the Bioconjucation Unit,” Press Release, 23 from glucose (12). company announced on 28 Sep. Feb 2017. On 26 Jan. 2017, Almac Group 2017. The new laboratory and office 15. Eurofins Scientific, “Eurofins to Invest announced that as part of its ongoing complex will approximately double the Millions in New UK Facility,” Press global expansion, the company has company’s space and is scheduled to Release, 20 March 2017. secured a new facility in Dundalk, be completed by the end of 2019 (18). 16. FUJIFILM Diosynth, “FUJIFILM Diosynth County Louth, Ireland. The new facility Biotechnologies Opens Dedicated will be located at IDA Business Park. The References State-of-the-Art Cell Culture Process new facility will increase the group’s 1. Recipharm, “Recipharm Completes Development Laboratories in Wilton European footprint by 32,000 ft2 (13). Strategic Acquisition in India,” Press Centre,” Press Release, 12 Sept. 2017. In February 2017, Novasep Release, 20 Feb. 2017 . 17. “Sartorius Opens New Manufacturing announced the opening of its new 2. Sartorius Stedim Biotech, “Sartorius Facility for Lab Instruments,” PharmTech. €11-million bioconjugation unit in the Stedim Biotech (SSB) Acquires Leading com, 13 Sept. 2017. company’s Le Mans site in France. The Biopharma Software Developer 18. Sartorius, “Ground-breaking Ceremony 2000-m2 facility includes two flexible Umetrics,” Press Release, 3 April 2017. for Sartorius Stedim Cellca,” Press GMP production suites equipped with 3. Lonza, “Lonza Acquires Micro- Release, 28 Sept. 2017. PTE

Pharmaceutical Technology Europe DECEMBER 2017 13 Advancement? Career Bio/Pharma Ingredients for What are the salary, recognition, and training. and recognition, salary, on opinions reveal experts bio/pharma uncertainty, regulatory and business Amid 14 Rita Peters Pharmaceutical Technology Europe to 2016. Respondents felt “more secure” in their their in secure” “more felt 2016.to Respondents 2017 in compared increased business that reported differences. significant some were there world, the around and States United the in counterparts their with agreed generally Europe in based respondents While priority. a top and indicated were career that opportunities better workloads, and compensation about reservations the current employment environment, expressed about opinions (1) shared survey employment Pharmaceutical Technology Europe’s employer priorities and employee career paths. between conflicts be may result final the and however, Brexit, to related uncertainties regulatory and business and costs, reduce to pressure payers, and shareholders from pressures financial in Mix industry. bio/pharmaceutical the in careers advance or start to seeking employees bio/pharma for picture employment apositive and employers retire. employees experienced as expertise and know-how in gaps faces also industry The workers. bio/pharma of sets skill required the increase will for manufacturing pharmaceutical technology Advanced methods. formulation sophisticated environment. regulatory and business uncertain current the in especially daunting, be can success for recipe the Synthesizing engineers. and scientists pharmaceutical experienced talented, A More than 45% of the Europe-based respondents respondents Europe-based the of 45% than More Respondents to Respondents bio/pharma for achallenge suggest factors These More complex molecules demand more and manufacturing operation is crafted by crafted is operation manufacturing and development drug effective n efficient, DECEMBER 2017 Pharmaceutical Technology/

PharmTech.com annual responses, more than 47% of the Europe-based Europe-based 47% the of than more responses, global the to Similar control/assurance. quality to manufacturing, R&D, to from responsibilities, (14.2%). groups government companies (40.2%), and non-profit/academic/ traded (40.4%), publicly companies held privately for medicines regenerative or therapy cell and vaccines, drugs, large-molecule and small- both manufacture (6.4%). firms (15.8%), consulting and organizations manufacturing and research contract (11.6%), companies manufacturing generic-drug innovator bio/pharmaceutical companies (33.8%), at (87.3% respondents) of employees permanent full-time, were primarily 2017.October Respondents and September in fielded was which survey, the to Europe—responded from 20% globe—nearly the around from professionals bio/pharma 480 than More respondent profile Survey compete for qualified candidates. qualified for compete applicants for open positions and employers must qualified few are there said 30% remaining The jobs. open than candidates qualified more are there competitive; was jobs for market the said audience) global for (25% audience 21.6% Europe-based the of Alternately, audience. global the for 44.3% with compared competitive, moderately was market job the said respondents Europe-based the of one-half secure in 2017 (26.6%) compared with 25.8% in 2016. in 25.8% with 2017 in (26.6%) compared secure less felt they said respondents however, more 2017 in 18.6% (21.9%) 2016 in (2); versus positions Respondents reported a range of job job of arange reported Respondents or develop companies represented The Opinions about the job market varied. Nearly Nearly varied. market job the about Opinions

Sergey Nivens/Shutterstock.com; Dan Ward Your Premier CMO for Specialized Sterile Injectables

Whether you face formulation challenges, clinical supply hurdles, surges PUKLTHUKK\L[VTHYRL[Å\J[\H[PVUZYPZRTP[PNH[PVUJVUJLYUZVYWH[LU[ L_WPY`JOHSSLUNLZ^LVќLY[HPSVYLK]LYZH[PSLZVS\[PVUZ¶HUKV]LY `LHYZ VMWHYLU[LYHSL_WLYPLUJL¶[VOLSW`V\HJOPL]L`V\YJVTTLYJPHSPaH[PVU VIQLJ[P]LZ

Learn more about us at baxterbiopharmasolutions.com

Baxter is a registered trademark of Baxter International Inc. 920810-02 2018 Graphics: Dan Ward 58.7% 16 2017 Employment Survey 2017 Employment Please rate your satisfaction with your current salary. yourcurrent with yoursatisfaction Please rate 60% I ampaid below market value, considering nraeDces No Change Decrease Increase Pharmaceutical Technology Europe my level of expertise and responsibility. 48.7% my job function, but at the low end of the range, considering my level Does your current salary Does yourcurrent I ampaid excessively for my level I ampaid within market value for 2.7% of expertise and responsibility. of expertise and responsibility. I ampaid fairly for my level of reflect achangeover reflect expertise and responsibility. 6.3% last year’slast salary? 38.7% ■ ■ DECEMBER 2017

2016 2017 45.0%

PharmTech.com 60% 1.8% 16.2% 14.7% 42.7% 46.9% 40.0% 2.7% 35.1% 21.9% ■ ■ oescr o esscr o No Change secure now Less More secure now

2016 2017 with last year? in yourjobcompared How securedoyoufeel 18.6% € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € 26.6% ■ ■

2016 2017 25.8% € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € 51.6% € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € € 50% 55.7% 2017 Employment Survey Bio/pharma workers contemplate ● Strongly Agree ● Somewhat Disagree job and career changes. ● Somewhat Agree ● Strongly Disagree

I would like to leave my job, I do not expect to leave my I would like to change careers and given the opportunity. job in the coming year. leave the bio/pharma industry.

In your career, how If it were necessary for you to change jobs this long, on average, year, how would you assess the job market? have you stayed with WORLDWIDE EUROPE It would be straightforward to find a job the same employer? comparable to the one I have now. 25.8% 26.9% It would take a while, but I would be able to find a job comparable to the one I have now. 44.4% 47.8% It would be straightforward to find a job, but it probably wouldn’t be as good as the one I have now. 14.8% 13.4% I would have to search hard and be prepared to take what I could get. 15.1% 11.9%

● Less than 2 years ● 6 to 10 years ● More than 20 years ● 3 to 5 years ● 11 to 20 years

My company provides adequate My company provides advanced training training for basic jobs skills. for employee professional growth. ● Strongly Agree ● Strongly Agree ● Agree ● Agree ● Disagree ● Disagree

Due to rounding, some percentages may not add up to 100%. Some questions allowed multiple answers.

Results based on 2017 Pharmaceutical Technology Europe employment survey.

Pharmaceutical Technology Europe DECEMBER 2017 17 2017 Employment Survey

responses work for companies with compensation. Similar to the global a small fraction cited factors that more than 5000 employees; 32% audience responses, 40% of the would cause them to quit their jobs; work for companies with fewer than respondents said they were paid at issues with management (19.4%), 500 employees. the low end of the salary range for work/life balance (14.9%), a long Compared with previous years, the their job function for their expertise commute (12.1%), and discrimination Europe-based respondents reported and responsibility; 14.7% said they (11.9%) were most frequently cited. more experience working in the bio/ were paid below market value. pharma industry; 26.8% had fewer Seeking better than 10 years of experience, 30.8% In for the long term? employment opportunities had 10–20 years, 35.9% had 20–35 While three-quarters of the More than half of the 2017 years of experience, and 6.4% have respondents have more than respondents (54.9%) “agreed worked in the industry for more 10 years of experience in bio/ somewhat” or “agreed strongly” that than 35 years. About half of the pharma, 35% stayed with the same they would “like to leave their job, respondents worked outside the bio/ employer—on average—for less given the opportunity,” up slightly pharma industry for up to five years. than five years compared with 24.9% from 2016. More than one-third for the global audience. More than said they were “likely to leave my More work, less play … one-third of the 2017 respondents job voluntarily in the coming year;” Workloads increased slightly in 2017, said they stayed with an employer only 9.9% expected to leave their with 64.2% reporting increases for an average of 6–10 years; 31.2% job involuntarily. In a somewhat compared with 56.6% in 2016. stayed with the same employer for concerning result, nearly 20% said Almost one-third of the respondents more than 10 years. they would like to change careers (32.9%) say they worked more hours In addition to salary and and leave the bio/pharma industry. in 2017 than two years ago, similar benefits, employee recognition While the desire to change to responses in previous years. While can play a role in job satisfaction. positions is strong, the number of 47.3% of Europe-based respondents Similar to the global audience people actually changing jobs is (56.3% for US respondents) said responses, most Europe-based significantly less, but growing. In they were contracted to work respondents said their work is 2016, 17.1% of respondents reported approximately 40 hours per week, fully valued by their employer a voluntary job change; in 2017, that only 25.7% (21.6% for US) reported (25.4% strongly agreed; 54.9% number jumped to 28.2%. working 40 hours. More than 17% agreed). More than 80% of Confidence levels of those (31.4% for US respondents) said they respondents said their skills and seeking new bio/pharma positions were contracted for more than 40 training are used to the fullest continued to rise in 2017; 26.9% hours per week; however, 52.7% of level. Only 52% see opportunity said it would be straightforward to the respondents (more than 70% for for career advancement in their find a comparable new job; 47.8% US) said they work 40 or more hours current position; 62% reported said it may take a while, but they per week. opportunities for professional would be able to find a comparable Vacation and paid time off benefits advancement at their current position. The percentage of less- were more generous in Europe; 87% companies, slightly lower rates optimistic job seekers declined of the European-based respondents than reported by the US audience. slightly, 13.4% said it would be reported four or more weeks of paid straightforward to find a job, but vacation, compared with 43.3% for Career intangibles the new job probably would not be US respondents. Of all respondents, Compared with responses from as good as the current position; 27.3% reported that they used their the global audience, Europe-based 11.9% anticipated a difficult full allotment of vacation, personal, respondents express strong opinions search and they would have taken and sick time. A similar percentage about single factors that would whatever position was available. (22.5%) said they used less than half motivate them to change jobs; of the available time off. European- professional advancement (38.8%), The global picture based respondents (70%) were more work/life balance (37.3%), and To view additional study results and a likely to use at least three-quarters intellectual challenge (31.3%) were report on global employment trends, of their paid time off compared to the top factors. visit www.PharmTech.com. US-based respondents (57.4%). Similarly, the respondents from Europe were more likely to define References But more pay single factors as “the main reason 1. 2017 Pharmaceutical Technology/ Salaries were up globally; in Europe, I come to work;” intellectual Pharmaceutical Technology Europe 58.7% reported a salary increase stimulation (40.3%), challenging Employment Survey, Pharmaceutical in 2017, up from 48.7% in 2016. projects (35.8%), and relationships Technology, 2017. Satisfaction with salary levels with colleagues (30%) were the top 2. 2016 Pharmaceutical Technology/ improved compared to the past reasons cited. Pharmaceutical Technology Europe two years; however, more than half Overall, respondents were tolerant Employment Survey, Pharmaceutical (54.7%) were dissatisfied with their of negative workplace activity; only Technology, 2016. PTE

18 Pharmaceutical Technology Europe DECEMBER 2017 PharmTech.com being approved to date are lipid- based formulations. “Softgels based on lipid formulations make use of the body’s digestive pathways. This approach is, therefore, a well- Opportunities established route for improving bioavailability, but it is sometimes overlooked or considered as a with Softgels key risk in development, mainly because of time and cost pressures Softgel capsules are a popular dosage form in early development, as companies among patients but they also provide a number of don’t want to overspend in early manufacturing benefits over liquid-filled hardgel capsules. development, when the probability of success is still low. The experienced formulators and senior management responsible for these compounds are aware of these risks and options to reduce them. However, because not all companies have the internal experience or know-how on softgel technologies, you still see programmes with suboptimal formulations, which could have been mitigated by considering softgel formulations early in development.” Adeline Siew, PhD he pharmaceutical industry is mainly dominated by tablet Tformulations, but softgels are gaining widespread acceptance “Softgels based on lipid as a preferred dosage form. “Softgel capsules are a popular formulations make use dosage form in the consumer healthcare market because of their of the body’s digestive unique benefits, such as ease of swallowing and quicker onset pathways.” of action in relation to tablet formulations,” says Kaspar van —van den Dries, Patheon den Dries, senior director of formulation sciences, solid dosage forms, and softgels at Patheon, part of Thermo Fisher. “These are important considerations for patients when they are choosing There are also other areas where treatment of pain or allergies.” He also notes that a softgel softgel formulations are being formulation can be used for lifecycle management approaches to considered, observes van den Dries. prescription, generic, and over-the-counter (OTC) drugs, for cases “For example, softgels can provide in which softgel technologies can be used to generate improved reduced exposure for highly potent versions of existing drugs. compounds (because no powders “In the consumer healthcare market, there are plenty of are involved in the manufacturing examples of softgel success stories. Compounds such as ibuprofen, process) and improved uniformity naproxen, and diclofenac, when formulated into softgels, have for low-dose APIs compared to improved performance, which is an important consideration for the tablets,” he says. patients,” van den Dries highlights. “Another example is chewable ibuprofen, a softgel formulation specifically designed for patients Softgel versus having difficulty swallowing. This product was launched through a liquid-filled hardgel lifecycle management approach to existing children’s suspension capsules products and has been well-received in the European market.” In terms of the manufacturing According to van den Dries, it is increasingly difficult and process, softgels provide a number complex to develop new compounds, especially with the majority of benefits over liquid-filled hardgel of lead compounds in the drug development pipeline presenting capsules. “Liquid-filled hardgel with solubility and bioavailability challenges. “In this case, a lipid- capsules are produced through a based formulation in a softgel capsule can provide significant two-step process. The first step advances by improving the bioavailability of these compounds is to fill a two-piece hardgel cap and increasing the chance to obtain proof of concept for these with liquid, and the second step is molecules,” he explains. the subsequent banding of these “Softgel is still the most popular enabling formulation for capsules. Small-scale batches bioavailability enhancement, compared to other solubilization are produced using a different approaches such as spray drying, hot melt extrusion, or particle type of equipment from that

size reduction,” van den Dries says, highlighting that most products used to make commercial-scale timquo/shutterstock.com

Pharmaceutical Technology Europe DECEMBER 2017 19 Formulation

batches,” explains van den Dries. to ingest for children, or people The burst strength test “In contrast, the production of who have difficulty swallowing Softgels are dynamic systems where softgel capsules, for both large- (e.g., elderly). With softgels, there the fill and shell compositions, and small-scale batches, can be are also opportunities to create fill–shell interaction, and process done on the same equipment an enteric-release formulation, or parameters can have a substantial without the necessity of banding. even a controlled-release, abuse- influence on the softgel integrity, This flexibility provides significant deterrent formulation. All of these highlights Melanie Bayarri, cost advantages, both on unit formulations can be produced on formulation development scientist price and total development costs. the same equipment. Globally, at Patheon, part of Thermo Fisher In addition, a softgel formulation there is more capacity available in Scientific. She observes that with is more versatile. By changing softgel manufacturing than there increasing quality requirements, the composition of the fill or the is available for liquid-filled hardgel there is a need for pharmaceutical gel material, you can obtain a capsules, hence, providing more manufacturers to focus on chewable, gummy formulation flexibility in the supply chain of making smart choices early in the that makes the medication easy products. development programme. “The

Bringing together the benefits of lipid-based formulations and modified-release drug delivery

Lipid-based systems with modified-release profiles present excit- According to Meissonnier, there are various ways of modifying the ing opportunities for drug developers. “On the one hand, lipid-based release of actives through the lipid-based fill or the soft capsule shell. formulations provide benefits such as solubility and permeability en- “Whereas monolithic softgels can be designed, the preference would be hancement, modulation of transporter, elimination of food effects, re- to leverage multi-particulate soft-gelatin capsules to further reduce vari- duction of inter-patient and intra-patient variability, greater API load- ability. These softgels can be designed to have a solid lipid matrix core ing, and the avoidance of dose dumping,” observes Julien Meissonnier, that will extend release rate through an erosion diffusion process. The vice-president of Science & Technology at Catalent. “On the other, with other option is a film-coated soft-gelatin capsule with a liquid fill where extended or sustained drug release, dosing frequency can be reduced; the drug release profile is facilitated using coated beadlets, and con- peaks and troughs of drug levels in the blood are dampened, which trolled by the nature of the coating polymer.” consequently optimizes therapeutic effectiveness while minimizing Meissonnier cites a case study where an extended-release lipid-based concentration-dependent adverse effects.” formulation was developed using Catalent’s OptiShell soft capsule tech- Meissonnier explains that in some cases, conventional approaches for nology. The formulation was approved by the United States Food and modified-release drug delivery may prove difficult because of physico- Drug Administration in 2016. chemical and pharmacokinetic challenges posed by the drug compounds. “This is the first FDA-approved treatment using OptiShell soft capsule “For example, most APIs in today’s development pipeline are poorly technology to deliver an extended-release semisolid formulation in a soluble or poorly permeable, and some have low melting points. When softgel format,” says Meissonnier. “The active ingredients are used to these physico-chemical challenges are not addressed properly by the increase vitamin D levels, but peak concentrations or ‘surges’ in 25-hy- formulation technology, it often results in extensive positive food effects, droxyvitamin D3 levels induce the expression of the metabolizing en- which when combined with a narrow therapeutic window, can trigger a zyme Cytochrome P450 subfamily 24, resulting in lesser activity attenu- potential risk to the patient, with the potential risk of dose dumping,” he ating the inhibition of parathyroid hormone,” he explains. “Controlling says. “Modified-release lipid-based formulations in softgel capsules can the drug release maintains 25-hydroxyvitamin D3 levels in the blood address these challenges. For poorly soluble compounds, lipid-based above the 30 ng/mL concentration, avoiding peaks that result in lesser formulations promote solubilization along the gastrointestinal tract; activity. In addition, gradual repletion of 25-hydroxyvitamin D3 could whereas for poorly permeable compounds, lipid-based systems facilitate provide more predictable maintenance of serum levels below the poorly transcellular or paracellular transport by exploiting the lipid assimilation defined safe upper limit of approximately 100 ng/mL, allowing for more pathway as well as potential uptake through the lymphatic pathways. consistent dosage.” Lipid excipients can be used to modulate transporter and pre-systemic The product’s controlled-release system is a semisolid lipid-based ma- metabolism. All these mechanisms result in increased drug exposure, re- trix and, according to Meissonnier, “lipid-based matrices, in which the duction of inter-patient and intra-patient variability, and elimination of drug is homogeneously dispersed/dissolved, are the system of choice food effects,” he explains. “In addition, dose dumping can be eliminated for low-dose potent compounds. Catalent’s OptiShell soft capsule tech- with lipid-based matrix systems.” nology uses a precisely controlled hot-filling process for encapsulation The dosage form of choice for a modified-release lipid-based formula- of the lipid-based matrix, providing content uniformity performance tion is a soft capsule. “Soft capsules are the proven dosage form for lipid- above standard oral solid forms.” He adds that the patented shell com- based formulations,” says Meissonnier. “They have good developability position can handle encapsulation of high-temperature fill formulations and manufacturability. They are compatible with the wider range of lipid for semisolid and highly viscous fill formulations. It can also handle liquid and semi-solid excipients and formulations. Moreover, soft capsules higher pH fill formulations. do not compromise the performance of the lipid-based fill.” —Adeline Siew, PhD

20 Pharmaceutical Technology Europe DECEMBER 2017 PharmTech.com Formulation

burst strength test is an important records as well the diameter (mm) of technique to support formulation and the softgels before compression and process choices made throughout at maximum compression,” Bayarri softgel product development. It is an highlights. “Using this test, we can established method to assess softgels evaluate the influence of critical shell robustness,” she says. parameters on the softgels shell “It is performed with a Dr. robustness related to the formulation Schleuniger Pharmatron 400 N model design (e.g., fill formulation, gel 6D(SG) softgel tester. The apparatus is formulation, fill-gel interaction), similar to a tablet tester and compliant process design (e.g., die design, ribbon with the specifications as laid down thickness, hardness, and drying time), in the European Pharmacopoeia— and storage temperature.” Chapter 2.9.8 (1) and the United States Pharmacopeia—Chapter <1217> (2). It “Softgels are dynamic is easy to operate,” Bayarri explains. THE “A softgel sample is placed individually systems where the fill and between two jaws that compresses shell compositions, fill–shell it at a fixed rate of 2.5 mm/second interaction, and process SCIENCE OF until the sample bursts or until the parameters can have a maximum force of 400 N. The force substantial influence on the COMPLIANCE (N) required to burst the sample is softgel integrity.” recorded and in case the softgel does —Bayarri, Patheon not burst, the result is noted as > 400N,” she says. “The evaluation of softgels shell “During product development, we robustness is not only based on the assess softgel shell robustness using number of bursts and the withstood the burst strength test, and we have force before burst, but also on the been able to establish a good correlation relative shell flexibility as the apparatus between the burst strength test

Advances in transdermal patch drug delivery and measurement

Medherant, a bioadhesives company formed as a spin-out from the University of Warwick (UK) in 2015, is developing its TEPI Patch technology, a higher-dosage drug-delivery patch with a constant rate of drug release. The patch is formulated by mixing the drug with an adhesive that enables high drug loading. The company’s first patch, containing ibuprofen, is The World Leader in UV, being manufactured for clinical trials. 9LVLEOHDQG1,5&HUWLĆHG Dr. Gabit Nurumbetov, principal scientist at Medherant, has developed an improved instru- Reference Materials ment to test the release of drugs from a transdermal patch. The device, patented by Medher- ant, is an improved, miniaturized, and multiplexed version of a Franz or diffusion cell, which ISO/IEC 17025 is a device commonly used to measure the amount of drug that permeates across human skin. Calibration “In essence, the cell is a vial with a modified top part where you can place human skin and your formulation (gel, cream, or patch). The volume below the skin is filled with a biological fluid, which NIST Traceable is taken out for analysis through a sampling port,” explains Nurumbetov. “The amount of drug ISO Guide 34 Reference permeated across the skin is then measured by means of chromatographic or/and spectroscopic methods allowing estimation of parameters such as API flux, patch area efficacy, and others.” Material Producer The improved diffusion cell, which is patented by Medherant, can test more than 100 for- Lifetime Guarantee mulations per day, compared to approximately 12 in the same period with traditional Franz cells, reports the company. Fast Recalibration Drug release in a transdermal formulation is complex. “It is affected by physico-chemical Service properties of the adhesive and drug and the presence or absence of additional excipients in a formulation,” says Nurumbetov. “Some adhesives can chemically ‘hold’ drug molecules leading to a lesser amount of drug delivered. Also, if the molar mass of a drug is higher than 500 Daltons, it is likely to be not suitable for transdermal applications. Additional chemicals [email protected] 0659 (permeation enhancers) in the formulation can also affect the drug-delivery performance.” www.starna.com

The new instrument will allow high-throughput testing for faster development. REFERENCE MATERIALS +44(0) 20 8501 5550 4001 —Jennifer Markarian

Pharmaceutical Technology Europe DECEMBER 2017 21 Formulation

results and product performance,” water activity (related to and transport activities,” Bayarri Bayarri says. According to her, the microbial safety) with hardness sums up. generated data are used to support and drying time impacting shell the selection of: robustness. References • Adequate shell formulation for a “The burst strength test is 1. EDQM, Ph. Eur., Chapter 2.9.8 particular product useful to establish formulation “Resistance to Crushing of Tablets” • The most suitable process and process parameters that not (EDQM, Strasbourg, France, 2016) parameters, such as the die only ensure optimum product p. 313. design, for a specific fill and shell performance through shelf life but 2. USP, USP General Chapter <1217>, combination also guarantee that the product “Tablet Breaking Force,” USP32–NF27 • The optimal target hardness will withstand physical stresses (US Pharmacopeial Convention, range per product, balancing that can occur during packaging Rockville, MD, 2007), p. 726. PTE

Critical parameters in transdermal patch manufacturing

Lyons (Tapemark): There are CMAs and CPPs for each process involved in developing a transdermal patch: blending, coating, con- verting (i.e., making the coated film into the finished patches), and pouching (i.e., packaging individual patches). The CMAs are associated both with the raw materials and the intermediate materials made from these raw materials. In blending for example, the raw materials are the adhesive, the API, and the different excipients. The viscosity of the adhesive and the purity and particle size of the API are important CMAs for these raw materials. The resulting blend is the raw material for the coating process. After blending, the intermediate blend’s CMAs are homogeneity, viscosity, and solids con- tent. The blend CPPs that impact the final blend CMAs are blending time, speed, and equipment design. A QbD approach can address Another example is the coating process. In this process, the blend CMAs of homogeneity, viscosity, and solids contents are key because they will manufacturing complexities impact the drug-in-adhesive laminate (another intermediate) CMAs such Transdermal patches are used to deliver drugs through the skin for ei- as drug homogeneity, assay, and residual solvents. In addition, the CPPs ther a local or systemic effect. This route can improve patient compliance that also impact the CMAs of the output drug-in-adhesive laminate are by avoiding the difficulties associated with swallowing or with injecting coating thickness, line speed, and drying conditions. drugs. Transdermal patch manufacturing, however, is relatively complex Quality control because it generally has more process parameters and material attributes PTE: What quality control tests should be performed on patches? that can impact performance, compared to some other dosage forms, says Lyons (Tapemark): There are specific quality control tests for each of Cormac Lyons, vice-president of R&D at Tapemark, a contract manufac- the CQAs noted previously. Two main types of testing are in-process test- turing organization specializing in transdermal patches, oral thin films, ing and finished-product testing. and topical drug delivery. A quality-by-design approach can help address In-process testing involves understanding how materials are af- these complexities, he says. Pharmaceutical Technology Europe spoke with fected during manufacturing. This testing can help create a more Lyons to learn more about the manufacturing parameters and quality robust production process and ensure the right controls are in place. control testing involved in transdermal patch manufacturing. In-process testing can include methods to ensure the blending process Critical attributes has achieved a homogenous mix. It also can include measuring and PTE: What are the critical quality attributes (CQAs) of a transdermal patch? quantifying adhesion characteristics throughout the manufacturing Lyons (Tapemark): The CQAs of a transdermal patch are the attributes process. essential or detrimental to the product’s safety and efficacy. These may Finished-product testing analyzes the final product’s physical proper- include: drug delivery, drug dissolution, patch assay, content uniformity, ties to help ensure the patch is produced with the desired physical charac- residual solvents, patch adhesion, patch removal from liner, adhesive teristics and performs as expected. Adhesion and tack testing, for example, shear resistance, adhesive cold flow, bioburden, crystallization, skin sen- can help determine if the product will adhere to a user’s skin for a given sitization, and product stability in primary packaging. These CQAs will be period of time. Manufacturers must first define what levels of adhesion different based on the type of patch being developed. level and tack are required in a finished product and then implement the PTE: What are the critical material attributes (CMAs) or critical process- methods or tools to measure for those levels. ing parameters (CPPs) that affect these CQAs? —Jennifer Markarian cristi180884/shutterstock.com

22 Pharmaceutical Technology Europe DECEMBER 2017 PharmTech.com ADVANCING DEVELOPMENT AND MANUFACTURING

CHECK OUT NEW PHARMACEUTICAL TECHNOLOGY’S ALL NEW MARKET RESOURCE!

Pharma Marketplace is your online resource to connect with pharma manufacturing suppliers around the world. Find global suppliers and resources for: ❯ Analytical Instruments ❯ Chemicals, Excipients, Ingredients & API ❯ Contract Services ❯ Facility Design and Operations ❯ Laboratory Instruments, Equipment & Supplies ❯ Manufacturing, Processing Equipment & Supplies ❯ Aseptic/Sterile Processing ❯ Drug Delivery Technology ❯ Packaging Equipment & Accessories ❯ Information Technology ❯ Compliance & Validation

www.pharmtech.com/marketplace CONTACT US TODAY! run Europe. Pharmaceutical Technology to editor acontributing is CCy 24 For Flow or Batch Choosing Hazardous Chemistry: yn n m nnin th ma hhi Pharmaceutical Technology Europe g i a A nny A n . ppro

f C low hha ces al m lle en sse n o es eer de r in

ha vo o s warranted. are methods production flow or batch whether determining when considered are factors Several manufacturing. product drug and substance drug both for degree some to manufacturing continuous embraced have manufacturers contract some and must be studied at much lower concentrations, which can make can which concentrations, lower much at studied be must often processes “Such group. manufacturing continuous Hovione’s of leader team Ataíde, Filipe to according equipment, smaller using stages development the during particularly chemistry, flow he observes. costs,” and time in investment the versus throughput required the consider should flow to move to decision the compromised, not is batch for a long time in a safe manner. In such where cases safety in performed been have reactions hydrolysis and hydrogenations catalytic “Many chemistry. flow to switched automatically are says. he chemistry,” flow using performed typically are conditions batch under controlled easily be cannot that hazards involve that “Reactions company. the with development chemistry process R&D director Loureiro, Rui to according candidates, good also are reactants toxic/corrosive highly with reactions and reactions exothermic highly examples, above the says. he temperatures,” low require that intermediates unstable involve that or temperatures, high at pressures, high under run are that reactions and reactions gas/liquid with deal to way excellent an is chemistry “Flow Chemistry. Snapdragon of CEO and president Bio, M. Matthew to according reactions, hazardous perform to need the by driven often is chemistry flow to batch from switch The hazards the Considering F lvin sa Reactions that involve suspensions are also often a challenge in achallenge often also are suspensions involve that Reactions reactions hazardous all not however, that note, does Loureiro to addition In identified. first is source hazard the At Hovione, to drug discovery laboratories. Most pharmaceutical companies companies pharmaceutical Most laboratories. discovery drug to relegated largely technology anovel longer no is chemistry low fet g h y a aza nd rdo DECEMBER 2017 o eeco us no ch om he m e mis ic

aadv PharmTech.com try a , nt ag gge s. delays be avoided,” he notes. and early designed be can reactors so development process of start the at preferably however, and possible, as soon as taken be should aprocess in chemistry flow use to manufacturing group. decision “The continuous Hovione’s in chemist R&D an Oliveira, Rudi agrees kinetics, the fit to designed be can equipment the since flow, to processes batch convert helps also asserts. he processes,” continuous be successfully developed as can flow for candidates poor as appear would glance first at that temperature), many reactions (e.g., pressure, flow in available the expanded processing windows still “With opportunities. presents however,reactions, chemistry flow slow these For large. quite are that reactors stirred-tank continuous or tubular in result would times reaction Long Bio. to according flow, in practical is reaction the whether to as indicator primary the comments. he process,” batch the in achieved be can what versus flow of benefits the define to difficult it for gas/liquid reactions, which which reactions, gas/liquid for points to tube-in-tube technology Ataíde issues. those around work to required be would batch in that routes synthetic long or reagents expensive of use the avoid and flow in safely processes hazardous certain perform to possible it make to years the over developed of engineering solutions have been explains. he efficiently,” generated heat the removing of capable be also should it but time, appropriate the in reaction the perform to dimensioned be must process this for designed equipment The exotherm. asignificant produces (< that 1sec) reaction fast a very is example “One hazards. different the mitigate also should it process, the of out performance best the obtain to assembled be must equipment the While Loureiro. to according conditions, flow key in is setup equipment the Designing cost considerations and Equipment Knowing the process kinetics kinetics process the Knowing usually is time/rate reaction The Loureiro also notes that a variety avariety that notes also Loureiro

Maram/shutterstock.com API Synthesis and Manufacturing

provides a different type of control material is variable, which can result developed laboratory platforms at the interface between the two in improved product quality relative to that directly translate to pilot-scale phases than is possible when simply batch, adds Bio. platforms to facilitate a rapid design bubbling a gas into the liquid phase, From an economic perspective, to delivery cycle. More analytical as an example. flow systems typically have tools specifically designed to work “The evolution of flow chemistry significantly lower capital costs than with flow systems are also needed. is highly dependent on the a comparable batch reactor and are “It is through these analytical tools engineering solutions that are readily automated, resulting in lower and the integration of them into the developed,” adds Loureiro. The operating costs, according to Bio. process control strategy where the arrival of 3D-printed reactors is true power of flow over batch is to a good step toward the required be realized,” Bio states. flexibility to better address the AAss flow chhemmisttry has various chemistries. mmoovved fromm a laabbooraattoory Real potential From a larger perspective, cuuriiossity too an aactuuaal for supply chain according to Bio, as flow chemistry proodductiionn teecchnolooggyy,, improvements has successfully moved from a thheerre aare oopppoorttuunnittiees The combination of small footprint laboratory curiosity to an actual too usee coontinnuuoouus and low capital and operating production technology, there are costs allows for new ideas in mmaannuffacctuuringg——nnoot juusstt opportunities to use continuous supply-chain management and manufacturing not just as a tool to ass a toool too addrreess a supply risk mitigation, according address a single problematic step, siinnggle prrobbleemmatiicc steepp—— to Bio. “Multiple flow plants can but as a technology that allows new buut ass a teechhnoolooggy thhaatt be built and deployed to ensure opportunities, both technical and allloowwss neww tecchhnniccaal and robust supply chains. The low economic, when an entire process ecconomiic opppoorrtuunnities. cost also means that there is end-to-end can be done in flow. minimal penalty for over building He also notes that while the production capacity, which cost of developing a commercial Barriers to switching can eliminate the risk of drug batch process need not be paid from batch to continuous shortages.” until late in development, the cost Despite the fact that flow chemistry In addition, Bio says that process of flow processes is generally paid can enable hazardous reactions to development chemists should strive up front, but in the long run can be be performed on a commercial scale to eliminate hazards where ever significantly lower. “Flow provides that cannot be safely conducted possible, and flow chemistry can be unique opportunities in automation under batch conditions, barriers a critical tool. Rather than storing that promise to greatly reduce the to the advancement of flow hundreds of tons of temperature- cost of development,” Bio says. chemistry do exist. “The biggest sensitive intermediates on site for Snapdragon is currently building barrier is the lack of expertise use in batch processes, small flow an autonomous flow chemical needed by process development reactors can be used to convert development platform that promises chemists. To truly develop robust stable, non-hazardous precursors to dramatically speed the discovery and scalable flow processes, to the required intermediates and development of flow processes. practitioners need to have a good on-demand. understanding of physical chemistry “An on-demand flow system Reasons for and reaction design, skill sets is an intrinsically safer situation going with the flow not widely available,” says Bio. where no explosion can occur,” Flow chemistry is typically safer Electrical engineering and computer Bio says. This approach would for hazardous reactions due to programming expertise are also also eliminate the need for trucks downsizing of the reactivity zone, needed for effective implementation and rail cars to carry hazardous which also provides increased of automation and real-time materials around the country. heat and mass transfer, and higher analytical technologies, also skills “The supply chain for most, if not precision in controlling process that many process development all, of these materials could be parameters, according to Oliveira. “A professionals do not have. Bio also re-imagined in terms of on-demand, flow system will always have a much notes that collaboration is needed point-of-use manufacture. Not smaller volume of reactive stream between chemists, engineers, and only would this greatly reduce and thus is intrinsically safer than analytical scientists. the human, environmental, and batch,” Bio explains. Flow systems From a technical standpoint, national security risk, but also are also typically small footprint Bio notes that the laboratory create resilient supply chains able reactors, so containment for highly tools available for flow chemistry to tolerate local disruptions,” he potent APIs is much easier. development today typically continues. Flow typically also provides much don’t easily translate to pilot or “The question really should be, greater control over the process commercial scale, which inhibits why do we need to run hazardous variables that could impact product adoption of the technology. To chemistry in batch; flow should be quality, even if the quality of the input address this issue, Snapdragon has the default,” Bio concludes. PTE

Pharmaceutical Technology Europe DECEMBER 2017 25 HUMAN DATA SCIENCE

Research & Development | Real-World Value & Outcomes

IMS Health and Quintiles are now IQVIA™ – created to advance your pursuits of human science by unleashing the power of data science and human ingenuity. Join the journey at iqvia.com/success

Copyright © 2017 IQVIA. All rights reserved. Commercialization | Technologies 28 Agnes Shanley Agnes A technology roadmap aims to drive and consolidate improvements improvements consolidate and drive to aims roadmap A technology in a process that has remained unchanged for more than 70 years. than more for unchanged remained has that aprocess in Pharmaceutical Technology Europe Lyophilization Modernizing L facility at Purdue University in 2016 to facilitate R&D and pilot testing. pilot and R&D 2016 in facilitate to University Purdue at facility ademonstration launched group The control. and training, instrumentation, analytics, design, equipment lyophilization to approaches modern more developing agencies—are regulatory with scientists and consultants, independent universities, as well as vendors, equipment and manufacturers pharmaceutical members—14 its University, Purdue at 2014.in Based consortium technology manufacturing advanced its of part as (LyoHUB) Hub Technology Lyophilization Advanced the funded Technology and Standards of Institute National the processes, lyophilization efficient (3). disagreement provoke can process the monitor to avial in sensor the place to where as questions basic such Even paper. awhite in noted scientists response,” common too all an is operationalbest practices. “’Because it’s always been done that way’ (2). technology monitoring quality inline of lack and processing, loop ofoperations, efficiency than less with 5%, energy dominance of open unit pharma’s of expensive and time-consuming most the of one remains lyophilization field, the in work who experts to According stable). remain and distances long shipped be to (Photo) penicillin as such medicines allowing in II War World during difference considerable a made 1940s (lyophilization the in introduced was it since change lyophilized. are drugs 10 top-selling world’s the of half and conjugates, drug antibody and antibodies monoclonal process to widely used is process The (1). introductions drug new such all of half up made 2015,by they but, drugs, infusible or 11.9% for injectable new all of accounted pharmaceuticals 1998, In lyophilized market. drug overall the of part prominent amore become biopharmaceuticals injectable as grow, to continues importance strategic Its use. of point the at reconstituted be can that lives shelf long with powders in results process The safely. dried be to drugs protein-based and antibiotics, vaccines, To help reduce variability and develop more uniform, consistent, and and consistent, uniform, more develop and variability To reduce help over level, facility individual the at debate, and uncertainty see Experts little seen has process drying freeze pharmaceutical basic Yet, the pharmaceutical manufacturing, because it allowed heat-sensitive heat-sensitive allowed it because manufacturing, pharmaceutical in development acrucial was drying, freeze or yophilization, DECEMBER 2017

PharmTech.com practices for process monitoring (3). (3). monitoring process for practices best describes papers white first the of One alternatives. into research of state the describe and practices journalsaccess to summarize current open- in papers practices” “best also focusing been on publishing have They industry. the for priorities key short-term as drying primary for models process and sensors, including wireless instrumentation, and sensors of development the (4).at University Cambridge developed methods using summarized and analyzed, elicited, were views whose experts academic and industry 100 than more of opinions the reflects roadmap The design. equipment and methods, analytical training, technology, process of terms in priorities foridentifying lyophilization for freeze pharmaceutical drying, roadmap technology a 10-year 1940s. the since much changed hasnot basic process the importance, growing Despite lyophilization’s (CFD). First used in aeronautics aeronautics in used (CFD). First dynamics fluid computational as such tools modelling advanced including simulation, and modelling of use noted. she containers, or vials of surfaces the on finishes the to even and types container between differences to sensitive very be cn others and dependent pressure are them of Some complex. are processes heat-transfer the step, drying primary the in while, said, transitions,she undergoes four phase-change molecule water Each lyophilization. in modelling of use the on (5) webcast 2017 April an in LyoHUB, of co-director and astronautics and aeronautics of Alexeenko, Purdue University professor Alina explained transfer,” mass and heat complex involves “Lyophilization operations. pharma other with compared complex so is process step multi- the because is lyophilization understanding in curve alearning on be still may pharma why reason the of Part complexity Inherent LyoHUB members currently view view currently members LyoHUB 2017, released September In LyoHUB LyoHUB is advocating greater greater advocating is LyoHUB

Everett Historical/shutterstock.com Lyophilization

and aerospace applications, CFD different vendors’ equipment. manufacturer IMA Life North America simulations can offer more detailed • Better process control, especially established a venture to commercialize views of what’s happening in the during the primary drying stage, a new lyophilizaton-monitoring equipment than sensor information during which the ice crystal platform, based on research that the alone can give, showing important structure is set, and with it, mass two companies did with Pfizer (8). details about vapour concentration transfer and drying rates. Currently, Driving the technology is Atonarp’s and temperature and pressure control is based on traditional open- miniature mass spectrometer, which distribution, Alexeenko said. loop approaches. As a result, such is said to take up less than half a For example, Alexeenko recalled variables as product temperature, cubic foot of space. Work with Pfizer one industrial-scale lyophilizer design drying rate, and residual moisture evaluated the device’s performance that was studied. Researchers found content are not monitored directly, in monitoring the presence of silicone that a relatively short section of so any deviations from optimal levels oil (a sign that heat transfer fluids are clean-in-place and steam-in-place (CIP may not receive enough attention. leaking from lyophilizer shelves). and SIP) piping, which accounted for • Development of process analytical roughly 3% of the equipment’s area, technology (PAT) tools, which will Experts see uncertainty resulted in a 20% reduction in vapour be required for closed-loop control. and debate, at the flow rate and overall throughput. These tools would monitor heat flow individual facility level, More widespread use of modelling and product temperature in real time. over best practices. and CFD programmes, such as • Improved container and closure ‘Because it’s always been Siemens’ Star CCM, could help improve systems. Currently, product is done that way’ is an all lyophilizer design and allow existing freeze dried in glass vials with too common response, equipment to be used more efficiently, rubber stoppers. LyoHUB is and LyoHUB is advancing those efforts. evaluating the use of plastics and scientists noted in a white Among other goals mentioned most developing data on the chemical paper. prominently in LyoHUB’s roadmap are: and physical interactions between • Development of continuous or pharmaceuticals and containers. Researchers also used the device semi-continuous processes based Among other plans, the group is successfully to detect endpoints for on technologies that include spray considering using vials or stoppers both primary and secondary drying. freezing, agitated vacuum drying, that have been embedded with For secondary drying, the spectrometer rotary shell freeze drying, and arrays of sensors to monitor proved to work better than the Pirani electrospinning. Over the past few temperatures and pressures gauges typically used. The technology years, the food industry has moved during processing and transport. was also used to detect vacuum leaks to continuous operations, resulting This approach would save money, online. Venture partners say that it in tremendous gains in product because it would allow out-of-range can be made Internet of Things (IoT)- uniformity. LyoHUB members vials within an otherwise compliant ready with an Ethernet connection and expect the same to be possible for product lot to be discarded, rather single 24-V power supply. Research is pharmaceutical freeze drying. than the entire lot. continuing, to evaluate the technology • Use of improved heating methods Farther off in the future, LyoHUB is for use with predictive approaches and involving infrared heaters or evaluating freeze drying’s potential use quantitative measurements. volumetric heating via microwave, with novel therapies such as cell- and which would allow for closer control gene-based therapies. Below are some Wireless sensors and of the process. recent developments that have taken heat-flux sensors • Use of spray-freeze drying, place within the roadmap’s focus areas. Other process-monitoring solutions particularly for making bulk APIs. developed for lyophilization include IQ • Alternative sterilization methods, Spin freezing and miniature Mobil’s Tempris wireless temperature such as hydrogen peroxide and mass spectrometers monitoring technology, as well as cold-plasma sterilization. Steam For the past few years, RheaVita, Millrock Technology’s measurement sterilization, using steam at based in the Netherlands, has been platforms based on heat-flux sensing, temperatures above 120 °C, is most working on a continuous lyophilization which have shown positive results in often used. The process, however, process based on spin freezing. recent tests run at Purdue (9). involves heating and recooling, Collaborating with Ghent University in Coriolis Pharma has evaluated resulting in equipment wear. In Belgium, researchers have developed heat-flux sensing as a PAT technique addition, the typical sterilization a prototype spin-freezing lyophilizer to for lyophilization (10). Researchers process can take more than develop comparative process data (6). found that direct measurement of six hours to complete. LyoHUB The researchers recently presented a heat transfer provided more insights members plan to evaluate lower- model and theoretical design space (as into the thermodynamics of the temperature alternatives. required by pharmaceutical quality by freezing process than traditional • Establishment of standards for design) for the continuous process (7). methods. It also allowed them to characterizing lyophilization In November 2017, Atonarp, an equipment performance, which instrumentation company in Tokyo, would facilitate scaleup using and the lyophilization equipment Contin. on page 40

Pharmaceutical Technology Europe DECEMBER 2017 29 Peer-Reviewed Methods for Identifying Out-of-Trend Data in Analysis of Stability Measurements— Part II: By-Time-Point and Multivariate Control Chart

Máté Mihalovits and Sándor Kemény

In Part I of this article series, the authors discussed his article is a continuation of Part I, in which the the regression control chart method for identifying authors discussed the identification of out-of-trend out-of-trend data in pharmaceutical stability (OOT) data in the stability studies of single batches studies. In Part II, the by-time-point method and the Tusing a regression control chart method (1). multivariate control chart method are investigated, If several batches are considered, there are two different time scales. The first one is the life within batches, which and improved approaches are suggested. The has been covered in Part I (1). The regression control chart method is illustrated using real data sets. uses this within-batch context. The second time scale is the order of batches. Two approaches are followed in this Part II article. The by-time-point method uses the between-batches context only, while the multivariate approach uses both be- tween-batches and within-batches contexts. Two statistical concepts have been suggested in the lit- erature (2). The first concept was based on known variance and expected value of distribution of measurements. This method was referred to as the Shewhart method in Part I. In the current situation, however, where only a small sample size is available, it is not justified to assume known variance and expected value. The second method suggested was to use the tolerance interval, but this is not a proper approach either. The tolerance interval gives the limits within which a certain proportion of population falls and is not relevant for a single data point. The proper concept that one should use when a single observation is in question is the prediction interval, using t-distribution (1).

Submitted: 5 April 2017 Detecting OOT data using the by-time-point method

Accepted: 27 June 2017 In this method, the result for the new batch is compared COM K. with points of earlier batches belonging to the same time TOC S CITATION: When referring to this article, please cite it as of batch life. M. Mihalovits and S. Kemény, “Methods for Identifying UTTER Out-of-Trend Data in Analysis of Stability Measurements— Use of by-time-point method, original proposal H/SH Part II: By-Time-Point and Multivariate Control Chart,” The Pharmaceutical Research and Manufacturers of Amer- Pharmaceutical Technology 41 (12) 2017. ENTO

ica (PhRMA) Statistics and Stability Expert Teams (2) K

30 Pharmaceutical Technology DECEMBER 2017 PharmTech.com suggest calculating the tolerance interval with ±ks limits Shewhart limits (α=0.05), confidence limits (α=0.05), and around the mean of data of earlier batches at the same time tolerance limits (P=0.99, γ=0.95) are calculated as well. point. From tables or calculating with approximations, k None of these limits are appropriate to use in the current can be found. If the new data fall out of the interval that be- situations, except the prediction limits. These limits are dis- longs to the respective time point, they are OOT. Along with cussed in detail below. the tolerance interval, Torbovska and Trajkovic-Jolevska (3) Shewhart limits can be calculated by Equation 3: calculate the earlier described Shewhart control limits (as- sumed known expected value and variance), based on a z [Eq. 3] (standard normal) statistic.

where σy is the assumed variance, equal to sy. As the Suggested use of by-time-point-method known variance is assumed, there is no room for pooling. In the by-time-point situation, neither the Shewhart interval One may, however, use the pooled standard deviation as a nor the tolerance interval are the proper intervals to use. As substitute of σy. The latter is falsely assumed to be known be- explained previously, the prediction interval is to be used cause of the small sample size. When the pooled estimated with Student’s t-distribution. variance is substituted, σy is taken to be equal to sp. Equation 1 gives the calculation for prediction interval: Confidence limits can be calculated by Equation 4:

[Eq. 4] [Eq. 1]

For the calculations with pooled standard deviation, sp

where, is the mean of the reference data that belongs is substituted with sy in Equation 4 and a new tα/2 is obtained 2 to the ith time point, is the new measured data at ith time with degrees of freedom of sp . point, sy(i) is the sample standard deviation of reference data Tolerance limits can be calculated by Equation 5: that belongs to the ith time point, and n is the number of reference data at the ith time point (number of historical [Eq. 5] batches). t(α/2) is the critical value of Student’s t-distribution at one sided α/2 level with (n-1) degrees of freedom. If the in- To calculate the tolerance factor (k1), different approxima- equality is satisfied, that is the is within the interval, the tions could be used. Howe (4) suggests the following formula data are accepted, otherwise they are OOT. In this method, (Equation 6): a 5% significance level was used instead of the 0.27% level, which is accepted in quality engineering applications as discussed under Shewhart method in Part I (1). The reason for this choice is to keep the level of error of the second kind sufficiently low. A type II error (second kind) occurs when the null hypothesis is false, but erroneously fails to [Eq. 6] be rejected. The calculation can be improved using pooled standard This approximation is recommended if deviation. For this purpose, it should be proven that the error variances at different time points are equal, which can be tested by Bartlett and Levene tests, for example. For the authors’ data, the hypothesis of homogeneity of variances [Eq. 7] is accepted (details of tests are not shown here). The pooled sample variance (sp) is calculated in Equation 2 as: conforms to the current situation. In Equation 6, n is the number of historical points, ν is the degrees of freedom of , is the critical value of standard normal distribution at one-sided (1-P) level, and is the critical value of chi- square distribution at one-sided (1-γ) level with ν degrees of [Eq. 2] freedom. For the calculations with pooled standard devia-

tion, sr is substituted with sy in Equation 5 and the degrees of where p is the number of time points. freedom of (ν) is used in Equation 6 ( also changes)

Also, a new tα/2 value is to be used in calculations, as the and in Equation 7. degrees of freedom of standard deviation is changed from It is important to note that the method does not use the (n-1) to p(n-1). time dependence function. This approach is an advantage, For illustrational purposes along with prediction limits, because an assumed function may falsify the conclusion. At

Pharmaceutical Technology DECEMBER 2017 31 Peer-Reviewed

s Table I: Prediction-, Shewhart-, confidence-, tolerance limits, by-time-point method using p. LPL is lower prediction limit, and UPL is upper prediction limit. LSL is lower Shewhart limit, and USL is upper Shewhart limit. LCL is lower confidence limit, and UCL is upper confidence limit. LTL is lower tolerance limit, and UTL is upper tolerance limit. The observed data in the row of the grey pair of boxes are OOT considering the limits specified in the columns. Time ysy* LPL UPL LSL USL LCL UCL LTL UTL (month) p i 0 99.6 1.481 100.9 96.4 102.7 96.7 102.5 98.5 100.6 94.6 104.6 3 98.1 1.481 97.3 95.0 101.3 95.2 101.0 97.1 99.2 93.1 103.1 6 97.6 1.481 97.7 94.4 100.7 94.7 100.5 96.5 98.6 92.6 102.6 9 97.4 1.481 98.4 94.3 100.6 94.5 100.3 96.4 98.5 92.4 102.4 12 96.5 1.481 96.5 93.3 99.6 93.6 99.4 95.4 97.5 91.5 101.5 18 95.5 1.481 99.5 92.3 98.6 92.6 98.4 94.4 96.5 90.5 100.5 24 95.5 1.481 96 92.4 98.7 92.6 98.4 94.5 96.6 90.5 100.5 36 92.2 1.481 93.7 89.1 95.3 89.3 95.1 91.2 93.2 87.2 97.2

Figure 1: Statistical intervals for the by-time-point method at 0-month time point. < >Shewhart ( ) Confidence [ ] Prediction { } Tolerance Historical data New data

95 100 105 Amount of active substance (%)

the same time, it is a drawback, since the functional time Detecting OOT batch by multivariate method dependence, which is an essential feature of stability data, In this section, the observed batch is compared to earlier is not used at all. batches. As compared to the previous section, whole sets of data within the batch are compared (time function itself as Example I: By-time-point method with regression control charts) to those of historical batches Using the data set found in Part I (1), the statistical intervals (as with by-time-point method). based on calculations with the pooled standard deviation The time function, if linearity is assumed, is character- (Equation 2) are given in Table I. The grey colouring indicates ized by two parameters: slope and intercept. If the time that the observed data in the row of the grey pair of boxes are function is unchanged, both parameters are unchanged.

OOT considering the limits specified in the columns. Consid- S. OR ering the correct interval (prediction limits), the data point at The originally proposed slope control chart method H AUT

18 months are OOT, while the other data are accepted points In the seminal paper by the Statistics and Stability Expert E H just as they were at regression control chart in the first ar- Teams (2), only the slopes are considered in the stability T

ticle of the series (1). The mistakenly used confidence interval study. It is checked if the slope of the new batch belongs to OF would not contain y* at the 0-, 18-, 36-month time points; the same distribution as that of the earlier batches. More SY therefore, these would be OOT, while if the tolerance intervals precisely, it is assumed that estimated slopes of batches fol- COURTE were used, all the points would be accepted. The Shewhart low a normal distribution with the same expected value ARE

limit approach would find the 18-month time point as OOT. and variance. This assumption needs to be checked. The S The calculated intervals at 0-month time point are illus- authors suggest constructing regression lines separately for FIGURE trated in Figure 1. The confidence interval is narrow and even each batch using data up to the time point in question. If

some historical points are out of that range. the slope of the new batch is out of the tolerance interval ALL

32 Pharmaceutical Technology DECEMBER 2017 PharmTech.com calculated for those of the historical batches, the data in of freedom at one sided α level. The (X-x*) is the matrix of question are OOT. the difference of mean vector of the historical parameters (X) and vector of the new parameters (x*): Remarks to the originally proposed slope control chart method As explained previously, the prediction interval is to be used given that the interval for one future observation (slope of a [Eq. 9] new batch) is in question. This is not only sound but advanta- geous as well, because the calculation of the prediction range The (X-x*)T is the transpose of the matrix: is simpler than that of the tolerance range. The prediction range is narrower than the tolerance range, thus the test cri- [Eq. 10] terion based on the prediction range is stricter. This method is an advantage for reducing the risk of false conclusion, en- S– is the inverse of the variance-covariance matrix: abling a manufacturing company to detect disorder earlier. A more profound improvement considers the trend line as a whole, thus both parameters (i.e., slope and intercept) are considered. The authors do not see any reason for allowing dif- ferent slopes but not different intercepts. The difficulty is that [Eq. 11] as the estimate of the intercept and slope are statistically not where det(S) is the determinant of S: independent, the prediction intervals may not be calculated separately. For separate intervals of two mutually dependent variables, Bonferroni inequality could be used for example; [Eq. 12] whereas for a joint interval, Hotelling T-square distribution could be used. Using Bonferroni inequality, a rectangle predic- Performing the matrix multiplications, Equation 13 is ob- tion region is obtained, which is easier to calculate, but is less tained: accurate. If using Hotelling T-square distribution, an ellipse region is calculated, which might be harder to handle but more accurate. This method is, in fact, profile monitoring, which is established in reference 5 and dealt with in many papers (6, 7). Another point of possible improvement is that for the historical batches, all points may be used for the regression, not just the ones until the time point in question (i.e., the most recent point of the test batch). This would lead to more [Eq. 13] sensitive test criterion because of the larger amount of infor- mation used. This approach gives additional difficulty as the where n is the number of reference batches, sb0 and sb1 are variance-covariance matrix of parameters estimated from the sample standard deviations of historical intercepts and previous batches and from the actual batch is different, thus slopes, respectively, cov(b0;b1 ) is the estimated covariance the homoscedasticity assumption is not justified. Therefore, between the parameters, and and are the means of the this improvement is not utilized for the time being; the same parameters of historical batches. number of points is considered for all batches. Covariance is estimated as follows: The calculations in the following can be used every time a new data point is obtained, and a new regression line is fitted with the new data included. The data of historical batches are taken into account only up to the time point of [Eq. 14] the new data of the observed batch, and separate regression * * lines are fitted to those data. If the inequality (Equation 13) is satisfied, the (b0 , b1 ) is The prediction region for the new pair of parameters is within the region and the batch is accepted, otherwise it is calculated in Equation 8: OOT. The acceptance region is a spatial shape. By calculat- * * ing and plotting b0 and b1 pairs to the critical value of F, the region can be obtained, as illustrated in the following. [Eq. 8] For illustrational purposes, regions calculated by the Shewhart method (Shewhart region) (α=0.05), confidence where n is the number of historical parameter pairs (his- region (α=0.05), and tolerance region (P=0.99, γ=0.95) are torical batches), p is the number of parameters (here 2), calculated as well. These calculations, however, are not ap-

Fp,n-p,α is the upper critical value of F-test with (p,n-p) degrees propriate to use in the current situations.

Pharmaceutical Technology DECEMBER 2017 33 Peer-Reviewed

Figure 2: Joint statistical regions for slope and intercept. This method is not sensitive enough when a single point is in question. The reason is that a single OOT data will 0.3 not have an impact big enough on the stability profile to make the observer 0.1 detect the batch as an OOT batch. However, the method is more sensitive -0.1 and, therefore, should be used when the question is whether the observed batch Slope -0.3 is OOT (in other words, all the points are OOT in the batch). Parameters of stability profile with less data are less -0.5 Historical data New data certain, therefore, the acceptance re- Shewhart Confidence Prediction Tolerance gion is wider. As more data become 90 95 100 105 available, the uncertainty of parame- Intercept ters gets smaller, and detection of OOT batch becomes more certain. One should start using this approach after the third data point is obtained in The Shewhart region is calculated by (8): the observed batch, and keep using the method at every time point when new data are obtained, until the end of the stability study. In the example calculation, all data of the [Eq. 15] observed batch (and, therefore, all data of historical batches) are considered, including the last point. Table II: Parameters of regression lines of batches. Example II: Hotelling T-square joint prediction region Intercept Slope In the example calculation, all data of the observed batch (and, Batch I. 97.92 -0.14 therefore, all data of historical batches) are taken into account. Batch II. 98.31 -0.14 Intercepts and slopes of Batch I –VIII from Table II were used Batch III. 99.19 -0.19 as reference data and the method was used to observe data Batch IV. 97.74 -0.19 of Batch IX. Using the terms from Table III, Equation 18 is obtained from Batch V. 99.09 -0.17 Equation 13: Batch VI. 98.98 -0.26

Batch VII. 99.84 -0.17 [Eq. 18] Batch VIII. 100.88 -0.20 Batch IX. 99.38 -0.14 Where F with degrees of freedom 2 and 6, at one-sided 0.05 level is 5.14. As the Equation 18 is satisfied, the batch can be accepted as non-OOT. The prediction region can be Table III: Terms to calculations in Equation 13. * * illustrated by calculating max values of (b0 , b1 ) to F2,6,0.05 * * d that satisfy Equation 13. Every (b0 , b1 ) within the region is accepted as non-OOT. Figure 2 illustrates the calculated re- 1.073 0.0015 -0.0124 -0.39 -0.04 8 gions. One should keep in mind that the prediction region is the proper approach in the current problem. The confidence region can be calculated as follows (8): As the new data (slope and intercept) are found within the prediction region, they are non-OOT. By mistakenly using the confidence region, some of earlier batches and the new [Eq. 16] batch are found to be OOT. If the tolerance region approach is used, all batches would be accepted as non-OOT. while the tolerance region is calculated by (8): Conclusion [Eq. 17] The by-time-point method and multivariate control chart were discussed in this article as methods that could be used

where k2 is the tolerance factor taken from reference 9 for to identify OOT data and OOT batches in pharmaceuti- P=0.99 and γ=0.95. Its value is 48.77. cal stability studies. The earlier suggested methods are im-

34 Pharmaceutical Technology DECEMBER 2017 PharmTech.com proved here. The most important part of the improvement 3. A. Torbovska and S. Trajkovic-Jolevska, Pharm. Tech. Europe 37 is the use of the prediction region concept instead of the (6) (2013). 4. W. G. Howe, Journal of the American Statistical Association 64 tolerance interval or Shewhart method concepts. Also, for (326) 610-620 (1969). the earlier suggested method, the slope control chart is im- 5. W. H. Woodall et al., Journal of Quality Technology 36 (3) 309–320 proved so that not just the slope of the observed batch is (2004). considered in the stability study but also the intercept. The 6. R. D. Guevara-González, J. A. Vargas-Navas, and D. L. Linero- multivariate control chart using Hotelling T-square distri- Segrera, Revista Colombiana de Estadística, 37 (1) 159-181 (2014). 7. W. H. Woodall, Production, 17 (3) 420–425 (2007). bution satisfies the requirements mentioned. 8. P. Jolicoeur, Introduction to Biometry, 266-274 (Springer US, New The by-time-point method is a way to identify OOT data, York, 1999). while the multivariate approach is less sensitive to detect 9. K. Krishnamoorthy and S. Mondal, Communications in Statistics - this kind of phenomena and should be used to detect an Simulation and Computation 35 (2), 461-478 (2006). PT OOT batch instead. Also, the multivariate approach uses the time dependence function within the batch, which means more information from the data set is used, hence, giving sound conclusions. The three methods discussed in Part I and Part II are possible ways to identify OOT data or batches in stability studies. The sensitivity of the methods to Máté Mihalovits is a PhD student, [email protected]. detect OOT results are not studied yet, therefore, one should hu; and Sándor Kemény* is an emeritus professor, Tel.: decide if the data can be accepted by using all methods and +36 309936307, [email protected], both at Budapest drawing the conclusion from the results. University of Technology and Economics, Faculty of Chemical Technology and Biotechnology, Department of Chemical and Environmental Process Engineering Hungary, References 1111. Budapest, Müegyetem rakpart 3. 1. M. Mihalovits and S. Kemény, Pharm. Tech. 41 (11) 45–53 (2017). 2. PhRMA CMC Statistics and Stability Expert Teams, Pharm. Tech. * To whom all correspondence should be addressed. 27 (4) 38–52 (2003).

♦ CALL FOR PAPERS ♦ CALL FOR PAPERS ♦ CALL FOR PAPERS ♦ CALL FOR PAPERS ♦

Pharmaceutical Technology Europe and Pharmaceutical Technology cover all as- pects of pharmaceutical drug development and manufacturing, including formu- lation development, process development and manufacturing of active pharma- ceutical ingredients (both small molecule and large molecules) and finished drug-products (solid dosage, semisolid, liquids, parenteral drugs and topical drugs), drug-delivery technologies, analytical methods development, analytical testing, quality assurance/quality control, validation and advances in pharmaceutical equipment, machinery, instru- mentation, facility design, and plant operations. We are currently seeking novel research articles for our peer-reviewed journal as well as manuscripts for our special issues. For peer-reviewed papers, members of the Editorial Advisory Board of Pharmaceutical Technology Europe and Pharmaceutical Technology and other industry experts review manuscripts on S technical and regulatory topics. The review process is double-blind. Manuscripts are reviewed on a rolling

IMAGE basis. Y

GETT Our single-themed issues, which include literature reviews and tutorials, address excipients and ingredients, S/ analytical testing, outsourcing, solid dosage and more. IMAGE

O

J Please visit our website, www.PharmTech.com/pharmtech-author-guidelines-and-editorial-calendars, to view O / our full Author Guidelines. Manuscripts may be sent to Editorial Director Rita Peters at [email protected]. ARRAUD

B We look forward to hearing from you. MARTIN

Pharmaceutical Technology DECEMBER 2017 35 36 Jennifer Markarian Pharmaceutical Technology Europe Designing Sustainable Sustainable Designing Innovative methods for water and energy conservation can Innovative can methods conservation for water and energy Pharma Facilities Pharma E he adds. investment,” on return quickest HVAC the is improving but percent, afew by efficiency improve can strategies, control implementing or chiller energy-efficient a more installing as such utilities, other (3,4). footprint carbon improving thus waste, and water, energy, reducing toward progress made already have (1, companies 2). Pharma Big experts say efficiency, and compliance GMP both attain to possible is it operation, of mode water-conserving or energy most the be not may requirements GMP where instances some are there Although costs. manufacturing its reduce as well as image “green” acompany’s improve water, can and energy as such resources, conserve to designed are that operations and Facilities concern that is beginning to be addressed (5). addressed be to beginning is that concern agrowing also is resistance, antimicrobial cause could that effluents particularly facilities, manufacturing API some from water polluted of (2). Discharge problem this address help would systems) sanitation building or towers (e.g., cooling uses other for processes pharma from water discharge repurposing including use, (2). Careful rise will cost its means which resource, limited increasingly an become to expected is manufacturing, pharma to input water, acrucial Drinking Water at EECO lead Science Life Beattie, Keith says 60–75%, for account HVAC may manufacturing, product drug in and use, energy site manufacturing of 35–40% for account HVAC may example, for manufacturing, API In manufacturing. of types all across system other any than energy more consume environment, process the of quality air the control to used systems, conditioning) air and ventilation, HVAC (heating, amounts, different in energy use processes manufacturing pharmaceutical of types different Although Energy manufacturing industries, and the pharma industry is no exception. exception. no is industry pharma the and industries, manufacturing many in concern agrowing is sustainability nvironmental reduce carbon footprint. 2 , a UK-based energy efficiency consultancy. “Optimizing “Optimizing consultancy. efficiency energy , aUK-based DECEMBER 2017

PharmTech.com maintenance. mechanical neglecting not and optimizing, monitoring, by systems should their maintain companies savings. Finally,energy says Beattie, creates example—also for fans, and motors high-efficiency using efficiently— more Conditioning efficiently. more run to system the allow can humidity and temperature for points set the widening and switched when off not needed, even or back set be can Systems air. the of conditioning into going is to minimize energy step the Asecond savings.” significant in result can amount a small even by flow air reducing and classification, their meet to required than rates change air higher use often “Cleanrooms Beattie. suggests used,” air of quantity the is to minimize step first “The them. and reengineering or optimizing systems existing using often use, HVAC energy reducing for methods methods, notes Beattie. Beattie. notes methods, traditional on based were methods validation current the because answered, be to needs that question a is asystem such validate to How efficiency.” improve and quality assure thus can system control This cleanroom. the of performance real the on data have we and level contamination the controlling are we view, of point a compliance From rate. change air the control to data these uses and time real in counters particle from data the “Our adaptive system analyzes system. traditional baseline efficient measured from an already energy- is system demand-based adaptive, that this savings energy using the reports He Beattie. says cleanroom, acommercial of representative is which facility, test company’s the in control predictive model of method this using 70% nearly by able consumption to reduce energy been has company The rate. change the traditional method of fixed air than rather rates, flow air varying by count) (i.e., particulate level quality air afixed maintains that system acontrol using efficient cleanroom operations even more to make approach innovative EECO straightforward some are There 2 has developed an developed has

petrmalinak/shutterstock.com Facility Design and Operations

Single-use systems impact mass and energy balances, M+W Environmental Design] certification in biopharma manufacturing looked at process, building, and are desired,” notes Estapé. “It is In biopharma manufacturing, utility systems for a generic necessary, however, to understand single-use systems are considered monoclonal antibody production what exactly contributes to the beneficial for various reasons, process using single-use systems environmental impact for a particular including significantly reducing the and modular construction for a facility, given its location and all water use required for cleaning of manufacturing facility located in aspects of its operation, not only traditional stainless-steel systems. China. The study concluded (7) factors such as energy-efficient Another benefit is that, because that transportation of the building lighting and HVAC. We can design they are closed systems, single-use modules (by ship) had a small the best facility but not truly solve systems can operate in a cleanroom percent of the total environmental the problem, if the majority of the with a lower grade classification, impact of the facility (only 1%). impact is outside the facility, in which corresponds to operational The building systems (particularly transportation, for example. Looking savings (6). HVAC) had a significant impact that at the LCA is crucial to addressing the To better understand the factors varied by facility output (28–38%). real impacts.” affecting the sustainability of a Surprisingly, the production and biopharmaceutical facility, the M+W disposal of single-use components References engineering construction company accounted for only 9–11% of the 1. PharmTech, “Energy Management in conducted a lifecycle assessment total impact, while transportation Bio/pharmaceutical Facilities” (20 Feb. (LCA) on a facility model. LCA is of the consumables to the facility 20), www.pharmtech.com/energy- standard methodology used to site accounted for 25–30% of the management-biopharmaceutical- evaluate environmental impact of a total. “The waste generated by facilities. product, process, or service (or in consumables has been raised as 2. J. Markarian, “Considering Water Use in this case, a facility), explains David a possible concern for single-use Pharma Manufacturing” (18 Oct. 2017), Estapé, technology manager for Life systems, but we found that waste www.pharmtech.com/considering- Sciences in the Global Business Unit, was, in reality, a relatively small water-use-pharma-manufacturing. Life Sciences & Chemicals, of M+W component. For a facility located at 3. J. Markarian, Pharm. Tech. 40 (1) 36-38 Group. An LCA can look at different a long distance from the single-use (2016). environmental impact categories; system source, air transportation of 4. J. Markarian, “Pharmaceutical this study considered climate change the consumables was the biggest Manufacturers Go Green” (Jan. 20, impact (i.e., carbon footprint in impact,” reports Estapé. Optimizing 2016), www.pharmtech.com/pharma- carbon dioxide equivalents). An LCA the supply chain for consumables is ceutical-manufacturers-go-green. from “cradle to grave” takes into thus important. “Facility location is 5. S. Milmo, Pharm. Tech. 41 (10) 6-8 account not just the facility operation, significant for transportation as well (2017). but all materials and resources from as for the ‘greenness’ of the energy 6. E. Bohn, Pharm. Tech. 41 (6) 42-43 construction to demolition of a source used in the LCA,” he adds. (2017). facility. Facility operation, however, “Sustainability of facility 7. D. Estape, “Sustainable Facilities: is the largest contribution to carbon design is increasingly important, Global Environment Impact of a footprint, the study confirmed (7). and programmes like LEED [the Biopharmaceutical Facility” presenta- Using a software programme United States Green Building tion at 2017 ISPE Annual Meeting & designed to evaluate LCA via Council’s Leadership in Energy and Expo (San Diego, 30 Oct. 2017). PTE

Cambrex improves environmental footprint with a new wastewater treatment plant.

Treating manufacturing effluents, particularly from API manufacturing, “The original wastewater treatment plant at our facility in Karlskoga, is a concern that is increasingly being recognized by manufacturers. Sweden was built in 2000, and this recent investment is to increase the “In Europe, this [need for improved effluent treatment] very much capacity of the plant for both existing and future needs. The investment depends on the Integrated Pollution Prevention and Control (IPPC) will also help improve our environmental footprint at the Karlskoga Directive, which is now part of the Industrial Emission Directive,” notes site,” explains Sandberg. Cambrex also recently completed an upgrade Bjarne Sandberg, managing director, Cambrex Karlskoga. The company of wastewater handling capabilities at its Milan, Italy manufacturing is currently constructing a new wastewater treatment plant at its facil- facility, he reports. ity in Karlskoga, Sweden to support the expansion of cGMP capacity for Reference small-molecule APIs, the company announced on 26 Sept. 2017. When 1. Cambrex, “Cambrex Opens API manufacturing Facility and Invests in completed, the wastewater facility will reduce the emission of nitro- Supporting Waste Water Treatment Plant at its Karlskoga, Sweden Site,” gen, total organic compounds, and suspended material, improving the Press Release, 26 Sept. 2017. site’s environmental footprint (1).

Pharmaceutical Technology Europe DECEMBER 2017 37 38 improvement. for areas and trends predict and forecasts, production for insights provide metrics, planning and risk identify rooms reliability Cross-functional Management Chain Move to Proactive Supply Reliability Rooms and the Ian Elliot Pharmaceuticals, Inc. Janssen at reliability, chain director, global supply Pharmaceutical Technology Europe is senior senior is healthcare providers. healthcare and i.e., patients customers, on focus aclear with but benchmarks, internal against performance measure to company the throughout functions different in employees allow would that structure atransparent with aprogramme create to wished leaders Corporate goals. these achieve help to years few past the for Pharmaceuticals risk and variability. mitigate that procedures and programmes as well as operations, manufacturing and chain supply from rigor and discipline quality, safety, and efficacy. Success demands consistent ensure but delivery product speed only not must Manufacturers Inspired by Toyota Production System and System by ToyotaInspired Production T 21 standard end-to-end reliability metrics. This allows teams to be be to teams allows This metrics. reliability end-to-end 21 standard on delivering is company the well how on transparency provide to making. the in problems chain supply any mitigate and of ahead get to team the allows approach This issues. emerging and new discern to basis aweekly on goals track facility Teams each at goals. performance of set own its with each facilities, chain supply global sites. manufacturing and functions chain supply all across improvement of areas and trends predict and metrics, risk and planning identify forecasts, production for insights provide and data analyze to designed are centres These (RRs). rooms reliability cross-functional global, implement improvements.” sustainable and robust enable that decisions sound fast, make to required is that information the all “gathering as roughly, translated, is concept this analytics, System principle, Toyota Production the from came programme this for Inspiration This article discusses efforts that have been underway at Janssen Janssen at underway been have that efforts discusses article This At its heart is an automated reliability metric dashboard, designed designed dashboard, metric reliability automated an is heart At its its across rooms reliability 20 than more up set has far,So Janssen used (JSC) Chain Supply 2011,In Janssen therapies and global supply chains become more complex. complex. more become chains supply global and therapies as rapidly, changing is production pharmaceutical of world he DECEMBER 2017 obeya . Grounded in pure, fundamental data data fundamental pure, in . Grounded

PharmTech.com obeya to create and and create to obeya Continual improvement Continual owners. process business respective with action drive to insights these sharing it, behind be might that patterns any locate to and disruption supply the of cause root the discover to collaborate teams addressed, been has it after Then, it. solve and address to deployed is force task aproject rooms, reliability the of channels the through recognized management. risk and delivery, on-time quality, readiness, supplier as such areas in network the across strategies and improvements cumulative the into insights new is result The products. and markets, across supply chains,performance predict and track, compare, to able chain-performance metrics are are metrics chain-performance supply- approach, this In balancing. supply around based factors other and metrics of stratification a through achieved are which identification and assessment, partners. supply-chain other and suppliers company’s the with shared be can that practices best identifies RR central the time, same At the actions. corrective and robust, sustainable preventative find to sites various at partners with working and chain supply the affect discovering systemic issuesthat priorities. shared of aset against results delivers team, one by executed plan, one that engineering. This approach ensures and logistics, quality, production, procurement, for plans discuss and meet can teams which in aphorum as serve also They chain. supply the of signs vital the monitoring for essential become have RRs out, rolled first future plans. any in embedded be might that risks any identify and causes root their or near-missesissues to identify escalate and performance review each with different perspectives, employees from different functions, that ensures It chain. supply the across improvement sustainable and consistent for allows readjustment improvement and internal This process of continual If a systemic trend or issue is is issue or trend asystemic If A core tenet of the RRs is risk risk is RRs the of tenet A core with charged is group A central were they since years six the In

Maisei Raman/shutterstock.com Good Distribution Practices

monitored against some thresholds Monitoring suppliers concerns about gathering the data, for which performance has been Assessment tools also provide making them visible, and ensuring correlated to impact. Thresholds a holistic picture of the level of attendance from the stakeholders at then indicate whether or not the contract partner and supplier risk each site amid busy schedules and problem is under control. and performance. The granularity eminent deadlines. Gradually, as the For example, there is a statistical of tracking will depend on the teams adopted the approach and correlation between certain metrics company’s level of dependency on started to see and feel the benefits, that are associated with stock outs the individual partner. each team adapted the approach in certain markets, which are fed to make it work best for them. As by certain sites. Knowing these If a [potential] supply a result, each room has a standard correlations allows targets to be set interruption can be configuration and standard data, but so that any supply disruptions can identified more than eight sites have the freedom to incorporate be avoided. Similarly, data have been weeks before it happens, extra information to optimize their correlated on the types of product- the company will be more effectiveness and efficiency. quality issues and their impact on the than 80% successful in supply chain. These correlations, and Training approaches thresholds, are then used to guide mitigating its impact. Because the company is global inventory stocking and business in outlook, training for the RRs continuity planning. Generally, the RRs track data tends to be built around a central on suppliers’ quality, delivery, communication or training plan, Using planning to track risk cost and risk profile, technology utilizing short video clips that explain Demand and planning can be used usage, innovation, audit results, system utilization. to track risk. The RRs, for example, and strategic alignment. In some This basic structure is then engage in monthly demand reviews to cases, their internal performance reinforced with traditional measure and monitor mean-absolute- is monitored in terms of capacity presentations, both self-study percent error and bias to forecast. utilization, schedule attainment, raw modules and interactive. This The company has also introduced material and work-in-progress levels, standard is maintained by a central a bias-tracking signal that effectively as well as audit status. team and then made accessible measures and identifies patterns These data provide transparency via internal networks. Training is in under- and over-forecasting. and a window into their internal also augmented, based on local or Using this signal helps ensure that performance, giving early warning regional practice, to accommodate the assumptions made in business signs of possible trouble. Data sharing local needs. forecasts are regularly and thoroughly takes place within a framework of reviewed. Regular review is essential partnership that encourages periodic Sustainable results to minimizing variability. business reviews and a spirit of Since their inception, RRs have had a The supply-chain function mutual improvement. measurable impact in in preventing is utilizing advanced analytical supply chain disruptions by allowing techniques to determine the optimum Managing information the company and employees algorithm for each product and At this point, RR’s collect data from to visualize any constraints, market. For example, for planning, sources that include the following: understand the business from an teams typically look at the demand/ • Business warehouses that store end-to-end perspective, and drive supply balancing during a 13-week data on commercial performance a more predictive mindset. The period. When and where gaps in • Online portals, laboratory RRs solve challenges and problems supply or atypical reductions in information systems, and every day, which can range from inventory show up, the RRs raise enterprise resource planning missed deliveries from suppliers to and review a short-term exception systems that store product quality accommodating changes in demand management (STEM) action. data to equipment improvements. Individuals from different functions • Procurement systems that provide One of the issues monitored has within the company jointly decide on supplier performance data. been the availability and correctness the best course of action, and results These data are then interfaced into of narcotics licenses that permit the are monitored weekly. In addition, an enterprise data warehouse (EDW), sale of some products in regulated the RRs keep a log of every potential using business filters and calculations countries. Through data collection supply interruption, early warning to derive performance data. The and analysis, key themes were indicator, and critical stock out, EDW is built on a Teradata platform, identified related to timeliness, tracking each issue and its resolution. and staged data are visualized and certain countries’ response rates, and So far, data have shown that, if a analyzed using a number of different the quality of documents. potential supply interruption can be software programmes, including identified more than eight weeks products from Spotfire, Tableau, Cross-functional approach before it happens, the company Qlikview, and Qliksense. A cross-functional team from quality, will be more than 80% successful in During the initial planning stages customer logistics, global planning, mitigating its impact. of the Janssen RRs, there were and affiliate services, facilitated by

Pharmaceutical Technology Europe DECEMBER 2017 39 Good Distribution Practices

the global reliability team, has put in but in safety, quality, cost, and approach is currently being rolled place a revised process, simplified impact on customers. out across the company’s network, procedures, developed personnel • Evaluation of progress. It is increasing the rigor in root cause training, and installed performance important to look at progress analysis and execution. monitoring on the process. As a against larger business plans, to result, the company have seen a 35% ensure that the organization is on Measuring both site reduction in issues, meaning more track to meet competitive goals, and overall performance “right-first-time” deliveries from deliver on the sites’ missions, and Looking to the future, performance affiliates and less risk of stock outs. launch new products. metrics will need to blend both site Janssen has seen a number and supply chain performance. Those of additional improvements and Since 2015, the company metrics, observations, and staff can successes from the RRs. Since 2015, has delivered a 100% then be used to identify and eliminate the company has delivered a 100% ‘launch on time’ success any waste in the system and make “launch on time” success rate for rate for new products. sure everything possible is being done new products. This is based on a to keep products continually affordable. supply chain that can deliver these Functional teams are made As the company moves new products to customers following accountable for reliability forward, the RRs will become regulatory approvals and in the Along the way, Janssen has had to increasingly connected to show how committed timeframe. revise its original approach. In 2016, performance is affecting overall for example, the company made supply chain effectiveness. The Connection to the customer functional groups more accountable organization already relies heavily As RRs develop, they remain centered for reliability so that the supply- on data analytics to help develop the around four key principles: chain function could take more of a optimum scenario for supply. In the • Commitment and connection supportive role. This approach has future, there will be an even greater to the customer. This requires helped the functional teams remain need for faster data collection. thinking about partners in order the drivers of the various parts and The RRs are proving to be a key to make the best decisions and has meant the solutions have greater process and capability. They help compromises to support them. internal buy-in, while also supporting ensure that the organization can • Ability to see and articulate broader-based improvement. predict and visualize issues, rather business priorities, as well as the The company has also updated the than simply react to them. commitments that have already RRs’ daily performance management been made. to standardize them around Johnson Reference • Performance, and the use of & Johnson’s production system and 1. The Johnson & Johnson Strategic a standard for tracking our values (1), which brings a single Framework, jnj.com, www.jnj.com/ performance, not only in reliability, standard to all company sites. This strategic-framework PTE

Lyophilization — contin. from page 29

use a “vial heat-transfer coefficient” ping-at-ifm/ 7. DeMeyer, L., et al., Int.J.Pharm, 532 (1), to monitor product temperature 3. LyoHUB, Lyophilization Technology 185-193 (2017). throughout primary drying. Roundup, lyohub.org, www. phar- 8. A. Rhoden, “The Utilization of Mass Advances are also being seen mahub.org/groups/lyo/lyohub_road- Spectroscopy for Equipment and with Tunable Diode Laser Absorption mapping Process Modeling in Lyophilization,”a Spectroscopy (TDLAS). One platform 4. S. Nail et al., AAPSPharmSciTech,18(7), presentation made on 12 Sept., that has been optimized for pharma October 2017, Springer.com, 2017, at IMA’s Process Symposium, freeze drying uses a spectrometer link.springer.com/content/ islyophilization.org/wp-content/ from Physical Sciences, Inc., and SP pdf/10.1208%2Fs12249-017-0733-1. uploads/2017/05/2017-East_Speaker- Scientific’s LyoFlux analyzer. pdf. 6-Alan-Rhoden_small.pdf 5. Siemens webcast, “CFD Methods 9. N. Huls, “Real-Time Temperature References and Lyophilization: Advancing and Heat Flux Measurements for 1. M. Arduini, “Freeze Drying Market Manufacturing Processes to Match Lyophilization...” millrocktech.com, Analysis,” Presentation at IMA Aseptic Growing Demands,”siemens.com, April 2017, www.millrocktech.com/ Processing Symposium, Amherst, NY, 27 April, 2017, www.mdx2.plm. wp-content/uploads/2017/04/Real- September 2016. automation.siemens.com/webinar/ Time-Temperature-and-Heat-Flux- 2. “Roadmapping at Cambridge cfd-methods-and-lyophilization- Measurements-for-Lyophilization- University’s Institute for advancing-manufacturing-processes- Process-Design-and-Monitoring.pdf Manufacturing,” ifm.eng.cam.ac.uk, match-growing-demands 10. I.Volrath et al., JPharmSci, 106 (5), 1249- www.ifm.eng.cam.ac.uk/ifmecs/ 6. DeMeyer, L. et al., Int.J.Pharm, 496 (1), 1257 (May 2017), jpharmsci.org/article/ business-tools/roadmapping/roadmap- 75-85 (2015). S0022-3549(16)41956-8/pdf PTE

40 Pharmaceutical Technology Europe DECEMBER 2017 PharmTech.com Baxter BioPharma Solutions

Company description vials, cartridges, frozen premix systems, Baxter’s BioPharma Solutions business liquid premix systems, diluents for collaborates with pharmaceutical reconstitution, powder-filled vials, and companies to support commercialization sterile crystallization. objectives for their molecules. As a Our drug categories include: small/ parenterals specialist with over 85 years large molecules, biologics, vaccines, of expertise, BioPharma Solutions offers proteins/peptides, packaging, cytotoxics, Halle/Westfalen, Germany— contract manufacturing form/fill/finish highly potents, biologics and disperse Recognized as a world class manufacturer services and solutions for injectables systems. of complex sterile manufacturing for designed to meet complex and traditional lyophilized cytotoxic parenterals, the sterile manufacturing challenges. As a Facilities Halle/Westfalen facility offers dedicated global injectables specialist, we can help Our award-winning, state-of-the-art clinical through commercialization solve unique challenges with confidence facilities specialize in sterile contract production with integrated services of delivery, service and integrity. manufacturing services and have primary and technologies. With over 60 years of locations in: expertise, this facility offers: Markets served Bloomington, Indiana USA—The • Cytotoxics Baxter’s expansive network offers more Bloomington facility is a leader in • Highly potents than 50 manufacturing facilities across sterile contract manufacturing and • Biologics six continents and our global presence offers form/fill/finish services and • ADCs provides opportunities for unique sterile solutions for injectables designed to • mAbs contract manufacturing collaborations. meet complex and traditional sterile • Biosimilars The power of an extensive global manufacturing challenges. As a full • Disperse Systems network lies in the coordination of, and service contract manufacturer (CMO), • Liposomes efficiencies resulting from, a systemic this facility serves client needs with • Micelles approach to cGMP manufacturing. Baxter clinical through commercial launch, • Nanoparticles has manufacturing sites across the including: manufacturing, packaging, Round Lake, Illinois USA—Baxter globe in support of a diverse portfolio quality systems, experience with is a leading provider of manufacturer- of delivery systems and manufacturing worldwide regulatory agencies, and our prepared IV solutions and our Round Lake solutions. Lyophilization Center of Excellence, an facility is a best-in-class aseptic solution industry-leading resource center focused manufacturer. Major products/services on the development of high-quality Our Parenteral Delivery Systems include: freeze drying. prefilled syringes, liquid/lyophilized

Contact details Baxter BioPharma Solutions 1 Baxter Parkway, Deerfield, IL 60015 Tel. US:1 800 4 BAXTER International: 1 224 948 4770 [email protected] www.baxterbiopharmasolutions.com

Pharmaceutical Technology Europe DECEMBER 2017 41 CORPORATE PROFILES

Catalent Pharma Solutions

Corporate Description Catalent is the leading global provider of advanced drug delivery technologies and development solutions, providing worldwide clinical and commercial supply capabilities for drugs, biologics, and consumer health products. With over 80 years serving the industry, we have proven expertise in bringing more customer products to market faster, enhancing product performance, and ensuring reliable product supply. We serve more than 1000 innovator customers—both established and emerging—in over 80 markets, including 85 of the top 100 branded drug marketers, 23 of the top 25 generics marketers, 23 of the top 25 biologics marketers, and 22 of the top 25 consumer health marketers globally. We manufacture 72 billion doses of nearly 7000 products annually, which equates to approximately 1 in 20 doses taken each year by patients or consumers around the globe. Technology Highlights • Catalent RP Scherer Softgel is a Our significant intellectual property With our wide range of expert services— global leader in innovative oral and includes over 1100 patents and patent including analytical, biologics, pre- topical softgel technologies. In the past applications, and our team, including formulation and formulation— we drive 25 years, nearly 90% of NCE softgel more than 1400 talented scientists, faster, more efficient development approvals by the USFDA have been introduced 183 new products onto timelines and produce better products. developed and supplied by us. the market in 2016/7. Supporting this These include: innovation is our team of 1,400 quality • Catalent Biologics—advanced and regulatory experts, who ensure technologies and tailored solutions for Catalent. More products. Better compliance and safety. Catalent was biologic and biosimilar development treatments. Reliably supplied.™ subject to 53 regulatory audits and over from DNA to commercial supply. 400 customer and internal audits in the Comprehensive analytical solutions, same period. biomanufacturing, and finished product We have made significant investments, supply in liquid and lyophilised vials, including approximately US$665 million prefilled syringes, and cartridges in the last five fiscal years in gross • GPEx® technology for advanced cell capital expenditures, to establish a expression global manufacturing network, and today • SMARTag® technology for antibody- employ over five million square feet of drug conjugation; precision design of manufacturing and laboratory space next-generation biologic therapies Contact details across five continents. • OptiForm® Solution Suite for rapid, Catalent Pharma Solutions Whether you are looking for a single, optimised dose form development 14 Schoolhouse Road tailored solution or multiple answers • Unique delivery technologies: Somerset, NJ 08873, USA throughout your product’s lifecycle, including OptiShell™ capsules, Zydis® Tel. +800 88 55 6178 (EU & ROW) we can improve the total value of your ODT, modified release and OptiMelt™ +1 888 765 8846 (USA) treatments—from discovery to market HME, as well as inhaled and injectable [email protected] and beyond. dose forms www.catalent.com

42 Pharmaceutical Technology Europe DECEMBER 2017 PharmTech.com Contec Inc

Company description sprays or 5L capped containers. Blended Contec is a leading manufacturer of with water for injection, the sterile contamination control products for version has a less than 0.25 EU/mL critical cleaning in manufacturing endotoxin level guaranteed. environments worldwide. With more than 30 years of experience behind us, Contec Disinfectants we understand the unique cleaning Contec’s disinfectant range includes a requirements of these highly regulated sterile and filtered fast acting sporicide; markets. Our sales and technical Contec ProChlor and a no residue, low support teams are fully trained to assist endotoxin 6% Hydrogen Peroxide; Contec customers in finding or creating a Contec HydroPure. Both are available in 1L product that best meets their needs. trigger sprays and 5L capped containers.

Markets served PROSAT and SATWipes Contec’s cleanroom wipes, mops Contec introduced the first presaturated and disinfectants are used in various wipes in 1993 and the range has industries across the globe including expanded to include sterile and biotechnology, pharmaceutical, medical non-sterile, knitted and non-woven device, healthcare, and other critical life presaturated wipes in many sizes, science applications. Contec has local formats, and substrates. distribution throughout Europe. Dry wipes Major products/services Dry wipes have been Contec’s core Facilities Contec’s extensive product line for business for the past 25 years. Contec can Contec has established a cleanroom cleanrooms and critical environments offer one of the widest ranges of sterile manufacturing facility and distribution includes: and non-sterile, knitted and non-woven centre in Europe which allows us to • Sterile and filtered 70% Alcohols dry wipes available for cleanroom use. locally support our European customers. • Sterile and filtered disinfectants Contec owns and operates further. • Mopping Systems and Cleaning Tool Mopping systems and cleaning tools manufacturing facilities in South Carolina, • Pre-saturated Wipes A variety of mopping systems and USA and Suzhou, China. Contec has a • Knitted and Non-woven Dry Wipes cleaning tools are available for all sizes team of technical specialists and sales • Spill Control Products, Sponges and and grades of cleanroom. From triple representatives in Europe, North and Swabs. bucket systems, bucketless systems and South America, and Asia. These facilities isolator cleaning tools Contec have a mop and dedicated team members give Contec Alcohols for every facility. Sterile and non-sterile, Contec the ability to provide product 70% IPA or denatured ethanol is available reusuable and single-use mops heads are and technical support to multi-national sterile and filtered in either 1L trigger available, in a wide variety of substrates. customers with global needs.

Contact details Contec Inc ZI du Prat - RP 3707, 56037, VANNES, FRANCE Tel. +33 (0) 2 97 43 76 98 [email protected] www.contecinc.com

Pharmaceutical Technology Europe DECEMBER 2017 43 CORPORATE PROFILES

GEA Group

Batch Processing & Materials Handling School Lane, Chandlers Ford Ind Est, Chandlers Ford SO53 4DG Eastleigh United Kingdom Tel +44 23 8026 7131

Test Facilities GEA Pharma Solids Center Continuous Processing Keerbaan 70 2160 Wommelgem Belgium Tel +32 3 350 1211 Fax +32 3 353 2055

Liquid Pharma/BioPharma Steven 1 31135 Hildesheim Company description scope of supply is recognised worldwide Germany GEA is a leading provider of process through its well established and Tel +49 5121 742 0 technology and packaging solutions for globally known brands for batch and Fax +49 5121 742 153 the pharmaceutical, biopharmaceutical, continuous granulation, drying, pelletizing biotechnology, and nutraceutical and coating; for contained materials Liquid Pharma/Lyophilization industries. Our portfolio includes single handling; for tablet compression; for Kalscheurener Str. 92 units, modular systems, and complete pharmaceutical freeze drying and 50354 Hürth (Cologne) production lines for powder processing, automated vial handling systems; for Germany oral solid dosage forms, parenterals, fermentation and liquid formulation; for Tel +49 2233 6999 0 sterile liquids, and semi-solids. separation, homogenization and cell Fax +49 2233 6999 10 disruption. Markets served Process solutions for: Facilities SOLIDS—(Formulation) Development, GEA Group Headquarters Anti-Cancer Treatments, Antibiotics Peter-Müller-Str. 12 & Anti-Infectives, Effervescents, High 40468 Düsseldorf Volume, Highly Potent API, Hormones, Germany Inhalable Fine Powders, MUPs, Pellets, Tel +49 211 9136-0 and Tablets Fax +49 211 9136-31087 LIQUIDS—Animal cell cultures, SOLIDS: Bacteria Cultures, Blood Fractionation, Continuous Processing E.Coli, Hormones & Steroids, Inhalable Keerbaan 70 Suspension, Insulin, Liposomes, 2160 Wommelgem Monoclonal Antibodies, Oncology, Belgium Parenteral/Intravenous Emulsion, Tel +32 3 350 1211 Therapeutical Proteins, and Vaccines Fax +32 3 353 2055 Contact details GEA Group Major products/services Tablet Compression Keerbaan 70, GEA combines trusted technology with Bergensesteenweg 186 2160 Wommelgem, Belgium a continual programme of innovation 1500 Halle Tel. +32 3 350 1211 aimed at maintaining price/performance Belgium Fax. +32 3 353 20 55 leadership for its pharmaceutical Tel +32 2 3638 300 [email protected] manufacturing customers. The GEA Fax +32 2 3560 516 www.gea.com

44 Pharmaceutical Technology Europe DECEMBER 2017 PharmTech.com Patheon, part of Thermo Fisher Scientific

Company description Markets served Facilities Patheon, a part of Thermo Fisher Small emerging, midsize, and large Details of location of headquarters and Scientific, provides end-to-end pharma/biopharma companies regional offices pharmaceutical services to support the (Patheon headquarters): entire biotechnology and pharmaceutical Major products/services 140 Kendrick Street, Building C lifecycle. Thermo Fisher’s pharma API process development and Suite 301 services solutions helps customers manufacturing, biologics drug substance, Needham, MA 02492 accelerate innovation and drive formulation, biomanufacturing, clinical productivity in the drug development and packaging and logistics services, 4815 Emperor Boulevard commercialization process—from small pharmaceutical development, solubility Suite 300 and emerging to large biotechnology and enhancement, technology transfer, Durham, NC 27703 pharmaceutical companies for both large commercial manufacturing, softgel and small molecules. www.thermofisher. manufacturing, steriles, complex oral com/patheon. solid dose, and OTC.

Contact details Patheon, part of Thermo Fisher Scientific 4815 Emperor Boulevard, Suite 300, Durham, N.C. 27703 Tel. 919-226-3200 Fax. 919-474-2269 [email protected] www.patheon.com

Pharmaceutical Technology Europe DECEMBER 2017 45 CORPORATE PROFILES

Shimadzu Europa GmbH

institutes, privately-run laboratories, remote-monitoring with smart devices administrations, and universities and the quick-batch-function for quick complete the list of clients. The systems and easy creation of sequential analyses are used in routine and high-end are added to make the i-Series Plus the applications, process and quality control, integrated HPLC system of choice. as well as R&D. Facilities Major products/services As a global player, Shimadzu operates CLAM-2000: fully automated steps Fully automated sample production facilities and distribution from sample pretreatment to LCMS preparation for LCMS centres in 76 countries. For almost 50 analysis The CLAM-2000 is the first system in years the European headquarter has the world able to perform all steps fully been located in Germany and in the Company description automated from pre-treatment of the year of the company’s 45th anniversary Shimadzu is one of the worldwide sample to LCMS analysis, requiring only in Europe, Shimadzu inaugurated its leading manufacturers of analytical the simple task of placing the blood or new training and testing facilities, and measuring instrumentation. The biological fluid collection tubes, reagents, Laboratory World, for customers from company’s equipment and systems are internal standards, and specialized pre- all over Europe. With over 1500 m2 floor used as essential tools for the quality treatment vials in the system. It also space, Shimadzu’s entire product range control of consumer goods in all areas of features excellent management functions is available for testing and customer food safety, environmental and consumer providing a dramatically improved demonstrations—from chromatographs, protection as well as in healthcare to workflow with better safety for clinical spectrophotometers, TOC analyzers, contribute to society through science research and higher reproducibility. It is mass spectrometers and balances to and technology. Chromatography, compatible with the LCMS TQ systems material testing machines. In addition, mass spectrometry, spectroscopy, LCMS-8040, LCMS-8045, LCMS-8050, and laboratory space for application life sciences, environmental analysis, LCMS-8060, giving a large choice to adapt development and seminar facilities have pharmaceutical and material testing to sensitivity needs. been expanded. In Europe, Shimadzu runs make up a homogeneous yet versatile subsidiaries in Austria, Belgium, Bosnia- offering. Along with many “industry first” Herzegovina, Croatia, Czech Republic, technologies and products Shimadzu France, Germany, Italy, The Netherlands, has created and invented since 1875, Russia, Slovakia, Switzerland, and the there has also been the exceptional United Kingdom. achievement of the 2002 Nobel Prize for Chemistry to Shimadzu engineer Koichi Tanaka for his outstanding contributions in the field of mass spectrometry. Shimadzu is focused on top quality when developing products, including ease of operation and optimum service. The company manufactures according to internationally renowned quality i-Series Plus systems standards, including Pharmacopoeia, ISO, USFDA, GLP, and GMP. New generation of integrated (U)HPLC systems Markets served The i-Series Plus, designed for covering Shimadzu’s analyzers and equipment conventional to ultra-fast LC applications, Contact details are applied in the food industry, clinical consists of the compact HPLC Shimadzu Europa GmbH and pharmaceutical field, automotive Prominence-i Plus and UHPLC system Albert-Hahn-Str. 6-10 industry, chemical, petrochemical, Nexera-i Plus. The instruments meet the 47269 Duisburg, Germany life sciences and biotech, cosmetics, needs of any analytical environment with Tel. +49-203-76 87 0 semiconductor, and nutrition high speed, outstanding performance, Fax. +49-203-7666 25 industry, as well as in the flavours maintainability, and economic efficiency. [email protected] and fragrances business. Research In addition, new functionalities, such as www.shimadzu.eu

46 Pharmaceutical Technology Europe DECEMBER 2017 PharmTech.com Starna Scientific Ltd

Company description Major products/services Starna Scientific is the world leader Certified Reference Materials (CRMs) for Certified Reference Materials for for UV/Visible/NIR and Fluorescence UV VIS & NIR applications, being the Spectroscopy (including NEW USP preferred supplier to many of the leading Chapter <857>!!): instrument manufacturers and the • CRMs for: Wavelength, Absorption/ majority of pharmaceutical companies Linearity, Stray Light, Instrument globally, as well as working closely with Resolution, Fluorescence, Plate reader a number of NMIs (National Metrology references, DNA 260/280 ratio Institutes). • Covering the Deep UV to the NIR Full range of precision Quartz/Glass Starna Scientific is also recognised • Fluorescence standards in liquid and Spectrophotometer cells world-wide as a quality manufacturer and polymer form, including traceable supplier of precision Quartz and Glass fluorescence references Facilities Spectrophotometer cells and optical • UKAS accredited to ISO 17025 (calibration) Starna is headquartered in Hainault, UK, accessories, with more than 50 years’ & ISO Guide 34 (CRM Manufacturer) which hosts the Starna UKAS accredited experience in the field. • Lifetime Guarantee Calibration Laboratory, Research & Starna’s ISO 9000 accredited • Fast re-certification service for CRMs Development, Manufacturing, and manufacturing facility is fully integrated Administration facilities. vertically; with full control of all processes Spectrophotometer Cells in house and complete traceability, from Dissolution, Flow, Micro, Semi-micro, ultra- Starna has sales offices in the US, raw material to finished product. micro, Cylindrical, Absorption, Polarimeter, Germany, Australia, and China. UHV, Dye Laser, Temperature control, Markets served Magnetic stirring Beyond this, Starna distributes through Worldwide Pharmaceutical, Analytical a world-wide dealer network and via Chemistry, Biotechnology, Biochemistry, Starna DMV-Bio Cell instrument manufacturers. Food, Gas, Oil, Academic & Research Demountable Micro-Volume Cell (DMV-Bio) Institutions, and OEM Instrument for DNA/RNA and concentrated small Manufacturers. volume applications

Contact details Starna Scientific Ltd 52/54 Fowler Road, Hainault Business Park, IG6 3UT Tel. +44 (0) 208 501 5550 Fax. +44 (0) 208 501 1118 [email protected] www.starna.com New USP <857> Certified Reference Materials set

Pharmaceutical Technology Europe DECEMBER 2017 47 CORPORATE PROFILES

Veltek Associates, Inc.

Company description detergents for manual, soak, or spray Veltek Associates, Inc. (VAI), with over 35 applications. Our process cleaners years of experience, has developed an remove a wide array of organic or extensive line of products and services inorganic soils. that offer solutions to the challenges • Cleanroom Documentation—VAI’s of contamination control within line of cleanroom documentation aseptic manufacturing and controlled offers a synthetic writing substrate environments. With over 135 patents, we with extremely low particulation, are committed to continual innovation customizable documentation, and a and improvement in our products to HEPA filtered printer to print directly in satisfy current and future regulatory controlled environments. requirements. • RFID Tracking—VAI’s Core2Scan system is an identification and • Cleaning Equipment—VAI offers Markets served tracking system that pairs RFID a completely sterilizable, all in one, • Pharmaceutical asset and procedural identification spray, mop, and fog cleaning system. • Biotechnology devices, readers, and software The Core2Clean is an innovative way to • Medical Device tracking technology with a facility’s ensure cleaning and disinfection within • Laboratory Research equipment, products, and/or the cleanroom is being done correctly • Healthcare/Hospitals procedures. and efficiently. • Compounding Pharmacies • Garments—VAI has launched a redesigned line of sterile disposable VAI’s technical services include: Major products/services garments that include low • Consulting Services VAI’s innovative products include: particulation, high breathability, and • Cleaning and Disinfection Systems • Chemicals—VAI offers a complete line comfort while maintaining an athletic Evaluation of sterile and non-sterile chemicals. design and personal protection. • Disinfectant Validation Studies With EPA registered disinfectants • Cart Transfer Systems—VAI’s • Anti-Microbial Effectiveness testing and sporicides and cleaners including Cart2Core® simplifies correct aseptic • Personnel Gowning Training buffers, water, residue removers, cart transference by allowing the cart • Aseptic Processing Systems and lubricants, operations are able to top to detach from the base. With • Viable Air Monitoring Evaluation maintain critical environments while one lift of the handle and a slide, any staying compliant. cart top is transferred from one cart Facilities • Dry and Saturated Wipes—VAI’s base to another, leaving the potential VAI is headquartered in Malvern, wipers offer excellent particulate contamination behind. PA USA with satellite sales offices performance and are for use in all • Environmental Monitoring—VAI’s located worldwide. VAI in addition, cleanroom settings. A variety of viable monitoring equipment has been is able to serve the pharmaceutical VAI’s sterile chemicals are available an industry standard for over 30 years and biotechnology industries in an in saturated wipers including sterile by helping operations monitor, capture, even greater capacity through our 120 sodium hypochlorite and hydrogen and evaluate the ingress of viable distribution partners. peroxide wipes. contamination. In addition to viable • Process Cleaners—VAI offers a monitoring, VAI offers a complete line complete line of clean-in-place of particle counters.

Contact details Veltek Associates, Inc. 15 Lee Blvd. Malvern, PA 19355 Tel. +1-610-644-8335 Fax. +1-610-644-8336 [email protected] www.sterile.com

48 Pharmaceutical Technology Europe DECEMBER 2017 PharmTech.com ask the expert

What’s in Your SOP?

SOPs need to reflect a company’s specific manufacturing or other operations, says Susan Schniepp, distinguished fellow at Regulatory Compliance Associates.

I recently transferred to the document control department US 21 Code of Federal Regulations (CFR) 200.10 discusses Q:and am working with people on creating and/or revising the relationship between a contract provider and a contract standard operating procedures (SOPs). My colleagues have very giver by stating, “The Food and Drug Administration is aware different ideas on how much information should be included that many manufacturers of pharmaceutical products utilize in the SOPs. Some want very detailed instructions and others extramural independent contract facilities, such as testing want minimal information. Can you please advise on how laboratories, contract packers or labelers, and custom detailed SOPs should be to fulfill regulatory expectations? grinders, and regards extramural facilities as an extension of the manufacturer’s own facility.” Companies that outsource There is no right or wrong answer regarding how much all or some of their operations should rely on their quality A:or how little information should be contained in an SOP. agreements and the SOPs of their contract providers to define Whether you work in the medical device, pharmaceutical, or how they perform the services being outsourced. Contract bio-technology industry, you are relying on SOPs to help you providers should not write an SOP that defines something perform the day-to-day activities associated with your job. they are not doing that they have contracted for another The purpose of an SOP is to define the steps, in logical order, entity to do. needed to perform a repeatable task and achieve a repeat- able outcome. SOPs document the steps of key processes to help ensure a consistent, quality output. SOPs are useful tools SOPs should be written to for operationalizing, optimizing, and communicating important corporate policies, government regulations, and best prac- allow your personnel to tices for ensuring consistent, reliable, and safe medications or medical devices to patients. conduct operations in a SOPs should be written to allow your personnel to conduct operations in a consistent manner that will assure regulatory consistent manner. compliance and product quality. They need to reflect a com- pany’s specific manufacturing or other operations. The more Some companies, in particular start-up companies, might repeatable and consistent an operation or procedure becomes, be tempted to purchase pre-written SOPs. This activity might the less waste there will be in the process. Consistency be acceptable on the condition that the purchased SOP is in work performance will lead to fewer deviations and reviewed and the appropriate changes be made to reflect the investigations associated with the process, which translates actual operations of the company who purchased the SOP. into less down time and fewer product rejections. This is just Failure to tailor purchased SOPs to the actual specific process good business sense. will most likely result in a regulatory citation for failure to follow written procedures. Regulations and SOPs SOPs should not be written for regulators, but should reflect SOP format

a company’s operations. Writing SOPs to appease regulators Another consideration for an SOP is the format for COM or because you think the regulatory authorities require them communicating the information. A company needs to keep an K. TOC

will only lead to confusion and regulatory citations. Writing open mind to various SOP formats and communication types. S an SOP for a process, procedure, or operation that you do All SOPs, regardless of format, should offer clear step-by-step not perform just because it is listed in the regulations is not instructions and may utilize various presentation styles as a UTTER

advised. This concept is particularly important when taking means of communicating the details of the SOP. The following S/SH PALU

into consideration today’s environment. They are many virtual examples are presentation styles to be considered when and small companies that outsource much of their operations. writing SOPs: DAMIAN

Pharmaceutical Technology Europe DECEMBER 2017 49 • General description: This describes in paragraph form technique of an individual. The use of video recording could the necessary elements that need to be performed to be most helpful for people who need to gown appropriately to successfully execute the SOP requirements. enter into an aseptic manufacturing area. • Play script: This is a simple step-by-step instructional SOP. Its format is a written set of instructions with a logical sequence flow (operator does a, then b, then c, etc.). It is similar to following a recipe for making a cake. The There is no set rule majority of SOPs utilize this type of format. • Flow chart: A flow chart SOP translates the elements of dictating the format of the written step-by-step instructions into a sequence of pictures that define what is needed to perform the SOP instructions. operation in the defined sequence of steps displayed in the flow chart. • Pictorial: A pictorial SOP uses only pictures to Remember there is no set rule dictating the format of the communicate to the user the appropriate steps in the SOP instructions, and it is up to the company to determine SOP and the order they are to be performed. This type of what works best for your facility. SOPs should be written SOP can be useful when there are language concerns. to reflect a company’s business practices, allowing them • Combination: A combination SOP uses multiple methods, to optimize efficiency and productivity of their operations. such as both words and pictures, to communicate to the It is important to tailor your procedures to the personnel user the critical information in the SOP and the order in performing your operations whether highly experienced or which the steps are to be performed. relatively new to the regulated environment. The training on an SOP is equally as important as the information contained in Training for effective SOPs the SOP, and companies need to consider the most effective The final consideration for effective SOPs is training. The way to train personnel on an SOP. The training presented traditional read/understood acknowledgement may not be may not be the same for all SOPs. Bottom line, SOPs and the enough to assure that an employee understands the content associated training should be easily understood and able to of the SOP. Companies should consider group trainings and be followed by the employees who rely on them to perform comprehension evaluations for determining the effectiveness their job responsibilities. PTE of the SOP. Keep in mind, however, that just because an employee does not pass an SOP comprehension test does not necessarily mean the employee doesn’t understand. It could be an indication of a poorly written SOP or ineffective training. Companies should also consider training on SOPs through Your opinion matters. the use of video recording. This could include presenting Have a common regulatory or compliance question? video demonstrating proper technique as well as using video Send it to [email protected] and it may appear in a future column. recordings as on the job training tools to evaluate proper Ad Index COMPANY PAGE COMPANY PAGE

Baxter Healthcare Corp ...... 15, 41 Patheon Pharmaceuticals Services Inc ...... 10–11,45

Catalent Pharma Solutions ...... 42, 52 Quintiles/IMS ...... 26–27

Contec ...... 2, 43 Shimadzu Europe ...... 46, 51

GEA Process Engineering NV (GEA Group)...... 5, 44 Starna Scientific ...... 21, 47

NSF Health Sciences ...... Outsert Veltek Associates Inc ...... 7, 48

50 Pharmaceutical Technology Europe DECEMBER 2017 PharmTech.com Clever co-workers Outstanding platform for automated method development

The Nexera Method Scouting system provides an VALIDAT® all-round solution for efficient HPLC method for an automated method validation workflow development and implementation. The automated from preliminary plan to a fully customized valida- method development solution comprises of four tion report software packages which complement each other in creating a seamless method development work- flow. Method Scouting Solution software enables automated, quick and simple column and solvent screening LabSolutions software for data evaluation DryLab®4 HPLC modeling software focuses on strategic method optimization by calculation and visualization of the design space

www.shimadzu.eu/method-scouting bioavailability proven solutions. deepest expertise. versatile lipid technologies.

As the #1 global leader in drug development, we have the passion to help you start smart and move to clinic faster. Catalent utilizes award winning accelerated parallel screening to identify the best technology to advance your molecule with extensive analytical data and materials. Combined with dose form development and manufacturing expertise, we deliver a complete bioavailability enhancement solution.

• most widely studied and commercially successful bioavailability enhancing technology • fast path to softgel, a proven and versatile dose form lipid • deepest expertise with 80+ years of experience particle size hot melt spray formulation reduction extrusion drying

Catalent. More products. Better treatments. Reliably supplied.™ us + 1 888 SOLUTION (765-8846) eu 00800 8855 6178 catalent.com/optiform

˝ 2017 Catalent Pharma Solutions. All rights reserved.