LCMS-9030Liquid Chromatograph Mass Spectrometer

JUNE 2019 Volume 31 Number 6

BRAT LE IN E G C

A N Y N R IVERSA

Bringing Drug Delivery Home FOR PERSONAL, NON-COMMERCIALto Patients USE

FORMULATION PEER-REVIEW ANALYTICS Solubility and Bioavailability Managing Raw Data Glycosylation for Biopharma Quadrupole Time-of-Flight LCMS-9030Liquid Chromatograph Mass Spectrometer

FOR PERSONAL, NON-COMMERCIAL USE Effortless performance The LCMS-9030 quadrupole time-of-flight (Q-TOF) mass Effortless performance spectrometer integrates the world’s fastest and most with less recalibration and easy switching between sensitive quadrupole technology with TOF architecture. ionization units It delivers high resolution accurate-mass detection with incredibly fast data acquisition for routine applications. Small footprint due to a simple and compact floor-standing design Greater accuracy and higher sensitivity based on patented Ultra-Fast technologies

Identify and quantify more compounds with greater confidence in food applications, forensics, drug identification, proteomics and metabolomics

www.shimadzu.eu/effortless-performance June 2019 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: daniilantiq2010/ in the pharmaceutical and biotechnology industries. Sylfida - stock.adobe.com Art direction: Dan Ward

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PharmTech.com

GOOD LABORATORY PRACTICES Features 31 Good Laboratory Practices: Getting on the Same Page Quality and compliance depend on the right approaches COVER STORY to training, standard operating procedures, and validation. 9 Bringing Drug Delivery Home to Patients More tools are available to help ensure success. Combination products aim for user-friendly subcutaneous drug delivery. ANALYTICS 33 Leveraging Computational Models API SYNTHESIS AND MANUFACTURING of Glycosylation for Biopharma QA 13 Enabling Technologies Advance Close collaboration between academic and Poorly Soluble Highly Potent APIs industrial groups is vital to ensuring glycosylation Excipients and new processing techniques models are fit for deployment. can make a real difference in the development of highly potent therapies. SUPPLY CHAIN 38 On the Right Track FORMULATION Proactive approaches that consider long-term supply 16 Looking Beyond the Solubility Horizon chain security compliance are recommended to ensure Exploration of various formulation techniques is vital companies stay on the right track. to provide effective delivery of poorly soluble drugs.

INHALATIONFOR DRUG PERSONAL, MANUFACTURING NON-COMMERCIAL40 Filling the Early Intermediate Security USEGap 26 Considering Connected Inhalation Drug Delivery With increased focus on supply chain security, A connected MDI may encourage compliance companies need to re-emphasize upstream manufacturing. and aid proper technique. Columns and Regulars SCALE UP 28 Batch or Continuous? Ask the 5 Editor’s Comment Right Questions During Scale Up As Easy as ABC? Continuous manufacturing may offer huge 6 EU Regulatory Watch opportunities but will not be right for every facility. Regulating Cannabis-Based Medicines in Europe

42 Ask the Expert Quality Agreements and Out-of-Specification Investigations

Peer-Reviewed Join PTE’s community 19 Defining and Managing Raw Manufacturing Data Join the Pharmaceutical Technology Europe group on LinkedIn™* Protecting the integrity of raw data is crucial and start discussing the issues that matter to you with your peers.

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Pharmaceutical Technology Europe JUNE 2019 3 EDITORIAL ADVISORY BOARD

PharmTech Group Contributing Editor Reinhard Baumfalk Luigi G. Martini Editorial Director Cynthia A. Challener, PhD Vice-President, R&D Chair of Pharmaceutical Rita Peters Global Correspondent Instrumentation & Control Innovation [email protected] Sean Milmo Sartorius AG King’s College London PharmTech Europe (Europe, [email protected]) Editor Art Director Rafael Beerbohm Thomas Menzel Dan Ward Felicity Thomas Director of Quality Systems Menzel Fluid Solutions AG [email protected] Publisher Boehringer Ingelheim GmbH Jim Miller Senior Editor Michael Tracey Agnes Shanley [email protected] Phil Borman, DSc Founder and Former President, [email protected] Sales Manager Director, Product PharmSource, A Global Data Linda Hewitt Managing Editor Development & Supply Company Tel. +44 (0) 151 353 3520 Medicinal Science & Susan Haigney [email protected] Colin Minchom [email protected] Technology Senior Sales Executive Senior Director Manufacturing Editor Stephen Cleland Pharma R&D Jennifer Markarian Tel. +44 (0) 151 353 3647 GlaxoSmithKline Pharmaceutical Sciences [email protected] [email protected] Evonne Brennan Shire Pharmaceuticals Science Editor Sales Operations Executive European Technical Product Clifford S. Mintz Feliza Mirasol Barbara Williams Manager, Pharmaceutical President and Founder [email protected] [email protected] Division, IMCD Ireland BioInsights Associate Editor C.A.S.T. Data and List Information Amber Lowry Michael Kushner Rory Budihandojo Tim Peterson [email protected] [email protected] Director, Quality and EHS Audit Transdermal Product Boehringer-Ingelheim Development Leader, Drug Published by Delivery Systems Division, 3M MultiMedia Healthcare LLC Christopher Burgess Hinderton Point Managing Director John Pritchard Lloyd Drive Cheshire Oaks Burgess Analytical Consultancy Consultant Cheshire CH65 9HQ, United Kingdom Ryan F. Donnelly Thomas Rades Tel. +44 151 353 3500 Fax +44 151 353 3601 Professor Professor, Research Chair Queens University Belfast in Formulation Design and President, MultiMedia Healthcare LLC: Tim Freeman Drug Delivery, University of Thomas W. Ehardt Managing Director Copenhagen VP & Managing Director, Freeman Technology Rodolfo Romañach MultiMedia Healthcare LLC: Dave Esola Filipe Gaspar Professor of Chemistry Vice-President, R&D University of Puerto Rico, Hovione Puerto Rico Sharon Grimster Siegfried Schmitt PTE’s ReNeuron Vice-President Technical Join community PAREXEL Join the Pharmaceutical Technology Europe group on LinkedIn™* Anne Marie Healy Stane Srcic andFOR start discussing PERSONAL, the issues that matter to you with your peers.NON-COMMERCIALProfessor in Pharmaceutics and USE Pharmaceutical Technology Professor Go to PharmTech.com/linkedin Trinity College Dublin, Ireland University of Ljubljana, Slovenia Griet Van Vaerenbergh *The linkedIn logo is a registered trademark of LinkedIn Corporation Deirdre Hurley and its affi liates in the United States and/or other countries Senior Director, Plant GEA Process Engineering Helsinn Birex Benoît Verjans Pharmaceuticals Ltd. CEO Editorial: All submissions will be handled with reasonable care, but the publisher assumes no responsibility for Arlenda safety of artwork, photographs, or manuscripts. Every precaution is taken to ensure accuracy, but the publisher Makarand Jawadekar cannot accept responsibility for the accuracy of information supplied herein or for any opinion expressed. Independent Consultant Tony Wright Subscriptions: Pharmaceutical Technology Europe is free to qualifi ed subscribers in Europe. Managing Director To apply for a free subscription, or to change your name or address, go to Henrik Johanning PharmTech.com, click on Subscribe, & follow the prompts. CEO, Senior Consultant, Exelsius To cancel your subscription or to order back issues, please email your request to fulfi [email protected], putting PTE in the subject line. Genau & More A/S Please quote your subscription number if you have it. Marina Levina Reprints: Reprints of all articles in this issue and past issues are available (500 minimum). Licensing and Reuse of Content: Contact our offi cial partner, Wright’s Media, about available usages, license Product Owner-OSD, TTC- fees, and award seal artwork at [email protected] for more information. Please note that Wright’s Media is the only authorized company that we’ve partnered with for MultiMedia Healthcare materials. Tablets Technology Cell, GMS GlaxoSmithKline

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4 Pharmaceutical Technology Europe JUNE 2019 PharmTech.com EDITOR’S COMMENT As Easy as ABC?

Big Pharma is partnering with Alphabet company, Verily, to modernize clinical trials and accelerate time-to-market for drugs.

ecently, it was encourage diversity in research to truly data for a greater understanding of Rannounced that understand health and disease, and to diseases, reconnecting trials to our several pharma provide meaningful insights about new patients’ healthcare journeys.” companies, namely medicines, medical devices, and digital Novartis, Sanofi, health solutions,” said Jessica Mega, Not in Europe, yet … Otsuka, and Pfizer, chief medical and scientific officer, So far, the project is solely focused on were to be Verily, in a press release (1). “Novartis, the United States, but the company is strategically aligned Otsuka, Pfizer, and Sanofi have been hopeful to expand it out on an with Verily, an early adopters of advanced technology international scale. However, there may Alphabet company, in an initiative aimed and digital tools to improve clinical be some bumps in the road ahead for at engaging more patients and clinicians research operations, and together we’re these plans, as European data protection in clinical research (1). As clinical trials taking another step towards making could prove a challenging obstacle to can sometimes prove to be a sticking research accessible and generating overcome. point for drug developers, in terms of evidence to inform better treatments Google is already facing investigation dwindling or even lacking participation and care.” by the Irish Data Protection Commission numbers, could this initiative offer a (DPC) surrounding the way it uses paradigm shift by making trials more Reinventing the clinical trial wheel personal data for targeted advertising (2) accessible? However, reinventing the clinical trial and whether or not this adheres to the wheel is not necessarily a brand-new 2018 General Data Protection Regulation, The basis of Project Baseline concept. There has been a plethora of which may mean Europe is not as Project Baseline was originally launched news items in recent years on how attractive as other regions for rollout of in 2017 by Verily with the goal of closing various companies or research bodies Project Baseline. the gap between clinical research and are implementing technological solutions It will be a case of waiting and patient care. Partners of the original to help accelerate the costly and watching as to whether data protection project included Duke University School time-consuming clinical trial process. becomes an issue for the initiative on of Medicine,FOR Stanford PERSONAL, Medicine, the The difference NON-COMMERCIAL that perhaps makes the whole and whether theUSE global uptake American Heart Association, and Verily’s Project Baseline stand out from the of stricter data regulations, a possibility sister company, Google. Technology and crowd is the ability of Verily to lean on given the political draw such issues can tools, including DNA tests and wearable its sister company, Google, to engage have, hampers the potential this project devices, were developed and built for with patients using tools such as may have on accelerating the lab the project, and were used to map out personalized advertising functionality for bench-to-bedside timeline of drugs in human health. engagement. For example, if a patient development. Now, Verily is looking to enrol more performs a Google search for treatments patients within its registry and the within a specific therapeutic area, an ad References aforementioned industry partners will that offers enrolment within a clinical 1. Verily, “Verily Forms Strategic Alliances leverage the Baseline Platform—an trial from Verily could be placed on the with Novartis, Otsuka, Pfizer, and Sanofi end-to-end evidence generation web page being viewed by said patient. to Transform Clinical Research,” Press platform—to support their clinical “Our scientific knowledge has Release, 21 May 2019. studies across a variety of therapeutic exploded over the past generation, but 2. DPC, “Data Protection Commission Opens areas. The ultimate aim is to create efficiently bringing these new Statutory Inquiry into Google Ireland patient-centric trial programmes that will breakthroughs from lab bench to patient Limited,” Press Release, 22 May 2019. deliver ‘real-world evidence’ for the requires us to greatly improve the way companies, which is certainly seems to we conduct these complex clinical trials,” be a buzz term currently experiencing said Lionel Bascles, global head of enthusiasm within the bio/pharma sector. clinical sciences and operations, Sanofi, Felicity Thomas “Evidence generation through research in a press release (1). “Project Baseline Editor of is the backbone of improving health will allow us to better recruit appropriate Pharmaceutical Technology Europe outcomes. We need to be inclusive and patients and more efficiently integrate [email protected]

Pharmaceutical Technology Europe JUNE 2019 5 EUROPEAN Sean Milmo REGULATORY WATCH is a freelance writer based in Essex, UK, [email protected].

Regulating Cannabis-Based Medicines in Europe

The current fragmented regulatory approach to cannabis medicines across Europe is challenging to harmonize.

fter a radical shift in public, medical, and scientific opinion Even countries with a relatively relaxed policy on the use Aabout the effectiveness of cannabis-based medicines in of cannabis as a medicine broadly followed a regulatory the treatment of certain conditions, most European countries framework laid down by an amended version of the 1961 CND. have legalized the use of these drugs. But European states, Compliance with the treaty’s requirements on medical use particularly in the European Union, have adopted a range of of cannabis is monitored by the Vienna-based International different regulatory policies for dealing with the medicines, Narcotics Control Board (INCB), which is responsible for the particularly with regard to the quality standards in the implementation of the UN drug control conventions, including cultivation of the cannabis crops and the manufacture and the CND. The CND requires that governments establish a distribution of their medicinal products. national cannabis agency to control the production and The vast majority of countries have approved cannabis regulation of the supply of cannabis for medical use, according medicines after they have gone through the standardized to the INCB’s latest annual report (3). authorization process based on good manufacturing practice “The national agency is required to license producers, (GMP) and positive clinical trials. Also, many have stipulated purchase and take possession of stocks, and maintain a

REGULATION & COMPLIANCE REGULATION that they should only be available by prescription. monopoly on wholesale trading and stocks,” says the INCB A growing number of countries, however, have begun (3). “All programmes for the medical use of cannabinoids must to allow access to the medicines through unconventional be developed and implemented under the full authority of the regulatory schemes with less quality controls on cultivation state concerned.” and manufacture and less importance given to evidence from The INCB is critical of what it regards as “poorly regulated” clinical trials. The result has been a fragmented regulatory medical cannabis programmes. These programmes approach across the region to cannabis medicines, which will include allowing the use of cannabis for a wide variety of be a challenge for regulators to harmonize. medical conditions in the absence of evidence of efficacy FOR PERSONAL, NON-COMMERCIALand safety from controlled clinical trials, the USE provision of The history of cannabis in Europe non-standardized cannabis products under minimal medical Although the Cannabis sativa plant has a long history as supervision, and the cultivation of cannabis by patients a source of medicines, its use as a means of treatment themselves or the purchase of it from commercial outlets that of illnesses had declined by the past century. In 1961, the produce cannabis illicitly. United Nations’ Single Convention on Narcotics Drugs (CND) The Netherlands, the first European country to relax rules categorized it as a drug with no medical use, effectively ending restricting use of medical cannabis, introduced a law in 2003 its availability as a legal medicine in the many European and allowing doctors to prescribe it for a wide range of conditions, other countries that signed the treaty (1). leaving the doctor to judge whether it would be an effective Its revival as a medical treatment over the past 20 years treatment (1). followed mounting scientific evidence that cannabinoids— In compliance with the 1961 CND but also to ensure quality substances found in the cannabis plant that act on specific control, a single, private Dutch company, Bedrocan, has been receptors in the human brain and body—could effectively treat granted a monopoly to produce cannabis, with its products conditions like chronic pain and neurological disorders such a mainly comprising the cannabinoids cannabidiol (CBD) and multiple sclerosis and epilepsy. Scientists also discovered that tetrahydrocannabinol (THC), the compound that gives cannabis the human body has its own cannabinoids—endocannabinoids— a euphoric effect. Bedrocan’s products are not only sold in the and that synthetic cannabinoids could be made in the laboratory. Netherlands but exported to several other European countries. In certain countries, there has been a sharp rise in consumption of cannabis medicines after they were allowed to Regulating cannabis for medicinal uses be prescribed or even made available without prescription. In After Germany changed its legislation two years ago to allow the Netherlands, the medical use of cannabis—mainly for the doctors to officially prescribe medicinal cannabis products, treatment of chronic pain prescribed by pharmacists—went the country’s Federal Institute for Drugs and Medical Devices up from 6.9 per 100,000 patients in 2010 to 24.6 per 100,000 (BfArM), its medicines licensing as well narcotics control body,

patients in 2016 (2). set up a German Cannabis Agency. IMAGES RF/GETTY ZOONAR GLOBE:

6 Pharmaceutical Technology Europe JUNE 2019 PharmTech.com MOVE PRODUCTS NOT CONTAMINATION

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“The functions of the Cannabis Agency are based on the proprietary cannabinoid product platform. This includes the requirements set out by the (amended 1961) Convention,” building-up of a library of internally generated novel cannabis explained Prof. Dr. Werner Knoess, head of the new agency, in types, development of in-house extraction, processing an interview in BfArM’s latest annual report (4). “We monitor and analytical techniques, and in-house formulation and the cultivation, harvest, quality assurance, storage, packaging, manufacturing capabilities. and distribution of cannabis to wholesalers and chemists or Despite following the standardized route to the manufacturers.” development and authorization of its products, GW is still The agency has been selecting suitable companies to subject in the UK and elsewhere to national regulations cultivate cannabis, which will then be purchased by the on controlled substances like cannabis. The company’s agency for distribution through third parties to medicine cultivation, manufacture, distribution, exporting, and importing producers and pharmacists. The BfArM had to draw up its own of cannabis and its medical derivatives has to be regularly pharmacopoeia monograph to ensure that the cannabis meets licensed by national narcotics agencies. pharmaceutical-grade standards. Because of what it regards as limited knowledge of the Maintaining control effectiveness and safety of cannabis medicines, the BfArM’s However, international monitoring organizations such as INCB narcotics control branch is conducting a five-year survey on are complaining that changes to national regulations to lift their application, due to be completed in 2022. restrictions on medicinal cannabis are undermining controls on An increasing number of European states are now the recreational use of the plant’s extracts, particularly THCs. permitting access to unlicensed cannabis-based medicines The long-established system, backed by international treaties, through individualized schemes like named-patient systems of strict curbs on cannabis consumption is also being weakened and compassionate or exceptional use. by the spread of applications of cannabis-based substances Under a law in Italy allowing any doctor to prescribe plant to skin-care cosmetics and toiletries. CBD oils are even being extracts, cannabis preparations for medical use can be made available as a food in Europe, although they have to be provided by any pharmacy as long as it complies with the given approval as a novel food product to be marketed.

REGULATION & COMPLIANCE REGULATION specifications on the prescriptions. In November 2018, the expert committee on drug After a review by its Home Office (interior ministry) dependence at the UN’s World Health Organization (WHO) in concluded that there was ‘conclusive’ or ‘reasonable’ evidence Geneva recommended a relaxation of restrictions on cannabis of the therapeutic benefits of cannabis-based medicines in the and cannabis-related substances. The deregulation of the treatment of certain medical conditions, the UK government cannabis market may work against pharmaceutical companies announced in October 2018 plans to change its Misuse of focused on the development of high-quality but highly regulated Drugs Regulations to allow doctors to prescribe unlicensed cannabis-derived medicines. cannabis medicines (5). The doctors would have to be CBD and THC are the only cannabinoids that have been specialistFOR physicians PERSONAL, with knowledge of cannabis medicines NON-COMMERCIAL researched in depth for their possible medical USE properties, but and the conditions for which they have therapeutic value. They there are at least 70 others that may be effective medical would be able to specify the formulation of the medicines to treatments. the manufacturer, which will have to meet GMP standards. “We are at the forefront of [a] new area of science,” says GW The United Kingdom is the home base of GW Pharmaceuticals, (6). But the potential of that science may be more difficult to which over the past 20 years has been pioneering the achieve with a decriminalized cannabis market in which the development of cannabis-based medicines through the divide between recreational and medical use will become standard authorization procedure for pharmaceuticals blurred. including GMP quality assurance and controlled clinical trials. The company’s lead product is Epidiolex, a CBD treatment References for two childhood-onset drug-resistant epilepsy syndromes, 1. European Monitoring Centre for Drugs and Drug Addiction (EMCDDA), Lennox-Gastaut and Draver. The drug was approved by the “Medical Use of Cannabis and Cannabinoids,” Rapid Communication US Food and Drug Administration (FDA) in June 2018 and (Lisbon, December 2018). was due to complete the European Medicines Agency’s 2. B. de Hoop, E.R. Heerdink, and A. Hazekamp, Cannabis Cannabinoid authorization process for marketing in the EU in the second Res., 2018 3(1) 54–55. quarter of 2019. 3. INCB, “Chapter I: Cannabis and Cannabinoids for Medical, Scientific, GW’s first cannabis medicinal product—Sativex, a mouth and ‘Recreational’ Use: Risks and Benefits,” 2018 Annual Report (Vienna, spray comprising 50/50 CBD and THC for relief of multiple 5 March 2019). sclerosis symptoms—was approved in the UK in 2010 and is 4. BfArM, 2017–2018 Annual Report (Bonn, June 2018). now available in numerous countries across the world under 5. MHRA, “The Supply, Manufacture, Importation, and Distribution of marketing agreements with international pharma companies Unlicensed Cannabis-Based Products for Medicinal Use in Human such as Bayer and Almirall. ‘Specials’,” Guidance Document (London, November 2018). The strategy being followed by GW is to maintain a world- 6. GW Pharmaceuticals, Annual Report and Accounts 2018 (Cambridge, leading position in cannabinoid medicines through its 2019). PTE

8 Pharmaceutical Technology Europe JUNE 2019 PharmTech.com daniilantiq2010/Sylfida - stock.adobe.com Jennifer Markarian FOR PERSONAL,NON-COMMERCIAL USE and thus have low annual quantities, notes Thompson. Thompson. notes quantities, annual low have thus and populations patient smaller target that drugs for important particularly is which cost-efficiency, manufacturing for important is therapies multiple for customized pharma companies, says Thompson. with trials feasibility in engaging is company the and (see 3–10 mL of range the in drugs antibody-based for injector developing YpsoDose as a prefilled, ready-to-use, patch is Ypsomed notes. he therapies,” immuno-oncology or autoimmune quarterly or monthly for space 3–10 mL the in be will injectors patch for key applications the believe “We Systems. Delivery Ypsomed at development business of vice-president Thompson, Ian says frequency, injection and volume injectable the on depends injector ahandheld than rather injector awearable Choosing platforms device New T delivery systems,delivery or wearable bolus injectors (WBIs). patch injectors, large-volume body injectors, on-body called be also may which autoinjectors, wearable volume, larger- these for need agrowing creating is doses volume larger- in delivered be must that biologics of use increasing The injector. ahandheld of dose smaller the for seconds to compared minutes, of amatter over dose volume larger a inject to skin the to attached is which autoinjector, wearable the is use, broader see to soon perhaps but today familiar as not device, of type Another pens. or autoinjectors handheld prefilled, with familiar be may Patients mind. in patients with designed and correctly use to easy are that products combination drug-device Using platform technologies that can be easily easily be can that technologies platform Using subcutaneous drug delivery is creating a need for for aneed creating is delivery drug subcutaneous home-based, self-administered, to trend he Figure 1 Figure ). Functional devices for testing are available, available, are testing for devices ). Functional battery life in cold storage conditions and reduces the the reduces and conditions storage cold in life battery electronic component also eliminates the limitations of the Eliminating Subcuject. of CEO Roested, Jesper cP,” 50 than more to up explains viscosities for minute per 1 mL around is rate flow injection The devices. electromechanical with aproblem be can which pressure, back tissue high or viscosities high with aproblem not therefore, is, it and pressure drive ahigh create can “Osmosis electronics. without drive, mechanical afully is which pump, osmotic an using 1–10 mL drug of deliver to commercialization, adds Yosef. and development in risk lowers solution aplatform Using containers. primary sized different accommodate to shelling outer the to modifications slight with mechanism, pumping same the on based are devices the all that notes Yosef apartner.” with commercialization to developed be can and stages earlier the in are configurations other The available. prototypes working has device 20-mL “The Medical. Sorrel Yosef, of CEO Andrei says partners,” pharmaceutical our by testing feasibility performing for available is and validated and verified fully been has configuration device 3-mL “The 1–20 mL. from ranging configurations in injectors wearable format. tub aready-to-fill in filled are that cartridges glass 10-mL standard, hold to designed are devices The connectivity. provide to place in already is circuitry electronic the and times, injection reproducible allow which rates, flow consistent ensures system drive This volumes. fill or viscosities different for programmable is system drive electromechanical the addition, In equipment. and tooling same the from customers and products multiple for devices produces Ypsomed Delivery Home Subcuject is developing a platform for prefilled WBIs WBIs prefilled for aplatform developing is Subcuject prefilled single-use, developing is Medical Sorrel Bringing Drug Bringing Drug Pharmaceutical Technology Europe Wearable and smart devices aim for user- for aim devices smart and Wearable friendly subcutaneous drug delivery. drug subcutaneous friendly to Patients to JUNE 2019 9 Drug Delivery Devices

in March 2018 for its expandable for self-injection can incorporate Figure 1. Ypsodose is Ypsomed’s elastomeric bladder and infusion “smart” sensors and mechanisms 3–10-mL prefilled, preassembled cannula system, and additional patent to communicate information from patch injector. applications are pending in the United the device to the user. Furthermore, States and other countries. Apellis wearable injectors can be connected Pharmaceuticals is conducting human through the Internet, typically using near- clinical trials using enFuse technology field connectivity (NFC) or Bluetooth, to deliver its immunotherapies, and to communicate information through a biopharmaceutical company UCB smart phone or other connected device entered a development agreement with to a patient or to others, such as their Enable Injections in November 2018 (1). medical team. West’s SmartDose technology On Sorrel Medical’s devices, for platform (see Figure 3) is an on-body example, smart sensors “include air and Figure 2. The enFuse On-Body infusor that uses a Daikyo Crystal occlusion detection, needle position, Infusor from Enable Injections is Zenith cartridge and a Flurotec- ensuring the primary container is in being developed as a platform coated piston containment system. place, and on-body detection, in addition for volumes from 5–50 mL. A combination product from Amgen to a series of internal system checks,” for a single, monthly dose of Repatha says Yosef. In addition, Sorrel’s devices (evolocumab) using West’s SmartDose have integrated NFC and Bluetooth technology was approved by the connectivity. US Food and Drug Administration In the enFuse device, a gauge and the (FDA) in July 2016 (2). In January 2019, button mechanism give active feedback scPharmaceuticals announced that it to the patient for delivery progress and had completed preliminary feasibility end-of-delivery cues, says Huddleston. studies of its Furoscix (furosemide) “Beyond this, an option in development with the SmartDose Drug Delivery for connectivity will be capable of System and was moving forward with interfacing with smartphone applications development in anticipation of filing a to give information such as the delivery new drug application in 2020 (3). West status of the device and the patient,” also announced a collaboration with fill/ he adds. “Connectivity could potentially finish provider Swissfillon to provide improve patient compliance, verify environmental impact of disposal, he bio/pharma customers with clinical fill/ proper device function, and increase says. The company is currently testing finish capability with the SmartDose patient safety by identifying possible performance of functional device technology (4). risks.” Management of confidential models, and the device is expected to be patient data, however, is a challenge, ready for regulatory development by the Primary container design and connectivity to a healthcare provider FOR beginningPERSONAL, of 2020. The WBI is designed NON-COMMERCIALMost wearable injectors are designed or other party can raise USE concerns about to have low cost of goods, and assembly to use conventional primary containers. data privacy. and filling is straightforward, says A new development programme from “Both pharmaceutical companies Roested. It is also designed to promote SCHOTT is aimed at bringing design and device manufacturers are aware of uncomplicated development at pharma freedom to the container, which the the vast potential in having data from companies by using a standard glass company says can give manufacturers connected drug delivery devices, and cartridge with a plunger of standard the ability to improve the design of how it may be utilized to benefit various material. wearables. Customized designs could patient populations,” agrees Yosef. “We The enFuse On-Body Infusor from reduce the container size to make the believe the question of how that data Enable Injections, shown in Figure 2, is device more discreet, for example, or will be used is one that must be had with being developed as a device platform add dimensional features (e.g., a ring, each individual pharmaceutical partner for volumes from 5–50 mL, says bar, or notch) to the container to improve based on the molecule, the indication, Matt Huddleston, Enable Injections alignment and allow easier assembly or and the patient population.” executive vice-president and chief improve the connection force between Connected devices are being technology officer. A unique aspect of the container and device, explains Tom developed for combination products the technology is the use of a constant- van Ginneken, global product manager besides wearable injectors. For pressure design using an elastomeric at SCHOTT. Such containers would use example, Haselmeier is collaborating pump, rather than a constant-flow standardized tub-and-nest transport with Common Sensing to develop design using an electromechanical packaging for the filling step. a smart, disposable injector pen pump. “This design allows the enFuse to platform. Haselmeier’s subcutaneous automatically adapt to the injection site Smart and connected devices drug delivery injection systems for back pressure, and it is hypothesized The move to self-administration at self-administration will be combined to potentially alleviate infusion site home rather than in a clinic makes with Common Sensing’s Gocap injector leakage and pain,” notes Huddleston. communicating information to monitoring technology to record the

The company received a US patent patients crucial. Devices designed time and amount of every injector INJECTIONS ENABLE OF COURTESY IS 2 FIGURE SYSTEMS; DELIVERY YPSOMED OF COURTESY IS 1 FIGURE

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module) will be important for bringing Figure 3. West’s SmartDose platform includes devices with dose down the cost of connected products, volumes of up to 10 mL and preloaded options. agrees Jansen. Another challenge is ensuring the electronics and software are compliant, including testing for data security and understanding and minimizing the risk of software bugs. Managing software updates can also be a challenge. “Pharma companies should be prepared for the unique challenges of being accountable for connected products,” Jansen says.

References dose, along with other information, to assess patient health and potential 1. Enable Injections, “Enable Injections such as storage temperature, says the exacerbations.” Although the initial cost Enters into Strategic Partnerships with company (5). Initially the monitoring may be a concern, Shankar believes that UCB and Apellis Pharmaceuticals,” Press cap will be an add-on, replacement the cost of connected devices will come Release, 13 Nov. 2018. cap, but is intended to eventually be down as increased adoption results 2. West, “West’s SmartDose Drug Delivery an integrated device, says Paul Jansen, in higher volumes. A key challenge for Technology Platform Selected by Amgen Haselmeier advisory board member. manufacturing connected devices is for Pushtronex System,” Press Release, “Initial products are expected to be managing the need for manual assembly 11 July 2016. focused on clinical trial use. In this of early-stage, low-volume devices 3. scPharmaceuticals, “scPharmaceuticals environment, patients are engaged and as well as the need for automated Inc. Announces Development Agreement motivated to collect data,” notes Jansen. assembly for higher volumes, he notes. with West Pharmaceutical Services for Connected devices are ideal tools Securing the supply chain for electronic Next-Generation FUROSCIX On-Body for disease management, says Sai components is crucial, adds Shankar. Infusor,” Press Release, 29 Jan. 2019. Shankar, vice-president, Global Digital Selecting known suppliers with medical- 4. West, “West and Swissfillon to Partner on Healthcare Systems, at Aptar Pharma, grade quality components, dual-sourcing an Integrated Solution for Clinical Filling of which offers both add-on and integrated components where feasible, and SmartDose Drug Delivery Platform,” Press connected devices for several different understanding the total cost of supply Release, 6 Feb. 2019. delivery routes. “They provide real- are key considerations. 5. Common Sensing, “Haselmeier and time analysis of dose adherence and Finding manufacturing efficiencies Common Sensing Enter Connected patterns of dose administration, and such as using automation or standard Injectable Medicine Collaboration,” Press they are potentially diagnostic tools parts (e.g., electronic chip or Bluetooth Release, 3 May 2018. PTE FOR PERSONAL, NON-COMMERCIAL USE Human factors engineering

Developers of drug-device combination products should use identified by the US Food and Drug Administration during review human factors (HF) studies to ensure that the product can be used are often related to concerns that specific use errors identified in effectively and safely and “eliminate or mitigate patient adverse HFE studies may lead to a potential underdose or overdose of the events and medication errors attributable to use-related errors” (1). drug constituent part. Without demonstrating that appropriate While device manufacturers are well-versed in HF, the final mitigations have been put in place to resolve these types of use responsibility lies with the pharma company submitting the errors, substantial design changes to the device constituent part combination product. Ypsomed, for example, performs its own may be required to gain product approval.” HF work and also supports its customers, who are expected to Failure to adequately integrate the drug and device constituent perform additional formative and summative HF work, explains parts within the overall design and development plan for the Ian Thompson, vice-president of business development at drug-device combination product is another problem, says Johns. Ypsomed Delivery Systems. “The bottom line is that drug and device constituent parts “Human factors engineering (HFE) studies are not a ‘check the cannot be developed independently or in silos; cross-functional box’ activity to meet submission requirements,” says Stefanie team members from both sides must communicate frequently Johns, Enable Injections associate director of Regulatory Affairs. and transparently.” “Complete response letters for drug-device combination products Reference are most frequently a result of HFE deficiencies. It is up to the 1. FDA, Human Factors Studies and Related Clinical Study marketing application holder to demonstrate safe and effective Considerations in Combination Product Design and use of the drug-device combination product by the intended Development, Draft Guidance (FDA, February 2016). users within the intended use environments. The HFE deficiencies —Jennifer Markarian FIGURE 1 IS COURTESY OF YPSOMED DELIVERY SYSTEMS; FIGURE 2 IS COURTESY OF ENABLE INJECTIONS ENABLE OF COURTESY IS 2 FIGURE SYSTEMS; DELIVERY YPSOMED OF COURTESY IS 1 FIGURE 12 Pharmaceutical Technology Europe JUNE 2019 PharmTech.com Shawn Hempel - Stock.Adobe.com Europe. Pharmaceutical Technology to editor acontributing is Challener A. Cynthia Highly Potent APIs Potent Highly Advance Poorly Soluble Technologies Enabling in the development of highly potent therapies. difference areal make can techniques processing new and Excipients FOR PERSONAL,NON-COMMERCIAL USE

overcome these hurdles. these overcome partners outsourcing their and makers drug helping are technologies enabling Several manufacturing. and development formulation to respect with challenges additional pose can HPAPIs soluble poorly morphologies, and moieties particular their upon dependent highly are world small-molecule the in and (HPAPIs) APIs potent highly challenges. permeability or solubility has also and handling special requires and/or potent highly is pipeline development drug to Pharmaceutical Technologyreported Europe &Nutrition Biotech (1). Pharma Lonza permeability) high solubility, (poor II Class being compounds these of majority the &Co., with Kline by Study a2015 to Market IV, or II according Class (BCS) System Classification Biopharmaceutics the into fall and solubility low exhibit pipeline pharmaceutical the in drugs of 70–80% Approximately areas. disease rare and chronic other and oncology for options treatment improve to seek product is not robustly formulated. robustly not is product the if large be can dosage absorbed of variability the consequence, a As McNaughton. to according sizes, larger their due limited is that permeability have often also effects, side minimizing while activity, observes. he timelines,” development meet to challenging it make can which needed, be can areas experimental dedicated enha bioavailability of challenges technical the With contamination. for concern without and safely work their do to able are operators that ensuring to dedicated be must manufacturers and companies “Biopharma & Nutrition. Biotech Pharma Lonza with director technical McNaughton, Alyn to according times, all at safe kept is operator the ensure to practice good and equipment, appropriate care, requires HPAPIs of handling Any challengesMultiple N While solubility and bioavailability challenges are not unique to to unique not are challenges bioavailability and solubility While As one example, complex molecules designed to provide targeted targeted provide to designed molecules complex example, one As the past decade as pharmaceutical and biotechnology companies companies biotechnology and pharmaceutical as decade past the over potency in increase to continued have entities molecular ew ncement, additional time and that 20% of the current current the of 20% that Pharmaceutical Technology Europe analytically may provide poor surface surface poor provide may analytically and challenging, more inherently is reactors cleaning means solubility over. “Low change at equipment in manufacturing the carryovers allowable low drives also compounds challenge,” he says. lyophilization presents a similar formulations, parenteral worker. For any for airspace breathing the in dust create to tends it since achallenge poses containment, tonot do impossible in appropriate while solids, of milling instance, For appropriate containment systems. with outfit to difficult more are drying spray and like micronization solubility improve to forms dosage solid for approaches API “Typical Alcami. at technology and science of manufacturing director senior global Kujath, Adam to according deployed for solubility enhancement, be can that technology the limit can notes. she product,” drug finished the of manufacturing the and engineering particle from resulting intermediates as well as substance, drug the of containment and handling the in expertise and processes specialized for aneed is There amounts. small extremely at exposure concerns for workers, even potential create can molecules associated with increased health risks. be can particles However, micronized and consequently absorption. transport drug facilitate to increased be will vessels blood and gut the the concentration gradient between Evonik, at solutions delivery drug oral for director marketing strategic Mueller-Albers, Jessica to according dissolution. With this approach, of rate the influence strongly says. he dosage,” specified the than, bigger even sometimes of, or portion alarge be may HPAPI the of particle individual an where product, the within homogeneity challengesecondary of achieving the presents situation “This adds. McNaughton less, or micrograms few a only low, often incredibly be can product the in required dosage the enabled, readily be can bioavailability The toxicity of highly potent potent highly of toxicity The containment in challenges fact, In these of potency high “The can APIs of size particle The where materials for Even JUNE 2019 13 API Synthesis & Manufacturing

recoveries or impact the achievable to a completely different area,” adds McNaughton adds. “Under certain cleaning method sensitivity. McNaughton. “The resulting process permeability-limited situations or Furthermore, if they happen to be commonly needs to be qualified to biological obstacles, there are specific organometallic compounds, you have ensure the containment is sufficient lipidic excipients that can provide to worry about not only the active for the product being manufactured some permeability enhancement, compound, but related organometallic so that any resulting operator others that inhibit efflux, and others and inorganic metallic species (such contamination is significantly below that could avoid first pass metabolism as mercury, arsenic, and platinum) as the level at which the HPAPI could have through utilization of the lymphatic typical byproducts,” Kujath explains. a therapeutic effect,” he continues. system,” he says. For contract drug-product Cleaning of processes involving The use of polymer-based manufacturers, the first hurdles can HPAPIs must also be conducted in a excipients is widely appreciated in the occur upon receipt of the HPAPI. closed system and is often the time formulation of poorly soluble HPAPIs, Packaging systems can vary widely, where there is the greatest risk of according to Mueller-Albers. They play and it is rare for the manufacturer exposure for the operator, according a key role in the formation of solid of an HPAPI and the product to McNaughton. A key challenge for solutions, stabilizing the amorphous manufacturer to use a common HPAPIs is the fact that cleaning must HPAPI in the solid state to prevent handling system, according to be conducted to a level at which recrystallization, and also helping to McNaughton. A suitable mechanism, there is no risk of contamination maintain HPAPI supersaturation in therefore, needs to be available for of subsequent products—a level physiological media, she explains. accessing the HPAPI in a safe and at which residual HPAPIs are often Polymeric excipients are also used in hygienic fashion. difficult to detect. When detection formulations prepared via granulation cannot be achieved, dedicated using high-shear mixing or fluid-bed Effective containment equipment or even facilities are spraying, which can under certain An effective containment strategy often required for a single product to conditions be applicable for poorly should include clear, standardized ensure no cross-contamination with soluble HPAPIs. processes for equipment startup, as other products is possible. well as defined cleaning procedures Even though risks are believed Enabling technologies and robust decontamination to be controlled or removed, The first HPAPIs were often formulated procedures, according to Mueller- McNaughton stresses that it is as liquids and then filled into capsules Albers. “It is integral to have important to ensure plans, systems, to reduce safety risks such as dust operators who are well-trained in and training are established so that formation. Liquids, however, present the operation of relevant equipment in a worst-case scenario, such as an challenges when solubility is an and procedures for the types of accidental release, there is no risk of issue, according to Kujath. “While substances being handled,” she adds. contaminating the environment and micronization and spray drying of Any handling, introduction, a mechanism is in place to clean the the HPAPI can be helpful for oral and transfer of powder between area back to a safe standard without solid formulations, these techniques FOR processingPERSONAL, steps must be conducted NON-COMMERCIALany risk to the operators. to drive initial dissolution USE for liquid in a closed or isolated system, formulations can present stability which requires more complex and Excipient options challenges, such as crystallization specialized equipment, according Excipients that are helpful in any of an initially dissolved amorphous to McNaughton. “Highly diligent low solubility drug are generally HPAPI from the vehicle or ripening in processes are required to prevent applicable to an HPAPI with a micronized dispersion,” he explains. operators and the surrounding low solubility. Solubilizers and Thermocycling during terminal environment from being exposed disintegrants are two examples, sterilization can also cause ripening or to dangerous airborne powders,” according to Kujath. Excipient recrystallization or break complexes Mueller-Albers adds. She notes that selection should be based on a formed by solubilizers such as in addition to closed systems for combination of the chemical and (2-hydroxypropyl) beta-cyclodextrin. milling, containment systems for physical properties of the HPAPI As the number of HPAPIs in spray drying have also improved and the target product profile, development has increased, however, considerably over the past decade, according to McNaughton. “Meeting manufacturers have aggressively which has created opportunities a target product profile for a poorly examined new processing techniques for the spraying of HPAPIs to form soluble API requires both the correct suitable for oral solid-dosage amorphous solid dispersions. technology selection and the forms, according to Mueller-Albers. For some technologies, equipment appropriate science-led formulation Particle-size reduction, or particle- may be specific to the individual development,” he comments. size design, amorphous dispersions, process and require specialized While there are no specific and lipid-based formulations are all handling protocols. “HPAPI product excipients that are suited to highly suitable techniques for improving the manufacturing is most straightforward potent materials, there are certain bioavailability for solubility-limited for processes that have minimal steps, aspects of some technologies that HPAPI, according to McNaughton can be serially conducted, and do not offer advantages if they are also the “Particle-size reduction is likely require the material to be transferred correct technology for the product, to lead to an increase in the rate of

14 Pharmaceutical Technology Europe JUNE 2019 PharmTech.com API Synthesis & Manufacturing

solubility for an API and may provide conjugates, which are useful for compensate. Understanding the some supersaturation effects, but targeted delivery of small-molecule active sites of drugs and what can be is unlikely to result in the same level HPAPIs, but also offer a means to potentially modified allows for better of potential increase that can be chemically modify a pharmacologically structural designs or the creation of achieved by amorphous dispersions active compound so it can be more pro-drug analogs to increase solubility or lipid-based formulations,” he says. effectively delivered if poorly soluble. and bioavailability,” he concludes. Lipids also offer a further advantage “In the small-molecule world, time for low-dose HPAPIs where these spent during molecular selection for Reference can be fully solubilized because the not only potency but solubility and 1. Kline & Co., “Solubility Enhancement potential for poor homogeneity is bioavailability should be a focus in in Pharmaceutical Oral Solid Dosage eliminated and accurate dosing can good drug design. That would reduce Forms: Global Market Analysis and be provided, even for the lowest the need for exotic formulations to Opportunities,” Report, March 2015. PTE possible dose. “Achieving such formulations may be impossible in the solid state, so a lipid/liquid approach can be enabling for the molecule to be advanced,” McNaughton states. Kujath notes, though, that while lipid-based solubilizers and the formation of nanoemulsions can be an Go green with: effective way to deliver an HPAPI of ® low solubility, these techniques should generally be combined with the use of Minichiller a low-energy means of sterilization. ® If the API is not “greasy” (logP < 3), & Unichiller lipids are unlikely to provide the same improvements that amorphous dispersions can, according to McNaughton. In addition, processing to achieve particle-size reduction can be simpler than developing an amorphous or lipid formulation.

Ongoing developments “Every day the industry is improving containment solutions, making it easierFOR to leverage HPAPI PERSONAL, handling NON-COMMERCIAL USE technologies that previously may have been less accessible,” says Kujath. He also notes that more and more focus has been placed on not just patient safety, but on worker safety. There are always new and improved excipients Eco-friendly being developed, new approaches, and better understanding of how to use them, agrees McNaughton. He adds that improved technologies to cooling solution remove the vulnerable operator from OLÉ Circulation Chiller – Go Green harm include more hygienic valves, in-line testing to minimize operator 5 interaction with potent molecules, and increased automation that completely removes the operator The compact Minichiller and Unichiller with OLÉ controllers convince as a cost-effective and from the vicinity of these process. environmentally friendly cooling solution for However, it is important, according numerous laboratory applications. Due to the low to Kujath, to remember that the purchase price, the investment pays for itself after issue of low solubility is not unique to a short time. HPAPIs and can be vastly improved in the active molecule design More information: www.huber-online.com Inspired by temperature process. For instance, he points to technologies such as antibody-drug

Pharmaceutical Technology Europe JUNE 2019 15 16 Felicity Thomas Felicity FOR PERSONAL,NON-COMMERCIAL USE Pharmaceutical Technology Europe P absorption may be enhanced,” Lee says. says. Lee enhanced,” be may absorption hence and dissolution for required is energy less state, non-crystalline a in API the “With form. amorphous the in drug the delivering by work dispersions solid amorphous adsorption, oral enhance and solubility delivery of poorly soluble drugs.” effective the provide to astrategy find to approaches potential the down narrow can scientists formulation tools, and knowledge proper the with “Armed continues. he pre-formulation,” during apparent become that challenges molecule-specific the address to adds. Lee industry, the within employed methods common the of some among are suspensions nano- and formation, complex dispersions, solid amorphous as such Approaches developed. be can bioavailability sufficient with product afinished that so rate dissolution its improve to or drugs of solubility enhance help to available techniques several are There techniques of A range molecules is vital.” complex these of rates dissolution or solubility improve to methods effective of exploration “Therefore, Sciences. Particle of president PhD, Lee, Robert states them,” from benefit to able be never may patients and pipeline, development the through progress never in-vitro during or theory in effective highly are that value. in limited severely are molecules therapeutic effective theoretically these such, as and humans, for bioavailable readily not are compounds soluble aqueous poorly Yet, entities. chemical complex molecularly more of development towards drive industry the of aresult as grow to continue to Used to overcome limited aqueous aqueous limited overcome to Used dispersions. solid Amorphous techniques of arange assess to development in important is “It “Without exploring alternative formulation techniques, actives actives techniques, formulation alternative exploring “Without pharma drug development and is a trend that is anticipated anticipated is that atrend is and development drug pharma bio/ within prevalent increasingly becoming is solubility oor

JUNE 2019 delivery of poorly soluble drugs. soluble poorly of delivery effective provide to vital is techniques formulation various of Exploration Horizon Solubility the Beyond Looking PharmTech.com testing may may testing we have encountered cases where where cases encountered have we Also, toxicity. perceived or real with associated be may and cyclodextrin of dose high arelatively is This API. of mg 300 encapsulate to cyclodextrin a 8gof take may it cases, some “In adequate complexation,” he notes. for required sometimes are excesses phenomena, so large molar equilibrium an is “Binding constants. binding equilibrium different have and thermodynamics by governed are complexes the solutions, be to intended are that as cyclodextrin formulations concentration.” right the at analogue best the select to ability the on relies development successful and available, are derivatives cyclodextrin “Different says. Lee actives,” soluble poorly of solubility aqueous the increase to agents complexing as used molecule. host the of cavity (fully or partially) within a hydrophobic encapsulated is API the as improved is stability example, for complexes, inclusion In product. drug the of stability the enhance also can and constant, association alow through APIs soluble poorly of bioavailability and dissolution augment complexes formed The acomplex. forming environment, aqueous an in interact matrix the and drug the technique, amorphous formulation.” asuccessful for critical are excipients of selection right the and processing Proper protocols. stability in assessed be should characteristics state solid- so programme, a stability into well until observed not is this form,” Lee. confirms “Sometimes crystalline stable amore to revert and metastable be may solids amorphous as approach this for required is API the of characteristics rates. dissolution and solubility the impact adversely can which affected, are API the of characteristics physical the form, crystalline the to reverts solid-state the If technique. the of limitation amajor is storage in form crystalline stable more the to revert to formulations amorphous Yet, Lee goes on to explain explain to on goes Yet, Lee been mainly have “Cyclodextrins Complex formation. solid-state the of “Knowledge for potential However, the In this this In

peshkov - stock.adobe.com Formulation

we had to optimize the encapsulation In top-down methods, the API and therefore content and dose process to obtain a true solution.” undergoes nanomilling to increase uniformity,” Lee says. Nano-suspensions. Useful for the exposed surface area, ultimately Nanoparticulate suspensions, oral and inhaled drug products and improving the rate of dissolution, therefore, behave in a similar fashion especially beneficial for parenterals, which is inversely proportional to to a molecular solution, and from nano-suspensions involve the the diameter of the drug particle. a manufacturing standpoint, Lee dispersion of nanometre-sized drug “Additionally, nanomilling improves states that the process overall is particles in an aqueous vehicle. the homogeneity of a drug product efficient, reproducible, and highly

Enhancing bioavailability with hot-melt extrusion

Hot-melt extrusion (HME) is a well-known process within industry, being is well placed to serve as an effective anchor for an integrated continuous used since the 1930s, and more recently has found prominence in the manufacturing line, whether that means sequencing a continuous blender pharma industry within the application of enhancing the bioavailability of to the extruder or sizing and compressing unit operations downstream. APIs. As the industry is witnessing a surge in the number of poorly soluble A well-developed ASD formulation and HME process is robust and well drug molecules entering the development pipeline, techniques to improve controlled, enabling the production of consistent product quality both intra- solubility will inevitably continue to experience growth. and inter-batch. Furthermore, HME provides an option to formulate drug To learn more about HME, its advantages, limitations, and recent advances, products for molecules which have zero or limited solubility in organic solvents. Pharmaceutical Technology Europe spoke with Michael Dennis, director of PTE: Are there specific limitations of HME that should be considered? technical operations, science and technology, and Bill Huang, senior principal Dennis and Huang (AbbVie): Since HME depends on melting the polymer research scientist, formulation sciences, both from AbbVie. and drug, thermally sensitive API molecules and potentially some polymers PTE: Can you give a brief overview of HME and how it can aid in may not be suitable. Additionally, as a result of the inherent characteristics of solubility/bioavailability enhancement? BCS Class II and IV API molecules, it isa ch llenging to attain high drug loading Dennis and Huang (AbbVie): Historically, HME was used tto conver in many cases. Further, the choice of pharmaceutical grade polymers and raw materials into a homogenous solid with a particular shape. In surfactants that are suitable for HME is still very limited. pharmaceuticals, it also enables dissolution of APIs into a polymer to form a PTE: Could you highlight the most recent advances in HME? matrix known as an amorphous solid dispersion (ASDs). ASDs achieve higher Dennis and Huang (AbbVie): Absolutely, there are numerous efforts apparent solubil ity and faster dissolution for enhanced absorption of poorly being made by industry to advance HME. For example, the understanding of soluble compounds (BCS Class II and IV). fundamental aspects of formulation and drug release has been dramatically In an ASD, solute molecules are dispersed molecularly randomly within improved in recent years, which is aiding HME product and process design the amorphous carrier. This allows for a drastic significant increase in the and development. We have also seen industry embrace the rigorous apparent solubility and dissolution rate achieving high bioavailability application of physicochemical characterization tools that are helping in and better human pharmacokinetic/pharmacodynamic performance. A the understanding of the impact of physical and thermal properties of rationaFORlly formulated PERSONAL, ASD generates drug-rich amorphous nanodrop NON-COMMERCIALlets materials (constituent components as well as drug-po USElymer and drug- that maximize the surface area of the compound for improved absorption surfactant interactions) on HME processing and product characteristics. We when contacting the dissolution medium as the carrier dissolves. are also seeing a surge in the use of one-dimensional and three-dimensional While this technology is gaining significant traction in the pharmaceutical computational models to optimize HME processes, which is a result of industry, especially in the oncology therapeutic area, it is key for anyone computational power increases and more efficient algorithms for discrete developing in this area to have a solid understanding of HME or to partner element models and computational fluid dynamics. Through this improved with someone with a strong and long tenure in understanding its nuances to understanding, it is becoming easier to develop robust formulations and ensure timely entry into the market. processes with reduced development time and costs. PTE: What are the advantages afforded by HME over other available Various custom in-house modelling tools have been developed by technologies/solutions aimed at enhancing solubility/bioavailability? companies, enabling scientists to select the appropriate polymers, Dennis and Huang (AbbVie): A major advantage is that it does surfactants, and drug concentration, which is supporting faster and more not use organic solvents. This significantly reduces or minimizes both efficient drug development. Additionally, in recent years, there have been environmental and safety concerns. In spray drying, an alternative method significant research efforts made by excipient suppliers to advance HME for manufacturing ASDs, for instance, organic solvents are required to through the development of new polymer systems (e.g., hypromellose dissolve the polymer and drug and then the solvents are removed during acetate succinate and graft polymers). spray drying and a subsequent product drying step. In addition to HME processes being applied to traditional solid oral Other benefits of HME when comparing to other techniques, such as drug products, they are also now being used in uthe form lation of spray-drying, is that it offers shorter cycle times, a smaller footprint, and biodegradable implantable products, such as poly lactic acid- and poly lower capital costs, which all add to its efficiency. Moreover, it is inherently glycolic acid-based implants. a continuous unit operation, allowing fast development aand sc lability. HME —The editors of Pharmaceutical Technology Europe

Pharmaceutical Technology Europe JUNE 2019 17 Formulation

scalable. “However, identifying the nanocrystals that result from a “Alternative lipid-based approaches proper formulation composition nanomilling process can be dosed by such as emulsions (hydrophobic core) and process are key, and a typical virtually all routes of administration,” or liposomes (hydrophilic core) offer challenge is identifying a formulation he says. a micro environment that is either that maintains its stability over time,” The improvement in bioavailability hydrophobic or hydrophilic but not he adds. “For a formulation to be that is gained through nanomilling can both. The LyoCell micro environment developed effectively, it requires be attributed to the fact that during offers both, and is therefore, highly experienced individuals who the milling process, drug particles are better suited for typical drug-like truly understand the process.” reduced in size to below 1000 nm, molecules that are often amphiphilic So, despite the seemingly typically as low as 100–200 nm, (i.e., containing both a non-polar simple concept of nanoparticulate Lee explains. “The conversion to hydrophobic region and a polar suspensions, development may not nanocrystals thereby increases hydrophilic region).” be as straightforward, with success the surface area-to-volume ratio of The technology is intended for a being dependent upon the right the API, which allows for greater range of applications, suitable for a combination of an experienced team interaction with water, which in turn wide variety of dosage forms, and of scientists and data interpretation increases the API dissolution rate,” employs generally recognized as safe to avoid formulation pitfalls. he adds. “Essentially, nanomilling (GRAS) ingredients. “Nanoparticulate suspensions generates smaller particles of API, tend to become unstable and which can dissolve more readily. This Conclusion agglomerate over time, due to high creates a high concentration gradient Industry has witnessed a surge in the surface energy of the particles, that facilitates the transfer of the API number of poorly soluble molecules and can also exhibit Ostwald across biological barriers including being targeted for development to Ripening, whereby small particles membranes (i.e., GI tract and blood treat specific diseases over the past preferentially dissolve and then brain barrier).” decade. As a result of this trend, re-crystallize onto the larger Furthermore, nanomilling can be solutions to overcome solubility and particles,” Lee says. applied to nearly all insoluble APIs, bioavailability challenges presented by Therefore, he explains that a Lee confirms, and the approach can these molecules are ever more vital key factor in generating a viable be evaluated easily with only minimal to ensure promising molecules can be formulation is the optimal selection quantities of API, which adds to its presented and delivered to market for of a stabilizer. Not only must appeal during initial proof-of-concept safe and effective use by patients. this selection process take into study stages of development. “Molecules will continue to require consideration the physicochemical “Nanomilling is also a particularly ever more complex and advanced and pre-formulation data on the efficient, reproducible process that is drug delivery technologies that API, but it must also factor in the very scalable. Once initial feasibility address insoluble compounds,” notes primary properties of the stabilizers has been assessed and a nanomilling Lee. “Not the ‘one-size-fits-all’ or ‘put themselves. process is optimized, there is minimal it in a tablet’ approach that may have FOR PERSONAL,“In general, there is no ‘one-size- NON-COMMERCIALvariation in particle size from batch worked in the past.” USE fits-all’ approach to the selection to batch,” he emphasizes. “This There are a variety of approaches of nanoparticulate suspension formulation approach is easy to available that can be employed by stabilizers, so often an iterative scale to production, as commercial formulators to tackle the issue of process of optimization of stabilizer nanomilling equipment typically uses solubility and increase bioavailability selection and concentrations is a recirculation process that allows of poorly soluble or insoluble necessary to achieve the final desired batch sizes to increase without APIs. However, experience and formulation,” Lee emphasizes. changing the process variables.” expertise on how to best apply “For example, in some cases, two these techniques is required to give nanoparticulate suspensions may Growing interest in formulations the best chance of have essentially identical particle size combination approach success, Lee stresses. distributions and physical stability but As an example of industry trends, “Challenges in overcoming vastly differ in oral bioavailability.” Lee reveals that Particle Sciences limited solubility won’t go away any has been witnessing a growing time soon. But by using a rational The appeal of nanomilling interest in its in-licensed technology, approach to drug development, we Out of all the approaches to LyoCell, which combines a lipid- can continue to overcome them formulating insoluble APIs, Lee based approach with nanoparticles. and expand our knowledge base,” specifies that nanomilling holds great “The technology uses a reverse Lee summarizes. “Central to this appeal, as it is a technique that is cubic-phase matrix, which assures knowledge base is being data driven useful for yielding a product with the hydrophobic and hydrophilic and utilizing a range of techniques improved delivery and bioavailability. domains in these nanoparticles are during formulation development “Used in FDA [US Food and Drug never more than a few nanometres alongside having the analytical and Administration]-approved drug apart, potentially leading to unique production support to take the drug products since the year 2000, the solubilization properties,” he explains. products forward.” PTE

18 Pharmaceutical Technology Europe JUNE 2019 PharmTech.com Peer-Reviewed

Defining and Managing Raw Manufacturing Data Orlando López

Protecting the integrity of raw data is crucial ata integrity ensures that information stored during phar- to regulatory compliance and to proving maceutical manufacturing is reliable and trustworthy. that manufacturing and quality operations Electronic records (e-records) pose special data integrity are being run and managed properly. Dchallenges. Links between electronic data, raw data (i.e., the first capture of information, whether recorded on paper or electronically [1]), metadata, and records must not be compro- mised or broken if the data and their relationships with other data are to be valid. Preserving the integrity of the raw electronic data generated by manufacturing and quality operations is crucial because these data provide the only evidence that these departments are being run and managed correctly and in a way that complies with regulations. It is the foundation for continuous process verification (CPV) and process validation. Technological controls must be in place to ensure the integrity of these data. This article discusses these controls and how they should be implemented for identification, storage, protection, retrieval, retention time, and disposition of current good manufacturing practice (cGMP) records (2). FOR PERSONAL, NON-COMMERCIALData lifecycle USE The data lifecycle (Figure 1) helps to map and explain the controls that are necessary to manage data, raw data, metadata, and records (3) properly. Data access control is crucial, for example, and any changes to an e-data point can only be made by someone who has been authorized to make those changes. Failure to address even one element of the data lifecycle will weaken the overall effectiveness of controls implemented for the computer system and for e-data integrity. During the data capture stage, data are collected and related actions are performed. Then, during transformation, the data are scaled and converted, and then built-in checks (summarized in European Union [EU] Annex 11-11 [4]) are performed to verify that all the data are correct after the transformation. Because the data transferred during this stage move between process equipment and the computer, the interface between the two should be validated and checked periodically to ensure ac- CITATION: When referring to this article, please cite it as, “Defining and Managing Raw Manufacturing Data,” Pharmaceutical curacy. The accuracy and reliability of the raw data depend not Technology 43(6) 2019. only on properly calibrated and maintained instruments and equipment, but also on the integrity of the raw data that have Submitted: 4 Jan. 2019 been recorded. When instruments and equipment cannot ensure

Accepted: 24 Jan. 2019 secure data access and administration of electronic data files, auremar - Stock.adobe.com

Pharmaceutical Technology Europe JUNE 2019 19 Peer-Reviewed

collected data can be passed directly to a secure environment (typically a supervisory control and data acquisition [SCADA] Figure 1: Data lifecycle. system or data historian) for processing and recordkeeping. After Commit to collect the data have been transformed and used, they must be moved Work in to a recordkeeping environment where they can be edited for as progress long as necessary as the data are retained. Capture and transformation During the active phase (i.e., when data are actively being used), raw data may be cleansed periodically to correct incon- Commit to use Data sistent values after they have been used. Periodically, data must change be reconciliated. Cleansing or data cleaning is performed to de- management tect and correct corrupt or inaccurate records from a record set, Active phase table, or database. This activity must be suitably managed and access and use

documented (e.g., by establishing an audit trail). Data Processable The inactive phase starts with records archival, which applies to inactive, superseded, replaced, and withdrawn data. These records must be kept to meet the data retention schedule and traceability requirements. These records usually maintain “read” Commit to archive and “view” attributes. There are exceptions, however, in which “processability” may be extended for the full life of the records Inactive phase through to discard.

Pharmaceutical manufacturing operations Archiving In these types of operations, data loaded from field sensors contain a measurable attribute of a physical entity, process, or event (5). The loaded data are recorded, becoming raw data, which are Discard Purging of records considered “original” or “source captured” (6). When multiple Deletion of records raw data are generated to satisfy a cGMP requirement, such raw data become a cGMP record (7). Examples of raw data in a typical manufacturing environment include: • Analogue readings (e.g., of temperature, pressure, flow rates, of undesired process variability so that the process remains levels, weights, central processing unit [CPU] temperatures, in control. mixer speeds, or fan speeds) • Digital readings (e.g., of valves, limit switches, motors on/ Identification of cGMP records off,FOR and discrete PERSONAL, level sensors) NON-COMMERCIALIdentification to the cGMP records (12) and associatedUSE controls • Product information (e.g., IDs for product, batch, material, are crucial to the success of any pharmaceutical manufacturing or raw material lot) operation. The characterization of these cGMP records usually • Quality info (e.g., process and product limits, custom limits) starts with a primary design document such as a process and • Alarm info (e.g., out-of limits or return-to- normal signals). instrumentation drawing (P&ID). A process flow diagram (PFD) The raw data hold the content of the e-record that will repro- or some other form of schematic may also be used. duce the full cGMP automated activities (8). Properly recorded Table I depicts the critical process parameters for a solid dosage and managed raw data are the foundation that is required to form manufacturing process. Process equipment incorporates demonstrate the product identity, strength, purity, and safety. instrumentation designed to control the process and acquire data The e-records associated with raw data demonstrate that the about each critical process parameter. manufacturer’s processes meet the requirements of cGMPs, in- The primary goal for controllers is that they work accurately cluding those for process sequencing and instructions (9). in the intended process. The controllers are dynamically verified Accurate management of data during entry or collection, during the qualification of the automated cell controller. The cell storage, transmission, and processing (10,11) provides con- controllers are typical Level 0 in the ANSI/ISA-95 and essential trols required for the processing and retention of loaded data, to ensure proper functioning of the process and product quality. raw data, and e-records. The integrity of manufacturing raw The input/output (I/O) list refers to the information that comes data is a basic prerequisite to CPV, an essential part of the US into and goes out of the manufacturing system. Food and Drug Administration’s (FDA’s) process validation In Table I, for example, the air temperature, air volume requirements. CPV is designed to provide continual assur- dew point, and product temperature are the I/Os associ- ance that the process remains in a state of control during ated with a fluid bed dryer (13). Field instruments provide commercial manufacturing. The collection of information measurements of these values from field instruments via

about the performance of the process will allow detection terminating wires in the digital system I/O processing sec- All figures courtesy of the author

20 Pharmaceutical Technology Europe JUNE 2019 PharmTech.com MORE TECHNOLOGY.

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Table I. Critical process parameters for solid dosage form manufacturing. Process Critical process parameters Blending time Blending Number of revolutions of the blender Kneading time High shear wet granulation Impeller and chopper speed Binder addition time Inlet air temperature Fluidization air volume Fluid bed drying Dewpoint Product temperature Roll gap Roll width Roller compaction Roll pressure Screen size Spray volume Fluid bed granulation Spray rate Inlet air temperature Milling Screen size Compression force Compression Compression speed Dwell time Spray rate Coating Inlet air temperature Speed of encapsulation Encapsulation Tamping pressure tion. After transformation, the data are transmitted to the mable logic controller (PLC). The associated alarm records SCADA system over the communications link. are saved in the corresponding repository system at the stor- TheFOR first step in documentingPERSONAL, the I/O requirements isNON-COMMERCIAL to com- age device level. Physical protection is important USE because en- pile a list of all the applicable points that are referenced on the vironmental effects can cause media to deteriorate. Copying P&ID. This is necessary so that the specific signal and termina- information without changing it offers a short-term solution, tion data can be associated with each point or each instrument. ensuring that information is stored on newer media before Alarms and reporting requirements must also be considered. the old media deteriorate to the point where the information can no longer be retrieved. Storage of records To ensure data integrity during storage, any changes that have Raw data are original records generated by means of computer been made to an e-record must be recorded, including the previ- systems and become the contents of an e-record. E-records stor- ous entry, who made the change, and when the change was made age devices record, store, or retrieve e-records from any medium, (14). To reduce the risk of losing the e-records in storage and to including the medium itself. This is considered a short retention guarantee that they will be ready for use, data must periodically environment. Design specifications or similar documents must be backed up. Backup data must be stored separately from the describe the file structure(s) in which the e-records are to be primary storage location, and at a frequency based on an analysis stored, as well as the capacity requirements of the storage, and of risk to cGMP e-records and the capacity of the storage device. how the security scheme is implemented. The file structure and The efficacy of the backup and restore processes must be veri- security are verified/tested during the qualification. fied as part of the qualification process. In addition, the capacity After the data are recorded and retained by computer stor- level of the storage must be monitored. age (e.g., historian/SCADA storage), the physical and logical As in archived e-records, the e-records in storage need controls to the e-records must be in place. These controls to be verified periodically for accessibility, readability, and include physical protections, stamped audit trail, data man- integrity. If changes are implemented to the computer in- agement, archival and retrieval of records. Alarms and the frastructure and/or application, then it is required to ensure associated actions to the alarms are managed by the program- and test the ability to retrieve e-records.

22 Pharmaceutical Technology Europe JUNE 2019 PharmTech.com Figure 2: Data integrity and e-records in process automation. SCADA is supervisory control and data acquisition and I/O is input/output.

Data collected directly from equipment and control signals between computers and equipment should be checked by verification circuits/ software to confirm accuracy and reliability. TGA, Code of GMPs, 2013. ER Controls for Those items defined as E-records Data integrity controls based upon risk

Instruments I/O card Controller Supervisory Historian / / equipment System SCADA

Time stamp Time stamped applied to alarms Controls process Data associated with records Data are transient Data are transient retained by computer storage.

E-records are collected from instruments / equipment In general not E-records

One critical element to consider is legal holds to the e-records, data written in the storage device be saved at the time they are which may exist when the manufacturer or contract manufac- generated (16). As appropriate, regulatory authorities expect that turer is involved in litigation. These records cannot be destroyed, the data written in the storage device must be saved at the time even if the data retention period has expired. The regulated entity the data are generated (17). is underFOR a legal obligation PERSONAL, to retain all relevant data, and NON-COMMERCIAL a legal USE holds record system or other mechanism must be implemented Protection of data and records to identify e-records that would be affected by a legal hold. The protection of transient data, raw data, and e-records cover In optimizing physical location requirements for the e- data in storage, during processing, and while in transit (18–20). data, web and database servers should ideally be separated. As shown in Figure 2, the protection of transient data, raw data, Database servers should be isolated from a website’s demili- and e-records may be set in two environments: transient data tarized zone (DMZ), based on security standards. A DMZ is before reaching the historian/SCADA and raw data. a physical or logical subnetwork that contains and exposes Transient data. At the PLC level, the analogue data are ex- an organization’s external-facing services to a larger and un- tracted from the PLC memory, transformed (i.e., digitized, trusted network, usually the Internet. The purpose of a DMZ validated, normalized, and scaled) and sent to the SCADA. is to add an additional layer of security to an organization’s The data collected directly from manufacturing equipment local area network (LAN); an external network node only has and control signals between equipment and a data server direct access to equipment in the DMZ, rather than any other (e.g., SCADA) may be regarded as transient and cannot be part of the network (15). edited by reasonable means or reprocessed by the human These servers can locate them on a physically separate net- user. Similar to the controls associated with e-records in transit, work segment from the web and other internet-accessible servers the data integrity controls for transient data are: that support the business. Preferably, one should partition the • Qualification of the infrastructure. The outcome of this qualifica- database server off from the web servers by a dedicated firewall. tion provides documentary evidence that accounts for the This firewall should only allow database traffic between the web correct implementation of integrated hardware and associ- server and database server. The firewall should also deny and log ated devices (21). all traffic from any other location, or other types of traffic from • Built-in checks for the correct I/Os. These built-in checks are, at the web server. Regulators, and particularly the FDA, expect that first, validated. During the operational stage, the built-in

Pharmaceutical Technology Europe JUNE 2019 23 Peer-Reviewed

checks must be periodically verified (as required by US FDA retention of batch documentation. The accompanying raw data 21 US Code of Federal Regulations [CFR] Part 211.68(b) and EU should be retained for a period at least as long as the records for Annex 11-5) (22 and 23). all batches whose release has been supported on the basis of that • Accuracy checks. Usually performed at the supervisory validation exercise. For a medicinal product, the batch documen- system level, accuracy checks are required for critical tation must be retained for at least one year after the expiry date data that have been entered manually by authorized per- of the batches to which it relates, or at least five years after the sonnel. These critical data require input verification to certification referred to in Article 51(3) of Directive 2001/83/EC, prevent incorrect data entries. whichever is the longer period. At least two years of data must After the data are recorded and retained, physical and logical be retrievable in a timely manner for the purposes of regulatory controls to the e-records must be implemented and executed. inspection. These controls include security, access authorization, backups, Applicable FDA regulations, 21 CFR 211.180(a), call for data periodic reviews, stamped audit trails, built-in checks (required that are part of the drug product production and control re- by FDA Compliance Policy Guide Section 425.400), and other rel- cords to be retained for at least one year after the expiration evant data-management controls. The PLC manages alarms and date of the batch or, in the case of certain over-the-counter associated actions, which are saved at the storage device level. (OTC) drug products lacking expiration dating because they Controls are required if the e-records and associated raw data meet the criteria for exemption under 21 CFR 211.137, for three must be transferred from the original processing environment. years after distribution of the batch. As the results of the trace- After the migration process, verification is required to ensure that ability requirements, the raw data will be retained as specified the information in the original e-records has not been altered. in 21 CFR 211.180(a). When computer systems are used instead of This verified copy becomes a true or certified copy. written documents, the manufacturer shall first validate the systems by showing that the e-records will be appropriately stored Retrieval of records during the anticipated period of storage. E-records stored by Access to e-records should be ensured throughout the retention those systems shall be made readily available in a legible form period (as required by EU Annex 11-7.1). The access to these re- and provided upon the regulators’ request. The electronically cords must be controlled to ensure the integrity of the e-records stored e-records shall be backed up and protected against loss in storage. The controls associated with e-records in storage allow or damage, and audit trails shall be maintained. those individuals who depend on the e-records to correctly ful- fill their job functions. During the Active Phase, manufacturing Disposition of records e-records will typically be held in the environment in which the If active records are transferred to another environment, valida- records were initially created. In this environment, the e-records tion should include checks that data have not been altered in are visible to the tools that created them. Any features designed value and/or meaning during this migration process, as required to allow them to be changed or deleted must ensure audit trails by EU Annex 11-4.8. E-records that are placed in retention envi- that record the reason for change or deletion, as well as other ronments, other than the environments that were used for their informationFOR as required PERSONAL, by the applicable regulation. NON-COMMERCIALoriginal creation, should preserve the integrity USE of the raw data, Periodic (or continuous) reviews must be performed after the associated e-record, and protection mechanisms used to prevent initial validation (as required by EU Annex 11-11) of the pro- informational loss and/or corruption. Should records require cessing environment. These reviews check stored, backup, and modifications in retention environments, a clear audit trail of archived e-records for accessibility, readability, and accuracy. change or replacement history, including record removal, should They also verify the output of the backup and the accuracy of be maintained. Once e-records have been placed in the retention the overall audit trail, verifying the accuracy and reliability of environments, they should never be directly modified. If techni- the e-records transferred (WHO 3.2). In addition, processes for cal limitations require the electronic record to be modified in the reading and managing e-records must ensure their data integ- retention environment, the change must have traceability to the rity. The infrastructure between the records in storage and the same change in the processing environment. The inactive phase processing environment must be a controlled environment and starts with records archival. These records need to be kept to must be qualified and checked for accuracy. meet retention schedule requirements and traceability. These records usually maintain read/view attributes. Finally, during Data retention time the deletion phase, the e-records are discarded. This is a phase The EU cGMPs establish that raw data supporting information of short duration and includes metadata and audit trails. in the marketing authorization (24), such as validation or stability data, should be retained while the authorization remains References in force. In some cases, periods up to 30 years’ worth of raw 1. UK Medicines and Healthcare Products Regulatory Agency data must be retained. It may be considered acceptable to retire (MHRA), GXP Data Integrity Guidance and Definition, assets. publishing.service.gov.uk (MHR, 2018), assets.publishing.service. certain documentation when the data have been superseded gov.uk/government/uploads/system/uploads/attachment_data/ by a full set of new data. In such cases, justification should be file/687246/MHRA_GxP_data_integrity_guide_March_edited_ documented and should take into account the requirements for Final.pdf.

24 Pharmaceutical Technology Europe JUNE 2019 PharmTech.com 2. ISO, ISO 9001:2000 Quality Management Systems—Requirements, 15. Health Canada, “Good Manufacturing Practices (GMP) Guide- 4.2.4 Control of Records, isorequirements.com, (ISO, 2015), www. lines for Active Pharmaceutical Ingredients,” GUI-0104, C.02.05, isorequirements.com/iso_9001_4.2.3_control_of_documents.html. Interpretation #15 (Health Canada, December 2013). 3. ISPE/PDA, Technical Report: Good Electronic Records Man- 16. B. Mitchell, “Using a DMZ in Computer Networking,” 6 Jan. 2019, agement (GERM), Collection of Felated Data Treated as a Unit. lifewire.com, www.lifewire.com/demilitarized-zone-computer- (ISPE/PDA, July 2002) networking-816407. 4. EU, Annex 11-11, www.ec.europa (EU, 2011), www.ec.europa.eu/ 17. FDA, 21 CFR Part 211.160, accessdata.fda.gov, https://www.access- health/sites/health/files/files/eudralex/vol-4/annex11_01-2011_ data.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=211.160 en.pdf. 18. EU, Chapter 4 Section 4.8 (EU, 2011), ec.europa.eu/health/sites/ 5. MHRA, MHRA CGMP Data Integrity Definitions and Guidance for health/files/files/eudralex/vol-4/chapter4_01-2011_en.pdf. Industry, (March 2015). 19. ICH, Q7 Section 6.14, www.ich.org/fileadmin/Public_Web_Site/ 6. ISPE/PDA, “Technical Report: Good Electronic Records Manage- ICH_Products/Guidelines/Quality/Q7/Step4/Q7_Guideline.pdf. ment (GERM),” July 2002. 20. NIST SP 800-33, “Underlying Technical Models for Information 7. MHRA, “GxP Data Integrity Guidance and Definitions,” March 2018. Technology Security,” December 2001, (Withdrawn: August 2018). 8. FDA, Data Integrity and Compliance with cGMP, Q&A—Guidance 21. FDA, 21 US Code of Federal Regulations (CFR) Part 211.68(b). for Industry (FDA, 2018). 22. EU Annex 11-5, ec.europa.eu, https://ec.europa.eu/health/sites/ 9. CFDA, Draft Data Integrity Guidance (CDFA, September 2017), health/files/files/eudralex/vol-4/annex11_01-2011_en.pdf https://drive.google.com/open?id=0B0GT88vUt4U4ZTBWRkd 23. O. López, Computer Infrastructure Qualification for FDA Regu- QWU0xOG8. lated Industries (PDA and DHI Publishing, LLC, 2006). 10. O. López, Preface, Data Integrity in Pharmaceutical and Medical 24. EU, Good Manufacturing Practice Medicinal Products for Human and Devices Regulation Operations,” pp.15–17 (CRC Press, Boca Raton, Veterinary Use, Volume 4, Chapter 4: Documentation, Section 4.12. Florida, USA, 2017). PTE 11. NIST SP 800-33, “Underlying Technical Models for Information Technology Security,” December 2001 (Withdrawn: August 2018). 12. FDA, Guidance for Industry—Process Validation: General Principles Orlando López has more than 20 years of experience in and Practices (FDA, 2011). global pharmaceutical, biopharmaceutical, and medical 13. L.T. Amy, Automation Systems for Control and Data Acquisition devices computer systems regulatory compliance for (ISA, 1992). companies that include Eli Lilly. He can be reached at 14. A Kane, Sidebar in A. Siew, “Designing Optimized Formulations,” [email protected]. Pharmaceutical Technology 41(4) (2017).

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Pharmaceutical Technology Europe JUNE 2019 25 PTE: What are some of the benefits of connecting inhalers to a smart device? Griffiths (3M): It stands to reason that you can get better patient engagement through ease of use, which can lead to improved compliance. My interpretation of compliance is twofold. The first element is adherence. Is a patient taking his/her medicine at the right time, in the right amount, as prescribed? On a daily basis? Morning and evening? The correct number of puffs each time, as necessary? Are they doing that routinely? The second element is technique. With inhalation therapy, the delivery Considering Connected of the medicine can be greatly affected by how a patient uses a Inhalation Drug Delivery device. We see many delivery issues with press-and-breathe inhalers, A connected MDI may encourage compliance and aid proper technique. soft mist inhalers, and dry powder inhalers. With some dry powder inhalers, a patient needs to use a lot of inspiratory force to deliver the drug, which is difficult for some patients Jennifer Markarian an “smart” drug-delivery devices improve patient compliance? with respiratory diseases to attain. CInnovators at 3M think so. Improving adherence and reducing Technology can help in both areas. use errors in noncompliant patients have been associated with An inhaler that is connected with a improved health outcomes, and smart inhalers have the potential smart device can send reminders to help accomplish this objective, says Stewart Griffiths, a product to a patient to help with adherence, commercialization manager for 3M Drug Delivery Systems Division. for example. It also has the potential “As a society, we’re growing more accustomed to getting the to help improve technique by information we want faster than ever before and in a way that is providing feedback to a patient. The tailored to our individual preferences,” he notes. “Everything is 3M Intelligent Control Inhaler was FOR PERSONAL,personalized and on demand. WeNON-COMMERCIAL are starting to see this becoming designed with the potentialUSE to do this. true with regard to how drugs are delivered to patients and the We wanted to have the ability to tell instant feedback they expect.” Pharmaceutical Technology Europe patients when they’re not breathing spoke with Griffiths about the 3M Intelligent Control Inhaler, which is in for long enough or when they’ve currently in development, and about some of the manufacturing and not shaken the medicine if it needs to regulatory considerations for connected combination drug-device be shaken. Technology gives us the products. ability to coach and guide patients in the real world, without having to be in Patient-centric design a doctor’s office. PTE: Can you briefly describe how the 3M Intelligent Control Inhaler PTE: How do you incorporate functions? human factors engineering into a Griffiths (3M): Most pressurized metered dose inhalers (pMDIs) on device design? the market require you to coordinate your inspiratory flow when you Griffiths (3M): From my press down on the canister to release the medicine. If you breathe in perspective, it is important to get and your lungs are nearly full by the time you press, you’ve pressed the device into the hands of patients too late. Conversely, you may press too early in the inspiratory cycle. as early as possible—for example, When you mistime it, less medicine than intended is absorbed. through formative human factors The 3M Intelligent Control Inhaler was designed such that it could studies in the early prototype stage. utilize the familiar MDI dosage form and add value by aiding patient These studies allow the scientist in coordination. It uses breath actuation to help correct the coordination the lab to use input from real patients problem, so you just breathe in and the drug is automatically delivered to design new inhalers that are easy when you are inhaling and before your lungs are full. In addition, to use, fit comfortably in hand, and the display can visually prompt patients on how to use it correctly. are easy to actuate, for example. This inhaler has been designed to be reusable. The main electronics Only when you put it into the hands

component is reusable with up to 12 monthly refills of the medicine. of patients will you discover that it stock.adobe.com - vladystock

26 Pharmaceutical Technology Europe JUNE 2019 PharmTech.com Inhalation Drug Manufacturing

may be fundamentally flawed. Those we need to clearly demonstrate how of electronic components. This formative human factors studies act they will benefit from the use of their not only requires updates to the as inputs that can inform the design data. Today, it is critically important manufacturing lines themselves, but of the device. When patients can to determine the data strategy before to the testing facilities. If historically easily operate a device, it means the going into design and development. you’ve worked only with plastic patient receives the correct dose 3M has addressed this by making materials, tests are purely physical and is more likely to comply with the security part of the up-front in nature. Electronics module testing therapy. development process. is very different. For instance, if your One of the key outputs of a human Finally, regulations around drugs connected inhaler utilizes Bluetooth factors programme is the instructions and devices are now becoming technology, electromagnetic for how to use the device. The findings intertwined with electronics and compatibility testing is required to will drive what goes into those software. 3M’s goal is to be ahead of prevent the device from interfering instructions. They will also inform how the curve and follow the regulations with other connected devices. the packaging is designed, to ensure as they evolve. The speed of Regulatory standards also change, that it is easy for patients to open. electronics and software evolution once a device is categorized as is at a much faster pace than connected. Regulatory considerations traditional pharmaceuticals by nature. Finally, with technology constantly PTE: What are the regulatory and data The industry needs to evolve to changing, the use of electronics security concerns with connected incorporate electronics but continue allows for rapid improvements and devices and how are they being in a safe way. the ability to address real patient addressed? PTE: What are some of the issues. For instance, improved Griffiths (3M): Protecting patient manufacturing challenges for battery technology can allow a privacy must be a top priority. There incorporating electronics into device to be used for a longer period are tremendous opportunities ahead inhalers? Are there special regulatory/ of time. At the same time, it is for collecting, sharing, and analyzing quality testing considerations for important to keep in mind that the data generated by digital delivery connected devices? pace of the pharmaceutical industry devices; however, we need to instill Griffiths (3M): From a is very different than the pace of the trust in patients from the very manufacturing point of view, technology industry. This can create beginning. To do that, we need to the arrival of connected devices major challenges on everything from make sure patients understand how requires a shift from purely plastic the design to the manufacture of a and why we’re using their data, and components to the incorporation device. PTE

Hovione Technology Develops Blister-Based Inhaler

Hovione Technology, a Hovione Ventures company, announced in a 15 April 2019 In addition to being simple to manufacture, devices need to be simple for press release that it has secured global rights to develop and commercialize a patients to use correctly. “Inhalers need to work in the hands of the patient. new,FOR affordable, mu lti-usePERSONAL, blister-based dry powder inhaler (DPI) patentedNON-COMMERCIAL by No matter how brilliant our inventions are, at the end of theUSE day they need to inventor Dr. Klaus-Dieter Beller, which wi ll be marketed as the Papillon DPI (1). bring benefit and value to the patients,” says Villax. He explains that human The blister-based inhaler is suitable for both chronic and acute treatments and factors engineering is central for new DPI developments. This systematic design can accommodate a single- or double-blister configuration. The patient loads a process can capture preferences towards design attributes that improve patient blister to take the daily dose and reuses the inhaler for a defined period of time, engagement with the device. typically 30 or 60 days. Creating a simple DPI is not a simple task. It is a difficult “marriage between The simplicity of the device, which is made from a single part, significantly device physics and formulation properties,” says Villax. “An inhaled combina- reduces development cost and risk compared to more complex devices, explain tion [drug] is a complex product, because you have to consider not just the drug Hovione Technology’s CEO Peter Villax and João Ventura, director of Technology product, not just the device, but also how they interact with each other. For Development and Licensing. “Because it is manufactured from a single mold, example: a powder inhaler turns an inspiratory effort into a force that disperses manufacturing and depreciation costs are much lower,” they add. and aerosolizes a powder and entrains the particles into the lung. How effi- Villax and Ventura say that simpler DPI designs, which are less costly to manu- ciently this dispersion and entrainment occur is a key feature of the inhaler, but facture, fulfi ll the need for readily accessible and affordable treatments, par- it depends just as much on the particles themselves and on how well they fly.” ticularly in less developed markets. “Innovators have traditionally used device Hovione Technology’s co-promotional agreement with API manufacturer complexity to increase development and cost barriers for generic competition. Hovione all ows the companies to integrate DPI device development with inha- [In addition,] smart and connected devices may have a role in the medium-term lation API formulation development and manufacturing. According to Hovione to further improve treatment effectiveness and adherence, especially in devel- Technology, Papillon is available for feasibility studies and integrated develop- oped markets,” notes Ventura. “But inhaler devices do not fundamentally need ment with formulation by pharmaceutical partners. to be complex; inhaled drugs can be delivered as effectively from devices made Reference of very few parts and assembly steps.” Ventura says that making simpler inhaler 1. Hovione Technology, “Hovione Technology Announces Papillon DPI,” devices is also a “greener” solution that consumes less resources. Press Release, 15 April 2019. —Jennifer Markarian

Pharmaceutical Technology Europe JUNE 2019 27 28 Agnes Shanley but it will not be right for every facility or product. or facility every for right be not will it but opportunities, huge offer may manufacturing Continuous During Scale Up Ask the Right Questions Continuous? or Batch FOR PERSONAL,NON-COMMERCIAL USE Pharmaceutical Technology Europe O dynamic than what was outlined in the first FDA guidance on FDA guidance first the in outlined was what than dynamic more much becoming is (QbD) design by quality pharmaceutical of concept the that suggested speakers of A number dynamic more becomes QbD from API to finished product. product. finished to API from manufacturing, continuous end-to-end advance help to underway projects and pilots highlighted Pharmaceuticals Continuus at officer business chief and cofounder Takizawa, Bayan findings. research summarized professors university while companies, their at underway programmes development pilot manufacturing continuous Takeda discussed and Merck from experts programme, At the manufacturing.” continuous embrace will manufacturers all not that is reality the “because said, he manufacturing,” batch via made be can they that so products manufactured continuously as approved were that drugs produce to able be to need also will “We Dubey. said made,” are they however medicines, of quality the promote to need we end, the In adopters? late for easier manufacturing continuous make we can “How requires. manufacturing continuous that knowhow and technology the in invest to States, United the in written prescriptions the of most supply which manufacturers, pharmaceutical programme. the on spoke who (USP), Pharmacopeia States United the at manufacturing pharmaceutical continuous pharmaceutical of director Dubey, Atul said manufacturing, continuous use (FDA) Administration Drug and Food US the by approval awaiting now are that products 20 than more and continuously, made being already are products commercial of Anumber manufacturing. pharmaceutical continuous by posed opportunities and challenges the examined Pharmacy A crucial question is what the incentives will be for generic generic for be will incentives the what is question A crucial the 11th annual Charles Jarowski Symposium in Industrial Industrial in Symposium Jarowski 11th Charles the annual York City, New in n 6May, 2019, University John’s St. at

JUNE 2019 PharmTech.com or two stories. stories. or two single tendtobe facilities legacy because especially facility,into abatch manufacturing continuous inject simply cannot One PharmTech.com. visit symposium, the on report afull For quality.” operate in order to ensure product to needs it which at conditions the find can system the that so tunable is “to make attributes quality critical University’s School of Engineering, Purdue at aprofessor Nagy, control. feedback of use greater to space design the from moving is emphasis the control, process advanced more with comfortable havemanufacturers become more pharmaceutical As topic. that question of return on investment,” a as up ended question capacity a as began “What conflicted. material raw and people of flows the scenario,continuous manufacturing goal. primary the was costs labour reducing said, he case, this In API. involve not did that aproduct (OTC) supplement, counter over-the- volume ahigh of expansion other, the facility, established an in process granulation adry using drug acommercial of expansion the involved One continuous. to convert to cost the justifying of challenges the illustrate to studies case different two used Rooney continuous. integrate vertically help not do distances floor-to-floor and stories, two or single be to tend facilities legacy because especially facility, abatch into manufacturing continuous inject simply cannot one explained, he As continuous. with process abatch replace or forms (OSD) dosage solid oral up scale to continuous approach manufacturing considering the implementation of a manufacturing operations face when existing that challenges the of some his presentation (1), he considered In Engineers. Genesis at engineering process of director Rooney, Michael was issues scale-up on Focusing up scale Considering The idea, according to Zoltan Zoltan to according idea, The In both cases, he said, using the the using said, he cases, both In

Ivan Traimak - stock.adobe.com Scale Up

he said. For one thing, with the In the end, companies must PTE: What would make a process branded drug company, it was found determine what will be more cost an ideal candidate for continuous that the building, which was only 25 effective: reducing operator labour manufacturing? feet high, would need to be 60 feet and facility costs or reducing time to Rooney: Generally, continuous will high to accommodate continuous market and starting to recoup product be most practical for processes that manufacturing. In addition, the shift revenue sooner. For most companies, involve direct compression or dry from batch manufacturing would the transition to continuous granulation. With direct compression, involve higher operating costs due to manufacturing will be driven by one is mixing components with need for highly skilled technicians to product development scientist and minimal manipulating. In dry attend to the PAT technology. engineers sooner than it will by the granulation, material is densifed operations group, Rooney said. In with a roller compactor, then milled, “People tend to emphasize addition, savings may often be more blended, and compressed with a the potential for pronounced in Phase II and Phase tablet press. Tablet press equipment continuous manufacturing III projects, rather than commercial has long been based on a continuous to reduce [costs] ... but production. In an interview after process, anyway. the conference, Rooney shared In addition, the percentage of it may require increased insights into continuous scale up with active shouldn’t be too low if a investment in PAT, Pharmaceutical Technology Europe. continuous approach is to work well, process development, or at least be easy to implement. In data handling and storage, Labour or time-to-market some new oncology drugs, the API is and recall strategies.” PTE: Are there some basic so potent that drugs may only contain — Michael Rooney, misunderstandings within the industry about 1–5% active ingredient. Using Genesis Engineers today about continuous manufacturing continuous manufacturing for these and how easy it is to scale up? products can be very challenging, Rooney: I’m a real proponent of even though it is possible, because of The company, which had continuous manufacturing, but it’s the need to guarantee plus or minus been trying to justify moving to not perfect for everything. 10% of label claims. continuous manufacturing on the back of one major product, is now working on building a continuous platform. “If you develop a platform for groups of product types, rather than try to replace existing batch Do Your Tablets capacity with continuous. It doesn’t have to run 100%. You can build a Make the Grade? platform and a portfolio over time,” RooneyFOR said. PERSONAL, NON-COMMERCIAL™ USE In the second case, with the OTC product, second-level infrastructure Tester costs hurt financials, and there CTX

was no subject matter expert Best value in a stand-alone on site to develop the process instrument for quality control analytical technology (PAT) required and product development for continuous manufacturing, Rooney said. In this facility’s case, Wide range of probes and fixtures moving to continuous had no real including: Bi-Layer Shear Jig impact on product cost, and the for bond strength testing company wound up investing more in two part tablets in its batch process to avoid undo risk. “Continuous manufacturing Offering the most test report may be great for flexibility, but it selections in it’s class should not be used as a capacity solution,” Rooney said. “People tend to emphasize the potential for continuous manufacturing to reduce the cost of goods sold (COGS), but it may require increased investment in PAT; process development; data handling and storage; and recall TEL 800-628-8139 or 508-946-6200 www.brookfieldengineeering.com strategies,” he said.

Pharmaceutical Technology Europe JUNE 2019 29 Scale Up

In addition, these formulas typically real-time release, eliminate testing is that it allows a facility to bring raw use a large number of other functional and product quarantine and release material containers straight into the components (e.g., pH neutralizers to distribution. There is no worry plant, instead of having to stop to and disintegrants). Sometimes up about batch size, because batches dispense individual batch materials. to 14 different components may be are defined by time, with process However, this is the opposite of required, all in differing quantities. validation documents establishing what batch plants have been doing So basically, the best candidates the maximum operating window. for the past 20 years. In most batch for scale up using continuous The challenge comes with using facilities today, the dispensary is manufacturing approaches are PAT. You have to characterize that the dividing line between cGMP products that involve dry granulation product that is going through the and non-cGMP operations. Bulk and direct compression, products process. Current PAT technology corrugated containers can introduce where API percentages aren’t too is capable of generating data contaminants into a facility. In general, low, and where there aren’t too many in a matter of seconds and the flows required for continuous diverse excipients in the formulation. accumulating data very quickly, that are counterintuitive to what people has to be controlled, stored, and generally have [in batch facilities], potentially retrieved at a later date. and there is a very different space “One of the ... advantages of The equipment cannot run without classification for each. continuous is that it allows a the PAT working, but then how facility to bring raw material does the PAT system know how to Gaining acceptance containers straight into the work? PAT learns the comparator for continuous plant ... However, this is the or monographs, which reflect PTE: What might convince more opposite of what people thousands of hours of development. generic and OTC pharmaceutical in batch plants have been PAT takes a snapshot of what is companies to invest in continuous doing for the past 20 years. moving past the analyzers, and manufacturing? compares that value to the value Rooney: I expect to see faster ... In general, the flows from a monograph. But what if some integration of continuous manufacturing required for continuous are peaks have shifted? There can be in the OTC market, particularly for counterintuitive to what different sources of variability, which supplements and vitamins. These people generally have, and require multivariate analysis. It’s not lines run at much higher speeds, and there is a very different strictly an equipment decision. labour is a big component of their cost space classification for each.” of goods. Continuous manufacturing — Michael Rooney, Facility layout issues allows OTC manufacturers to reduce Genesis Engineers PTE: Do people underestimate the operating costs. challenges posed by facility layout For generic pharmaceuticals, and design considerations? however, the issues are different. PAT requirements must be Rooney: With continuous, one Branded companies are not all FOR carefullyPERSONAL, considered NON-COMMERCIALattempts to solve a lot of problems going to share their USE development PTE: Are there considerations with particulate separation by databases, monographs, and that people may forget when they coupling everything (e.g., placing approaches to PAT, so, if generics propose continuous manufacturing feeders near blenders, and blenders manufacturers are to adopt projects to corporate managers? near mills). Another challenge in the continuous, they would have to Rooney: On the manufacturing conversion of a formulation from invest in the same development side, the idea to use continuous batch to continuous is considering that branded companies have to often comes from managers the number of raw materials to be do. I expect to see more contract who see continuous as a way to included in the process. One may only development and manufacturing reduce labour and equipment be able to blend three raw material organizations (CDMOs) investing footprint. Continuous will save ingredients in one blender, so if many in continuous manufacturing both, but there are other factors ingredients are involved, a pre-blend knowhow. Generic pharmaceutical to consider. For example, in batch may be necessary that will then go manufacturers would be more likely OSD plants, when material is moved into another blender. One will then to work with these CDMOs, to avoid around, it promotes segregation have to add more material and send having to invest in the technology or unblending. Continuous it to yet another blender. In addition, and development themselves. minimizes this movement, so one must select the best place for managers may think that adopting the PAT system. In short, it involves Reference continuous technology will help stacking operations vertically, with 1. M. Rooney, “Continuous Manufacturing reduce segregation and even many systems vulnerable to failure or Commercialization Challenges and reduce the need to wash bins as inaccuracies. Misconceptions,” a presentation at the frequently. In addition, based on Also consider that all these feeders 11th Annual Jarowski Symposium in data gathered during continuous must be fed via bulk containers. One Industrial Pharmacy, St. John’s University, manufacturing, facilities can use of the big advantages of continuous New York City, 6 May, 2019. PTE

30 Pharmaceutical Technology Europe JUNE 2019 PharmTech.com Gorodenkoff - stock.adobe.com Agnes Shanley More tools are available to help ensure success. ensure help to available are tools More validation. and procedures, operating standard training, to approaches right the on depend compliance and Quality the Same Page Practices: Getting on Good Laboratory FOR PERSONAL,NON-COMMERCIAL USE both GLPs and for good manufacturing practices (GMPs). practices manufacturing good for and GLPs both for citations, regulatory in found frequently also are conditions OOS investigating to approaches Incorrect SOPs. and training, integrity, data approach labs quality-control and preclinical companies’ some findings. (OOS) out-of-specification of documentation and investigation and collection, data maintenance, and calibration equipment for requirements set also GLPs equipment. laboratory maintain and use to how and tests specific out carry to how explain which (SOPs), procedures operating standard for guidelines establish (1). GLPs labs Global research of anumber at integrity data and training, documentation, in problems serious found survey of 126 biopharmaceutical and pharmaceutical executives in the the in executives pharmaceutical and 126 of biopharmaceutical survey a released Insights 2019, May In Health IDC plant. the as well as lab the affects challenge This industry. the for challenge amajor as utilization protocols. lab and data study incomplete were faulted (3). Also validated properly been not had reagents and antibodies, lines, cell materials, reference and reagents biological others, in guidelines; vendor on based efficiently (2). alone States United the in year each billion) (US$28 billion €25 roughly wastes and products new of development the delay to continues that aproblem reproduced, be not could research preclinical published of 50% that found (GBSI) Institute Standards Biological 2015, Global In the laboratory). innovator an in conducted research original in published results the replicate cannot laboratories other which in (i.e., asituation reproducibility of lack is GLPs with compliance inadequate to traced be can that problem major Another reproducibility of Lack L Decades later, regulators still find deficiencies in the way that that way the in deficiencies find still later, regulators Decades Industry executivesIndustry have pointed to and cross-functional access data used being not was equipment found, researchers cases, some In enacted in 1979 after US Food and Drug Administration observers observers Administration Drug and Food US 1979 in after enacted were (GLPs) practices laboratory good regulations, crucial ike many Pharmaceutical Technology Europe voice recognition, and machine machine and recognition, voice intelligence, artificial Combining 2019 Philadelphia. BIO in at assistant lab voice-activated anew introduce will company The trail. data digital the from out locked not are experiment any to relevant details important that ensure can scientists so thatvoice-activated technology and troubleshooting. resources, and protocols of sharing the and collaboration facilitates also platform The software. analysis data to transferred be then can data gathered All notes. detailed including project, each for ahistory create to and procedures of libraries build to tool the use can They project. aresearch on work they as (5) data important other and SOPs protocols, relevant most the to directly (ELNs). notebooks lab electronic of deficiencies the of some around get scientists to help designed platform digital interactive an LabStep, is example One intelligence. artificial of elements and language machine of use feature them of some and systems, software various from extracted be to data allow platforms these of it. need might who all to accessible and used, is experiment a specific to relevant input all that ensure to notes, paper and data electronic between gap the bridge to designed been have tools These reproducibility. and efficiency laboratory improve to data, more use and capture scientists lab help to available are platforms and applications digital of number A growing Improving data access help them reach either of those goals. to place in strategy aclear have not did they that said 51% surveyed those of way. However, same the intelligence and/oradvanced analytics artificial apply to ability the 94%and described strategies, business their to important very or important was access data cross-functional that said respondents of 98% (4). than More data harnessing for strategies their and need their between gap asignificant found which US, the and Kingdom United LabTwin, based in Germany, uses uses Germany, in LabTwin, based refer to users allows LabStep many storage, cloud-based Using JUNE 2019 31 Good Laboratory Practices

language, the hands-free device Jones: Initial training, especially PTE: Reproducibility has been allows researchers to document with newer employees, can be done cited as a major problem for steps taken and save explicit details through reading, lecture, and/or biopharmaceutical preclinical research. that cannot currently be saved in some type of knowledge or learning Is that also the case for pharma quality ELNs (6). Labfolder (7) is yet another assessment, but the best results control labs? What best practices do platform that aims to enable occur when that theoretical work you recommend regarding validation of more laboratory data to be saved, is followed up and supplemented materials and methods? accessed, and used throughout any by hands-on training. This is Jones: We have found that, after organization. The application allows accomplished most effectively by research and development of the users to create or import a wide teaming new employees with method by our R&D scientists, it variety of different types of text experienced staff, using training goals is important to involve the sample and graphics files, and to upload that have been established within a analysis team in performing some, if and share file formats with other predetermined curriculum. not all, of the validation experiments, research team members. Some measure of refresher with technical assistance provided, training should also be required on as needed, by the R&D scientists who Searching and collaborating at least an annual basis and it should developed the method. To improve search, it allows for full be consistent across all employee This approach allows for a tagging and filtered search. Users can experience levels. Metrics that have shared collaboration between the also define individual access levels to been generated around unplanned research and production teams, and the platform, and manage projects, protocol and SOP deviations, as well continues into sample analysis to while team mates can transfer as human error, should be used as ensure reproducible results from the protocols and SOPs and share indicators in determining the course developed and validated method. templates to improve collaboration. and effectiveness of current training Best practices include following Ultimately, compliance with GLPs plans, as well as for planning future the proper bioanalytical method depends on following best practices. training programmes. validation guidances, the bridging Stuart Jones, regulatory quality of critical reagents, analyst method assurance professional in good “It is important to involve qualification and scientific expertise/ laboratory practice (RQAP-GLP) and the sample analysis knowledge of the assay, as well as the director of quality assurance at PPD team in performing use of incurred sample reproducibility Laboratories’ Bioanalytical Laboratory some, if not all, of the testing as one of the bioanalytical shared recommendations with validation experiments, lab’s means of proving the method Pharmaceutical Technology Europe. can be reproduced. with technical assistance Best GLP work practices provided by the R&D References PTE: What GLP problems do you scientists who developed 1. H. Danan, Pharmaceutical Technology frequently encounter at pharma and the method. This allows 15(6) (2003). FOR biopharmaPERSONAL, companies, and how can NON-COMMERCIALfor shared collaboration, 2. L. Freedman et al, BioPharmUSE they be prevented? and continues into International 28(10) pp 14–21 (2015). Jones: Because we work in such a sample analysis to ensure 3. M. Williams, Current Protocols regulated environment, a seemingly reproducible results.” 81(1) (2018). minor matter can have a significant — Stuart Jones, 4. Accenture, “The Case for Connectivity impact on quality. As such, training PPD Laboratories in the Life Sciences,” Infographic, is an important best practice, from accenture.com, 22 May 2019, www. the time of hire, to retraining when a accenture.com/_acnmedia/PDF-101/ deviation occurs. Destroying silos Accenture-INTIENTInfographic-IDC.pdf. Annual refresher training as well as PTE: What best practices do you 5. Lab Twin, Press Release, “Voice specific group remedial training also recommend to make data less siloed Activated Laboratory Assistant to should be provided when needed. and more accessible to those who may Launch at BIO 2019,” www.scrip. Meanwhile, the use of automated need it (on cross functional teams?) pharmaintelligence.informa.com/ or electronic systems, such as Jones: One of the best ways to SC125243/LabTwin-Voice-Activated- laboratory e-notebooks, can be establish a more cross-functional Lab-Assistant-To-Launch-At-Bio especially beneficial in maintaining approach and enhance data 6. J. Gould, “How Technology Can Help the most accurate documentation. accessibility is to use one system Solve Science’s Reproducibility Crisis,” across all sites. If one across-the- 25 April 2019, www.nature.com/ Training is a challenge board system is not a possibility, then articles/d41586-019-01333-0#MO0. PTE: GLP training seems to come the multiple systems must be able 7. S. Bungers, “The Electronic Lab up as a recurring problem in FDA to work in tandem. Data portals and Notebook in 2019,” labfolder.com, citations. How do you recommend SharePoint sites also can be utilized www.labfolder.com/electronic-lab- that companies tackle this, especially to securely share information on a notebook-eln-research-guide/ PTE in biopharm companies? real-time basis.

32 Pharmaceutical Technology Europe JUNE 2019 PharmTech.com Good Studio - stock.adobe.com [email protected]. Ireland, Dublin, College Engineering, University &Bioprocess Chemical of School the at professor del JiménezIoscani is vital to ensuring glycosylation models are fit for deployment. for fit are models glycosylation ensuring to vital is groups industrial and academic between collaboration Close for Biopharma QA Models of Glycosylation Computational Leveraging Val FOR PERSONAL,NON-COMMERCIAL USE is assistant is assistant focuses on how different modelling strategies can be leveraged to to leveraged be can modelling strategies different how on focuses review This manufacture. TGP with associated issues (QA) assurance quality more or one addressing toward potential demonstrated have models all diverse, been have process glycosylation the describe mathematically to strategies the Although decade. past the over developed been have glycosylation protein for models mathematical TGPs (1). of (CQA) attribute quality acritical as regarded widely is glycosylation pharmacodynamics, and pharmacokinetics, to its bioprocess-associated variability and impact on safety, Due patients. to administered be cannot that product yield and glycosylation (1,3) of process intracellular the impact may pH and ammonia, temperature, oxygen, dissolved availability, nutrient in variations subtle even culture, cell During platforms (5). production used most-commonly the being lines cell Sp2/0) and (NS0 myeloma murine and (CHO) ovary hamster Chinese with (TGPs), glycoproteins therapeutic all of manufacture the for used is culture cell mammalian Large-scale conditions (1). bioprocess manufacturing product (4). among different commercial of lots the same biopharmaceutical variation glycosylation considerable found that work by highlighted is which heterogeneity (3), protein therapeutic of source amajor as acknowledged widely also is Glycosylation biopharmaceuticals (2). therapeutic mechanisms (pharmacodynamics) of the aforementioned to influence the safety, life serum-half (pharmacokinetics), and the _ (e.g., motifs glycan different of abundance relative and presence the turn, In backbone (1). peptide their to bound covalently (glycans) carbohydrates complex contain (tPA) activator plasminogen tissue Regeneron]), interferon gamma (IFN- Bayer/ [Eylea, aflibercept and Amgen/Pfizer] [Enbrel, (etanercept M -1,3 and sialylation) are well-known core fucosylation, galactose, In the context of biopharmaceutical quality assurance, 21 assurance, quality biopharmaceutical of context the In Biopharmaceutical glycosylation variability is determined by monoclonal antibodies (mAbs), Fc-fusion proteins proteins Fc-fusion (mAbs), antibodies monoclonal including therapeutics, protein highest-grossing the of any a ), erythropoietin (EPO),), erythropoietin and Pharmaceutical Technology Europe • High levels of ` of levels High • fucose core of absence The • • Tandem Presence of high-mannose glycans, • presented in of TGPspharmacodynamics are the safety, pharmacokinetics, and influence to known are that motifs glycosylation individual following The of protein therapeutics efficacy and safety the Glycosylation impacts elsewhere (6). outlined been have models glycosylation on details Technical manufacture. and development ofstages biopharmaceutical product different the QAacross product in aid oncolytic mAbs. of attribute a preferable is, therefore,galactosylation ADCC (14). ` and High (CDC) (13) cytotoxicity dependent complement- their enhance mAbs of Fcglycans the on (Gazyva, Roche). obinutuzumab and Kirin) Kyowa mogamulizumab (Poteligeo, glycoengineered mAb products, commercially-available two in core fucosylation have resulted to eliminate strategies engineering in 50-fold to up activity ADCC mAb has been reported to enhance Cetuximab (9,11). with treatment to prior allergy _ for screened now are patients reactions, these avoid bites (9,11). tick to exposure To by caused likely a condition _ to allergic were who patients in occurred cases These Squibb/Merck) (9,11). Bristol-Myers (Erbitux, Cetuximab with treated patients in anaphylaxis fatal cause to reported been has residues of Presence cells (10). CHO in observed been also has and Sp2/0 (9) and NS0 as such lines, cell murine by produced is that motif glycosylation human mAbs. of activity oncolytic the improves that amechanism (ADCC) (8), dependent cellular cytotoxicity antibody- enhance also may Man5 antibodies (7). of half-life serum the reduces (Man5), glycan five-mannose the particular, in in-vitro _ studies (12). Cell Cell studies (12). -1,3 galactose is anon- is -1,3 galactose Figure 1: _ -1,3 galactose -1,4 galactosylation JUNE 2019 -1,4 -1,4 -galactose, -galactose 33 Analytics

addition of N-acetylgalactosamine Figure 1. Glycans as therapeutic glycoprotein (TGP) quality (GalNAc) to serine or threonine attributes. residues on the protein backbone (19). After this first step, the glycan is modified by a sequence of enzyme- catalysed monosaccharide addition reactions that extend its branching and length (19). CHO cells produce only two O-glycosylation variants, which consist of the mono- and bi-sialylated ‘Core 1’ structures shown in Figure 1 (20). For the purposes of this review, the glycosylation process is considered to have two distinct inputs. The first encompasses the enzymes, which catalyse the monosaccharide removal and addition reactions (glycoenzymes). The second input for the glycosylation processes consists of nucleotide sugar donors (NSDs), which are metabolites that provide monosaccharides for The Man5 glycan (A) reduces the serum half-life of TGPs (7) and the sugar addition reactions of may also yield enhanced oncolytic activity (8). Tandem _1,3-linked the glycosylation process. NSDs galactosylation residues (B) may cause fatal anaphylaxis in certain are endogenously synthesized patient populations (9,11). Absence of core fucose (12) and high by the production cell lines using `-1,4 galactosylation (13,14) (C) on the Fc glycans of monoclonal common nutrients, such as glucose antibodies (mAbs) enhance their oncolytic activity. _-2,3 Nue5Ac and glutamine, as substrates (21). sialylation (D) increases TGP serum half-life (17). The O-linked glycans Thus, NSDs are the direct link produced by Chinese Hamster Ovary (CHO) cells are limited to mono between cellular metabolism (E) or bi-sialylated (F) Core 1 structures (20) that also influence (i.e., nutrient availability) and TGP TGP quality. Symbols representing the monosaccharides, which glycosylation. Many cell culture constitute TGP glycans, are shown at the bottom. NSD precursor feeding strategies have been developed to tune TGP FOR PERSONAL, NON-COMMERCIALglycosylation (22,23). USE

• High levels of _-2,6 sialylation Protein glycosylation Models of therapeutic protein have been linked with enhanced in mammalian cells glycosylation (2009 to 2019) anti-inflammatory activity in Protein asparagine (N)-linked The first model for N-glycosylation, intravenous immunoglobulin glycosylation occurs in two published in 1996, aimed to describe (IVIg) therapies (15) and would, steps (18). The first occurs while the addition of glycans to the thus, be a desirable attribute of the protein is being synthesized peptide backbone of proteins (24). immune-modulating TGPs, such in the endoplasmic reticulum and From then, N-glycosylation models as adalimumab (Humira, AbbVie) entails the covalent addition of expanded to include the extent and Enbrel. Importantly, the a large unprocessed precursor of glycan processing within the anti-inflammatory properties of oligosaccharide to asparagine Golgi apparatus, thus aiming to sialylation are exclusive to the residues of the protein backbone. depict the variability observed glycosidic bond conformation The glycoprotein is then transferred, in TGP glycosylation profiles. (_-2,6) and the sialic acid species via vesicles, to the Golgi apparatus, Descriptions of glycosylation soon (N-acetylneuraminic acid, Neu5Ac) where the second and final step of required strategies for automatically involved (15). CHO, NS0, and Sp2/0 the N-glycosylation process occurs: generating the complex reaction cell lines only produce _-2,3 bonds while transiting through Golgi, the networks involved in the process and and may also produce sialylation protein-bound glycan is sequentially were pioneered by Krambeck and with N-glycolyl neuraminic acid modified by several enzyme- Betenbaugh in 2005 (25). Building on (Neu5Gc), a moiety that may be catalysed carbohydrate removal and these seminal studies, more than immunogenic in humans (16). addition reactions. 20 mathematical models for protein Higher Neu5Ac sialylation has also Serine/threonine (O)-linked glycosylation have been developed been reported to increase the glycosylation occurs entirely in the to date. Based on structure and serum half-life of TGPs (17). Golgi apparatus and begins with the solution strategy, the mathematical ALL FIGURES ARE COURTESY OF THE AUTHOR.

34 Pharmaceutical Technology Europe JUNE 2019 PharmTech.com Analytics

models of TGP glycosylation can be shifts in TGP glycosylation often areas for the different modelling grouped into three categories: kinetic observed in cell culture processes. strategies results from their models, flux-based models, and This limitation has been recently underlying features. Because kinetic statistical models. addressed by including parameters models aim to mechanistically representing dynamic shifts in TGP describe the glycosylation process, residence time within Golgi (30). they are capable of covering … mechanistic Statistical models are all QA application areas. Flux models are, abstract black-box mathematical models are well-suited to define representations where process cell glycoengineering strategies conceptually, inputs are quantitatively related, because they focus on the rates of via statistical regression strategies, glycoenzyme-catalysed reactions. more versatile with TGP glycosylation profiles. By definition, statistical models than their Examples of statistical models of quantitatively represent correlations TGP glycosylation are design of between bioprocess conditions statistical experiment (DoE) surface response and TGP glycosylation. Therefore, models (23) and partial least squares they are particularly adept for counterparts … regression (33,34). Advantages of bioprocess control and optimization statistical models are that they QA applications when mechanistic Kinetic models attempt to capture do not require a priori knowledge bioprocess knowledge is lacking. the time-dependent mechanisms of the process, require little or no Although the deployment of underlying glycosylation and are end-user modelling expertise, and statistical models in industry based on dynamic material balances can therefore be deployed with is increasing at an accelerated for all TGPs and NSDs present in relative ease. Statistical models are pace (49), the use of mechanistic Golgi (26–28). Given the inherently limited in that they are exclusively glycosylation models remains to dynamic nature of cell culture data-driven and, thus, are unable to be widespread. This disparity may processes, kinetic models are yield insight into the mechanisms arise from the use of specialized particularly suited to describe the underlying TGP glycosylation. software and the perceived need for effects bioprocess conditions have Furthermore, the predictive capability expert user input associated with on TGP glycosylation. A fundamental of statistical models may break down mechanistic modelling. Despite these drawback of kinetic models is that if model inputs drift outside the challenges, mechanistic models are, they require a substantial amount input space with which they were conceptually, more versatile than of experimental data to determine calibrated. their statistical counterparts because robust values for their unknown Table I presents the glycosylation they are based on the biochemical parameters (e.g., enzyme kinetic rate models that have been developed mechanisms underlying the constants). since 2009 and highlights how glycosylation process. An interesting Flux-based glycosylation models each model has been used toward example where these limitations consistFOR of material balancesPERSONAL, for all potential TGP quality NON-COMMERCIAL assurance are addressed is the GLYMMER USE TGPs present in the Golgi apparatus applications. (ReacTech) software platform, which and are built using reaction networks is based on the work by Bennun et that define the production and Deployment of glycosylation al. (37), runs on Microsoft Excel, and consumption stoichiometry of each models for biopharma QA requires only moderate user input species. To solve flux models, steady Table I shows that all published and expertise. state is assumed, and the resulting glycosylation models have been system of linear equations is solved used for applications that can Conclusion for the rates (fluxes) at which all TGPs directly support TGP QA practices. The deployment of different are interconverted. Because the Four QA application areas stand glycosylation modelling strategies resulting system of linear equations out: (i) data analytics, (ii) bioprocess depends entirely on the TGP quality is usually underdetermined (more characterization, (iii) cell line assurance application they will be unknown fluxes than equations), engineering/development, and used for. Statistical models can be flux models must be solved (iv) manufacturing bioprocess readily deployed in the industrial using constraint-based linear optimization and control setting for bioprocess design, control, programming (29,30) or probabilistic (21,26,27,29–48). and optimization (33,43) with minimal methods, such as Markov chain Kinetic models appear to be user input and expertise. Mechanistic Monte Carlo simulations (31,32). A the most versatile, having been models (kinetic and flux-based) have key advantage of flux-based models used for all four application areas. been shown to be particularly robust is that their solution requires reduced Flux-based models have mainly for cell line characterization (27,50) amounts of experimental data. The focused on cell line selection and and glycoengineering (26,31) as main drawback of flux-based models glycoengineering, and statistical well as for bioprocess design and is that their solution inherently models have been used for optimization (42,47). assumes steady-state, which limits bioprocess characterization, control, To fully exploit the advances in their ability to describe the dynamic and optimization. The application glycosylation modelling toward

Pharmaceutical Technology Europe JUNE 2019 35 Analytics

Table I. Mathematical models of protein glycosylation (2009–2019).

Therapeutic glycoprotein (TGP) Study Year Model type glycosylation quality assurance (QA) applications Matrix-assisted laser desorption/ionization-time of ﬂ ight (MALDI-TOF) Krambeck et al. I (35) 2009 Kinetic glycan data analysis for cell line characterization. del Val et al. (36) 2011 Kinetic In-silico cell line glycoengineering. MALDI-TOF glycan and transcriptomic data analysis for cell line Bennun et al. (37) 2013 Kinetic characterization. Design-of-experiments (DoE) surface response model for at-line Grainger & James (23) 2013 Statistical bioprocess control. Predicts dynamic variations in monoclonal antibody (mAb) glycans Ohadi et al. (38) 2013 Kinetic for bioprocess characterization. Predicts dynamic variations of mAb glycans from extracellular Jedrzejewski et al. (21) 2014 Kinetic nutrient availability for bioprocess characterization. Hang et al. (29) 2015 Flux-based Glycan data analysis for protein and cell line characterization.

Predicts dynamic variations of mAb glycans for bioprocess del Val et al. I (26) 2016 Kinetic characterization, cell line selection and in-silico glycoengineering.

Reconstruc- Deﬁ nes the nucleotide sugar donor (NSD) demand towards cellular del Val et al. II (39) 2016 tion glycosylation for cell line characterization and bioprocess control.

Reconstruc- Automated framework for O-glycosylation reaction network McDonald et al. (40) 2016 tion reconstruction for cell line characterization. Spahn et al. (31) 2016 Flux-based In-silico Chinese hamster ovary (CHO) cell line glycoengineering. Predicts dynamic variations of mAb glycans from cell culture Villiger et al. (41) 2016 Kinetic conditions for bioprocess characterization and control. Predicts dynamic variations of mAb glycans from manganese Hutter et al. (30) 2017 Flux-based supplementation for bioprocess characterization and control. Kinetic & Compares kinetic and statistical models for perfusion bioprocess Karst et al. (42) 2017 Statistical optimization and control. MALDI-TOF glycan and transcriptomic data analysis for cell line Krambeck et al. II (27) 2017 Kinetic characterization and in-silico cell line glycoengineering. Used to design cell culture media to achieve glycosylation Sokolov et al. I (43) 2017 Statistical FOR PERSONAL, NON-COMMERCIALbiosimilarity of a mAb (bioprocess optimization USE and control). Predicts dynamic variations of mAb glycans from cell culture Sokolov et al. II (34) 2017 Statistical conditions for bioprocess characterization and control. Predicts dynamic variations of mAb glycans from cell culture Sou et al. (44) 2017 Kinetic conditions for bioprocess characterization and control. Spahn et al. (32) 2017 Flux-based In-silico CHO cell line glycoengineering for glycosylation biosimilarity. Aghamohseni et al. Kinetic+ﬂ ux- Predicts galactosylation from cell culture conditions for bioprocess 2017 (45) based characterization and control. Kremkow & Lee (46) 2018 Flux-based In-silico CHO cell line glycoengineering. Predicts dynamic variations of mAb glycans from cell culture Sokolov et al. III (33) 2018 Statistical conditions for bioprocess characterization and control. Used to design an optimal NSD precursor feeding strategy that Kotidis et al. (47) 2019 Kinetic maximizes mAb galactosylation while maintaining product titre. Reconstruc- Automated framework for O-glycosylation reaction network Le et al. (48) 2019 tion reconstruction/visualization for cell line characterization.

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5. A.L. Grilo and A. Mantalaris, Trends Biotechnol. 37 (1) 9–16 (2019). 6. C. Kontoravdi and I.J. del Val, Curr. Opin. Chem. Eng. 22 89–97 (2018). 7. A.M. Goetze, et al., Glycobiology 21 (7) 949–959 (2011). 8. M. Yu, et al., MAbs 4 (4) 475–87 (2012). The leading 9. J.W. Steinke, T.A. Platts-Mills, and S.P. Commins, J. Allergy Clin. Immunol. 135 (3) 589–596 (2015). print and digital 10. C.J. Bosques, et al., Nat. Biotechnol. 28 (11) 1153–1156 (2010). 11. T.A. Platts-Mills, et al., Immunol. Allergy. Clin. North Am. 35 (2) 247–260 (2015). information 12. T. Shinkawa, et al., J. Biol. Chem. 278 (5), 3466–3473 (2003). 13. B. Peschke, et al., Front. Immunol. 8 646 (2017). source for 14. M. Thomann, et al., Mol. Immunol. 73 69–75 (2016). 15. R.M. Anthony, et al., Science, 320 (5874) 373–376 (2008). bio/pharma 16. A. Noguchi, et al., J. Biochem. 117 (1) 59–62 (1995). 17. B. Yin, et al., Biotechnol. Bioeng. 112 (11) 2343–2351 (2015). 18. P. Stanley, N. Taniguchi, and M. Aebi, “N-Glycans”, in Essentials of professionals Glycobiology, A. Varki, et al., Eds., pp. 99–111, (Cold Spring Harbor, New York, NY, 2nd ed., 2015). worldwide 19. I. Brockhausen and P. Stanley, “O-GalNAc Glycans”, in Essentials of Glycobiology, A. Varki, et al., Eds., pp. 113–123 (Cold Spring Harbor, New York, NY, 2nd ed., 2015). 20. S. Houel, et al., Anal. Chem. 86 (1) 576–584 (2014). 21. P.M. Jedrzejewski, et al., Int. J. Mol. Sci. 15 (3) 4492–4522 (2014). 22. N.S. Wong, et al., Biotechnol. Bioeng. 107 (2) 321–336 (2010). 23. R.K. Grainger and D.C. James, Biotechnol. Bioeng. 110 (11) 2970–2983 (2013). 24. M. Shelikoff, A.J. Sinskey, and G. Stephanopoulos, Biotechnol. Bioeng. 50 (1) 73–90 (1996). 25. F.J. Krambeck and M.J. Betenbaugh, Biotechnol. Bioeng. 92 (6) 711–728 (2005). 26. I.J. del Val, Y. Fan, and D. Weilguny, Biotechnol. J. 11 (5) 610–623 (2016). 27. F.J. Krambeck, et al., PLoS One 12 (5), e0175376 (2017). 28. T.K. Villiger, et al., Biotechnol. Prog. 32 (5) 1135–1148 (2016). Manufacturing Trends 29. I. Hang, et al., Glycobiology 25 (12) 1335–1349 (2015). Process Development 30. S. Hutter, et al., Metab. Eng. 43 (Pt A) 9–20 (2017). 31. P.N. Spahn, et al., Metab. Eng. 33 52–66 (2016). Formulation 32. P.N.FOR Spahn, et al., Biotechnol. PERSONAL, J. 12 (2) (2017). NON-COMMERCIALAnalytical Technology USE 33. M. Sokolov, et al., Biotechnol. J. 13 (4) e1700461 (2018). Regulatory Compliance 34. M. Sokolov, et al., Biotechnol. Prog. 33 (5) 1368–1380 (2017). Quality Assurance 35. F.J. Krambeck, et al., Glycobiology 19 (11) 1163–1175 (2009). Best Practices 36. I.J. del Val, J.M. Nagy, and C. Kontoravdi, Biotechnol. Prog. 27 (6) 1730–1743 (2011). API Synthesis 37. S.V. Bennun, et al., PLoS Comput. Biol. 9 (1) e1002813 (2013). Packaging and Outsourcing 38. K. Ohadi, et al., IFAC Proceedings Volumes 46 (31) 30–35 (2013). 39. I.J. del Val, K.M. Polizzi, and C. Kontoravdi, Sci. Rep. 6 28547 (2016). 40. A.G. McDonald, K.F. Tipton, and G.P. Davey, PLoS Comput. Biol. 12 (4) e1004844 (2016). 41. T.K. Villiger, et al., J. Biotechnol. 229 3–12 (2016). 42. D.J. Karst, et al., Biotechnol. Bioeng. 114 (9) 1978–1990 (2017). 43. M. Sokolov, et al., Biotechnol. Prog. 33 (1) 181–191 (2017). 44. S.N. Sou, et al., Biotechnol. Bioeng. 114 (7) 1570–1582 (2017). 45. H. Aghamohseni, et al., J. Ind. Microbiol. Biotechnol. 44 (7) 1005–1020 (2017). 46. B.G. Kremkow and K.H. Lee, Metab. Eng. 47 134–142 (2018). 47. P. Kotidis, et al., Biotechnol. Bioeng. In press (2019) DOI: 10.1002/bit.26960. Sign up for a FREE subscription today 48. T. Le, et al., Biotechnol. Bioeng. In press (2019) DOI: 10.1002/bit.26952. pharmtech.com/subscribe-pharmtech 49. P. Kroll, et al., Pharm. Res. 34 (12) 2596–2613 (2017). 50. S.V. Bennun, et al., J. Mol. Biol. 428 (16), 3337–3352 (2016). PTE

Pharmaceutical Technology Europe JUNE 2019 37 38 Thomas Felicity FOR PERSONAL,NON-COMMERCIAL USE Pharmaceutical Technology Europe compliance are recommended to ensure companies stay on the right track. right the on stay companies ensure to recommended are compliance Proactive approaches that consider long-term supply chain security chain supply long-term consider that approaches Proactive D is dealing with products and services directly impacting human health, health, human impacting directly services and products with dealing is which industry, pharmaceutical the “For smuggling. and theft, or damage product products, counterfeit of terms in particularly Inspections, ACG of CEO Cucchetti, Ettore concurred consumers, to services and products supply or impacting patient safety.” of continuity the impacting without to, responded and quickly detected are deviations any that so business end-to-end the across tracked proactively are security and risk of elements the importantly, “Most TraceLink. strategist, digital chief Martin, Roddy full,” in adds and time on delivered and compliant, safe, are patient the reaching products all that ensure to product.” adrug of legitimacy the determine or track effectively cannot we measures, security chain supply Without drugs. falsified of circulation the minimize and prevent to abid in chains supply around strategies surveillance and legislation new established have regulators health “As aresult, Recipharm. projects, corporate director Widengren, Staffan asserts issue,” awidespread become consequently and society mainstream into trickled has black-market pharmaceutical the that meant chain. supply the of security the protect to regulations implementing been have authorities many health, patient to risk the and market the of size the (2). Given year $217 to per (US$163 billion billion) billion €200 €150 to from billion range to estimated market, global the within sold goods illicit of proportion alucrative represent medicines falsified business, consulting strategy (1). papers published previously of review aliterature on based countries, middle-income to low- in falsified or substandard are products 10 in medical one that estimates (WHO) Organization Health World The health. patient to importantly, more and, companies to risks significant poses generic, or branded whether medicine, authorized an mimic to Security of the supply chain is critical for all companies that offer offer that companies all for critical is chain supply the of Security abusiness in capability end-to-end a core is security chain “Supply has general, in Internet the and pharmacies, online of proliferation “The PricewaterhouseCoopers’ Strategy&, by reported as terms, financial In so on, a drug that has been fraudulently manufactured and distributed distributed and manufactured fraudulently been has that adrug on, so and fake, falsified, counterfeit, used, terms various being there espite

JUNE 2019 PharmTech.com Right TrackRight On the through the supply chain.” supply the through move they as medicines of authenticity the verify and medicines of journey the around data access to identifiers unique scan can market to drugs getting in involved partner “Each continues. he chain,” supply the through progressing from medicines falsified prohibit and products of movement the track also but dispense, of point the at aproduct of authenticity the determine only not can pack. the on included identifier unique the scanning by patient the reaches adrug before legitimacy product verify to ability the through serialization, gain dispensers patients,” adds Widengren. “Essentially, (FMD) regulation to of protect the safety directive medicines falsified the of part requirements were implemented as serialization EUmarket, the “In approach. traceability full the using is latter the while approach, verification point-of-dispense the employing former The approaches. different adopt the says Widengren. security,” chain supply improve and facilitate both can traceability full and “Verification country-to-country. from vary approaches and States, United the and Union, European the into law, China, including Turkey, India, approach atraceability signed already chain. supply the within hands change they time every occurs products of tracing and tracking the as nature in complex more is which traceability, full is model other The bottom. the at also then and chain supply the of top the at occurs verification where point-of-dispense verification approach a have to is model (3). One adopted be can that models traceability two are 2019, there level abasic at February reported in their policy paper in McCurdy Denise and Pisa Michael As approaches Different line,” says. he bottom its ultimately, and, image, brand integrity, product acompany’s of terms in crucial more becomes security chain supply particular as a result of the need to deal deal to need the of aresult as particular in industry, impacted inevitably has world the across implemented Each traceability approach being data with Dealing “Whereas, track-and-trace systems chose example, for US, EUand The have regions and countries Many

Gribanov - stock.adobe.com Supply Chain

with vast amounts of data. “Due to the in logistics and distribution channels, will use early stage technology to do sheer amount of data generated by using the complete supply chain data to so,” Martin adds. serialization requirements, organizations optimize the supply chain.” have been required to evaluate and Safeguarding adopt software technology solutions to Regulatory initiatives future supply chains create, capture, store, report, and share “Regulatory and government bodies “Companies should always be mindful compliance data at scale,” notes Martin. are looking into all available and of new ways they can safeguard their “This question of technology scalability emerging technologies for securing supply chains, especially when the remains a real concern when it comes supply chains,” notes Cucchetti. “Each political landscape is in a state of flux,” to simply meeting the requirements regulatory body has multiple objectives, emphasizes Widengren. “It is essential of these legal mandates themselves, but the preliminary goal remains the to consider long-term prospects so which is one of the critical reasons that same—to secure the product from that a plan can be made around new a cloud-based, network platform is manufacturer to end consumer.” legalities. As such, pharmaceutical optimal,” he continues. Giving some examples, Cucchetti manufacturers should invest time In agreement, Widengren states that highlights Russia, which has mandated into understanding the markets they cloud-based networks have been found crypto tail into barcoding processes; operate in, as well as the ones they may to be the most successful in terms of Indonesia, which is assessing product potentially pursue. This way they can connecting supply chain partners and authentication techniques; and the US, design a strategy that will help facilitate enabling the exchange of serialization which is looking to evaluate blockchain market entry and progression with as data. “As well as enabling compliance with serialization. “Currently, most little complexity and limitation possible.” with serialization regulations, these of the regulatory requirements are For Cucchetti, a proactive approach platforms also offer the opportunity focused towards serialization and track to supply chain security is key as for businesses to improve supply chain and trace, as well as mandates for the it can afford companies time to be visibility and gain additional value from pharmaceutical industry,” he says. able to adapt to all changes required their investment,” he says. “By giving “Going forward, it is likely that similar when complying with regulations. companies greater insight into their regulations will be applicable to all other “Companies should form a dedicated operations, businesses can make more industries as well. Government and team with all business functions informed decisions in areas such as regulatory bodies will be more stringent involved in the serialization project, supply and demand forecasting, product in regulation—considering consumer documenting all regulatory and business recalls, and even achieve engagement health and safety requirements. As the requirements,” he says. “At all times, with patients.” technologies evolve, each government organizations should work alongside Additionally, Martin emphasizes will be evaluating possible technological the implementation partner and that as industry looks to the future implementations to secure supply possibly with the regulation bodies to and leveraging the data gained from chains to fight against counterfeiters, understand the upcoming changes and serialization, there will be a shift away and also to have complete visibility of work towards accommodating them.” from the fragmented silo nature of the industry.” As a final note, Widengren explains the bio/pharmaFOR supply PERSONAL, chain that has Specifically focusing NON-COMMERCIAL on the US and that for companies to be able to reap USE existed previously as a fractious supply its exploration of methods to enhance the benefits of supply chain security chain hinders visibility and impacts the safety and security of the supply requirements and for optimum performance. “Instead, serialization chain, Martin discusses the US Food preparedness and future safeguarding, should be used as a lens to look at the and Drug Administration’s (FDA’s) Drug companies should consider end-to-end digital supply chain and, if Supply Chain Security Act (DSCSA) pilot implementing aggregation capabilities. done right, will lead to transformative programme. “Recently, FDA announced “Aggregation is not always a mandatory benefits in terms of increasing business a pilot programme project seeking measure,” he summarizes, “but it is value through more collaborative supply innovative and emerging approaches expected to become part of legislative chains and end-to-end visibility into for enhanced tracing and verification of requirements in the future.” value networks,” he explains. prescription drugs in the US to ensure “Blockchain will be considered as one suspect and illegitimate products References of the critical factors when it comes do not enter the supply chain,” he 1. WHO, “A Study on the Public Health and to selecting a supply chain partner in confirms. “TraceLink was accepted Socioeconomic Impact of Substandard the future,” adds Cucchetti. “Product into the pilot programme and will focus and Falsified Medical Products,” Report, traceability and recalls are known to on two workstreams; blockchain and November 2017. be the biggest challenges for most digital recalls.” 2. Strategy&, “Fighting Counterfeit industries, and blockchain landscape Companies of varying sizes will be Pharmaceuticals New Defences for can be used to secure the transaction included in the TraceLink pilot project, an Underestimated—and Growing— between the supply chain partners. covering the end-to-end supply chain. Menace,” Report, 29 June 2017. With blockchain, companies can “Together, through network connectivity 3. M. Pisa and D. McCurdy, “Improving address counterfeit issues through the and innovative software solutions, Global Health Supply Chains Through authentication process, and they can participants will explore and collaborate Traceability,” Center for Global perform product recall smoothly. This on ways to improve the safety and Development Policy Paper 139, can help them to identify the issues security of the drug supply chain and February 2019. PTE

Pharmaceutical Technology Europe JUNE 2019 39 40 Thomas Felicity intermediates, companies need to re-emphasize upstream manufacturing. upstream intermediates, need companies to re-emphasize non-cGMP of security chain supply the on focus increased an With Gap Security IntermediateEarly Filling the FOR PERSONAL,NON-COMMERCIAL USE Pharmaceutical Technology Europe Current challenges S producers to compete based on price. The dependence on regional regional on dependence The price. on based compete to producers Western for difficult it made and capacity, excess tremendous provided significantly, balance supply/demand the shifted costs lower at capacity additional This costs. low very at materials produced that capacity chemical in invested producers Chinese 2000s, early and 1990s late the In particularly. China into East, the towards shifted have production intermediate non-cGMP and materials raw while manufacturing cGMP downstream on focused largely chain? supply the impacted this has how and EIs that traditionally supply materials. regions the in concerns environmental and quality address to regulations increased and materials non-cGMP of supply regional on over-dependence the from comes largely supply unstable The EIs. or intermediates cGMP non- the including chain, supply the of value the re-evaluate to customers forced has this and stable, less far become have price, the as well as PTE: chain security landscape. chain security supply changing the about more out find to &Biotech, Pharma Lonza Europe chain. supply integrated an customers offer to Switzerland, Visp, in located facilities production chemical its use will company the initiative, this (1). APIs Through small-molecule for initiative an launched Switzerland, in headquartered &Biotech, Pharma well. as chain supply the of parts earlier across security greater ensure to adrive been has (EI)—there intermediates intermediates—early non-cGMP with particularly apparent, become challenges more and shifts industry the However, as stages. later the on focused been has chains supply around Diver (Lonza): PTE: Diver (Lonza): To address the concerns around the supply and quality of EIs, Lonza Lonza EIs, of quality and supply the around concerns the To address scrutinized within the pharmaceutical industry. Much of the attention attention the of Much industry. pharmaceutical the within scrutinized extensively and deliberated long been has security chain upply What are the current challenges with the EI supply chain? EIsupply the with challenges current the are What spoke with Sean Diver, director of business development at at development business of Diver, director Sean with spoke Why has there been such an industry trend towards outsourcing of of outsourcing towards trend industry an such been there has Why

JUNE 2019 In recent years, the reliability of supply of materials, materials, of supply of reliability the years, recent In Over the past 15 years, Western producers have have producers Western 15 years, past the Over PharmTech.com Pharmaceutical Technology global shortage of a drug could occur. could adrug of shortage global a adrug, of source single the is site one if as such cases, extreme more In shortages. supply to lead can producers of set asmall on overreliance site, one at contaminated being API the to due recalled are products when generally, Speaking patients. to medicines saving and most importantly, supply of life- time, money, of alot cost can problems correcting these quality-related addition, In EI. an from impurities to due States, United the as well as Europe, in products sartan many recall to need the product. end the to way their make easily very can EIs these from impurities The controlled. and monitored closely changes with and process, well-defined a with manufactured be EIs that critical is It impacted. be easily could product drug and API, intermediates, advanced of quality downstream the as severe, are EIs quality inconsistent or poor quality? inconsistent or poor of be to found are EIbatches if chain the in later PTE: Downstream consequences producers. Western with broadly more working companies seeing are we Today supply. of source the to related horizon their broadening are companies adriver, as strong as not is price and materials, these around decisions the driving is supply of security As shifted. has EIs of supply the pricing, higher considerably and capacity, of materials, closures of significant recently. until utilized and accepted widely been has suppliers Eastern Europe, with deep experience in quality quality in experience deep with Europe, in those as such partners, Western Eastern region and engaging with traditional the beyond Going materials. cGMP production as well as non-cGMP engaging suppliers with for assets value chain. the of security the address to EIs the include to need philosophies ownership of Total cost supply. API of innovation and sustainability, quality, robustness, ensure help can chain’ a‘value as chain EIsupply? of quality and security the PTE: chain’ ‘value the Embrace A recent example of this is seen in in seen is this of example A recent Diver (Lonza): supply the in shifts to However, due Companies can benefit from from benefit can Companies Diver (Lonza): What are the potential ramifications ramifications potential the are What How can manufacturers improve improve manufacturers can How The implications of of implications The Embracing the supply supply the Embracing

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management systems, technology, PTE: Are there other regulatory from a supply chain mindset to that of manufacturing, and innovation for the challenges impacting the supply of EIs? a value chain, where companies can pharmaceutical industry can increase Diver (Lonza): Enhanced approaches extract and unlock value—such as quality systemically and provide the to environment, health, and safety data, increased quality protection, and manufacturing and delivery services (EHS) regulations has weakened the responsiveness—from every facet. needed to ensure uninterrupted supply value of the supply chain as costs Additionally, the Western chemical and availability of critical medicines have risen in certain regions. In China, capacity must re-emphasize upstream for patients. The right suppliers can increasingly rigorous EHS requirements manufacturing and invest in local enhance the value chain by engaging and substantial environmental taxes assets, or their own assets, to better the appropriate technologies in have put pressure on manufacturing distribute the global supply of APIs, and the appropriate facilities that drive facilities and even shut down a number intermediates to stabilize sustainability, compliance and competitiveness. of them due to poor environmental cost, and quality of supply. conditions. With such a reliance In summary, the industry has seemed Regulatory impacts on supply of materials from China, to learn a lesson that being overly PTE: In Europe, we are seeing a drive to customers’ supply chains have seen dependent on one region for global improve supply chain security through substantial price increases or have been supply has serious risk. Pharmaceutical the falsified medicines directive (FMD). left with no qualified suppliers of non- supply chains seem to be thinking about Has this revised regulation impacted cGMP materials due to environmental region-by-region strategies as well companies’ decisions on procurement regulatory requirements. This is why as global ones, and find tremendous of ingredients, in your opinion? European and US suppliers are now value in it. In the future, look for supply Diver (Lonza): The FMD has being reconsidered for supply of these of materials to come from sources created a more rigorous system to materials as rigorous EHS programmes that have a culture of compliance, protect and regulate the supply chain, have been in place and proven for innovation, and efficiency. The supply manufacturing process, and delivery many years. of these EIs will be treated more of medicines. In essence, the directive strategically than they have been over will influence companies to continue to Looking to the future the last era. seek data-rich and technology-driven PTE: Over the coming five to 10 years, solutions that optimize, streamline, and what may we expect to see trending, in Reference unlock value within their supply chains, terms of the EI supply chain? 1. Lonza, “Lonza Launches starting from the very initial upstream Diver (Lonza): The unstable supply Early-Intermediates Supply Initiative for phases including extraction and of EIs and new regulations will require Small-Molecule APIs,” Press Release procurement of ingredients. pharmaceutical companies to transition (14 Sept. 2018). PTE

Ask The Expert — contin. from page 42 FOR PERSONAL, NON-COMMERCIAL USE concluded in 24 hours or less. The expectation of when the for Good Manufacturing Practice for Medicinal Products for contract lab will inform you of any OOS obtained should be clearly Human and Veterinary Use, Chapter 7, Outsourced Activities defined in your quality agreement. The sooner a laboratory error (EC, 31 January 2013). can be ruled out as the cause of the OOS result, the sooner the 4. EC, EudraLex, The Rules Governing Medicinal Products in full-blown manufacturing investigation can be started. the European Union, Volume 4, EU Guidelines for Good Taking the time to establish a quality agreement and Manufacturing Practice for Medicinal Products for Human investigate the details of their OOS procedure is the first and Veterinary Use, Part 1, Chapter 6: Quality Control (EC, step in establishing a good working relationship with your October 2014). contract test laboratory. This working relationship will become 5. EC, EudraLex, The Rules Governing Medicinal Products in invaluable when an OOS occurs. The final product testing the European Union Volume 4, Good Manufacturing Practice, procedure for OOSs isn’t the only one you need to review, Medicinal Products for Human and Veterinary Use, Part II: however. You should also look at the quality agreement Basic Requirements for Active Substances used as Starting and OOS procedure being used by your manufacturer for Materials (EC, September 2014). in-process test results, assuming they are different entities. 6. FDA, Guidance for Industry, Investigating Out-of- The same information required in the final product OOS Specification (OOS) Test Results for Pharmaceutical procedure should be the same for in-process testing. Production (FDA, October 2006). PTE

References 1. US 21 CFR 200.10 (b) 2. FDA, Contract Manufacturing Arrangements for Drugs: Your opinion matters. Quality Arrangements: Guidance for Industry (FDA, Have a common regulatory or compliance question? November 2016). Send it to [email protected], and it may appear in a future column. 3. European Commission, The Rules Governing Medicinal Products in the European Union, Volume 4, EU Guidelines

Pharmaceutical Technology Europe JUNE 2019 41 ask the expert

Quality Agreements and Out-of-Specification Investigations

A good working relationship between sponsor and contractor will become invaluable when an OOS occurs, says Susan J. Schniepp, executive vice-president of post-approval pharma and distinguished fellow, Regulatory Compliance Associates.

I’m responsible for quality at a small, virtual startup what needs to be in an OOS procedure. The EU addresses Q.company, and we contract out all of our activities. I’m the need to investigate OOSs in their GMPs. EudraLexx Part working on documentation to contract out our product testing 1, Section 6.35 states, “Out of specification or significant and was wondering what information there is regarding atypical trends should be investigated. Any confirmed out- quality agreements and laboratory investigations. of-specification result, or significant negative trend, affecting product batches released on the market should be reported The best place to start is to take a critical look at to the relevant competent authorities. The possible impact on A.existing guidance documents and regulations that batches on the market should be considered in accordance govern quality agreements and out-of-specification (OOS) with Chapter 8 of the GMP Guide and in consultation with the investigations. relevant competent authorities” (4). Part 2 of the EU GMP guide The basic philosophy when establishing any quality for APIs states in section 11.15 that: “Any out-of-specification agreement is to understand that the contract provider and result obtained should be investigated and documented contract giver are partners and their behaviours reflect according to a procedure. This procedure should require on each other. In the United States, 21 Code of Federal analysis of the data, assessment of whether a significant Regulations (CFR) 200.10(b) confirms this concept by problem exists, allocation of the tasks for corrective actions, stating: “The Food and Drug Administration is aware that and conclusions. Any re-sampling and/or retesting after OOS many manufacturers of pharmaceutical products utilize results should be performed according to a documented extramural independent contract facilities, such as testing procedure” (5). laboratories,FOR contract PERSONAL, packers or labellers, and custom NON-COMMERCIALThe best guidance, however, on conducting USE OOS grinders, and regards extramural facilities as an extension investigations is the information provided in FDA’s Guidance of the manufacturer’s own facility” (1). The next document for Industry, Investigating Out-of-Specification (OOS) Test to review for quality agreements is the US Food and Drug Results for Pharmaceutical Production (6). The responsibilities Administration (FDA) guideline titled Contract Manufacturing for the laboratory analyst and supervisor are clearly defined Arrangements for Drugs: Quality Agreements. Section B, in this guidance and should be reflected in any laboratory OOS Elements of a Quality Agreement, Part e. Laboratory controls, procedure. A well-written standard operating procedure (SOP) states that a quality agreement should include: “Designation on OOSs should require investigations to be thorough, timely, of responsibility for investigating deviations, discrepancies, unbiased, well documented, and scientifically sound. Often, failures, out-of-specification results, and out-of-trend the procedure will contain a checklist that assists in identifying results in the laboratory, and for sharing reports of such obvious laboratory errors. The checklist assesses the investigations” (2). This confirms that the responsibility for suitability of analyst qualification and training, use of correct OOS investigations is shared and communication between the procedure and specification, the calibration and performance contract giver and contract provider is critical. The European of the equipment, correct preparation of test solutions and Union also addresses the need for a relationship between dilutions, use of proper reagents and standards, calculations, you and your outsourced laboratory in EudraLexx, Chapter etc. A thorough checklist and analyst documentation are 7 (7.15) on Outsourced Activities by stating: “The Contract critical in identifying true laboratory error. The SOP should should describe clearly who undertakes each step of the also discuss the sample retesting requirements when a true outsourced activity, e.g. knowledge management, technology laboratory error is determined to be the cause of the OOS. transfer, supply chain, subcontracting, quality and purchasing The most important and critical element for OOS of materials, testing and releasing materials, undertaking investigations is specifying the timeliness. This should be production and quality controls (including in-process controls, stipulated in the SOP and, in most cases, the investigation into sampling and analysis)” (3). the OOS, from the laboratory perspective, should be The above regulations establish the need for quality

agreements that cover laboratory activities but doesn’t define contin. on page 41 DAMIAN PALUS/SHUTTERSTOCK.COM

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