APRIL 2020 Volume 32 Number 4

Building Better Manufacturing Facilities Development Accelerating Vaccine Development Optimizing Drug Delivery Manufacturing HPAPI Tabletting Safety Quality/Regulations Supplier Oversight Analytics Cleaning Validation Operations Cold-Chain Packaging Outsourcing Continuous Bioprocessing

Peer-Review Research Identifying Impurity in Topical Gel

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GL-CM-2000006 AD_04.20 Pharma Technology Europe_CPhI North Philadelphia_LOGOS_03.indd 1 16/3/20 11:39 April 2020 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: nasir1164 - Stock.adobe.com in the pharmaceutical and biotechnology industries. Art direction: Maria Reyes

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OPERATIONS Features 29 Packaging Preserves the Cold Chain COVER STORY: MANUFACTURING More sustainable and functional 9 Building Better Manufacturing Facilities cold-chain packaging protects biologics Whether refitting existing spaces or building and other temperature‑sensitive drugs. new, the need for quick build times, flexibility, QUALITY/REGULATIONS and production efficiency is driving trends 33 Being Vigilant in Supplier Oversight in bio/pharma facility construction. Risk assessments, audits, and good DEVELOPMENT communication between sponsor and 13 Can Vaccine Development supplier are key elements of supplier oversight. Be Safely Accelerated? OUTSOURCING Biopharma companies responding to the 36 Biomanufacturing: Demand COVID-19 outbreak think accelerating the for Continuous Bioprocessing Increasing development of vaccines is safe. But are innovations sufficient to increase adoption? CMOs are demanding better 16 Delivering the Goods continuous bioprocessing options. The new molecules entering the development pipeline are bringing forth ANALYTICS exciting challenges in drug delivery. 39 Alternative Cleaning Validation Methods for Biologics MANUFACTURING Because conventional cleaning methods 26 Understanding Containment for Tabletting can risk product loss, biopharmaceutical Risk levels should be considered when manufacturers are often reluctant to use designing equipment to enhance operator safety. PDE/ADE limits to validate cleaning processes.

Peer-Review Research Columns and Regulars 5 Editor’s Comment 20 Identifying the Structure of an Making Every Effort Unknown Impurity in a Topical Gel 6 European Regulatory Watch This case study highlights analytical instrumentation Learning Lessons in Crisis Management and techniques that were used to identify an unknown impurity detected during routine 41 Ad Index release testing of a topical gel drug product. 42 Ask the Expert Critical Knowledge for Preparing Audits

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STERILE.COM For more information, visit our website at sterile.com/particlecounters VELTEK ASSOCIATES, INC. EDITORIAL ADVISORY BOARD PharmTech Group PharmTech Europe Editorial Director Editor Reinhard Baumfalk Luigi G. Martini Rita Peters Felicity Thomas [email protected] [email protected] Vice-President, R&D Chair of Pharmaceutical Senior Editor Publisher Instrumentation & Control Innovation Agnes Shanley Michael Tracey Sartorius AG King’s College London [email protected] [email protected] Rafael Beerbohm Thomas Menzel Sales Manager Managing Editor Director of Quality Systems Menzel Fluid Solutions AG Susan Haigney Linda Hewitt Tel. +44 (0) 151 705 7603 [email protected] Boehringer Ingelheim GmbH Jim Miller [email protected] Manufacturing Editor Phil Borman, DSc Founder and Former President, Senior Sales Executive Jennifer Markarian Stephen Cleland Director, PharmSource, [email protected] Tel. +44 (0) 151 705 7604 Product Development & Supply A Global Data Company Science Editor [email protected] Medicinal Science & Technology Colin Minchom Feliza Mirasol Sales Operations Executive Pharma R&D [email protected] Barbara Williams GlaxoSmithKline Senior Director [email protected] Pharmaceutical Sciences Assistant Editor Evonne Brennan Lauren Lavelle VP & Managing Director, Shire Pharmaceuticals TM [email protected] MJH Life Sciences International Technical Marketing Dave Esola Manager, Pharmaceutical Clifford S. Mintz Senior Art Director C.A.S.T. Data and List Information Marie Maresco Division, President and Founder Michael Kushner IMCD Ireland BioInsights Graphic Designer [email protected] Maria Reyes Rory Budihandojo Tim Peterson Director, Quality and EHS Audit Transdermal Product Boehringer-Ingelheim Development Leader, Drug MJH Life SciencesTM Vice President, Human Resources Christopher Burgess Delivery Systems Division, 3M Chairman and Founder & Administration Managing Director John Pritchard Mike Hennessy, Sr Shari Lundenberg Burgess Analytical Consultancy Technical Director Vice Chairman Vice President, Business Jack Lepping Intelligence Ryan F. Donnelly Philips Respironics President and CEO Chris Hennessy Professor Thomas Rades Mike Hennessy, Jr Vice President, Marketing Queens University Belfast Professor, Amy Erdman Chief Financial Officer Tim Freeman Research Chair in Formulation Neil Glasser, CPA/CFE Executive Creative Director, Managing Director Design and Drug Delivery, Executive Vice President, Creative Services Freeman Technology University of Copenhagen Operations Jeff Brown Tom Tolvé Filipe Gaspar Rodolfo Romañach Published by Senior Vice President, Content Vice-President, R&D Professor of Chemistry Multimedia UK, LLC Silas Inman Sycamore House, Suite 2 Hovione University of Puerto Rico, Lloyd Drive Puerto Rico Senior Vice President, I.T. & Sharon Grimster Enterprise Systems Cheshire Oaks Cheshire Siegfried Schmitt John Moricone ReNeuron Ch65 9HQ, United Kingdom Vice‑President Technical Senior Vice President, Audience Tel. +44 151 705 7601 Anne Marie Healy PAREXEL Generation & Product Fulfillment Professor in Pharmaceutics and Joy Puzzo Pharmaceutical Technology Stane Srcic Trinity College Dublin, Ireland Professor University of Ljubljana, Slovenia Deirdre Hurley Senior Director, Plant Griet Van Vaerenbergh Helsinn Birex GEA Process Engineering Pharmaceuticals Ltd. 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4 Pharmaceutical Technology Europe APRIL 2020 PharmTech.com EDITOR’S COMMENT Making Every Effort

hile the majority Regulatory response that are not yet proven to be effective in W of the world is in The global pandemic of COVID-19 the treatment of COVID-19. As reported isolation to try to slow has been pushing the boundaries of by The Guardian people suffering from the spread of the virus regulatory possibilities both within lupus are now facing empty pharmacy responsible for COVID- Europe and around the rest of the world. shelves that would normally contain a 19, companies and Guidance on how to best manage clinical vital medicine used for their treatment, regulatory bodies in the trials in the current situation, deferral of hydroxychloroquine (3). The emptying of bio/pharma industry non-essential inspections, prioritization the shelves can be attributed to the, as are facing numerous of COVID-19 treatment applications, of yet unproven, link with the drug having challenges and committing significant expediting applications, and funding efficacy in the treatment of COVID-19. efforts to support the development of novel are some of the measures being taken Therefore, in this current climate, it therapeutics and monitor supply chains. by European authorities to support the is imperative that pertinent scientific industry. information that can be of reassurance Drug and vaccine development These practical measures being and informative be disseminated According to the European Federation of implemented by European regulatory with due diligence and care. So, in Pharmaceutical Industries and Associations enforcers have undoubtedly been more addition to thanking all those working (EFPIA), its members are actively engaged in easily formulated as a result of lessons tirelessly to develop potential vaccines the development of collaborative research learned from previous outbreaks. In this and treatments, the Pharmaceutical programmes that will assist in accelerating issue’s European Regulatory Watch (pages Technology Europe team invites you to the advancement of therapeutics for 6–8), Sean Milmo delves into this topic in keep up-to-date with industry efforts via COVID-19 (1). Some examples of work being more detail, looking at specific examples our website, www.PharmTech.com where performed by EFPIA member companies from past outbreaks and how closer there will be regular COVID-19 coverage in tackling the COVID-19 outbreak relationships built up by agencies in spanning drug development, research, include: companies, such as Bayer and Europe with companies and researchers supplier news, and regulatory updates. GlaxoSmithKline, joining the COVID-19 is advantageous for the current situation. Stay safe and healthy. Therapeutics Accelerator Initiative and opening up compound libraries; the Supply chain concerns References donation of supplies, such as Merck’s Another important aspect being looked 1. EFPIA, “European Pharmaceutical Industry donation of interferon beta-1a, to be used at by regulatory bodies and industry Response to COVID-19,” efpia.eu, Press in clinical trials; provision of expertise associations, which has the potential Release, 25 Feb. 2020. and advice to relevant stakeholders; and to be detrimentally impacted by the 2. Pharmaceutical Technology Editors, “Indian leveraging previous vaccine development COVID-19 pandemic, is that of supply Government Restricts Export of APIs and work to potentially enable a more rapid chain. For example, industry concerns Formulations Due to COVID-19,” PharmTech. development of a COVID-19 vaccine, such were raised when the Indian government com, 6 March 2020. as work being done by Sanofi (1). revealed it would be restricting the export 3. The Guardian, “Vital Drug for People with Some notable drugs and vaccines for of 26 APIs and formulations, including Lupus Running Out After Unproven COVID-19 COVID-19 in development are: paracetamol, progesterone, and vitamin Link,” theguardian.com, 27 March 2020. PTE • Messenger RNA vaccines, from CureVac B12, as a result of COVID-19 early in and BioNTech, are in preclinical stages. March 2020 (2). • Remdesivir, from Gilead Sciences, And, it isn’t just trepidations around Felicity Thomas originally developed to treat Ebola, is in the availability of ingredients, there is Editor of Pharmaceutical Technology Europe Phase III clinical trials. also the added issue of hoarding drugs [email protected] • SNG001, from Synairgen Research, is an inhaled formulation of interferon-beta-1a Join PTE’s community that is entering Phase II clinical trials. Join the Pharmaceutical Technology Europe group on LinkedIn™* and start discussing the issues • Chloroquine and hydroxychloroquine are that matter to you with your peers.

currently being investigated in clinical Go to PharmTech.com/linkedin trials and are being donated by various

companies for evaluation. *The linkedIn logo is a registered trademark of LinkedIn Corporation and its affiliates in the United States and/or other countries

Pharmaceutical Technology Europe APRIL 2020 5 EUROPEAN REGULATORY WATCH

Learning Lessons in Crisis Management

Regulatory emergency planning has been put to the test with the COVID-19 pandemic.

uropean medicine regulators have, over the Disease Prevention and Control commented in a bulletin E past few decades, been drawing up a series of on 12 March 2020 (3). “In addition, there is presumably detailed plans for the emergency development and no pre-existing immunity in the population against the mass‑scale production of vaccines, antivirals, and other new coronavirus and everyone in the population is medicines, as well as diagnostics to combat epidemics assumed to be susceptible.” or pandemics. Regulatory bodies have been confronted Fortunately, regulators had learned a lot from other, by a range of diseases from outside Europe, such as smaller-scale, outbreaks, particularly those of swine flu severe acute respiratory syndrome (SARS) in 2002, in 2009 and the 2014–2016 wave of the Ebola virus. The H5N1 and H7N9 bird flues in 2003 and 2013, Middle East European Medicines Agency (EMA), responsible for the Sean Milmo is a respiratory syndrome (MERS), and H1N1 swine flu in EU’s central medicines authorization process and for freelance writer based in 2009. Among the most dangerous has been the Ebola coordinating the EU’s medicines licensing network down Essex, UK, seanmilmo@ virus, which first appeared in 1976 and still has not been to national level, performed “lessons to be learned” btconnect.com. completely eradicated (1). exercises after the swine flu and Ebola episodes. Most of these infectious diseases have high death Swine flu highlighted the importance of providing a rates—from 10% for SARS to 53% for H5N1 flu—but scientific platform for quick research into new vaccines have a relatively low transmission level. Although posing and medicines, working closely with partners such as major threats to the health of the region, they have not public health agencies, and improved collaboration had a major impact on Europe. with international organizations active both inside and However, the novel coronavirus disease, COVID-19, outside Europe. which emerged in China in late December to become a The regulatory effectiveness of the current response pandemic with over 600,000 cases and close to 30,000 to COVID-19 has been helped by closer relationships deaths globally by 29 March 2020 (2), has been an built up by medicines agencies in Europe with entirely different matter. With a high transmission rate researchers and drug companies working on new and a relatively low death rate, it has changed the whole medicines. Regulators now frequently become involved regulatory process of dealing with sudden pandemics. at an early stage in the development of new drugs to speed up time-to-market. A massive challenge As a result, many of the companies submitting In Europe, COVID-19 has been a massive challenge to candidates for anti-COVID-19 vaccines and medicines national healthcare services, public health policies, and for approval are already known to regulators, who have scientists striving to develop vaccines and medicines often been acquainted with the technologies behind to fight the virus as rapidly as possible. The carefully them as well. worked out emergency-response plans of the regulators to help bring new vaccines and medicines to the market An international dimension to research has been severely tested. Regulators are having to cope with a growing By late March 2020, Europe had become the global international dimension to the emergency research epicentre of the outbreak when growth in infections into new vaccines and therapeutics, whose ultimate in China started to slow and cases in the World Health objective is to bring to the market as quickly as possible Organization’s (WHO’s) European Region rose to more products with a potential for global application. National than 360,000 with over 20,000 deaths (2). agencies are tending to play a limited role amid this “There are no vaccines available (for COVID-19), and drive to globalize anti-COVID-19 vaccines and medicines there is little evidence on the effectiveness of potential with availability across Europe being only the first move therapeutic agents,” the EU’s European Centre for to a worldwide market. beugdesign - Stock.adobe.com - beugdesign

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CureVac, a German biotech company based at Tuebingen, large-scale GMP production in Europe, we plan to seek which is developing a messenger RNA (mRNA) vaccine MHRA and then EMA approvals.” against COVID-19, is already known to German and EMA However, similar to a lot of other European companies regulators because of its progress with work on a rabies developing vaccines and COVID-19 therapeutics, Stabilitech is vaccine, company officials said in a phone press conference looking to China as a fast-track option for global distribution. on 17 March 2020 (4). After the COVID-19 outbreak, It has already established links with the Chinese Academy of CureVac’s mRNA technology quickly made it a frontrunner Sciences, the country’s leading research institute. for the development of a global coronavirus vaccine, a role in which it is competing with BioNTech, another German mRNA An alternative distribution route specialist. Another route to global distribution is being provided by The attraction of the CureVac and other mRNA WHO, which has been playing a major role in controlling technologies is that its production can be scaled up without the pandemic. WHO quickly published an updated difficulty to good manufacturing practice (GMP) standards version of its Emergency Use Listing (EUL) procedure for to produce low-cost vaccines that can be relatively easily emergency distribution of unlicensed products two days stored and distributed without the need for refrigeration. after the Chinese announced the genome sequence for Messenger RNA vaccines have the added advantage of the COVID-19 virus in early January 2020. The new version being effective in small doses, and they can be modified simplified the EUL application process for manufacturers fairly quickly to counter new strains of a virus. after it resulted in no new vaccines or therapeutics being With vaccines based on more traditional technologies listed in the 2014–2016 Ebola outbreak (7). necessitating refrigeration, European regulators have pointed Unlicensed vaccines, medicines, and in-vitro diagnostic to the problem of storing and administering investigational devices on the list can be made available throughout products to clinical trial participants who have had to self- the world. Under the scheme, which is part of the 2005 isolate. With the early backing of regulators, CureVac’s International Health Regulations backed by all 194 WHO COVID-19 vaccine seems destined to reach the market member countries, dossiers on products submitted for quickly. Clinical trials are due to start in the summer 2020 (4). listing are thoroughly assessed by an expert committee, Senior company executives met Ursula van der Leyen, with the first endorsements likely to be made in March or the European Commission’s (EC’s) president, in March 2020. April 2020 (7). This was followed by the commission offering an €80 million The EUL is seen by WHO as a process running parallel with (US$97 million) grant for the building at Tuebingen of a mass those operating in individual countries or regional entities, production plant for the vaccine (5). Also in March 2020, such as the EU, and as a result should not interfere with company executives met in Washington, DC with President ongoing clinical trials (7). Additionally, WHO stresses that EUL Donald Trump and members of his administration. This inclusion is not equivalent to authorization by a medicines meeting prompted media reports of an American plan to buy licensing agency (7). all of CureVac’s COVID-19 vaccine output or even to acquire The organization also refers to the EUL scheme covering the whole company, all of which has been strongly denied by one or more additional waves of COVID-19. Both itself and CureVac executives. other medicines and public health agencies are preparing for Even for small companies, such as the UK-based start-up COVID-19 to be around for some time. vaccine developer and producer Stabilitech, national regulatory approval of their COVID-19 vaccine is regarded as References merely a stepping-stone to global distribution. A global goal 1. WHO, “WHO Recommended Criteria for Declaring end of the is especially the case for UK-based companies because the Ebola Virus Disease Outbreak,” who.int, Technical Information country formally left the EU on 31 January 2020 and, hence, Note, 4 March 2020. also left the EU’s medicines licensing network. 2. WHO, “Coronavirus Disease 2019 (COVID-19): Situation Report, Prior to the COVID-19 pandemic, Stabilitech’s technology 69,” apps.who.int, 29 March 2020. platform was already known to the UK’s Medicines and 3. ECDC, “Rapid Risk Assessment: Novel Coronavirus Disease Healthcare products Regulatory Agency (MHRA) because of 2019 (COVID-19) Pandemic: Increased Transmission in the company’s plans for authorization of a vaccine against the EU/EEA and the UK—Sixth Update,” ecdc.europa.eu, the Zika virus (6). The company has developed a formulation 12 March 2020. technology that enables vaccines to be produced in 4. CureVac, “Conference Call on Current Developments,” temperature-resistant capsules, simplifying distribution and curevac.com, 17 March 2020. administering to patients. 5. EC, “Coronavirus: Commission Offers Financing to Innovative “Before COVID-19, we have been talking a lot to MHRA Vaccines Company CureVac,” ec.europa.eu, Press Release, about our Zika vaccine, whose technology is similar to that 16 March 2020. for our COVID-19 vaccine,” Jeff Drew, Stabilitech’s chief 6. WHO, “Zika Epidemiology Update,” who.int, 2 July 2019. scientific officer, told Pharmaceutical Technology Europe. 7. WHO, “Emergency Use Listing Procedure—Version 9 January “After clinical trials and completion of arrangements for 2020,” who.int, 9 Jan. 2020. PTE

8 Pharmaceutical Technology Europe APRIL 2020 PharmTech.com Building Better Manufacturing Facilities Whether refitting existing spaces or building new, the need for quick build times, flexibility, and production efficiency is driving trends in bio/pharma facility construction.

Jennifer Markarian n adding manufacturing capacity—whether through containment and cleaning operations are other active I new, greenfield sites or by retrofitting existing areas in OSD, he adds. spaces—biopharma and pharma companies seek An ongoing drive toward closed processing simplifies flexible and efficient production. Getting a facility up facilities and allows lower room air cleanliness and running quickly with a tight budget is increasingly classifications, which corresponds to savings in capital important. and operational costs, adds Eric Bohn, partner at Flexibility is crucial in biopharmaceutical JacobsWyper Architects. Similarly, the smaller equipment manufacturing, because companies increasingly have associated with continuous processing and the smaller- multiple modalities (e.g., monoclonal antibodies, cell scale processing associated with advanced therapy therapies, and gene therapies) in their pipelines. New medicinal products (ATMP) result in smaller production biopharma facilities often use single-use technology, suites that are easier to support and operate, says Bohn. and modular buildings and systems are becoming “Facilities are being more closely tailored to the needs of more popular. the process,” he notes. “The biggest challenge is to map the current need for flexibility in manufacturing processes to the Renovating facilities facility,” says Stefan Kappeler, technology manager for In the past year, multiple life-sciences companies life sciences at Exyte. He notes that facilities must be have updated or expanded manufacturing capacity prepared for changes in process flow, in scale, and in by renovating existing facilities. In the United States, manufacturing technologies. GlaxoSmithKline (GSK), for example, completed a Flexibility is important in oral solid dosage drug (OSD) retrofit of its Rockville, MD site in October 2019 that manufacturing, as well. Manufacturers are seeking increased capacity for its injectable drug Benlysta to “right size” their operations and capacity based on (belimumab) and involved demolition of existing suites their product portfolios and to upgrade processes, and installation of new equipment (1). The company equipment, and technology for improved efficiency and also renovated its Upper Merion, PA site and updated faster product changeovers, notes Dave DiProspero, laboratory and manufacturing capabilities, including director of pharmaceutical process technology at adding single-use bioreactors (2). A nearby, former GSK

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Pharmaceutical Technology Europe APRIL 2020 9 Cover Story: Manufacturing Trends

biotech campus, which announced in to build their own capacity using industry is changing, agrees Noel January that it would be the home of modular, box-in-box facilities that can Maestre, Life Science Core Team The Center for Breakthrough Medicines, be delivered in a year or less. leader at CRB. “These novel therapies a new contract development and “In many cases, having a facility are quickly proving a need for process manufacturing organization for cell and up-and-running and licensed may be closure and automation, which in gene therapies (3). the critical path to gaining approval for turn is driving equipment vendors Renovating an existing facility can a new product. As such, site startup to create and test novel equipment save time compared to a greenfield timing is critical,” says Mitch Lower, solutions,” notes Maestre. site, where approvals can be complex vice-president of global engineering for and potentially last a year or more, AveXis, a Novartis company specializing OSD trends says Bohn. Although renovations in gene therapies. The company In OSD manufacturing, facility typically have costs for demolition, received an honourable mention in layout is becoming more important waste disposal, and the need to bring the 2019 International Society for as equipment and processes are roof structures up to current building Pharmaceutical Engineering (ISPE) moving toward greater integration, codes, for example, a significant Facility of the Year Awards (FOYA) for says DiProspero. Continuous cost savings is often found in site being one of the first companies to manufacturing and processes such infrastructure, he notes. scale up a gene-therapy manufacturing as direct compression, which are “The most common refurbishments process and doing so on a short growing in use, are examples of we see are from mothballed timeline. To build its Libertyville integrated systems, but integrating facilities,” says John Noble, vice- site near Chicago, IL, AveXis used unit operations is also preferred in president and general manager, G-CON Manufacturing’s prefabricated more traditional OSD processes. life sciences, at Jacobs. “If you cleanroom PODS—built off-site in “A typical integrated equipment can start with a building shell that parallel with facility construction— train will incorporate material accommodates your process and which expedited startup. handling, high shear granulation, meets planning needs, you can save AveXis also purchased and wet milling, fluid bed drying, dry nine-plus months in construction.” refurbished a facility in Longmont, milling, and granulation collection in Facility refurbishment and CO in 2019 to add manufacturing a linked, semi-continuous contained renovations represent more than capacity. The facility is operational operation,” explains DiProspero. 60% of Fluor’s work, adds Dave and is undergoing the remaining Efficient product flow is crucial. Watrous, vice-president, advanced steps to become licensed, which the “Good facility design is marked by technologies and life sciences, Fluor company expects to occur in 2021. uninterrupted uni-flow process Corporation. Reconfiguring existing A facility the company is building in direction, with appropriate hold life-sciences manufacturing space North Carolina is also anticipated to and work-in-progress spaces and or using suitable vacant buildings for become licensed in 2021. minimization of cross/backflow. a box-in-a-box approach can both “There are benefits and challenges Specifically, modern washing accelerate speed to market. to both purchasing an existing facility operations make use of a dirty- and building a new facility,” says wash-clean uni-flow arrangement for ATMP capacity crunch Lower. “Purchasing an existing facility improved efficiency and compliance.” Speed is crucial in biologics may be more cost effective and Modular and prefabricated manufacturing, especially in the have an expedited startup schedule. construction is being used in fast-growing cell therapy and gene However, the existing infrastructure OSD manufacturing. “This type of therapy industry as products are and facility layout may drive additional construction is well suited for powder reaching clinical phase and there is a costs to retrofit to accommodate the processing operations due to good lack of manufacturing capacity. necessary manufacturing process. cleanability, visual aesthetics, and “For manufacturing these When building a completely new the ability for use of glass to bring advanced therapies, CDMOs [contract facility, the timeline may be longer; light into the spaces and provide development and manufacturing however, you will have the flexibility for a user/operator-friendly working organizations], can be scheduling six to build the facility to meet the environment,” says DiProspero. to 18 months out, and this wait time needs of your unique and novel is disruptive to a company’s go-to- manufacturing processes.” Modular approaches market strategy,” says Joe Makowiecki, Although AveXis is today mainly using Modular approaches are transforming Enterprise Solutions director of manual processes, it is moving towards the way the industry builds facilities. business development at GE Healthcare automation in its existing and new Both modular design methods using Life Sciences. He says that despite equipment and facilities, says Lower. standardized templates and modular CDMOs adding capacity, many cell and The lack of automation that is construction methods for buildings gene therapy companies are deciding currently common in the novel ATMP and systems can improve speed

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to market, says a report by the reports that it has sold close to 70 Standardized equipment improves BioPhorum Group (4). FlexFactories globally to date. Four speed to market. For example, WuXi Modular construction includes of these FlexFactories were installed Biologics moved from purchase order factory-fabricated utility skids, wall inside of the company’s KUbio facility, of the Vanrx workcell to their first GMP panels, or entire rooms or building which is the FlexFactory inside of a batch release in only 15 months, says sections, which can save time and modular, prefabricated facility. Pfizer’s Procyshyn. Placing standardized filling improve quality and construction Biotechnology Center located in machines inside a modular cleanroom safety, explains Bohn. He points Hangzhou, China, for example, is a further increases speed, he adds. out that, although the initial cost of KUBio facility, and it won an ISPE FOYA The Microcell POD is an integrated modular construction is typically more 2019 award for project execution. solution from Vanrx and G-CON than that of field-built alternatives, the In 2019, GE Healthcare launched that meets the “increasing industry savings that comes from a shortened the KUBio Box for viral-vector-based need for rapidly deployable turnkey timeline is quantifiable. Factory gene therapy manufacturing; in this aseptic filling capability for small testing reduces problems in the field box-in-box approach, the FlexFactory batch therapies, specifically in the and makes commissioning, validation, platform in a modular cleanroom cell and gene therapy space,” adds and start-up faster. facility is intended to be placed Powers. Standardization lends itself G-CON’s PODs, for example, are inside a new or repurposed space or to “scaling out” rather than “scaling prefabricated, autonomous, plug-and- shell-building. The KUBio box for viral up.” The standard POD design can play cleanroom environments, which vectors is a cGMP, biosafety level 2 be replicated to rapidly increase can be installed within an existing modular facility solution. manufacturing capacity, he notes. facility or as part of new greenfield “We’re also having discussions construction, for any type of bio/ around building biomanufacturing Collaborating on integration pharma manufacturing, including campuses and shell facilities to house Although standardizing improves OSD, aseptic filling, and cell and gene the modular boxes. A best practice quality and speed, integration of the therapy, says Dennis Powers, vice- approach here is to build for what equipment into the facility building president of business development and you need today but allow for enough is still important. For example, in sales engineering at G-CON. The mobile space in your facility or facility shell to building the Bayer facility in California facilities provide flexibility because they expand,” explains Makowiecki. in 2019 using GE’s FlexFactory, Fluor’s can be transported anywhere to quickly Makowiecki also expects the team helped design the optimal add or subtract capacity. KUBio box offering will expand into people, product, and material flows Modular construction started out in additional product modalities and around the established FlexFactory the bio/pharma industry for building biomanufacturing scales. set-up, and then integrated these infrastructure in developing countries flows in the building envelope and with a lack of skilled construction Standardizing associated utilities and infrastructure. capabilities, but now speed is the Standardization of facility modules, This collaborative process with an primary driver. “Modular construction equipment, unit operations, integrated end result reflects the and prefab cleanrooms are often must- automation, and consumables are future of the industry, says Watrous. have components in any new facility. essential to the speed of deploying Even in very mature market locations, modular facilities and efficient and References these strategies help simplify and effective technical transfer. These 1. PharmTech, “GSK Completes Retrofit accelerate the market delivery strategy capabilities support the trend to of Maryland Facility,” PharmTech.com, for most products,” adds Watrous. distributed manufacturing, with the 4 Oct. 2019. “The modular facility concept same company manufacturing a drug 2. GSK, “GSK Invests $120 Million in Next- is a paradigm shift that provides in multiple regions rather than one Generation US Biopharmaceutical companies with options for centralized location, notes Makowiecki. Manufacturing Facility,” Press Release, establishing rapid and flexible “Standardized, closed systems 25 Sept. 2019. in-house production,” says provide optimal aseptic processes 3. The Discovery Labs, “The Center for Makowiecki. “With standardized, that support very high drug product Breakthrough Medicines is Building the modular systems, typically 80% of quality,” adds Chris Procyshyn, World’s Largest Cell and Gene Therapy the design work has been completed, CEO and co-founder of Vanrx CDMO to Launch in King of Prussia, which reduces design time and Pharmasystems, which makes closed PA,” Press Release, 23 Jan. 2020. results in faster speed to delivery,” robotic workcells. He notes that other 4. BioPhorum Group, “Improving the explains Makowiecki. industries rely on standardization for Biomanufacturing Facility Lifecycle using GE Healthcare’s FlexFactory is a reliability and safety, and he says that a Standardized, Modular Design, and modular end-to-end biomanufacturing the pharma industry needs to move Construction Approach,” White Paper, platform, and the company to this model. June 2019. PTE

12 Pharmaceutical Technology Europe APRIL 2020 PharmTech.com immune system protects against viral infections and can rapidly identify the critical parts of a new virus to target for vaccine development,” he says.

Platform technologies are ideal Traditional vaccines, like the seasonal flu vaccine, are made by growing up large quantities of the virus and in some way killing or inactivating it so that it can be used safely as a vaccine. This approach is an old technology from the middle of the past century, according to von Hofe. “The main problem here is the time it takes to produce the Can Vaccine Development vaccine, which is at least a year and can be several. Ideally, we’d have a platform technology that could be used Be Safely Accelerated? to produce a vaccine in a few months,” Biopharma companies responding to the COVID-19 outbreak he observes. think accelerating the development of vaccines is safe. Such technology platforms should be flexible enough to respond to any new viral threat. “We would like to Cynthia A. Challener uman coronaviruses (HCoVs) in the past were considered to cause have a simple ‘plug-and-play’ setup is a contributing editor to H nothing more than the common cold in healthy people. That changed where the critical components of a Pharmaceutical Technology with the advent of severe acute respiratory syndrome coronavirus new virus required to make the vaccine Europe. (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV) can be determined by rapid computer in the past decade. The latest coronavirus—2019-nCoV, since renamed by analysis and plugged into the platform the World Health Organization as COVID-19—emerged in December 2019 in to generate a vaccine,” von Hofe notes. Wuhan, China. As of late February 2020, it had sickened tens of thousands “Getting all of the critical components and killed nearly 3000 people. produced and structured in a way that Four of these large, enveloped, positive-strand RNA viruses are endemic perfectly models the vaccine is the big globally and thought to cause 10–30% of upper respiratory tract infections challenge,” he adds. in adults (1). They possess a surface spike (S) glycoprotein that binds to host cell receptors, and the nature of this protein is believed to determine the A reductionist main properties of each coronavirus. SARS-CoV was the first coronavirus to approach is best jump from animals to humans; MERS-CoV and COVID-19 have as well. The best way, von Hofe says, is to The genetic sequence for COVID-19 was released to public databases follow a reductionist strategy to on 10 January 2020 by the Shanghai Public Health Clinical Center & identify key viral components that School of Public Health (1). The three-dimensional (3-D) structure of the alone produce complete protection spike protein suggests that it binds more tightly to human cell surface in a safe vaccine that can be receptors than SARS-CoV, a possible reason that this coronavirus exhibits manufactured rapidly and in a cost- greater infectivity (2). effective manner. “Clearly this is a tall Platform diagnostic methods have been rapidly adapted to include order, but we’re making good progress COVID-19 for early identification of cases. Several academic and industrial in that direction,” he asserts. researchers have also focused on applying novel vaccine development As an example, he points to the and manufacturing platforms to the accelerated development of a development of subunit vaccines that COVID-19 vaccine. rely on recombinant DNA to encode In terms of vaccine development and protection against dangerous a critical subunit of the vaccine that viral pathogens, there is nothing particularly unique about coronaviruses, generates a response. There are according to Eric von Hofe, chief scientific officer of NuGenerex Immuno- additional challenges to this approach, Oncology. “All of the recent potentially pandemic viruses, including SARS however. “While responses can be and MERS and two flu viruses (avian and swine flu), have the common produced, the protection may be feature that they simply had never been seen before by the human short-lived, as there is no guarantee

Mongkolchon - Stock.adobe.com - Mongkolchon immune system. That said, we now know a lot about how the human that immunological memory will be

Pharmaceutical Technology Europe APRIL 2020 13 Development

generated as is possible with a whole (CEPI). The collaboration with Beijing new vaccine. The rapid discovery virus vaccine,” von Hofe comments. Advaccine is anticipated to accelerate approach and the manufacturing developed on INO-4800 in China by agility of mRNA vaccine design and The DNA approach providing access to not only its vaccine production also make it an effective against COVID-19 expertise, but also its relationship platform technology. San Diego, CA, USA-based Inovio and experience with Chinese Just 42 days after sequence Pharmaceuticals is one company regulatory authorities and clinical trial selection, Moderna shipped the first developing a DNA-based vaccine management in the country. batch of mRNA-1273 to NIAID for use against COVID-19. The biotech was the in a planned Phase I clinical study in first to advance a vaccine (INO-4700) Prophylactic mRNA Vaccines the US. The mRNA vaccine encodes against MERS-CoV into human testing Two companies, both also supported for a prefusion stabilized form of the and is currently preparing to initiate a by grants from CEPI, have developed COVID-19 S protein. Phase II trial for INO-4700 in the Middle platform technologies based on German biotech CureVac also has an East. This vaccine, however, cannot be messenger RNA (mRNA). Cambridge, mRNA platform technology for vaccine used against COVID-19 because the two MA-based Moderna—which has development and manufacturing suited coronaviruses are too different. developed numerous prophylactic for rapid response to viral outbreaks, To develop a new vaccine, Inovio mRNA vaccines with positive Phase it says (6). Using an extensive in-house first converts the virus’ RNA into I clinical readouts and also has a nucleotide sequence library, CureVac is DNA and identifies short sections fully integrated clinical-material able to identify optimum sequences for that will, according to computer manufacturing site—is progressing its any given vaccine target and eliminate simulations, generate the greatest COVID-19 vaccine candidate (mRNA- the need for chemical modification, immune response. The plasmids are 1273) into the clinic (4,5). The Vaccine shrinking the development timeline. then produced in large quantities using Research Center (VRC) of the National The company has also developed bacteria. The overall development Institute of Allergy and Infectious specific carrier molecules for its mRNA and approval timeline is thereby Diseases (NIAID), part of the National products, including lipid nanoparticles significantly reduced. Institutes of Health (NIH), collaborated (LNPs), developed in partnership with Inovio began animal testing of INO- with Moderna to design the vaccine. Acuitas Therapeutics and Arcturus 4800, its COVID-19 vaccine candidate, NIAID will conduct investigational new Therapeutics. It is developing The RNA in February 2020 and is aiming to begin drug-enabling studies and a Phase I Printer, a mobile, automated production human safety testing in early summer clinical study in the US. unit for rapid supply of LNP-formulated 2020. The company will conduct tests Moderna’s mRNA vaccines can mRNA vaccine candidates. in both the United States and China, contain multiple mRNAs coding for the latter in collaboration with Beijing different proteins and mimic natural Stabilizing the Advaccine Biotechnology Co. (3). Work infection, thus stimulating a more pre-fusion virus form in the US is supported by a $9-million potent response, according to the A fourth group receiving funding (€8.2 million) grant from the Coalition company. Only the coding region of from CEPI for application of a vaccine for Epidemic Preparedness Innovations the mRNA must be changed for each platform technology to accelerated

J&J ramps up COVID-19 vaccine R&D Johnson & Johnson (J&J) plans to initiate human clinical trials The company also announced plans to ensure rapid production of its lead COVID-19 vaccine candidate by September 2020 and of a vaccine—with the goal of providing 1 billion doses of a vac- have the first batches available for emergency use authoriza- cine globally—by establishing new US vaccine manufacturing tion in early 2021, the company announced on 30 March 2020 capabilities and scaling up capacity in other regions. The company (1). J&J also announced plans to expand its vaccine manufac- “is committed to bringing an affordable vaccine to the public on a turing capacity, as well as a joint commitment of more than not-for-profit basis for emergency pandemic use” (1). $1 billion (€915 million) with the Biomedical Advanced Research Under the agreement with BARDA, J&J will use its validated and Development Authority (BARDA) at the US Department of vaccine platform and allocate personnel and infrastructure as Health and Human Services to fund vaccine research, develop- needed to focus on the R&D efforts. ment, and clinical testing. Reference J&J said the company selected a lead COVID-19 vaccine candi- 1. Johnson & Johnson, “Johnson & Johnson Announces a Lead Vaccine Candidate for COVID-19; Landmark New Partnership date from several that have been in development since January with US Department of Health & Human Services; and Com- 2020 using Janssen’s AdVac technology. If trials are launched in mitment to Supply One Billion Vaccines Worldwide for Emer- September 2020, the company expects to have clinical data on gency Pandemic Use,” Press Release, 30 March 2020. safety and efficacy by the end of the year. —The editors of Pharmaceutical Technology Europe

14 Pharmaceutical Technology Europe APRIL 2020 PharmTech.com Development

development and manufacture of fragments of the virus needed to Sanofi’s insect (baculovirus) expression a COVID-19 vaccine is located at produce an immune response. These platform. The technology is used for Australia’s University of Queensland short fragments of proteins are Sanofi’s licensed recombinant influenza (UQ) School of Chemistry and identified by a computer algorithm vaccine and a SARS vaccine that has Molecular Biosciences (7). Its and can be made rapidly by entirely been shown in non-clinical studies to rapid response technology relies synthetic means. They are modified be immunogenic and afford partial on molecular clamp technology, to ensure that they activate immune protection in animal challenge models. an approach developed by UQ cells that are key in producing researchers and patented by immunological memory. “While these References UniQuest. virus fragments may not produce 1. C. I. Paules, H. D. Marston, and A. The molecular clamp technology as complete a response as whole S. Fauci, JAMA, online, doi:10.1001/ is used to create subunit vaccines inactivated viruses, they basically jama.2020.0757 (23 January 2020). against class I and III enveloped produce a ‘memory’, so when a 2. T. Hesman Saev, “To Tackle the New viruses by stabilizing the pre-fusion person treated with our vaccine does Coronavirus, Scientists Are Accelerating form of viral fusion proteins, thus encounter the virus, he or she is the Vaccine Process,” www.science- mimicking the protein conformation more prepared to mount an effective news.org, 21 February 2020. found on live virus and generating response,” von Hofe explains. 3. Inovio, “Inovio Collaborating with a strong immune response. A The technology is also a platform Beijing Advaccine To Advance INO-4800 polypeptide is used to maintain the approach because it can be applied Vaccine Against New Coronavirus in pre-fusion structure and prevent the to virtually any virus that may emerge China,” Press Release, 30 January 2020. protein from folding after entry into as a threat. 4. Moderna, “Moderna Announces the cell. Funding Award from CEPI to Accelerate The platform technology, which Big Pharma Development of Messenger RNA does not require prior knowledge has programmes too (mRNA) Vaccine Against Novel of a protein’s quaternary structure, While these smaller biotechs Coronavirus,” Press Release, 23 January facilitates the expression of have generated attention for their 2020. recombinant viral glycoproteins accelerated development platforms, 5. Moderna, “Moderna Ships mRNA without loss of native antigenicity (8). Big Pharma companies have also been Vaccine Against Novel Coronavirus It has previously been used to actively working on COVID-19 vaccine (mRNA-1273) for Phase 1 Study,” Press produce chimeric polypeptides that candidates. Both Johnson & Johnson Release, 24 February 2020. mimic the pre-fusion conformations and Sanofi are collaborating with the 6. CureVac, “CureVac and CEPI extend of several enveloped viruses. The US Department of Health & Human their Cooperation to Develop a Vaccine goal is to complete preclinical Services (HHS). against Coronavirus nCoV-2019,” Press development within 16 weeks and Johnson & Johnson’s Janssen Release, 31 January 2020. then progress directly to Phase I Pharmaceutical Companies unit is 7. University of Queensland, “Race to clinical trials, with completion of collaborating with the HHS’ Biomedical Develop Coronavirus Vaccine,” Press that step in 10 weeks, followed by Advanced Research and Development Release, 24 January 2020. large-scale production of more than Authority (BARDA) to rapidly advance 8. K. Chappell, D. Watterson, and P. Young, 200,000 doses in eight weeks. the initial stages of Janssen’s COVID-19 “Rapid Response Pipeline for Stabilized For its COVID-19 vaccine, the UQ vaccine development programme, Subunit Vaccines,” Presentation at the researchers created a first candidate which is based on its AdVac and PER. Vaccine Technology VIII Conference in the laboratory in just three weeks C6 platform technologies (10). BARDA (June 2018). (9). This work confirmed that the is funding accelerated development 9. University of Queensland, “Significant engineered vaccine candidate is of a candidate into Phase I clinical Step in COVID-19 Vaccine Quest,” Press readily recognized by the immune trials, while Janssen is upscalling its Release, 21 February 2020. system and triggers a protective manufacturing capacities (Sidebar). 10. Johnson & Johnson, “Johnson & immune response. Plans for preclinical Sanofi Pasteur, the vaccines Johnson Announces Collaboration with testing were underway as of late global business unit of Sanofi, is also US Department of Health & Human February, and the researchers hope to collaborating with BARDA, using Services to Accelerate Development of begin clinical testing by mid-2020. its established recombinant DNA a Potential Novel Coronavirus Vaccine,” technology platform to accelerate the Press Release, 11 February 2020. Leveraging development of a potential COVID-19 11. Sanofi, “Sanofi Joins Forces with computer technology vaccine (11). This technology produces US Department of Health and NuGenerex Immuno-Oncology is an exact genetic match to proteins Human Services to Advance a Novel focusing on what von Hofe refers found on the surface of the virus, Coronavirus Vaccine,” Press Release, 18 to as the smallest and simplest which are then expressed using February 2020. PTE

Pharmaceutical Technology Europe APRIL 2020 15 and clinical testing, has been a challenging task,” she states. For Rich Shook, director, Drug Product Technical Services and Business Integration, Cambrex, there are two main obstacles facing developers in ensuring the optimal level of drug substance is available with a targeted window of transit in the gastrointestinal tract (GI). “One of the main obstacles is the pH dependent solubility and/or degradation of the API, which can decrease the overall absorption of the drug substance and result in a negative impact to the intended therapeutic response,” he says. “The other obstacle is in-vivo delivery Delivering the Goods of a specific therapeutic dose at a targeted therapeutic site in the GI The new molecules entering the development tract based on the mechanism of pipeline are bringing forth exciting challenges in drug delivery. action. Some drug substances have a topical mechanism of action on a disease making it important to ensure Felicity Thomas s drug pipelines have expanded to include a wide range of the release of a high dose of drug A novel, and sometimes difficult-to-handle molecules, so too substance to that targeted area.” has the number of methods available to deliver these innovative “In terms of inhalation delivery, therapies and drugs. Not only do developers need to consider the the main challenge is the diversity route of administration, but it is also necessary to consider solubility, of molecules coming through the bioavailability, the precise target of the active ingredient, patient pipeline into development,” adds convenience and safety, and reducing toxicity, among other factors. Sandy Munro, vice-president, “It is now more common for formulators to be presented with Pharmaceutical Development, ‘non-druglike’ molecules and yet be tasked with formulating them Vectura. “Historically, the inhalation to achieve high oral bioavailability, good pharmacokinetic properties space was dominated by small- with minimal toxicity, and good stability,” emphasizes William Wei-Lim molecule therapies for moderate Chin, manager, Global Scientific Affairs, Catalent. “The key challenges asthma and chronic obstructive of these molecules can be attributed to their poor aqueous solubility, pulmonary disease treatments. These poor permeability, or in worst cases both.” days, the interest is much broader both in terms of the diseases that the Challenging aspects developers are interested in, and also These challenging attributes of molecules entering the development the range of molecule types.” pipeline are largely associated with the increasing complexity of molecules, agrees Srini Shanmugam, technical director, Pharma Available approaches Product Development and Manufacturing, Avomeen. “Formulators There are several approaches must balance targeted release profiles for therapeutic efficacy with available that are in use by patient safety and convenience of use,” he says. “Furthermore, every developers to help overcome drug delivery system has unique characteristics that come with the challenges associated with specific formulation challenges.” drug delivery. Approaches such Developing the optimal drug delivery strategy for molecules that as pH adjustment, co-solvent are classified as poorly soluble according to the biopharmaceutical complexation, solid‑dispersion, classification system (BCS)—that is those molecules in class II and micellar formulations, among others, class IV—is a major challenge for industry, notes Archana Akalkotkar, help to improve solubility, confirms PhD, research scientist II, Charles River. “To come up with alternative Akalkotkar. approaches that are appropriate for the drugs’ physicochemical “A tremendous amount of properties, as well as the limitations of choice of excipients, which knowledge has been accumulated

are safe-to-use in the intended species dosed during the preclinical in modern pharmaceutics so that stock.adobe.com Serhii-

16 Pharmaceutical Technology Europe APRIL 2020 PharmTech.com Development

now there are several sets of in-silico combined with enteric components to Within the field of inhalation guidelines correlating the influence resist release of the drug substance delivery, there has been some of an API’s physiochemical properties until it reaches a targeted region of evolution, explains Munro, but the on oral absorption,” adds Chin. the GI tract,” he says. traditional platforms, pressurized “Today, formulators use data to make Additionally, Shook notes that metered dose inhalers (pMDIs), decisions about their formulation enteric coated tablets or multi- dry powder inhalers (DPIs), and strategy because there is a range of particulates can be used to nebulizers, are still the mainstay. solubilization techniques to choose overcome pH dependent solubility “Even within these long-established from. However, sometimes it is easy issues. “The ratio of types of routes of delivery are technology to get lost in the choice, as data are co-polymers in the coatings can evolutions,” he asserts. “For only as valuable as the insights you be modulated for a specific pH example, breath activated pMDIs can draw from them.” release profile using in-vitro models that overcome the issues associated By way of example, Chin explains to target an in-vivo release of the with the coordination of actuation that by combining the developability drug substance in the GI tract,” he and inhalation, high-dose DPIs classification system (DCS) confirms. “This ensures that the that are better able to cope with along with physiologically-based optimal level of drug substance the demanding new molecules pharmacokinetics (PBPK) modelling, is presented to the targeted in development, and smart jet it is possible to gain insights into therapeutic region and absorbed.” nebulizers and smart mesh a molecule’s developability and An emerging route of oral delivery nebulizers that guide the patient the route for selection of the most is in the form of oral thin films inhalation manoeuver to maximize appropriate solubilization technology. (OTFs), adds Shanmugam. “OTFs are lung delivery.” “If a compound is classified as a polymeric films intended to deliver DCS IIa, it means that the in-vivo therapeutic moieties either locally Specific considerations absorption of the compound is or systemically in the oral cavity or Patient adherence to a therapeutic limited by its dissolution rate, and through gastrointestinal absorption,” regimen can be particularly tricky technologies such as particle size he notes. “OTFs are an attractive if the route of administration has reduction, salt or co-crystal formation novel drug delivery option and come not been considered appropriately. approaches can be employed to in two major categories—oromucosal “When targeting paediatric and develop simple formulations that and orodispersible. Oromucosal films geriatric dosing, taste and difficulty improve dissolution rate,” he says. are ‘mucoadhesives’, designed to in swallowing can hinder patient “For a DCS IIb compound that is stick to the inside of the oral cavity compliance,” confirms Shook. limited by its intrinsic solubility, the and release drugs slowly across Difficulties with swallowing tablets preferred technology would include the mucous membrane, and are is now thought to affect 37% of the lipid formulation or amorphous fast-acting with high bioavailability. population, states Shanmugam (5). dispersion via spray drying or hot- Orodispersible films are non- “Children, the elderly, and those melt extrusion.” mucoadhesive and are designed experiencing dysphagia or nausea For those compounds with to break down immediately upon often struggle to swallow tablets permeability issues (classified as contact with saliva.” and capsules, and, therefore, stand DCS III or DCS IV), it is a little more This mode of drug delivery to benefit significantly from drugs complicated. “As there are several is relatively new and so there delivered without swallowing,” he causes of low permeability, a are limited options currently says. “OTFs have potential in these formulator will need to identify a commercially available, none of populations. In fact, the growing strategy to either stabilize the API which are generic, Shanmugam size of the elderly population is from degradation in gastric acid, continues. Yet, the available OTFs predicted to drive the growth of the stimulate lymphatic transport, inhibit do treat a wide range of diseases OTF market. Because the elderly P-glycoprotein (P-gp), prevent drug and disorders, and studies have population is more prone to chronic metabolism in the gut, or to alter the shown that poorly soluble drugs illness, the demand for safe and permeability of the membrane in the can be incorporated into films (1–4). hassle-free drug delivery methods will GI tract itself,” Chin continues. “However, as this is a streamlined only increase.” According to Shook, high molecular drug delivery system relying on “A multi-particulate approach weight polymer matrices or polymers to increase drug solubility, can be used in a form of a sachet hydrogels, which use high molecular formulators must explore new ‘sprinkle’ formulation with taste- weight polymers to blend to the drug particle engineering techniques and enhancing ingredients,” asserts substance, can create a slow eroding find innovative ways to solubilize Shook. “This dose would be added matrix to enable API passage through OTFs and incorporate a wide variety to water or juice which the patient the GI tract. “These matrices can be of water-insoluble drugs,” he adds. would then drink.” It is also possible

Pharmaceutical Technology Europe APRIL 2020 17 Development

to manufacture multi-particulates of a broader disease (e.g., severe offer. “Also,” he continues, “OTFs as a powder for oral suspension uncontrolled asthma) or for a that are now being developed to (POS) formula, where water is added particular development strategy enhance solubility can become to the bottles at the pharmacy and (e.g., fast to clinic development for instrumental in delivering poorly given to the patient as a ready-to- a biologic).” soluble new molecular entities to dose suspension, he continues. Discussing biologics, Chin reveals paediatric and geriatric populations, “These methods of drug delivery that the advantages these large, as well as in extending the lifecycle help address patient compliance complex molecules can afford over of such medications that are while maintaining the target drug small-molecule therapies include approaching patent expiration.” substance in-vivo absorption profile,” more target-specificity and minimal For Shook, the development of Shook says. side-effects, but delivery can be more nanotechnology will be critical for “In paediatric drug development, difficult. “Oral delivery of biologics developers to be able to deliver large many published studies have is far more challenging than it is for and small molecules to a specific site reported the acceptability and small molecules, and because of of treatment. “Nanotechnology will preference of certain dosage forms this, biologics have conventionally ensure that the therapy is introduced based on evidence gathered in clinical been delivered in intravenous and actively initiated at the right trials involving children,” adds Chin. forms,” he says. “However, there are time and place to disrupt the disease Providing examples, Chin highlights technologies available to improve the with precision,” he adds. that minitablets and syrups have permeability of high-molecular weight The role of connectivity in been found to be the most acceptable biologics and to prevent gastric understanding patient behaviour formulation for toddlers and infants, degradation (e.g., enteric coatings). In and adherence to medications is whereas neonates were found to addition, spray drying in combination important for the future, according have increased swallowability of with certain excipients is a promising to Munro. Additionally, he explains minitablets when compared with method for the stabilization of that complex combination products syrup (6–9). “For the older children, biologics that are usually formulated and smart formulations will be vital a preference for chewable and as liquids.” for the inhalation space. orodispersible preparations were For Akalkotkar, targeted drug “Alongside the traditional observed when compared with multi- delivery approaches are more small‑molecule monotherapy particulates,” he notes. suitable for oncology drugs. “These products in development, there are When considering therapies that approaches help reduce the risk of complex combination products, are inhaled, the most appropriate side effects,” she adds. “Continued large molecules, and biologics,” method of delivery can depend on research is ongoing in this field to Munro concludes. “All of these new the level of coordination, so, for develop novel therapeutic modalities. molecule types are bringing fresh example, younger patients that may Examples include, magnetic challenges in terms of formulation struggle with coordination would be nanoparticles, pH sensitive carriers, and the range of doses that may more suited to nebulizer therapy or and conjugated polymers.” need to be delivered.” a pMDI used with a spacer, explains Munro. For older children and adults, In great demand References the delivery method can be more “Novel drug delivery systems 1. S.M. Krull, et al., Drug Dev. Ind. Pharm., individual and based on patient offering impactful solutions for the 42 (7) 1073–1085 (2016). preference, he continues, but the development of new or improved 2. S.M. Krull, et al., Int. J. Pharm., 489 most appropriate delivery platform therapeutics are in great demand (1–2) 45–57 (2015). may also be driven by the technical currently, and are highly sought after 3. L. Sievens-Figueroa, et al., Int. J. requirements of the molecule. by pharmaceutical companies,” says Pharm. 423 (2) 496–508 (2012). “Smart nebulizer devices come Shanmugam. “In the next 5–10 years, 4. R. Susarla, et al., Int. J. Pharm., 455 into their own where there is a we will see a push toward such (1–2) 93–103 (2013). particular need for efficient lung systems that address a broad range 5. J. T. Schiele, et al., Eur. J. Clin. delivery to maximize the probability of clinical and patient objectives, Pharmacol., 69 (4) 937–948 (2013). of success for a given drug, and including higher efficacy and 6. V. Klingmann, et al., J. Pediatr., 167 (4) where the disease indication can bioavailability enhancement, better 893–896.e2 (2015). tolerate the higher cost of goods safety, and improved compliance.” 7. N. Spomer, et al., Arch. Dis. Child., 97 associated with this type of device,” Therefore, as a result of industry (3) 283–286 (2012). Munro says. “Sometimes this demands, Shanmugam believes that 8. D.A. van Riet-Nales, et al., Arch. Dis. indication is in niche diseases such OTFs will grow in importance thanks Child., 98 (9) 725–731 (2013). as idiopathic pulmonary fibrosis to the dosing capabilities, packaging, 9. V. Klingmann, et al., J. Pediatr., 163 (6) (IPF), or in particular sub-categories and film stability advantages they 1728–1732.e1 (2013). PTE

18 Pharmaceutical Technology Europe APRIL 2020 PharmTech.com Now offering Aseptic-filled Liquid Captisol. Facilitate your drug discovery and development activities with Liquid Captisol. Liquid Captisol is a 50% aqueous concentrate of Captisol ® (Betadex Sulfobutyl Ether Sodium USP/NF) that has been aseptic-filled into 250 mL plastic bottles. The product will help you to move quickly into phase solubility studies, formulation development or safety studies. Now quickly dilute to your desired concentration and determine solubility or dose preclinically. Captisol has been used extensively to provide improved solubility, stability, bioavailability and dosing of challenging ingredients. Liquid Captisol is protected under our all-aqueous patented process and included within our extensive safety database. Accelerate your drug discovery and development and order non-clinical grade Liquid Captisol.

CAPTISOL.com Peer-Review Research Identifying the Structure of an Unknown Impurity in a Topical Gel

Jerry Neal, Jerry Mizell, Richard Durham, and Matt Casteen

It is not uncommon for pharmaceutical analytical mpurities in pharmaceutical products are defined as chemists to observe unknown impurities during “substances in the product that are not part of the API routine drug product testing using general itself or the excipients that are used to manufacture the chromatographic methods such as high-pressure drug product” (1). These impurities are unwanted chem- Iical entities that remain with the API or finished drug prod- liquid chromatography/ultraviolet or gas uct and may develop during manufacturing or upon storage. chromatography/flame ionization detection. An impurity can be inorganic or organic. In some cases, Discovery of an unknown impurity triggers an impurities can be residual traces of solvents that are used investigation, along with a shift in priorities from in synthesis or manufacturing. During routine drug prod- routine to more specific specialized testing in uct testing using general chromatographic methods such as order to be able to answer key questions about high-pressure liquid chromatography/ultraviolet (HPLC/ UV) or gas chromatography/flame ionization detection (GC/ the impurity. This case study highlights analytical FID), discovering an unknown impurity triggers investiga- instrumentation and techniques that were used tions and specialized testing in order to answer several basic to identify an unknown impurity detected during questions about the unknown, including: routine release testing of a topical gel drug product. • What is it? • Is it toxic? • How much of it is present? • Where is it coming from? Answering these questions can be difficult without access to specialized instrumentation and analytical techniques that can provide structural information about the unknown, allowing a useful toxicological assessment to be made. Classifying impurities The impurity may be classified either as a degradation prod- uct resulting from chemical reaction of the API during man- ufacturing and storage, or as a foreign substance that was introduced into the product by contamination or adultera- tion. Classification of impurities permits the development of adequate control measures to minimize unwanted im- purities in the final product. It is important to note that the presence of an impurity, in and of itself, is not necessarily problematic. The introduction of trace levels of impurities is CITATION: When referring to this article, please cite it inevitable during the manufacturing or storage of pharma- as J. Neal, J. Mizell et al., “Identifying the Structure of an Unknown Impurity in a Topical Gel,” Pharmaceutical ceutical products. In fact, scientists expect impurities to be Technology 44(4), April, 2020. present, hence the requirement that any and all of them be identified and controlled and their presence and concentra- Submitted: 12 Sept., 2019. tions monitored. In many cases, the presence of an impurity

Accepted: 22 Nov., 2019. may not pose any safety, quality, or efficacy issues for the STOCK.ADOBE.COM - LIGHTPOET

20 Pharmaceutical Technology Europe APRIL 2020 PharmTech.com drug product. In theory, however, the presence of any impurity Table I: Unknown impurity profiles for a topical gel, could influence the efficacy and safety of the finished product. using high-pressure liquid chromatography (HPLC) At the very least, impurities confer no therapeutic benefit. In the worst case, they can be toxic. Several authorities, including and ultraviolet (UV) detection methods. Relative the International Council for Harmonization (ICH) and the Retention Molar retention Molecular United States Food and Drug Administration (FDA), regulate Impurity time response time weight (in minutes) factor impurity levels in all pharmaceutical products. (in minutes) Ensuring the purity of an API or finished drug product re- Impurity 1 6.7 0.128 0.43 138.16 quires identifying, quantifying, and controlling any impurity once it has been observed. An impurity can be controlled by Impurity 2 32.2 0.614 0.99 314.42 establishing appropriate control methods at all points where Impurity 3 33.1 0.630 1.26 316.44 they enter or form during the manufacturing process. Ac- Impurity 4 34.8 0.636 0.67 314.42 cording to ICH guidelines on impurities in new drug sub- Impurity 5 41.8 0.797 0.57 316.44 stances and new drug products (1), identification of impuri- Impurity 6 43.7 0.800 0.57 316.44 ties below the 0.1% level is not necessary unless the potential Impurity 7 44.3 0.810 1.36 316.44 impurities are expected to be unusually potent or toxic. Impurity 8 51.3 0.940 --- 220.35 Materials and methods Impurity 9 53.7 0.983 1.63 300.44 This case study used the analytical instrumentation and tech- Impurity 10 54.1 0.990 1.36 300.44 niques listed below to identify an unknown impurity that was API 54.6 1.00 --- 300.44 detected during routine release testing of a topical gel drug Impurity 11 55.7 1.02 1.66 300.44 product. The impurity was detected by a validated HPLC/UV method with a known impurity profile (Table I) and was out Figure 1: High-pressure liquid chromatography (HPLC) of specification for the product. chromatogram of unknown impurity in a topical gel. • Liquid chromatography–mass spectrometry/quadru- pole time-of-flight (LC/MS/Q-TOF) • Gas chromatography mass spectrometry/electron impact mass spectrometry (GC/MS EI/MS) • Fraction collection • Infrared spectroscopy. Results and discussion After detecting an unknown impurity during routine release testing, a pharmaceutical company requested that investiga- tional testing be performed on its topical gel drug product to identify the impurity and determine whether it was an API degradation product, a process impurity, or a contaminant that had been introduced during the manufacturing process. The HPLC/UV chromatographic impurity profile of the topical gel release lot is shown in Figure 1. When compar- ing the known impurity profile (Table I) to the HPLC/UV chromatogram (Figure 1), scientists observed that a single first step in identifying the unknown impurity was testing the unknown impurity eluted past Impurity 11 (55.7 min.) at drug product by LC/MS using Q-TOF detection. This method approximately 71 minutes. Other chromatographic peaks provides key information about the identity of the unknown by that were observed eluting after the unknown itself were generating highly accurate mass data. Having highly accurate considered evidence of impurities from solvents that were mass information for the unknown significantly reduces the used to prepare the sample for HPLC testing and considered number of possible molecular formulas or compound identities to be blank-related. generated by the molecular formula software. While this testing provides key information about the un- Outlining the process known, it does not always provide positive identification of the One of the most challenging problems encountered is the unknown, because hundreds of compounds may share the same identification of unknowns at trace levels in pharmaceu- molecular formula. Additional experimental data are needed to tical drug products. This is due mainly to the significant rule out other compounds and identify the unknown. With this differences in detection limits for each analytical technique impurity, the mass (M+1) of the unknown was determined to be

ALL FIGURES COURTESY OF THE AUTHORS. THE OF COURTESY FIGURES ALL that is used to confirm unknown impurities. In this case, the 447.3476 from Q-TOF LC/MS experiments (Figure 2).

Pharmaceutical Technology Europe APRIL 2020 21 Peer-Review Research

Figure 2: HPLC Spectra. HPLC is high-pressure liquid Table II: Conditions used for gas chromatography/mass chromatography, LC is liquid chromatography, MS is mass spectrometry/electron impact (GC/MS/EI) testing. spectroscopy, and EI is electron impact. A. LC/MS +EI product ion scan of unknown in a topical gel eluting at approximately 71 Gas chromatograph: Agilent 6890N Agilent DB-1ms capillary column 30 m x 0.25 mm, minutes. B. LC/MS +EI product ion of unknown in a topical gel Analytical column: eluting at approximately 71 minutes (M+1 = 447.3476). 0.25 µm (P/N: 122-0132) Injection port type: Split / Splitless Injector temperature: 290 °C Injection mode: Split Split ratio: 5:1 Carrier gas type: Helium at 1.2 mL/minutes 60 °C for 0.5 min. to 300 °C at 20 °C Oven programme: held for 17.5 minutes. Mass spectrometer: Agilent 5975 Inert XL Transfer line temp.: 300 °C MS temp.: 230 °C (Source); 150 °C (Quad) MS mode: Electron Impact (EI), Scan Scan range: 50–500 atomic mass units (amu) Solvent delay: 3 minutes Autosampler: Leap Technologies PAL Combi-xt Cycle: Gas chromatography – injection (GC – Inj.) Using the unknown’s accurate mass information and the mo- Syringe: 10 µL lecular formula generator, the unknown was determined to have Sample volume: 1.0 µL the molecular formula C28H46O4. The exact mass calculation Air volume: 0 µL for the molecular formula was 446.3396. Pre Cln Slv1: 3 strokes Using the exact mass from the Q-TOF LC/MS experi- Pre Cln Slv2: 0 strokes ments and the molecular formula, scientists performed a United States National Institute of Standards and Technol- Pre Cln Spl: 2 strokes ogy (NIST) database search and identified a total of 88 po- Fill volume: 5 µL tentially matching species within the database, with the top Fill speed: 2 µL/second. search result being diisodecyl phthalate (DIDP) (2). Fill strokes: 5 Knowing the impurity’s exact mass and having a molec- Pullup del: 5 seconds. ular formula from the LC/MS data is invaluable in helping Inject to: GC Inj1 narrow down its identity from hundreds of potential com- Inject speed: 50 µL/second pounds with the same molecular formula. Other analytical techniques must then be used to rule out or confirm the Pre Inj Del: 500 ms impurity’s structural identity. Pst Inj Del: 500 ms One disadvantage of using LC/MS data is that database Pst Cln Slv1: 3 strokes libraries with searchable mass spectral data do not exist. Pst Cln Slv2: 0 strokes However, extensive searchable database libraries are avail- able for GC/MS testing. Thus, the next step in identifying library. To enhance the probability of performing a successful the unknown was to test it by GC/MS. Obtaining electron GC/MS run, scientists prepared a concentrated sample of the impact (EI) mass spectra of the unknown would allow for drug product to ensure that the impurity could be adequately positive identification with a database match. detected, since the sensitivity of the various analytical tech- The LC/MS Q-TOF experiments indicated that the unknown niques used to confirm identity can vary significantly. could be diisodecyl phthalate, which is volatile and thermally Multiple injections of both dilute and concentrated sample stable enough to be detected by GC/MS. A potential problem were made onto an HPLC/UV system to generate a chromato- associated with GC/MS testing, however, was the fact that, if the graphic profile similar to that in Figure 1. The HPLC eluent from unknown proved not to be DIDP, it might not be sufficiently multiple injections was collected for approximately one minute volatile to be detected by GC/MS. on either side of the expected retention time of the impurity. In addition, if the unknown were not present at a high enough The fractions were combined and further concentrated at least concentration, it would not be possible to obtain electron impact 10,000-fold to ensure adequate sensitivity for detection. Injec- mass spectra of sufficient quality to search against the database tions of the concentrated solution were made on the GC/MS

22 Pharmaceutical Technology Europe APRIL 2020 PharmTech.com Figure 3: Gas chromatography/mass spectrometry (GC/MS) electron impact (EI) results. A. GC/MS EI total ion chromatogram of concentrated unknown. B. GC/MS EI spectra of concentrated unknown. C. Best database match - Diisodecyl Phthalate (DIDP).

using the conditions outlined in Table II. GC/MS results not contain spectral elements that contradicted the mass (Figure 3) confirmed that concentrated unknown electron spectroscopy data and were also consistent with NIST ref- impact (EI) mass spectra were consistent with the best data- erence spectra of diisodecyl phthalate (Figure 4). base match for DIDP and the exact mass obtained by LC/MS As a final confirmation, a known standard of DIDP was pre- Q-TOF experiments. Scientists used infrared spectroscopy pared as a marker at multiple concentrations to estimate the to test the concentrated impurity, and results further sup- concentration of unknown observed in the sample. The DIDP ported the probability of the unknown being DIDP. Fourier markers, along with a sample preparation, were injected using Transform-Infra-Red (FT-IR) spectra of the unknown did the original HPLC/UV assay conditions (Figure 5).

Figure 4: A comparison of Fourier-Transform-Infra-Red (FT-IR) spectra A and B. A. Concentrated unknown impurity B. National Institute for Standards and Technology (NIST) spectra for diisodecyl phthalate (DIDP).

Pharmaceutical Technology Europe APRIL 2020 23 Peer-Review Research

Figure 5: High-pressure liquid chromatography (HPLC) and ultraviolet (UV) overlay (markers and unknown). Reflects results for diisodecyl phthalate (DIDP) markers and a sample of topical gel unknown.

Evaluation of all the experimental data collected from the degradation product of the API, since the molecular weight of investigational experiments demonstrated that the unknown DIDP is higher than that of the API. Instead, the impurity was impurity detected in the topical gel drug product during release most likely a contaminant that resulted when the API or drug testing was DIDP (Figure 3c). product came in contact with a source of plastic that was in- It should be noted that commercially available DIDP actu- troduced during the manufacturing process. To date, no other ally is a mixture of two phthalates. The other component is batches of this drug product have contained this impurity. diisononyl phthalate (DINP). DIDP is composed of a complex mixture of branched C9-C11 isomers containing mainly C10 REFERENCES isomers of C28H46O4. Significant amounts of toxicological 1. ICH, Q3B(R2),Impurities in New Drug Products, 1-12, 2 June, 2006. data for DIDP are available for review (3). 2. NIST, Chemistry WebBook, NIST Standard Reference Database DIDP is one of eight individual phthalate esters that the US Number 69 (2017). Environmental Protection Agency (EPA) has deemed appropriate 3. US Consumer Products Safety Commission (CPSC), Toxicity Re- subjects for developing assessment and management strategies. It view of Diisodecyl Phthalate (DIDP); 1-29, 7 April, 2010. 4. EPA, Phthalate Action Plan; 1-16, 14 March, 2012. is the main plasticizer used for polymers in wire and cable 5. The Minister of the Environment and the Minister of Health Can- applications. It also is used in anti-corrosion and anti-foul- ada, State of the Science Report (SOS), Long-chain Phthalate Esters ing paints, sealing compounds, and textile inks (4). Major DIDP and DUP; 1-144, August 2015. PTE identified sources of DIDP internationally include food and pharmaceutical packaging as well as printing inks (5). DIDP also is used as an additive in the production of plastics to Jerry Neal, BS, is senior analytical chemist; Jerry Mizell, BS, is director of analytical services; Richard Durham, PhD, is chemistry, make them more flexible. manufacturing and control (CMC) quality liaison; and Matt Casteen, In this case, the source of the impurity was not definitely BS, is team leader, all with Metrics Contract Services. determined; however, scientists believe it was unlikely to be a

24 Pharmaceutical Technology Europe APRIL 2020 PharmTech.com Headspace Gas Ingress Testing for Container Closure Integrity

ON-DEMAND WEBCAST: Aired Wednesday, March 18, 2020

Register for this free webcast at: http://www.pharmtech.com/pt_p/closure_integrity

Event Overview Presenter Are you revising your container closure integrity (CCI) testing Derek Duncan, PhD. strategy? Regulators are paying closer attention to the proper design of robust CCI studies. This webcast will introduce the Director Product Line headspace gas ingress testing approach, a robust detection LIGHTHOUSE method of critical leaks. This rapid, non-destructive, analytical measurement can be scientifically validated and is an upgrade to the blue dye test. Topics to be discussed include the following: Moderator

• Evolution in industry best practices and regulatory Rita Peters requirements for CCI testing Editorial Director • Introduction to headspace gas ingress testing Pharmaceutical Technology

• Advantages of the headspace gas ingress testing method compared with blue dye testing Who Should Attend • Method development and the use of positive controls • Parenteral drug packaging engineers • Industry case studies and formulation scientists, parenteral manufacturing,sterility quality Key Learning Objectives assurance, regulatory affair scientists, pharma packaging development • Receive an update on industry best practices for container and manufacturing staff, analytical closure integrity (CCI) testing. development etc.

• Learn about headspace gas ingress testing and how it compares to blue dye testing. Sponsored by • Learn about method development and how to validate this CCI test method.

For questions or concerns, email [email protected]. Presented by be given to the use of specialized technology that includes features specifically designed to contain dust or allow for precleaning prior to breaching containment, for example, thereby mitigating the risk factors. Different end users will employ different strategies for protecting their equipment operators, but what remains constant across manufacturers is a legal obligation for taking such measures. Containment solutions must ensure that established limit values for highly active ingredients can be reliably maintained during the manufacturing Understanding process. The International Society for Pharmaceutical Engineering Containment for Tabletting (ISPE) Containment Manual acts as a guidepost for technical solutions Risk levels should be considered pertaining to hazardous substance when designing equipment to enhance operator safety. handling in pharmaceutical facilities and can provide further information (2).

Matt Bundenthal ablet manufacturing is evolving, and the use of highly potent OEB and OEL is director of sales and T active pharmaceutical ingredients (HPAPIs) is increasingly Figure 2 depicts the relationship marketing at Fette prevalent. The inhalation of hazardous, airborne particulates can between OEB bands and OEL or PDE Compacting America. represent a real risk for those operating the equipment used to limits, illustrating how equipment compress final tablets. It is due largely to these facts that the users can identify the level of concept of contained tabletting equipment is gaining prominence in containment to be considered for pharmaceutical manufacturing facilities. various applications. It is important to Any discussion of containment involving pharmaceutical tablet mention that while the OEB and OEL compression is likely to include a number of common acronyms. The categories do quantify limit levels, following are some of those most commonly encountered: their interpretation and the way that • Occupational exposure banding (OEB) is a process whereby APIs are various end users will seek to achieve assessed and categorized for toxicological concentration. operator safety can be highly variable. • Occupational exposure limit (OEL) is an upper limit on the acceptable concentration of an airborne particulate API, in terms of Safety guidelines the risk associated with an individual’s exposure to the API, usually Different containment requirements expressed as a value of micrograms per cubic meter (µg/m³). necessitate a wide array of • Permitted daily exposure (PDE) is the amount of a specific active equipment needs, and many tablet substance for which the occurrence of an adverse effect is unlikely in press vendors offer options that are an individual exposed to this dose, or to lower values, for a lifetime (1). suitably configurable. It is imperative • Personal protective equipment (PPE) is clothing, respirators, to note that containment projects are etc. used to create a protective barrier between operators and inherently complicated, both from an potentially toxic substances. equipment and facilities perspective. Figure 1 depicts the various topics of consideration that come into Consider the following steps. play when operator safety is considered. A product should be initially Evaluate the API. The first step assessed for the amount of dust it is capable of creating, as well as is to determine if a particular active the amount of highly active substance it contains relative to its overall ingredient is potentially hazardous dosage (i.e., dilution). The manufacturer will also need to decide enough to those working with it, such what protective measures to take with regards to the operator— that it warrants the use of contained which may well include the use of PPE—and how it will quantify the equipment in the first place. There risk levels associated with a particular product (i.e., measurement are differing philosophies on how protocols). Finally, after determining that a particular product does, in best to approach such situations,

fact, constitute an exposure risk for the operator, consideration may which can include the avoidance of Stock.adobe.com - vchalup

26 Pharmaceutical Technology Europe APRIL 2020 PharmTech.com Manufacturing

of equipment containment is actually Figure 1. Areas to consider for protecting the operator during tablet necessary. production with potentially hazardous ingredients. Although the scope of this article does not allow for a detailed exploration of personal protective equipment (PPE), it should be noted that those having the most experience with compressing highly active substances generally elect to use some form of PPE, regardless of the efficacy of the contained system being utilized. PPE can be important given the fact that with virtually all contained systems, final cleaning will still include manual steps. Choose a qualified vendor. Identify equipment manufacturers that can meet your needs and who, ideally, have a proven track record with such applications. Asking for surrogate test results is a good way of vetting for this purpose. Qualified vendors will not only perform such testing, but also offer systematic methodology for scientifically Figure 2. Occupational exposure limits (OEL) and permitted daily exposure matching a specific containment (PDE) can be corresponded to occupational exposure bands (OEB). target (when one has been clearly stated) to a well-defined equipment system. This testing can bolster internal risk-assessment processes the end user conducts under ISPE’s Standardized Measurement of Equipment Particulate Airborne Concentration guidelines (3), as the methodology itself will result in a standardized, objective, and reproducible determination of a specific system’s capabilities. Select containment-specific features and attributes. Identify the level of containment the press will need to maintain and select the options necessary for reaching that goal. For example, an ingredient with an OEL level of 50 µg/m³ (OEB 3) will commonly require less containment than one with a level of 8 µg/m³ (OEB 4). the ingredient all together (essentially OEB data shown in Figure 2 are the If a particular set of containment- a fool-proof approach), the use of PPE rule of thumb for pharmaceutical related requirements necessitate alone (the least effective approach), manufacturers seeking to quantify dry-clean, low-dust production only, or something in between. Figure 3 a risk level. These categories, when then a press fitted with glove- and illustrates this continuum. considered in addition to the drug rapid transfer ports, as well as need- Quantify the risk. Once a load for a particular product (i.e., specific process equipment, may determination has been made that the ratio of active ingredient to the prove to be the ideal fit. Glove ports an ingredient does have associated overall dosage or dilution), will lead to typically utilize fail-safe technology

FIGURES ARE COURTESY OF FETTE OF COMPACTING COURTESY ARE FIGURES risks, it is time to define them. The greater clarity in terms of what level that prohibits the operator from

Pharmaceutical Technology Europe APRIL 2020 27 Manufacturing

Act early. Due to this inherent Figure 3. Methods for protecting operators from hazardous ingredients complexity of containment projects, fall on a continuum of efficacy, with personal protective equipment (PPE) whether they necessitate dry- or as the least effective. wet-cleaning, they always present challenges extending beyond those of a non-contained endeavour. It is therefore strongly recommended that end users identify their equipment vendors as far in advance as possible. Making a selection early will allow for the commencement of project-critical dialogue between the end user and their chosen supplier. It should also be worth noting that contained presses often have lead-times of up to 50% longer than their non- contained counterparts.

Safety is the goal The sole purpose of investing in contained compression equipment is to ensure the safety of one’s operators. Nothing else could, or should, be of more paramount importance. Take the time to properly identify potential risk factors, methodically match those factors gaining access while a press is the machines. This set-up allows for to suitable equipment, and create running. When the machine is in the binding of airborne particulates a safer, more efficient working a static state, the ports provide with water molecules, which are environment. access to the interior of the press for then drained away before access simple operations such as cleaning doors are opened. Integrated, internal Acknowledgement a punch tip or changing a fill cam, spray wands may be available, with The author would like to thank without breaching containment. A which the operator can essentially Dr. Martin Schöler (author of rapid-transfer port allows for either pre-clean the compression zone Containment, Fette Compacting introducing a small component into prior to letting the automated wash GmbH, 2019) for his constructive the press or removing it, similarly system perform its function. For OEB insight and feedback during the without a breach. Utilizing split-valve 5 applications, process equipment creation of this article. technology for charging the press, in such as de-dusters, metalcheck units, addition to high efficiency particulate and quality control testers may be References air (HEPA) filtration and dust-tight installed in separate but connected 1. EMA, Guideline On Setting Health- discharge chutes, applicable models isolators, ensuring that the entire Based Exposure Limits For Use In Risk that are correctly configured can tabletting system is fully contained Identification In The Manufacture Of potentially provide containment levels and safe. When tackling these Different Medicinal Products In Shared of approximately 5 µg/m³ (i.e., the products that warrant higher levels Facilities. European Medicines Agency, middle of the OEB 4 band). of containment, sophisticated air Committee For Medicinal Products For Hazardous active ingredients management systems are available Human Use (CHMP), Guideline EMA/ necessitating wet cleaning, where the that provide automated safeguards CHMP/CVMP/SWP/169430/2012, 2014. press will run itself through various against risk factors, such as power 2. ISPE, Community of Practice (CoP) wash and rinse cycles (i.e., wash-in- loss, and maintain predetermined set Containment D/A/CH Affiliate: place systems), are often classified points (i.e., vacuum) across variable Containment Manual (English at the higher levels of the OEB 4 band run conditions. The caveat to the Translation) (ISPE, 2017). and into OEB 5 or above. Such press latter approach is that project costs 3. ISPE, ISPE Good Practice Guide: systems are far more complex and are generally much higher, as related Assessing the Particulate Containment are designed to introduce various equipment and facility considerations Performance of Pharmaceutical forms of water and detergent into are proportionately more complex. Equipment (ISPE, 2012). PTE

28 Pharmaceutical Technology Europe APRIL 2020 PharmTech.com an increasingly complex web of local, regional, and international connections that require a broad range of transport modes (1). The third trend identified in the survey is the need to optimize the total cost of ownership (TCO) due to relentless competition and margin pressures. A full 70% of survey respondents agree that TCO is “important” or “very important,” while 10% consider only basic packaging costs and transport rates. This exploration of TCO is spurring interest in reusable containers, with 79% of survey respondents saying reusable Packaging Preserves the containers—though more expensive than single-use containers—are worth the investment. More than one-third Cold Chain of respondents (37.6%) are already More sustainable and functional cold-chain packaging using reusable rental programmes in protects biologics and other temperature-sensitive drugs. their cold-chain logistics operations, and 25% are actively exploring this option (1). Hallie Forcinio roper storage and transport temperatures for drugs, especially As a result, validated, off-the- is Packaging Editor at P biologics, are essential to protect product efficacy and patient shelf, or customized protective Pharmaceutical Technology safety. “As strong growth continues across the global pharmaceutical packaging options continue to evolve Europe, editorhal@ industry, the sub-category of temperature-controlled products is for all temperature ranges, including sbcglobal.net. surging ahead—growing at twice the rate of the industry overall,” said controlled room temperature, David Williams, president of Pelican BioThermal in a press release (1). refrigerated, frozen, and cryogenic. Joe Cintavey, product specialist at W.L. Gore, agrees, noting, “The challenge is optimizing the “The pipeline of biologic drugs in development is becoming more design, materials, and components temperature-sensitive, resulting in an increase in storage of bulk drug to minimize overall size and weight substance at frozen temperatures (-40 to -70 °C).” of the shipping solutions,” says Rory Davidson, Business Development Manager at Almac Pharma Mark Barakat, general manager of Services, adds that labelling, packing, and distributing cell and gene Cryopak, a subsidiary of Integreon therapy products often requires products to be stored and processed (formerly TCP Reliable). He continues, at ultra-low temperatures (-20 to -80 °C), with the products only being “Achieving peak performance while defrosted immediately prior to use. “If these products are not kept in minimizing size, weight, and cost is exact conditions, they become unusable. We have seen some cases typically contradictive.” Cold-chain of product becoming unusable within a minute of being out of frozen engineering experience and tools conditions and so we need to be able to handle and process product like thermal modelling software and at these ultra-low temperatures as quickly and efficiently as possible,” testing equipment play important notes Davidson. roles in optimizing temperature- controlled packaging. Packaging trends In addition to the growing number of temperature-sensitive products, Meeting requirements three trends are driving the need for temperature-controlled There is also strong demand for more packaging, according to a survey by Pelican BioThermal. First, sustainable designs, including re-use quality demands increase as more sensitive products bring logistics programmes to reduce the carbon complexity and greatly expanded risk. Yet, while awareness of footprint. Interest in temperature- temperature-controlled requirements is high, the survey shows controlled packaging also is being temperature excursions happen frequently (1). impacted by changing regulations Second, the distribution range is expanding as products move and standards. For example, further and through more climatic zones. More than half of survey “Temperature profiles issued by

felipecaparros - Stock.adobe.com - felipecaparros respondents (51.8%) regularly ship products internationally, creating ISTA [International Safe Transit

Pharmaceutical Technology Europe APRIL 2020 29 Operations

Association] have changed within the qualified with repetitive testing to products,” reports Corbin. “Part of past five years,” reports Barakat. assure consistency and performance the initiative is ongoing education for “Regulations governing these repeatability,” explains Barakat. “The their consumers on the benefits of types of highly sensitive products are real shipment is then monitored with recyclable materials,” he adds. growing stricter,” adds Adam Tetz, temperature data loggers to prove In addition to Kodiakotton liners, director of worldwide marketing at operational performance and quality Kodiakooler offers the patented Pelican BioThermal. “For example,” he assurance,” he concludes. Kwikpack system. This is a bundled says, “China has become particularly To test the durability of reusable, kit of two Kodiakotton liners with an strict and requires real-time tracking passive thermal packaging systems, easy-to-remove, recyclable band. The on all pharmaceutical shipments.” Pelican BioThermal is developing liner bundle cuts insertion time and Many local governments want a mechanical test method. In results in a packout-ready shipper in to reduce or eliminate the use of addition to mimicking the real- less than six seconds (4). expanded polystyrene foam (EPS), a world use environment, the test common insulating material, because method also allows assessment Sustainability continues it is rarely recycled. “California and of the impact of dynamic use on to be a major driving New York are limiting the amount of thermal performance. Tetz reports force. Work continues EPS foam that can be delivered into that results are promising. He says, on developing designs their states,” says M. Ryan Corbin, “The test standard would give that meet performance director of marketing at Kodiakooler. pharmaceutical manufacturers even requirements and will These requirements are forcing more confidence in choosing reusable be more renewable, makers of temperature-sensitive drugs thermal packaging over single-use recyclable, reusable, and biologics to look for alternatives. options to reduce costs and advance and/or compostable. In addition to insulation, environmental initiatives.” temperature-controlled packaging “Current standards assess parcel Fibre-based options, which can be includes single-use and reusable thermal packaging systems during recycled in the corrugated or waste- parcel and pallet shippers, thermal one intense shipment from point A to paper streams, also are popular. pallet covers, and phase-change point B,” explained Bill Mayer, director To address this market, Thermo materials. Sometimes, customized of research and development at Fisher Scientific has developed the designs are needed, especially Pelican BioThermal. “Throughout the Invitrogen Paper Cooler. The 100% for products that will experience development of this new test method, paper alternative to EPS foam coolers particularly hostile conditions or we addressed the challenges of meets thermal requirements for need to be maintained at cryogenic exposing systems to the multi-leg and overnight shipments (5). Another temperatures. Regardless of the multi-mode shipping route and more paper-based product, ClimaCell application, optimized temperature- of an average trip with parcel thermal insulation from TemperPack, is controlled packaging depends on the packaging used multiple times” (2). designed to replace EPS insulation answers to three questions: Where is and reduce packaging waste. In it being shipped? What temperature Cold-chain options addition to being recyclable in the must be maintained? How long Innovations in temperature- corrugated stream, the ClimaCell does that temperature need to be controlled packaging centre on material protects temperature- maintained? In addition, “Seasonal sustainability, performance, and sensitive shipments for up to 80 temperature changes can substantially cost. To improve sustainability, hours. The material also is moisture- affect the internal facility environment OptumRx, a pharmacy care services resistant and can be customized with and shipping environment,” warns provider, has transitioned from printed graphics/messages (6). Joe Luke, vice president of sales and rarely recycled foam packaging to Another player in the insulation marketing for Reed-Lane, a New recyclable packaging made from market, va-Q-tec, has opened a US Jersey-based provider of contract renewable cotton-based Kodiakotton headquarters and production facility packaging services. from Kodiakooler, which was recently in Langhorne, PA, to manufacture acquired by Airlite Plastics. The its small boxes and containers. Testing Kodiakotton insulating material The location also serves as a rental To ensure packaging will perform as is biodegradable, compostable, and repair station. The company, specified, Cryopak tests it against reusable, and recyclable. OptumRx which is headquartered in Germany, extreme ambient temperature projects the new packaging will save specializes in vacuum insulation profiles in its ISTA-certified lab millions of gallons of water, pounds panels and phase-change materials following protocols and internal of carbon dioxide, and kilowatt-hours that offer five-day temperature standard operating procedures. of energy (3). “OptumRX has had protection without the need for “Our shipping systems are then great success with our sustainable external energy sources. A rental

30 Pharmaceutical Technology Europe APRIL 2020 PharmTech.com Operations

service business offers a fleet of cold- Reed-Lane recently added cold provide email alerts should any chain containers and boxes (7). storage (2–8 °C) capabilities and a specified environmental conditions Reuse is possible with the AcuTemp dedicated climate-controlled room be exceeded,” says Luke. He explains, Plus Series of shippers from CSafe for vial and ampoule kitting at its “Additional sensors are deployed to Global through its Repaq programme. packaging facility in Wayne, NJ (see provide alerts pertaining to … power Proprietary, high-performance Figure 1). Temperature and humidity outages, which would result in an ThermoCor vacuum-insulated panels sensors constantly monitor the cold immediate onsite power generator control payload temperatures. Simple storage area to document conditions startup to maintain specified to deploy, the shippers are available and ensure there are no product- temperature continuity.” in multiple sizes and temperature damaging temperature excursions. The dedicated room for kitting profiles with integrated track-and- “Most crucially, our environmental temperature-sensitive products trace options (8). monitoring solutions are able to includes space for labelling vials and Although reusable packaging has gained ground, one-way shippers remain a viable choice and continue to evolve. AeroSafe Global, a supplier of reusable shippers, has added a Hot. Hotter. disposable option to its portfolio. The A20 insulated shipper is designed to serve shipments needing protection for 24 to 48 hours. It is fully prequalified to ISTA 7D summer and Chili winter profiles. Minimal components simplify packouts (9). Gore Sta-Pure flexible freeze containers from Gore PharmBIO Products are designed to protect high-value bulk drug substances from container breakage or leakage during frozen handling. “Traditional single-use bags are constructed from materials that typically become brittle when exposed to temperatures below -40 °C, which can lead to cracks or leaks in the bags,” explains Cintavy. The proprietary high-strength fluoropolymer material used for the Sta-Pure flexible freeze containers is durable after freezing at -86 °C (-123 °F) and offers the convenience and scalability of a single-use system that efficiently uses freezer space. In addition to durability, the container’s chemically inert, biocompatible, high-purity fluoropolymer composite film has a low extractables profile (10). Inspired by temperature Gore Sta-Pure flexible freeze With the new Chili, Huber Kältemaschinenbau containers come in sizes from 50 mL to presents a compact, low volume, hydraulically 12 L with tubing and connector options sealed heating thermostat for use with closed to meet different pharmaceutical and temperature control circuits from +65 to +300 °C. Find out more: www.huber-online.com bioprocess applications. A hard-shell carrier is available for easier handling. If carbon dioxide or oxygen permeation is a concern, an optional, vacuum- sealable, secondary barrier wrap minimizes ingress (11).

Pharmaceutical Technology Europe APRIL 2020 31 Operations

Figure 1. Reed-Lane recently added cold storage capabilities and a References dedicated climate-controlled room for vial and ampoule kitting at its 1. Pelican BioThermal, “Pelican packaging facility in Wayne, NJ, United States. BioThermal Reveals 2019 Biopharma Cold Chain Logistics Survey Insights Amid Surge of Temperature-Controlled Products,” Press Release, 26 July 2019. 2. Pelican BioThermal, “Pelican BioThermal to Present Development of Laboratory Mechanical Testing Protocol for Reusable Thermal Packaging at ISTA Forum,” Press Release, 14 May 2019. 3. OptumRx, “OptumRx Introduces 100% Sustainable Packaging for Medication Home Delivery,” Press Release, 16 Aug. 2018. 4. KodiaKooler, “Kwikpack, Assembly Instructions,” Video, https://kodi- akooler.com/kwikpack/. 5. Thermo Fisher Scientific, “Invitrogen Paper Cooler,” Thermofisher.com/ ampoules and assembling them with from biopharma customers and order/catalog. other components such as printed in anticipation of more stringent 6. TemperPack, “TemperPack Launches literature. Its location adjacent to government regulations. The ClimaCell, a Certified Recyclable the cold storage area minimizes shippers are dedicated to human Packaging Solution for Perishable intra-facility travels and exposure to use and certified as such. Validated Shipments,” Press Release, 10 May 2018. temperature excursions. to ISTA 3A and 7E Transportation 7. va-Q-tec, “va-Q-tec Expands in US,” Introductions from Pelican Standards, a new vapour plug design Press Release, 19 Jan. 2018. BioThermal include a new version further doubles the holding time if 8. CSafe Global, “CSafe Expands Cold of its ProEnvision web-based asset shippers are mis-orientated during Chain Offerings for the Cell and Gene management track-and-trace transit. The shippers also provide Therapy Market with Launch of High- software, which allows integration complete traceability of use history Performing Acutemp Plus Series of of its CoolPall Flex bulk shipper into and assurance that each dewar is Temperature-Controlled Packaging,” the Internet of Things. The CoolPall requalified for each trip for physical Press Release, 13 Dec. 2019. Flex shipper serves refrigerated, suitability, cleanliness, liquid 9. AeroSafe Global, “AeroSafe Global frozen, and room temperature nitrogen capacity, and shipment Introduces Lower-Cost, Single-Use A20 ranges. A high level of flexibility hold times. Validated cleaning Insulated Shipper Line,” Press Release, allows the system to address processes reduce the risk of cross- 23 Oct. 2018. different time, weight, and payload contamination during use, delivery, 10. W.L. Gore & Associates, Inc., “Gore requirements. and distribution (13). to Launch GORE STA-PURE Flexible For cryogenic products, SAVSU Freeze Containers at BioProcess Technologies has expanded its Future possibilities International,” Press Release, 24 portfolio of dry vapour shippers, Sustainability continues to be a August 2018. which maintain biologic payloads at major driving force with suppliers 11. W.L. Gore & Associates, Inc., “GORE -196 °C during storage and transport. and users of temperature-controlled STA-PURE Flexible Freeze Containers,” Positioned between the DV4 and the packaging. As a result, work Gore.com. DV10 shippers, the DV7 unit offers continues on developing designs that 12. SAVSU Technologies, “SAVSU seven days of thermal autonomy and meet performance requirements and Technologies Launches Two New evo a more compact form factor with a will be more renewable, recyclable, Smart Shipper Models to Improve payload capacity similar to the DV10 reusable, and/or compostable. Apheresis Collection Shipments shipper. With its smaller size, the Kodiakooler, for example, is working and Cryopreserved Cell and Gene DV7 shipper is easier to handle and on biodegradable EPS foam. “We Therapies,” Press Release, 22 Jan. 2019. store and less expensive to ship (12). are constantly looking for ways 13. Cryoport, Inc., “Cryoport Introduces Cryoport Express Advanced to reduce the carbon footprint of Cell & Gene Industry’s First Dedicated Therapy Shippers from Cryoport have temperature-controlled packaging Shipper for Advanced Therapies,”

been developed to meet demand materials,” says Corbin. Press Release, 18 Sept. 2019. PTE REED-LANE. OF COURTESY FIGURE

32 Pharmaceutical Technology Europe APRIL 2020 PharmTech.com The sponsor should “[establish] a process for continued monitoring of the supplier and the quality of incoming materials,” according to IPEC-Americas.

Qualifying suppliers How do sponsor companies choose and monitor material suppliers to ensure the ingredients they are purchasing are fit for purpose? Linda Evans O’Connor, vice president and chief of staff at Lachman Consultant Services, Inc. suggests that sponsors start by obtaining information from the supplier about its capabilities and compliance history through a Being Vigilant in questionnaire. Material samples should also be obtained to determine if they are fit for their intended purpose. Supplier Oversight Site audits should be performed, and quality agreements should be put in Risk assessments, audits, and good communication place, she says. Finished product trials between sponsor and supplier are key elements of supplier oversight. should be performed if the materials meet the requirements. Batches should Susan Haigney he bio/pharmaceutical industry is a global network that ties then be tested for stability. Periodic T together an array of developers, manufacturers, and suppliers. monitoring of the supplier should Bio/pharmaceutical companies, therefore, may source APIs and be performed with data reviewed excipients from companies thousands of miles away. This global on a predefined basis in addition aspect of the industry, naturally, creates a complex supply chain that to performing surveillance audits, could leave patients vulnerable if not properly overseen. The discovery according to O’Connor. IPEC-Americas of nitrosamine impurities, including N-nitrosodimethylamine (NDMA) stresses, however, that an appropriate and N-nitrosodiethylamine (NDEA), found in angiotensin II receptor risk assessment cannot be performed blocker (ARB) medicines (1) in 2018 is an example of how ingredient without onsite audit information. issues can affect patients and the supply chain and the importance of Susan J. Schniepp, executive testing ingredients. Now, the global COVID-19 coronavirus pandemic vice-president of post-approval has the potential to disrupt supply chains, site inspections, and other pharma and distinguished fellow, activities associated with supplier qualification and oversight. Regulatory Compliance Associates, Sponsor companies and manufacturers are responsible for ensuring says that companies should begin the components they use are safe and effective. The United States the qualification with an onsite audit. Food and Drug Administration (FDA) has cited companies for failing “Once the audit is performed and to test their incoming API and raw materials “to determine their any identified concerns resolved, the identity, purity, strength, and other appropriate quality attributes” (2). two parties, purchaser and supplier, According to a spokesperson for IPEC-Americas, sponsor companies can enter into a quality agreement. must verify the quality of materials, which includes qualification of the After the quality agreement is supplier through on-site good manufacturing practice (GMP) audits approved, the purchasing company and/or a third-party GMP certification. Incoming materials should have can start the process of ‘qualifying’ their identification verified and the quality department should give its the supplier. This qualification usually approval to release the materials for use. This includes performing— involves testing of the material to at a minimum—an identification test, and may include other tests confirm the supplier’s certificate necessary to ensure the quality for the intended use as per US 21 of analysis (CoA) is accurate and Code of Federal Regulations 211.84(d), advises IPEC-Americas. develop a history that demonstrates Risk assessments of both suppliers and materials should also be the ability of the supplier to performed, according to IPEC-Americas, with a specific focus on continually provide a suitable the intended use of the material. The risk assessment should also product,” says Schniepp. evaluate possible concerns with efficacy, variability, safety, and The supplier should then be

duncanandison - stock.adobe.com - duncanandison quality. And this evaluation should not end with the risk assessment. placed on an approved supplier

Pharmaceutical Technology Europe APRIL 2020 33 Quality/Regulations

list, according to Schniepp. “The Laboratories used by either the supplier and other information (3). FDA has initial qualification for a supplier or the purchaser should be audited and been known to cite companies for to be considered an approved included as an element of the risk plan,” incomplete or incorrect information supplier usually involves complete says Schniepp. on CoAs (4). So, how reliable are these confirmatory testing on the first 10 Auditing under difficult documents and how much emphasis lots of material received and then a circumstances. Having a should sponsors put on them when it periodic check and confirmation by consistent and properly executed comes to ensuring material quality? the purchaser of the entire testing audit programme is paramount to O’Connor suggests that sponsor regimen listed on the CoA received maintaining the timeliness and integrity companies create a library of CoAs from the supplier.” of the supply chain, says Schniepp. or labels so they can verify that Audits, and the information obtained the information is correct. “Also, Performing audits during them, allow one to assess a maintaining a relationship with Performing audits of material suppliers supplier’s risk, especially during crises suppliers is key. Anything unusual is key for ensuring the quality of such as the COVID-19 pandemic. needs to be flagged,” says O’Connor. materials, but how often should “Having the baseline knowledge of your Building trust between the sponsor these audits be performed? O’Connor suppliers’ operations will help assess and supplier is important, agrees suggests that a risk-based approach where critical resources need to be IPEC-Americas. “A rt obuss upplier should be used to determine when and allocated during a crisis period. While qualification programme, including how often a supplier is audited. “Many not ideal, audits can still be performed an onsite GMP assessment of a factors can go into the risk model, such on suppliers through the use of supplier, by either the sponsor or a as type of material (e.g., API, excipient, questionnaires and video conferencing. qualified third party, and development sterile, non-sterile, complex dosage If visuals are required for the supplier of a partnership with the excipient form, etc.), location, past regulatory or assessment, the use of an electronic supplier are necessary to establish audit history, recalls, quality of incoming device or video streaming options could and build trust in the validity of their goods, complaint history, importance to be employed. Bottom line, to keep the CoA,” says IPEC-Americas. the business of the materials (i.e., Is this supply chain viable during crisis mode Annual confirmation testing of an API for your blockbuster drug and we need to think outside of our normal CoA results is also necessary, says lack of supply would have a material operating procedures and experiences,” IPEC-Americas (5). “Full testing of an impact on the business?). A minimum says Schniepp. excipient is required until a robust frequency per material type should If travel is limited due to global supplier study has been completed be defined (i.e., for an API, every two situations such as the COVID-19 and a reduced testing programme years),” O’Connor says. epidemic, O’Connor suggests getting has been approved. Only once IPEC-Americas agrees. “Whether the creative. “For example, performing trust has been established can the supplier is an excipient manufacturer, a virtual audit, while not ideal, is sponsor move to a reduced testing contract manufacturer, distributor, or a possibility, and would require programme. However, identification service provider (e.g., a contract testing cooperation of the sponsor and the testing is always required to ensure lab), the initial audit frequency should manufacturer. Document review the identity of incoming materials.” be based on results from the initial and interviews can be performed To establish that the quality supplier/excipient risk assessment remotely. Companies could even look testing information included in along with any additional mitigation at virtual facility tours using appropriate the CoA is accurate, incoming measures identified. Based on on-going technology. However, these types materials must be tested against the monitoring, a sponsor company should of audits are not ideal, and shouldn’t requirements in the CoA, Schniepp determine whether to adjust the audit replace on-site audits. Another solution insists. “The best way to ensure the frequency.” is to partner with a local company that CoA is accurate is through complete A quality risk management plan has the local resources to perform the testing. In cases of falsification of the is key, agrees Schniepp. Frequency on-site portion of the audit. This will CoA, results testing is mandatory to of audits should be based on the allow on-site audits to occur even when make sure the material is suitable criticality of the material and the past international travel bans are in effect,” for use; however, it must be coupled performance of the supplier. “This plan says O’Connor. with a review of the supplier’s overall should identify supplier vulnerability quality system. Even if the material (i.e., single source, secondary supplier, The role of CoAs meets the testing qualifications etc.), which should help determine CoAs provide manufacturers with listed on the CoA, it may not audit frequency. The quality agreement detailed information about materials be suitable for use due to other should reflect the risk plan but there including material manufacturer, potential GMP v iolations that might should always be a contingency to quality testing information, be present at the supplier facility,” allow for-cause audits as needed. specifications, batch numbers, she says.

34 Pharmaceutical Technology Europe APRIL 2020 PharmTech.com Quality/Regulations

“In the case of falsification, the in the quality agreement and both Causes of the Safety Issues,” Press purchaser should be concerned parties must be willing to work Release, 25 Jan. 2019. with data integrity issues that lead outside the defined ‘communication 2. FDA, Warning Letter to Henan Kangdi to the falsification in the first place. schedule’ of the quality agreement Medical Devices Co. Ltd, MARCS-CMS If a purchaser suspects a supplier to avoid unnecessary supply-chain 587699, 3 Dec. 2019. is falsifying the results on a CoA interruptions.” 3. A. Shanley, Pharm.Tech. 42 (4) 60-69 they need to initiate a for-cause (April 2018). audit and quarantine the suspect References 4. FDA, Warning Letter to Spectrum material until they can confirm it was 1. FDA, “FDA Statement on the FDA’s Laboratory Products, Inc., MARCS-CMS satisfactorily manufactured following Ongoing Investigation into Valsartan 579958, 31 July 2019. cGMP [current GMPs] expectations. and ARB Class Impurities and the 5. CFR Title 21, 211.84(d) (Government v102_Pharmaceutical_technology_Europe_Half_Page.pdf 1 27/03/2020 15:40 Passing test results does not confirm Agency’s Steps to Address the Root Printing Office, Washington, DC). PTE compliance to cGMPs,” Schniepp explains.

Ensuring quality is about vigilance Maintaining a safe supply chain is crucial in the bio/pharmaceutical industry. The efficacy and safety of the materials used in drug products Wait. What? Pfizer can is of utmost importance. And it is the manufacture my product sponsor’s responsibility to ensure for clinical trials and the quality of all materials used in commercial supply? their products. Sponsors must not rely on others to ensure quality, says O’Connor. Also, not all suppliers should be treated the same. “Clearly, some suppliers have greater risk than others, either based on the product C We sure can. Collaborate with Pfizer CentreOne. type, location, etc. These suppliers And access Pfizer’s global manufacturing M should receive more scrutiny,” she network and scale-up expertise. says. Sponsors also must not cut Y corners or do what is convenient, saysCM O’Connor. For example, she notes, MY it is inconvenient, but necessary to audit suppliers in China and India. In CY Listening. Pfizer CentreOne® is a global CDMO addition, sponsors should also not CMY embedded within Pfizer and excels in the make supplier decisions based on Solving. K manufacture of oral solid dosage forms. price or availability instead of quality Guiding. and safety, says IPEC-Americas. Intelligent collaboration with Pfizer CentreOne. Communication is key to supplier oversight, says Schniepp. “Both Working together with our customers, we combine our technical and commercial knowledge with open parties need to be willing to talk as dialogue to solve challenges. We have integrated frequently as needed to address cGMP pilot facilities dedicated to process optimization, issues before they manifest into a clinical drug manufacturing, and scale-up technology disruption in the supply chain. The transfers. We o„er commercial manufacturing for frequency of these conversations are global / large-volume solid forms production. not necessarily defined in a quality agreement. They are important in establishing an open relationship between the supplier and the Let’s For more information contact us at pfizercentreone@pfizer.com or visit purchaser so issues can be solved collaborate us at www.pfizercentreone.com before supply chain disruption occurs. Not all problems can be solved through the terms included

Pharmaceutical Technology Europe APRIL 2020 35 bioprocessing options over the past five years, and the data support ongoing interest in the coming year (Figure 1). Approximately 55% of facilities surveyed are actively or informally evaluating continuous processing technologies in the coming year. Although there are a number of technologies providing process intensification and continuous purification steps, it appears that more robust continuous chromatography Biomanufacturing: technologies, such as simulated moving bed (SMB) and periodic countercurrent chromatography, Demand for Continuous are generally not yet ready yet for commercial-scale adoption (other than Bioprocessing Increasing adoptions performed using single-use upstream equipment generally limited But are innovations sufficient to increase adoption? to 2000-L scale). CMOs are demanding better continuous bioprocessing options. Outsourcing and continuous bioprocessing Eric S. Langer is president n nearly all other manufacturing technologies, cost considerations Contract manufacturing organizations and managing partner I dictate that continuous production will be the rule. But in (CMOs) are often on the leading at BioPlan Associates, bioprocessing, the normal evolution from batch to continuous edge of new technology adoption. Inc., a biotechnology and operations has not moved as quickly as many had expected. For continuous bioprocessing life sciences marketing Continuous processing upstream has been around for decades and process intensification, research and publishing firm as perfusion (e.g., fiber-based perfusion bioreactors for fused-cell BioPlan’s Annual Report shows that established in Rockville, hybridoma culture in the 1980s). But that’s essentially the only significantly more CMOs will be MD in 1989; elanger@ continuous-adapted upstream unit process, with such things as testing these technologies over the bioplanassociates.com, culture media and additives preparation still done in batch processing. next 12 months (53% of CMOs will be +1 301.921.5979. In some respects, perfusion has overall been a commercial failure. evaluating downstream options, vs Sales of the leading alternating tangential flow (ATF) perfusion 38% of biomanufacturing facilities). systems from leading suppliers, after more than 15 years, are under On the upstream side, again it is the US$20 million (€18.3 million). And continuous processing downstream CMO outsourcing organizations that is still largely lacking and, where implemented, involves just a few are seeking better products and of the many unit processes involved in downstream processing. more improvements. More CMOs Multi-column, countercurrent, and other variations of continuous than biomanufacturers (40% vs 28%) chromatography units are just starting to enter the market. The classic are indicating they want vendors to and still predominant approach to bioprocessing, both upstream and focus greater efforts on developing downstream, remains batch processing, with manufacturing batch continuous upstream technologies (1). fluids essentially moving incrementally en-masse from one process step and set of equipment to the next. Budgets for adoption Downstream processing continues to create bottlenecks in of continuous bioprocessing production, and improvements in batch processing are not really BioPlan’s annual report for emerging. Therefore, the industry continues to seek solutions from 2020 also evaluated adoption of innovators for better continuous processes that offer further process bioprocessing technologies based intensification and lower costs. In fact, 70.6% of bioprocessing on new technology purchases. professionals are either testing continuous bioprocessing downstream When evaluating new expenditures, technologies or considering them. This is up from 68% based on data industry decision-makers were from our 2016 Annual Report (1). asked about new technologies they According to BioPlan’s 17th Annual Report and Survey on were budgeting for. Of the nearly Biopharmaceutical Manufacturing Capacity and Production (2), there 20 technologies identified, the top

has been a slow increase in assessment of the various continuous technologies this year included Stock.adobe.com - valdistorms

36 Pharmaceutical Technology Europe APRIL 2020 PharmTech.com Outsourcing

Figure 1: Facilities evaluating continuous bioprocessing (downstream) technologies in the next 12 months (2016–2020).

single-use bioreactors (noted by 45.9% There are many benefits to Many upcoming continuous of respondents), followed by cell operating bioprocesses continuously bioprocessing technologies are culture media including optimization, rather than in batch mode, very novel. For example, a single and then continuous bioprocessing with many of these similar and 50-L bioreactor is expected to be (upstream), and continuous complementing those of single-use able to manufacture the same bioprocessing (downstream), and modular systems: quantity of product, often at better according to preliminary data. • Reduced costs: Operating quality, comparable to a 5000-L BioPlan data in general indicate continuously allows use of bioreactor over the same time that the direction of the industry is significantly smaller-scale period. Case studies and other more toward single-use novel devices, equipment, with a smaller reports of such performance will those that allow rapid transitioning volume bioreactor. further promote rapid adoption. from project to project, and options • Increased productivity: Because There will be increasingly rapid for continuous bioprocessing. Some much of the bioprocessing adoption of single-use systems for of these technologies also support the equipment is operated new commercial manufacturing increasing demand for biologics that continuously, there is little need over the next five years; and may be called for in smaller quantities. for large transfer/storage vessels continuous bioprocessing, particularly Figure 2 shows the economic and no halts between processes. upstream processing, is expected commitment decision-makers Bioprocessing thus tends to to follow a similar trajectory. Use are focusing on continuous move much more smoothly. of continuous bioprocessing is bioprocessing, as evidenced • Improved quality: Biological likely to further increase with the by companies’ top three new molecules are expressed arrival of more hybrid systems expenditures including both upstream continuously, and compared to that use bolt-on-type technology, and downstream continuous batch culture, continuous culture which retrofit components unit bioprocessing equipment, which was tends to be more controllable, operations for existing systems. noted by a robust 25.9% and 16.5% less intense and stressful, Other conventional downstream response from decision-makers. including less shear and media continuous adaptable technologies, nutrient levels kept constant. such as centrifugation, will also see Trends making continuous • Increased flexibility: Continuous increasing adoption in coming years. bioprocessing attractive manufacture enables more Potentially revolutionary capillary Several technological advances and adaptability and efficient fiber perfusion bioreactors and other related trends are making continuous facility utilization, similar to the new technologies, including those for bioprocessing attractive. Some advantages of single-use devices. downstream processing, will be likely established bioprocessing facilities Bioprocessing also becomes coming online and be more widely are being retrofitted and upgraded for much more portable, and adopted for commercial manufacture

ALL FIGURES COURTESY OF THE AUTHOR. more continuous operations. facilities more cloneable. over the next 10 years.

Pharmaceutical Technology Europe APRIL 2020 37 Outsourcing

many of the problems long associated Figure 2: New expenditures, 2020. with perfusion and continuous bioprocessing have been resolved in recent years through the application of innovative technologies, including new developments in single-use equipment. On the other hand, perfusion processing is now significantly less complex, less prone to contamination, and more readily scalable than previously. Negative assessments from within the industry of continuous perfusion fed-batch processing overall may reflect a lack of direct exposure or experience with continuous technology. Continuous processing perfusion (other products use In BioPlan’s annual report, for trends in bioprocessing continuous centrifugation). example, key areas where most When respondents were asked BioPlan studies have shown respondents reported they perceive about their ‘single most’ important approximately 5% of bioreactors that perfusion as presenting more biomanufacturing trend, or are over desktop-size use perfusion, concerns (vs. fed-batch) included: operational area on which the mostly for feeder, not production, • Process operational complexity industry must focus its efforts, bioreactors. There is more adoption (perfusion noted by 72% as more upstream and downstream of perfusion for early stage vs. large/ operationally complex vs. batch) continuous bioprocessing declined commercial-scale manufacturing. • Contamination risks dramatically over the past six years, BioPlan studies have shown that few • Upstream development and from 9.1% to 1.25% for upstream, processes are scaled-up, particularly characterization time and 10% to 4.7% for downstream for commercial good manufacturing • Process development control continuous bioprocessing. practice (GMP) manufacture, using challenges While this might imply that interest perfusion in continuous upstream • Process development general in continuous bioprocessing is bioprocessing CP USP. Perfusion adds challenges waning, combined with the increased considerable mechanical complexity • Validation challenges expenditures in the area, it suggests and regulatory uncertainties (i.e., it • Need for greater process control that continuous bioprocessing is avoided for GMP manufacturing, • Cell line stability problems is becoming a more mainstream expert staff are needed, etc.), as • Ability to scale-up process. bioprocessing area, and therefore, well has having limited equipment Interestingly, while approximately less trend-relevant, thus, the lower options and universal industry inertia 76% believe downstream continuous trend ‘score.’ restraining adoption. bioprocessing will be a long time in Large-scale continuous coming, 66% believes that perfusion Implementation of downstream processing, particularly systems will be adopted by most continuous bioprocessing chromatography operations, remain bioprocessing facilities. This shows Although this is beginning to change, rare. Even where continuous the expectation that continuous implementation of continuous downstream processing has been bioprocessing is here for the long haul, bioprocessing is and has been slow. implemented, it involves at best but widespread adoption may not be At best, a few unit process/steps only one or few out of the usual in the near future. both up- and/or downstream have multiple chromatography and been implemented as continuous by a other downstream processing References minority of facilities. Some commercial unit processes/steps having been 1. BioPlan Associates, 16th Annual Report biopharmaceutical products that implement as continuous. and Survey on Biopharmaceutical essentially require perfusion’s Survey data suggests that Manufacturing Capacity and generally milder/less intense bioprocessing professionals may Production (Rockville, MD, April 2019). processing conditions, including believe continuous processing is more 2. BioPlan Associates, 17th Annual Report Factor VIII (the largest recombinant ready for broad adoption for more unit and Survey on Biopharmaceutical molecule biopharmaceutical) and processes than it currently is. Notably, Manufacturing Capacity and coagulation factors, have been continuous processing equipment Production, Preliminary Data (Rockville, manufactured for decades using manufacturers and users report that MD, March 2020). PTE

38 Pharmaceutical Technology Europe APRIL 2020 PharmTech.com manufacturing system is clean. Because of this, the agency recommends that companies challenge the analytical method used for detection by combining it with sampling methods. This allows manufacturers to show that contaminants can still be recovered from equipment surfaces after cleaning. After all, a negative test (i.e., where no contaminants are detected) could be due to poor sampling Alternative Cleaning technique. Sampling techniques are important for determining contamination Validation Methods levels, and FDA accepts two general types: direct surface sampling and for Biologics rinse solutions (1). Direct surface sampling allows accessible but hard- Because conventional cleaning methods can risk product loss, to-clean areas to be evaluated, so biopharmaceutical manufacturers are often reluctant to use that data can be used to establish an PDE/ADE limits to validate cleaning processes. acceptable residue or contamination level per given surface area. Dried residue, or residue that is Feliza Mirasol leaning validation for biologics, particularly those that are insoluble, can easily be sampled by C manufactured in commercial stainless-steel equipment, has physically removing it. However, FDA always been tricky. One worrisome issue has been the potential loss has cautioned manufacturers that, of product as the result of the cleaning process. Cleaning processes in order to do direct sampling, they can degrade protein molecules, and biologic products—such as must first determine early on in their therapeutic antibodies—have been known to degrade and denature cleaning validation programme what under extreme conditions, such as high heat and high or low pH. This type of sampling material they will can often result in loss of pharmacological activity. Yet, the cleaning use and how the material will affect of biomanfacturing equipment often requires that equipment surfaces test data because there is potential be exposed to extreme pH and temperatures to ensure sterilization. for the sampling material to interfere with testing. FDA cleaning requirements For the rinse sample method, The US Food and Drug Administration (FDA) expects manufacturers advantages include use of a larger to have written procedures on how their cleaning processes will be surface area for sampling and validated (1), and expects the validation procedure to specify the ability to test inaccessible systems personnel responsible for performing and approving the validation study. (e.g., ones that cannot be routinely Companies must also indicate staff members who will be responsible for disassembled). However, the residue establishing the acceptance criteria for the validation and the timing for or contaminant may not be soluble, when revalidation will be required. or may be obstructed by the physical The agency further expects companies to prepare specific, written structure of the equipment. As a cleaning validation protocols before carrying out studies that they result, evaluation of any system’s expect to perform on each piece of manufacturing equipment. The cleanliness should not rely solely on written protocols should address important issues, such as the evaluation of the rinse solution, but company’s sampling procedures, the analytical methods that will be rather evaluation of the equipment used, and the sensitivity of those methods. itself. The rinse solution should not Fortunately, advances in analytical technology have made it simply be tested for water quality, possible to detect even very low levels of residue left behind from but rather for the presence of specific manufacturing and cleaning processes, according to FDA. However, contaminants. when residue or contamination is not detected, that may be due to a Data must be recorded and limitation in the sensitivity of the analytical method used. documented during the sample Absence of detectable levels of residue or contamination is testing procedures. Testing uncleaned

littlewolf1989 - Stock.adobe.com - littlewolf1989 not itself a guarantee that a piece of equipment or the entire equipment will establish what an

Pharmaceutical Technology Europe APRIL 2020 39 Analytics

unacceptable result would look like molecule candidates for worst-case Polymers such as nylon, with indirect testing methods. product were subjected to cleanability polytetrafluoroethylene, and silicone and solubility tests, with the caveat are necessary components of Where alternative that a worst-case product must equipment used in raw material methods are justified be more difficult to clean than the manufacturing and are also used in Alternative cleaning validation actual biologic product. This would bags or containers meant for raw methods involve using a gauge ensure that acceptable cleaning material storage. These substances other than permitted daily exposure settings would be established for the can be a source of raw material (PDE) or acceptable daily exposure bioreactor when manufacturing the impurities. Likewise, mineral silicates, (ADE), or changing the limits set by actual biologic product (4). lubricants, and siloxanes can also be regulators for these standards. It has Going through this exercise helped sources of raw material impurities, been argued that protein molecules the researcher demonstrate the all of which can appear in bioprocess are degraded by the cleaning multidisciplinary nature of cleaning preparation tanks (6). processes used to meet PDE or ADE validation, which is one aspect of Common cleaning approaches that limits (2), which has led to a search good manufacturing practices (GMP) pharmaceutical manufacturers use for alternative cleaning validation regulations that is still not well to combat these common residues methods. understood or gets little attention (4). include increasing spraying (e.g., In the European Medicines Agency’s employing a rotating spray device), (EMA’s) guideline on setting health- Loss of biological product raising cleaning temperature to based exposure limits (3), the agency during cleaning processes around 75 °C to 85 °C, and using states that it would be acceptable can be costly. a formulated cleaning agent. In to use approaches other than PDE/ addition, the industry may increase ADE limits to determine health- FDA’s requirements largely the concentration of the cleaning based exposure limits, provided focus on the need to record and agent and/or use an oxidizing that the alternative approaches document all steps used in cleaning cleaning agent or a detergent additive are “adequately and scientifically” processes. To that end, a company combined with an alkaline cleaning justified. EMA also understands that, must be meticulous in its cleaning solution (so long as temperature is because the cleaning methods for validation documents, including kept between 50 °C and 65 °C). “therapeutic macromolecules and defining the equipment that is cleaned peptides” can result in the degradation as well as the equipment used in References or denaturation of those molecules cleaning processes; demonstrating 1. FDA, “Validation of Cleaning Processes due to their exposure to extreme understanding of the given drug’s (7/93), Guide to Inspections Validation heat and/or pH, “the determination properties; and describing analytical of Cleaning Processes,” fda.gov, of health based exposure limits using methods used to determine the accessed 16 March 2020. PDE limits of the active and intact level of cleanliness (or presence 2. A. Walsh, BioPharm International’s The product may not be required” (3). of contaminants). Sample residue Future of Bioprocessing eBook 28 (14) collection from surfaces must also 14–22 (2015). The worst-case product be recorded. The overall approach to 3. EMA, Guideline on Setting Health Loss of biological product during cleaning validation, therefore, requires Based Exposure Limits for Use in Risk cleaning processes can be costly, expertise in various disciplines and Identification in the Manufacture of and especially challenging when cooperation among those disciplines. Different Medicinal Products in Shared a company is testing its cleaning Facilities (CHMP, CVMP, November validation method on a potentially Recognizing residues 2014). new biologic product. To help mitigate Air-liquid residues can be detrimental 4. D. Steyaert, “Cleaning Validation of expensive losses, companies may for biologics manufacturing and Biologicals: Determination of a Worst- look for alternatives to their molecule can come from a variety of sources, Case Product for RTH 258,” Master’s that they can use as a “worst-case including hydrocarbons, polymers, Thesis Paper (2016–2017). product” scenario for their cleaning mineral silicates, lubricants, and 5. Novartis, “Novartis Receives FDA validation methods. siloxanes (found in valves, gaskets, Approval for Beovu, Offering Wet AMD In one study, a worst-case and tubing) (6). Hydrocarbons such as Patients Vision Gains and Greater product scenario was tested for the steramide, erucamide, and oleamide, Fluid Reductions vs Aflibercept,” Press cleaning validation of brolucizumab are mold-release agents used to Release, 8 Oct. 2019. (4), Novartis’ Beovu, prior to its prevent caking of powders. They 6. B. Kroeger, “Current Trends in Cleaning approval by FDA in October 2019 for are often used in manufacturing the Validation,” presentation for Parenteral treating wet age-related macular bags (e.g., those used for storage and Drug Association, PDA.org/docs, degeneration (5). In the study, five transport) and biologics equipment. accessed 11 Feb. 2020. PTE

40 Pharmaceutical Technology Europe APRIL 2020 PharmTech.com Ask the Expert — Contin. from page 42 successfully implemented at a company (11). Having the plan available for discussion and demonstrating a knowledge of the address this issue in an inspection is to demonstrate that the plan, how it is incorporated into the culture, and making sure it is company has a plan to update its facility over time. The plan revised as needed to reflect current practices is critical to having should indicate what needs to be updated and a timeline for a successful outcome should you be audited on this topic. implementation. The bottom line is that the regulatory landscape is changing, and it is conceivable that companies will begin to be audited Investigations/CAPA on programmes and process that are more subjective than The need for a robust investigation/CAPA process is clearly tangible. To be prepared for an audit that touches on the defined in global regulations, but it seems the industry still intangibles of a functioning quality management system, struggles with conducting and documenting root cause when companies should begin to formulate programmes and it comes to investigations based on FDA 483 observations (6). systems that address the aforementioned topics. The purpose of an investigation is to identify the root cause of a deviation and take appropriate action to correct the issue across References the manufacturing/product line. The best way to demonstrate 1. FDA, Office of Pharmaceutical Quality, FDA Pharmaceutical proper control of this process during an investigation is to ensure Quality Oversight, One Quality Voice, FDA whitepaper. 2. S. Schniepp, Pharmaceutical Technology 43 (10) 2019. you have a robust investigation process, which routinely identifies 3. World Health Organization, Annex 5, Guidance on Good Data root cause and that once the correction is made, it does not recur and Record Management Practices (WHO, June 2016). (7). The ability to demonstrate this depends on the understanding 4. S. Schniepp, Pharmaceutical Technology 42 (10) 2018. and training of the people involved in the investigation process 5. S. Schniepp, Pharmaceutical Technology 40 (8) 2016. and data that shows the problem was addressed and solved (8, 9). 6. S. J. Schniepp, Pharmaceutical Technology 43 (12) 2019. 7. S. Schniepp and A. Harrison, Pharmaceutical Technology 40 (2) 2016. Risk management 8. S. Schniepp and A. Harrison, Pharmaceutical Technology 39 Every company should have a quality risk management plan (10). (10) 2015. A well-written and well-implemented quality risk management 9. S. Schniepp and A. Harrison, Pharmaceutical Technology 39 plan is an integral and valuable element of an effective quality (8) 2015. system. Quality risk management plans are important because 10. S. Schniepp, Pharmaceutical Technology 44 (2) 2020. PT they help improve a company’s ability to provide quality product 11. S. Schniepp, Pharmaceutical Technology 43 (8) 2019. to patients. They are contingency plans with identified actions that help to ensure a continuous supply of product to the Your opinion matters. market that meets the expectations of being safe, effective, and Have a common regulatory or compliance question? available. They are dynamic documents that require integration Send it to [email protected], and it may appear in a future column. into and data inputs from all departments in order to be

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Pharmaceutical Technology Europe APRIL 2020 41 ask the expert

Critical Knowledge for Preparing Audits

Addressing data integrity, quality culture, aging facilities, investigations/corrective actions and preventive actions, and risk management is key when conducting audits, says Susan J. Schniepp, executive vice- president of post-approval pharma and distinguished fellow, Regulatory Compliance Associates.

I am preparing my site for an audit and consequences for violating the company’s data integrity Q. have prepared and trained our employees policy, etc. The programme should also address the frequency on the usual topics (training programme, standard operating and effectiveness of employee training on this topic. The procedures [SOPs], change control, etc.). I am concerned that programme should demonstrate an understanding of this traditional approach may not be enough in the current regulatory expectations as well as an explanation of how regulatory environment. Can you offer some guidance into those expectations are incorporated into the data integrity other issues I should focus on in preparing for the audit? programme. The programme needs to go beyond the concepts This is a great question and shows an insight into the of ALCOA (attributable, legible, contemporaneous, original, A. changing regulatory landscape. I think it will be critical accurate) and include the four new attributes in ALCOA+ in the coming years to focus on addressing certain intangible (complete, consistent, enduring, available) (2, 3). topics during routing regulatory audits. These topics should be addressed as part of your company’s overall improvement Quality culture plans and programmes. The concept of quality culture came about with the I would focus on the following topics as a part of preparing introduction of quality metrics. FDA introduced the concept for any routine audit: data integrity, quality culture, aging of collecting quality metrics in 2013 (4). Since that time, the facilities, investigations/corrective actions and preventive industry and regulatory authorities worldwide have embraced actions (CAPA), and risk management. I am of the opinion that the idea that in order to rely on the metrics collected, the these topics will become routine areas of focus for regulatory company needs to have a culture that supports an open, inspections regardless of the affiliation of the regulatory transparent reporting of “deviations, errors, omissions and authority performing the audit. These topics are not new to aberrant results at all levels of the organization, irrespective the industry. There has been much discussion on their impact of hierarchy” (3). There has been work done by the Parenteral on drug shortages. It is my opinion that developing robust Drug Association and University of St. Gallen suggesting the programmes addressing these issues and incorporating there is a correlation between mature quality attributes and them into everyday routine operations will improve the quality culture behaviours. To address the issue of a quality drug shortage situation, improve a company’s operating culture during a regulatory inspection, the company should performance, and improve the outcome of regulatory be able to demonstrate their quality system is functional and inspections for the company. identifies gaps so the company can implement changes to The US Food and Drug Administration (FDA) has been ensure continuous improvement. publishing guidance on these issues over the years, and now as the agency gets ready to finalize the New Inspection Aging facilities Protocols Project (NIPP), it is time to revisit some of these Aging facilities are of concern because they can lead to recommendations and implement some of the advice offered. drug shortages. It is hard to achieve compliance to current The intent of the NIPP programme (1) is to provide inspectional regulatory expectation when manufacturing new and assessments to support tracking and improvement of novel products on manufacturing lines that are more than performance across pharmaceutical manufacturers and 30 years old and the analytical results rely on outdated products and enhance the production, utility, and consistency methodology (5). The age of the line usually indicates that of the establishment inspection reports. the processes being run on those lines are non-automated and require human driven steps. In these situations, it is Data integrity critical a company demonstrates it has a quality mindset Every company should have a programme to address because of the human/product interface. The best way to data integrity issues that includes guidance on what data

integrity is, how to recognize it, how to prevent violations, Contin. on page 41 - STOCK.ADOBE.COM LEIGH PRATHER

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