From Syringe to Autoinjector

Volume 40 Number 6 Number 40 Volume

Blow-Fill-Seal Data Integrity Using Modular JUNE 2016 Volume 40 Number 6 PLUS: Technology Training Construction

PHARMACEUTICAL TECHNOLOGY PHARMACEUTICAL From Syringe to

JUNE 2016 Autoinjector Building a Better Self-Injection Solution PharmTech.com PEER-REVIEWED Qualifying Personnel to Visually Inspect Cleaned Equipment, Part II

SINGLE -USE SYSTEMS FORMULATION API SYNTHESIS & MANUFACTURING Integrating Single-Use Systems Customizing HPMC Adoption of Continuous Processing Advancing Drug Delivery Through Superior Polymer Design

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Member of OPTIMA pharma GmbH | 74523 Schwaebisch Hall | Germany | www.optima-pharma.com OPTIMA Machinery Corporation | Green Bay, WI, 54304 | USA | www.optima-usa.com EDITORIAL SALES Editorial Director Rita Peters [email protected] Senior Editor Agnes Shanley [email protected] Publisher Mike Tracey [email protected] Managing Editor Susan Haigney [email protected] Mid-West Sales Manager Irene Onesto [email protected] Science Editor Adeline Siew, PhD [email protected] East Coast Sales Manager Joel Kern [email protected] Manufacturing Editor Jennifer Markarian [email protected] Science Editor Randi Hernandez [email protected] European Sales Manager Linda Hewitt [email protected] Community Manager Caroline Hroncich [email protected] European Senior Sales Executive Stephen Cleland [email protected] Art Director Dan Ward Executive Assistant Barbara Sefchick [email protected] Contributing Editors Jill Wechsler [email protected]; Jim Miller [email protected]; Hallie Forcinio [email protected]; Susan J. Schniepp ADDRESS [email protected]; Eric Langer [email protected]; and Cynthia A. Challener, PhD [email protected] 485 Route One South, Building F, Second Floor, Iselin, NJ 08830, USA Correspondent Sean Milmo (Europe, [email protected]) Tel. 732.596.0276, Fax 732.647.1235 485 Route One South, Building F, Second Floor, Iselin, NJ 08830, USA PharmTech.com Tel. 732.596.0276, Fax 732.647.1235, PharmTech.com

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4 Pharmaceutical Technology JUNE 2016 PharmTech.com Veltek Associates, Inc. offers two garment product lines, which are both pre-folded in our system. Comfortably styled and ﬁtted with elastic thumb loops to reduce shifting, as well as tunnelized elastic wrists and ankles. 1600 Garments 1700 Garments Face Masks t Breathable t High filtration efficiency t Breathable t Comfortable t Low particulate and shedding t Reduces goggle fogging due t High bacterial efficiency performance to absorption efficiency t Excellent water repellency t Soft and comfortable June 2016 Volume 40 Number 6 Pharmaceutical Technology is the authoritative source of peer-reviewed research and expert analyses for scientists, engineers, and managers engaged in process development, manufacturing, formulation and drug delivery, API synthesis, analytical technology and testing, packaging, IT, outsourcing, and regulatory compliance in the pharmaceutical and biotechnology industries.

COVER STORY 18 Building a Better Self-Injection Solution Experts discuss the key considerations in the development of an autoinjector.

the cover Cover Design by Dan Ward; Images: Jared Eygabroad/Getty Images On FEATURES ON PHARMTECH.COM

FORMULATION VIEWPOINT What’s Behind NIH’s 24 Customizing HPMC to 39 PAT: “Gateway Drug” Quality Problems? Minimize Drug Variability to the 21st Century for Drug manufacturing lapses The authors evaluated the the Pharma Industry undermine NIH research programs. performance and robustness of Process analytical technology paved www.pharmtech.com/what-s-behind- controlled-release tablets made the way for continuous manufacturing. nih-s-quality-problems-0 with HPMC blends of unimodal and SINGLE-USE SYSTEMS bimodal molecular weight distribution. Any Chance for “Cures” Legislation This Year? API SYNTHESIS & MANUFACTURING 42 Integrating Single-Use Systems in Biomedical innovation 30 Steps Closer Pharma Manufacturing legislation may stall in 2016. to the Adoption of Industry experts discuss the benefits and www.pharmtech.com/any-chance- Continuous Processing challenges of using single-use systems cures-legislation-year Application of flow chemistry for small- in pharmaceutical manufacturing. molecule API synthesis continues to EU on a Mission to Boost R&D FACILITY DESIGN expand thanks to research efforts. In a move to encourage drug 45 Deciding When to development, EU regulators are Use Modular Construction offering scientific advice to companies Different types of modular systems on major efficacy, safety, and quality have advantages and disadvantages. issues at an early stage. www.pharmtech.com/eu-mission- boost-rd

Continued on page 8

PEER-REVIEWED RESEARCH

EQUIPMENT CLEANING 34 Qualifying Personnel to Visually Inspect Cleaned Equipment, Part II: Small vs. Large Group Training This article presents recommendations based on a program that was set up to qualify members of a large, diverse team at one oral solid-dosage-form manufacturing facility.

PharmTech.com

Continued from page 6 NEWS & ANALYSIS REGULATION DEPARTMENTS/

FROM THE EDITOR & COMPLIANCE PRODUCTS 10 Industry US REGULATORY WATCH 12 Product Spotlight Moves Closer 14 Modern 55 Showcase/Marketplace to Continuous Manufacturing 57 Ad Index Manufacturing Comes of Age With technology advances, continuous FDA and bio/pharma companies manufacturing shows steady progress get serious about continuous to more widespread adoption. manufacturing to ensure product quality.

STATISTICAL SOLUTIONS ASK THE EXPERT 47 Demonstrating a 58 Make Data Integrity State of Control Integral to CGMP Training Do you have acceptable control of your Susan Schniepp, distinguished instruments and analytical procedures? fellow at Regulatory Compliance Associates, discusses training TROUBLESHOOTING personnel on data integrity. 49 Examining Blow-Fill-Seal Technology for Aseptic Processes Industry experts discuss common considerations and recent technological advancements in blow-fill-seal technology.

OUTSOURCING OUTLOOK 52 Watch Out for the Hangover Acquisition binges often lead to hangovers; here’s what to watch out for.

PHARMACEUTICAL TECHNOLOGY (Print ISSN: 1543-

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PharmTech.com magentablackcyanyellow ES788117_PT0616_009_FP.pgs 05.26.2016 02:59 ADV FROM THE EDITOR Industry Moves Closer to

Continuous Manufacturing IMAGES GREUEL/PHOTODISC/GETTY JORG Pharmtech.com/pt/forumPharmTech.com/forum Rita Peters With technology advances, continuous manufacturing shows steady progress to more widespread adoption.

ontinuous manufacturing of phar- tions to Modernize the Pharmaceutical nology and BioPharm International. The maceuticals is one of five manufac- Manufacturing Base (2), published in time needed to develop a process is often Cturing technology areas of emerging December 2015. underestimated because the process is priority, according to an April 2016 re- more involved than people expect. In port on advanced manufacturing issued Progress, but work to be done addition, single use is not practical to use by the National Science and Technology There has been some progress in con- for very large volumes, such as 10,000 L; Council (NSTC), a government organi- tinuous manufacturing. In April 2016, practical use of the system, versus vol- zation that sets national goals for federal FDA approved a continuous manufac- ume, must be considered. science and technology investments (1). turing line, which replaced an existing A continuous supply of consumables is FDA has been actively encouraging batch process, for the manufacture of vital to both batch and continuous man- bio/pharmaceutical companies to adopt PREZISTA (darunavir) 600 mg tablets ufacturing processes. At INTERPHEX, continuous manufacturing processes as by Janssen Supply Chain in Gurabo, suppliers reported increased demand for part of efforts to update manufacturing Puerto Rico. The development of the custom formulations and packaging, and facilities, improve quality and efficien- continuous process that integrates all quality control reports. Several suppliers cies, and ultimately, reduce drug short- manufacturing steps (weighing, mill- reported facility expansions to increase ages. The National Science Foundation ing, blending, compression, and coating) capacity and offer redundant operations (NSF), National Institutes of Health, into one single line is a result of a five- to ensure a continuity of supply of vital National Institute of Standards and year partnership with Rutgers Univer- materials in the event of manufacturing Technology, Department of Defense, sity and the University of Puerto Rico. problems at another facility. Another and the Biomedical Advanced Research The Janssen Supply Chain conver- trend is a shift toward in-line dilution and Development Authority (BARDA) sion is a positive step forward in the and systems that provide access to large are also promoting the use of continu- move to continuous manufacturing. volumes of buffers without having to ex- ous manufacturing. On the biologics drug manufacturing pand buffer storage areas. In addition, as FDA has accelerated side, with more complex manufactur- With a goal to provide a continuous approvals of breakthrough drugs, it has ing processes, progress has been slower supply of quality drugs to patients, the identified the need for earlier scale-up and incremental. At INTERPHEX bio/pharma industry is seeing some chemistry, manufacturing, and con- 2016 in April, equipment manufactur- incremental progress. It is up to bio/ trols (CMC) work. To meet the devel- ers displayed systems that fit process pharma companies to see that this opment needs, FDA outlined a plan to development and scale-up continuum trend continues. develop an understanding these new that could help drug companies move technologies, in advance of the review forward in these efforts. Several equip- References process, in its draft guidance, Advance- ment manufacturers displayed systems 1. Executive Office of the President, Na- ment of Emerging Technology Applica- that could work in a progressive chain, tional Science and Technology Council “Advanced Manufacturing: A Snapshot eliminating some batch process steps. of Priority Technology Areas Across the Single-use systems are key compo- Federal Government,” by the Subcom- nents of the adoption of continuous mittee for Advanced Manufacturing of manufacturing. Complexity and scale, the National Science and Technology however, are two stumbling blocks to the Council (April, 2016). 2. FDA, Draft Guidance–Advancement of Rita Peters is editorial implementation of single-use systems on director of Pharmaceutical Emerging Technology Applications to Technology. Send your the commercial manufacturing scale, Modernize the Pharmaceutical Manufac- thoughts and story ideas according to participants in a panel dis- turing Base (Rockville, MD, December to [email protected]. cussion hosted by Pharmaceutical Tech- 2015). PT

10 Pharmaceutical Technology JUNE 2016 PharmTech.com

PRODUCT SPOTLIGHT

Washdown Duty Acoustic Separator Ribbon Blenders Streamlines Clarifications Washdown duty ribbon The Cadence Acoustic blenders from Ross, Charles & Separator (CAS) from Pall Life Son can be used to mix dry Sciences enables the blends such as grains, powders, purification of bioprocesses pellets, and flakes. Small fluids without the use of amounts of liquid may be primary depth filters or sprayed throughout the batch centrifuges. CAS was during the blending cycle for developed by FloDesign Sonics uniform distribution. Wet and is licensed by Pall. CAS’s acoustic wave separation (AWS) applications such as pastes, technology applies acoustic forces across a countercurrent flow of slurries, and suspensions can bioprocess fluid to generate three-dimensional standing waves that also be prepared in these trap cells in their nodes. The cells in the bioprocess fluid will blenders. The blenders feature a horizontal agitator with agglomerate and eventually sediment as it loses its buoyancy. characteristic inner and outer helical ribbons pitched to move the The CAS does not cause any significant increase in temperature or materials in a well-balanced axial and radial flow pattern. The damage to cells or proteins. The CAS system allows for the reduction blenders are equipped with all washdown components including the of 75% of the filtration area and associated buffer volume motor, safety limit switch, variable frequency drive, stuffing boxes, requirements. AWS technology is applicable for the clarification of and knife gate discharge valve. The dust-tight cover includes a biologic products, including recombinant therapeutic proteins and charging port with safety grating, and the U-shaped trough is monoclonal antibodies. In addition, the CAS is a single-use surrounded by a 100-psi ASME-stamped jacket for heating/cooling. clarification system that enables continuous processing.

Ross, Charles & Son Pall Life Sciences www.mixers.com www.pall.com

Dropper Eliminates Need Sensors Allow for for Isolation and Insertion Bluetooth Connectivity The MD-Dropper Cap from HealthStar is a new The ArcAir communication dropper bottle technology for blow-fill-seal (BFS) package from Hamilton technology. The design produces metered-dose Company enables Bluetooth 4.0 eye drops with standard BFS technology, wireless connectivity in all without the added step of isolation/insertion environments. The Bluetooth technology. The containers are molded using capability allows users to view or standard BFS manufacturing machines and control Hamilton Arc Sensors procedures. Cycle times are maintained at from devices including smart normal BFS output levels, typically around 12 phones and tablets. ArcAir apps seconds. The pre-assembled and sterilized are available online for Android containers are snapped onto the BFS containers and iOS platforms. The arc post manufacturing in a cleanroom sensors are measuring tools that environment. The contents of the bottle are contain a built-in microprocessor and provide direct digital and never in contact with the MD-Dropper Cap until analog communication. The ArcAir mobile application for Arc pH, activated by the patient. dissolved oxygen, and conductivity measurement can communicate wirelessly with up to 30 individual sensors at the same time. Hamilton HealthStar also offers a Bluetooth version of its GMP Compliance Package, www.healthstaronline.com which works with ArcAir Advanced and provides centralized management of users and validation reports for calibration, verification, configuration, and communication within the GMP guidelines for all Arc sensors.

Hamilton Company www.hamiltoncompany.com

12 Pharmaceutical Technology JUNE 2016 PharmTech.com Unifying SFE/SFC Workﬂ ows Sample Prep to Analysis in One Click

Nexera UC on-line SFE-SFC is the first system Automatic extraction of up to 48 samples to break the technology barrier between automated with seamless transfer to SFC/MS provides: sample pre-treatment and chromatographic analysis Q Rapid separation harnessing the unique characteristics of using supercritical mobile phase. supercritical mobile phase Q Efficient separation of isomers and enantiomers Learn more about Shimadzu’s Nexera UC. Call (800) 477-1227 or visit us online at Q High-sensitivity detection using a variety of separation modes www.ssi.shimadzu.com/UC Q Split-less introduction to MS for enhanced trace analysis Q Order consumables and accessories on-line at http://store.shimadzu.com Reduced environmental impact and mobile phase cost Shimadzu Scientific Instruments Inc., 7102 Riverwood Dr., Columbia, MD 21046, USA compared to typical organic solvents Jill Wechsler is Pharmaceutical Technology’s Washington editor, tel. 301.656.4634, [email protected].

Modern Manufacturing Comes of Age

FDA and bio/pharma companies get serious about continuous manufacturing to ensure product quality.

he need for more efficient methods to produce break- According to press reports, GlaxoSmithKline is building a CM Tthrough therapies and biosimilars, along with strategies to facility in Singapore, and Eli Lilly is investing in a CM operation manufacture conventional drugs more economically and reli- in Cork, Ireland. Amgen has been shifting to more flexible ably, is sparking industry investment in more sophisticated and production operations for its protein-based drugs for several innovative systems for making drugs and biologics. The shift years, most notably at a $200-million plant in Singapore to personalized or precision medicine and cellular and gene that features modular designs and continuous processing. therapies puts a premium on fast production of small batches Amgen also is working with contract manufacturer Patheon to of cutting-edge medicines. At the same time, pressure to develop additional capacity for innovative production of new reduce manufacturing costs and to avoid shortages and recalls therapies in additional global markets. demands more reliable methods for ensuring the quality of Industry experts are encouraging such moves, as large batches of conventional drugs. seen in a May 2015 report from Deloitte on “Advanced At a Congressional briefing on breakthrough therapies in Biopharmaceutical Manufacturing” (5). The study summarizes April 2016 (1), Janet Woodcock, director of FDA’s Center for how continuous manufacturing, single-use systems, and other Drug Evaluation and Research (CDER), noted that the need technological innovations are transforming drug production, to achieve more streamlined product development for noting that the need to devise more effective drug-delivery breakthroughs and other complex biopharmaceuticals is systems and combination products makes manufacturing prompting a shift away from batch processing to continuous “more central to the effectiveness of medicine.” Pharma manufacturing (CM) systems. Accelerated product companies thus are collaborating more with component development means that manufacturers have less time to manufacturers and technology developers to devise portable refine processes, putting a premium on flexible systems able manufacturing components that can be deployed quickly to to produce small batches quickly and efficiently. More flexibility critical locations. in stability testing also has become accepted for breakthrough products that have small lots sizes and are consumed quickly Policy support and thus have less need for two-year stability profiles upfront. Such industry investment decisions are gratifying to Woodcock and other FDA officials, who have been urging pharma adop- FDA encourages investment tion of modern manufacturing for years, most visibly as part of Regulatory decisions are encouraging industry adoption of the agency’s 2002 Pharmaceutical cGMPs for the 21st Century new manufacturing technologies after years of reluctance. In initiative. A 2004 guidance urged adoption of a process analyt- August 2015, FDA approved for the first time a 3D printed pill, ical technology (PAT) framework for innovative pharmaceutical a form of the epilepsy drug Spirtam (levetiracetam) produced development that builds quality testing into pharmaceutical by Aprecia Pharmaceuticals of New Jersey; it disintegrates manufacturing processes (6). more rapidly in the patient’s mouth to aid those who have dif- Manufacturers, however, were reluctant to invest millions ficulty swallowing (2). of dollars in such systems without assurance that innovation In a landmark decision on a manufacturing change, FDA won’t slow product approval or draw objections from plant authorized a switch from batch production to a continuous inspectors. CDER’s Office of Pharmaceutical Quality (OPQ) manufacturing process at Johnson & Johnson’s Janssen has renewed the quality manufacturing campaign by offering plant in Guarbo, Puerto Rico (3). J&J expects its new CM line early advice on innovative systems and coordinating review for producing the HIV drug Prezista (darunavir) will reduce and inspection to avoid delays. CDER published guidance manufacturing and testing cycle time by 80% and cut waste by in December 2015 outlining how its Emerging Technology a third. Entire batches will not have to be discarded if a problem Team (ETT) will coordinate assessment of new manufacturing appears, and the process requires only two rooms instead of technologies to facilitate approval of such systems and seven. J&J expects to make three-fourths of its high-volume processes (7). products through continuous manufacturing within a decade. So far the ETT has participated in more than 25 Vertex has drawn attention to its CM process for producing meetings with sponsors to discuss manufacturing design its cystic fibrosis drug Orkambi (lumacaftor/vacaftor), approved and development issues and to offer recommendations for by FDA in 2015. The firm announced an agreement with submission content for innovative technologies. The aim, contract manufacturer Hovione to establish a CM plant in New says OPQ director Michael Kopcha, is to identify and address Jersey that will expand production for Vertex and give Hovione “potential roadblocks” and prevent delays related to adopting

the capability of offering similar services to other clients (4). promising new technologies. IMAGES RF/GETTY ZOONAR GLOBE:

14 Pharmaceutical Technology JUNE 2016 PharmTech.com

The Obama administration also is encouraging investment in parts are especially important for producing specialty orphan advanced manufacturing technologies to facilitate efficient and or breakthrough drugs and emergency treatments. Support reliable production of both conventional drugs and innovative for advancing bio/pharma manufacturing methods already is cellular products and regenerative medicines. A report issued in coming from the National Institutes of Health, the Department of April 2016 by the White House National Science and Technology Defense, the National Institute of Standards and Technology, and Council identifies these topics as areas of “emerging priority” the Biomedical Advanced Research and Development Authority that warrant further federal government investment and public- (BARDA) in the Department of Health and Human Services. And private collaboration to move forward (8). Cutting-edge biologics FDA is working with BARDA to support enabling technologies that require process control methods able to overcome technical encourage commercial adoption of continuous manufacturing. challenges in developing new enzymes and proteins that can lead Many of these issues were discussed in April at a to regenerative therapies able to repair or replace non-functioning conference on continuous manufacturing in Baltimore, MD, tissues and organs. And continuous manufacturing, which is sponsored by the International Society for Pharmaceutical widely used in the food, chemical, and petroleum industries, has Engineering (ISPE). Panels addressed whether CM creates the potential to provide multiple benefits for pharmaceutical and unique considerations for process validation, managing biotech manufacturers, including smaller size plants, less raw deviations in real time, and use of sensors and monitoring materials, streamlined storage and testing requirements, reduced systems. Key issues for CM implementation include batch product waste, and shorter manufacturing cycles. definition, materials traceability, and control strategy support The White House panel notes that such systems may be for integrated drug specifications. CM for bioprocessing, particularly important in producing medical countermeasures moreover, involves new approaches for dealing with and treatments for infectious diseases, which often demand deviations, ensuring microbial control, and using inline rapid responses to emerging threats. Modular and plug-and- measurements to confirm proper process performance. play equipment with reusable, flexible, or interchangeable A related challenge is that all these innovations require manufacturers to identify and train specialized workers to have the expertise and experience needed to operate and manage modern production systems.

References 1. J. Wechsler, “Modern Manufacturing Required for Breakthrough Drugs,” PharmTech.com, April 15, 2016, www.pharmtech.com/ modern-manufacturing-required-breakthrough-drugs-0 2. Aprecia Pharmaceuticals, “FDA Approves the First 3D Printed Drug Product,” Press Release, Aug. 3, 2015, www.multivu.com/ players/English/7577251-aprecia-pharmaceuticals-spritam/ 3. L. Yu, “Continuous Manufacturing Has a Strong Impact on Drug Quality,” FDAVoice blog, April 12, 2016, http://blogs.fda.gov/ fdavoice/index.php/2016/04/continuous-manufacturing-has- a-strong-impact-on-drug-quality/?source=govdelivery&utm_ medium=email&utm_source=govdelivery 4. Hovione, “Hovione and Vertex Partner in Continuous Manu- facturing,” Press Release, March 10, 2016, www.hovione.com/ press-room/press-release/hovione-and-vertex-partner-continuous-manufacturing 5. Deloitte, “Advanced Biopharmaceutical Manufacturing: An Evolu- tion Underway,” White Paper, www2.deloitte.com/content/dam/ Deloitte/us/Documents/life-sciences-health-care/us-lshc-advanced-biopharmaceutical-manufacturing-white-paper-051515.pdf 6. FDA, Guidance for Industry PAT—A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality As- surance (CDER, CVM, ORA, September 2004). 7. FDA, Advancement of Emerging Technology Applications to Modern- ize the Pharmaceutical Manufacturing Base, Draft Guidance (CDER, December 2015), www.fda.gov/downloads/Drugs/GuidanceCom- SEE US AT AACC BOOTH #3949 plianceRegulatoryInformation/Guidances/UCM478821.pdf 8. Subcommittee for Advanced Manufacturing, “Advanced Manu- facturing: A Snapshot of Priority Technical Areas Across the Federal Government,” Executive Office of the President, Na- tional Science and Technology Council, April 2016, www.whitehouse.gov/sites/whitehouse.gov/files/images/Blog/NSTC%20 SAM%20technology%20areas%20snapshot.pdf PT

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including the importance of human factor engineering. Development challenges PharmTech: Can you discuss the challenges of developing an autoinjector? Gould and Walker (Owen Mumford): The key challenges encountered in the development of an autoinjector are the com- peting requirements, which include size, cost, and mass. With design freedom in these parameters, one can be confident of achieving any reasonable requirement. But this is seldom the case. At a minimum, size and mass can directly influ- ence usability and therefore combination product efficacy. Building a Better Ensuring user safety is, of course, the primary concern. Being intelligent in how one achieves that level of safety, or indeed, Self-Injection Solution exceeding established safety benchmarks will benefit the end-user and can set one apart from the competition. Q&A by Adeline Siew, PhD Efficacy is, generally, a close second in priority and, dependent upon the treatment, may be inseparable from safety. Ef- ficacy broadly groups accuracy, reliability, and usability. Some of the greatest challenges in autoinjector development come Experts discuss the key considerations from doing more to achieve excellence in in the development of an autoinjector. safety and efficacy (particularly in usability) whilst maintaining a cost-effective product solution. elf-administration is fast becoming “The autoinjector market grows Time to market is always an impor- a trend in today’s healthcare as the because pharmaceutical and biologic tant factor in product-based organiza- Spharmaceutical industry contin- companies are constantly looking to tions. Driven by more stringent regu- ues to tap into the potential of autoin- differentiate their drug-device offer- lation and increased expectations of jectors as a drug-delivery solution that ings and provide intellectual-property pharmaceutical partners, the rigor in can offer improved patient experience (IP) protection against competition,” developmental investigations, in com- and compliance. As a result, the market highlight Oli Gould, design team bination with increasing complexity of for autoinjectors is expanding rapidly, manager, R&D, and Gareth Walker, device solutions, puts a strain on proj- driven primarily by two factors, says human factors specialist, both from ect timescales. Kevin Deane, medical device expert at Owen Mumford. It is crucial that prod- Deane (PA Consulting): The key chal- PA Consulting Group, “the prolifera- uct differentiation goes beyond the lenges in developing an autoinjec- tion of biologic compounds, which are molecule, especially when facing the tor are cost of goods, drug viscosity, filling pharma’s pipelines, and the need patent cliff. According to Gould and and freedom within a crowded IP to move drug administration away Walker, custom-developed autoinjec- landscape. from clinics and hospitals into home tors can provide opportunities for pat- The requirement to minimize the use and self-administration.” Deane ented product differentiation, thereby, cost of goods drives the designer to notes that Humira (adalimumab) and helping companies to maintain their minimize the number of parts in Enbrel (etanercept), which are among margins and market share. the device. This is most effectively the top five best-selling drugs, are In this article, Deane, Gould, and achieved by placing multiple functions self-administered by patients using Walker discuss the different aspects on each part, but this adds to the com-

autoinjectors. involved in developing an autoinjector, plexity and increases the importance JARED EYGABROAD/GETTY IMAGES

18 Pharmaceutical Technology JUNE 2016 PharmTech.com The Parenteral Drug Association presents... 2016 PDA Universe of Pre-fi lled Syringes & Injection Devices October 17-18, 2016 | Huntington Beach, CA Hyatt Regency Huntington Beach Resort and Spa Exhibition: October 17-18 | 2016 PDA Drug Delivery Combination Products Workshop: October 19 | Courses: October 20-21

Register before August 5 and save Exploring the latest trends in devices, up to $600! connectivity, safety and compliance

The 2016 PDA Universe of Pre-fi lled Syringes & Injection Devices brings together industry and regulatory experts to tackle the most pressing issues and latest advancements in pre-fi lled syringes.

During the course of this Conference, you will learn how to identify, address and explain key challenges in the development, approval and manufacture of drug delivery combination products to peers and management, recognize potential liabilities and opportunities within your organization with regard to pre-fi lled syringes and more! For more information and to register, visit pda.org/2016prefi lled.

Immediately following this event, PDA will host the 2016 PDA Drug Delivery Combination Products Workshop. Pharmaceutical and medical device professionals will share the challenges they have faced or are currently facing through sessions on topics such as:

Human Factors/Risk Management Design Verifi cation Testing, Critical Clinical Studies/Level of Design Future Solutions to the Patient Quality Attributes, Release & Controls Phase I, II & III Experience/Challenges with Drug Stability Testing GMPs, Inspections & Change Delivery Devices Design/Technology Transfer Management Learn more and register at pda.org/2016combo.

And, on October 20-21, PDA’s Education Department will hold two courses complementing what you have learned:

Understanding and Addressing Technical, Quality, and Regulatory Challenges for Drug Delivery Combination Products (October 20) Essential Elements of Extractables and Leachables: From Material Extraction to Final Report (October 21) Learn more and register at pda.org/2016Prefi lledCourses. #2016prefi lled Cover Story: Autoinjectors of design for manufacture and assem- the user is exposed to inconsistent in- ment within the container (from fric- bly activities. jection depths and variable injection tion), strength of the container, resis- Drug viscosity can prove a challenge times. Moreover, there is a risk of dam- tance of the needle shield to removal, both at high and low viscosities. At aging the syringe, presenting a safety and general geometry (including rela- high viscosity, a high power source is risk to the user. The designer can solve tive position of the stopper in particu- required to ensure the injection time is some of these problems with complex lar) are key parameter considerations acceptably short for the user. Retaining mechanisms (e.g., electromechanical when integrating prefilled syringes such high loads throughout the shelf life closed-loop feedback systems), but to and containers into an autoinjector. of the device and ensuring the device effectively integrate the syringe re- However, what may be an even more still functions, are challenging and requires extensive testing and character- important consideration than the quire extensive modeling and acceler- ization. The characterization is compli- nominal state of these parameters is ated aging to simulate high stress and cated by the lack of access to multiple their natural manufacturing varia- long life. At low viscosity, the challenge syringe manufacturing batches (both tions. For example, many autoinjectors is lengthening the injection time to unfilled and filled) and the difficulty make use of a compression or torsion avoid pain, but at the same time, avoid- of capturing the force to expel the drug. spring to evacuate the container and ing device stall as friction loads domi- Access to multiple batches can be im- thus, the force exerted decreases as the nate the injection. Both of these aspects possible if the drug is in development, fluid is evacuated. Conversely, a stop- can be partially solved by modification and filling is not representative of the per within a poorly lubricated con- of the needle size, but this change is not production fill. Even in later stages, get- tainer may increase its resistance as it available to the designer. ting hold of multiple batches to assess reaches the end of evacuation. The de- The IP landscape for autoinjectors is process variability is difficult due to the sign of the autoinjector must allow for crowded, particularly in the space of- mismatch in syringe and autoinjector this change, and any variation, within fering the simplest and most reliable production volumes. This issue necessi- its design. device architecture. A sleeve actuated tates that characterization activities con- The strength of a container is often autoinjector, which is becoming the tinue throughout the development. a key consideration also. We’re seeing standard embodiment, is not a com- Capturing the force to expel the a trend in increasing formulation vis- plex device. The function can be ful- drug is challenging as the typical cosities as drug technologies change filled with a small number of parts, autoinjector power source, a spring, and the frequency of injection reduces. and thus, there are a limited number generates a decaying force during the These more viscous fluids require of mechanisms that will provide the delivery of the dose. Some theoretical greater delivery loads and more stress functionality. As a result, there are lim- modeling is possible, but limited in its on the container as a result. Well-en- ited opportunities to innovate without validity. Empirical testing presents its gineered support for the container and infringing existing IP. To overcome own challenge as standard test equip- control over impact velocities are nec- this design constraint and avoid the ment does not exist. Dynamic force essary to maintain container integrity. need to license, the designer is driven testers are available but have limited to move to less elegant design solutions, functionality. Thus, typically a com- Regulatory guidelines typically introducing additional parts bination of constant force, constant PharmTech: Human factors are a key or suboptimal mechanisms, with a velocity, and device power pack testing consideration when developing a drug knock-on impact on molding and as- is used to measure the force to expel delivery device, such as an autoinjec- sembly complexity as well as the inevi- the drug. tor. What guidelines have regulators table impact on cost of goods. Cartridges require the same force such as FDA and EMA provided on characterization, but the geometry this aspect? Prefilled syringes and cartridges specification is much tighter. The ad- Gould and Walker (Owen Mumford): The PharmTech: How can prefilled syringes ditional challenge of the cartridge is development of medical devices is and cartridges be effectively integrated designing the interface with the needle. governed by a number of regulations into an autoinjector? In its simplest form, this design can be that can sometimes be baffling in their Deane (PA Consulting): The prefilled user applied (which has associated us- complexity. Even within the realms of syringe was never designed to be ability challenges and user safety risks). regulations relating to human factors, mounted within an automated deliv- In the more complex form, the device ease of comprehension is sometimes ery device such as an autoinjector. As must automatically couple the needle overlooked. To address this aspect a result, the geometry and emptying to the cartridge, piercing the septum and help manufacturers understand force are poorly defined and controlled. as part of the injection process. the regulatory requirements, a num- Unlike a person, an autoinjector can- Gould and Walker (Owen Mumford): The ber of guidance documents have been not adapt to this variability and thus, resistance from the stopper to move- created. Most recently, in April 2016,

20 Pharmaceutical Technology JUNE 2016 PharmTech.com The Parenteral Drug Association presents... ARLINGTON, VA – 2016 PDA Workshop: Current Challenges in Aseptic Processing, Potential Changes in EMA/PIC/S Annex 1 Revision Addressing the Unanswered Questions of How to Use Risk- and Science-Based Approaches to Meet Global Health Authority Expectations and Improve Aseptic Processing October 26-27, 2016 | Arlington, VA Hyatt Regency Crystal City Exhibition: October 26-27 #2016annex Register before September 9 and save up to $200

Workshop Theme: Points to Consider in Modern Aseptic Manufacturing – with Special Reference to the On-going Revision of the European GMPs for Sterile Medicines

The 2016 PDA Workshop: Current Challenges in Aseptic Processing, Potential Changes in EMA/PIC/S Annex 1 Revision will serve as a forum for industry and regulatory professionals to discuss science- and risk-based approaches that support modern aseptic processing and control strategies, and explore critical topics that may be addressed in the revised EU GMP Annex 1 guidance.

This interactive Workshop is a unique opportunity to engage with peers, industry leaders and experts on a wide range of topics, including: 6 Physical Environment and 6 Personnel and Material 6 Cleaning, Disinfecting, 6 Aseptic Processing Environmental Monitoring Transfer Sterilization and Critical Moving Forward 6 Process Simulation Utilities Make sure you are a part of this important conversation that will shape the future of aseptic processing.

For more information and to register today, please visit pda.org/2016annex1east

To off er you the most fl exibility, this interactive Workshop will be presented multiple times in diff erent locations in 2016. To learn more, please visit pda.org/2016annex Cover Story: Autoinjectors

FDA published guidance on Applying capability might affect their interaction FDA has provided guidance on Human Factors and Usability Engineer- with an autoinjector; what the context of which aspects of an autoinjector should ing to Medical Devices. This guidance use would be and how that might affect be tested, including: in particular aims to provide clarity on the interaction with the device; and what t The ability of users to the activities that should be undertaken training would be expected. read and understand the during the development of medical de- For example, an autoinjector for autoinjector instructions vices, and how to adapt human factors rheumatoid arthritis may have two t The ability to set up to deal with the different challenges distinct user groups: healthcare pro- the autoinjectors created by the various applications of fessionals and lay users. The design of t The ability to perform drug-delivery devices. Such guidance the device would need to consider their an injection allows manufacturers to understand physical impairment (reduced hand t The ability to dispose the scope of activities expected by reg- strength and mobility) and the size of the injector. ulators, and what types of techniques of device (larger proportion of female should be adopted. The guidance has patients, generally adults). Because Verification and validation removed some of the uncertainty that people with rheumatoid arthritis are PharmTech: How do you verify and vali- previously existed about what bod- generally older adults, consideration date your autoinjector? What tests do ies, such as FDA, would want to see in would also be needed for age-related you have to carry out? terms of human factors evidence. decline in visual acuity and hearing. Deane (PA Consulting): Verification of FDA has also highlighted the im- The next stage is to incorporate performance against functional speci- portance of human factors data for human factors into risk management fications is a critical part of the regula- drug-delivery devices by putting auto- to identify foreseeable misuse scenar- tory approval process for autoinjectors. injectors on their list of highest prior- ios and to identify which use steps are Verification planning begins early, in ity devices for human factors review. related to patient safety and the ability parallel with the development of func- This means any autoinjector going to deliver medication effectively. These tional specifications, and continues forward for FDA approval through so-called critical tasks help inform throughout the design process. De- the premarket submission route must what usability testing should be done. velopment test data are used to under- provide FDA with a report summariz- During the design and development stand key risk areas for the design and ing the human factors processes they phase, formative usability testing helps highlight potential measurement chal- have followed, including any analyses inform and iterate the design as well lenges. A design verification matrix es- and evaluation activities, along with as identifying unforeseeable misuse tablishes full traceability between func- the human factors validation testing scenarios that would need to be tested tional specifications and the planned performed, the results obtained, and during the final simulated use human set of verification tests, defining the the conclusions drawn. factors validation study (previously scope of the verification test program. European regulatory bodies have known as a summative study). Wherever possible, test methods are approached the matter with a lighter Formative testing during the design based on automated measurement pro- touch, leaving more to the manufac- phase is generally with small groups cesses to effectively remove the opera- turer’s discretion. However, regardless (5–8 participants) and may be aimed tor contribution to gauge variability. A of which regulatory body you are en- to look at one aspect of the design, wide range of measurements, generally gaging with, there is clear and strong an early sketch model, or high fidel- including delivered dose, needle depth, emphasis placed on ensuring safe and ity prototype. These experiments are needle protection override force, and effective use through the application of not preference studies but are aimed audible dose indicator performance, human factors to all medical devices. to uncover key usability and safety are all integrated into a single mea- issues related to the design. Human surement sequence, streamlining the Human factor engineering factor validation studies need to be method validation and test processes. PharmTech: Can you discuss human run like a repeatable scientific study, Acceptance criteria are derived in ac- factor engineering and how it can be although they are generally not clini- cordance with ISO 11608, combining ac- integrated in the development of an cal studies. FDA recommends using a curacy (process mean and specification autoinjector? minimum of 15 participants per dis- limits) and precision (process standard Deane (PA Consulting): Human factors tinct user group. The tasks carried out deviation) into a single, target tolerance- work is most efficient and productive in the human factors validation study limit factor that defines a minimum when planned from the start as part of an should be linked to the tasks identified required pass rate at a given confidence iterative development program. Initial in the human factors risk assessment level. Analysis methodologies are fully research should be carried out to under- and be comprehensive in scope to rep- defined before commencement of testing stand the intended users and how their resent generalized use. and are focused on assessment against

22 Pharmaceutical Technology JUNE 2016 PharmTech.com the predefined acceptance criteria. Sub- This risk identification can be achieved t The volume delivered, tleties include taking into account the though theoretical analysis but, more measured with mass and underlying distribution of the measure- frequently, physical testing is employed converted using density ment data; for example, injection times to confirm alignment of output perfor- t Correct operation of for mechanical autoinjectors generally mance with input requirements. safety features (frequently, follow a log-normal distribution. It is important that risk identifica- needle shielding) Design validation uses inputs from tion and assessment methods are un- t Force to operate the device. regulatory guidance, risk analysis, dertaken to identify areas of investiga- These tests will be undertaken fol- formative user studies, client require- tion during development of the device. lowing a range of pre-conditioning ments, and verification results to de- Significant effort should be employed operations, which may include: sign a user study with a representa- to understand the effect of environ- t Free-fall from 1 meter tive end-user population. This design ment, time, and manufacturing on onto a steel plate validation study comprehensively ad- the expected device performance so t Very high temperature dresses the high-level product require- as to design-out any concerns at an exposure for a short period ments identified with user needs and early stage. t Very cold temperature intended product uses, in addition to Several international standards exposure for a short period foreseeable misuse scenarios. (notably ISO 11608, parts 1 and 5) t Cyclical operation (a Gould and Walker (Owen Mumford): De- describe test methods designed to lifetime’s operation) sign verification is confirmation that tackle the majority of autoinjector t Accelerated aging design input requirements have been functions. A typical range of tests un- t Transportation simulation. met. Thus, the types and means of dertaken includes: The tests are also undertaken under verifying a design input are developed t The time taken to deliver a range of operational conditions: from the identified risks of the device the required dose using a t High ambient temperature failing to meet those requirements. timing device and/or video t Low ambient temperature. PT

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Pharmaceutical Technology JUNE 2016 23 Formulation

difficult to develop good in vitro-in vivo correlations for controlled-release matrix systems due to variations in GI conditions. Benecel K250 PH PRM HPMC, K750 PH PRM HPMC, and K1500 PH PRM HPMC (Ash- land) grades were developed to ob- viate the need for blending (see Figure 1) and offer a potential solution to the problem of dissolution variability. These custom Benecel HPMC grades are of intermediate viscosity and have tight, unimodal MW distribution. In this study, the dissolution performance and robustness of matrix tablets developed with these custom Benecel HPMC grades under varying hydrodynamic stress conditions and in dissolution media of varying ionic strengths were investigated. Formulations containing blends of Benecel K4M and K100LV PHARM HPMC to achieve analogous viscosities were used as comparators (see Table II). Glipizide (GLIP; aqueous solubility ~ 37 mg/L) and carbamazepine (CBZ; aqueous The authors evaluated the performance and solubility ~ 17.7 mg/L) were chosen as robustness of controlled-release tablets made model low-solubility drugs. with HPMC blends of unimodal and bimodal Methods Wet granulation. One kg batches com- molecular weight distribution. prising polymer (30%; blends of Benecel K4M and K100LV PHARM ypromellose (HPMC) is a con- of the historically limited number of HPMC or the equivalent custom vis- trolled-release polymer that commercially available MW grades, cosity grade), drug (25% for GLIP and Hhas found widespread adoption formulators would blend various MW 67% for CBZ), and quantity sufficient in controlled-release dosage forms. grades to tailor release profiles to microcrystalline cellulose were wet Generally, higher molecular weight meet specific therapeutic objectives granulated in a high shear mixer. The (MW) grades are preferred for highly and to accommodate the wide spec- granules were dried, milled, and lubri- soluble drugs, where drug release trum of drug solubilities encountered cated with 0.5% magnesium stearate. is predominantly controlled through in daily practice. Among the issues Matrix tablets (400 mg for GLIP and diffusion through a swollen gel layer. that arise when blending is used to 600 mg for CBZ) were compressed on Lower MW grades are preferred for achieve intermediate MW and release a Manesty Beta Press equipped with an low-solubility drugs where matrix behaviors are the potential increase AIM-Metropolitan Computing Corpo- erosion is required for effective release in release profile variability, reduced ration data acquisition system. of the drug (see Table I). As a result predictability, and lack of robustness. Blend ratios were calculated accord- Dissolution variability due to blending ing to the following formula: is exacerbated in the presence of varia- Divya Tewari is technical director, 1/8 = 1/8 + 1/8 tions in gastrointestinal (GI) tract hy- 1 1 2 2 Global Pharmaceutical R&D; and Thomas Durig is senior director, Global drodynamic conditions and GI fluid Pharmaceutical and Nutrition R&D, both compositional factors such as fat, bile Where, η = viscosity of the polymer

at Ashland, Wilmington, Delaware, US. salt content, and ionic strength. It is and c = weight fraction of the polymer. ALEXSL/GETTY IMAGES

24 Pharmaceutical Technology JUNE 2016 PharmTech.com Drug-release profiles. Dissolution was Table I: Commercially used grades of Benecel hypromellose (HPMC). tested at 37 °C with 7.5 pH phosphate Nominal buffer with 0.1% polysorbate 80 for Molecular weight Dominant release Benecel HPMC Grade viscosity GLIP and 1% sodium lauryl sulfate (kDa) mechanism (2%, mPa.s) in distilled water for CBZ. The hydrodynamic effects were simulated by K100M Pharm HPMC 100,000 1150 Swelling/ running the dissolution with a United diffusion States Pharmacopeia (USP) Apparatus K15M Pharm HPMC 18,000 750 Swelling/ I at 100 and 150 revolutions per minute diffusion (rpm) or with USP Apparatus III (Bio K4M Pharm HPMC 4000 500 Swelling/ Dis, Varian Inc.) at 5 and 25 dips per diffusion/erosion minute (dpm). The effect of fluid com- K100LV Pharm HPMC 100 120 Erosion position was determined by running the dissolution in media of varying Figure 1: Glipizide drug release profiles with different Benecel HPMC grades. pH (2 hr in 0.1 N HCl and then in cor- responding buffer) and ionic strength Benecel K250 HPMC (adjusted with NaCl). 100 Benecel K750 HPMC Erosion profiles. Tablet erosion and Benecel K1500 HPMC uptake of the dissolution medium were Benecel K4M HMPC determined gravimetrically under the 80 Benecel K15M HPMC same dissolution conditions as used for d Benecel K100M HPMC

dissolution testing. Three tablets were

ease Benecel K100LV HPMC used per time point. At predetermined l 60 re

times, the tablets were removed and e d i

patted to remove excess surface water. z 40 ipi

After determining the wet weight, the l

tablets were dried at 70 °C for 10 days, G % before reweighing to determine the dry 20 weight (1). Water uptake and mass loss were determined gravimetrically according 0 to Equation 1: 0 246810 12 14 16 18 20 22 24 Time (Hr)

Dissolution medium uptake (%) = 100 (Wet weight – remaining dry weight) Remainin g dr y wei ght Remaining mass (%) = 100 (remaining dry weight) an aluminum probe with a diameter and standard deviations at individual Original dry weight of 6.4 mm. The compression stress time points of up to 15% (see Figure 2). [Eq. 1] (resistance of the gel layer) applied to Table II details substitution and viscosi- the tablet was plotted against the true ties of the lots that were compared in Cloud point. The cloud point value compression strain (the degree of gel the study. was determined using a FP900 cloud layer deformation). For hydrophilic matrix polymers, point analyzer (Mettler Toledo) at 1.0% erosion rate is known to vary with MW concentration in differing dissolution Results and discussion in a nonlinear inverse manner (Equa- media, plotting the light transmission Effect on dissolution profiles. Release pro- tion 2):

through the polymer solution as a files for repeat lots of Benecel K750 -a Erosion rate = KM function of the temperature. HPMC were superimposable with n Rheology (gel strength). The GLIP tab- a t50% of 12 hr and standard devia- [Eq. 2] lets were placed in pH 7.5 phosphate tions at individual time points of less buffer with 0.1% polysorbate 80 for 2 than 5%. It can be seen that tablets where K is a constant that is polymer-, hr at 37 °C. The deformation of the gel made of equivalent viscosity blends solvent-, and temperature-dependent,

layer on the tablet was analyzed using of Benecel K4M HPMC and K100 LV M n is number average molecular a rheometer (Model # AR-G2, TA In- HPMC had slower and more vari- weight, and a is calculated from the

ALL FIGURES ARE COURTESY OF THE AUTHORS. ALL FIGURES ARE COURTESY struments) in compression mode and able drug release with t50% of 15–18 hr slope of the erosion curve. In addition,

Pharmaceutical Technology JUNE 2016 25 Formulation

netics are obtained for bimodal blends Table II: Substitution and viscosity data for custom Benecel K750 and where the higher MW fraction (Bene- analogous blends used in the study. cel K4M HPMC) dominates. This ob- Lots Viscosity Methoxyl, % Hydroxypropyl, % servation was seen for 750 cps and 1500 cps blends in comparison with custom K750 lot 1 680 22.1 8.1 made K750 and K1500. In contrast, for K750 lot 2 650 22.7 8.1 blends where the lower MW fraction K750 lot 3 790 23.4 8.5 (Benecel K100LV HPMC) dominates, 750 cps blend 1 K4M: 3756 K4M: 21.5 K4M: 8.6 comparatively faster release kinetics K100LV: 86 K100LV: 22.2 K100LV: 9.3 are obtained, as observed for the 250 750 cps blend 2 K4M: 3816 K4M: 21.6 K4M:8.6 cps blend in comparison with custom K100LV: 101 K100LV: 22.3 K100LV: 9.8 made K250 (data not shown). 750 cps blend 3 K4M: 3776 K4M: 21.6 K4M:8.5 Carbamazepine tablets made K100LV: 83 K100LV: 21.9 K100LV: 8.9 with repeat lots of custom Benecel K750 HPMC also exhibited consistent release profiles with a t of 7 Table III: Maximum standard deviation under various testing conditions at 50% the 8-hour time point. HPMC is hypromellose, rpm is revolutions per minute, hr and standard deviations at indi- dpm is dips per minute. vidual time points of less than 5% (see Figure 3). However, it can be seen that Benecel tablets made of equivalent viscosity Drug HPMC Grade 100 rpm 150 rpm 25 dpm 5 dpm or Equivalent blends of Benecel K4M HPMC and Benecel K100LV HPMC had much Carbamazepine K750 HPMC 2.6 0.2 5.2 2.1 more variable drug release with t50% of K4M/K100LV 8–12 hr and standard deviations at in- HPMC Blend 5.4 4.3 9.1 1.95 dividual time points of up to 7%. Glipizide K750 HPMC 4.6 5.3 0.3 3.12 Effect of hydrodynamic stress conditions. K4M/K100LV HPMC Blend 6.6 12.6 24.7 24.21 Table III shows the impact of increasing hydrodynamic stress on the variability of glipizide and carbamazepine tablets Figure 2: Drug-release profiles of glipizide tablets made with Benecel K750 HPMC and made with Benecel K750 HPMC and Benecel K4M/K100LV HPMC blend. HPMC is hypromellose. the equivalent 750 cps viscosity Bene- cel K4M/K100LV HPMC blend, at the

100 8-hr time point. Increasing the basket stirring rate from 100 to 150 rpm in 90 the USP Apparatus I had only a mar- 80 ginal effect on Benecel K750 HPMC. d 70 However, variability increased greatly ease l 60 for formulations containing the blend re

e 50

d of HPMC grades with standard devia- i z 40 tion of individual time points exceed- ipi l G 30 ing 15%. Extreme variability, including % controlled-release failure, was seen 20 Benecel K4M/K 100LV HPMC Blend when formulations containing a blend 10 Benecel K750 HPMC of Benecel K4M/K100LV HPMC were 0 0 5 10 15 20 25 subjected to testing in USP apparatus Time (Hr) III (reciprocating cylinder) at 5 and 25 dpm. By contrast, the custom Benecel K750 HPMC with tight, unimodal the opposite relationship applies to role in matrix erosion and swelling. In distribution showed extremely robust matrix swelling (i.e., polymer solubil- the case of the bimodally distributed dissolution behavior with a small in- ity increases with MW up to a limiting HPMC blends, variability is greater crease in rate when agitation was in- MW threshold) (2). However, Figure 2 than that of unimodally distributed creased from 5 to 25 dpm. These re- shows that in addition to average MW, custom grades, irrespective of the vis- sults may be of particular significance the MW distribution also plays a key cosity. Furthermore, slower release ki- when considering the in vivo behavior

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Figure 3: Drug-release profiles of carbamazepine tablets made with Benecel K750 of HPMC matrix tablets dosed under HPMC and Benecel K4M/K100LV HPMC blend. HPMC is hypromellose. fed and fasted conditions, when significant mechanical attrition and hydrodynamic stress is expected in fed 100 conditions (3). Effect of pH and ionic strength. When d

e 80 subjected to pH change from acidic

as simulated gastric fluid (SGF) to pH 7.5

ele simulated intestinal fluid (SIF), no sig- r

e 60 nificant differences were seen between in formulations made with Benecel K750 ep 40 HPMC or the equivalent viscosity K4M/K100LV HPMC blend. However, amaz

b when subjected to increasing levels of 20 Car Benecel K750 HPMC ionic strength, the tablets made with % Benecel K4M/K100LV HPMC Blend Benecel K750 HPMC and glipizide 0 and with carbamazepine continued to 0 2 4 6 8 1012141618202224 release drug in a robust and predict- Time (hours) able manner, while tablets made with the equivalent viscosity Benecel K4M/ K100LV HPMC blend resulted in increased variability and showed evi- Figure 4: Cloud point effects of the polymer solutions at different ionic strengths. dence of polymer salting out and dose HPMC is hypromellose. dumping. 100 Benecel K750 HPMC, lonic Strength = 0.075 These differences in release profile Benecel K750 HPMC, lonic Strength = 0.090 90 Benecel K750 HPMC, lonic Strength = 0.150 for unimodal custom Benecel K750 80 Benecel K4M/K100LV HPMC 750 Blend, lonic Strength = 0.150 HPMC and the equivalent viscos- Benecel K4M/K100LV HPMC 750 Blend, lonic Strength = 0.090 70 Benecel K4M/K100LV HPMC 750 Blend, lonic Strength = 0.150 ity K4M/K100LV HPMC blend were

e (%) 60 further studied by examining cloud anc 50 tt points (see Figure 4) of the respective 40 polymer solutions at different ionic

ransmi 30

T strengths and by measuring the gel 20 strengths (see Figure 5) of hydrated 10 matrix tablets. The bimodal K4M/ 0 K100LV HPMC blend showed greater 40 45 50 55 60 65 70 75 80 85 90 susceptibility to cloud point depres- Temperature (°C) sion in the presence of media of different ionic strengths as opposed to the unimodal Benecel K750 HPMC. Figure 5: Gel strengths of hydrated matrix tablets made with Benecel K750 HPMC and Additionally, gel strength was found to Benecel K4M/K100LV HPMC blend. HPMC is hypromellose. be significantly higher for the custom Benecel K750 HPMC. 3000 Benecel K750 HPMC While the cloud point effects in

2500 Figure 4 appear modest, these effects

a Benecel K4M/K100LV HPMC 750

, P Blend need to be understood in the context

ss 2000 e r

t of the dilute polymer solvent system, s

ve 1500 which is far removed from the physical ssi e

r reality of hydrating gel matrices where p 1000 free water is limited. Mechanistically, Com 500 hydrating gel matrix tablets can be understood as a solvent-lean environ- 0 -0.05 -0.04 -0.03 -0.02 -0.01 0.00 ment, in which HPMC is only margin- True compression strain ally soluble. For such systems, the net free energy of solution increases as

28 Pharmaceutical Technology JUNE 2016 PharmTech.com molecular weight increases. This mo- bimodal blends. Matrix tablets com- Bimodally distributed blends result in lecular weight dependent solubility of prising equivalent viscosity HPMC greater variability and, in some cases, HPMC under marginal solvent con- blends showed significantly higher failure to control release as compared ditions would be further exacerbated variability and the release profiles with HPMC grades with unimodal with an increase in ionic strength. It MW distribution. is, therefore, expected that the HPMC blends, having a larger component of Bimodally References higher MW HPMC and displaying ear- 1. T. Dürig, R. Fassihi, J. Controlled Release lier onset of clouding, as seen in Figure distributed blends 80 (1–3) 45–56 (2002). 4, will show dramatically different gel result in greater 2. J.E. Brady, T. Dürig, and S.S. Shang, properties. “Polymer Properties and Characteriza- In essence, salting out of the higher variability. tion,” in Developing Solid Oral Dosage MW polymer species results in in- Forms: Pharmaceutical Theory and Prac- soluble gel domains, leading to dis- tice, Y.H. Qiu, Y.S. Chen, G.G.Z. Zhang, ruption in gel network integrity and were dependent on the MW of the L.R. Liu, and W.R. Porter, (Eds.) Elsevier, faster, highly variable erosion, which higher percentage component of the New York, pp 187–217 (2009). is also reflected in lower gel strength blend. In addition, custom Benecel 3. B.R. Rohrs, J.W. Skoung, and G.W. Hal- (see Figure 5). HPMC grades were more robust in stead, “Dissolution assay development the simulated gastrointestinal envi- for in vitro-in vivo correlations: theory Conclusion ronment in comparison with blends of and case studies,” in Advances in Experi- The custom Benecel (K250, K750, similar viscosities. For erosion depen- mental Medicine and Biology: In Vitro-in and K1500) HPMC grades have fun- dent dosage forms, both average MW Vivo Correlations, Vol. 423, D. Young, J. damentally different behaviors when and the MW distribution are impor- Devane, and J. Butler (Eds.) Springer, compared with equivalent viscosity tant for matrix erosion and swelling. New York, pp. 17–30 (1997(. PT

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Pharmaceutical Technology JUNE 2016 29 API Synthesis & Manufacturing the selective nitration of 1-methyl-4- (methylsulfonyl)benzene in 98% yield using 80 weight percent (wt%) sulfuric acid (3). The short residence time of 5 s led to a significant reduction in byproduct formation. Notably, the spent acid could be reused multiple times after concentration under a vacuum. Swedish researchers established a protocol for the transcarbamylation/ transesterification of sulfonylcarba- mates with alcohols via microwave heating under continuous-flow conditions (4). Using transparent boro- silicate tube reactors, the scientists Steps Closer to the Adoption prepared two series of O-alkylsul- fonylcarbamates. They also applied the methodology to the synthesis of three of Continuous Processing angiotensin II type 2 receptor ligands. Scientists at the University of Graz Cynthia A. Challener (Austria) and Noramco report the continuous flow production of hydroco- done from thebaine via selective olefin Application of flow chemistry for reduction to form 8,14-dihydrotheba- ine followed by hydrolysis (5). Selective small-molecule API synthesis continues transfer hydrogenation using hydra- zine hydrate (N H t) O) and O is not to expand thanks to research efforts. 2 4 2 2 possible under batch conditions due to the high explosion potential of the ontinuous flow manufacturing for there are significant rewards. FDA en- reaction mixture. The reported contin- small-molecule drug synthesis re- courages others in the pharmaceutical uous high-temperature/high-pressure Cceived a vote of confidence in April industry to consider similar efforts.” method is efficient, safe, and scalable. 2016 when FDA approved a change Pharmaceutical companies are cer- The process involves four consecutive from batch to continuous processing tainly interested as well, as indicated by feeds of liquid N2H4t)2O with separate for Janssen Products’ Prezista (daruna- the numerous reports of API synthetic residence times for completion of the vir), a drug for the treatment of HIV-1 methods designed to be operated under reaction in 1 h. infection. This decision is the first such continuous flow conditions. A sum- Researchers from The Netherlands approval for a change from batch to con- mary of selected processes is presented developed an intensified, solvent-free tinuous manufacturing, and the second in the following. continuous process for the conversion for a continuous process; Vertex received of alcohols to chlorides using hydrogen approval in July 2015 for the continuous Continuous-flow experiments chloride gas (6). A separate dry zone production of its cystic fibrosis drug Researchers in China report a continu- was used to deliver the hydrogen chlo- Orkambi (lumacaftor/ivacaftor). ous-flow process for the preparation of ride gas and prevent corrosion. Less In a blog posted on April 12, 2016, m-nitrothioanisole via diazotization of than half the equivalents of HCl are Lawrence Yu, FDA’s deputy director of m-nitroaniline to afford a diazonium needed due to the use of the gas instead the Office of Pharmaceutical Quality chloride intermediate, which is then of hydrochloric acid, and only water is in the Center for Drug Evaluation and subjected to azo coupling with sodium generated as a byproduct. The reaction Research, expounded on the benefits of thiomethoxide to give 1-(methylthio)- is typically complete within 20 min. continuous manufacturing: greater re- 2-(3-nitrophenyl)diazene, followed by Scientists from Eli Lilly and Com- liability, safety, efficiency, responsive- dediazonization to provide m-nitro- pany and Vanderbilt University re- ness/flexibility, and reduced costs (1). thioanisole in high yield (2). A flow ported the conversion of a batch-based He stated, “Although it is not easy for process was developed to minimize stereoselective aza-Henry reaction be- drug manufacturers to transition from accumulation of the energetic inter- tween an arylnitromethane and Boc- batch to continuous manufacturing, mediate diazonium salt and enable protected aryl aldimine using a homo- large-scale production. geneous Brønsted acid-base catalyst to Cynthia A. Challener is a contributing The same scientists also devel- an automated intermittent-flow pro-

editor to Pharmaceutical Technology. oped a continuous flow process for cess with product crystallization and IMAGES ANSONSAW/E+/GETTY

30 Pharmaceutical Technology JUNE 2016 PharmTech.com API Synthesis & Manufacturing slow reagent addition (7). The organo- odology was developed that allows Meanwhile, scientists at Bayer Tech- catalytic enantioselective reaction in- separation of the Buchwald–Hartwig nology Services report the running of cluded recycle of the catalyst, resulting product into the aqueous stream as a continuous process for the lithiation in increased process intensity main- a salt while retaining the aryl bro- of fluoroaromatics in a microreactor taining a high catalyst concentration mide starting material in the organic demonstration unit (12). A higher tem- in the reactor. The researchers per- stream with the catalyst. perature was possible in this case, too, formed a continuous campaign with The flow reaction was performed in leading to higher space–time yields the automated system and obtained a microreactor at the gram scale using compared to those observed for the high throughput and high selectivity continuous workup conditions involv- batch reaction. Temperature control while minimizing catalyst usage. ing acidic extraction of the product was found to be critical, though; optimization was necessary to identify the “Although it is not easy for most appropriate reaction conditions, hardware, and reactant purification drug manufacturers to transition from methods to achieve minimal salt precip- itation and prevent runaway conditions. batch to continuous manufacturing, Investigation of continuous processing has not been limited to chemical there are significant rewards.” syntheses. There has also been significant interest in developing continuous —Lawrence Yu, FDA biocatalytic reactions, which are more complex and challenging to implement. Researchers from Eli Lilly have also and on-stream recycling of the catalyst German researchers reported the inte- achieved a continuous Grignard reac- in the organic phase (10). The custom- gration of microfluidic reactor tech- tion using a continuous stirred tank designed rector for running heteroge- nology with solid–liquid biocatalytic reactor (CSTR) (8). The process was neous reactions in flow combines the reactions (13). As a case study, they developed after mapping the operation flexibility of CSTRs with the smooth reported the biocatalytic conversion space using knowledge about CSTR operation, low residence time distri- of styrene to (S)-styrene oxide using process parameters, the reaction ki- bution and excellent heat transfer ca- catalytic biofilms in a microreactor. netics, magnesium (Mg) sequestration pability of a conventional flow reactor, efficiency, equipment characterization, according to the researchers. References and the impact of process disturbances 1. Lawrence Yu, FDA Voice, April 12, 2016 on steady-state conditions. A reaction Low-temperature batch http://blogs.fda.gov/fdavoice/index. php/2016/04/continuous-manufacturing- kinetics model was also developed, and to continuous processes has-a-strong-impact-on-drug-quality. computational fluid dynamics (CFD) The conversion of low-temperature 2. Z. Yu, et al., Org. Process Res. Dev., Article models were applied to the equipment batch reactions to continuous pro- ASAP, Web publication, March 24, 2016. design. This approach enabled the de- cesses is attractive because in many 3. Z. Yu, et al., Org. Process Res. Dev. 20 (2), velopment of a highly robust and safe cases higher temperatures can be used 199–203 (2016). 4. I.Kumpina, et al., Org. Process Res. Dev. commercial-scale process. to achieve equal or better results. For 20 (2), 440–445 (2016). Researchers at AztraZeneca, in example, scientists from Eisai report 5. B. Pieber, D.P. Cox, and C.O. Kappe, Org. combination with various European the continuous production of eribulin Process Res. Dev. 20 (2), 376–385 (2016). university groups, have focused on the mesylate via the diisobutylaluminum 6. S. Borukhova, T. Noël, and V. Hessel, Org. development of continuous Buchwald- hydride reduction of an ester followed Process Res. Dev. 20 (2), 568–573 (2016). 7. S.V. Tsu kanov, et a l., Org. Process Res. Hartwig reactions. In one report, the by n-butyllithium-mediated coupling Dev. 20 (2), 215–226 (2016). scientists used the highly active pal- of the resultant aldehyde to a sulfone 8. S.-W. Wong , et a.l, Org. Process Res. Dev. ladium N-heterocyclic carbene (NHC) fragment to afford a sulfone-diol as 20 (2), 540–550 (2016). precatalyst [Pd(IPr*)(cin)Cl] 4 (IPr* a key intermediate, all without the 9. A.Chartoire, et al., Org. Process Res. Dev. = 1,3-bis(2,6-bis(diphenylmethyl)- need for cryogenic conditions (11). 20 (2), 551–557 (2016). 10. S. Falss, et al., Org. Process Res. Dev. 20 (2), 4-methylphenyl)imidazol-2-ylidene; The reduction was run at -50 °C in- 558–567 (2016). cin = η3-cinnamyl), a universal ap- stead of -70 °C, yet a better selectiv- 11. T. Fukuyama, et al., Org. Process Res. Dev. proach for continuous workup and ity and yield were obtained, while the 20 (2), 503–509 (2016). purification, and a methodology for butyllithium-mediated coupling when 12. S. Laue, V. Haverkamp and L. Mleczko, catalyst recycling and reuse (9). Before run under flow conditions at 10 °C Org. Process Res. Dev. 20 (2), 480–486 (2016). implementing the flow reaction, the proceeded with a better conversion 13. R. Karande, A. Schmid, and K. Buehler, catalyst’s stability in water was inves- rate than the batch reaction when Org. Process Res. Dev. 20 (2), 361–370 tigated and an effective workup meth- performed at -70 °C. (2016). PT

Pharmaceutical Technology JUNE 2016 31 API Synthesis & Manufacturing

Indian pharma is committed to the future, says Biocon managing director

Recently, there have been more reports of compliance issues at API and drug manufacturing practice (cGMP) guidelines, backed by quality by design (QbD). ufacturing facilities in India. Kiran Mazumdar-Shaw, chairperson and managing They will need to bring in more checks on manufacturing processes and director of Biocon, told Pharmaceutical Technology in an interview that invest- rigorously focus on monitoring, causality, and documentation. ment in talent and infrastructure, more quality-by-design skills, and increased It is also imperative that Indian companies ramp up skills on QbD. There is communication with global regulators will be needed. a need to build a strong quality brand to sustain leadership on the mantra of FDA compliance issues ‘highest quality at the lowest cost’. PharmTech: What do you think might have contributed to the FDA com- India’s role in the global market pliance issues that some Indian drug manufacturers have had over the PharmTech: What unique strengths do you see Indian pharma contributing past few years? to the global market over the long term? What will be needed to get there? Mazumdar-Shaw: India has nearly 380 FDA-registered facilities, Mazumdar-Shaw: The Indian pharmaceutical industry has played a which is the largest number outside the United States. Seen in that con- disruptive role by developing critical drugs at relatively affordable lev- text, the non-compliance warnings received by Indian companies are not els. By bringing down the prices of drugs used to treat life-threatening disproportionate to those received by companies in China and other coun- diseases such as HIV, tuberculosis, and cancer by as much as 90%, In- tries. India’s growing market share in the US draws greater FDA scrutiny. dian generic-drug makers have enabled access and saved millions of lives Despite all the media noise around compliance issues, the fact remains across the developing world. that Indian drug makers have the second-largest share of abbreviated India’s strengths in drug development and cost-effective drug manufac- new drug application (ANDA) approvals from FDA after US producers. turing can be key to realizing the vision of addressing unmet medical needs A report recently released by FDA’s Office of Generic Drugs (OGD) (1) shows through affordable biopharmaceuticals globally. India can make as much of that, out of 90 first-time generic drug approvals in 2015, up to 14 were won an impact on global healthcare with biosimilars in the coming years as it has by Indian drug companies, most of them for specialized treatments (2). done with small-molecule generics in the past. Over the past few years, regulators across the globe have opted for Access to capital, quality infrastructure, high-end talent, and an optimal stricter norms to ensure the quality of medicines, which is evident from ecosystem that encourages innovation in the country will spur India’s evolu- the fact that the total number of product recalls and warning letters to tion as a biopharma hub and the preferred destination for innovation. pharma companies globally tripled between 2008 and 2014. Biosimilars outlook Indian pharma companies are working overtime to align their opera- PharmTech: What are your plans in the biosimilars business? What role do tions and improve their quality control procedures to meet Western regu- you see Indian suppliers playing in this niche? latory expectations, and I expect the number of warnings to come down Mazumdar-Shaw: Biocon, with its rich pipeline of biosimilars under in due course. development, is preparing to meet the widespread global demand for af- Investments in facilities and training needed fordable biosimilars from patient advocacy groups, non-profits that sup- PharmTech: What will be needed to change the situation? port healthcare initiatives, and governments with overstretched healthcare Mazumdar-Shaw: Despite the recent spate of quality-related issues, the budgets. The global market opportunity for biosimilars is estimated to reach reality is that Indian pharmaceutical manufacturers continue to command around US$24 billion in 2019 (3). a good reputation in pharmaceutical manufacturing. Besides the FDA-ap- Today, Biocon has one of the largest portfolios of generic insulins and bi- proved facilities, there are 1400 manufacturing plants with World Health Or- osimilar protein therapeutics in advanced stages of development and is on ganization (WHO) GMP approval and over 250 plants that have been cleared track to file for regulatory approvals in US and Europe for four of them in fiscal by the European Directorate of Quality Medicines (EDQM). year 2017. Biocon is confident that, together with our partners around the The Indian pharma industry will need to focus and invest more in high- world, we can build a strong global presence in biosimilars to address the huge quality manufacturing to maintain its edge as a destination of choice for need for affordable access to these life-saving and life-enhancing biologics. the production of safe, effective, and affordable medicines. Besides invest- India has been among the early adopters, and established the regulatory ing in physical infrastructure, companies must invest in talent to ensure an framework for biosimilars as early as 2012. The industry is well poised to pro- optimal mix of quality control staff and shop floor personnel for delivering vide cost-effective alternatives to expensive reference biologics for patients the highest quality. There is also a need for greater dialogue with Western and an opportunity for governments across the world to rein in burgeoning regulators to keep pace with the evolving quality and regulatory regime and healthcare costs. align people and processes accordingly. References Rebuilding market credibility 1. FDA, Annual Report, 2015, Office of Generic Drugs, www.fda.gov/Drugs/Devel- PharmTech: There has been some retrenching and ‘onshoring,’ as some US opmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalAp- plications/AbbreviatedNewDrugApplicationANDAGenerics/ucm494187.htm. companies have begun to source APIs and other materials from the US and 2. A. Malik, “USFDA Grants 14 First-Time Generic Drug Approvals to Indian Firms Europe. What will be needed to reverse this trend and regain any lost cred- in 2015,” Indian Business Times, April 15, 2016, www.ibtimes.co.in/india-wins- ibility, on the part of some API suppliers? 14-key-first-time-generic-drug-approvals-usfda-2015-674776. Mazumdar-Shaw: To achieve the goal of ‘make in India for the world,’ 3. C. Challener, “Focus on Biosimilars,“ PharmTech.com, Oct. 6, 2014, www.pharmtech.com/focus-biosimilars. Indian pharmaceutical companies will have to adhere to current good man- —Agnes Shanley

32 Pharmaceutical Technology JUNE 2016 PharmTech.com The Parenteral Drug Association presents the... 2016 PDA/FDA Joint Regulatory Conference Celebrating 25 Years of Shaping Global Regulatory Strategy September 12-14, 2016 | Washington, DC Renaissance Washington, DC Downtown Hotel EXHIBITION: SEPTEMBER 12-13 | PDA DATA INTEGRITY WORKSHOP: SEPTEMBER 14-15 | COURSES: SEPTEMBER 15-16

Conference Theme: Aligning Manufacturing Goals with Patient Needs through Successful Innovation and Compliance

For 25 years, the PDA/FDA Joint Regulatory Conference has provided attendees the chance to hear directly from regulatory experts as they discuss current Agency initiatives and their potential impact on the development of global regulatory strategies. This year is no diff erent! The 2016 PDA/FDA Joint Regulatory Conference agenda is fi lled with opportunities to expand your knowledge and network with colleagues. You can attend fi ve plenary sessions, which include the ever-popular Compliance and Center updates; nine breakfast sessions; and 14 Interest Group sessions. Concurrent sessions will be off ered in three concurrent tracks focusing on Product Quality, Science & Innovation, and Lifecycle Management – Regulatory Challenges & Opportunities. To learn more and to register, visit pda.org/2016pdafda. Immediately following the Conference, Sept. 14-15, the 2016 PDA Data Integrity Workshop will be held. This Workshop will include a blend of presentations from regulatory and industry experts, case studies and round table discussions. Special focus on exploring the multiple facets of data integrity, such as quality culture, human behavior, training needs and technology requirements, will help attendees get a broad perspective on common factors, and cause and eff ect on data integrity issues. To learn more and to register, visit pda.org/2016dataeast. And, on Sept. 15-16, PDA Education will host six courses to complement what you learned in the Conference. Course off erings include: The Impact of CGMPS on Biomanufacturing Facility Design and Operation (September 15) Establishing and Implementing an Eff ective GMP Auditing Program (September 15) Implementing Quality Risk Management for Pharmaceutical and Biotechnology Manufacturing Operations (September 15-16) Register Preparing for Regulatory Inspections for the FDA and EMA (September 15-16) before July 1 Investigations – Best Practices (September 15-16) Environmental Control and Monitoring for Regulatory and save Compliance (September 16) up to $600 To learn more and to register, visit pda.org/2016PDACourses. #2016pdafda PEER-REVIEWED

Qualifying Personnel to Visually Inspect Cleaned Equipment Part II: Small vs. Large Group Training

Richard J. Forsyth

oth the European Eudralex (1) and the US Code of Federal BRegulations (CFR) (2) require that cleaned pharmaceutical manufacturing equipment be visually inspected and determined to be clean, both after completion of the cleaning process and again immediately before manufacturing of the next batch or product begins. Visual inspection is designed to assess all of the visually accessible product contact surfaces of the pharmaceutical manufacturing equipment, and determine that the equipment is free from any visible residues. Manufacturing cannot begin until this assessment has been made, because it is crucial to patient safety and to verifying that the equipment has been adequately cleaned. A visual inspection is a routine part of cleaning and the first criterion for cleaning validation, and inspection results must Cleaned equipment must be visually inspected, both be deemed acceptable before any swab samples can be col- after cleaning and again before product manufac- lected from the cleaned equipment. turing begins. Manufacturing and quality profes- Visual inspections are conducted by a variety of site sionals must be qualified to do visual inspections. personnel. Equipment cleaning staff routinely inspect Small training groups are recommended for the equipment during and after manual cleaning. A second training required, but a different approach can be person, in addition to the cleaning crew, must confirm used for larger groups. This article presents recom- and document visual cleanliness of cleaned equipment. mendations based on a program that was set up to Before manufacturing of the next batch of product can qualify members of a large, diverse team at one oral begin, manufacturing and quality staff must visually inspect solid-dosage-form manufacturing facility. all process equipment for cleanliness and document cleanliness in the manufacturing batch record. Quality and validation personnel also inspect cleaned equipment periodically as part of their work function. Staffers responsible for conducting visual inspections have traditionally been trained by observing a seasoned employee perform this work. More experienced staffers would coach and advise them on issues or intricacies of the individual pieces of equipment, and then observe them when they conducted their own visual inspections. The approach worked, but could lead to subjectivity and inconsistent visual inspection results. Professionals at regulatory agencies believed that this approach could be improved if it were formalized and documented. As part of a cleaning validation program, staff members who take swab samples have been routinely qualified to Richard J Forsyth is a principal consultant with Forsyth determine that they can adequately recover residues from Pharmaceutical Consulting, 907 Shamrock Ct, Royersford, PA 19468, equipment surfaces. Laboratory personnel are qualified 484.535.1688, [email protected]. to test the cleaning samples. Cleaning and testing Submitted: Sept. 14, 2015. Accepted: Oct. 2, 2015.

procedures are validated to demonstrate consistent MONTY RAKUSEN/GETTY IMAGES 34 Pharmaceutical Technology JUNE 2016 PharmTech.com Equipment Cleaning

execution. Establishing a qualification criterion for the visual The use of more coupons might prevent the opportunity inspection of cleaned equipment is a logical extension of to spike and present all site residues for qualification this philosophy that would improve cleaning validation and during one training session, which would lengthen the time ensure that the training for all people who visually inspect required for qualification. cleaned equipment is objectively documented. Training staffers in visual inspection poses a number of Large group logistics logistical challenges, however. Ideally, such training is done Training and qualification for visual inspection for a large group for small groups, within a laboratory setting (3). Qualifying were subject to several practical constraints to qualify all per- a large, diverse group of personnel would be beneficial sonnel most efficiently and minimize disruption of ongoing because it would provide a site with a routine, redundant, operations. Three shifts were trained; therefore, training ses- and rugged confirmation of the effectiveness of site cleaning sions were held at the end or beginning of the shift. One large procedures. Such training and qualification, however, is not group training session was held for each shift to familiarize per- practical in a laboratory setting. sonnel with the concepts and goals of the training and qualifi- At one oral solid-dosage-form manufacturing site, such cation exercise. A knowledge assessment was conducted with a training program was offered to all operations and each group to confirm its grasp of the training concepts. inspections staff. Due to the size and diverse schedules Visual inspection qualification was conducted in one of members of this group, it proved to be more practical of the manufacturing suites with more limited space. to bring the visual qualification testing to the personnel in Space in which to view the spiked coupons was also the manufacturing area. Qualification was conducted using limited. Therefore, smaller groups of 5–10 were brought spiked coupons, and, because the coupons were spiked in to observe the spiked coupons. The small groups were with formulations that contained API, for safety reasons, qualified either after their shift completed or during the qualification was conducted in an empty suite in the their shift, as job duties allowed. Once the groups were manufacturing area rather than a meeting room. assembled, additional instructional training was conducted The site did not have visible residue limits (VRLs) established prior to the qualification to emphasize the effects of for its product portfolio. Rather than expend the time and the viewing parameters, especially the viewing angle, resources required to establish the product VRLs, the company the condition of the coupon surface, and the relative decided to spike coupons with the formulation at two levels appearance of the spiked residues. only. One coupon was spiked at the acceptable residue limit (ARL) for the compound, and a second coupon was spiked at Qualification parameters 50% of the ARL.It was reasoned that, if personnel could see the A survey of manufacturing equipment at the site concluded two spiked coupons, then they would be qualified to distinguish that all equipment surfaces could be visually inspected from visually soiled equipment before it became a cleaning failure a distance of 10 feet or less. The light levels measured in the based on the ARL. By spiking coupons at 50% of the ARL, there manufacturing suites ranged from 725–1930 lux. The viewing would be a margin of safety between the visual level detected angles of the equipment were only slightly restricted, but and a cleaning failure against the ARL. The choice of spiking at multiple viewing angles were possible for all cleaned equip- the 50% ARL level was a compromise between spiking at as ment surfaces. The viewing parameters for the qualification low a level as practical while assuring personnel had the best were based on these findings. opportunity to detect the residues visually. The material of construction (MOC) for the visual inspection qualification was stainless steel, the most Small group logistics prevalent MOC at the site. Residues for visual inspection Training and qualification for visual inspection for small groups qualification included all products manufactured at the site. was discussed in a previous article (3). There are a number Each residue was spiked at 100% and 50% of the ARL as of options for presenting the spiked coupons, including pre- shown in Table I and Figure 1. The residues tested for the senting just the VRL levels or several spike levels down to visual inspection qualification showed that the qualified the VRL. The former option uses fewer coupons but requires inspector should be able to visually detect residues on the additional training to reduce the risk of qualification failure. manufacturing equipment during a visual inspection both The latter approach uses more coupons but has a lower risk of after cleaning and again before manufacturing. failure, and offers a more thorough approach that provides a For viewing, coupons were presented on a table and greater understanding of visual inspection parameters. positioned at a 15º–20º angle so that, when viewed at 10 Neither option, however, works well to train and qualify a feet, the minimum viewing angle for the coupons was large group. Qualification using just the VRL levels requires greater than or equal to 30º. Staffers in the training program extensive up-front training to acquaint personnel with the first viewed the coupons at two feet, where they were appearance of residues at their VRL levels. Qualification acquainted with the appearance of the residues and the using several spike levels down to the VRL would require effect on stainless steel. The grain of the stainless steel had more time for each individual of the large group to little impact on their ability to see the easily visible residues, understand the concepts of visual inspection parameters. but had a more significant impact on how easily they could Pharmaceutical Technology JUNE 2016 35 Equipment Cleaning

After recording observations at two feet and 90º, trainees Table I: Spiking levels for visual inspection qualification. moved into a position at five feet with a 60º viewing angle Acceptable to repeat the observations, and then moved back 10 feet at residue limit a 30º viewing angle. The ambient light level in the suite was (ARL) 950 lux and, based on past ruggedness work (4), this was (μg/25cm2 100% spike 50% spike Compound swab) level (μg) level (μg) deemed suitable for light levels down to 200 lux. Trainees responded whether or not they were able to see the 100% P1 497.8 497.8 248.9 and 50% ARL level residues. P2 497.8 497.8 248.9 Training P3 7.1 7.1 3.55 Qualification for visual inspections of cleaned equipment P4 92.2 92.2 46.1 is just one part of the training required to assure reliable, P5 14.2 14.2 7.1 thorough visual inspection of cleaned pharmaceutical manufacturing equipment. As shown in Table II, adequate training P6 92.2 92.2 46.1 should start with a review of the standard operating pro- P7 14.2 14.2 7.1 cedures (SOPs) for visual inspection and visual inspection qualification, which describe the process for inspection and P8 92.2 92.2 46.1 documentation of cleaned equipment, and the visual inspec- P9 1.1 1.1 0.55 tion qualification process. If available, equipment diagrams P10 56.9/7.1 56.9/7.1 28.45/3.55 showing dimensions and swab locations with associated jus- tification should be reviewed to familiarize trainees with the DTG 92.2 92.2 46.1 manufacturing equipment and problem areas for cleaning. Before they can be qualified, each staff member must be Figure 1: Visual inspection qualification using trained in how to determine VRLs of different types so that acceptable residue limit (ARL) levels. DTG is detergent. they can detect low levels of residues for cleaning. It is a good idea to discuss the relationship of the VRL to the cleaning limit or ARL, and to clarify the relationship between the cleanability Visual inspection qualification of the different residues from various MOCs. This clarification would help impart an understanding of the confidence level in

P1 P2 P3 P4 P5 P6 P7 P8 P9 P10 DTG the cleaning procedure and the visual inspection. 100% 100% 100% 100% 100% 100% 100% 100% 100% 100% 100% On-the-job training should consist of a supervised inspection of the manufacturing equipment, including P1 P2 P3 P4 P5 P6 P7 P8 P9 P10 DTG 50% 50% 50% 50% 50% 50% 50% 50% 50% 50% 50% the hard-to-clean locations and those most likely to have product buildup, for each piece of cleaned equipment P1 P2 P3 P4 P5 P6 P7 P8 P9 P10 DTG BI BI BI BI BI BI BI BI BI BI BI identified for cleaning validation. The final step, after training and qualification, should consist of a monitored visual inspection of a cleaned piece of equipment, ensuring that the proper procedures are followed, a thorough visual Table II: Training for visual inspection qualification.SOP is inspection is conducted for the equipment, and the visual standard operating procedure. inspection is properly documented. Step Training These aspects of training required considerably more time SOP review: Visual Inspection of Cleaned with a large group. Training consisted of a group session for 1 Manufacturing Equipment each shift and then, as each small group was brought in for SOP review: Qualification of Personnel for the Visual qualification, a short (three-to-five-minute) discussion of 2 Inspection of Product Contact Areas the viewing parameters, the residues and their appearance Review of equipment diagrams showing hard to clean was completed at the two-feet distance. The risk for the 3 areas and areas of product buildup abbreviated training was that some trainees might not sufficiently understand the importance of the viewing 4 Visible residue limit (VRL) examples parameters or the significance of the training for their day- 5 VRL vs. cleaning limit discussion to-day jobs, and that they might misidentify coupons. 6 On-the-job training Experimental Individual formulations were suspended into organic or detect residues that were more difficult to see (e.g., the aqueous solvents and diluted as necessary to obtain con- detergent). Personnel were also instructed on the effects of centrations at five times the ARL level. To obtain the 100% the viewing distance and the viewing angle. ARL level, 200μL of the stock solutions were spiked onto 36 Pharmaceutical Technology JUNE 2016 PharmTech.com Equipment Cleaning

individual coupons; to obtain the 50% ARL level, 100μL of Figure 2: Residues not visually detected by individual the stock solutions were spiked onto individual coupons. personnel. The ARL spike levels of the 11 residues are shown in Table I. The cleaning residue limits ranged from 1.1 μg/swab up to 8 497.8 μg/swab. Blank coupons spiked with solvent were also 7 prepared. The spiked and blank coupons were arranged for 6 qualification in a manufacturing suite, the light level was 5 measured, viewing distances were marked, and small group 4 observations subsets of the large group were brought in for additional 3 instruction and qualification. 2

Missed 1 Qualification acceptance criteria 0 1 6 1 6 1 6 1 6 11 16 21 26 3 3 41 46 5 5 61 66 71 76 81 86 9 9 The logical acceptance criteria for visual inspection qualifi- 101 106 111 116 cation are that all personnel identify all of the spiked cou- Observers pons as “visible,” and all of the blank coupons as “blank.” Realistically, with a large group, the risk of misidentification of a coupon is more likely. For a blank coupon, a misidenti- fied coupon would not necessarily have to be considered a Table III: Large group qualification results summary. failure. A blank coupon deemed visible is a mistake on the Number side of caution and could be tolerated. If a spiked coupon is Qualification result of not identified as such, it is more problematic. Potentially, a personnel visually soiled piece of equipment could be deemed as clean Saw all residues and differentiated from blanks 31 and released for subsequent manufacturing. The equipment could be used to manufacture a different product, which Variability in residue identification 41 could be cross-contaminated. Or the visible residue on Did not see all residues under some defined con- 46 the equipment could be identified during redundant visual ditions inspections, either by quality assurance personnel (QA) or Total 118 before the next batch. In either case, the equipment would need to be re-cleaned and an investigation would need to be launched to identify the root cause of the visual failure. Results of the qualifications are summarized in Both options could cause problems for the site. Table III, and the individual residue results are shown in As a result of the accepted risk of abbreviated training, Table IV. Table III shows that a two-thirds majority were the qualification resulted in misidentification of spiked able to see the residues under the established viewing coupons for a small percentage (<5%) of the trainees. parameters, although there was some variability in a number of responses: the ability to see one of the spiked residues for Results and discussion a particular formulation while not seeing the other was the The visual inspection qualification for a large group presents variation most often noted. Of the 46 observations where several logistic and timing challenges. Processing a large residues were not visually detected, the vast majority were group requires a fair amount of time and must be conducted for Product 7 and/or the detergent. in an area with sufficient space. In-depth training for VRLs Table IV provides a more detailed list of the number of and viewing parameters, although preferable, is neither prac- personnel that were able to detect the individual residues. tical nor does it add sufficient value. It is also more difficult to Eight of the 11 residues were visible out to 10 feet and gauge the effectiveness of training in a large group environ- beyond with less than a 5% standard deviation. Product 5 ment. Therefore, a scaled-back, more expedient and efficient was not consistently visible at 10 feet but was visible at five training program was implemented for large group qualifica- feet. Of the 11 residues, the Product 7 formulation and the tion. This approach did not employ the true VRLs for produc- detergent were not consistently visible at all distances on a tion residues, but did assure that personnel could visually consistent basis. detect process residues prior to a cleaning failure based on The detergent (DTG) results are not applicable unless a the swab limit. The margin of safety between the lower res- component of the detergent is identified for the cleaning idue level tested and the swab limit provided some measure limit because the results are based on the total weight of of confidence that visually soiled equipment would not pass the detergent. The detergent is 66% water, which means visual inspection. The majority of personnel were able to that only 34% or 31.3 μg of total solids were spiked onto the visually detect all residues within the viewing parameters, 100% level coupon. and any risk of inadequate visual inspection was mitigated by The individual personnel results were examined for redundant visual inspection proceduralized at the facility. consistency and to determine if there were any individuals Pharmaceutical Technology JUNE 2016 37 Equipment Cleaning

Table IV: Large group qualification results—118 personnel. DTG is detergent. ARL is acceptable residue limit. Residues Distance/ visible P1 P2 P3 P4 P5 P6 P7 P8 P9 P10 DTG angle (Y/N ) 100% ARL 114 116 117 118 110 117 77 118 118 115 94

10ft/30º 50% ARL 116 117 108 117 109 118 72 118 118 108 43

100% ARL 114 115 116 117 116 114 91 118 118 116 100

5ft/45º 50% ARL 118 118 109 118 114 118 102 118 118 113 69

100% ARL 117 115 118 118 116 118 110 117 118 117 108

2ft/90º 50% ARL 118 118 116 118 115 118 113 118 118 117 90

Average 116 116 114 118 113 117 94 118 118 114 84

Standard deviation 1.8 1.4 4.3 0.5 3.1 1.6 17.1 0.4 0.0 3.4 24.0 who had a particular problem visually detecting residues. of the residues and be retested. In this case, the risk of visually The results for Product 7 and the detergent were ignored soiled equipment passing visual inspection is mitigated by because they were difficult to detect for a large number of validation of the respective cleaning procedures, by the personnel. The results of the individual analysis are shown in restricted viewing parameter limitations (e.g., five feet) for Figure 2. One individual missed the visible residue on seven specific residues and by the redundant visual inspection coupons, suggesting that he or she either be trained on the immediately after cleaning by the equipment cleaner, the appearance of residues, encouraged to perform any visual confirmatory inspection after cleaning and the visual inspection from two feet, or be excluded from signing off on inspection immediately prior to the subsequent manufacturing. visual inspections. Additional training might also be advised Risk could be further mitigated or eliminated by adding for the two individuals who missed the visible residue on training using spiked coupons prior to the qualification four coupons and the five individuals who missed the visible exercise. This would acquaint personnel with the viewing residue on three coupons. parameters and their effect on the ability to visually detect spiked residues. This could be done with the entire large Conclusion group but would probably be more effective with each A large group of personnel were successfully qualified for small group prior to qualification. The small group training visual inspection of cleaned equipment at an oral solid-dose could be done immediately prior to qualification using an manufacturing facility. The qualification was implemented additional trainer and would extend the entire process by an for all products made at the facility and conducted within additional 10–15 minutes. the time and space constraints of the production schedule. Qualification of personnel for visual inspection of cleaned The visual inspection procedure for a large personnel pharmaceutical manufacturing equipment product contact group were considered qualified for Products 1–4, 6, 8, 9, and surfaces is a necessary complement to both a cleaning 10 for a light level of > 200 lux; a viewing distance of < 10 ft; validation program and the manufacturing operations at a site. and a viewing angle of > 15º. The visual inspection procedure Visual inspection qualification is just one facet of an overall is appropriate to verify cleaning process effectiveness to training program to assure that personnel are equipped to acceptably remove formulation residues from equipment provide a consistent, thorough and accurate evaluation of during cleaning validation and routine monitoring. The cleaned surfaces for ongoing pharmaceutical operations. visual inspection procedure was considered qualified for Product 5 for a light level of > 200 lux; a viewing distance References of < 5 ft; and a viewing angle of > 15º. Equipment cleaned 1. EMA, Eudralex, Volume 4, EU Guidelines for Good Manufacturing after manufacture of Product 7 formulations should be Practice for Medicinal Products for Human and Veterinary Use, Annex 15: viewed from as close a distance as practical using multiple Qualification and Validation, Section 10.2 angles under ambient light (> 200Lux) to provide the highest 2. FDA, Code of Federal Regulations, Title 21, Food and Drugs (Government confidence of visually detecting any remaining formulation. Printing Office, Washington, DC), Part 211.67 Trainees who had difficulty visually detecting the spiked 3. R. J. Forsyth, Pharm. Technol. 38 (1), 42 – 46 (2014) residues could receive additional training on the appearance 4. R. J. Forsyth, Pharm. Technol. 33 (3), 102-111 (2009). PT 38 Pharmaceutical Technology JUNE 2016 PharmTech.com Viewpoint

pation of need, storing the product until packaged and shipped. All in all, there was a massive overhead involved, which was folded into the cost of goods sold (COGS). For more than 50 years, pharmaceutical product manufacturers were content to hum along, doing the same thing, year after year. They received the raw materials; quarantined them until QC managed to perform some arcane, compendial assays and either passed or failed them; blended the API and excipients and stored the mix; granulated, dried and stored the blend; punched tablets or filled capsules, and stored PAT: “Gateway Drug” them; finally, coated the tablets and stored them until QC approved them to be bottled and sold. to the 21st Century for There was little pressure to change because most proprietary brands had little to no competition from other the Pharma Industry branded products or the few generic houses in existence at the time. Why Emil W. Ciurczak would they spend the time and money to make any adjustments in the manner the products were manufactured? And, for analytical purity and “good- Process analytical technology paved ness,” taking only 20 units for assay was pretty good, especially when the batch the way for continuous manufacturing. just numbered in the thousands. As far as testing the raw materials, quick n the 1970s, the analytical device in- red (IR) range from “merely” midrange- compendial checks were good enough, dustry introduced laboratory instru- IR to near-IR (NIR) and later (c. 2005) because the supply chain (a word not yet Iments that performed titrations, better to a viable, information-rich far-IR, being bandied about) was domestic and thermal analyzers to show crystallinity, now dubbed “terahertz.” Despite the most large companies synthesized their and all types of chromatography (e.g., speed, accuracy, and throughput of own APIs. gas-liquid chromatography [GLC], cap- modern analytical instrumentation, it illary gas chromatography [GC], high- has remained safely ensconced in the Affect of outsourcing performance liquid chromatography laboratory, year after year. With the trend to outsource every facet [HPLC], and ultra high-pressure liquid Production samples were obtained by of the business (e.g., manufacturing, chromatography [UHPLC]), which took operators from the process line, labeled, API production, packaging, clinical tri- off like a rocket and became the back- and hand-carried to the QC lab. Sam- als, and even basic research), the term bone of the R&D, quality control (QC), ples were logged and assigned to ana- “supply chain” came to the forefront. and stability departments. In the 1980s, lysts for assay while the lots were held Many pieces of the pharma puzzle be- near-infrared and Raman instruments in quarantine in the warehouse until came opaque. APIs previously taken became accurate and operator-friendly analytical results were delivered, often for granted because they were made in and the first commercial Chemomet- a week or so later. The slow turn-around house now came into question because ric software packages were introduced. meant stocking more raw materials of their external and possibly offshore Thus, the industry expanded the infra- than immediately needed and more origin. In addition, simple United States product than orders for those products. Pharmacopeia (USP) or European Phar- Campaigns—where many process lines macopoeia (Ph. Eur.) tests proved inad- Emil W. Ciurczak, Doramaxx were incorporated for the same product equate (e.g., heparin). The 10–20 tablets

Consulting, [email protected]. for weeks on end—were run in antici- taken for “goodness check” and the mere ANDREY PROKHOROV/E+/GETTY IMAGES

Pharmaceutical Technology JUNE 2016 39 Viewpoint

six dissolution samples for “performance Several things happened simultane- “dry until dried” or “vary hardness to testing” suddenly seemed a trifle thin in ously. Pfizer wanted a way to speed the give proper dissolution” were anath- the face of multi-million unit lots, pos- production and release of Viagra, and emas to QA. sibly made by a surrogate (branch or the US Congress, alarmed at loss of jobs A number of companies, however, contract manufacturing organization and production to overseas pharma learned that assuring a product is well- [CMO]) in a developing country. companies, suggested that FDA help made during the process is preferable For the companies still making their domestic companies to compete. Part to failing “X” number of lots (or having own products, the cost of in-house proof the initiative came with a number of major recalls) every year. And, to help duction under the 50-year-old produc- guidance documents and initiatives (1). smooth the way for PAT, quite indepen- tion paradigm kept rising. Also, because The FDA draft guidance for process dently, Pfizer was developing tools for of the increasing number of question- analytical technologies (PAT) was is- PAT to become feasible. able products being imported and the sued in 2002 and generated so much exploding number of generics—with debate that the comments section of The development of PAT tools the concomitant exploding number of the FDA webpage almost crashed the The first major tool was a stand-alone, GMP violations cited by the European system with the number (and tone) of wireless, battery-operated near-infrared Medicines Agency (EMA) and FDA—the submissions, and it took more than analyzer, designed to be mounted on a agencies increased their scrutiny of their two years to get the final guidance re- blender. Working at its Sandwich, UK domestic, formerly above reproach, large leased (2). It seems that the quality as- facility with technicians from Zeiss branded products. Unfortunately, the surance (QA) departments went wild (Switzerland), Pfizer designed, tested, agencies were finding that “after the pro- at the thought of using “good scientific and built a unit for determining end- cess” tests were not as good a measure of judgement” in lieu of hard and fast pro- points for blend “uniformity.” The au- product goodness for large lots as the old cedures. The idea of flexible parameters, thor points out that powders cannot “mother’s kitchen”-sized lots of the past. such as “blend until well-blended” or be “homogeneous;” only solutions may

Improving Pharma Systems with Process Analytical Technology

Pharmaceutical Technology spoke with Melissa Topp, director of Global Mar- PAT and tech transfer keting at ICONICS, about the latest in process analytical technology (PAT). PharmTech: How can PAT be used in tech transfer of pharmaceutical Benefits and challenges of PAT manufacturing operations? PharmTech: What are the benefits and challenges of PAT? Topp (ICONICS): Any solution that helps users capture, store, and analyze their Topp (ICONICS): The key benefit to PAT is in providing users with the means data is a valuable application of process analytical technology. But true insight is to measure performance, productivity, and quality and thereby provide only achieved when real-time data are visualized alongside retrieved historical guidance toward improvement. However, in order to best guide decision- benchmark production performance data. Quality analysis, including standard making, as many factors (or data points) as possible need to be included SPC calculations such as X-bar, R-bar, Sigma, moving range, Media, moving for analysis. A challenge for PAT going forward, as more companies seek to average, exponentially weighted moving-average (EWMA), process capability move their production data to the cloud, is ensuring that any increase in the index (Cpk), and process performance index (Ppk), can work in tandem with a complexity of process measurement can be visualized, stored, and analyzed robust (one capable of over 100,000 tag per second logging) data historian. This as quickly and cost-effectively as possible, using the right combination of stored comparative performance data can then be useful in tech transfer between hardware and software. organizations, facilities, departments, etc. Improving system quality PAT innovation PharmTech: How can PAT be used to improve system productivity and PharmTech: Are there any new and innovative PAT tools being used in the quality? industry? What does the future hold? Topp (ICONICS): A comprehensive PAT strategy can include both Topp (ICONICS): One of the most exciting developments is the emergence of the productivity and quality analyses. Solutions like ICONICS Productivity Internet of Things (IoT) and cloud-based technology in production environments. Analytics help establish manufacturing context with knowledge point The connection of production equipment (via low-cost bridging devices known indicatiors (KPIs) such as overall equipment effectiveness (OEE), cycle time, as ‘gateways’) to large, external, Web-connected networks (e.g., Microsoft Azure, mean time between failures (MTBF), Takt time, efficiency, and throughput. Amazon Web Services, etc.) via comprehensive software suites allows users to Quality AnalytiX provides real-time statistical process control (SPC) that make a decision as to where the process analyses take place; either via on-premises can guide users towards increased production yields, reduced scrap, and IT hardware or in the cloud. Either choice has its benefits. The innovation lies in now variation prevention. being able to make that choice. —Susan Haigney

40 Pharmaceutical Technology JUNE 2016 PharmTech.com be described as such. A more accurate als; follow the blending, granulating, CM equipment, it is the next logical term is simply, “well-blended.” When a and drying of the mixture; direct the step in the march to the 21st Century. series of measurements (moving aver- tableting and coating processes; even Vertex received FDA approval of their age) came to a constant standard de- check the fill (mostly blister packs) CM-based new drug application for viation, the blending was halted. There and identity of the final package. This their cystic fibrosis medicine and Jans- were estimated times, but, depending was PAT, which begat quality by design sen retro-validated an existing product on the size of the lot and the variable (QbD). FDA published several more to a continuous process (3,4). parameters of the excipients and APIs, guidance documents and the Inter- A CM unit consists of a series of the end-time would vary. national Council on Harmonization serially connected operating pieces: weighing units for APIs and excipients, dispensing powders into a screw-like Once industry process development blender, optional in-line granulators, or people wrapped their heads around ribbon blender (or direct compression), a drier when a granulator is used, com- variables in master manufacturing pression, followed by coating (if needed) or filling into capsules. formulas, in-process testing started to In most processes, within an hour of start-up, the first tablets begin coming sound reasonable. off the line, ready for packaging. Why not send these tablets to QC for analy- Once industry process development (ICH) generated a series of guidances sis? All the pieces of a real-time release people wrapped their heads around (ICH Q8, Q9, Q10, and Q11) to stan- procedure are in place: proper amounts variables in master manufacturing dardize how one finds design space of each component are weighed (and formulas (MMFs), in-process testing (i.e., allowable variations within a pro- recorded at all times); the blending is started to sound reasonable. It was cess, determined by experimentation continuously monitored and controlled; Pfizer, again, that started using in- using design of experiment software the ribbon compaction or granulation process sampling and NIR analyses of and synthetic batches) and conducts a is monitored and controlled; the tab- Viagra. Using primitive, yet effective QbD program. let pressing (or capsule filling) is con- methods, they continuously sampled trolled (weight, assay, and even disso- two lines and brought samples to a PAT as a gateway to lution prediction); and, if coated, the number of NIR instruments in a “lab” continuous manufacturing coating procedure is monitored and constructed between the two produc- The industry now has encouragement controlled. Therefore, if PAT leads to tion lines. Thus, they analyzed up to from FDA, ICH, and EMA to perform CM, what comes next? Does the phrase 20 tablets per hour per production line. modern, real-time monitoring/adjust- “3-D printing for orphan drugs” sound For a 12-hour run, a minimum of 240 ments and begin to consider “real-time” interesting? samples (taken sequentially throughout release (on-line, not after-the-fact the run) was analyzed. Compare this to in the QC lab). The use of process- References scooping 20 tablets at the end of the run. hardened NIR, Raman, terahertz, and 1. FDA, Pharmaceutical cGMPs for the 21st Obviously, if any problems were seen, other tools have rendered after-the-fact Century–A Risk-Based Approach (Rock- ville, MD, September 2004). the tableting could be either suspended analyses moot. 2. FDA, Guidance for Industry, PAT—A or corrected. The costs of traditional process lines Framework for Innovative Pharmaceutical From these humble beginnings, places branded companies out of the ge- Development, Manufacturing, and Qual- many instruments were designed spe- nerics marketplace—resulting in dump- ity Assurance (Rockville, MD, September cifically for the production line. Aside ing or licensing a product at or near its 2004). from NIR, Raman, terahertz, chemi- patent expiry date—and making change 3. L. Yu, “Continuous Manufacturing Has a Strong Impact on Drug Quality,” cal imaging (e.g., NIR, Raman, and a little less odious. FDAVoice blog, April 12, 2016, http://blogs. fluorescence) are just some of the tools Because the values of all the pieces fda.gov/fdavoice/index.php/2016/04/ available to control the process. Add of QbD (based on PAT) save time and continuous-manufacturing-has-a-strong- to this the qualification of raw mate- money, improve quality of the product, impact-on-drug-quality/ rials and one can monitor and, more and essentially eliminate recalls, it is 4. S. E. Kuehn, “Janssen Embraces Continu- importantly, control every step of the time to take the next logical step: con- ous Manufacturing for Prezista,” Phar- maceuticalManufacturing.com, Oct. 8, production stream. tinuous manufacturing (CM). 2015, www.pharmamanufacturing.com/ That is, one can characterize APIs, Now that more than one manufac- articles/2015/janssen-embraces-continu- raw materials, and packaging materi- turer of process equipment also supplies ous-manufacturing-for-prezista/ PT

Pharmaceutical Technology JUNE 2016 41 Single-Use Systems

contamination and cleaning, reducing water consumption, ability to run multi-molecules in the same facility, and small-scale commercial production with low numbers of batches per year. Monge (Sartorius Stedim Biotech): All those processes that require 1000 kgs per annum of product or less and can be manufactured in single-use bioreactors up to 2000-L scale or less can benefit enormously from working in single- use systems. Single-use [systems] offer increased flexibility to adapt to a wide variety of different processes at different scales coming through the pipeline. Sin- gle-use systems also enable increased productivity and reduced cost of goods. Integrating Single-Use There are many end-user case studies out there to prove this is the case. Systems in Pharma Antibodies, proteins, vaccines, cell therapy, and gene therapy all fall into categories of molecules that can ben- Manufacturing efit from being manufactured in fully single-use, end to end processes. Susan Haigney Chen (WuXi Biologics): Production scales between 15 L to 2000 L can all benefit from the use of single-use systems. Tra- ditional fed-batch cell culture process as Industry experts discuss the benefits well as perfusion processes can be eas- and challenges of using single-use systems ily implemented in single-use systems. WuXi Biologics, an open-access R&D in pharmaceutical manufacturing. capability and technology platform company dedicated to biologics and a WuXi o gain perspective on the use of larly when manufacturers are producing AppTec company, has embraced single- single-use systems in pharmaceuti- buffer solutions or cell-culture media. use technologies at full steam since 2010. Tcal manufacturing, Pharmaceutical Single-use systems reduce the time re- The rapid adoption of single-use tech- Technology spoke with Nandu Deorkar, quired to perform cleaning and cleaning nologies has enabled us to quickly build PhD,vice-president of Research and validation. They also allow manufactur- up and expand our production capacities. Development at Avantor Performance ers to more easily—and quickly—turn As a contract development and manufac- Materials; Steve Miller, global head of over from one product to another, or turing organization, single-use technol- Next Generation System Development, from one batch to another batch. In ad- ogy allows us to significantly reduce capi- Life Science, Upstream and Systems dition, single-use systems can connect tal cost and facility construction time and Business Field Millipore S.A.S; Miriam two unit operations, thereby minimizing increase running rate by quick turning- Monge, director of process development hold time and enabling continuous pro- around between different products and and bioprocess platforms, Integrated So- cessing. Finally, single-use systems are eliminating cross-contamination risks. lutions at Sartorius Stedim Biotech; and shown to reduce overall operating costs Dr. Chris Chen, CEO of WuXi Biologics. by minimizing or eliminating the need Ensuring compatibility for clean in place (CIP)/sterilize in place PharmTech: What measures should be Benefits of single-use systems (SIP), reducing analytical quality control taken when ensuring system compat- PharmTech: Which manufacturing pro- costs—specifically for raw materials— ibility between single-use systems? cesses benefit most from the use of and improving facility utilization time. What about between single-use and single-use systems? Miller (Millipore S.A.S): The main driv- stainless-steel equipment? Deorkar (Avantor): Both upstream and ers for single use have altered little Chen (WuXi Biologics): Different single- downstream manufacturing processes over the past 10 years. The processes use products could have significant dif-

benefit from single-use systems, particu- benefiting most have issues around ferences on design details, which might IMAGES/GETTY IMAGES ARTIFACTS

42 Pharmaceutical Technology JUNE 2016 PharmTech.com pose different degree of challenges when such as ensuring skids from different Monge (Sartorius Stedim Biotech): There it comes to system compatibility between vendors have compatible connectors are certain connectors that have become products from different suppliers. For ex- and common spare components such pretty standardized across the different ample, agitation/mixing and gas sparg- as clamps. Other, lesser-known chal- suppliers, so connectivity between dif- ing designs are quite different among the lenges are related to packaging, installa- ferent single-use systems is not really an single-use bioreactors from the several tion and disposal, as each manufacturer issue today. When talking about connec- major suppliers. The end-users need to may have different approaches, making tivity between single-use and stainless carefully understand and evaluate the operator life more complex and intro- (in the case that a hybrid process design design features of the various products. ducing opportunities for more errors. has been selected), autoclavable stainless The same challenges exist between sin- Deorkar (Avantor): Single-use system steel systems can be connected to single- gle-use system and the stainless steel sys- components are typically made using use systems with a sterile connector, such tems. Process transfer using the actual flexible polymer films or plastic. Be- as the Opta from Sartorius. The Opta is production cell line and processes must cause of this, you need to make sure autoclavable and can be connected to a be carried out to ensure system compat- there are no extractables or leachables, stainless-steel vessel and then autoclaved ibility, with special attention on potential which could impact cell growth, com- together with the vessel. This vessel can product quality impacts. Another chal- ing out of the system. These issues can then be connected to a single-use system lenge for a single-use bioreactor system impact product yield, quality, or stabil- equipped with the Opta counterpart. is the lack of reliable scale-down model. ity. More importantly, you should eval- PharmTech: Have you seen any spe- Representative scale-down models of uate the equivalency of the yield and cific challenges in compatibility be- single-use bioreactors are typically at 50L the product quality coming out of the tween single-use systems? Can you scale, which is too expensive and also not single-use system versus a stainless-steel provide examples? practical/convenient to use. system. If there is a difference between Monge (Sartorius Stedim Biotech): One of Miller (Millipore S.A.S): Implementing the cell growth in the stainless steel ver- the challenges when testing single-use single use brings with it new challenges sus single-use systems, you might see a systems is that you need to compare the that traditional facilities do not face, difference in product, yield, and quality. different testing methodologies used by

Pharmaceutical Technology JUNE 2016 43 Single-Use Systems the different suppliers. This is the case applications in single-use. Recent in- Assessing the supplier’s process know- for extractables and leachables, pre-use dustry reports demonstrate that current how, supply chain, manufacturing pro- and post-use integrity testing, and vis- biocompatibility testing did not always cesses, support organization, and field ible and non-visible particulates. It is not detect cell growth issues. The discovery force are much more important. always easy to compare like with like. of a cytotoxic leachate raised industry Another big difference for single-use Deorkar (Avantor): The long-term storage awareness of the need for new evaluation versus traditional technologies is the im- of solutions, such as buffers or cell-culture techniques and testing to determine po- portance of evaluating all scales of equip- media, in single-use systems can gener- tential impacts of plastics used in single- ment, even if the procurement exercise is ate extractables and leachables, which use systems on cell culture plastics for the small scale only. A technology may may cause impurities. One way to ad- Deorkar (Avantor): Before making a work fine at a 50-L scale; however, when dress this challenge is to prepare buffer media or buffer selection, manufactur- you scale to 2000-L processes, ergonom- or media on an as-needed basis by using ers should discuss packaging options ics and process robustness/optimization solid materials that are customized for with their materials suppliers. Often, the become a huge factor in the commercial one single-use tank, rather than concen- composition of packaging films in which operation. The difference with single use trated buffer solutions that are already in a material is supplied is just as important is that customers can be stuck with the liquid form. We have provided customers as the material itself, because the packag- technology they chose at the small scale with single-use powder materials in bags ing can impact the quality of the product. and the conversion to alternative suppli- or other containers that are pre-weighed Manufacturers should consider the ers, even if there are significant advan- and compatible with single-use systems. impact that different buffer solutions or tages at the large scale, are too big a risk The packaging that contains the solid can cell-culture media may have on the integ- on the timeline to consider switching. be attached directly to a tank and the bi- rity of the single-use component—bags, Monge (Sartorius Stedim Biotech): This opharmaceutical manufacturer can then for example—in which they are supplied. is best verified through a supplier qual- make the solution, avoiding the long-term For example, some packaging for liquids ity and supply chain audit. This includes extractable/leachable compatibility issue. supplied for single-use systems may not reviewing the supplier quality system and be 100% impermeable to air. This could manufacturing systems and ensuring that Media and buffer selection change the buffer pH, conductivity, or these are cGMP compliant. Ensure that PharmTech: What should be considered stability of some solutions. By seeking out the level of compliance is consistent across in regard to media and buffer selection a supplier that can provide pre-weighed supplier sites, check the manufacturing when using single-use systems? solid materials in packaging that is com- environment in which the single-use Monge (Sartorius Stedim Biotech): It is very patible with single-use equipment, manu- systems are manufactured (ISO class 7 important to review what tests are being facturers may be able to avoid this com- manufacturing environment for single- carried out on the single-use systems and mon issue. This type of packaging may use systems is what the majority of end- to which industry standards they comply. also eliminate time-consuming material users specify as a requirement), verify For example, at Sartorius we are align- subdivision and kitting steps, which can customer change notification process, ing our testing methodologies with the reduce total cost of ownership, improve and complaint management process. industry standards that are identified as efficiency, and reduce the potential for Another important part of your single- creating the greatest consensus in the contamination. use supplier audit includes supply chain industry both by suppliers and indus- security to ensure that the supplier has try end-users and are recognized by the Validation and qualification the systems in place to ensure delivery regulatory authorities. In this context, of single-use systems performance and offer best assurance of we are engaging actively notably with the PharmTech: What steps should be taken supply and business continuity. American Society for Testing and Mate- when validating suppliers of single-use PharmTech: What are the challenges rials (ASTM) E55 working groups (E55: equipment? of qualifying single-use equipment? Manufacture of Pharmaceutical and Bi- Miller (Millipore S.A.S): There are many Miller (Millipore S.A.S): The challenges opharmaceutical Products) developing similarities to validating suppliers of here are making the process robust. standards for extractables and leachables, traditional equipment: checking that the Qualifying the perfect scenario is easy, integrity testing at vendor factory and at proposed equipment matches the pro- but anticipating damaged or dropped end-user site, particulates at vendor fac- cess and is compliant with regulations assemblies, qualifying how assemblies tory, and at end-user site and cell growth. and surface contact compatibility. What move from grey to clean space, and dis- When thinking about selection of sin- is different is that choosing single-use posal are all exaggerated versus tradi- gle-use systems and films for media, the equipment is the beginning of a multi- tional facilities. These challenges can be cell growth issue is of particular concern. year relationship between the customer minimized by ensuring equipment and Here we have proposed the development and the supplier. Therefore, ensuring the assemblies come from the same supplier, of a new standard assay assessing the suit- supplier’s commitment is more akin to a as they should have qualification proce- ability of specific plastics for cell growth filter purchase than a system purchase. dures as part of the total solution. PT

44 Pharmaceutical Technology JUNE 2016 PharmTech.com Facility Design

special and often unique considerations. As a consequence, modular packages end up being “optimized”; for all intents and purposes they are designed to order. When facility changes become necessary, plug-and-play is not Deciding When the only scenario. Over time, changes to the prefabricated components themselves will be required. The reality is, to Use Modular due partially to the tight tolerances afforded by assembly in a factory, pre- Construction fabricated components can be difficult and expensive to modify once in the Eric Bohn field. On a direct capital comparison, modular construction usually represents greater initial costs. When there is savings, it is usually not found in the first cost, but in associated costs such as operational or validation savings. Equipment/process skids Probably coming closest to meeting the Different types of modular systems ideals imagined for modular design is have advantages and disadvantages. the skid mounting of various process and utility equipment. Most tank, valve, and pump-based operations can be skid odular construction is a loose The notion of modularity, by itself, is mounted. Some examples include various term used to define a number of appealing. The idea of discrete, standard- process components, clean-in-place/ster- Mdifferent prefabrication strate- ized components that can be assembled ilize-in-place systems, valve clusters, and gies. In general, it is a technique of in different configurations offers benefits cleanroom utilities. To fit on a skid, all assembling components in a factory that are easy to imagine. Combining components need to be installed within that, once completed, are transported standard components in multiple ways a defined footprint. This type of installa- to the construction site. The term is symbolizes flexibility and scalability. It tion requires careful coordination to en- used to distinguish it from the tra- suggests an ability to increase capacity sure there is adequate access for both op- ditional practice of field fabrication, by merely plugging in new modules and erations and maintenance activities. Too where basic materials are assembled the potential for reuse by removing and tight a footprint can result in a contorted on site. Modular construction, how- relocating existing modules. Fabrica- configuration. Valves and components ever, is a term used indiscriminately tion in the controlled setting of a fac- may be oddly located and difficult to ac- to describe many unrelated approaches tory represents dependable, repeatable cess, hindering operations and mainte- ranging from process/utility skids and quality that reduces or even eliminates nance activities. Provided the plan allows pre-engineered, modular cleanroom rework. In addition, it promises greater enough space, discrete unitized skids can wall systems up to the prefabrication safety for the construction workers. The be quickly and easily installed and capac- of entire buildings. Using modularity conditions within a factory also imply ity readily expanded. The efficient layout, or field fabrication directly impacts schedule benefits. Not being subject to build quality, and space efficiencies pro- the design process, the construction the variable conditions found in the vided by skidded equipment can be well cost, and even operations and their field—such as weather, difficult access, worth the additional cost. attendant costs. Understanding the and inefficient sequencing—results in Similar to equipment skids, but dif- advantages and disadvantages of differ- fewer delays. Finally, these attributes ferent in level of integration, is mod- ent types of modular construction can often combine, leaving the impression ularized equipment. This approach contribute to a more informed decision. that modular design can reduce costs. uses multiple packaged units that are Due to the demands of the pharma- assembled to operate in parallel or se- ceutical industry, however, the ability ries and can be expanded by plugging Eric Bohn is partner at JacobsWyper to standardize has significant limita- in additional units. This approach is Architects, 1232 Chancellor St., Philadelphia, PA, 19107, tel: 215.985.0400, tions. Every facility has process and readily applied to boilers, compres-

www.jacobswyper.com. installation conditions that demand sors, vacuum pumps, etc., and it can IMAGES GAVNI/GETTY

Pharmaceutical Technology JUNE 2016 45 Facility Design be a good choice when a facility has expectations for fu- Because these systems are designed to be demountable, there ture expansion. While the cost for a modular system will is potential for wall reconfiguration. Demounting and rein- be higher than a similar sized conventional unit, it is still stalling prefabricated components generates little dust and is a less than buying a single unit that is oversized for an antici- much cleaner process than reconfiguring conventional walls, pated future capacity. Such underutilized equipment oper- but the seamless integration of wall and ceiling makes this a ates inefficiently. Meanwhile, the future capacity may never more complicated undertaking. The modifications that seem arrive. If and when the need does arise, a modular system is to happen most relate to changes of equipment and their utili- expandable to meet the demand, and a high level of operat- ties. Cutting panels that are already installed requires a skilled ing efficiency and built-in redundancy are achieved. and experienced technician to achieve a clean outcome. Unless one employs the panel installer, this is difficult to execute well. Modular cleanroom wall systems With modular cleanroom systems the advantages need to Pre-engineered, modular cleanroom wall systems are de- be weighed against the initial high cost. There are, however, signed specifically for GMP-compliant operations. The best potential tax advantages that can be considered. As tangible systems provide an integrated system of walls and ceilings personal property, modular walls can be depreciated over a with a finish that is truly seamless. The cleanability of such much shorter period than conventional construction. smooth surfaces is unsurpassed. Wall thicknesses are less than traditional, field-assembled construction, being roughly Prefabricated buildings half the thickness of drywall. In a large facility, these inches Perhaps the pinnacle of modularity is buildings entirely add up, and reasonable increases in usable space are possible. composed of prefabricated modules. Such modular struc- Utilities, however, do not fit well within the thickness of mod- tures come in various forms. All of them, however, are in- ular walls. Some systems are UL listed for the installation of tegrated assemblies that join together to create facilities of power cabling, but other piped utilities are not accommo- significant size, housing multiple functions and pieces of dated as easily. Unlike drywall partitions, where larger studs equipment. Because they are transported over the road, their can provide for most piping conditions, modular cleanroom dimensions are limited. Fairly representative of the largest walls require that chases be built for piped services. prefabricated unit is a typical 8-feet wide by 40-feet long intermodal container. While a temporary office might use a single unit, a pharmaceutical facility typically uses multiple units assembled side by side and often stacked one on top of another. In some cases, only the mechanical areas, such PharmSource as penthouses and central utility plants, are modularized. Lead Sheet Besides the greater initial capital cost, perhaps the largest limitation is the relatively small dimension of the module. dŚĞĚĞĮŶŝƟǀĞƐŽƵƌĐĞĨŽƌ Comparatively, the structure of an 8- by 40-foot unit is nearly ƚĂƌŐĞƚĞĚŶĞǁďƵƐŝŶĞƐƐ 75% smaller than a relatively typical 30- by 40-foot site- erected structural bay. The increased number of columns ŽƉƉŽƌƚƵŶŝƟĞƐŝŶ in a modular building can make the layout inefficient and ďŝŽͬƉŚĂƌŵĂĐĞƵƟĐĂů may result in a larger footprint. There are many instances, ĐŽŵƉĂŶŝĞƐ͘ however, where modular is a superior choice, such as for re- mote locations where the knowledge and skills to construct a sophisticated pharmaceutical facility are not readily avail- X “A superb direct source to Used and respected current, well-suited leads so we can by the top CMOs, able. Also, off-site fabrication allows overlapping activities, ŽƉƟŵŝǌĞŽƵƌĐůŝĞŶƚďĂƐĞ͘” CDMOs and CROs potentially shortening the construction schedule, particu- –Head of Sales, NA around the world. larly when commissioning and validation are considered. X ͞/ƚ͛ƐĂƉŚĞŶŽŵĞŶĂůůĞĂĚ ŐĞŶĞƌĂƚŽƌ͘/ǁŽƵůĚƐĂǇŝƚŚĂƐ Focused. Conclusion ĚŽƵďůĞĚŽƵƌŽƉƉŽƌƚƵŶŝƟĞƐ͘͟ Timely. On a first-cost basis, modular construction is more expensive –Dir., Global BD than field fabrication. It impacts facility design and must be X ͞dŚŝƐŚĂƐůĞĚƚŽŵĂŶǇŝŵƉŽƌƚĂŶƚ Accurate. integrated early. However, in the right circumstance there ŵĞĞƟŶŐƐĂŶĚŽƉƉŽƌƚƵŶŝƟĞƐ͘͟ are many benefits. The higher level of control in a factory –VP of Business Development, setting provides dependable quality, worker safety, and reli- Global CMO able scheduling. Modularity can allow flexibility and future нϭ͘ϳϬϯ͘ϯဒϯ͘ϰဓϬϯDirect expansion. Higher capital costs can be offset by operational ϭ͘ဒဒဒ͘ϳϳϳ͘ဓဓϰϬToll-free in USA and even tax benefits. While not a panacea, modular con- [email protected] | www.pharmsource.com struction can be a great choice to meet a facility’s needs, but only after a thorough review of the costs and benefits. PT

46 Pharmaceutical Technology JUNE 2016 PharmTech.com STATISTICAL SOLUTIONS

Demonstrating a PHOTODISC/GETTY IMAGES State of Control PharmTech.com/statsPharmTech.com/stats

Christopher Burgess Do you have acceptable control of your instruments and analytical procedures?

perators of analytical laboratories following is a quotation from a NIST surements are traceable within accept- in a regulated environment are CRM, which NIST calls a standard able limits to the accuracy defined by Oalways concerned about being in reference material (SRM), certificate SRM 1930 the user must first deter- a demonstrable state of control. One for glass filters used for the calibration mine the required tolerances or accept- important aspect of this ‘state of control’ of the absorbance scale of a spectro- able uncertainty for the application in is the proper use of certified reference photometer (1): “An acceptable level question. It is recommended that a materials in the calibration of instru- of agreement between the user’s mea- number of replicate measurements be ments and the performance of proce- surements and the certified value and made for each filter and wavelength, dures. This article looks at a structured its expanded uncertainty overlaps any with removal and replacement of the approach to decision rules for user part of the user’s tolerance band de- filter between replicate measurements.” measurements with certified reference fined by the measured mean and the Assume that, at a particular wave- materials to guard against bias. user-defined level of acceptability.” length, the certified value is 0.4326 Decision rules Asking if one’s systems and procedures How do you construct the acceptance are in a state of control might seem to be an easily answerable question, espe- limits for user measurements of a CRM? cially if one used a traceable certified reference material (CRM) from the Na- NIST appears to propose that one absorbance units and the uncertainty tional Institute for Science and Tech- needs just two elements to construct is ±0.0029 absorbance units (U). Also nology (NIST), for example. After all, an acceptable level of agreement with assume that the mean value measured the CRM comes with a certified value the certified value and the user’s re- on the user’s spectrometer is 0.4251 together with an expanded measure- quirements. The first part is simple. and that the spectrometer has a speci- ment uncertainty doesn’t it? Actually, Take the value of the certified standard fication for absorbance accuracy of the methodology required to answer value from the certificate, xo , and its ±0.0035 absorbance units (A). this question is not as well known as it expanded uncertainty U. Hence the Therefore xo ± (U + A) becomes the ac- should be. The question becomes: How uncertainty interval at 95.45% confi- ceptance limits (AL)0.4326 ± (0.0029 + do you construct the acceptance limits dence (k=2) is xo± U. 0.0035) or 0.4262 to 04390. As the mean for user measurements of a CRM? NIST then introduces the concept of measured value found was 0.4251, which Let’s look first at an example of an user acceptability based upon the mea- falls outside this range, the spectrom- instrument calibration for absorbance surement capability of the instrument eter is considered inaccurate. One can accuracy of a spectrophotometer. The or the laboratory, A. So if one simply clearly confirm the effectiveness of this adds the SRM expanded uncertainty to decision rule by running a Monte Carlo Chris Burgess, PhD, the spectrophotometer manufacturer’s simulation (MCS)model using the SRM is an analytical scientist tolerance to the measurement capabil- values and setting the acceptance limits at Burgess Analytical ity, A, then these form the acceptance as above. The result is shown in Figure 1. Consultancy Limited, ‘Rose Rae,’ The Lendings, limits for satisfactory calibration or The simple approach presented, Startforth, Barnard Castle, Co method performance, i.e., xo ± (U + A). however, is not sufficient, especially as Durham, DL12 9AB, UK; In addition, this certificate states the certificate method mentions repli- Tel: +44 1833 637 446; chris@ burgessconsultancy.com; that the measurement process should cate measurements and a mean value. www.burgessconsultancy.com. be “to demonstrate that a user’s mea- Therefore, one needs to include the

Pharmaceutical Technology JUNE 2016 47 Statistical Solutions

metrological uncertainty of the user’s Figure 1: Monte Carlo simulation (MCS) model in Minitab Devize for standard reference measurement in the acceptance limits. materials certified value of 0.4326 absorbance units and s=0.075 (N=50,000) with The SRM certificate references acceptance limits (U+A). LSL is lower specification limit. USL is upper specification limit. NIST Special Publication 829 (2) as the source document for acceptance lim- LSL USL 4000 its and, in section E3a, the statistically correct calculation for the AL required is defined as Equation 1: 3000 s AL = ± t + (U + A) Mean (0.05, n-1) √n 2000 Measured Absorbance [Eq. 1]

1000 This is because the above simpler approach does not take into account 0 0.420.425 0.43 0.435 0.44 0.445 the metrological uncertainty of the mean measured value, which depends on the standard error of the mean of n measurements. If one takes six mea- Figure 2: Monte Carlo simulation (MCS) model in Minitab Devize for standard reference surements and calculates the standard materials certified value of 0.4326 absorbance units and s=0.075 (N=50,000) with deviation, s, of 0.0015 absorbance units acceptance limits based on metrological uncertainty+(U+A). (Equation 2), s t = 0.0015 = (0.05, n-1) 2.571 0.0016 LSL USL √n 2.449 4000 [Eq. 2]

3000 then the ALs become AL = ±0.0016 Mean + (U + A) = ±0.0080 giving an accep- 2000 Measured Absorbance tance range of 0.4246 to 0.4406. After taking into account the met- 1000 rological uncertainty, the mean measured value, 0.4251, now falls within this range, so the spectrometer is con- 0 0.420.425 0.430.435 0.44 0.445 sidered sufficiently accurate. This enhanced decision rule is confirmed once again by MCS modeling Figure 2. For those readers wishing for more Figure 3: Monte Carlo simulation (MCS) model in Minitab Devize for certified reference statistical background and excellent materials certified value of 99.46% and s=0.075 (N=50,000) with acceptance limits discourse, please read Churchill Eisen- based on metrological uncertainty+(U+A). hart’s classic paper of 1963 on “Real- istic evaluation of precision and accu-

LSL USL racy of instrument calibration systems” 4000 (3), which is freely available from the NIST archive as is NIST Special Pub- 3000 lication 829.

2000 Standard control If this acceptance limit approach works for calibration, will it work for stan- 1000 dards and methods? Yes, it will if one has a certified and traceable CRM with 0 99.2 99.3 99.4 99.5 99.6 99.7 99.8 a measurement uncertainty.

Contin. on page 54

48 Pharmaceutical Technology JUNE 2016 PharmTech.com TROUBLESHOOTING Equipment and Processing Examining Blow-Fill-Seal DANLEAP/GETTY IMAGES DANLEAP/GETTY Technology for Aseptic Processes PharmTech.com/Troubleshooting Caroline Hroncich Industry experts discuss common considerations and recent technological advancements in blow-fill-seal technology.

low-fill-seal (BFS) provides a sterile cations are just a few of the components with the plastic resin. Rommelag has solution for aseptic technology by impacting the success of BFS processes. standard test kits with sterile 10-mL Breducing human intervention in Pharmaceutical Technology sat down containers made from various plastics the fill/finish process. FDA’s guidance with Hartzel, Kram, and Goll to discuss for this purpose. Extractable profiles for the industry, Sterile Drug Products common considerations and technologi- for the plastics need to be examined Produced by Aseptic Processing—Current cal advancements in BFS technology. for potential incompatibilities with Good Manufacturing Practice, defines BFS as “an automated process by which containers are formed, filled and sealed “The temperature rise inside the vial is in a continuous operation” (1). BFS ma- totally dependent on the process and chinery must be designed to “prevent the potential for extraneous contamina- application.” tion,” FDA writes. Bill Hartzel, director, strategic execution, Catalent Pharma —Andy Goll, Weiler Engineering Solutions, says BFS can be used with a range of products, from simple solu- BFS and plastics the products. Accelerated and normal tions to complex biologics. Tim Kram, PharmTech: What types of plastic materi- stability studies will be performed to general manager, Rommelag USA, says, als can be used with BFS? find out what leachables are present “BFS is best suited for single dose (unit- Hartzel (Catalent): The primary materi- and what the impacts are. This is the dose) aseptic and terminally sterilized als used are medical grade polyolefins. same process that would be performed drug products.” Some drug products For ophthalmic and respiratory prod- on a glass vial and its rubber stopper. suitable for BFS include respiratory, ucts, where squeezability and flexibility The plastic needs to be able to pro- ophthalmic, oral, and injectable drugs. are important for administration, low- vide the function the intended use re- BFS is internationally accepted as density polyethylene (LDPE) predomi- quires. This may be a simple twist-off an advanced aseptic liquid processing nates. For containers intended for stor- top or a more complicated feature. The technology, says Andy Goll, director of age, high-density polyethylene (HDPE) plastic material will also be evaluated sales and marketing at Weiler Engineer- is more common, and polypropylene for water vapor permeability and gas ing. Goll attributes this recognition to (PP) may be used if broader chemical permeability. Polyolefins have a good the “inherent safety” in BFS processing resistance, enhanced barrier properties, water vapor barrier but a gas barrier of drug products, since there is very lit- or greater thermal stability are required. that is not sufficient for products that tle, if any, human intervention during Goll (Weiler): The main plastic materi- are highly sensitive to oxygen or other BFS processing. While BFS may reduce als used are LDPE, HDPE, and PP. gases. Products that need additional the likelihood of product contamina- Kram (Rommelag): The most com- barrier protection commonly use section, there are several things to consider mon are polyolefins: polyethylene (PE) ondary foil overwraps. before selecting BFS technology. Prod- and PP. BFS is an aseptic filling technology, ucts must be able to withstand momen- PharmTech: What are the consider- but in the case of injectable products tarily high temperatures and long-term ations when choosing a type of plastic there is a regulatory requirement to per- exposure to polymer (2). Factors such as for an application? form an overkill terminal sterilization wall thickness, material compatibility, Kram (Rommelag): The first check is to (if the product can withstand the pro- sterility assurance, and product appli- see if the product is directly compatible cedure). The most common route for

Pharmaceutical Technology JUNE 2016 49 Troubleshooting sterilization is steam autoclaving. The ide mixture may be required, HDPE is batching, which adds an extra level of standard here is 121 °C. PP materials quite frequently used due to the high cooling to the internal surfaces of the are the most suitable for this application. extrusion temperatures and homoge- vial or bottle. The temperature rise in- Injectable products have a regulatory nous mixing characteristics of the two side the vial is totally dependent on the requirement to be inspected for visible materials. HDPE is probably the least process and application. Heat transfer particulate. Other product types find common resin chosen in most BFS ap- studies have been conducted where the it beneficial to have clearer containers. plications. product inside the vial could see a tem- Resins with better clarity are typically perature rise from 10 °C to 12 °C. This preferred over others. Cost is a consid- “Wall thickness is is dependent on the product tempera- eration when considering all the resin ture entering the vial, internal volume options available. a critical process of the vial, and fill volumes inside the Goll (Weiler): The main considerations vial or bottle. when choosing a plastic are the applica- condition.” Hartzel (Catalent): This is one of the tions. When filling injectable products, most frequently asked questions in for example, you will most likely need —Tim Kram, Rommelag BFS, especially as more thermally sen- to terminally sterilize the products. If sitive molecules (i.e., biologics), are the product is not heat sensitive and Hartzel (Catalent): When choosing a evaluating the value of BFS. Catalent can withstand a terminal sterilization plastic for a primary container closure; has been producing a thermally sen- cycle of 121 °C, then you would want to safety, efficacy of the product, and func- sitive biologic using this technology. choose a PP that has the proper barrier tion of the container need to be consid- Additionally, the industry has done a characteristics to withstand the high ered. To check the compatibility, stabil- significant amount of work to under- temperature sterilization. The resin ity studies are required as well as the stand and optimize the control param- characteristics of PP are somewhat sim- matching of the physical characteristics eters to minimize the heat impact the ilar to that of glass. It is a much harder or function of the container to deliver BFS process can have on the product. and more rigid material and often times the product. For example, if you have This concern is derived from the fact can be a little more difficult to open de- eye drops that are applied by squeez- the temperature of the molten plastic pending on the application. ing the container to express a drop, as it enters the mold is around 180 °C. For most other applications where you would choose LDPE. Alternatively, However, from the data we have gener- a high temperature terminal steriliza- if you need to terminally sterilize the ated, the heat is dissipated extremely tion cycle is not required, LDPE would product with an autoclave you would efficiently allowing the plastic mate- be the resin of choice. LDPE offers de- choose the higher thermal stability of rial to cool rapidly in the mold. The cent oxygen barrier characteristics and a PP container. Often, barrier proper- main contributing variable is the is quite successful in most extractable ties are questioned because plastics are container design itself, control of the and leachable profiles depending on the semipermeable. Even though there are container wall thickness, and fill vol- product. There are many new LDPE res- different rates of permeation depend- umes. Through the implementation ins which actually have characteristics ing on plastics (e.g., PP has better bar- of additional temperature controls on that allow for a higher terminal steril- rier properties than LDPE), the use of the formulation side of the BFS process, ization temperature up to 115 °C. Most a foil overwrap is a common practice such as cooling the bulk solution and pharmaceutical blow molding grade to provide barrier properties that are insulation, an average product tem- LDPE resins offer very nice molding similar to glass. perature of approximately 23 °C can capabilities that allow for intricate de- be maintained. tail for forming of the main body of the Temperature considerations Kram (Rommelag): Methods are avail- vial, and also opening features that may PharmTech: How long is the product/con- able to keep the heat impact upon the be more complicated when using PP or tainer at an elevated temperature and product minimal. Under normal situ- HDPE resins. are there any concerns related to this? ations, a product can either be filled HDPE resins are more commonly Goll (Weiler): The BFS molds have under room temperature (20 °C) or used for large irrigation and eye-wash chilled water running through the in- be brought back to room temperature bottles where a preservative may be ternal structure of the mold housings. within a few minutes. Most products used in the formulation. HDPE has As soon as the mold closes around the have heat sensitivity based on a tem- very good oxygen permeation/barrier parison, the cooling process begins perature for a certain amount of time, characteristics to ensure a stable prod- immediately. Additional cooling is or do not exceed a temperature. Typi- uct with a slightly longer shelf life. In applied simply due to the filling pro- cally, we are able to modify the BFS applications where a combination of cess of the liquid drug product. Most system to accommodate these product the HDPE resin and a titanium diox- product formulations are chilled after requirements. In the end, all products

50 Pharmaceutical Technology JUNE 2016 PharmTech.com Troubleshooting need to be tested with the BFS process. proper utilities, training of operators, cess that automates the formation and Not all products will be compatible. and understanding the BFS process filling of a primary container closure. will ensure success to anyone entering The technology can then be leveraged Optimizing processes the field of BFS technology. for new markets, and change the way a PharmTech: What should be considered product is delivered to the patient. It is when optimizing the processing condi- Technology advancements evident in the creation of new container tions of the BFS equipment? PharmTech: How have recent technology closures that meet specific patient Kram (Rommelag): The most common improvements advanced BFS processing? needs, such as closures with multiple considerations when optimizing BFS Goll (Weiler): As product applications ports, or a flat design that fits within equipment processing conditions are become more accepted globally, mar- a more compact delivery device. Ulti- container function and closure integ- kets requiring more stringent regulatory mately, the technology facilitates con- rity. These two items are related. Wall guidance are demanding process en- tainer designs that can deliver products thickness is a critical process condition hancements, which minimize risk for more effectively. for a twist-off top on a unit-dose drug container or a piercing point for a container feeding aseptic liquid to a device. “The true innovation has revolved [If the wall is too thick] the torque required to remove the twist-off, or en- around leveraging the BFS technology ergy to pierce the container, will be too to create better primary packages that high. [If the wall is too thin], the twist- off may be damaged during secondary ultimately assist patients and caregivers.” packaging or transport and result in a leaking container. For container clo- —Bill Hartzel, Catalent Pharma Solutions sure integrity, the most critical point is where the container is to be opened. At an added level of safety to the patient. Kram (Rommelag): Disposable fill sys- that point, the container has been pur- The most recent advance for Weiler tems have been developed that work posely weakened so the closure func- BFS technology is the introduction with BFS technology. This will allow tions properly. Optimization involves of NO2 gas sterilization for the grade higher-value products to be filled several mechanical systems found on A filling zone. In collaboration with with lower losses than the traditional the BFS equipment. Noxilizer, this new technology offers a time-pressure-dosing systems, and Hartzel (Catalent): Product quality and safe and effective means of a complete reduce the time necessary to set up a ensuring sterility are the most impor- 10³ endotoxin reduction. Since the machine compared to the standard tant considerations and this is always grade A filling zone is the critical fill- clean in place/sterilize in place process. at the forefront of our process design. ing zone, NO2 offers the assurance of a Rommelag has also developed a single We need to understand the critical con- complete decontamination or depyro- mold variation for their closed parison trol parameters and ensure the sterile genation (customer dependant) cycle rotary technology. This new system boundary is maintained and the pro- prior to the start of a filling campaign. adds flexibility while keeping the high cess creates inert containers. As the Hartzel (Catalent): In recent years, aseptic assurance levels offered by the next step, we evaluate the production there have been several innovations, closed parison technology. Other addi- efficiency, which is heavily influenced for example the introduction of a filling tions include automated vial inspection by the formulation, container design, technology that can reduce particulates, systems that perform IPC tests that are and the packaging requirements of and enhanced temperature controls of commonly done by hand, adding re- the product. Often times the industry the process formulation. But the true peatability and the ability to give direct focuses on just the BFS front but sec- innovation has revolved around le- feedback to the BFS system. Automated ondary packaging requirements are a veraging the BFS technology to create particle inspection for injectable prod- significant contributor to the overall better primary packages that ultimately ucts has also been introduced. efficiency and many hidden costs. assist patients and caregivers. The mar- Goll (Weiler): For the BFS process ket is gaining a better understanding of References alone, special consideration should be how and where BFS fits into primary 1. FDA, Guidance for Industry, Sterile Drug given to process parameter develop- packaging design and the processing of Products Produced by Aseptic Processing— ment prior to the validation stage, in aseptic products. The major technology Current Good Manufacturing Practice the form of an engineering study and improvements lie in companies taking (Rockville, MD, September 2004). proper execution of the process valida- advantage of the true value of BFS as an 2. R. Hernandez, BioPharm International, tion. Facility design, the utilization of advanced aseptic manufacturing pro- 28 (7) 2015. PT

Pharmaceutical Technology JUNE 2016 51 OUTSOURCING OUTLOOK

Watch Out for the Hangover SVETA DEMIDOFF/GETTY IMAGES DEMIDOFF/GETTY SVETA PharmTech.com/ptoutsource Jim Miller Acquisition binges often lead to hangovers; here’s what to watch out for.

erger and acquisition (M&A) ac- point, typically five years or so after culture that can take years and a lot tivity remains robust across all their initial acquisition, when the own- of cash. Companies pushed to show Mindustries, including contract ers are looking to sell. profits that justify the deal may not be pharmaceutical services, as low interest willing or able to make the investments rates and slow organic growth create Pharma pitfalls necessary for successful integration. both the opportunity and the rationale However, flurries of acquisition activ- The resulting complexity can have for doing deals. Recent events suggest ity, such as those seen in the past few negative implications ranging from that the world may have reached the years, invariably lead to hangovers that delayed financial reports (which can boundaries of what is doable, how- can impact the operations and even violate loan covenants) to high staff ever, as some large deals, such as the the viability of the buyers. In times turnover to, in extreme cases, compli- proposed combination of Pfizer and of strong end-market demand, such ance issues because facilities operate Allergan in pharma and Halliburton as the contract services industry has under different quality and standard and Baker-Hughes in petroleum, have been enjoying, there is intense desire to operating procedure (SOP) regimes. fallen apart over issues of tax policy, antitrust, and global commodity prices. Flurries of acquisition activity Volatility in the world’s stock markets is also making it more difficult to do invariably lead to hangovers that deals where payment is to be made in shares rather than cash. can impact the operations and Deals in the contract manufacturing organization (CMO) world aren’t likely even the viability of the buyers. to be affected by those macro-economy issues because of their relatively small close deals to broaden capabilities and Sustaining capex. Some acquirers are size and scope, and it is expected that build market share. In the rush to do piling on debt in order to fund their a number of them will be announced deals while financial markets are ac- acquisitions. In the current financial in the later part of 2016. A number of commodating, companies can outrun environment, interest rates are low, factors will continue to drive M&A in their operating and financial capabili- but interest, principal repayment, and the CMO sector including a difficult ties. The following are some potential loan covenants may limit cash avail- initial public offering (IPO) market, pitfalls that bio/pharma companies able for investment in new plant and the scramble for strategic assets, facil- need to watch out for when doing their equipment. Further, as noted above, ity divestments by global bio/pharma due diligence on service providers that integration may require investment in companies, and a number of private have been active acquirers. new information technology and other equity-owned companies reaching the Integration challenges. Putting man- capabilities that compete with the need ufacturing, sales, human resources, for new or replacement manufactur- Jim Miller is president and accounting operations on the ing equipment. Customers can be per- of PharmSource same platform is a big, expensive un- suaded to pay for some new investment, Information Services, dertaking that companies may fail to but that is usually for specialized dedi- Inc., and publisher of Bio/Pharmaceutical anticipate. Integration often requires cated equipment, not basic capabilities. Outsourcing Report, investments in new software platforms, Strategic effectiveness. Acquisition- tel. 703.383.4903, additional senior executive leadership, driven companies can be susceptible Twitter@JimPharmSource, [email protected], intensive staffing retraining, and ulti- when the underlying strategy proves www.pharmsource.com. mately the creation of a new corporate to be inappropriate or difficult to ex-

52 Pharmaceutical Technology JUNE 2016 PharmTech.com

Outsourcing Outlook ecute. For instance, the full service impact on the CMO industry, the fund- organization (CDMO) industry vet- CMO model looks to be an appropriate ing slowdown could impact the industry erans may also recall what happened response to the efforts by bio/pharma in 2017–2018 if it continues. to AAIPharma 10 years ago when it companies to consolidate their sup- tried to transition from a CDMO to a plier base. But just as a chain is only Bad examples pharmaceutical company. Corporate as strong as its weakest link, a CMO’s While acquisitions are an important executives may challenge the boundar- reputation can suffer badly if any part and legitimate avenue for companies ies of ethical and legal practices when of the full service offering falls below to broaden their capabilities and gain their market and business assumptions acceptable standards of performance. market share, it’s important to remem- prove unrealistic. Adverse market changes. Given the high ber that such strategic considerations Most of the major players in the prices paid for acquisitions and the use of aren’t always what is driving deal ac- CDMO industry are well-managed and debt to fund them, acquirers may be es- tivity. Often acquisitions are sought as conduct careful due diligence when car- pecially susceptible to any downturns in a remedy for slow organic growth (i.e., rying out their acquisition strategies. But demand for contract services. Especially the inability of the current core business bio/pharma companies that depend on in a fixed-cost business such as manu- to grow as quickly as the owners would CDMOs for product development and facturing, small declines in demand can like). Also, it should be noted that pri- in-market supply owe it to themselves lead to disproportionately large declines vate equity firms are paid to put capital to be especially diligent when qualify- in profitability, and any profit declines to work and may be driven to do deals in ing suppliers that have been actively ac- put debt servicing and loan covenant part to demonstrate to investors that they quiring new businesses. Inquiring about compliance at risk. are doing just that. integration activities and capital struc- External funding for early stage bio/ While Valeant Pharmaceuticals ture may not be part of the usual due pharma companies has always been cycli- is not a CMO, its recent travails are diligence questionnaire but the answers cal, and there was a sharp drop-off in ex- a close-to-home illustration of what could be crucial to the success of the ternal funding in the first quarter of 2016 can happen when the assumptions relationship. Even if the survival of the as valuations of early stage bio/pharma underlying an acquisition-driven supplier is not immediately threatened, companies came down sharply. While strategy prove to be unrealistic. Con- clients need to be aware of potential dis- there may not be an immediate negative tract development and manufacturing ruptions to the business. PT

Statistical Solutions— contin. from page 48

Assume one has a primary CRM with The difference between the cer- the NIST basis for it discussed. The a certified value of 99.46%, with an ex- tified value and the mean value is approach has been confirmed using Δ = x X = . ∣Δ∣ < Δ panded uncertainty of 0.15 (i.e., xo ± U . o – 0.23 As c; there- Monte Carlo simulations. If laborato- If one has generated a working standard fore, at 95% confidence, there is no evi- ries adopt this approach, they will have that has been assayed six times against dence that the working standard does a sound statistical basis for deciding if this primary standard, and finds a mean not lie within the combined acceptance an instrument or method is ‘fit for pur- value of 99.23 with a sample standard limits set by the laboratory requirement, pose’ or not. deviation of 0.062, from an analytical the metrological uncertainty, and the viewpoint, the laboratory has decided measurement uncertainty of the CRM. References that it is acceptable to have a bias be- Using MCS (Figure 3), it is clear that 1. NIST, SRM 1930 Glass Filters Certificate, tween the standards of ±0.05%. the combined acceptance limits en- www-s.nist.gov/srmors/certificates/ar- Using the full equation for the ac- compass the large majority of the dis- chive/1930.pdf Δ 2. D. Becker et al., “Use of NIST Standard ceptance range, c, and including the tribution of the CRM values and that metrological uncertainty, this becomes less than 0.03% of the values is likely to Reference Materials for Decisions on Per- formance of Analytical Chemical Meth- Equation 3: lie outside these limits. ods and Laboratories,’” NIST Special 829 s Publication (1992), http://nvlpubs. Δ = t + (U + A) Conclusion nist.gov/nistpubs/Legacy/SP/nistspe- c (0.05, n-1) √n The method for calculating accep- cialpublicatiot n829.pdf 0.062 tance limits for calibrations based on = (2 .5 71 √ )+ (0.15 + 0.05) = 0.27 3. C. Eisenhart, J. Res. Natl. Bur. Stand., 6 user measurements of certified refer- 67C, 161 (1963) https://archive.org/de- [Eq. 3] ence materials has been described and tails/useofniststandar829beck. PT

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Pharmaceutical Technology JUNE 2016 55 Compliance is Key Solutions to Decrease the Likelihood of Receiving a Form 483

LIVE WEBCAST: Thursday, June 23, 2016 at 11:00 am EDT Register for free at www.pharmtech.com/pe/compliancesolutions

EVENT OVERVIEW: Compliance to regulations requires in depth knowledge and adherence to the latest GMP guidelines and sustaining these Presenter guidelines and technical standards in the laboratory environment. TARA HUNDLEY Quality and Recent FDA inspections have exposed a lack of data integrity, Compliance Manager incomplete audit trails, and inadequate procedures as regulators Anton Paar USA continue to tighten their approach to inspections for drug license holders and contract service organizations. It’s crucial for scientists Moderator and managers to understand the key issues surrounding FDA RITA PETERS compliance. Editorial Director Pharmaceutical This 45-minute webinar will look at what constitutes a FDA Form Technology 483, recent warning letters issued by the agency, and the top 10 pharmaceutical and medical device citations for non-compliance Who Should Attend: in 2015. The presentation will include recent 483 excerpts and areas for improvement in basic laboratory controls to prevent data ■ Research scientists from analytical manipulation. One instrument manufacturer’s practical solutions development, formulation and raw to improve data integrity and 21 CFR Part 11 concerns will be material laboratories discussed. ■ Quality control and quality assurance personnel Key Learning Objectives: ■ Contract research manufacturing ■ Understand differences between a Form 483 and warning organization, laboratory staff and letter quality assurance personnel ■ Review recent Form 483 citations ■ Laboratory managers, laboratory ■ Recognize what needs to be addressed to ensure compliance supervisors, and production managers within a GMP environment ■ Interested parties understanding the ■ Learn about approaches to improve quality and compliance in importance of following cGMPs a laboratory environment