Ideas and Incentives for Advanced Manufacturing

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PEER-REVIEWED Evaluating a New Quality Control Test for Soft Gelatin Rectal Capsules

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4 Pharmaceutical Technology JANUARY 2019 PharmTech.com SMA MicroParticle ICS Non-Viable Particle Counters

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STERILE.COM For more information, visit our website at sterile.com/particlecounters VELTEK ASSOCIATES, INC. January 2019 Volume 43 Number 1 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 technologytechnologgyay andand testing,testing, packaging,pacp kagaging, IT,IT, outsourcing, and regulatory compliance in the pharmaceuticalphaharmaceutical and biotechnologybiotechnolooloogygy industries.ind

r COVERCO STORY e v 1616

o Bio/PharmaB Needs Ideas and c

IncentivesInc to Advance Manufacturing

e WhileWWhhiile pharma is proving its capabilities to develop novel therapies,

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CoverCCoovveer Design by Dan Ward

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SPECIAL REPORT: EMPLOYMENT SURVEY FORMULATION REGULATORY UPDATE 24 Solving Bio/Pharma 34 Considering Protein 46 Data Integrity Employee Career and Peptide Delivery Topped 2018 Priorities Advancement Demands New approaches seek to address This year promises to bring more Keeping valuable employees happy— formulation and delivery challenges focus on risk management and and on the job—may test for these complex molecules. building a quality culture, says bio/pharma business decisions. consultant Susan Schniepp. BIOPHARMACEUTICAL API SYNTHESIS & MANUFACTURING MANUFACTURING ANALYTICS: SOLUBILITY 30 FDA Marks Record Year 38 Continuous Processing: 48 The Solubility for New Drug Approvals Challenges and Opportunities Conundrum Orphan and cancer drugs continue of Virus Filtration Early adoption of the right to lead, but treatments for many common Requirements for virus filtration approach to address solubility diseases were also approved in 2018. must be considered in developing can deliver significant benefits. continuous downstream processes. PACKAGING 52 Smarter Packaging Comes to the Pharma Market Active and intelligent packaging technologies benefit brand owners, caregivers, and patients.

PEER-REVIEWED RESEARCH

PEER-REVIEWED Continued on page 8 41 Evaluating a New Quality Control Test for Soft Gelatin Rectal Capsules Soft gelatin capsules (SGC) are popular dosage forms; however, rectal capsules must dissolve in minimal fluid and hydrodynamics. This article demonstrates how qualitative physical attributes testing can be used to characterize SGC rupture/disintegration for rectal administration.

PharmTech.com

Continued from page 6 NEWS & ANALYSIS REGULATION & DEPARTMENTS/

FROM THE EDITOR COMPLIANCE PRODUCTS 10 Internal and REGULATORY WATCH 12 Product Spotlight External Challenges 14 CDER Priorities 60 Pharma Capsules to Pharma in 2019 for 2019: Opioids, 61 Showcase/Marketplace Pricing pressures, investment Quality, Safety, volatility, and government and Innovation 61 Ad Index dysfunction greet Pharma in 2019. FDA plans to support initiatives OUTSOURCING OUTLOOK to ensure that all medicines are safe, effective, and of high quality. 56 The Outlook for CMO Outsourcing in 2019 ASK THE EXPERT Outsourcing of manufacturing 62 Global Inspection activities is expected to increase in 2019. Harmonization Understanding the differences in inspection processes is the key to successful global expansion, according to Siegfried Schmitt, PhD, vice-president Technical, PAREXEL Consulting.

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Internal and External Challenges to Pharma in 2019

Rita Peters Pricing pressures, investment volatility, and government dysfunction greet Pharma in 2019.

ood news about a record-setting is enthusiasm over new therapies, Bristol-Myers Squibb announced on number of new drug approvals in these products must prove com- January 3 that it will acquire Celgene G2018 was tempered by financial mercial success to maintain inves- in a cash and stock transaction val- and political pressures external to the tor interest in biologic products, the ued at $74 billion. industry. Questions on Bio/Pharma’s report said. 2019 agenda include pressure to lower A Deloitte report (3) in mid-2018 Restructuring FDA? drug prices and contain costs, and deal said the majority of US companies While the pharma industry—and the with a volatile investment market and were interested in investing in R&D, rest of the nation—awaited a resolu- contentious federal government. business operations, and capital tion to the partial government shut- In an annual GlobalData outlook re- projects, including some US opera- down, a white paper (4) based on port (1), 51% of respondents said drug tions, as a result of the corporate tax input from seven former FDA com- pricing and reimbursement constraints reforms of the Tax Cuts and Jobs Act missioners, recommended FDA be will have the greatest negative impact enacted in December 2017. The bio/ reconfigured as an independent fed- on the pharmaceutical industry in pharma executives surveyed said eral agency. A new structure is needed, 2019. While some drug companies self- they were likely or very likely to in- they argued, to promote science-based imposed price freezes in 2018—under vest in R&D (67%), capital projects decisions, increase transparency, pressure from the Trump Administra- (57%), general business operations streamline processes for developing tion and Congress—many kicked off (50%), share buybacks (50%), and regulations and guidance documents, 2019 with price increases for more than M&A (42%). Lower priority invest- and allow for more responsive and 100 drugs averaging 6.3%. ments were compensation/pension predictable decision making. funding (40%) and hiring (40%). The white paper stopped short Investment options of recommending a new model for The investor market resembled a roller Big deals agency operations but defined sev- coaster in 2018, ending on a downward The 2016 presidential election and eral major shortcomings of current trend. The Vantage 2019 Preview re- tax reform debate of 2017 put some operations. With federal government port (2) said it was difficult to predict mergers and acquisition activity on operations on hold over political how much further the market may fall, hold, according to the Deloitte report; squabbling, it was nice to see con- and those interviewed for the report however, deals picked up in the first structive efforts to address what ails expected a more volatile year. half of 2018. the industry. Companies looking for funding In three weeks spanning the end will have to work harder in 2019, but of 2018 and start of 2019, several References the report says financing options are large deals were reported. Pfizer 1. GlobalData, The State of the Biopharma- not expected to dry up. While there and GlaxoSmithKline announced ceutical Industry–2019, January 2019. 2. A. Brown, J. Gardner, and E. Elhmirst, on Dec. 19, 2018 that the companies Vantage 2019 Preview, December 2018. will merge their consumer health- 3. D. Green, M. Zellars, and C. Chang, “Life care products businesses and form a Science Companies More Bullish on US separate consumer-focused company. Investment Post Tax Reform,” Deloitte Rita Peters is editorial On Jan. 7, 2019, Eli Lilly announced Insights, 2018. director of Pharmaceutical 4. The Aspen Institute, Seven Former Technology. Send your an agreement to acquire Loxo On- FDA Commissioners Recommend: thoughts and story ideas to cology for $8 billion. And, in one of FDA Should be an Independent Federal

[email protected]. the largest pharma acquisitions ever, Agency, White Paper, January 2018. PT PATPITCHAYA/SHUTTERSTOCK.COM

10 Pharmaceutical Technology JANUARY 2019 PharmTech.com pda.org/2019BiopharmWeek 2019 PDA Biopharmaceuticals Week Cell and Gene Therapy, Virus Safety, Biosimilars and Vaccines

Save the date for PDA’s inaugural Biopharmaceuticals Week, May 6-10 in Long Beach, CA. This exciting new week-long meeting format features three events focused on biopharmaceutical manufacturing, including: • 2019 PDA Cell and Gene Therapy Conference • 2019 PDA Virus Safety Forum • 2019 PDA Biosimilars and Vaccines Conference: Lifecycle Similarities and Challenges Plan to attend one, two, or all three of these events, with expert perspectives on the information you need about these evolving areas!

Throughout the week, industry and regulatory experts will share the latest on key breakthroughs; industry research; and new areas of inquiry, including lifecycle management for biosimilars and vaccines, facility segregation and design for cell and gene therapy, virus detection, and knowledge management, among others.

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Improved Mixer Lift Tabletop Spray Dryer and Seal Designs Fluid Air’s portable PolarDry Electrostatic Spray Dryer Model Charles Ross & Son Company has 0.1 is compact in size while made improvements to the dual- retaining the same features of post hydraulic lift and seal design previous spray dryers. The spray of its 1500-gallon Multi-Shaft Mixer dryer’s smaller dimensions Model PVM-1500. The new lifting allow the system to fit inside design is a double-acting, fully spaces such as most lab hydraulic cylinder operating at a fume or containment hoods. higher pressure, allowing for a The dryer produces small- smaller cylinder and less oil for scale samples with minimum operation. David Hathaway, vice- product loss and can be easily disassembled for autoclave president of Ross Engineering, states sterilization, the company reports. The system is compatible that with the new design, the lifting with optional high temperature and ultrasonic spray drying system provides faster lifting speed nozzles that ensure efficient microencapsulation. The ultrasonic when raising and lowering the agitators. nozzle is suited for creating small particles less than 10 microns, The new seal arrangement allows seal replacement and formulators still have the choice to use the Model 0.1 as without removing agitator shafts. Unlike the historical a standard spray dryer with two fluid nozzles. Other features design, seal replacement no longer requires removal of the include a programmable logic controller system with data- mixer from the tank nor tank entry to access the seal. logging, zero need for an atomizing heat, and low volatility loss. The PVM-1500 features three independently driven agitators: a screw auger, a high-speed disperser, and a three-wing anchor Fluid Air agitator. The sides and bottom of the changeable mixing vessel www.fluidairinc.com are insulated and jacketed for up to 50 psig. According to the company, this vacuum-rated machine can run continuously and is supplied with rugged touchscreen controls showing digital read- Microplate outs for speed, cycle time, vacuum level, and batch temperature. Spectrophotometer Ross,Charles & Son www.mixers.com The Epoch 2 Microplate Spectrophotometer from BioTek Instruments has added features that Electrical Position Indicator include monochromator-based individual wavelength selection or wavelength for Linear Actuators scanning from 200–999 nm to accom- modate a range of assays, including GEMÜ’s 1205 electrical position indicator nucleic acid and protein quantification, is suitable for demanding applications enzyme-linked immunosorbent assay, microbial growth, endo- in category 2, zone 1, and/or zone 21 toxin, reactive oxygen species assays, and enzyme kinetics. New “atmosphères explosibles” or equipment onboard software eliminates the need for a separate computer and for potentially explosive atmospheres includes predefined common protocols for rapid assay setup and (ATEX) areas, as well as for robust use recall. Custom protocol definition, storage, and selection are easily at low temperatures down to -20 °C. accomplished via the optional color touchscreen interface. Endpoint, The indicator has an aluminum kinetic, and spectral scanning applications are all available from the flameproof enclosure and an ‘increased touchscreen; data can be output to a USB flash drive or printer. safety’ ignition protection type, with The spectrophotometer is compatible with 6- to 384-well all interior movable components microplates and cuvettes as well as the company’s Take3 Micro- intended for a long mechanical life, Volume Plate for dilution-free nucleic acid quantification in vol- the company reports. Additionally, umes as low as 2 μL. Advanced shaking profiles include linear, the indicator has continuously adjustable microswitches for orbital, and double orbital, and 4-Zone incubation to 65 ºC and recording end positions with which the closed and/or open posi- Condensation Control facilitate temperature-sensitive assays. tion can be reliably recorded with a valve stroke of 2–70 mm. BioTek Instruments GEMÜ www.biotek.com www.gemu-group.com/en

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Customer Service: 1-800-848-8483 regulatory watch CDER Priorities for 2019: Opioids, Quality, Safety, and Innovation Jill Wechsler FDA plans to support initiatives to ensure that all medicines are safe, effective, and of high quality.

t will be a challenge for FDA to match Ensuring quality review process to better manage product or exceed its success in 2018 in ap- CDER has launched a two-year program changes through the drug lifecycle. Iproving record numbers of innovative to improve oversight of drug safety, fea- and generic drugs. These achievements turing new methods to evaluate the more Accelerating approvals reflect the ability of biopharma compa- than two million adverse event reports An important goal for Woodcock is to nies to capitalize on important advances received in 2018 on marketed drugs. The complete the overhaul of the new drug in science, as well as strong support from agency is pressing drug companies to review process. She recently named Peter regulators in clarifying requirements and comply more fully with GMPs through Stein director of the Office of New Drugs R&D policies. While the Center for Drug more targeted inspections and recalls (OND), and long-time CDER guru Bob Evaluation and Research (CDER) will for those failing to meet standards. Drug Temple will become OND senior advisor, strive to further enhance its operations, compounding pharmacies and outsourc- positioned to address the more contro- it also will support initiatives to ensure ing facilities will remain in the spotlight versial and difficult drug development that all medicines are safe, effective, and in 2019, as FDA inspectors continue to and review issues. Woodcock hopes to of high quality. find violations at these operations. A finalize the OND reorganization by next Amidst these advances, CDER Direc- related initiative is to continue to imple- summer, but it has been delayed by diffi- tor Janet Woodcock cites the importance ment requirements for tracking drugs culties in gaining Congressional approval of addressing the nation’s opioid epi- through the supply chain to detect un- of a new user fee program for improving demic as FDA’s top priority for 2019. The authorized medicines, an effort designed the regulation of over-the-counter drugs. immediate need is to reduce the more to have “a big impact on the gray market,” Modernizing the review process will than 200 million outpatient prescriptions Woodcock commented. CDER’s Office of involve implementing new automation for these drugs each year. Legislation (1) Pharmaceutical Quality (OPQ) will con- tools for managing drug applications, instructs FDA to develop evidence-based tinue to seek more timely inspections of study data, and review documents under prescribing guidelines and to explore manufacturing facilities, a process that a “multi-disciplinary, issue-based review how manufacturers can provide pain should be facilitated by a new inspection document” system. CDER also will con- medicines in more secure packaging, protocol for drugs, beginning with sterile tinue to carry out provisions of the 21st Woodcock pointed out at the FDA/CMS drug manufacturing facilities. Century Cures Act and reauthorized user Summit in December 2018. At the same These efforts may be enhanced by fee programs to further advance patient- time, FDA will develop guidelines on visible progress in industry implement- focused drug development, expanded developing non-opioid medications for ing advanced manufacturing systems. use of real-world evidence, novel clinical acute and chronic pain to improve treat- Woodcock noted at the Summit that trial design, and added authorities to hire ment for patients. five firms have filed applications with more experts needed to carry out these continuous manufacturing components, multiple drug regulatory programs. and that generic-drug makers are moving in this direction. Other federal agencies Reference support such efforts as a way to enhance 1. US Congress, HR 6, Substance Use–Dis- surge capacity when additional treat- order Prevention that Promotes Opioid Recovery and Treatment for Patients and Jill Wechsler ments are needed to manage infectious Communities Act, Oct. 24, 2018, www.con- is Pharmaceutical disease outbreaks or bioterrorism attacks. gress.gov/bill/115th-congress/house-bill/6/ Technology’s Washington editor, OPQ also aims to launch a structured ap- all-info. PT

[email protected]. proach to the manufacturing supplement CAM/SHUTTERSTOCK.COM ORHAN

14 Pharmaceutical Technology JANUARY 2019 PharmTech.com Regulatory Watch

Digital health Digital health became an increasingly important focus area for FDA in 2018. References After launching the Digital Health Innovation Action Plan in 2017, which is 1. Scott Gottlieb, “Statement from FDA Commissioner Scott Gottlieb, MD, and Center for Devices and Radiological Health Director Jeff Shuren, MD, JD, on seeking to modify the agency’s approach to digital health products (1), FDA Agency Efforts to Work with Tech Industry to Spur Innovation in Digital formed the internal data science incubator, the Information Exchange and Data Health,” FDA Statement, Sept. 12, 2018, www.fda.gov/NewsEvents/Newsroom/ Transformation (INFORMED), in 2018. The agency has also proposed to create a PressAnnouncements/ucm620246.htm 2. FDA, “FDA Permits Marketing of Artificial Intelligence-Based Device to Detect Center of Excellence for Digital Health in its Fiscal Year 2019 Budget. Certain Diabetes-Related Eye Problems,” Press Release, April 11, 2018, www.fda. Also in 2018, FDA approved the first medical device that combined a special gov/NewsEvents/Newsroom/PressAnnouncements/ucm604357.htm. camera and artificial intelligence to detect greater than a mild level diabetic 3. FDA, “FDA Permits Marketing of Artificial Intelligence Algorithm for Aiding Providers in Detecting Wrist Fractures,” Press Release, May 24, 2018, www.fda. retinopathy in adults who have diabetes in a primary care setting (2) and per- gov/NewsEvents/Newsroom/PressAnnouncements/ucm608833.htm. mitted the marketing of an artificial intelligence algorithm for aiding providers 4. Conor Hale, “New Apple Watch Receives FDA Clearance for Built-in ECG,” in detecting wrist fractures (3). Most recently, FDA awarded de novo clearance FierceBiotech, September 12, 2018. www.fiercebiotech.com/medtech/new- apple-watch-receives-fda-clearance-for-built-ecg. to Apple’s Series 4 model of the Apple Watch (4). —Cynthia A. Challener, contributing editor FDA Commissioner Scott Gottlieb has indicated that digital technology requires “a reimagination of healthcare delivery” (1). The agency is committed More in regulatory news to fostering, not hindering, innovation in digital health technology. Gottlieb Visit PharmTech.com to read the following: hopes the new Center of Excellence will “help establish more efficient regu- • FDA Issues Sentinel Five-Year Strategic Plan latory paradigms, consider building new capacity to evaluate and recognize www.pharmtech.com/fda-issues-sentinel-five-year-strategic-plan third-party certifiers, and support a cybersecurity unit to complement the • EMA Authorized 84 Drugs in 2018 advances in software-based devices.” www.pharmtech.com/ema-authorized-84-drugs-2018 From artificial intelligence technologies such as deep learning and natural • EMA Publishes Draft Guidance on Antibiotic Development language processing to smart devices and advanced software and apps, digital www.pharmtech.com/ema-publishes-draft- technologies will clearly play an increasing role in drug and medical device guidance-antibiotic-development-0 development going forward.

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Pharmaceutical Technology JANUARY 2019 15 Bio/Pharma Manufacturing

A Deloitte/GlobalData study (2) reported that R&D returns at 12 Big Pharma companies hit 1.9% in 2018, the lowest level in nine years, down from 10.1% in 2010. Costs to bring a biopharmaceutical drug to market have Bio/Pharma almost doubled since 2010 from $1.18 billion to $2.18 billion while forecast Needs peak sales per asset have fallen from $816 million in 2010 to $407 million in 2018, the report notes. Ideas and Four small, specialized biopharma companies analyzed for the report fared better than the Big Pharma companies Incentives with returns on R&D of 9.3%. Higher development costs ($2.8 billion) were offset by higher anticipated sales ($1.17 billion). to Advance In light of ongoing criticism of the high cost of drugs, raising prices may Manufacturing not be the answer; bio/pharma companies need to find innovative ways to improve efficiencies. Rita Peters Warning signs In 2016, the number of warning letters issued by FDA for good manufacturing practice infractions doubled and main- While pharma is proving its capabilities to tained that high level in 2017 and 2018. The number of drug products recalled develop novel therapies, the industry still by FDA’s Center for Drug Evaluation and Research (CDER) has declined in needs to work on manufacturing innovation. the past two years; however, the number of recall events increased to the sec- 2003 Wall Street Journal ar- saw the approval of new treatments ond highest level in the past 10 years (3). ticle noted a pharmaceuti- for infections, the first novel antiviral While efforts over the past five years have A cal industry “secret;” as the treatment for the flu in 20 years, the cut the number of new shortages from industry develops “futuristic new first drug with an indication for treat- 251 in 2011 to 35 in 2017, as of Jan. 3, drugs, its manufacturing techniques ment of smallpox, the first non-opioid 2019, FDA listed 114 drugs as “currently lag far behind those of potato- treatment for the management of opi- in shortage” and 207 as discontinued (4). chip and laundry-soap makers” (1). oid withdrawal symptoms, and the Two examples demonstrate the impli- Since the article was published, the first drug that contains a purified drug cations of substandard quality and inef- introduction of quality-by-design substance derived from marijuana. fective drug manufacturing on patients practices, new monitoring technolo- The upswing in approvals of novel and company bottom lines. gies, and advances in science and therapies indicates that bio/pharma Recalls of angiotensin II receptor engineering have improved some bio/ companies are embracing innovation blocker (ARB) drug products from mul- pharma manufacturing processes. In in R&D. However, analysts report that tiple manufacturers—due to the pres- too many cases, however, manufac- R&D efforts show diminishing re- ence of probable human carcinogens turing and quality practices are still turns. And, the ongoing pace of FDA traced to API manufacturers—were inadequate or too expensive. warning letters, observations, recalls, launched in 2018 and continued in early The number of drugs approval by and drug shortages demonstrates 2019. As the recalls widened, regulatory FDA—as well as innovative “firsts” that the bio/pharma industry still has authorities around the world scrambled designed to address patient needs— work to do to achieve efficient, cost- to identify the root cause of the impuri- accelerated in the past two years. Fol- effective manufacturing, quality, and ties and implications for patients. lowing the 2017 approvals of the first analysis to ensure a safe, sufficient Frustrated with the high cost and

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16 Pharmaceutical Technology JANUARY 2019 PharmTech.com

Bio/Pharma Manufacturing hospitals, seven health organizations technologies that may not be efficient ability of advanced technologies does not representing 500 US hospitals formed or cost-effective in the long term. necessarily mean they are widely adopted, Civica Rx, a not-for-profit generic drug Some advanced manufacturing tech- however. For example, “significant ad- company; the new organization plans to nologies—such as continuous manufac- vances are being made in rapid AA detec- manufacture drugs for use by patients turing for solid-dose drugs, 3D print- tion utilizing next-generation screening at the member hospitals. In September ing of drug products, and single-use that are yet not being broadly throughout 2018, the company announced that it bioreactors—have demonstrated ef- the industry,” Carbonell explains. has identified 14 hospital-administered fectiveness. Recent FDA approvals of The equipment, instrument, or pro- generic drugs and will either directly continuous manufacturing processes cess-related steps that bio/pharma should manufacture generic drugs or sub-con- for oral solid-dose drugs has spurred take to improve development and manu- tract manufacturing to contract manu- interest and innovation for advanced facturing varies from organization to or- facturing organizations (5). manufacturing processes. The Engi- ganization based on a number of factors, The Deloitte study authors stressed neering Research Center for Structured Hausner says. “In general, though, for the need for a “transformational change” Organic Particulate Systems (C-SOPS) powder-based manufacturing, an invest- in R&D productivity that uses technol- at Rutgers University (NJ) works with ment in physical property characteriza- ogy—artificial intelligence, robotic industry and FDA to modernize phar- tion coupled with advanced data analytics process automation, natural language maceutical manufacturing processes fo- of the resulting data can greatly improve processing and generation, and machine cusing on continuous processing with organizational familiarity with ingredi- learning—to replace or augment work predictive control and the next genera- ents and what works for various applica- done by humans. Partnerships, collabo- tion of dosage forms. tions. This enables organizations to gain rations, and non-traditional operational “There is a lot of technology out formulation manufacturability experi- models will be necessary to compete in a there, but the largest challenge re- ence, which is additive, and can greatly digital environment and companies will mains in bringing it all together in a expedite process development over time.” have to compete with non-pharma orga- timely and cost-effective manner,” says nizations for the technical talent needed Douglas B. Hausner, associate director The fear of being first to operate a digitally-driven company. of C-SOPS. “This is a challenge with Bio/pharma companies operate in a Many of the predicted applications of modern advanced methods that have regulated environment and face pres- information technology focus on drug greater complexity and require greater sures to control end-product prices discovery, clinical trial, and patient upfront effort and investment to then while driving investor return on monitoring applications. There are, run smoothly thereafter. Much of this costly R&D efforts. The tendency to however, opportunities to adopt other pertains to software, sensor, and control take a conservative approach to the new technologies for drug formulation, integration. Some companies are look- adoption of new technologies or ma- process development, manufacturing, ing to form partnerships and ‘pre-inte- terials is not surprising. and supply chain phases. grate’ where possible to minimize this.” “There are significant efforts within Many technological advances and large biopharma companies and sup- Advanced manufacturing materials are needed to reduce the costs pliers in the testing and evaluation of technology needed of biopharmaceutical manufacturing, novel approaches to cost-effective man- While bio/pharma companies have says Ruben G. Carbonell, chief technol- ufacturing,” says Carbonell. “Adoption demonstrated success at turning out ogy officer at the National Institute for of these technologies has been slow new therapies, the uptake of advanced Innovation in Manufacturing Biophar- because of perceived risks of not being manufacturing technologies to pro- maceuticals (NIIMBL), a public-private approved for new products or processes.” duce these products, or better ways to partnership that advances biopharma- Hausner notes that when assessing manufacture existing products, has ceutical manufacturing innovation and new technologies or processes to ad- been slower. workforce development. In-line process vance drug production, companies are Manufacturing issues, delays or ca- analytical technology (PAT) for product initially cautious and calculated, skepti- pacity issues, and loss of manufacturing quality and process control is one of the cal of regulatory acceptance, followed site account for two-thirds of the causes areas of greatest need, to enable contin- by enthusiasm and looking for rapid of drug shortages, FDA reports (6). uous and hybrid processes, he says. solutions and regulatory clarity. Capital costs, lost production time for Automated bioreactors and purifica- “Given the significant costs associated retrofitting, and the need for regulation processes for cell-therapy manu- with biopharmaceutical products, it is tory review for process changes deter facturing; rapid adventitious agent (AA) not surprising that biopharma compa- some companies from investing in new detection and novel materials for viral nies take a conservative approach to in- technologies for established product clearance; and other technologies to re- novation because they strive to ensure lines. The urgency to get a new drug to duce release times for biotherapeutics are market is incentive to stick to proven other areas of need, he says. The avail- Contin. on page 22

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Contin. from page 18 tise often in the form of new hires or at While the agency has issued guidance least vendor/consultant relationships. on emerging technologies and promotes acceptance by regulatory agencies,” says There needs to be true organizational the adoption of advanced technologies Carbonell. “One of the main barriers buy in for an advanced integrated tech- at industry meetings., a broader effort to adoption of new technologies is in- nology. It can be much closer to buy- by the agency is needed, wrote FDA deed the perceived risk of not achieving ing or building a new plant than a new Commissioner Scott Gottlieb in a July regulatory acceptance. The biopharma piece of hardware like a tablet press.” 2018 blog (7). industry, manufacturers and suppliers, “The bottom line is this: drug mak- should work side by side with regulatory FDA funding to fuel innovation ers won’t switch to these systems until agencies to evaluate new technologies to FDA actively encourages the adoption we create a clear path toward their ensure rapid adoption.” of advanced manufacturing processes. adoption and provide more regulatory “There is the obvious financial cost/ In 2014, the agency initiated an Emerg- certainty that changing over to a new benefit and the fact that unknowns ing Technology Program, which enables manufacturing system won’t be an and unproven tech are always harder, meetings between drug development obstacle to either new or generic drug but beyond this it often seems to come companies and FDA Emerging Technol- approvals,” wrote Gottlieb. “The FDA down to organizational readiness,” says ogy Team members to address potential recognizes that it’ll require additional Hausner. “Many new technologies are concerns about a novel technology prior investment in policies and programs complex and require additional exper- to filing a regulatory submission. that’ll provide regulatory clarity to

Addressing external pressures

Drug companies have traditionally outsourced research, development, Barry: The industry is starting to consider more carefully the effect or manufacturing processes to gain needed expertise and expedite reimbursement policies are having on pharma manufacturing. FDA development and manufacturing. What role can the contract services market Commissioner Scott Gottlieb announced this summer a task force to look play in improving drug development and manufacturing? What industry into this question. trends are impacting manufacturing strategies? Fiona Barry, associate editor, Gottlieb cited the problem that reimbursement policies by Medicare and PharmSource, a GlobalData product, shared industry research perspective on Medicaid and other payers could be making it difficult for companies to strategies to reduce production costs, the impact of reimbursement policies, manufacture certain drugs profitably. and global regulator collaboration with Pharmaceutical Technology. Another problem is that the current set-up inadvertently discourages drug PharmTech: The call by government officials, payers, and patients to companies from manufacturing drugs that are more likely to go into shortage, reduce drug prices will pressure drug companies to produce products more so it is likely the FDA will tackle this problem with financial incentives. cost-effectively. Will pressures to reduce drug prices encourage or discourage PharmTech: What actions can regulatory authorities take to help innovation? What are some strategies to reduce production costs? transform bio/pharma development and manufacturing? Barry (PharmSource, a GlobalData product): We predict a ‘Starbucks Barry: The major national regulatory authorities are generally very open approach’ to speeding new molecules through development while to innovation that helps the industry and keeps patients safe. For instance, maintaining quality, as biopharma companies, especially those with a large- the mutual recognition agreement (MRA) program allows the FDA and molecule pipeline, take advantage of technology and outsourcing to make regulators of select European Union countries to recognize each other’s production cheaper and more efficient. inspections. When it comes to making decisions about investments in bioreactors, The scheme has now spread to 21 countries following the addition of biopharma companies will ‘scale out’ to contract manufacturing Belgium, Denmark, Estonia, Finland, and Latvia in November 2018. If organizations (CMOs) rather than ‘scale up’ internally. regulators spread it to the rest of the EU, this would be a great step for Scale-up can throw up unexpected costs and quality problems. Companies industry and regulators alike: by avoiding duplicate inspections, compliant will be able to prevent this by choosing a bioreactor size early in the facilities would be spared from unnecessary visits, and regulators’ resources development process, and then increasing the number of batches; this avoids will be freed up to focus on problem plants. committing to a larger facility that might turn out to be unnecessary. As manufacturing markets mature in the rest of the world, MRAs could Recent developments—like GE HealthCare’s KUBio mAb facilities—show spread even further. Regulators seem open to this: for instance, the European flexible biologic facilities can be built and put into operation in under two Medicines Agency and Health Canada said last month they are considering years. This approach will allow flexibility around market size, and even mutual recognitions of inspections and batch certification. means companies could create plants when and where they are needed, The industry would also benefit from widening the scope of MRAs: for instead of using a single facility to support the global market. example, plasma-derived pharmaceuticals and clinical trial drugs are PharmTech: What do changes in other sectors of the drug development currently excluded from the MRAs between the FDA and European regulators, continuum, such as real-world evidence, biomarkers for clinical trials, and and from the MRA between the EMA and the Japanese regulator PMDA. new reimbursement schemes mean for the drug formulation, process —The editors of Pharmaceutical Technology development, and manufacturing sector?

22 Pharmaceutical Technology JANUARY 2019 PharmTech.com enable these new methods to be more costly and more risky in pharma. What “PBOA has worked with a cross-in- quickly and widely adopted.” results is the need for some sort of per- dustry consortium on FDA’s Quality The fiscal year 2019 budget includes ceived advantage in order for the cost/ Metrics guidances, providing feedback $58 million to accelerate the develop- benefit analysis to work, and this often from a CMO/CDMO perspective about ment of the regulatory and scientific comes in the form of regulatory accep- this well-intended but potentially dam- architecture, Gottlieb wrote. In August tance, exclusivity (biosimilars), expedi- aging program,” says Gil Roth, presi- 2018, the agency issued nearly $6 mil- tion (breakthrough designation), etc.” dent of PBOA0. “We’ve also worked lion in grants to Rutgers University, the Pre-competitive efforts have paid with FDA’s serialization team and their Massachusetts Institute of Technology, off in other industries, explained Car- new drug shortages task force.” and the Georgia Institute of Technol- bonell. “Years ago, the microelectronics In 2019, PBOA will continue work on ogy to study improvements to continu- industry created large, pre-competitive drug shortage issues, the implementation ous manufacturing, monitoring, and non-profit consortia of manufacturers, and rollout of the Drug Supply Chain Se- control techniques (8). An additional academic and research institutions, and curity Act and other regions’ serializa- $2.4 million in grants were awarded to government agencies to evaluate new tion laws. In addition, Roth says, they six universities to investigate improve- technologies, such as SEMATECH, to plan to educate FDA about the potential ments to continuous manufacturing for standardize and harmonize equipment, drawbacks of its quality metrics program biologic-based drugs (9). connectors, and measurement devices and address state and local bio/pharma and approaches,” he said. “These ef- laws that may impact CMO/CDMOs. More transparency? forts played a key role in reducing costs Increased transparency by regulatory and advancing the chip manufacturing References authorities about review and enforce- industry in the US.” 1. L. Abboud and S. Hensley, “New Prescrip- ment processes could inform other bio/ “Pre-competitive industry organization for Drug Makers: Update the Plants,” WSJ, Sept. 3, 2003. pharma companies about potential pit- tions play a major role by helping to 2 M. Steedman, et. al., Unlocking R&D falls in development or manufacturing inform the public consensus on new Productivity. Measuring the Return from processes. The need for confidentiality technology. This aids in regulatory un- Pharmaceutical Innovation, Deloitte, 2018. and protection of trade secrets, however, derstanding, acceptance, and approval,” 3. FDA, Enforcement Activity, www.fda.gov/ restricts information that can be released. said Hausner. “These groups perform a ICECI/EnforcementActions/ucm247813. htm. FDA warning letters disclose a limited soft harmonization on technology and 4. FDA, Drug Shortages, www.fda.gov/ amount of information about violations. nomenclature ahead of more official Drugs/DrugSafety/DrugShortages/de- Observations reported on Form 483 groups like regulatory bodies and stan- fault.htm. documents often are not revealed. Is- dard-setting organizations.” 5. Civica Rx, “Not-for-Profit Generic Drug sues noted in complete response letters “Industry-university-non profit- Company Officially Established, Attracts Interest of More Than 120 Health Orga- are rarely publicized. And, pharma com- government consortia such as NIIMBL nizations,” Press Release, Sept. 6, 2018. panies have released information about can play a key role in accelerating the 6. FDA, Drug Shortages Infographic, www. clinical trials that was contrary to FDA adoption of novel manufacturing ap- fda.gov/Drugs/DrugSafety/DrugShort- findings (10). The FDA commissioner has proaches. New technologies that show ages/ucm441579.htm. authority under 21 Code of Federal Reg- promise in the laboratory can be tested 7. S. Gottlieb, “FDA Budget Matters: Invest- ing in Advanced Domestic Manufactur- ulations 20.82 to disclose records under and de-risked in an industrial setting ing,” FDA Blog, July 13, 2018, www.fda. certain circumstances, but rarely does. taking into account regulatory expecta- gov/NewsEvents/Newsroom/FDAVoices/ tions,” said Carbonell. “These consortia ucm614919.htm More collaboration and research reduce the costs of technology develop- 8. FDA, “FDA Supports Critical Research to Although the complexities of drug ment and significantly reduce the risk to Spur Innovation for Continuous Manu- facturing Technology to Support and Ad- manufacturing may exceed that of other an individual company of developing a vance Drug and Biologics Development,” industries—including snack foods and new approach that may not be approved FDA in Brief, Aug. 1, 2018, www.fda.gov/ laundry soaps—can bio/pharma learn because it is not broadly accepted.” NewsEvents/Newsroom/FDAInBrief/ from other industries about adopting ucm615431.htm. new technologies? Contract services perspective 9. FDA, “FDA Awards Grants to Foster Innovation for Advanced Manufactur- “I would like to say yes, but in my Contract services organizations play ing Technology as Part of the Agency’s experience the answer is no. The dif- a key role in developing and manufac- Efforts to Ensure a Robust and Reliable ference in how bio/pharma develops turing drugs; in 2014, the Pharma & Supply of Biological Products,” FDA products with clinical trials and is reg- Biopharma Outsourcing Association in Brief, Sept. 20, 2018, www.fda.gov/ ulated relative to most other industries (PBOA) was formed to represent drug NewsEvents/Newsroom/FDAInBrief/ ucm621180.htm. makes a big difference,” said Hausner. industry contract manufacturing organi- 10. J. Sharfstein, et. al., Journal of Law, “In other industries, it is much easier to zation/contract development and manu- Medicine & Ethics, 45 (2) suppl, De- try other technologies, but this is more facturing organizations (CMO/CDMO). cember 2017. PT

Pharmaceutical Technology JANUARY 2019 23 Special Report: Employment Survey

accomplish a task contributed to job dissatisfaction. Nearly 70% voiced “issues with management” as a source of dissatisfaction. Intellectual stimulation was a leading reason people go to work.

Respondent profile More than 335 bio/pharma professionals from around the world responded to the survey, which was fielded in No- vember and December 2018. Respon- Solving Bio/Pharma dents primarily were full-time, perma- nent employees (87.3% of respondents) Employee Career at innovator bio/pharmaceutical companies (29.5%), generic-drug manufac- Advancement Demands turing companies (17.9%), and contract research and manufacturing organizations (16.7%). Rita Peters The represented companies develop or manufacture both small- Keeping valuable employees happy— and large-molecule drugs (48.1%), small-molecule drugs only (28.7%), and on the job—may test biologic-based drugs only (5.2%), vac- bio/pharma business decisions. cines (3.1%), and cell therapy or gene therapies (2.1%). he bio/pharma industry has found employer’s potential for success. (See Respondents reported a range of job itself under the microscope as ex- the infographic on pages 26–27 for an responsibilities including formulation, Tecutives search for answers to criti- overview of survey results.) quality control/assurance, R&D, ana- cisms about high drug prices, shortages Salary ranked ninth on a list of 12 lytical studies, process development, of vital therapies, and the industry’s factors contributing to job satisfaction. validation, drug delivery, and manu- role in the opioid epidemic. Meanwhile, Intellectual stimulation and challeng- facturing. More than 41% of respon- a record number of new drug approving projects were the top “main reasons dents work for companies with more als and the emergence of innovative I come to work,” followed by supportive than 1000 employees; more than 49% therapies demonstrate the potential of management, the company’s potential work for companies with fewer than bio/pharma R&D efforts. for success, a good work/life balance, 500 employees. Bio/pharma development and manu- relationships with colleagues, job se- Nearly 40% of the respondents held facturing relies on skilled and knowl- curity, and tolerance and opportunity doctorate or higher degree; one-third edgeable workers. Hiring and retaining for all employees. Employees based in held at least a Master’s degree. Com- this expertise should be a top priority. Europe placed more emphasis on in- pared with previous years, the respon- With the unemployment rate at record tellectual stimulation and challenging dents reported more experience work- lows, career opportunities for US-based work, compared with all respondents. ing in the bio/pharma industry; 21.9% bio/pharma employees should be prom- North America-based workers leaned had fewer than 10 years of experience, ising. Insight provided by respondents more toward salary and benefits fac- 24% had 10–20 years, 42.4% had 20–35 to Pharmaceutical Technology’s annual tors than the Europe-based peers. years of experience, and 11.8% have employment survey (1) suggests that Nearly 80% of all respondents, worked in the industry for more than employee satisfaction is tied to the chal- however, said that short timelines and 35 years.

lenges presented by the work and the insufficient budgets and resources to Text contin. on page 28 IQONCEPT/STOCK.ADOBE.COM

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60% 62.9% Does your current salary How secure do you feel 60% reflect a change over in your job compared last year’s salary? with last year?

54.1% 51.2%

■ 2018 ■ 2018 ■ 2017 ■ 2017 44.7%

37.1%

32.5%

24.7%

19.1%

8.8% 30.6% 4.7% 27.8%

Increase Decrease No Change More secure now Less secure now No Change

■ 2018 Please rate your satisfaction with your current salary. ■ 2017

I am paid below market value, considering 20.5% 50% my level of expertise and responsibility. 18.7%

I am paid within market value for my job function, 38.2% but at the low end of the range, considering my level of expertise and responsibility. 35.3%

I am paid fairly for my level of 39.2% expertise and responsibility. 43.6%

I am paid excessively for my level 2.1% of expertise and responsibility. 2.3% GRAPHICS: DAN WARD. CURRENCY: STILLFX - STOCK.ADOBE.COM CURRENCY: GRAPHICS: DAN WARD.

26 Pharmaceutical Technology January 2019 PharmTech.com Bio/pharma workers contemplate ●● Strongly Agree ●● Somewhat Disagree job and career changes. ●● Somewhat Agree ●● Strongly Disagree

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

60% What is your If it were necessary for you to change jobs this year, prediction for your how would you assess the job market? company’s business 2018 2017 prospects in the It would be straightforward to find a job 52.7% coming year? comparable to the one I have now. 27.4% 25.8% It would take a while, but I would be able to ■ Global find a job comparable to the one I have now. 44.3% 44.4% ■ Europe It would be straightforward to find a job, but it probably wouldn't be as 37.9% 39.4% good as the one I have now. 12.7% 14.8% I would have to search hard and be prepared to take what I could get. 15.6% 15.1% 30.2% In your career, how long, on average, have you stayed with the same employer?

●● Less than 2 years ●● 3 to 5 years ●● 6 to 10 years ●● 11 to 20 years Due to rounding, ●● More than 20 years some percent- ages may not add up to 100%. Some questions allowed multiple answers.

17.2% 22.7% Results based on 2018 Pharmaceutical Technology employment Improve Decline No Change survey.

Pharmaceutical Technology January 2019 27 Special Report: Employment Survey

Text contin. from page 24 Geography influences job Salary, time, and benefits Which statement best describes security and business outlook Salary dissatisfaction increased slightly Respondents were split on job secu- compared with the 2017 survey (2). the job market for scientific rity. Almost one-quarter of respon- More than 20% said they were paid or technical positions in bio/ dents said they felt more secure in below market value; 38% said their pay pharmaceutical development their position compared with the was at the low end of the salary range for previous year; only 19.1% felt more their expertise and responsibility. Just and manufacturing in your secure in 2017. However, 30.6% of all over 41% said they were paid fairly or geographic area? respondents said they were less se- excessively, compared with 46% in 2017.. cure, compared with 27.8% who said The most significant—and negative—— they felt less secure in 2017. survey response involved salary increases.. Geographic differences, and per- In 2018, only 54.1% reported an increase,, haps uncertainty created by the compared with nearly 63% in 2017.. Brexit, resulted in a more negative Nearly 9% reported a decrease in salary outlook for business prospects by in 2018, compared with 4.7% in 2017. European-based respondents. Of all respondents, 23.1% reported While 52.7% of all respondents that they used their full allotment expect business to improve, fewer of vacation, personal, and sick time.. than 40% of European-based Nearly 30% said they used less than respondents had a positive outlook. half of the available time off. Nearly one-quarter (22.7%) of the ● Competition for open positions is strong. Bonuses, profit sharing, and retire- ● Competition for open positions is moderate. Europe-based respondents expect ment benefits were largely unchanged ● Employers compete for qualified candidates. business to decline; 37.9% expect no year over year. However, one-quarter significant change. In comparison, reported an increase in the cost of Salary was the third most cited 17.2% of all respondents project health insurance. single reason for job change, trailing business will decline; 30.2% expect Fewer respondents reported in- professional advancement and intellec- no significant change. creased workloads in 2018 compared tual challenge. Job security and scien- In the past two years, nearly one- with previous years. Only 56.1% re- tific opportunities were other leading third of the respondents reported that ported heavier workloads in 2018, com- reasons noted. their companies had been through a pared with 60.9% reporting increases Most respondents were confident downsizing or restructuring, and in 2017. More than one-third of the they would be able to secure a job com- 18.1% experienced a merger or acqui- respondents (37.8%) say they worked parable to the one they currently hold; sition. Nearly 40% reported a change more hours in 2018 than two years ago, 27.4% said it would be straightforward in responsibilities due to the changes similar to responses in previous years. to find a new position; 44.3% said the in company structure. Only 10% said search would take a while. they left the company due to an acqui- Employment opportunities Respondents were divided almost sition, downsizing, or restructuring. Globally, one-third of respondents said evenly when assessing the pool of quali- One-quarter of the respondents they stayed with the same employer, on fied candidates and available job open- said they voluntarily changed jobs average, for five or fewer years. Nearly ings; 30.3% said there are few qualified in the past two years; among the 36% stayed for 11 or more years. US- candidates for open scientific/technical reasons cited—with multiple choices based respondents were more mobile; positions, 34.2% said there were more allowed—were to pursue a better ca- more than 33% said they stayed with qualified candidates than open posi- reer opportunity (48.7%), find more one employer, on average, for five or tions, and 35.6% said there was moderate challenging work (31.1%), or to seek a fewer years. The responses were con- competition for open positions. Respon- better work-life balance (20.3%). sistent with the 2017 responses. dents were not impressed by the skill sets Nearly 56% said they would like to or knowledge of new hires for their job References leave their jobs, given the opportunity, function; 75.2% said the new hires were 1. 2018 Pharmaceutical Technology/Phar- up slightly from 2017 responses. Al- adequately trained but not exceptional; maceutical Technology Europe Employ- most two-thirds said they do not ex- 17.8% said they were poorly trained. ment Survey, Pharmaceutical Technol- pect to leave in the coming year; nearly Respondents reported a slight in- ogy, 2018. 17% expect to leave. A similar number, crease in employer-provided training 2. 2017 Pharmaceutical Technology/Phar- 18%, said they would like to change for basic skills compared with previous maceutical Technology Europe Employ- careers and leave the bio/pharma in- years; however, training for advanced ment Survey, Pharmaceutical Technol- dustry, down from nearly 23% in 2017. functions declined slightly. ogy, 2017. PT

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© 2018 Merck KGaA, Darmstadt, Germany and/or its aﬃliates. All Rights Reserved. MilliporeSigma, the vibrant M, Millipore, and Emprove are trademarks of Merck KGaA, Darmstadt, Germany or its aﬃliates. All other trademarks are the property of their respective owners. Detailed information on trademarks is available via publicly accessible resources. MS_AD1937EN ver. 1.0 API Synthesis & Manufacturing releases issued by FDA and the drug license holders. Links to references and a list of 2018 drug approvals are published online on www.PharmTech. com/pt/2018approvals. Many accelerated drug approvals Based on information in FDA and company press releases, approximately half of the new drugs were approved under an expedited review process— Fast Track, Breakthrough Therapy, Pri- ority Review, Accelerated Review—or orphan drug status. These results suggest that both pharma companies and FDA remain committed to leveraging FDA Marks Record Year the shorter approval pathways made possible in the 2012 Food and Drug for New Drug Approvals Administration Safety Innovations Act. Nearly one-third of the new drugs Cynthia A. Challener were granted orphan drug designation, clearly reflecting the shift taking place in the industry away from the develop- Orphan and cancer drugs continue ment of blockbuster drugs to the development of therapies for rare diseases. to lead, but treatments for many common Despite all of the hype about and diseases were also approved in 2018. investment in biologic drugs, only one quarter of medicines approved in 2018 by FDA were biologic-based drugs. n 2018, FDA had a very active year. Also in June, FDA issued the first The agency investigated ways to of four draft guidance documents in- New ways to fight infections Iimprove the drug approval process, tended to inform patients and product In response to concerns about the grow- increase the efficiency of drug develop- developers about rigorous approaches ing prevalence of drug-resistant bacteria ment and better incorporate patient for obtaining and incorporating pa- and the ongoing need for medications voices in the process, increase access tient input in product development to treat a variety of infections, FDA has for the public to less expensive generics, and how the agency will incorporate placed an emphasis on approving new and develop solutions for the preven- this information into its regulatory antibiotics and antivirals. tion of drug shortages. decision-making (2). Paratek Pharmaceuticals received To speed drug development, FDA approval for its modernized tetracy- Reorganization and new guidance announced in October 2018 that the cline antibiotic Nuzyra (omadacy- In June 2018, FDA Commissioner Scott agency is developing technology- and cline) for the treatment of adults with Gottlieb issued a statement about a disease-specific regulatory frame- community-acquired bacterial pneu- proposal to modernize the agency’s works for innovations that may not monia and acute skin and skin struc- drug review office (1). The proposed have previously had a clear develop- ture infections. Nuzyra is specifically changes at the Office of New Drugs in ment pathway, including moderniza- designed to overcome tetracycline re- the Center for Drug Evaluation and tion of the agency’s approach to clini- sistance and exhibits broad-spectrum Research (CDER) were intended to cal trial design (3). It also issued several activity. It is also the first and only provide its “clinicians and scientists guidance documents for newer trial once-daily intravenous (IV) and oral more time, better tools, and greater designs and the development of next- antibiotic approved for the treatment support to advance the clinical and generation therapies. of both types of infections. Its use en- regulatory principles that the FDA uses These changes may have helped—or ables physicians to transition patients to evaluate new drugs for safety and certainly not hindered—the ability of from IV to oral treatment and poten- efficacy.” the agency to review new drug appli- tially reduce hospitalizations. Xerava cations. In 2018, CDER had approved (eravacycline) from Tetraphase Phar- 59 novel drugs (4), 13 more than ap- maceuticals is a novel, broad-spectrum Cynthia A. Challener is a contributing proved in 2017 (5). The following in- antibiotic approved for the treatment

editor to Pharmaceutical Technology. formation was sourced from press of complicated intra-abdominal infec- CONSTANTINE_PAPP/STOCK.ADOBE.COM

30 Pharmaceutical Technology JANUARY 2019 PharmTech.com ® O Original Wurster Technolgoy I N

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&RDWLQJ3ODFH,QF3DROL6W32%R[ VHURQD :LVFRQVLQU6$ ZZZFRDWLQJSODFHFRPLQIR#FRDWLQJSODFHFRP API Synthesis & Manufacturing tions, the most common infection site diated amyloidosis in adults, is the first momab pasudotox-tdfk) injection from in intensive care units. RNA-targeting therapeutic designed to AstraZeneca Pharmaceuticals is the first New antiviral medications ap- reduce the production of human trans- CD22-directed cytotoxin approved for proved in 2018 include Shionogi’s thyretin protein. the treatment of adult patients with re- Xofluza (baloxavir marboxil) for the Takhzyro (lanadelumab) from Shire lapsed or refractory hairy cell leukemia treatment of acute uncomplicated in- is a plasma kallikrein inhibitor and who have received at least two prior fluenza (flu), the first new antiviral flu the first monoclonal antibody (mAb) systemic therapies, including treat- treatment with a novel mechanism of approved in the United States to treat ment with a purine nucleoside analog. action approved by FDA in nearly 20 patients 12 years and older with types Kyowa Kirin’s Poteligeo (mogamuli- years, and Tpoxx (tecovirimat), the I and II hereditary angioedema, a rare zumab-kpkc) injection is the first drug first drug approved for the treatment and serious genetic disease that leads approved by FDA for the treatment of of smallpox. Tpoxx was developed by to unpredictable episodes of severe Sézary syndrome, a rare and hard-to- SIGA Technologies in conjunction swelling in different areas of the body. treat type of non-Hodgkin lymphoma. with the US Department of Health Dompé farmaceutici’s Oxervate (ce- Erleada (apalutamide) from Jans- and Human Services’ Biomedical Ad- negermin) is the first drug approved by sen Pharmaceutical Companies is vanced Research and Development FDA for the treatment of neurotrophic the first FDA-approved treatment for Authority; SIGA received a Material keratitis, a rare disease affecting the non-metastatic, castration-resistant Threat Medical Countermeasure Pri- cornea, providing an alternative to prostate cancer. The approval was the ority Review Voucher. surgical intervention. first to use the endpoint of metastasis- Four new treatments for HIV pa- Galafold (migalastat) from Amicus free survival, measuring the length tients were also approved by FDA in Therapeutics is the first oral medica- of time that tumors did not spread to 2018. Biktarvy (bictegravir 50mg/ tion for the treatment of adults with other parts of the body or that death emtricitabine 200mg/tenofovir alaf- Fabry disease and specifically for pa- occurred after starting treatment. It enamide 25mg, BIC/FTC/TAF) from tients who have a genetic mutation de- was the first participant in FDA’s Clini- Gilead Sciences is a once-daily single termined to be responsive to treatment cal Data Summary Pilot Program, an tablet regimen for the treatment of with Galafold based on laboratory data. effort to provide stakeholders with HIV-1 infection; Trogarzo (ibali- Unlike enzyme replacement therapy, more usable information on the clini- zumab-uiyk) from TaiMed Biologics this drug increases the activity of the cal evidence supporting drug product is the first drug in a new class of an- body’s deficient enzyme. approvals. tiretroviral medications that can pro- Crysvita (burosumab-twza) is the Lutathera (lutetium Lu 177 dotatate) vide significant benefit to patients who first drug approved for the treatment from Advanced Accelerator Applica- have run out of HIV treatment options. of x-linked hypophosphatemia, a rare, tions (since acquired by Novartis) is Merck’s Delstrigo (doravirine/lamivu- inherited form of rickets that does not the first radiotherapy approved for the dine/tenofovir disoproxil fumarate) is respond to vitamin D therapy; Ultrag- treatment of gastroenteropancreatic a once-daily fixed-dose combination enyx Pharmaceutical received the 14th neuroendocrine tumors, which affect tablet, and Pifeltro (doravirine) is a Rare Pediatric Disease Priority Review the pancreas or gastrointestinal tract. new non-nucleoside reverse transcrip- Voucher awarded by FDA. Palynziq The drug binds to the somatostatin tase inhibitor; both were developed (pegvaliase-pqpz) from BioMarin receptors of tumor cells, enabling its for the treatment of HIV-1 infection Pharmaceutical is a novel enzyme ther- entry and their ultimate destruction. in adult patients with no prior antiret- apy approved for the treatment of adult In late November, FDA approved roviral treatment experience. patients with phenylketonuria, a rare Vitrakvi (larotrectinib) from Loxo genetic disease, who have uncontrolled Oncology for the treatment of adult First drugs for rare diseases concentrations of phenylalanine in and pediatric cancer patients with a Treatments for rare genetic diseases, all their blood even on current treatment. specific genetic feature, or biomarker, with the orphan drug designation, re- on their tumors. The approval marks ceived approval by FDA. Onpattro (pa- New cancer treatments the second time FDA has approved a tisiran) infusion from Alnylam Phar- Treatments for both common and rare cancer treatment based on a common maceuticals is the first FDA-approved cancers were approved by FDA in 2018, biomarker across different types of treatment for patients with polyneurop- including Regeneron Pharmaceuticals’ tumors rather than the location in the athy caused by hATTR and is the first in PD-1 checkpoint inhibitor Libtayo body where the tumor originated. a new class of drugs referred to as small (cemiplimab-rwlc) injection, the first interfering ribonucleic acid treatments. approved treatment for metastatic or Other firsts Akcea Therapeutics’ Tegsedi (inotersen), locally advanced cutaneous squamous Several other firsts were achieved by FDA also for the treatment of the polyneu- cell carcinoma, the second most com- in 2018. Approval of the first non-opioid ropathy of hereditary transthyretin-me- mon skin cancer. Lumoxiti (moxetu- treatment for the management of opioid

32 Pharmaceutical Technology JANUARY 2019 PharmTech.com withdrawal symptoms went to US World- Agios Pharmaceuticals received ap- malaria in patients aged 16 years and Meds’ Lucemyra (lofexidine hydrochlo- proval for Tibsovo (ivosidenib), the older who are receiving appropriate ride), an oral, selective alpha 2-adrenergic first isocitrate dehydrogenase-1 inhibi- antimalarial therapy for acute P. vivax receptor agonist that reduces the release tor, for the treatment of adult patients infection. of norepinephrine. Epidiolex (cannabi- with relapsed or refractory acute my- Two other interesting examples diol) from GW Research for the treat- eloid leukemia (AML) who have a spe- are the first approval of a vaginal ment of seizures associated with Lennox- cific genetic mutation. Patients must ring contraceptive: the Population Gastaut syndrome and Dravet syndrome, be identified using the FDA-approved Council’s Annovera (segesterone two rare and severe forms of epilepsy, is RealTime IDH1 Assay from Abbott acetate and ethinyl estradiol vaginal the first FDA-approved drug that con- Laboratories. system); and Omegaven, a fat emul- tains a purified drug substance derived The combination of BRAFTOVI sion manufactured by Fresenius Kabi from marijuana and the first drug ap- (encorafenib) and MEKTOVI (bin- and demonstrated by researchers at proved for the treatment of patients with imetinib) from Array BioPharma was Boston Children’s Hospital to be ef- Dravet syndrome. approved for the treatment of for pa- fective for preventing liver disease AbbVie’s Orilissa (elagolix) is the tients with unresectable or metastatic associated with parenteral nutrition first FDA-approved oral treatment melanoma with a BRAF V600E or in children. for the management of moderate to V600K mutation. The mutation must severe pain associated with endome- be detected using the FDA-approved In the approval pipeline triosis in over a decade, and the only THxID BRAF Kit from bioMérieux. Most of the drugs on FDA’s approval oral gonadotropin-releasing hormone docket through early 2019 include antagonist specifically developed for New development paradigms treatments for many common con- women with moderate to severe en- One interesting trend is the develop- ditions, including heart disease, dometriosis pain. ment of new drugs by non-profit or- immune deficiency, diabetes, and FDA also approved new medica- ganizations, sometimes in collabora- influenza. There are also several treat- tions for the prevention of migraines. tion with pharmaceutical companies. ments for neurological and psychol- Aimovig (erenumab-aooe) from Two drugs approved to treat tropical ogy disorders, such as Parkinson’s dis- Amgen is a once-monthly self-injection diseases were developed using this ap- ease and depression. Several drugs for and the first FDA-approved preventive proach. The not-for-profit company pain management are under review, migraine treatment in a new class of Medicines Development for Global as are treatments for skin infections, drugs that work by blocking the activ- Health (MDGH), in collaboration with glaucoma, breast cancer, and erectile ity of calcitonin gene-related peptide. the World Health Organization Special dysfunction. Several new drugs for Teva Pharmaceutical Industries’ Ajovy Program for Research and Training in the treatment of rare cancers are also (fremanezumab-vfrm) injection is the Tropical Diseases, received FDA ap- awaiting FDA decisions. first and only anti-CGRP treatment for proval for moxidectin 8 mg oral for the the prevention of migraine with quar- treatment of river blindness, which is References terly and monthly dosing options. Eli caused by the parasite Onchocerca vol- 1. FDA, “Statement from FDA Commis- Lilly’s Emgality (galcanezumab-gnlm) vulus. It is the first new drug approved sioner Scott Gottlieb, M.D., on Proposed Modernization of FDA’s Drug Review also received approval. for the treatment of river blindness in Office,” Statement, June 4, 2018. 20 years. MDGH received a priority 2. FDA, “Statement from FDA Commis- Targeted therapies, diagnostic tests review voucher (PRV), a saleable item sioner Scott Gottlieb, M.D., on New Several drugs that received FDA ap- that enables the owner to receive ac- Agency Efforts to Advance the Patient proval in 2018 were targeted thera- celerated review of a new drug appli- Voice in Medical Product Development and FDA Regulatory Decision-Making,” pies, and some were even approved cation (NDA)—the first not-for-profit Statement, June 12, 2018. with specific diagnostic tests. Pfizer’s company to do so under the tropical 3. FDA, “Statement by FDA Commissioner Talzenna (talazoparib), a poly (ADP- disease PRV program. Scott Gottlieb, M.D., on FDA’s New Steps ribose) polymerase (PARP) inhibitor, Similarly, GlaxoSmithKline (GSK) to Modernize Drug Development, Im- was approved for the treatment of for received a tropical disease PRV for its prove Efficiency and Promote Innova- tion of Targeted Therapies,” Statement, patients with deleterious or suspected part in the development of the first new Oct. 15, 2018. deleterious germline BRCA-mutated, treatment for Plasmodium vivax (P. 4. FDA, “Novel Drug Approvals for 2018,” HER2 negative locally advanced or vivax) malaria in more than 60 years. www.fda.gov/Drugs/Developmen- metastatic breast cancer. The BRA- Single-dose Krintafel (tafenoquine) tApprovalProcess/DrugInnovation/ CAnalysis CDx test from Myriad was developed in collaboration with ucm592464.htm. 5. FDA, “Novel Drug Approvals for 2017,” Genetic Laboratories, Inc. was also Medicines for Malaria Venture and www.fda.gov/Drugs/Development approved to identify patients who are received FDA approval for the radical ApprovalProcess/DrugInnovation/ eligible for the new drug. cure (prevention of relapse) of P. vivax ucm537040.htm. PT

Pharmaceutical Technology JANUARY 2019 33 Formulation

thus have a lower risk for off-target toxicity, a characteristic of many chemical molecules. An example is chemotherapy agents (such as cispla- tin) being used for cancer treatment, versus targeted antibodies that block and prevent specific cell growth.” Yet, despite the therapeutic advantages these macromolecules offer, they are also associated with several notable disadvantages, such as limited bioavailability as well as physi- Considering cal and chemical instability. These disadvantages have proven problem- atic for developers looking to create Protein and the best formulation and delivery method for these compounds and Peptide have limited their use. Formulation and delivery: Delivery Challenges to success As reported by Cleland and Langer more than 20 years ago, “The success Felicity Thomas of most peptide and protein drugs is dependent upon the delivery of the biologically active form to the site of action” (3). To achieve this, Cleland and Langer stressed that developing New approaches seek to address formulation the most stable formulation possible and delivery challenges for these complex is a requirement, and consideration of multiple routes of administration molecules. is important for future formulation development (3). ince the first recombinant pro- benefits that they offer over conven- Production considerations. Produc- tein therapeutic, human insulin, tional small molecules could be ating protein or peptide therapeutics Swas approved by FDA in the tributed to their structural and func- is highly complex and can include early 1980s (1), there have been tional similarities to endogenous many more critical process steps significant advances in the biophar- biochemicals in the human body. than those required for a small- maceutical market. The industry is This similarity translates into better molecule drug (4). Additionally, currently witnessing the emergence drug targeting, lesser side effects, manufacturers typically use living of protein and peptide therapeutics and new treatment options for vari- cells or organisms to synthesize the across a multitude of indications, ous diseases where complex chemis- macromolecules, which can impact such as oncology, infectious diseases, try is restricted in small molecules.” the characteristics of the final prod- endocrinology, and immunology. Susanne Joerg, head of formula- uct (4). Research into protein-engi- The high selectivity and specific- tion development, Drug Product neering strategies during drug de- ity of these macromolecules offer Services, Lonza Pharma & Biotech velopment aims to address complex increased treatment efficacy while adds, “Protein and peptide thera- manufacturing processes (4). also potentially reducing the side ef- peutics have the potential to provide “Structural modification with PE- fects and toxicity that are sometimes safer and more targeted therapies. Gylation, cyclization, chemical con- present with alternative therapeutic They consist of amino acids and can jugation, use of enzyme inhibitors, options (2). interact with target receptors or li- absorption enhancers, encapsulated “There is enormous therapeutic gands to convey their pharmacologic carriers, and so on, are all being em- potential in proteins and peptides,” action. As they specifically have the ployed to address the challenges of says Rashmi Nair, senior scientist, potential of a more targeted interac- stability and delivery of protein and

Formulations at Dr Reddy’s. “Major tion with receptors or ligands, they peptide therapeutics,” adds Nair. “A TWINDESIGNER/STOCK.ADOBE.COM

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#AMP#REEK0ARKWAY37s"UILDING 3UITEs!TLANTA '! INFO GEMUCOMs4EL www.gemu.com Formulation combination of approaches is often “Two major drug delivery routes hydrophilicity of the molecule, and required that takes into consider- are oral and parenteral,” states Nair. the fact that our bodies have been ation the route of administration “While parenteral delivery is more designed to digest proteins through and required target bioavailability.” commonly used, it has its own chal- the oral route.” Direct structural modification, lenges with a short half-life of the Yet, she notes an advance in a more such as cyclization, PEGylation, and drug resulting in frequent drug dos- patient-centric approach to delivery chemical conjugation, are considered ing and eventually less patient com- that has been garnering increasing to be key strategies in improving bio- pliance.” attention lately is the use of autoin- availability and stability of peptide Joerg adds, “The size and hydro- jectors, syringes, or pens as delivery therapeutics (5). Co-administration philicity of proteins make it dif- devices. “For example, monoclonal techniques, such as with enzyme in- ficult to achieve sufficiently large antibody therapies for subcutaneous hibitors, absorption enhancers, and and robust bioavailability without administration often are used with encapsulated carriers are being as- parenteral administration, which syringes or even large-volume patch sessed to improve the ability to de- includes intravenous, intra-arterial, pump devices,” she adds. These tech- liver the macromolecules. subcutaneous, intramuscular, intra- niques, along with improved focus For Joerg, the most appropriate thecal, and intravitreal/intraocular on formulation evaluation and using formulation development is vital administration. All these routes of a more systemic approach of follow- in overcoming stability issues with administration have specific chal- ing quality by design for process unit these complex drug products for lenges in terms of allowed volume operations, are all helping to prog- parenteral administration. “While for administration, pH, and osmo- ress delivery, she further explains. freeze-drying usually provides the lality requirements, and, of course, “However, appropriate product de- best stability, liquid dosage forms are all parenteral preparations must be sign and thorough planning of clinical preferred due to lower complexity for sterile and compliant with regards to (or patient) use, adequate in-use test- use and administration,” she says. endotoxin and particle requirements, ing, and instructions for use (IFUs) “To ensure appropriate product for example.” are of utmost importance,” Joerg quality during manufacturing, in- Low bioavailability and meta- cautions. “For example, syringes and tegrated approaches for drug sub- bolic liability have also limited the autoinjector systems can often facili- stance and drug product processing oral administration of protein and tate self-injections of patients. But, a are critical, including the evalua- peptide therapeutics (5–7). “Proteins properly designed IFU and appropri- tion of ultrafiltration/diafiltration and peptides do not sustain the rigor ate training of the patient is required approaches, the composition of of the gastrointestinal tract. Chemi- to ensure compliance.” drug substance and product, and cal degradation in gastric fluids, thorough evaluation of all drug extensive metabolism in luminal A multidisciplinary substance and drug product manu- spaces, and first pass metabolism are approach needed for the future facturing unit operations and oper- major concerns with oral delivery of Over the past 30 years, there has been ating ranges,” Joerg continues. “For proteins and peptides,” says Nair. extensive research into improving example, the choice of a wrong fill However, oral delivery is con- the stability and delivery of protein pump can render a whole batch of sidered to be the preferred route of and peptide therapeutics. The suc- protein product instable and non- administration due to the benefits cess of this work is being reflected in compliant.” it offers—patient convenience and the fact that increasing numbers of Administration route considerations. acceptance, which in turn leads to these therapies are being approved by Drug delivery challenges posed by increased patient compliance (6,7). regulatory bodies (8) and, in terms of protein and peptide therapeutics “Even in the few examples where pep- delivery, the growth of the oral pep- are many. Not only are the molecules tides have sufficient bioavailability tides and proteins market (9). large in size but they are hydrophilic, after oral or inhalation administra- In the near future, Joerg antici- cannot easily cross biological barri- tion for systemic use, there are vari- pates that more attention will be put ers, are degraded by enzymes, rap- ous other challenges to be managed on the integrated development of idly leave the circulation system, and overcome, such as cost-of-goods, the drug substance and product and and are highly charged, all of which safety, or toxicity of the compounds more systemic evaluations of all pa- complicate the delivery strategy. and variability in patients,” contin- rameters. “There is an increasingly Commonly, as a result of these chal- ues Joerg. “The numerous attempts considerable demand coming from lenges, parenteral formulations and to try and overcome parenteral ad- the industry for an integrated solu- routes of administration have gener- ministration have seen very lim- tion from a sole vendor who has a ally been the ‘go-to’ for these promis- ited success—primarily due to the combination of scientific and regu- ing therapeutic options. inherent complexity of structure, latory experience,” she says. “As we

36 Pharmaceutical Technology JANUARY 2019 PharmTech.com 5. B.J. Bruno, G.D. Miller, and C.S. Lim, see pipelines moving to progressively References Therapeutic Delivery 4 (11) 1443–1467 complex biologics—for example, an- 1. D.V. Goeddel et al., Proc. Natl Acad. Sci. (2013). tibody drug conjugates, bispecific an- USA 76 (1) 106–10 (1979). 6. J.H. Hamman, G.M. Enslin, and A.F. 2. C. Cao, Pharm. Tech. 40 (11) 22–24 Kotze, BioDrugs 19 (3) 165–177 (2005). tibodies, fusion proteins, and other (2016). second-generation antibody thera- 7. J. Shaji and V. Patole, Indian J. Pharm. 3. Cleland and Langer, Formulation and Sci. 70 (3) 269–277 (2008). pies—the question of drug product Delivery of Proteins and Peptides ACS 8. B.G. de la Torre and F. Albericio, Mol- becomes even more pertinent. Many Symposium Series (American Chemical ecules 23 (3) 533 (2018). companies are therefore looking for Society, Washington, DC, 1994). 9. MarketWatch, “Oral Proteins and Pep- 4. H.A.D. Lagassé et al., F1000Research 6 tides Market,” Press Release as May 8, expertise that they may not have in- (F1000 Faculty Rev) 113 (2017) ternally to solve these challenges.” 2018. PT In terms of drug delivery, Joerg notes that, even though there have been numerous attempts at progress- ing alternatives to parenteral administration, injections or infusions remain, at this moment in time, the primary option. “In order to facilitate administration, devices will play a key role,” she continues, “with increasing connectivity to the Internet of things.” For Nair, the past decade has been particularly encouraging for proteins and peptides. “Many new drug design tools, in-silico screening software, and predictive simulations Power, reliability, sanitary designs, have helped drug development pro- “No edges, No ledges” and an grams. Stably folded, cell-penetrating “Air-Tight Performance GuaranteeTM”. proteins and peptides have advanced Proudly servicing the pharmaceutical in clinical studies. Carrier-mediated industry with 65 years of application drug delivery with microspheres and expertise in vacuum conveying over 10,000 various powders & granular liposomes has enabled the commer- bulk materials - since 1954. cialization of many promising drugs,” Signature SeriesTM she adds. “No Edges, No Ledges” In the coming decade, Nair pre- vac-u-max.com/SignatureSeries dicts that there will be more devel- (800) VAC-U-MAX opment into the use of polymers for 1500 Series & 3500 Series drug delivery, which could protect “from handfuls to 3500 lbs/hr” proteins and peptides from physical and chemical degradation and 1954-2019 also help to sustain the drug release profile through depots or prolonged blood circulation times. “But, an important point,” Nair concludes, “is the consideration of integrated drug substance and drug product projects in drug development programs. Through this, overcoming the challenges of protein and peptide drug delivery will be increased as this is essentially a multidisciplinary sci- SANITARY/USDA-ACCEPTED • PNEUMATIC CONVEYING COMPONENTS & SYSTEMS • BATCH & CONTINUOUS OPERATION MULTI-INGREDIENT HANDLING SYSTEMS • BATCH WEIGHING & SCALING SYSTEMS • UL-CONTROLS & CONTROL PACKAGES ence that requires an understanding FDA-APPROVED/CERTIFIED MATERIALS OF CONSTRUCTION • 21 CFR PART 11 COMPLIANCE of organic chemistry, biochemistry, MOBILE VACUUM CONVEYING SYSTEMS • CIP DESIGNS • INDUSTRIAL VACUUM CLEANERS pharmaceutical technology, and 69 WILLIAM STREET • BELLEVILLE, NJ 07109 • (800) VAC-U-MAX • [email protected] physical chemistry.”

Pharmaceutical Technology JANUARY 2019 37 Biopharmaceutical Manufacturing

carefully considered when implementing continuous bioprocesses to ensure patient safety. There are several differences between batch and continuous virus filtration process parameters. The unit operations in batch mode typically last for four to six hours, while continuous processes can be performed for days. Operating pressures are also much lower during continuous virus filtration, and an adsorptive pre-filter is essential for the removal of potential aggregates that might lead to fouling of the virus filter. Batch systems are open with manual or Continuous Processing: semi-automated control, while continuous processes are closed, more complex, Challenges and and highly automated. The feedstream for a batch process is homogeneous, but in continuous virus filtration, variability Opportunities in protein concentration, pH, and conductivity from the elution peaks of the previous chromatography step will chal- of Virus Filtration lenge the virus filter (1).

Birte Kleindienst, Peter Kosiol, and Anika Manzke Design space of continuous viral filtration In batch processing, it is known that protein concentration, pH, conductiv- Requirements for virus filtration ity, buffer type, viscosity, additives, op- must be considered in developing erating pressure, and pressure release times can affect virus filter performance. continuous downstream processes. The question is: which of these process variabilities are relevant for continuous ioprocessing technologies have Steady-state conditions with continu- virus filtration? To begin answering this evolved rapidly and significantly ous process approaches have been intro- question, a design-of-experiment (DoE) Bduring the three decades the bio- duced to decrease cycle times, reduce study was conducted to define the de- pharmaceutical sector has been in exis- capital and operating costs, and enable sign space for continuous virus filtration. tence. Despite the success of operational faster scale-up with more consistent qual- DoE. A full factorial DoE (23) was improvement programs and measurable ity and greater manufacturing flexibility performed including a total of 10 ex- increases in productivity, biomanufac- (3, 4). At this point, end-to-end, fully in- periments that varied the length of the turing continues to face challenges (1). tegrated continuous processing has not run, the operating pressure, and either Increased cost, quality and production been implemented outside the laboratory. a monoclonal antibody (mAb) or buffer pressures, oncoming competition from Solutions are still being investigated for feed. Depending on the total length of biosimilars, and the growing impor- realizing enclosed, bioburden-free, fully each run, pressure was applied for 24 or tance of emerging markets and person- automated, fully continuous processes 48 hours twice with a 30-minute pres- alized medicines are creating the need from bioreactor to formulated drug prod- sure release after each filtration period as for further evolution in bioprocessing uct with global process control that run shown in Figure 1. For the 48-hour runs, technologies (2, 3). for long durations (1, 2). In the meantime, an additional pressure release of 60-min- hybrid or semi-continuous approaches utes was conducted. Fractions were col- Birte Kleindienst is product manager, are being implemented by early adopters lected in the beginning of each filtration Virus Clearance, birte.kleindienst@ of continuous bioprocessing. and before and after each filtration pe- sartorius-stedim.com; Peter Kosiol is riod and pressure release to evaluate any scientist, Membrane Development; and Batch vs. continuous virus filtration Anika Manzke is product manager, impacts of the pressure profile. Virus Clearance, all at Sartorius Stedim Virus filtration is a crucial downstream Filtration parameters. Because continu-

Biotech. processing operation that must be ous virus filtration is operated at much ARTEMEGOROV3@GMAIL/STOCK.ADOBE.COM

38 Pharmaceutical Technology JANUARY 2019 PharmTech.com Figure 1: Pressure profile over the virus filter during a design-of-experiment study. the pre-filter did not remove bacteriophage PP7 in a significant amount. Results. Results for the DoE study using the buffer and mAb feed are shown in Figure 2. Notably, in both cases, retention without any virus breakthrough was achieved over the entire filtration period for each experiment.

Therefore, a robust log10 reduction value (LRV) of greater than four was achieved independent of operating pressure, pressure release time, and overall filtration time. The titer of PP7 bacteriophages de- Figure 2: Design-of-experiment results of virus retentive bacteriophage PP7 clined over the course of 96 hours from capacities of a filter (Virosart HF, Sartorius Stedim Biotech), in either monoclonal 106 down to 105 pfu/mL, whereas the antibody (mAb) or buffer feed, over the course of a continuous virus filtration. LRV is mAb feed seemed to stabilize the titer.

log10 reduction value. Separately, the stability of typical model viruses used for validation studies of virus filters was investigated under the long processing time present in continuous manufacturing. Simple infectivity tests were conducted for Minute virus of mice (MVM) and Murine leukemia virus (MuLV) in the buffer and mAb feed used for the DoE study. The results over 96 hours are shown in Figure 3. MVM and MuLV infectivity decreased during the 96-h operation time. The decline in MVM infectivity of 0.5 LRV is within the variation of the assay. MuLV, a large enveloped virus known to be a less stable virus, showed a higher decrease of titer with 1 LRV.

lower flow rates, longer filtration times riophage is an established model system Virus clearance validation often involve longer pressure releases that is often used to evaluate the removal New ways of manufacturing, such as than are observed with batch filtration; capabilities of virus filters (5). The filters continuous processing, bring up new these operating parameters were in- were challenged with a minimum titer challenges for process validation. A cluded in the DoE study. Although con- of 106 pfu/mL. representative feedstream for the virus tinuous filtration is typically run at con- Product feed. A mAb feed (non-opti- validation studies needs to be defined. In stant flow rather than constant pressure, mized after ion exchange chromatogra- addition, while the DoE results presented for ease of experimentation, a constant phy at 0.3 g/L in 20 mM, pH 7.2 TRIS here indicate that filtration parameters pressure range of 0.1 bar (1.5 psi) up to hydrochloric acid and 150 mM sodium do not have a significant impact on 0.5 bar (7.2 psi) was covered to represent chloride) and a buffer solution (20 mM virus retention, such performance must a maximum of 25% of the flow used in KPI buffer, pH 7.2) were used to test be confirmed by end users under their batch operations at 2.0 bar (30 psi). Fil- virus retention in the presence and ab- specific process conditions. One pos- tration times of 48 to 96 hours were used sence of protein to exclude the possibil- sible approach is to conduct a DoE type to keep the operating time within the ity of interactions between the mAb, the of validation by identifying the critical normal five-day work week. PP7, and the virus retentive membrane parameters (e.g., concentration, flow, pH, Virus model. Pseudomonas aeruginosa (commercial, down-scaled 1.7 cm2 Viro- conductivity) and then validating only bacteriophage PP7 (ATCC 15692-B2), a sart HF filter with a down-scaled 5.0 cm2 the representative worst-case conditions. single stranded, 20–25 nm, non-envel- Virosart Max adsorptive 0.1 μm inline The manner in which the virus should oped, ssRNA bacteriophage from the pre-filter, both from Sartorius Stedim be spiked has also to be addressed. Typi-

FIGURES ARE COURTESY OF THE AUTHORS. FIGURES ARE COURTESY Leviviridae family, was used. PP7 bacte- Biotech). It was determined upfront that cally, in batch processing, the “spike and

Pharmaceutical Technology JANUARY 2019 39 Biopharmaceutical Manufacturing

Figure 3: Infectivity of Murine leukemia virus (MuLV) (top) and Minute virus of mice achieved in a sterile manner to avoid (MVM) (bottom) over 96 hours in monoclonal antibody (mAb) and buffer feeds. LRV the need for steam-in-place and clean- is log reduction value. in-place operations. 10 Passed IT of virus filters are essential in order to release a batch, which is a challenge in continuous processing (7). Risk assessments have to be performed in order to minimize the risk of failed post-use IT in production. Some potential approaches like conducting pre-use, post-sterilization IT (PUPSIT) on all filters are currently discussed in the industry to mitigating the risk. This approach could potentially be incorporated into an end-to-end, integrated continuous process from bioreactor to fill/finish. Conclusion In this study, the design space for continu- Figure 4: Possible process implementation of continuous virus filtration showing ous virus filtration was defined with re- operation mode (left) and preparation mode with integrity testing (IT) (right). spect to filtration parameters, and parameters such as low flow rates, long filtration Continuous WFI Product Buffer times, and increased pressure releases showed no impact on the filter tested. Commercially available virus filters can

FF be run in continuous mode. Although Preparation Mode: Operation Mode: • Buffer flush some challenges for validation of continu- • Filtration of • Wetting for Post-use IT monoclonal antibody P P • Post-use IT ous virus filtration must still be addressed, • Uninstallation of filter • Installation of new filter parallel filtration lines that allow in-line Pre-Filter Pre-Filter • Wetting • Pre-use IT filter testing are one concept for allow- • Equilibration ing implementation of continuous virus Virus Filter Virus Filter filtration in commercial manufacturing. Acknowledgements Next Unit WasteOperation Waste The authors would like to thank Mag- nus Warnke and the bacteriophage team from Sartorius for conducting run” method is used, in which the spike Process implementation the studies. is added to the pooled feedstream prior One possible process implementa- to the virus filtration. This approach is tion for virus filtration in continuous References difficult to realize with a continuous flow processing is to use a set-up with two 1. R. Godawat et al., J. Biotechnology, 213, of product. Inline spiking for continuous filtration lines that can be operated in- 13–19 (2015). 2. S. Klutza et al., J. Biotechnology, 213, 120– dosing into the feed seems to be the most dependently of each other in a prepara- 130 (2015). likely workable approach in the industry. tion mode or operation mode (2, 6), as 3. J. Walther et al., J. Biotechnology, 213, 3–12 This method can overcome the chal- shown in Figure 4. Each line has a pump, (2015). lenges of loss virus infectivity over time flow and pressure sensor, adsorptive 4. K. Konstantinov and C. Cooney, J. Pharm. because fresh virus can be continuously pre-filter, virus filter, and buffer and Sci. 104 (3) 813–820 (2015). 5. PDA, “Technical Report No. 41: Virus Fil- introduced. Inline spiking involves a water-for-injection supply. Steps such tration,” Pharm. Sci. Technol. Suppl. 59 (2) complex setup and equipment, however. as flushing, equilibration, filtration, 1–42 (2005). Numerous other challenges for vali- buffer flush, wetting for integrity tests 6. G. Subramanian, Ed. Continuous Bio- dation of continuous virus filtration (IT), and IT are performed in prepara- manufacturing: Innovative Technologies must be addressed, such as the use of tion mode, whereas the product filtra- and Methods (Wiley, 2017). 7. FDA, Guidance for Industry: Sterile Drug an inline pre-filter and potential filter tion is performed in operation mode. Products Produced by Aseptic Processing— blockage by the feedstream and/or virus Ideally all valves would be fully auto- Current Good Manufacturing Practice itself with increasing volume. mated, and implementation would be (Rockville, MD, Sept. 2004). PT

40 Pharmaceutical Technology JANUARY 2019 PharmTech.com Peer-Reviewed Evaluating a New Quality Control Test for Soft Gelatin Rectal Capsules

Yasvanth Ashokraj, Swati Laud, Kalpesh Sawant, Prashant Modak, and Praveen Date

Soft gelatin capsules (SGC) are popularly used oft gelatin capsules (SGC) are popularly used pharma- pharmaceutical dosage forms, whose critical ceutical dosage forms, wherein the active ingredient is delivered in a non-aqueous vehicle, either as solu- quality attributes are efficient opening/rupture, tion, suspension, or semisolid, through various routes disintegration, and dissolution. Unlike oral S of administration. SGC offers unique advantages of filling capsules, however, rectal capsules must dissolve high doses of poorly water-soluble drugs, loading of ultra-low in minimal fluid and hydrodynamics, without dose drugs accurately (e.g., cardiac glycosides and vitamin D digestive enzymes to break down the crosslinking analogs), and providing the option of filling excipients that of gelatin, if any. Therefore, a reliable biomimetic inhibit P-glycoprotein for better bioavailability (1). Quality control of SGC is crucial to ensure the product’s method is needed to characterize SGC rupture/ intended in-vivo performance, and a variety of quality con- disintegration during rectal administration. This trol tests are available to use for evaluation (2, 3). The critical article demonstrates how qualitative physical quality attributes are efficient opening/rupture, disintegra- attributes testing, a method that has recently tion, and appropriate dissolution in biological fluid. been approved for use by the World Health Table I (4,5,6) lists methods that assess the disintegration or Organization, can be used to achieve these goals. rupture of SGCs. However, these tests are best suited to orally administered SGCs because they require a large volume of fluid (e.g., 500 mL). Rectal SCGs are exposed to very different conditions (i.e., limited fluid volume [7] and hydrodynamics). Hence, a suitable test that is biorelevent in terms of media, volume, hydrodynamics, and capability to quantify the disintegration or rupture events of SGC for rectal use is essential. Artesunate SGCs were developed as a pre-refferal treatment option for malarial infection in children under six years of age living in remote tropical areas with limited access and to provide a standard care of treatment (intramuscular artesunate) in hospitals (8). Suppositories hold an advantage over oral therapy when treating severely ill children who are vom- iting and who may be weak or losing consciousness, because they act faster than the oral dosage forms. The authors tested a new apparatus and method, termed qualitative physical attributes testing (QPAT), which was developed to address this need. The results of the test using artesunate SGCs are summarized in this article. Materials and methods Materials. For buffer preparation, potassium dihydrogen Submitted: Sept. 4, 2018 phosphate (analytical reagent [AR] grade, S.D.Fine Chem),

Accepted: Oct. 16, 2018 sodium hydroxide (AR grade, S.D.Fine Chem), orthophos- ADRAGAN/STOCK.ADOBE.COM

Pharmaceutical Technology JANUARY 2019 41 Peer-Reviewed

Table I. Disintegration test/rupture test for soft gelatin capsules described in pharmacopeia. Test Method • Medium–water; 500 mL <2040> Disintegration and dissolution of • Apparatus & rpm–USP II & 50 dietary supplements–rupture test for soft • Time–15 min shell capsules (4) • The capsule shell is considered ruptured if breached, exposing or allowing the fill contents to escape • Medium–water. (When justified and authorized, 0.1 M hydrochloric acid or artificial gastric juice may be used.) Disintegration test for oral soft capsules • Apparatus–disintegration apparatus. (Ph. Eur. Method 2.9.1) (5) • Time–30 min • All of the dosage units have disintegrated completely. • Medium–water Disintegration Test for Suppositories and • Apparatus–specially designed setup Pessaries–rectal or vaginal gelatin shell • Method–rupture of the gelatin shell of rectal or vaginal capsules occurs allowing release of the contents (Ph. Eur. Method 2.9.2) (6) • Time–30 min • Rupture of the gelatin shell of rectal or vaginal capsules occurs allowing release of the contents

Figure 1. A prototype setup to observe the physical events of whole setup was placed on a magnetic stirrer with hotplate. Figure 1 artesunate soft gelatin capsule. depicts the set-up of the equipment. Experimental procedure. The critical steps of the experiment are described below. These steps will ensure reproducibility and accuracy of experimentation and measurements: • A large bar magnet was placed at the bottom of the outer water bath. • The water bath was filled with water to the specified depth at room temperature and placed on a magnetic stirrer with hot plate and heated to 37±2 °C. • Three cylindrical glass-holding tubes were lowered into the water bath and positioned at specified height. • A small bar magnet was placed at the bottom of each of the cylindrical glass holding tube. • Stainless steel mesh screen was placed in each of the cylindrical glass holding tube. phoric acid (laboratory reagent (LR) grade, Rankem), cetyl- • A suitable volume (10 mL or less) of medium was poured trimethyl ammonium bromide (CTAB) (extrapure AR grade, into each of the cylindrical glass holding tube. Sisco Research Laboratories), and purified water were used. • Rotations for the bar magnet were started at the speci- Preparation of buffer medium. The buffer solution used as fied settings. the medium for the QPAT study was prepared by dissolving • Temperatures in the outer water bath and the cylindri- potassium dihydrogen phosphate and sodium hydroxide in cal glass holding tube were recorded until the tempera- purified water, to which a suitable quantity of CTAB was ture was stable at 37±2 °C for at least 5 min. added to prepare phosphate buffer (pH 7.2, 1.5% CTAB). • One dosage unit (artesunate SGC) was introduced into Equipment (prototype). The researchers assembled a tem- each of the cylindrical glass holding tubes. perature-controlled glass water bath that consisted of an • The time was noted and designated as T=0 min. appropriate cylindrical glass-holding tube (vessel) capable • Physical behavior of the dosage unit was observed for of holding 10 mL or less of selected medium with controlled any changes (not in any order of significance), such as hydrodynamics and a platform (stainless steel mesh screen) physical disintegration, first traces of rupture, release to support the unit dosage form. The glass container had an of blend from SGC, progressive deformation leading to opening with the required diameter to facilitate the intro- change in shape, softening (considering gelatin based duction of the unit sample (one rectal SGC). The water bath SGC) of the dosage unit, etc. could hold three glass containers, which facilitated QPAT SGC are prone to soften over the duration of the test/ of three units individually and simultaneously. Additionally, experiment while disintegrating and releasing the drug the glass assembly facilitated visual observation of the physi- contained within. Therefore, the critical events need to be cal events that each unit dosage form was undergoing during observed over the QPAT, individually and collectively and the duration of QPAT. The hydrodynamics of the water bath need to be noted. Accordingly, the critical events noted and medium in the holding tube were controlled by appro- below were observed during the disintegration process of

priately sized bar magnets in the respective chambers. The artesunate SGC and mapped as a function of time: AUTHORS. THE OF COURTESY FIGURES

42 Pharmaceutical Technology JANUARY 2019 PharmTech.com • A–first sign of physical breakdown of the surface thereby stantial deformation of the shape of SGC effecting release of the embedded blend of drug product • Not longer than 15 min: near to complete disintegra- • B–progressive disintegration of the dosage unit tion of SGC. • C–substantial deformation of the shape of the dosage Accordingly, the data collected on submission batches at unit initial and stability samples (Figure 3) were assessed against • D–substantial decrease/change in the size of the dos- the acceptance criteria. A significantly low co-efficient of age unit variation clearly indicates the reproducibility on observation • E–near-to-complete disintegration of the dosage unit unit-to-unit. The first event of physical breakdown of the • F–physical disintegration of the soft rectal capsule surface occurred (event A) consistently within one minute • G–others relating to the physical structure/character of on initial samples and after the storage of the samples in the dosage unit (soft rectal capsule). controlled temperature and humidity of 25 °C/60% relative QPAT for artesunate SGC was performed in phosphate buffer (pH 7.2, 1.5% CTAB) on initial and stability samples, whereas only initial samples were evaluated in water. The change in physical nature/ap- pearance at every two-minute in- terval was recorded as photographs. Results The QPAT method was developed using artesunate SGC manufactured during scale-up trials. Be- cause there was no suitable biorelevant rectal fluid reported in literature, the media recommended for the dissolution testing experiment were phosphate buffer (pH 7.2, PIXEL 1.5% CTAB) and water. CTAB at a concentration of 1.5% was selected after evaluating several commonly used surfactants in dissolution me- PRECISE dium at different concentrations using saturation solubility studies and dissolution trials (these data are yet unpublished and are cur- LASER DRILLING rently recorded on file). Typically, the complete disintegration of artesunate SGC occurs within 15 Ideal for R&D and Small Batch minutes. Figures 2a and 2b depict the Drilling of Single or Bi-Layer Tablets typical events observed in 10 mL of phosphate buffer (pH 7.2, 1.5% • cGMP and FDA compliant CTAB) and water, respectively, dur- • CO air-cooled laser drilling system ing method development, based on 2 which of the following acceptance • Fume extraction system criteria was set to assess the qual- • Touch screen operator control with 21 CFR 11 compliance ity of the product in routine quality control: • Singulates and orients 1-25 tablets • Not longer than 5 min: first sign of physical breakdown of the surface thereby effecting Why settle for less? 856-234-3626 • [email protected] release of the contained drug/ www.ackleymachine.com formulation • Not longer than 10 min: sub-

Pharmaceutical Technology JANUARY 2019 43 Peer-Reviewed

Figure 2a. Qualitative physical attributes testing (QPAT) performed humidity (RH) for 18 months. Similarly, substantial defor- on artesunate soft gelatin capsules in pH 7.2+1.5% CTAB/10 mL. mation of the shape of SGC (event C) occurred in less than 10 min. However, the third critical event of near-to-complete disintegration (event E) occurred not longer than 20 min., which was higher than the pre-set acceptance criteria of not longer than 15 min. Thus, the acceptance criteria was reset to not longer than 20 min. for the third event (event E) in the final quality specifications. Discussion Acceptable disintegration and dissolution in relevant biological fluids is essential for the required performance of the SGC in vivo. With respect to the disintegration test of SGC, various pharmacopeia offer standardized procedures to evaluate the disintegration or rupture of SGC. The Figure 2b. Qualitative physical attributes testing (QPAT) United States Pharmacopeia (USP) describes a rupture test performed on artesunate soft gelatin capsules in water/10 mL. for quality control of SGC containing dietary supplements, performed in dissolution apparatus two (paddle) at a rota- tional speed of 50 rpm with 500 mL of immersion medium (4). British Pharmacopoeia (BP) prescribes a standard disintegration apparatus for SGC not administered by rectal or vaginal route using water as the immersion medium, or 0.1M hydrochloric acid/ artificial gastric juice can be used when justified and authorized. In the case of rectally/vagi- nally administered SGC, BP uses a different apparatus to contain four to 12 L of immersion medium and a specially designed holder to place the dosage forms. Apparently, these methods do not mimic the biorelevant conditions prevalent in the rectal region, where the volume of liquid is reportedly relatively low (1–3 mL) and the pH neutral at pH 7–8 with low buffer capacity (9). Further, the rectal region is signifi- Figure 3. Qualitative physical attributes testing (QPAT) events cantly static compared to the other regions of the gastroin- compared as a function of time between initial and stability testinal tract (10). Hence, development of suitable methods samples in phosphate buffer (pH 7.2, 1.5% CTAB/10mL). Data given for evaluating the physical attributes of the disintegration in mean±standard deviation (N=3). Event identification codes of rectally administered SGC in biologically relevant condi- given in X-axis are described as follows: A–first sign of physical tions is useful for efficient quality control. breakdown of the surface, thereby effecting release of the blend of SGCs fail to disintegrate in vitro primarily due to gelatin drug product contained within; B–progressive disintegration of the cross-linking upon aging, when exposed to physical condi- dosage unit; C–substantial deformation of the shape of the dosage tions such as high temperature and humidity, ultraviolet unit; D–substantial decrease/change in the size of the dosage unit; radiation, gamma-radiation, rapid drying, and chemical E–near-to-complete disintegration of the dosage unit; F–physical substances such as aldehydes, ketones, imines, and car- disintegration of the soft rectal capsule. bodiimides (1). However, gelatin cross-linking does not impact the in-vivo performance of orally administered SGC, because the digestive enzymes (i.e., pepsin or pancreatin) present in the gastrointestinal tract digest the gelatin cross- linking, enabling the disintegration or dissolution of the gelatin shell in vivo. In contrast, the rectal region does not contain digestive enzymes to dissolve cross-linked gelatin, which could lead to product failure. Hence, a biomimetic method to evaluate the disintegration/rupture of rectally administered SGC is even more important to ensure product quality throughout its shelf-life. The QPAT method developed in this experiment offers a simple, flexible, robust and reproducible way of quality control of rectal SGC. The proposed method can be adopted

44 Pharmaceutical Technology JANUARY 2019 PharmTech.com even in a setup with limited resources. It also provides op- References portunity to handle less volume of fluid (<10mL) while 1. R.P. Gullapalli. J Pharm Sci. 99 (10) 4107–4148 (2010). maintaining desirable hydrodynamics and visualization 2. R.I. Mahato and A.S. Narang, “Capsules,” in Pharmaceutical Dos- age Forms and Drug Delivery: Third edition Revised and Expanded, of disintegration events. These events can also be video re- pp.509-531 (CRC press, Taylor & Francis Group, 2018). corded or photographed for robust data maintenance. The 3. M.S.Uddin, et al., Br J Pharm Res. 9 (2) 1–9, 2016. opportunity to compare the change in various events dur- 4. USP, USP 39-NF 34 General Chapter <2040>, “Disintegration and ing disintegration as a function of time (i.e., during shelf Dissolution of Dietary Supplements” (US Pharmacopeial Conven- life) in QPAT setup is unique. Though the current scope of tion, Rockville, MD, 2015). 5. BP, British Pharmacopoeia Appendix XII A, “Disintegration of QPAT is only for rectal SGC, it can be conveniently applied Tablets and Capsules” (BP, 2017). to other types of SGC, such as vaginal SGC. 6. BP, British Pharmacopoeia Appendix XII A, “Disintegration Test The International Council for Harmonization (ICH) for Suppositories and Pessaries” (BP, 2017). guideline Q6A, Specifications: Test Procedures and Ac- 7. R.A. Speerhas, A. Bragalone, and S. Wagner, “Medication Delivery ceptance Criteria for New Drug Substances and New Drug in Intestinal Failure,” in Intestinal Failure and Rehabilitation: A Clinical Guide, L.E. Matarese, E. Steiger, and D.L. Seidner. Eds., Products: Chemical Substances, provides guidance on the pp.313-343 (CRC press, Taylor & Francis Group, 2005). setting and justification of acceptance criteria and the se- 8. World Health Organization, “Rectal Artesunate for Pre-Referral lection of test procedures (11). Accordingly, the decision Treatment of Severe Malaria,” October 2017, http://apps.who.int/ tree #7.1 in the guidance document allows disintegration iris/bitstream/handle/10665/259356/WHO-HTM-GMP-2017.19- testing, instead of dissolution testing, to be used as a per- eng.pdf?sequence=1 9. V. Jannin, et al., Adv Drug Deliv Rev. 73, 34–49 (2014). formance/quality control test for rapidly dissolving dosage 10. J.H. Rytting and J.A. Fix. “Drug Delivery—Rectal Route,” in En- forms (Q>80% in 15 minutes) containing highly soluble cyclopedia of Pharmaceutical Technology, J. Swarbrick, J.C. Boylan. drugs (Biopharmaceutic Classification System class I/III), Eds., pp. 1298-1310 (Informa Healthcare USA, Inc., New York, 3rd if a relationship between dissolution and disintegration ed., 2007). has been established. Similarly, the QPAT method could 11. ICH, Q6A Specifications: Test Procedures and Acceptance Crite- ria for New Drug Substances and New Drug Products: Chemical potentially replace the dissolution testing of rectal SGC Substances, 2000. containing liquids. 12. World Health Organization, “Artesunate 100 mg Suppositories,” A major shortcoming of the developed method is the April 2018, https://protect-eu.mimecast.com/s/DRZGC91EEsxA difficulty in observing the physical events when the SGC 9qZFo8OCz?domain=extranet.who.int. PT or its contents have intense color. However, this could be overcome by adopting a continuous replacement system using a reciprocating pump or intermittent replacement of whole fluid. Conclusion For rectal suppositories, a bio-mimetic disintegration test enables efficient quality control of SGC to assure product Yasvanth Ashokraj*, [email protected], Swati quality throughout the shelf-life. In order to simulate con- Laud, Kalpesh Sawant, Prashant Modak, and Praveen ditions within the human body, this method should not Date all work in Integrated Product Development at CIPLA. replicate requirements for oral gelatin capsules, but must *To whom all correspondence should be addressed. show acceptable disintegration in lower volumes of a medium that is free of digestive enzymes at milder hydrodynamics. QPAT offers a methodology that can be readily Read more about quality control testing adopted for routine quality control. This method offers the advantage of easy setup, even with limited resources. For more about quality control testing, read these articles at PharmTech.com: The World Health Organization has already accepted the • Improving Production: How IT, OT, and Quality Can method for quality control of artesunate SGC for disinte- Collaborate gration events (12). www.pharmtech.com/improving-production-how-it-ot-and- quality-can-collaborate Acknowledgements • Sartan Recalls Beg the Question: Is Compendial Impurity The authors would like to thank Preeti Raut and Anita Desai Testing Enough? for their critical inputs during the study. Special thanks to www.pharmtech.com/sartan-recalls-beg-question-compen- Geena Malhotra, head of R&D, for her continuous encour- dial-impurity-testing-enough agement. The authors also wish to thank Prof. Umesh Bana- • Pharma Collaboration Proposes Retirement of Obsolete kar, Banakar Consulting Services, for his critical inputs in Heavy Metals Tests developing QPAT as a quality control tool. www.pharmtech.com/pharma-collaboration-proposes-retirement-obsolete-heavy-metals-tests

Pharmaceutical Technology JANUARY 2019 45 Regulatory Update

out the Mutual Reliance Agreement (MRA) with the European Union. An example of MRA in action that he pointed to is the International Active Pharmaceutical Ingredient Inspection Program, which was recently used to share information on valsartan API facility inspections. For manufacturers and quality spe- cialists, what were the key regulatory achievements in 2018, and what issues promise to dominate this year? Susan Schniepp, executive vice-president of post-approval pharma and distinguished fellow at Regulatory Compli- ance Associates, shared some insights with Pharmaceutical Technology. New emphasis on quality culture Data Integrity Topped PharmTech: What key regulatory trends do you expect to take shape for 2019? Schniepp: Many of them will focus 2018 Priorities on quality. The fact that FDA is re- thinking its quality metrics program, Agnes Shanley and that the agency asked for sites to volunteer to be inspected in 2018, was pretty significant. We don’t know what FDA’s final program is going to look This year promises to bring more focus like, but we did see signs in its data in- on risk management and building a quality tegrity guidances that FDA would be increasing its attention on how manu- culture, says consultant Susan Schniepp. facturers approach the task of building a quality culture. lthough the impact of the US • Establishing a framework for over- This emphasis will bring FDA more federal government shutdown re- seeing the safety and quality of in line with other global agencies, Amains unclear (1), leaders within compounded drugs which did not jump on the quality met- FDA say they are encouraged by the • Modernizing the Office of New rics bandwagon but have been more progress made within the agency and Drugs interested in quality culture issues. industry during 2018. • Implementing new user fee goals According to reports published by and tracking the implementation Need leading, not lagging, indicators the Regulatory Affairs Professionals of serialization legislation. PharmTech: Were there weaknesses in Society (RAPS) (2), Janet Woodcock, FDA Commissioner Scott Gottlieb, FDA’s original quality metrics plans? director of FDA’s Center for Drug Eval- speaking at the FDLI Enforcement Schniepp: The agency will continue uation and Research (CDER), singled Litigation and Compliance Conference to tie quality metrics to drug short- out generic drugs as a key area where on Dec. 12, 2018, emphasized the images, which will still be an issue in 2019. improvement was seen in 2018. She portance of risk-based inspection and This approach makes sense, since, once noted an increase in productivity in efforts to ensure that the regulatory we see metrics, we can do surveillance new molecular entity (NME) develop- burden placed on drug manufacturers to identify where problems are devel- ment and review at the FDA/Centers is aligned with public health priori- oping and how these problems can be for Medicare and Medicaid Services ties (3). Gottlieb also noted efforts to deflected, diverted, and remediated be- Summit in Washington, D.C. on De- strengthen FDA’s Office of Regulatory fore they develop into drug shortages. cember 11, according to RAPS. Affairs (ORA) mentioning a program However, the metrics that FDA For 2019, the report said, Wood- designed to integrate ORA and CDER originally selected (e.g., corrective and cock’s top manufacturing and quality- more closely. He also spoke of global preventive action [CAPA] turnaround

related priorities for CDER include: inspection harmonization, singling time) were lagging rather than leading DUSANPETKOVIC1/STOCK.ADOBE.COM

46 Pharmaceutical Technology JANUARY 2019 PharmTech.com ones. The industry would benefit more from metrics that making large lots of product and sending it to hospitals, as indicate when facilities are heading into a problem (e.g., permitted by 503b of the Drug Quality and Security Act. scrap rates, which signal manufacturing problems and tie Some of the guidelines that surround traditional asep- in closely to the issue of aging facilities). tic processing are new to them (e.g., they are performing manual manipulations of product under a hood), yet they Data integrity and compounding issues may not understand why they need to do a media fill or why PharmTech: Will aging facilities receive more attention from a particle count is important. the industry and regulators in 2019? They may also fail to understand how final product test- Schniepp: This issue will continue to play out in 2019. At ing relates to production and what a certificate of analysis the Parenteral Drug Association (PDA), we’ve spent a lot of really means. Another question is how should they approach time working on post-approval changes, to allow manufac- stability? Traditional manufacturers work on container clo- turers to get regulatory relief so that they can modernize sure issues, but compounders are manipulating closures, facilities more easily. Until this process becomes easier, we and often their product expires within 90 days. will continue to see problems with aging facilities and a rise in scrap rates, reject rates, and aborted lots. These are the References metrics that should be tracked. 1. Pharmaceutical Technology editors, “Critical FDA Functions Con- There are also cost-vs-benefit questions [that tie into drug tinue as US Government Shutdown Hits the One-Week Mark,” pharmtech.com, December 29, 2018, www.pharmtech.com/criti- recalls and commodity drug shortages] and fit right into the cal-fda-functions-continue-us-government-shutdown-hits-one- aging facilities problem. For example, manufacturers may week-mark ask, ‘Why modernize a sodium chloride line when it will 2. Z. Brennan, “Woodcock Lays Out Top CDER Priorities for 2019,” not bring any profit?’ raps.org, December 12, 2018, www.raps.org/news-and-articles/ PharmTech: PDA has been actively involved in a number of news-articles/2018/12/woodcock-lays-out-top-cder-priorities- for-2019 regulatory issues and in communicating with FDA. Where 3. S. Gottlieb, “Remarks By Scott Gottlieb at the FDLI Enforcement has PDA made the greatest progress in this regard in 2018? Litigation and Compliance Conference,” fda.gov, December 12, Schniepp: One important achievement was the develop- 2018, www.fda.gov/NewsEvents/Speeches/ucm628140.htm PT ment of best practices for laboratory data integrity, and PDA is now working on best practices for manufacturing data integrity, encompassing not only computerized and hybrid, but paper-based systems. It’s so interesting that data integrity keeps coming up as an issue for pharmaceutical manufacturers. Even though the industry went through this in the 1980s with the Barr decision, data integrity continues to rear its head. PharmTech: What are the greatest challenges ahead for building a quality culture within the industry? Schniepp: Investigations into CAPA, things that have gone wrong, and deviations, will continue to be significant problems. Another looming challenge is the fact that, as we move forward with individualized stem and gene therapies, quality risk-based decision making will also have to advance. These issues will challenge the traditional quality professional. How will one release a lot, for example? And how will investigations into manufacturing problems proceed on site? How is quality going to integrate with manufacturing, so that we get out of our desk chairs and perform lab and site investigations in real time as problems happen, and ensure that the results are meaningful? PharmTech: Do you expect a framework analogous to current good manufacturing practices (cGMPs) to be brought to bear on compounders? Schniepp: It will be interesting to see how FDA manages compounding pharmacies in 2019. Remember, these facilities are essentially making uncontrolled drugs. They don’t have a new drug application (NDA) or filing associated with them, yet a number of large compounding companies are

Pharmaceutical Technology JANUARY 2019 47 Analytics: Solubility

solubility is also greatly affected by the composition of the solvent system (pH, nature, strength of drug-solvent attrac- tions), which is often underestimated when using aqueous solubility as an indicator for a drug’s solubility in biological conditions.” Oral ingestion— the importance of permeability Irrespective of route of administration, pharmaceutical drugs need to be in solution form in order to be absorbed (3), however, considering that the majority of drugs sold in the United States and Europe are administered orally (2) then intestinal permeability is also important. “Solubility, along with permeability, are The Solubility the two most important factors affecting oral drug absorption and underlying the Biopharmaceutics Classification System Conundrum (BCS) and Developability Classification System (DCS),” say Meissonnier and Savla. BCS and DCS are classification sys- Felicity Thomas tems used to predict what will impact the in-vivo performance of drugs (4,5). Predictions performed with these systems are restricted using solubility and Early adoption of the right approach to permeability as parameters (2). Drugs are considered to be highly soluble when address solubility can deliver significant benefits. the highest-dose strength is soluble in 250 mL (or less) of aqueous solution (ac- urrently, a significant proportion of impacts a drug’s solubility. “However, cording to the BCS) or when the highest drugs that are approved or in the solubility is a deceptively complex phe- total dose in 500 mL (or less) of aqueous Cdevelopment pipeline are poorly sol- nomenon, and its minutiae can lead to buffer pH 6.5 (according to the DCS). uble (1). This proportion may proliferate different conclusions,” they add. “On the However, for pharmaceuticals, the further as a result of the increasing drive surface, it is simply dissolution of a sol- solvent of choice is water, in which most to develop new chemical entities (NCEs) ute (drug molecule) in a solvent (buffer drugs are poorly soluble (2). Solubility, that are molecularly more complex. or media). But, there are dozens of fac- being the most important rate-limiting Yet, despite offering noteworthy ad- tors that affect solubility.” parameter for orally administered drugs, vantages—high selectivity and speci- Solubility of a substance happens is a major challenge for the formulation ficity, for example—more complex under dynamic equilibrium (2), which scientist. “The increasing numbers of molecules also incur their own set of means that dissolution and precipitation poorly soluble NCEs increase the impor- disadvantages. “As drugs become more happen both simultaneously and in an tance of bioavailability enhancing tech- complex, there is a trend towards higher opposing fashion. Therefore, it can be nologies to enable development success,” molecular weight and increased lipophi- reasoned that intermolecular interac- add Meissonnier and Savla. licity that can decrease aqueous solubil- tions between the solute (or drug) and ity,” confirms Jessica Mueller-Albers, solvent must be a consideration along Overcoming solubility challenges strategic marketing director for oral with environmental factors, such as Solubility improvements can be achieved drug delivery solutions at Evonik. temperature and pressure. through several means, which fall under Julien Meissonnier (vice-president, “The factors considered to have the two main categories. “The two main Science and Technology) and Ronak most influence are molecular descrip- methods to alter the solubility or disso- Savla (scientific affairs manager), both tors such as molecular size, shape, flex- lution of a drug substance are through from Catalent Pharma Solutions, agree ibility, and hydrogen-bonding ability,” either material engineering or formula-

that increasing molecular complexity say Meissonnier and Savla. “A drug’s tion development,” says Mueller-Albers. RADACHYNSKYI/STOCK.ADOBE.COM

48 Pharmaceutical Technology JANUARY 2019 PharmTech.com pda.org/2019Annual

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“A mix of competencies that can be tai- drug metabolism at the gut wall and in therapeutic window, so that the desired lored to the specific needs of a project, the liver may be the main hurdles.” therapeutic effect is achieved without including particle engineering, milling, Using the DCS, formulators can deter- adverse side effects,” Mueller-Albers solid dispersions, silica technologies, and mine whether dissolution kinetics (DCS states. “The effectiveness of any oral formulations that enable rapid disinte- IIa) or intrinsic solubility (DCS IIb) is dosage form depends upon the intrin- gration can be leveraged to enhance the the main hurdle. If solubility is the main sic ability of the drug to reliably dissolve solubility and bioavailability of drugs.” hurdle to formulation success, then le- in the fluids of the gastrointestinal tract An initial step in tackling solubility veraging the right model to bridge drug- prior to it being absorbed into the blood challenges for Meissonnier and Savla is substance properties with formulation stream. The rate of dissolution is a criti- optimization of the drug molecule itself technology becomes critical, according to cal factor in this process.” through chemical design, followed by Meissonnier and Savla. “One of the most An important tool used within the evaluation of the physical form of the important features of the DCS model is pharma industry to determine the per- molecule and its impact on solubility. factoring in the total dose in relation to formance of oral solid dosage forms is “Despite these efforts, a growing num- solubility,” they say. “In the very first ani- that of dissolution testing (6). “Dissolu- ber of molecules reach the preclinical mal studies, drugs are often tested at 10s– tion testing is a standardized method for and clinical development stage with 100s of milligrams per kilogram of body measuring the rate of drug release from persisting solubility issues, requiring ad- weight, which magnifies the solubility a given dosage form to optimize the for- vanced formulation technologies,” they hurdle and may suggest the selection of mulation,” adds Mueller-Albers. “Tests add. “Several formulation technologies the most complex technologies, whereas must not only be robust and reproducible, are designed to resolve solubility issues.” more simple solutions would be required but be able to detect any key changes in However, they note that only a few of for human clinical studies.” product performance between different these formulation technologies demon- There are numerous solubility en- formulations or batches. It is also essential strate all the criteria desirable in drug hancing technologies available, and for that in-vitro dissolution matches in-vivo development that can be used through- companies developing innovative drugs, conditions. If the dissolution procedure is out clinical development and commer- selecting the best technology can be a dif- well designed, it should help to accelerate cialization. ficult process. “Among many technolo- drug development by an effective selec- gies, only a few have made it successfully tion of prototype formulations and de-risk Formulation considerations to the clinic, and on to market. For DCS the clinical studies, which are necessary in “First and foremost, formulating a poorly IIa molecules, particle size reduction (mi- the drug product approval process.” soluble molecule requires an in-depth cronization and co-micronization) can Meissonnier and Savla say that the first characterization of its underlying bio- overcome the slow dissolution rate, and step should be to establish whether the dis- availability challenge,” stress Meisson- for DCS IIb molecules, only lipid-based solution testing is intended to be used to nier and Savla. “Way too often, formu- formulations and amorphous dispersions predict in-vivo performance or for quality lation scientists jump on the solubility (made via spray drying and hot melt ex- assurance/control (QA/QC). “There are challenge and try to resolve a partially trusion) have demonstrated commercial guidance documents and guidelines pub- defined or wrongly defined problem.” success,” explain Meissonnier and Savla. lished by regulatory authorities and scien- For example, they explain, if trying “Therefore, parallel screening of those tific organizations that deal with scale-up to improve solubility of a formulation technologies to select the most appropri- and post-approval changes, bioequiva- when the issue actually lies with disso- ate to the development stage is key.” lence, and biowaivers,” Meissonnier and lution rate, chemical instability, and/or Mueller-Albers also notes the impor- Savla continue. “A design-of-experiments high first-pass metabolism, time and ef- tance of a parallel approach. “It’s recom- (DoE) approach should be applied to de- fort could be wasted on the wrong devel- mended to use predictive tools that can velop a control strategy and define a de- opment pathway. “The most important minimize development costs, as well as sign space. The API solubility and stability consideration revolves around employing process technologies and equipment in the dissolution media should be part of the right models to characterize the mole- that avoid interactions with the API, en- the test set-up. Part of the dissolution test cule’s developability problems,” they con- able higher drug loadings, and improve validation should assure that other com- tinue. “It is key to leverage and develop stability,” she says. “Finally, it’s always ponents (i.e., excipients) do not interfere the right physiologically based pharma- important to review the physical proper- with ultraviolet absorbance, and that the cokinetic (PBPK) models to evaluate if ties of the drug, ease-of-manufacturing, calibration curve is linear and covers the the absorption hurdle is only solubility and the patent position.” lowest to highest concentration achieved based. According the Biopharmaceuti- during testing.” cal Drug Disposition and Classification Dissolution testing When specifically looking at develop- System (BDDCS), most poorly soluble “A fundamental goal of pharmaceutical ment projects involving poorly soluble and highly permeable drugs are subject to development is to optimize drug lev- drugs, Mueller-Albers explains that bio- liver metabolism, and in several instances, els available in the body to match the relevant media, such as fasted (FaSSIF)

50 Pharmaceutical Technology JANUARY 2019 PharmTech.com or fed-state simulated intestinal fluid that are incompatible with conventional (intra- and inter-patient) and a positive (FeSSIF), can be employed. “These media processing technologies. Despite many food effect (sometimes translated into contain solubilizing ingredients such as pharmaceutical companies establishing a marked increase in serum concentra- bile salts and phospholipids at physi- standard processes for the development tions of tenfold or higher). These detri- ological concentrations that are more and manufacturing of drug products mental properties, often combined with precise in simulating the in-vivo solubil- with poor solubility, in my opinion, there a narrow therapeutic index, can lead to ity and dissolution rate of poorly soluble is still a strong need to select develop- significant challenges in patients and compounds than pure buffer media,” she ment partners that can provide rapid, avoidable black box warnings,” Meis- says. “Dissolution volumes used in the reliable support into clinical studies.” sonnier and Savla warn. “Therefore, the in-vitro test can also be adapted to better Considering oncology, Meissonnier early adoption of the right formulation reflect the physiological situation. Disso- and Savla state that this trend of com- technology to address poor solubility lution testing for QC purposes may also pounds reaching patients with unad- can deliver significant patient benefits require a non-physiological pH, or the dressed solubility issues is magnified as and complement market differentiation.” addition of solubilizers, such as sodium clinical development pathways are often lauryl sulfate, to enable different product accelerated, leading to the first formula- References qualities to be differentiated based on the tion that is investigated making it through 1. S. Kalepu and V. Nekkanti, Acta Pharma- dissolution behavior.” to market launch. “So, poorly soluble on- ceutica Sinica B, 5 (5) 442-453 (2015). 2. K.T. Savjani, A.K. Gajjar, and J.K. Savjani, cology molecules (e.g., most protein ki- ISRN Pharmaceutics, 2012 Article ID Conclusion nase inhibitors) can reach the market with 195727 (2012). “Poor solubility was once considered to sub-optimal formulations and persistent 3. A. Chaudhary et al., J.Advanced Pharmacy be a ‘show-stopper’ in formulation de- solubility shortcomings,” they note. Education & Research, 2 (1) 32-67 (2012). velopment,” summarizes Mueller-Albers. If these solubility issues are not 4. L.Z. Benet, J. Pharm. Sci., 102 (1) 34-42 (2013). 5. J.M. Butler and J.B. Dressman, J. Pharm “However, while the risk of solubility has addressed, there may be dire conse- Sci., 99 (12) 4940-4954 (2010). been reduced, there are still many drug quences. “Solubility issues may result 6. A. Siew, Pharm. Tech., 40 (11) 56-64 candidates with physical characteristics in higher pharmacokinetic variability (2016). PT

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Pharmaceutical Technology JANUARY 2019 51 Packaging

dicators only revealed heat tampering. Lyle Small, the founder of Chromatic Technologies, explains, “Criminals have figured out that the way to get around high-heat tampering indicators is to ‘go cold’ by exposing packaging to very low temperatures. This can ‘delaminate’ many adhesives without activating a tamper-heat indicator. The BlindSpotz Tamper Heat and Tamper Freeze inks eliminate both threats” (2). Printable on seals, tape, labels, and packaging substrates, the technology activates within a 5 °C window and can be printed with adhesives and over- print varnishes. The Tamper Freeze ink turns from clear to blue when exposed to temperatures below -10 °C, while Tamper Heat ink turns from gray to orange (or gray to pink) if exposed to Smarter Packaging Comes heat greater than 65 °C (see Figure 1). In addition, Tamper Heat ink maintains color if exposed to high temperatures to the Pharma Market (greater than 100 °C) and lasts much longer on the shelf than existing “heat- Hallie Forcinio irreversible” systems (2). The temperature-sensitive messages are easily incorporated into existing Active and intelligent packaging technologies graphics. “If the stakeholder seeks an overt message, it will be easy for every- benefit brand owners, caregivers, and patients. one in the supply chain to recognize if tampering has taken place. But if mart packaging offers benefits to or deliver information. Associated tech- an investigation is underway, covert each stakeholder in the pharma- nologies include QR codes, near-field symbols can appear (to confirm tam- Sceutical supply chain. It can en- communication (NFC) and radio fre- pering) without alerting the bad actors hance patient compliance/adherence; quency identification (RFID), printed that they’ve been detected,” says Pat- confirm authenticity; support tracking, electronics, smartphones, smartphone rick Edson, chief marketing officer at anti-counterfeiting, and addiction pre- apps, the Cloud, and the Internet. Chromatic Technologies. vention efforts; protect shelf life; and “Technological progress is providing The BlindSpotz line also includes bolster sustainability profiles. new possibilities for drug packaging,” printable freeze alert technology so Divided into two segments, active says Benjamin Rist, product manager at caregivers and consumers can verify packaging and intelligent packaging, August Faller Group. “The Smart Pack- a cold-sensitive drug has not been ex- global demand for smart packaging is aging Solutions show how drug pack- posed to freezing and is viable for in- forecast to grow at a compound annual aging will improve patient compliance jection. If the product has experienced growth rate of 8% to reach a projected and facilitate the handling of drugs in freezing conditions, the ink reveals a value of $7.8 billion by 2021 (1). Active the future.” “Frozen. Do Not Use.” message or a packaging enhances functionality and frown-face icon. The technology offers includes technology such as scavengers, Active packaging an inexpensive way to monitor the flow desiccants, and color-changing inks. In- Color-changing BlindSpotz Tamper of drugs such as cholera, influenza, telligent packaging is more interactive Heat and Tamper Freeze inks from and HPV vaccines being shipped in- and provides a way to receive, store, and/ Chromatic Technologies enable the ternationally. “All these vaccines need detection of product tampering by an easy alert tool to indicate if, at the Hallie Forcinio is packaging editor for heat and sub-zero temperature expo- time of injection, they have been dam- Pharmaceutical Technology, editorhal@ sure. Before the development of the aged by temperature or tampering,”

sbcglobal.net. Tamper Freeze inks, most tamper in- says Edson. LEOWOLFERT/STOCK.ADOBE.COM

52 Pharmaceutical Technology JANUARY 2019 PharmTech.com Figure 1: Color-changing inks from Intelligent packaging technology with pressure-sensitive, Chromatic Technologies enable “This is the era of smart-everything,” shrink-sleeve, or roll-fed labels. Digi- the detection of product tampering reports Steve Tallant, director of Prod- talizing products via NFC labels en- by exposure to heat or sub-zero uct Management and Marketing at ables the real-time management of temperatures. Systech. He continues, “It is an expec- promotions and personalized mobile tation and not an option to distribute promotions and provides a way to connected products. And connected reward customers directly through does not mean just a printed link to a the product and increase brand loy- website. True, two-way communication alty. Talkin’ Things also can provide is an ever-increasing reality and norm. Multi-Color with intelligent packaging Pharmaceutical packages need to be au- technology based on RFID, augmented thentic, safe, and now connected.” reality, Internet of Things sensors, or As a result, intelligent packaging electronic article surveillance (anti- technology is being incorporated into theft) protection (4). caps, labels, folding cartons, and flexible packaging materials. These formats offer high potential “for patient compli- Intelligent ance, safety, and therapeutic success,” notes Rist. packaging provides For example, Kisico’s NFCap, a way to receive, equipped with an NFC chip, works with a smartphone app and provides covert store, and deliver product protection. Functions include product authentication, recording of information. when and where the bottle was opened, presentation of dosage instructions and Schreiner MediPharm introduced product information, and dosage and an NFC-equipped label for autoin- Figure 2: A near-field communication expiration date reminders. jectors in October 2018 at the PDA tag embedded in a cap from Closure Closure Systems International (CSI) Universe of Pre-filled Syringes and Systems International, based on has introduced a range of NFC chip- Injection Devices in Orlando, FL. Eas- technology from Talkin’ Things, equipped caps through a partnership ily adapted to existing label designs, enables real-time interaction between with Talkin’ Things (see Figure 2) (3). the Autoinjector-Label wraps around consumer and brand owner at the point Instructions in words or pictures on the unit, including the cap, and can of consumption. the package label or shrink sleeve direct be read via a smartphone app. Before consumers to use their phone to initiate opening the cap for the first time, the the interaction. patient can confirm the product is in One-stage tags support direct-to- its original sealed condition. The NFC consumer communication, while a technology also allows pharmaceuti- two-stage tag adds an anticounterfeit- cal manufacturers to present interac- ing function. David McCall, Business tive product information, demo vid- Development, Diversified Markets at eos, or special apps to help patients CSI, explains, “CSI’s two-stage Talkin’ through the self-medication process. Cap provides brands with an extra Integrated geo-tracking makes it pos- level of protection and traceability sible to detect gray market activities. to fight against global counterfeiting. The digital Autoinjector-Label adapts Every day, pharmaceutical companies to existing label designs and does not fight consumer health risks and com- affect the normal operation of the de- He continues, “Current sensor tech- pany financial risks associated with vice (5). nology for drugs and pharma requires a the counterfeiting of their products. One criticism of NFC and RFID tags separate label or device to be used and Our goal is to work with companies to is the presence of non-recyclable ma- can cost $1–$5 each, and then there is implement a technology that will mini- terials. Stora Enso eliminates that ob- the additional cost of application. [Print- mize and mitigate that very real and jection with its ECO sustainable RFID able technology provides] highly accu- costly threat of global counterfeiting.” tag technology. The paper-based RFID rate, affordable, and scalable solutions A partnership between Multi-Color tag eliminates plastic and is recyclable

FIGURE 1 IS COURTESY OF CHROMATIC TECHNOLOGIES; FIGURE 2 IS COURTESY OF TALKIN’ THINGS. OF TALKIN’ TECHNOLOGIES; FIGURE 2 IS COURTESY OF CHROMATIC FIGURE 1 IS COURTESY that can be implemented for pennies.” Corp. and Talkin’ Things melds NFC along with the paper label (6).

Pharmaceutical Technology JANUARY 2019 53 Packaging

geographies. [When products are e- moving the bottle from the carton. Flat Figure 3: Intelligent packaging from Fingerprinted, manufacturers can] electronics with an economical micro- August Faller is equipped with a inspect product globally and identify controller, tiny battery, and adhesive e- small e-paper display and electronic diverted product immediately … and paper display integrate into the medi- controls. stop the practice. This helps keep med- cation packaging without significantly icines in the countries that need them increasing the size of the box (8). desperately.” For flexible packaging and labels, Patients and drug makers benefit the SecuriLam laminate from TruTag from trusted authenticity and safety Technologies offers both authentica- globally. Drug makers gain significant tion and traceability functionality. Mi- supply-chain protection from diver- croscopic, encoded silica particles, or sion and counterfeiting. TruTags, are pre-embedded into stan- Smart Packaging prototypes from dard adhesive laminate film. The food- August Faller Group showcase other grade silica particles are invisible to the With e-Fingerprint technology potential benefits. “With our Smart naked eye, do not affect the finish of from Systech, any printed barcode Packaging solutions, we have developed the laminate or final product, and are can serve as a unique identifier. The three prototypes that take into account readable via proprietary authentication winner in the Excellence in Pharma: the advancing digitalization in the e- devices. Programmability allows brand Supply Chain, Logistics, and Distri- health market and the growing inter- owners to segment their packaging. bution Category at the CPhI Pharma est in interactive packaging solutions,” Programmed information can include Awards in October 2018, the e-Finger- says Rist. The Counting Device folding manufacturing location, product type, print technology relies on microscopic carton is equipped with a small e-paper or authorized geography to authenti- variations in substrate and print and a display and electronic controls (buttons) cate product and identify diversion (9). smartphone app (7). “Systech’s e-Fin- to improve compliance (see Figure 3). In gerprinting solution changes every- use, the patient confirms he/she has References thing about smart packaging without taken the tablet by pressing a button 1. Smithers Pira, “The Future of Smart changing anything at all,” states Tal- on the front of the folding carton. If the Packaging to 2021,” www.smitherspira. com/industry-market-reports/packag- lant. He explains, “Due to the inherent supply of tablets starts to get low, the ing/smart-packaging-to-2021, accessed characteristics of the printing process, e-paper display shows a warning and re- Nov. 14, 2018. there are micro-differentiations in minder to refill the prescription. A tiny 2. Chromatic Technologies, “CTI Launches printed output.” As a result, the digital microcontroller (storage medium-on- High-Tech Inks to Reduce Product Tam- e-Fingerprint is completely covert and chip) is powered via a battery integrated pering and Counterfeiting,” Press Re- lease, Nov. 8, 2018. non-replicable by counterfeiters. The in the packaging. The flat structure of 3. Closure Systems International, “Closure technology relies on Systech’s vision the electronics was a central require- Systems International & Talkin’ Things capabilities to look microscopically, at ment for easy integration in a pharma- Team up to Bring You the Latest in Pack- line speed, at the printed output and ceutical package and was accomplished aging Technology,” Press Release, Sept. derive a unique e-Fingerprint for each via a printed circuit board mounted on 27, 2018. 4. Multi-Color, “Multi-Color Corporation package. “Then, using a smartphone the back of the carton and an e-paper and Talkin’ Things Establish a Strategic app, a user is able to authenticate the display on the front (8). Partnership to Offer Connected Prod- item [from] anywhere in the world. The Counting Device is one of three ucts,” Press Release, Feb. 27, 2018. Because the item is uniquely identified, Smart Packaging prototypes developed 5. Schreiner MediPharm, “New NFC-La- additional information … like expiry, by Faller in conjunction with MSC Tech- bel by Schreiner MediPharm for Digital Authentication of Autoinjectors,” Press lot, batch, ingredients, and recall no- nologies and Pforzheim College. The Release, Sept. 20, 2018. tices can be presented interactively other two designs include a Level Indi- 6. Stora Enso, “Stora Enso Introduces Sus- with a user,” says Tallant. cator, which calculates how much liquid tainable RFID Tag Technology ECO for He reports, “We have pharmaceu- remains in an opaque bottle of fluid Intelligent Packaging,” Press Release, tical companies deploying our e-Fin- medication, and the Medical Prescription Nov. 7 2018. 7. Systech, “Systech Wins Excellence in gerprint solution globally to fight not carton, which counts the tablets, provides Pharma Award at CPhI 2018,” Press Re- just counterfeiting, but diversion of an alert when a dose is due, and transmits lease, Oct. 10, 2018. product out of the legitimate supply refill orders via Bluetooth (8). 8. August Faller Group, “Intelligent Fold- chain. Because of vastly different price The Level Indicator carton also ing Carton with Fill Level Measurement,” points for medicines globally, it can be relies on a small e-paper display and Press Release, March 2018. 9. TruTag Technologies, “TruTag Technol- very lucrative to divert medicines out electronic controls. The push of a but- ogies Launches SecuriLam Intelligent of low/no-cost geographies and send ton on the front of the carton shows Laminates,” Press Release, February 27, them for great profits into high-price how much liquid remains without re- 2018. PT OF AUGUST FALLER. FIGURE 3 IS COURTESY

54 Pharmaceutical Technology JANUARY 2019 PharmTech.com HPAPI Best Practices: Development, Manufacturing, and Particle Engineering

ON-DEMAND WEBCAST Aired December 13, 2018

Event Overview Who Should Attend Improved candidate compound screening and more targeted drug ■ Large pharma, mid-size pharma, biotech action are bringing more highly potent active pharmaceutical ingre- companies dients (HPAPIs) to the drug development pipeline. Many of these ■ Technical positions involved in process compounds require particle engineering to meet target product development and scale-up — early to profiles. HPAPIs and their intermediates require specialized handling late development or commercialization — of highly potent compounds capabilities and expertise for safe development, scale-up, and manufacturing. In this webcast, learn about best practices and review ■ Scientists, Engineers, R&D Managers, representative case studies for HPAPIs across the development cycle. Senior Managers

Key Learning Objectives ■ Key criteria for containment in development and manufacturing highly potent/extremely potent compounds Presenters Maurits Janssen, PhD ■ Glove-box design optimization and procedures for particle-size Senior Director, reduction of HPAPIs Head of Commercial Development ■ Effective approaches for accelerated scale-up and technology Lonza Pharma & Biotech transfer Milko Leone, Eng Head of Engineering Department Lonza Monteggio

Moderator Sponsored by Presented by Rita Peters Editorial Director Pharmaceutical Technology

For questions contact Kristen Moore at [email protected]

magentablackcyanyellow ES54521_PT0119_055_FP.pgs 01.19.2019 04:27 UBM outsourcing outlook

The Outlook for CMO Outsourcing in 2019

Ronald A. Rader and Eric S. Langer Outsourcing of manufacturing activities is expected to increase in 2019.

ssentially all biopharmaceutical novator drug companies continue to CMOs’ involvement in earlier-phase industry-related indicators and retain manufacturing and develop- aspects of product development and Etrends are supporting continued ment of their prospective blockbusters manufacturing is even larger than with incremental increases in outsourcing in-house. commercial manufacturing. CMOs of pre- and commercial API and bio- also play an important role in new pharmaceutical product manufactur- bioprocessing technology development ing services to contract manufacturing The financial and adoption, with CMOs often the organizations (CMOs). This is positive first (compared with developer com- news for CMOs. BioPlan Associates’ outlook for panies) to implement new technologies. survey of bioprocessing professionals CMOs often have much more technical overall confirms that outsourcing to CMOs is solid. expertise than developer companies, CMOs is being viewed increasingly as including with new technologies, with a desirable option, with expectations The financial outlook for CMOs is CMOs having worked on more prod- for more outsourcing in the future (1). solid, with growth in revenue tracking ucts/projects and using a wider variety CMOs are already a core component that of the overall biopharmaceutical of technologies. of the biopharmaceutical industry, and sector, which consistently grows at A decade or more ago, Big Pharma their use and importance will further more than 12% annually. CMOs con- and other well-established developer incrementally increase over time. Rou- tinue to expand capacity, staff, etc., to companies outsourced as much work tine services and products with smaller try to retain clients as their products as possible to CMOs, often without markets will be outsourced more fre- advance in development. Total annual critical analysis. Most biopharmaceu- quently, and products requiring novel biopharmaceutical CMO revenue was tical companies traditionally turned bioprocessing, where expertise or approximately $3.4 billion in 2018 and to outsourcing to control costs and/ capacity remain limited, will also be is expected to grow to about $3.8 bil- or manage their internal staff and outsourced more frequently, such as lion in 2019. Biopharmaceutical CMOs resources. Biopharma companies are cellular and gene therapies. Most in- remain a relatively small niche, how- now increasingly taking a more stra- ever, with chemical substance-based tegic view of outsourcing and seeking drug outsourcing revenue more than to outsource as much as possible. Most 10 times that of the biopharmaceutical companies periodically re-evaluate sector. their core competencies and ratio- Despite being just a small part of nally decide how they will manage Ronald A. Rader is the overall biopharmaceutical indus- their R&D, manufacturing, and re- senior director of technical research at BioPlan try, CMOs play important roles. CMOs lated outsourcing. As a result, almost Associates. currently commercially manufacture every area of R&D and manufacturing approximately 30% of marketed main- is considered a candidate for outsourc- stream (recombinant) commercial ing (1). products, although this remains con- The number of products in devel- centrated among a few, large-capacity opment continues to grow, with this Eric S. Langer is CMOs. Most CMOs primarily support carrying over to CMO outsourcing. president and managing R&D and early-phase support—and FDA approved approximately 25 new partner at BioPlan Associates, Inc., elanger@ only a minority performing commer- biopharmaceuticals in 2018 (1), and

bioplanassociates.com cial manufacturing—so, in general, the number of annual approvals is LIGHTSPRING/SHUTTERSTOCK.COM

56 Pharmaceutical Technology JANUARY 2019 PharmTech.com Outsourcing Outlook expected to increase in coming years, Figure 1: Biopharmaceutical manufacturing facilities outsourcing no as new classes of products receive ap- production 2006–2018. provals, particularly biosimilars and cellular and gene therapies. In the next five years, the number of approved bio- (% Organizations Manufacturing 100% In-house) similars will exceed the number of ap- (No Outsourced Manufacturing, 2006-2018) proved mainstream products. 30.0% 44.2% 41.2% 35.3% 50.0% 46.2% Mammalian Cell 47.1% The evolving mix of 44.6% Culture 57.0% 52.5% 52.4% 55.6% biopharmaceuticals 57.6%

43.1% 67.6% in the development 45.2% 39.9% 42.4% 2018 Microbial 34.8% pipeline is expected 50.0% 2017 Fermentation 43.8% 64.2% 2016 60.3% 2015 58.3% to increase 60.5% 2014 58.1% 2013 outsourcing to 34.1% 2012 2011 2010 CMOs. Cell or Gene 2009 Therapies 2008 2007 The evolving mix of biopharma- 2006 ceuticals in the development pipeline is also expected to increase outsourcing to CMOs, because CMOs often have more capabilities and expertise in new areas of bioprocessing than developer companies. Product types, classes, and the underlying molecular structures of products in R&D continue to diversify. Rather than just familiar-type recombinant proteins MORE TECHNOLOGY. and monoclonal antibodies, CMOs are often the pioneers in terms of manufacturing novel products, including antibodies with novel core structures/backbones, antibody- drug conjugates (ADCs), cellular therapies, gene therapies, RNAi, pegylated proteins, and other novel types of products. Also, lesser innovative classes of products are often outsourced; CMOs report a 15% increase in business in recent years from biosimilars projects. Essentially, every successful CMO is continually ex- panding its capacity and staff/expertise. The industry With many Cyclodextrins, you’re only adding is starting to see a major trend for CMOs adding 1000– new issues into the equation. Not with Captisol. 2000-L single-use bioreactor process lines for commer- With revolutionary, proprietary technology, cial manufacturing as products currently in development Captisol is rationally engineered to signiﬁcantly manufactured with single-use systems advance to ap- improve solubility, stability, bioavailability and provals. dosing of active pharmaceutical ingredients.

In the past year, BioPlan has identified approximately SOLVE PROBLEMS WITH CAPTISOL SOLUTIONS. 180,000 L of single-use systems with capacities greater than 1000 L added as CMO expansions or new facilities (2). As CMOs develop this ‘entry-level’ commercial scale single-use capacity, the number and percentage of mar- CAPTISOL.com keted products commercially manufactured by CMOs will further increase, at the expense of stainless steel- based bioprocessing.

Pharmaceutical Technology JANUARY 2019 57 Outsourcing Outlook

Figure 2: Country selections as destination for international outsourcing of tations/plans to outsource more bio- biomanufacturing. pharmaceutical API manufacturing in the next two years, increasing from

(All global respondents) 12.4% in 2010. The US continues to be the des- Destination for International Outsourcing tination for the largest portion of “Consider your facility’s current plans for INTERNATIONAL capacity expansion over outsourcing to foreign CMOs, with the next 5 years (2023)”, All Respondents “Where have you been considering production outsourcing 30.1% of respondents citing US fa- outside your own country? cilities as likely being considered for USA 14.6% 15.5% 30.1% CMO work within five years. Figure Germany 6.8% 18.4% 25.2% 2 shows the top 10 countries, other China 12.6% 8.7% 21.4% than their own, survey respondents India 8.7% 9.7% 18.4% said they expected to be a destination Ireland 6.8% 8.7% 15.5% % Strong Likelihood for outsourcing of their international United Kingdom 2.9% 10.7% 13.6% % Likelihood Switzerland 3.9% 9.7% 13.6% expansions in the next five years. France 2.9% 9.7% 12.6% Among US respondents, China was Singapore 3.9% 6.8% 10.7% the top destination, cited by more Korea 2.9% 6.8% 9.7% than 50%. Despite these industry expectations of more outsourcing to China, CMOs are not fully permitted in China; Survey data and trends malian or microbial work has gener- just a few select companies currently Developers generally outsource a ally decreased (i.e., percent report- participate in government-run CMO higher percentage of projects/prod- ing some outsourcing has increased) pilot programs (3). Once China turns ucts involving mammalian vs. micro- since 2006. Comparable small por- on its domestic bioprocessing indus- bial expression systems. The historical tions, approximately 15%, report try, China may become a major off- picture of respondents to the annual outsourcing the majority of their shoring destination, even if these BioPlan survey reporting that they do mammalian and microbial work. CMOs are hired to only manufacture not outsource bioproduction is shown Growth and trends in outsourcing products for China’s massive domestic in Figure 1. of microbial work remain somewhat market. unclear, with the largest CMO mar- BioPlan expects Chinese CMOs to ket, the United States, relatively lack- capture business, potentially doing Biopharma ing in microbial CMOs and GMP this at the expense of Indian CMOs. capacity greater than 100–200 L; Eu- India appears to be focusing on serv- companies are now rope is the clear leader in microbial ing its own and international markets CMOs and GMP capacity. for lesser-regulated biogenerics, while, increasingly taking When developer respondents to according to BioPlan studies, nearly a more strategic the 2018 survey were asked about 85% of the Chinese biopharmaceutical expectations for outsourcing any industry targets GMP manufacture view of outsourcing work (any expression system) in five for their own domestic and Western years, 72.3% projected at least some markets (3). and seeking to mammalian and 58.3% said they expected to outsource at least some References outsource as much microbial work. More than 61% of 1. E.S. Langer, et al. Report and Survey of respondents are currently outsourc- Biopharmaceutical Manufacturing Ca- as possible. ing at least some API manufactur- pacity and Production, 15th Edition. ing. BioPlan Associates: Rockville, MD, In 2018, 30% of survey respon- But this percentage was lower than April 2018, www.bioplanassociates. dents reported no mammalian for many tasks outsourced to contract com/15th outsourcing, meaning that 70% research organizations (CROs), in- 2. BioPlan Associates, Top1000Bio.com, outsourced at least some of their cluding 77.8% outsourcing some an- www.top1000bio.com. mammalian projects/products; 43% alytical testing/bioassays, and 72.6% 3. V.Q. Xia, et al., Advances in Biopharma- reported no (57% reported some) outsourcing at least some toxicology ceutical Technology in China (BioPlan outsourcing of microbial work. The testing. More than one-quarter of Associates, November 2018), www.bio- percent not outsourcing of any mam- the respondents (27.7%) cited expec- planassociates.com/china PT

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suites to its existing facilities Catalent Invests AbSci, Sanofi in Rentschler in North Carolina. These $200 Million in Manufacturing Biopharma additions will increase cell-culture manufacturing Wisconsin and Partnership Completes capacity by approximately Indiana Sites On Jan. 9, 2019, AbSci, a Acquisition of US 25% and microbial capacity biotherapeutic discovery and by approximately 50% at Catalent announced on manufacturing technology Manufacturing Site its North Carolina location. Jan. 7, 2019 a $200-million company, announced a Rentschler Biopharma, a The company expects that investment in its biologics manufacturing collaboration contract development the increased production business to expand drug- with Sanofi to improve two of and manufacturing capacity will be ready for substance manufacturing Sanofi’s biotherapeutics. Under organization (CDMO) cGMP manufacture by early capacity and drug-product the terms of the agreement, for biopharmaceuticals, 2020. Fujifilm has committed fill/finish capacity. The AbSci will apply its Escherichia completed the acquisition to grow its CDMO business investments, phased over a coli (E. coli) manufacturing of a manufacturing facility to meet a JPY 100 billion three-year program, will be platform, SoluPro, and its from an affiliate of Shire, the sales target by March 2024. carried out at the company’s optimization assay system, to company announced in a biologics manufacturing two of Sanofi’s biotherapeutic January 3, 2019 press release. sites in Madison, WI, and molecules. AbSci reports that The 93,000-ft2 site with Bloomington, IN. This Cambrex Acquires its technology platform can approximately 70 employees follows a December 2018 rapidly achieve optimized, is located near Boston in announcement the company Avista Pharma scalable, high-quality, high- Milford, MA, and it is the was investing $14 million On Jan. 3, 2019, Cambrex, titer production of any class German company’s first in packaging capabilities a provider of generic APIs, of biotherapeutic molecule, manufacturing facility in at the Bloomington site. small molecule, and finished including traditionally difficult- the United States. Under Mammalian cell-culture dosage form products to-manufacture molecules and the terms of the agreement, capacity will be increased at and services, announced next-generation scaffolds. The Rentschler Biopharma will Madison with the build-out that it completed the collaboration will take place at continue to manufacture for of two new suites, each with $252-million acquisition of AbSci, located in Vancouver, WA, Shire at the site. a 2 x 2000-liter single-use Avista Pharma Solutions, and funded by Sanofi. bioreactor system, providing a contract development, During development, additional clinical and manufacturing, and SoluPro can reportedly produce commercial production Fujifilm Invests in testing organization, from gram quantities of material capacity at the 2000- or Ampersand Capital Partners. for preliminary screenings in Biopharmaceutical 4000-liter batch scale as well Cambrex reports that the a matter of days instead of new laboratories. Work is transaction, announced in weeks. AbSci states that the Production Capacity expected to be completed by November 2018, strengthens platform has a demonstrated Fujifilm plans to invest mid-2021 and will more than Cambrex’s position as a track record expressing difficult approximately JPY 10 double Catalent’s commercial small-molecule CDMO across proteins and achieves higher billion (approximately biomanufacturing capacity, the entire drug lifecycle. protein production levels US$90 million) to expand its the company reports. Avista’s four sites in than mammalian systems, biopharmaceutical CDMO Additionally, fill/finish Durham, NC; Longmont, which allows scientists to business, FUJIFILM Diosynth capacity at the Bloomington CO; Agawam, MA; and access previously elusive and Biotechnologies (FDB), the site will be expanded by Edinburgh, Scotland, UK untestable therapeutic proteins. company announced on Jan. 79,000 ft2, with both GMP will be integrated into Once therapeutic candidates 7, 2019. and non-GMP capabilities. Cambrex’s global network, have been identified, the This investment will A high-speed flexible vial as well as the company’s platform scales seamlessly include the expansion of line, using both ready-to-use service offerings ranging for commercial production, existing production facilities components and bulk filling from API and drug therefore eliminating the at its North Carolina location. at a filling speed of 300 units product development six-to-12-month cell-line Further investments are per minute, will be installed and cGMP manufacturing development process. By planned at the company’s along with a high-speed to stand-alone analytical, returning biomanufacturing other locations. flexible syringe/cartridge microbiology testing, and to its E. coli roots, AbSci says it Investments will include line with a filling speed of solid-state sciences. aims to replace Chinese hamster the addition of 2000-L more than 300 units per ovary cell and other mammalian single-use cell-culture minute, and a fully automated expression platforms as the manufacturing trains, cell- vial inspection machine. preferred expression host. culture purification suites, and new microbial recovery UDOMSOOK/SHUTTERSTOCK.COM

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Pharmaceutical Technology JANUARY 2019 61 ask the expert

Global Inspection Harmonization

Understanding the differences in inspection processes is the key to successful global expansion, according to Siegfried Schmitt, PhD, vice-president Technical, PAREXEL Consulting.

We are a medium-sized company in Europe, specializing in the agency’s expectations. The United Kingdom’s Medicines and Q. gene-therapy products. So far, we have only marketed our Healthcare products Regulatory Agency (MHRA), for example, products in Europe, but we are planning a global expansion. By has a blog (4). FDA publishes guidance for industry documents now, we are familiar with the European inspectors and how they (5), and Australia’s Therapeutic Goods Administration updates inspect. How can we prepare for inspections from overseas agen- information on their inspection approaches regularly on their cies? We hear that there is no harmonization in expectations? website (6). It is essential to stay informed on the inspection Congratulations on your plans and being proactive in process, as some agencies may have specific requirements. A.preparing for these inspections. To some degree, inspec- Russia’s Roszdravnadzor, for example, requires you to provide torates from around the world are making attempts at harmo- certified third-party translators with good manufacturing nizing how they inspect. Regulatory agencies that belong to practice expertise for its inspection; or Colombia’s National Pharmaceutical Inspection Co-operation Scheme (PIC/S) follow Food and Drug Surveillance Institute (INVIMA) expects you to a harmonized inspection process. It is sensible to familiarize have all observations resolved by end of inspection. Here, the oneself with these procedures, which are freely available on difficult part is that not all the expectations are included in the PIC/S website (1). the guidance documents. The best way to get access to such Other drivers for harmonization are mutual recognition detailed information is to use the help of professional service agreements (MRAs), which require agencies to recognize providers and to interact with peers (e.g., at conferences or each other’s competence and equivalence. Currently, the through industry associations). United States and the European Union (EU) are in the process The last point, namely an inspector’s personal opinions, is one of finalizing such an MRA (2). As you will already be aware, you simply have to address at the time of the inspection. As with inspectorates of the EU’s member states, the National all inspections, courtesy and professionalism will go a long way. Competent Authorities, are all peers (i.e., recognizing each To answer your question: be prepared by having a sound other’s inspections as completely equivalent) (3). understanding of the regulations and the regulatory inspection That said, you may still encounter differences in inspection processes, including the unwritten expectations. Regulatory process and style, and moreover, differences in opinion from intelligence is essential as regulations change continuously and your inspectors. Why might this be? There are three main so do the inspection processes. contributions: • The law: different national regulations References • The approach: country-specific inspection processes and 1. PIC/S, www.picscheme.org. requirements 2. EC, Public Health blog, http://ec.europa.eu/newsroom/sante/ • The human factor: personal preferences of the inspectors. newsletter-specific-archive-issue.cfm?newsletter_service_ To make your inspections as smooth and successful as id=327&lang=default possible, you need to acquaint yourself with all three aspects 3. S. Mylona and E. Donovan, “Module 09–Good Practice and and prepare for them. A pharmaceutical firm is legally required Inspections,” Presentation at the 2nd International Awareness to comply with the national regulations in any country it wishes Session–The EU Medicines Regulatory System and the Euro- pean Medicines Agency, March 8–9, 2018, www.ema.europa.eu/ to market its products. Therefore, you must be familiar with the documents/presentation/presentation-module-9-good-practice- regulations. For example, your products will have to comply not inspections_en.pdf merely with the pharmacopeia in your native country, but also 4. MHRA, MHRA Inspectorate Blog, mhrainspectorate.blog.gov. with those of the country the overseas inspector is from. Do not uk. be surprised if an inspector wants to see that you do possess a 5. FDA, Compliance Program Guidance Manual, www.fda. copy of that document and that you can read it if it isn’t in your gov/iceci/compliancemanuals/complianceprogrammanual/ native language. ucm2005382.htm.

Many agencies publish details on how they inspect and often 6. TGA, Manufacturing Inspections, www.tga.gov.au/manufactur- DAMIAN PALUS/SHUTTERSTOCK.COM also provide additional information on the inspection process and ing-inspections. PT

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