Solubility Challenges: Unlocking a Drug’S Potential JULY 2015 Pharmtech.Com

JULY 2015 Volume 39 Number 7 Volume 39 Number 7 Number 39 Volume Cleaning Stability Tablet Count PLUS: Validation of Biologics in Packaging PHARMACEUTICAL TECHNOLOGY PHARMACEUTICAL

Solubility Challenges: Unlocking a Drug’s Potential JULY 2015 PharmTech.com

PEER-REVIEWED Using In-Situ Gelling to Optimize Opthalmic Drug Delivery

DRUG DELIVERY OPERATIONAL EXCELLENCE API SYNTHESIS & MANUFACTURING Targeting Drugs to the Colon Data Integrity Continuous API Synthesis

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4 Pharmaceutical Technology July 2015 PharmTech.com

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magentablackcyanyellow ES639142_PT0715_005_FP.pgs 07.06.2015 20:46 ADV July 2015 Volume 39 number 7 Pharmaceutical Technology is the authoritative source of peer-reviewed research and expert analyses for scientists, engineers, and managers engaged in process development, manufacturing, formulation and drug delivery, aPi synthesis, analytical technology and testing, packaging, it, outsourcing, and regulatory compliance in the pharmaceutical and biotechnology industries.

coVer sTory 20 Solving Poor Solubility to Unlock a Drug’s Potential modern methods and modeling offer a better way to understand

the cover solubility issues and solve today’s complex formulation challenges.

images: adam gault/getty images; Dan Ward On FeatureS DePartmentS/

drug deliVery cleaning ValidaTion ProDuctS 28 Mission Possible: 44 Getting Scientific 11 Product Spotlight Targeting Drugs to the Colon About Cleaning Validation 63 Ad Index Prodrugs and drug-delivery systems an iSPe guidance document, four controlled by time, ph, and osmosis are years in the making, brings risk- 64 Pharma Capsules being used to prevent drug degradation based thinking, statistics, and lean 65 Showcase/Marketplace in the stomach and small intestine and Six Sigma to cleaning validation. ensure drug release in the colon. Qa/Qc: oPeraTional excellence aPi synThesis & manufacTuring 46 A Risk-Based 30 Lack of Expertise Approach to Data Integrity Hinders Adoption of heightened regulatory scrutiny of Continuous API Synthesis data integrity highlights the need FDa, congress, and early adopters for comprehensive procedural look to speed up the use of reviews and strategies for managing continuous aPi manufacturing. mission-critical information.

Continued on page 8

Peer-reVieWeD reSearch

oPTimiZing oPThalmic formulaTion 34 Beyond the Blink: Using In-Situ Gelling to Optimize Opthalmic Drug Delivery Delivery systems that allow drugs to be administered as liquids, but form gel within the eye, promise to improve efficacy and patient compliance.

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neWS & analySiS StanDarDS &

from The ediTor TroubleshooTing regulationS 10 Big Ideas 60 Testing the us regulaTory waTch Demand Big Action Stability of Biologics 14 Breakthrough the bio/pharma industry Biologics exhibit greater variability Drugs Raise Devel- enjoys success, but it cannot ignore in stability testing than do small- opment and Produc- patient access to medications. molecule drugs, and maintaining a tion Challenges stable test environment is crucial. sTaTisTical soluTions manufacturers and FDa look for innovative ouTsourcing ouTlook strategies to meet accelerated timeframes. 52 Is Your Calibration Really a Good Straight Line? 62 CDMOs euroPean regulaTory waTch Statistical procedures give statistical Cautiously answers, not analytical judgement. Address Expansion 16 Unravelling the While all market signs are pointing up, Packaging forum Complexity of EU’s memories of past setbacks may discourage ATMP Regulatory Framework cDmos from expanding capacity. 56 Ensuring the european union has a challenging task Correct Tablet Count ahead as it strives to harmonize regulations electronic counters on advanced therapy medicinal products. are flexible and allow quick ask The exPerT changeover between products. 66 Compliance with US and EU Internal Audit Requirements Siegfried Schmitt, principal consultant, PareXel, discusses how to handle internal audit reports during inspections.

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Big Ideas Demand Big Action Pharmtech.com/pt/forumPharmTech.com/forum IMAGES GREUEL/PHOTODISC/GETTY JORG Rita Peters

The bio/pharma industry enjoys success, but it cannot ignore patient access to medications.

t the 2015 Biotechnology Industry the US to more than $1 trillion for the ideas. Partisan politics, cable news, so- Organization (BIO) convention, first time, E&Y reports. cial media, and professional and ama- Aheld in Philadelphia in mid-June, The report authors, however, warned teur political commentators contribute all indicators showed that the industry that the biotechnology industry cannot to a lack of direction and desire to solve was riding a record wave of success. afford to become complacent, but must the nation’s pressing issues. According to a BIO post-event press work with patients, payers, providers, To illustrate how the desire to release (1), more than 15,800 industry and governments to develop new prod- achieve a “big idea” requires coopera- players from 69 countries, 47 states, ucts for unmet medical needs, as well tion and sacrifice, Brokaw recounted the District of Columbia, and Puerto as ways to improve care delivery and the efforts of US paratroopers in the Rico attended. A record number of health outcomes. The industry must D-Day invasion of Europe in 1944. partnering meetings—27,279 meetings also play a role in developing payment When the soldiers dropped behind between 3100 companies—illustrated schemes to give patients better access enemy lines in France, they were sepa- the convention’s business focus. to breakthrough drugs. rated from their units and were scattered across the countryside. They as- Biotech on a high sembled with others near them to form Business was good for the biotech in- The US needs makeshift units and accepted their dustry in 2014; in fact, it was a record- new orders. The soldiers did not stop setting year, reports Ernst & Young a “big idea” debate to argue about what platoons or units (E&Y) in its 29th annual report, Beyond on healthcare. the fighters were from; they simply Borders, Biotechnology Industry Report went about the business of liberating 2015 (2). The report cites record reve- Europe, a “big idea” of those times. nues, profitability, financing, and drug The right thing to do In his 1998 best-selling book, The approvals as signs of a healthy market. In a keynote discussion, Tom Bro- Greatest Generation, Brokaw related In the established biotech areas of kaw, the award-winning journalist, that the soldiers who fought in World the United States, Europe, Australia, reiterated the need for a discussion War II did so because it was the right and Canada, revenues increased 24% in about patient access to crucial drugs. thing to do. 2014; R&D spending increased by 20%. A long-time observer of US business, The current generation of politi- A robust stock market and large num- politics, culture, and society, Brokaw cians, payers, patients, and drug com- ber of initial public offerings pushed has added first-person experience as panies are challenged with determin- the biotech industry capitalization in a patient undergoing treatment for ing “the right thing to do” to achieve multiple myeloma. one of today’s “big ideas”—affordable, Brokaw noted that patients, drug effective drug therapies for all patients. companies, and doctors do not speak This time, the enemy may be us. the same language. The nation, he says, needs an all-inclusive health plan that References makes the price of drugs affordable to all. 1. Biotechnology Industry Organization, Rita Peters is editorial To achieve this, the US needs a “big “The 2015 BIO International Convention director of Pharmaceutical Closes in Philadelphia,” Press Release Technology. Send your idea” debate on healthcare, Brokaw (Philadelphia, PA, June 18, 2015). thoughts and story ideas said. However, in the current Ameri- 2. Ernst & Young, Beyond Borders, Biotech- to [email protected]. can political system, there are no big nology Industry Report 2015 (2015). PT

10 Pharmaceutical Technology JULY 2015 PharmTech.com

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magentablackcyanyellow ES639148_PT0715_013_FP.pgs 07.06.2015 20:46 ADV Jill Wechsler is Pharmaceutical Technology’s Washington editor, tel. 301.656.4634, [email protected].

Breakthrough Drugs Raise Development and Production Challenges

Manufacturers and FDA look for innovative strategies to meet accelerated timeframes.

he FDA program to expedite the development and approval submission, accepting amendments during the review cycle, Tof innovative drugs for serious and life-threatening condi- and increasing postmarketing commitments to cover residual tions is a great success, but the abbreviated development risk, explained Dorota Matecka, acting branch chief in the timeframe involved raises numerous difficulties for manufac- Office of New Drug Products in CDER’s Office of Pharmaceutical turers seeking to ensure product quality and timely supply. Quality (OPQ), at the DIA workshop and again at the ISPE/FDA/ Expert review teams in the Center for Drug Evaluation and PQRI Quality Manufacturing Conference in June 2015. Matecka Research (CDER) and the Center for Biologics Evaluation and noted that CDER will schedule CMC-specific meetings during Research (CBER) are meeting deadlines and goals for assessing development to advise on these issues, often including CDER breakthrough designation requests and for expediting reviews upper management and subject matter experts. of these drugs, but the process is resource intensive and has Robert Wittoft, pharmacist in OPQ’s Office of Process and raised questions about how FDA can keep up with a growing Facilities (OPF), similarly urged early discussion of residual number of candidates. product quality risks. Manufacturers need to decide When the breakthrough program was established as part dosage form and methods validation strategies much of the FDA Safety and Innovation Act of 2012, stakeholders sooner, he said at the CMC workshop, and should “plan for envisioned about two to three designations a year. By the end the unexpected,” such as facility qualification failures and of May 2015, FDA had received 308 requests for breakthrough changes in manufacturing schedules. Effective communication status and had granted the designation for 90, approximately with contract manufacturers is crucial, as is a transparent 30%. Nearly 15 important new therapies have come to market presentation in the application of design evolution and a more quickly as a result, contributing to the recent rise in new rationale for commercial manufacturing process and controls. drug approvals. FDA acting commissioner Stephen Ostroff John Groskoph, senior director at Pfizer, observed that for pointed out at the annual meeting of the Food & Drug Law most breakthrough therapies, market applications are being filed Institute (FDLI) in April 2015 that two-thirds of 2014’s near- with FDA after Phase II studies, approximately two years ahead record 51 new molecular entities (NMEs) took advantage of at of a traditional NDA that is based on Phase III data. The time least one expedited review program, and many were first-in- reduction presents “significant challenges to the development class therapies. team,” he commented, and may be further complicated if the Achieving fast approval of a breakthrough therapy creates firm seeks to file simultaneous applications in Europe, Japan, and challenges for manufacturers looking to develop CMC data emerging markets, as well as in the United States. in roughly half the time, noted Brian Kelley, vice-president Japan, for example, has established the SAKIGAKE for bioprocess development at Genentech. The process, he designation program for innovative medicines and medical explained at the April 2015 CMC workshop sponsored by the devices that are developed first in Japan and offer “radical Drug Information Association (DIA), is resource intensive, improvement” over existing therapies to treat critical diseases, and accelerated timelines necessitate new approaches to explained Yoshihiro Matsuda of Japan’s Pharmaceuticals and product and process development to ensure a reliable supply Medical Devices Agency (PMDA), at the CMC workshop. He of a quality product at launch. The breakthrough designation described a greatly accelerated development and approval “does not mean that sponsors can do less,” he said; they just process for such therapies, combined with stronger “need to start sooner.” This may involve front-loading of crucial postmarketing oversight. The initiative, he noted, requires risk- product and process characterization activities, and reaching based assessment strategies and a product quality lifecycle agreement with FDA on which actions for optimizing process management plan, combined with clear analysis of what can and methods can wait until after launch. be evaluated during review, and what can be analyzed later after approval. High priority for FDA Groskoph noted that successful launch of a breakthrough Expedited quality assessments raise difficulties for FDA, as drug involves addressing numerous issues: data availability, well. New drug applications (NDAs) for breakthrough thera- meaningful and practical specifications, robust manufacturing pies often contain less manufacturing information than usual, processes, clinical or commercial site production, site requiring innovative risk-mitigation strategies to ensure product readiness for pre-approval inspection, deferral of Phase III

safety. Agency reviewers are agreeing to less stability data at studies to post approval, and the need for comparability GLOBE: ZOONAR RF/GETTY IMAGES

14 Pharmaceutical Technology JULY 2015 PharmTech.com

magentablackcyanyellow ES639413_PT0715_014.pgs 07.07.2015 01:08 ADV 20 years

protocols to facilitate postapproval changes. Communication with FDA is important throughout the breakthrough development process, he added, to facilitate agreement on Sift-N-Blend™ strategies for dealing with unexpected production problems. Technology For biologics, breakthrough designation may prompt greater focus on the reliability of the Phase I cell line, process and VersaPress™ formulation, as shorter pivotal trials may truncate optimization of the Phase III process, added Kelley of Genentech. A key decision for manufacturers is whether to devote more resources to the project early to front-load process characterization and validation activities, even before gaining the breakthrough designation. Such an approach may involve SimpleBlend™ testing lots before assay validation is completed; filing with Blenders broader specifications with the aim of tightening them post- launch; launching from the clinical site and transferring to commercial post-launch; and including a postapproval lifecycle management plan in the application to support deferral of certain activities. But, Kelley commented, “you can’t place bets” on potential breakthroughs too frequently without overly straining company resources.

Sustainable program? The growth in breakthrough designation requests is prompting FDA and stakeholders to examine options for refining breakthrough criteria so that FDA will be able to manage the program. The agency is examining past designation decisions and why it turned down certain requests to see if the bar is too low; a goal is to better educate manufacturers on which promising experimental products really qualify for breakthrough status. FDA “can’t sustain a program where everything is a New breakthrough,” commented John Jenkins, director of GP-Mill-5™ CDER’s Office of New Drugs, at an April 2015 workshop on breakthrough therapy designation criteria organized by the Brookings Institution. FDA officials explained that extensive GP Cone Mill resources are involved in determining designations and in supporting development and accelerated review of GP-HSG-5 breakthrough candidates. Manufacturers acknowledged Granulator that designation denials could decrease if sponsors sought breakthrough status only for therapies that offer truly substantial improvements in patient care. And they indicated that additional resources from industry are warranted to support the unexpectedly large breakthrough program. While FDA can quickly approve products with clear outstanding value, Jenkins noted that such efforts may be stymied by manufacturing problems and inspection delays. There are situations where the clinical data are good, but where sponsors “have to get manufacturing and facilities in MaxiBlend® Lab line,” he said. Sites for inspections need to be identified early, Blender Jenkins advised, especially for overseas facilities that may raise Formulation to Pilot Scale Blenders both Stand Alone & travel difficulties. Kay Holcombe, senior vice-president of the Interchangeable Vessel Models - Granulators- Mills Biotechnology Industry Organization, urged close examination -Powder, Liquid & Semi-Solid Samplers - Valves - Cleaning Validation Tools- Powder Segregation Testers - of ways to prevent approval delays due to difficulties in making www.globepharma.com a drug according to specifications. “If this is a hurdle at the end,” she said, “we need to deal with it more effectively.” PT

Pharmaceutical Technology JULY 2015 15

magentablackcyanyellow ES639412_PT0715_015.pgs 07.07.2015 01:08 ADV Sean Milmo is a freelance writer based in Essex, UK, [email protected].

Unravelling the Complexity of EU’s ATMP Regulatory Framework

The European Union has a challenging task ahead as it strives to harmonize regulations on advanced therapy medicinal products.

he European Medicines Agency is approving a growing number Data requirements Tof advanced therapy medicinal products (ATMP) despite claims One onerous requirement is the amount of data needed on starting that their commercialization is being hampered by increasingly materials and their detailed characterization. In addition, a complete complex regulatory and standards requirements. The creation description, including source, characteristics, and testing details, of of ATMPs by a 2007 European Union regulation (1), backed by a all materials used during the manufacture of products is needed. specialist committee for advanced therapies (CAT) within EMA, Some developers of ATMP products complain about the regula- aimed to boost development of medicines derived from progress tors making demands for data that existing analytical technologies in cellular and molecular biology. Initially, the regulation seemed cannot yet provide. There have also been complaints about EMA to have little impact on the number of advanced medicines on wanting unnecessary high levels of purity in cell-therapy treatments, the market after the start of its implementation in early 2009. By especially those comprising mixtures of undifferentiated cells. mid-2013, there were only four marketing authorizations from Another matter of contention has been EMA’s insistence 10 applications in the three ATMP categories of gene therapy, that marketing authorization applicants for tissue-engineered somatic cell therapy, and tissue engineering (2). products must demonstrate through pharmacokinetics the Over the past few years, however, there have been signs of a longevity or persistence of their medicines. “From the point of surge in ATMP development. The number of medicine applications view of our members, pharmacokinetics does not include longevity, recommended by CAT to be classified as advanced therapies but resorption, distribution, and excretion of a drug,” Matthias rose by 26% in 2014 (3). In late 2014, EMA recommended for EU Wilken, head of European drug regulatory affairs at the German approval the first advanced therapy medicine containing stem cells. Pharmaceutical Industry Association (BPI), told Pharmaceutical It is also the first drug for the treatment of moderate to severe Technologyy. “The requirement to demonstrate longevity might lead limbal stem cell deficiency (LSCD), a rare eye condition due to to extensive clinical studies that would be an undue burden to physical or chemical burns to the eyes that can result in blindness. pharmaceutical entrepreneurs,” he explained. In some cases, the regulators are seen as taking too much of Complex regulations a “generic” approach to advanced technologies and not making a At the same time, the quality, safety, and efficacy rules under strong enough distinction with conventional pharmaceuticals. “The existing and proposed EMA guidelines on ATMPs have been assessors and members of EMA scientific committees often come becoming more complex. One reason is that expanding knowl- from the field of conventional medicinal products,” said Wilken. edge about the new therapies has raised new concerns, particu- “Initially, there was a lack of understanding of the peculiarities of larly relating to issues regarding the quality of starting materials ATMPs. But this [understanding] is getting better, as is shown, for and drug substances. The regulators have gradually become example, by the fact that EMA, along with the Commission, is more aware of the biological variability and intricacy of ATMPs. currently working on tailoring GMP requirements for ATMPs.” This tightening of standards seems to be deterring big pharmaceutical companies rather than small- and medium-sized enter- Risk management prises (SMEs) from developing advanced therapy products. The big regulatory difference between ATMPs and chemical- In a 2014 report (2) on the application of the 2007 regulation, based pharmaceuticals is the greater emphasis needed with the European Commission, the Brussels-based EU executive, biological products on quality issues, mainly because of the found that the majority of ATMP research was being done by small gaps in knowledge about ways of managing their risks. However, companies and entities. Approximately 70% of sponsors of ATMP EMA has acknowledged the limitations of applying uniform rules clinical trials were SMEs or not-for-profit organizations, while large to ATMPs by adopting a risk-based approach that allows the pharmaceutical companies accounted for less than 2%. products to be assessed on a case-by-case basis. The report concluded that because there are “still many The distinct approach needed for ATMPs has been highlighted unknowns” with advanced therapies, “it is important to put in by the latest EMA guidance (4) on advanced therapies, which place adequate controls to prevent detrimental consequences covers the quality, preclinical, and clinical aspects of gene for public health” (2). Nonetheless, it is also acknowledged therapy. The draft guideline (4) on gene therapy was issued in that “too burdensome requirements” could have adverse May 2015 for a period of public consultation ending in August. It consequences for public health because they could prevent the replaces a guidance note (5) published in the early phase of gene-

marketing of valid treatments for unmet medical needs. therapy development in 2001. GLOBE: ZOONAR RF/GETTY IMAGES

16 Pharmaceutical Technology JULY 2015 PharmTech.com

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magentablackcyanyellow ES639168_PT0715_017_FP.pgs 07.06.2015 20:46 ADV Since the 2007 ATMP regulation was implemented, EMA mammalian and bacterial cell banks. All raw materials used during has had to deal with three applications for gene-therapy manufacture have to be tested and characterized. authorizations, only one of which has so far been successful. “[From a quality perspective], there were no major changes or Hospital-based research inconsistencies in the 2001 guideline that required an immediate Partly due to the detailed EU quality and safety requirements for revision,” an EMA spokesman informed Pharmaceutical advanced therapies, companies developing ATMPs are critical of Technology. “However, some updates were necessary, for an exemption to EU rules granted to hospitals involved in R&D and example, to reflect novel methodologies for testing and the manufacture of the products. Hospital-based research and characterization, and also to ensure cross references to new production in the sector are increasing in Europe mainly because legislation and guidelines that were developed separately.” some EU states are using these hospitals as ATMS development Also, the format of the sections on quality and manufacturing centers at the core of national regenerative medicine programs. aspects in the revised guideline has been changed to follow The United Kingdom, for example, has a network of cell-therapy that in the harmonized Common Technical Document (CTD) centers of excellence based in leading hospitals. for marketing authorization application dossiers, according to Under the 2007 EU regulation on ATMPs, member states EMA. “This is expected to be helpful for the small developers of are allowed to give hospitals exemption from the legislation as gene-therapy products when compiling their dossiers,” said the long as the hospital’s advanced therapies are being provided EMA spokesman. As a result, 40% of the 42-page draft guideline on a “non-routine basis” to its own individual patients. Some covers quality matters, 30% non-clinical issues, many of which organizations are calling for the “non-routine” provision, which relate to assessing risks linked to quality management, and only is open to different interpretations, to be extended to cover 10–15% to clinical development. products only when a fully validated, EU-approved advanced A lot of the obligations in the guideline requirements relate to therapy alternative cannot be used. the quality of the components in the vectors or delivery systems “While the hospital exemption rule allows the early development of the products. Details of the quality of all starting materials and and delivery of ATMPs that meet an otherwise unmet clinical their sources have to be provided, including virus seed as well as need in a patient, the exemption should only be used to deliver a product if there is no licensed alternative, with proven efficacy and safety, available,” says Michael Werner, executive director of the US-based Alliance for Regenerative Medicines, a global advocacy group representing stakeholders in the ATMP sector. Its European arm has been among the leading critics of criteria applied for the exemption, particularly those relating to manufacturing standards. Sceptics about the potential of exempted hospital-based development systems contend that they encourage the avoidance of the strict EU data requirements because the hospitals have to adhere only to national quality and safety standards, although these standards should be consistent with those at the EU level. Even the European Commission in its report (3) on the impact of the ATMP regulations concedes that the exemption can enable hospital-based centers to have lower development costs than commercial ATMP organizations because of the advantages of being subject to less rigorous standards. A major objective behind the EU’s ATMP regulation was the introduction of harmonized standards across Europe but the way the hospital exemption is operating shows that there is still some distance to go before full harmonization is achieved.

References 1. EC 1394/2007 Regulation on advanced therapy medicinal products (Brussels, November 2007). 2. European Commission, Report in accordance with Article 25 of EC 1394/2007 on advanced therapy medicinal products (Brussels, March 2014). 3. EMA, Annual Report 2014 (London, April 2015). 4. EMA, Guideline on the quality, non-clinical and clinical aspects of gene therapy medicinal products–draft (London, March 2015). 5. EMEA, Note for guidance on the quality, preclinical and clinical aspects of gene therapy medicinal products (London, April 2001). PT

18 Pharmaceutical Technology JULY 2015 PharmTech.com

magentablackcyanyellow ES639373_PT0715_018.pgs 07.07.2015 00:44 ADV magentablackcyanyellow ES639145_PT0715_019_FP.pgs 07.06.2015 20:46 ADV Cover Story: Solubility Challenges

According to Marshall Crew, PhD, vice-president, Global PDS Scientific Ex- cellence, Patheon, there are two aspects that must be understood in a comprehensive way before proceeding toward the best solubilization technology—the drug molecule and the target product profile. “The dosage form, dosage, and other requirements for the drug product must be taken into consideration, along with the molecular properties and profile of the API,” he says. “Modern pre-formulation approaches begin by understanding the Solving Poor target product attribute space, and lever- age modeling to more fully characterize and understand the molecule.” Crew Solubility to explains that this approach enables solubilization formulation scientists to know Unlock a Drug’s the starting point and direction of the process from the earliest stage to formulation design and optimization. Potential “Once the drug product requirements have been understood and the API characterized, solubilization tech- Adeline Siew, PhD nologies can be screened to identify the best fit for the particular drug and desired outcome,” Crew adds. After the technology has been identified, the Modern methods and modeling offer a better next step is to conduct experiments involving a range of excipient/polymer way to understand solubility issues and solve models in combination with the drug. today’s complex formulation challenges. Crew advocates the use of computational screening, which allows a greater number of options to be explored more oor solubility is an ongoing challenge been a tremendous amount of research efficiently, thereby increasing the likeli- in pharmaceutical development. A going on in the industry to overcome hood of identifying the best approach. Pdrug must be in solution form for it the challenges in bringing poorly Dan Dobry, vice-president, Bend to be absorbed regardless of the route of soluble drugs to the market.” Research, a division of Capsugel Dosage administration. The solubility of an API, Form Solutions, also recommends a therefore, plays a crucial role in bioavail- Improving drug mechanistic, model-based approach. ability given that drug absorption is a development success rates “Simple modeling and characteriza- function of solubility and permeability. Selecting a suitable drug-delivery tion tools can relate physicochemical Modern drug discovery techniques, approach for these challenging NCEs aspects of the compound and therapy to with advances in combinatorial chem- depends on various parameters, ex- potential delivery challenges,” he notes. istry and high throughput screening, plains Praveen Raheja, associate “The models are often not quantitative continue to fill drug-development director, Formulations, at Dr Reddy’s in early development, but give context to pipelines with a high number of CPS, “for example, the drug solubility, experiments, in vitro and in vivo, to help poorly soluble new chemical entities chemical composition, melting point, shape the problem statement and pair (NCEs). “Estimates have varied over absorption site, physical characteristics, the right delivery technology.” the years, but it is reported that 40%– pharmacokinetic behavior, dose, route Mastering multiple delivery tech- 70% of NCEs are poorly water-soluble,” of administration, and intended thera- nologies, from formulation through to observes Sampada Upadhye, PhD, peutic concentration, to name a few.” scale-up and manufacturing, reduces technology platform leader for bio- An analysis of all these parameters is bias for a particular technology, says availability enhancement & OptiMelt, required to determine the most appro- Dobry, and allows each technology’s

Catalent Pharma Solutions. “There has priate method of drug delivery, he says. sweet spot to be exploited, rather than dAn WArd ImAGes; AdAm GAult/Getty

20 Pharmaceutical Technology July 2015 PharmTech.com

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magentablackcyanyellow ES639165_PT0715_021_FP.pgs 07.06.2015 20:46 ADV Cover Story: Solubility Challenges

trying to force fit a technology to a problem statement. He reduction, and the use of lipids or amorphous dispersions. further adds that integrating appropriate enabling technolo- These proven approaches can be selected based on the in- gies into lead selection (instead of using them in a rescue dividual drug’s properties and specific problem statement. mission during mid-development, when it may already be Each method, however, has its limitations and may pose too late), can streamline the process and help identify the new formulation challenges, notes Upadhye. Strategies such most effective combination of molecule and drug-delivery as polymorphism, salt formation, co-crystal formation, and technology. the addition of excipients may marginally increase drug solu- Dieter Lubda, PhD, director, Process Chemical Solutions bility, but often have limited success in increasing bioavail- R&D Franchise Formulation, Merck Millipore KGaA, ability, according to her. In some cases, they can even increase Darmstadt, Germany, finds that conventional solubilization drug toxicity, resulting in negative side effects, she says. approaches such as physical modifications of APIs, microni- Although particle size reduction may be a safe way to zation, or nano-milling tend to have limited results. “The increase drug solubility, it does not alter the solid-state formulation of new drugs often needs new technologies and properties of the drug particles, Upadhye observes. In excipients that can induce specific solubility- and bioavailabil- addition, solid dispersions, solid solutions, amorphous ity-enhancing properties,” he says. However, Lubda stresses generation, and lipid-based formulations each has its own that the interaction of new technologies and the excipients set of challenges that can affect drug stability and drug used is a far more complex scenario. Instead of focusing on loading capacity, she adds. one technique, it is important to consider how a range of One of the greatest formulation challenges today, accord- excipients or approaches could work best for the poorly soluble ing to Dobry, is the fact that poorly soluble compounds often API under development. “This helps increase the success rate of present other problems, such as metabolism or permeability selecting suitable drug-delivery solutions,” he asserts. challenges, drug-to-drug interactions in a combination dosage form, or the need to modify pharmacokinetics (e.g., blunting Tackling solubility challenges the maximum concentration [Cmax] or extending drug re- When considering solubility, Dobry says the industry has a lease). “These challenges rapidly increase as the dose increases range of commercial solutions to choose from, such as size and desire for dosage form burden comes down,” Dobry notes. According to Stephen Tindal, director, Scientific Affairs, Softgel R&D, Catalent Pharma Solutions, dose is the number one problem. “Unless you can get significant increases in bioavailability, the patient has to take multiple large PHARMSOURCE unit doses whether they’re tablets, capsules, or softgels,” states Tindal. Another problem is because APIs are not STRATEGIC ADVANTAGE designed with enabling technologies in mind, there can be a suboptimal fit between the API and the dosage form. Expert global sourcing “It can be beneficial to not fix the salt form or the poly- intelligence in an instant morph form too early,” says Tindal. “For example, if the API salt form has been selected with water solubility in mind, this may not be the ideal form for presentation as a lipid based drug delivery system.” If you procure, manage or sell contract drug Lubda explains that the first key consideration in for- development and manufacturing services, mulation development is the route of administration. “The you need the industry’s most respected main question here is where the API needs to go in the body outsourcing information web portal. It puts and how the drug can best be formulated to reach this tar- hard-to-fnd information at your fngertips, geted location,” he continues. “In this challenge, the pre- requisite for API bioavailability is to increase its solubility including the strategic tools you need to make and permeability. These parameters must be optimized to the right decisions. achieve optimal release properties and the desired plasma Contact us today for a complimentary review profile within the required therapeutic window.” “Depending on the properties of the API, we have to assess of PharmSource STRATEGIC ADVANTAGE if the drug can be formulated with standard formulation Focused | Timely | Accurate technologies or whether we need to explore non-conventional approaches,” Lubda expands further. “Developing a 1.888.777.9940 Toll-free in USA good formulation is not easy per se. The excipients used +1.703.383.4903 Direct could interfere with the drug during the formulation process [email protected] | www.pharmsource.com (e.g., a pH shift during wet granulation) and result in a lower therapeutic effect.”

22 Pharmaceutical Technology July 2015 PharmTech.com

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magentablackcyanyellow ES639164_PT0715_023_FP.pgs 07.06.2015 20:46 ADV Cover Story: Solubility Challenges

Developing an oral formulation best balance of dose, polymer, and drawbacks—a buffer-based system According to Raheja and Lubda, the API loading to allow the final drug could result in precipitation in the GI. main challenges encountered during product to have the required stability, In such cases, anti-nucleating polymers the development of oral formulations manufacturability, and performance. could be used to overcome this prob- for poorly soluble drugs are: “To accomplish this type of local opti- lem. “These agents maintain a high • ensuring the stability of the mization within a global context, using degree of supersaturation and help im- formulation during processing a modern approach is essential,” he prove bioavailability,” Raheja explains. and in the gastrointestinal (GI) notes. Crew recommends a systematic “Other solubilization techniques such tract (e.g., avoiding precipitation methodology, employing rigorous sci- as complexation and solid dispersions of the drug in gastric fluids) entific practices, and then performing can also be considered for compounds • achieving consistent drug release extensive in-silico simulations. “Fortu- with a log P in the range of 1.0 to 3.0. rates nately, the computational intensity of For compounds with a log P of 5, it is • considering food effects, such as this type of exploration and analysis is better to explore lipid-based systems.” different levels of drug absorption now feasible,” he adds. Each solubilization technique has during fed or fasted states its pros and cons, Upadhye observes, • taking into account the presence Choosing a suitable and only a careful consideration of the of p-glycoprotein and cytochrome solubilization strategy API’s physical, chemical, and thermal P450 (CYP) enzymes. When selecting a solubilization strat- properties as well as its mechanical A common problem, as Raheja high- egy, a number of considerations, such as properties, will allow the best solubili- lights, is determining the combination the physicochemical and physiological zation technique to be selected. of suitable excipients and the enabling properties of the drug, should be taken While most experts would agree on technology that increases solubility, as into account. Lubda lists the following the list of key factors guiding a solu- well as determining the appropriate key factors to consider: bilization strategy, Dobry stresses the tool to predict the solubility in-vivo • dosage form importance of having a framework or so that an in-vitro in-vivo correlation • administration route model that puts method selection into (IVIVC) can be established. • mode of action (e.g., oral local or a broader context that also considers Lubda emphasizes the importance oral systemic for fungal drugs) the mechanism of dissolution and ab- of choosing the best excipients for • API dose per unit or API load sorption, and allows for problem state- the formulation, adding that process • physicochemical properties of the ment definition, risk assessment, and conditions such as heat or moisture API (i.e., pH-dependent solubility, sensitivity analysis. “In this context, it during drug development are also pKa value(s), log P, temperature sen- is important to have basic pharmaco- crucial. “In the end, it comes down to: sitivity, shear sensitivity, solubility in kinetic data of the crystalline drug in How can we cost-effectively formulate suitable solvents, known undesirable animal models to guide initial model APIs with good content uniformity?” interactions with excipients, poly- development,” he continues. “We find he asserts and highlights some key morphs, properties of crystalline this aspect to be so important that we questions that should considered: state vs amorphous state) have developed discovery stage for- • Can we simplify complex formu- • suitability of the manufacturing mulation tools to generate pharmaco- lations (requiring large number process for the API kinetic/pharmacodynamic data in ani- of excipients) that can lead to • scalability of the formulation mals, even for poorly-soluble actives.” unexpected excipients interactions process While the drug molecule plays the and limited drug stability? • differences in performance during key role in the decision, Crew adds • How can we influence the recrys- feasibility studies and screenings that other crucial considerations in- tallization of amorphous APIs and • availability of necessary equip- clude the amount of API available at what are the pH effects on their ment for process and method used the earliest stage of development and stability? • stability of the final formulation the drug product’s goals. “In some Lubda sums up that the ultimate and shelf life instances, the initial assessment and goal is to achieve a robust manufac- • total cost of ownership process development can employ one turing process that takes into account • intellectual property and licensing technology, and then, when the formu- disintegration and dissolution of the considerations. lation design has been completed, an- oral dosage form, hardness, content Raheja offers a real-world example. other technology can come into play,” uniformity, waste, and productivity “If a compound has an acidic or basic he says. Crew provides an example: with high tableting speed. functional group and the log P is creating an amorphous solid disper- According to Crew, developing a between 1.0 to 3.0, one could explore sion, for which either spray drying or customized formulation for poorly buffer systems to solubilize it,” he hot-melt extrusion (HME) might be soluble drugs requires achieving the says. However, he notes some possible used. In this case, the API dictates the

24 Pharmaceutical Technology July 2015 PharmTech.com

magentablackcyanyellow ES639786_PT0715_024.pgs 07.07.2015 22:53 ADV options available, he explains, and the Lubda. “One approach is to influence highlighting the potential stability decision tree includes such factors as: the surface area of the API particles problems that could occur due to the • the amount of API using micronization, nanonization, high energy input, apart from the dif- • chemical properties co-grinding, or precipitation from su- ficulty in achieving content uniformity • log P percritical fluids. The other alternative in the solid-dosage form. “Surfactants • melting point is to increase the solubility with solu- can be seen as a straightforward ap- • solubility of API in solvent or bilizers (polymers, surfactants, or cy- proach to influence API solubility,” he polymer clodextrins), lipid-based formulations adds. “But because they are not inert • size of molecule. (e.g., self-emulsifying or self-micro- excipients, surfactants can interact These are only some of the factors, but emulsifying drug delivery systems with APIs and other excipients. Their they can only be derived from a thor- [SEDDS/SMEDDS]), polymorphs, salt effects are hard to predict and surfac- ough characterization of the molecule, formation, or co-crystals.” He notes tants potentially have an influence on Crew points out. Because the amount that some newer solubilization tech- biological membranes as well as pos- of API required for early formulation niques attempt to address both the sible side effects.” Lubda views porous using spray drying is significantly less surface area and solubility through the inorganic carriers (e.g., silica) as well as than what is required for HME, an early formation of liquid and solid disper- liquid and solid dispersions as prom- feasibility study might be done using sions or porous inorganic carriers such ising technologies to solve solubility that technology, if the API lends itself to as mesoporous silica. “The overall goal challenges. HME (i.e., if its melting point does not is to improve API solubility and achieve Poor solubility is clearly a problem exceed 200 °C–225 °C).” a higher dissolution rate, which facili- that will continue to challenge drug tates faster drug absorption,” he says. developers. As Crew points out, the Weighing up the different According to Lubda, micronization number of insoluble molecules con- solubility-enhancement approaches of API is challenging, especially at pro- tinues to rise. “During the decade of “Several technologies are available to duction scale. “Batch-to-batch homo- the 1970s, only 0.6% of FDA-approved overcome solubility challenges,” states geneity is poor,” he observes, further molecules had been solubilized,”

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Pharmaceutical Technology July 2015 25

magentablackcyanyellow ES639790_PT0715_025.pgs 07.07.2015 22:53 ADV Cover Story: Solubility Challenges

Crew observes. “The next two decades active ingredients in an inert carrier platform for the implementation of showed increases, and by the 2000s, matrix. In these dispersions, the process analytical technology (PAT),” this category accounted for more than drug can be present in a fully crystal- Upadhye says. 10% of approved drugs.” line state (in the form of coarse drug For amorphous solid dispersions, According to Crew, Patheon ana- particles), in a semi-crystalline state, or a primary challenge is the stability lyzed the number of drugs approved in fully amorphous state (in the form of the amorphous drug, according to by FDA between 1970 and 2013, which of a fine particle dispersion, or molec- O’Donnell. “Improperly formulated used diverse solubilization platforms ularly distributed within the carrier). systems may recrystallize into more (including lipids, amorphous solid Such systems prove to be very effective thermodynamically stable and less dispersions, nanocrystals, and other for enhancing the dissolution rate of soluble forms, resulting in dramatic alternative technologies). While lipid low solubility drugs.” changes in the dissolution, absorp- systems were the most widely used in Dobry says that the approach is tion, and therapeutic effect of the the 1980s, and continue to be favored broadly applicable because of its API,” he points out. “The stability of today, Crew says that solid dispersions mechanism of stabilization and crystalline formulations is also of great saw a steep increase in the mid-2000s, dissolution, as well as a scalable, concern if a high-energy polymorph is and continue on a rapid growth rate precedented process. “The most selected, due to the risk of polymorphic even today. Findings from Patheon’s prominent advantage of solid disper- transformations that can have negative study show that lipids dominated with sions is the purely physical change of effects.” a 50% share, solid dispersions took the active compound (mainly from the “Another challenge consistently second place with 30%, ahead of the crystalline to the amorphous state). If observed is that many poorly soluble next closest technologies at less than the change is performed in a controlled drugs require delivering a high dose of 10%. Catalent’s softgel expert Tindal manner, you don’t have to deal with the API to the patient,” Porter notes. concurs that lipid-based formulations concerns about undesired effects from “This issue creates complexity in have a historic advantage over solid chemical changes of the compound,” designing adequately sized dosage dispersions, but notes that use of solid Lubda adds. forms and can result in adverse drug dispersions is increasing. According to O’Donnell, until effects and poor patient compliance.” recently, the number of methods Porter explains that while amorphous Solid dispersions continue available to a formulator to generate solid dispersions may reduce the to show broad applicability an amorphous solid dispersion was required dose circumventing this issue, Solid dispersions are widely used as limited. “However, recent growth in a high drug load lowers the amount a solubilization technique. Kevin the techniques capable of generating of stabilizing polymer present in the O’Donnell, PhD, and William Porter an amorphous solid dispersion—such formulation, which can result in the III, PhD, who are both associate as spray drying, HME, precipitation aforementioned stability concerns. research scientists at Dow Pharma methods, co-milling, KinetiSol Raheja sees great potential in solid & Food Solutions, attribute it to the dispersing, cryogenic methods, dispersions citing a growing number ability of solid dispersions to drasti- and others—has created processing of commercial products and those in cally improve the solubility of most flexibility, allowing almost any API to development. “In the past decade, a APIs. “While solid dispersions present be formulated into a solid dispersion,” lot of understanding on formulation their own challenges, they eliminate he notes. components, analytical tools, and the issues associated with traditional Spray drying and HME are currently scale-up challenges have improved,” techniques,” O’Donnell observes. the most commonly used methods to he states. “Our own experience “Non-ionizable APIs or those that do produce solid dispersions. “Spray dry- with this technology has brought not fit in complexing agents can now ing is highly effective at generating the products into different clinical and find success.” amorphous form of an API and can be commercial stages.” “Owing to its simplicity from both used for APIs that have low degrada- “While simple solid dispersions will manufacturing and process scalabil- tion temperatures,” Porter observes, continue to be a cornerstone technol- ity standpoints, solid dispersion has adding that selecting the appropriate ogy for enhanced bioavailability, we become one of the most active and polymer and solvent will ensure the need to continue to innovate,” says promising research areas and is there- resulting product is homogenous. Dobry. “This will include the evolution fore of great interest to pharmaceutical HME, on the other hand, is a ver- and combination of the best aspects of companies,” comments Upadhye. “The satile process that does not require multiple technologies, such as combin- term ‘solid dispersion’ refers to solid- solvent. “Moreover, because it is a ing manufacturability and solid-state state mixtures, prepared through the continuous process with narrowly de- stability of amorphous dispersions dispersion, typically by solvent evapo- fined output quality attributes, HME with rapid dissolution and permeabil- ration or melt mixing, of one or more represents an ideal manufacturing ity enhancement of lipid formulations.”

26 Pharmaceutical Technology July 2015 PharmTech.com

magentablackcyanyellow ES639789_PT0715_026.pgs 07.07.2015 22:53 ADV Mesoporous silica gains recognition in the past, might have been considered too insoluble to According to Lubda, the use of silica has been gaining proceed into the next drug-development phase. “An impor- traction since it was first used as a drug carrier in the tant advancement has been in solid-state characterization 1980s. Most research has focused on the use of ordered and stability prediction of amorphous dispersions,” Dobry mesoporous silica. “Materials such as SBA-15 (Santa Barbara observes. “Five to 10 years ago, this was seen as an Achilles Amorphous-15) or MCM-41 (Mobile Composition of heel. Now, it is one of several important aspects to address Matter-41) are pure silicon dioxide particles with an ordered in a risk assessment, he says. “Continued innovation will be mesoporous structure but remain on scientific production needed in this area, as molecules and formulations become levels. Silica materials with unordered mesopores are most more complex.” widely used because their manufacturing process is easily The ability to characterize dissolution mechanisms has scalable and the pore structures are known to be pressure been a major achievement, Dobry says, especially since resistant,” he elaborates. today’s formulation problems tend to transcend simple These mesoporous silica particles are inert and have a insolubility. “In many cases, there is a need to incorporate large internal surface area (potentially exceeding 1000 m²/g) enabling technology into the discovery interface,” he that provides space for the drug molecule to be absorbed, explains. Integrating quality-by-design principles in which is crucial for drug loading capacity, Lubda says. development, for example, allows interaction between the The challenge, however, will be making this surface area process and formulation attributes to be identified, enabling accessible to the drug molecule. the manufacturing space to be optimized, while allowing Different silica carriers can be used for drug delivery, performance and stability targets to be met. Lubda explains, but it is important that they are mono- As formulations become increasingly complex, new graph-compliant and have GRAS (generally regarded as approaches tackle the problems of solubility and safe) status. The underlying solubilization technology is to bioavailability in different ways. The future promises to impregnate an amorphous drug form into the pores, with bring more solutions to what may once have been viewed as the help of an organic solvent in a pre-formulation step, insoluble problems. PT and to prevent recrystallization during dissolution in the body, Lubda says. The result after drying and removal of the solvent is an intermediate, in powder form, of silica with the API. In most cases, he notes, such intermediates enhance the solubility (by supersaturation), dissolution rate, and stability of the poorly soluble small molecules. “This solubilization Twin Screw approach is applicable to a broad range of drugs, as the API only needs to be soluble in a volatile organic solvent,” Extruders and Systems says Lubda, adding that the final formulation can easily be compressed into a tablet and the process is scalable. Experience Counts! Recent advances in the field Given the range of solubilization technologies available, poor • nano-scale twin screw extruders solubility does not necessarily prevent a drug from reaching the • Production twin screw extrusion systems market anymore, notes Lubda. Research promises to expand the • Pharmaceutical Extrusion Seminars range of technologies available in the future. “There is an increasing focus on understanding solu- • Process laboratory for melt/granulation extrusion bility and more importantly, the bioavailability of drugs • Validation documentation and services in general,” Lubda remarks. Experts notice the increasing collaboration between pharmaceutical manufacturers and academic research groups to develop more appropriate, better fitting test systems for in-vitro and in-vivo studies that Leistritz Extrusion will help provide deeper insights into drug properties and A Business Unit of Leistritz Advanced Technologies Corp. 175 Meister Avenue, Somerville, NJ 08876, USA further the understanding of solubilization strategies. “The Ph 908-685-2333 E-mail [email protected] ability to model both molecules and excipients separately www.leistritz-extrusion.com and then in combination in silico allows access to a broader solution space, and also significantly increases the predictability of solubilized outcomes,” Crew adds. Dobry notes that, during the past decade, significant advancements have been made in improving the stability, Melt extrusion + Granulation + Dosage Forms + Transdermals bio-performance, and manufacturability of NCEs that,

Pharmaceutical Technology July 2015 27

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tive drug molecule. Linkages such as azo, amide, glucuronide, and glycosidic bonds are often used in prodrug formation for colon-specific drug delivery. Ruiz et al. reported on the development of a double prodrug system for colon targeting of benzenesulfonamide cyclo-oxygenase-2 (COX-2) inhibitors (3). The prodrug was first activated by azoreductases followed by cyclization to release the active drug. According to the researchers, the prodrug demonstrated good stability in human intestinal extracts and was only activated under specific conditions of the colon, hence achieving targeted drug release. pH- and time-dependent drug-delivery Mission Possible: systems. In this approach, drug release is triggered by a change in pH as the dosage form passes through the gut. It is generally Targeting Drugs to the Colon accepted that the pH of the GI tract pro- gressively increases from the stomach (pH Adeline Siew, PhD 1–2 in fasted state and pH 4 during diges- tion) to the small intestine (pH 6–8). The important thing is for the formulation to Prodrugs and drug-delivery systems controlled by remain intact until it reaches the colon. Such formulations typically incorporate time, pH, and osmosis are being used to prevent polymer coatings that are insoluble in an drug degradation in the stomach and small acidic environment but become soluble as the pH increases. Commonly used intestine and ensure drug release in the colon. pH-sensitive polymers include Eudragit L and S, polyvinyl acetate phthalate, hy- ral formulations, which are still sorption enhancers, protease inhibitors, droxyl propyl methyl cellulose phthalate, the most widely used dosage and bioadhesive and biodegrable poly- and cellulose acetate, to name a few. Oforms, can be designed to release mers compared with other regions of the Time-dependent systems take a dif- the drug at specific sites of the gastro- gut (1). The challenge, however, comes in ferent approach by delaying drug release intestinal (GI) tract. Today, the colon is ensuring that the drugs are intact when after a specific period of time. Taking becoming a more attractive target, not they eventually reach the colon, which into account gastric emptying and intes- only for treating diseases of the colon is often a problem with traditional oral tinal transit times, swellable systems that such as Crohn’s disease, ulcerative coli- dosage forms. A number of different ap- incorporate different combinations of tis, and colorectal cancer, but also for proaches are being used to target drug hydrophilic and hydrophobic polymers GI therapies in general. For example, release in the colon. This article will sum- as the coating material are used to adjust colon targeting can be used to systemi- marize key trends, including the use of the time lag. Recent approaches often cally deliver proteins and peptides that prodrugs, pH- and time-dependent sys- combine both pH- and time-dependent are susceptible to enzymatic degrada- tems, as well as newer approaches based systems to achieve more targeted drug tion in the stomach or small intestine. on osmotic-controlled drug delivery. delivery to the colon. Ofokansi and This approach has been found to pro- Prodrugs. The prodrug strategy exploits Kenechukwu, for example, prepared vide safe and effective therapy with the presence of the colonic microflora, ibuprofen tablets using Eudragit EL 100 proven bioavailability enhancement as which is in the order of 1011–1012 colony- and chitosan to form interpolyelectrolyte well as a lower incidence of drug toxic- forming unit (CFU) per mL in the colon, complexes (4). The formulation showed ity and unwanted side effects. compared with 103–104 CFU/mL in the pH-dependent swelling properties and Colon-specific drug delivery exploits stomach and small intestine (2). To form prolonged drug release in vitro (4). The the differences in anatomical and physi- the pharmacologically inactive prodrug, electrostatic interaction between the car- ological features of the upper and lower the parent drug is attached to a chemi- bonyl (-CO-) group of Eudragit RL 100 segments of the gut. Research has shown cal group, and enzymatic degradation by and the amino (-NH3+) group of chito-

that the colon is more responsive to ab- the bacteria in the colon then frees the ac- san was thought to prevent drug release SCIEPRO/GETTY IMAGES

28 Pharmaceutical Technology July 2015 PharmTech.com

magentablackcyanyellow ES639379_PT0715_028.pgs 07.07.2015 00:45 ADV in the stomach and small intestine, facili- cyclomine hydrochloride and diclofenac bile drugs such as proteins and peptides, tating colon-targeted drug delivery. potassium for colon targeting (5). The drugs that degrade in the stomach and Osmotic-controlled drug delivery. Osmotic bilayer coating consisted of a micropo- small intestine or undergo extensive systems are commonly used for con- rous semipermeable membrane and an first pass metabolism, as well as for trolled-release purposes but the concept enteric polymer. The tablets showed acid topical treatment of inflammatory can be applied in colon drug delivery as resistance and time release in in-vitro diseases of the colon. While progress well. The system consists of the drug, an dissolution studies, demonstrating the is being made in achieving more spe- osmotic agent, and a semi-permeable potential for colon-specific drug deliv- cific targeting of drugs to the colon, membrane with an orifice for drug re- ery to treat irritable bowel syndrome. the complexity of these drug delivery lease. An additional enteric coating is ap- Nath et al. incorporated Sterculia systems will require validated dissolu- plied on top of the membrane to prevent gum, which is a polysaccharide, into tion methods and establishing in-vitro/ drug release in the stomach and upper osmotic tablets for colon-specific drug in-vivo correlation. GI tract. As the dosage form enters the delivery of azathioprine (6). Sterculia small intestine, the increase in pH causes gum is digested by the colonic entero- References the enteric coating to dissolve, exposing bacteria and swelling of the polysac- 1. V. Sinha et al., Crit Rev Ther Drug Car- the semi-permeable membrane. Water charide forces the drug out of the tablet rier Syst. 24 (1) 63–92 (2007). 2. V.R. Sinha and R. Kumria, Pharm Res. 18 enters the drug core and the expanding core. To ensure that drug release does (5) 557–564 (2001). volume forces the drug out the osmotic not occur in the upper GI regions, a 3. J.F. Ruiz et al., Bioorg Med Chem Lett. 21 system through the orifice. double-layer coating of chitosan/Eu- (22) 6636–6640 (2011). A number of research groups are dragit RLPO (ammonio-methacrylate 4. K.C. Ofokansi and F.C. Kenechukwu, working on the development of innova- copolymer) and enteric polymers is ISRN Pharm. o n l i n e , D O I : tive osmotic tablets for the treatment of used to impart acid- and intestinal- 10.1155/2013/838403, Aug. 6, 2013. 5. A. Chaudhary et al., Eur J Pharm Bio- inflammatory bowel disease. Chaud- resistant properties to the tablet. pharm. 78 (1) 134–140 (2011). hary et al., for example, developed mi- In short, the colon offers an alterna- 6. Nath et al., PDA J Pharm Sci Technol. 67 croporous bilayer osmotic tablets of di- tive drug delivery approach for acid-la- (2) 172–184 (2013). PT

Trend and Out-of-Trend Analysis Purchase before Microbial Risk and July 31 and save up for Pharmaceutical Quality and to 15% using Investigations Manufacturing Using Minitab campaign code Edited by: Karen Zink By: Lynn Torbeck TAPQ McCullough and PDA MEMBER PRICE: $210 $178.50 Jeanne Moldenhauer NONMEMBER PRICE: $259 $220.15 PDA MEMBER PRICE: $260 go.pda.org/TAPQ NONMEMBER PRICE: $325 The need for a trend analysis book is justif ed by the continued interest This book will provide you with a in the subject matter and the lack of a widely accepted, clearly def ned wealth of information on microbial approach by the industry that lends itself to consistent interpretation and investigations and dealing with uniform application. Trend and Out-of-Trend Analysis for Pharmaceutical aberrant data. Many of the chapters Quality and Manufacturing Using Minitab, answers this call, contributing to include case studies that can provide an industry/regulatory dialogue and consensus that will serve and benef t guidance for common situations that all stakeholders, and patients in particular. It presents a basic introduction may occur at your facility. to data and Trend and Out-of-Trend def nitions, and proposes go.pda.org/MRIG terminology to clarify the use of the word “control” in several contexts.

PDA stays current with new advances and technologies in pharmaceutical manufacturing and shares that information through our technical books, reports and other resources. PDA Technical Books are scientif c and regulatory books specif cally developed for the resource needs of pharmaceutical and biopharmaceutical professionals. For a complete list of PDA Technical Books, please visit store.pda.org.

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industry will then have to scramble to catch up, and the early adopters and fast followers should reap the rewards of their forward-thinking actions. At that point, the entire industry—out of necessity to remain competitive—likely would shift its view on flow technology,” he explains. Most large pharmaceutical companies, according to Peter Poechlauer, in- Lack of Expertise novation manager with Patheon, have at least installed advocate groups with a mission to showcase successful appli- Hinders Adoption of cations of flow processes. Dominique Roberge, head of chemical technologies Continuous API Synthesis with Lonza Pharma & Biotech agrees that flow chemistry has become an ac- Cynthia A. Challener cepted technology for small-molecule manufacturing, largely for the development of new chemical reactions that have not been feasible in batch opera- FDA, Congress, and early adopters look to speed tions, to reduce the cost of goods, and to decrease capital expenditures (CAPEX) up the use of continuous API manufacturing. via process intensification. “These projects are significantly more focused and espite a few significant invest- however, a dearth of industry person- give a better understanding of what is ments in continuous manufactur- nel with expertise in flow chemistry achievable via flow chemistry. As a re- Ding facilities by pharmaceutical is a hindrance to rapid adoption of sult, we have moved past focusing on companies, including Vertex Pharma- continuous technologies. feasibility studies only and are now ceuticals, Johnson & Johnson, Glaxo evaluating projects that are more mature SmithKline, and Novartis (1), the Early adopters and for tech transfer and scale-up,” he notes. adoption of flow chemistry for com- fast followers drive change “The decision to develop a certain mercial production of APIs generally “While the industry as a whole is in the step as a flow process is, however, op- remains in the early stages. FDA has early stages of adopting flow chemistry portunistic and may be motivated encouraged the adoption of continu- for small-molecule API manufacturing, by the speed provided in early devel- ous manufacturing since 2004, but the early adopters and fast followers not opment, the need for smooth scale- specific guidelines are lacking from the only recognize that flow chemistry is up of hazardous reactions, and/or agency and other regulators around the the future of manufacturing, but also the savings in investment for a new globe. Both former FDA Commissioner believe that they can implement it effec- drug whose future is still uncertain,” Margaret Hamburg (1) and Center for tively,” asserts Tim Jamison, professor Poechlauer observes. In addition, he Drug Evaluation and Research Direc- of chemistry and incoming department notes that these criteria apply to single tor Janet Woodcock (2) have been more head at the Massachusetts Institute of steps of multi-step pharmaceutical vocal about the issue, particularly in Technology (MIT) and CEO of Snap- syntheses, and therefore hybrid ap- relation to the proposed 21st Century dragon Chemistry, a new company proaches that combine continuous Cures Act. This legislation requires dedicated to catalyzing the adoption of and batch operations are most com- FDA to support the development and continuous flow synthesis. “Ultimately, mon; few companies have developed implementation of continuous manu- when these companies realize the many end-to-end continuous syntheses of facturing for drugs and biologicals as benefits of flow chemistry, including pharmaceuticals that combine drug- one of several approaches to speeding reduced operating costs, footprint, substance manufacturing and drug- up drug development and commer- and capital expenditures combined product formulation. cialization (3). In addition to a lack of with improved process efficiencies, “Continuous flow manufacturing comprehensive regulatory guidance, control, and product quality, investors occupies a similar position to where a likely will modify their expectations technology like spray drying was 10–15 Cynthia A. Challener, PhD, is a and demand this increased value from years ago. It shows great promise but

contributing editor at Pharmaceutical Technology. the industry as a whole. The rest of the the ‘mainstream’ commercial viability PM IMAGES/GETTY IMAGES

30 Pharmaceutical Technology July 2015 PharmTech.com

magentablackcyanyellow ES639283_PT0715_030.pgs 07.07.2015 00:29 ADV within the pharmaceutical industry has yet to mature,” says Patrick Kaiser, a principal scientist in the process development business of SAFC. He believes that, like spray drying, a clear commercial pathway and, more importantly, a clear regulatory pathway will drive more entrants as developers embrace the technology’s promise. Even so, Kaiser expects there will be limitations to its full embrace, because certain systems lend themselves to be more relevant to continuous processing, while 0$67(5 others make less sense to perform via 385,),(':$7(5 pak continuous means, and this dissonance complicates the pathway forward. “The reality is that CMOs must embrace such disruptive technologies moving for- PURIFIED WATER PERFECTED. ward to ensure long-term competitive- Pretreatment, RO, EDI and service you can rely on. ness in the marketplace,” he concludes. Expanding toolbox A positive indication for the future of flow chemistry is its increasing use for different types of reactions and downstream separation/purification operations. With respect to chemical reactions, using flow processes allows better control of yield and selectivity, which have a direct influence on purification and separation steps, according to Roberge. “The best approach is to develop new processes that can and will lead to a significant improvement in the synthetic route, but will typi- Exceptional service is part of the package. cally not work in a traditional batch process,” he comments. His examples MECO’s MASTERpak™ system is a complete solution for include various oxidation reactions producing Puriﬁed Water as well as pretreating water (with molecular oxygen or hydrogen for Multiple-Effect stills and Pure Steam generators. It peroxide), azide chemistry, and high- integrates MECO’s Pretreatment, RO and EDI product temperature/pressure reactions devel- technologies on a single packaged skid. MASTERpak™ is oped via microwave chemistry. validated and supported by a service team that knows Jamison adds that the use of flow the importance of being responsive. From remote online chemistry for photochemical and elec- monitoring and diagnostics to on-site service, MECO is trochemical reactions is also exciting, there when and where you need us. because these reaction classes are typically difficult to carry out and control and also challenging to translate from laboratory scale to pilot or manufacturing scale, but afford significant opportunities to access completely novel chemical scaffolds and greatly stream- mecomasterpak.com / 866-363-0813 line current synthetic routes. “By using ASIA/Europe/UAE/USA flow chemistry to gain better control, predictability, and scalability for these

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reaction classes, chemists can increase infrastructure to optimize multiple re- likely be a short- to mid-term lack of their utilization, which will ultimately action platforms,” asserts Roberge. human resource supply,” Jamison says. result in significant advances and Rhony Aufdenblatten, manager of broader adoption in the pharma in- Shortage of expertise small-molecule business development dustry,” Jamison states. In fact, the inadequate supply of sci- with Lonza Pharma & Biotech, agrees Integration of chemical synthesis re- entific talent and expertise necessary that flow chemistry remains a special- actions in flow with an increasing diver- to implement continuous flow technol- ized technology, because it requires sity of work-up operations in flow, such ogy at scale is perhaps the largest fac- specific technical know-how that can as continuous extraction, membrane tor hindering more rapid adoption of only be developed over years of manu- processes, and the crystallization and flow chemistry for small-molecule API facturing different chemical products. separation of solids, is also an important synthesis, according to Jamison. “It’s “The key challenge for any small-mol- development, according to Poechlauer. not as simple as asking current chem- ecule development program is manage- He further notes that the application of ists to start working with continuous ment of scale-up of the lab process for parallel, analytical instruments with flow technology. That is like asking a industrialization. Moving this type of sufficiently short response times have saxophonist to play oboe. While both scale-up into a new platform like flow been developed, allowing efficient con- instruments are woodwinds, a saxo- chemistry can only be handled by the trol of these processes. phone uses one reed, while the oboe few players who have experience work- The development of a complete uses two. Thus, saxophonists can cer- ing with a variety of chemistries and toolbox of flow reactors that can be tainly become oboists, but it is not au- processes,” he observes. used for all types of reaction rates tomatic; there will be a learning curve Poechlauer is not convinced that and phases (e.g., liquid-liquid, solid- in most, if not all cases. Currently, continuous processing is “experts only” liquid, etc.) is also necessary for the flow chemistry is generally not in most territory any longer, but he also believes broad application of flow chemistry to university chemistry curricula. Thus, that this perception certainly affects de- be achieved, according to Roberge. To there will continue to be a lack of ex- cisions regarding adoption of the tech- address some of this need, Lonza has pertise in this area until this situation nology. As a result, he does believe that developed the pulsating coil reactor is changed,” he explains. “In the long CMOs with a proven track record in for liquid-liquid phase reactions and run, industry demand will accelerate continuous processing may be favored an efficient de-plugging system based such changes; as the industry requires as demand for this capability increases. on ultrasound technology. “Ultimately, more expertise in this area, education/ true innovation in this field will come training standards will shift to meet Regulatory and infrastructure issues from a few key players in the market this demand. This shift will not occur Two other factors that are influencing who have the variety of experience and immediately, however, and there will the rate of adoption of flow chemistry

Assistance for end-to-end implementation of flow chemistry Snapdragon Chemistry—a new company launched in early May 2015 by CEO implementing the technology,” he adds. Snapdragon Chemistry has already Tim Jamison, a professor of chemistry and incoming department head at the formed partnerships with companies, such as drug-discovery service provider Massachusetts Institute of Technology (MIT), with Boston University assistant Paraza Pharma and equipment manufacturer Zaiput Flow Technologies, to professor of chemistry Aaron Beeler—intends to provide drug companies with bring the most innovative and effective continuous flow solutions to clients, assistance in developing flow chemistry strategies and systems. according to Jamison. “Snapdragon Chemistry has the capability to help a drug-maker from CMOs continue to build expertise end-to-end in implementing continuous flow manufacturing,” Jamison says. SAFC has the capability to manufacture products using continuous systems on a Backed by a scientific advisory board that includes Steve Buchwald and Klavs 1–50 kg/day basis and currently is producing monomers, reagents, and building Jensen, well-respected MIT chemistry and chemical engineering professors, respectively, the company is offering solutions services that include evalua- blocks for pharmaceutical and high-technology applications. The company is tion of entire portfolios of molecules in development to identify the greatest also investigating the addition of cGMP capacity that will include continuous opportunities for implementation of continuous flow chemistry. The company manufacturing technologies. also offers the translation of desired organic syntheses end-to-end into a con- Lonza has produced many intermediates on kilogram and hundreds of kilo- tinuous-flow format, including the selection and/or design and development gram scales for APIs in clinical trials. In 2013, for instance, the company completed of laboratory- to commercial-scale continuous reactors. a technology transfer to a large-scale manufacturing process under high-temper- “Our goal is to help adapt flow technology solutions to the context of a ature and pressure conditions that were not possible in a batch process, according specific company. We have the deep technical expertise across chemical syn- to Rhony Aufdenblatten, manager of small-molecule business development with thesis and engineering to help companies make the appropriate decisions on Lonza Pharma & Biotech. Lonza has also used flow chemistry for the multi-ton where to invest in flow chemistry and increase their probability of success in production of a niacin product under GMP conditions.

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for API synthesis include a lack of clear The mentality of the process devel- comments. The best strategy to combat regulatory guidelines and the exist- opment function must also be consid- this challenge, according to Kaiser, is ing batch-based manufacturing infra- ered, according to Kaiser. The use of to have experienced flow chemistry structure. Although FDA representa- flow chemistry earlier in development experts recognize where continuous tives recently made a number of public requires both the innovator and CMO systems provide the greatest opportu- comments in support of continuous to be open to using continuous systems nity for results early on in the process manufacturing in the pharmaceutical as an option in their process develop- development effort. industry, from a regulatory standpoint, ment efforts. Doing so potentially re- there remains a need to develop clear, quires developing an initial batch pro- References harmonized guidelines accepted across cess backed up by a second-generation 1. J.D. Rockoff, “Drug Making Breaks Away the various regulatory authorities that flow process, perhaps simultaneously if From Its Old Ways,” The Wall Street Journal, February 8, 2015, www.wsj. will facilitate the development of con- the drug is on an accelerated approval com/articles/drug-making-breaks-away- tinuous manufacturing routes in a man- pathway, which is not a small shift in from-its-old-ways-1423444049, accessed ner that guarantees a consistent way to today’s “fast-fail” drug development June 2, 2015. monitor/regulate their output, accord- business. “Development companies 2. J. Wechsler, “Congress Encourages Mod- ing to Jamison. In addition, while there are generally averse to investing too ern Drug Manufacturing” Pharmaceu- tical Technology website, May 1, 2015, are a growing number of flow processes much in the manufacturing process www.pharmtech.com/congress-encour- being filed with auditors despite this lack until there is good clinical data to show ages-modern-drug-manufacturing, ac- of clarity, Poechlauer notes that there is manufacturing on a larger scale is nec- cessed June 2, 2015. little experience with respect to the au- essary. Unfortunately, waiting too long 3. Energy & Commerce Committee, United diting of continuous process steps. to develop a continuous process also States House of Representatives, “Full Committee Vote on the 21st Century The International Conference on complicates a company’s regulatory Cures Act,” May 19, 2015, http://ener- Harmonization (ICH) may be an ef- strategy and potentially a challenge gycommerce.house.gov/markup/full- fective body for achieving international with different impurity profiles from committee-vote-21st-century-cures-act, guidelines. The organization may in different manufacturing processes,” he accessed June 2, 2015. PT fact be making continuous flow manufacturing a focus issue over the next year to 18 months. The impact of existing batch plants is less straightforward. For companies with unused batch capacity, Aufden- blatten notes that additional motiva- tion for further investment into large- scale flow chemistry will be needed to overcome the additional CAPEX for flow infrastructure. “Typically, a gain in yield of 2–3% will not be sufficient; reduced cost of goods, safer processes, and breakthroughs in process platforms must also be considered,” he explains. Jamison points out, though, that existing infrastructure is in various stages of maturity, and new capacity (whether batch or continuous) could be established naturally, with continuous plants being built in place of new batch plants, as appropriate. “In addition,” he says, “continuous manufacturing plants could have a 10- to 100-fold smaller footprint than a batch plant of com- parable output. Therefore, the CAPEX investment is smaller, which might sway the economic analysis to favor the business case of mothballing a significant number of existing batch-mode plants.”

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Beyond the Blink: Using In-Situ Gelling to Optimize Opthalmic Drug Delivery Delivery systems that allow drugs to be administered as liquids, but form gel within the eye, promise to improve efficacy and patient compliance.

Jigar N. Shah, Rakesh K. Patel, Hiral J. Shah, and Tehal A. Mehta

Conventional ophthalmic solutions frequently show poor pthalmic drug delivery systems, such as eye bioavailability and a weak therapeutic response because Odrops, ointments, and soft gel capsules, are they are often eliminated before they can reach the cornea, typically used to treat diseases of the eye. when patients blink or their eyes tear. Use of in-situ gel However, the eye’s protective mechanisms often forming solutions may help improve performance and patient reduce their therapeutic effect. When a drug solu- compliance. These solutions are delivered as eye drops, but tion is dropped into the eye, there is typically a undergo a sol-gel transition in the conjunctival sac (cul de 10-fold reduction in the drug concentration within sac). This article describes how an ion-activated in-situ gelling 4–20 min, due to the effective tear drainage and system was designed to deliver an ophthalmic formulation of blinking action (1). The cornea’s limited permea- the antibacterial agent, Levofloxacin. bility contributes to the low absorption of ocular The delivery system uses gellan gum, a novel ophthalmic drugs. Due to tear drainage, most of the adminis- vehicle that gels in the presence of mono or divalent cations tered dose passes via the nasolacrimal duct into in the lacrimal fluid. This gum was used alone and combined the gastrointestinal tract, leading to side effects with sodium alginate as a gelling agent and hydroxypropyl (2). Rapid elimination of both the solutions and the methylcellulose (HPMC) Methocel F4M as a viscosity enhancer. suspended solid administered often results in A 32 full factorial design approach was used, with two blurred vision, poor patient acceptance, and short polymers: Gelrite and HPMC, as independent variables. Gelling duration of the therapeutic effect, making more strength, bioadhesion force, rheological behavior, and in-vitro frequent dosing necessary (3). New preparations drug release after 10 h were selected as dependent variables. have been developed to prolong the contact time Both in-vitro release studies and rheological profile studies on the ocular surface and slow down drug elimi- indicated that the combined Gelrite–HPMC solution retained nation (4, 5). Ocular inserts (5) and collagen shields the drug better than the gellan gum alone or a combination of (6) can also be used, but they pose challenges. gellan gum–alginate–HPMC. The developed formulations were These delivery challenges can be overcome therapeutically efficacious and provide sustained release of by using in-situ gel-forming ophthalmic drug the drug over a 12-h period in vitro. These results demonstrate delivery systems prepared from polymers that that the Gelrite–HPMC Methocel F4M mixture can be used as exhibit reversible phase transitions (sol–gel–sol) an in-situ gelling vehicle to enhance ophthalmic bioavailability and pseudoplastic behavior. Such formulations and patient compliance. minimize interference with blinking (7). Changes to the gel phase (8) can increase pre-corneal residence time and enhance ocular

Jigar N. Shah, PhD,* is assistant professor at Nirma University’s Institute of bioavailability. Three types of systems have Pharmacy’s Department of Pharmaceutics in Ahmedabad, Gujarat, India. He can be been used: pH-triggered systems including reached at [email protected] or [email protected]. cellulose acetate hydrogen phthalate latex (9, 10) Rakesh K. Patel, PhD, is professor at S.K. Patel College of Pharmaceutical Education and carbopol (11–15); temperature-dependent & Research, Ganpat University, Kherva, Gujarat, India. systems including pluronics (7, 16–20), tetronics Hiral J. Shah, PhD, professor, J. Arihant School of Pharmacy & Bioresearch Institute, (21, 22), and polymethacrylates (23); and ion- Adalaj, Gandhinagar, Gujarat, India. Tejal A. Mehta, PhD, is professor, Institute of Pharmacy, Nirma University, activated systems including Gelrite (24–26), Ahmedabad, Gujarat, India. gellan (27–28), and sodium alginate (29). The authors used an ion-activated in-situ *To whom all correspondence should be addressed. Submitted: October 8, 2014. Accepted: November 17, 2014. gelling system to deliver Levofloxacin, a fourth- generation fluoroquinolone anti-infective 34 Pharmaceutical Technology July 2015 PharmTech.com

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Table I: Composition of prepared in-situ gelling systems.

Batch Gellan (%w/v) SA (%w/v)* HPMC (%w/v) Gelling capacity Drug content (%) LV 0.2 - - + 97.23±1.27 LV1 0.3 - - ++ 98.35±1.09 LV2 0.3 0.27 - +++ 99.38±0.94 LV3 0.3 0.29 0.5 +++ 98.17±1.12 LV4 0.3 - 0.5 +++ 99.47±0.89 LV5 0.4 - - +++ 99.25±0.79 LV6 0.4 0.27 - +++ 99.52±0.95 LV7 0.4 0.29 0.5 +++ 98.93±0.67 LV8 0.4 - 0.5 +++ 99.4 2±1.13 + gels slowly and dissolves; ++ gelation immediate and remains for a few hours; +++ gelation immediate and remains for an extended period. *Amount of Sodium alginate was adjusted (equivalent to 0.25% w/v)

agent, which can be used to treat conditions including drops (0.5% w/v). These drops would undergo gelation when acute and subacute conjunctivitis, bacterial keratitis, and instilled into the cul-de-sac of the eye, and provide controlled keratoconjunctivitis. The goal was to demonstrate prolonged release of the drug in treatment of ocular infections. action and show antibacterial activity against gram-positive and gram-negative bacteria directly at the site of infection Materials and methods. without loss of dosage. The combination of Gelrite (gellan Materials. Levofloxacin was obtained from Zydus gum) and hydroxypropyl methylcellulose (HPMC) (Methocel Healthcare, Gelrite from CP Kelco, and HPMC (Methocel F4M) was used to prepare the gelling system, which was used F4M) was provided by Colorcon Asia Pvt. Ltd. All other rea- with and without sodium alginate to prepare Levofloxacin eye gents, chemicals, and solvents were of analytical grade.

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Table II: Composition and results of 32 full factorial design batches. Variable levels Actual Units Batch VI x 10 GS (s) BF x 105(N) CP10 (%) Code HPMC F4M (Pa.s) Gelrite X1 X1 (% m/V) X2 (% m/V) X2 LF1 -1 -1 0.3 0.3 105 ±1.12 1955±26.09 1200 99.56 LF2 -1 0 0.3 0.5 108±2.02 1922±78.01 1556 96.45 LF3 -1 +1 0.3 0.7 117±2.68 2020±78.01 1867 90.15 LF4 0 -1 0.4 0.3 111±0.68 2740±78.01 1339 94.86 LF5 0 0 0.4 0.5 116±1.13 2969±26.09 1794 90.59 LF6 0 +1 0.4 0.7 125±2.02 3132±128.1 2121 87.66 LF7 +1 -1 0.5 0.3 118±2.68 4603±128.1 1534 88.43 LF8 +1 0 0.5 0.5 122±3.04 4701±26.09 1984 75.15 LF9 +1 +1 0.5 0.7 134±0.97 4832±26.09 2429 68.39 LF10* -0.5 0.5 0.35 0.6 112±1.53 2800±78.01 1850 92.62 LF11* 0.5 -0.5 0.45 0.4 113±1.02 3400±128.1 1550 87.60 GS is gel strength; BF is bioadhesion force; VI is viscosity; CP10 is cumulative percentage drug release after 10 h. * indicates check point batch

Methods. Method of preparation. Gelrite-based in-situ The main effects (X1 and X2) represent the average result

gelling systems were prepared by dissolving gellan, alone of changing a factor at a time. The interaction term (X12) and combined with sodium alginate and/or HPMC in hot shows how the response changes when the factors are

phosphate buffer (pH 7.4, 70˚C), by continuous stirring at simultaneously changed. Polynomial terms (X11 and X22) are 40-45 ˚C for 24 h, as shown in Table I. Then the weighed included to investigate nonlinearity. quantities of levofloxacin (0.5% w/v), mannitol, and Statistical analysis and two-way analysis of variance preservatives, such as methyl paraben and propyl paraben, (ANOVA) were used to evaluate the significance of each were added to the solution and stirred until dissolved. The factor to the response at different levels. Three-dimensional solutions were then transferred into previously sterilized response surface plots and two-dimensional contour plots amber-colored glass vials, capped, and sealed with of the data were generated using Design Expert software aluminum caps. The formulations were sterilized by terminal (Version 8). autoclaving at 121 ˚C, 15 PSI for 20 min. The sterilized formulations were stored in a refrigerator at 4–8 ˚C until use. Evaluation of formulation The following were used to evaluate the formulation. Experimental design Gelation studies were carried out in a vial containing A 32 full factorial approach was taken to design the gel- the gelation solution and simulated tear fluid (STF) solution, ling system. Two factors were selected, and a total of nine composed of 0.670 g of sodium chloride, 0.200 g of sodium experimental trials were performed using all possible com- bicarbonate, 0.008 g of calcium chloride dehydrate, and binations. The concentrations of Gelrite (cation-sensitive purified water, quantum satis to 100 g.

in-situ gelling polymer) as X1 (0.3, 0.4, and 0.5%, m/V) and The preparation was carefully taken into the vial using a

HPMC (viscosity imparting agent) as X2 (0.3, 0.5, and 0.7%, micropipette, and 2 mL of gelation solution (STF) was added m/V) were selected as independent variables. slowly. Gelation was assessed by visual examination (26). Gel strength (GS in s), bioadhesion force (BF in N), viscosity Rheological studies. Viscosities of sample solutions were (VI) in Pa.s, and cumulative percent drug release after measured in a Brookfield synchrolectric viscometer (LVDVI 10 h (CR10) were selected as dependent variables. The prime) at different angular velocities at a temperature of design is shown in Table II. Equation 1 summarizes the 37±1˚C. The angular velocity was increased from 0.5 to 100 experimental design, using two independent variables and rpm with 6 s between two speeds. The sequence of the three levels (low, medium, and high) of each variable: angular velocity was reversed. The average of two readings was used to calculate viscosity. Evaluations were conducted

Y = b0 + b1X1 + b2X2 + b11X11 + b22X22 + b12X1X2 (Eq 1) in triplicate (26). Drug content uniformity. Vials containing the

where Y is the dependent variable, b0 is the mean formulation were shaken for 2–3 min, and the preparation

response of the nine runs, and bi is the estimated coefficient was transferred aseptically to sterile volumetric flasks. The

for factor Xi. final volume was made up with phosphate buffer pH 7.4. The 36 Pharmaceutical Technology July 2015 PharmTech.com

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concentration of Levofloxacin present was determined at the formulation. The membrane was kept in contact 287 nm using UV spectrophotometry (26). with the formulation for 5 min. Weight was slowly added In-vitro drug release studies. The studies were carried to the right pan slowly, in increments of 0.5 g, until the out using a Franz diffusion cell, with STF (pH 7.4) as formulation detached from the membrane surface. The dissolution medium. The cell consists of glass donor and excess weight on the right pan was taken as the measure receptor compartments, separated by a dialysis membrane. of the bioadhesive strength. The force of adhesion was then The optimized formulation was placed in the donor calculated using the following formula (13). compartment, and freshly prepared STF was placed in the receptor compartment. The whole assembly was placed in a Force of adhesion = Bioadhesive strength x 9.81 / 1000. temperature-controlled shaker water bath maintained at 37 ˚C ± 0.5 ˚C. A sample (1 mL) was withdrawn at predetermined Infrared spectroscopy and DSC studies. Infrared (IR) time intervals up to 24 h and the same volume of fresh spectroscopy and differential scanning calorimetry (DSC) medium was replaced. The withdrawn samples were were then used to analyze the pure drug, gellan, HPMC, analyzed by UV spectrophotometer at 287 nm. physical mixture of drug-gellan-HPMC, and optimized Bioadhesive strength measurement. Freshly excised formulation. Resulting spectra were then compared with goat conjuctival membrane was used to measure reference spectra. bioadhesive strength. The membrane was placed in an Antimicrobial efficacy studies. The solution’s aerated saline solution at 4 ˚C until used. It was tied to the antimicrobial efficacy was determined using agar diffusion lower side of the hanging polytetrafluoroethylene (PTFE) and commercial Levofloxacin eyedrops as a control. The cylinder using thread, and the cylinder was fixed beneath of sterilized solutions were poured into cups bored into sterile left pan of a pan balance. The formulation was placed into a agar nutrient seeded with test organisms (Pseudomonas sterile petri plate that was kept on the platform beneath the aeruginosa and Staphylococcus aureus). After allowing left pan. The two sides of the pan balance were balanced by diffusion of the solutions for two hours, the plates were keeping a 2-g weight on the right pan. incubated at 37 ˚C for 24 h, and the zone of inhibition (ZOI) The 2-g weight was then removed, lowering the left was measured around each cup and compared with control’s pan and allowing the membrane to come in contact with ZOI. The entire process, except for the incubation, was carried

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in days. The degradation Figure 1: Rheological profiles of the formulations LV1-LV8. rate constant was calculated using the equation: slope Rheological profles of batches LV1 to LV8 = k/2.303, where k is a 1800 LV1 1600 LV2 degradation rate constant. 1400 LV3 The shelf life of the developed LV4 1200 formulation was calculated LV5 1000 using the Arrhenius plot. LV6 800 LV7

Viscosity (cp) 600 LV8 Results and discussion 400 Composition of various 200 batches of the prepared in- 0 situ gelling formulations are 0 10 20 30 40 50 60 70 80 90 100 shown in Table I. In the batch Shear rate (rpm) containing gellan alone, the concentration of gellan was kept at a maximum of 0.4% Figure 2: In-vitro release profile of prepared gelling systems of Levofloxacin LV1 – LV8. (w/v). Higher concentration beyond 0.4% caused gelation In vitro release profles of LV1 - LV8 upon cooling to 40 ˚C. In the combination 100 batches, the concentration 90 LV1 of gellan was varied and 80 the concentration of LV2 70 sodium alginate was kept LV3 60 at approximately 0.25% LV4 (by compensating the 50 concentration difference 40 LV5 CPR (%) due to reduction in viscosity LV6 30 after autoclaving for 20 LV7 sodium alginate) to give a 10 LV8 maximum of 0.65% polymer 0 concentration, because 0 2 4 6 8 10 12 an increase beyond this Time (Hrs) concentration resulted in gelation during formulation. To maintain the proper pseudoplastic behavior of out under laminar flow units in an aseptic area (Class 10,000). formulation, HPMC was used with gellan alone and with Each solution was tested three times. Both positive and combination of gellan and sodium alginate. The drug content negative controls were maintained throughout the study (26). and gelling capacity of the formulations were found to be In-vivo ocular irritation and stability studies. In-vivo satisfactory as mentioned in Table I, and the formulations ocular irritation studies were performed using the Draize were liquid at both room temperature and when refrigerated. technique (30) and guidelines set by the Organization for Viscosity and gelling capacity (speed and extent of gelation) Economic Cooperation and Development (OECD) (31). Six are the most important criteria for any in-situ gelling system. albino rabbits, each weighing 2–3 kg, were used for this All batches exhibited pseudoplastic behavior, as showed study. The sterile formulation was administered to the in Figure 1. All batches showed low viscosity at high shear test rabbits twice a day for 21 days and the rabbits were rate and high viscosity at low shear rate. Autoclave process observed periodically. had not affected the viscosity of the formulations, except for International Council for Harmonization (ICH) guidelines those containing sodium alginate where viscosity was reduced were used to determine the optimized formulation’s stability. around 8–15%. Therefore, the concentration of sodium The gel was stored in a stability chamber at ambient alginate was adjusted to compensate (25). All measurements humidity between 2 ˚C to 8 ˚C, ambient temperature at were taken three times and showed good reproducibility. 40 ˚C ±0.5 ˚C for six months. The samples were withdrawn Figure 2 shows the cumulative percentage of at regular intervals and analyzed. The logarithms of percent Levofloxacin released versus time profiles for batches

drug remaining were calculated and plotted against time LV1 to LV8. These results suggested that Levofloxacin All figuresAre courtesy of theAuthors. 38 Pharmaceutical Technology July 2015 PharmTech.com

magentablackcyanyellow ES639291_PT0715_038.pgs 07.07.2015 00:29 ADV Trends in Quality Agreements & Communications: A CMO Perspective

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Table III: Comparison of the actual value with predicted GS (gel strength) = 115.33 + 7.33*X1 + 7X2 (Eq. 2) values of checkpoint batches. BF (bioadhesion force) = 3069.44 + 989.83*X1 + 314.33*X2 + 116*X1^2 (Eq. 3) Actual values VI (viscosity) = 1771.11 + 220.66*X1 + Batch VI x 10 GS (s) BFx105 N CP10 (%) 390.66*X2 + 57 X1*X2 (Eq. 4) code (Pa.s) CR10 (cumulative LF10 112 2800 1850 92.62 percentage drug LF11 113 3400 1550 87.60 release after 10 hs) = 90.51 – 9.03*X1 – 6.1*X2 (Eq. 5) Predicted values All the polynomial equations were found to be statistically LF10 115.66 2874.9 1815 91.67 significant (P < 0.05) and in good agreement with results. LF11 116 3235.04 1645 88.74 From Equation 2, it can be concluded that both gellan gum GS is gel strength; BF is bioadhesion force; VI is viscosity; and HPMC significantly affect the gelling strength (25, 13). CP10 is cumulative percentage drug release after 10 h. Formulation batches LF1 and LF2 showed poor gelation strength, which might be due to the minimum amount of Table IV: Analysis of variance for dependent variables of gellan and/or HPMC. the 32 full factorial design. The results are shown in Table II. The studies showed Source F-value R2 P that, in the presence of HPMC, as the amount of gellan increased, gel strength increased as well; this effect must Gel strength (GS) 287.4 0.998 0.00032 be due to the additional effect of concentration of polymer. Bioadhesion Force (BF) 1301.908 0.999 0.000033 Figure 3(a) shows the response surface plot illustrating Viscosity (VI) 559.04 0.999 0.00012 the effect of gellan gum and HPMC on the gelling strength. CP10 (%) 17.65 0.970 0.0196 Studies confirmed that both polymers significantly affect the gelling strength. F is Fischer’s ratio, p is signifcance level, CP10 is cumulative percentage drug release after 10h. From Equation 3, it can be concluded that both polymers have a predominant effect on bioadhesive force. The formulation contained gellan gum, which is a mucoadhesive Table V: Antimicrobial efficacy of optimized formulation. agent. Studies show that polymers with charge can serve Concentration Zone of Inhibition (cm) (% effciency) as good mucoadhesive agents. It has also been reported (μg/ml) STD LF5 that polyanion polymers are more effective bioadhesives S. aureus than polycations or nonionic polymers (33, 34). This polymer adheres to the mucin of the eye, which leads to prolonged 1 1.4 1.5 (107) retention of the formulation inside an eye (13). Figure 3(b) 10 2.0 2.4 (120) depicts the response surface plot, showing the influence of 100 3.2 3.9 (121.88) both polymers on bioadhesion force. The studies confirmed P. aeruginosa that, as the concentration of gellan gum or HPMC is 1 1.4 1.6 (114.3) increased, bioadhesion also increases. Equation 4 shows that HPMC has a predominant effect 10 2.2 2.5 (113.63) on viscosity compared to gellan gum. Normally, water- 100 3.8 4.4 (115.8) soluble polymers such as HPMC produce two effects: STD = standard (commercial eye drops of levofoxacin); • Lowering surface tension and improving mixing with the LF5 = optimized formulation from design shown in Table II. precorneal tear film Values in parenthesis indicate the percent effciency; • Increasing viscosity and prolonging contact time, thereby percent effciency was calculated by (ZOI of test/ZOI of resisting drainage of drug from eye (13). standard) x 100. Gellan gum can significantly increase viscosity of the formulation upon exposure to lachrymal fluid. So, by was sustainably released from formulation LV8, when optimizing the concentration of HPMC viscosity-enhancing the content of gellan gum was 0.4% and 0.5% of HPMC agent, one can decrease the amount of gellan gum in the Methocel F4M (Table I). A similar release pattern is reported preparation to improve patient compliance. Figure 3(c) for pilocarpine (32) from alginate systems, wherein an shows the response-surface plot of effect of gellan gum inverse relationship between drug release and polymer and HPMC on viscosity. From Equation 5, gellan gum and concentration was observed. HPMC are inversely related to the amount of drug released. The results of in-vitro release studies show that the Experimental design formulations retain drug for the duration of the study Based on studies of response variables, the polynomial rela- (12 h). The movement of the eyelid and eyeball provide tionships are expressed in Equations 2 to 5. shearing action for faster dissolution of gels in the cul- 40 Pharmaceutical Technology July 2015 PharmTech.com

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de-sac. Figure 3(d) depicts the response-surface plot, Figure 3. Response surface plot for effects of the showing the influence of both polymers on drug release amount of Gelrite and HPMC Methocel F4M on (a) gel after 10 h respectively. Checkpoint batches LF10 and LF11 strength; (b) bioadhesive force; (c) viscosity; (d) were prepared (Table II) to validate the evolved model. cumulative percentage drug release after 10 h. The actual values of GS, BF, VI, and CR10 of batches LF10 and LF11 are given in Table III. Checkpoint batches were 3D Surface response for gelation found in good agreement with the actual values. Results of ANOVA are shown in Table IV. 140 Release of an optimized batch fitted to a Higuchian matrix 135 equation showed a high R-squared value (0.99), least SSR 130 125 value, and F value {21} as compared to other batches. Thus, 120

it can be concluded that release of drug was based on a Gelation 115 110 1.0 0.5 Higuchian-matrix, diffusion-controlled mechanism. 105 100 0.0 Conc of Gelrite 0.5 -0.5 0.0 Conc of HPMC-0.5 -1.0 Bioadhesive strength and thermogram results -1.0 The bioadhesive strength measurement of designed (a) batches is shown in Table II. Differential scanning calorimetry (DSC) thermograms showed characteristic 3D surface plot of bioadhesive force peaks of Levofloxacin at 230.50˚C and 111.55˚C, gellan gum

at 266.11˚C, and HPMC at 288.55˚C and 79.79 ˚C (Figure 4). 5000

The peak of Levofloxacin was found to be reduced in 4500 intensity in physical mixture of drug, gelling agent, and 4000 3500 polymer ( ) and could not be seen in optimized

Figure 4e 3000 Bioadhesive formulations of DSC thermogram (Figure 4c), indicating the 2500 1.0 in-situ 2000 0.5 entrapment of drug in the matrix gel system of gellan 0.0 Conc of Gelrite 1500 0.5 -0.5 gum and HPMC. 0.0 Conc of HPMC-0.5 -1.0 The optimized formulation (LF5) showed antimicrobial -1.0

activity when tested microbiologically by the cup-plate (b) technique. Clear ZOIs were obtained in the case of the optimized formulation and marketed eye drops. 3D surface plot of viscosity The diameters of the ZOIs produced by the optimized

formulation against both test organisms were either on par 2600 or higher than those produced by marketed eye drops as 2400 2200

shown in Table V. The antimicrobial effect of levofloxacin 2000 gel formulation is probably due to its rapid initial release 1800 Viscosity 1600 into the viscous solution and followed by formation of a 1400 1.0 drug reservoir that attributed to the slow and prolonged 1200 0.5 0.0 Conc of Gelrite 1000 diffusion from the polymeric solution due to its higher 0.5 -0.5 0.0 -0.5 viscosity (26). Conc of HPMC -1.0 -1.0 Ocular irritation studies (35) indicated that the (c) formulation is well tolerated by rabbit eyes (36). No ocular damage or abnormal clinical signs were observed (37). 3D surface plot of drug release in 10hr The optimized formulation of Levofloxacin was kept for stability studies at refrigeration temperature (4 ˚C), ambient temperature (25 ˚C), and elevated temperature (40 ˚C) for a 105 period of six months. Samples were withdrawn at regular 100 time intervals and were evaluated for appearance, gelation 95 studies, drug content, and in-vitro drug release. 90 85

Rel in 10hr in Rel 80 -1.0 Stability studies 75 -0.5 The formulation was found to be sterile at the end of six 70 0.0 Conc of Gelrite months. The drug degraded to a negligible extent and the 65 -0.5 0.5 0.0 degradation rate constant for optimized formulation was 0.5 Conc of HPMC 1.0 very low (1.12 x 10-4). Because the overall degradation is -1.0

<5%, a tentative shelf life of two years may be estimated the (d) formulation (13). Pharmaceutical Technology July 2015 41

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sustained drug release, higher viscosity, longer pre-corneal Figure 4: Differential Scanning Colorimetry thermogram residence time, and better miscibility with the lacrimal fluid. of (a) Pure Levofloxacin; (b) HPMC Methocel F4M; (c) Optimized formulation LF5; (d) Gellan gum; (e) These benefits promise to improve patient acceptance and Physical mixture of Levofloxacin, gellan gum and HPMC compliance. Methocel F4M. References 1. D.M. Maurice, “Kinetics of topically applied ophthalmic drugs,” in

267.22 C Ophthalmic Drug Delivery Biopharmaceutical, Technological and Clinical Aspects, M.F. Saettone, M. Bucci, and P. Speiser, Eds. (Fidia Research Series, Padova: Liviana Press, Springer, New York, 1987), pp. 19-26.

266.11 C 2. D.L. Middleton, S.S. Leung, and J.R. Robinson, “Ocular bioadhesive delivery systems,” in Bioadhesive Drug Delivery Systems, V. Lenaerts, and R. Gurny, Eds. (Boca Raton, FL: CRC Press, 1st ed., 1990), pp. 179- 230.82 C (e) 202. 3. O. Olejnik, “Conventional systems in ophthalmic drug delivery systems,” in Ophthalmic Drug Delivery Systems, A.K. Mitra, Ed. (Marcel Dekker,

96.77 C New York, 1993), pp. 179-193. 4. C.L. Boularis, et al., Prog. Retin. Eye Res. 17 (1), 33-58 (1998). (d) 5. S. Ding, Pharm. Sci. Technol. Today 8 (1), 328-335 (1998). 6. J.M. Hill et al, “Controlled collagen shields for ocular delivery,” in 91.40 C Ophthalmic Drug Delivery Systems, A.K. Mitra, Ed. (Marcel Dekker, New (c) York 1993), pp. 261–275. 7. A.H. El-Kamel, Int. J. Pharm. 241 (1) 47-55 (2002). 8. O. Sechoy, et al., Int. J. Pharm. 207 (1-2) 109-116 (2000). 9. R. Gurny, Pharm. Acta. Helv. 56 (4-5) 130-132 (1981). 10. R. Gurny, T. Boye, and H. Ibrahim, J. Contr. Rel. (2), 353-361 (1985).

80.78 C 11. B. Srividya, et al, J. Contr. Rel. 73 (2-3), 205–211 (2001). 288.55 C 12. D. Aggarwal and I.P. Kaur, Int. J. Pharm. 290 (1-2) 155-159 (2005). 13. Y. Sultana et al., Pharm. Dev. Technol. 11 (3) 313-319 (2006). 14. C. Wu et al., Yakugaku Zasshi 127 (1) 183-191 (2007). 15. H.R. Lin and K.C. Sung, J. Contr. Rel. 69 (3) 379-388 (2000). 16. S.C. Miller and M.D. Donovan, Int. J. Pharm. (12), 147-152 (1982). DSC 17. S.D. Desai and J. Blanchard, J. Pharm. Sci. 87 (2) 226-230 (1998). mW (b) 18. K.Y. Cho et al., Int. J. Pharm., 260 (1), 83-91 (2003). 0.00 19. M.K. Yoo et al., Drug Dev. Ind. Pharm. 31 (4-5) 455-463 (2005). 79.79 C 20. H. Qi et al., Int. J. Pharm. 337 (1-2) 178-187 (2007). (a) -5.00 21. M. Vadnere et al., Int. J. Pharm. 22 (2-3) 207-218 (1984). 22. C.W. Spancake et al, Int. J. Pharm. 75 (2-3) 231-239 (1989). 111.55 C

-10.00 23. G.H. Hsiue et al., Biomaterials 24 (13), 2423-2430 (2003). 24. A. Rozier et al., Int. J. Pharm. 57 (2), 163-168 (1989). 25. J. Balasubramaniam et al, Acta Pharm. 53 (4) 251-261 (2003). -15.00 230.50 C 50.00 100.00 150.00 200.00 250.00 300.00 26. Balasubramaniam and J.K. Pandit, Drug Deliv. 10 (3) 185-191 (2003). Temp [c] 27. Y.D. Sanzgiri et al., J. Contr. Rel. 26 (3) 195-201 (1993). 28. J.N. Shah et al, PharmaInfo.net, 5 (6) 2007 www.pharmainfo.net/ reviews/gellan-gum-and-its-applications-%E2%80%93-review, 12 Sep. 2010. Conclusion 29. Z. Liu et al., Int. J. Pharm. 315 (1-2) 12-17 (2006). An ion-activated in-situ gel formulation of Levofloxacin was 30.J.H. Draize et al, J. Pharmacol. Exp. Ther. 82 (3) 377–390 (1944). successfully formulated using gellan gum in combination 31. OECD Publication Office (Paris, Oct. 2012) Guidelines for testing the with HPMC. The formulation underwent gelation in the chemicals, Section 4, Test No. 405: Acute eye irritation/corrosion. conjunctival sac (cul-de-sac), allowing for sustained drug 32. S. Cohen et al., J. Control. Rel. 44 (2-3) 201–208 (1997). release over a 12-h period without any adverse effect to the 33. K. Park and J.R. Robinson, Int. J. Pharm. 19 (2) 107–127 (1984). ocular tissues. 34. S. Wee and W.R. Gombotz, Adv. Drug Deliv. Rev. 31(3) 267-285 (1998). Stability data confirmed that the formulation is stable 35. J.F. Griffith et al., Toxic Appl. Pharmacol. 55 (3) 501-513 (1980). for a six-month period in given storage conditions. This 36. H. Sasaki et al., J. Control. Rel. 27 (2) 127 -137 (1993). new formulation can enhance bioavailability through its 37. Z. Liu et al., Drug Dev. Ind. Pharm. 31 (10) 969-975 (2005). PT 42 Pharmaceutical Technology July 2015 PharmTech.com

magentablackcyanyellow ES639424_PT0715_042.pgs 07.07.2015 03:28 ADV Controlling the Physical Properties and Performance of Semi-solid Formulations through Excipient Selection

ON-DEMAND WEBCAST Originally aired June 10, 2015

EVENT OVERVIEW: Semi-solid formulations are in a non-equilibrium state composed of numerous possible microstructures including API polymorphs, surfactant phases, crystalline lipophiles, polymer networks and lipo- phile-surfactant gel or liquid crystalline phases. The selection of excipients in topical semisolid formulations can determine the structure of microscopic phases that form during processing. The infuence of these phases on the formulation physical properties can be observed when measuring viscosity and observing microstructure. Exemplary data will demonstrate how specifc excipients were used to modify formulation performance, correct formulations that showed aqueous Presenter: phase separation or weeping and improve stability. Norman Richardson Global Development and Key Learning Objectives: Technical Marketing Manager, n Participants will be introduced to some simple case studies Skin Delivery where the choice of excipients and their quantity had a specifc BASF infuence on semisolid product quality and performance. Moderator: n Participants will learn basic methods for observing or Rita Peters characterizing the infuence of excipients on semisolid behaviors. Editorial Director n Participants will see how BASF oleochemical-based excipients Pharmaceutical Technology and/or polymers have been employed to solve common formulation problems and to tailor formulations to meet design criteria.

Who Should Attend: Sponsored by n Dermatological and Topical Product Development Scientists

n Formulators

n Analytical Chemists who work with topical products

n Pharmaceutical Scientists Presented by n Raw Material QA and QC Specialists

For questions contact Sara Barschdorf at [email protected]

magentablackcyanyellow ES639143_PT0715_043_FP.pgs 07.06.2015 20:46 ADV Cleaning Validation

1/1000th as the dose limit and a majority used 10 ppm as the default limit. But the limits themselves are inconsistent. In some cases (for some compounds and at some facilities), these limits will leave large amounts of API residue, and in others, small amounts nearly impossible to measure. The 10 ppm default was added to account for this problem, but this value is arbitrary and some companies even have trouble meeting it. PharmTech: Do dose-based and de- Getting Scientific About fault cleaning validation limits differ- entiate between compounds, based on Cleaning Validation potential risk to the patient or operator? Walsh: The current method of limit Agnes Shanley setting is not science-based. Some manufacturers will take the lowest dose of any given API or drug, divide by a thousand, and set limits based on the results, even though they may not An ISPE guidance document, four years in the really be safe. Most of the time, however, the limits are set too low, so that making, brings risk-based thinking, statistics, cleaning validation runs fail when and Lean Six Sigma to cleaning validation. there really is no need and the residue levels present absolutely no risk to the patient. leaning is such a basic concept Pharmaceutical Technology spoke with But setting cleaning validation lim- that it may be difficult to view Walsh about the guidance, which is ex- its is a big deal. The industry has set Cscientifically, but getting it right, pected to be published in 2015. them incorrectly for years, using re- and validating the approach taken, verse logic. That’s why the ISPE pub- is critical to patient safety and drug Cleaning validation limits lication is so important, especially the quality. Some pharmaceutical manu- PharmTech: What’s wrong with the idea sections dealing with statistical analy- facturers may still approach cleaning of limits, as they’re currently defined sis. Also important are the concept of validation in a somewhat random way, and used by pharmaceutical manufac- measuring the level of risk through using imprecise and outdated methods. turers? process capability. Andrew Walsh, principal and owner Walsh: First, companies are applying Today, many manufacturers use of the PharmaClean Group, LLC and them inconsistently. Back in 1992, the an acceptable daily exposure limit of an industry professor in Stevens Insti- Pharmaceutical Manufacturers Associ- 1/1000th but that fails to take into ac- tute of Technology’s Pharmaceutical ation (now PhRMA) surveyed industry count potential product risk. As a re- Manufacturing and Engineering pro- professionals and found that they were sult, a 1/1000th limit set for low-dose gram, has been an outspoken advocate using 44 different criteria, based either aspirin is much lower than the limits of changing the status quo. He urges on dose (e.g., 1/10th of a therapeutic that have been set for some drugs with pharmaceutical industry profession- dose or 1/1000th of the lowest dose, potentially teratogenic or immuno- als to apply risk-based principles and or 1/50th of the maximum therapeu- genic effects. science, and concepts such as Lean Six tic dose), or on default limits (e.g., no The pharmaceutical industry is Sigma and Process Analytical Technol- greater than 1 ppm or 3 ppm) (2). unique in that it has an enormous ogy (PAT) to their cleaning validation Fourteen years later, the Parenteral amount of data on its compounds programs. Drug Association (PDA) surveyed its available from toxicological and clini- Walsh led the global multidisciplinary members and found the same dispar- cal studies and these can be used to set team that drafted the science, risk and ity in practice, with respondents using appropriate limits for patient exposure. statistics-based Cleaning Process De- dose-based only, or a combination of So it’s important to have a toxicologist

velopment and Validation for ISPE (1). dose-based and default. Most used and pharma manufacturing profes- 4X-IMAGE/E+/GETTY IMAGES

44 Pharmaceutical Technology July 2015 PharmTech.com

magentablackcyanyellow ES639824_PT0715_044.pgs 07.07.2015 23:07 ADV sionals work together on setting limits Lean manufacturing The key goals for Lean Six Sigma are based on real risks and plant floor re- PharmTech: What role do you see Lean eliminating waste and reducing vari- alities, and not just by simply taking a Six Sigma playing in cleaning valida- ability, and that can apply to cleaning dose and dividing it by a number. tion and cleaning? validation and cleaning, too. More Concepts from ICH Q9 and ISPE’s Walsh: Lean Six Sigma concepts are manufacturers need to ask themselves RiskMaPP guide will also be very im- very applicable to cleaning validation; such questions as ‘Why are we rinsing portant in setting science-based limits so applicable that the original name for for 15 minutes?’ I have made Value for API and detergent residue. my company was ‘Clean6Sigma’ and we even trademarked and use the term. Contin. on page 50 Working with toxicologists PharmTech: Should toxicologists be working more closely with manufacturing and quality teams at pharma companies? Walsh: At some companies, they already are, but other manufacturers are not using their expertise enough. I would like to see a closer connection between Toxicology departments and QA and validation. The Secret to Pharmaceutical toxicologists are mainly PhDs, and tend to be a tightly knit group. Many have known each other for decades. They actually all Uptime meet once a year, and have done a lot of work on how to set limits, but they tend to publish in their own special- STVM (Silent Type Venturi ized journals, which does not get the Mixer) Technology in the message out to the rest of the industry. STVM Washdown Station is Generally, toxicologists are getting the secret to maximum more closely involved in GMP issues uptime. With a single moving today, but more of them need to be part, the thermal actuator given the GMP perspective, and some within the mixing valve cartridge better understanding of how the GMP ensures long, uninterrupted world works, from people in that world. use and silent operation, even A cross-functional perspective will be in high mineral content water very important in many situations, for conditions. Rather than example, in setting limits for early dis- disassembling the entire unit covery compounds. for cleaning and service, simply remove our STVM cartridge Scientific approach to cleaning validation for quick and easy cleaning and PharmTech: Are more companies em- reinsert it into the Washdown bracing the more scientific approach Station to continue use within to cleaning validation? a matter of minutes. Walsh: I see it starting to happen. I also see a move to risk-based tools using statistics, and drawing from the FDA’s revised process validation guid- To learn more, visit www.ThermOmegaTech.com/Washdown. ance. But I also feel that many workers don’t have a strong mastery of statistics (877) 379-8258 www.ThermOmegaTech.com or a clear understanding of risk and how to measure it, and are reluctant to THE WORLD LEADER IN SELF-ACTUATED TEMPERATURE CONTROL SOLUTIONS revise their standard operating procedures (SOPs).

Pharmaceutical Technology July 2015 45

magentablackcyanyellow ES639826_PT0715_045.pgs 07.07.2015 23:06 ADV QA/QC: Operational Excellence

will concentrate on these types of systems and their respective audit trails. Two other important aspects of data integrity include the validated state of a process or a computerized system (ensuring accuracy of generated or recorded data), and the management of critical authorizations (protection of data to avoid integrity breaches during operation). When implementing measures to establish, maintain, and review data integrity across an organization, the following steps should be followed: • Awareness. It is crucial that employ- ees at all levels understand the importance of data integrity and the influence that they can have on A Risk-Based Approach the data with the authorizations assigned for their job roles. This understanding can be achieved to Data Integrity with a relatively short, simple training session across an organi- Kurt In Albon, Daniel Davis, and James L. Brooks zation. More detailed sessions are required for process, system, and data owners; this training should describe the responsibilities for data within each employee’s remit, Heightened regulatory scrutiny of data integrity as well as accountability for and consequences of accidental or in- highlights the need for comprehensive tentional integrity breaches. procedural reviews and strategies for • Standardization. The standardization step should be based on avail- managing mission-critical information. able regulatory guidance, such as the definitions (2) from the UK’s he regulatory requirement for data business information with which data Medicines & Healthcare products integrity is not new and was stated integrity issues can occur. Regulatory Agency (MHRA), to Tin 21 Code of Federal Regulations Reviewing regulatory citations ensure a common understand- (CFR), Part 11 in 1997 (1). In the area of concerning data integrity, including ing of terms and concepts. This cGMP, regulatory focus on the integrity FDA warning letters and European step should include, but not be of electronic and paper-based data has Medicines Agency statements of GMP limited to, interpretation of avail- increased sharply. Systems that formerly non-compliance, invariably leads to able government regulations and were given only superficial reviews have the conclusion that the current focus guidelines, internal procedures, started to come under intense scrutiny. of the regulator lies strongly with sys- terminology and concepts, as well Standalone raw data-generating systems tems involved in generation of quality- as levels of risk for data. and business processes, as well as inter- control data. Numerous early citations • Gap analysis. A subsequent gap faced business and production control were caused by fraudulent behavior; analysis of processes and systems, systems, present a large pool of crucial therefore, focus also has been on the with emphasis on the existing con- few tools that can detect such behavior trols for data integrity and their after the fact. The primary detection compliance with regulations, will Kurt In Albon, [email protected], is tool is a system’s capability to write a yield the basis for the next step in head of global IT quality, Daniel Davis, PhD, detailed audit trail subject to the rules the process: the determination of is a global GMP compliance specialist, and James L. Brooks is a global quality control of 21 CFR 11. Therefore, some industry the risk associated with each pro-

systems manager, all with Lonza Group Ltd. approaches to ensuring data integrity cess or system and the data gen- IMAGES/GETTY IMAGES BUENA VISTA

46 Pharmaceutical Technology July 2015 PharmTech.com

magentablackcyanyellow ES639255_PT0715_046.pgs 07.07.2015 00:28 ADV Addressing Formulation Needs With A Different Technology: Say “Hello” to Ion Exchange Resins

ON-DEMAND WEBCAST originally aired Wednesday, June 24, 2015

Event Overview: Ion exchange resins have long been in the formulator’s toolkit, but only recently has there been an increased interest in their use as excipients. Amie Gehris, technical service manager for Dow Pharma Solutions, will discuss the value and benef ts ion exchange resins bring to drug formulation challenges such as taste masking, abuse deterrence, controlled release, and more.

Key Learning Objectives: Attendees will learn about: t The chemistry and history of pharmaceutical ion exchange resins t Processing and use of ion exchange resins t Ion exchange resins drug delivery applications and case studies

Who Should Attend: t Pharmaceutical formulators t Pharmaceutical R&D scientists t R&D and formulation managers t Process and materials engineers and manufacturing experts KEDDY_PHOTO/GETTY IMAGES

Presenters: Amie Gehris Moderator: Technical Service Manager Rita Peters The Dow Chemical Company Editorial Director True L. Rogers R.Ph., Ph.D PT Technologies Leader The Dow Chemical Company

Presented by PT Sponsored by Dow

® Trademark of The Dow Chemical Company. For questions contact Sara Barschdorf at [email protected]

magentablackcyanyellow ES639196_PT0715_047_FP.pgs 07.06.2015 20:51 ADV QA/QC: Operational Excellence

Table I: Data integrity challenges in pharmaceutical manufacturing systems. System type Review type Quality control lab Manufacturing Business (data acquisition) (data acquisition) (data processing) Validated state Stable, usually easy to control Stable, usually easy to control Highly variable, frequent and maintain (no frequent and maintain (for single-product changes, numerous interfaces changes) facilities) Audit trails Limited, usually compact and Limited, usually easy to analyze Extensive, difficult to separate relatively easy to analyze (operator logs), critical data in by batch/product, difficult to batch records analyze Critical authorizations Diversified, difficult to manage Limited, easy to manage Extensive, difficult to manage (physical and logical access) centrally, frequent access by (exception: package units, skids) and control diverse people

erated or modified by it. As with tion of such rules will generate a large cal process parameters controlled and any risk assessment, thresholds number of reviews of perfectly accurate measurements recorded by a control for mitigating action should be audit trails, revealing no untoward ac- system during manufacturing, should set before assigning criticalities to tivity, and—ultimately—not generat- be established. There should be a strong the individual data elements and ing value, ensuring product quality, or relation between the criticality of test their controls. In general, any such improving patient safety. results and the frequency and depth of risk-based approach should be To perform meaningful audit trail review of associated audit trails. Audit based on accepted standards, such reviews, it is important to ask what the trails for analytical tests that do not as ICH Q9, Quality Risk Manage- review aims to accomplish. A review have bearing on CQAs do not have to ment (3). to determine whether an audit trail is be reviewed to the same degree. To sup- • Risk determination. The completed functioning correctly should be limited port this practice, a scientifically sound risk determination will provide to the initial validation phase of a com- definition of the CQAs is required prior the basis for implementation of puterized system. Typically, for the sys- to implementation of the review cycle. new required controls, in addition tems listed in Table I, audit trail func- Development of analytical methods, to existing ones. GMP-compliant tionality is a standard, off-the-shelf manufacturing, or business processes businesses often will have data feature, possibly configurable to define should include the definition of these integrity under good control. The what activities the end user wants to critical attributes. If these attributes are determined level of risk should be record in the audit trail. There is no not defined, it will be difficult to de- taken into account when deciding need to requalify the correct function cide at a later time which data integrity whether to implement technical or of an audit trail on a periodic basis. A breaches are critical in terms of patient procedural controls. proper operational qualification test safety and which are not. Once implemented, the systems, will establish valid functionality, and For a chromatography data system, controls, and data should be reviewed requalification should be limited to for example, analysts will require some periodically, at a frequency commen- system tests after major software up- flexibility to work with the data ac- surate with the determined risk, type grades. Of course, prior to implemen- quired by the system and the connected of system, and industry guidance/reg- tation, an audit trail should demon- instrument to account for changes in ulatory requirements. Table I indicates strate it is capable of recording events system performance. Extensive ma- the difficulties associated with the dif- with sufficient granularity. If this is not nipulation, however, can have the ef- ferent types of systems. possible, it will be difficult to perform fect that results—which were outside of meaningful and value-adding reviews specification during data acquisition— Audit trails of the recorded information. can later be in specification. For such According to agency warning letters, Reviewing an audit trail to establish analytical tests, critical entries in the FDA expects that reviews of audit data integrity requires prior defini- audit trail to be reviewed for high-risk trails are done as part of the release of tion of critical items to be reviewed. (release) samples must include manual each single batch. Equally, the notion For this definition to be meaningful, integration events or changes to pro- that reviews of audit trails from ana- the relationship between the audit cessing method integration events. lytical release tests should be done for trail elements and the critical qual- In another example, the completion each test is widespread. It is obvious, ity attributes (CQA) being tested by of sample well templates on microti- though, that indiscriminate applica- an analytical instrument, or the criti- ter plate readers after data acquisition

48 Pharmaceutical Technology July 2015 PharmTech.com

magentablackcyanyellow ES639252_PT0715_048.pgs 07.07.2015 00:28 ADV causes a misordering of events, which will only appear in the audit trail. Table II: Suggested review frequencies for software by risk class. Audit trail entries indicating such de- Good Automated Manufacturing Practices (GAMP 5) Software Category Risk class viations from established procedure 5 4 3 1 should be included in the review. In system audit trails or logs (as op- High 3 months 6 months 12 months 24 months posed to data audit trails), certain pat- Medium 6 months 12 months 24 months For Cause terns of activities should be reviewed. Low 24 months 36 months For cause For cause Repeated failed logins, which may indicate fraudulent break-in attempts, are a prime example. Algorithms for the lowest amount of effort to control considered critical, because activities detecting such activities that are built access security, because these systems of these users may cause incorrect data into a system should be enabled. A re- typically are physically separated from further along the management process. view of the output of such an algorithm other systems (non-networked) and, in Authorizations needed to create re- replaces the actual physical review of many cases, are only accessible using cords in the system or to initiate the the raw audit trail for these events. physical access controls (badges, keys). generation or acquisition of informa- Read/write errors to and from data Access to laboratory systems and tion need not necessarily be classed storage, which could indicate a breach processes will be highly varied, with as critical authorizations, and as such of data integrity due to hardware fail- stand-alone instruments and linked in- would not be included in the periodic ures, should also be checked. strument computers. For each instru- review (except for business reasons, Events not included in the list of ment, the requirements for data integ- such as license retirement, etc.) critical items that will not improve rity apply, whether the system complies patient safety or compliance, or add with 21 CFR Part 11 or the test results Validated state value, should be excluded from any are printed and the electronic informa- A properly validated computer sys- review by default. This action be- tion is discarded. Commonly, access tem or business process will support comes especially important for the to data and instruments is based on the maintenance of data integrity. It review of audit trails from enterprise what the drug manufacturer consid- is therefore crucial that the baseline resource planning (ERP) software ers to be critical authorizations; these validation is kept up to date to show used in the supply chain and materials permissions warrant periodic review. that all changes have been tested in management. When configured ac- As with the audit trail events, critical accordance with assigned risk criteria. cordingly, these systems can generate authorizations must be defined prior to Often, the primary aim of a review large amounts of audit-trail data with launching the review cycle to generate of the validated state of a system is to normal daily transactions. Business consistent and useful reviews. Notably, show that it still complies with regula- process steps executed automatically the review of critical authorizations tions for computerized systems, such as by the system, such as the promotion will not include analysis for fraudulent 21 CFR Part 11 or EU GMP Annex 11 of a document from one status to the access attempts, but only the status and (4). For systems subject to few or even next after an electronic signature by history of authorization levels and is- no changes, there may not be added the user to release a document for pro- sued permissions. value in reviewing this documentation duction, can generate many audit trial System administrator permissions periodically. Unless there is a degrada- entries. In a company with hundreds for all systems, regardless of the area in tion of performance of the system due of system users, this activity may result which they are used, should be reviewed to its nature or mode of action, a re- in hundreds of megabytes of audit trail periodically. System administrations view of the validated state at an appro- information to review. A restrictive fil- can act outside enforced business propriate frequency will confirm the state tering process is needed to eliminate cess and have direct access to database of control and compliance required by all non-critical events and focus the tables via management tools that may regulations. review on the critical entries. On these not include input validation or other In particular, business systems such types of business systems, a clear defi- data-integrity protection safeguards. It as large-scale ERP or document man- nition of the critical entries is the only is crucial to control these authorizations agement systems are often subject to way to perform a meaningful review in to a high degree to avoid intentional or frequent changes in configuration support of data integrity. accidental data corruption. and functionality. For these types of Super-user permissions, which may systems, a periodic review—includ- Critical authorizations be needed to change recipes on pro- ing all change control records, service As shown in Table I, data acquisition cess control systems or test methods tickets, and documentation changes— systems in manufacturing may require on laboratory systems, also should be will be extensive. Determination of the

Pharmaceutical Technology July 2015 49

magentablackcyanyellow ES639254_PT0715_049.pgs 07.07.2015 00:28 ADV QA/QC: Operational Excellence

cumulative effect of changes is also followed by subsequent corrective and may take place during transmission. difficult and not always entirely accu- preventive action. This action can in- The knowledge generated from these rate under these circumstances. It is, clude, if warranted, an increase in the data and information is directly used therefore, necessary during collection frequency of the particular review in the manufacture of drugs. Data in- of information for the review to only cycle. Table II offers guidance for re- tegrity and its practical maintenance select changes and modifications that view frequencies, based on the Good are therefore crucial to the safety of may have a potential impact on data Automated Manufacturing Prac- patients and the quality of healthcare integrity for the area of patient safety tices (GAMP 5) software categories products. By using a risk-based ap- and product quality. For a cGMP de- of a system (5) and an arbitrary scale proach and the presented principles, termination of data integrity, human of risk (high/medium/low). The scale it is possible to generate meaningful capital information, or financial data should to be determined according to reviews and proof of data integrity. integrity may not be applicable and the proximity of the system to the reg- can be excluded from review. Tickets ulated product and by the potential im- References and change requests in these areas can pact a data integrity breach would have 1. Code of Federal Regulations, Title 21, be omitted during such an assessment. on patient safety and product quality. Food and Drugs (Government Printing It has proven useful to tag change re- Office, Washington, DC), Part 11, pp. quests as GMP-relevant or business- Conclusion 13465-13466. relevant during an impact assessment The number of computerized data ac- 2. MHRA, GMP Data Integrity Definitions by the quality unit as part of the regu- quisition and processing systems in and Guidance for Industry, March 2015. 3. ICH, Q9, Quality Risk Management, step lar change control process. Such a tag the pharmaceutical industry is grow- 4 version (2005). will allow easy filtering during review ing quickly and with it the number of 4. EMA, EudraLex Volume 4 Good Man- of the validated state. The same prin- records generated that are inextrica- ufacturing Practice, Part 1, Annex 11 ciple should be applied to business bly linked with the regulated products Computerised Systems (revision January process deviations or help-desk tickets. manufactured by the industry. The 2011), 2011. For all types of reviews and for all situation is complicated by the integra- 5. ISPE GAMP 5: A Risk-Based Approach to types of systems, the actual detection of systems, interfaces between the Compliant GxP Computerized Systems, tion of a data integrity breach should systems, and conversions, calculations, International Society of Pharmaceutical cause process deviations to be raised and compression of information that Engineering, 2008. PT

Cleaning Validation — contin. from page 45

Stream Maps of cleaning processes, measurement, using their portable sys- pharmaceutical manufacturers a lot of and there is clearly a lot of wasted time tem. This way, instead of taking swab time. and water in most cleaning processes. samples to the lab, you take the lab to There is a definite need to move For example, why should a procedure the line. With their instrument, there away from the old ‘three batches’ and take an hour when it could easily be is a real promise of parametric release dose-based approach, towards continu- done in two minutes? Many companies of equipment after cleaning, and this ous monitoring where necessary. TOC, are discovering that capacity issues are is one of the goals of the ISPE guide. conductivity, and visual inspection closely tied to cleaning, so there is a PharmTech: What other analytical will help lead the way. real need to shorten cycle times, but techniques should be used to improve In addition, manufacturers should pay it can be challenging, since it requires cleaning validation? close attention to equipment design and revalidation. Walsh: High-pressure liquid chroma- invest in equipment that can be thor- tography is commonly used and also a oughly and easily cleaned. They should Process analytical technology good tool, but so is simple visual in- also be subjecting their current and new PharmTech: What role could process spection in low- to moderate-risk situa- SOPs to risk assessements, to eliminate analytical technology (PAT) play in tions. We are working with companies any problems before they can occur. cleaning validation, and cleaning in right now on a simple, cost effective general? program using standard coupons for References Walsh: PAT has a lot of potential. We qualifying operators to release equip- 1. A.Walsh, Pharm. Engineer, Vol. 31 (6), have been doing some work with GE ment visually. TOC, conductivity, (November/December, 2011). Analytical Instruments (Sievers) in and visual inspection used together in 2. A. Walsh, Pharm. Engineer, Vol. 31 (4), the area of total organic carbon (TOC) a comprehensive program could save (July/August, 2011). PT

50 Pharmaceutical Technology July 2015 PharmTech.com

magentablackcyanyellow ES639825_PT0715_050.pgs 07.07.2015 23:06 ADV Strategies to Accelerate Early Phase Clinical Trials Patient Recruitment, Biomarker Analysis, & Adaptive Design

ON-DEMAND WEBCAST Originally aired June 23, 2015

EVENT OVERVIEW: Presenters: Lengthy lead times for the development and clinical testing of new pharmaceuticals have frustrated both drug developers and Steven DeBruyn patients. New strategies and approaches can help reduce the time Medical Director Early Phase SGS Life Science Services required to get a drug to market.

Adaptive clinical trials can reduce the cost, time and number of Rabia Hidi Director Biomarkers & patients needed in a study, and help drug sponsors reach deci- Biopharmaceutical Testing sion points earlier. Patient recruitment strategies, biomarkers, and SGS Life Science Services advances in analytical testing also facilitate clinical trial activities.

In this webcast, learn about the advantages and challenges of Moderator:

adaptive trial designs. In addition, experts will address patient Rita Peters recruitment for early phase trials, the use of multiplex assays to Editorial Director analyze nine or more analytes at once, and a diagnostic instrument Pharmaceutical Technology for high volume automated analysis.

Key Learning Objectives:

n Understand the benefts and challenges of adaptive clinical trials n Review strategies to improve patient recruitment for early phase trials Sponsored by n Learn how multiplex assays can accelerate analysis of small clinical sample volumes

Who Should Attend:

n Clinical trial managers and designers n Laboratory managers Presented by n Regulatory afairs managers

For questions, contact Sara Barschdorf at [email protected]

magentablackcyanyellow ES639167_PT0715_051_FP.pgs 07.06.2015 20:46 ADV StatiStical SolutionS is Your calibration Really

a Good Straight line? IMAGES PHOTODISC/GETTY PharmTech.com/stats Chris Burgess Statistical procedures give statistical answers not analytical judgement.

inear calibration is usually considered easy, particularly for high- table i: anscombe’s Quartet data set (2). lperformance liquid chromatogra- Anscombe’s quartet phy (HPLC) methods. After all, the I II III IV procedure and the rules have been XYXYXYXY unchanged for 20 years (1). The International Conference on 10.0 8.04 10.0 9.14 10.0 7.4 6 8.0 6.58 Harmonization (ICH) requirements (1) 8.0 6.95 8.0 8.14 8.0 6.77 8.0 5.76 are simple and well known: 13.0 7.58 13.0 8.74 13.0 12.74 8.0 7.71 • “A linear relationship should be 9.0 8.81 9.0 8.77 9.0 7.11 8.0 8.84 evaluated across the range of the 11.0 8.33 11.0 9.26 11.0 7.81 8.0 8.47 analytical procedure. • “Linearity should be evaluated by 14.0 9.96 14.0 8.10 14.0 8.84 8.0 7.04 visual inspection of a plot of sig- 6.0 7.24 6.0 6.13 6.0 6.08 8.0 5.25 nals as a function of analyte con- 4.0 4.26 4.0 3.10 4.0 5.39 19.0 12.50 centration or content. 12.0 10.84 12.0 9.13 12.0 8.15 8.0 5.56 • “If there is a linear relationship, test results should be evaluated by ap- 7.0 4.82 7.0 7.26 7.0 6.42 8.0 7.91 propriate statistical methods, for ex- 5.0 5.68 5.0 4.74 5.0 5.73 8.0 6.89 ample, by calculation of a regression line by the method of least squares The ICH requirements appear to be issue two: the assumption that the bigger over a minimum of five concentra- straightforward. Simply carry out the the value of the correlation coefficient r2 is tions over the analytical range. required experiments and put the num- the better the straight line. The statement • “Data from the regression line itself bers into a statistical package or even that ‘the bigger the value of the corre- may be helpful to provide mathemati- Excel. How is one to know, however, if lation coefficient r2’ is wrong. r2 mea- cal estimates of the degree of linearity. it is a good straight line? This column sures amount of variation accounted for o The correlation coefficient discusses some of the issues, assump- by the data model, not linearity. This o The y-intercept tions, and limitations of ordinary least truth is not always recognized by ana- o The slope of the regression line squares (OLS) regression, illustrated lytical chemists or by quality assurance and residual sum of squares using an extraordinary data set. (QA) personnel who may rely on r2. o An analysis of the deviation of More than 40 years ago, Anscombe the actual data points from the issues, assumptions, and wrote a paper illustrating this issue of regression line may also be help- limitations of olS regression slavishly following calculated statisti- ful for evaluating linearity.” issue one: Proving the calibration is a good cal parameters particularly r2 (2). He straight line. One cannot prove the showed a table of four X,Y datasets Chris Burgess, PhD, calibration is a good straight line. The (table i), which when submitted to OLS is an analytical scientist problem comes from inferential statis- regression gave the same calculated at Burgess Analytical tics in that the null hypothesis is that statistical parameters within round- Consultancy Limited, ‘Rose Rae,’ The Lendings, it is a good straight line; however, one ing error (table ii). Startforth, Barnard Castle, Co can’t prove the null hypothesis. All one He then showed the plot of the four Durham, DL12 9AB, UK; can do is show that the alternative hy- data sets (Figure 1). It is readily appar- Tel: +44 1833 637 446; chris@ burgessconsultancy.com; pothesis (i.e., that it is in fact a curve) is ent that blind obedience to calculated www.burgessconsultancy.com. unlikely at a given degree of probability. parameters is not sensible.

52 Pharmaceutical Technology July 2015 PharmTech.com

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table ii: anscombe’s Quartet; some calculated statistical Figure 1: anscombe’s Quartet of ‘linear’ Regression parameters (2). data set (GraphPad Prism v6.05). Regression equation Y=0.500*X+3.00 X (I), Y(I) X (III), Y(III) mean X 9.00 14 14 mean Y 7.50 12 12

10 Sx/y 1.237 10 Correlation coefficient r2 0.666 8 8 6 6 Y VALUE Y VALUE 4 4

table iii: linearity data set with normalized response 2 2

recently posted on the Minitab network on linkedin. 0 0 0 2 4 6 8 10 12 14 16 18 20 0 2 4 6 8 10 12 14 16 18 20 % concentration Conc. mg/L Peak area Normalized X VALUE X VALUE or of target response X (II), Y(II) X (IV), Y(IY) 14 14 20% 0.004 101030 25257500 12 12 20% 0.004 100987 25246750 10 10 8 8 20% 0.004 101663 25415750 6 6 Y VALUE 30% 0.006 148937 24822833 4 Y VALUE 4 2 2 30% 0.006 150090 25015000 0 0 0 2 4 6 8 10 12 14 16 18 20 0 2 4 6 8 10 12 14 16 18 20 30% 0.006 150008 25001333 X VALUE X VALUE

50% 0.010 252579 25257900

50% 0.010 252289 25228900 Figure 2: Residuals normal probability plot from 50% 0.010 251375 25137500 anscombe’s Quartet data (Minitab 17).

80% 0.016 417534 26095875 Probability plot of residuals Normal - 95% CI 80% 0.016 416060 26003750 99

80% 0.016 417033 26064563 95 90 100% 0.020 506341 25317050 80 70 60 100% 0.020 506401 25320050 50 40 Percent 30 100% 0.020 506959 25347950 20 10 150% 0.030 762321 25410700 5

150% 0.030 761557 25385233 1 -4 -3 -2 -1 0 1 2 3 4 Residuals 150% 0.030 761701 25390033

issue three: the olS model assumes that all the error is in the Y Perhaps surprisingly, the plot of the residuals from Anscombe’s (or response) variable. Issue three is another assumption that Quartet shows only one point beyond the 95% confidence interval is not always valid or recognized. In HPLC, the response (see Figure 2). The wave-like data shape should give cause for suspi- variable (Y) is usually peak area and the X variable is con- cion, however, and prompt further investigation. centration. Are the concentrations really error free? issue five: the variance is constant over the analytical range (Ho- issue four: the model residuals are normally distributed. This assump- moscedasticity requirement). With main peak assays with large tion is often overlooked; although, ICH suggests plotting the resid- response function values over a limited analytical range, for uals. A residual is simply the difference between the observed value example 80% to 120% of target, this is a good assumption. and the value predicted by the regression model. The evaluation of Even over larger ranges, for example 20% to 150% of target, normal distribution is usually relatively small because the amount this may well be a reasonable assumption. For low concentra- of data. However, it is easy to construct a normal probability plot tions of impurities requiring calibration from the reporting using standard statistical packages, for example, Minitab 17. Ide- threshold to 120% of target, however, this is likely to be untrue,

ALL fIGURES ARE COURTESY Of THE AUTHOR. ally all the data should lie closely scattered around the center line. and alternative least squares procedures should be used (e.g.,

Pharmaceutical Technology July 2015 53

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Figure 3: olS regression plot of table iii data with 99% Figure 5: Residual plot of the mean values from the confidence contours of regression (GraphPad Prism v6.05). regression data in table iii (GraphPad Prism v6.05).

800000 10000

Y = 2.54884e+0.007*X - 618.269 9000 700000 Intercept: -618.269 ± 2101.67 8000 r2 = 0.999618 7000 600000 6000

500000 5000

4000 400000 3000 Peak area 300000 2000 Peak area residuals Peak area 1000 200000 0

-1000 100000 -2000

0 -3000 0.000 0.002 0.004 0.006 0.008 0.010 0.012 0.014 0.016 0.018 0.020 0.022 0.024 0.026 0.028 0.030 0.000 0.002 0.004 0.006 0.008 0.010 0.012 0.014 0.016 0.018 0.020 0.022 0.024 0.026 0.028 0.030 Concentration mg/mL Concentration mg/mL

Figure 4: normal probability plot of the residuals from olS Figure 6: normal probability plot of the residuals from olS plot of data from table iii (Minitab 17). plot of data from table iii excluding the data at 0.016% (Minitab 17). Normal probability plot (response is peak area) Normal probability plot (response is peak area excluding data at 0.016%) 99 99 95 90 95 90 80 70 80 60 70 50 60 40

Percent 50 30 40 Percent 20 30 20 10 5 10 5 1 -10000 -5000 0 5000 10000 1 Residuals -2000 -1000 0 1000 2000 Residuals

example weighting). It should be apparent that statistical pro- First, let’s look at the residual plot, as suggested by ICH cedures deliver statistical answers, not analytical judgement. and shown in Figure 5. Clearly there is something strange about the concentration data at 0.016%. Let us assume that Example we have evidence that there was a preparation error at this A user of the Minitab Network on LinkedIn posted the fol- concentration; therefore, we exclude it from the analysis lowing example of a linearity data set (3). The raw data are (Figure 6). Is everything okay now? shown in table iii. Triplicate standard preparations were made It appears this has solved the problem, but is there more at six concentrations covering a concentration range of 0.004 to learn? Let’s look at the revised regression data and its mgL-1 to 0.030 mgL-1 representing 20% to 150% of a target plot (Figure 7). concentration. The OLS regression plot is shown in Figure 3. Well the slope hasn’t changed a lot, and r2 has even in- It can be seen that r2 is 0.999618, and the intercept is indis- creased to almost unity. The intercept, however, has and tinguishable from zero at 95% confidence. How about that is now more negative and significantly different from zero. for a straight line? However, as the data set poster remarked, The intercept is small, approximately 0.4% of the response how are the residuals distributed (see Figure 4)? Definitely at 100% of target, but the possibility of a negative peak area not normally distributed, but why? for a positive concentration should worry chromatographers.

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Figure 7: olS regression plot of table iii data with 99% Figure 8: Sensitivity plots of table iii data including and confidence contours of regression excluding data at excluding data at 0.016% (GraphPad Prism v6.05). 0.016% (GraphPad Prism v6.05). 2.620x107 800000 2.610x107 Y = 2.54473e+0.007*X - 1980.08 2.600x107 700000 Intercept: -1980.08 ± 455.743 2.590x107 r2 = 0.999986 2.580x107 600000 2.570x107 2.560x107 500000 2.550x107 Mean = 2.537x10-7 2.540x107 400000 2.530x107

Peak area 2.520x10 300000 2.510x107 2.500x107 Response factor (area/concentration) 200000 2.490x107 2.480x107 100000 2.470x107 2.460x107 0 0.000 0.002 0.004 0.006 0.008 0.010 0.012 0.014 0.016 0.018 0.020 0.022 0.024 0.026 0.028 0.030 Concentration mg/mL 0.000 0.002 0.004 0.006 0.008 0.010 0.012 0.014 0.016 0.018 0.020 0.022 0.024 0.026 0.028 0.030 Concentration mg/mL 2.620x107 2.610x107

7 Help is at hand, because there is a useful, but little known, 2.600x10 2.590x107 simple diagnostic plot not mentioned in ICH known as a 2.580x107 Sensitivity Plot (4) . If the peak area response is divided by 2.570x107 the concentration (a normalized response), theoretically you 2.560x107 should get a constant value or, in practice, a straight line 2.550x107 parallel to the X axis with a small random scatter due to 2.540x107 7 measurement noise. The mean normalized response is the 2.530x10 Mean = 2.524x10-7 slope of the calibration line. If the sensitivity plots for the 2.520x107 7 data in table iii are produced with and without the values at 2.510x10 2.500x107 0.016%, the results are shown in Figure 8. Response factor (area/concentration) 2.490x107 The following are three important features in Figure 8 that 2.480x107 are readily apparent: 2.470x107 • The normalized responses are not linear. 2.460x107 •

Excluding the 0.016% data merely shifts the mean line 0.000 0.002 0.004 0.006 0.008 0.010 0.012 0.014 0.016 0.018 0.020 0.022 0.024 0.026 0.028 0.030 (the slope of the calibration line) slightly downwards Concentration mg/mL (approximately 0.5%). • The range of values at below 0.016% are much larger than those above suggesting the variance may not con- interesting to investigate the laboratory records of the ex- stant over the analytical range (issue five). The statisti- ample data set to try and establish root cause(s) for the ob- cal term for this is heteroscedasticity (the violation of served calibration data issues. homoscedasticity) when the size of the variance dif- fers across values of an independent variable, in this References instance, concentration. 1. ICH, Q2(R1), Validation Of Analytical Procedures: Text And Meth- odology (ICH, Oct. 27, 1994, Nov. 6, 1996, incorporated November conclusion 2005). 2. F. J. Anscome, American Statistician, 27, 17-21 (1973). Statistical procedures give statistical answers not analytical 3. Gamal M. Mohamed, data set posted on the Minitab Network judgement. The statistical tools, in this instance OLS linear on LinkedIn, Feb. 12, 2015, www.linkedin.com/grp/post/166220- regression, require sound interpretation by the analytical 5970966595894288384. practitioner, not slavish adherence to statistical significance 4. J. Ermer and P. Nethercote (Eds), Method Validation in Pharma- of parameters especially r2. Always look at the data and do ceutical Analysis, 2nd Edition), Section 5.5.1.2.1, p. 153 (Wiley- sensitivity plots. Given the findings herein, it would be most VCH, 2015). PT

Pharmaceutical Technology July 2015 55

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Ensuring Correct Tablet Count TETRA IMAGES/GETTY IMAGES

Hallie Forcinio PharmTech.com/pack Electronic counters are flexible and allow quick changeover between products.

ackaging of solid-dosage drugs gener- features include simpli- Figure 1: The next-generation SP2 tablet counter from ally occurs by counting rather than fied product flow and IMA relies on dust-immune electrostatic field sensors by weight or volume. Slat fillers re- tool-less changeover (1). P to ensure an accurate count and boost uptime. Photo is main commonplace, especially for large The Countec DMC- courtesy of IMA. batches. Demand is continuing to grow, 60T Multi-channel elec- however, for electronic counters, which tronic counter, equipped are now approaching slat-filler speeds and with a 12-track count- tend to be more flexible. ing tray and twin filling “Flexibility to handle a wide range of nozzles, is handled in the products is critical now,” reports Darren US by Key International Meister, vice-president of sales at IMA and counts up to 6000 North America (Safe Division). This need tablets per minute. The for flexibility also generates demand for DMC series of counters counters that are easier to clean and faster have programmable logic to change over. “Cleaning and changeover controllers, touchscreen are responsible for a lot of downtime right operator interfaces, and now,” explains Meister. infrared and LED optical Consistency is needed too. Pro- sensors with dust-sens- grammed settings ensure a product/count ing windows. The sen- runs the same way each time. Integrated sors detect each dose on multiple planes so IMA’s SwiftPharm 2 (SP 2) counter is a quality control is another wish-list entry. data can be analyzed from each object that second-generation, high-speed machine There is a focus on quality assurance to passes. “The machine collects data about (see Figure 1). Dust-immune electro- ensure correct count and eliminate any the wholeness of the tablet or capsule and static field sensors replace the photoeyes broken or rogue doses. checks if multiple doses are falling past at or optics used by competing systems. The the same time,” explains Jonathan Braido, electrostatic field sensors not only ensure Today’s counters marketing manager at Key International. accurate counting, but also increase up- Today’s electronic counters share several Dark-time adjustability helps detect bro- time because there’s no need to stop the attributes: flexibility, tool-less changeover, ken or double tablets. “If the Countec ma- line mid-run to clean the sensor when easy cleanability, and faster speeds. The chine identifies a broken tablet, it will trace handling extremely dusty products. In RX-12 Enhanced solid-dose counter from the dose to a bottle, then reject the bottle,” operation, the falling product disturbs BellatRx can be specified in single, twin, reports Braido. The flexible Countec unit the field. Measuring this disturbance al- or quad configurations to achieve speeds handles metal, glass, or plastic contain- lows the detection of overlapping product up to 240 bottles/min (bpm). The flexible ers up to 120 mm in diameter. Large ac- as well as the differing mass of broken system handles solid doses from 2–40 cess areas, tool-less disassembly, quick- pieces so bottles containing fragments mm and containers from 1–4 in. Other release connectors for product-contact can be rejected. In addition, an optional parts, perforated stainless-steel product dual-sensor configuration provides a Hal lie Forcinio feeding trays for dust and chip collection, redundant count. Both sensors must is Pharmaceutical and dust-collection ports expedite clean- agree each dose is correct and properly Technology’s ing and changeover. “It will usually take counted. IMA also equips its counters Packaging Forum editor, 4708 about an hour to fully clean the machine,” with machine-vision systems built by An- Morningside Drive, says Braido. Changeover to a different tares Vision. Cameras mounted over the Cleveland, OH 44109, container (same product) involves a few trays detect broken and chipped doses as tel. 216.351.5824, fax 216.351.5684, minutes to change container funnels and well as rogue product. Tool-less disassem- [email protected]. make a few tool-less adjustments. bly means one operator can remove all

56 Pharmaceutical Technology JULY 2015 PharmTech.com

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product-contact parts, clean the machine, In addition, a patented and install another set of product-contact system, which relies on Figure 2: The CFS-622*4 tablet counter, equipped with parts so the counter can run while the linear servo technology, Optel Vision’s CountSafe inspection system with auto- first set of product-contact parts is being feeds tablets out of the mated rejection system, captures any flawed dose before it cleaned. This changeover requires as little hopper. Changeover to a enters the container. Photo is courtesy of NJM Packaging. as 30 minutes. When changeover only in- new bottle (same prod- volves a different container size (product uct) takes 10–15 min. remains the same), changeover time can Cleaning in preparation drop to less than five minutes. for filling another prod- The next generation CFS-622*4 tablet uct can be accomplished counter from NJM Packaging, shown in in as little as 20–25 min, Figure 2, offers cleanability, quality con- depending on standard trol, and onboard inspection. The CFS- operating procedures. 622*4 tablet counter can be equipped Product-contact parts with a CountSafe inspection system from can be removed without Optel Vision plus an automated rejection tools, leaving a simple- system. The system features a two-axis to-clean frame. linear robot that can be adapted and To further reduce line integrated to Cremer electronic coun- clearance time, NJM ters. The tool-less ejector rejects defects: Packaging offers the TFE Figure 3: NJM Packaging’s TFE (tablet-free entrapment) wrong shape, wrong color, wrong size, (tablet-free entrapment) conveyor design minimizes line clearance time. Image is broken product, or rogue. Different alarm conveyor (see Figure 3). courtesy of NJM Packaging. levels make it possible to stop the line if a Generally installed after rogue product is detected, but simply re- the counter, it eliminates ject the fragment, if a broken solid dose is the time-consuming located. The vacuum-reject arm captures task of disassembling or any flawed solid-dose product before it removing the conveyor falls into a container and deposits it into chain between runs to a closed bin. Virtually all other inspec- check for trapped prod- tion systems reject filled containers with ucts. The TFE conveyor a flawed solid dose, resulting in consider- chain drops down for able rework or waste. A preseparator col- tablet recovery, and inte- lector and HEPA filter prevent the escape gral windows and lights of any substance or dust. help operators see any Figure 4: Monoblock machines, such as IMA’s Uniline sys- The intermittent-motion Cremer trapped tablets inside the tem, combine multiple functions on one base to enhance CFS-622*4 tablet counter consists of four conveyor. flexibility and reduce floor space requirements. Photo is modules. It relies on a feedscrew for con- Monoblock systems courtesy of IMA. tainer transport and reaches speeds up to also are available and 200 bpm. A continuous-motion model, offer a high level of flex- the Cremer CFI-622 tablet counter, can ibility. IMA’s four-in-one be configured with up to 10 modules, Uniline machine inte- handles containers with starwheels, and grates desiccant dispens- reaches speeds up to 400 bpm. ing, solid-dose counting, A servo-motor-driven mechanical cottoning, and capping vibration system eliminates the me- on a single base (see chanical springs used in other vibra- Figure 4). Changeover tory systems. The result is a stable and occurs with the push of controlled movement of the solid dose, a button. which provides the consistent action Uhlmann’s Integrated needed for a camera inspection and Bottle Center can in- efficient counting accuracy. “Proper tegrate counting and separation and delivery of the product capping with desiccant feeding, cotton- model, capable of speeds of 150 bpm, and into the container are key to having an ing, and induction sealing, plus inspec- the faster IBC 240 machine (240 bpm). accurate count,” explains Mark Laroche, tion systems such as cameras and metal The IBC 120 model handles a slightly vice-president of sales at NJM Packaging. detectors. Options include the IBC 120 broader container range with volumes

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path is removable for cleaning with soap stream equipment and communication Figure 5: The compact KL1 counter from and water or alcohol and a lint-free cloth. between machines so stop and restart Kirby Lester replaces manual counting for Another small unit designed to con- signals can be sent when problems quality control checks and is fast enough firm counts, the Countec DMC-CQ2 arise and are cleared. It’s also impor- to handle short production and low-count tablet verification counting machine tant to plan sufficient accumulation fills. Photo is courtesy of Kirby Lester. from Key International, “can replace a vi- between machines to prevent down- sual count inspection and ensure quality time for minor faults. “You don’t want of the tablets or capsules,” reports Braido. the counter to stop because it’s waiting Suitable for quality checks on the pack- for bottles, nor do you want containing line or in the lab, the counter handles ers backing up into the filler due to a tablets or capsules of any shape or size and downstream slowdown or stoppage,” counts up to 9999. An easy-to-use touch says Meister. screen with a built-in printer supports QC Finally, is onboard inspection needed? and data management. An adjustable con- “Inspection of tablets has been a number tainer platform accommodates different one wish-list item for a long time,” reports bottle heights and diameters. Laroche. However, onboard inspection can slow production speeds, and small, Selecting a counter acceptable variations have been known Selecting the best counter for an applica- to cause false rejects. tion involves many considerations. First and foremost, “Understand what you What’s next? from 30–1500 cc, diameters from 25–125 want to accomplish,” advises Laroche of New technologies will be able to count mm, and heights from 45–200 mm (2). NJM Packaging. and fill even faster and more efficiently. Romaco also supplies integrated sys- Braido notes that other questions to “Future counting machines will be easier tems with Romaco Bosspak RTC Series or be asked include: What products are to to operate, which leads to less user error VTC Series counters as the centerpiece (3). be handled (e.g., tablets or capsules)? Is and will provide better data management The RTC counters feature rotary continu- the product coated or uncoated? Dusty capabilities,” says Braido. ous-motion container filling and tool-less or not dusty? How big are the batches to Meister predicts we’ll see more coun- changeover. Positive tablet/capsule separa- be handled? How many counted tablets ters equipped with inspection systems. tion and vibration-free stream filling help and/or bottles/minute are needed for your “There’s always the push for more quality,” ensure products enter the container singly production line? he explains. and maximize count accuracy. A range of “If the machine is changing over three Laroche agrees. “Inspection is what cus- models offer one, two, four, or 12 counting times a day, an electronic counter is bet- tomers are requesting. It will take a while, stations and speeds from 15–200 bpm (4). ter suited,” says Meister of IMA Pharma. but once we start seeing integrated inspec- At the opposite end of the solid-dose “If one product runs all day, a slat counter tion systems, it will become a requirement.” counting spectrum, there are smaller might make the most sense.” units for quality control (QC) counts, “Machines also should be user-friendly References stock checks, and short runs. Kirby Les- for operating, cleaning, and changeover,” 1. BellatRx, “Rx-12 Enhanced,” www.bellatrx. ter’s latest standalone tablet counter, the says Braido. Other considerations include com/newsletter/News-06-2014.html, accessed May 5, 2015. KL1 model, features a reduced footprint, bottle sizes, cost and labor requirements, 2. Uhlmann, “Integrated Bottle Center 120,” fast counting speed, and interchange- room size, and changeover complexity and Machine Product Information, http:// able product-contact parts (see Figure 5). related downtime. Many pharmaceutical fileadmin.uhlmann.de/fileadmin/Redak- Sharp Packaging Solutions purchased manufacturers and contract packagers teure/Info_Download/Produktinfo/EN/in- tegratedbottlecenter120.pdf, accessed May seven units plus product-contact parts for specify a counter with dedicated product- 19, 2015. each product it runs to perform hourly contact parts. “They need a solution where 3. Romaco, “Romaco Tablet and Capsule QC checks on all bottling lines and small they can swap out the entire ‘pill path’ to Counting Machines—Suited for All Re- quantity bottle filling. Return on invest- eliminate any chance of cross-contami- quirements,” www.romaco.com/pharma- ment is expected within 10 months (5). nation between counting runs of different tablet-counting-solutions, accessed May 21, 2015. Patented optic sensing technology “sees” medications,” explains Mike Stotz, senior 4. Romaco, “RTC Series from Romaco doses falling past the batch sensors to marketing manager at Kirby Lester. “They Bosspak,” www.romaco.com/romaco- count up to 15 doses/sec. After complet- want to change these parts out quickly, bosspak-rtc-series, accessed May 21, 2015. ing the count, the tablets/capsules are clean them easily, and store them for spe- 5. Kirby Lester, “Pharma Packager: QC Time Reduced by 50%,” Case Study, www.kirb- emptied from the KL1’s clear tray into cific NDC [National Drug Code] batches.” ylester.com/case_study/Case_Study_Sharp_ a waiting bottle or vial. Cleaning takes Specifications also must consider Pkg_Services_PA_KL1.pdf, accessed May 8, approximately 60 seconds. The entire pill integration with upstream and down- 2015. PT

58 Pharmaceutical Technology JULY 2015 PharmTech.com

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magentablackcyanyellow ES639194_PT0715_059_FP.pgs 07.06.2015 20:51 ADV TROUBLESHOOTING Equipment and Processing Testing the DANLEAP/GETTY IMAGES Stability of Biologics PharmTech.com/Troubleshooting Ashley Roberts Biologics exhibit greater variability in stability testing than do small-molecule drugs, and maintaining a stable test environment is crucial.

number of factors can influence appearance, pH, and particle size. Of range of some freezers. While this is stability, especially with highly- these, particle-size measurements are relevant to real storage on the market, Acomplex biomolecules. The in- gaining increasing focus, but the first it can lead to a sudden change that has creased risk of instability requires test to fail is still often appearance. no reflection on the period of storage. more stringent practices to maintain Also, for frozen storage, consistency in stability throughout the shelf life of the Maintaining a stable environment thawing approaches are vital for data product. In addition to this, measures PharmTech: What are some of the chal- comparison between time points. need to be taken to minimize exposure lenges of maintaining a stable environ- to environmental factors that can affect ment throughout testing? Accelerated vs. real-time the integrity and efficacy of a product. Bradford and Wake (Intertek): The main PharmTech: What are some of the advan- Kerry Bradford, analytical projects challenge here is the need for constant tages associated with accelerated stability manager, and Ashleigh Wake, bio- monitoring. Modern stability cham- tests vs. real-time stability tests? pharmaceutical services leader, both at bers are able to maintain conditions Bradford and Wake (Intertek): Accord- Intertek; Kim Cheung, senior director within the International Conference on ing to the Arrhenius equation, samples of quality at Genzyme; and Niall Din- Harmonization tolerances with little undergo the same degradation after 32 woodie, global coordinator of analyti- input, however, excursions caused by days at 25 °C as after one year at 5 °C. cal testing, biologics testing solutions at mechanical failure need to be quickly There are obvious cost benefits to ac- Charles River, spoke with Pharmaceuti- identified in order to prevent them celerated time periods, particularly cal Technologyy about the challenges in from exceeding 24 hours. This re- to quickly eliminate poor candidates maintaining a stable environment for quires a 24/7 alarm system to monitor when at the early stages of development biologics, how to determine shelf life, all chambers and a dedicated team of of either a new drug substance, drug the effects of upstream processing tech- staff to respond to emergencies and fix product, or package. The accelerated niques on the end product, and biolog- any breakdowns. tests can also be used to submit early ics versus small-molecule drugs and the Cheung (Genzyme): The biggest chal- data to regulatory authorities; however, importance of stability testing. lenge is controlling the condition of accelerated storage data must always shipments, from stability chambers to be backed up with real-time data in Securing cGMP requirements testing locations and storage at these the long term. PharmTech: What standard methods are locations. Tracking chain of custody Cheung (Genzyme): Accelerated tests used to ensure cGMP requirements for stability samples, and maintaining can demonstrate comparability for ma- during stability testing? sufficient back-up chambers and ca- terial associated with process changes Dinwoodie (Charles River): The standard pacity ensures stability studies are not in a shorter period of time (e.g., six test methods for stability testing are, on impacted by equipment malfunction or months) than long-term real-time the whole, traditional quality control physical capacity constraints. studies. The tests can assess whether techniques for biologics. They include Dinwoodie (Charles River): Biologics a degradation profile for an attribute size exclusion; ion exchange and reversed present a number of challenges in is expected to be linear or non-linear. phase high-performace liquid chroma- ensuring a stable environment and When temperature excursions happen tography; sodium dodecyl sulfate poly- comparability of results across time during transport, there is a specific acrylamide gel electrophoresis or capil- points. The glass transition point for procedure that is followed to deter- lary electrophoresis; potency assays; and highly concentrated protein products mine whether the product can be used physicochemical measurements such as can occur within the normal operating or whether it must be discarded. The

60 Pharmaceutical Technology July 2015 PharmTech.com

magentablackcyanyellow ES639287_PT0715_060.pgs 07.07.2015 00:29 ADV Troubleshooting

accelerated data are leveraged within pathways of any biologic is key to gain- PharmTech: How does stability testing that procedure in which we’ve docu- ing a true shelf life. Achieving this un- of biologics and small-molecule drugs mented the allowable excursion tem- derstanding is definitely complicated compare? peratures and times during processing, by the structural diversity of biologics. Bradford and Wake (Intertek): Issues as- shipping, and handling, and the data Regardless, if we are working on an an- sociated with instability are potentially are used to respond to physicians’/pa- tibody, peptide, or oligonucleotide, our more significant and perhaps more tients’ questions about mishandling. general approach is the same, and in likely to be observed with biologics than Dinwoodie (Charles River): Accelerated many ways, weighted before any sam- their small-molecule counterparts. Bio- tests are commonly used to confirm ple is placed on stability. During early logics are inherently unstable, and this that the test methods being applied stage development, the material will be can manifest in many ways, but what to the product indicate stability. The stressed under extreme conditions of differentiates them the most is their ten- methods are qualified early on in a pH, temperature (60 ºC is high), light, dency toward aggregation, a phenom- stability program to ensure that the and oxidative conditions, as well as enon which is both frequently observed real-time data reflect the true stability physical forces such as prolonged agita- and yet difficult to control. Aggregation of the product. tion, orientation of storage, and freeze- can present considerable detrimental ef- PharmTech: What are some of the thaw. The potential pathways of degra- fects to the safety as well as efficacy of a challenges or disadvantages associ- dation are then evaluated using various molecule. Formulations are optimized ated with using accelerated stability analytical techniques such as circular to reduce or at least slow down the pro- tests for the determination of kinetic dichroism (for higher order), Fourier- cess of aggregation, but often, aggrega- degradation? transform infrared, nuclear magnetic tion is the predominant change to the Bradford and Wake (Intertek): While use resonance, mass spectrometry, chro- molecule observed on storage. of accelerated stability tests in conjunc- matography, and electrophoresis. Cheung (Genzyme): Both stability testing tion with Arrhenius calculations is a The use of orthogonal approaches for large-molecule and small-molecule good predictor of degradation rates is, where possible, always applied in drugs are important to ensure that a prod- for straightforward reaction kinetics, it response to the complexity of analyt- uct maintains specifications throughout does not account for physical changes ics. The final stability program is then its shelf-life. For small-molecules, criti- in the sample, or more complex systems designed based on the results observed cal quality attributes and degradation such as emulsions and suspensions. For and the potential degradation path- products may be better understood for example, elevated temperatures may ways elucidated. Stability storage is each product and shelf-life specifications promote slight solubility of a suspended then initiated accordingly, remember- for the degradation products can be set drug particle, leading to significant deg- ing that chemical/structural integrity based on toxicology studies. In my expe- radation that would not occur in the is not enough. All biologic evaluations rience, there is more lot-to-lot consistency equivalent room-temperature sample. of potency upon storage should also be for stability testing of small-molecules, Cheung (Genzyme): For biologics, deg- documented. A simple ‘box ticking’/ so interpretation of results is straight radation observed under accelerated checklist approach does not work for forward. Also, in my experience with conditions is not necessarily predictive biologics, as what works for one will biologics, stability testing encompasses of long-term conditions. not necessarily work for another. many more product attributes and the Dinwoodie (Charles River): Complex PharmTech: Do upstream processing degradation profiles may be inconsistent molecules such as biologics rarely, if techniques have an effect on the stabil- from product-to-product and/or lot-to-lot, ever, obey the Arrhenius equation. ity of end products? making understanding identified trends There are different pathways for deg- Bradford and Wake (Intertek): The short and interpreting results more difficult. radation to occur, both chemically and answer is yes. However, this is depen- Test methods may be more variable, again structurally, so no single degradation dent on the drug and the downstream making it difficult to interpret results. rate can be determined. The acceler- process. A lot of this is covered with Dinwoodie (Charles River): There is less ated conditions will also influence the assessment of the drug product as well predictability for biologics. Similar degradation observed and may lead to as substance. formulations of different proteins can steps being missed or inappropriate Cheung (Genzyme): For biologics, yes. behave in a different manner and have molecules being targeted as the indi- For example, hold times of upstream quite different shelf-lives, and the con- cation of degradation. materials can impact critical quality centration often has a greater effect than attributes and ultimately affect the it does for small-molecule drugs. The in- Stability testing and biologics stability of drug substances and drug dustry has seen many examples where PharmTech: What factors are involved in products. Therefore, stability studies process changes have led to changes in determining shelf life? are executed on all intermediate pro- the stability of products that could not Bradford and Wake (Intertek): Under- duction materials held longer than 24 have been predicted. The use of commit- standing the potential degradation hours. ted stability tests for biologics is vital. PT

Pharmaceutical Technology July 2015 61

magentablackcyan ES639293_PT0715_061.pgs 07.07.2015 00:30 ADV OUTSOURCING OUTLOOK

CDMOs Cautiously SVETA DEMIDOFF/GETTY IMAGES Address Expansion PharmTech.com/ptoutsource

Jim Miller While all market signs are pointing up, memories of past setbacks may discourage CDMOs from expanding capacity.

hese are high times for contract activity in the late 1990s, funding and nearly 60% of the increased external development and manufacturing development activity declined sharply funding flowing into early stage bio/ Torganizations (CDMOs) and con- in the early 2000s as a result of the dot- pharma companies has come from ini- tract research organizations (CROs). A com bust and some major clinical fail- tial public offerings (IPOs) and second- record flood of external financing is ures. Then just as things were recover- ary offerings by companies that are al- flowing into the bio/pharmaceutical ing in mid-decade, the global financial ready public (see Figure 1). But the rapid industry. Global bio/pharmaceutical crisis once again cut the product devel- run-up in bio/pharma stock prices has companies are outsourcing more of opment pipeline to a trickle. given rise to increased concern about their development activity, and FDA whether the “biotech bubble” is about is being especially accommodating. to pop. R&D spending is growing, and the The explosion clinical development pipeline is really of development Funding stability coming to life. PharmSource has been looking closely The explosion of development ac- activity is pushing at the funding issue, and while the pos- tivity is pushing the contract services sibility of the biopharma bubble burst- industry capacity to its limits, particu- the contract ing is a concern, a disruption in indus- larly for early development. Providers try funding activity is not likely to be of preclinical research services, such services industry as damaging today as it was in 2008. as Charles River Laboratories and This optimism is based on several key Covance, are rushing to reactivate ca- capacity to its limits. observations: pacity that was mothballed following Global bio/pharma companies in- the financial crisis. CDMOs that were New manufacturing and analyti- creasingly depend on early-stage com- fighting for survival two years ago are cal capacity can take a year or more panies to feed their own pipelines, so now telling clients there is a three- to to construct, equip, and validate, and they have a strong interest in support- six-month wait for a production slot. in that time an upset in industry or ing them. Partnered or acquired prod- macroeconomic conditions can leave ucts account for 50% or more of ap- To expand or not to expand CDMOs with a lot of unused capacity provals received by global bio/pharma Despite the strong market environ- that still has to be paid for. So it is not companies in recent years, while up- ment, the decision to expand capac- surprising that CDMO executives are front payments from partnering deals ity is not an easy one for CDMO ex- careful in committing to new capacity. with global biopharma companies pro- ecutives, who were burned twice in the Executives’ concerns are warranted vided 20% of the total funding received past decade. After a period of robust because the surge in funding that is by early-stage companies. Investment propelling demand is driven by the in partner relationships, including li- Jim Miller is president skyrocketing valuations of biopharma censing, may exceed 30% of total R&D of PharmSource companies. Valuations of publicly- spending at the global bio/pharmaceu- Information Services, traded bio/pharma companies (as mea- tical companies. Inc., and publisher of Bio/Pharmaceutical sured by the Nasdaq Biotech Index) Venture capital is not nearly as Outsourcing Report, have climbed 300% since 2010, three volatile as public financing. Venture tel. 703.383.4903, times faster than the broader stock capital funding for bio/pharma com- Twitter@JimPharmSource, [email protected], market (as measured by the S&P 500). panies stayed fairly consistent through www.pharmsource.com. Thanks to that surge in equity prices, the financial crisis and has risen only

62 Pharmaceutical Technology July 2015 PharmTech.com

magentablackcyanyellow ES639285_PT0715_062.pgs 07.07.2015 00:29 ADV Outsourcing Outlook

gradually in the past several years. Global bio/pharma licensing activity Figure 1: External financing for early-stage bio/pharmaceutical companies. will continue to provide an exit for $35.0 venture capital investors even if public equity markets shrink. $30.0 The early-stage companies have $25.0 plenty of cash. PharmSource analysis Upfront license fees indicates that 70% of the public bio- $20.0 Venture capital Secondary offering pharma companies have more than $15.0 two year’s cash on hand, assuming IPO current levels of spending. $10.0 Private equity Other $5.0

CDMOs can $- expand with the 2008 2009-12 2013/14 confidence that but the biggest challenge for CDMOs however. Tight capacity conditions demand for their will be getting enough technical and are likely to help CDMOs improve project management staff to meet the their profitability, just like they have services should growing demand. CDMOs and contract for the airlines. After years of being labs are already hiring aggressively, and beaten up on price by clients, espe- remain robust. poaching of staff, fed by rising salaries, cially the global biopharma companies, has become a big problem. This poach- CDMOs and contract labs finally find CDMOs, therefore, can expand with ing is especially true for people with the themselves with some pricing power the confidence that demand for their higher-order technical skills needed for and the ability to improve their bottom services should remain robust for the prime growth segments like advanced lines. A healthy and profitable CDMO foreseeable future. Capital for expan- formulations and analytical services for sector is in the best interest of the bio/ sion should be readily available given biopharmaceuticals. pharmaceutical industry as outsourc- market conditions and a growing will- Restrained growth of capacity may ing becomes increasingly core to its ingness on the part of bankers to lend, not be the worst thing for CDMOs, business model. PT Ad Index

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Pharmaceutical Technology July 2015 63

magentablackcyanyellow ES639298_PT0715_063.pgs 07.07.2015 00:30 ADV Pharma CaPsules

& with Office of Generic Drugs Q A allergan acquires but does not apply to Kythera for approved ANDAs already on Gerard Creaner, president at GetReskilled $2.1 Billion the market. The guidance is specific to tablets and Together with cut-e, GetReskilled has developed the Behavioral Kythera announced on June capsules and does not apply Positioning System, designed to assess the characteristics and 17, 2015 that it entered into a to other oral dosage forms. behaviors required to drive quality in pharmaceutical develop- definitive agreement to be ment and manufacturing environments. acquired by Allergan, maker of PharmTech: What made you set up the joint venture with Botox, for $2.1 billion in cash Business Confidence cut-e and develop the Behavioral Positioning System? and equity. The acquisition in Pharma and Creaner: One of the challenges [the pharma industry has] gives Allergan’s pipeline a been facing is an increasing number of quality problems with facial aesthetics boost with Biotech sectors our products. Pharmaceutical companies and the industry have the recently FDA-approved Continues been driving more cGMP training programs and emphasizing Kybella (deoxycholic acid) cGMP-compliant procedures to a greater extent than ever. Yet, injection for contouring Emerging therapeutic the results do not reflect this emphasis. We’re getting a diver- moderate to severe submental categories and a string of gence in quality rather than a convergence. This challenge led fullness, commonly known breakthrough drug approvals me to ask whether there might be another way to approach the as double chin. Allergan’s are powering key drug problem by addressing the people factor. People want to do pipeline will also be bolstered sales across the US and the right thing, but we realized they didn’t have the necessary by Kythera’s development Europe, fueling a projected quality behavioral traits (QBTs) to do it right all the time—con- product setipiprant (KYTH- 5% increase in global scientiousness, compliance, and discipline for example. If we 105), which is designed for prescription sales over the could find a way of measuring and strengthening these QBTs, male pattern baldness and next five years according to then we could get ahead of the curve and become proactive in other early-stage candidates. the “EvaluatePharma World addressing manufacturing quality issues before they happen. Preview 2015, Outlook to 2020” Behavioral scientists have broken human behavior down FDa Issues Guidance report from life-science market into categories based on behavioral traits, and developed huge intelligence firm Evaluate Ltd. databases with millions of responses, to study specific behav- on Generic Tablets The report cites FDA’s iors that impact performance. This combination of pharma- and Capsules approval of 50 drugs in 2014, ceutical science and behavioral science came together around eight of which are forecast to the same time that the industry began to grapple with drug FDA issued guidance on have sales of more than shortages and [began] discussing the need for a quality culture. June 18, 2015 regarding $1 billion five years after At this point, more professionals asked whether anything might the physical attributes of launch, as an indicator that be underpinning manufacturing and quality problems that we generic tablets and capsules. sustained R&D productivity weren’t getting at. The partnership between GetReskilled and The guidance states that, may be within reach. cut-e looks at measuring critical behavioral traits, and having although generic drugs must “Any fears that the an intervention program in place, with a view to strengthening be pharmaceutically and pharmaceutical industry them when that is needed. therapeutically equivalent How important is the idea of tracking changes might be heading towards a PharmTech: to the brand-name version, over time? slowdown after the last two the agency is concerned Creaner: That is an important part of the system. What is years of phenomenal growth that a difference in the needed is a combination of being able to assess and measure can be put to rest for now,” size and shape of a tablet critical behavioral traits and having a customized training pro- said Lisa Urquhart, Editor of or capsule might affect gram that can be delivered online in a practical manner that EP Vantage, the editorial arm patient compliance or lead works around operations department needs and the practi- to medication errors. FDA of Evaluate, in a statement. calities of manufacturing. Then you can follow pre-interven- recommends that generic- “However, for the industry tion performance by post-intervention analysis and track the drug makers consider the to sustain this impressive changes in operators’ and technicians’ performance. If we can physical attributes of a drug growth they will have to make assess and measure critical behavioral traits, such as conscien- when they develop quality compromises around global tiousness, and deliver a customized online program that can target product profiles pricing and market access. be delivered in bite-sized pieces over an extended period of for generic products. As such, pharmaceutical time, we can help drive behavioral change. Then, we measure The guidance applies companies need to either performance again at the far end. This approach can drive a to abbreviated new drug accept lower prices for its cultural change, focusing on the behavioral side of the equa- applications (ANDAs) and their products, or persuade payers tion, and on the goals and results that matter for the industry supplements for additional that the therapeutic benefits and the patient. strengths submitted to the outweigh the cost of disease.”

64 Pharmaceutical Technology July 2015 PharmTech.com

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Pharmaceutical Technology JULY 2015 65

magentablackcyanyellow ES639922_PT0715_065_CL.pgs 07.07.2015 23:54 ADV ASK THE EXPERT Compliance with US and EU Internal Audit Requirements

Siegfried Schmitt, principal consultant, PAREXEL, discusses how to handle internal audit reports during inspections.

Our internal audit procedure is due for revision. It cur- critical observation. EU inspectors are known to have Q. rently states that internal audit reports will not be made terminated inspections because of critical observations. This is available to inspectors from regulatory agencies and that the similar to FDA’s “refusal to co-operate with the inspection” in reports can be destroyed once all corrective actions have which FDA would terminate the inspection. been completed. Is this still compliant with United States and In the EU, the requirement for self-inspections extends to European Union (EU) regulations? drug substance (i.e., API) manufacturers as specified in the Delegated Act of 28.5.2014 supplementing Directive 2001/83/ Internal audits, or self-inspections as they are called in EC (5), which says, “The manufacturer shall conduct regular A.the EU, help assess a pharmaceutical company’s quality internal audits and follow-up on the findings.” system and compliance status. When a company performs While you are revising your internal audit procedure, it internal audits, it is essential to have a procedure in place, would be beneficial to check and ensure that it covers which your company does have. The US and the EU have dif- a review of the effectiveness of your governance systems ferent regulations regarding internal audit records. In short, if for data integrity and traceability (6). Updating procedures you destroy your internal reports, you would be compliant with when new legislation and guidance is issued will help ensure US regulations, but not with EU regulations. compliance (7). To further elaborate, it’s important to realize that the US To recap, you are still compliant with US regulations, but as cGMP regulations (21 Code of Federal Regulations [CFR] Parts detailed above, this is not the case for EU regulations. It is good 210 and 211) do not describe specifically a requirement to practice to design your quality system so that it complies with conduct or keep records of an internal quality assurance audit. even the most stringent regulations that apply to your business. Considering this, your procedure would be compliant. According to published FDA policy, during routine FDA inspections and References investigations conducted at any regulated company that has 1. FDA, CPG Sec. 130.300 FDA Access to Results of Quality Assur- a written quality assurance program, FDA will not review or ance Program Audits and Inspections (FDA, June 2, 2007). www. copy reports and records that result from internal audits under fda.gov/ICECI/ComplianceManuals/CompliancePolicyGuid- the written quality assurance program (1), and additionally, for anceManual/ucm073841.htm, accessed June 1, 2015. medical device manufacturers, the policy is codified at Title 2. FDA, CFR Title 21, Part 820.180 (Government Printing Office, Wash- ington, DC, revised April 1, 2014), www.accessdata.fda.gov/scripts/ 21, CFR, Section 820.180(c) (2). Consequently, you could, if you cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=820.180, accessed June 1, 2015. so wish, destroy the report once all corrections have been 3. FDA, CFRR Title 21 Part 211, www.accessdata.fda.gov/scripts/cdrh/ performed and implemented. However, you do have to retain cfdocs/cfcfr/CFRSearch.cfm?CFRPart=211, accessed June 1, 2015. the documentation on the corrective actions as these are 4. European Commission, EudraLex, The Rules Governing Me- covered in 21 CFR 211 (3). dicinal Products in the European Union, Vol. 4, EU Guidelines On the other hand, the EU GMP regulations for medicinal for Good Manufacturing Practice for Medicinal Products for products for human use have a chapter dedicated to self- Human and Veterinary Use Part 1, Chapter 9: Self Inspection, inspections (4), which specifically mention the need for an http://ec.europa.eu/health/files/eudralex/vol-4/pdfs-en/cap9_ internal audit report: “All self-inspections should be recorded. en.pdf, accessed June 1, 2015. Reports should contain all the observations made during the 5. European Commission, Commission Delegated Regulation (EU) No inspections and, where applicable, proposals for corrective 1252/2014 Of 28 May 2014, http://ec.europa.eu/health/files/eudralex/ vol-1/reg_2014_1252/reg_2014_1252_en.pdf, accessed June 1, 2015. measures. Statements on the actions subsequently taken 6. MHRA, MHRA expectation regarding self inspection and data should also be recorded.” integrity (MHRA, Dec. 16, 2013), http://webarchive.nationalar- Therefore, self-inspection reports must be prepared, chives.gov.uk/20141205150130/http://www.mhra.gov.uk/How- retained in accordance with documentation retention weregulate/Medicines/Inspectionandstandards/GoodManufac- requirements, and most importantly, be provided to the turingPractice/News/CON355490, accessed June 1, 2015. regulators when requested. In fact, refusal to provide the 7. S. Schmitt, Pharm. Tech. 39 (5) (May 2015), www.pharmtech.com/ internal audit report in an inspection can be considered a how-stay-abreast-shifting-regulations-and-remain-compliant. PT 66 Pharmaceutical Technology JULY 2015 PharmTech.com

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