Rita Peters is the former editorial director of 

Pharmaceutical Technology, Pharmaceutical Technology Europe

Rita C. Peters

	The term “fake news” has been a hot-button issue recently. By definition, “fake” news is news that is false; this content may be disseminated as “true” to influence opinion or to deceive. In the current contentious political environment, some people identify any information that runs counter to their opinions as “fake news.”

	Thanks to special-interest online publications and blogs, cable news channels, and even traditional news outlets, finding news that is “real” to you is only a click away. Your “real” news, most likely, is “fake” to those with opposing views. Facts, scientific consensus, and real-word evidence have become secondary to opinion and vested interests in the political arena. Fact-based information, however, is still the foundation for discussions and decisions in science-driven industries.

 routinely screen pitches from representatives of supplier companies about the importance and capabilities of new products or the quality of the services they offer. Experts at bio/pharma companies look to promote their capabilities or receive recognition for their achievements. We embrace our role as gatekeepers, sorting through the sometimes overtly promotional pitches to compile objective information and insight about industry trends and developments.

	We also receive article contributions from industry experts whose primary objective is to share information to help advance the science and technology of pharmaceutical development. We are grateful for their contributions.

	When the editors survey opinions in our annual readership studies, readers say they prefer articles that provide practical descriptions of technical topics, as well as peer-reviewed papers. These article formats are the foundation of our coverage. While the editors interview and work with experts for the practical, technical features, we turn to experts to provide the peer-reviewed contributions.

	While other publications offer pay-for-publish models or require authors to have their papers reviewed prior to submission, manuscripts submitted to 

 for peer review are double-blind reviewed by the publication’s editorial advisory board using procedures standard for scholarly and technical journals. The board members conducting the peer review do not know who authored the paper, and the author does not know who is reviewing their submission. Thus, this peer-review process validates the credibility of the scientific or technical work described in the paper.

 are considered: standard data-driven, novel research papers; technical case studies/application notes; topical literature or patent reviews; and science-based opinion papers.

	The review period typically takes four to six weeks. Accepted papers are scheduled for publication in 

on a first-accepted basis and usually are published four to six months following acceptance.

	All submissions must be original and cannot have been published previously in any format--including company literature or website postings. The paper cannot have been published previously in another language.

	The contributed paper must be objective and cannot promote a company’s products or services. Authors are expected to provide suitable references to published third-party literature to support all statements in submitted manuscripts.

 explains the submission process, provides links to the editorial guidelines for submissions, and contact information. The guidelines explain article rights, originality, and licensing; provide instructions for preparing an article for submission; list acceptable file types for figures, tables, and images; and include a style guide for references.

www.PharmTech.com and click the Author’s Guidelines

 link on the navigation menu. Or, you can contact me directly at 

	When referring to this article, please cite it as R. Peters, “Just the Pharma Facts, Please," 

Articles

Amid contentious debate about “fake news,” peer-review papers offer vital, objective insight.

Just the Pharma Facts, Please

 magazine, which was published in June 1977, Publisher Edward D. Aster described the new publication as “committed to serving the needs and interests of quality-assurance, quality-control, and production-management personnel engaged in the manufacture of drug and pharmaceutical preparations, clinical diagnostics, and cosmetics” (1).

         Four decades later, we are pleased to publish this special issue commemorating 40 years of technical articles, peer-review papers, news, new technology reports, and analysis for bio/pharmaceutical formulation, development, and manufacturing. 

         In the years since the initial publication, 

 has expanded its coverage to meet market dynamics, added a European edition, developed a comprehensive Internet presence through 

, and provided the insight needed to successfully bring drugs to market.

         The magazine’s success is the result of contributions from pharma industry leaders, scientists, formulators, and technical experts. We extend our thanks to the authors, advisory board members, and contributors who have shaped the editorial focus of the publication. 

          In business-to-business publishing, where the publication is supported financially through advertising, the editors strive to maintain objective coverage of developing technologies and services. We appreciate the patronage of advertisers that provided financial support for the publication while recognizing the importance of an independent source of pharmaceutical development and manufacturing information. 

           Above all, we would like to thank the loyal readers who turn to the print magazine, website, newsletters, and other PharmTech media properties for information about bio/pharma development and manufacturing.

          In this issue, the editors interview industry experts involved drug development and manufacturing processes, to reflect on industry progress and suggest areas that need improvement. 

: Washington columnist Jill Wechsler reviews significant legislation enacted in the past 40 years that changed the way drugs are developed and manufactured.

: The history of poly(lactide-glycolide) for parenteral drug formulations with extended-release properties and the need for a safe supply of the product are reviewed.

: Tablet and capsule coatings have progressed from sugar coatings to copolymers, thanks to advances in formulations and equipment (page 34). 

: Advances in automation, containment, robotics, and drug delivery devices have improved the quality and cost-effectiveness of drug manufacturing.

: The regulatory approval of the first continuous manufacturing lines for oral solid-dosage drugs is sparking interest among other drug companies and contract manufacturers.

: Single-use technology, more productive bioreactors, and improved upstream and downstream processes set the stage for flexible manufacturing.

: Representatives from instrument manufacturing companies identified advances in analytical technology that have improved accuracy, performance, characterization, and in-process monitoring.

: Drug companies continue to develop innovative packaging to promote patient adherence to prescribed drug regimens, including smartphone options (page 72).

: The history of outsourcing, as well as future prospects for the market segment, are discussed in two features.

	1. E.D. Aster, “Welcome”, Pharm. Tech., 1(1) 5 (1977).

	When referring to this article, please cite it as R. Peters and M. Tracey, “The Commitment Continues,” 

Pharmaceutical Technology marks 40 years covering the bio/pharma industry.

The Commitment Continues

 magazine was first published, the pharmaceutical industry has weathered shifts in medical, scientific, regulatory, and business practices to discover, develop, and manufacture medicines for patients globally. Genomic studies have provided insight into disease conditions. Materials research in particle sciences and nanotechnology have fostered advances in formulation and drug delivery. Biologic-based drugs have addressed previously untreated diseases. And advances in analytical technologies have enabled more comprehensive and accurate studies of cellular and chemical behavior. 

	The drug development and manufacturing process in 2017 is more technologically advanced, and has benefited from the application of scientific, risk-based approaches. Still, the industry faces challenges including shrinking internal pipelines, market-share incursions from generic drugs, regulatory inconsistencies from region to region, supply chain threats, aging equipment and facilities, drug pricing pressures, and investor demands for financial performance.

	While the bio/pharmaceutical industry has witnessed many changes during the past 40 years, some sentiments expressed in 1977 still ring true. In a guest editorial the first issue of 

 (1), George H. Hopkins, president of the Parenteral Drug Association at the time, commented that pharmaceutical scientists and companies enjoyed the respect of society at large; however, he wrote, “the times, they are a-changing. Society is beginning to challenge many institutions and agencies that were once held in awe.” 

	People have lost faith in the integrity of elected officials, he continued, “due, in a large part, to demonstrated venality on the federal, state, and local levels.” And, he noted, “the pharmaceutical industry has been accused of setting prices that yield exorbitant profits on some drug products.”

	Payer and policymaker concerns about the high cost of drug products continue today fueled by high-profile examples of price inflation by Turing Pharmaceuticals, under the leadership of Martin Shkreli, and Mylan Pharmaceuticals. The contentious debate over healthcare in the United States also centers on drug costs.

Patent expirations of blockbuster drugs have had a significant impact on the pharmaceutical companies and their approaches to research and development. As drug innovator companies lost exclusivity to high-revenue generating drugs in the early 2010s, Big Pharma adopted business alternatives such as developing drugs for unmet medical needs, adding generic-drug businesses, partnering with other companies, acquiring or licensing therapies from startup companies, or marketing their drug products in new geographic areas. 

	From 1977-2016, FDA approved, on average, 26 new molecular entities (NMEs) per year. The number of NMEs per year has trended slightly upward since 1977, with banner years for approvals in 1996 (53 approvals), 2014 (41 approvals), and 2015 (45 approvals) (2, 3). 

	In recent years, FDA’s expedited approval pathways--fast track, breakthrough, priority review, and accelerated approval--have played a major role in bringing new drugs, particularly for orphan or rare diseases, to market. Nearly three-quarters of the NMEs approved in 2016 were reviewed under one or more expedited approval pathway. Biologic-based drugs represent a growing share of the approved NMEs; small molecule drugs, however, remained the primary type of drug approved.

	In 1977, Hopkins lamented the “sometimes conflicting regulatory constraints” from a range of health and environmental agencies as “each new scientific discovery creates for society a fresh set of problems, and each new set of problems creates in turn new controls and a new bureaucracy to administer these controls.”

	On the regulatory front, legislation, supporting regulations, and guidance documents shaped manufacturing practices and business approaches. Drug license holders looking to extend their product distribution to new geographic regions faced varying regulatory requirements and approval processes from region to region. 

 Parts 210 and 211 were issued, establishing good manufacturing practices for drug products. The Orphan Drug Act of 1983 provided incentives for drug companies to develop therapies for patients with rare diseases. Generic drugs gained an abbreviated approval pathway in 1984 via the Hatch-Waxman Act. The Prescription Drug User Fee Act of 1992 funded FDA resources to reduce the time needed for drug approvals. 

	More recently, the Patient Protection and Affordable Care Act of 2009 created an abbreviated licensure pathway for biological products that are “biosimilar” or “interchangeable” with an FDA-licensed biological product; a June 2017 Supreme Court decision eased the path for biosimilar approvals. 

	The Food and Drug Administration Safety and Innovation Act of 2012 established regulations for tracking drug products through the supply chain, measures needed to prevent global prescription drug theft and diversion. Implementation dates in the US, however, were extended as the industry struggled to meet deadlines.

	The 21st Century Cures Act of 2016 provided alternatives to expedite clinical trials, encouraged patient involvement in drug development, and provided for FDA staffing to reduce a backlog of generic-drug applications. 

	Pressures to lower manufacturing costs and improve the financial bottom line enticed drug license holders to seek less costly materials and manufacturing services offshore, often with limited US regulatory oversight. In addition, some companies were deterred from investing in new equipment or facilities due to low return on investment, or concerns about a costly post-approval change process. Resulting quality issues led to ongoing drug shortages, particularly for low-cost parenteral drugs.

 survey (4) of US bio/pharma quality and manufacturing professionals, respondents said that FDA could improve drug quality by inspecting more offshore facilities, and favored the use of self-reporting and inspection waivers to facilities that meet predefined quality metrics.

	In recent years, FDA has stepped up inspections of API and drug product manufacturers and issued more warning letters to facilities in India and China. The agency also proposed proactive measures to address quality through a quality metrics program. After several years of industry study and debate, the program remained at the draft guidance stage as of June 2017.

	Nearly half of the survey respondents who reported quality-related problems attributed the issues to human error and documentation practices; nearly one-third cited manufacturing-related issues.

	During facility inspections in fiscal years 2012-2106 (5), however, FDA identified shortfalls in quality procedures and processes--a lack of written quality control procedures, lack of investigation to batch discrepancies, lack of scientifically sound laboratory controls, and a lack of written procedures for production and process controls--as the leading sources of quality issues. 

	Despite these agency findings, more than 40% of the respondents could not identify a formal quality management system used at their facility and many noted that their facilities lacked formal maintenance programs.

 promoted equipment, supplies, and materials-the predecessors of today’s technologies-including tablet coating and manufacturing systems, sterilizers, packaging components, tubing, filters and filter cartridges, freeze dryers, powder media, dissolution testing instruments, biohazard process isolation equipment, water purification systems, and particle counters.

	Product descriptions reflected the technology of the era, which may seem dangerous or antiquated, by today’s standards. Several filter manufacturers noted that their products were “asbestos-free.” A data acquisition system was touted for its ability to gather information from a “computer-directed analyzer”, store it on a tape cartridge, and automatically collate and print results. 

	In 1977, high-performance liquid chromatography (HPLC) was gaining acceptance in pharmaceutical development. Since that time, HPLC, mass spectrometry, differential scanning calorimetry, and other instruments have become more sophisticated and accurate, providing more information about small molecules and biologics. These instruments have helped drug developers meet the requirements of orthogonal testing techniques encouraged by FDA.

	The early application of computer-controlled pharmaceutical manufacturing was profiled in a February 1978 article (6) about Merck Sharp & Dohme’s $23 million ($89 million in 2017 dollars) “fully computer-controlled tableting plant” in Elkton, VA. The facility was opened to “launch America into a new era of pharmaceutical manufacturing that is as far removed from apothecarial compounding as the space shuttle is from the Pilgrims’ Mayflower.”

	The facility featured the “awesome absence of human beings.” Two employees monitored computer operations; four people, with two-way radios, monitored a continuous production operation that had 420 regulating and sensing devices. The process included an aqueous coating process, continuous granulating and blending, continuous fluidizing of coating film, and a computer system to print data for batch records.

	While this facility represented cutting edge technology in 1978, return on investment was an overriding concern. In the article, Merck Chairman and CEO John J. Horan noted that the innovation demonstrated in the plant would be threatened if public policy led to “government reimbursement at levels that do not support this kind of activity.”

	Despite this early attempt at continuous manufacturing, batch processes remained the primary manufacturing approach in the ensuing decades. To address quality issues and reduce the potential of drug shortages, FDA encouraged drug makers to embrace modern manufacturing methods. The agency’s approval of two continuous manufacturing processes in 2016--a new manufacturing process and the transition of a legacy batch manufacturing process to continuous mode--has encouraged other drug manufacturers and contract manufacturers to explore continuous processing.

	Other technology advances are discussed in the 40th anniversary section of this issue.

	In the 1977 guest editorial, Hopkins warned about legislators and scientists operating in silos and not communicating, or intentionally ignoring advice. “If we accept the fact that many of today’s problems stem from technological advances evolving at a pace faster than our present ability to assimilate them, we must also recognize that these same technological capabilities are our major resource in developing solutions to our problems,” he wrote. “The scientist cannot continue to innovate in his ivory tower, leaving the potential applications of his new discoveries to outside agencies of uncertain technical competence.”

	As technology and information channels advance at a rapid pace, and patient, payer, investor, and politically connected groups maneuver for a voice in the bio/pharma industry, the need for bio/pharmaceutical companies, industry suppliers, and regulators to innovate and communicate in concert once again rings true.

. 1 (1) 16-17.
	2. FDA, New Drugs at FDA, www.fda.gov/Drugs/DevelopmentApprovalProcess/DrugInnovation/default.htm, accessed July 2, 2017.
	3. FDA, Summary of NDA Approvals & Receipts, 1938 to the Present, www.fda.gov/aboutfda/whatwedo/history/productregulation/summaryofndaapprovalsreceipts1938tothepresent/default.htm accessed July 2, 2017.
	4. Pharmaceutical Technology, “Quality Practices: Meeting and Exceeding Regulatory Expectations,” Presentation, CPhI North America (Philadelphia, May 17, 2017).
	5. FDA, Inspection Observations, www.fda.gov/iceci/inspections/ucm250720.htm accessed July 2, 2017.
	6. J. Dickinson, 

	When referring to this article, please cite it as R. Peters, “Pharma’s Past Serves as Prologue to Its Future,” 

The more pharma science and technology change, the more business and policy concerns stay the same.

Pharma’s Past Serves as Prologue to Its Future

	With infrequent inspections by regulatory authorities--and time lapses between the identification of a violation and remedial or regulatory action--patients place trust in the self-enforcement of quality practices by API and drug manufacturers. How is the bio/pharma industry addressing quality practices?

	Based on FDA data, the number of warnings for API and drug product manufacturing nearly doubled from 2015 to 2016 (1). Typical warning letter violations included failure to validate processes, determine a root cause, implement corrective action and preventive action (CAPA) plans, establish or follow written procedures for the prevention of microbiological contamination, conduct routing environmental monitoring tests, and investigate unexplained discrepancies in batches. The agency also cited firms for the lack of quality plans, supporting data, control over data and laboratory records, and scientific evidence to support procedures.

	In fiscal year 2016, FDA issued almost 700 Form 483 observations, slightly above the average issued in the previous three years (2). The most frequently cited observations were:

		Quality control unit procedures were not written or fully followed.

		Scientifically sound laboratory controls or procedures were not employed.

		Failure to thoroughly investigate discrepancies or failures in batches.

		A lack of written procedures for production and process controls designed to assure that the drug products have the identity, strength, quality, and purity they purport or are represented to possess.

		Deficient environmental monitoring systems in aseptic processing areas.

	What happens when FDA is not watching? In an industry-wide study, the editors of 

 examined quality practices as described by experts in quality, regulatory affairs, analytics, and manufacturing and production roles at companies serving the US market. The results will be revealed in a session, Quality Practices: Meeting and Exceeding Regulatory Expectations, at the CPhI North America event (May 16-18, 2017) in Philadelphia.

	The survey examined the role of the quality control department in a bio/pharma organization and its impact on GMPs, the prevalence of quality management systems and quality-by-design programs, factors contributing to quality problems, and the company’s approach to regulatory compliance.

	Survey respondents also evaluated the performance and contributions of FDA in providing information to address quality-related problems; the usefulness of FDA regulations, guidance documents, and agency expertise; and initiatives such as quality metrics and data integrity. Respondents also commented on actions FDA can take to improve the quality of drugs manufactured for the US market.

	The study participants also commented on equipment failures, production errors, inadequate method development, and failures by the quality control team. Relationships with contract service organizations and materials and equipment suppliers--including quality agreements and supplier oversight--are also reviewed.

	The presentation is scheduled for May 17 from 2:30-3:15 pm in the exhibit hall. For more information, visit www.cphinorthamerica.com.

nspections, Compliance, Enforcement, and Criminal Investigations

	When referring to this article, please cite it as R. Peters, “Keeping an Eye on Quality," 

New study will reveal bio/pharma practices and performance on quality issues.

Keeping an Eye on Quality

	In my role as editorial director of a bio/pharmaceutical industry publication, I attend many trade shows and conferences. The largest events, sponsored by CPhI, a sister brand of 

 at UBM plc, have a long track record of gathering pharmaceutical development and manufacturing buyers and sellers in one location to hear about the latest trends, network, and conduct business.

	On May 16-18, 2017, the CPhI brand will host CPhI North America in Philadelphia, PA bringing together bio/pharma experts from the United States, Canada, and beyond. The following are some highlights.

	The CPhI North America exhibition will be home to more than 600 global companies including API and excipient suppliers, packaging and drug delivery suppliers, small- and large-molecule contract development and manufacturing organizations, as well as equipment and other contract service providers.

	In educational programming, CPhI Connect features keynote and master class sessions focused on drug development, drug manufacturing, outsourcing, and quality and regulatory issues. The sessions, led by experts from the bio/pharma industry, contract services and supplier community, and academia, present solutions for both small-molecule and biologics drug development and manufacturing for a range of dosage forms.

	Topics include: continuous API processing, accelerating product development, formulation trends for topical dosage forms, advances in solubility and bioavailability, legal and policy strategies, novel technology to improve drug R&D productivity, critical excipient properties, inhalation product development, novel container/closure technologies, bioconjugates and biotherapeutics, economies of capability vs. economies of scale, track and trace in a post-serialized world, biophysical characterization of protein therapeutics, continuous biopharmaceutical manufacturing, continuous solid dose manufacturing, biocatalysis for the synthesis of pharma compounds, pharmaceutical impurities, good supply practices, re-shoring drug ingredient manufacturing, navigating GDUFA, and quality metrics.

	In Insight Briefing sessions, attendees can listen to updates on technical and business issues. Topics include formulation techniques for controlled-release powders to create patient-friendly products; liquid stick packs for unit dosing; process safety evaluations for contract development and manufacturing API operations; worker protection in life-science laboratory and production environments; and bio/pharma business opportunities in the Middle East-North Africa region. The briefings will be held in the Insight Briefings Theater during the three days of CPhI North America; admission is free to anyone with an exhibition, conference, or exhibitor badge.

	During a briefing on May 17 at 2:30 pm the editors of 

 will release the results of a study on quality practices in drug development and manufacturing organizations serving the US market. The briefing, based on a comprehensive survey and additional research, will reveal current quality-related practices in bio/pharma organizations and contract manufacturers producing drug products for patients in the US.

	In another highlighted session, bio/pharma industry expert Jim Miller, president of PharmaSource Information Services, will share his perspective on the contract services landscape and suggest strategies for outsourcing companies looking to grow in this sector in the session The Contract Services Market: Status and Strategies. 

 will host this special session on Wednesday, May 17, from 8:30-10 am, in the conference area of the Pennsylvania Convention Center.

	For more details on the exhibition, conference, briefings, or networking opportunities at the event, see the CPhI Planning Guide in 

’s Solid Dosage and Manufacturing supplement that was mailed with this issue. You can also visit www.cphinorthamerica.com.

 will be at CPhI North America, booth 2640. See you there!

	When referring to this article, please cite it as R. Peters, “Now Arriving: CPhI North America," 

Philadelphia plays host to CPhI North America on May 16-18, 2017.

Now Arriving: CPhI North America

	During the past 20 years, the overall median total time required by FDA to approve a new molecular entity (NME) new drug application (NDA) or biologic license application (BLA) dropped from 12 months in 1996 to 7.8 months in 2016 (1). In that same time, FDA’s Center for Drug Evaluation and Research (CDER) accelerated the median total approval time to approve a standard NDA or BLA from 17.8 months to 10.1 months. The median total approval time for priority review applications was relatively steady during those 20 years; however, the 2016 time of eight months was less than half of the 20.5 months required in 1993 (2).

	While FDA has reduced approval times, a recent report by Quintiles-IMS (3) revealed other factors that may contribute to the time required to bring a drug to market. The study authors examined time trends for two segments of a drug product’s lifetime. The first segment--where those professionals involved in drug development have an impact--is the time from the patenting of a new drug molecule to the time it first reaches patients. The second segment--when the drug owner can recover its investment in the research and development of the drug product--is the time the molecule has exclusivity on the market thanks to patent or other protections.

	The study was based on 667 innovative small- and large-molecule drugs launched in the United States between 1996 and 2015. More than 300 groups filed original patents that became the basis for the 667 drugs. Large Pharma accounted for 60% of new drugs; companies classified as mid pharma and small pharma each represented 20%. Oncology, orphan, biologic-based, and specialist-driven therapies all increased market shares during the time studied.

	The filing of a patent is a business decision and can occur years in advance of, or close to, a launch date. The mean time from initial patent filing to launch for all molecules for the US market in the 20-year period was 12.8 years, the study reports, with an upper quartile of 16.3 years and lower quartile of 8.2 years.

	The shortest time from patent to launch was 128 months in 1998; the longest was 211 months in 2008 when FDA approved fewer drugs (19) than any other year during the study. While some in industry attributed the drop to a more conservative approach by FDA following the withdrawal of Vioxx from the market in 2004, FDA cited a drop in new drug applications. Since 2008, the time from patent to launch has steadily declined to an average of 158 months for the five most recent years, a drop of four years or 25%. This increase in speed brings time to approval back to levels experienced in 1996-2000.

	An analysis of drug type showed that oncology drugs, on average, launched 34 months faster than other drug types. Drugs that achieved at least $1 billion in US sales by 2015 reached the market 27 months faster than drugs with lower sales.

	The dynamic licensing, partnering, and acquisition nature of the bio/pharma industry, however, may be a greater factor in delaying the introduction of a new drug, the study suggests. Nearly three-quarters of the patented molecules were launched as drugs by a company that was different from the one that originally filed the patent. Those drugs launched by the same company that filed the original patent, however, took an average of 36 months less time to be launched than those that changed ownership, the authors reported. The transfer of a molecule from one company to another for development funding, technical expertise, or corporate strategy may ultimately get a drug to market. The path, however, may be longer than desired.

	1. J. Jenkins, CDER New Drug Review: 2016 Update, Presentation, FDA/CMS Summit, Dec. 14, 2016.
	2. FDA, 

, www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/DrugandBiologicApprovalReports/NDAandBLAApprovalReports/ucm373415.htm accessed Feb. 13, 2017.
	3. M. Aitken and M. Kleinrock, 

Lifetime Trends in Biopharmaceutical Innovation

, QuintilesIMS Institute Report (Parsippany, NJ, January 2017).

	When referring to this article, please cite it as R. Peters, “Strategizing a Shortcut to Market," 

Drug type, potential sales, and ownership factor in the race to get drugs to market.