Rita Peters is the former editorial director of 

Pharmaceutical Technology, Pharmaceutical Technology Europe

Rita C. Peters

	In announcing a new report on drug shortages, FDA noted “their [drug shortages] impact is likely underappreciated” (1). The seriousness of shortages of crucial drugs is not lost on doctors, caregivers, and patients.

	For example, the ongoing heparin shortage has caused surgeons to reconsider heart surgeries and implement emergency plans. Drugs for childhood cancers, palliative care, septic shock, anesthesia, and sedation are also experiencing shortages. In addition, ongoing shortages are not being resolved. In fact, after declining from a peak in 2011, the number of ongoing drug shortages has increased, with some shortages continuing for eight years.

	While production- and quality-related issues have previously been cited as the reasons specific drugs may experience shortages, the report had a direct assessment of the root cause: economic factors are the cause of drug shortages.

	Under the direction of Congress, FDA in July 2018 established an Agency Drug Shortages Task Force, which was charged with identifying the root causes of drug shortages and suggesting potential long-term solutions. The task force included representatives from FDA, the Centers for Medicare & Medicaid Services, and other federal agencies impacted by drug shortages.

	The resulting report “Drug Shortages: Root Causes and Potential Solutions” (2), published in October 2019, was based on FDA analysis of data on 163 drugs that went into shortage from 2013 to 2017, as well as comparisons to similar drugs that were not in short supply. The report also considered published research, comments at public meetings, and input from representatives from the public and private sectors. Not surprisingly, drugs that are relatively low in price, “financially unattractive” drugs, and sterile injectables are more likely to be in short supply.

	The task force’s report identified an unusual business pattern that does not follow “textbook” practices during a product shortage. After a typical shortage, the report said, prices go up and other suppliers are incentivized to enter the market. With drug shortages, this scenario does not occur.

	Instead, “prices rarely rose after shortages began, and during shortages, production typically did not increase enough to restore supply to pre-shortage levels. Many manufacturers reported discontinuing the production of drugs before a shortage for commercial reasons (e.g., loss of profitability),” FDA reported in a statement announcing the report. “These results suggest a broken marketplace, where scarcity of drugs in shortage or at risk for shortage does not result in the price increases predicted by basic economic principles,” the statement continued.

	Three root causes identified are a lack of incentives for manufacturers to produce less profitable drugs; no recognition for manufacturers that have mature quality systems that focus on continuous improvement and early detection of supply chain issues; and logistical and regulatory challenges make it difficult to recover from a disruption.

	The task force suggested a shared understanding of the impact of drug shortages be created, including quantifying the harms of shortages, developing a quantitative characterization of the shortage, and more transparent pricing from contract manufacturers. Development of a rating system to encourage drug manufacturers to invest in quality management maturity for their facilities, and the promotion of sustainable private sector contracts to make sure there is a reliable supply of important drugs were also suggested.  

Statement on FDA’s New Report Regarding Root Causes and Potential Solutions to Drug Shortages

Drug Shortages: Root Causes and Potential Solutions


	Vol. 43, No. 11
	November 2019
	Page: 10

	When referring to this article, please cite it as R. Peters, “Breaking the Drug Shortage Cycle," 

Articles

FDA report says drug shortages are underappreciated and patients pay a price.

Breaking the Drug Shortage Cycle

	A recent Gallup poll concluded “Americans are more than twice as likely to rate the pharmaceutical industry negatively as positively.” 

	In an August 2019 Gallup assessment of perceptions of US business industry sectors, 1525 adults ranked pharma last among 25 industries; 58% of the respondents gave a negative rating and only 27% gave pharma a positive rating. This grading-pharma’s lowest net rating ever in nearly 20 years of the survey-ranks it behind often-criticized business segments such as airlines, banks, oil and gas, the legal field, healthcare, and advertising and public relations. Even the federal government was viewed more positively than drug manufacturers (1).

	Other studies ranked pharma in a similarly negative light. In a 2018–2019 global study conducted by PatientView, only 41% of patients rated the pharma industry’s corporate reputation as “excellent” or “good,” down slightly from the previous study. Pricing appears to be a major factor in the perceptions that patients form about drug companies. Only 9% of the respondents rated pharma’s fair pricing policies as excellent or good (2).

	When looking at individual companies, reputation does not fare much better. Only four pharma companies are listed in the top 100 of the Reputation Institute’s Global RepTrak 100, which was compiled from a survey of more than 165,000 individuals. Johnson & Johnson was the highest ranked pharma company, placing at number 82 (3).

	While some executives may take the path of satisfying shareholders over patients, positive reputations can be crucial for securing investments and partnerships and sustaining innovation. Press releases, lobbying, or social responsibility mission statements can whitewash over some public perception problems. Resolving core issues-such as quality problems and drug shortages-requires investigations of the root cause of the problem and permanent fixes.

	As confidence in drug companies falters, the industry also becomes less attractive to skilled researchers, who may turn to more respected fields of science and innovation. Patients who lose faith in pharma’s ability to provide quality medicines at affordable prices may look elsewhere, turning to online or overseas pharmacies that sell products of questionable quality.

	Problems with mainstream, regulated drugs can also undermine patient trust in the pharma industry. Consider the recent discovery of nitrosamines in a third classification of drugs (4) and the suspected manipulation of product testing data used in the development of a gene therapy’s manufacturing process (5).

	Drug development and manufacturing professionals do not have the authority to influence drug pricing or other business decisions. They can, however, make a difference in the quality of drugs produced.

	A quality culture should be adopted throughout an organization, said Patrizia Cavazzoni, deputy director of operations at FDA’s Center for Drug Evaluation and Research, at the September 2019 PDA/FDA Joint Regulatory Conference. Executive management is ultimately responsible for assuring reliable manufacturing operations and high-quality standards, Cavazzoni said, noting that warning letters are directed to the top company executive to emphasis the importance of quality throughout the organization (6).

	Organizations should design quality into all systems, invest in manufacturing technologies, guard against decay in operational effectiveness, and ensure suppliers are aligned with your quality practices, she recommended.

	1. J. McCarthy, “Big Pharma Sinks to the Bottom of US Industry Rankings,” www.Gallup.com, Sept. 3, 2019.
	2. PatientView, “Corporate Reputation of Pharma in 2018-the Patient Perspective,” Press Release, April 18, 2019.
	3. Reputation Institute, 

2019 Global RepTrak: The Most Reputable Companies in the World

 (2019).
	4. FDA, “Statement Alerting Patients and Health Care Professionals of NDMA Found in Samples of Ranitidine,” Press Statement, www.fda.gov, Sept. 13, 2019.
	5. FDA, “Statement on Data Accuracy Issues with Recently Approved Gene Therapy,” Press Statement, www.fda.gov, Aug. 6, 2019.
	6. P. Cavazzoni, “Advancing Drug Innovation Through Investment in Quality,” Presentation at the 2019 PDA/FDA Joint Regulatory Conference (Washington, DC, Sept. 16, 2019).


	Vol. 43, No. 10
	October 2019
	Page: 10

	When referring to this article, please cite it as R. Peters, “Image Repair Must Get to the Root Cause," 

Climbing out of a reputation hole starts with adopting a quality culture.

Image Repair Must Get to the Root Cause

While patients generally trust that the drugs they take are safe, product recalls, drug shortages, reports of potential contaminants, and publicized regulatory enforcement actions can shake public confidence in the drug supply. While FDA looks to encourage voluntary compliance over the “stick” approach of tighter enforcement, bio/pharma companies are encouraged to build a quality culture throughout the organization, starting with top executives at the company.

, September 2019
	September 2019
	Pages: 4–5

	When referring to this article, please cite it as R. Peters, “Quality Culture Drives Patient Confidence in Drug Products," 

Pharmaceutical Technology Regulatory Sourcebook

While overall industry performance is trending positive, quality failures continue to negatively impact patients and the bio/pharma industry.

Quality Culture Drives Patient Confidence in Drug Products

	September-the traditional back-to-school time-has arrived, and the annual holiday shopping season is sure to follow quickly. Personally, I don’t like rushing the holidays and shop at the last minute. The publishing profession, however, forces me to plan and work well ahead of the calendar.

	While we have yet to enter the last quarter of 2019, the editorial team is looking ahead to 2020, planning topics, special issues, and features that 

 will cover next year. It is also prime time to remind readers of the opportunities to share knowledge about bioprocessing by contributing a technical article or peer-review paper to the publication.

	Through peer-reviewed papers, technical articles, technology reports, regulatory and business columns, and expert commentary, Pharmaceutical Technology publishes objective information related to process development, formulation, manufacturing, analytics, drug delivery, packaging, and distribution topics in print magazines, digital publications, ebooks, and online at 

’s coverage of scientific and technical advances in biopharmaceutical development and manufacturing. Four types of peer-review papers are considered: standard data-driven, novel research; topical literature or patent review; technical case studies/technical application notes; and science-based opinion papers. Manuscripts for peer-review papers are accepted and reviewed on an ongoing basis; papers are published in the order in which they are accepted by the editorial advisory board. The review, revision, and acceptance process takes 6–8 weeks.

	Pharmaceutical Technology editors also welcome technical articles that are not peer-reivewed from experts at bio/pharmaceutical companies, regulatory authorities, industry suppliers, and consultants. The magazine’s editorial calendar lists the topics scheduled for the monthly print issues, supplements, ebooks, or online at 

. All submissions are reviewed and edited by the editorial team; final publication is determined by the editors.

	Ideas for contributions should be discussed with the editors in advance, preferably four months prior to the publication date. The editors will review an abstract (250 words) describing the article focus and other details. If the topic is suitable, a word count-typically 1800–2000 words-and deadline are assigned. Final articles, figures, and signed license agreements are due approximately two months prior to publication.

	The article/paper must be objective and cannot promote a company or its products; it must be original and submitted to Pharmaceutical Technology on an exclusive basis. The article/paper cannot have been published previously in any format, including a company website or marketing literature. Manuscripts should not be under consideration for publication elsewhere, including on the Internet. All authors must sign a license agreement that provides 

 permission to publish the original article and its associated figures/tables in print and online.

	The editors also interview industry experts from biopharma companies, contract service providers, industry suppliers, regulatory authorities, and consulting groups for technical articles on drug development and manufacturing topics. And, similar to contributed articles, responses to questions must be objective and non-promotional. To be considered for an interview, consult the editorial calendar for scheduled topics and contact the editors approximately four months prior to the publication date.

’s 2020 editorial calendar, which lists topics scheduled for publication next year, is available on the Submission Guidelines page on 

. In addition, prospective contributors can find more information about the submission process, link to sample articles, and use an online form to submit an article idea to the editors.

	When referring to this article, please cite it as R. Peters, “Plan Now to Share Your Expertise in 2020," 

The editors welcome technical article contributions from the bio/pharma industry.

Plan Now to Share Your Expertise in 2020

	The summer of 1969 was a watershed moment for science when, on July 20, man first walked on the Moon. The story of the Apollo 11 flight is well-known. Astronaut Neil Armstrong’s words as he stepped on to the surface, “That’s one small step for man, one giant leap for mankind,” resounded around the world and became one of the most recognized quotes of a generation.

	I observed the Moon landing as a child and can confirm: a man walking on the Moon was a very big deal. My parents let me stay up past bedtime to watch the flickering images on the television. We were amazed at what was transpiring on this other world.

	The technology used for the trip to the Moon pales in comparison to current materials, instruments, computing, and communication capabilities. The computing power in the Apollo 11 ship was less than that of an average cell phone today. The astronauts appeared ghostlike as they moved about the Moon; technology limits prevented transmission of higher resolution images.

	In his 1962 “We choose to go to the Moon” speech at Rice University in Houston, President John F. Kennedy talked about the need for the nation to accelerate space exploration efforts (1). At the time, the United States was racing to catch up in a space race with the Soviet Union.

	On July 20, 1969, the US crossed the Moon’s finish line first. On subsequent missions to the Moon, astronauts stayed longer and conducted more sophisticated experiments. But public interest lagged; going the Moon was no longer an achievement. Later manned missions to the International Space Station (ISS), and unmanned missions to other corners of the universe, generated valuable information but did not reach the prominence of Apollo 11. As the novelty of space exploration wore off, funding dried up. In recent years, the private sector has entered the race for the commercialization of space.

	Space exploration, however, generated scientific benefits and practical applications beyond the spectacle of the Moon walks. A less-publicized statement in Kennedy’s 1962 speech described the prospects: “The growth of our science and education will be enriched by new knowledge of our universe and environment, by new techniques of learning and mapping and observation, by new tools and computers for industry, medicine, the home as well as the school,” he said.

	The ISS, an orbiting laboratory 248 miles above Earth, functions as “an unparalleled opportunity to investigate how gravity and the extreme environment of space influence observations in the physical and life sciences-exploiting these effects to understand basic phenomena and advance commercial pursuits” (2).

	The ISS website describes how studies of the effects of spaceflight on living organisms will enable scientists to learn more about biology, medicine, and biotechnology, and, in turn, advance pharmaceutical development. The laboratory also has unique features not found on Earth. Microgravity causes changes in gene expression, DNA regulation, cellular function and physiology, and 3D aggregation of cells. It also affects fluid dynamics, allowing improved growth of protein crystals and optimization of nanofluidics systems (3). Implementation partners serve as payload developers, preparing research studies for deployment in space.

	Life-sciences experiments conducted on the ISS include protein crystallization studies to improve drug design; cell culture experiments to study osteoporosis and immunodeficiency; stem cell experiments for cardiovascular disease; fluid dynamics studies for diagnostics and drug delivery systems; and model-organism research to explore potential repurposing of existing drugs for other uses.

	The journey to the Moon demonstrated man’s capabilities to innovate and explore. The ongoing benefits of an orbiting research lab are a testimony to that legacy.

John F. Kennedy Moon Speech–- Rice Stadium

Life Sciences Research Onboard the ISS National Lab

	When referring to this article, please cite it as R. Peters, “The Moon, the Stars, and the Science Lab," 

Fifty years after the man walked on the Moon, space-based science is benefiting Earth.

The Moon, the Stars, and the Science Lab

Guiding an innovator drug through development, clinical trials, regulatory approval and, ultimately, to market is a delicate balancing act. For small, innovator bio/pharma companies, the focus frequently is on the clinical trial pathway, with limited time, resources, and expertise available to address the crucial elements of process development.

	A new drug’s progress-and external funding-is often measured by the completion of clinical trial milestones. While these trials are evaluating the safety and efficacy of the drug, however, formulation and manufacturing processes must be developed, as well as analytical methods to characterize the drug and test its stability, potency, and other properties.

	And, complex information about the drug, its properties, safety, test methods, and manufacturability must be documented for regulatory filings as described in the chemistry, manufacturing, and controls (CMC) section of the 

) for an investigational new drug application (IND) (1).

	Sponsors of innovative therapies need to plan for manufacturing processes with the same forethought they give to clinical studies, determine how much product is needed at launch, how the product will be supplied, and how to validate production processes, said Steven Kozolowski, director of FDA’s Office of Biotechnology Products at a 2016 WCBP symposium (2).

	While mid- to large-pharma companies typically have a regulatory affairs team to address CMC requirements, small companies may delegate these tasks to one or a few individuals who also juggle other responsibilities for the company. Securing the technical, scientific, and regulatory expertise to complete CMC steps while deciding the most cost-effective use of limited resources, can test the capabilities of these innovator companies.

	To keep all balls in the air at once, small bio/pharma companies frequently seek external assistance from a range of service providers, from individual consultants and consulting firms that provide CMC advice and strategy development, to contract research and development firms that not only develop CMC programs but also execute the testing, formulation, process development, and manufacturing steps.

	Technology innovations for analysis, modeling, and formulation development may be cost-prohibitive for most small companies. Due to the complexity of drug molecules, small bio/pharma companies often rely on multiple contract service providers to perform varied product development and analysis steps. In recent years, large contract service providers have acquired smaller outsourcing firms with specialized technology capabilities to offer a “one-stop-shop” for a range of formulation and manufacturing services.

	While contracting with an external service provider for vital development tasks can be a viable option, the drug sponsor needs to monitor and manage the contractor and ensure protection for the intellectual property associated with the molecule and its development. The challenge for small companies is to know what expertise is needed at various stages of the drug development and regulatory filing process, and how to best budget valuable resources for external support.

	FDA’s accelerated review process has complicated CMC efforts; the shorter timelines for clinical review give drug companies less time to develop and validate manufacturing processes compared with traditional review timelines.

	Drugs receiving a breakthrough therapy designation may face a number of CMC-related challenges including reduced real-time stability for commercial material; unavailable commercial manufacturing facilities, necessitating the launch of drug with initial commercial supplies from a clinical trial manufacturing facility; and limited data sets for specification acceptance criteria (3).

	With insufficient time to complete the traditional CMC studies, breakthrough programs should prioritize resources using a risk-based approach to gather the information needed to support a new drug application filing. The sponsor should expect additional post-approval activity will be needed including additional stability data and process robustness studies; in addition, changes in formulation, manufacturing, and raw material suppliers may be required (3).

	FDA representatives have said the agency is trying to be more flexible in accepting for accelerated review applications with less complete data on product specifications, process validation, and stability to expedite the approval process (2).

	The CMC process, as outlined by FDA regulations, is to ensure the drug is manufactured safely and consistently from testing through commercialization and the post-approval lifecycle of the drug. While the primary function of a CMC strategy is to meet obligations for regulatory filings, the process of developing an effective CMC program can offer immediate and long-term benefits including lower development costs and avoiding unnecessary delays.

	Much has been written-in FDA and ICH guidance documents, presentations, articles, and books-about best practices for CMC programs. Because each novel drug has unique characteristics, dosage forms, patient groups, and other factors, a one-size-fits all approach to CMC development may not be an effective approach. Tailoring a program for a specific therapy starts with understanding the drug and its characteristics.

	By establishing and documenting a quality target product profile, critical quality attributes, and critical process parameters in early development phases, companies can develop a strong understanding of process requirements and change control for the lifecycle of the product. And, for companies looking for development partners or seeking to sell an early-stage molecule, an effective CMC program can make the drug more attractive to potential suitors.

	Defining manufacturing needs early in the development process presents risk and challenges. FDA has noted that shortfalls in the manufacturing segment of CMC information can be a stumbling block for some applications; in recent years, FDA has reported an increase in complete response letters due to CMC deficiencies, delaying drug approvals (4).

	Typical CMC failures include not auditing suppliers or setting up quality agreements; not characterizing raw materials or finding alternate suppliers; not identifying critical process parameters or a quality target profile; not developing and validating proper assays for stability, potency, and other factors; and not using quality risk management (5). In addition, vendor-related non-compliance problems can upset a drug sponsor’s carefully defined CMC plans (

	FDA defines the requirements for CMC filings in 21 

 312. The regulation specifies that the CMC section of an IND should describe the composition, manufacture, and control of the drug substance and the drug product. Uncertainty about how much information needs to be filed with FDA, and when it needs to be submitted, can lead to confusion, delays in the development and the clinical trial approval process, and cost overruns.

	Strategizing a phase-appropriate approach is crucial to filing of too little or too much information, too early or too late in the process. Regulations and FDA guidance documents promote this staged approach. The regulation reads: “Although in each phase of the investigation sufficient information is required to be submitted to assure the proper identification, quality, purity, and strength of the investigational drug, the amount of information needed to make that assurance will vary with the phase of the investigation, the proposed duration of the investigation, the dosage form, and the amount of information otherwise available” (1).

	Recognizing that the drug substance, dosage form, and preparation methods will likely change as a drug moves through development, FDA notes that a Phase I submission should focus on the identification and control of raw materials and the new drug substance. As the drug progresses from pilot-stage to clinical trial manufacturing, the sponsor should amend the initial information on the chemistry, manufacturing, and control processes with additional information that is appropriate to the scope of the investigation. Final specifications for the drug substance and drug product are not expected until the end of the investigational process.

	The required information about a drug substance and drug product is listed in 21 CFR 312.23 and includes a description of the physical, chemical, or biological characteristics of the drug substance; the components of the drug product, including alternatives for inactive compounds and components used in the manufacturing process; a general description of the manufacturing procedure, acceptable limits and analytical methods used to assure the identity, strength, quality, and purity of the drug substance and product; drug stability information; and the name and address of the manufacturer.

	FDA’s website lists 70 guidance documents in the Pharmaceutical Quality/CMC category, the earliest from 1989. These guidance documents state FDA’s thinking on requirements for different clinical phases, different drug types, analytical testing, and post-approval changes (6). FDA also recommends agency-sponsor meetings to discuss CMC-related questions in advance of IND filings. 

	In addition to the complexities inherent in new therapies, inconsistencies in the CMC requirements of different global regulatory authorities further complicate the development and approvals of novel therapies, according to a recent review article.

	“There is a desperate need for a consistent form of regulation where global approaches to regulatory strategies can be harmonized, and specific CMC challenges can be dealt with using the appropriate science and risk-based tools,” the authors wrote (7).

	The proposed International Conference for Harmonization Q12 guideline (8), which provides guidance on the management of post-approval CMC changes, is one global effort; however, inconsistencies still remain for approval stages.

, Title 21, Food and Drugs, Part 312 (Government Printing Office, Washington, DC).
	2. J. Wechsler, “

Improving CMC Review for Breakthrough Therapies

, 35 (1) 1-11 (January/February 2015).
	4. C. Challener, 

, 41 (1) 26–29 (January 2017).
	5. A. Shanley, 

, 42 (11) 20–23, 56 (November 2018).
	6. FDA, 

, accessed July 29, 2019.
	7. N.S. Cauchon, et. al., 

, 108(7), 2207-2237 (July 2019).
	8. ICH, Q12 

Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management

Vol. 43, No. 8
	August 2019
	Pages: 16–19

	When referring to this article, please cite it as R. Peters, “Balancing CMC Priorities," 

A risk-based approach to CMC enables drug sponsors to focus on clinical and manufacturing development paths.