Rita Peters is the former editorial director of 

Pharmaceutical Technology, Pharmaceutical Technology Europe

Rita C. Peters

	Legendary basketball coach John Wooden advised his players to “be quick, but don’t hurry” to improve their performance on the court. This is sound advice for the bio/pharma industry, also.

 marks 30 years of publishing information about scientific, technical, and business advances in biologic-based drug development as science pushes technologies into unexplored areas.

	In covering the industry, the editors carefully balanced optimism-or, in some cases, hype-about promising therapies with the reality of challenges that drug developers face. Every day, we receive press releases extolling the potential of a drug in development. These pitches are part of a process to gain attention for the company or therapy, secure investments, or build partnerships. Sometimes, however, these messages build false hope for patients waiting for needed therapies.

	For a patient afflicted with a debilitating or terminal disease, a lengthy drug development and approval process can be frustrating-or a death sentence. They seek hope from any possible treatment. The ability of drug companies to serve these patients is tempered by their scientific knowledge, legal and regulatory restrictions, and limited financial support for ongoing research and development. It is a tricky balance that the industry needs to communicate honestly to patients.

, enacted in May 2018, gives terminally ill patients access to therapies that have passed Phase 1 safety trials, but have not been approved by FDA. The legislation has been criticized as being duplicative of similar laws in individual states, potentially causing unknown harm, conflicting with scientific goals of clinical trials, and undermining the regulatory authority of FDA.

	At the same time, FDA faces criticism that it is approving drugs too quickly. A recent article (1) argued that while FDA is approving more drugs and at a faster pace, the expedited approach involves more risk for patients because approvals are based on limited information about safety or effectiveness from shorter clinical trials, not survival rates or cures.

	At its 2018 annual meeting in Boston on June 5–7, 2018, the Biotechnology Innovation Organization (BIO), also celebrated an anniversary, marking 25 years of promoting the evolution of the biotech and biopharmaceutical industries. At the event, speakers recalled milestones in the industry’s development, including ethical questions raised by scientific efforts such as animal cloning or stem cell research and biotech-fiction fears driven by the movie Jurassic Park.

	During a session, Jim Greenwood, BIO president and CEO, recounted his negative reaction when a fertility doctor said in a 2001 television interview that he could-and planned to- clone a human being. Greenwood, then a US Congressman from Pennsylvania, said he called for a hearing with the goal to outlaw human cloning. A visit from BIO CEO Carl Feldbaum, who explained the potential of therapeutic cloning, converted Greenwood into a proponent for biologics industry development, leading to his appointment as head of the organization a few years later.

	The past 30 years has seen the biopharma industry witness the emergence of protein-based therapeutics. The next chapter in the biopharma story-cell and gene therapies-brings a new theme, that of providing a cure for disease and conditions. The “cure” word was used multiple times in discussions at the BIO event, presenting a new set of science, business, technical, and ethical challenges for the industry in the years ahead.

	In addition to being quick, biopharma companies and the regulatory industry also need to be smart, be honest, and keep patients at the forefront of all of their activities, not just their press releases.

FDA Repays Industry by Rushing Risky Drugs to Market

	When referring to this article, please cite it as R. Peters, “Be Quick, But Don’t Hurry" 

Articles

After 30 years of biologic-drug advances, the industry and patients still have a lot to learn.

Be Quick, But Don’t Hurry

	Graduation ceremonies fill the calendar during this time of year as students mark their promotion from one level of schooling to another, or from academic life to the business world. The familiar rhyme “no more pencils, no more books …” rings across schoolyards and college campuses as students mark the end of formal learning.

	Don’t toss away those books too quickly, however. While ‘commencement’ ceremonies celebrate the achievements of graduates, another meaning of the word denotes a beginning or start. Countless graduation speakers have reminded graduates that one must never stop learning, a subtler way of saying “you don’t know everything” and “you will forget what you have learned if you do not put the knowledge into practice.”

	These messages also have meaning for experienced bio/pharmaceutical development and manufacturing employees and companies. Evonne Brennan, international technical marketing manager, IMCD Ireland, urged the audience to “mind the gap” in their knowledge base during a presentation, “Bridging the Knowledge Gap in Formulation and Processing,” at ExcipientFest 2018 in San Juan, Puerto Rico in May 2018. Brennan cited examples of failures in drug formulation and development due to a lack of knowledge or expertise by members of the development team. She also noted how a lack of communication between formulators and equipment manufacturers can lead to development delays.

	Knowledge gaps form in several ways. When experienced chemists, formulators, and other development, manufacturing, or quality personnel leave a company or the industry, they take their knowledge with them. And, when companies are resistant to change-due to financial constraints or regulatory concerns-a gap in technology or scientific expertise can grow.

	In some cases, information to resolve a potential drug development problem may exist within an organization; however, it resides in data silos, inaccessible to the experts who can interpret the data into knowledge. In other cases, industry players are hesitant to share knowledge due to competitive concerns.

	Emerging technologies, such as continuous manufacturing and 3D printing, demand new ways to address formulation and manufacturing. Gaps in know-how for material handling, properties, and behaviors, as well as process analytics can slow adoption of these technologies.

	Industry publications, conferences, reference books, compendial organizations, and academia are valuable information sources for ongoing career knowledge development. Despite improvements in communication channels such as the Internet, however, it is more difficult to get industry experts to share technical expertise on core pharma development topics. Bio/pharma companies and contract service organizations are sharing less in the trade press, citing confidentiality concerns.

	At several recent industry events, I listened to several experts from different segments of the bio/pharma spectrum-APIs, medicinal chemists, formulators, regulators, process developers, equipment manufacturers, and more-engage in verbal finger pointing, arguing that the other industry players were the roadblocks to progress in drug development. Others argued that the industry needs to work together on these issues.

	Christopher Welch, a principal with Welch Innovation, shared two examples of cross-pharma collaborations during a presentation at CPhI North America in Philadelphia in April 2018. The Enabling Technologies Consortium, a collaboration of pharmaceutical and biotechnology companies, works on a pre-competitive basis to identify, develop, and improve scientific tools and techniques to support drug development and manufacturing. Projects include an automated solubility platform, a probe for drying processes, and particle measurement. Welch also is involved in a new venture, the Indiana Consortium for the Analytical Sciences, scheduled to launch in 2019.

	These collaborations are bridging the knowledge gaps and promoting the route to ongoing learning essential to industry advancement.

	When referring to this article, please cite it as R. Peters, “Let the Learning Commence" 

By minding knowledge gaps, bio/pharma companies can avoid development pitfalls.

Let the Learning Commence

	Trade shows are a good opportunity to assess where an industry stands on new technologies, ongoing challenges, and future opportunities. It also is a good time to assess attitudes about prospects for the road ahead. As I write this, I am half way through three consecutive weeks of industry events, each with a unique market focus, revealing the potential of biopharma to address patient needs and the work that must be done to achieve that goal.

	Continuous manufacturing, which has gained momentum for small-molecule drugs with FDA approval of several therapies, was a popular discussion topic at INTERPHEX in New York, NY in mid-April. The strong interest is an indication that the pharma industry may be looking to consider advanced technologies that are common in other industries. In the biologics arena, the move to continuous manufacturing will be more difficult; experts on a panel hosted by Pharmaceutical Technology magazine noted that while some segments of a bioprocess may have continuous operations, an end-to-end continuous process will be difficult to achieve.

	At CPhI North America in Philadelphia, PA, medical futurist Bertalan Mesko shared his vision of bringing science fiction to medical reality through the use of digital technologies and data management and identified actions that must be taken today to get the most out of future technologies. Smartphone-based monitoring, drone delivery of medications to remote regions, use of blockchain for data security of drug products, and Internet-based monitoring of patient medical conditions in their homes are a few advances he identified.

	In another keynote address at CPhI North America, Nik Leist, senior director of ingestible sensor manufacturing and site leader at Proteus Digital Health, demonstrated how some digital technologies are currently available for monitoring patient adherence. In November 2017, Proteus and Otsuka Pharmaceutical Co. received FDA approval for the first digital medicine system, a drug-device combination product comprised of Otsuka’s oral aripiprazole tablets embedded with an ingestible event marker (IEM) sensor. Leist explained how the sensor, the size of a grain of sand, can be incorporated into a conventional drug tablet production system with some modifications. Regulatory approval could pave the way for other sensor-based applications.

	Mesko noted, however, that the lack of doctors, money, and patient trust in medicine can hinder the acceptance of innovation for medical applications. New digital technologies will generate vast amounts of data that must be managed by artificial intelligence (AI), he said, but fear of the power of AI is a hurdle that must be overcome.

	The cost of new technologies may be high, creating a divide between those that can afford it and those that cannot, Mesko warned, and including the patient in the design of the medical advances-by asking them what they want-is crucial.

	Mesko also noted that technology is only part of the solution; people are needed to implement this vision. The lack of a trained, qualified workforce to operate bioprocessing facilities spurred a partnership between Philadelphia-based Thomas Jefferson University and the National Institute for Bioprocessing Research and Training (NIBRT) of Dublin, Ireland to establish the Jefferson Institute for Bioprocessing, the first education and training institute for biopharmaceutical processing in North America. The partnership was announced in February 2018; further details were provided during the CPhI North America event by Mary Lynne Bercik, founder and CEO, GenZinnovation, and Ronald G. Kander, Dean, Kanbar College of Design, Engineering & Commerce Associate Provost for Applied Research at Jefferson.

	When operational in 2019, the Jefferson Institute for Bioprocessing is expected to serve 2500 people annually, including an academic program for bioprocessing engineering from undergraduate through doctorate levels, industry training, workforce training through community college partnerships, and bioprocessing certifications through regional university partnerships.

	When referring to this article, please cite it as R. Peters, " Key Ingredients to Healthcare’s Future" 

A skilled workforce is needed to deliver on technology’s promising medical advances. 

Key Ingredients to Healthcare’s Future

	In the past few years, therapies for orphan and rare diseases have been approved by FDA in increasing numbers. Personalized therapies made their mark in 2017 with three approvals of individualized patient treatments. In addition, several big-name blockbuster drugs are scheduled to go off patent in the next few years. Is the bio/pharma industry prepared to address the internal and external factors that will influence the types of drugs that are developed and how patients pay for these therapies?

 report (1), Clarivate Analytics predicted a record number of blockbuster drugs would reach the market in 2018. The report forecasted 12 new drugs would achieve annual sales of $1 billion or more by 2022, up from a predicted eight blockbusters in 2017, and the most since the report was first issued in 2013. Three drugs-Hemlibra (Roche/Chugai), Biktarvy (Gilead), and Ozempic (Novo Nordisk)-are expected to exceed $3 billion in annual sales by 2022.

	The prospective blockbusters are both large- and small-molecule drugs-including the first cannabidiol-based medicine for the US market-and treat a range of diseases including diabetes, endometriosis, epilepsy, HIV, hemophilia, migraine, opioid addiction, and shingles. Only one anticipated blockbuster is for cancer; in the 2017 projections, more than half of the anticipated blockbusters were for cancer treatment.

	Through the first 11 weeks of 2018, FDA approved six new novel drugs, including two on Clarivate’s blockbuster list (Biktarvy and Johnson & Johnson’s Erleada). This overall drug approval rate is similar to the number approved in the first quarter of 2017 when a record-breaking 46 novel therapies were approved (2).

	If the trends of recent years continue, however, a significant percentage of new drug approvals will address orphan or rare diseases, with small patient populations, and therefore smaller sales volume. A report from the IQVIA Institute (3) suggests that bio/pharma faces several “turning points” that may force companies to adjust to evolving business, regulatory, and technical factors from both inside and outside of the industry.

	The IQVIA report noted that branded medicine spending will be flat in developed markets for 2018–2020 but specialty medicines will drive spending growth. Patent expirations, including biologics, will be 37% higher than the previous five years; new medicine growth will be slower in 2018–2022 than from 2013–2017. The report authors also project slower growth in China and other pharmerging markets.

	The industry has reached a “breaking point,” said Graham Lewis, IQVIA’s vice-president, global pharma strategy, during a presentation at DCAT Week ‘18.

	Payers are not willing-or in some cases able-to pay more for healthcare and medications. This price squeeze will impact developed and emerging markets for branded, generic, and specialty drugs; limited resources could slow the adoption of new therapies.

	Lewis warned of trends in the transformative space that are not about drugs, and the pharma industry will need to look outside itself to embrace change. Factors to consider include: FDA’s adoption of real-world data to accelerate drug approvals, the use of mobile health apps and wearable sensors for patient treatment; and telehealth programs that replace the traditional doctor’s office visits; and more mainstream use of personalized biotherapeutics.

	There are significant differences between a therapy that treats millions and a therapy that treats one patient. Both blockbusters and personalized therapies will be needed. The bio/pharma industry must be flexible enough to discover, develop, manufacture, and market therapies for both ends of the spectrum, and all patient needs in between.

New Drugs at FDA: CDER’s New Molecular Entities and New Therapeutic Biological Products

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	3. M. Aitken, M. Kelinrock, and D. Nass, 201

	When referring to this article, please cite it as R. Peters, "When One Therapy No Longer Fits All" 

New therapies and tighter budgets challenge bio/pharma to think outside the industry.

When One Therapy No Longer Fits All

	If you look back one year, the bio/pharma industry faced a number of questions. Drug approvals were down. President Trump had issued an executive order calling for reducing the number of regulations. And, the position of FDA commissioner was vacant.

	A recent report from PwC’s Health Research Institute (1) summarizes long-term trends and changes in FDA activities that occurred in 2017, and the implications for the bio/pharma industry, and offers a performance evaluation for the agency and industry. According to the report, FDA had a good year in 2017; the agency approved 45 new molecular entities, the second highest total in history, and the most generic drugs ever (763 full approvals and 174 tentative approvals). These approval successes came as the number of new regulations declined but enforcement efforts increased.

	In addition, a record number of drugs (476) received orphan drug designation in 2017, an indication of the ongoing trend of companies developing specialty and oncology drugs for smaller patient populations. Under the 2017 tax legislation, the tax credit for research and development costs for orphan drugs was cut in half, to 25%, lowering incentive for companies to pursue such research.

	The report notes only six economically significant regulations-all unrelated to pharmaceuticals or biotechnology-were released by FDA in 2017, compared with 30 or more in the previous four years. This slowdown was the sole significant “sudden change” observed by the report authors. Rulemaking, however, increased in the second years of the Bush and Obama administrations; the report notes that 18 pharmaceutical regulations are under development and could be published in 2018.

	While the number of rules decreased in 2017, FDA continued to make policy by issuing guidance documents with user fees, generic drugs, and procedural topics receiving the most attention. The 174 draft and final guidance documents exceeded the average of 152 per year issued under the Obama Administration. Nearly 100 guidance documents are on the Center for Drug Evaluation and Research’s (CDER) agenda for 2018, dealing with procedural changes; quality; chemistry, manufacturing, and controls; and generic drugs.

	Overall, FDA issued fewer warning letters in 2017 (510) compared with previous years. However, the 85 letters issued by CDER in 2017 were nearly double the amount issued in 2014. This jump in the number of warning letters was triggered by increased enforcement efforts authorized by the Drug Quality and Security Act of 2013 and many targeted offshore API and drug product manufacturing facilities. Drug quality and data integrity were the frequently listed violations. The number of deficiencies found during inspections held steady; failure to have or follow written procedures, failure to scientifically validate testing procedures, and failure to fully investigate discrepancies in manufacturing or testing processes were the most frequent offenses.

	Scott Gottlieb, who took over as FDA commissioner in May 2017, has demonstrated a strategy to “provide regulatory relief where appropriate, introduce competitive policies and eliminate restrictive ones, and promote innovation and the exchange of information” (1).

	That approach should appeal to pharmaceutical executives surveyed by PwC; 36% of the respondents would like to see standards for approval, including minimized regulations for lower-risk products, streamlined. Only 6% would like to see streamlined manufacturing regulations, including manufacturing quality and inspections.

	1. PWC Health Research Institute Insight, “Continue to Take as Prescribed,” February 2018.

	When referring to this article, please cite it as R. Peters, "Regulatory Role in Pharma Progress" 

FDA enforcement efforts and drug approvals trend upward. 

Regulatory Role in Pharma Progress

While some drug innovations are the result of surprises during research phases, a surprise that occurs during development--such as formulation or manufacturing problems--could result in approval delays or failure for a drug product.

	To reduce the risk of late-phase surprises, some experts recommend that additional screening efforts in early development can smooth the pathway in later development stages. Developers of promising compounds emerging from drug discovery must balance the need to better understand potential formulation challenges and the manufacturability of the drug product with the reality of time and budget constraints.

	For investigational new drug applications, drug owners are expected to provide information about the pharmacological and toxicological effects of a prospective drug product, as well as its physical, chemical, or biological characteristics and the stability of the drug substance during the toxicological studies and planned clinical studies. The application also requires information about inactive components planned for the drug product and “any reasonable variations that may be expected during the investigational stage” (1).

	In the regulations, FDA notes that “modifications to the method of preparation of the new drug substance and dosage form and changes in the dosage form itself are likely as the investigation progresses” (1). For a Phase I submission, drug companies should focus on the identification and control of raw materials and the new drug substance, the Code specifies; the agency does not expect final specifications for the drug substance and drug product until the end of the investigational process.

	For drug development companies, particularly small startups, the focus is often short-term: get the compound to clinic or get an investor or buyer interested in the potential drug. This approach can be short-sighted, experts note, and drug companies would be better served by focusing on getting the drug to market. In presentations, consultants and representatives of contract development and manufacturing organizations (CDMOs) proposed that moving some formulation steps normally conducted in Phase I or Phase II to the preclinical stage can help identify potential formulation and manufacturability roadblocks earlier in the development process and avoid later problems.

	While speed is the top priority for most small pharma companies with molecules in discovery phases, drug candidate quality should be the top consideration, said David Elder, principal consultant, David P. Elder Consultancy, in a webcast (2).

	If more work is done in medicinal chemistry stages to optimize a molecule, formulation challenges may be easier to solve, said Elder. Historically, formulation scientists were expected to “rescue” molecules that were intrinsically insoluble. To get more drug candidates with fewer solubility issues, drug companies should focus more on the quality of the candidate molecule--its lipophilicity, molecular weight, and ring systems--and not just its potency.

	Drug companies that fail to evaluate the physicochemical characteristics and manufacturability of a drug candidate in early development stages will not have adequate risk assessments of challenges that may arise later in development stages, experts agree. Drug candidates with demonstrated data on solubility, intestinal permeability, dissolution, bioavailability, and dose will be more attractive to potential partnerships, acquisitions by other pharma companies, or financing from investors.

	Often, preclinical efforts are geared to achieving a desired pharmacokinetic response in an animal model while minimizing formulation development time and cost. However, 

 relationships are often not straightforward and, therefore, require additional time and cost to establish, experts note. Pharmacokinetic studies using the API in a hydroxypropyl methylcellulose suspension, may not give accurate results and can result in formulation delays later in the development process (3).

 modeling tools are available to screen drug candidates to predict degradation, metabolism, toxicity, solubility, and other characteristics, while conserving valuable API. Modeling also is used to evaluate manufacturing approaches and excipient selection, and for scale up and design of experiments.

	As drug molecules become more complex, solubility has become a major hurdle in the development process. Drugs are frequently cited as fitting into one Biopharmaceutics Classification System (BCS) (4) classification; however, this system is a regulatory tool to identify efficacy and patient safety, said Julien Meissonnier, vice-president, science and technology, Catalent Pharma Solution, in a webcast (2). A better tool for evaluating new drug development issues including permeability, solubility, dose, and dissolution rate is the Developability Classification System (DCS) (5), he said.

	Like the BCS, the DCS tool also categorizes molecules based on solubility, dose, dissolution, and permeability. It further classifies Class II compounds, which have low solubility and high permeability: Class IIa are dissolution-rate limited and Class IIb are solubility-limited. The dissolution of Class IIa molecules can be enhanced by reducing particle size. Knowing where a drug candidate fits on the classification scheme can expedite the formulation process, Meissonnier said.

	Catalent works with drug companies to characterize a molecule using high-throughput screening to identify physicochemical properties and a DCS classification. Drug metabolism and pharmacokinetics modeling is used to understand formulation parameters. Parallel screening--at a small scale--of different solubility enhancing technologies (e.g., lipids, hot-melt extrusion, spray drying, and micronization) is used to assess stability, drug load, solubility, and concentration increase. Based on the screening results, the best candidate molecule can be selected for animal studies.

	In a presentation (6), Sanjay Konagurthu, a senior director at Patheon, part of Thermo Fisher Scientific, described a solubility enhancement formulation platform that uses algorithms to analyze a drug’s structure against manufacturing methods including solid dispersions, lipids, particle size reduction, crystalline forms, and cyclodextrin complexes. The results indicate the potential of each technology on a scale. The tools can be used to view a drug’s molecular properties, identify potential excipients, and computationally screen excipients and drug loading prior to experimentation.  

	In the typical drug discovery/early development scenario, a company may have only a few grams of the compound, and most likely has not attempted to synthesize the substance on a larger scale, or to formulate it to a drug product.

	Changes in a formulation during process development can sidetrack a drug’s development, and these potential risks are best assessed in early development stages, explained Jon Sutch, senior manager of formulation development, Patheon, in a webcast (7). Drug owners need to understand the risks involved with moving from one phase to another and how the formulation may change moving from process to process. Experimental work can mitigate some of the risk, he explained.

	Drug owners should plan, in early development stages, to develop a synthesis platform that is sustainable--environmentally acceptable, socially acceptable, and profitable--throughout a drug’s life cycle, said Peter Poechlauer, innovation manager, API, Patheon, in a webcast (8).

	Initially, in Phase I and II clinical trials, a drug’s API is expensive because there is so little material available; once the drug has reached Phase III trials, the API manufacturing process has been refined and the API cost drops, Poechlauer explained. While innovator drugs are expensive when launched, the API represents only 8-12% of the drug product cost. The cost of the drug product declines as it moves toward patent expiration; however, the API represents a greater percentage of the total drug cost.

	For this reason, Poechlauer says, drug owners must develop the foundation for efficient, reliable, and scalable processes in the early clinical trial phases even before it is certain that the drug will succeed. An analysis of the original synthesis process for the compound may reveal alternate, more efficient methods required for large-scale production.

	A challenge for drug owners in early development is balancing what they don’t know, what they can afford to investigate, and what they need to know. A better understanding of an API’s properties, polymorph forms, interactions with excipients, and the overall performance of the formulation can help avoid problems and expensive rework of formulation steps during scale up to commercialization.

	For small pharma companies, limited financial resources may restrict their ability to conduct preclinical formulation screens. The added upfront costs may slow early phase development and increase costs, suggested FDA Commissioner Scott Gottlieb (see 

 312, Investigational New Drug Application.
	2. Catalent Pharma Solution. “From Candidate to Clinic: Strategies to Select, Assess, Formulate, and Deliver the Right Drug Candidate in the Early Phase,” Webcast, Oct. 10. 2017.
	3. A. Siew, 

, 41 (10) 20-27 (2018).
	4. FDA, Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate-Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System, Guidance for Industry (Rockville, MD, December 2017).
	5. J.M. Butler and J.B. Dressman, 

, 99 (12) 4940-4954 (2010).
	6. S. Konagurthu, “Spray-Drying of Amorphous Solid Dispersions: A Structure-based Approach to Formulation Design and Scale-Up,” Presentation, AAPS Annual Meeting, October 2017.
	7. Patheon, “Ensure the Scalability of Your Molecule with a Science-Driven, Phase-Appropriate Approach,” Webcast, Aug. 29, 2017.
	8. Patheon, “Challenges in the Development of Complex Small-Molecule Drugs,” Webcast, Nov. 7, 2017.

will host a panel discussion, Detecting Potential Formulation Roadblocks in Early Drug Development, on April 24, 2018 at CPhI North America. For details, see 


	Vol. 42, No. 3
	March 2018
	Pages: 18–21

	When referring to this article, please cite it as R. Peters, " Can Early Development Strategies Avoid Later-Stage Disasters?" 

Assessing potential formulation and manufacturing issues in early development phases can improve a drug’s chances for success.