Rita Peters is the former editorial director of 

Pharmaceutical Technology, Pharmaceutical Technology Europe

Rita C. Peters

IVT’s 5th Annual        Validation Week EU

In its Strategic Plan for Preventing and Mitigating Drug Shortages, FDA reiterated its position that shortages of drugs and biologics pose a significant public health threat and preventing drug shortages remains a top priority. The agency also identified two central goals: improving mitigation response to shortages and implementing strategies for the long-term prevention of shrotages by focusing on the root causes of shortages.

FDA cites some recent success in working with manufacturers to mitigate shortages and restore lost production. A six-fold increase in early notification of possible shortages, combined with allocation of additional FDA resources, resulted in a decrease in the number of new shortages from 251 in 2011 to 117 in 2012, FDA reports. Despite this improvement, there is still much work to be done, particularly to address manufacturing and quality issues that are the root cause of drug shortages.

FDA strategies to move toward long-term prevention include the establishment of a proposed Office of Pharmaceutical Quality within the Center for Drug Evaluation and Research (CDER) and the establishment of risk-based approaches to identify early warning signs for manufacturing and quality problems. In response to FDA calls for input on a third strategy, the broader use of manufacturing metrics to assist in the evaluation of manufacturing quality, two industry associations have offered proposals for potential metrics programs.

In December 2013, the International Society of Pharmaceutical Engineers (ISPE) released 

ISPE Proposals for Quality Metrics Program - Whitepaper

, in which the organization proposed “an initial list of quality metrics which are reportable to FDA to support a risk-based inspection program as given in sections 704 to 706 of US Food and Drug Administration Safety Act (FDASIA) and assist industry in moving towards the ‘desired state’.”

The ISPE team, with representatives from a range of pharmaceutical organizations, identified metrics that are mostly site-based. The intention, ISPE reports, is to start with indicator metrics and consider refinement in subsequent phases to better link to FDA’s six systems used in the inspection program and to products.

The initial six metrics, all lagging indicators, are batch rejection rate, rework and reprocessing rate, confirmed out-of-specification (OOS) rate unconfirmed OOS rate, critical complaints rate, and % annual product quality reviews complete on time. ISPE also offered definitions for these metrics, suggested alternative metrics, an implementation program, and options for next steps. For more information, see www.ispe.org/quality-metrics-initiative.

The Parenteral Drug Association (PDA) developed a “

” document, which puts forth the current thinking of the organization’s membership. The Inside PDA column (see pages 18 and 22) details the organization’s position on metrics and its approach to developing the document. PDA recommends that FDA collect and assess both product and site quality metrics. Trend metrics collected per product include confirmed product quality complaint rate by product; batch reject rate by product; and confirmed OOS rate (drug substance and drug product) by product. Suggested trend metrics collected by site are confirmed OOS rate (drug substance and drug product) by site and batch reject rate by site. 

These initial efforts of ISPE and PDA to provide some guidance to FDA should be commended. However, there is much work to be done. We will be monitoring developments in these pages and on www.pharmtech.co.


Rita Peters is the editorial director of 

Articles

ISPE and PDA take on the challenge of recommending quality metrics.

Defining Quality Metrics is No Easy Task

	
	The critically acclaimed television show 

 told the tales of a high school chemistry teacher who, after a diagnosis of advanced cancer, started a methamphetamine laboratory in order to support his family. While this is not the career path the chemical industry wants to endorse, the popular show did demonstrate applied science in action. At InformEx 2014, Donna Nelson, professor of organic chemistry at the University of Oklahoma and a scientific advisor for the program, will discuss her role in the program.

	However, InformEx 2014, scheduled for Jan. 21-24 in Miami Beach, Fla., also features more mainstream conference topics. 

are scheduled for Jan. 22-23 and will be located on the show floor. Exhibits are open Jan. 21-24.

	The scheduled topics include an analysis of the current state of the pharmaceutical industry, where growth may come from, what new molecules may look like, and services drug manufacturers may require.

	Another presentation will discuss, through case studies, challenges encountered in formulation development and manufacture of clinical trial material when moving from Phase 1 to Phase 2 and 3 studies. Participants can also learn how pharmaceutical companies and CDMOs are aligning sustainability policies and how these programs can generate a significant return on investment.

	Other sessions will address vulnerabilities in the chemical supply chain, intellectual property protection, recent advances in chemical technologies for the synthesis of glyochemicals and glycoconjugates, creating value in partnerships between pharma and technology providers, and market opportunities in personalized medicine for the fine, custom and specialty chemicals industry.

	Networking breakfasts, as well as the InformEx 30

 Edition Celebration, provide opportunities for interaction.

	More than 3,500 attendees from top pharmaceutical, fine chemical and specialty chemical companies - along with 

 - will take part in InformEx 2014, organizers report.

The critically acclaimed television show Breaking Bad told the tales of a high school chemistry teacher who, after a diagnosis of advanced cancer, started a methamphetamine laboratory in order to support his family. While this is not the career path the chemical industry wants to endorse, the popular show did demonstrate applied science in action. At InformEx 2014, Donna Nelson, professor of organic chemistry at the University of Oklahoma and a scientific advisor for the program, will discuss her role in the program.

Conference Programs Highlight InformEx 2014

In a recent survey of current trends and practices in biopharmaceutical manufacturing, 

 readers revealed a preference for disposable systems, identified challenges for different therapies, and suggested technology enhancements to improve process efficiencies (1).

Survey respondents represented research, development, formulation, and process development functions, as well as quality control/assurance, validation, and laboratory management titles at branded and generic-drug companies in the United States, Europe, and Asia. More than half of the respondents work for organizations that produce both small- and large-molecule drugs; 25% added a biopharmaceutical-manufacturing program in the past year. 

The responses indicate some signs of manufacturing growth. More than half of all respondents said their companies increased biomanufacturing capacity in 2013. Less than 3% reported a drop in production. Only 8.1% said their companies decreased spending for biopharmaceutical equipment and services in 2013 compared to 2012; 37.8% reported increased spending; spending was flat for 33.8% of respondents. Nearly 40% expect spending to increase in 2014 compared to 2013; only 5.4% expect a decrease.

The top reasons for increased capacity were the addition of new products and increased production of existing products. More than 40% of respondents said that internal development of new products spurred the need for additional capacity. About 20% said capacity was added due to the acquisition of another company or in-licensing of a drug product

Almost 45% of the respondents reported that their organizations manufacture therapeutic monoclonal antibodies (mAbs); more than 55% of those surveyed said they manufacture protein-based drugs other than mAbs. More than 40% of the respondents said their companies manufacture vaccines; 17.7% develop cells for tissue and/or cell therapies; 10.4% manufacture nucleic-acid based drugs.

. Facilities that manufacture protein-based drugs reported use of multiple purification technologies. Ion-exchange chromatography was the most frequently reported (71.6%) followed by chromatography with other resins (62.7%), chromatography with Protein A (56.7%), and membrane-based filters (53.7%).

Protein stability led the list of reported technical challenges, cited by 53.7% of the respondents. Producing sufficiently high product yields was a close second at 52.2%; purifying high product yields was the third most frequently cited at 49.3%. Protein aggregates, formulation issues, creating/cloning cell lines, regulatory issues, and analytics were mentioned by more than 25% of the respondents (see 

. Although they represented a smaller subset of the respondents, those that manufacture nucleic-acid based drugs reported multiple manufacturing challenges. Purification (reported by 45.5%), stability (36.4%), drug delivery (31.8%), and scale up (27.3%) led the list (see 

. Process development for cells for tissue- or cell-based therapies created technical challenges for half of the respondents. Scale up (35.7%), cell viability (31%), and cell stability (28.6%) were also listed as top technical issues. Regulatory issues, costs, analytics, and inadequate bioreactor volumes were other challenges (see 


  More than half of the respondents reported using process analytical technology (PAT) in manufacturing operations. High-performance liquid chromatography was the clear leader, used by 71.7% of those that implement PAT. Use of Fourier transform infrared spectroscopy was reported by 41.3%; almost one-third use near-infrared spectroscopy. More than one-quarter use disposable sensors


  Hybrid manufacturing systems, which feature traditional stainless steel and disposable, single-use equipment, were used by almost three-quarters (74.4%) of the respondents; 16.3% use all stainless; 9.5% use all disposable.

All respondents, those who used and did not use disposables, shared perceptions about the value of single-use systems. Nearly 70% cited reduced contamination as an advantage. Time savings, ease of use, and flexibility for multiproduct manufacturing were identified as advantages by more that half of the respondents (

). While 38.1% said disposables offered cost savings, 55.6% said high cost was a challenge to using a disposable system. Other challenges were limitations on size and leaching of the disposable material into the product (


  Improved process understanding (68.4%), improved product quality (66.7%), and reduced variability in product quality (57.9%) were the top advantages identified by the respondents who have implemented quality-by-design (QbD) principles in their biopharmaceutical manufacturing operations. Nearly half reported improved manufacturing efficiency as a result. However, almost 32% of the respondents have not implemented QbD. Reasons cited for not implementing QbD include a lack of guidance and direction from regulatory agencies (46.2%), no process or quality advantage to be gained (30.8%), a lack of understanding of the QbD initiative (23.2%), or it is too costly.


  Respondents revealed insight about recent innovations that have improved process efficiencies.  Equipment and products related to disposable systems were most frequently mentioned. 

There is, however, room for improvement. Better disposable systems, including bags that do not leak, reduced leaching, larger bioreactors and fermenters, and disposable sensors were identified as desired new technologies to improve process efficiencies. Better filtration, chromatography columns, automation, and process analytical technologies also were identified as ways to improve manufacturing efficiencies.
  an Alternative:


  Outsourced manufacturing plays a prominent role among the companies represented in the survey. Almost 40% reported outsourcing of some component of biopharmaceutical manufacturing. Leading outsourced function, are drug substance manufacturing, API and finished products manufacturing, and clinical trial-materials manufacturing. More than one-third of the companies outsource full-scale commercial manufacturing. Limited internal manufacturing capabilities and cost-effectiveness were the leading reasons cited for outsourcing different functions in biopharmaceutical manufacturing.

BioPharm International Manufacturing Trends 2014 Survey

A survey of BioPharm International readers found that single-use systems and other technologies are driving process efficiencies in biomanufacturing, but there is room for improvement.

2014 Manufacturing Trends and Outlook

	While the Affordable Care Act, Pope Francis, and the government shutdown were top general news stories in 2013, the bio/pharmaceutical industry had its own headlines. 

 analyzed the hundreds of news stories published in 2013, and found the top 10 most-read articles, based on reader clicks. To no surprise, the most-read articles reflect major bio/pharmaceutical business announcements and regulatory activity.

Merck Cuts 8,500 Positions, Moves Headquarters 

Scientist Jailed for Falsifying Research Data 

FDA Lists Guidance Documents Planned for 2013

Ben Venue Laboratories Enters Consent Decree

AstraZeneca Announces an Additional 2300 Layoffs

Hameln Pharmaceuticals Receives FDA Warning Letter

Novartis Receives FDA Warning Letter for cGMP Violations at Austrian Plant

AstraZeneca to Cut 1600 Positions in R&D Reorganization

	To stay on top of pharmaceutical industry news in 2014, subscribe to a


	The latest in business, scientific and regulatory news shorts, plus upcoming events and webcasts delivered to your inbox every Thursday. 

Pharmaceutical Technology Europe e-Alert | Weekly 


	The latest in business, scientific and regulatory news shorts, with a special focus on the European marketplace, delivered to your inbox every Tuesday. 


	Analysis of pharmaceutical development, manufacturing, and the supply chain. 

Equipment and Processing Report | Monthly


	Focus on pharmaceutical manufacturing processes and technology, providing analysis of manufacturing news, related regulatory issues, and current trends. 

Receive free technical whitepapers and application notes submitted by leading pharmaceutical manufacturing product and solution providers. 

While the Affordable Care Act, Pope Francis, and the government shutdown were top general news stories in 2013, the bio/pharmaceutical industry had its own headlines.

Most-Read News Stories of 2013

The underlying question for any drug in development is: What price can (or will) patients pay for the needed therapy? Patient sticker shock, government austerity programs, blockbuster drugs falling off the patent cliff, and varying medical and regulatory practices worldwide continue to shape the financial outlook of bio/pharmaceutical companies.

The Global Use of Medicines: Outlook through 2017

, IMS Institute for Healthcare Informatics projects that in 2014 total global spending on medicines will, for the first time, exceed $1 trillion. In 2017, the total will reach almost $1.2 trillion. 

In 2012, developed markets (United States, Japan, Germany, France, Italy, Spain, United Kingdom, Canada, and South Korea) reduced spending for the first time largely due to patent expirations, austerity measures, and moves toward generic drugs. Annual growth in spending levels will reach a low point in 2013, the report says, but will rebound from negative $3 billion in 2012 to $20–25 billion by 2017. 

In emerging markets (more than 20 nations including China, Brazil, India, Russia, Mexico, and Turkey), growth will increase from $26 billion in 2012 to $30–50 billion in 2017, primarily due to increased access to medicines.
  In 2017, spending on medicines for specific diseases will differ between mature and emerging markets, the report says. In developed markets, increasingly aged and obese populations drive spending in oncology and diabetes, a trend that is increasing in emerging markets. Specialty pharmaceuticals that treat complex, serious diseases will grow in importance in developed markets; traditional therapies will drive spending in emerging markets.


  Biologics have a growing impact on the drug market and prices. In 2002,  biologics represented 11% of total drug sales; in 2012, the number was 18%. IMS estimates biologic agents will continue to outpace overall pharma spending growth and will represent 19–20% of the total market value by 2017. Monoclonal antibodies and human insulin will spur this growth.

Competition generated through established biosimilar pathways will drive down the high costs of biologics in Europe, the US, and some emerging countries. However, in markets with less rigorous IP protection, IMS reports a surge in non-original biologics—copies of innovator brands that have not been approved a dedicated pathway. Biosimilars account for less than 0.5% of biologic spending in mature markets; in emerging markets, non-original biologics represent more than 10% of all biologics spending.


  The mix of total global spending on medicines will shift toward generic drugs, rising from 27% to 36% of the total by 2017; however, brand drugs will account for more than two-thirds of spending in developed markets. In emerging markets, generic-drug products will represent 63% of spending.

Traditional pharmaceuticals used to treat chronic diseases in primary care will increasingly be dispensed as generics; total spending will only rise 5% by 2017 in developed countries. In emerging markets, total spending on traditional pharmaceuticals is expected to rise from $199 billion in 2012 to $336 billion in 2017 as patients gain access to affordable generic drugs.

IMS reports spending on specialty medicines in developed markets is expected to increase by 30% over the next five years; the use of specialty medicines in emerging markets is at very low levels, but the costs are expected to rise by nearly 90% between 2012 and 2017.


  The report identifies challenges, but also indicates opportunities for the industry to improve the lives of patients. The editors of Pharmaceutical Technology wish you a safe, healthy, and successful New Year in all your endeavors.


 1. IMS Institute for Healthcare Informatics, 

Generics, market dynamics, and global demand are changing drug-spending patterns.

New Dynamics in Drug Pricing and Prescribing

In 2012, developed markets (United States, Japan, Germany, France, Italy, Spain, United Kingdom, Canada, and South Korea) reduced spending for the first time largely due to patent expirations, austerity measures, and moves toward generic drugs. Annual growth in spending levels will reach a low point in 2013, the report says, but will rebound from negative $3 billion in 2012 to $20-25 billion by 2017. 

In emerging markets (more than 20 nations including China, Brazil, India, Russia, Mexico, and Turkey), growth will increase from $26 billion in 2012 to $30
50 billion in 2017, primarily due to increased access to medicines.

In 2017, spending on medicines for specific diseases will differ between mature and emerging markets, the report says. In developed markets, increasingly aged and obese populations drive spending in oncology and diabetes, a trend that is increasing in emerging markets. Specialty pharmaceuticals that treat complex, serious diseases will grow in importance in developed markets; traditional therapies will drive spending in emerging markets.


Biologics have a growing impact on the drug market and prices. In 2002,  biologics represented 11% of total drug sales; in 2012, the number was 18%. IMS estimates biologic agents will continue to outpace overall pharma spending growth and will represent 19-20% of the total market value by 2017. Monoclonal antibodies and human insulin will spur this growth.

Competition generated through established biosimilar pathways will drive down the high costs of biologics in Europe, the US, and some emerging countries. However, in markets with less rigorous IP protection, IMS reports a surge in non-original biologics--copies of innovator brands that have not been approved a dedicated pathway. Biosimilars account for less than 0.5% of biologic spending in mature markets; in emerging markets, non-original biologics represent more than 10% of all biologics spending.


The mix of total global spending on medicines will shift toward generic drugs, rising from 27% to 36% of the total by 2017; however, brand drugs will account for more than two-thirds of spending in developed markets. In emerging markets, generic-drug products will represent 63% of spending.


  1.	IMS Institute for Healthcare Informatics, 

Generics, market dynamics, and global demand are changing drug spending patterns.