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July/August 2009

Building a Road Map

E55 Navigates Pharmaceutical Manufacturing

In 2008, pharmaceutical sales in the United States totaled approximately $189 billion while global sales reached more than $288 billion. The U.S. Food and Drug Administration approved close to 100 new drug applications, and spending on pharmaceutical research and development was an estimated $65.2 billion.1,2

When it comes to pharmaceutical manufacturing, a global industry whose products can literally mean the difference between life and death, quality and efficiency are major concerns. ASTM International Committee E55 on Manufacture of Pharmaceutical Products is working to help improve on the current level of quality and efficiency by introducing standards for the pharmaceutical manufacturing industry.

“We’re creating a road map of standards, a foundation that companies can build upon,” says David Radspinner, chair of Subcommittee E55.03 on General Pharmaceutical Standards and head of marketing, cell culture and bioprocessing business, Thermo Fisher Scientific Inc., Logan, Utah. “Having international standards in manufacturing will help save money, simplify jobs, gain consistency and allow for more predictability during audits,” he says.

By encouraging consistency, simplicity and agreement, E55 standards will help streamline the pharmaceutical manufacturing process and ensure the quality of potentially lifesaving products. The work begins with a trio of standards published by the committee:

  • E2476, Practice for Risk Management as it Impacts the Design and Development of Processes for Pharmaceutical Manufacture (to be published shortly);
  • E2500, Guide for Specification, Design and Verification of Pharmaceutical and Biopharmaceutical Manufacturing Systems and Equipment; and
  • E2503, Practice for Qualification of Basket and Paddle Dissolution Apparatus.

It’s PAT

The E55 standards are an expansion of the Process Analytical Technology Initiative, a program developed by the FDA to overhaul pharmaceutical manufacturing processes.

“The word analytical in PAT is broadly used to include chemical, physical, microbiological, mathematical and risk analysis conducted in an integrated manner,” says Chris Watts, Ph.D, team leader, standards and technology, Office of Pharmaceutical Science, Center for Drug Evaluation and Research, FDA, Silver Spring, Md. “Simply put, PAT is based on the idea that quality cannot be tested into a product — it should be built in, included by design. Once the PAT guidance was published we recognized the need for more specific recommendations for companies wanting to implement the guidelines. That’s where ASTM and E55 entered the picture.”

The Standards

E55’s newest standard, E2476, has a clear purpose: to identify and eliminate risk at the earliest point of the manufacturing process, during its initial design. “This is a very timely standard,” says Duncan Low, Ph.D, chair, Subcommittee E55.01 on PAT System Management and scientific executive director, Amgen, Thousand Oaks, Calif. “It’s going to be very helpful for companies who are incorporating risk management into their quality by design efforts.”

Like E2476, E2500 focuses on risk. In fact, E2500 is being heralded as representing a “new paradigm” in standards. “The paradigm shift is in the risk-based approach to equipment specification,” says Radspinner. “In the ‘classic’ approach, each piece of equipment is viewed the same way, using a standard protocol relating to that piece of equipment with limited consideration for the end product. But, the risk-based approach says that if my equipment is being used in a specific way, then I should qualify my equipment based on that specific use and address the risks to my process based on that specific use.”

“E2500 has proven to be a very successful and significant standard,” says Bruce Davis, principal consultant, Bruce Davis Global Consulting, Surrey, United Kingdom, and member, board of directors, International Society for Pharmaceutical Engineering. “It puts in place science and risk-based principles supported by good engineering practices. It clarifies what is essential to verify to ensure product quality.”

The third standard, E2503, specifically relates to the mechanical testing equipment used by tablet manufacturers. Are my tablets a consistent dosage? How quickly and completely do they dissolve? How do changes in my process affect these and other properties? How do I accurately test my product to get these answers? These are the types of questions addressed by E2503.

“During testing, there are many variables to consider — equipment setup, test methods, etc. — and every product will have a different sensitivity to those variables,” says Lucinda Buhse, Ph.D., director, Division of Pharmaceutical Analysis, FDA, St. Louis, Mo. “Identifying and minimizing the variables caused by equipment and test methods will help increase confidence that the resulting data is an accurate picture of the product’s properties and not a function of the testing process or equipment.”

As an added benefit, following this standard should also lead to reduced costs, notes Buhse. More accurate test results mean less repeat testing, fewer “good” batches being discarded because of inaccurate test data and fewer “bad” batches slipping through quality control.

While each standard is a separate entity, they work well in combination, notes Radspinner. “If I wanted to produce a product in tablet form, I would start by using E2476 to design a manufacturing process that addressed questions such as ‘What are the critical attributes of my product? What is its intended use? How do I design my process to reduce risk?’” he says. “Next I would refer to E2500 to determine exactly what equipment I needed and how I should set up and test that equipment so that my end product would have all of the qualities I wanted. Finally, when my tablet was ready I would use E2503 to make sure my testing process was sound so that when I tested my product I could be confident that the data was as accurate as possible.”

Changing The Industry

Both Radspinner and Low have seen a lot of interest in the E55 standards.

“It’s evident both in the number of people requesting copies of the standard, and in the number of people referring to them during conferences, presentations, meetings, etc.,” says Radspinner.

“The interest from my European colleagues has been high, and representatives from the EMEA, the European version of the FDA, have attended E55 meetings,” remarks Low.

Both also agree that even with such high interest it will be some time before the full effect of these standards is realized.

“Although there are some large companies using the standards as a base for their own operating procedures, it’s still too early to say that there have been definite improvements in pharmaceutical manufacturing,” Low says. “Since the development of a pharmaceutical product takes 10 to 15 years, the result of changes in process may not be quick to reveal themselves. However, there’s no question that E55’s standards will facilitate the adoption of changes, which in turn will allow for better quality and manufacturing efficiency.”

Davis agrees, “It’s not easy to provide quantitative evidence, but the standards certainly appear to have helped provide more clarity and hence potentially more efficiency for the industry.”

Low believes that the use of standards will also open the door for additional benefits, such as the development of new manufacturing technologies. “The pharmaceutical industry has been quick to embrace new ways to develop and create drugs, but its ability to develop more modern manufacturing technology has lagged behind by comparison,” he says. “I think E55’s work will encourage the implementation of newer technologies which in turn will lead to even greater efficiency.”

Another potential benefit should be increased confidence in decision making, notes Radspinner. “If companies follow these standards they’ll have the added benefit of knowing that should they ever need to defend their actions to a regulatory body, those actions are backed by an accepted international standard.”

In Development

“This is just the beginning for E55 standards,” says Davis. “There are a number of anticipated standards still in the development stage.”

One such standard in progress is WK5935, Practice for Process Understanding Related to Pharmaceutical Manufacture and Control. This standard will build on PAT protocols and encourage a holistic approach to process understanding. “Why do things happen, or not happen in a process?” says Radspinner. “When completed, this standard will challenge companies to examine the concepts behind their processes and force them to look beyond basic approaches to product development. That’s not to say that companies don’t understand their processes, but this will provide a standardized way for them to consider what they need to know about their process and how they might go about gathering that information.”

Traditionally, pharmaceutical products have been produced in batches, but switching to continuous processing should lead to greater efficiency in the manufacturing process, according to Low. “In principle it should work,” he says, “but in practice there are issues around how it might be implemented.”

WK9192, Guide for the Application of Continuous Processing Technology to the Manufacture of Pharmaceutical Products, will attempt to address those issues by helping companies identify and neutralize any potential problems with the transition to continuous processing without adversely affecting their end product.

For More Information

For more information on Committee E55 and its standards activities, visit the ASTM Web site at, or contact Pat Picariello, director of developmental operations, ASTM International (phone: 610-832-9720).

1. Pharmaceutical Research and Manufacturers of America. PhRMA Annual Membership Survey, 2009.
2. US FDA Center for Drug Evaluation and Research. FDA Approved Drugs. Available at:


Kessel Nelson is a freelance writer whose work has appeared in national and international publications, covering subjects ranging from art to energy to schizophrenia. He has a B.A. in history from the University of Pennsylvania, and he spends his time between Philadelphia and New York City.