Mapping a Course
Insulin shots help the body to process sugar. Antibiotics help clear up infections. Aspirin and ibuprofen ease headaches. When someone takes a twice a day capsule, a once a month pill or an injection, which may clear up a sinus infection, help slow osteoporosis or control diabetes, each taps into a global pharmaceutical market that was anticipated in 2011 to reach $880 billion.1
Each and every pharmaceutical represents a complex and extensive effort to produce an effective and safe therapy for a health condition. In the United States last year, as reported by the U.S. Food and Drug Administration, 35 novel medicines received approval, including new treatments for hepatitis C, lymphoma and lupus, and others to prevent heart attack and stroke.2 In each case, from discovery to dispensation, the pharmaceutical has also involved extensive regulatory oversight.
No matter what the medicine, standards and proposed standards from ASTM International Committee E55 on Manufacture of Pharmaceutical Products aim to help both pharma firms and regulators. "There continues to be a need to develop global standards that facilitate and support the introduction of new manufacturing technologies and the adoption of modern approaches to quality assurance," says U.K.-based E55 chairman Graham Cook, Ph.D., director of process knowledge/quality by design, in Pfizer's Global Quality Strategy organization.
To support its ongoing standards work, the committee is reaching out to industry professionals to raise awareness and recruit new committee members.
In 2002, the U.S. Food and Drug Administration issued its Pharmaceutical cGMPS [Current Good Manufacturing Practices] for the 21st century initiative to protect and advance America's health. "PAT [process analytical technology] was an initiative promoted by FDA to encourage the pharmaceutical industry to adopt some of the modern approaches to monitoring and controlling manufacturing processes instead of relying on end product testing to assure quality," says Cook. At the time, FDA and industry came to ASTM International to develop PAT standards in support of the initiative, and the new Committee E55 held its organizational meetings in 2003.
From its PAT focus, E55 expanded its scope and changed its name to manufacture of pharmaceutical products in 2006. Now, with the recent addition of biopharmaceutical standards bringing the committee's portfolio to 26, E55's 164-member group - pharmaceutical and biopharmaceutical companies, regulatory agencies, suppliers, academic institutions and consultancies representing 20 countries - is setting standards for the manufacture of more traditional pharmaceuticals as well as cutting edge biopharmaceutical products.
Committee E55 is well-positioned for its work. "ASTM is differentiated from other bodies in the pharmaceutical industry where regulators and industry collaborate… because of the collaboration and type of organization it is, it can write and issue and publish voluntary consensus standards," says Philip Crooker, director of global regulatory strategy – chemistry, manufacturing and controls, Shire Development LLC, Wayne, Pa., and an E55 member. Other groups can write and publish guidance documents that a national health authority can adopt, he adds, but they may not be able to issue standards.
In its standards work, "it is important that E55 avoids working on items that duplicate or compete but instead develops standards that complement the global regulatory framework and add value for all stakeholders," says Cook. E55 is setting a course toward this goal with a standards road map.
E55 looks to its standards road map for strategic planning. It's a living document that Subcommittee E55.95 on Road Map for Standards Development has been refining in preparation for rolling out a completed version by the end of the year.
Crooker, who is chairman of Subcommittee E55.95, says that the road map describes steps along the continuum of drug design, development and manufacture: "We want to come away with a systematic approach to product design, product development, commercial manufacture and life cycle management." And, he adds, through its standards, E55 wants to facilitate the assurance of product performance and quality, and consistency in regulatory decision making for drug production applications and during manufacturing facility inspections.
The road map begins at the point when a company feels it has a viable possibility for a medicine - how a molecule might work in the body or a way to prove its beneficial effects - and is ready to make a business case for producing it, according to Crooker. The drug discovery process itself (and also the clinical aspects of drug development) lies outside E55's scope.
The road map divides pharmaceutical product performance and quality into the broad categories of:
For each category, the road map breaks down each area into steps where standards or proposed standards exist as well as where standards would be beneficial. In the product and process design category, for example, identified standards areas currently include:
For product and process design systems, for example, E2500, Guide for Specification, Design and Verification of Pharmaceutical and Biopharmaceutical Manufacturing Systems and Equipment, applies concepts and principles introduced in the FDA cGMP initiative, and FDA cites the standard in its document, Guidance for Industry\; Process Validation: General Principles and Practices. "Guidance documents describe the agency's current thinking on a topic and should be viewed only as recommendations," says Paul Seo, Ph.D., standards and technology, FDA, and vice chairman of E55. Also, a standard is under way on continuous processing, WK34349, Guide for Application of Continuous Processing in the Pharmaceutical Industry, which aims to assist companies in considering and implementing this approach in an industry where the overwhelming majority of manufacturing processes are batch processes. FDA also cites E2503, Practice for Qualification of Basket and Paddle Dissolution Apparatus, a standard that addresses measurement systems calibration.
A new focus for E55 came earlier this year through the creation of a subcommittee specifically for biopharmaceuticals. Unlike such chemically synthesized medications as pain-relieving ibuprofen and depression-fighting venlafaxine, biopharmaceuticals are produced with living cells.
In the last 20 to 30 years, biopharmaceutical firms have developed new therapies to fight disease, and the industry has introduced new options to treat diabetes, heart problems, cancer and other conditions. These medicines are made from proteins and peptides, which consist of amino acids - the body's basic building blocks - in linear chains of about 10 to 20 amino acids for a peptide, and 100 to 400 or more for proteins.
These "big" molecules bind more specifically to other proteins in the body, which can result in targeting the disease with fewer side effects, according to Robert Steininger, senior vice president, manufacturing, Acceleron Pharma, Cambridge, Mass., and chairman of the new Subcommittee E55.04 on General Biopharmaceutical Standards. "The big molecules are advantageous because they tend to focus in on the one particular biological protein that you want to regulate," he says.
To produce a biopharmaceutical, "you usually need an organism to make that protein for you," says Steininger. That may be E. coli, yeast or mammalian cells. For example, some insulin, a peptide drug, is produced using E. coli.
In the past, proteins and peptide drugs were often derived from animal organs, human blood or other animal-human sources (for example, insulin, Factor VIII and antibodies). In some cases, that has caused transmission of disease to people when the starting raw material is contaminated with a virus or another organism. With protein drugs made by recombinant technology - where genes are moved from one cell and combined in another to make a certain protein - there is a much lower risk of transmission of disease since one has a lot better control of the raw materials and the purification process.
Steininger says, "If we can show that if you make a drug according to a standard and to specific parameters then you will get a more consistent removal or inactivation of impurities like viruses… We [pharmaceutical companies] do a small-scale validation of many of the purification steps to show that they either inactivate or remove viruses in a consistent fashion every time." Such purification is regulated, requiring companies to demonstrate that possible virus impurities have a low probability of remaining as an infective impurity in the final product.
A new group of planned standards from E55.04 should streamline the validation. The first one, WK36552, Practice for Process for Inactivation of Retrovirus by pH, is close to completion, and the additional potential standards on virus inactivation by surfactant and filtration are likely to be drafted soon.
The standards could particularly help smaller companies. Steininger says that large companies have a great deal of experience in producing biopharmaceuticals, but "much of the development of new potential biopharmaceuticals is done by smaller companies that could benefit from the past knowledge learned and put in the form of standards."
The purpose in every case is to ensure that the drug is safe for human use. Standards could help industry to develop drugs more effectively and more quickly as well as reduce costs. The new viral inactivation standards would be based on validations that companies have been performing for decades.
E55.04 is also reviewing the biopharmaceutical standards that came into the committee earlier this year with the transfer of more than a dozen standards formerly under the umbrella of Committee E48 on Biotechnology. The standards have been assigned to subcommittee members for initial review before proceeding with further action. The group plans to coordinate this effort with the U.S. Pharmacopeial Convention (USP), which has developed many standards for cell culture testing, raw material and final product testing, to ensure that efforts are not duplicated.
To further its standards work, E55 is emphasizing outreach to increase awareness of the committee and participation. "We're not going to make progress if we don't sell our case," says Crooker.
The committee is taking a message of progress and capability to groups that could benefit from understanding and using E55 standards. In April 2012, Cook and Christine DeJong, ASTM's E55 staff manager, gave a presentation about E55 at a meeting with the European Medicines Agency - a group similar to the FDA. The duo described ASTM International and its European presence, the E55 road map and the committee's vision for contributing standards for pharmaceutical product and process design, development, manufacturing and performance.
E55 is targeting additional conferences and events to let industry representatives know about the committee. The October 2012 annual meeting of the American Association of Pharmaceutical Scientists, a group intended to foster information exchange among its 12,000 members worldwide to enhance contributions to public health, is on the list. A poster has also been developed to display at industry gatherings.
E55 hopes its outreach will also broaden representation on the committee. The current international complement of main committee officers, notes Crooker, should help. Steininger says he plans to tap into his industry connections to help recruit additional participation for the biopharmaceutical standards table. Another move to further this objective is the appointment of a member at large from the European Medicines Agency to the E55.90 executive subcommittee. Discussions are also under way about further increasing European agency participation in E55.
"For historical reasons, there is diversity in the regulations covering the industry around the world, and the differences in the regulations can lead to duplication of work, increased complexity and reduced efficiency. Internationally accepted standards can help the industry, and also regulatory agencies, by providing a globally accepted standard in a particular area, particularly where regulatory guidance does not exist," says Cook.
To that end, E55's efforts to involve more global participation in its standards development should benefit regulators and industry and, ultimately, patients worldwide.