Taking the Plunge to Harmonize Pharmaceutical Regulations

March 4, 2010
Within the past five years, more of world's regulatory agencies and pharmacopeias have gotten on the same wavelength.

International standards tend to proceed at a glacial pace, especially when anything complex is involved, but efforts to streamline global pharmaceutical regulations are stepping up. Mandated by the increasingly global nature of drug manufacturing, harmonization can only help the industry improve efficiency, but its ultimate goal is to ensure that more people in the world have access to the medicines they need.

Some may complain that this goal is still a long way off. Filing clinical documentation for a new drug can be 15%-20% of the costs of trials running in the hundreds of millions of dollars. Meanwhile, the costs of supporting multiple and redundant agency plant inspections are high, running to $130,000 to $400,000 per day and 1,000 to 2,500 person hours per inspection. Citing these figures and data from a survey by EFPIA, John O’Connor, senior director of corporate inspection management of Genentech, reiterated the need for increased harmonization of plant inspections at BIO 2009 last May. “These resources aren’t being directed toward other quality efforts,” he said.

However, most observers agree that the past decade, and the last five years in particular, have seen great progress in harmonizing R&D and clinical requirements, as well as overall regulations for finished drug products, active ingredients and excipients.

The guiding force for much of this work has been ICH, the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use. Next month marks the twenty-first year of the group’s mission: to eliminate redundant paperwork, and streamline the costly and difficult process of developing and making pharmaceuticals around the world. 

ICH is far from the only group working on harmonization. Pharmacopeias have their own projects and collaborations going on, including USP’s Pharmacopeial Discussion Group (PDG), which started just a few years before ICH was established. 

Update on Japan

For many years access in Japan to drugs approved for use in the U.S. and Europe lagged by at least four years. In 2007, when only 28 of the world’s 88 best-selling drugs were available to the Japanese market, Akira Miyajima, head of the Japanese Pharmaceuticals and Medical Devices Agency, said he planned to bring Japan’s new drug approvals inline with those of the U.S. and Europe by 2012, and to cut approval times by 2.5 years. The Agency was to hire 240 new reviewers at the time.

Japan’s regulatory environment is changing, due to a change in government leadership, according to Masaru Kitamuru, who commented in February’s edition of Who’s Who Legal Life Sciences Roundtable. Regulators are working to expedite clinical trials and drug approvals, adding more requirements for post-marketing surveillance, he says.  Japan has also set guidelines for approving biosimilar products, he says, expecting downward cost presures and promotion of generics. 

Major changes have been seen in the amendment of the Pharmaceutical Affairs Law, which took effect last June, says Satoru Nagasaka, a partner with TMI Associates. A key change has been implementing risk-based standards for information to the public. The law now categorizes nonprescription drugs depending on their risks: Type 1 drugs, which are of particularly high risk (e.g., H2 blocker); Type 2 drugs, which are of relatively high risk, such as cold medicine; and Type 3 drugs, which are of relatively low risk, such as vitamin pills. Each drug’s level of risk must now be indicated on the outside of the box, and regulations on labels and point of sale have been changed.

 The World Health Organization is also working on harmonization, as are the Pan American Network on Drug Regulatory Harmonization (PANDRH), various national groups focused on active pharmaceutical ingredients, and IPEC, which concentrates on pharmaceutical excipients. 

However, ICH, which is made up of regulatory bodies, pharmacopeias and drug industry members from the U.S., Europe and Japan, provided a broad framework and focus for a project that might otherwise have been too diffuse and difficult. So far, it can claim substantial gains.

Big Picture Improvements

The U.S. and Europe have come a long way toward harmonizing their regulatory requirements, says Mukesh Kumar, senior director of regulatory affairs and quality assurance for Amarex Clinical Research (Germantown, Maryland). “They’re following ICH guidelines on quality, and, by using the common technical document format, they’ve standardized on how on how an application is submitted,” he says. “They now offer a joint application for orphan drugs.” 

Even Japan, which, despite its ICH membership, had seemed to be on its own track five years ago, continues to demonstrate its commitment to harmonization (Box). When I contacted USP for this article, Nobuo Uemura, a senior staff member at Japan’s Pharmaceuticals and Medical Devices Agency MHLW/PMDA, had just arrived in Rockville, Maryland to begin a 15-month stint working at USP offices, a visible sign of JP’s and USP’s interests in closer collaboration.

Perhaps the most tangible 21st century symbol of progress is the electronic common technical document (eCTD), which a growing number of companies are now using for their IND’s, NDA’s, ANDA’s, BLA’s, and DMF’s. Dr. Kumar jokes about the days when documentation for a new drug had to be delivered to FDA by truck.

Thinking Globally, Acting Locally

But harmonization today is only an outgrowth of the reality that pharmaceutical regulation has become an increasingly global affair, since most of the new DMF’s being filed are from India, and most API’s being manufactured in India or China. Two years ago, both FDA and the United States Pharmacopeia began moving offshore, and over the next year, set up satellite branches in China, India, and Latin America. 

USP was the first to move offshore, which allowed it to advise FDA when the Agency established foreign bases as part of its Beyond our Borders program, says Susan de Mars, USP’s chief documentary standards officer. As FDA and USP work together to update compendial test methods, such as uniformity of content (mass), having an offshore presence only increased USP’s collaboration with FDA, while strengthening its local connections with regulators, industries and pharmacopeias, de Mars says. “It’s part of our efforts to work outside of ICH regions, and areas that are part of our PDG, particularly with countries that have constrained resources but are becoming a more important factor in drug imports in the U.S.,” de Mars says.

Pharmacopeial Progress

USP’s PDG has made good progress, says de Mars, and so far has finished harmonizing 27 out of the 34 general chapters that were part of its original Work Plan, and 40 of 63 excipient monographs. However, she concedes, it’s still “a slow and laborious process,” and the PDG only covers 15% of the excipient monographs and 20% of the general chapters within the USP. 

However, efforts are also moving forward with finished drug substances, which are outside the scope of PDG. In one pilot program, USP and the European Pharmacopeia (EP) are jointly developing harmonized monographs, as well as reference standards for two drug substances. What’s novel is that, this time around, the work will be done from the beginning, instead of harmonizing retroactively, as was necessary with PDG.

Overall, pharmacopeial harmonization really began to take off 10 years ago, when USP decided to focus on harmonization by attribute. “We decided to look at the main tests and monographs—for instance, assays and identity tests—and to focus efforts on harmonizing where we can agree, always understanding that there will be some cases, with some tests and regional requirements, where it won’t be possible,” says Kevin Moore, senior scientific liaison for USP.

Over that time, there has been good alignment across USP, EP and JP, although de Mars concedes that Japan has special challenges, since they publish less frequently, have fewer staff members and must translate everything from Japanese into English.

This year, USP will decide whether or not to expand PDG. Still outstanding on the PDG list, Moore says, are chapters on the uniformity of content, mass, and the chapter on instrumental methodology of color. “We hope to have a good amount of progress over the next year by the time we next meet in June,” he says. 

China Bridges the Gap
China has been observing ICH activity closely and has also been working to bring its quality systems and regulatory standards more in line with those of Europe and the U.S. Bikash Chatterjee of Pharmatech Associates notes changes in its approaches to GMP in an editorial which will run in our next issue and is excerpted here.

In January 2010 the SFDA, China’s regulatory authority, attempted to close the gap between its practices and quality and regulatory standards in the U.S. and Europe with GMP 10. Updating GMP 8, which had been issued in 2008, it borrows heavily from European guidance for finished drug products. SFDA is soliciting comments, both from within and without China. It is significant because it emphasizes the quality management system, specifically on the need for Deviation Control, Corrective Action and Preventative Action (CAPA) systems and a Product Quality Review (PQR) system.

In addition to the GMP 10 guidance, the SFDA has also created an annex to the main guidance which specifies the requirements for sterile API, sterile manufacturing and terminally sterilized product. What is interesting about this document is the specific requirements called for concerning facility design and environmental conditions. To date, the GMP guidances have relied on a general discussion of the end result, e.g.: “Article 6, Annex 1; The Manufacture of products should be carried out in clean areas, entry to which should be carried out through airlocks for personnel and/or equipment and materials.”  This has allowed each inspector to interpret the requirements as they saw fit for each manufacturer.

Other goals Moore says are harmonizing general chapters and excipients, in collaboration with ICH’s Q4B working group, which focuses on the interchangeability of harmonized general chapters. Originally, he says, ICH had charted Q4B to look at 11 chapters for examining, but five additional chapters were added last year.

APIs and Excipients

Variable active ingredient and excipient quality have surfaced as key global quality issues that are being addressed on all harmonization fronts.USP plans to have a monograph for any excipient listed in FDA’s inactive ingredients database, Moore says, but progress is challenged by the diverse approaches used to regulate them, globally. One initiative at USP has been an international working group established for good distribution practices.

The European Directorate for the Quality of Medicines & HealthCare (EDQM) has established bilateral confidentiality agreements with FDA and Australia’s Therapeutic Goods Administration (TGA) to share confidential inspection information related to API’s and excipients, and a pilot project for harmonizing inspections was launched last year.

A number of routes are being considered—either applying GMP’s to excipients or establishing a program where plants would be inspected by a voluntary program in which inspections would be handled by third-party certified inspectors. FDA has recently launched a pilot third-party inspection program for medical devices.

“We still believe that self-regulation for excipients is the preferred pathway, but we need to provide best practices and guidance,” says Janeen Skutnik, Chair of IPEC Americas, and Vice Chair of the IPEC Federation. IPEC aims to do this by establishing standards and best practices in the form of guidances. This approach, she says, allows users to take care of the basic GMP’s, and leave a company’s Audit teams to focus on the individualized and specific needs of their use of that excipient. It also allows them to focus more time on relationship management and monitoring. 

IPEC Americas has been actively converting IPEC’s GMP’s (not required for manufacturers) into an ANSI standard that would allow regulators to refer to a universally recognized benchmark during inspections, Skutnik says. The group is also working on guidance documents for Pedigree, GMP’s, GDP’s, Excipient Qualification, Quality Agreements, and guides for audits, Significant Changes and Certificates of Analysis.

IPEC Americas is meeting with FDA and the USP to ensure consistency and harmonization of standards and monographs, Skutnik adds. From the FDA perspective, they are engaged in the ANSI project to convert the IPEC PQG GMP’s guide into an ANSI guide. (This work is supported by OMB Circular A-119). “The formal ANSI teams are being assembled and we expect to complete the drafts this year,” she says. 

Additionally, International Pharmaceutical Excipients Auditing (IPEA) has applied to ANSI to become an accredited organization. Significant progress was made in this project last year, Skutnik says, and she expects IPEA to receive accreditation soon, so that it could handle third-party audits. 

Managing Risk

Harmonization doesn’t mean replication. There will always remain differences between styles, across regulatory agencies. For instance, one can either go the centralized route for introducing a new drug in Europe (via EC) or via each regional authority. In addition,
drug approvals are “phased” in Europe, where manufacturers must get reapproved, based on safety.

FDA’s Risk Evaluation and Mitigation Strategy, part of the FDAAA act of 2007, effectively harmonizes practices, closing the gap between the EU (which requires postmarketing safety data) and U.S. (which hasn’t), by asking manufacturers to collect patient safety data. So far, Kumar says, one drug approved by FDA has already undergone REMS. Depending on the drug involved, the costs can be high, he says, running from $50-$100 million for a psychotropic drug but much less for niched cancer therapies.

There will always be differences, too, in such things as plant inspection practices.  EFPIA’s survey noted regional flavors, with FDA focusing on deviations and investigations, buildings and facilities, validation and equipment cleaning and maintenance.  The EU meanwhile, focused on room classifications and cleanliness, equipment maintenance, laboratory controls and quality agreements, where Japan’s inspectors emphasized raw material and facility cleanliness and product appearance.

About the Author

Agnes Shanley | Editor in Chief