Asia Raises Bar for New Drugs, Manufacturers With Tougher CMC Reviews, GMP Inspections (Part 1)

As Asian drug regulatory authorities gain confidence in their ability to regulate new drug products, they are subjecting applicants to increasingly extensive chemistry, manufacturing and controls reviews, more like those of first-tier authorities in the U.S. and Europe.

Asian CMC reviews can be even more extensive, including elements that the U.S. FDA and the European Medicines Agency would set aside for review during inspection.

Even so, most have so far insisted on remaining second-tier players in the global pharmaceutical marketplace by only agreeing to review applications after the manufacturers show they have already won approval elsewhere.

Consequently, their CMC reviews are not only increasingly time-consuming, but they also remain delayed, and this has slowed the flow of new drugs into Asia.

One country, Taiwan, is so fed up with the delays that it decided last month to, in its words, "scrap" its requirement for certificates of pharmaceutical products, or CPPs, which show that applicants had won approval from mostly Western "reference countries."

Another nation, Japan, takes a first-tier approach to applicants. But even so, its reviews take much longer than those of the U.S. and the European Union, resulting in a "drug lag" that the country has been chipping away at and is hoping to further reduce.

One of the issues for Japan and many of the other Asian nations is their desire for clinical trials to have statistically valid results for their domestic population, which differs genetically from that of the West. There are efforts under way to reduce the delays associated with accommodating these requirements.

Asian Regulators On GMP Standards

Meanwhile, Asian drug regulatory agencies are working to strengthen their GMP requirements and the ability of their inspectorates to ensure quality domestically and abroad.

South Korea and China are particularly focused on upgrading GMP requirements to international levels and enforcing them more rigorously as a way to protect their citizens from substandard drugs and to help their domestic pharmaceutical industries become more competitive globally.

Asia is advancing its CMC review and GMP oversight in the context of global harmonization, and the region is hoping to adapt its regulations to global standards like those of the International Conference on Harmonization, or ICH, and the Pharmaceutical Inspection Cooperation Scheme, or PIC/S.

Industry sees an opportunity in this regard to work with the regulatory agencies in Asia to bring their CMC reviews and GMP inspections in line with global standards, thereby simplifying and rationalizing the global compliance process.

Members of the International Society for Pharmaceutical Engineering's new Asia-Pacific Focus Group recently discussed some of the key issues and idiosyncrasies associated with CMC review and GMP compliance in Asia.

The group presented a country-by-country regulatory CMC and GMP update of the region Nov. 10 at ISPE's annual meeting in Orlando, Fla.

First-tier Inspectorates Lead The Charge

One point that came out of the discussion was that Asian inspectorates could reduce the inspection-hosting burden on global manufacturing facilities by accepting the findings of first-tier inspectorates, as their reviewers do for new drug applications.

This is something Roche's Global Quality Manager Stephan Ronninger, who is also co-chair of the PDA Regulatory Affairs and Quality Control Committee, recently encouraged countries that were still developing their pharmaceutical inspectorates to consider. They could follow the lead of Colombia, which is using the "reference country" approach to focus its own GMP inspections on facilities in other Latin American countries .

This concept arose again at ISPE's Asia-Pacific session. Given that most Asian countries require CPPs for applications, Jeffrey Ferguson, Eli Lilly director of global regulatory affairs, CMC, asked, "Can't we extend that philosophy to inspections?"

There was also discussion of whether Asian inspectorates might be favoring domestic manufacturers. A GMP inspection of a recently acquired domestic manufacturer seemed easier, one participant said a colleague had remarked. Another participant suggested that what really benefits domestic manufacturers in Asia during inspections is the lack of a language barrier.

ISPE's Asian-Pacific Focus Group

Pfizer's Global Regulatory CMC Executive Director Chi-wan Chen explained that the ISPE Asian-Pacific Focus Group, formed in mid-2009, consists of regulatory CMC and GMP professionals from various companies who have responsibilities in the Asia Pacific region.

"We looked around and there was just no regulatory CMC GMP type of networking group in any trade organizations or other professional societies," Chen said. "So we decided to form this group. And the goal of the group is to share our regulatory intelligence and experience and also share the experience with the ISPE community at large and also to pursue harmonization of regulatory policy and implementation in the region."

The session's program was the group's first experience "to share with you our knowledge and experience about CMC and GMP in these countries," Chen said.

The focus was on new and emerging regulations and guidelines rather than learning how to do filings. "It's for us to stay at a high level to share with you what's new, what's the trend in this region or in the specific country."

ASEAN's Role

The Association of Southeast Asian Nations, or ASEAN, is an association of 10 countries that aim "to work together more as a single voice," said Lilly's Susan Stolz.

ASEAN seeks to remove trade barriers among its members - Thailand, Singapore, Indonesia, Malaysia, Vietnam and the Philippines, Myanmar, Cambodia, Brunei and Laos (Also see "ASEAN Signs MRA To Ensure All Exports Meet GMP Standards In Southeast Asia By 2011" - Scrip, 17 Apr, 2009.).

In part, it plans to remove such barriers by harmonizing member countries' regulation of pharmaceuticals. But progress is slow because out of respect for members' sovereignty, ASEAN only adopts guidelines when there is full consensus, said Stolz, who is principle consultant, regional centers, CMC regulatory affairs, Eli Lilly. Her primary responsibility is post-approval CMC changes for marketed products.

There is no centralized review body in the association like there is with the EU's European Medicines Agency, so applicants for marketing authority must approach each country separately.

As with most of Asia, all but one of the ASEAN nations require applicants to provide a CPP from a regulator such as FDA or EMA confirming that it has approved the product for its market. The exception is Singapore, which has a process for independently assessing applications.

Over the past decade, the ASEAN nations have required increasingly detailed CMC dossiers, she noted.

Review and approval can take a long time, typically nine to 18 months for new products.

Regional Variation On ICH

The countries cooperate on the content and format of a regional variant of the International Conference on Harmonization's Common Technical Document, used globally for marketing authorization submissions. Indonesia has the lead on quality aspects of the ASEAN Common Technical Document (Also see "ASEAN Makes Slow But Steady Progress Toward Harmonization Of Pharmaceutical Regulations" - Scrip, 5 Oct, 2009.).

The countries also cooperate on guidelines, with Indonesia taking the lead on stability studies, Malaysia on variations, and both on bioavailability and bioequivalence studies.

Because the ASEAN CTD differs somewhat from the ICH CTD, "it causes additional documents for CMC Regulatory to have to manage," Stolz said. An added factor is that each country takes a different approach to the two CTD formats. Singapore will accept either. So will the Philippines, although it may approve ASEAN CTDs more quickly. Thailand requires the ASEAN CTD for new products, but will accept the ICH CTD for variations and renewals of existing products.

GMP documentation also can be challenging, she said. The ASEAN countries may request GMP certificates in addition to CPPs, for example. The association formed a task force in 2005 to "look at what their common GMP requirements would be." Industry has proposed simply relying on Europe's EudraGMP database instead of original GMP certificates. There's also discussion about the ASEAN countries at least cross-referencing among themselves.

Stolz said the task force is encouraged that ASEAN countries have been joining PIC/S, which sets standards for inspections and GMP documentation (Also see "‘Global Allegiance’ of Inspectorates Emerging" - Pink Sheet, 1 Nov, 2010.).

ASEAN Mutual Recognition Of GMP Audits Will Help

GlaxoSmithKline CMC Advocacy and Regulatory Intelligence Director Bekki Komas said an April 2009 ASEAN mutual recognition agreement on GMPs will reduce duplication of GMP audits, at least within the ASEAN region, thereby saving both industry and regulators time and money.

A July 2010 draft revised ASEAN stability guideline shows the region is harmonizing, with many of the provisions adopted from the World Health Organization's 2009 guideline and the ICH Q1E guideline.

ASEAN is also revising its July 2004 bioavailability and bioequivalence guideline, which is based on the biopharmaceutics classification system, or BCS, she noted.

ASEAN nations also have nation-specific requirements. For example, labels must clearly state porcine content under Indonesia's Pork Decree, a requirement that she said was likely related to the country's large Muslim population.

Also, Singapore requires a specific format for the quality overall summary, while Malaysia requires translated SOPs for analytical testing with validation results for new chemical entities and line extensions, and Vietnam wants signatures on dossier pages.

Validation Requirements Unclear

Malaysia's analytical validation requirements have generated a lot of work among applicants. "In most of the new submissions lately, we've been experiencing a lot of detailed questions on methods and methods validation, even for compendial type methods where you would not expect to provide validation." Much of the questions concern details that manufacturers would normally just provide upon inspection.

Similarly, in the area of process validation, Malaysia has been asking applicants for validation summary reports for manufacturing performance qualification, even though it is outside the ASEAN guidelines. Reviewers have been using a checklist, a copy of which her organization has recently obtained, enabling it to provide information up front and justify it better.

In summary, she said the ASEAN countries present some real opportunities. They have a goal to act as a single market by 2020; they have a task force on mutual recognition agreements; and they are adding major, minor and do-and-tell categories to the ASEAN variation guideline.

"This is an incredible market that's emerging, and we have a lot of opportunity to influence those markets with our response to these guidance documents."

But there are challenges: ASEAN members want a lot of stability data to support a submission, 12 months or more for shelf-life dating. Also each market's requirements vary, and requests from inspectors for details on methods and process validation pose challenges.

- Bowman Cox ([email protected])

[Editor's note: This is part one of a longer story that appeared in the December 2010 issue of the Gold Sheet. PharmAsia News will be publishing additional sections of this story in subsequent issues. Not a subscriber of the Gold Sheet? Click here to receive a complementary copy.]