Before Dr. Sharfstein’s address, Richard Johnson was introduced as the new PDA president. Former association president Bob Myers retired earlier this year. “I’m very excited about challenges we face as an association going forward and am committed to continuing the tradition of PDA,” said Johnson, whose term became effective September 1. “Our commitment to our mission is equally clear and so we will be continuing to live up to that mission as we go forward…. We are going to continue connecting people in science and regulation.”

Next, FDA’s Rick Friedman, co-chair of the conference along with Martin Van Trieste of Amgen, briefly discussed the focus of the conference, “Securing the Future of Medical Product Quality: A 2020 Vision.” He noted that after a series of contamination events, including diethyl glycol [DEG] and heparin, industry and regulators have learned many lessons. “We’ve learned together in the last years that as your unknowns in the supply chain increase, so does cumulative uncertainly and risk. We’ve also learned that integrity can be compromised either by those lacking understanding of how to properly manufacture or handle drugs or by those with bad intentions. The question we have to collectively deal with is how do we improve the system to prevent these grave risks?”

Sharfstein began his address by noting the title of the conference and how it “takes a little courage in the world of medical product technology to look ahead,” he said. “It’s so important to look forward to the next stage in innovation and science for product quality…. Helping to shape the future is one important reason why [FDA Commissioner Dr. Hamburg and I] accepted these positions.” Sharfstein and Hamburg started their positions at FDA this past spring.

Referring to the May 2009 New England Journal of Medicine article in which he and Dr. Hamburg outlined their vision of the agency as a public health agency, Sharfstein outlined four principles guiding their definition of a public health agency.

First, a primary principle of public health is prevention, he said. “Rick Friedman mentioned economic adulteration as a problem, diethylene glycol, supply-chain management, and others, and I think all of these things are amenable to a preventive approach,” he explained. “When one company falters because of a quality problem, it’s their problem to fix and prevent. But when a problem occurs across the industry, when it causes the kind of quality-system problems…it’s everyone’s problem and it’s FDA’s problem to help think about solutions.”  

Sharfstein also brought up the quality trio guidelines finalized by the International Conference on Harmonization, ICH Q8, Q9, and Q10, as an example. “The goal of these efforts is to understand from the start what makes a product of high quality rather than waiting to discover a problem after the fact,” he said. “We would like to foster more such productive collaboration that leads to concrete results in preventing problems.”

The second principle of a public health approach requires the best available science, said Sharfstein. FDA is working to identify key projects that can help product quality, streamline approval pathways, and improve scientific training. “We’d like to see more guidance documents emerge out of these scientific efforts to provide a clear and transparent process to address long-standing quality issues and to help bring important products to the market.”

Sharfstein pointed out that both basic science and regulatory science are needed to improve industry, and then provided a rowboat analogy. If a rower has one massive right arm and a puny left arm, it’s no surprise that the result is not forward moving, he said. “Industry has an important responsibility for helping to move regulatory science forward.”

Third, a public agency by definition involves the public, he said, pointing to the new transparency initiatives at FDA such as its website, public meetings, and blog. He encouraged industry to improve its transparency as well, noting that sometimes, companies are reluctant to issue a press release or conduct a recall when things go wrong.

“In the next decade, with speed of information only accelerating, it’s a good assumption that product quality problems will eventually come to light. It’s better for companies to develop effective and transparent communication systems now rather than stumble when others are providing key messages about your products for you,” he said.

Sharfstein emphasized his point by stating, “When public health is at stake, FDA is going to take this basic position: You can explain this problem to the public or we will.”

He discussed the fact that, based on his experience as the Baltimore City Health Commissioner, the public seems to understand two basic messages: this product is totally safe or totally unsafe. But he noted that companies can’t not react for fear of scaring the public. “Having that challenge of risk communication is not a reason to not to tell the public what they need to know…. We need to work together to establish messages besides ‘totally safe’ and ‘totally unsafe.’ …One such message would be that there are both benefits and risk and that we believe the benefits exceed the risks.”

Fourth and finally, Sharfstein discussed the premise of public health as one in which the health of the public matters. “In evaluating product quality issues for 2020, I would imagine there are many ways to resolve key challenges as you face them, however, I urge you to consider the health of the public as the North Pole for your compass.”

A brief question-and-answer session followed (Sharfstein had to head to the White House for a budget meeting). One audience participant asked about FDA’s new enforcement approach, which Dr. Hamburg discussed recently at the Food and Drug Law Institute.

“Enforcement is an important tool and for it to be effective tool, it has to be timely and meaningful and it has to address issues that are important. What Dr. Hamburg mentioned [in the Food and Drug Law Institute talk is that…] the enforcement system at FDA has not always met that goal all the time.” With this in mind, when FDA sees the public health in danger, it will be acting more quickly. “We may not even send a Warning Letter if we think that it’s that serious. At the same time, we want to give an incentive for people to fix it as quickly as possible…. One incentive would be a letter from the agency that the problem has been resolved.”

He pointed out that when he was the Baltimore City Health Commissioner, if there was a problem in the city, the mayor expected him to fix it right away, not exchange memos about it for several months. “Our hope [at FDA] is that we’re able to send a message that there are certain product quality things to be avoided in the first place, but if they happen, the agency can act very quickly on them and also have them resolved quickly.” 

In a bit of a candid statement during the Q&A session, Sharfstein admitted that he’s been reading the trade press and watching TV reports about FDA since he and Dr. Hamburg began their transition at the agency. He’s been quite interested in the media’s take on whether the agency will be pro-industry or anti-industry. “Dr. Hamburg and I feel very strongly that a public health approach is not pro- or anti- industry. To the extent that we can articulate that something is worth it, we think it’s okay to take the risk….. At meetings that I’m at, we’re saying, what would make something great possible? Let’s not be so risk-averse that we lose opportunities for really important innovation and progress….. In the end, we’ll be judged on whether we can make those changes happen at FDA…and that’s something that we’re working on.”

I have to point out that FDA does accept electronic submissions for ANDAs, drug master files, and other filings [see their electronic submission list]. They even have a platform for electronic adverse event reports, which demonstrates that the agency has the technical know-how and capacity to go 100% digital. And in June, FDA issued guidance that drug establishment registrations and drug listings be submitted in electronic format only, with paper filings to be accepted only with a waiver, but a final rule making this a requirement has yet to be set.

For the sake of time—and the employees at FDA—I hope these proposed rules for adverse event filings are finalized quickly and that the agency—and industry—can let go of paper submissions once and for all.

ICH got on board with the electronic age in November 2003 when it finalized the electronic specs that applicants can use when submitting filings to regulators in various regions around the world. Known as the electronic Common Technical Document, or eCTD, submissions in this format grew by 300% between 2005 and 2008. Although the eCTD format is required for any electronic submission and “preferred” by regulators compared with paper, paper CTDs are still allowed. Perhaps ICH will follow suit of FDA and go fully digital in the near-term as well. For in our global age, being able to communicate quickly and electronically is crucial to public safety.

We’ve all heard that quality by design and science/risk-based approaches to pharmaceutical manufacturing require a paradigm shift among industry. Well, that message was reinforced again today at the 3rd Annual Pharmaceutical Technology Conference in Philadelphia, PA.

Christine Moore, acting deputy director of the Office for New Drug Quality Assessment at FDA, said that industry needs to be more willing to share information with regulators. In the past, industry may have been afraid to share details for fear of receiving more questions from the agency. But with the quality initiatives being undertaken by FDA, said Moore, it’s now okay to say, “There are risks with our product.” FDA just wants to know that you can control those risks, she said.

It’s also important to make sure your company has the financial and management support it needs to implement quality by design and quality systems. You have to be able to colloborate with and work with other departments and functions involved in your product’s life cycle, including with other regions in our growing global pharma market, explained Moore.

Gerry Migliaccio, vice president of quality at Pfizer Global Manufacturing, added to Moore’s point. Pfizer, says Migliaccio, has seen first hand all the benefits that can come from using QbD-based manufacturing, including saved cost and time. But to accomplish this, the company had to change its thinking. For example, instead of approaching a problem with corrective action, they focus on continuous improvement throughout the product’s full life cycle. Instead of analyzing proven acceptable ranges, they focus on design space. Instead of working toward blind compliance (i.e., doing what works to obtain regulatory approval), they work toward science- and risk-based compliance, which satisfies the regulators and can be justified scientifically.

This shift in process and thought is not expected overnight but it is taking over the industry. Moore reported that FDA is now receiving more QbD-based applications than it received during the CMC pilot program, which began in 2005. But, added Migliacchio, more culture changes are pending. With fading blockbusters, increasing costs, and additional IP challenges and safety concerns, industry also needs to be rethinking its full supply chain and examining it in ways it never has before. For example, said Migliaccio, Pfizer is now sending its ICH Q8 managers on site to ensure that suppliers are using and following a quality system. The company is also working to monitor pricing and supply gaps and working to help emerging markets that have immature regulatory systems to learn how a process and quality management system should work.

FDA and industry worked together the past several years to draft, approve, and implement the ICH quality guidances, Q8, 9, and 10. But today, much more work is outsourced to markets outside of the ICH region, such as India and China. It’s up to industry, says Migliacchio, to train the companies we outsource to. And if they don’t comply, we have to avoid buying from them or contracting with them. This requires yet another cultural change among pharma. But all of these changes—this re-education if you will—are critical to keeping our supply chains and products safe.

The quality trio guidances aren’t meant to teach industry about quality, said Dr. Cappuccino, industry has been manufacturing quality products for years. The guidances are meant to help industry address quality issues. Quality isn’t supposed to be “tested,” it’s supposed to “built in,” explained Dr. Cappuccino, who provided the following example of a traditional quality approach compared with today’s enhanced approach.

A traditional product approach might include these steps:

• Gain market input
• Develop API
• Formulation
• Develop process
• Implement finished product control, including submitting any changes via a regulatory supplement.

The enhanced approach, discussed in ICH Q8, 9, and 10, proposes these steps instead:

• Create a target product profile
• Conduct a risk assessment
• Complete API studies as well as formulation studies (this is where design space enters the process)
• Conduct process studies and develop a control strategy
• Control  process
• Real-time release
• Note that any changes or improvements within the design space do not require regulatory supplement filings.

The overall benefit of compiling more information in the beginning and understanding more about the process is that manufacturers have more flexibility and less regulatory oversight, said Dr. Cappuccino.

Additional quality sessions are being held later today and tomorrow at the PharmTech conference. Stay tuned for more blog posts. And also stay tuned, says Dr. Cappuccino, for potential ICH guidance revisions. Being considered by the steering committee are changes to Q3A/B and Q6A/B in light of Q8, 9, and 10. Also coming soon from ICH are a third group of Q&As that address the quality trio guidances. Two groups of Q&As are already on the site at www.ich.org.

The US Food and Drug Administration is focusing its efforts on Institutional Review Boards (IRBs), which approve and monitor clinical trials. The agency recently told a hearing of the House Subcommittee on Oversight and Investigations that it will require IRBs to register with them, beginning in July 2009. The registration process will be the basis for a database of IRBs, and this tool will help FDA monitor and inspect these bodies. The agency also said it would establish voluntary guidelines for drugmakers and IRBs.

FDA was stirred to action when the Government Accountability Office (GAO) reported that it had successfully set up a phony IRB, registered it with the US Department of Health and Human Services, and gotten approval to test an imaginary medical device on human subjects. The GAO also obtained a real IRB’s approval for a fake protocol for human-subjects research, although the protocol contained demonstrably false claims that the device to be tested had FDA approval.

Last week the Association for the Accreditation of Human Research Protection Programs gave Pfizer its accreditation for protecting the rights of its human clinical trial subjects, and the company pledges to carry out trials according to the International Conference on Harmonization’s international standards of good clinical practice. Despite Pfizer’s good will, I think FDA needs binding, not voluntary, rules to ensure that all pharmaceutical companies protect their trial patients’ safety. Human life is precious and demands no less.

Also meeting in Brussels last week was the implementation working group for the quality guidelines: Q8 Pharmaceutical Development, Q9 Quality Risk Management, and Q10 Quality Pharmaceutical System. The group discussed items that needed further clarification, including  knowledge management, real-time release testing, and control strategy. The group also discussed training issues and plans for the next six months.

The next implementation working group meeting will take place in June 2009 in Yokohama, Japan.

Just as the ICH steering committee and expert working groups are discussing next steps for the implementation of Q10 Pharmaceutical Quality System and possible adoption of the Q8 annex to Pharmaceutical Development in Brussels this week, ASEAN’s* harmonization scheme is taking another divergent turn.

An article in the November Regulatory Focus discusses the Southeast Asian association’s harmonization efforts, which Malaysia, a member state, initiated in 1992 (note that the first ICH meeting was in 1990). The association established a Pharmaceutical Product Working Group (PPWG) in 1999 to develop harmonized pharma regulations and a common technical document for ASEAN member states. Since then, the group has consulted with ICH and even adopted applicable ICH guidelines and procedures. And although I’m happy to report that ASEAN did not completely go out on its own—it did rely on already existing ICH documents as well as US and UK pharmacopeias—it strikes me as odd that ASEAN would not just join ICH. Why not participate in the international body?

ASEAN issued a new common technical dossier (for the registration of pharmaceuticals for human use) that is to be implemented in 2009, according to the Regulatory Focus article. Its format and structure are similar to that of the ICH common technical document (CTD) but different enough that the dossier cannot be easily formatted for those drug manufacturers working globally. The list of drugmakers without a multinational presence, as we know, is growing shorter every day.

This begs a second question. Why would ASEAN go through all the extra work of managing a pharmaceutical group and developing guidance and documentation that already exist and have been agreed upon by market-leading countries (i.e., the United States, Europe, and Japan)? Why not just adopt the ICH CTD version?

The other day, PharmTech’s editor-in-chief shared a related story with me about her recent trip to China for the Interphex China show. She relayed that SFDA officials seem intent on developing their own guidance and GMP practices rather than borrowing from FDA or EU. Aside from Japan, an ICH member, it seems as though the majority of Asian countries are determined to be as independent as possible when it comes to the pharmaceutical industry and regulation. As Thomas Friedman, author of The World is Flat, would argue, there simply is no justification for this approach or attitude anymore.

…

*ASEAN stands for the Association of Southeast Asian Nations. The association’s roots are tied to economic unity and date back to 1967. Today, the association consists of Brunei, Cambodia, Indonesia, Laos, Malaysia, Myanmar, Philippines, Singapore, Thailand, and Vietnam.

This month is quite exciting for those in the pharmaceutical industry paying attention to harmonization and international regulatory efforts—which frankly, should be everyone if your company wants to stay in the game. Last week, PDA/FDA held its annual joint regulatory conference with nearly 20 high-level speakers representing the US Food and Drug Administration, including Dr. Janet Woodcock, director of the agency’s Center for Drug Evaluation and Research. Several European representatives presented as well, including the European Medicine Agency’s Emer Cooke. And to give China’s perspective after a very harsh year due to the heparin contamination, Tang Minhao, deputy director of the Shanghai Municipal Food and Drug Administration, was on site as well. Harmonization was the theme of the conference and both industry and regulators were pumped up about recent progress such as the adoption of ICH Q10: Pharmaceutical Quality System (read reports from the floor). The regulatory conference was followed by a second PDA/FDA meeting focusing specifically on supply-chain issues.

This week, the World Health Organization is holding the 13^th International Conference of Drug Regulatory Authorities in Bern, Switzerland, to discuss everything from proving interchangeability and regulations for biosimilars to anticounterfeiting and inspection information-sharing.

And in two months (Nov. 10–13), the steering committee and expert working groups of the International Conference on Harmonization will gather in Brussels, Belgium, to discuss implementation of ICH Q10, revision of ICH Q8R: Pharmaceutical Development, and several other topics regarding international cooperation. FDA is holding a public meeting to prepare for the ICH gathering on Oct. 21 in Rockville, MD.

Some in industry have been slow to adopt or wary of harmonization efforts, but clearly, it’s the issue everyone is talking about and pursuing worldwide. With a global economy and global pharmaceutical marketplace, there’s really no other direction to go in. Pharmaceutical Technology will be reporting on international cooperation efforts all fall but we’d also like to hear what you think about the subject. Leave a comment below or email the editors at adrakulich@advanstar.com.

Also on the table at this week’s expert working group meeting is ICH Q11: Development and Manufacture of Drug Substances. The ICH steering committee endorsed a final concept paper and a business plan on Q11 in April. The proposed Q11 guidance is focused on harmonizing the technical principles relevant to the design, development, and manufacture of drug substances as part of a total control strategy designed to ensure product quality and consistency. The guidance, in general, is for APIs, including both chemical and biological entities, and is meant to further clarify guidance for those substances defined in ICH Q6A and Q6B. ICH Q11 is expected to move to Step 2 of harmonization by the end of 2009 and to Step 4 by the end of 2010.

If reached, Q11 will “fill a gap in the regulatory framework,” according to the business plan, and describe in more detail what’s expected in the ICH M4 common technical document regarding the drug substance manufacturing process and process controls, material control, critical step and intermediate control, process validation, and process development.  Q11 is also expected to help save costs in four major areas: assessor time spent searching, requesting, and reassessing information; scientific writing of initial documentation for marketing authorization applications; preparation and reviewing queries for regional documentation requirements; and updating regional documentation.

Pharmaceutical Technology and SGS are hosting a webcast June 12 at 11 am EDT to discuss the results of the expert working group meeting. Some of the panelists in the webcast are participating in the expert group discussions. Sign up for the webcast and be one of the first to hear the latest on Q10 and Q11 here .