Angie Drakulich was editorial director of Pharmaceutical Technology.

Angie Drakulich

I attended the annual PDA/FDA Regulatory Conference last month to put an ear to the latest Washington buzz regarding harmonization, the theme of this year's meeting. Most of the discussions focused on the newest step taken toward international cooperation—the adoption of ICH Q10: 

. But there seemed to be an underlying theme to the talks as well.  

Both the regulatory speakers and the industry speakers brought up the notion of "increased complexity." But they weren't talking about more complex regulations or supply chains, but rather, more complex science. The idea being that new technologies and advancements in drug delivery, testing, automation systems, and so forth are creating challenges for both drug manufacturers and reviewers. 

For example, rapid microbial testing methods and cell-tissue combinations on the biologics side have been especially difficult to review, said Christopher Joneckis, senior advisor for CMC issues at the US Food and Drug Administration's Center for Biologics Evaluation and Research. A "scientific foundation," an "understanding of risk and risk management," and an integration of "product knowledge from multiple sources" are all needed to effectively communicate among individuals of different scientific backgrounds and to regulate properly, he said. 

Alyson Saben, deputy director of FDA's Office of Enforcement in the Office of Regulatory Affairs, echoed that thought, adding that FDA needs to have laboratory methods at the same scale as companies to test and validate products properly. 

For this reason, the need for continuous training and updating of FDA reviewers and inspectors has greatly increased over the past few years. There's no doubt that the modernization of science is good for pharmaceutical companies and patients, but it's proving to be another challenge for the agency in charge of its oversight. Read more about what was said at this year's PDA/FDA conference at 

Articles

Advancements add yet another challenge for industry's already overextended regulatory body.

Complex Science

A public meeting is being held today to discuss over-the-counter cough and cold medications for pediatric use. Called by the US Food and Drug Administration’s Center for Drug Evaluation and Research (CDER), the meeting is meant to provide the agency with public input as it proceeds with rulemaking for ingredients in these particular drugs. 

 Specifically, FDA is developing a proposed rule to revise the pediatric labeling contained in the Final Monograph for Cough, Cold, Allergy, Bronchodilator, and Anti-asthmatic Drug Products for Over-the-Counter Human Use. In January of this year, FDA issued a Public Health Advisory recommending that cough and cold medications not be used to treat infants and children under age 2 because serious and potentially life-threatening side effects can occur. The advisory also indicated that FDA had not yet completed its review of the safety of these medicines in children over age 2.

  for the public meeting on Sept. 29, 2008. Nearly 30 speakers, representing health departments, medical universities, healthcare associations, hospitals, pharmaceutical companies, and more will  present their thoughts on the issues at stake. 

 Government panel members include: Jane A. Axelrad,  associate director for policy at CDER; John K. Jenkins, director at CDER’s Office of New Drugs; Gerald Dal Pan,  director of CDER’s Office of Surveillance and Epidemiology; Charles Ganley,  director of CDER’s Office of Nonprescription Products; Lisa Mathis,  associate director on CDER’s pediatric and maternal health staff; Michael Levy,  director of CDER’s Division of New Drugs and Labeling Compliance; Robert “Skip” Nelson,  a pediatric ethicist in FDA’s Office of Pediatric Therapeutics, and Dan Budnitz,  a medical officer in the Division of Healthcare Quality Promotion at the Centers for Disease Control  and Prevention. 

The meeting runs from 8 am to 5 pm, at the Sheraton Washington North Hotel, 4095 Powder Mill Rd., Beltsville, MD. The open public-comment period will be held from 3:30 to 4:45 pm.

 Look for our coverage of the meeting’s results in next week’s 

Public Comment on Cough and Cold Meds for Kids

A public meeting is being held today to discuss over-the-counter cough and cold medications for pediatric use.

Pediatric Drug Rulemaking Open for Public Comment

-Janet Woodcock, director, Center for Drug Evaluation and Research (CDER)

"Heparin was a wakeup call," demonstrating that we "need vigilance throughout the supply chain," said Woodcock. Solving these issues is "going to take a lot of harmonization" given the challenges. These challenges include: an explosion of global manufacturing, increased complexity of the supply chain, greater potential for exploitation, a global regulatory system that is still fragmented, US erosion of inspectional coverage, and a lack of modern information technology systems.  

"Globalization is taking over as the standard of the day....," added Woodcock. To move forward from here, we need "seamless, effective global regulatory collaboration" with a worldwide safety net and increased effectiveness of inspectorates in developing countries. We also need fully harmonized quality standards in ICH (International Conference on Harmonization) and non-ICH regions, manufacturing modernization, harmonization of pharmacopeial stands, agreed-upon methods for supply-chain security, and better information technology, including better automation and standardization of global inventory. 

In terms of responsibility, Woodcock discussed the fact that manufacturers must take responsibility for pharmaceutical quality of their products and for the integrity of their own supply chains. Regulators must adopt standards that ensure a safety net and take actions against poor quality, while enabling continuous improvement. Standards and technical organizations need to reach consensus on technical standards. Professional and technical societies must develop and update standards and disseminate them to industry 

For its part, said Woodcock, FDA is continuing with its Pharmaceutical Quality for the 21st Century initiative, intensifying its international outreach with programs such as Beyond our Borders, and keeping track of inventory of manufacturing establishments as well as movement of product. More efforts may crystallize after the upcoming presidential election with regard to legislation currently circulating within Congress. 

-Jeffrey Shuren, associate commissioner for policy and planning, Office of the Commissioner

The Interagency Working Group on Import Safety, established by executive order in July 2007, issued a strategic framework for an Import Safety Action Plan last November. We no longer want a "snapshot at the border, but rather a streaming video feed" of when risk arrives and how we can rapidly respond, said Shuren. The goal is to have a level playing field regarding standards, corporate responsibility, and global partnerships. Companies who are outsourcing or contracting out services need to "trust the 'good actors' but verify their compliance and impose stiff penalties on 'bad actors,'" he said.  

According to Shuren, FDA is continuing to work on "good importer practices" guidance, which will be available for comment. Guidance may involve certification of compliance with FDA standards before imports are allowed into the United States. 

-Joe Famulare, deputy director, Office of Compliance, CDER

"There are many initiatives on the table regarding third-party certification of suppliers, including parts of the Import Safety Action Plan and proposals on Capitol Hill," said Famulare. [The action plan calls for FDA to have the authority to require that producers of certain high-risk products in a particular country, under an agreement with that country, certify that their products meet FDA standards in order to export to the US.] "Other types of possible legislation changes may mandate that companies audit their suppliers," he added. "The main effort in this area is within ICH Q7: 

Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients (APIs)

, and the voluntary standards of the International Pharmaceutical Excipients Council and International Pharmaceutical Excipients Auditing," he said.  

Table I: Supply chain changes since 2001. 

In another conference session, Famulare discussed supply chain qualification. "We have a task force within CDER compliance and there could be a guidance in that area forthcoming. We also enhanced ICH Q10: 

Section 2.7 regarding outsourcing to lay out a basic form of supply chain control by industry," said Famulare. "We're still studying the lessons learned from heparin and how to prevent it from happening again, but really, industry has to have the intelligence on their own supply chains." 

"For external supplier quality systems, whether you contract out or are getting supply, the regulations are specific regarding the testing to do to receive those materials and validate them," explained Famulare. "Now, with ICH Q10, having a program to audit that system and facility supplying you is very important—it goes beyond testing.... Having the intelligence to understand what may adversely impact that supply is also important. We don't expect the external supplier to have a mirror image of your quality system but we do expect it to mesh...and work with your quality system." 

-Deborah Autor, director, Office of Compliance, CDER

"We all share these new challenges and we all need to give serious thought to what we do.... It's not as simple as more inspections. We need to change the system," said Autor. "The old system was directed toward a domestic industry; that's not what we have anymore. Regulators and industry need to do more.... 

"We need more corporate responsibility. We're not in the shoe business. People are relying on these products to protect their health. We need to know where a product has been, where it was made, its integrity..." and so forth, she explained. "Management needs to be able to vouch for its products.... We can no longer say, 'FDA has to prove a drug product is bad.... We have to know a drug is 'good.'"  

Autor also talked about how industy needs to shift to international cooperation in the longterm. "The job is simply too big for one regulator to do," she said. The European Medicines Agency/FDA joint inspection pilot is ongoing for information-sharing on European Union and US sites, and on API sites in third countries.  

Author closed with the following: "In a global economy, manufacturers must bear clear responsibility for the integrity and quality of all ingredients. If you disagree with that, please let me know. Regulators must work together to adopt a worldwide approach. Together, we have to ensure that drugs are what we want ourselves and our families to take and to feel good about." 

Pharmaceutical Technology has summarized recent statements by FDA officials on supply chain issues to provde the agency's most up-to-date views and expectations.

FDA Talks about Supply Chain Challenges

 to FDA Commissioner Andrew C. von Eschenbach, Rep. Henry Waxman (D-CA) questions the agency’s priorities, specifically poking at FDA’s political appointees and whether they are promoting industry at the expense of the public’s health. 

Waxman chairs the US House of Representatives’ Committee on Oversight and Government Reform. According to his letter, the committee received copies of internal agency emails that “raise questions about who is setting agency’s priorities and why.” 

One particular set of emails between Sheldon Bradshaw, Scott Danzis, and Tevi Troy that are mentioned in Waxman’s letter seem to demonstrate special attention paid to FDA guidances that are of interest to the drug and device industries. Internal agency emails also seem to show that certain projects are being rushed through, says Waxman, with “unprecedented speed.” For example, the proposed rule to amend regulations that permit companies to update drug and device labels with new safety information was proposed on Jan. 16, 2008 and finalized on Aug. 15, 2008. Also, the draft guidance on distribution of journal articles was issued Feb. 16, 2008. 

Waxman suggested that the agency’s priorities should be different, as pointed out by the FDA Science Board in November 2007. The Board noted the current import system, development of new therapies, and information infrastructure as sources of risk and therefore, in need of FDA attention. These items were not in the emailed list of priorities between Bradshaw, Danzis, and Troy.

The Oversight committee has asked FDA to respond to Waxman’s letter by Oct. 6, 2008.  

In a Sept. 17 letter to FDA Commissioner Andrew C. von Eschenbach, Rep. Henry Waxman (D-CA) questions the agency's priorities, specifically poking at FDA's political appointees and whether they are promoting industry at the expense of the public's health.

House Questions FDA's Priorities

In November, representatives to the International Conference on Harmonization will meet in Brussels, Belgium, to discuss several international cooperation initiatives, including ICH Q10: 

. In preparation, the US Food and Drug Administration is holding a public meeting to provide information and receive comments to take to the ICH meeting, according to a Sept. 16 

At last week’s 2008 PDA/FDA Joint Regulatory Conference in Washington, DC, FDA Office of Compliance Deputy Director Joe Famulare speculated that ICH Q8R: 

 may be finalized in Brussels. Q8R will provide more clarity on quality by design and specifically “design space.” In addition, the Implementation Working Group for ICH Q10, which is in Step 5 of the harmonization process, is expected to discuss next steps in Brussels. 

The public meeting will be held Oct. 21 from 3 pm-5:30 pm at 5600 Fishers Lane, 3rd floor, Conference Rooms D and E, Rockville, MD. Contact Tammie Jo Bell in the Office of the Commissioner at 

In November, representatives to the International Conference on Harmonization will meet in Brussels, Belgium, to discuss several international cooperation initiatives, including ICH Q10: Pharmaceutical Quality System and ICH Q8R: Pharmaceutical Development.

Preparation for ICH-Brussels Begins

-Earlier this month, the US Food and Drug Administration announced that it will be posting quarterly reports on its website regarding potential drug safety issues. The 

 went live Sept. 5 with 20 drugs named as having potential adverse effects. According to an FDA release, the drugs were identified based on a review of reports in the agency’s Adverse Event Reporting System (AERS) and are currently being evaluated for potential safety issues.

  The new reports are meant to inform the public of new safety information and potential signals of serious risk, and are required as part of the Food and Drug Administration Amendments Act (FDAAA), which was signed into law in September 2007. 

  According to the release, “the appearance of a drug on this list does not mean that FDA has concluded that the drug has the listed risk, or that FDA has identified a causal relationship between the drug and the listed risk. It is on the list only because FDA has identified a potential safety issue.”

  Center for Drug Evaluation and Research Director Janet Woodcock, M.D., further clarified that message by stating in the release, “Don't stop taking your medicine. If your doctor has prescribed a drug that appears on this list, you should continue taking it unless your doctor advises you differently.”

  The AERS database contains millions of reports of adverse events submitted to FDA by drug manufacturers, healthcare professionals, and patients. If a drug to appears on the quarterly report list, according to the release, it means an FDA reviewer has determined there is a reason to examine a drug more closely based on either the seriousness or number of AERS reports associated with the drug.

Earlier this month, the US Food and Drug Administration announced that it will be posting quarterly reports on its website regarding potential drug safety issues.