May 2007

Published on: 
Pharmaceutical Technology, Pharmaceutical Technology-05-02-2007, Volume 31, Issue 5

Sanofi to Close Irish Plant, FDA Inspections and Warning Letters Continue to Decline, FDA Submits Final Proposals for PDUFA IV, and more.


Debate Continues over Follow-On Biologics

Washington, DC (Mar. 26)—The biggest issue in biopharmaceuticals continues to be the ongoing debate over regulation and oversight of follow-on biologics. Regulatory agency representatives, academia, and several professional industry organizations sounded off last month, voicing strong opinions and warnings of potential backlashes to healthcare, the economy, and scientific innovation.

The congressional Committee on Oversight and Government Reform (, chaired by Rep. Henry Waxman (D-CA) touched off the debate when it held a hearing to evaluate the cost of biotech drugs as well as strategies for establishing a process for the US Food and Drug Administration's approval of generic versions of these drugs. Janet Woodcock, MD, deputy commissioner for operations and chief medical officer at FDA was among those making a statement at the hearing entitled "Safe and Affordable Biotech Drugs—The Need for a Generic Pathway."

Woodcock attributed part of the increasing interest in follow-on versions of approved protein products to "advances in manufacturing technology, process control, and characterization" of these products. She acknowledged that the nature of protein products makes comparisons of one protein to another and establishing safety and efficacy "more scientifically challenging" than for small-molecule drugs. Nonetheless, Woodcock also stated that the agency has "considerable experience with reviewing some protein products, including cases where the agency has considered the extent to which existing conclusions about safety and effectiveness of a protein product could be applicable to another protein product based on data and information showing the similarity of the products."

The Biotechnology Industry Organization (BIO, continues to voice strong opposition to the "Access to Life-Saving Medicine Act" (H.R. 1038), stating that the bill is "deeply flawed" because it "raises numerous patient safety concerns...It would eviscerate incentives to develop life-saving new medicines...[and] lacks data exclusivity for innovative biologics." In its letter to the committee, BIO also states that the potential savings in healthcare costs resulting from the establishment of a pathway for regulatory approval of follow-on biologics is "substantially overestimated."

Emphasizing a "vast difference" between generic pharmaceuticals and follow-on biologics, Jim Greenwood, BIO president and CEO, stated that "high manufacturing costs, the need for additional safety and efficacy in trials to test these products, and augmented efforts directed at doctors to encourage the use of similar, but not identical, drugs are expected to add to the prices associated with the follow-on product."

Caroline Loew, senior vice-president of the Pharmaceutical Research and Manufacturers of America (PhRMA, expressed reservations regarding follow-on biologics. Although she maintained that PhRMA would support the establishment of a regulatory pathway for follow-on biologics, the organization worries that the current legislative proposals could put patient safety at risk. PhRMA cites the "significant differences between biologic products from different manufacturers" and the fact that innovator biologics are not identical to follow-on biologics as factors that could affect patients. In addition, PhRMA is concerned that existing legislation allows for a follow-on biologic to be replaced with a similar product, even though the similar product could have a different makeup, at pharmacies, hospitals, and physicians' offices.

Company Notes

Loew goes on to state that clinical trials are necessary to prove the safety and effectiveness of follow-on biologics. Current legislative proposals regarding follow-on biologics do not call for clinical trials.

Meanwhile, Kathleen Jaeger, president and CEO of the Generic Pharmaceutical Association (GPhA, released a statement emphasizing Woodcock's statement that FDA "has the scientific expertise to review" generic biologics and the "same scientific principles that apply to the review of changes made to brand products after approval would also be underpinning the review of biogenerics."

"[The] hearing also proved that the claim by PhRMA and BIO that the legislation will restrict FDA's ability to require testing is simply false," said Jaeger, claiming the organizations are "playing the scare-tactics card."

-Maribel Rios, Brianne Harrison


Sanofi to Close Irish Plant

Paris (Mar. 15)—Sanofi-Aventis ( plans to close its manufacturing site in Waterford, Ireland.

The company attributes the closure to increasing pressure from generics. Sanofi came to the decision after evaluating its plant network and concluding that other sites had excess capacity and could take over the manufacturing currently performed at the Waterford site with minimal extra investment.

The Waterford plant currently manufactures mature and over-the-counter products, including "Essentiale" for liver protection and "Flagyl" for microbial infections. Manufacture of these two products will be taken over by Sanofi plants in France and Germany.

The site is expected to close by the end of the year, with the loss of about 200 jobs.

-Brianne Harrison



FDA Inspections and Warning Letters Continue to Decline

Rockville, MD (Mar. 1)—The number of US Food and Drug Administration ( inspections of biologic and drug-manufacturing facilities declined to 4237 in fiscal 2006, according to a report by the Office of Regulatory Affairs. This total has decreased since 2002, when the agency reported 4570 inspections.

The report states that the Center for Drug Evaluation and Research (CDER) conducted 2411 domestic and foreign inspections in 2006, compared with 2682 in 2005. The number of CDER inspections is at its lowest point since 2002, when the center reported 2585 inspections.

The Center for Biologics Evaluation and Research (CBER) also conducted fewer inspections in 2006. The center reported 1826 domestic and foreign inspections in 2006, a decline from the 1931 inspections during 2005. CBER's inspections have decreased since 2003, when the center's annual total was 2205.

In contrast, both CDER and CBER issued more Class I recalls in 2006 than in 2005.

A recall is an action taken by a firm either to remove a product from the market or to conduct a field correction. A Class I recall is a situation in which there is a reasonable probability that the use of or exposure to a product will cause serious adverse health consequences or death, according to FDA.

CDER's total of 45 Class I recalls in 2006 is the greatest number of the past five years and an increase from the 18 such recalls in 2005. CBER issued 13 Class I recalls in 2006, compared with a single such recall in 2005. In 2006, CBER issued more Class I recalls than in 2005 and 2004, but fewer than its recent peak of 24 in 2003.

The report also shows that the number of Warning Letters issued by the two centers has declined during the past 10 years. In 2006, CDER issued 66 Warning Letters, and CBER issued 22 Warning Letters.

-Erik Greb


FDA Submits Final Proposals for PDUFA IV

Rockville, MD (Mar. 23)—The US Food and Drug Administration (FDA, submitted to Congress its final proposals for reauthorizing the fourth Prescription Drug User Fee Act (PDUFA IV), which will follow the expiration of the current user fee on September 30, 2007. The law provides user-fee funds paid by brand drug and biotechnology companies that help support the review of new drugs.

According to an FDA release, annual user fees under PDUFA IV would increase to $392.8 million, an $87.4 million increase over PDUFA III.

The funds would support "key goals," including enhancing premarket review and creating a modern postmarket drug safety system that follows products across their full life cycle.

"Our proposed recommendations for PDUFA IV aim to strengthen our drug safety system and upgrade resources to enhance FDA's information technology capability," said Commissioner of Food and Drugs Andrew C. von Eschenbach, MD.

-Maribel Rios


DHS Releases Interim Final Rule on Chemical Site Security

Washington, DC (Apr. 2)—The US Department of Homeland Security (DHS, released an interim final rule that imposes federal security regulations on high-risk chemical facilities. The new rule gives the department authority to seek compliance through the imposition of civil penalties of as much as $25,000 per day and the ability to shut down noncompliant facilities.

Under the rule, DHS will require owners of chemical facilities that house certain quantities of specified chemicals to complete a preliminary screening assessment that determines the level of risk associated with the facility. If a chemical facility preliminarily qualifies as high-risk, its owners will be required to prepare and submit a security vulnerability assessment (SVA) and site-security plan. Submissions will be validated through audits and site inspections. The department will provide technical assistance to facility owners and operators as needed. Security standards will be required to achieve specific outcomes such as securing the perimeter and critical targets, controlling access, deterring theft of potentially dangerous chemicals, and preventing internal sabotage.

Facilities contacted by the department will have 120 days from the publication of the regulation in the Federal Register to provide information for the risk-assessment process. Other requirements will follow that time period. Additional facilities will follow a similar timeframe after future Federal Register publications.

Some states have existing laws for regulating chemical facilities. Only state laws and requirements that conflict or interfere with these regulations or the purpose of the regulations will be preempted. DHS says the department currently has no reason to conclude that any existing state laws are applied in a way that would impede the federal rule.

DHS says the final regulation will be published in the Federal Register and also may be found at

SOCMA responds to new rule

The Synthetic Organic Chemical Manufacturers Association (SOCMA, Washington, DC,, the US-based trade association representing custom and batch manufacturers, including contract manufacturers of active pharmaceutical ingredients and intermediates, outlined its concerns about the new rule.

"SOCMA wants to commend DHS for their hard work in promulgating these regulations," said Joe Acker, the group's president, in a prepared statement. "We support the phased-in approach to the rules, but would like to have seen more time given for companies to perform their SVA, especially small companies with limited resources. The shortened timeframe will make it extremely difficult for companies to evaluate the new rules and then perform the appropriate tasks in the prescribed timeframe required by the rule."

Company Notes

SOCMA pointed out issues relating to the type of facilities able to conduct alternative SVAs. "DHS's decision to limit alternative SVAs to only Tier 4 facilities is disappointing," said Acker. "Facilities that have taken the proper action over the last five years, which include all of SOCMA's member facilities, will need to unnecessarily reconduct risk assessments, even though nothing has changed in their overall risk profiles."

Under the rule, DHS places facilities in one of four risk-based tiers, ranging from Tier 1, which contains the highest-risk covered facilities, to Tier 4, which contains the lowest-risk covered facilities.

SOCMA also raised concerns about the possible omission of certain risk-reduction measures in DHS guidance. "SOCMA understands and supports DHS's intent to use guidance for assisting facilities in meeting the new security standards," said Acker. "SOCMA expects that many risk-reduction measures that could be taken by facilities will not be captured in the guidance. These risk-reduction measures should be given the same consideration as measures found in the DHS guidance materials."

-Patricia Van Arnum


GlaxoSmithKline Plans Investment in Irish Manufacturing Facility

London (Mar. 29)—GlaxoSmithKline (GSK, plans to invest EUR 250 million ($334 million) in its production site at Currabinny, Ireland over the next five years, according to a release issued by the Irish Development Agency (IDA Ireland, Dublin,

The investment will support production for lapatinib, the active ingredient in GSK's "Tykerb," a new oral treatment for advanced breast cancer. In March 2007, the US Food and Drug Administration (Rockville, MD, approved Tykerb in combination with "Xeloda" (capecitabine), an anticancer treatment from Roche (Basel, Switzerland,, for treating advanced or metastatic breast cancer.

"We are delighted to have been chosen as the production site for the Tykerb active ingredient following years of committed research and development work by GSK employees around the world," said Finbar Whyte, site director at GSK Cork.

GSK Cork is a strategic global new product introduction site within GSK that manufactures the active ingredients of medicinal compounds. The Currabinny site was established in 1975 and employs more than 600 people. The new investment will create as many as 150 new high-level positions, according to IDA Ireland, an Irish government agency responsible for securing new investment from overseas in the manufacturing and internationally traded services sectors.

-Patricia Van Arnum


Advances and concerns regarding nanotechnology presented at conference

Washington, DC (Mar. 26)—Representatives from pharmaceutical companies, universities, and governmental agencies gathered for the Strategic Research Institute's 2nd Annual Nanomedicine conference in Arlington, Virginia March 26 and 27. The two-day conference included presentations on patents, nanomedicine business trends, and developments in drug delivery using nanotechnology.

Company Notes

Speakers from the US Food and Drug Administration and the National Institutes of Health discussed regulation and evaluation strategies for nanotechnology-based emerging therapies and devices. Representatives from the US Patent and Trademark office also were on hand to explain nanotechnology-related issues, including classification and examination. Experts from industry and academia outlined nanotechnology research for drug delivery to tumors.

Although many speakers were hopeful that the work in nanomedicines would bear fruit in the near future, some admitted that there were significant difficulties to be overcome, particularly in scale-up manufacturing. Most, however, were optimistic about the work and nanomedicines' potential to provide more effective treatments for cancers.


Nanocrystals Enable Carrier-Free Drug Delivery

Buffalo, NY (Mar. 7)—Scientists at the University at Buffalo's ( Institute for Lasers, Photonics, and Biophotonics and Roswell Park Cancer Institute (RPCI, Buffalo, NY, have developed a drug-delivery system comprising 100-nm nanocrystals of pure HPPH, (2-devinyl-2-1'-hexyloxyethyl pyropheophorbide). The unique characteristic of the system is that it is carrier free; the drug itself acts as the carrier.

Company Notes

The hydrophobic, photosensitizer drug currently is undergoing Phase I–II human clinical trials at RPCI for the treatment of various cancers.

Research revealed that tumors effectively took up the nanocrystals in vivo, with results comparable to those of surfactant-based delivery models but without the toxicity that has been associated with those conventional systems. The study also showed that nanocrystals of the amphiphillic HPPH self-assembled in solution such that the clusters formed were not too big to settle to the bottom of the solution. The aggregation resulted in a controlled, colloidally stable suspension of nanosized crystals.

The research team plans to conduct additional in vivo trials and is considering the application of the delivery system to other hydrophobic drug compounds.

-Maribel Rios