Regulatory and association news

Regulatory and association news

The latest regulatory and association news for pharmaceutical manufacturers and contract manufacturing organizations

Rockville, MD (Apr. 5)–The US Food and Drug Administration (FDA, www.fda.gov) concluded its reinspection of Wyeth's (Madison, NJ, www.wyeth.com) manufacturing facility in Guayama, Puerto Rico. Conditions at the Guayama facility prompted a Warning Letter in May 2006.

The 2006 Warning Letter cited several violations of current good manufacturing practice (CGMP) regulations stated in 21 CFR Parts 210 and 211. One of the most prominent violations was the company's failure to investigate unexplained discrepancies and out-of-specification results in batches of Triphasil 21 and 28 tablets as required under 21 CFR 211.192. A stability interval assay test for the tablets indicated an unknown peak at high levels, and subsequent tests confirmed the presence of the peak. FDA contends that Wyeth did not take any action against the affected lots of Triphasil or describe corrective or preventive measures the firm planned to take to prevent future peaks. The Warning Letter noted that between December 2003 and August 2005, 17 other incidents of unknown peaks were inadequately investigated.

FDA claimed that Wyeth violated 21 CFR 211.67(a) by failing to clean and maintain its packaging equipment, and the company also did not adequately inspect its packaging and labeling equipment as required under 21 CFR 211.130(e). In addition, Wyeth did not submit NDA Field Alert Reports in a timely manner in accordance with 21 CFR 314.81, and the company's quality control unit did not review production records to ensure that no errors occurred or fully investigate errors that occurred during the manufacturing process as stated under 21 CFR 211.22(a).

Wyeth intends to respond to any observations issued by the FDA inspector no later than mid-April. In addition to being reinspected by FDA, the Guayama site underwent a CGMP inspection by representatives of the European Medicines Agency (EMEA, London, www.emea.eu.int) during the week of March 26.

Washington, DC (Apr. 2)–The US Department of Homeland Security (DHS, www.dhs.gov) 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 www.dhs.gov/xlibrary/assets/IP_ChemicalFacilitySecurity.pdf.

The Synthetic Organic Chemical Manufacturers Association (SOCMA, Washington, DC, www.socma.org), 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."

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,"

Washington, DC (Apr. 3)–The Synthetic Organic Chemical Manufacturers Association (SOCMA, www.socma.org) adopted a policy of Inherently Safer Technology (IST) at its March meeting. SOCMA is the US-based trade association representing custom and batch manufacturers, including contract manufacturers of active pharmaceutical ingredients and intermediates supplying the pharmaceutical industry.

The goal of IST is to use traditional engineering, chemistry, and other scientific concepts to reduce the risk associated with chemical processing. SOCMA approved its policy to state its support for the philosophy of IST and "the belief that it should not be mandated in any regulatory regime," said SOCMA in a prepared statement.

In issuing its policy position, SOCMA said that no federal mandate of IST exists in the US Department of Homeland Security's April 2007 interim final rule on chemical-site security.

"While the concepts of IST are not appropriate in a regulatory context, the US Department of Homeland Security should encourage the private sector to incorporate IST as a means to reduce security risks at chemical facilities wherever possible," said SOCMA.

In explaining its position of IST, SOCMA said that IST does not necessarily involve reducing the amount of hazardous chemicals used in manufacturing and processing. "IST is a conceptual framework that covers chemical-processing procedures, equipment protection, and, when feasible, the use of safer substances. Many non-scientists have been led to believe that the only road to inherent safety is by way of reducing the amount of hazardous chemicals used in manufacturing and processing. IST, however, is limited by the laws of physics: a simple reduction in the use of hazardous chemicals is often not possible or may only result in the redistribution of risk without actually reducing it."