FDA Offers More Flexibility on Residual Solvents in Generic Drug Applications

More flexibility on residual solvents obtained from FDA's Office of Generic Drugs.

FDA's Office of Generic Drugs has taken a more flexible approach in implementing the U.S. Pharmacopeia's General Chapter <467> on residual solvents.

OGD's new policy allows manufacturers to verify excipient makers' statements that their materials are within specified residual solvent limits without submitting underlying test data attesting to the accuracy of these statements.

OGD issued the policy on its website Oct. 28 as a question-and-answer page on residual solvents in abbreviated new drug applications.

The revision appears to allay the concerns of generic drug manufacturers and excipient suppliers who had complained that OGD's earlier interpretation of USP Chapter <467> went beyond its original intent (see "The Gold Sheet," September 2008).

In response to industry's concerns about meeting these new requirements, FDA also announced in the revised policy that drug manufacturers will have six months upon approval of their applications to verify excipient makers' statements for controlling residual solvents.

In May 2008, OGD announced that starting on July 1, manufacturers must demonstrate in their ANDAs that their drugs comply with the residual solvent limits specified under USP Chapter <467> (see "The Gold Sheet," June 2008).

The USP chapter is modeled on the ICH Q3C guideline, which is meant to control impurities in 59 residual solvents. The ICH guideline, which was adopted in July 1997, establishes three classes of solvents according to their toxicity levels: Class 1 for solvents that are known to cause unacceptable risk, Class 2 for solvents with less severe toxicity and Class 3 for the least toxic solvents.

FDA did not address at that time the type of data or controls that would be acceptable to demonstrate control of residual solvents.

And then in August 2008, OGD issued an "additional information" guidance which stated that "dependence by the applicant on vendor statements and/or vendor COAs that USP <467> is met, without verification by the applicant, does not demonstrate compliance and will be considered a deficiency."

At issue was what was meant by the term "verification."

Industry had interpreted this verification provision to mean that it must perform in-house testing to ensure that its supplier statements are accurate and that raw materials are within acceptable limits.

Pharmaceutical industry trade groups said that this policy was interpreted in an unexpectedly rigorous manner, resulting in the rejection of dozens of ANDAs because testing data was not submitted. They pointed out that the Office of New Drugs, in its interpretation of Chapter <467>, allows manufacturers to verify excipient makers' statements without submitting the underlying test data.

The recently formed Coalition for Rational Implementation of USP General Chapter <467> comprised of pharmaceutical and excipient trade groups met with OGD officials on Oct. 10 to discuss its concerns with OGD's implementation of this chapter.

The group consists of the International Pharmaceutical Excipients Council of the Americas, IPEC Europe, the Generic Pharmaceutical Association, the Consumer Healthcare Products Association, the Pharmaceutical Research and Manufacturers of America, and the Synthetic Organic Chemical Manufacturers Association's Bulk Pharmaceutical Task Force.

According to the minutes from an Oct. 10 meeting with FDA officials, the coalition wrote that "clarification is needed concerning what type of supplier qualification information must exist to support supplier statements concerning the levels of residual solvents which are 'likely to be present' in ingredients when testing is not performed. Industry believes that the focus should be on the controls that are used as opposed to testing. Information to demonstrate compliance should typically be kept at the drug manufacturing site and assessed by FDA through GMP inspections rather than have to be filed with regulatory submissions."

In response to these comments, OGD said that it has "carefully considered these comments and suggestions and is providing the following clarifying questions and answers. The clarifications include a flexible, stepwise approach to application of USP <467> to ANDAs to ensure availability of low cost, high quality, safe, and effective generic drugs that meet USP <467> requirements."

New Policy Clears Up Verification

The revised policy states that to verify supplier statements, an ANDA sponsor can choose either of the following approaches:

· The ANDA sponsor tests the residual solvents as part of the complete testing protocol to demonstrate the capability to perform the tests and to verify the excipient manufacturer's data for each identified residual solvent. Once the excipient manufacturer's data is validated and verified, the ANDA sponsor can implement a valid vendor validation program under 21 CFR 211.84(d)(2).

· As an alternative, excipient manufacturers or ANDA sponsors can submit "evidence that the level of understanding and control of the manufacturing process are sufficient to conclude that that the acceptance criteria will always be met provided the process is run within the range of the critical parameters."

It further notes that "an excipient manufacturer's statement that solvents are not used does not require the ANDA sponsor's verification."

The policy also clarifies the information that should be included in excipient manufacturers' statements on residual solvents:

· A listing of all Class 1 solvents used or generated;

· All Class 2 solvents "likely to be present;"

· Whether any Class 3 solvents are "likely to be present" and the identity of all Class 3 solvents present at greater than 0.5 percent;

· All other solvents "likely to be present;" and

· The expected control limits for the solvents listed above.

In response to these changes, David Schoneker, IPEC Americas chairman and global regulatory affairs director of Colorcon, said that "they definitely moved in the right direction and we're happy with that. It clears up a lot of questions."

Schoneker further noted that the coalition "has some additional questions" on the policy and would soon be meeting with OGD officials to clear up some of these lingering areas of concern, which he declined to identify.

- Joanne S. Eglovitch ([email protected])