2011-20852. Guidance for Industry on Residual Drug in Transdermal and Related Drug Delivery Systems; Availability

AGENCY:

Food and Drug Administration, HHS.

ACTION:

Notice.

SUMMARY:

The Food and Drug Administration (FDA) is announcing the availability of a guidance for industry entitled “Residual Drug in Transdermal and Related Drug Delivery Systems.” This guidance provides recommendations to developers and manufacturers of transdermal drug delivery systems (TDDS), transmucosal drug delivery systems (TMDS), and topical patch products regarding use of an appropriate scientific approach during product design and development—as well as during manufacturing and product life-cycle management—to ensure that the amount of residual drug substance at the end of the labeled use period is minimized. The guidance is applicable to investigational new drug applications, new drug applications, abbreviated new drug applications, and supplemental new drug applications for TDDS, TMDS, and topical patch products.

DATES:

Submit either electronic or written comments on Agency guidances at any time.

ADDRESSES:

Submit written requests for single copies of this guidance to the Division of Drug Information, Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Ave., Bldg. 51, rm. 2201, Silver Spring, MD 20993-0002. Send one self-addressed adhesive label to assist that office in processing your requests. See the SUPPLEMENTARY INFORMATION section for electronic access to the guidance document.

Submit electronic comments on the guidance to http://www.regulations.gov. Submit written comments to the Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT:

Terrance Ocheltree, Center for Drug Evaluation and Research, Food and Drug Administration, Bldg. 21, rm. 1609, 10903 New Hampshire Ave., Silver Spring, MD 20993-0002, 301-796-1988.

SUPPLEMENTARY INFORMATION:

I. Background

FDA is announcing the availability of a guidance for industry entitled “Residual Drug in Transdermal and Related Drug Delivery Systems.” This guidance provides recommendations to developers and manufacturers of TDDS, TMDS, and topical patch products regarding use of an appropriate scientific approach during product design and development—as well as during manufacturing and product life-cycle management—to ensure that the amount of residual drug substance at the end of the labeled use period is minimized. In the Federal Register of August 3, 2010 (75 FR 45640), FDA announced the availability of the draft version of this guidance. The public comment period closed on November 1, 2010. A number of comments were received from the public, all of which the Agency considered carefully as it finalized the guidance and made appropriate changes. Any changes to the guidance were minor and made to clarify statements in the draft guidance.

Existing TDDS, TMDS, and topical patches contain a larger amount of the drug substance than what is intended to be delivered to the patient. This excess amount of drug substance is needed to facilitate delivery of the intended amount of the drug to the patient and remains as residual drug in the used system. The amount of residual drug substance in TDDS, TMDS, and topical patches has a significant potential to impact the products' quality, efficacy, and safety (including abuse potential). Consequently, it is necessary to ensure that an appropriate scientific approach is used to design and develop these products. The approach should ensure that the amount of residual drug substance is minimized consistent with the current state of technology.

Currently marketed TDDS, TMDS, and topical patches may retain 10 to 95 percent of the initial total amount of drug as the residual drug after the intended use period. This raises a potential safety issue not only to the patient, but also to others, including family members, caregivers, children, and pets. For example, adverse events due to a patient's failure to remove TDDS at the end of the intended use period have been reported and are generally related to an increased or prolonged pharmacological effect of the drug. Also, some children have died from inadvertent exposure to discarded TDDS. Reported adverse events resulting from various quality problems pertaining to TDDS have lead to product recalls, withdrawals, and public health advisories.

To reduce some of these risks, the Agency recommends that a robust design and development approach be considered when developing and manufacturing TDDS, TMDS, and topical patches. One example of such an approach is quality by design, as described in the International Conference on Harmonization guidance for industry entitled “Q8(R2) Pharmaceutical Development.” The Agency also recommends that sufficient scientific justification to support the amount of residual drug in TDDS, TMDS, or topical patches be included in an application. The justification should include an evaluation of the safety risks involved with the formulation and system design, as well as support the amount of drug load in the TDDS, TMDS, or topical patch based on the proposed quality target product profile and formulation studies. Most important, the justification for applications of products with known safety issues—such as those with fentanyl-containing liquid reservoir systems—should demonstrate that the safety risk factors have been adequately mitigated.

In all cases, the level of information in the justification should be sufficient to demonstrate product and process understanding and ensure that a scientific, risk-based approach has been taken to minimize the amount of residual drug in a system after use to the lowest possible level. It is expected that the amount of residual drug in a newly developed system (including new generic drug products) will not exceed that of similar FDA-approved products.

This guidance is being issued consistent with FDA's good guidance practices regulation (21 CFR 10.115). The guidance represents the Agency's current thinking on residual drug in transdermal and related drug delivery systems. It does not create or confer any rights for or on any person and does not operate to bind FDA or the public. An alternative approach may be used if such approach satisfies the requirements of the applicable statutes and regulations.

II. Comments

Interested persons may submit to the Division of Dockets Management (see ADDRESSES) either electronic or written comments regarding this document. It is only necessary to send one set of comments. It is no longer necessary to send two copies of mailed comments. Identify comments with the docket number found in brackets in the heading of this document. Received comments may be seen in the Division of Dockets Management between 9 a.m. and 4 p.m., Monday through Friday.

III. The Paperwork Reduction Act of 1995

This guidance refers to previously approved collections of information found in FDA regulations. These collections of information are subject to review by the Office of Management and Budget (OMB) under the Paperwork Reduction Act of 1995 (44 U.S.C. 3501-3520). Information in an application on the product and process development and justification for the final formulation and system design is approved under OMB control numbers 0910-0001 and 0910-0014.

IV. Electronic Access

Persons with access to the Internet may obtain the document at either http://www.fda.gov/​Drugs/​GuidanceComplianceRegulatoryInformation/​Guidances/​default.htm or http://www.regulations.gov.

Dated: August 10, 2011.

Leslie Kux,

Acting Assistant Commissioner for Policy.