QbD for TDS: FDA´s new draft guidance

FDA´s new draft guidance for Transdermal and Topical Delivery Systems (TDS) provides recommendations regarding the pharmaceutical development and quality information to include in new drug applications (NDAs) and abbreviated new drug applications (ANDAs). Comments and suggestions regarding this draft document should be submitted within 90 days to the agency.

TDS can be as simple as a single drug substance dissolved in a single adhesive, or highly complex, multi-component, multi-adhesive, multi-laminate matrices. Excipients and components in TDS can include various adhesive systems, permeation enhancers, rate controlling or non-rate controlling membranes, solubilizers, plasticizers/softeners, or tackifiers.

Topics included in the document are:

Regulatory Status

According to the document, TDS are combination products and must therefore comply with 21 CFR part 4 subpart A (Current Good Manufacturing Practice Requirements for Combination Products). Within 21 CFR part 4, there is description of how requirements from drug cGMPs and device Quality System regulations apply to combination products. In particular, design controls apply to drug-device combination products (design control activities should confirm that there are no negative interactions between constituent parts and assure that their combined use results in a combination product that is safe, effective and performs as expected).

Extractables and Leachables (E&Ls)

This evaluation should include assessments of E&Ls, consistent with United States Pharmacopeia (USP) General Chapter <1663> and <1664> (Assessment of Extractables and Leachables Associated  with Pharmaceutical Packaging/Delivery Systems).

Proposed Manufacturing Changes

Scale-up proposals and other process changes may be proposed in an original NDA or ANDA. The level of additional information needed to support these changes will generally be in relation with the risk of the change to adversely impact product quality. In general, "changes to TDS after the conduct of pivotal clinical studies should be avoided when possible because of the sensitivity of TDS to small changes in formulation and manufacturing process", the agency states.

Low-risk changes may be adequately supported with updated master batch records and batch formulas. Examples include

  • scale-up of solvent-based and aqueous mixtures within a factor of 10 using equipment of the same design and operating principles, or
  • converting and pouching equipment of the same design and operating principle.

Moderate-risk changes may warrant additional developmental studies and stability data on commercial scale batches to demonstrate that they will not result in an adverse impact on the quality of the product. Examples of such changes may include

  • scale-up of hot-melt mixtures within a factor of 10,
  • scale-up of screw-based mixing processes, and
  • changes to coating/drying/laminating equipment of the same design and operating principle.

High risk changes to quality may warrant additional in vivo studies. An example is changing the manufacturing process to incorporate equipment of a different design and operating principle. 

Control of TDS Product

Section 3.2.P.5 of the application should contain the following information on control of the TDS product:
• Specification
• Analytical procedures
• Validation of analytical procedures
• Characterization of impurities
• Batch analyses
• Justification for the proposed specification

Typical CQAs (Critical Quality Attributes) included in TDS specification are:
• Description
• Identification
• Assay
• Impurities and degradation products
• Uniformity of dosage units
• Permeation enhancer content, when applicable
• Adhesion
• Release liner peel
• Tack
• Shear
• Cold flow
• In vitro drug release
• Drug substance crystal presence
• Pouch integrity
• Microbial limits, when applicable
• Moisture content, when applicable
• Residual solvents

Stability Studies

In addition to the standard stability and photostability studies for drug substance and drug products discussed in ICH Q1, TDS applicants and manufacturers should conduct stability studies under challenge conditions that include

  • temperature excursions,
  • freeze/thaw,
  • and/or crystal seeding,
  • in-use photostability testing (for certain TDS formulations, depending on backing membrane opacity, duration of wear, and its expected exposure to light when in use).

Special Topics

The agency recommends assessing the adhesion of a TDS by In vivo, in-use adhesion studies. Applicants should demonstrate that reasonable efforts were made to optimize adhesive characteristics of the TDS. 
In addition, the TDS storage conditions should be supported by stability data and stated in the label. Depending on the nature of the product, special instructions may be required to prevent exposure to children and caregivers, which could result in significant safety-related consequences.

More information can be found in FDA´s draft guideline "Transdermal and Topical Delivery Systems - Product Development and Quality Considerations".

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