Approval Letter Other 210063 (Jan 1, 2019)

The safety of the proposed levels of medium chain triglycerides (MCT) excipient in the drug product to be administered by intramuscular injection was not adequately justified. The potential impact of this excipient on local tissue toxicities as it compares to the listed drug was not adequately addressed. MCT were not listed as a component of the vehicle or in the Certificate of Analysis in the reports for the rat and rabbit toxicology studies, and their levels and fatty acid composition were not provided, rendering these studies inadequate.

Recommended response: Provide an adequate justification for the safety of the proposed levels of MCT in your drug product administered by intramuscular injection. Submit a final report from a GLP nonclinical bridging toxicology study in a single species comparing your Fulvestrant Injection formulation to the listed drug product (Faslodex) at a clinically relevant dose, including assessment of local tissue effects and toxicokinetics.

Long-term leachability data, including the safety evaluation report of the leachable from the syringe components, is required to cover the shelf life period. Alternatively, data from accelerated leachable studies may be included.

Recommended response: Provide long term leachability data including the safety evaluation report of the leachable from the syringe components to cover the shelf life period, or include data from accelerated leachable studies.

Adopt specifications for tensile and elongation of the plunger rod covering the shelf life as a part of quality control.

Recommended response: Adopt specification for tensile and elongation of the plunger rod covering the shelf life as a part of quality control.

The extractables/leachables study protocol was provided, but the study reports with data are missing.

Recommended response: Provide the extractables/leachables study reports with data.

The NDA does not include any design requirements and/or specifications for your prefilled syringe. Essential performance requirements, including expelled volume (accuracy), breakloose force, and glide force, should be included within the NDA.

Recommended response: Include essential performance requirements and specifications for the prefilled syringe, such as expelled volume (accuracy), breakloose force, and glide force, within the NDA.

To review the information within the referenced 510(k) (K951254) for verification testing, a Letter of Authorization (LOA) needs to be submitted.

Recommended response: Submit a letter of authorization (LOA) to review the information within the 510(k) (K951254) to support the NDA.

The 510(k) should include a clinical use study that mimics actual clinical use by patient substitutes to evaluate the sharps injury prevention feature. If the 510(k) does not provide such a study, documentation of a clinical use study per FDA guidance is required, recommending a sample size of 500 with zero failures.

Recommended response: If the 510(k) does not provide a simulated use study, provide documentation of a clinical use study per FDA guidance document 'Medical devices with Sharps Injury Prevention Features,' dated August 9, 2005.

The 510(k) should include a biocompatibility evaluation of the final finished needle component of the pre-filled syringe per ISO 10993-1 guidance. Recommended endpoints for systemic contact include cytotoxicity, sensitization, irritation, acute systemic toxicity, hemolysis, and material-mediated pyrogenicity.

Recommended response: Ensure the 510(k) includes a biocompatibility evaluation of the final finished needle component per ISO 10993-1, addressing the recommended endpoints based on the type and duration of contact.

The release specifications submitted under section 3.2.P.5.1 do not include the breakloose and glide force. These specifications should be included in the release testing for the combination product.

Recommended response: Update your release specifications to include the breakloose and glide force.

Stability testing does not include the testing of the essential performance requirements of the device constituent of the combination product. Stability data supporting the proposed shelf-life, including expelled volume (dose accuracy), breakloose, and glide force, is required.

Recommended response: Provide stability data supporting the proposed shelf-life of the combination product, including testing of the expelled volume (i.e., dose accuracy), breakloose, and glide force of the combination product.

The Agency was unable to locate a risk assessment of the combination product. A risk analysis characterizing and evaluating the risks to the user or patient during normal use, reasonably foreseeable misuse, and potential system failure states, including planned mitigations and acceptability of remaining risks, is needed.

Recommended response: Provide the risk analysis information which characterizes and evaluates the risks to the user or patient both during normal use, reasonable foreseeable misuse, and potential system failure states, including planned mitigations, verification of risk mitigations, as well as the acceptability of remaining risks.

A description of materials, including the material composition (trade name and common name), material supplier, and whether the material is drug and/or patient contacting, was not provided. This should include any additives, processing agents, colorants, etc.

Recommended response: Provide a description of materials including the material composition (trade name and common name), material supplier, and whether the material is drug and/or patient contacting, including any additives, processing agents, colorants, etc.