US FDA•United StatesAL•Approval Letter

Approval Letter Other 205394 (Jan 1, 2023)

Issued January 1, 2023

Issued

January 1, 2023

Application

Other • 205394

Review center

Other

Stage

Final Decision

Letter type

Approval Letter

Response due January 1, 2024Product may be marketed.

Summary

The FDA issued a Complete Response letter for New Drug Application (NDA) 205394 for Rizaport (rizatriptan) oral film 10 mg to IntelGenx Corp., indicating that the application cannot be approved in its current form. The letter details significant deficiencies related to drug product stability, manufacturing facility inspections, and various aspects of prescribing information and carton/container labeling that must be addressed.

Key points

Submit 12 months of long-term stability data for exhibit batches manufactured as recommended in Comment 1.
Perform stability testing using fully validated methods and verify the suitability of analytical equipment prior to use.
Provide raw HPLC data for all corrected analytical results if using 2017 or 2018 batch stability results as supportive data.
Conduct further investigation for INV-2019-017 to identify the root cause for out-of-specification (OOS) stability results.
Achieve satisfactory resolution of objectionable conditions observed during the drug substance manufacturing facility inspection.
List all communications submitted to or held with the Agency regarding the resolution of observed objectionable conditions/deficiencies at the facility.
Review FDA labeling resources, including PLR Requirements, Pregnancy and Lactation Labeling Final Rule, and the Selected Requirements for Prescribing Information (SRPI) checklist.
If revising labeling, use the SRPI checklist to ensure conformity with format items in regulations and guidances.

Cited reasons

Insufficient Stability Data for Product Shelf Life Establishment
Unresolved Objectionable Conditions at Drug Substance Manufacturing Facility
Unresolved Objectionable Conditions at Drug Product Manufacturing Facility and Need for New Exhibit Batches
Inadequate Prescribing Information Labeling
Inconsistent Dose Statement on Carton/Container Labeling
Missing Temperature Scale Designations on Carton/Container Labeling
Undefined Expiration Date Format on Container Labels
Missing Barcode on Immediate Container Label

Recommended actions

Submit 12 months of long-term stability data for exhibit batches manufactured as recommended in Comment 1.
Perform stability testing using fully validated methods and verify the suitability of analytical equipment prior to use.
Provide raw HPLC data for all corrected analytical results if using 2017 or 2018 batch stability results as supportive data.
Conduct further investigation for INV-2019-017 to identify the root cause for out-of-specification (OOS) stability results.
Achieve satisfactory resolution of objectionable conditions observed during the drug substance manufacturing facility inspection.
List all communications submitted to or held with the Agency regarding the resolution of observed objectionable conditions/deficiencies at the facility.
Review FDA labeling resources, including PLR Requirements, Pregnancy and Lactation Labeling Final Rule, and the Selected Requirements for Prescribing Information (SRPI) checklist.
If revising labeling, use the SRPI checklist to ensure conformity with format items in regulations and guidances.

Deficiency summary

The application for Rizaport (rizatriptan) oral film 10 mg cannot be approved due to significant product quality issues related to stability data and manufacturing facility deficiencies, as well as unresolved labeling concerns for both prescribing information and carton/container labels. New exhibit batches and stability data are required, and objectionable conditions at manufacturing facilities need satisfactory resolution.

Findings

Insufficient Stability Data for Product Shelf Life Establishment

Severity: major

The stability data from existing exhibit batches cannot be used as primary data due to manufacturing process deficiencies. The agency recommends submitting 12 months of long-term stability data from new exhibit batches manufactured according to cGMPs. If older batch data is used as supportive, raw HPLC data for corrected analytical results is required, and further investigation into the root cause of OOS stability results (INV-2019-017) is needed.

Recommended response: Submit 12 months of long-term stability data for new exhibit batches. Provide raw HPLC data for any supportive older batch data. Investigate root cause for OOS stability results (INV-2019-017).

Unresolved Objectionable Conditions at Drug Substance Manufacturing Facility

Severity: critical

A recent inspection of the drug substance manufacturing facility revealed objectionable conditions. Satisfactory resolution of these observations is required before approval.

Recommended response: Provide documentation of communications and actions taken to resolve objectionable conditions at the drug substance manufacturing facility.

Unresolved Objectionable Conditions at Drug Product Manufacturing Facility and Need for New Exhibit Batches

Severity: critical

Inspections of IntelGenx Corp. (FEI 3005721224) for oral film products revealed objectionable conditions at the drug product manufacturing facility. The agency recommends manufacturing new exhibit batches tested in accordance with cGMPs, and a follow-up Pre-approval inspection may be needed.

Recommended response: Resolve objectionable conditions at the drug product manufacturing facility. Manufacture new exhibit batches under cGMPs. Prepare for potential follow-up Pre-approval inspection.

Inadequate Prescribing Information Labeling

Severity: minor

The agency reserves comment on proposed labeling until the application is otherwise adequate but encourages review of PLR requirements and SRPI checklist. The response must include updated content of labeling in structured product labeling (SPL) format.

Recommended response: Revise prescribing information according to PLR requirements and SRPI checklist. Submit updated content in SPL format.

Cited: 21 CFR 314.50(l)(1)(i)

Inconsistent Dose Statement on Carton/Container Labeling

Severity: minor

The usual dose statement needs improvement for consistency with PLR-formatted prescribing information. Recommended revision: 'Recommended Dosage: See prescribing information.'

Recommended response: Revise the usual dose statement on carton and container labels to 'Recommended Dosage: See prescribing information.'

Missing Temperature Scale Designations on Carton/Container Labeling

Severity: minor

Temperature statements lack '°C' or '°F' after each numerical value, which could lead to misinterpretation and drug degradation risk. Example revision: '59°F to 77°F (15°C to 25°C)'.

Recommended response: Add temperature scale designations (°C or °F) after each numerical value in temperature statements on carton and container labels.

Undefined Expiration Date Format on Container Labels

Severity: minor

The format 'YYYY MM' is unclear regarding numerical or alphabetical month characters. FDA recommends YYYY-MM-DD format for human-readable expiration dates, including a non-zero day if space permits, or YYYY-MM/MMM if only year and month.

Recommended response: Clarify the proposed expiration date format (numerical/alphabetical month). Adopt FDA-recommended YYYY-MM-DD or YYYY-MM/MMM format for human-readable expiration dates on container labels.

Missing Barcode on Immediate Container Label

Severity: major

The immediate container label lacks a barcode, which is an important safety feature. The agency requests adding the product’s linear barcode to each individual pouch.

Recommended response: Add the product's linear barcode to each individual pouch on the immediate container label.

Cited: 21 CFR 201.25(c)(2)

Lack of Usage Instructions on Container Label

Severity: major

The container label lacks instructions on how to use the film, posing a risk of wrong technique administration errors. A statement like 'How to use: Use dry hands. Place film on tongue. Keep in place until film dissolves.' is recommended.

Recommended response: Add clear usage instructions to the container label to minimize administration errors.

Overly Prominent Net Quantity Statement on Carton Labeling

Severity: minor

The net quantity statement (e.g., '18 Films') competes in prominence with the proprietary name, established name, and product strength. It should be decreased in prominence.

Recommended response: Decrease the prominence of the net quantity statement on carton labeling.

Inconsistent Strength Layout on Container Label

Severity: minor

The layout of the strength is not consistent with current guidance for presentation of proprietary name, established name, dosage form, and strength. The strength statement should follow the established name on the principal display panel.

Recommended response: Relocate the strength statement to follow the established name on the principal display panel of the container label.

Regulatory context

Submission stage: final decision
Regulatory pathway: 505(b)(2) NDA

Impact

Impact score: 0.95
Estimated delay: 365 days
Estimated rework cost: $0
Subsequent action: resubmission

Strategic insights

The application was not approved primarily due to significant manufacturing and quality control issues, including insufficient stability data and objectionable conditions at both drug substance and drug product manufacturing facilities. Additionally, several deficiencies were identified in the proposed prescribing information and carton/container labeling, impacting clarity and patient safety.

Regulatory change impact: Pending sponsor mitigation plan

Approval likelihood after response: 5%

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