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US FDA•United StatesAL•Approval Letter

Approval Letter Other 211302 (Jan 1, 2020)

Issued January 1, 2020

Issued

January 1, 2020

Application

Other • 211302

Review center

Other

Stage

Final Decision

Letter type

Approval Letter

Response due December 31, 2020Product may be marketed.

Summary

This is a Complete Response Letter from the FDA to Recordati Rare Diseases Inc. regarding their New Drug Application (NDA) for Cystadrops (cysteamine ophthalmic solution) 0.37%. The FDA has determined that the application cannot be approved in its present form due to manufacturing facility compliance issues, inadequate manufacturing methods and controls, unresolved data deficiencies, and pending labeling and safety update requirements.

Key points

  • Ensure manufacturing facilities comply with current good manufacturing practice (cGMP) regulations in 21 CFR 210 and 211.
  • Resolve deficiencies identified during the inspection of Baccinex SA, FEI# 3007272813, if this facility remains in the application.
  • Ensure methods and facilities for manufacture, processing, packing, and holding of the drug product are adequate to preserve its identity, strength, quality, purity, stability, or bioavailability.
  • Submit data to demonstrate specific parameters, supported by development data and/or registration batch manufacturing data, to resolve deficiencies from the November 5, 2019 amendment.
  • Revise the master batch record to reflect changes pertaining to (b)(4) and (b)(4).
  • Provide the results of the (b)(4) study intended to simulate (b)(4) prior to manufacture of commercial batches.
  • Review labeling review resources, including PLR Requirements for Prescribing Information and Pregnancy and Lactation Labeling Final Rule websites, regulations, and related guidance documents.
  • Use the Selected Requirements for Prescribing Information (SRPI) checklist to ensure revised labeling conforms with format items in regulations and guidances.

Cited reasons

  • cGMP Non-Compliance at Manufacturing Facility
  • Inadequate Manufacturing Methods and Controls
  • Labeling Comments Reserved
  • Proprietary Name Resubmission Required
  • Safety Update Required
  • Stability Update with Particulate Matter Testing
  • Analytical Method Transfer Report
  • The FDA issued a Complete Response Letter for Cystadrops due to significant manufacturing deficiencies, including cGMP non-compliance at a key facility and inadequate methods/controls for drug product manufacture. Additional issues include the need for a comprehensive safety update, reserved comments on labeling, and administrative requirements for proprietary name resubmission and specific CMC data updates.

Recommended actions

  • Ensure manufacturing facilities comply with current good manufacturing practice (cGMP) regulations in 21 CFR 210 and 211.
  • Resolve deficiencies identified during the inspection of Baccinex SA, FEI# 3007272813, if this facility remains in the application.
  • Ensure methods and facilities for manufacture, processing, packing, and holding of the drug product are adequate to preserve its identity, strength, quality, purity, stability, or bioavailability.
  • Submit data to demonstrate specific parameters, supported by development data and/or registration batch manufacturing data, to resolve deficiencies from the November 5, 2019 amendment.
  • Revise the master batch record to reflect changes pertaining to (b)(4) and (b)(4).
  • Provide the results of the (b)(4) study intended to simulate (b)(4) prior to manufacture of commercial batches.
  • Review labeling review resources, including PLR Requirements for Prescribing Information and Pregnancy and Lactation Labeling Final Rule websites, regulations, and related guidance documents.
  • Use the Selected Requirements for Prescribing Information (SRPI) checklist to ensure revised labeling conforms with format items in regulations and guidances.

Deficiency summary

The FDA issued a Complete Response Letter for Cystadrops due to significant manufacturing deficiencies, including cGMP non-compliance at a key facility and inadequate methods/controls for drug product manufacture. Additional issues include the need for a comprehensive safety update, reserved comments on labeling, and administrative requirements for proprietary name resubmission and specific CMC data updates.

Findings

cGMP Non-Compliance at Manufacturing Facility

Severity: critical

The facilities and controls used for the manufacture, processing, packing, and holding of the drug product do not comply with current good manufacturing practice (cGMP) regulations in 21 CFR 210 and 211. An inspection of Baccinex SA (FEI# 3007272813) revealed deficiencies that require satisfactory resolution before approval.

Recommended response: Address all cGMP deficiencies identified during the inspection of Baccinex SA. Ensure all submitted facilities are in compliance with cGMP before resubmission.

Cited: 21 CFR 210, 21 CFR 211

Inadequate Manufacturing Methods and Controls

Severity: major

The methods, facilities, and controls for manufacture, processing, packing, and holding of the drug product are inadequate to preserve its identity, strength, quality, purity, stability, or bioavailability. This includes a lack of adequate data for evaluation, the need to revise the master batch record, and results from a (b)(4) study.

Recommended response: Submit data to demonstrate parameters, supported by development and/or registration batch manufacturing data. Revise master batch records to reflect changes. Provide results of the (b)(4) study.

Labeling Comments Reserved

Severity: info

The agency reserves comment on the proposed labeling until the application is otherwise adequate. The sponsor is encouraged to review PLR Requirements, Pregnancy and Lactation Labeling Final Rule, and SRPI checklist. If labeling is revised, updated content of labeling in SPL format is required.

Recommended response: Review labeling resources (PLR, PLLR, SRPI) and prepare to submit updated content of labeling in SPL format once other deficiencies are resolved.

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

Proprietary Name Resubmission Required

Severity: info

The proposed proprietary name, Cystadrops, was found acceptable pending approval of the application in the current review cycle. It needs to be resubmitted when responding to application deficiencies.

Recommended response: Resubmit the proposed proprietary name with the response to application deficiencies.

Safety Update Required

Severity: major

A safety update, as described at 21 CFR 314.50(d)(5)(vi)(b), must be included when responding to deficiencies. This update should include data from all nonclinical and clinical studies/trials regardless of indication, dosage form, or dose level.

Recommended response: Prepare a comprehensive safety update including all nonclinical and clinical data as per 21 CFR 314.50(d)(5)(vi)(b) for resubmission.

Cited: 21 CFR 314.50(d)(5)(vi)(b)

Stability Update with Particulate Matter Testing

Severity: minor

A stability update including particulate matter testing is requested for the NDA resubmission, acknowledging the revised drug specifications. This is not an approvability issue but a data request.

Recommended response: Provide a stability update incorporating particulate matter testing results in the resubmission.

Analytical Method Transfer Report

Severity: minor

The complete analytical method transfer report from one facility to another is requested for the NDA resubmission. This is not an approvability issue but a data request.

Recommended response: Submit the complete analytical method transfer report in the NDA resubmission.

Regulatory context

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

Impact

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

Strategic insights

The primary themes for the Complete Response are significant manufacturing quality control issues, including cGMP non-compliance and inadequate methods/controls, which directly impact product quality and approvability. Secondary themes involve the need for a comprehensive safety update and administrative/labeling adjustments.

Regulatory change impact: Pending sponsor mitigation plan

Approval likelihood after response: 5%

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