Approval Letter Other 202158 (Jan 1, 2018)

Summary

This is a Complete Response letter from the FDA to NorthStar Medical Radioisotopes, LLC regarding their New Drug Application (NDA) 202158 for TechneGen Generator System for Preparation of Sodium Pertechnetate Tc99m Injection. The FDA has determined that the application cannot be approved in its present form due to multiple deficiencies identified in clinical aspects (labeling, user manuals, training, human factor testing), product quality microbiology (sterility assurance, microbiological control, process validation, cleaning protocols, sterilization confirmation, manufacturing information), deficiencies in a referenced Drug Master File (DMF), and inadequate manufacturing facility inspections.

Key points

• Address deficiencies in product labeling, user manuals, training materials, and package insert related to instructions for preparation and safe use of the TechneGen system.
• Design and conduct a human factor testing study to provide meaningful data to support the safe use of the generator.
• Provide sufficient data to determine whether the proposed system can provide the expected sterility assurance level.
• Provide data sufficient to support the ability of the proposed TechneGen system to remain in a state of microbiological control over the in-use period.
• Demonstrate that tubing, valves, and connectors may be used as described without increased risk of microbial contamination/proliferation within the non-sterile manufacturing system.
• Address the risk of biofilm formation on the tubing and in the valves.
• Address the risks posed by the possibility of leaking connections and encrusted connections, and develop a procedure to assess and correct these malfunctions.
• Provide data that demonstrate the TechneGen system is a 'closed process' to justify proposed deviations from industry best practices.

Cited reasons

• Deficiencies in product labeling, user manuals, and training materials related to safe use and preparation.
• Insufficient data for sterility assurance level.
• Lack of data for microbiological control during in-use period.
• Unsubstantiated claim of 'closed process'.
• Inadequate cleaning protocol validation.
• No confirmation of final patient dosage form sterilization and filter integrity testing.
• Inadequate process validation studies and lack of aseptic processing simulations.
• Missing English translations for sterilization validation report appendices.

Recommended actions

• Address deficiencies in product labeling, user manuals, training materials, and package insert related to instructions for preparation and safe use of the TechneGen system.
• Design and conduct a human factor testing study to provide meaningful data to support the safe use of the generator.
• Provide sufficient data to determine whether the proposed system can provide the expected sterility assurance level.
• Provide data sufficient to support the ability of the proposed TechneGen system to remain in a state of microbiological control over the in-use period.
• Demonstrate that tubing, valves, and connectors may be used as described without increased risk of microbial contamination/proliferation within the non-sterile manufacturing system.
• Address the risk of biofilm formation on the tubing and in the valves.
• Address the risks posed by the possibility of leaking connections and encrusted connections, and develop a procedure to assess and correct these malfunctions.
• Provide data that demonstrate the TechneGen system is a 'closed process' to justify proposed deviations from industry best practices.

Deficiency summary

The application cannot be approved in its present form due to multiple deficiencies across clinical, product quality microbiology, manufacturing facilities, and labeling. Key issues include insufficient data to support sterility assurance, microbiological control, process validation, and human factors for safe use, as well as unresolved deficiencies in a referenced Drug Master File and inadequate manufacturing facilities.

Findings

Regulatory context

Submission stage

final decision

Regulatory pathway

505(b)(2)

Impact

Impact score

0.95

Estimated delay

365 days

Estimated rework cost

$0

Subsequent action

resubmission

Strategic insights

The primary themes are insufficient data to demonstrate product safety and quality (microbiological control, sterility, process validation), inadequate manufacturing facilities, and deficiencies in user instructions/human factors for safe use. Resolution of a deficient Drug Master File is also critical.

Regulatory change impact: Pending sponsor mitigation plan

Approval likelihood after response: 5%