What to Submit for ANDA Stability Testing

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The Food and Drug Administration (FDA) released a question and answer guidance on Abbreviated New Drug Application (ANDA) stability testing. This guidance will go into effect on June 20, 2014 and will cover all new ANDAs. However, it will not cover changes made after approval of an ANDA.

Affecting primarily generic manufacturers, the guidance is intended to make the FDA’s recommendations regarding stability testing data for an ANDA clearer. The recommendations should be followed regardless of the status of a patent.

 

The areas that are most affected are the types of data that need to be submitted with respect to stability studies; the timing for initiating stability studies; the manufacturing, packaging, and storage of samples; and the size of the samples to be submitted. The following are some points that manufacturers of pharmaceuticals need to know.

What to Submit

Applicants should file studies and executed batch records for a minimum of three batches of at least pilot scale in the Drug Master File. Studies for two pilot-scale batches and one small-scale batch and studies for at least three production-scale batches are also acceptable.

These consist of studies for all suggested dosage forms, including the active dose and the placebo. The pilot batch sizes can depend on the type of drug being manufactured, but following requirements should be met:

  • Scored tablets and capsules should be at least ten percent of the proposed commercial batch or 100,000 finished dosage units.
  • Powders, solutions, and suspensions should be at least ten percent of the proposed commercial batch.
  • Solutions, powders for solutions, suspensions, and sterile topicals should be at least ten percent of the proposed commercial batch or fifty liters.
  • Transdermal patches should be least ten percent of the proposed commercial batch or 25,000 units.
  • Creams, lotions, and gels should be at least ten percent of the proposed commercial batch or 100 kilograms.
  • Sample sizes for aerosols and nasal sprays are determined according to the appropriate guidances for the industry.

In all cases, the largest sample that meets the requirements stated (ten percent or a given unit) should be used. However, the samples can be smaller if the reference drug is listed as an orphan drug, the substance is a controlled substance subject to drug enforcement, or the size of the test sample is the same as that of the commercial sample. In the latter case, the manufacturers should submit a prior approval supplement when they conduct a scale-up of the substance.

Information on chemistry, manufacturing, and controls should be provided. The applicant should provide justification for pilotscale batches that do not meet the International Conference on Harmonisation’s recommendations with respect to size.

The Drug Master File also should contain stability protocols, responsibilities, and data showing that stability studies have started. Although at least two different lots of active pharmaceutical ingredients should be used, the FDA recommends using least three lots for nasal sprays and aerosols.

Studies of pilot-scale batches should include six months of accelerated stability data and six months of long-term data. Manufacturers should test the samples after they initially make the substance, at three months after the substance was produced, and at 6 months after the initial manufacture. Manufacturers should update the ANDA with twelve months of long-term data during the review cycle. Additional long-term data for the three batches can be submitted in an amendment.

What to Submit if any of the Three Batches Tested During an Accelerated Study Fail or Significantly Change

Manufacturers should submit data from the intermediate studies for all three batches. If the accelerated data reveal a change or indicate that any of the characteristics have failed, manufacturers should submit six months of intermediate data. They should also conduct a failure analysis and submit it.

A manufacturer should initiate accelerated studies, intermediate studies, and long-term studies simultaneously. That way, even if the accelerated studies do not work, the appropriate data will be available when the manufacturer needs to submit the ANDA.

How to Manufacture, Package, and Store Samples

The samples should be manufactured according to current Good Manufacturing Practices (cGMP). Manufacturers should use commercial equipment to package the samples and they should store the samples in the proposed packaging. Manufacturing them in a research setting, using noncommercial equipment, or packaging them by hand is not recommended.

The samples used in the studies should generally be stored for one year after the ANDA is approved. However, manufacturers should follow the appropriate recommendations in the FDA Code of Federal Regulations with respect to storing the samples used in the studies.

What it Means for Manufacturers

The significance of the new guidelines depends on when the ANDA was submitted. For instance, ANDAs submitted before June 20, 2014, will be subject to the guidelines that were in effect before that time. However, ANDAs submitted after June 20, 2014, will be subject to the new guidelines.

These guidelines provide clearer, more stringent recommendations with respect to the size of samples, the timing for initiation of stability studies; the manufacturing, packaging, and storage of samples; and the sample size.

Looking for FDA regulatory consultants to help with ANDAs? Get in touch with the FDA Group - visit the contact us page.

For Further Reading
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM366082.pdf

Topics: FDA regulatory consultants