The FDA guidance “Investigating Out-Of-Specification (OOS) Test Results for Pharmaceutical Production Guidance for Industry” (May 2022) (here) applies to APIs and other raw materials, as well as finished products, but does not address specific considerations for APIs and excipients.  Here at Lachman, we work with manufacturers of multiple product types and have the following advice for manufacturers of  APIs and excipients, as well as finished‑dosage‑form manufacturers receiving these materials for manufacture into finished goods.

Things to consider if an OOS result is obtained for an API or excipient:

  • Is this a repeat manufacturer lot?

It is important to verify that the same manufacturer lot number was not previously received and released by your company.  Companies usually assign an internal lot number to materials received and may not assess whether this lot of material was received before.  If it has, and it has been used in manufacturing, the impact of the OOS (even if the previous lot received was not OOS) must be assessed.

  • Is this material on a reduced testing program?

If the material is on a reduced testing program and is now OOS, all vendor-received lots that were not tested for the relevant test parameter are in scope of the OOS investigation.  Testing of retains of material lots received back to the last time full testing was performed (and met acceptance criteria) should be considered as part of the OOS investigation if the OOS result is confirmed.

  • Does an OOS for a raw material always require rejecting the material?

The manufacturer should conduct an investigation and contact you, the customer, with its results.  The course of such an investigation may vary.  In some instances, the test is straightforward, the OOS is clear, and rejection of the material is indisputably necessary.  In this scenario, the laboratory OOS investigation is sometimes closed and the information is forwarded to your company’s Supplier Quality Management group for follow up in the form of a vendor complaint.  Alternatively, your laboratory may keep the OOS investigation open until the manufacturer’s investigation is complete.

In other instances, the test may be ambiguous and your Quality Control group may need to work closely with the vendor to optimize the test method (through documented and pre‑approved test plans).  In such cases, it is important to fully document all communications with the vendor and make sure that any changes to the test procedure are justified and validated.

  • Is the manufacturer/vendor investigation documented as a Phase I or Phase II investigation?

If the material is a repeat lot or was on reduced testing, an assessment of impact on manufactured batches should take place in a Phase II investigation.  Otherwise, since the FDA does not stipulate how raw‑material investigations are to be documented, it is incumbent on the company to specify, in its OOS SOP, how raw material OOS investigations will be conducted and documented.

While these scenarios are not explicitly addressed by the FDA, it’s important to recognize and incorporate such potential factors into consideration to ensure that all materials utilized in manufacturing of a product meet all requirements and cGMP practices.  If you have any questions or need assistance in evaluating your firm’s quality plan for incoming materials, please contact us at