Why do warning letters cite compounders for violations of current good manufacturing practice (CGMP) violations?

FDA cites compounders for violations of current good manufacturing practice (CGMP) requirements if they produce drugs that are not eligible for an exemption from CGMP requirements. FDA generally cites violations of CGMP requirements in two situations:

• First, if a licensed pharmacist in a state-licensed pharmacy or federal facility, or a licensed physician, compounds drugs in accordance with section 503A of the Federal Food, Drug, and Cosmetic Act (FD&C Act), those drugs are exempt from CGMP requirements (as well as from drug approval and certain labeling requirements). However, if the compounder does not produce the drugs in accordance with the conditions of section 503A, the drugs are subject to CGMP requirements.

• Second, drugs compounded by entities that are registered with FDA as outsourcing facilities are subject to CGMP requirements. There is no exemption in federal law from CGMP requirements for outsourcing facilities. 

Whether they are made by an outsourcing facility, in a state licensed pharmacy or federal facility or by a physician, no drug may be prepared, packed, or held under insanitary conditions.

Why has FDA issued warning letters to compounders that produced drugs in accordance with the conditions of section 503A?

When a compounder produces drugs in accordance with the conditions of section 503A, the drugs are exempt from three sections of the FD&C Act only:

• section 501(a)(2)(B) – CGMP requirements;
• section 502(f)(1) – labeling with adequate directions for use; and
• section 505 – new drug approval requirements.

The drugs remain subject to all other provisions of the FD&C Act including, for example, section 501(a)(2)(A) – which says that drugs are deemed adulterated if they are prepared, packed, or held under insanitary conditions whereby they may be contaminated with filth or rendered injurious to health.

When FDA issues a warning letter to a compounder that produced drugs in accordance with the conditions of section 503A, it is because FDA’s inspection revealed violations of federal law from which the drugs were not exempt. Often, such warning letters cite insanitary conditions.

When does FDA inspect a compounder?

FDA conducts surveillance, for-cause, and follow-up inspections of compounders. Specifically, FDA conducts risk-based inspections of outsourcing facilities, and of state-licensed pharmacies of which the agency is aware. FDA conducts for-cause inspections in response to complaints, such as reports of serious adverse events or product quality concerns like drug contamination.

In addition, FDA conducts follow-up inspections to assess corrections that compounders implement.

What action might FDA take when it encounters a refusal during an inspection of a compounding facility?

On occasion, FDA encounters an improper action, inaction, or circumstances that may constitute delaying, denying, or limiting an inspection, or refusing to permit entry for an inspection, which can prevent FDA from evaluating, for example, whether the drugs are being compounded in insanitary conditions., FDA may seek an inspection warrant, where appropriate.

How do I find out when a compounder has adequately corrected the violations identified in the warning letter?

When FDA has verified that a compounder has adequately addressed the violations described in the warning letter, the agency issues a warning letter close-out letter and posts it on its website.

How do I know if FDA’s inspection was satisfactory?

When FDA determines that a surveillance inspection is considered closed and that the agency does not intend to pursue further any action based on the inspection, FDA issues a Field Management Directive 145 and posts the letter on its website.

FDA generally issues a letter referring inspectional findings to state regulatory agencies when, based on FDA’s inspection, a state-licensed pharmacy appears to obtain valid prescriptions for identified individual patients, has committed to taking any necessary corrective actions, and FDA believes that the needed corrective actions can be appropriately overseen by the state.

If a compounder receives an FMD-145 or a warning letter close-out letter, does that mean that I should source my drugs from that compounder?

Purchasers of drugs compounded at an outsourcing facility that has had a recent satisfactory FDA inspection will have some assurance that the conditions at that facility met applicable CGMP standards at the time of the inspection, and the compounded drugs are labeled with the required information. However, FDA inspections are a snapshot in time. Conditions at the facility can change at any time. In addition, FDA reviews a sample of the records available at a facility during an inspection and must draw conclusions about the conditions and practices at the facility from that sample of records. Purchasers should look at other available information about the compounder that can provide them with additional insight with regard to the compounder’s operations.

When selecting a compounder, FDA encourages purchasers to consider obtaining those drugs from compounders that are registered with FDA as outsourcing facilities because these facilities are subject to routine FDA inspections according to a risk-based schedule and CGMP requirements.

What’s the difference between a Form FDA-483 and a warning letter?

A Form FDA-483 lists FDA investigators’ observations from an inspection. Those observations do not represent a final agency action regarding compliance.

A warning letter advises the compounder of violations of regulatory significance. When FDA issues a warning letter, the agency takes into consideration response(s) that the compounder provided in response to the Form FDA-483.