FDA Inspection: How to Respond

Until the 1930s, pharmacies were subject to very little government oversight. Beginning in the first half of the 20^th century, particularly with the advent of the Food and Drug Administration (FDA) and the Drug Enforcement Administration (DEA), the federal government began to take an increasing role in regulating pharmacies. There are several reasons for this change, including the New England Compounding Center tragedy.

The end result is that the FDA is more aggressively looking at compounding pharmacies. While the FDA, generally, has no jurisdiction over pharmacies, the FDA takes the position that it has jurisdiction over pharmacies that cross the line from “being a pharmacy” to “being a manufacturer.” If the FDA believes that a pharmacy has crossed this line, then it will conduct an inspection.

FDA Inspection: Overview

The Federal Food, Drug, and Cosmetic Act (“Act”) allows FDA investigators to inspect facilities in which drugs are manufactured. FDA inspections are usually unannounced. Communications with FDA investigators require the utmost professionalism. Do not create an adversarial environment; it is counterproductive. The degree of the pharmacy’s cooperation will be reflected in the investigator’s Establishment Inspectional Report (“EIR”).

A pharmacy Inspection Leader should be assigned to deal with the inspector. This leader should be aware of the pharmacy’s policies, operations, and record-keeping. The leader should accompany the investigator throughout the inspection.

The investigator should be made aware at the outset that there is a pharmacy policy for working with the FDA. An investigator will more readily accept a denial based on established policy than a refusal based on an “instant policy” created on the spot.

Inspection Authority

The Act deems a drug to be adulterated if “it has been manufactured … in any … establishment and the owner of such … establishment … denies … an inspection.” If the pharmacy refuses inspection, the FDA’s recourse will be to obtain a search warrant allowing it entry onto the premises. There is no legal basis for refusing an inspection.

The investigator will want to examine “manufacturing” records to see if the pharmacy is complying with current good manufacturing practices (“cGMPs”) for drugs. It is not. The issue is not cGMP compliance; it is whether the pharmacy is a “pharmacy” or a “manufacturer.” The pharmacy should politely try to persuade the investigator to focus on this point, and not on cGMP compliance.

Proprietary Information

Special attention should be paid to records that contain proprietary information. These documents should be marked “CONFIDENTIAL - TRADE SECRET,” and this fact should specifically be called to the attention of the investigator.

The pharmacy will have patient records. The pharmacy can reasonably ask that the investigator not seek to copy records that contain patient identifiers. Alternatively, the pharmacy may tell the investigator that the pharmacy wishes to delete patient identities from copied documents.

Information to Which the FDA Is Not Entitled

The FDA does not have authority to obtain financial information, sales data, pricing data, research data, personnel data, and marketing plans.

Copying of Documents

If the FDA inspector asks to copy records, the pharmacy should make the copies for the investigator. Always make a duplicate set of copies for the pharmacy’s own records.

Do not let the investigator have free access to the photocopying machine. Someone should be present with the investigator at all times. Have someone perform the copying for the investigator. Nor should the pharmacy let the investigator have unrestricted access to the files -- provide only those documents that are specifically requested.

Samples

If the FDA collects samples of products, the pharmacy should take the following steps:

• Take a duplicate sample from the same batch to be independently reviewed and tested.
• Ask the inspector what tests are going to be performed so that duplicate tests can be performed by the pharmacy’s laboratory.
• The pharmacy should obtain a Receipt for Sampling Form FDA-484 from the investigator.

Photographs — Samples

The FDA Investigations Operations Manual says, “photographs are one of the most effective and useful forms of evidence.” The best pharmacy policy is “NO CAMERAS ARE ALLOWED IN THE FACILITY.” A sign stating this policy should be posted at the reception desk.

Signing Official Documents

The FDA has no authority to compel the pharmacy to sign anything. Signing a document does not benefit the pharmacy in any way. The better approach is to have pharmacy officials refuse to sign or to even give an oral “OK” that a statement is correct.

Establish an Inspections File

During the inspection, the pharmacy should create a separate file. This file will include the notes taken during the inspection by pharmacy employees, the forms filled out regarding the inspection, duplicates of the records copied by the investigator, the FDA-482 Notice of Inspection, the FDA-483 Notice of Observations, the FDA-484 Receipt of Samples, the pharmacy’s analytical results for samples tested, and any subsequent correspondence with the FDA.

FDA-483 (List of Observations) Response

At the inspection’s end, the investigator will have an exit interview with management to detail the findings of the inspection and to obtain the pharmacy’s comments. If an FDA-483 is issued, the investigator will request a response. It would be advisable to review each point for clarification with the investigator, but make no comments regarding follow-up action. The pharmacy should not sign the FDA-483.

During the exit interview, do not reject observations out-of-hand, become defensive, or be unwilling to listen; on the other hand, make commitments sparingly. The pharmacy should submit a response letter to the FDA-483. The main purpose of the response letter is to persuade the FDA not to issue a Warning Letter. The FDA’s current policy is to issue Warning Letters within a few weeks of the completion of the inspection. A Warning Letter will state that the pharmacy has violated the law in some respect; this letter is made publicly available.

Each observation in the FDA-483 will be separately numbered. The response letter should address each point individually. Give a detailed reason for any disagreement with the findings. When responding to a valid point, concisely explain how the pharmacy will modify its conduct or what changes will be made. Do not admit that there was an error; rather, just describe the new procedures. Give a target date for corrective actions to be implemented.

Letter Response to FDA Form 483

The response letter to the FDA-483 can include some or all of the following language:

• “The Food and Drug Administration (“FDA”) conducted an inspection of _______ (the “Pharmacy”). Please accept this letter as the Pharmacy’s response to the observations raised in the FDA Form 483. We respectfully request that this response, excluding the attachments, be posted on the FDA’s website with the Form 483 and be included every time the FDA provides a copy of the Form 483 to any individual or entity outside the FDA.”
• “To the extent the observations cited in the Form 483 are based on the current Good Manufacturing Practices (“cGMPs”) for finished pharmaceuticals, such observations are inapplicable to the operations of the Pharmacy.”
• “The Pharmacy operates in compliance with the requirements of 21 U.S.C. § 353a, applicable state laws and regulations governing pharmacy compounding, and with the United States Pharmacopoeia (“USP”) chapters <795> and <797>.” “With this response, the Pharmacy has sought to address all of the FDA’s observations and concerns. While cGMP requirements are not applicable to the pharmacy’s operations, we have accepted the FDA’s observations as suggestions for improvement and will implement additional best practices to the extent feasible and compatible with our obligations under state law and the USP guidelines.”

FDA Warning Letter to Pharmacy

Notwithstanding the response letter, the FDA may send a “Warning Letter” to the pharmacy that includes some or all of the following language:

• “From _____ to _____, US FDA investigators conducted an inspection of your facility.”
• “During this inspection, the FDA investigators observed serious deficiencies in your practices.”
• “FDA issued a Form FDA 483 to your firm on _____.”
• “We acknowledge your responses to the Form FDA 483 inspectional observations, dated _____. Although several of your proposed corrective actions appear adequate, others are deficient.”
• “FDA strongly recommends that your management immediately undertake a comprehensive assessment of your operations.”

Reply to FDA Warning Letter

The reply letter by the pharmacy to the Warning Letter should say something like the following:

• “Our office recently received the above-referenced Warning Letter.”
• “This letters serves as Pharmacy’s formal response to the Warning Letter, and we ask that the FDA publish this letter, excluding any exhibits, on the FDA’s website and disclose this information any time the FDA provides a copy of Pharmacy’s Form 483 or the Warning Letter to a person or entity outside of the agency.”
• “As we stated in our initial response letter, the deficiencies cited by the FDA Form 483 and the Warning Letter are inappropriately based upon the current Good Manufacturing Practices (“cGMPs”).”
• “As Pharmacy employs a state-licensed pharmacist to compound drug products primarily for identified individual patients pursuant to a valid prescription order, Pharmacy is exempt under 21 U.S.C. § 353a(a) from complying with 21 U.S.C. § 351(a)(2)(B), which requires that a drug product and any facilities used in its manufacturing conform with cGMPs.”
• “The outstanding issues identified in the Warning Letter have also been addressed by Pharmacy’s current policies and procedures to the extent that such observations constitute a “best practice” that, if adopted, would benefit the safety of Pharmacy’s patients.”

______________________________________________________________________________

Jeffrey S. Baird, Esq. is Chairman of the Health Care Group at Brown & Fortunato, P.C., a law firm based in Amarillo, Texas. He represents pharmacies, home medical equipment companies, and other health care providers throughout the United States. Mr. Baird is Board Certified in Health Law by the Texas Board of Legal Specialization. He can be reached at (806) 345-6320 or jbaird@bf-law.com.