Preparing for FDA Foreign Drug Inspection

By EAS Senior Consultant Robert C. Fish

An FDA drug inspection can be a very stressful experience. If it is a pre-approval inspection there is a lot at stake concerning the outcome. If the company does not pass, the application (NDA/ANDA) may not be approved or the approval may be significantly delayed. But with proper preparation the stress level can be significantly reduced and the chances of a successful outcome can be greatly increased.

Foreign drug firms have an advantage over domestic U.S. companies in that the foreign firms are given prior notification concerning when the inspection will be done. This is not usually done for domestic U.S. company inspections.

In my last position with FDA as Director of the Division of Field Investigation, I was responsible for the management of the FDA foreign inspections. We found that if we did not give foreign companies prior notice we often arrived and the management staff required to complete the inspection were not present because of vacation or other travel. As a result it has been a longstanding FDA policy that foreign companies will get prior notice of planned inspections.

Foreign drug inspection pre-approval inspections are conducted under compliance program (CP) 7346.832 Pre-Approval Inspections. The three stated program objectives are:

  1. Readiness for Commercial Manufacturing.
  2. Conformance to Application.
  3. Data Integrity Audit.

Compliance Program CP 7356.002, Drug Manufacturing Inspections may be used in conjunction with the pre-approval program. The Drug Manufacturing Inspections program uses a “systems” approach to the inspection where coverage may be given to two or more of the following systems:

  1. Quality System.
  2. Facilities and Equipment System.
  3. Materials System.
  4. Production System.
  5. Packaging and Labeling System.
  6. Laboratory Controls System.

In your preparation for the inspection you should carefully study these compliance programs. They will give you good insights into what to expect. You must also conduct training of all staff that will be involved in the inspection. The compliance programs should be a part of that training and it should cover the “do’s and don’ts” during an inspection. All staff should:

  1. Support preparation efforts.
  2. Insure that work areas are orderly.
  3. Insure that all equipment and instruments are clean and calibrated.
  4. Insure that all logs and records are filled out completely, accurately, and legibly at time of performance.
  5. Answer questions honestly.
  6. Answer questions directly.
  7. “I Don’t Know” is usually acceptable (refer to person with knowledge and responsibility).
  8. Be professional.
  9. Be courteous.
  10. Be cooperative.

Staff should not:

  1. Volunteer information.
  2. Guess.
  3. Provide any misinformation.
  4. Provide any misleading information.
  5. Be confrontational or argumentative.

You should conduct “mock inspections” to help train staff. EAS Consultants often do this for companies and it is a very good exercise for inspection preparation.

You should also have an inspection plan with details concerning how all activities will be handled from the time the investigator arrives until he/she leaves. The plan should include provisions for taking notes during the inspection, maintaining copies of any documents that the investigators takes and duplicate samples if any are taken. As part of the plan, staff should be identified to accompany the investigator at all times.

The plan should also include provisions for a “war room” for use during the inspection. In the war room, staff will make a quick review of all documents provided to the investigators before they are presented. With this review, staff can be prepared to respond to questions if there are deficiencies noted in the documents and should not be surprised by the questions.

If there are deficiencies noted during the inspection the investigator will issue the FDA 483, List of Observations at the conclusion of the inspection. There normally will be daily wrap up discussions concerning the findings for the day. Those discussions can provide an opportunity to begin some corrections before the inspection is completed. The observation may still appear on the FDA 483 at the end of the inspection, but if corrections have been made the investigator will note those in the report.

If you do receive an FDA 483 at the conclusion of the inspection the investigator will have detailed discussion with management concerning the items. The investigator will expect management to say what corrective action will be taken. If possible, commitments for corrective action should be made. But be certain that whatever commitments are made can in fact be accomplished as FDA may return to confirm corrections.

If you do receive an FDA 483, a written response should be provided to FDA as soon as possible, but at least within 14 days. The response should detail all corrective actions that have been made or are planned. If there are a number of corrective actions and their completion will take considerable time, follow up status reports should be provided to FDA.

When investigators complete an inspection they prepare a written report, Establishment Inspection Report (EIR). The EIR details all of the findings of the inspection. The report is reviewed by FDA management and is classified as:

  1. No Action Indicated (NAI).
  2. Voluntary Action Indicated (company corrections should be made, but likely FDA will not take any administrative or regulatory action).
  3. Official Action Indicated. With this classification the drug application could be withheld and/or a Warning Letter may be issued.

In summary, with adequate preparation, the stress level of an FDA inspection can be decreased and the desired outcome can be made more certain. With a good plan and proper staff training you will likely have a successful outcome.

FDA Revises Definition of “Qualified Auditor” in the Preventive Controls Rule

The Food and Drug Administration released two key FSMA-mandated regulations last month — a final rule on current good manufacturing practices (CGMPs) and risk-based preventive controls for food for humans and a related final rule on food for animals. The rules were released on September 10 and formally published September 17 in the Federal Register.

FDA now plans to release numerous guidance documents to help covered companies comply with the new requirements. For human foods, the agency is preparing guidance on hazard analysis and preventive controls, environmental monitoring, allergen controls, validation of process controls, and a compliance guide for small and very small businesses. For the animal food rule, it is developing guidance on CGMPs, hazard analysis and preventive controls, human food by-products for use as animal food, and on compliance for small or very small businesses.

The new preventive controls regulations apply equally to domestic U.S. operations and to international exporters of food to the U.S. market. With this in mind, the agency has translated its fact sheets on the two preventive controls rules into 12 major languages — including Arabic, traditional and simple Chinese, Spanish, French, Italian, Japanese, Korean, Portuguese, Russian, Thai and Hindi. Given the increasing importance of imported food in the U.S. market. Effective outreach to the international community will be a key component of a successful implementation of FSMA’s preventive control principles and I believe it is one of the biggest challenges facing the agency.

For the most part, the final rules reflect the proposed and supplemental rules, but they include some revisions made in response to comments from stakeholders. In a notable revision relating to auditing of facilities covered by the new rules, FDA revised the definition of a “qualified auditor.” The final rules use the term “qualified individual” rather than “preventive controls qualified individual.”

In response to a question about the qualifications needed for a preventive controls qualified auditor, the agency said a qualified auditor might get the necessary auditing expertise in part through education, as well as through training and experience, and it revised the definition of qualified auditor. But it concluded that a person must have some actual experience in auditing to meet the definition of a qualified auditor and that the technical expertise cannot be obtained solely through education and/or training.

Further clarification of the qualifications needed by auditors will be included in a separate Proposed Rule on Accreditation of Third-Party Auditors which has yet to be finalized.

Because the new provision refers to provisions in a future third-party certification rule, FDA plans to publish a document in the Federal Register announcing the effective date of the provision once the third-party certification rule is finalized.

EAS has a network of auditors with both the training and experience needed to conduct audits to assess compliance with the risk-based preventive controls rules. They are also available to conduct a gap-analysis for facilities wishing to ensure that they will be in compliance with the new CGMP and risk-based preventives controls requirements by the appropriate deadline.