Presentation on 21 CFR Part 11

Best Practices for Handling FDA Inspections (Pharmauptoday)

Best Practices for Handling FDA Inspections

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Like death and taxes, FDA inspections are inevitable. The agency conducted at least 40,000 inspections in 2012, according the FDAZilla blog. While the FDA is required to inspect drug manufacturing facilities every two years, the agency can conduct additional inspections such as for Pre-Approval Inspections (PAIs) and “For-cause” inspections in case of a drug recall, adverse event, etc.

Because routine and for-cause inspections can be unannounced, biotechs and their outsourcing partners need to be prepared and constantly vigilant. The challenge is that as manufacturing has become much more complex, the FDA has announced sweeping new regulatory guidance along with heightened compliance requirements based on cGMP — current good manufacturing practices. Drug facilities have always had to maintain a paper trail; the difference now is that how paper trail is maintained can become an issue.

Successfully managing an FDA inspection begins with the development of a clear company policy. It requires frequent employee training so they are in a position to maintain best practices regarding day-to-day procedures. Companies also need to make sure they define the roles and responsibilities of all company employees during an inspection.

Based on 15 years of experience and eight successful FDA inspections, here are some best practices to prepare for a successful FDA Inspection.

Before Inspections

§  Pay attention to the latest guidelines. This isn’t a nice to-do, as it might be in other industries. Not staying current could generate a form 483. One way to stay abreast is to check out 483s, available online, to understand what sort of issues are being identified by inspectors. There are various resource centers, blogs and webinars that offer insight, including an FDA Inspections group on LinkedIn that has more than 37,000 members who share information about the latest inspection trends.

§  Define roles for key employees such as the Director of Quality, Regulatory Director, Quality Assurance Manager or Production Manager. Identify one employee to serve as the main liaison or company representative with the FDA inspector to reduce any possible miscommunication.

§  Make sure employees who get promoted get briefed on their new responsibilities and make sure backups are trained, in case a key executive is away, either on business or vacation.

§  Conduct regular training sessions to keep employees aware of the changes and best practices. You might even consider conducting a mock inspection to ensure people know how to deal with the stress and strain of a real inspection.

§  Keep in mind: Because inspections can happen any time, your personnel must be prepared at all times.

At the Start of an Inspection

§  The inspection process generally begins when the FDA Inspector presents a notice of Inspection (FD-482) and proper FDA credentials. But employees should know whom to notify – and should contact that person immediately – if they are approached by an FDA investigator outside of normal business hours (i.e. after 5:00 p.m. and/or outside of the facility on the company grounds.

§  If the investigator does not present an FD-482 or credentials, the investigator should not be allowed to begin the investigation until you can authenticate the person’s identity with FDA Field Operations.

§  Once credentials have been approved for the investigator(s), reentry on subsequent days during the same inspection does not require additional approval.

§  The company liaison should make sure all relevant managers and departments are aware that the FDA inspector is on the premises. Additionally, the liaison should proceed without delay to meet the FDA investigator and attend to his/her requirements.

§  While regular company business must continue as normal during the regulatory audit, that’s not the case for the corporate liaison, who must focus on the FDA inspection.

§  The liaison should set aside an empty conference room for the inspector to use as the base of operation while the inspection is being conducted, to review records.

§  The company representative will need to provide adequate time for a brief company orientation and allow time to answer any other questions the inspector may have in order to conduct the Investigation. The rep should escort the investigator(s) on any tour of any areas of the facility.

§  Keep in mind:

§  Facility inspections are designed to determine that cGMP standards are being met and that you are maintaining appropriate records.

§  FDA inspections may not delve into company financial, business, or planning information, or audits by or for the Company performed to self-monitor compliance such as internal audits.

§  In any interaction with the inspector, employees should be cooperative and avoid conflict. But they should be quick to redirect any inappropriate discussions (such as those that cover company finance).

§  It is important to maintain the right attitude; rather than grumble to the inspector about the disruption – since the inspector is just doing his or her job – think of this an opportunity to show that your company is meeting or exceeding cGMP standards.

§  The company liaison should be the sole contact for requests of documents, samples, or information. The liaison’s job is to make all reasonable efforts to meet appropriate requests from the inspector. If you’re not sure what the inspector is requesting, don’t guess: Ask for clarification.

During an FDA Inspection

§  The company representative should determine from the investigator the scope and purpose of the inspection. This allows the company to organize the visit properly to determine the approximate length of time the inspector will need to be on site.

§  During the visit, the inspector will need to do a proper document review, conduct appropriate interviews, and other inspection activities.

§  Company policies and procedures that will or may have an impact on the inspection should be reviewed with the inspector, including:

§  Access to restricted areas.

§  Restricted behaviors including the wearing of lab coats (in required areas).

§  The absence of food or eating in animal labs.

§  Any policy prohibiting the use of cameras, tape recorders or other audio and/or photographic equipment.

§  Requests for copies, materials, and/or drug samples must be made through the company representative.

§  Keep in mind: The inspection usually involves a combination of physical plant inspection and document and record review, including complaints, production records, QC records and storage and shipping records. The investigation may also delve into procedures related to equipment and process controls and vendor and design specifications.

§  The company liaison and any assistant should keep a detailed record of dates, times, areas inspected, observations made, questions or remarks by the FDA inspector, and responses or remarks by any employee during the inspection. Duplicate copies of all material provided to the investigator should be retained by the company.

§  During the Inspection, the company liaison should request that the investigator(s) identify areas, procedures, or documents which are judged as not good practices. That way, the company can address and correct the issue during the inspection. The company rep should show the inspector that the practices are now in compliance.

§  At the end of each day of the inspection, after the FDA inspector has left the facilities, the liaison should brief senior management to keep them apprised. If there were any issues identified by the inspector, the managers of the impacted department should, when practical, prepare and implement the appropriate corrective preventive actions.

§  If an issue has been corrected during the inspection, the liaison should ask the inspector to review the corrective actions at the start of the next inspection day. The goal is to close out all non-compliances prior to the completion of the inspection. This demonstrates the company’s commitment to quality and provide it with the opportunity to review the proposed corrective action with the inspector and make any corrections should the inspector feel the corrective action did not resolve the issue.

Information and Drug Sample Requests

§  When copies of records or documents are requested, company personnel should be the ones to make copies. FDA personnel should not be allowed to make copies nor should they take or write on the original data or documents.

§  All materials given to the investigator must be marked “Confidential” and/or “Proprietary,” and should be documented and listed by document title and number. The company should maintain a complete set of copied records and reports.

§  Requests for access to and copies of records and reports related to pre-clinical and clinical data conducted under the provisions of an IND are permitted under FDA authority.

§  No raw data or original documents may be taken off-site. The original documents should not be written on by the investigator.

§  Raw material, product samples or any other samples provided to the inspector should be listed by name, lot or batch number, and quantity on the FDA form (FDA 484). The company should retain a triplicate sample from the same lot for confirmatory testing. After the inspection is completed, a Freedom of Information (FOI) Request should be made to the FDA laboratory for a copy of its test results. The company may bill the FDA for samples taken.

§  Actual labels and labeling, (e.g. package inserts) and packaging may be collected by the investigator. Duplicates should be collected for the Company Record of the Inspection.

§  The inspector may ask for customer names and shipping records of products sold. This information should be provided. However, complete customer lists should not be provided during a routine inspection since this is confidential business information.

Exit Interview Protocol

§  Upon completion of the inspection, the inspector will present a written FDA form (FDA 483) that contains a list of any negative observations that constitutes violation of Food and Drug law. The inspector is then available for an exit interview to review any notes including any 483s. The liaison, senior management, other company personnel with responsibility in the areas inspected should attend this meeting.

§  During the exit interview, the company should take extensive notes and make sure that its people understand the issues around all 483 items, and how to correct those issues. Don’t be afraid to ask clarifying questions as appropriate.

§  Any preliminary verbal response to a 483 observation by the company should be brief. It is not appropriate to vigorously argue a point with the FDA investigator during the exit meeting. However, if you feel a 483 observation is in error or the result of a misunderstanding or incomplete information, you should compile the proper documentation to support the company’s position. If an issue remains unresolved, request the inspector to annotate the FDA 483 and his Establishment Report to reflect the differences.

§  If corrective action on an observation has been taken during the course of the investigation, this should be duly noted during the exit interview.

Post Inspection Protocol

The inspection is over but there may still be work to be done.

§  The company representative should prepare a written report and maintain a file of the subjects, operations, documents, and activities that were inspected and/or performed during the FDA inspection.

§  The file shall contain duplicate copies of all records copied and taken by the FDA inspector. The report shall be reviewed by senior management and maintained by QA and should contain the following:

§  Reference the date of inspection and name(s) of members of inspection team, reason for written response, response to each cited deficiency, including observations resolved/corrected during the inspection and observed by the Investigator(s), description of preventive and corrective action to be taken regarding each observation for those items not resolved at the time of written response and a schedule for completion, items still in dispute between the company and the FDA shall be addressed with necessary supporting information and documentation.

§  The Quality or Regulatory Director should submit the written response to the FDA within 10 working days of the exit interview.

§  After the inspection, the FDA inspector will write a narrative report called the Establishment Inspection Report (EIR). The Quality Director should submit a Freedom of Information (FOI) request for both a purged (confidential information removed) and an unpurged copy of the EIR. This should be sent directly to the FDA Freedom of Information Office in Rockville, Maryland.

§  The Quality Director should review all information received from the FDA after the inspection and coordinate all communication with the FDA. Any incorrect information should be communicated in writing to document the company’s position.

There are a lot of steps to ensure a successful FDA inspection. The most important is to ensure your facility implements current compliance procedures. Building on that, you need to develop and test your inspection plan, and train your employees so that everyone understands his/her role for before, during and after an inspection. Inspections can be a hassle but they are necessary to ensure the public safety.

With a detailed, thoughtful approach, you will be in a better position to pass inspections with a minimum

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