Navigating an FDA GMP and Validation Inspection- Best Practices and Pitfalls

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1 Navigating an FDA GMP and Validation Inspection- Best Practices and Pitfalls Sonali P. Gunawardhana FDA Practice Group Wiley Rein LLP 1776 K Street NW Washington, DC (202) sgunawardhana@wileyrein.com IVT S 20 th Annual Validation Week October 28-30, 2014 Philadelphia, PA

2 FDA Enforcement Statistics Summary Fiscal Year 2013

3 Warning Letters by FDA Center Fiscal Year CDRH CDER CFSAN CBER CVM CTP

5 Ready for your GMP Inspection?

6 Types/ Classifications of Inspections Pre Market Routine For Cause NAI- No Action Indicated VAI- Voluntary Action Indicated OAI- Official Action Indicated

7 Understanding the Purpose of the FDA Form 483 An FDA Form 483 is issued to firm management at the conclusion of an inspection when an investigator(s) has observed any conditions that in their judgment may constitute violations of the Food Drug and Cosmetic (FD&C) Act and related Acts. FDA investigators are trained to ensure that each observation noted on the FDA Form 483 is clear, specific and significant. Observations are made when in the investigator s judgment, conditions or practices observed would indicate that any food, drug, device or cosmetic has been adulterated or is being prepared, packed, or held under conditions whereby it may become adulterated or rendered injurious to health. The FDA Form 483 does not constitute a final Agency determination of whether any condition is in violation of the FD&C Act or any of its relevant regulations. The FDA Form 483 is considered, along with a written report called an Establishment Inspection Report, all evidence or documentation collected on-site, and any responses made by the company.

8 Number of 2013 FDA Form 483 s Issued By Specific Centers Devices = 1099 Drugs= 690 Biologics= 191 Bioresearch Monitoring= 273 For more statistical information please see the following website:

9 2013 Most Frequent FDA Form 483 Device Violations Noted (372) 21 CFR (a) Lack of or inadequate procedures; Procedures for corrective and preventive action have not been [adequately] established. (259) 21 CFR (a) Lack of or inadequate complaint procedures; Procedures for receiving, reviewing, and evaluating complaints by a formally designated unit have not been [adequately] established. (140) 21 CFR Lack of Written MDR Procedures Written MDR procedures have not been [developed] [maintained] [implemented]. (126) 21 CFR Purchasing controls, Lack of or inadequate procedures; Procedures to ensure that all purchased or otherwise received product and services conform to specified requirements have not been [adequately] established.

10 2013 Most Frequent FDA Form 483 Device Violations Noted (378) 21 CFR (a) Lack of or inadequate procedures Procedures for corrective and preventive action have not been [adequately] established. (245) 21 CFR (a) Lack of or inadequate complaint procedures Procedures for receiving, reviewing, and evaluating complaints by a formally designated unit have not been [adequately] established. (133) 21 CFR (b) Documentation Corrective and preventive action activities and/or results have not been [adequately] documented. (127) 21 CFR (a) Lack of or inadequate process validation. A process whose results cannot be fully verified by subsequent inspection and test has not been [adequately] validated according to established procedures. (124) 21 CFR Lack of Written MDR Procedures Written MDR procedures have not been [developed] [maintained] [implemented].

11 2013 Most Frequent FDA Form 483 Drug Violations Noted (155) 21 CFR (d) Procedures not in writing, fully followed; The responsibilities and procedures applicable to the quality control unit are not [in writing] [fully followed]. (131) 21 CFR Investigations of discrepancies, failures; There is a failure to thoroughly review [any unexplained discrepancy] [the failure of a batch or any of its components to meet any of its specifications] whether or not the batch has been already distributed. (106) 21 CFR (a) Absence of Written Procedures; There are no written procedures for production and process controls designed to assure that the drug products have the identity, strength, quality, and purity they purport or are represented to possess.

12 2013 Most Frequent FDA Form 483 Drug Violations Noted (99) 21 CFR (b) Scientifically sound laboratory controls; Laboratory controls do not include the establishment of scientifically sound and appropriate [specifications] [standards] [sampling plans] [test procedures] designed to assure that [components] [drug product containers] [closures] [in-process materials] [labeling] [drug products] conform to appropriate standards of identity, strength, quality and purity. (77) 21 CFR (b) Written procedures not established/followed Written procedures are not [established] [followed] for the cleaning and maintenance of equipment, including utensils, used in the manufacture, processing, packing or holding of a drug product. (76) 21 CFR (b) Procedures for sterile drug products Procedures designed to prevent microbiological contamination of drug products purporting to be sterile are not [established] [written] [followed].

13 CPG Sec Process Validation Requirements for Drug Products and Active Pharmaceutical Ingredients Subject to Pre-Market Approval Conformance batches: New drug applications may be approved by the Center prior to the completion of the initial conformance batch phase of process validation. The manufacture of the initial conformance batches should be successfully completed prior to commercial distribution, except as identified below.

14 Inspection of validation activities during a pre-approval inspection If a pre-approval inspection is performed, the inspection team should audit and assess any available process validation protocols, activities, data, and information, whether or not completed, and report to the firm any deficiencies. The district should recommend withholding approval of an application if any completed validation efforts include data of questionable integrity or demonstrate that the process is not under control and the firm has not committed to making appropriate changes. If during a pre-approval inspection, process validation activities are found significantly deficient for an approved product made by a process similar to that of the subject of the pre-approval inspection and for which a warning letter or regulatory action will be proposed, the district should recommend withholding approval of the application.

15 Inspection of validation activities during a post- approval inspection: If the initial conformance batch validation activities for a particular approved product were not substantially inspected and found satisfactory during the pre-approval inspection, the district should cover this activity for the approved application or a substantially similar process/product during the next routine CGMP inspection (see Compliance Programs for human drugs, and for animal drugs).

16 Completion of initial conformance batch manufacture prior to commercial distribution For some products, the completion of the initial conformance batch phase of process validation before the distribution of any one batch would require the manufacture of unneeded batches (e.g., certain orphan drug products) or be impractical for a product with a very short shelf-life or that is intended for limited use (e.g., some radiopharmaceuticals).. The agency's evaluation of a firm's decision to release batches concurrent with the manufacture of the initial conformance batches should include review and/or audit and assessment of: the firm's basis for justifying the distribution of individual batches prior to completion of the initial conformance batches (to include review of the product/process development effort); the firm's protocol/plan and available data to verify that there are adequate batch controls and testing prior to release for distribution of each batch, and provides for adequate and timely assessment of the validity of the process once all initial conformance batches have been manufactured; and, the firm's program for monitoring distributed batches and provisions for a rapid response to information suggesting the process is not under control (e.g., subsequent batch failures, production problems related to process design or equipment performance, complaints).

17 Completion of initial conformance batch manufacture prior to commercial distribution (cont.) Advanced pharmaceutical science and engineering principles and manufacturing control technologies can provide a high level of process understanding and control capability. Use of these advanced principles and control technologies can provide a high assurance of quality by continuously monitoring, evaluating, and adjusting every batch using validated in-process measurements, tests, controls, and process endpoints. For manufacturing processes developed and controlled in such a manner, it may not be necessary for a firm to manufacture multiple conformance batches prior to initial distribution. Agency staff (field and Center) should discuss the need for conformance batches prior to distribution with the designated agency contacts when inspecting firms employing these advanced pharmaceutical science and engineering principles and control technologies.

18 Understanding the Inspection Process Based upon the statistics- it is apparent that the FDA inspections focus on GMP regulations primarily in the areas of procedures and corrective action plans. Of course, there are other areas such as design verification, lab controls as well as monitoring that are a point of focus. Understanding which regulations apply to your facility and the business conducted will allow you to understand the where your focus needs to be. It is important to also think about the regulations that pertain to your clinical sites- they are inspected less often but violations documented could have significant bearing on the data the FDA will consider.

19 Preparation of Internal Stakeholders for a FDA Inspection Develop Written Procedures that are not overly broad or too prescriptive- strike the correct balance. Train internal staff on procedures and document the training/ refresher training as appropriate. Identify appropriate personnel to be points of contact during the inspection- contacts should be high level management. Treat FDA investigators with appropriate respect.

20 Management of the Ordinary Requests from FDA Inspectors Understanding what type of inspection is being conducted is key- FDA Investigators are trained to follow Compliance Policy Manuals which outline the steps for each type of inspection this will allow you to be prepared. Understand if the inspection is routine or for cause as they differ. If the request being made is out of the ordinary- first discuss internally with management and if you believe it is still inappropriate, respectfully request to speak with the FDA District Office supervisor.

21 Communication With FDA Should a Dispute Arise During the Course of the Inspection Communication is key- try to understand exactly what is being asked for- if is not appropriate for the investigator to request the information/ documentation, ask to speak to the FDA investigator s District Office supervisor. If you still do not believe it is appropriate- you may always elevate your concern to FDA Headquarters but this must be balanced in terms of the information being requested. If it is a question of trade secret redacted copies may be an option.

22 Suggestions on How Best to Communicate with the FDA During the Closeout Meeting Only senior management that can answer questions on behalf of the company should be present at this meeting- should be some of the same personnel that assisted with the course of the inspection. If you have any questions regarding the inspection you should ask the field investigators right away waiting until the closeout may make the close out meeting adversarial. Be sure to ask any questions about the FDA Form 483 Observations at the close out meeting, so that you are able to respond appropriately.

23 After the Inspection is Over If a FDA Form 483 has been issued- be sure to respond within 15 days with a substantive response (i.e., corrective action plan with solid dates for completion) If you can challenge any of the observations with additional information that establishes that the observation is inappropriate include it in your response to the FDA Form 483. You may also request a meeting with the District Office/ Headquarters to discuss future corrective action. If it is truly adversarial the Ombudsman is an option.

24 Take Away Message/Best Practices Always be prepared for an FDA inspection Understand that procedures and documentation are how you will be assessed. Train your personnel first and often but be sure to document it. Listen to your personnel if they have a complaint and you are not listening- they will inform the FDA. Have a FDA inspection procedure in place for the facility which includes appropriate personnel as diplomats.

25 Questions? Comments? Discussion? 25

26 Sonali P. Gunawardhana is Of Counsel in Wiley Rein LLP s FDA Practice. She draws on her nearly 10 years experience as an attorney at the U.S. Food and Drug Administration (FDA) to offer clients detailed and practical guidance on how to avoid and resolve FDA regulatory challenges. Ms. Gunawardhana received her LL.M. from Washington College of Law, American University and her J.D. from the University of New Hampshire School of Law. She also holds an M.P.H. from Boston University, an M.A. from Webster University and a B.A. from Syracuse University. Sonali P. Gunawardhana Wiley Rein LLP 1776 K Street NW Washington, DC (202) (office) sgunawardhana@wileyrein.com

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