Best Practices: Responding to FDA Form 483s

John R Godshalk Biologics Consulting Group Alexandria, VA USA

Outline
Importance of 483 Response New FDA Program: 483 review and Warning Letters How the 15 day guideline affects your response Key components of a good 483 response How to define CAPAs and include them Warning letter example for significant violations of cGMPs

The 483 and Response

Objective of Form 483 from FDAs viewpoint is to fix problem areas and bring company into compliance; it can also be used as a legal record for compliance actions (warning letter or other) No law or regulation says company has to respond to 483 483 Response is current expectation of FDA (policy) The 483 Response demonstrates to the FDA that the company takes the list of observations seriously and wants to improve compliance The 483 Response is an important record of the CAPA plan to address the FDA Observations/non-compliance citations

FDAs Notice on Review of PostInspection Responses*

Response to FDA 483 Observations received within 15 business days will have a detailed review Any warning letter issued will acknowledge 483 response and comment on firms corrective actions Purpose is to optimize resource utilization, issue warning letters promptly, and promote prompt voluntary compliance
*Fed Register Vol. 74, No. 153, Aug. 11,2009, p. 40211, FDA-2009-N-0335

Timing of 483 Response is part of Commissioner Hamburgs Initiatives for FDA

Post Inspection Deadlines. If FDA inspection findings identify a serious problem (significantly out of compliance), the firm will have no more than 15 days to respond before a warning letter or enforcement action Speed the issuance of warning letters. Only significant legal issues will be reviewed by Chief Counsel Work with local, state and international officials to take rapid action, alert public and prepare longer term responses Prioritize enforcement follow up after warning letter or recall, such as reinspection or investigation FDA will no longer issue multiple warning letters before taking enforcement action. Immediate action will be considered for egregious violations Some warning letter close-out letters will be issued after FDA determines the firm has fully corrected violations in a warning letter (usually by re-inspection)

The 15 Day Post Inspection Response Deadline

It is in the companys best interest to respond to the FDA 483 within 3 weeks (15 business days)
A prompt response will allow FDA to review the response in this timeframe In the unlikely event of a warning letter, the response will be acknowledged A prompt response lets FDA know that your company understands the expectation and take the 483 seriously

The 483 Response does not have to be extremely detailed

Key Steps for 483 Response

At the inspection close-out make sure you understand each observation and the thinking or rationale behind it You should understand what the FDA inspector/investigator wants the firm to do
Some observations are poorly written; its up to you to understand what the FDA inspector wants if the observation is unclear

Basic Response contains:

Reiteration of the Observation (The Citation) The Corrective Action or CAPA (The Action) The due date (The Timing)

Defining CAPA
The corrective action (CA) should describe the action that corrects the specific observation The preventive action (PA) should address any systemic concerns which may be part of the observation Any impact on product quality should be addressed An observation may have just a CA or a full CAPA. It may have neither if you disagree with the observation
If you disagree with an observation, offer data or a position paper; dont ignore it

Outline for 483 Response

The Observation
Restate the observation. If done in BOLD, it is easier to read

The CA, CAPA or other action (the Plan)

What is the firm going to do about the observation to fix the problem or address it; correct the non-compliance

The Completion Date

When the correction will be in-place

Example 1
Observation 16. The OQ for the UF/DF was insufficient in that flowrates and pressures were not explored for the design range. Response: An OQ protocol for the UF/DF skid will be written and subsequently reviewed and approved by QA. The approved protocol will be executed by the validation team and incorporated into a validation report. The completed OQ validation report will be reviewed and approved by QA. Completion Date: The OQ Protocol will be completed and approved by Dec 21, 2009. The OQ Validation will be completed by Jan 15, 2010.

Example 2
Observation 12a(1). The final filtration step for Xygram IV had no pre approval by QA for the part of the process that contained the viral filtration validation or the bioburden control records. {Look back in notes: found that the inspector did not like the signoff form for viral clearance validation and also did not like the form for routine bioburden at this step. She noted that you could not figure out why QA is signing or where they are signing.} Response: The specific form for QA approval of viral clearance validation was changed to include a clear signatory by QA. The SOP for same was modified to include the meaning of this signatory. In addition, all QA approvals for all validations were modified to include a clear QA signatory. The bioburden test form was modified to include a clear signatory for QA approval. In addition, all test forms were modified to include same. {note that this response contains a CA and a PA} Completion Dates: all forms and SOPs will be modified/corrected by Dec 20, 2009.

483 Response Letter: Intro

The 483 Response ideally begins with a compliance statement Indicate that it is the commitment of the company to comply with the applicable laws and FDA regulations Indicate that the company is serious about correcting cGMP compliance issues and following the law

For Critical 483 Observations

For critical 483 observations that may lead to a warning letter, include the following:
Provide an assessment of product impact Describe the scope of the CAPA plan with the root cause Include the investigation summary Include brief supporting documentation

483 Response Best Practices

Set attainable and realistic completion dates Follow the format: Observation, Response/Plan, Completion Date The response should be complete, concise, and well-organized, proof-read The response should be factually correct Critical observations should have a more indepth response

Warning Letter vs. 483

The Form 483 is from the inspection team alone The warning letter is from a higher level FDA official or officials The warning letter indicates that upon official review, serious violations may exist Warning letters are issued for violations of regulatory significance

WL: 320- 09-11

August 24, 2009 Mr. Shinji Kawamura General Manager, Gifu Plant Sumitomo Chemical Company Limited 3750 Juhachicho Maid, Anpachi-Cho, Anpachi-Gun Gifu Prefecture, Japan 503-0125

Warning Letter example

This is regarding an April 6-9, 2009, inspection The inspection revealed significant violations from U.S. current good manufacturing practice (CGMP) in the manufacture of APls. The CGMP violations were listed on an Inspectional Observations (FDA-483) form issued to you at the close of the inspection. These violations cause the APls manufactured by your firm to be adulterated within the meaning of Section 50 I(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (the Act) [21 USC 351(a)(2)(B)]. Section 501 (a)(2)(B) of the Act requires that all drugs, as defined in the Act, be manufactured, processed, packed, and held according to CGMP. We have received your firm's responses of May 14 and August 12,2009, and note that they lack sufficient corrective actions. Specific violations observed during the inspection include, but are not limited, to: 1. Your firm does not assure that suitable processing (b)(4) is used for the (b)(4) step of the Hydralazine HCI manufacturing process. This API is intended for use in parenteral drug products. Your firm currently uses (b)(4) and does not test this (b)(4) for endotoxins and total microbial count. [FDA-483 Observation 8] Your written response states that you do not intend to conduct endotoxin testing for (b)(4) or sanitize your (b)(4) system. It is essential that non-sterile APls intended for use in parenteral drug products are manufactured using (b)(4) that is suitable for the process stage and that routine monitoring is performed to ensure ongoing (b)(4) system control. Our inspection found that your firm uses (b)(4) at the (b)(4) and (b)(4) stage, and failed to test for total microbial count and endotoxins. Please refer to ICH Q7A Guidance for Industry for guidance regarding" quality of active pharmaceutical ingredients intended for use in parenteral drug products. 2. Your firm's (b)(4) system is not designed to minimize the risk of microbial contamination. [FDA-483 Observation 8] Your written response states that you are in the process of relacin the distribution pipes, connections, and flexible hoses. However, your (b)(4) tank #(b)(4) cannot be drained and has been in use since 1990. Your (b)(4), approximately 100- meter, distribution pipe contains numerous threaded connectors, at least two flexible hoses, and has no mechanism for (b)(4). This design is not conducive for controlling the (b)(4) system's microbial and endotoxin levels. We continue to have serious concerns about the impact of your (b)(4) system's design on endotoxin and microbial load. Please provide us with a corrective action plan for how you will address these concerns.

Summary
Importance of 483 Response New FDA Program: 483 review and Warning Letters How the 15 day guideline affects your response Key components of a good 483 response How to define CAPAs and include them Response best practices and examples Warning letter example for significant violations of cGMPs

Risk management in responding

Contact Info

John R Godshalk Sr Consultant Biologics Consulting Group 703-485-6139 jgodshalk@bcg-usa.com