Godshalk-ProvenBestPracticesforRespondingtoForm483s[1]

7/31/2019 Godshalk-ProvenBestPracticesforRespondingtoForm483s[1]

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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


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The 483 and Response

Objective of Form 483 from FDAs viewpoint is to fixproblem areas and bring company into compliance; it canalso 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 thecompany takes the list of observations seriously and wantsto improve compliance

The 483 Response is an important record of the CAPA planto address the FDA Observations/non-compliance citations


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FDAs Notice on Review of Post-

Inspection Responses*

Response to FDA 483 Observations receivedwithin 15 business days will have a detailedreview

Any warning letter issued will acknowledge483 response and comment on firmscorrective actions

Purpose is to optimize resource utilization,issue warning letters promptly, and promoteprompt voluntary compliance

*Fed Register Vol. 74, No. 153, Aug. 11,2009, p. 40211, FDA-2009-N-0335


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Timing of 483 Response is part of Commissioner

Hamburgs Initiatives for FDA

Post Inspection Deadlines. If FDA inspection findings identify a seriousproblem (significantly out of compliance), the firm will have no morethan 15 days to respond before a warning letter or enforcement action

Speed the issuance of warning letters. Only significant legal issues will bereviewed by Chief Counsel

Work with local, state and international officials to take rapid action, alertpublic and prepare longer term responses

Prioritize enforcement follow up after warning letter or recall, such as re-inspection or investigation

FDA will no longer issue multiple warning letters before takingenforcement action. Immediate action will be considered for egregiousviolations

Some warning letter close-out letters will be issued after FDAdetermines the firm has fully corrected violations in a warning letter(usually by re-inspection)


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Key Steps for 483 Response

At the inspection close-out make sure youunderstand each observation and the thinking orrationale 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 theobservation is unclear

Basic Response contains: Reiteration of the Observation (The Citation)

The Corrective Action or CAPA (The Action)

The due date (The Timing)


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Defining CAPA

The corrective action (CA) should describe the actionthat corrects the specific observation

The preventive action (PA) should address any systemicconcerns 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


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Outline for 483 Response

The Observation

Restate the observation. If done in BOLD, it iseasier 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


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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 willbe 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 Dec21, 2009. The OQ Validation will be completed by Jan 15, 2010.


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Example 2

Observation 12a(1). The final filtration step for Xygram IV had no pre approval by QA for thepart of the process that contained the viral filtration validation or the bioburden controlrecords.

{Look back in notes: found that the inspector did not like the signoff form for viral clearancevalidation 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 includea clear signatory by QA. The SOP for same was modified to include the meaning of thissignatory. In addition, all QA approvals for all validations were modified to include a clear QAsignatory. The bioburden test form was modified to include a clear signatory for QAapproval. 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.


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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


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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 in-

depth response


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Warning Letter exampleWL: 320-09-11

August 24, 2009

Mr. Shinji KawamuraGeneral Manager, Gifu PlantSumitomo Chemical Company Limited3750 JuhachichoMaid, Anpachi-Cho, Anpachi-GunGifu Prefecture, Japan 503-0125

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 toyou 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 FederalFood, 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 theAct, 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. ThisAPI is intended for use in parenteral drug products. Your firm currently uses (b)(4) and does not test this (b)(4) for endotoxins andtotal 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 thatnon-sterile APls intended for use in parenteral drug products are manufactured using (b)(4) that is suitable for the processstage 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 containsnumerous threaded connectors, at least two flexible hoses, and has no mechanism for (b)(4). This design is not conducive for controllingthe (b)(4) system's microbial and endotoxin levels. We continue to have serious concerns about the impact of your (b)(4) system'sdesign on endotoxin and microbial load.

Please provide us with a corrective action plan for how you will address these concerns.


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Summary

Importance of 483 Response

New FDA Program: 483 review and WarningLetters

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


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Risk management in responding


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Contact Info

John R Godshalk

Sr ConsultantBiologics Consulting Group

703-485-6139

[email protected]

Documents

Godshalk-ProvenBestPracticesforRespondingtoForm483s[1]