responding to 483s & warning letters · responding to 483s & warning letters greg levine...
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ROPES & GRAY LLP
Responding to 483s & Warning Letters
Greg LevineRopes & Gray LLPJanuary 24, 2014
ROPES & GRAY
483 vs. Warning Letter: A Distinction with a Difference
“This document lists observations made by the FDA representative(s) during the inspection of your facility. They are inspectional observations, and do not represent a final Agency determination regarding your compliance.”
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ROPES & GRAY
483 vs. Warning Letter: A Distinction with a Difference• A Warning Letter communicates FDA’s
position that a firm has violated the law
• FDA uses this language to establish “prior notice
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ROPES & GRAY
483 vs. Warning Letter: A Distinction with a Difference
• WLs are “advisory” actions intended to elicit voluntary correction
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ROPES & GRAY
Responding to a 483
“As a general rule, a Warning Letter should not be issued if the agency concludes that a firm’s corrective actions are adequate and that the violations that would have supported the letter have been corrected.”
- FDA Regulatory Procedures Manual
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ROPES & GRAY
Responding to a 483
Under the program, before issuing awarning letter, FDA will generally allowfirms 15 business days to provide aresponse to FDA 483 observations…. If we issue a warning letter after reviewing a firm’s timely response, the warning letter will … reply as to the apparent adequacy of the firm’s corrective actions set forth in theresponse.
FDA will conduct an assessment of the program after approximately 18 months…. After the 18-month time period, FDA will evaluate this program and decide whether to continue it with or without adjustments.
Dated: August 4, 2009
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ROPES & GRAY
Warning Letters
• Ongoing or promised actions do not preclude a WL• When a firm is in the process of correcting violations or
has made a promise to do so, the Regulatory Procedures Manual instructs a district office or center to consider the following factors in deciding whether to issue a WL:– The firm's compliance history– The nature of the violation– The risk associated with the product and the impact of the violations
on such risk– The overall adequacy of the firm's corrective actions – Whether documentation of the corrective actions was provided – Whether the timeframe for the corrective action is appropriate– Whether the corrective action taken ensures sustained compliance
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ROPES & GRAY
Warning Letters
• FDA will likely issue a warning letter if:– Response fails to address observation at all
“[W]e are concerned that these instances of discrepancies observed during the March 2008 inspection are indications of continuing, systemic CGMP deficiencies[.]”
“These deficiencies in equipment cleaning and batch production and control records heighten our concerns regarding the conduct, adequacy, and oversight of the Quality System at the [facility.]”
“For example, assay methods used by your contract testing laboratory to test your finished products … for release have not been validated. Your response is inadequate because you failed to address this deficiency.”
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ROPES & GRAY
Warning Letters
• FDA will likely issue a warning letter if:– Response addresses observation, but is deemed
inadequate
“[W]e are concerned that these instances of discrepancies observed during the March 2008 inspection are indications of continuing, systemic CGMP deficiencies[.]”
“These deficiencies in equipment cleaning and batch production and control records heighten our concerns regarding the conduct, adequacy, and oversight of the Quality System at the [facility.]”
“You identified nine additional incidents where OOS results were averaged with passing results.... Your firm concluded that these OOS results were within the accepted variation of the analytical method and that the quality of these batches was not affected. We disagree with your rationale and conclusion.”
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ROPES & GRAY
Warning Letters
• FDA will likely issue a warning letter if:– Response is vague
“[W]e are concerned that these instances of discrepancies observed during the March 2008 inspection are indications of continuing, systemic CGMP deficiencies[.]”
“These deficiencies in equipment cleaning and batch production and control records heighten our concerns regarding the conduct, adequacy, and oversight of the Quality System at the [facility.]”
“Your response is inadequate because it does not describe the specific changes you will make to your procedures or the timeframes for their completion and implementation, nor did you describe any additional process controls to prevent contamination of the API.”
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ROPES & GRAY
Warning Letters
• FDA will likely issue a warning letter if:– Deficiencies are sufficiently serious
“[W]e are concerned that these instances of discrepancies observed during the March 2008 inspection are indications of continuing, systemic CGMP deficiencies[.]”
“These deficiencies in equipment cleaning and batch production and control records heighten our concerns regarding the conduct, adequacy, and oversight of the Quality System at the [facility.]”
“[O]ur investigative team documented numerous instances where persons or supervisors reportedly verifying equipment cleaning activities or supervising or checking significant manufacturing steps were not present at the…facility on the dates or times that these activities occurred.”
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ROPES & GRAY
Warning Letters
• FDA will likely issue a warning letter if:– Pattern of violative conduct
“Your firm failed to thoroughly investigate any unexplained discrepancy or failure of a batch…This is a repeat observation from the August 2012 inspection[.]”
“Your firm failed to ensure your container closure system provided adequate protection against foreseeable external factors in storage and use that can cause deterioration or contamination of the drug product…This is a repeat violation[.]”
A November 2012 inspection “revealed that numerous HEPA filters, HEPA filter supporting grid work, HEPA filter screens and HEPA filter screen tracks contained… chipping paint, multicolored coalescing droplets, and clumps of dark material that FDA testing later revealed was mold… This was a repeat observation from the August 2012 inspection[.]”
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ROPES & GRAY
Warning Letters
• FDA will likely issue a warning letter if:– Response fails to address root cause
“Your firm failed to thoroughly investigate any unexplained discrepancy or failure of a batch…This is a repeat observation from the August 2012 inspection[.]”
“Your firm failed to ensure your container closure system provided adequate protection against foreseeable external factors in storage and use that can cause deterioration or contamination of the drug product…This is a repeat violation[.]”
“In your response, you state that you have not identified any other defects of this nature. Your response is inadequate since you have not addressed the potential root cause of a vial defect as identified in your investigation.”
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ROPES & GRAY
Warning Letters
• FDA will likely issue a warning letter if:– Response fails to assess product quality impact
“Your firm failed to thoroughly investigate any unexplained discrepancy or failure of a batch…This is a repeat observation from the August 2012 inspection[.]”
“Your firm failed to ensure your container closure system provided adequate protection against foreseeable external factors in storage and use that can cause deterioration or contamination of the drug product…This is a repeat violation[.]”
“Your response is inadequate because you did not provide the scientific rationale … for naming these types of defects “cosmetic defects.” In addition, your response did not include any assessment of the lot ([b4]) sent to your site in [b4] although this lot also exhibited these defects.”
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ROPES & GRAY
Warning Letters
• FDA will likely issue a warning letter if:– Actions are not complete
“Your firm failed to thoroughly investigate any unexplained discrepancy or failure of a batch…This is a repeat observation from the August 2012 inspection[.]”
“Your firm failed to ensure your container closure system provided adequate protection against foreseeable external factors in storage and use that can cause deterioration or contamination of the drug product…This is a repeat violation[.]”
“Your firm has provided an overview of a plan to ensure that all processes have been adequately validated to current industry standards. Your firm states that it will undertake a comprehensive validation review and revalidation program…. Your firm has also provided timelines for these activities. The response is not adequate because your firm has not completed the documentation, which includes a description and evidence of implementation of the corrective action.”
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ROPES & GRAY
Warning Letters
• FDA will likely issue a warning letter if:– Company’s response is “late”
“Your firm failed to thoroughly investigate any unexplained discrepancy or failure of a batch…This is a repeat observation from the August 2012 inspection[.]”
“Your firm failed to ensure your container closure system provided adequate protection against foreseeable external factors in storage and use that can cause deterioration or contamination of the drug product…This is a repeat violation[.]”
“We acknowledge receipt of your written response dated October 3, 2011,to Form FDA-483 issued to your firm on September 9, 2011, but note that your response was received more than 15 working days from the close of the inspection. Thus, while we have reviewed the response, we have not included a discussion of the response in this letter, as per the Commissioner's Enforcement Initiative announced August 11, 2009. ”
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ROPES & GRAY
Warning Letter Response
• Dual purpose: avoid FDA enforcement (civil or criminal), but also consider other potential legal risks such as– False Claims Act lawsuits
– Shareholder derivative suits
– Business litigation for breach of contract
– Government contract violations
– Product liability
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Common Pitfalls
• Going to extremes: trivializing or self-flagellation• Blaming everything on lack of training• Arguing that the company is acting in accordance with
industry practice rather than CGMP• Providing inadequate supporting documentation or
documentation inconsistent with response • Setting unattainable/unrealistic goals• Failing to follow through and implement promised
corrections• Sacrificing quality to meet self-imposed deadlines• Failing to update FDA proactively on progress,
including changes in actions or timelines
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ROPES & GRAY
Posting the WL Response
• FDA will post WL responses upon request– Firm must provide the response electronically in a
word processing format
– FDA reserves the right not to post responses that “likely would mislead the public about the safety or efficacy of a regulated product.”
– The issuing district or center must redact the response to the extent permitted by the Freedom of Information Act.
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