Preliminary Concepts to Govern Resolution of Disagreements

Between Industry and FDA

Regarding Technical GMP Issues

-   General

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-   [Three tiers]{.underline}. Issue resolution processes should be
    available for the resolution of disagreements over technical issues
    relating to GMP that arise (a) during an inspection, (b) after
    issuance of a Form 483 but before issuance a Warning Letter, and (c)
    after issuance of a Warning Letter. There should be three levels
    (tiers) to the issue resolution process, and the tiers should
    correspond with the three periods during which issues may need
    resolution (i.e., during an inspection, after a Form 483, and after
    a Warning Letter).

-   [Relationship to other relief]{.underline}. This issue resolution
    process would be designed to provide "real time" solutions to issues
    that arise on the facility floor during inspections or shortly after
    issuance of a Form 483. It should have no bearing on the
    manufacturer's ability to seek appeal of agency decisions pursuant
    to 21 C.F.R. § 10.75. Similarly, there should be no relationship
    between use of this process and use of the Ombudsmen (CDER/CBER and
    FDA).

-   [Exhaustion]{.underline}. Again, this process would be designed to
    provide a "real time" solution to a technical issue. Therefore,
    there should be no requirement that the manufacturer raise the issue
    with the inspector's superiors before starting this process.

-   [Form of proposal]{.underline}. FDA should proceed with a guidance
    document, rather than waiting for statutory language or issuing
    proposed regulations.

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-   Tier One

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-   [Dialogue]{.underline}. Inspectors should be encouraged to
    communicate with manufacturers throughout inspections so that
    misunderstandings and technical disagreements can be resolved
    through the Tier One process prior to issuance of a Form 483.

-   [Initiation of Tier One]{.underline}. The manufacturer should be
    entitled to initiate Tier One issue resolution at any point during
    the inspection.

-   [Format]{.underline}. A "hotline" should be available for resolution
    of technical issues during the inspection process. A bank of
    qualified experts (probably CDER/CBER employees) should be available
    to respond to technical issues. These individuals should have both
    the substantive knowledge base and the decision-making authority to
    resolve the issues in question. A system to send all calls to one
    triage point should be established.

-   [Deletion of resolved issues from Form 483]{.underline}. When an
    issue is resolved at the Tier One stage, there should be no
    observation on the Form 483 reflecting the issue or its resolution.

-   [Annotation of Form 483 to indicate unresolved issues]{.underline}.
    Where the hotline process was initiated but resolution at Tier One
    was not possible, the Form 483 should be annotated at the
    manufacturer's option to indicate the technical disagreement and an
    attempt at Tier One resolution.

-   [Extension of Tier One process for 48 hours after closing
    conference]{.underline}. A Form 483 issued at the closing conference
    should be considered "provisional" (and not subject to release under
    FOIA) and subject to changes that may be required by continuing Tier
    One discussions. The Form 483 should become final 48 hours later to
    include any changes required as a result of conclusion of the Tier
    One process. (This might include an annotation that resolution at
    the Tier One stage was not possible in the time allotted.) The extra
    48 hour window would allow manufacturers to initiate the Tier One
    process with respect to technical issues that arise on the last day
    of the inspection and with respect to technical issues that become
    evident only when the Form 483 is provided to the company.

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-   Tier Two

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-   [Format]{.underline}. FDA should establish sitting panels to resolve
    technical issues that arise in the field. There should be multiple
    panels, responsible for each general area within GMP (e.g., HVAC,
    validation, Part 11, etc.). The panels could be composed of both
    outside experts and FDA employees.

-   [Selection of individuals for panels]{.underline}. The individuals
    tasked with resolving technical issues should have the appropriate
    technical background (appropriate education, qualifications, and
    experience to resolve the technical issues in question). Industry
    might have a voice in the selection process.

-   [Nature of process]{.underline}. The process before the panel should
    not resemble that of a hearing before an administrative law judge.
    It should be more structured and more effective than an ombudsman,
    but less legalistic than an administrative hearing with paper
    filings. Either the inspector or the manufacturer should be able to
    start the process.

-   [Use of experts]{.underline}. The panel should have the option, when
    considering an issue, to seek the input of an outside expert.
    Presumably the inspector and the manufacturer should have the option
    of requesting (but not requiring) that the panel seek the input of
    an outside expert. The expert could be either chosen solely by the
    panel or chosen jointly by the agency and the company.

-   [Consultation with other FDA employees]{.underline}. The panel might
    in some cases believe that consultation with other segments of the
    agency is desirable (e.g., with the Office of Chief Counsel or with
    relevant officials in CDER/CBER). Presumably that consultation
    should occur only with the consent of both parties and should be
    transparent to both sides.

-   [Form of decision]{.underline}. The panel's decision should be
    binding. Probably the decision should be provided orally at first,
    in order to enable "real time" resolution of the issue. It should
    probably also be memorialized in a written statement, which could be
    sent to the manufacturer and the inspector.

-   [Public disclosure]{.underline}. Publication of panel decisions
    would ensure consistency over time and make the agency's thinking on
    GMP issues more transparent to industry. At the same time, however,
    publication of panel decisions would likely slow down the panel's
    decision-making process. There is a tension between the desire for
    immediate resolution of issues and the desire for consistency and
    transparency. Rapid resolution of technical issues is, however, the
    more important goal. A useful alternative to immediate publication
    of panel decisions would be the establishment of some sort of
    technical committee to review and periodically publish decisions
    that set policy (i.e., those affecting more than just the company
    inspected). Care should be taken that confidential commercial
    information and trade secrets are not disclosed.

-   [Urgency of issues]{.underline}. If an issue cannot be resolved
    during Tier Two, FDA should communicate to the sponsor whether, and
    to what extent, the issue is likely to affect the approval of
    pipeline products. This communication should occur during the Tier
    Three process -- after the issuance of a Warning Letter but before
    the agency initiates an enforcement action or preparatory
    investigative work.

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-   Tier Three

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-   [General]{.underline}. The Tier Three process, which would occur
    after issuance of a Warning Letter, should be more formal and
    legalistic. Shaping and implementing the Tier Three process should
    be a lower priority than shaping and implementing the Tier One and
    Tier Two processes.