Guidance for Industry
Formal Dispute Resolution: Scientific and Technical Issues Related
to Pharmaceutical CGMP
(PDF version of this document)
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Center for Biologics Evaluation and Research (CBER)
Center for Veterinary Medicine (CVM)
Office of Regulatory Affairs (ORA)
Pharmaceutical CGMPs
January 2006
OMB Control Number 0910-0563
Expiration Date: 05/31/2008
See additional PRA statement in Section VI of this guidance
Guidance for Industry
Formal Dispute Resolution: Scientific and Technical Issues
Related to Pharmaceutical CGMP
Additional copies of this Guidance
are available from
Office of Training and
Communications
Division of Drug
Information,
HFD-240
Center for Drug Evaluation and Research
5600 Fishers
Lane, Rockville, MD 20857
Phone 301-827-4573
Internet:
http://www.fda.gov/cder/guidance/index.htm
or
Office of Communication, Training
and
Manufacturers Assistance, HFM-40
Center for Biologics Evaluation and Research
1401 Rockville Pike, Rockville, MD 20852-1448
Phone 800-835-4709 or 301-827-1800
Internet:
http://www.fda.gov/cber/guidelines.htm
or
Communications Staff, HFV-12
Center for Veterinary Medicine
7519 Standish Place,
Rockville, MD 20855
Phone 240-276-9300
Internet:
http://www.fda.gov/cvm/guidance/published.htm
U.S. Department of Health and Human
Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Center for Biologics Evaluation and Research (CBER)
Center for Veterinary Medicine (CVM)
Office of Regulatory Affairs (ORA)
Pharmaceutical CGMPs
January 2006
Guidance for Industry
Formal Dispute Resolution:
Scientific and Technical Issues Related to Pharmaceutical CGMP
This
guidance represents the Food and Drug Administration's (FDA's)
current thinking on this topic. It does not create or confer any
rights for or on any person and does not operate to bind FDA or
the public. You can use an alternative approach if the approach
satisfies the requirements of the applicable statutes and
regulations. If you want
to discuss an alternative approach, contact the FDA staff
responsible for implementing this guidance. If you cannot
identify the appropriate FDA staff, call the appropriate number
listed on the title page of this guidance.
This document is intended to provide
guidance to manufacturers of veterinary and human drugs, including
human biological drug products, on how to resolve disputes of
scientific and technical issues relating to current good
manufacturing practice (CGMP) requirements. This document is not
intended to cover medical devices regulated by the Center for
Devices and Radiological Health (CDRH) or foods or dietary
supplements regulated by the Center for Food Safety and Applied
Nutrition (CFSAN).
Disputes related to scientific and
technical issues may arise during FDA inspections of pharmaceutical
manufacturers to determine compliance with CGMP requirements or
during the Agency's assessment of corrective actions undertaken as a
result of such inspections. As these disputes may involve complex
judgments and issues that are scientifically or technologically
important, it is critical to have procedures in place that will
encourage open, prompt discussion of disputes and lead to their
resolution. This guidance describes procedures for raising such
disputes to the Office of Regulatory Affairs (ORA) and center levels
and for requesting review by the Dispute Resolution Panel for
Scientific and Technical Issues Related to Pharmaceutical CGMP (DR
Panel).
Manufacturers
are encouraged to seek clarification of scientific or technical
issues with the inspection team at any time during an inspection.
Although there are existing processes to encourage dialogue between
FDA and manufacturers, the processes described in this document
apply to CGMP questions raised during inspections and are intended
to supplement the dispute resolution processes currently in place,
including:
·
21 CFR 10.75, Internal Agency Review of Decisions.
Allows manufacturers to ask for a review of Agency decisions at each
successive supervisory level through the chain of command, ending
with the FDA Commissioner's
office.
·
CDER/CBER guidance for industry entitled Formal
Dispute Resolution: Appeals Above the Division Level.
Describes procedures a sponsor may use to formally appeal
disputes to the office or center
level on scientific and procedural issues that arise during drug
development, new drug review, and post-marketing oversight
processes. The guidance may be found on
CDER’s and
CBER's Web
sites.
·
CVM guidance for industry #79 entitled Dispute
Resolution Procedures for Science-Based Decisions on Products
Regulated by the Center for Veterinary Medicine (CVM), July
2005. Describes procedures for handling requests for internal
review of scientific controversies relating to decisions affecting
animal drugs or other products that are regulated by CVM. The
guidance may be found on
CVM's
Web site.
·
Investigations
Operations Manual (IOM), Chapter 5, Subchapter 510, Sections 512
(Report of Observations) and
516 (Discussions with Management). Describes processes for
discussing inspectional observations with a manufacturer. The
IOM
is available on
ORA's
Web site.
For the purposes
of this document, the term manufacturer
includes any domestic or foreign applicant or manufacturer of a
human or veterinary drug, or human biological drug product regulated
by the Agency under the Federal Food, Drug, and Cosmetic Act (the
Act) or section 351 of the Public Health Service Act (the PHS Act).
FDA's guidance documents, including this
guidance, do not establish legally enforceable responsibilities.
Instead, guidances describe the Agency's current thinking on a topic
and should be viewed only as recommendations, unless specific
regulatory or statutory requirements are cited. The use of the word
should in Agency guidances means that something is suggested
or recommended, but not required.
The policies and procedures described in this
guidance document cover all disputes
on scientific or technical
issues related to CGMP that arise as the result of CGMP and
preapproval inspections (PAI) for manufacturers of veterinary and
human drug products, including related Active Pharmaceutical
Ingredients (APIs). For
disputes that arise during prelicense and preapproval inspections
for human biological drug products regulated by CBER or for
application review issues that arise during PAI inspections for
human or veterinary drug products, the existing CDER/CBER and CVM
guidances listed in Section I of this document should continue to be
used.
This guidance
does not cover disputes over procedures or administrative matters
that may arise during the inspection process. At any time, a
manufacturer may informally raise a procedural or administrative
matter with ORA or with the CDER, CBER, or CVM Ombudsman, in
accordance with 21 CFR 10.75. The procedures described in this
guidance do not apply to such informal dispute resolution through
the CDER, CBER, or CVM Ombudsman.
If a dispute
involves a combination product including a device component, the
dispute may be addressed through CDRH's dispute resolution process,
depending on the nature of the dispute.
During
inspections of manufacturers, investigators are expected to make
every reasonable effort to discuss observations relating to
manufacturing quality as they are observed, or on a daily basis to
minimize surprise, errors, and misunderstandings when a Form FDA 483
is issued. At the conclusion of an inspection, investigators will
normally meet with the manufacturer's management to again discuss
observations and solicit views and additional relevant information.
These processes are described in detail in the Investigations
Operations Manual (IOM), Sections 512 and 516, as listed in Section
I of this document.
When a scientific or technical issue
arises during an inspection, we recommend that a manufacturer
initially attempt to reach agreement on the issue informally with
the investigator. A manufacturer should discuss with the
investigator any observation that the manufacturer believes is not
justified from a scientific or technical standpoint. As
appropriate, the investigator can consult with FDA management or
program officials, or appropriate product or technical experts. The
investigator may invite the company to participate in certain
consultative discussions. If agreement on the issue is not reached
with the investigator prior to issuance of the Form FDA 483, a
manufacturer can formally request dispute resolution after the
investigator issues the Form FDA 483.
Certain scientific or technical issues may be
too complex or time-consuming to resolve during the inspection. If
resolution of a scientific or technical issue
is not accomplished through informal mechanisms prior to the
issuance of a Form FDA 483,
manufacturers can use the formal two-tiered dispute resolution
process described in this guidance.
·
Tier one of the formal dispute resolution process
refers to scientific or technical issues raised to the ORA and
center levels.
·
Tier two of the formal dispute resolution process
refers to scientific or technical issues raised to the DR Panel.
These processes
are described in detail in the following subsections.
Pharmaceutical
manufacturers can formally dispute the scientific or technical basis
for CGMP inspectional observations after issuance of a Form FDA
483. In such cases, the formal dispute resolution process starts in
the appropriate ORA unit
as listed below and may advance to the applicable center.
·
For domestic
manufacturers of veterinary and human drugs, the formal dispute
resolution process begins in the appropriate district office, ORA.
·
For foreign
manufacturers of veterinary and human drugs, the formal dispute
resolution process begins in the Division of Field Investigations,
ORA.
·
For domestic or foreign
manufacturers of human biological drug products inspected by Team
Biologics, the formal dispute resolution process begins in the
Office of Enforcement, ORA.
A manufacturer
should seek clarification of a disputed scientific or technical
issue within 30 days of issuance of the Form FDA 483. (FDA defines
days to mean calendar days throughout this guidance.) FDA
may refuse to address a dispute resolution request not raised during
this time frame. The Agency, at its discretion, may contact the
manufacturer to obtain additional information and/or seek
clarification.
If a manufacturer disagrees with the
scientific or technical basis for an
observation listed by an investigator on a Form FDA 483, the
following steps may be taken:
1. The manufacturer may file a written request for formal
dispute resolution with the appropriate ORA unit as listed above.
The manufacturer should provide
all supporting documentation and arguments for review.
2.
The appropriate ORA unit may evaluate the written request for
formal dispute resolution, and may include Agency staff not
previously involved in the dispute, as appropriate.
If the ORA unit agrees with the manufacturer,
·
The ORA unit will issue a written response
to the manufacturer within 30 days of
receipt of the request, noting its agreement with the
manufacturer and resolution of the
dispute. The resolution may
take the form of a letter. It may also take the form of an addendum
to the existing Form FDA 483.
·
All disputes resolved
at the ORA level will be copied to the relevant program center for
information and public dissemination following appropriate
redaction.
If the ORA unit
disagrees with the manufacturer,
·
The ORA unit will issue
a written response to the manufacturer generally within 30 days of
receipt of the request. Responses that disagree with a
manufacturer's position will incorporate a review and decision by
the relevant program center, which may require additional time as
described below.
·
The written response
will be copied to the relevant program center for information and
public dissemination after appropriate redaction, in accordance with
applicable requirements.
If the ORA unit
is unable to complete its review of the request and respond within
30 days, the ORA unit will notify the manufacturer, explain the
reason for the delay (which may include the need for an additional
30 days for center review), and discuss the time frame for
completing the review.
3. If a
manufacturer disagrees with the
tier-one decision, the manufacturer can appeal that decision
to the DR Panel.
The DR Panel provides a formal way for
manufacturers to defend the science in
their manufacturing and quality
control processes before a neutral panel of experts and to appeal an
ORA and center-level decision concerning the science
underlying the inspectional observation.
The DR Panel resides
at the Office of the Commissioner.
The DR Panel considers requests for tier-two dispute resolution by
manufacturers and provides an
opportunity for a manufacturer to present its case in support of its
position on a scientific or technical
issue. The DR Panel’s membership includes representatives from each
of the program centers and ORA, as well as the Chair of the FDA
Council on Pharmaceutical Quality, but will not include decision
makers who have addressed the disputed issue at the ORA and center
level.
If a
manufacturer disagrees with the tier-one decision in the formal
dispute resolution process, the manufacturer can file a written
request for formal dispute resolution by the DR Panel. The
manufacturer should provide the written request for formal dispute
resolution and all supporting documentation and arguments to the DR
Panel for review within 60 days from issuance of the tier-one
decision.
The DR Panel
will evaluate the written request for formal dispute resolution.
The DR Panel will determine whether or not to consider the specific
issue in the appeal. If necessary,
additional internal and external experts, as well as attorneys from
the Office of Chief Counsel (OCC), may be added to the DR Panel to
facilitate evaluation of the specific issue.
If the DR Panel
determines that the request is appropriate for review, it will
schedule a meeting to discuss the issue within 90 days. The DR
Panel may communicate with the manufacturer at its discretion and
may request the manufacturer to be present during the meeting.
·
The executive secretary
of the DR Panel will issue a written response to the manufacturer
within 30 days of the
meeting, noting its agreement with the manufacturer and resolution
of the dispute.
·
All disputes resolved at the DR Panel level will be
copied to the relevant FDA units
for their information and public dissemination
after appropriate redaction, in
accordance with applicable requirements.
If the DR Panel disagrees with the manufacturer
on the issue,
·
The executive secretary
of the DR Panel will issue a written response to the manufacturer
within 30 days of the meeting, noting its decision on the issue,
except as provided below.
·
The executive secretary
of the DR Panel will notify the relevant FDA units of the DR Panel’s
decision for their information and public dissemination after
appropriate redaction, in accordance with applicable requirements.
If the DR Panel
determines that the request does not qualify for review (see Section
IV), the executive secretary of the DR Panel will notify the
manufacturer in writing within 30 days of receipt of the appeal and
communicate the DR Panel's decision to the program offices.
If FDA is unable
to complete its review of the request and respond within 30 days,
the executive secretary of the DR Panel will notify the
manufacturer, explain the reasons for the delay, and discuss the
time frame for completing the review.
All Agency
decisions in the formal dispute resolution process will be based on
the manufacturer's documentation that was available at the time of
the inspection, unless a manufacturer can provide a reasonable
explanation why it did not present relevant information during the
inspection or the manufacturer was specifically requested to provide
new information as part of the Agency’s dispute resolution review.
Submission of new information may result in the dispute being
returned to an earlier point in the process, as the Agency deems
appropriate.
The following
list of addresses can be used to request formal dispute resolution.
1. For a tier-one dispute
resolution request from domestic manufacturers of veterinary and
human drugs, the request should be submitted to:
Director of the district office
responsible for the inspection
The following Internet site lists district office addresses:
http://www.fda.gov/ora/inspect_ref/iom/iomoradir.html
2. For a tier-one dispute
resolution request from foreign manufacturers of veterinary and
human drugs, the request should be submitted to:
Director, Division of Field
Investigations
Office of Regional Operations
Office of Regulatory Affairs
Food and Drug Administration
Mail Code: HFC-100
5600 Fishers Lane, Room 13-64
Rockville, Maryland 20857
3. For a tier-one dispute
resolution request from domestic or foreign manufacturers of human
biological drug products inspected by Team Biologics, the request
should be submitted to:
Director, Division of Compliance
Management and Operations
Office of Enforcement
Office of Regulatory Affairs
Food and Drug Administration
Mail Code: HFC-210
5600 Fishers Lane
Rockville, MD 20857
4. For a tier-two dispute
resolution request, the request should be submitted to the
appropriate center contact as listed below:
·
For CDER:
Formal Dispute Resolution Project
Manager (DPRM)
Office of Compliance
Center for Drug Evaluation and Research
Food and Drug Administration
Mail Code: HFD-320
5600 Fishers Lane
Rockville, MD 20857
·
For CVM:
Ombudsman
Office of the Center Director
Center for Veterinary Medicine
Food and Drug Administration
Mail Code: HFV-7
7519 Standish Place
Rockville, MD 20855
·
For CBER:
Assistant to the Director for Policy
Office of Compliance and Biologics Quality
Center for Biologics Evaluation and Research
Food and Drug Administration
Mail Code: HFM-600
1401 Rockville Pike, Suite 200N
Rockville, MD 20852
All requests for formal dispute
resolution should be in writing and include adequate information to
explain the nature of the dispute and to allow the Agency to act
quickly and efficiently. Each request should include the
following:
1.
Cover sheet that clearly identifies the submission in bold,
uppercase letters:
REQUEST FOR TIER-ONE DISPUTE
RESOLUTION
or
REQUEST FOR TIER-TWO DISPUTE RESOLUTION (REVIEW BY THE
Dispute Resolution Panel for
Scientific and Technical Issues Related to Pharmaceutical CGMP)
2. Name
and address of manufacturer inspected (as listed on the Form FDA
483)
3. Date
of inspection (as listed on the Form FDA 483)
4. Date
the Form FDA 483 issued (from the Form FDA 483)
5. FEI
Number, if available (from the Form FDA 483)
6. Names and titles of FDA
employees who conducted inspection (from the Form FDA 483)
7. Office responsible for the
inspection, e.g., district office, as listed on the Form FDA 483
8.
Application number if the inspection was a preapproval inspection
9.
Comprehensive statement of each issue to be resolved
·
Identify the
observation in dispute.
·
Clearly present the
manufacturer’s scientific position or rationale concerning the issue
under dispute with any supporting data.
·
State the steps that
have been taken to resolve the dispute, including any informal
dispute resolution that may have occurred before the issuance of the
Form FDA 483.
·
Identify possible
solutions.
·
State desired outcome.
10. Name, title, telephone and
fax number, and e-mail address (as available) of manufacturer
contact.
FDA will respond
in writing to all requests for dispute resolution filed under the
procedures described in this guidance. The written response should
specifically agree or disagree with the outcome desired by the
manufacturer, agree or disagree with parts of the proposed outcome,
or indicate a resolution that is different from that proposed by the
manufacturer. If the Agency does not agree with the manufacturer’s
position, the response should include reasons for the disagreement.
The Agency official responsible for
replying to a request for dispute resolution should make all
reasonable efforts to resolve the dispute and provide a written
response to the manufacturer according to timelines suggested above
in Section III. A and B.
The Agency may, under appropriate
circumstances, take regulatory action while a request for formal
dispute resolution is pending.
Any dispute
involving a scientific or technical issue related to CGMP
regulations that arises during an FDA inspection, as discussed
above, may be suitable for the dispute resolution process described
in this guidance.
The following
text provides examples concerning the appropriateness of several
issues for the dispute resolution process detailed in this
guidance.
According to 21
CFR 211.100(a), a manufacturer producing a finished pharmaceutical
product must have written procedures for production and process
controls, and these written procedures must be designed to ensure
that the drug has the identity, strength, quality, and purity it
purports or is represented to have.
·
Failure to have written
procedures for production and process controls would be a failure to
comply with a precise element of the CGMP regulations and would not
be appropriate for the formal dispute resolution process described
in this document.
·
However, observations
pertaining to the adequacy of the process and production control
design activities could be subject to scientific debate and may be
appropriate for dispute resolution as described in this guidance.
Another example
relates to the regulatory provisions governing the testing and
approval or rejection of components, drug product containers, and
closures (21 CFR 211.84), which require appropriate sampling,
testing, or examination of each lot of components, drug product
containers, or closures.
·
Failure to conduct
testing or examination of each lot would be failure to comply with a
precise element of the regulations and would not be appropriate for
the formal dispute resolution process described in this guidance.
·
However, the
appropriateness of a particular test or sampling scheme could
involve the exercise of scientific judgment. A disagreement between
a manufacturer and an investigator concerning the adequacy of a
particular test or sampling scheme could be subject to
scientific debate and may be
appropriate for dispute resolution as described in this guidance.
A third example
relates to the CGMP regulation requirements that a manufacturer
thoroughly investigates any unexplained discrepancy associated with
its review of product production and control records (21 CFR
211.192).
·
Failure to investigate
an unexplained discrepancy would be a failure to comply with a
precise element of the CGMP regulations and would not be appropriate
for the formal dispute resolution process described in this
guidance.
·
However, the extent or
adequacy of the investigation could be subject to scientific
debate. Observations pertaining to the adequacy of an investigation
into an unexplained discrepancy may also be appropriate for dispute
resolution as described in this guidance.
If, as part of
the conditions established in an approved application, a
manufacturer is required to conduct a particular test on a finished
product and the manufacturer fails to conduct that test, this
failure represents a failure to comply with a precise requirement
established in an approved application. Any disagreement about the
need for such a test should be raised in the application review
process. Such disagreement is not appropriate for the dispute
resolution process described in this guidance, but may be raised
using the processes described in the CDER/CBER and CVM guidances
listed in Section I of this document.
The CGMP
regulations require that all changes to production and process
control procedures be approved by the quality control unit (21 CFR
211.100(a)). If a manufacturer makes a change in production and
process control procedures, but does not obtain approval of those
procedures by the manufacturer’s quality control unit, this would be
a failure to comply with a precise requirement of the CGMP
regulations. The manufacturer may contend that the failure in this
particular case was not significant because it
did not have an adverse effect
on product quality and may convey this contention to the Agency
through existing informal communication channels, including Form FDA
483-response correspondence.
In such a case,
the significance of this observation would not be appropriate for
dispute resolution as
described in this guidance, as the
observation concerns a failure to comply with a precise requirement
of the regulations. The regulatory significance of an observation
is determined by the Agency after considering all relevant
information, including the manufacturer's response to the
inspectional observations. The Agency encourages manufacturers to
provide all information relevant to the regulatory significance of
an observation as part of this response, but such disputes are not
within the scope of this guidance on scientific and technical
disputes concerning the interpretation and application of CGMP
requirements.
Manufacturers
must have internal written production and process control procedures
(21 CFR 211.100(a)) and, as part of these procedures, manufacturers
often establish procedural action limits that are tighter
than release specifications. When the action limits
are exceeded, the internal written procedures may call for some type
of investigation to determine if the process is drifting toward a
loss of control, or the procedures may call for other assessments to
determine if the product will meet appropriate specifications
throughout its expected shelf life. If a manufacturer's internal
written procedures require certain actions when action limits
are exceeded, failure to follow these written production and process
control procedures is a failure to comply with 21 CFR 211.100(b).
The manufacturer may contend that this failure is not significant in
that the product met all regulatory specifications when released.
As discussed above, this contention about significance is not
appropriate for the formal dispute resolution process described in
this guidance.
If, during an
inspection, an investigator notes what appears to be an
objectionable condition and a manufacturer disagrees with that
observation, the manufacturer should voice its disagreement with the
investigator. By doing so, the investigator has the opportunity to
evaluate the manufacturer's position and consult, as needed, with
Agency experts. The Agency may not accept a request for dispute
resolution concerning a disagreement that was not initially raised
by the manufacturer during the inspection unless a manufacturer can
provide a reasonable explanation why it did not present relevant
information during the inspection.
V.
Communication of dispute resolution decisions
FDA believes that decisions made in
the dispute resolution process, along with all supporting
documentation, should be publicly available consistent with FDA’s
disclosure regulations (21 CFR Part 20) and applicable statutes,
unless the decisions involve information that would otherwise be
withheld under these regulations and statutes. The Agency will
redact, as appropriate, any documents requested through the Freedom
of Information process.
When appropriate, a summary of the
relevant issues and Agency views will be provided in a question and
answer format and posted on the FDA Web site with all identifying
information excluded. Information gained from these decisions
should promote consistent application and interpretation of
pharmaceutical CGMP requirements.
This guidance contains information collection
provisions that are subject to review by the Office of Management
and Budget (OMB) under the Paperwork Reduction Act of 1995 (44 U.S.C.
3501-3520).
The time required to complete this information
collection is estimated to average 30 hours to prepare and submit
each request for tier-one dispute resolution and 8 hours to prepare
and submit each request for tier-two dispute resolution. This
includes the time to review instructions, search existing data
resources, gather the data needed, and complete and review the
information collection. Send comments regarding this burden
estimate or suggestions for reducing this burden to Edward M.
Sherwood, Center for Drug Evaluation and Research (HFD-3), Food and
Drug Administration, Rockwall II, Rm. 7231, 5515 Security Lane,
Rockville, MD 20857,
301-594-2847.
An
agency may not conduct or sponsor, and a person is not required to
respond to, a collection of information unless it displays a
currently valid OMB control number. The OMB control number for
this information collection is 0910-0563 (expires 05/31/2008).
1
This guidance has
been prepared by the Dispute Resolution Working Group formed as
part of the August 2002 FDA Initiative, Pharmaceutical cGMPs for
the 21st Century: A Risk-Based Approach. The
Working Group included representatives from the Center for Drug
Evaluation and Research (CDER), the Center for Biologics
Evaluation and Research (CBER), the Center for Veterinary
Medicine (CVM), and the Office of Regulatory Affairs (ORA).
CDRH guidance
document, Resolving Scientific Disputes Concerning the
Regulation of Medical Devices, A Guide to Use of the Medical
Devices Dispute Resolution Panel; Final Guidance for
Industry and FDA, July 2, 2001.
Back
to Top
Back to Guidance Page
PDF requires the free Adobe
Acrobat Reader
Date created: January 11, 2006 |