Guidance for Industry: Formal Dispute Resolution; Scientific and Technical Issues Related to Pharmaceutical Current Good Manufacturing Practice

Guidance for Industry
Formal Dispute Resolution:
Scientific and Technical Issues
Related to Pharmaceutical CGMP

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: 09/30/2011 (Note: Expiration date updated 05/04/2011)
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

Contains Nonbinding Recommendations
TABLE OF CONTENTS
I.

INTRODUCTION............................................................................................................. 1

II.

SCOPE OF THE GUIDANCE ........................................................................................ 2

III.

DISPUTE RESOLUTION PROCESS ............................................................................ 3

A.

Tier-One Dispute Resolution at the Office of Regulatory Affairs and Center Levels ............. 4

B.

Tier-Two Dispute Resolution with the DR Panel on Scientific and Technical Issues.............. 5

C.

How to Request Formal Dispute Resolution................................................................................ 6

D.

Supporting Information to be Provided by Manufacturers....................................................... 8

E.

FDA Response to Requests for Dispute Resolution .................................................................... 9

IV.

SUITABILITY OF ISSUES FOR FORMAL DISPUTE RESOLUTION................... 9

A.

Failure to Comply With a Precise Element of CGMP Regulations......................................... 10

B.

Failure to Comply With a Precise Requirement Established in an Approved Application.. 11

C.

The Regulatory Significance of Failing to Comply With a Precise Requirement .................. 11

D.

Issues Not Raised During the Inspection ................................................................................... 12

V.

COMMUNICATION OF DISPUTE RESOLUTION DECISIONS .......................... 12

VI.

PAPERWORK REDUCTION ACT OF 1995.............................................................. 12

Contains Nonbinding Recommendations

Guidance for Industry 1

1
2

Formal Dispute Resolution:
Scientific and Technical Issues Related to Pharmaceutical CGMP

3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37

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.

I.

INTRODUCTION

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

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).
1

Contains Nonbinding Recommendations

38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
66
67
68
69
70
71
72
73
74

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. 2

•

CVM guidance for industry #79 entitled Dispute Resolution Procedures for ScienceBased 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. 3

•

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. 4

For the purposes of this document, the term manufacturer 5 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.
II.

SCOPE OF THE GUIDANCE

2

The CDER/CBER guidance can be found on the Internet at http://www.fda.gov/cder/guidance/index.htm and
http://www.fda.gov/cber/gdlns/dispute.htm.

3

The CVM guidance can be found on the Internet at: http://www.fda.gov/cvm/Guidance/published.htm#79.

4

The IOM can be found on the Internet at: http://www.fda.gov/ora/inspect_ref/iom/iomtc.html.

5

The activities of a manufacturer encompass the processes and functions described in 21 CFR 207.3(8), 21 CFR
210.3(12), and 21 CFR 600.3(t).
2

Contains Nonbinding Recommendations

75
76
77
78
79
80
81
82
83
84
85
86
87
88
89
90
91
92
93
94
95
96
97
98
99
100
101
102
103
104
105
106
107
108
109
110
111
112
113
114
115
116

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. 6
III.

DISPUTE RESOLUTION PROCESS

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.
6

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.

3

Contains Nonbinding Recommendations

117
118
119
120
121
122
123
124
125
126
127
128
129
130
131
132
133
134
135
136
137
138
139
140
141
142
143
144
145
146
147
148
149
150
151
152
153
154
155
156
157

•

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.
A.

Tier-One Dispute Resolution at the Office of Regulatory Affairs and Center
Levels

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 7 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.

7

For the purposes of Sections III A and B in this document, the phrase ORA unit will refer to the district office, the
Division of Field Investigations, or the Office of Enforcement, as appropriate.
4

Contains Nonbinding Recommendations

158
159
160
161
162
163
164
165
166
167
168
169
170
171
172
173
174
175
176
177
178
179
180
181
182
183
184
185
186
187
188
189
190
191
192
193
194
195
196
197
198
199
200
201
202

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.
B.

Tier-Two Dispute Resolution with the DR Panel on Scientific and Technical
Issues

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

5

Contains Nonbinding Recommendations

203
204
205
206
207
208
209
210
211
212
213
214
215
216
217
218
219
220
221
222
223
224
225
226
227
228
229
230
231
232
233
234
235
236
237
238
239
240
241
242
243
244
245
246
247

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.
If the DR Panel agrees 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 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.
C.

How to Request Formal Dispute Resolution

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

6

Contains Nonbinding Recommendations

248
249
250
251
252
253
254
255
256
257
258
259
260
261
262
263
264
265
266
267
268
269
270
271
272
273
274
275
276
277
278
279
280
281
282
283
284
285
286
287
288
289
290
291
292

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

7

Contains Nonbinding Recommendations

293
294
295
296
297
298
299
300
301
302
303
304
305
306
307
308
309
310
311
312
313
314
315
316
317
318
319
320
321
322
323
324
325
326
327
328
329
330
331
332
333
334
335
336
337

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
D.

Supporting Information to be Provided by Manufacturers

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)

8

Contains Nonbinding Recommendations

338
339
340
341
342
343
344
345
346
347
348
349
350
351
352
353
354
355
356
357
358
359
360
361
362
363
364
365
366
367
368
369
370
371
372
373
374
375
376
377
378
379
380
381

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
•
•
•
•
•

10.

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.

Name, title, telephone and fax number, and e-mail address (as available) of manufacturer
contact.
E.

FDA Response to Requests for Dispute Resolution

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.
IV.

SUITABILITY OF ISSUES FOR FORMAL DISPUTE RESOLUTION

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.

9

Contains Nonbinding Recommendations

382
383
384
385
386
387
388
389
390
391
392
393
394
395
396
397
398
399
400
401
402
403
404
405
406
407
408
409
410
411
412
413
414
415
416
417
418
419
420
421
422
423
424
425
426

The following text provides examples concerning the appropriateness of several issues for the
dispute resolution process detailed in this guidance.
A.

Failure to Comply With a Precise Element of CGMP Regulations

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.

10

Contains Nonbinding Recommendations

427
428
429
430
431
432
433
434
435
436
437
438
439
440
441
442
443
444
445
446
447
448
449
450
451
452
453
454
455
456
457
458
459
460
461
462
463
464
465
466
467
468
469
470
471

B.

Failure to Comply With a Precise Requirement Established in an Approved
Application

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.
C.

The Regulatory Significance of Failing to Comply With a Precise
Requirement

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.

11

Contains Nonbinding Recommendations

472
473
474
475
476
477
478
479
480
481
482
483
484
485
486
487
488
489
490
491
492
493
494
495
496
497
498
499
500
501
502
503
504
505
506
507
508
509
510
511
512
513
514
515

D.

Issues Not Raised During the Inspection

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.
VI.

PAPERWORK REDUCTION ACT OF 1995

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 09/30/2011 (Note: Expiration date updated
05/04/2011)).

12