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

Administrative guidance, not enacted legislation. This captured publisher edition preserves the listed document and attachments; later developments are not independently consolidated.

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 No. 0910-0563
Current expiration date available at https://www.reginfo.gov
(Search ICR and enter OMB control number)
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........................................... 9
B. 	Failure to Comply With a Precise Requirement Established in an Approved Application .. 10
C. 	The Regulatory Significance of Failing to Comply With a Precise Requirement .................. 11
D. 	Issues Not Raised During the Inspection ................................................................................... 11
V. 	COMMUNICATION OF DISPUTE RESOLUTION DECISIONS .......................... 12
VI. 	PAPERWORK REDUCTION ACT OF 1995.............................................................. 12

Contains Nonbinding Recommendations
1
Guidance for Industry1	
1
2
Formal Dispute Resolution:	3
Scientific and Technical Issues Related to Pharmaceutical CGMP	4
5
6
This guidance represents the Food and Drug Administration's (FDA's) current thinking on this topic. It	7
does not create or confer any rights for or on any person and does not operate to bind FDA or the public.	8
You can use an alternative approach if the approach satisfies the requirements of the applicable statutes	9
and regulations. If you want to discuss an alternative approach, contact the FDA staff responsible for	10
implementing this guidance. If you cannot identify the appropriate FDA staff, call the appropriate	11
number listed on the title page of this guidance.	12
13
14
15
I. 	INTRODUCTION	16
17
This document is intended to provide guidance to manufacturers of veterinary and human	18
drugs, including human biological drug products, on how to resolve disputes of scientific	19
and technical issues relating to current good manufacturing practice (CGMP) requirements.	20
This document is not intended to cover medical devices regulated by the Center for Devices	21
and Radiological Health (CDRH) or foods or dietary supplements regulated by the Center	22
for Food Safety and Applied Nutrition (CFSAN).	23
24
Disputes related to scientific and technical issues may arise during FDA inspections of	25
pharmaceutical manufacturers to determine compliance with CGMP requirements or during	26
the Agency's assessment of corrective actions undertaken as a result of such inspections. As	27
these disputes may involve complex judgments and issues that are scientifically or	28
technologically important, it is critical to have procedures in place that will encourage open,	29
prompt discussion of disputes and lead to their resolution. This guidance describes	30
procedures for raising such disputes to the Office of Regulatory Affairs (ORA) and center	31
levels and for requesting review by the Dispute Resolution Panel for Scientific and	32
Technical Issues Related to Pharmaceutical CGMP (DR Panel).	33
34
Manufacturers are encouraged to seek clarification of scientific or technical issues with the	35
inspection team at any time during an inspection. Although there are existing processes to	36
encourage dialogue between FDA and manufacturers, the processes described in this document	37
apply to CGMP questions raised during inspections and are intended to supplement the dispute	38
resolution processes currently in place, including:	39
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 21 st 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 ).

Contains Nonbinding Recommendations
2
40
• 	21 CFR 10.75, Internal Agency Review of Decisions. Allows manufacturers to ask for a	41
review of Agency decisions at each successive supervisory level through the chain of	42
command, ending with the FDA Commissioner's office.	43
44
• 	CDER/CBER guidance for industry entitled Formal Dispute Resolution: Appeals Above	45
the Division Level. Describes procedures a sponsor may use to formally appeal disputes	46
to the office or center level on scientific and procedural issues that arise during drug	47
development, new drug review, and post-marketing oversight processes. The guidance	48
may be found on CDER’s and CBER's Web sites.2	
49
50
• 	CVM guidance for industry #79 entitled Dispute Resolution Procedures for Science-	51
Based Decisions on Products Regulated by the Center for Veterinary Medicine (CVM),	52
July 2005. Describes procedures for handling requests for internal review of scientific	53
controversies relating to decisions affecting animal drugs or other products that are	54
regulated by CVM. The guidance may be found on CVM's Web site.3	
55
56
• 	Investigations Operations Manual (IOM), Chapter 5, Subchapter 510, Sections 512	57
(Report of Observations) and 516 (Discussions with Management). Describes processes	58
for discussing inspectional observations with a manufacturer. The IOM is available on	59
ORA's Web site.4	
60
61
For the purposes of this document, the term manufacturer5 includes any domestic or foreign	62
applicant or manufacturer of a human or veterinary drug, or human biological drug product	63
regulated by the Agency under the Federal Food, Drug, and Cosmetic Act (the Act) or section	64
351 of the Public Health Service Act (the PHS Act).	65
66
FDA's guidance documents, including this guidance, do not establish legally enforceable	67
responsibilities. Instead, guidances describe the Agency's current thinking on a topic and should	68
be viewed only as recommendations, unless specific regulatory or statutory requirements are	69
cited. The use of the word should in Agency guidances means that something is suggested or	70
recommended, but not required.	71
72
II. 	SCOPE OF THE GUIDANCE	73
74
The policies and procedures described in this guidance document cover all disputes on scientific	75
or technical issues related to CGMP that arise as the result of CGMP and preapproval inspections	76
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).

Contains Nonbinding Recommendations
3
(PAI) for manufacturers of veterinary and human drug products, including related Active	77
Pharmaceutical Ingredients (APIs). For disputes that arise during prelicense and preapproval	78
inspections for human biological drug products regulated by CBER or for application review	79
issues that arise during PAI inspections for human or veterinary drug products, the existing	80
CDER/CBER and CVM guidances listed in Section I of this document should continue to be	81
used.	82
83
This guidance does not cover disputes over procedures or administrative matters that may arise	84
during the inspection process. At any time, a manufacturer may informally raise a procedural or	85
administrative matter with ORA or with the CDER, CBER, or CVM Ombudsman, in accordance	86
with 21 CFR 10.75. The procedures described in this guidance do not apply to such informal	87
dispute resolution through the CDER, CBER, or CVM Ombudsman.	88
89
If a dispute involves a combination product including a device component, the dispute may be	90
addressed through CDRH's dispute resolution process, depending on the nature of the dispute.6	
91
92
III. 	DISPUTE RESOLUTION PROCESS	93
94
During inspections of manufacturers, investigators are expected to make every reasonable effort	95
to discuss observations relating to manufacturing quality as they are observed, or on a daily basis	96
to minimize surprise, errors, and misunderstandings when a Form FDA 483 is issued. At the	97
conclusion of an inspection, investigators will normally meet with the manufacturer's	98
management to again discuss observations and solicit views and additional relevant information.	99
These processes are described in detail in the Investigations Operations Manual (IOM), Sections	100
512 and 516, as listed in Section I of this document.	101
102
When a scientific or technical issue arises during an inspection, we recommend that a	103
manufacturer initially attempt to reach agreement on the issue informally with the investigator.	104
A manufacturer should discuss with the investigator any observation that the manufacturer	105
believes is not justified from a scientific or technical standpoint. As appropriate, the investigator	106
can consult with FDA management or program officials, or appropriate product or technical	107
experts. The investigator may invite the company to participate in certain consultative	108
discussions. If agreement on the issue is not reached with the investigator prior to issuance of	109
the Form FDA 483, a manufacturer can formally request dispute resolution after the investigator	110
issues the Form FDA 483.	111
112
Certain scientific or technical issues may be too complex or time-consuming to resolve during	113
the inspection. If resolution of a scientific or technical issue is not accomplished through	114
informal mechanisms prior to the issuance of a Form FDA 483, manufacturers can use the formal	115
two-tiered dispute resolution process described in this guidance.	116
117
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.

Contains Nonbinding Recommendations
4
• 	Tier one of the formal dispute resolution process refers to scientific or technical issues	118
raised to the ORA and center levels.	119
• 	Tier two of the formal dispute resolution process refers to scientific or technical issues	120
raised to the DR Panel.	121
These processes are described in detail in the following subsections.	122
123
A. 	Tier-One Dispute Resolution at the Office of Regulatory Affairs and Center	124
Levels	125
126
Pharmaceutical manufacturers can formally dispute the scientific or technical basis for CGMP	127
inspectional observations after issuance of a Form FDA 483. In such cases, the formal dispute	128
resolution process starts in the appropriate ORA unit7 as listed below and may advance to the	129
applicable center.	130
131
• 	For domestic manufacturers of veterinary and human drugs, the formal dispute resolution	132
process begins in the appropriate district office, ORA.	133
134
• 	For foreign manufacturers of veterinary and human drugs, the formal dispute resolution	135
process begins in the Division of Field Investigations, ORA.	136
137
• 	For domestic or foreign manufacturers of human biological drug products inspected by	138
Team Biologics, the formal dispute resolution process begins in the Office of	139
Enforcement, ORA.	140
141
A manufacturer should seek clarification of a disputed scientific or technical issue within 30 days	142
of issuance of the Form FDA 483. (FDA defines days to mean calendar days throughout this	143
guidance.) FDA may refuse to address a dispute resolution request not raised during this time	144
frame. The Agency, at its discretion, may contact the manufacturer to obtain additional	145
information and/or seek clarification.	146
147
If a manufacturer disagrees with the scientific or technical basis for an observation listed by an	148
investigator on a Form FDA 483, the following steps may be taken:	149
150
1. 	The manufacturer may file a written request for formal dispute resolution with the	151
appropriate ORA unit as listed above. The manufacturer should provide all supporting	152
documentation and arguments for review.	153
154
2. 	The appropriate ORA unit may evaluate the written request for formal dispute resolution,	155
and may include Agency staff not previously involved in the dispute, as appropriate.	156
157
If the ORA unit agrees with the manufacturer,	158
159
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.

Contains Nonbinding Recommendations
5
• 	The ORA unit will issue a written response to the manufacturer within 30 days of receipt	160
of the request, noting its agreement with the manufacturer and resolution of the dispute.	161
The resolution may take the form of a letter. It may also take the form of an addendum to	162
the existing Form FDA 483.	163
164
• 	All disputes resolved at the ORA level will be copied to the relevant program center for	165
information and public dissemination following appropriate redaction.	166
167
If the ORA unit disagrees with the manufacturer,	168
169
• 	The ORA unit will issue a written response to the manufacturer generally within 30 days	170
of receipt of the request. Responses that disagree with a manufacturer's position will	171
incorporate a review and decision by the relevant program center, which may require	172
additional time as described below.	173
174
• 	The written response will be copied to the relevant program center for information and	175
public dissemination after appropriate redaction, in accordance with applicable	176
requirements.	177
178
If the ORA unit is unable to complete its review of the request and respond within 30 days, the	179
ORA unit will notify the manufacturer, explain the reason for the delay (which may include the	180
need for an additional 30 days for center review), and discuss the time frame for completing the	181
review.	182
183
3. 	If a manufacturer disagrees with the tier-one decision, the manufacturer can appeal that	184
decision to the DR Panel.	185
186
B. 	Tier-Two Dispute Resolution with the DR Panel on Scientific and Technical	187
Issues	188
189
The DR Panel provides a formal way for manufacturers to defend the science in their	190
manufacturing and quality control processes before a neutral panel of experts and to appeal an	191
ORA and center-level decision concerning the science underlying the inspectional observation.	192
193
The DR Panel resides at the Office of the Commissioner. The DR Panel considers requests for	194
tier-two dispute resolution by manufacturers and provides an opportunity for a manufacturer to	195
present its case in support of its position on a scientific or technical issue. The DR Panel’s	196
membership includes representatives from each of the program centers and ORA, as well as the	197
Chair of the FDA Council on Pharmaceutical Quality, but will not include decision makers who	198
have addressed the disputed issue at the ORA and center level.	199
200
If a manufacturer disagrees with the tier-one decision in the formal dispute resolution process,	201
the manufacturer can file a written request for formal dispute resolution by the DR Panel. The	202
manufacturer should provide the written request for formal dispute resolution and all supporting	203
documentation and arguments to the DR Panel for review within 60 days from issuance of the	204
tier-one decision.	205

Contains Nonbinding Recommendations
6
206
The DR Panel will evaluate the written request for formal dispute resolution. The DR Panel will	207
determine whether or not to consider the specific issue in the appeal. If necessary, additional	208
internal and external experts, as well as attorneys from the Office of Chief Counsel (OCC), may	209
be added to the DR Panel to facilitate evaluation of the specific issue.	210
211
If the DR Panel determines that the request is appropriate for review, it will schedule a meeting	212
to discuss the issue within 90 days. The DR Panel may communicate with the manufacturer at	213
its discretion and may request the manufacturer to be present during the meeting.	214
215
If the DR Panel agrees with the manufacturer on the issue,	216
217
• 	The executive secretary of the DR Panel will issue a written response to the manufacturer	218
within 30 days of the meeting, noting its agreement with the manufacturer and resolution	219
of the dispute.	220
221
• 	All disputes resolved at the DR Panel level will be copied to the relevant FDA units for	222
their information and public dissemination after appropriate redaction, in accordance with	223
applicable requirements.	224
225
If the DR Panel disagrees with the manufacturer on the issue,	226
227
• 	The executive secretary of the DR Panel will issue a written response to the manufacturer	228
within 30 days of the meeting, noting its decision on the issue, except as provided below.	229
230
• 	The executive secretary of the DR Panel will notify the relevant FDA units of the DR	231
Panel’s decision for their information and public dissemination after appropriate	232
redaction, in accordance with applicable requirements.	233
234
If the DR Panel determines that the request does not qualify for review (see Section IV), the	235
executive secretary of the DR Panel will notify the manufacturer in writing within 30 days of	236
receipt of the appeal and communicate the DR Panel's decision to the program offices.	237
238
If FDA is unable to complete its review of the request and respond within 30 days, the executive	239
secretary of the DR Panel will notify the manufacturer, explain the reasons for the delay, and	240
discuss the time frame for completing the review.	241
242
C. 	How to Request Formal Dispute Resolution	243
244
All Agency decisions in the formal dispute resolution process will be based on the	245
manufacturer's documentation that was available at the time of the inspection, unless a	246
manufacturer can provide a reasonable explanation why it did not present relevant information	247
during the inspection or the manufacturer was specifically requested to provide new information	248
as part of the Agency’s dispute resolution review. Submission of new information may result in	249
the dispute being returned to an earlier point in the process, as the Agency deems appropriate.	250
251

Contains Nonbinding Recommendations
7
The following list of addresses can be used to request formal dispute resolution.	252
253
1. 	For a tier-one dispute resolution request from domestic manufacturers of veterinary and	254
human drugs, the request should be submitted to:	255
256
Director of the district office responsible for the inspection	257
The following Internet site lists district office addresses:	258
http://www.fda.gov/ora/inspect_ref/iom/iomoradir.html.	259
260
2. 	For a tier-one dispute resolution request from foreign manufacturers of veterinary and	261
human drugs, the request should be submitted to:	262
263
Director, Division of Field Investigations	264
Office of Regional Operations	265
Office of Regulatory Affairs	266
Food and Drug Administration	267
Mail Code: HFC-100	268
5600 Fishers Lane, Room 13-64	269
Rockville, Maryland 20857	270
271
3. 	For a tier-one dispute resolution request from domestic or foreign manufacturers of	272
human biological drug products inspected by Team Biologics, the request should be	273
submitted to:	274
275
Director, Division of Compliance Management and Operations	276
Office of Enforcement	277
Office of Regulatory Affairs	278
Food and Drug Administration	279
Mail Code: HFC-210	280
5600 Fishers Lane	281
Rockville, MD 20857	282
283
4. 	For a tier-two dispute resolution request, the request should be submitted to the	284
appropriate center contact as listed below:	285
286
• 	For CDER:	287
288
Formal Dispute Resolution Project Manager (DPRM)	289
Office of Compliance	290
Center for Drug Evaluation and Research	291
Food and Drug Administration	292
Mail Code: HFD-320	293
5600 Fishers Lane	294
Rockville, MD 20857	295
296
• 	For CVM:	297

Contains Nonbinding Recommendations
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298
Ombudsman	299
Office of the Center Director	300
Center for Veterinary Medicine	301
Food and Drug Administration	302
Mail Code: HFV-7	303
7519 Standish Place	304
Rockville, MD 20855	305
306
• 	For CBER:	307
308
Assistant to the Director for Policy	309
Office of Compliance and Biologics Quality	310
Center for Biologics Evaluation and Research	311
Food and Drug Administration	312
Mail Code: HFM-600	313
1401 Rockville Pike, Suite 200N	314
Rockville, MD 20852	315
316
D. 	Supporting Information to be Provided by Manufacturers	317
318
All requests for formal dispute resolution should be in writing and include adequate information	319
to explain the nature of the dispute and to allow the Agency to act quickly and efficiently. Each	320
request should include the following:	321
322
1. 	Cover sheet that clearly identifies the submission in bold, uppercase letters:	323
324
REQUEST FOR TIER-ONE DISPUTE RESOLUTION	325
326
or	327
328
REQUEST FOR TIER-TWO DISPUTE RESOLUTION (REVIEW BY THE	329
DISPUTE RESOLUTION PANEL FOR SCIENTIFIC AND TECHNICAL ISSUES	330
RELATED TO PHARMACEUTICAL CGMP)	331
332
2. 	Name and address of manufacturer inspected (as listed on the Form FDA 483)	333
334
3. 	Date of inspection (as listed on the Form FDA 483)	335
336
4. 	Date the Form FDA 483 issued (from the Form FDA 483)	337
338
5. 	FEI Number, if available (from the Form FDA 483)	339
340
6. 	Names and titles of FDA employees who conducted inspection (from the Form FDA 483)	341
342
7. 	Office responsible for the inspection, e.g., district office, as listed on the Form FDA 483	343

Contains Nonbinding Recommendations
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344
8. 	Application number if the inspection was a preapproval inspection	345
346
9. 	Comprehensive statement of each issue to be resolved	347
348
• 	Identify the observation in dispute.	349
• 	Clearly present the manufacturer’s scientific position or rationale concerning the issue	350
under dispute with any supporting data.	351
• 	State the steps that have been taken to resolve the dispute, including any informal	352
dispute resolution that may have occurred before the issuance of the Form FDA 483.	353
• 	Identify possible solutions.	354
• 	State desired outcome.	355
356
10. 	Name, title, telephone and fax number, and e-mail address (as available) of manufacturer	357
contact.	358
359
E. 	FDA Response to Requests for Dispute Resolution	360
361
FDA will respond in writing to all requests for dispute resolution filed under the procedures	362
described in this guidance. The written response should specifically agree or disagree with the	363
outcome desired by the manufacturer, agree or disagree with parts of the proposed outcome, or	364
indicate a resolution that is different from that proposed by the manufacturer. If the Agency does	365
not agree with the manufacturer’s position, the response should include reasons for the	366
disagreement.	367
368
The Agency official responsible for replying to a request for dispute resolution should make all	369
reasonable efforts to resolve the dispute and provide a written response to the manufacturer	370
according to timelines suggested above in Section III. A and B.	371
372
The Agency may, under appropriate circumstances, take regulatory action while a request for	373
formal dispute resolution is pending.	374
375
IV. 	SUITABILITY OF ISSUES FOR FORMAL DISPUTE RESOLUTION	376
377
Any dispute involving a scientific or technical issue related to CGMP regulations that arises	378
during an FDA inspection, as discussed above, may be suitable for the dispute resolution process	379
described in this guidance.	380
381
The following text provides examples concerning the appropriateness of several issues for the	382
dispute resolution process detailed in this guidance.	383
384
A. 	Failure to Comply With a Precise Element of CGMP Regulations	385
386
According to 21 CFR 211.100(a), a manufacturer producing a finished pharmaceutical product	387
must have written procedures for production and process controls, and these written procedures	388

Contains Nonbinding Recommendations
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must be designed to ensure that the drug has the identity, strength, quality, and purity it purports	389
or is represented to have.	390
391
• 	Failure to have written procedures for production and process controls would be a	392
failure to comply with a precise element of the CGMP regulations and would not be	393
appropriate for the formal dispute resolution process described in this document.	394
395
• 	However, observations pertaining to the adequacy of the process and production	396
control design activities could be subject to scientific debate and may be appropriate	397
for dispute resolution as described in this guidance.	398
399
Another example relates to the regulatory provisions governing the testing and approval or	400
rejection of components, drug product containers, and closures (21 CFR 211.84), which require	401
appropriate sampling, testing, or examination of each lot of components, drug product	402
containers, or closures.	403
404
• 	Failure to conduct testing or examination of each lot would be failure to comply with	405
a precise element of the regulations and would not be appropriate for the formal	406
dispute resolution process described in this guidance.	407
408
• 	However, the appropriateness of a particular test or sampling scheme could involve	409
the exercise of scientific judgment. A disagreement between a manufacturer and an	410
investigator concerning the adequacy of a particular test or sampling scheme could be	411
subject to scientific debate and may be appropriate for dispute resolution as described	412
in this guidance.	413
414
A third example relates to the CGMP regulation requirements that a manufacturer thoroughly	415
investigates any unexplained discrepancy associated with its review of product production and	416
control records (21 CFR 211.192).	417
418
• 	Failure to investigate an unexplained discrepancy would be a failure to comply with a	419
precise element of the CGMP regulations and would not be appropriate for the formal	420
dispute resolution process described in this guidance.	421
422
• 	However, the extent or adequacy of the investigation could be subject to scientific	423
debate. Observations pertaining to the adequacy of an investigation into an	424
unexplained discrepancy may also be appropriate for dispute resolution as described	425
in this guidance.	426
427
B. 	Failure to Comply With a Precise Requirement Established in an Approved	428
Application	429
430
If, as part of the conditions established in an approved application, a manufacturer is required to	431
conduct a particular test on a finished product and the manufacturer fails to conduct that test, this	432
failure represents a failure to comply with a precise requirement established in an approved	433
application. Any disagreement about the need for such a test should be raised in the application	434

Contains Nonbinding Recommendations
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review process. Such disagreement is not appropriate for the dispute resolution process	435
described in this guidance, but may be raised using the processes described in the CDER/CBER	436
and CVM guidances listed in Section I of this document.	437
438
C. 	The Regulatory Significance of Failing to Comply With a Precise	439
Requirement	440
441
The CGMP regulations require that all changes to production and process control procedures be	442
approved by the quality control unit (21 CFR 211.100(a)). If a manufacturer makes a change in	443
production and process control procedures, but does not obtain approval of those procedures by	444
the manufacturer’s quality control unit, this would be a failure to comply with a precise	445
requirement of the CGMP regulations. The manufacturer may contend that the failure in this	446
particular case was not significant because it did not have an adverse effect on product quality	447
and may convey this contention to the Agency through existing informal communication	448
channels, including Form FDA 483-response correspondence.	449
450
In such a case, the significance of this observation would not be appropriate for dispute	451
resolution as described in this guidance, as the observation concerns a failure to comply with a	452
precise requirement of the regulations. The regulatory significance of an observation is	453
determined by the Agency after considering all relevant information, including the	454
manufacturer's response to the inspectional observations. The Agency encourages manufacturers	455
to provide all information relevant to the regulatory significance of an observation as part of this	456
response, but such disputes are not within the scope of this guidance on scientific and technical	457
disputes concerning the interpretation and application of CGMP requirements.	458
459
Manufacturers must have internal written production and process control procedures (21 CFR	460
211.100(a)) and, as part of these procedures, manufacturers often establish procedural action	461
limits that are tighter than release specifications. When the action limits are exceeded, the	462
internal written procedures may call for some type of investigation to determine if the process is	463
drifting toward a loss of control, or the procedures may call for other assessments to determine if	464
the product will meet appropriate specifications throughout its expected shelf life. If a	465
manufacturer's internal written procedures require certain actions when action limits are	466
exceeded, failure to follow these written production and process control procedures is a failure to	467
comply with 21 CFR 211.100(b). The manufacturer may contend that this failure is not	468
significant in that the product met all regulatory specifications when released. As discussed	469
above, this contention about significance is not appropriate for the formal dispute resolution	470
process described in this guidance.	471
472
D. 	Issues Not Raised During the Inspection	473
474
If, during an inspection, an investigator notes what appears to be an objectionable condition and	475
a manufacturer disagrees with that observation, the manufacturer should voice its disagreement	476
with the investigator. By doing so, the investigator has the opportunity to evaluate the	477
manufacturer's position and consult, as needed, with Agency experts. The Agency may not	478
accept a request for dispute resolution concerning a disagreement that was not initially raised by	479

Contains Nonbinding Recommendations
12
the manufacturer during the inspection unless a manufacturer can provide a reasonable	480
explanation why it did not present relevant information during the inspection.	481
482
V. 	COMMUNICATION OF DISPUTE RESOLUTION DECISIONS	483
484
FDA believes that decisions made in the dispute resolution process, along with all supporting	485
documentation, should be publicly available consistent with FDA’s disclosure regulations (21	486
CFR Part 20) and applicable statutes, unless the decisions involve information that would	487
otherwise be withheld under these regulations and statutes. The Agency will redact, as	488
appropriate, any documents requested through the Freedom of Information process.	489
490
When appropriate, a summary of the relevant issues and Agency views will be provided in a	491
question and answer format and posted on the FDA Web site with all identifying information	492
excluded. Information gained from these decisions should promote consistent application and	493
interpretation of pharmaceutical CGMP requirements.	494
495
VI. 	PAPERWORK REDUCTION ACT OF 1995	496
497
This guidance contains information collection provisions that are subject to review by the Office	498
of Management and Budget (OMB) under the Paperwork Reduction Act of 1995 (44 U.S.C.	499
3501-3520).	500
501
The time required to complete this information collection is estimated to average 30 hours to	502
prepare and submit each request for tier-one dispute resolution and 8 hours to prepare and submit	503
each request for tier-two dispute resolution. This includes the time to review instructions, search	504
existing data resources, gather the data needed, and complete and review the information	505
collection. Send comments regarding this burden estimate or suggestions for reducing this	506
burden to Edward M. Sherwood, Center for Drug Evaluation and Research (HFD-3), Food and	507
Drug Administration, Rockwall II, Rm. 7231, 5515 Security Lane, Rockville, MD 20857,	508
301-594-2847.	509
510
An agency may not conduct or sponsor, and a person is not required to respond to, a collection of	511
information unless it displays a currently valid OMB control number. The OMB control number	512
for this information collection is 0910-0563. The current expiration date is available at	513
https://www.reginfo.gov (search ICR and enter OMB control number).	514
515