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 
2   
3  Formal Dispute Resolution:   
4  Scientific and Technical Issues Related to Pharmaceutical CGMP  
5   
6   
7  This guidance represents the Food and Drug Administration's (FDA's) current thinking on this topic.  It 
8  does not create or confer any rights for or on any person and does not operate to bind FDA or the public.  
9  You can use an alternative approach if the approach satisfies the requirements of the applicable statutes 
10  and regulations.  If you want to discuss an alternative approach, contact the FDA staff responsible for 
11  implementing this guidance.  If you cannot identify the appropriate FDA staff, call the appropriate 
12  number listed on the title page of this guidance. 
13   
14   
15   
16  I.  INTRODUCTION 
17   
18  This document is intended to provide guidance to manufacturers of veterinary and human 
19  drugs, including human biological drug products, on how to resolve disputes of scientific 
20  and technical issues relating to current good manufacturing practice (CGMP) requirements.  
21  This document is not intended to cover medical devices regulated by the Center for Devices 
22  and Radiological Health (CDRH) or foods or dietary supplements regulated by the Center 
23  for Food Safety and Applied Nutrition (CFSAN).   
24   
25  Disputes related to scientific and technical issues may arise during FDA inspections of 
26  pharmaceutical manufacturers to determine compliance with CGMP requirements or during 
27  the Agency's assessment of corrective actions undertaken as a result of such inspections.  As 
28  these disputes may involve complex judgments and issues that are scientifically or 
29  technologically important, it is critical to have procedures in place that will encourage open, 
30  prompt discussion of disputes and lead to their resolution.  This guidance describes 
31  procedures for raising such disputes to the Office of Regulatory Affairs (ORA) and center 
32  levels and for requesting review by the Dispute Resolution Panel for Scientific and 
33  Technical Issues Related to Pharmaceutical CGMP (DR Panel). 
34   
35  Manufacturers are encouraged to seek clarification of scientific or technical issues with the 
36  inspection team at any time during an inspection.  Although there are existing processes to 
37  encourage dialogue between FDA and manufacturers, the processes described in this document 
38  apply to CGMP questions raised during inspections and are intended to supplement the dispute 
39  resolution processes currently in place, including: 
 
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  
 
 
40   
41    21 CFR 10.75, Internal Agency Review of Decisions.  Allows manufacturers to ask for a 
42  review of Agency decisions at each successive supervisory level through the chain of 
43  command, ending with the FDA Commissioner's office.  
44   
45    CDER/CBER guidance for industry entitled Formal Dispute Resolution:  Appeals Above 
46  the Division Level.  Describes procedures a sponsor may use to formally appeal disputes 
47  to the office or center level on scientific and procedural issues that arise during drug 
48  development, new drug review, and post-marketing oversight processes.  The guidance 
49  may be found on CDERs and CBER's Web sites.2 
50   
51    CVM guidance for industry #79 entitled Dispute Resolution Procedures for Science-
52  Based Decisions on Products Regulated by the Center for Veterinary Medicine (CVM), 
53  July 2005.  Describes procedures for handling requests for internal review of scientific 
54  controversies relating to decisions affecting animal drugs or other products that are 
55  regulated by CVM.  The guidance may be found on CVM's Web site.3   
56   
57    Investigations Operations Manual (IOM), Chapter 5, Subchapter 510, Sections 512 
58  (Report of Observations) and 516 (Discussions with Management).  Describes processes 
59  for discussing inspectional observations with a manufacturer.  The IOM is available on 
60  ORA's Web site.4  
61   
62  For the purposes of this document, the term manufacturer5 includes any domestic or foreign 
63  applicant or manufacturer of a human or veterinary drug, or human biological drug product 
64  regulated by the Agency under the Federal Food, Drug, and Cosmetic Act (the Act) or section 
65  351 of the Public Health Service Act (the PHS Act). 
66   
67  FDA's guidance documents, including this guidance, do not establish legally enforceable 
68  responsibilities.  Instead, guidances describe the Agency's current thinking on a topic and should 
69  be viewed only as recommendations, unless specific regulatory or statutory requirements are 
70  cited.  The use of the word should in Agency guidances means that something is suggested or 
71  recommended, but not required. 
72   
73  II.  SCOPE OF THE GUIDANCE 
74   
75  The policies and procedures described in this guidance document cover all disputes on scientific 
76  or technical issues related to CGMP that arise as the result of CGMP and preapproval inspections 
 
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  
 
 
77  (PAI) for manufacturers of veterinary and human drug products, including related Active 
78  Pharmaceutical Ingredients (APIs).  For disputes that arise during prelicense and preapproval 
79  inspections for human biological drug products regulated by CBER or for application review 
80  issues that arise during PAI inspections for human or veterinary drug products, the existing 
81  CDER/CBER and CVM guidances listed in Section I of this document should continue to be 
82  used. 
83   
84  This guidance does not cover disputes over procedures or administrative matters that may arise 
85  during the inspection process.  At any time, a manufacturer may informally raise a procedural or 
86  administrative matter with ORA or with the CDER, CBER, or CVM Ombudsman, in accordance 
87  with 21 CFR 10.75.  The procedures described in this guidance do not apply to such informal 
88  dispute resolution through the CDER, CBER, or CVM Ombudsman.   
89   
90  If a dispute involves a combination product including a device component, the dispute may be 
91  addressed through CDRH's dispute resolution process, depending on the nature of the dispute.6    
92   
93  III.  DISPUTE RESOLUTION PROCESS 
94   
95  During inspections of manufacturers, investigators are expected to make every reasonable effort 
96  to discuss observations relating to manufacturing quality as they are observed, or on a daily basis 
97  to minimize surprise, errors, and misunderstandings when a Form FDA 483 is issued.  At the 
98  conclusion of an inspection, investigators will normally meet with the manufacturer's 
99  management to again discuss observations and solicit views and additional relevant information. 
100  These processes are described in detail in the Investigations Operations Manual (IOM), Sections 
101  512 and 516, as listed in Section I of this document.   
102   
103  When a scientific or technical issue arises during an inspection, we recommend that a 
104  manufacturer initially attempt to reach agreement on the issue informally with the investigator.  
105  A manufacturer should discuss with the investigator any observation that the manufacturer 
106  believes is not justified from a scientific or technical standpoint.  As appropriate, the investigator 
107  can consult with FDA management or program officials, or appropriate product or technical 
108  experts.  The investigator may invite the company to participate in certain consultative 
109  discussions.  If agreement on the issue is not reached with the investigator prior to issuance of 
110  the Form FDA 483, a manufacturer can formally request dispute resolution after the investigator 
111  issues the Form FDA 483. 
112   
113  Certain scientific or technical issues may be too complex or time-consuming to resolve during 
114  the inspection.  If resolution of a scientific or technical issue is not accomplished through 
115  informal mechanisms prior to the issuance of a Form FDA 483, manufacturers can use the formal 
116  two-tiered dispute resolution process described in this guidance.   
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. 
 
  3  Contains Nonbinding Recommendations  
 
 
118    Tier one of the formal dispute resolution process refers to scientific or technical issues 
119  raised to the ORA and center levels.   
120    Tier two of the formal dispute resolution process refers to scientific or technical issues 
121  raised to the DR Panel.   
122  These processes are described in detail in the following subsections.  
123   
124  A.  Tier-One Dispute Resolution at the Office of Regulatory Affairs and Center 
125  Levels 
126   
127  Pharmaceutical manufacturers can formally dispute the scientific or technical basis for CGMP 
128  inspectional observations after issuance of a Form FDA 483.  In such cases, the formal dispute 
129  resolution process starts in the appropriate ORA unit7 as listed below and may advance to the 
130  applicable center.  
131   
132    For domestic manufacturers of veterinary and human drugs, the formal dispute resolution 
133  process begins in the appropriate district office, ORA. 
134   
135    For foreign manufacturers of veterinary and human drugs, the formal dispute resolution 
136  process begins in the Division of Field Investigations, ORA.  
137   
138    For domestic or foreign manufacturers of human biological drug products inspected by 
139  Team Biologics, the formal dispute resolution process begins in the Office of 
140  Enforcement, ORA.  
141   
142  A manufacturer should seek clarification of a disputed scientific or technical issue within 30 days 
143  of issuance of the Form FDA 483.  (FDA defines days to mean calendar days throughout this 
144  guidance.)  FDA may refuse to address a dispute resolution request not raised during this time 
145  frame.  The Agency, at its discretion, may contact the manufacturer to obtain additional 
146  information and/or seek clarification.  
147   
148  If a manufacturer disagrees with the scientific or technical basis for an observation listed by an 
149  investigator on a Form FDA 483, the following steps may be taken:   
150   
151  1.  The manufacturer may file a written request for formal dispute resolution with the 
152  appropriate ORA unit as listed above.  The manufacturer should provide all supporting 
153  documentation and arguments for review.   
154   
155  2.  The appropriate ORA unit may evaluate the written request for formal dispute resolution, 
156  and may include Agency staff not previously involved in the dispute, as appropriate.  
157    
158  If the ORA unit agrees with the manufacturer, 
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. 
  4  Contains Nonbinding Recommendations  
 
 
160    The ORA unit will issue a written response to the manufacturer within 30 days of receipt 
161  of the request, noting its agreement with the manufacturer and resolution of the dispute.  
162  The resolution may take the form of a letter.  It may also take the form of an addendum to 
163  the existing Form FDA 483.  
164   
165    All disputes resolved at the ORA level will be copied to the relevant program center for 
166  information and public dissemination following appropriate redaction.   
167   
168  If the ORA unit disagrees with the manufacturer,  
169   
170    The ORA unit will issue a written response to the manufacturer generally within 30 days 
171  of receipt of the request.  Responses that disagree with a manufacturer's position will 
172  incorporate a review and decision by the relevant program center, which may require 
173  additional time as described below.  
174   
175    The written response will be copied to the relevant program center for information and 
176  public dissemination after appropriate redaction, in accordance with applicable 
177  requirements. 
178   
179  If the ORA unit is unable to complete its review of the request and respond within 30 days, the 
180  ORA unit will notify the manufacturer, explain the reason for the delay (which may include the 
181  need for an additional 30 days for center review), and discuss the time frame for completing the 
182  review. 
183   
184  3.  If a manufacturer disagrees with the tier-one decision, the manufacturer can appeal that 
185  decision to the DR Panel. 
186   
187  B.  Tier-Two Dispute Resolution with the DR Panel on Scientific and Technical 
188  Issues  
189   
190  The DR Panel provides a formal way for manufacturers to defend the science in their 
191  manufacturing and quality control processes before a neutral panel of experts and to appeal an 
192  ORA and center-level decision concerning the science underlying the inspectional observation.   
193   
194  The DR Panel resides at the Office of the Commissioner.  The DR Panel considers requests for 
195  tier-two dispute resolution by manufacturers and provides an opportunity for a manufacturer to 
196  present its case in support of its position on a scientific or technical issue.  The DR Panels 
197  membership includes representatives from each of the program centers and ORA, as well as the 
198  Chair of the FDA Council on Pharmaceutical Quality, but will not include decision makers who 
199  have addressed the disputed issue at the ORA and center level.   
200   
201  If a manufacturer disagrees with the tier-one decision in the formal dispute resolution process, 
202  the manufacturer can file a written request for formal dispute resolution by the DR Panel.  The 
203  manufacturer should provide the written request for formal dispute resolution and all supporting 
204  documentation and arguments to the DR Panel for review within 60 days from issuance of the 
205  tier-one decision.  
  5  Contains Nonbinding Recommendations  
 
 
206   
207  The DR Panel will evaluate the written request for formal dispute resolution.  The DR Panel will 
208  determine whether or not to consider the specific issue in the appeal.  If necessary, additional 
209  internal and external experts, as well as attorneys from the Office of Chief Counsel (OCC), may 
210  be added to the DR Panel to facilitate evaluation of the specific issue. 
211   
212  If the DR Panel determines that the request is appropriate for review, it will schedule a meeting 
213  to discuss the issue within 90 days.  The DR Panel may communicate with the manufacturer at 
214  its discretion and may request the manufacturer to be present during the meeting.  
215   
216  If the DR Panel agrees with the manufacturer on the issue, 
217   
218    The executive secretary of the DR Panel will issue a written response to the manufacturer 
219  within 30 days of the meeting, noting its agreement with the manufacturer and resolution 
220  of the dispute.  
221   
222    All disputes resolved at the DR Panel level will be copied to the relevant FDA units for 
223  their information and public dissemination after appropriate redaction, in accordance with 
224  applicable requirements. 
225   
226  If the DR Panel disagrees with the manufacturer on the issue, 
227   
228    The executive secretary of the DR Panel will issue a written response to the manufacturer 
229  within 30 days of the meeting, noting its decision on the issue, except as provided below. 
230   
231    The executive secretary of the DR Panel will notify the relevant FDA units of the DR 
232  Panels decision for their information and public dissemination after appropriate 
233  redaction, in accordance with applicable requirements.  
234   
235  If the DR Panel determines that the request does not qualify for review (see Section IV), the 
236  executive secretary of the DR Panel will notify the manufacturer in writing within 30 days of 
237  receipt of the appeal and communicate the DR Panel's decision to the program offices.  
238   
239  If FDA is unable to complete its review of the request and respond within 30 days, the executive 
240  secretary of the DR Panel will notify the manufacturer, explain the reasons for the delay, and 
241  discuss the time frame for completing the review.   
242   
243  C.  How to Request Formal Dispute Resolution 
244   
245  All Agency decisions in the formal dispute resolution process will be based on the 
246  manufacturer's documentation that was available at the time of the inspection, unless a 
247  manufacturer can provide a reasonable explanation why it did not present relevant information 
248  during the inspection or the manufacturer was specifically requested to provide new information 
249  as part of the Agencys dispute resolution review.  Submission of new information may result in 
250  the dispute being returned to an earlier point in the process, as the Agency deems appropriate.  
251   
  6  Contains Nonbinding Recommendations  
 
 
252  The following list of addresses can be used to request formal dispute resolution. 
253   
254  1.  For a tier-one dispute resolution request from domestic manufacturers of veterinary and 
255  human drugs, the request should be submitted to: 
256   
257  Director of the district office responsible for the inspection 
258  The following Internet site lists district office addresses: 
259  http://www.fda.gov/ora/inspect_ref/iom/iomoradir.html. 
260   
261  2.  For a tier-one dispute resolution request from foreign manufacturers of veterinary and 
262  human drugs, the request should be submitted to: 
263   
264  Director, Division of Field Investigations 
265  Office of Regional Operations 
266  Office of Regulatory Affairs 
267  Food and Drug Administration   
268  Mail Code:  HFC-100 
269  5600 Fishers Lane, Room 13-64 
270  Rockville, Maryland 20857 
271   
272  3.  For a tier-one dispute resolution request from domestic or foreign manufacturers of 
273  human biological drug products inspected by Team Biologics, the request should be 
274  submitted to: 
275   
276  Director, Division of Compliance Management and Operations 
277  Office of Enforcement  
278  Office of Regulatory Affairs 
279  Food and Drug Administration  
280  Mail Code:  HFC-210 
281  5600 Fishers Lane 
282  Rockville, MD  20857 
283   
284  4.  For a tier-two dispute resolution request, the request should be submitted to the 
285  appropriate center contact as listed below:  
286   
287    For CDER: 
288   
289  Formal Dispute Resolution Project Manager (DPRM) 
290  Office of Compliance  
291  Center for Drug Evaluation and Research 
292  Food and Drug Administration  
293  Mail Code:  HFD-320 
294  5600 Fishers Lane 
295  Rockville, MD  20857  
296   
297    For CVM:  
  7  Contains Nonbinding Recommendations  
 
 
298   
299  Ombudsman 
300  Office of the Center Director 
301  Center for Veterinary Medicine 
302  Food and Drug Administration  
303  Mail Code: HFV-7 
304  7519 Standish Place 
305  Rockville, MD  20855 
306   
307    For CBER: 
308   
309  Assistant to the Director for Policy 
310  Office of Compliance and Biologics Quality 
311  Center for Biologics Evaluation and Research 
312  Food and Drug Administration 
313  Mail Code: HFM-600 
314  1401 Rockville Pike, Suite 200N 
315  Rockville, MD 20852 
316   
317  D.  Supporting Information to be Provided by Manufacturers  
318   
319  All requests for formal dispute resolution should be in writing and include adequate information 
320  to explain the nature of the dispute and to allow the Agency to act quickly and efficiently.  Each 
321  request should include the following: 
322   
323  1.  Cover sheet that clearly identifies the submission in bold, uppercase letters:   
324   
325  REQUEST FOR TIER-ONE DISPUTE RESOLUTION 
326   
327    or 
328   
329  REQUEST FOR TIER-TWO DISPUTE RESOLUTION (REVIEW BY THE 
330  DISPUTE RESOLUTION PANEL FOR SCIENTIFIC AND TECHNICAL ISSUES 
331  RELATED TO PHARMACEUTICAL CGMP)  
332   
333  2.  Name and address of manufacturer inspected (as listed on the Form FDA 483) 
334   
335  3.  Date of inspection (as listed on the Form FDA 483) 
336   
337  4.  Date the Form FDA 483 issued (from the Form FDA 483) 
338   
339  5.  FEI Number, if available (from the Form FDA 483) 
340   
341  6.  Names and titles of FDA employees who conducted inspection (from the Form FDA 483) 
342   
343  7.  Office responsible for the inspection, e.g., district office, as listed on the Form FDA 483 
  8  Contains Nonbinding Recommendations  
 
 
344   
345  8.  Application number if the inspection was a preapproval inspection 
346   
347  9.  Comprehensive statement of each issue to be resolved 
348   
349    Identify the observation in dispute. 
350    Clearly present the manufacturers scientific position or rationale concerning the issue 
351  under dispute with any supporting data. 
352    State the steps that have been taken to resolve the dispute, including any informal 
353  dispute resolution that may have occurred before the issuance of the Form FDA 483. 
354    Identify possible solutions. 
355    State desired outcome. 
356   
357  10.  Name, title, telephone and fax number, and e-mail address (as available) of manufacturer 
358  contact. 
35 9 
360  E.  FDA Response to Requests for Dispute Resolution 
361   
362  FDA will respond in writing to all requests for dispute resolution filed under the procedures 
363  described in this guidance.  The written response should specifically agree or disagree with the 
364  outcome desired by the manufacturer, agree or disagree with parts of the proposed outcome, or 
365  indicate a resolution that is different from that proposed by the manufacturer.  If the Agency does 
366  not agree with the manufacturers position, the response should include reasons for the 
367  disagreement. 
368   
369  The Agency official responsible for replying to a request for dispute resolution should make all 
370  reasonable efforts to resolve the dispute and provide a written response to the manufacturer 
371  according to timelines suggested above in Section III. A and B. 
372   
373  The Agency may, under appropriate circumstances, take regulatory action while a request for 
374  formal dispute resolution is pending.  
375   
376  IV.  SUITABILITY OF ISSUES FOR FORMAL DISPUTE RESOLUTION 
377   
378  Any dispute involving a scientific or technical issue related to CGMP regulations that arises 
379  during an FDA inspection, as discussed above, may be suitable for the dispute resolution process 
380  described in this guidance.  
381   
382  The following text provides examples concerning the appropriateness of several issues for the 
383  dispute resolution process detailed in this guidance.    
384   
385  A.  Failure to Comply With a Precise Element of CGMP Regulations 
386   
387  According to 21 CFR 211.100(a), a manufacturer producing a finished pharmaceutical product 
388  must have written procedures for production and process controls, and these written procedures  
  9  Contains Nonbinding Recommendations  
 
 
389  must be designed to ensure that the drug has the identity, strength, quality, and purity it purports 
390  or is represented to have.  
391   
392    Failure to have written procedures for production and process controls would be a 
393  failure to comply with a precise element of the CGMP regulations and would not be 
394  appropriate for the formal dispute resolution process described in this document.   
395    
396    However, observations pertaining to the adequacy of the process and production 
397  control design activities could be subject to scientific debate and may be appropriate 
398  for dispute resolution as described in this guidance. 
399   
400  Another example relates to the regulatory provisions governing the testing and approval or 
401  rejection of components, drug product containers, and closures (21 CFR 211.84), which require 
402  appropriate sampling, testing, or examination of each lot of components, drug product 
403  containers, or closures.   
404   
405    Failure to conduct testing or examination of each lot would be failure to comply with 
406  a precise element of the regulations and would not be appropriate for the formal 
407  dispute resolution process described in this guidance. 
408   
409    However, the appropriateness of a particular test or sampling scheme could involve 
410  the exercise of scientific judgment.  A disagreement between a manufacturer and an 
411  investigator concerning the adequacy of a particular test or sampling scheme could be 
412  subject to scientific debate and may be appropriate for dispute resolution as described 
413  in this guidance. 
414   
415  A third example relates to the CGMP regulation requirements that a manufacturer thoroughly 
416  investigates any unexplained discrepancy associated with its review of product production and 
417  control records (21 CFR 211.192). 
418   
419    Failure to investigate an unexplained discrepancy would be a failure to comply with a 
420  precise element of the CGMP regulations and would not be appropriate for the formal 
421  dispute resolution process described in this guidance. 
422   
423    However, the extent or adequacy of the investigation could be subject to scientific 
424  debate.  Observations pertaining to the adequacy of an investigation into an 
425  unexplained discrepancy may also be appropriate for dispute resolution as described 
426  in this guidance.  
427   
428  B.  Failure to Comply With a Precise Requirement Established in an Approved 
429  Application  
430   
431  If, as part of the conditions established in an approved application, a manufacturer is required to 
432  conduct a particular test on a finished product and the manufacturer fails to conduct that test, this 
433  failure represents a failure to comply with a precise requirement established in an approved 
434  application.  Any disagreement about the need for such a test should be raised in the application 
  10  Contains Nonbinding Recommendations  
 
 
435  review process.  Such disagreement is not appropriate for the dispute resolution process 
436  described in this guidance, but may be raised using the processes described in the CDER/CBER 
437  and CVM guidances listed in Section I of this document. 
438   
439  C.  The Regulatory Significance of Failing to Comply With a Precise 
440  Requirement   
441   
442  The CGMP regulations require that all changes to production and process control procedures be 
443  approved by the quality control unit (21 CFR 211.100(a)).  If a manufacturer makes a change in 
444  production and process control procedures, but does not obtain approval of those procedures by 
445  the manufacturers quality control unit, this would be a failure to comply with a precise 
446  requirement of the CGMP regulations.  The manufacturer may contend that the failure in this 
447  particular case was not significant because it did not have an adverse effect on product quality 
448  and may convey this contention to the Agency through existing informal communication 
449  channels, including Form FDA 483-response correspondence.   
450   
451  In such a case, the significance of this observation would not be appropriate for dispute 
452  resolution as described in this guidance, as the observation concerns a failure to comply with a 
453  precise requirement of the regulations.  The regulatory significance of an observation is 
454  determined by the Agency after considering all relevant information, including the 
455  manufacturer's response to the inspectional observations.  The Agency encourages manufacturers 
456  to provide all information relevant to the regulatory significance of an observation as part of this 
457  response, but such disputes are not within the scope of this guidance on scientific and technical 
458  disputes concerning the interpretation and application of CGMP requirements.  
459   
460  Manufacturers must have internal written production and process control procedures (21 CFR 
461  211.100(a)) and, as part of these procedures, manufacturers often establish procedural action 
462  limits that are tighter than release specifications.  When the action limits are exceeded, the  
463  internal written procedures may call for some type of investigation to determine if the process is 
464  drifting toward a loss of control, or the procedures may call for other assessments to determine if 
465  the product will meet appropriate specifications throughout its expected shelf life.  If a 
466  manufacturer's internal written procedures require certain actions when action limits are 
467  exceeded, failure to follow these written production and process control procedures is a failure to 
468  comply with 21 CFR 211.100(b).  The manufacturer may contend that this failure is not 
469  significant in that the product met all regulatory specifications when released.  As discussed 
470  above, this contention about significance is not appropriate for the formal dispute resolution 
471  process described in this guidance.  
472   
473  D.  Issues Not Raised During the Inspection  
474   
475  If, during an inspection, an investigator notes what appears to be an objectionable condition and 
476  a manufacturer disagrees with that observation, the manufacturer should voice its disagreement 
477  with the investigator.  By doing so, the investigator has the opportunity to evaluate the 
478  manufacturer's position and consult, as needed, with Agency experts.  The Agency may not 
479  accept a request for dispute resolution concerning a disagreement that was not initially raised by 
  11  Contains Nonbinding Recommendations  
 
 
480  the manufacturer during the inspection unless a manufacturer can provide a reasonable 
481  explanation why it did not present relevant information during the inspection.  
482   
483  V.  COMMUNICATION OF DISPUTE RESOLUTION DECISIONS  
484   
485  FDA believes that decisions made in the dispute resolution process, along with all supporting 
486  documentation, should be publicly available consistent with FDAs disclosure regulations (21 
487  CFR Part 20) and applicable statutes, unless the decisions involve information that would 
488  otherwise be withheld under these regulations and statutes.  The Agency will redact, as 
489  appropriate, any documents requested through the Freedom of Information process.  
490   
491  When appropriate, a summary of the relevant issues and Agency views will be provided in a 
492  question and answer format and posted on the FDA Web site with all identifying information 
493  excluded.  Information gained from these decisions should promote consistent application and 
494  interpretation of pharmaceutical CGMP requirements.   
495   
496  VI.  PAPERWORK REDUCTION ACT OF 1995   
497   
498  This guidance contains information collection provisions that are subject to review by the Office 
499  of Management and Budget (OMB) under the Paperwork Reduction Act of 1995 (44 U.S.C. 
500  3501-3520).   
501   
502  The time required to complete this information collection is estimated to average 30 hours to 
503  prepare and submit each request for tier-one dispute resolution and 8 hours to prepare and submit 
504  each request for tier-two dispute resolution.  This includes the time to review instructions, search 
505  existing data resources, gather the data needed, and complete and review the information 
506  collection.  Send comments regarding this burden estimate or suggestions for reducing this 
507  burden to Edward M. Sherwood, Center for Drug Evaluation and Research (HFD-3), Food and 
508  Drug Administration, Rockwall II, Rm. 7231, 5515 Security Lane, Rockville, MD  20857,  
509  301-594-2847. 
510   
511  An agency may not conduct or sponsor, and a person is not required to respond to, a collection of 
512  information unless it displays a currently valid OMB control number. The OMB control number 
513  for this information collection is 0910-0563. The current expiration date is available at 
514  https://www.reginfo.gov (search ICR and enter OMB control number).    
515   
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