Field Alert Report

Submission
Questions and Answers
Guidance for Industry
DRAFT GUIDANCE
This guidance document is being distributed for comment purposes only.

Comments and suggestions regarding this draft document should be submitted within 60 days of
publication in the Federal Register of the notice announcing the availability of the draft
guidance. Submit electronic comments to https://www.regulations.gov. Submit written
comments to the Dockets Management Staff (HFA-305), Food and Drug Administration, 5630
Fishers Lane, rm. 1061, Rockville, MD 20852. All comments should be identified with the
docket number listed in the notice of availability that publishes in the Federal Register.

For questions regarding this draft document, contact (CDER) Mamta Gautam-Basak 301-796-
0712; (CBER) Office of Communication, Outreach and Development, 800-835-4709 or 240-
402-8010; or (ORA) Rachel Harrington 410-779-5441.

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)
Office of Regulatory Affairs (ORA)

July 2018
Pharmaceutical Quality/Manufacturing Standards (CGMP)
 Field Alert Report
Submission
Questions and Answers
Guidance for Industry
Additional copies are available from:
Office of Communications, Division of Drug Information
Center for Drug Evaluation and Research
Food and Drug Administration
10001 New Hampshire Ave., Hillandale Bldg., 4th Floor
Silver Spring, MD 20993-0002
Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353
Email: [email protected]
https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm
and/or
Office of Communication, Outreach and Development
Center for Biologics Evaluation and Research
Food and Drug Administration
10903 New Hampshire Ave., Bldg. 71, Room 3128
Silver Spring, MD 20993-0002
Phone: 800-835-4709 or 240-402-8010
Email: [email protected]
https://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.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)
Office of Regulatory Affairs (ORA)

July 2018
Pharmaceutical Quality/Manufacturing Standards (CGMP)
 Contains Nonbinding Recommendations
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TABLE OF CONTENTS

I. INTRODUCTION............................................................................................................. 1
II. BACKGROUND ............................................................................................................... 1
III. QUESTIONS AND ANSWERS ....................................................................................... 2
1. What is a FAR and what triggers its submission? ...................................................................... 2
2. Who is responsible for submitting the FAR? .............................................................................. 6
3. When should I submit a FAR? ..................................................................................................... 6
4. How do I submit a FAR? ............................................................................................................... 6
5. Where do I submit a FAR? ........................................................................................................... 8
6. Should I submit a follow-up or final FAR? ................................................................................. 9
 Contains Nonbinding Recommendations
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1 Field Alert Report Submission

2 Questions and Answers
3 Guidance for Industry 1
4
5
6 This draft guidance, when finalized, will represent the current thinking of the Food and Drug
7 Administration (FDA or Agency) on this topic. It does not establish any rights for any person and is not
8 binding on FDA or the public. You can use an alternative approach if it satisfies the requirements of the
9 applicable statutes and regulations. To discuss an alternative approach, contact the FDA staff responsible
10 for this guidance as listed on the title page.
11
12
13
14
15 I. INTRODUCTION
16
17 This guidance provides the agency’s current thinking regarding the requirements for submission
18 of field alert reports (FARs) by applicants of new drug applications (NDAs) and abbreviated new
19 drug applications (ANDAs) and outlines FDA’s recommendations for FAR submissions to help
20 increase their consistency and relevancy. The guidance also addresses certain frequently asked
21 questions.
22
23 In general, FDA’s guidance documents do not establish legally enforceable responsibilities.
24 Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only
25 as recommendations, unless specific regulatory or statutory requirements are cited. The use of
26 the word should in Agency guidances means that something is suggested or recommended, but
27 not required.
28
29
30 II. BACKGROUND
31
32 The FAR regulations found in 21 CFR 314.81(b)(1) and 314.98(b) establish an early warning
33 system to help protect patient health. Under these regulations, NDA and ANDA applicants must
34 submit certain information to FDA about distributed drug products regulated by the Center for
35 Drug Evaluation and Research (CDER) or the Center for Biologics Evaluation and Research
36 (CBER). Specifically, an NDA or ANDA applicant 2 must submit a FAR to FDA within
37 3 working days of receiving the following kinds of information for distributed drug product(s):
38

1
This guidance has been prepared by the Center for Drug Evaluation and Research in cooperation with the Center
for Biologics Evaluation and Research and the Office of Regulatory Affairs at the Food and Drug Administration.
2
For purposes of this guidance, applicant has the meaning set forth in 21 CFR 314.3. Under § 314.98(b), each
ANDA applicant must make the reports required under § 314.81.

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39 (i) Information concerning any incident that causes the drug product or its
40 labeling to be mistaken for, or applied to, another article.
41
42 (ii) Information concerning any bacteriological 3 contamination, or any significant
43 chemical, physical, or other change or deterioration in the distributed drug
44 product, or any failure of one or more distributed batches of the drug product to
45 meet the specification established for it in the application.
46
47 On May 2, 2013, FDA issued a Federal Register notice to notify the pharmaceutical industry
48 about a voluntary pilot project using extensible markup language (XML) functionality to
49 automate Form FDA 3331, NDA-Field Alert Report. The pilot, a collaborative effort between
50 CDER and the Office of Regulatory Affairs (ORA), was the first step in moving FDA away from
51 manual data entry to a more automated system of receiving FARs. It also allowed both CDER
52 and ORA to receive FAR information simultaneously. All firms were encouraged to participate.
53
54 In June 2017, the pilot project was completed and a new version of the automated form—Form
55 FDA 3331a, NDA/ANDA Field Alert—which incorporates feedback from pilot project
56 participants, was approved by the Office of Management and Budget (OMB). Form FDA 3331a
57 is available on FDA’s Field Alert Reports website. 4 Although CBER did not participate in the
58 pilot program, applicants holding NDAs or ANDAs regulated by CBER may also use the new
59 form.
60
61
62 III. QUESTIONS AND ANSWERS
63
64 This section outlines your responsibilities as an NDA or ANDA applicant regarding FAR
65 submissions and makes recommendations about providing information to FDA about any root
66 cause investigations, corrective actions, and other actions you take in response to a FAR.
67
68 1. What is a FAR and what triggers its submission?
69
70 a. What is a FAR?
71
72 FARs are part of an early warning system to protect patient health. Per § 314.81(b)(1), you must
73 submit a FAR for distributed drug products and articles to FDA if you receive information of the
74 following kinds:
75

3
FDA has interpreted the term bacteriological used in § 314.81(b)(1)(ii) to mean microbiological, which includes
any kind of microbial contamination, such as bacteria, yeast, fungus, or virus. The contamination of distributed drug
product by yeast, fungus, or virus would also be reportable as a change or deterioration in the distributed drug
product, or as a failure of one or more distributed batches of the drug product to meet the specification established
for it in the application.
4
See https://www.fda.gov/drugs/guidancecomplianceregulatoryinformation/surveillance/ucm529729.htm.

2
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76 • Information concerning any incident that causes a drug product or its labeling to be
77 mistaken for, or applied to, another article.
78
79 • Information concerning any bacteriological contamination, or any significant chemical,
80 physical, or other change or deterioration in the distributed drug product, or any failure of
81 one or more distributed batches of the drug product to meet the specification established
82 for it in the application.
83
84 You should submit a FAR using Form FDA 3331a (see question 4a). In that form, and in this
85 guidance, the term problem refers to the incident 5 or possible/actual quality issue 6 that is the
86 subject of the FAR.
87
88 b. What are initial, follow-up, and final FARs?
89
90 This guidance uses the terms initial, follow-up, and final FARs, consistent with the language in
91 Form FDA 3331a.
92
93 • Initial FAR refers to the FAR that you submit to comply with the requirements of
94 § 314.81(b)(1), and it is the first time you have submitted a FAR about a specific problem
95 as described in question 1a.
96
97 • Follow-up FAR refers to any subsequent FARs you submit to provide additional
98 information about the problem identified in the initial FAR. Examples of additional
99 information include significant findings of the ongoing investigation; additional facilities
100 or lots identified within scope; and sample analyses, laboratory test results, or potential
101 root causes identified.
102
103 • Final FAR refers to the FAR you submit to close out the initial FAR identifying the root
104 cause and describing any corrective actions taken or to be taken.
105
106 Although follow-up and final FARs are not required, they are recommended. For more
107 information on follow-up and final FARs, see III.6 in this guidance.
108

5
See § 314.81(b)(1)(i).
6
See § 314.81(b)(1)(ii).

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109 c. What is considered a significant chemical, physical, or other change or deterioration in
110 the distributed product?
111
112 To determine whether a chemical, physical, or other change or deterioration in the distributed
113 drug product is significant, you should evaluate the potential impact of the change or
114 deterioration on the drug product’s identity, strength, purity, stability, and efficacy and how that
115 change or deterioration could impact an individual using the product. Any such assessment
116 should be based on factors specific to your distributed product. These factors could include
117 intended use, route of administration, dosage, length of treatment, and patient population.
118
119 You should also clearly document an investigation conducted according to 21 CFR 211.192
120 (production record review) or 211.198 (complaint files), including the determination of whether
121 a problem resulted in a significant chemical, physical, or other change or deterioration, along
122 with the rationale (including factors considered) for the determination. (See, e.g., question 1d for
123 information about consumer complaints.)
124
125 d. Does every consumer complaint warrant submission of a FAR?
126
127 No. Every consumer complaint should be evaluated within 3 working days to determine if the
128 information provided in the complaint meets the criteria outlined in § 314.81(b)(1). You must
129 submit a FAR within that time frame if you determine that the information identified in the
130 complaint meets the criteria for a FAR.
131
132 e. Do I have to submit a FAR for packaging or components used in the manufacture of the
133 distributed product?
134
135 If you receive information about packaging or components that meets the criteria set forth in
136 § 314.81(b)(1), you must submit a FAR within 3 working days of your receipt of that
137 information. For example, if you receive information that a stopper used for a vial could result in
138 contamination of a distributed batch, the information must be submitted in a FAR.
139
140 f. If the product approved under an NDA/ANDA is only distributed outside the United
141 States, am I still subject to the FAR requirements?
142
143 Yes. Any drug product marketed under an approved NDA or ANDA, whether distributed
144 domestically or abroad, is subject to FAR requirements. 7
145
146 g. If a product has not been distributed and an out-of-specification (OOS) result is
147 discovered, is a FAR still required?
148
149 No. A FAR is only required for distributed drug products. However, if you discover an OOS
150 result and your investigation 8 for example, indicates a failure of one or more distributed batches

7
See § 314.81(b)(1).
8
See § 211.192.

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151 of the drug product to meet the specification established in the application, or other kinds of
152 information as specified in § 314.81(b)(1), then you must submit a FAR. 9
153
154 h. If an OOS result for a distributed drug product is discovered during stability testing, but
155 the result is invalidated within 3 working days, do I need to submit a FAR?
156
157 No. OOS results for a distributed drug product that are scientifically invalidated (e.g., an
158 analytical laboratory error is confirmed) within 3 working days do not require a FAR. If an OOS
159 result is not scientifically invalidated, you must submit a FAR within 3 working days of your
160 initial receipt of the OOS information.
161
162 i. Do aseptic process simulation (media fill) failures for a distributed drug product require
163 a FAR?
164
165 A media fill validation failure indicates a potential problem related to sterility assurance that
166 requires an investigation, including assessment of the impact on distributed drug products
167 produced since the last successful media fill. 10 As such, you must submit a FAR for any
168 distributed drug product within the scope of the media fill failure investigation within 3 working
169 days of receiving information about such a failure if the information meets the criteria set forth in
170 § 314.81(b)(1).
171
172 j. If the root cause of a problem related to a distributed drug product is identified and
173 corrected within 3 working days, should I still submit a FAR?
174
175 Yes, if you receive information as outlined in § 314.81(b)(1), you must submit a FAR within 3
176 working days regardless of whether an investigation identifies a root cause or leads to a
177 corrective action. The report should include detailed information regarding the identified root
178 cause and any completed or ongoing corrective action.
179
180 k. Is a FAR required if a recall is initiated?
181
182 If the recall is for an NDA/ANDA product and the information leading to the recall meets the
183 criteria under § 314.81(b)(1), you must submit a FAR. You should also submit a recall
184 notification to FDA through your local recall coordinator
185 (http://www.fda.gov/Safety/Recalls/IndustryGuidance/ucm129334.htm). If the recall is initiated
186 after an initial FAR is submitted, we encourage you to submit a follow-up or final FAR at the
187 time of the recall notification. 11

9
See also guidance for industry Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical
Production. We update guidances periodically. For the most recent version of a guidance, check the FDA guidance
web page at https://www.fda.gov/RegulatoryInformation/Guidances/default.htm.
10
See § 211.192.
11
See 21 CFR part 7; FDA, 2016, Chapter 7: Recall Activities, Investigations Operations Manual; and guidance for
industry Product Recalls, Including Removals and Corrections.

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188
189 2. Who is responsible for submitting the FAR?
190
191 As the NDA/ANDA applicant, you must submit the FAR. 12 If you have a contractual agreement
192 with another person or entity to perform manufacturing, holding, packaging, labeling, or
193 distribution activities or services for your products, you still hold ultimate responsibility for
194 reporting FARs. You should establish, maintain, and follow a procedure for receiving and
195 responding to any reportable information from contracted entities concerning your products. 13
196
197 3. When should I submit a FAR?
198
199 a. What is the required time frame for the submission of a FAR?
200
201 You must submit a FAR within 3 working days of receipt of the information described in
202 § 314.81(b)(1). We consider working days to be any day from Monday through Friday,
203 excluding U.S. Federal holidays. For example, if any information meeting the criteria requiring a
204 FAR is identified on Friday (day 0), then day 1 begins on the first working day after the
205 information is identified (Monday), and you must submit the FAR by close of business on
206 Wednesday (day 3). This time frame applies regardless of where the information meeting the
207 criteria requiring a FAR is identified. For example, the day a contract lab learns of a sterility
208 failure is day 0, and you must submit the FAR by close of business on day 3.
209
210 b. What will happen if I do not submit a FAR within the 3-day time frame?
211
212 If you fail to submit a required FAR within this time frame, you would—at a minimum—be in
213 violation of § 314.81(b)(1). You would also be in violation of section 505(k) of the Federal
214 Food, Drug, and Cosmetic Act (FD&C Act). 14 Violating section 505(k) is a prohibited act under
215 section 301(e) of the FD&C Act. 15 We may include this as an observation on Form FDA 483,
216 Inspectional Observations. Any FDA finding that you have failed to submit a FAR, as required,
217 may result in a regulatory action, whether or not the finding was cited on a Form FDA 483.
218
219 4. How do I submit a FAR?
220
221 a. Is a form available to submit FARs?
222
223 Yes. We recommend that you use Form FDA 3331a to submit your FARs electronically.
224 Submitting electronically will expedite FDA’s review process and fulfill your obligation to
225 submit the FAR to the relevant district office. We will, however, accept other types of
226 submissions as described in § 314.81(b)(1).

12
See §§ 314.81(b) and 314.98(b).
13
See guidance for industry Contract Manufacturing Arrangements for Drugs: Quality Agreements.
14
21 U.S.C. 355(k).
15
21 U.S.C. 331(e).

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227
228 Form FDA 3331a and its instructions are available on the FAR website at
229 https://www.fda.gov/drugs/guidancecomplianceregulatoryinformation/surveillance/ucm529729.h
230 tm.
231
232 b. Is it necessary to submit a paper copy of a FAR if the FAR has been submitted
233 electronically?
234
235 No. Electronic submission of Form FDA 3331a as outlined in the Form FDA 3331a instructions
236 meets FAR requirements under § 314.81(b)(1).
237
238 c. Does submission of FDA Form 3331a satisfy the written follow-up requirement for FARs
239 submitted initially by telephone?
240
241 Yes, using Form FDA 3331a as instructed will satisfy the written follow-up requirement for
242 FARs initially submitted by telephone or other rapid means as set forth in § 314.81(b)(1). Once
243 you use Form FDA 3331a to submit your FAR electronically, the information you entered will
244 be available to CDER or CBER and the FDA district office responsible for the facility involved.
245
246 d. Can FARs associated with multiple NDAs/ANDAs be submitted on one form?
247
248 No. If multiple NDAs or ANDAs are involved, submit one Form FDA 3331a for each NDA or
249 ANDA. See question 4e for additional information on submitting FARs for a facility-wide
250 problem that affects drug products covered by multiple applications or application types.
251
252 e. How should I report a facility-wide problem that affects drug products covered by
253 multiple applications or application types?
254
255 You must submit a separate initial FAR for each application (NDA or ANDA) that is affected by
256 the problem. 16 If you conduct a single comprehensive investigation into the problem at a facility
257 and you submit a follow-up or final FAR, you can submit one follow-up and/or final FAR that
258 references all of the affected products, including the NDA/ANDA number(s) and the date(s) the
259 problem was identified.
260
261 f. What if I don’t know the information asked for on Form FDA 3331a at the time of
262 submission?
263
264 In an initial FAR, provide whatever information you have that is related to the problem within 3
265 working days of receipt of the information described in § 314.81(b)(1). Please be sure to report
266 the NDA/ANDA number, the drug product generic name and trade/brand name (if any), the
267 product quality issue, and your contact information. When you learn more about the problem
268 reported in the initial FAR, we recommend that you submit any new information in a follow-up
269 or final FAR (see III.6).

16
See § 314.81(a).

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270
271 g. Form FDA 3331a asks for the “date when notified about problem(s) or when problem(s)
272 first became known to application holder.” Is this the date when the information was
273 confirmed as an actual problem?
274
275 No, it is the date you received information of the kinds outlined in § 314.81(b)(1). Any follow-up
276 and final FARs should contain the same initial date.
277
278 5. Where do I submit a FAR?
279
280 When you use the automated features of Form FDA 3331a, your FAR will be submitted
281 simultaneously to CDER and to the FDA district office you select on page ii of the form. CDER
282 will forward FARs to CBER, as appropriate. Form FDA 3331a provides contact information
283 (e.g., email and postal addresses) for all district offices. For specific information about which
284 district office to select on page ii of the form, see the questions and answers below.
285
286 a. If the problem occurs at a domestic facility in the United States, where do I indicate that
287 facility’s information on the FAR and where should I submit the FAR?
288
289 You should list the facility information in Form FDA 3331a’s box 1—“Firm Name and Address
290 Where Problem Occurred”—and select the FDA district office responsible for that facility on
291 page ii of the form. We recommend that you also cc: the district office where your headquarters
292 is located if different from the FDA district office you selected on the form.
293
294 b. If the problem occurs at a foreign facility, where do I indicate that facility’s information
295 on the FAR and where should I submit the FAR?
296
297 You should list the foreign facility information in Form FDA 3331a’s box 1—“Firm Name and
298 Address Where Problem Occurred”—and, on page ii, select the FDA district office where your
299 firm’s attorney, U.S. agent, or other authorized official resides or maintains a place of business in
300 the United States. 17
301
302 c. If multiple firms or locations are implicated in an investigation, which firm or location
303 should I list on the FAR as the site where the problem occurred?
304
305 You should enter the name and address of the finished drug product manufacturer for the NDA
306 or ANDA in Form FDA 3331a’s box 1—“Firm Name and Address Where Problem Occurred.”
307 However, if the problem involves the active pharmaceutical ingredient (API) or any raw
308 material, you should list the supplier’s facility information in box 1 instead. If the problem
309 involves a firm other than the finished drug product manufacturer, such as a labeling and
310 packaging firm, you should list that firm’s information in box 1. If any firm other than the
311 finished drug product manufacturer is listed in box 1, you should include the name and address

17
See 21 CFR 207.40 and 314.50(a)(5).

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312 of the finished drug product manufacturer in box 14, “Remarks,” as well as any additional sites
313 implicated but not already included in box 1.
314
315 d. If it is unclear where the problem occurred, which location should I list on the FAR and
316 where should I submit the FAR?
317
318 If it is unclear where the problem occurred, you should list the site where, to the best of your
319 knowledge, the problem most likely occurred (see question 5c) in Form FDA 3331a’s box 1—
320 “Firm Name and Address Where Problem Occurred”—and, on page ii, select the FDA district
321 office responsible for that location. For example, if your NDA/ANDA product is found to have
322 one or more bottles containing the wrong tablet at the time the FAR is submitted, it could be
323 unclear if the problem occurred at the tableting facility or during distribution in bulk containers
324 to the contract packager, packaging at a contract facility, subsequent shipping and handling, or
325 dispensing at the pharmacy. We recommend that you cc: the FDA district office where your
326 headquarters are located if different from the district office responsible for the location where the
327 problem occurred. List additional sites implicated in box 14, “Remarks.”
328
329 If during the course of an investigation you wish to change the information initially provided or
330 you have determined where the problem occurred, you should update the establishment name,
331 address, and/or facility establishment identifier (FEI) number or the data universal numbering
332 system (DUNS) number of the firm where the problem occurred in a follow-up FAR. If a new
333 district office is the receiving district for your follow-up FAR, please also cc: the original district
334 office that received the initial FAR.
335
336 6. Should I submit a follow-up or final FAR?
337
338 Although follow-up and final FARs are not required under § 314.81(b)(1), we recommend that
339 you submit these additional voluntary reports, when warranted, as soon as possible. 18 We use the
340 information in these reports to assess the risk to public health and the adequacy of the firm’s
341 response.
342
343 a. When should I submit a follow-up FAR?
344
345 Though not required, we encourage you to submit follow-up FARs when (1) there are significant
346 findings during any investigation for the same problem as that identified in the initial FAR (e.g.,
347 additional lots impacted, different locations identified) or (2) you learn that information
348 submitted in a previous FAR is incorrect.
349
350 b. During the open investigation, if I discover that additional lots of the same drug product
351 have the same issues as those identified in the initial FAR, should I submit a new FAR?
352
353 If you choose to submit a follow-up FAR, you should submit a follow-up FAR that identifies the
354 additional lots. In the follow-up FAR, you should reference the discovery date from the initial

18
For a description of follow-up and final FARs, see question 1b.

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355 FAR, update FDA on the progress of the investigation, identify corrective actions that you have
356 taken as well as those you intend to take, and provide the anticipated date for closing out the
357 investigation in Form FDA 3331a’s box 14 “Remarks.”
358
359 c. If I receive an additional consumer complaint while there is a FAR for the same problem
360 still being investigated, should I submit a follow-up FAR?
361
362 No. A follow-up FAR should not be submitted if all of the following are true:
363
364 • The problem is the same as that identified in the initial FAR.
365 • The drug product is covered under the same NDA/ANDA as originally reported.
366 • The investigation into the root cause of the initial FAR is still ongoing.
367 • The drug product is part of the same lot as originally reported.
368
369 When there is an ongoing root cause investigation for a FAR (i.e., one for which no final FAR
370 has been submitted), we recommend that you provide a cumulative list of related complaints in
371 your final FAR rather than submitting a FAR for every consumer complaint received.
372
373 d. When should I submit the final FAR?
374
375 We recommend submitting final FARs promptly to inform FDA when you identify the root
376 cause, take corrective action, or close the investigation. Investigations should be closed as soon
377 as possible.

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