Using the Inactive 
Ingredient Database 
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DRAFT GUIDANCE 
 
This guidance document is being distributed for comment purposes only.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 90 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publication in the Federal Register of the notice announcing the availability of the draft 
guidance.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) Susan Zuk 240-402-9133.  
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
 
July 2019 
Pharmaceutical Quality/CMC 
 
 
   
Using the Inactive 
Ingredient Database 
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: druginfo@fda.hhs.gov  
https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
 
July 2019 
Pharmaceutical Quality/CMC 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
TABLE OF CONTENTS 
 
 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 1 
III.  DEFINITION OF IID ....................................................................................................... 3 
A.  IID Contents ................................................................................................................................... 3 
1.  Ingredient Name .............................................................................................................................. 3 
2.  Route of Administration ................................................................................................................... 3 
3.  Dosage Form ................................................................................................................................... 3 
4.  Chemical Abstracts Service (CAS) Registry Number ...................................................................... 3 
5.  Unique Ingredient Identifier (UNII) ................................................................................................ 4 
6.  Maximum Potency ............................................................................................................................ 4 
B.  IID System ...................................................................................................................................... 4 
1.  IID Excipient Data ........................................................................................................................... 4 
2.  IID Dynamics ................................................................................................................................... 4 
IV.  SPECIFIC TOPICS .......................................................................................................... 5 
A.  Nomenclature and Identity ........................................................................................................... 5 
1.  Excipient Preferred Terms ............................................................................................................... 5 
2.  Unique Ingredient Identifier (UNII) ................................................................................................ 5 
B.  Excipient Level Listing (Maximum Potency) .............................................................................. 6 
1.  Difference Between Maximum Potency and Maximum Daily Exposure (MDE) ............................. 6 
2.  Listing of Maximum Potency for Various Dosage Forms ................................................................ 6 
3.  Omissions ......................................................................................................................................... 7 
V.  INVESTIGATIONAL NEW DRUGS (INDS), NDAS, AND ANDAS ......................... 7 
A.  INVESTIGATIONAL NEW DRUGS (INDs) ............................................................................. 8 
B.  NEW DRUG APPLICATIONS (NDAs) ...................................................................................... 8 
C.  ABBREVIATED NEW DRUG APPLICATIONS (ANDAs) ..................................................... 8 
VI.  QUESTIONS AND COMMUNICATIONS WITH FDA .............................................. 9 
A.  IID Update Mailbox ....................................................................................................................... 9 
B.  GSRS Mailbox ................................................................................................................................ 9 
C.  Controlled Correspondence .......................................................................................................... 9 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1  Using the Inactive Ingredient Database 
2  Guidance for Industry1 
3   
4   
5  This draft guidance, when finalized, will represent the current thinking of the Food and Drug 
6  Administration (FDA or Agency) on this topic. It does not establish any rights for any person and is not 
7  binding on FDA or the public. You can use an alternative approach if it satisfies the requirements of the 
8  applicable statutes and regulations. To discuss an alternative approach, contact the FDA staff responsible 
9  for this guidance as listed on the title page. 
10   
11   
12   
13  I.  INTRODUCTION 
14   
15  This guidance describes the Food and Drug Administrations (FDAs) Inactive Ingredient 
16  Database (IID) and provides recommendations for how to use the IID in the development of drug 
17  products.2 The guidance also describes how the IID can be used in evaluating excipient3 safety, 
18  which can affect application filing and scientific review. In addition, this guidance discusses how 
19  the IID is structured; the data regarding excipients in the IID; and how nomenclature, maximum 
20  potency levels, and units of measure are presented in the IID. Lastly, the guidance is intended to 
21  give IID users a clearer understanding of the databases benefits and limitations. 
22   
23  In general, FDAs guidance documents do not establish legally enforceable responsibilities. 
24  Instead, guidances describe the Agencys 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  II.  BACKGROUND 
30   
31  The IID provides information on excipients present in FDA-approved drug products.4 Prior to 
32  the establishment of the IID, FDA made available information about excipients present in FDA-
                                                 
1 This guidance has been prepared by the Office of Pharmaceutical Quality in the Center for Drug Evaluation and 
Research at the Food and Drug Administration.  
2 The IID can be accessed at http://www.accessdata.fda.gov/scripts/cder/iig/index.cfm. 
3 In this draft guidance, we use the term excipients to mean any inactive ingredients that are added intentionally to 
therapeutic and diagnostic products, but that are not intended to exert therapeutic effects at the intended dosage, 
although they may act to improve product delivery (e.g., enhance absorption or control release of the drug 
substance). Historically, we used the term inactive ingredient in naming the database, however, we believe that the 
term excipient is more accurate because it recognizes that these ingredients may have some biological activity 
even though they are not intended to exert therapeutic effects. Therefore, the term excipient is used throughout 
this guidance in lieu of inactive ingredient, although we are not changing the name of the database. 
4 The current IID includes excipients in drug products that are the subject of approved New Drug Applications 
(NDAs) and Abbreviated New Drug Applications (ANDAs). Excipients used in approved Biologics License 
Applications (BLAs) are not entered into the IID. If drug products are withdrawn from the market after approval or 
are reformulated for safety reasons, the excipients used in those products may be removed from the IID.  
 
  1  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
33  approved drug products by making available an inactive ingredient guide. The inactive 
34  ingredient guide was first made available in 1987 in a hardcopy paper format. FDA began 
35  making the information available in an online database in 2003. This information about 
36  excipients has been used by all segments of industry as an aid in developing new drug products. 
37  If an excipient is used in approved drug products for a particular route of administration, the 
38  excipient generally is not considered new and may warrant less extensive review the next time it 
39  is included in a new drug product. For example, if the IID includes a particular excipient at a 
40  specified potency for a certain route of administration, a sponsor could generally consider the 
41  excipient at that potency safe for use in a similar manner for a similar type of product.5 
42   
43  The Agency may consult the IID when performing regulatory filing reviews of applications and 
44  during the technical review of applications as part of an evaluation of whether the levels of 
45  excipients in drug product formulations are acceptable or require additional documentation to 
46  support the proposed level. The IID, however, does not currently provide information regarding 
47  the different exposure models (e.g., maximum daily intake based on the dosing recommendations 
48  indicated in the labeling, safety in pediatric populations, acute versus chronic use) that may be 
49  needed during such a technical review, nor does inclusion of an excipient at a level described in 
50  the IID necessarily satisfy the requirements in FDA regulations with respect to maximum 
51  allowable limits for specific categories of products.6 However, the IID is one of the tools the 
52  Agency uses to confirm prior use of particular excipients. 
53   
54  The Agency has solicited stakeholder engagement and feedback to improve the IID. For 
55  example, FDAs Inactive Ingredients Database Working Group (IID Working Group), created in 
56  September 2011, has worked with industry stakeholders to identify the IIDs limitations and 
57  improve the IID. FDA also published a Federal Register notice in 2015 to obtain input from 
58  stakeholders and invited questions and corrections directly from a wide range of individual IID 
59  users through an electronic mailbox (see section VI).7 Upon consideration of that input, this 
60  guidance provides recommendations for how applicants can optimize use of the IID. 
61   
62  The Agency notes that changes will be made to the IID in the future in accordance with the 
63  GDUFA II commitments letter.8 By October 1, 2020, FDA will complete enhancements to the 
                                                 
5 In this guidance, the term sponsor is used to denote the submitter of an Investigational New Drug Application 
(IND), NDA, or ANDA. 
6 For example, during technical review, the Maximum Daily Intake (MDI) of elemental iron and any color additive 
must be verified to not exceed the maximum amount specified in 21 CFR 73.1200(c) (i.e., 5 mg/day) for iron and in 
21 CFR Parts 73 (subpart B), 74 (subpart B), or 82 (subparts B and C) for color additives. As prescribed by law, a 
color additive must be shown to be safe and be listed in the CFR before it may be used to color foods, drugs, 
cosmetics, or certain medical devices. Refer to the guidance for industry Color Additive Petitions - FDA 
Recommendations for Submission of Chemical and Technological Data on Color Additives for Food, Drugs, 
Cosmetics, or Medical Devices (July 2009) for additional recommendations. Applicants should reference relevant 
CFR sections in their submissions. We update guidances periodically. To make sure you have the most recent 
version of a guidance, check the FDA Drugs guidance web page at 
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm. 
7 See Federal Register Volume 80, Number 161 [FR Doc No: 2015-20556] August 20, 2015, Technical Document 
for Using the Inactive Ingredient Database, Establishment of a Public Docket, Government Publishing Office. 
8 GDUFA Reauthorization Performance Goals and Program Enhancements Fiscal Years 2018-2022 (GDUFA II 
Commitment Letter) at 17. 
 
  2  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
64  Inactive Ingredient Database so users can perform electronic queries to obtain accurate Maximum 
65  Daily Intake and Maximum Daily Exposure9 information for each route of administration for which 
66  data is available. FDA will update the Inactive Ingredient Database on an ongoing basis, and post 
67  quarterly notice of updates made. Such notices will include each change made and, for each change, 
68  the information replaced. 
69   
70  III.  DEFINITION OF IID 
71   
72  A.  IID Contents 
73   
74  The IID is a listing of excipients used in approved New Drug Application (NDA) and 
75  Abbreviated New Drug Application (ANDA) products, regardless of whether the products 
76  remain on the market, if no safety concerns have been identified. It includes the following 
77  specific information about each excipient: 
78   
79  1.  Ingredient Name 
80   
81  The ingredient name is the preferred term for the excipient as it appears in the Global Substance 
82  Registration System (GSRS).10 
83   
84  2.  Route of Administration 
85   
86  The route of administration refers to the route of administration of the approved drugs in which 
87  the excipient was or is currently used that are the basis for the listing. 
88   
89  3.  Dosage Form 
90   
91  The dosage form of the excipient is the dosage form of the approved drugs in which the excipient 
92  was or is currently used that are the basis for the listing. 
93   
94  4.  Chemical Abstracts Service (CAS) Registry Number11 
95   
96  The CAS Registry Number associated with the excipient is a recognized chemical identifier 
97  linked to chemical structure and other information associated with the excipient.   
98   
                                                 
9 Maximum Daily Exposure (MDE) is the total amount of the excipient that would be taken or used in a day based 
on the maximum daily dose (MDD) of the drug product in which it is used. MDE is calculated as the dosage unit 
level of the excipient multiplied by the maximum number of dosage units recommended per day (excipient (mg) x 
number units). MDE may also be referred to as maximum daily intake (MDI) for oral drug products. Where an 
MDD is not provided in the product labeling, FDA will consider the applicants rationale for an MDD when 
calculating excipient MDE.  
10 See https://fdasis.nlm.nih.gov/srs. The GSRS (also known as SRS) is used to generate permanent, unique, 
unambiguous identifiers for substances in regulated products, such as ingredients in drug products. 
11 See http://www.cas.org/content/chemical-substances/faqs. 
 
  3  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
99  5.  Unique Ingredient Identifier (UNII)12 
100   
101  Assigned by GSRS, a UNII is a unique alphanumeric code that identifies a substance based on 
102  molecular structure and/or descriptive information. A UNII is displayed with excipients to 
103  facilitate Structured Product Labeling (SPL), which requires that a UNII be used for all 
104  ingredients, including excipients used in FDA-approved drugs.13  
105   
106  6.  Maximum Potency 
107   
108  Maximum potency is the highest level of the excipient used in approved products. The IID lists 
109  the highest level per dosage unit of the excipient in each dosage form in which it is used. For 
110  topical products and other products where excipients are expressed as a percentage of the product 
111  formula, maximum potency is the highest formula percentage for products included in the IID.  
112   
113  B.  IID System 
114   
115  1.  IID Excipient Data 
116   
117  All product formulas are entered into the Agencys internal master database as part of the 
118  application record. The IID is a public database that is a subset of information derived from 
119  FDAs internal master database. When an excipient is included in the IID, the IID will list the 
120  largest value for each route of administration and dosage form available for listing from FDAs 
121  master database, but does not reveal the formulation of any particular product. The retrieved 
122  largest value appears as the maximum potency listed for the excipient for that route of 
123  administration and dosage form in the published IID on the FDA website.  
124   
125  2.  IID Dynamics 
126   
127  With each subsequent IID update, the IID grows longer as new excipients, routes of 
128  administration, and dosage forms are added. This reflects the growing number of approved drug 
129  products. However, FDA may also remove entries from the IID if the Agency has reason to 
130  question the safety of excipients, including when drug products are reformulated or withdrawn 
131  from sale for safety reasons that implicate the excipients. Further, FDA updates the IID with 
132  corrected information if FDA identifies a discrepancy. If an applicant wishes to search 
133  previously published versions of the IID for an ingredient, archival files, organized by fiscal 
134  quarter from 2009 to present, can be downloaded through the IID web page.14  
135   
136     
                                                 
12 See https://www.fda.gov/ForIndustry/DataStandards/SubstanceRegistrationSystem-
UniqueIngredientIdentifierUNII/ucm127839.htm. 
13 See http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm. 
14 Applicants generally should not reference archival records to justify a proposed level of excipient. An applicant 
should rely on current IID information as the most up-to-date information to support a proposed route of 
administration and level of use of an excipient, or should provide other adequate justification for Agency review and 
consideration. 
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137  IV.  SPECIFIC TOPICS 
138   
139  A.  Nomenclature and Identity 
140   
141  1.  Excipient Preferred Terms 
142   
143  The identities of most excipients in the IID are drawn from GSRS. Although applicants may 
144  provide a trade name or common name of an excipient in the original application, the IID 
145  displays the preferred term for the excipient as it appears in GSRS to promote consistency in 
146  nomenclature in the IID. GSRS preferred terms generally identify single ingredient substances. 
147  When the United States Pharmacopeia/National Formulary (USP/NF) identifies an excipient as a 
148  single ingredient substance, the GSRS preferred term is the same as the USP/NF monograph title 
149  for that excipient. However, in cases where the USP/NF monograph title covers multiple 
150  substances, the GSRS preferred terms for each of those ingredient substances might differ from 
151  the monograph. In such cases, the preferred term in the IID and the USP/NF monograph title 
152  may differ.  
153   
154  Co-processed excipients and excipient mixtures that have USP/NF monographs generally retain 
155  their monograph names in GSRS and the IID and are updated in GSRS and the IID to be 
156  consistent with the USP/NF monograph if the monograph title is revised. One example is 
157  emulsifying wax, which is an excipient mixture with a USP/NF monograph. This excipient 
158  appears in the IID under the USP/NF name. If a co-processed excipient or excipient mixture does 
159  not have a USP/NF monograph or GSRS preferred term, it will generally be listed in the IID by 
160  the name provided in the source applications or some other unique identifier provided by 
161  applicants. One example is the excipient mixture glyceryl oleate/propylene glycol, which appears 
162  in the IID under the name the applicants provided. 
163   
164  2.  Unique Ingredient Identifier (UNII)  
165   
166  Most entries in the IID now have a UNII, a unique alphanumeric code that identifies the 
167  substance. The UNII, which is generated by GSRS, has been designed to support health 
168  information technology initiatives by providing unique identifiers for substances in drugs, 
169  biologics, foods, and devices based on molecular structure and/or descriptive information. In the 
170  IID, the UNII is displayed with excipients to facilitate Structured Product Labeling (SPL), which 
171  includes UNIIs for all ingredients, including excipients.  
172   
173  Not all excipients have been assigned UNIIs. Certain ingredients and mixtures are considered 
174  formulations and are not currently assigned UNIIs.15 When an excipient does not have a UNII, 
175  the IID UNII field displays NA (not applicable). For excipients that should be assigned but have 
176  not yet been assigned a UNII, a request for UNII assignment by industry may be made directly to 
177  GSRS.  
178   
179     
                                                 
15 The IID, however, does not disclose the specific formulation (i.e., each ingredient and the quantity of each 
ingredient) for these excipients. 
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Draft  Not for Implementation 
180  B.  Excipient Level Listing (Maximum Potency) 
181   
182  When an excipient is included in the IID, the maximum potency shown is generally described as 
183  the maximum level of the excipient per dosage unit for each route of administration and dosage 
184  form in which the excipient has been used. Maximum potency does not represent the maximum 
185  daily exposure (MDE) of an excipient unless the MDE of products that were the basis for the 
186  listing is only a single unit. Maximum potency does not represent a maximum permissible daily 
187  intake or acceptable daily intake of the excipient; rather, maximum potency reflects the level per 
188  unit of the excipient that has been used previously in approved drug products. 
189   
190  1.  Difference Between Maximum Potency and Maximum Daily Exposure (MDE) 
191   
192  Because there has been confusion over the years about the difference between maximum potency 
193  and MDE, an example is provided here to illustrate the difference. In a hypothetical case, where 
194  the maximum potency of an excipient is listed as 500 mg in the IID for the oral route of 
195  administration in oral capsules, if the maximum daily dose (MDD), the highest level of active 
196  ingredient dosed in a day (generally determined by following the instructions on the product 
197  labeling) is provided by two capsules per day, then the MDE would be 1,000 mg of the excipient. 
198  The MDE would not be reflected in the IID because the IID currently only shows the maximum 
199  potency (the maximum amount per dosage unit), which is 500 mg. Although the IID currently 
200  provides only the maximum potency per unit dose, it is important for applicants to consider the 
201  total daily exposure of excipients when developing new drug products.  
202   
203  2.  Listing of Maximum Potency for Various Dosage Forms 
204   
205  The units of measure differ for different dosage forms. For example, the IID provides the 
206  maximum potency for solid oral dosage forms in weight, typically in milligrams (mg).  
207   
208  Excipients in liquid oral dosage forms are also provided as weight per dosage unit; however, the 
209  dosage unit of a liquid oral dosage form is a volume, typically in milliliters (mL). Therefore, 
210  excipients in this dosage form are listed as weight per volume (X mg/X mL), where the weight is 
211  the level of the excipient (X mg), and the volume (X mL) is the liquid volume of one dose. Until 
212  2015, liquid oral dosage forms were listed in the IID as a percentage of total formula weight. The 
213  conversion to weight per dosage unit was done to standardize the units and facilitate better use of 
214  the IID. 
215   
216  Topical products are listed in percentage weight/weight (%w/w), weight/volume (%w/v), or 
217  volume/volume (%v/v). Since topical dosage forms often do not have an exact dosage unit, FDA 
218  has determined that percentage is the best representation of the maximum potency. The 
219  maximum potency of excipients in parenteral dosage forms is also shown as a percentage of the 
220  total formula weight, in which percentage is the percent weight per volume (%w/v). Excipient 
221  potencies of parenteral products that are marketed as powders or lyophilized powders for 
222  reconstitution are generally shown as the percentage of the excipient in the product after 
223  reconstitution. The IID Working Group is working to standardize potency units in the IID to 
224  provide consistent representation of maximum potency for excipients listed in the IID. IID users 
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Draft  Not for Implementation 
225  are encouraged to contact the IID Update mailbox if the units for an entry differ from the 
226  descriptions provided above. 
227   
228  3.  Omissions 
229   
230  A small number of entries in the IID lack a maximum potency value. In some cases, this is 
231  intentional; some values are difficult to verify because they are associated with very old 
232  products. In other cases, the use of the term NA in place of a maximum potency may be used 
233  when the quantity of the excipient is variable (e.g., pH adjusters that are indicated in the formula 
234  as quantity sufficient). There are also IID entries for excipients where the potency of the 
235  excipient is not relevant. For example, the excipients in certain drug-device combination 
236  products are included in the IID, but no potency is specified for device components. This is 
237  because the device components are not evaluated in the same manner as excipients in drugs. 
238  Since a potency level generally is not appropriate for components of devices, the IID contains 
239  qualitative information for such components (e.g., components of membranes and films of 
240  transdermal systems and insoluble polymers in vaginal drug-delivery systems).16 The Agency 
241  periodically reviews the IID and makes corrections if the omission of maximum potency was not 
242  intentional, but rather found to be an error. 
243   
244  V.  INVESTIGATIONAL NEW DRUG APPLICATIONS (INDs), NDAs, AND ANDAs 
245   
246  The IID is often used by applicants to help justify the levels of excipients in Investigational New 
247  Drug Applications (INDs), NDAs, and ANDAs. An applicant may wish to use an excipient that 
248  is found in the IID, but at a higher level or in a different route of administration than listed in the 
249  IID. In such cases, the IID alone does not provide sufficient information to determine the safety 
250  of the proposed level of the excipient, and the applicant should provide evidence of safety for the 
251  excipient at the proposed level or for the proposed route of administration taking into 
252  consideration the context of use (e.g., patient population, dosage, and duration of exposure). For 
253  additional information on the type of data recommended for review, applicants should refer to 
254  the guidance for industry on Nonclinical Studies for the Safety Evaluation of Pharmaceutical 
255  Excipients.  
256   
257  In an application, when referencing the IID to justify the use of an excipient, additional 
258  information may be warranted. For example, when referencing the IID for an excipient with 
259  multiple grades, it is best to specify the proposed grade and reference the IID listing for that 
260  grade, or if that is not possible, explain the link between the grade in the referenced IID listing 
261  and the excipient grade being proposed. When referencing the IID for complex mixtures, 
262  including color additives, flavorings, and combinations of pre-existing excipients, a quantitative 
263  breakdown of the mixture is recommended so that individual excipients in the mixture may be 
264  easily referenced to IID listings.17 
                                                 
16 The safety of these components will be the subject of interdisciplinary review for INDs, NDAs, and ANDAs, and 
additional studies and safety justification may be requested. 
17 If Generally Recognized as Safe (GRAS) status or FDA food regulations are referenced in the application, 
supporting information should be provided that is relevant to the context of use of the drug product when the IID 
alone does not support the excipient and its level. When the submission is for an NDA, contact the specific drug 
 
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Draft  Not for Implementation 
265   
266  A.  INVESTIGATIONAL NEW DRUGS (INDs) 
267   
268  During the IND stage, excipients are reviewed for safety as appropriate for the phase of study. 
269  The IID may be consulted for evidence of previous use. In addition, any nonclinical or clinical 
270  studies conducted with the excipients or proposed clinical formulations submitted in the IND 
271  application are evaluated. An overall assessment of the appropriateness of excipients in the 
272  formulation is conducted by the review team and can be based on several factors, including, for 
273  example, total daily exposure, dosage form, route of administration, and patient population.  
274   
275  FDA encourages innovations in drug development during the IND stage, including use of novel 
276  excipients to address drug development problems and produce new drug products. The Agency 
277  recommends that sponsors have early discussions regarding formulations proposed for use in 
278  clinical trials.18 
279   
280  B.  NEW DRUG APPLICATIONS (NDAs) 
281   
282  As noted above, the IID is often used by applicants to help justify the levels of excipients in 
283  NDAs. An applicant may wish to use an excipient that is found in the IID, but at a higher level or 
284  in a different route of administration than listed in the IID. In such cases, the IID alone does not 
285  provide sufficient information to determine the safety of the proposed level of the excipient for 
286  the proposed route of administration, and the applicant should provide evidence of safety for the 
287  excipient in its NDA.19 
288   
289  C.  ABBREVIATED NEW DRUG APPLICATIONS (ANDAs) 
290   
291  The Agency evaluates each submitted ANDA individually to determine whether the ANDA can 
292  be received. The receipt of an ANDA means that the Agency made a threshold determination 
293  that the ANDA is substantially complete; that is, that the ANDA on its face is sufficiently 
294  complete to permit a substantive review.20 The excipients proposed in the ANDA are initially 
295  assessed during this filing review. For ANDA receipt, applicants can justify excipient levels by 
                                                 
products review division with questions. When the submission is for an ANDA, submit a controlled correspondence 
via email to GenericDrugs@fda.hhs.gov. For the definition of a controlled correspondence as well as the process to 
submit a controlled correspondence, see the draft guidance for industry Controlled Correspondence Related to 
Generic Drug Development. When final, this guidance will represent the FDAs current thinking on this topic. 
18 Sponsors are encouraged to follow FDAs guidance to industry Nonclinical Studies for the Safety Evaluation of 
Pharmaceutical Excipients (May 2005) in developing their safety rationale to support the use of novel excipients. To 
avoid subsequent delays in development programs, the use of any novel excipients should be noted in original INDs 
and subsequent amendments. 
19 Novel excipients should be addressed during the IND stage (see V.A Investigational New Drugs (INDs)). If the 
first appearance of a novel excipient is in an NDA, this is a cause for concern as it suggests that information has not 
been communicated to the Agency during clinical development and that subjects in a clinical trial may have been 
exposed to an unknown risk. As noted in section V.A. of this draft guidance (Investigational New Drugs (INDs)), 
early discussions during clinical development before use in clinical trials will facilitate a full safety evaluation of 
excipients before submission of an NDA. 
20 See 21 CFR 314.101(b)(1). 
 
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296  referencing the applicable current IID listing or submit a justification supporting the safety of the 
297  excipient at the proposed level.21 
298   
299  The multidisciplinary technical review of an ANDA includes evaluation of the acceptability of 
300  each excipient in the generic drug formulation. Although the IID currently provides only the 
301  maximum potency per dosage unit, during the technical assessment of an ANDA the MDE of 
302  excipients is considered for the proposed context of use. If evidence of safety for the appropriate 
303  route of administration cannot be determined by reference to the IID and any additional 
304  information submitted by the applicant, the Agency may request supporting safety information.22 
305   
306  VI.  QUESTIONS AND COMMUNICATIONS WITH FDA  
307   
308  The Agency welcomes input from IID users. Different FDA mailboxes are available depending 
309  on the subject of the communication. The IID Update mailbox was established to allow users to 
310  inform FDA of errors in the IID and to ask questions about IID listings. Questions about the 
311  preferred terms in the IID should be addressed to the GSRS mailbox. Questions related to the use 
312  of excipients in generic products under development should be addressed to OGD as Controlled 
313  Correspondence. A brief description of each of these mailboxes follows.  
314   
315  A.  IID Update Mailbox 
316   
317  The IID update mailbox can be contacted via email to IIDUpdate@FDA.HHS.GOV. This 
318  mailbox is used to receive questions about changes in the IID listings, reports of errors, requests 
319  for clarification of units or names, and other questions that are not application-specific. The 
320  inquiries are assigned to IID working group staff in the Office of Policy for Pharmaceutical 
321  Quality in the Office of Pharmaceutical Quality.  
322   
323  B.  GSRS Mailbox 
324   
325  The GSRS mailbox can be contacted via email to FDA-GSRS@FDA.HHS.GOV. This mailbox 
326  is used primarily for UNII requests, but also to communicate questions about specific UNIIs and 
327  other general GSRS questions such as the preferred term for an excipient listed in the IID. These 
328  inquiries are assigned to GSRS staff in the Office of Health Informatics.  
329   
330  C.  Controlled Correspondence 
331   
332  Controlled Correspondence should be submitted to OGD via email to 
333  GenericDrugs@FDA.HHS.GOV. Applicants preparing ANDAs may submit application-specific 
334  questions relating to drug development, including questions about the acceptability of excipient 
                                                 
21 When referencing an IID listing that differs from the proposed excipient in nomenclature, molecular weight, 
viscosity, or grade, applicants should provide justification for citing the IID listing as the basis for the excipient and 
its proposed level of use. 
22 A proposed drug product that contains an excipient that would require clinical investigations to establish safety of 
the excipient for use in a particular drug product would not be permitted in an ANDA, but may be submitted in a 
505(b)(2) application. See guidance for industry Determining Whether to Submit an ANDA or a 505(b)(2) 
Application.  
 
  9  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
335  levels, to the Agency as a Controlled Correspondence as recommended in the guidance for 
336  industry on Controlled Correspondence Related to Generic Drug Development. The Controlled 
337  Correspondence will be processed in accordance with current GDUFA timelines. If the response 
338  to a Controlled Correspondence is relevant to an original ANDA, applicants should include a 
339  copy of the response within the ANDA submission. 
  10