Considerations for Waiver 
Requests for pH Adjusters 
in Generic Drug Products 
Intended for Parenteral, 
Ophthalmic, or Otic Use  
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DRAFT GUIDANCE 
 
  This guidance document is being distributed for comment purposes only.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publication in the Federal Register of the notice announcing the availability of the draft 
guidance.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 Melissa Mannion (CDER) at 
Melissa.Mannion@fda.hhs.gov or 301-796-2747.  
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
April 2022 
Generic Drugs 
 
   
Considerations for Waiver 
Requests for pH Adjusters 
in Generic Drug Products 
Intended for Parenteral, 
Ophthalmic, or Otic Use  
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/guidance-compliance-regulatory-information/guidances-drugs  
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
 
April 2022 
Generic Drugs 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
TABLE OF CONTENTS 
 
 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 2 
A.  Statutory and Regulatory Provisions Regarding Inactive Ingredients in ANDAs  .................. 2 
B.  Waiver of Certain Regulatory Requirements for ANDAs ......................................................... 4 
III.  WAIVERS FOR pH ADJUSTERS IN GENERIC DRUGS INTENDED FOR 
PARENTERAL, OPHTHALMIC, OR OTIC USE MAY BE APPROPRIATE IN 
CERTAIN CIRCUMSTANCES ...................................................................................... 5 
A.  The Role of pH Adjusters .............................................................................................................. 6 
B.  A Q1 or Q2 Difference in pH Adjuster May Be Appropriate in an ANDA in Certain 
Circumstances ................................................................................................................................ 7 
IV.   INFORMATION FDA MAY CONSIDER WHEN EVALUATING A REQUEST 
FOR WAIVER FOR A pH ADJUSTER IN AN ANDA ................................................ 9 
V.  TIMING AND PROCESS FOR SUBMISSION AND FDA CONSIDERATION OF  
A 314.99(b) WAIVER REQUEST ................................................................................. 11 
A.  Process and Format for Requesting a Waiver ........................................................................... 11 
B.  Content of a Waiver Request ...................................................................................................... 12 
C.  Waiver Request Outcome ............................................................................................................ 13 
D.  Effect on Eligibility to Use Certain Approaches to Show Bioequivalence .............................. 13 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1  Considerations for Waiver Requests for pH Adjusters in Generic 
2  Drug Products Intended for Parenteral, Ophthalmic, or Otic Use 
3  Guidance for Industry1 
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 describes how FDA (the Agency, or we) intends to evaluate a request for a waiver, 
18  with regard to a pH adjuster, under 21 CFR 314.99(b) (hereinafter waiver) of the requirement in 
19  21 CFR 314.94(a)(9)(iii) and (iv) that a drug product intended for parenteral, ophthalmic, or otic 
20  use generally must contain the same inactive ingredients and in the same concentration as the 
21  reference listed drug identified by the applicant. This guidance also provides recommendations 
22  regarding the timing and process for requesting such a waiver of the requirement in  
23  314.94(a)(9)(iii) and (iv) (waiver request). 
24   
25  This guidance is intended to assist abbreviated new drug application (ANDA)2 applicants that 
26  reference a reference listed drug (RLD) intended for parenteral, ophthalmic, or otic use but are 
27  seeking approval of a drug that is qualitatively (Q1) different or quantitatively (Q2) different3 
28  from the RLD with respect to a pH adjuster(s).4 This guidance is intended to identify the type of 
29  information FDA may generally consider in evaluating a waiver request for pH adjusters in 
30  generic drug products intended for parenteral, ophthalmic, or otic use and provide 
31  recommendations to ANDA applicants regarding the submission and content of such a waiver 
32  request.  
33   
 
1 This guidance has been prepared by the Office of Generic Drugs in the Center for Drug Evaluation and Research at 
the Food and Drug Administration.  
2 See section 505(j) of the FD&C Act. 
3 OGD interprets quantitative sameness to mean a concentration that is within 95-105% of the reference listed drug 
concentration. That is, sameness as discussed herein does not suggest an exact value, but rather a range of values. 
4 There may be circumstances where a proposed difference in pH adjuster is not acceptable in an ANDA. Examples 
of such circumstances are discussed further in section III.B. below.   
  1  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
34  The recommendations in this guidance are limited to inactive ingredients in ANDAs that adjust 
35  the pH of a drug product intended for parenteral, ophthalmic, or otic use, and do not apply to 
36  other inactive ingredients.5   
37   
38  The contents of this document do not have the force and effect of law and are not meant to bind 
39  the public in any way, unless specifically incorporated into a contract. This document is intended 
40  only to provide clarity to the public regarding existing requirements under the law. FDA 
41  guidance documents, including this guidance, should be viewed only as recommendations, unless 
42  specific regulatory or statutory requirements are cited. The use of the word should in FDA 
43  guidance means that something is suggested or recommended, but not required. 
44   
45   
46  II.  BACKGROUND 
47   
48  The Drug Price Competition and Patent Restoration Act of 1984, commonly referred to as the 
49  Hatch-Waxman Amendments, created a statutory ANDA pathway by amending section 505 of 
50  the Federal Food, Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. 355).6 To obtain approval, 
51  the ANDA applicant generally must show, among other things, that the proposed generic drug 
52  product (1) has the same active ingredient(s), dosage form, route of administration, strength, 
53  conditions of use, and, with certain exceptions, labeling as the RLD; and (2) is bioequivalent to 
54  the RLD.7  
55   
56  A.  Statutory and Regulatory Provisions Regarding Inactive Ingredients in ANDAs  
57   
58  The FD&C Act does not require an ANDA product to have the same inactive ingredients as the 
59  RLD.8  Section 505(j)(4)(H) of the FD&C Act does, however, state that an ANDA shall not be 
60  approved: 
61   
62   . . . if information submitted in the application or any other information available to the 
63  Secretary shows (i) the inactive ingredients of the drug are unsafe for use under the 
64  conditions prescribed, recommended, or suggested in the labeling proposed for the drug, 
65  or (ii) the composition of the drug is unsafe under such conditions because of the type or 
66  quantity of inactive ingredients included or the manner in which the inactive ingredients 
67  are included.9  
68   
69  The Agency has interpreted section 505(j)(4)(H) of the FD&C Act as permitting the Agency to 
70  deny approval of an ANDA if there is a reasonable basis to conclude that its inactive ingredients 
71  or composition raise serious questions about the drugs safety.10 In its implementing 
 
5 The scientific principles described in this draft guidance may be relevant, in certain circumstances, to requests to 
use an in vitro approach to demonstrate bioequivalence (BE) for a proposed generic product intended for parenteral, 
ophthalmic, or otic use that is not Q1 or Q2 the same as the RLD. FDA encourages an applicant who proposes such 
a product that is not Q1 or Q2 the same as the RLD with respect to a pH adjuster(s), to contact the Agency to discuss 
its proposed approach to establish BE for its proposed drug product. 
6 Public Law 98-417 (Sept. 24, 1984). 
7 See generally, 21 CFR 314.94(a). 
8 See section 505(j)(2)(A) of the FD&C Act (setting forth the required contents of an ANDA). 
9 Section 505(j)(4)(H) of the FD&C Act. 
10 21 CFR 314.127(a)(8)(ii); 54 FR 28871 at 28903 (July 10, 1989).  
  2  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
72  regulations, FDA explicitly noted that FDA may identify changes in inactive ingredients that 
73  may adversely affect a drug products safety or efficacy based on the Agencys experience 
74  with reviewing inactive ingredients and other information available to it.11 In its regulations, the 
75  Agency has also provided non-exhaustive examples of changes in inactive ingredients in 
76  proposed generic drug products that may raise serious questions of safety,12 including, for 
77  example: 
78   
79    A change in an inactive ingredient so that the product does not comply with an 
80  official compendium;13 
81   
82    A change in composition to include an inactive ingredient that has not been 
83  previously approved in a drug product for human use by the same route of 
84  administration;14 
85   
86    A change in the composition of a parenteral drug product to include an inactive 
87  ingredient that has not been previously approved in a parenteral drug product;15 
88   
89    A change in composition of a drug product for ophthalmic use to include an inactive 
90  ingredient that has not been previously approved in a drug for ophthalmic use;16 and 
91   
92    A change in composition to include a significantly greater content of one or more 
93  inactive ingredients than previously used in the drug product.17 
94   
95  The regulations at  314.94(a)(9)(iii) and (iv), with parallel provisions in the approval 
96  regulations at 21 CFR 314.127(a)(8)(ii)(B) and (C), further specify that FDA will consider an 
97  inactive ingredient in, or the composition of, a generic drug product intended for parenteral, 
98  ophthalmic, or otic use to be unsafe and will refuse to approve the ANDA unless the generic 
99  drug product contains the same inactive ingredients (with certain listed exceptions) in the same 
100  concentration as the RLD.18 These regulations also identify permissible differences in certain 
101  inactive ingredients for drug products intended for parenteral, ophthalmic, or otic use, commonly 
102  referred to as exception excipients, if the ANDA contains sufficient information to 
103  demonstrate that any differences do not affect the safety or efficacy of the drug product; for 
104  example: 
105   
 
11 21 CFR 314.127(a)(8)(ii)(A). 
12 See 54 FR 28871 at 28902 (discussing FDAs interpretation of section 505(j)(3)(H) (now 505(j)(4)(H)) of the 
FD&C Act in the context of proposed rule 314.127 on the refusal to approve ANDAs). 
13 21 CFR 314.127(a)(8)(ii)(A)(1). 
14 21 CFR 314.127(a)(8)(ii)(A)(2). 
15 21 CFR 314.127(a)(8)(ii)(A)(3). 
16 21 CFR 314.127(a)(8)(ii)(A)(4). 
17 21 CFR 314.127(a)(8)(ii)(A)(6). 
18 In evaluating drug product formulation and inactive ingredients, an ANDA applicant should compare its proposed 
generic drug to the RLDs formulation, not the formulation of the reference standard (where the reference standard 
is not the RLD). See FDA guidance for industry Referencing Approved Drug Products in ANDA Submissions 
(October 2020). We update guidances periodically. For the most recent version of a guidance, check the FDA 
guidance web page at https://www.fda.gov/regulatory-information/search-fda-guidance-documents. 
  3  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
106    Drug products intended for parenteral use generally must contain the same inactive 
107  ingredients in the same concentration as the RLD; however, an applicant may seek 
108  approval of a drug product intended for parenteral use that differs from the RLD in 
109  preservative, buffer, or antioxidant provided that the applicant identifies and characterizes 
110  the differences and provides information demonstrating that the differences do not affect 
111  the safety or efficacy of the proposed drug product.19  
112   
113    Drug products intended for ophthalmic or otic use generally must contain the same 
114  inactive ingredients in the same concentration as the RLD; however, an applicant may 
115  seek approval for a drug product intended for ophthalmic or otic use that differs from the 
116  RLD in preservative, buffer, substance to adjust tonicity, or thickening agent provided 
117  that the applicant identifies and characterizes the differences and provides information 
118  demonstrating that the differences do not affect the safety or efficacy of the proposed 
119  drug product.20   
120   
121  When proposing these regulations, the Agency provided a brief discussion for its reasoning in 
122  implementing the inactive ingredient requirements for drug products intended for parenteral, 
123  ophthalmic, or otic use: 
124   
125  [E]ach parenteral, ophthalmic, and otic drug product represents an individual 
126  pharmaceutical system with its own characteristics and requirements. In the formulation 
127  of parenteral drug products, certain added substances are used to maintain solubility, 
128  stability, sterility, and to increase patient comfort (i.e., by adjusting toxicity[sic] and 
129  reducing tissue irritation). Added substances selected for parenteral drug products must 
130  be known to be of the highest quality, must be known to not interfere with the therapeutic 
131  effectiveness of the product and must be known to be nontoxic in the quantities used. The 
132  sensitivity of inactive ingredients in parenteral drug products is reflected in regulations 
133  under 21 CFR 201.100 which require that certain added substances and their 
134  concentrations be listed on the label of the product. Similarly, added substances are used 
135  in the formulation of products intended for ophthalmic and otic use such as buffers, 
136  antimicrobial preservatives, chemicals to adjust toxicity [sic], and thickening agents.21 
137   
138  B.  Waiver of Certain Regulatory Requirements for ANDAs 
139   
140  When FDA updated its new drug regulations in the 1980s, the Agency promulgated a waiver 
141  provision intended to give applicants flexibility to seek alternative ways of complying with the 
142  statutory standards for drug approval.22 FDA has since codified a waiver provision applicable to 
143  ANDAs at 21 CFR 314.99(b),23 under which an applicant may ask FDA to waive under this 
 
19 See 21 CFR 314.94(a)(9)(iii); see also 21 CFR 314.127(a)(8)(ii)(B). 
20 See 21 CFR 314.94(a)(9)(iv); see also 21 CFR 314.127(a)(8)(ii)(C). The regulations also specify that for products 
intended for ophthalmic use, an applicant may not change a buffer or substance to adjust tonicity for the purpose of 
claiming a therapeutic advantage over or difference from the RLD. See 21 CFR 314.94(a)(9)(iv). 
21 See 54 FR 28872 at 28883 (July 10, 1989) (emphasis added). Both references to adjusting toxicity appear to be 
an inadvertent error for adjusting tonicity. 
22 See 47 FR 46622 at 46637-38 (Oct. 19, 1982). 
23 See 54 FR 28872 at 28889 (Jul. 10, 1989) (proposing to retain the current requirement under  314.90 under 
which an applicant may obtain a waiver of requirements for the submission of information in an application. The 
 
  4  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
144  section any requirement that applies to the applicant under 314.92 through 314.99. As described 
145  in  314.99(b), the applicant must comply with the requirements for a waiver under 21 CFR 
146  314.90 and FDA may grant a waiver if it finds one of the following: 
147   
148  (1) The applicants compliance with the requirement is unnecessary for the agency to 
149  evaluate the [A]NDA or compliance cannot be achieved; 
150   
151  (2) The applicants alternative submission satisfies the requirement; or 
152   
153  (3) The applicants submission otherwise justifies a waiver.24 
154   
155  Even if FDA grants a waiver of a requirement in  314.92 through  314.99 in a particular 
156  application, the application still must meet all applicable statutory requirements for approval.25   
157  If FDA grants the applicants waiver request with respect to a requirement under  314.92 
158  through  314.99, the waived requirement will not constitute a basis for refusal to approve an 
159  ANDA under  314.127.26   
160   
161   
162  III.  WAIVERS FOR pH ADJUSTERS IN GENERIC DRUGS INTENDED FOR 
163  PARENTERAL, OPHTHALMIC, OR OTIC USE MAY BE APPROPRIATE IN 
164  CERTAIN CIRCUMSTANCES 
165   
166  Over time there has been increased interest in and questions about waivers of the applicable 
167  inactive ingredient requirements for pH adjusters in ANDAs. FDAs current thinking is that pH 
168  adjusters function in such a way that, in some circumstances, a waiver of the inactive ingredient 
169  requirements in  314.94(a)(9)(iii)-(iv) for a pH adjuster in a generic drug product intended for 
170  parenteral, ophthalmic, or otic use may be appropriate. In particular, how pH adjusters function 
171  or react in some formulations support the possibility that there may be circumstances where 
172  certain differences in pH adjusters in an ANDA as compared to the RLD may be scientifically 
173  appropriate and acceptable in an ANDA, as described in more detail below.  
174   
175  Accordingly, FDA believes that permitting such differences to pH adjusters through a waiver 
176  under  314.99(b), as appropriate, is one way the waiver provision may enable flexibility in how 
177  a particular applicant meets the statutory standards for approval. Determining whether a 
178  particular difference in pH adjuster as compared to the RLD is scientifically acceptable and 
 
applicable sections are those set forth under new proposed Subpart C. FDA may not, however, waive statutory 
requirements). 
24 See 21 CFR 314.99(b) (citing 21 CFR 314.90(b)). 
25 For example, when an ANDA applicant seeks approval for a parenteral formulation that is the same as that 
previously (but not currently) marketed for the RLD, FDA has determined that, in appropriate circumstances, 
pursuant to 21 CFR 314.99(b), it may waive the requirement in the regulation that the inactive ingredients in a 
parenteral drug product approved under an ANDA be the same as those in the RLD (except for preservatives, 
buffers, and antioxidants), as long as the statutory requirement regarding safety of inactive ingredients has been met. 
See section 505(j)(4)(H) of the FD&C Act. In determining whether to grant such a waiver, the Agency considers, 
among other things, whether the previously marketed formulation was discontinued for reasons of safety or 
effectiveness. See, e.g., letter from Janet Woodcock to Steven H. Sklar and Peter O. Safir (November 7, 2012), 
Docket Nos. FDA2011-P-0339 and FDA-2012-P-0507. 
26 See 21 CFR 314.99(b). 
  5  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
179  appropriate in an ANDA is a fact-specific assessment within the context of a specific application 
180  and a specific  314.99(b) waiver request. As noted in the preceding section, an application for 
181  which FDA grants a waiver must still meet all applicable requirements for approval.  
182   
183  A.  The Role of pH Adjusters 
184   
185  The primary function of a pH adjuster, which is commonly an acid or base, is to change the 
186  equilibrium concentration of hydronium ions in solution (i.e., the pH). In general, the greater the 
187  concentration of hydronium ions in solution, the lower the pH value, which is measured on a 
188  logarithmic scale. For example, in an aqueous solution (H O), the balance of hydronium ions 
2
189  (H O+) and hydroxide ions (OH-) determines whether the pH of the solution is acidic ([H O+] > 
3 3
190  [OH-]), basic ([H O+] < [OH-]), or neutral ([H O+] = [OH-]). As the pH adjuster role is to change 
3 3
191  the equilibrium concentration of hydronium ions in solution, the pH value is routinely used as a 
192  surrogate to control the amount of pH adjuster added. For example, the amount of hydrochloric 
193  acid (HCl) pH adjuster added to an aqueous solution generates an equivalent amount of 
194  hydronium and chloride ions. Therefore, a measure of the hydronium ion concentration (i.e., pH) 
195  is correlated to the amount of HCl added:  
196   
197  HCl + H O    H O+ + Cl- 
2 3
198   
199  In FDAs experience reviewing applications for drug products intended for parenteral, 
200  ophthalmic, or otic use, pH adjusters are typically used on an as-needed basis to achieve a 
201  specified pH range in the drug product. These drug products often express the quantity of pH 
202  adjuster used as quantum satis (q.s.), which means the quantity added is as much or as little 
203  (which may be none) as necessary to achieve a specified pH range for any given batch of drug 
204  product. Thus, this specified pH range of the drug product is the primary aim, and the amount of 
205  pH adjuster used to achieve the pH of the drug product is adjusted accordingly.   
206   
207  In cases where a formulation contains other ingredients that may act as a buffer, pH adjusters 
208  react with and may function as part of the buffer system to control the pH. In general, a buffer 
209  system is composed of a weak acid that is in equilibrium with its conjugate base, or vice versa.  
210  A buffer can be created in various ways; for example, by adding defined ratios of the weak acid 
211  and conjugate base or by adding a pH adjuster to convert some of the weak acid into the 
212  conjugate base. Thus, a pH adjuster can become an indistinguishable part of the buffer. For 
213  example, an acetic acid (CH COOH) sodium acetate (CH COONa) buffer may be created by 
3 3
214  mixing a ratio of these two ingredients in solution or by adding a sodium hydroxide (NaOH) pH 
215  adjuster to acetic acid. In solution, the buffer component species (i.e., acetic acid and sodium 
216  acetate) and pH adjuster (i.e., sodium hydroxide) are not distinguishable species, but the ionic 
217  species (i.e., sodium ion) and the buffer system containing the weak acid (i.e., acetic acid) and its 
218  conjugate base (i.e., acetate) are. Regardless of the components used in creating the buffer, the 
219  equilibrium of these species in the solution is dependent on the pH of the drug product:   
220   
221  CH COONa + H O    Na+ + CH COO- + H O 
3 2 3 2
222   
223  Na+ + CH COO- + H O   CH COOH + Na+ + OH- 
3 2 3
224   

  6  Contains Nonbinding Recommendations 
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225  Buffers are considered exception excipients in drug products intended for parenteral, 
226  ophthalmic, or otic use, meaning that a Q1 or Q2 difference is permitted, provided that the 
227  ANDA applicant identifies and characterizes the difference and provides information 
228  demonstrating that the difference does not affect the safety or efficacy of the proposed drug 
229  product.27 In some instances, where a drug product intended for parenteral, ophthalmic, or otic 
230  use lists a pH adjuster separate from a buffer, the pH adjuster may act as part of the buffer 
231  system, but will nonetheless be treated as a pH adjuster, a non-exception excipient.  
232   
233  In achieving its intended purpose (i.e., adjusting the pH), a pH adjuster may also interact with 
234  components in the formulation to form a salt. For example, a simple neutralization reaction as 
235  shown below can occur where a base inactive ingredient (XOH) is neutralized by adding 
236  hydrochloric acid (HCl), which may also be used as a pH adjuster, to form the salt of the inactive 
237  ingredient (XCl) and water:  
238   
239  HCl + XOH   XCl + H O   
2
240   
241  Notably, the same chemical composition can be achieved through different routes (e.g., in the 
242  prior example, the same result could also be achieved by adding XCl to H O).28   
2
243   
244   
245  B.  A Q1 or Q2 Difference in pH Adjuster May Be Appropriate in an ANDA in 
246  Certain Circumstances  
247   
248  The Agencys experience with pH adjusters, coupled with the specific role pH adjusters 
249  generally play in drug formulations, support the conclusion that in certain circumstances it may 
250  be appropriate for FDA to consider a waiver to permit a Q1 or Q2 difference in a pH adjuster(s) 
251  in a generic drug product intended for parenteral, ophthalmic, or otic use.    
252   
253  The Agency has approved many new drug applications for RLDs intended for parenteral, 
254  ophthalmic, or otic use where the applicant specifies the amount of pH adjuster used as q.s.  
255  Where an RLD is approved with a q.s. amount of pH adjuster, it is possible for a relative amount 
256  of pH adjuster added to a specific batch of the RLD to differ from batch to batch, based on the 
257  amount of pH adjuster needed to achieve the specified pH or pH range for a particular RLD 
258  batch. In approving an application under these circumstances, the Agency has determined as a 
259  scientific matter that the acceptability of the finished product (containing the as-needed amount 
260  of the pH adjuster) is assured by controlling the drug products physicochemical characteristics 
261  (e.g., pH, osmolality, viscosity). In some instances, the use and amount of pH adjuster between 
262  batches of the RLD may exceed 5% while not changing the drug products final attributes in an 
263  unacceptable manner (e.g., changing the pH or physicochemical characteristics that may be 
264  critical to the drug products performance) or affecting the safety or efficacy of the RLD. Thus, 
 
27 See 21 CFR 314.94(a)(9)(iii), (iv); see also 21 CFR 314.127(a)(8)(ii)(B), (C). 
28 An ingredient that solely acts to convert an active ingredient (e.g., from a base form to a salt form) during 
manufacturing of the drug product is not considered an inactive ingredient (because it becomes part of the active 
ingredient) and is therefore outside of the intended scope of this guidance, which concerns the requirements for 
inactive ingredients in drug products intended for parenteral, ophthalmic, or otic use. 
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Draft  Not for Implementation 
265  wide ranges in the amount of pH adjuster may be acceptable provided that the drug products 
266  final attributes are adequately controlled. 
267   
268  Applying these scientific principles to instances where the RLD is approved with a fixed amount 
269  of pH adjuster, FDA has also concluded that there may be circumstances where an ANDA 
270  applicant can establish that a greater than 5% difference in the amount of pH adjuster in an 
271  ANDA product compared to the RLD would not change the proposed drug products final 
272  attributes in an unacceptable manner (e.g., changing the pH or physicochemical characteristics 
273  that may be critical to the drug products performance) or cause the drug product to not meet the 
274  statutory standards for approval of an ANDA.29 For example, an ANDA applicant may choose to 
275  submit, and the Agency will review and consider, a waiver request to use an amount of a pH 
276  adjuster that is more than 5% higher than the amount contained in the RLD. In such a 
277  circumstance, a waiver request under  314.99(b) should include supportive information to 
278  scientifically justify the difference in pH adjuster. For instance, with respect to the safety of a 
279  proposed quantitative difference in pH adjuster, an applicant may include supportive information 
280  from the Inactive Ingredients Database (IID),30 and/or other information as needed, as part of its 
281  scientific justification for the difference in pH adjuster.  
282   
283  It is also notable that RLD application holders for drug products intended for parenteral, 
284  ophthalmic, or otic use may elect to include in their composition tables one or multiple pH 
285  adjusters, which are used on an as-needed basis. Thus, although included in the composition 
286  table, a pH adjuster(s) may, or may not, be present in a given RLD batch. For example, an RLD 
287  application holder may indicate in a composition table that pH adjuster A and/or B may be 
288  used q.s. Under this scenario, only pH adjuster A, only pH adjuster B, both pH adjusters, or 
289  neither pH adjuster may be included in any given RLD batch.    
290   
291  The scientific principle underlying this practice for an RLD may also support the conclusion that 
292  the omission or addition of a pH adjuster in an ANDA product referencing such an RLD, like the 
293  omission or addition of an exception excipient enumerated in  314.94(a)(9)(iii) and (iv),  may, 
294  in certain circumstances, not change the ANDAs final attributes in an unacceptable manner 
295  (e.g., change the pH or physicochemical characteristics that may be critical to the drug products 
296  performance). In such case, such a change might be permissible in an ANDA if a waiver is 
297  requested and granted and as long as the drug product meets the standards for approval of an 
298  ANDA.31 For example, an ANDA applicant may choose to submit, and the Agency will review 
299  and consider, a waiver request to use a pH adjuster that has been previously used in an approved 
300  drug product for the same route of administration32 but that is not used in the RLD. In such a 
301  circumstance, a waiver request under  314.99(b) should include supportive information to 
302  scientifically justify the difference in pH adjuster. For instance, with respect to the safety of a 
303  proposed qualitative difference in pH adjuster, an applicant may include supportive information 
 
29 See infra Part IV (providing recommendations on the type of information that can be submitted to support a 
waiver request, including information showing that the Q1 or Q2 difference does not affect safety or efficacy). 
30 See id; see also FDAs draft guidance for industry Using the Inactive Ingredient Database (July 2019). When 
final, this guidance will represent FDAs current thinking on this topic. 
31 See infra Part IV (discussing the type of information that can be submitted to support a waiver request, including 
information showing that the Q1 or Q2 difference does not affect safety or efficacy). 
32 See, e.g., 21 CFR 314.127(a)(8)(ii)(A)(2), (3), (4). 
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304  from the IID, and/or other information as needed, as part of its scientific justification for the 
305  difference in pH adjuster.  
306   
307  It is important to note, however, that determining the acceptability of any particular difference in 
308  pH adjuster is a fact-specific inquiry based on the circumstances of a particular application. 
309  There are differences that will likely not be acceptable for an ANDA and thus FDA would deny 
310  a waiver request submitted for such differences. For instance, FDA will deny a waiver request if 
311  the difference in pH adjuster: forms a different form of the active ingredient than the RLD in the 
312  final product; or uses or forms a novel inactive ingredient in the final product that has not been 
313  used in an FDA-approved drug product, the safety of which cannot be established without 
314  clinical testing. These types of pH adjuster differences are not appropriate for an ANDA. In 
315  addition, FDA may deny a waiver request if the difference in pH adjuster impacts the physical or 
316  chemical properties critical to the performance of the product or where those property changes 
317  raise potential safety concerns. For example, there may be potential safety concerns where an 
318  ANDA uses a different pH adjuster to the RLD, and that difference gives rise to either a new 
319  counter-ion species not present in the RLD or a different concentration of the counter-ion species 
320  than the RLD. Additionally, a change in counter-ion concentration or species may impact the 
321  physicochemical properties of complex formulations, which may alter the performance of the 
322  drug product in ways that may not be appropriate for approval in an ANDA (e.g., final pH is 
323  different from the pH listed by the RLD). 
324   
325   
326  IV.   INFORMATION FDA MAY CONSIDER WHEN EVALUATING A REQUEST 
327  FOR WAIVER FOR A pH ADJUSTER IN AN ANDA 
328   
329  As described above, in certain cases, a proposed Q1 or Q2 difference in a pH adjuster(s) in a 
330  generic drug product intended for parenteral, ophthalmic, or otic use may be acceptable in an 
331  ANDA. The general principles discussed in Section III above regarding the role pH adjusters 
332  play may support a waiver of the Q1 requirement when an ANDA applicant seeks to omit a pH 
333  adjuster, add a pH adjuster, or use a different pH adjuster compared to the RLD; and/or a waiver 
334  of the Q2 requirement when the RLD has specified a fixed quantity for a pH adjuster and an 
335  ANDA applicant seeks to use a different quantity. If an ANDA applicant believes it is 
336  appropriate to seek approval for a product with such a difference from its RLD, the ANDA 
337  applicant should submit a waiver request under  314.99(b) to support the proposed difference.33  
338  However, as noted above, there may be instances where certain differences in pH adjuster may 
339  not be appropriate in an ANDA. To assist FDA in evaluating whether a waiver request for a pH 
340  adjuster in an ANDA intended for parenteral, ophthalmic, or otic use is appropriate, FDA 
341  recommends that applicants provide certain information, described below. 
342   
343  To support a waiver request, FDA recommends that applicants submit information about a 
344  proposed products physicochemical characterization. Physicochemical characterization 
 
33 Where an RLD denotes the pH adjuster quantity used as q.s., the Agency has determined that the RLD is safe and 
effective despite the fact that the amount of pH adjuster used may vary, as needed, from batch to batch. Under 
FDAs current practice, an ANDA that relies on such an RLD can propose to use a q.s. or a fixed amount of the 
same pH adjuster, which FDA will generally consider to be Q2 same with respect to the pH adjuster, such that a 
waiver request with respect to that pH adjuster would not be necessary.  
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345  information might be included in an ANDA generally to identify essential physical and chemical 
346  properties of a product that may be critical to its performance. Physicochemical characterization 
347  information may also be submitted in support of a  314.99(b) waiver request. Scientific 
348  advances have enhanced the accuracy and sensitivity of physicochemical characterization, and 
349  such characterization may be useful in evaluating the effect, if any, of a difference in pH adjuster 
350  on the performance of a proposed generic drug product compared to its RLD.  
351   
352  For example, as discussed above, comparative pH can be used to support similar hydronium 
353  concentrations between the RLD and generic drug product, which helps to ensure a similar 
354  physicochemical environment including any protonation and/or deprotonation of other 
355  ingredients in the formulation. In addition, comparative buffer capacity can be used to support 
356  similar capacities to resist changes in pH between the RLD and generic drug product, which 
357  helps to ensure that the generic drug product has a similar physicochemical environment as the 
358  RLD, and that drug product stability for the proposed generic drug product is not affected.  
359  Comparative osmolality can be used to support similar total solute concentrations between the 
360  RLD and generic drug product, which helps to ensure the safety and stability of the drug product.  
361  Further, for some complex formulations, comparative viscosity34 and electrophoretic mobility 
362  can be used to support similar concentrations of charged species between the RLD and generic 
363  drug product, which helps to ensure drug product quality. Similarly, in vivo or in vitro studies 
364  showing comparable active ingredient release rates between the RLD and generic drug product 
365  can be used to support a waiver concluding that differences in type or amounts of pH adjuster 
366  between the RLD and generic drug product will not preclude approval of the proposed product in 
367  an ANDA. 
368   
369  In addition to information regarding physicochemical characterization, other information 
370  regarding the safety of a proposed difference in pH adjuster may be relevant to assess whether a 
371  waiver for a pH adjuster difference in an ANDA would be appropriate. For example, if the 
372  generic drug product proposes to contain a different pH adjuster or a higher amount of pH 
373  adjuster than that used in the RLD, then the Agency recommends that the ANDA applicant, at a 
374  minimum, include in support of its waiver request information showing that (1) the proposed pH 
375  adjuster has been used in drug products previously approved by FDA for the same route of 
376  administration, and (2) the amount of pH adjuster used can be considered safe based on the 
377  amount of that pH adjuster in previously approved drug products for the same route of 
378  administration.   
379   
380  In summary, the Agency recommends applicants consider submitting the following types of 
381  information for the proposed generic drug product and its RLD to assist FDA in evaluating a 
382  waiver request for a difference in pH adjuster in a proposed ANDA intended for parenteral, 
383  ophthalmic, or otic use (more or less information may be necessary depending on the proposed 
384  difference):35   
 
34 Because viscosity may be an important attribute that governs availability of the drug at the site of action, 
comparable viscosity can support a showing that differences in pH adjuster between the generic drug product and its 
RLD should not affect BE. 
35 For example, in general, the information that would be recommended to support a waiver request for a solution 
may be less extensive than the information recommended to support a waiver request for a suspension, gel, or 
emulsion.  
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385   
386    Comparative pH, buffer capacity, or both (where applicable). 
387   
388    Comparative osmolality. 
389   
390    Comparative viscosity. 
391   
392    Comparative electrophoretic mobility. 
393   
394    Comparative concentration of the pH adjuster ingredient being reacted with to form the 
395  new salt or free base/acid species,36 including data or information that demonstrates that 
396  the new salt or free base/acid species does not affect the safety of the proposed drug 
397  product, for example, reference to the IID. 
398   
399    Other comparative physicochemical data (e.g., which may support the use of pH adjusters 
400  in concentrations greater than 5% of the amount used in the RLD). 
401   
402    Data or information that demonstrates that the difference in the amount of pH adjuster, 
403  the number or identity of pH adjusters, or both (as applicable) between the proposed drug 
404  product and its RLD does not affect the safety of the proposed drug product, including, 
405  for example, reference to the IID. 
406   
407    Data or information that demonstrates that the difference in the amount of pH adjuster or 
408  the number or identity of pH adjusters between the proposed drug product and its RLD 
409  does not affect bioequivalence (BE). For example, pharmacokinetic data from in vivo BE 
410  studies for non-solution products or in vitro release testing data from in vitro BE studies. 
411   
412   
413  V.  TIMING AND PROCESS FOR SUBMISSION AND FDA CONSIDERATION OF 
414  A 314.99(b) WAIVER REQUEST 
415   
416  A.  Process and Format for Requesting a Waiver  
417   
418  FDA recommends that an ANDA applicant developing a proposed drug product intended for 
419  parenteral, ophthalmic, or otic use submit a controlled correspondence37 requesting an evaluation 
420  of the proposed formulation and the RLD. If the response to the controlled correspondence 
421  indicates that the proposed formulation does not meet the inactive ingredient requirements 
422  applicable to the product, and the ANDA applicant believes that this failure to meet such 
423  requirements is due to a difference in pH adjuster(s), the ANDA applicant may consider 
424  submitting a  314.99(b) waiver request to support the pH adjuster difference in its ANDA 
425  submission.   
426   
 
36 The formation of a new salt or free base/acid species discussed here does not include a new salt or free base/acid 
species of the active ingredient(s). 
37 See FDAs guidance for industry Controlled Correspondence Related to Generic Drug Development (December 
2020).   
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427  If an ANDA applicant chooses to submit its ANDA without utilizing the controlled 
428  correspondence process and believes its formulation may not meet the inactive ingredient 
429  requirements in  314.94(a)(9)(iii)-(iv) with respect to one or more pH adjusters, FDA 
430  recommends such ANDA applicant submit a  314.99(b) waiver request with the ANDA.  
431   
432  In accordance with  314.99(b) (by reference to 21 CFR 314.90(a)), the waiver request and its 
433  supporting documentation must be submitted in an ANDA, or in an amendment or supplement to 
434  an ANDA (hereinafter referred to as an ANDA submission) where appropriate (e.g., an 
435  amendment or supplement seeking to change the drug product formulation). The Agency will 
436  refuse to receive an ANDA for a proposed product intended for parenteral, ophthalmic, or otic 
437  use that contains a Q1 or Q2 difference in pH adjuster compared to its RLD but does not include 
438  a waiver request.38  In addition, FDA does not consider an inquiry about a waiver request via 
439  controlled correspondence or pre-ANDA meeting request to constitute a waiver request. FDA 
440  will not consider a waiver request unless the request and the accompanying documentation are 
441  included in an ANDA submission, consistent with the requirements of  314.90 and  314.99(b).  
442   
443  FDA recommends that an ANDA submission containing a waiver request prominently identify in 
444  the cover letter to the submission in Module 1 of the Common Technical Document that a waiver 
445  request is included.39  FDA recommends that applicants submit the waiver request in the module, 
446  section, and subsection of the ANDA submission that would otherwise address the regulatory 
447  requirement for which the waiver request is being submitted.40  For additional recommendations 
448  about the information that should be ordinarily submitted in the applicable modules, sections, 
449  and subsection of ANDA submissions, please consult FDAs guidance for industry ANDA 
450  SubmissionsContent and Format (June 2019). 
451   
452  B.  Content of a Waiver Request 
453   
454  As noted above, a waiver request must be submitted (with supporting documentation) in an 
455  ANDA submission.41  Under the applicable regulations, a waiver request must contain at least 
456  one of the following: 
457   
458  (1) An explanation why the applicants compliance with the requirement is unnecessary or 
459  cannot be achieved; 
460   
461  (2) A description of an alternative submission that satisfies the purpose of the requirement; or 
462   
463  (3) Other information justifying a waiver.42 
464   
 
38 See 21 CFR 314.94(a)(9)(iii), (iv); see also FDAs guidance for industry ANDA SubmissionsRefuse-to-Receive 
Standards (December 2016) at Part V.A.2. (discussing product quality deficiencies for changes to non-exception 
inactive ingredients in drug products intended for parenteral, ophthalmic, or otic use). 
39 See FDAs revised guidance for industry Providing Regulatory Submissions in Electronic FormatCertain 
Human Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications (January 
2019) for more information on the contents of Module 1 of the Common Technical Document.  
40 Id. 
41 See 21 CFR 314.99(b) (referencing 314.90(a)). 
42 See 314.90(a). 
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465  To ensure the Agency is clear on which information in the ANDA submission is intended to 
466  support the waiver request, FDA recommends applicants include the following information in 
467  the ANDA submission cover letter in the section that specifically discusses the waiver request:  
468   
469    Relevant RLD(s), as applicable, including application number, proprietary (brand) name, 
470  manufacturer, active ingredient, dosage form, and strength(s);  
471   
472    Statement describing the Q1 or Q2 difference in pH adjuster for which the applicant is 
473  requesting waiver of the applicable regulatory requirement;   
474   
475    Summary of the type of information submitted to support the waiver request; and 
476   
477    Identification of the module, section, and subsection of the ANDA submission that 
478  contains the waiver request and the information submitted to support the waiver request.  
479   
480  C.  Waiver Request Outcome  
481   
482  The Agency may grant a waiver request if it finds one of the following: 
483   
484  (1) The applicants compliance with the requirement is unnecessary for the Agency to 
485  evaluate the ANDA or compliance cannot be achieved; 
486   
487  (2) The applicants alternative submission satisfies the requirement; or 
488   
489  (3) The applicants submission otherwise justifies a waiver.43 
490   
491  The acceptability of a waiver request will be determined during the scientific review of an 
492  ANDA. FDA will inform applicants of the Agencys decision regarding a waiver request when 
493  FDA acts on the ANDA containing the waiver request.44   
494   
495  D.  Effect on Eligibility to Use Certain Approaches to Show Bioequivalence 
496   
497  FDA recognizes that where an ANDA applicant wishes to seek a waiver of the inactive 
498  ingredient requirements at  314.94(a)(9)(iii) or (iv) for a Q1 or Q2 difference in pH adjuster 
499  compared to its RLD, that applicant might also seek to utilize an in vitro approach to 
500  demonstrate BE. However, if FDA grants a waiver for an ANDAs Q1 or Q2 difference in pH 
501  adjuster, then that ANDA product necessarily does not contain the same inactive ingredients in 
502  the same concentration as its RLD. Thus, such an ANDA product would not be eligible under 21 
503  CFR 320.22(b)(1) for a waiver of evidence of in vivo BE. Under 21 CFR 320.24(b)(6), however, 
504  an approach deemed adequate by FDA to ... establish bioequivalence may be utilized to 
505  establish BE of a drug product where scientifically appropriate. FDA encourages an applicant 
506  who submits a waiver of the inactive ingredients requirement at  314.94(a)(9)(iii) or (iv) for a 
 
43 See 21 CFR 314.90(a). 
44 See GDUFA Reauthorization Performance Goals and Program Enhancements, Fiscal Years 2018-2022, available 
at https://www.fda.gov/media/101052/download (Act on an application  means FDA will either issue a complete 
response letter, an approval, a tentative approval, or a refuse-to-receive action.). 
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507  difference in pH adjuster and who also seeks to use an in vitro approach to demonstrate BE, to 
508  contact the Agency to discuss the particular approach to establish BE for that particular drug 
509  product.    
510   
511  Similarly, FDAs product specific guidances (PSG) may recommend that an ANDA product 
512  contain the same inactive ingredients in the same concentration as its RLD to use a particular 
513  approach recommended in the PSG to demonstrate BE. Recommendations in PSGs are not 
514  binding, and applicants may use an alternative approach if it satisfies the requirements of the 
515  applicable statutes and regulations. The scientific principles described in this guidance that 
516  provide support for a waiver of the inactive ingredient requirements under  314.94(a)(9)(iii) and 
517  (iv) for a difference in pH adjuster may, in some cases, also provide support for an applicants 
518  scientific justification for use of a particular BE approach. As noted above, FDA encourages an 
519  applicant, who submits a waiver of the inactive ingredients requirement at  314.94(a)(9)(iii) or 
520  (iv) for a difference in pH adjuster and who also seeks to use an in vitro approach to demonstrate 
521  BE, to contact the Agency to discuss the particular approach to establish BE for that particular 
522  drug product.    
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