Use of Liquids and/or Soft Foods 
as Vehicles for Drug 
Administration:  General 
Considerations for Selection and 
In Vitro Methods for Product 
Quality Assessments 
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DRAFT GUIDANCE
 
 
  This guidance document is being distributed for comment purposes only.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publication in the Federal Register of the notice announcing the availability of the draft 
guidance.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.  
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
July 2018 
Pharmaceutical Quality/CMC 
15520 draft 
07/13/18   
Use of Liquids and/or Soft Foods 
as Vehicles for Drug 
Administration:  General 
Considerations for Selection and 
In Vitro Methods for Product 
Quality Assessments 
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  
http://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 2018 
Pharmaceutical Quality/CMC
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
TABLE OF CONTENTS 
 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 2 
III.  GENERAL CONSIDERATIONS AND RECOMMENDATIONS .............................. 3 
A.  Selection of Liquids and Soft Foods: Compatibility and Suitability ......................................... 4 
B.  Impact of Vehicle on the Drug Product ....................................................................................... 5 
C.  Patient Adherence and Acceptance: Palatability and Swallowability ...................................... 5 
D.  Drug Product and Vehicle ............................................................................................................. 6 
1.  Preparation and Handling Procedures ........................................................................................... 6 
2.  Dose and Dosing Volume................................................................................................................. 7 
E.  Drug Product and Vehicle Mixtures for Repeated Use or Multiple Users ............................... 7 
F.  Special Case: Administration of Drug Product and Vehicle Mixtures via Feeding Tubes ..... 8 
G.  Information from In Vivo and In Vitro Studies .......................................................................... 8 
H.    Recommendations for Labeling .................................................................................................... 8 
IV.  IN VITRO METHODS RECOMMENDED FOR ASSESSING IMPACT OF A   
VEHICLE ON PRODUCT QUALITY ATTRIBUTES .............................................. 10 
A.  Analytical Method ........................................................................................................................ 10 
B.  Assessment of the Drug Substance in the Mixture ................................................................ 10 
1.  Sample Handling ............................................................................................................................ 10 
2.  Integrity, Potency, Stability, and Homogeneity ............................................................................. 11 
3.  Dissolution/Drug Release Testing ................................................................................................. 12 
4.  Dosage Form Specific Considerations .......................................................................................... 13 
V.  LOCATION OF DATA IN SUBMISSIONS ................................................................ 13 
APPENDIX A .............................................................................................................................. 14 
Commonly Used Soft Foods and Liquids With Their Approximate pH Range ..................... 14 
APPENDIX B .............................................................................................................................. 15 
Examples of Labeling Language ................................................................................................. 15 
APPENDIX C .............................................................................................................................. 16 
Sample Handling and Qualification Decision Tree ................................................................... 16 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1  Use of Liquids and/or Soft Foods as Vehicles for Drug 
2  Administration:  General Considerations for Selection and In Vitro 
3  Methods for Product Quality Assessments 
4  Guidance for Industry1 
5   
6   
7  This draft guidance, when finalized, will represent the current thinking of the Food and Drug 
8  Administration (FDA or Agency) on this topic.  It does not establish any rights for any person and is not 
9  binding on FDA or the public.  You can use an alternative approach if it satisfies the requirements of the 
10  applicable statutes and regulations.  To discuss an alternative approach, contact the FDA staff responsible 
11  for this guidance as listed on the title page.   
12   
13   
14   
15  I.  INTRODUCTION  
16   
17  This guidance applies to orally administered drug products and provides recommendations to 
18  sponsors2 who will use or recommend use of liquids3 and/or soft foods as vehicles for drug 
19  administration in investigational new drug applications (INDs), new drug applications (NDAs), 
20  Biologics License Applications (BLAs), as applicable, and in supplements to these applications.4 
21  This guidance addresses the approaches recommended for suitability determination of vehicles 
22  intended for use with specific drug products by providing the following: 
23   
24    Considerations for selection of liquids and/or soft foods as vehicles.  
25   
26    Standardized in vitro methodology and data recommendations for drug product quality 
27  assessments to qualify vehicle(s) for drug product administration.  
28   
                                                 
1 This guidance has been prepared by a multidisciplinary team including offices within the Center for Drug 
Evaluation and Research and the Office of Pediatric Therapeutics in the Office of the Commissioner at the Food and 
Drug Administration. 
2 For the purposes of this guidance, the term sponsor includes applicant and application holder. 
3 Liquid, other than water. 
4 This guidance does not address use of vehicles for the purpose of demonstrating bioequivalence in generic drug 
products.  For abbreviated new drug applications (ANDAs), recommendations for in vivo bioequivalence studies 
involving administration with liquids or soft foods will continue to be communicated in the respective product-
specific Agency guidance.  With respect to ANDAs and the recommendations contained in this guidance, we note 
that immediate-release solid oral dosage forms generally are considered to be products for which formulation 
differences between generic products and their reference listed drug (RLD) would not impact administration with  
vehicles.  The vehicle studies on the RLD would establish the compatibility of the active ingredient with the 
recommended vehicles, and need not be repeated in an ANDA unless there is a risk that the formulation of the 
ANDA product would have a different impact on dosing with vehicles.  When needed, the in vitro approaches in this 
guidance could be used to confirm that the formulation of a generic product is compatible with the vehicles of 
administration in the RLD label.  If FDA determined that in vivo data are needed to support use of a vehicle for a 
generic product, the Agency would describe such data in its recommended product-specific bioequivalence studies. 
 
  1  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
29    Recommendations to communicate acceptable (qualified) vehicles in drug product 
30  labeling. If certain foods are found unacceptable, they should also be included in the 
31  labeling.  
32   
33  This guidance and the methods it describes do not replace existing guidance documents that 
34  address food-effect assessments on the drug product5 or dosage form, or stability testing 
35  conducted to support a shelf-life determination.6 For those drug products marketed with a 
36  vehicle for administration (i.e., the vehicle is co-packaged with the drug product), the 
37  recommendations regarding selection and methods provided in this guidance are applicable, 
38  but additional considerations and recommendations may also apply. 
39   
40  If a different approach than those recommended in this guidance is used, sponsors are 
41  encouraged to discuss the proposed approach with the appropriate FDA quality assessment staff 
42  before conducting the studies.  
43   
44  In general, FDAs guidance documents do not establish legally enforceable responsibilities.  
45  Instead, guidances describe the Agencys current thinking on a topic and should be viewed only 
46  as recommendations, unless specific regulatory or statutory requirements are cited. The use of 
47  the word should in Agency guidances means that something is suggested or recommended, but 
48  not required.  
49   
50   
51  II.  BACKGROUND 
52   
53  There are many commercial drug product dosage forms such as granules, pellets, powders, or 
54  tablets for which the drug product labeling includes instructions for the optional use of soft foods 
55  or liquids as vehicles for their administration. 
56     
57  In the absence of availability of a dosage form that is appropriate for the targeted patient 
58  population (e.g., pediatric, geriatric), small amounts of liquids and/or soft foods as described in 
59  the FDA-approved product labeling can be used as a suitable vehicle(s) for oral administration 
60  and immediate ingestion of the specific drug product. Generally, drug products mixed in small 
61  amounts of liquids (5 to 15 mL) or soft foods are used in pediatric and other patient populations 
62  who are unable to swallow solid oral dosage forms. Although sponsors are required to develop 
63  age-appropriate formulations as part of a pediatric drug development program7 occasionally the 
64  development of age-appropriate dosage forms and formulations proves to be exceedingly 
65  complex. The use of a liquid such as infant formula or breast milk and/or soft food as a 
66  vehicle(s) may be the only option for delivering the drug substance to the targeted patient 
67  population. Liquids and/or soft foods that are shown not to alter performance of the drug 
                                                 
5 See guidance for industry Food-Effect Bioavailability and Fed Bioequivalence Studies and guidance for industry 
Bioavailability and Bioequivalence Studies Submitted in NDAs or INDS-General Considerations.  
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. 
6 See ICH guidance for industry Q1A(R2) Stability Testing of New Drug Substances and Products. 
7 See section 505B(a)(4)(C) of the Federal Food, Drug, and Cosmetic Act (FD&C Act). 
  2  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
68  product, and are deemed compatible and suitable for use in the targeted patient populations, are 
69  considered suitable for use as vehicles with the specific drug product. The drug product-vehicle 
70  mixture is not considered a new dosage form of the existing drug.  
71   
72  To ensure consistency in drug product quality when administered with a vehicle, it is important 
73  to standardize the methodology supporting vehicle selection, and the supportive data to designate 
74  vehicle suitability. Standardization of the preparation and use instructions for the drug product-
75  vehicle mixture is also important, as ambiguity in instructions or incomplete information can 
76  lead to unintended outcomes, including dosing errors and/or misuse of the drug product.   
77   
78  The methodology described in this guidance is intended to improve consistency in these areas 
79  and applies to potential use of vehicles during different stages of drug development, including 
80  lifecycle management as follows: 
81     
82    During development (IND stage):  to select a vehicle for administering the test drug 
83  product to populations who are unable to swallow solid oral dosage forms (e.g., children, 
84  older adult patients); and for some bioavailability (BA) studies conducted for 
85  formulation development and optimization. 
86   
87    Prior to marketing application (NDA stage):  to propose a vehicle(s) for use of the drug 
88  product for the original or additional condition of use (e.g., a new indication or new 
89  patient population).  
90   
91    Postapproval or supplement submission:  to propose changes to the drug product or its 
92  labeling that necessitate reassessment of compatibility and suitability of the approved 
93  vehicle.   
94   
95  Considerations and in vitro methods described in this guidance are also applicable for selecting 
96  vehicles out of necessity in unusual circumstances, such as when considering counterterrorism 
97  measures.8 In such cases, when the benefits outweigh risks and alternate dosage forms are 
98  unavailable, liquids and/or soft foods may be used as vehicles for specific drug products.   
99   
100   
101  III.  GENERAL CONSIDERATIONS AND RECOMMENDATIONS 
102   
103  Only those liquids and/or soft foods demonstrated to have no appreciable effect on drug product 
104  performance should be proposed as vehicles. The potential impact of a vehicle on drug product 
105  performance is determined by assessment of drug product quality attributes, including potency 
106  (assay), in vitro dissolution/release, and other pertinent attributes when the drug product is used 
107  with the proposed vehicle(s). In section IV, standardized in vitro methods for evaluating 
108  compatibility of the proposed liquid and/or soft food are described.    
109   
                                                 
8 Refer to the following:   
http://www.fda.gov/Drugs/EmergencyPreparedness/BioterrorismandDrugPreparedness/ucm130996.htm and 
http://www.fda.gov/Drugs/EmergencyPreparedness/BioterrorismandDrugPreparedness/ucm063814.htm. 
 
  3  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
110  In the subsequent sections of this document, an intact drug product refers to solid oral dosage 
111  forms such as granules, pellets, powders, as well as certain specific modified release drug 
112  products such as coated mini-tablets or beads that are labeled to be administered via sprinkling 
113  (e.g., capsules or packets containing beads).9 When a drug product requires handling to make it 
114  suitable for administration in a vehicle, such as crushing a tablet, emptying capsule contents, 
115  making serial dilutions, or mixing syrup into a vehicle, the resultant product is referred to as a 
116  manipulated drug product in this document. If critical manipulations are needed, such as 
117  emptying capsule contents or crushing a tablet to mix with the vehicle for ease of administration, 
118  the impact of the manipulations should be studied. The preparation and use instructions provided 
119  in labeling should give clear instructions that can be followed by the patient, caregiver, or 
120  healthcare professional in a homecare setting or a healthcare facility.10 
121   
122  The following are key considerations and recommendations for selection and use of vehicles for 
123  drug product administration and are intended to ensure that any liquid or soft food proposed as a 
124  vehicle does not compromise drug product performance.  
125   
126  A.  Selection of Liquids and Soft Foods: Compatibility and Suitability 
127   
128  Using liquids and soft foods as vehicles for drug administration can prove to be challenging 
129  because many factors such as seasonal, regional and climate conditions can influence the 
130  composition of natural food substances. Liquids and soft foods that have relatively small 
131  fluctuations in their composition and characteristics (such as sugar content, acidity, viscosity) 
132  may be better candidates for screening as potentially compatible liquids and/or soft foods with 
133  drug products for further testing. Liquids and/or soft foods should be screened with consideration 
134  of the following characteristics:  1) the drug substance, 2) the drug product, 3) the properties of 
135  the proposed vehicle, such as its acidity/alkalinity and binding/chelating characteristics, and 4) 
136  the target population. For liquid dosage forms, composition of the drug product (including use of 
137  stabilizing, emulsifying, and suspending agents) should be considered when selecting possible 
138  vehicles to mix with the drug product. If possible, sponsors should identify more than one 
139  compatible vehicle to provide options for patients with allergy or intolerance to a single vehicle.   
140   
141  For compatibility assessments, the pH value of proposed liquids and soft foods should be 
142  considered before further testing for their compatibility with the intact or manipulated drug 
143  product, including products with coatings. For example, for drug products with an intact enteric 
144  protective coating suitable for an acidic environment with pH values up to pH 5, the proposed 
145  vehicle should not have a pH value higher than 5, as exposing the coating to higher pH values 
146  will disrupt and remove the coating from the drug product.11,12 See Appendix A for commonly 
147  used soft foods and liquids with their approximate pH ranges.  
148   
                                                 
9 See guidance for industry Size of Beads in Drug Products Labeled for Sprinkle. 
10 See guidance for industry The Content and Format for Pediatric Use Supplements. 
11 Wells KA and Losin WG, 2008, In Vitro Stability, Potency, and Dissolution of Duloxetine Enteric-Coated Pellets 
After Exposure to Applesauce, Apple Juice, and Chocolate Pudding, Clin Ther, 30(7):1300-1308. 
12 Jurecki ER, Cunningham A, Mahoney JJ, Tingley D, Chung S, James N, Cohen-Pfeffer JL, 2014, Sapropterin 
Dihydrochloride Mixed with Common Foods and Beverages, Top Clin Nutr, 29 (4), 325-331. 
  4  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
149  It is important that a comprehensive suitability determination is performed to evaluate potential 
150  use of the proposed vehicle in the targeted patient population. Suitability determinations should 
151  include a composite assessment of multiple factors, such as the patients medical condition; 
152  perceptions of the product-vehicle mixture such as flavor, texture, and mouthfeel; and age-
153  related responses to physical characteristics of the mixture. For example, perception of mouthfeel 
154  of the intact or manipulated drug product in the vehicle mixture will vary with the targeted 
155  patient population. Graininess of the drug product and vehicle mixture can trigger chewing in 
156  young patients.   
157   
158  If a certain liquid or soft food is considered unsuitable for the targeted patient population, even if 
159  the proposed vehicle(s) and the intact or manipulated drug product are chemically compatible, 
160  the indicated soft food or liquid may not be considered an acceptable vehicle for use. For 
161  example, adding a drug product to applesauce or another soft food is inappropriate if the targeted 
162  patient population is infants who are not yet eating solid food. Such data, when available, for 
163  liquids and soft foods evaluated and found to be unacceptable should also be submitted, 
164  including the rationale for avoiding their use as vehicles. 
165   
166  B.  Impact of Vehicle on the Drug Product  
167   
168  A direct assessment of the impact of the proposed vehicle on the intact or manipulated drug 
169  product should be conducted to determine the compatibility of the proposed vehicle with the 
170  drug product. Specifically, a liquid or soft food is considered suitable for use as a vehicle for 
171  drug product administration when it has no appreciable effect on drug product stability or 
172  performance. The resulting drug product-vehicle mixture should exhibit no change in potency (as 
173  determined by assay) over the proposed use time period and no significant change in drug release 
174  characteristics. See section IV for recommended methods. 
175   
176  Once combined, the drug product and vehicle mixture should be ingested immediately (or as 
177  directed in the labeling) to avoid dosing errors or inadvertent dosing, and inadvertent 
178  contamination of the drug product-vehicle mixture. When the labeling calls for immediate use of 
179  the mixture, such use should be adequately supported by product quality assessments that are 
180  carried out at pre-determined times over two hours after preparation of the mixture. The two-
181  hour assessment period is considered to provide the necessary time window to ensure physical 
182  and chemical stability of the drug product-vehicle mixture. Microbiological testing is not needed 
183  for the drug product-vehicle mixture if it is intended to be used within two hours because the risk 
184  of microbial proliferation to harmful levels is miminal. See section IV for recommended test 
185  methods.   
186   
187  C.  Patient Adherence and Acceptance: Palatability and Swallowability13    
188   
189  Adherence is defined as the degree of constancy and accuracy with which a patient takes a drug 
190  product as instructed by his or her healthcare provider, and is a key factor in successful 
191  therapeutic intervention. Factors that impact adherence include:  1) patient acceptance of the 
                                                 
13 Thompson CA, Lombardi DP, Sjostedt P, Squires LA, 2013, Industry Survey on Current Practices in the 
Assessment of Palatability and Swallowability in the Development of Pediatric Oral Dosage Forms, Therapeutic 
Innovation and Regulatory Science 47(5):542-549. 
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Draft  Not for Implementation 
192  drug product; 2) the willingness of the patient to use a drug product as intended; and 3) the 
193  ability of the caregiver to administer the drug product as intended.   
194   
195  Acceptance of the drug product is determined in part by palatability and swallowability that 
196  would determine the patient adherence. Palatability is defined as the quality of a drug product 
197  that makes it pleasant or acceptable in terms of taste, after-taste, smell, and texture and is a 
198  critical factor in determining patient acceptance of oral dosage forms. Swallowability may be 
199  defined as the patient being able to take the drug without gagging or choking. Taste sensation 
200  develops early in life and evolves with age. In general, the goal should be to develop drug 
201  formulations with a neutral taste that would be acceptable to the majority of patients. Although 
202  taste-masking technology is advancing rapidly, for those drug products where taste-masking is 
203  not possible, alternate approaches such as mixing with appropriate liquids and/or soft foods to 
204  mask taste can be employed to improve palatability of a finished dosage form. In cases where the 
205  drug substance dissolves in the vehicle, the drug product and vehicle mixture should be 
206  adequately taste-masked, if necessary for palatability. 
207   
208  Palatability of a drug product mixed with a vehicle can be influenced by factors including, but 
209  not limited to, concomitant disease, condition or medication and targeted patient population (e.g., 
210  pediatric or geriatric). Disease states can also influence a patients sensory perceptions and affect 
211  the patients ability to swallow certain dosage forms. In addition, cultural aspects such as diet 
212  and societal influences can impact a patients preference for certain liquids or soft foods as 
213  vehicles. Therefore, the palatability and swallowability of the drug product mixed with the 
214  vehicle should be determined in the intended population of use.  
215   
216  Methods for quantitative assessments of palatability and swallowability for drug products are 
217  advancing and continue to evolve.14,15 Sponsors should discuss their planned approach to assess 
218  palatability and swallowability of their drug product with the appropriate review divison. The 
219  assessments should consider relevant patient characteristics (such as age, disease or medical 
220  condition, concomitant medications, etc.), characteristics of the vehicle mixture(s) (such as taste, 
221  flavor, texture, and mouthfeel), and the ability of patients in the targeted population to swallow 
222  the drug product-vehicle mixture.   
223   
224  D.  Drug Product and Vehicle 
225   
226  1.   Preparation and Handling Procedures 
227   
228  In the selection of the vehicle, consideration should be given to the complexity of the 
229  preparation, homogeneity of the mixture, and handling procedures as these can result in 
230  decreased accuracy in dose delivery. Mixing drug products (intact or manipulated) with liquids 
231  or soft foods may allow masking of an unpleasant taste, after-taste, smell and/or texture, or may 
                                                 
14 Squires LA, Lombardi DP, Sjostedt P, Thompson CA, 2013, A Systematic Literature Review on the Assessment 
of Palatability and Swallowability in the Development of Oral Dosage Forms for Pediatric Patients, Therapeutic 
Innovation and Regulatory Science, 47(5):533-541. 
15 Stokes JR, Boehm MW, Baier SK, 2013, Oral Processing, texture and mouthfeel: From rheology to tribology and 
beyond, Curr Opinion in Colloid & Interface Science, 18:349-359. 
 
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232  aid to facilitate swallowing of solid oral dosage forms. For ease of administration and to ensure 
233  dosing accuracy, as appropriate, an oral syringe or measuring spoon should be included with the 
234  drug product along with clear use instructions.16  
235   
236  Carrying out dilutions accurately in a homecare setting can be difficult. To enable accurate 
237  dosing, tablet splitting of non-scored tablets or dilutions should be avoided, unless stated in the 
238  label. Even with functionally scored tablets, there are limitations in accurately dividing a tablet 
239  into dose strengths beyond that provided by the scoring.17 For example, we recommend against 
240  dividing nonfunctionally scored tablets into smaller doses (such as one-fourth of a tablet), 
241  because it can result in crumbling of the tablet and inaccuracy of the recommended dose. For 
242  unscored tablets the manufacture/availability of multiple strengths of the drug product is highly 
243  encouraged. 
244   
245  2.   Dose and Dosing Volume 
246   
247  The suggested volume of the vehicle for mixing with solid oral dosage forms should take into 
248  consideration the age, size, and average consumption of the vehicle by the targeted patient 
249  population. For example, children younger than two years old may not be able or willing to 
250  ingest large volumes of liquids or soft foods at one time, whereas this volume may be acceptable 
251  for an older child or adult. To ensure administration of the full dose of the drug and to facilitate 
252  swallowing, the smallest volume of vehicle(s) sufficient to provide acceptable taste-masking, 
253  roughly 5 to 15 mL, should be used to prepare the drug product and vehicle mixture. In addition, 
254  homogeneous (i.e., uniform) mixing of the drug product in a smaller volume of vehicle is 
255  generally easier and will facilitate complete administration of the dose. If the homogeneous 
256  mixing of the intact or manipulated drug product with a small volume of the vehicle is difficult 
257  and requires a large volume (e.g., more than 15 mL) of the vehicle for dosing, exploring alternate 
258  vehicles should be considered to avoid incomplete dosing if all of the drug product and vehicle 
259  mixture cannot be readily ingested.  
260   
261  E.  Drug Product and Vehicle Mixtures for Repeated Use or Multiple Users  
262   
263  Generally, use of vehicles for drug administration refers to single use of the preparation where 
264  the drug product, once mixed with the liquid or soft food, is consumed immediately by a single 
265  patient. Under certain circumstances, use of the drug product-vehicle mixture preparation for 
266  multiple doses (e.g., one or more patients) can be considered acceptable (i.e., in a healthcare 
267  facility or in another setting where qualified professionals are responsible for preparing the drug 
268  product-vehicle mixtures and dosing the patients). Adequate characterization of the drug product 
269  and vehicle mixture (including adequate in-use stability data and microbiological assessments), 
270  and instructions for preparing the drug product-vehicle mixture, should be included in the 
271  submission to support such multiple dose labeling statements.   
272    
273   
                                                 
16 We recommend that ANDAs for which the RLD contains these materials submit data and information in the 
application to demonstrate the proposed generic product contains equivalent materials (e.g., dosing/adminstration 
device) and labeling.   
17 See guidance for industry Tablet Scoring: Nomenclature, Labeling, and Data for Evaluation. 
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274  F.  Special Case: Administration of Drug Product and Vehicle Mixtures via Feeding 
275  Tubes 
276   
277  In cases where the drug product labeling describes feeding tube administration, orally 
278  administered drug products can be given through a feeding tube (oral or enteral) to pediatric or 
279  adult patients who are unable to ingest solid or liquid dosage forms.18 In addition to the 
280  recommended assessments in this guidance, the feasibility and risk of administration of the drug 
281  product-vehicle mixture through a feeding tube should be addressed. For example, if the product 
282  may be administered by feeding tube, then an assessment demonstrating delivery of full volume 
283  of the mixture with no loss of drug product or potency is necessary, and should include the 
284  volume of solution to be used to rinse the feeding tube to ensure complete administration of the  
285  mixture. Similarly, factors that can result in the risk of drug aspiration or blockage of the tube 
286  should be evaluated. 
287   
288  G.  Information from In Vivo and In Vitro Studies   
289   
290  If the sponsor anticipates use of liquid or soft foods as vehicles for drug administration during 
291  drug development and/or after market approval, data from in vivo and in vitro studies should be 
292  submitted. Studies to support the compatibility and suitability of the selected vehicle(s), the 
293  supporting methodology, and timing of such studies should be discussed with the appropriate 
294  review division early in drug development (such as during pre-IND, end-of-phase 2 (EOP2) 
295  meetings), or postapproval, as applicable.  
296   
297  If a liquid or soft food is ultimately recommended as a vehicle(s) for drug administration, patient 
298  dosing information should be included in the labeling. For example, this includes the studied 
299  vehicle(s), volume of the vehicle(s), frequency of dosing, along with the pharmacokinetic 
300  information, if available, which should be included in the Pharmacokinetics subsection of the 
301  CLINICAL PHARMACOLOGY section of labeling. For complete information, see section H: 
302  Recommendations for Labeling.  
303  WG STOPPED  
304  Under special circumstances the Agency may request additional studies and in vivo 
305  bioavailability data if deemed appropriate (e.g., if there is reason to believe there may be 
306  interactions requiring further assessment).  
307   
308  The in vitro methods described in this document are for selection and qualification of vehicles; 
309  they do not replace in vivo food-effect studies.19   
310   
311  H.    Recommendations for Labeling  
312   
313  If a liquid or soft food is qualified as a vehicle(s) and recommended for the administration of a 
314  drug for the target indicated population (or sub-population), such information should be 
315  summarized in labeling. The labeling should include sufficient information to ensure that the 
                                                 
18 Williams NT, 2008, Medication administration through enteral feeding tubes, Am J Health-Syst Pharm, 65:2347-
2357.   
19 See guidance for industry Food-Effect Bioavailability and Fed Bioequivalence Studies and guidance for industry 
Bioavailability and Bioequivalence Studies Submitted in NDAs or INDs-General Considerations. 
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316  healthcare provider, patient, and/or caregiver has the essential information to use the 
317  recommended vehicle(s) to administer the drug safely and effectively and to avoid substitutions 
318  that are unacceptable. Labeling should include, as applicable: 
319   
320    Recommended type(s) of soft food or liquid vehicle(s);   
321   
322    Detailed vehicle use information, such as the volume and temperature range of the 
323  qualified vehicle(s) that are approved for use;  
324   
325    Recommended critical manipulations, such as emptying capsule contents or crushing a 
326  tablet for ease of administration;   
327   
328    For repeated or multiple use dosing, information concerning the conditions to support 
329  preparation of the drug product-vehicle mixture and instructions for its storage between 
330  uses;   
331   
332    Information on compatibility of the recommended vehicle(s) with feeding tube 
333  characteristics;  
334   
335    Information on liquids and soft foods found to be unacceptable, and the rationale for 
336  avoiding their use as vehicles. 
337   
338  A succinct summary of the compatability and suitability study and data that supports the use of 
339  liquid or soft food vehicles in the target population as well as relevant data concerning 
340  unacceptable vehicles should be discussed in the Pharmacokinetics subsection of the CLINICAL 
341  PHARMACOLOGY section.20  
342   
343  The DOSAGE AND ADMINISTRATION section should include directions for administering 
344  the drug using the recommended liquid or soft food vehicle.22 This section should also include 
345  information on the target indicated patient population for delivering the drug using a liquid or 
346  soft food vehicle (e.g., pediatric patients, older adults who have difficulty swallowing solid oral 
347  dosage forms) as well as the preparation, administration, and storage of the mixed drug product-
348  vehicle. The Instructions for Use should contain detailed patient-appropriate directions for the 
349  preparation, administration, and storage of the mixed drug product-vehicle by a patient or 
350  caregiver, if applicable.  
351   
352  A cross-reference to the CLINICAL PHARMACOLOGY section for additional details 
353  concerning the liquid or soft food vehicles should be included. See Appendix B for examples for 
354  the preparation, administration, and storage of the mixed drug product-vehicle in the DOSAGE 
355  AND ADMINISTRATION section.   
356   
357   
358   
                                                 
20 See guidance for industry Clinical Pharmacology Section of Labeling for Human Prescription Drug and 
Biological Products-Content and Format. 
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359  IV.  IN VITRO METHODS RECOMMENDED FOR ASSESSING IMPACT OF A 
360  VEHICLE ON PRODUCT QUALITY ATTRIBUTES 
361   
362  The following approaches are recommended to determine whether a proposed vehicle is 
363  compatible and suitable for use with the drug product. Also, see Appendix C (Sample Handling 
364  and Qualification Decision Tree) and section IV.B.  
365   
366  The product quality data generated from the following studies, as applicable for the dosage form, 
367  should be included in a report to support qualification of each proposed vehicle and to support 
368  that the drug product quality is maintained when the drug product is mixed with the qualified 
369  vehicles.   
370   
371  A.  Analytical Method  
372   
373  A validated analytical method should be used to quantify the amount of drug substance in the 
374  vehicle mixture for the assessments described in section B below. The drug substance may or 
375  may not be exposed to the vehicle depending on the dosage form and sample preparation. If the 
376  dosage form remains intact in the vehicle, changes in assay (potency) and drug product 
377  performance/integrity are not expected, but the absence of such changes should be verified.  
378   
379  The analytical method for assay of drug substance in the proposed vehicle should be developed 
380  and validated in accordance with the principles outlined in guidances.21,22,23,24 The source of 
381  analytical interferences, if observed, between ingredients in liquids or soft foods with the drug  
382  substance and the excipients in the dosage forms should be determined.   
383   
384  B.  Assessment of the Drug Substance in the Mixture  
385   
386  A series of assessments should be performed to qualify the proposed vehicle for a specific drug 
387  product as outlined in the Sample Handling and Qualification decision tree in Appendix C.   
388  The following describes the sequence of the assessments in the decision tree: 
389   
390  1.   Sample Handling 
391   
392  A basic screen should be carried out to determine stability of the drug substance in standard GI 
393  buffer media and in Fed State Simulated Gastric Fluid (FeSSGF), which is buffer media 
394  containing milk. Sample handling processes, depending on the stability of the drug substance in 
395  the screening media, or the ability of a drug product coating to prevent exposure to a drug 
396  substance that is unstable in the screening media, are described in the decision tree in Appendix 
397  C.  
398   
                                                 
21 See guidance for industry Analytical Procedures and Methods Validation for Drugs and Biologics. 
22 See ICH guidance for industry Q2R1Validation of Analytical Procedures: Text and Methodology. 
23 See ICH guidance for industry Q2A Text on Validation of Analytical Procedures. 
24 See ICH guidance for industry Q2B Validation of Analytical Procedures: Methodology. 
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399  For sample preparation approach B, described in Appendix C, the intact drug product or 
400  particulate material containing the drug substance should be separated from the mixture, and 
401  integrity and dissolution tests should be performed on the solid particles.  
402   
403  2.   Integrity, Potency, Stability, and Homogeneity 
404   
405  Integrity:  A qualified vehicle should be shown to maintain the drug substance quality attributes. 
406  If the drug product has a coating and is used intact, the qualified vehicle should have no impact 
407  on the coating and as a result, on the integrity of the drug substance within the drug product. In 
408  the cases where a coated tablet is to be crushed before mixing and the integrity of the coated 
409  tablet is intentionally compromised, or where the drug product dissolves in the vehicle, exposing 
410  the drug substance, the potential for the proposed vehicle to impact the integrity of the drug 
411  substance (e.g., changes in polymorphic form, loss of bead integrity) should be evaluated.  
412   
413  Potency (assay):  Potency assessment should determine the amount of the drug substance in the 
414  drug product-vehicle mixture to support the recommended labeled use time. The testing should 
415  be carried out after mixing or dissolving and again two hours after incubating the drug product 
416  with the vehicle to support immediate use. If the proposed labeling will include manipulation of 
417  the drug product prior to mixing with the vehicle (e.g., emptying capsule contents or crushing a 
418  tablet), this should be done prior to the potency assessment. Samples should be collected at 
419  predefined time points and assayed for determination of potency. The test should demonstrate a 
420  lack of significant change in assay from the original value (where a significant change is defined 
421  as no more than five percent of the original value).25  
422   
423  When providing mass balance (total recovery) calculations for products where the sample 
424  contains particulate material (sample preparation approach B), the amount of drug substance 
425  extracted from particulate or intact drug product (such as coated beads, pellets) and the amount 
426  of drug substance dissolved/released into the drug product and vehicle mixture should be 
427  determined. The recovery data should be consistent with the labeled claim.  
428   
429  Stability:  Stability assessment of the drug product-vehicle mixture should be provided to 
430  support labeling instructions for its preparation and labeled use time. To qualify a vehicle for 
431  immediate drug administration, a two hour stability assessment (USP controlled room 
432  temperature: 20o C-25o C)26 should be conducted in a manner consistent with immediate use of 
433  the mixture as described in the labeling. Additionally, stability assessment under refrigerated 
434  conditions (USP controlled cold temperature: 2o C-8o C) may be needed.   
435   
436  If potency testing of the drug product and the vehicle mixture suggests possible interactions (e.g., 
437  a significant loss in the amount of the drug substance is observed), the stability assessment 
438  should include testing for degradation products to verify drug substance and drug product 
439  integrity, as applicable. Stability-indicating methods should be used to determine the presence of 
440  an impurity (in amounts exceeding the accepted threshold) or formation of new degradants as a 
441  result of a potential interaction between the multiple components of the drug product and vehicle 
442  mixture.  
                                                 
25 See ICH guidance for industry Q1A(R2) Stability Testing of New Drug Substances and Products. 
26 See USP 40-NF 35, General Chapter <659> PACKAGING AND STORAGE REQUIREMENTS. 
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443   
444  Homogeneity (dose uniformity):  The proposed vehicle(s) should also be suitable for 
445  preparation of homogeneous mixtures. The drug product should be thoroughly mixed with the 
446  liquid or soft food to ensure a homogeneous mixture. Even though the drug product and vehicle 
447  mixture is prepared for immediate use, it is possible that the patient may not ingest all of the 
448  mixture immediately. In such cases, the more homogeneous the mixture is, the more reliable the 
449  estimate of the ingested dose. To evaluate the homogeneity of the mixture, the drug product and 
450  vehicle mixture should be divided into equal portions (n=3 to 6) and tested.  
451   
452  3.   Dissolution/Drug Release Testing 
453   
454  Composition of soft foods or liquids such as added thickeners, sweetening agents, and other 
455  ingredients can alter release and delivery of drug substance from the drug product.27 In cases 
456  where the drug substance is not immediately dissolved in the liquid or soft food, dissolution/ 
457  release testing of drug substance from the dosage form mixed with the proposed vehicle should 
458  be carried out according to established methods.28 Dissolution testing should be conducted in 
459  media typically used for testing solid oral dosage forms and USP Apparatus I or Apparatus II can 
460  be used. The following dissolution media are generally recommended:  (1) 0.1 N HCl or 
461  simulated gastric fluid USP without enzymes; (2) USP buffer at pH 4.5; (3) USP buffer at pH 6.8 
462  or simulated intestinal fluid USP with or without enzymes; and (4) FFESSGF.29,30 The sample 
463  preparation process should enable assessment of drug dissolution/release patterns for the drug 
464  product-vehicle mixture in a manner consistent with drug dissolution/release characteristics and 
465  claims for the drug product.   
466   
467  Typically, 12 individual units of the dosage form are used for dissolution testing of a drug 
468  product. This information should be included in the vehicle qualification report or cross-
469  referenced to the drug product information in the submission. For dissolution/release testing of 
470  drug substance from the drug product-vehicle mixture, data from six units mixed into the 
471  proposed vehicle should be collected at each pre-determined sampling time. A comparison of the 
472  dissolution profile for the original product with the drug product mixed with the proposed 
473  vehicle should meet the similarity factor (f2) acceptance criteria.31 
474   
475  Depending on the targeted patient population, dosage form, and drug substance characteristics, 
476  additional in vitro testing may be appropriate to understand the effect of the proposed vehicle(s) 
477  on the in vivo dissolution of the drug product. 
478   
479     
                                                 
27 Manrique, YJ, Lee, DJ, Islam, F, Nissen, LM, Cichero, Stokes, JR, Steadman, KJ, 2014, Crushed Tablets: Does 
the Administration of Food Vehicles and Thickened Fluids to Aid Medication Swallowing Alter Drug Release? J 
Pharm Sci 17(2):207-219. 
28 See guidance for industry Dissolution Testing of Immediate Release Solid Oral Dosage Forms. 
29 Klein, S, 2010, The use of Biorelevant media to forecast in vivo performance of a drug, AAPSJ, p 397-406. 
30 Marques, MRC, Loebenberg, R, and Almukainzi, M, 2011, Simulated Biological Fluids with Possible Application 
in Dissolution Testing, Dissolution technologies, p 15-28. 
31 Ibid. 
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480  4.   Dosage Form Specific Considerations 
481    
482  For liquid drug products such as syrups, emulsions, or similar dosage forms, it may be possible 
483  to mix the drug product homogenously with the vehicle. In vitro methods for product quality and 
484  performance assessments should follow sample preparation and handling, see Appendix C, 
485  Approach A of the Decision Tree.    
486   
487  Dosage form characteristics and composition of the drug product should be considered to ensure 
488  that sample preparation and handling approaches are consistent with the intended in vivo 
489  performance of the drug product.    
490   
491  Certain use conditions, such as emergency use, and/or use in a professional healthcare setting, 
492  may necessitate other testing approaches that are not discussed in this guidance. We recommend 
493  that sponsors consult with the appropriate review division for cases that require unique 
494  considerations.    
495   
496   
497  V.  LOCATION OF DATA IN SUBMISSIONS 
498   
499  The information supporting selection and qualification of the vehicle to be mixed with the drug 
500  should be provided as a separate report in the 3.2.P.2 (Pharmaceutical development) section of a 
501  common technical document (CTD)32-formatted application.  
502   
503  In the proposed labeling portion of a submission, information related to the drug product-vehicle 
504  mixture including important preparation and administration instructions should be included in 
505  the DOSAGE AND ADMINISTRATION section, and any relevant pharmacokinetic 
506  information, if available, should be included in the Pharmacokinetics subsection of the 
507  CLINICAL PHARMACOLOGY section of labeling.  
508     
                                                 
32 See ICH guidance for industry M4Q(R1) Technical Requirements for Registration of Pharmaceuticals for Human 
Use. 
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509  APPENDIX A 
510   
511  Commonly Used Soft Foods and Liquids With Their Approximate pH Range  
512   
  pH range   
Apples (puree)  3.34  3.90  
Apple juice  3.35  4.00 
Applesauce  3.10  3.60 
Baby food, unstrained  5.95  6.05 
Bananas (puree)  4.5  5.2 
Buttermilk  4.41  4.83 
Carrots (puree)  5.88  6.40 
Chocolate pudding(a)  5.5  6.0 
Coconut milk  6.1  7.0 
Cranberry juice  2.30  2.52 
Drinking water (b)  6.5  8.5 
Fruit jellies    3.0  3.5 
Fruit jam   3.5  4.5 
Grapefruit juice (c)   2.90  3.25 
Honey (d)  3.70  4.20 
Infant formula  5.7  6.0 
Maple syrup (e)   4.6  5.15 
Milk  6.4  6.8 
Orange juice  3.30  4.19 
Orange marmalade  3.00  3.33 
Peanut butter  6.28 
Pineapple juice  3.30  3.60 
Rice pudding (a)  4  5 
Soybean milk  7 
Strawberries  3.00  3.90 
Strawberry jam  3.00  3.40 
Yogurt   4.4  5.0 
513   
514  Reference, unless otherwise noted, 
515  https://www.clemson.edu/extension/hgic/food/pdf/hgic3030.pdf. 
516   
517  a: Clin. Ther. 2008, 30 (7), 1300-1308. 
518  b: National Secondary Drinking Water Regulations (http://www.water-research.net/index.php/standards/secondary-
519  standards). 
520  c: Grapefruit juice is not recommended for using as a vehicle 
521  (www.health.harvard.edu/fhg/updates/update0206d.shtml). Its inclusion here is for reference purposes only. 
522  d: Honey is not recommended for children under age of 12 (Spika JS, N Shaffer, N Hargrett-Bean, S Collin, KL 
523  MacDonald, PA Blake, 1989, Risk Factors for Infant Botulism in the United States, Am J Dis Child, 143(7):828-
524  832, and https://www.cdc.gov/dotw/botulism/index.html). 
525  e: http://elitepublishing.net/ph_foods.html. 
526   
527     
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528  APPENDIX B  
529   
530  Examples of Labeling Language  
531   
532  The following examples illustrate labeling text for the DOSAGE AND ADMINISTRATION 
533  section for drug products (as is or in a manipulated form) that can be mixed with liquids or soft 
534  foods. The labeling should include specific use information, such as the volume and temperature 
535  of the qualified vehicle(s) approved for use.   
536   
537    Drug X capsules should be swallowed intact with a glass of water.  For patients with 
538  swallowing difficulties, Drug X capsules can be opened and the contents sprinkled onto 
539  a teaspoon (5 mL) or tablespoon (15 mL) of soft food and ingested immediately.  Use 
540  only foods that do not require chewing, such as apricot, banana, or sweet potato baby 
541  food; applesauce; and instant pudding.  Contact of the capsule contents with foods such 
542  as milk, custard, ice cream, and many other dairy products can dissolve the protective 
543  (or enteric) coating and destroy the drug substance.   
544   
545    Drug Y packet contents can be administered 1) dissolved in 1 teaspoonful (5 mL) of 
546  cold or room temperature milk or breast milk, or 2) mixed with a teaspoonful (5 mL) 
547  of cold or room temperature applesauce or banana puree.  Puddings or formula 
548  containing soybean flour, and vegetable purees should not be used because the fiber in 
549  these foods can bind the drug substance.  Liquids or other foods can be ingested 
550  subsequent to the administration of Drug Y packet contents. 
551   
552    Once Drug Y packet is opened, the full dose (with or without mixing with milk, breast 
553  milk, or the apple and banana puree) must be administered immediately.  If all of the 
554  mixture is not ingested, discard any unused portion.  Any unused contents of Drug Y 
555  packet must not be stored for future use.   
556 
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557  APPENDIX C 
558   
559  Sample Handling and Qualification Decision Tree 
560   
561  Approaches for sample preparation and handling are described to support drug product quality 
562  assessments to determine whether the selected soft food or liquid qualifies for use as a vehicle. 
563   
564   
565   
566   
567  * Drug product labeling should describe the qualified vehicle and any studied vehicles that cannot be used. 
568   
569  Sample handling Approach A (drug substance is completely dissolved and particulate 
570  material, if any, is not the drug substance): 
571   
572  Depending on the type of sample (diluted soft food or liquid), sample preparation may involve a 
573  simple filtration step followed by chromatographic separation and analysis of the drug substance; 
574  in some cases, an additional extraction step from the soft food or liquid may be required before 
575  sample analysis. 
576   
577  Sample handling Approach B (sample contains particulate material and some of the drug 
578  can be in the particulate material): 
579   
580  a)  Once the sample is taken from the media (soft food or liquid), the particulate matter is 
581  washed and separated for further analysis. 
582   
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583  b)  The wash and the remaining soft food or liquid is combined and processed for assaying 
584  for the drug substance.  
585   
586  c)  The particulate matter (such as pellets) retrieved from the vehicle and washed as in 
587  Approach A above should be tested according to the dissolution method to determine 
588  release characteristics, as well as the amount of remaining drug substance in the 
589  particulate material. 
590   
591  d)  Depending on the type of sample (diluted soft food or liquid), sample preparation in 
592  Approach B above may involve a simple filtration step followed by chromatographic 
593  separation and analysis of the drug substance; in some cases an additional extraction step 
594  from the soft food or liquid may be required before sample analysis. 
595   
  17