Use of Liquids and/or Soft Foods as Vehicles for Drug Administration: General Considerations for Selection and In Vitro Methods for Product Quality Assessments

Administrative draft guidance, not enacted legislation. This captured publisher edition preserves the listed document and attachments; later developments are not independently consolidated.

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
DRAFT GUIDANCE
This guidance document is being distributed for comment purposes only.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publication in the Federal Register of the notice announcing the availability of the draft
guidance.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

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., 4 th 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Draft — Not for Implementation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
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1
Use of Liquids and/or Soft Foods as Vehicles for Drug	1
Administration: General Considerations for Selection and In Vitro	2
Methods for Product Quality Assessments	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
I. 	INTRODUCTION	15
16
This guidance applies to orally administered drug products and provides recommendations to	17
sponsors2 who will use or recommend use of liquids3 and/or soft foods as vehicles for drug	18
administration in investigational new drug applications (INDs), new drug applications (NDAs),	19
Biologics License Applications (BLAs), as applicable, and in supplements to these applications.4	
20
This guidance addresses the approaches recommended for suitability determination of vehicles	21
intended for use with specific drug products by providing the following:	22
23
• 	Considerations for selection of liquids and/or soft foods as vehicles.	24
25
• 	Standardized in vitro methodology and data recommendations for drug product quality	26
assessments to qualify vehicle(s) for drug product administration.	27
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.

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• 	Recommendations to communicate acceptable (qualified) vehicles in drug product	29
labeling. If certain foods are found unacceptable, they should also be included in the	30
labeling.	31
32
This guidance and the methods it describes do not replace existing guidance documents that	33
address food-effect assessments on the drug product5 or dosage form, or stability testing	34
conducted to support a shelf-life determination.6 For those drug products marketed with a	35
vehicle for administration (i.e., the vehicle is co-packaged with the drug product), the	36
recommendations regarding selection and methods provided in this guidance are applicable,	37
but additional considerations and recommendations may also apply.	38
39
If a different approach than those recommended in this guidance is used, sponsors are	40
encouraged to discuss the proposed approach with the appropriate FDA quality assessment staff	41
before conducting the studies.	42
43
In general, FDA’s guidance documents do not establish legally enforceable responsibilities.	44
Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only	45
as recommendations, unless specific regulatory or statutory requirements are cited. The use of	46
the word should in Agency guidances means that something is suggested or recommended, but	47
not required.	48
49
50
II. 	BACKGROUND	51
52
There are many commercial drug product dosage forms such as granules, pellets, powders, or	53
tablets for which the drug product labeling includes instructions for the optional use of soft foods	54
or liquids as vehicles for their administration.	55
56
In the absence of availability of a dosage form that is appropriate for the targeted patient	57
population (e.g., pediatric, geriatric), small amounts of liquids and/or soft foods as described in	58
the FDA-approved product labeling can be used as a suitable vehicle(s) for oral administration	59
and immediate ingestion of the specific drug product. Generally, drug products mixed in small	60
amounts of liquids (5 to 15 mL) or soft foods are used in pediatric and other patient populations	61
who are unable to swallow solid oral dosage forms. Although sponsors are required to develop	62
age-appropriate formulations as part of a pediatric drug development program7 occasionally the	63
development of age-appropriate dosage forms and formulations proves to be exceedingly	64
complex. The use of a liquid such as infant formula or breast milk and/or soft food as a	65
vehicle(s) may be the only option for delivering the drug substance to the targeted patient	66
population. Liquids and/or soft foods that are shown not to alter performance of the drug	67
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).

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product, and are deemed compatible and suitable for use in the targeted patient populations, are	68
considered suitable for use as vehicles with the specific drug product. The drug product-vehicle	69
mixture is not considered a new dosage form of the existing drug.	70
71
To ensure consistency in drug product quality when administered with a vehicle, it is important	72
to standardize the methodology supporting vehicle selection, and the supportive data to designate	73
vehicle suitability. Standardization of the preparation and use instructions for the drug product-	74
vehicle mixture is also important, as ambiguity in instructions or incomplete information can	75
lead to unintended outcomes, including dosing errors and/or misuse of the drug product.	76
77
The methodology described in this guidance is intended to improve consistency in these areas	78
and applies to potential use of vehicles during different stages of drug development, including	79
lifecycle management as follows:	80
81
• 	During development (IND stage): to select a vehicle for administering the test drug	82
product to populations who are unable to swallow solid oral dosage forms (e.g., children,	83
older adult patients); and for some bioavailability (BA) studies conducted for	84
formulation development and optimization.	85
86
• 	Prior to marketing application (NDA stage): to propose a vehicle(s) for use of the drug	87
product for the original or additional condition of use (e.g., a new indication or new	88
patient population).	89
90
• 	Postapproval or supplement submission: to propose changes to the drug product or its	91
labeling that necessitate reassessment of compatibility and suitability of the approved	92
vehicle.	93
94
Considerations and in vitro methods described in this guidance are also applicable for selecting	95
vehicles out of necessity in unusual circumstances, such as when considering counterterrorism	96
measures.8 In such cases, when the benefits outweigh risks and alternate dosage forms are	97
unavailable, liquids and/or soft foods may be used as vehicles for specific drug products.	98
99
100
III. 	GENERAL CONSIDERATIONS AND RECOMMENDATIONS	101
102
Only those liquids and/or soft foods demonstrated to have no appreciable effect on drug product	103
performance should be proposed as vehicles. The potential impact of a vehicle on drug product	104
performance is determined by assessment of drug product quality attributes, including potency	105
(assay), in vitro dissolution/release, and other pertinent attributes when the drug product is used	106
with the proposed vehicle(s). In section IV, standardized in vitro methods for evaluating	107
compatibility of the proposed liquid and/or soft food are described.	108
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.

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In the subsequent sections of this document, an “intact” drug product refers to solid oral dosage	110
forms such as granules, pellets, powders, as well as certain specific modified release drug	111
products such as coated mini-tablets or beads that are labeled to be administered via sprinkling	112
(e.g., capsules or packets containing beads).9 When a drug product requires handling to make it	113
suitable for administration in a vehicle, such as crushing a tablet, emptying capsule contents,	114
making serial dilutions, or mixing syrup into a vehicle, the resultant product is referred to as a	115
“manipulated” drug product in this document. If critical manipulations are needed, such as	116
emptying capsule contents or crushing a tablet to mix with the vehicle for ease of administration,	117
the impact of the manipulations should be studied. The preparation and use instructions provided	118
in labeling should give clear instructions that can be followed by the patient, caregiver, or	119
healthcare professional in a homecare setting or a healthcare facility.10	
120
121
The following are key considerations and recommendations for selection and use of vehicles for	122
drug product administration and are intended to ensure that any liquid or soft food proposed as a	123
vehicle does not compromise drug product performance.	124
125
A. 	Selection of Liquids and Soft Foods: Compatibility and Suitability	126
127
Using liquids and soft foods as vehicles for drug administration can prove to be challenging	128
because many factors such as seasonal, regional and climate conditions can influence the	129
composition of natural food substances. Liquids and soft foods that have relatively small	130
fluctuations in their composition and characteristics (such as sugar content, acidity, viscosity)	131
may be better candidates for screening as potentially compatible liquids and/or soft foods with	132
drug products for further testing. Liquids and/or soft foods should be screened with consideration	133
of the following characteristics: 1) the drug substance, 2) the drug product, 3) the properties of	134
the proposed vehicle, such as its acidity/alkalinity and binding/chelating characteristics, and 4)	135
the target population. For liquid dosage forms, composition of the drug product (including use of	136
stabilizing, emulsifying, and suspending agents) should be considered when selecting possible	137
vehicles to mix with the drug product. If possible, sponsors should identify more than one	138
compatible vehicle to provide options for patients with allergy or intolerance to a single vehicle.	139
140
For compatibility assessments, the pH value of proposed liquids and soft foods should be	141
considered before further testing for their compatibility with the intact or manipulated drug	142
product, including products with coatings. For example, for drug products with an intact enteric	143
protective coating suitable for an acidic environment with pH values up to pH 5, the proposed	144
vehicle should not have a pH value higher than 5, as exposing the coating to higher pH values	145
will disrupt and remove the coating from the drug product.11,12 See Appendix A for commonly	146
used soft foods and liquids with their approximate pH ranges.	147
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.

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It is important that a comprehensive suitability determination is performed to evaluate potential	149
use of the proposed vehicle in the targeted patient population. Suitability determinations should	150
include a composite assessment of multiple factors, such as the patient’s medical condition;	151
perceptions of the product-vehicle mixture such as flavor, texture, and mouthfeel; and age-	152
related responses to physical characteristics of the mixture. For example, perception of mouthfeel	153
of the intact or manipulated drug product in the vehicle mixture will vary with the targeted	154
patient population. Graininess of the drug product and vehicle mixture can trigger chewing in	155
young patients.	156
157
If a certain liquid or soft food is considered unsuitable for the targeted patient population, even if	158
the proposed vehicle(s) and the intact or manipulated drug product are chemically compatible,	159
the indicated soft food or liquid may not be considered an acceptable vehicle for use. For	160
example, adding a drug product to applesauce or another soft food is inappropriate if the targeted	161
patient population is infants who are not yet eating solid food. Such data, when available, for	162
liquids and soft foods evaluated and found to be unacceptable should also be submitted,	163
including the rationale for avoiding their use as vehicles.	164
165
B. 	Impact of Vehicle on the Drug Product	166
167
A direct assessment of the impact of the proposed vehicle on the intact or manipulated drug	168
product should be conducted to determine the compatibility of the proposed vehicle with the	169
drug product. Specifically, a liquid or soft food is considered suitable for use as a vehicle for	170
drug product administration when it has no appreciable effect on drug product stability or	171
performance. The resulting drug product-vehicle mixture should exhibit no change in potency (as	172
determined by assay) over the proposed use time period and no significant change in drug release	173
characteristics. See section IV for recommended methods.	174
175
Once combined, the drug product and vehicle mixture should be ingested immediately (or as	176
directed in the labeling) to avoid dosing errors or inadvertent dosing, and inadvertent	177
contamination of the drug product-vehicle mixture. When the labeling calls for immediate use of	178
the mixture, such use should be adequately supported by product quality assessments that are	179
carried out at pre-determined times over two hours after preparation of the mixture. The two-	180
hour assessment period is considered to provide the necessary time window to ensure physical	181
and chemical stability of the drug product-vehicle mixture. Microbiological testing is not needed	182
for the drug product-vehicle mixture if it is intended to be used within two hours because the risk	183
of microbial proliferation to harmful levels is miminal. See section IV for recommended test	184
methods.	185
186
C. 	Patient Adherence and Acceptance: Palatability and Swallowability13	187
188
Adherence is defined as the degree of constancy and accuracy with which a patient takes a drug	189
product as instructed by his or her healthcare provider, and is a key factor in successful	190
therapeutic intervention. Factors that impact adherence include: 1) patient acceptance of the	191
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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drug product; 2) the willingness of the patient to use a drug product as intended; and 3) the	192
ability of the caregiver to administer the drug product as intended.	193
194
Acceptance of the drug product is determined in part by palatability and swallowability that	195
would determine the patient adherence. Palatability is defined as the quality of a drug product	196
that makes it pleasant or acceptable in terms of taste, after-taste, smell, and texture and is a	197
critical factor in determining patient acceptance of oral dosage forms. Swallowability may be	198
defined as the patient being able to take the drug without gagging or choking. Taste sensation	199
develops early in life and evolves with age. In general, the goal should be to develop drug	200
formulations with a neutral taste that would be acceptable to the majority of patients. Although	201
taste-masking technology is advancing rapidly, for those drug products where taste-masking is	202
not possible, alternate approaches such as mixing with appropriate liquids and/or soft foods to	203
mask taste can be employed to improve palatability of a finished dosage form. In cases where the	204
drug substance dissolves in the vehicle, the drug product and vehicle mixture should be	205
adequately taste-masked, if necessary for palatability.	206
207
Palatability of a drug product mixed with a vehicle can be influenced by factors including, but	208
not limited to, concomitant disease, condition or medication and targeted patient population (e.g.,	209
pediatric or geriatric). Disease states can also influence a patient’s sensory perceptions and affect	210
the patient’s ability to swallow certain dosage forms. In addition, cultural aspects such as diet	211
and societal influences can impact a patient’s preference for certain liquids or soft foods as	212
vehicles. Therefore, the palatability and swallowability of the drug product mixed with the	213
vehicle should be determined in the intended population of use.	214
215
Methods for quantitative assessments of palatability and swallowability for drug products are	216
advancing and continue to evolve.14,15 Sponsors should discuss their planned approach to assess	217
palatability and swallowability of their drug product with the appropriate review divison. The	218
assessments should consider relevant patient characteristics (such as age, disease or medical	219
condition, concomitant medications, etc.), characteristics of the vehicle mixture(s) (such as taste,	220
flavor, texture, and mouthfeel), and the ability of patients in the targeted population to swallow	221
the drug product-vehicle mixture.	222
223
D. 	Drug Product and Vehicle	224
225
1. 	Preparation and Handling Procedures	226
227
In the selection of the vehicle, consideration should be given to the complexity of the	228
preparation, homogeneity of the mixture, and handling procedures as these can result in	229
decreased accuracy in dose delivery. Mixing drug products (intact or manipulated) with liquids	230
or soft foods may allow masking of an unpleasant taste, after-taste, smell and/or texture, or may	231
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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aid to facilitate swallowing of solid oral dosage forms. For ease of administration and to ensure	232
dosing accuracy, as appropriate, an oral syringe or measuring spoon should be included with the	233
drug product along with clear use instructions.16	
234
235
Carrying out dilutions accurately in a homecare setting can be difficult. To enable accurate	236
dosing, tablet splitting of non-scored tablets or dilutions should be avoided, unless stated in the	237
label. Even with functionally scored tablets, there are limitations in accurately dividing a tablet	238
into dose strengths beyond that provided by the scoring.17 For example, we recommend against	239
dividing nonfunctionally scored tablets into smaller doses (such as one-fourth of a tablet),	240
because it can result in crumbling of the tablet and inaccuracy of the recommended dose. For	241
unscored tablets the manufacture/availability of multiple strengths of the drug product is highly	242
encouraged.	243
244
2. 	Dose and Dosing Volume	245
246
The suggested volume of the vehicle for mixing with solid oral dosage forms should take into	247
consideration the age, size, and average consumption of the vehicle by the targeted patient	248
population. For example, children younger than two years old may not be able or willing to	249
ingest large volumes of liquids or soft foods at one time, whereas this volume may be acceptable	250
for an older child or adult. To ensure administration of the full dose of the drug and to facilitate	251
swallowing, the smallest volume of vehicle(s) sufficient to provide acceptable taste-masking,	252
roughly 5 to 15 mL, should be used to prepare the drug product and vehicle mixture. In addition,	253
homogeneous (i.e., uniform) mixing of the drug product in a smaller volume of vehicle is	254
generally easier and will facilitate complete administration of the dose. If the homogeneous	255
mixing of the intact or manipulated drug product with a small volume of the vehicle is difficult	256
and requires a large volume (e.g., more than 15 mL) of the vehicle for dosing, exploring alternate	257
vehicles should be considered to avoid incomplete dosing if all of the drug product and vehicle	258
mixture cannot be readily ingested.	259
260
E. 	Drug Product and Vehicle Mixtures for Repeated Use or Multiple Users	261
262
Generally, use of vehicles for drug administration refers to single use of the preparation where	263
the drug product, once mixed with the liquid or soft food, is consumed immediately by a single	264
patient. Under certain circumstances, use of the drug product-vehicle mixture preparation for	265
multiple doses (e.g., one or more patients) can be considered acceptable (i.e., in a healthcare	266
facility or in another setting where qualified professionals are responsible for preparing the drug	267
product-vehicle mixtures and dosing the patients). Adequate characterization of the drug product	268
and vehicle mixture (including adequate in-use stability data and microbiological assessments),	269
and instructions for preparing the drug product-vehicle mixture, should be included in the	270
submission to support such multiple dose labeling statements.	271
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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F. 	Special Case: Administration of Drug Product and Vehicle Mixtures via Feeding	274
Tubes	275
276
In cases where the drug product labeling describes feeding tube administration, orally	277
administered drug products can be given through a feeding tube (oral or enteral) to pediatric or	278
adult patients who are unable to ingest solid or liquid dosage forms.18 In addition to the	279
recommended assessments in this guidance, the feasibility and risk of administration of the drug	280
product-vehicle mixture through a feeding tube should be addressed. For example, if the product	281
may be administered by feeding tube, then an assessment demonstrating delivery of full volume	282
of the mixture with no loss of drug product or potency is necessary, and should include the	283
volume of solution to be used to rinse the feeding tube to ensure complete administration of the	284
mixture. Similarly, factors that can result in the risk of drug aspiration or blockage of the tube	285
should be evaluated.	286
287
G. 	Information from In Vivo and In Vitro Studies	288
289
If the sponsor anticipates use of liquid or soft foods as vehicles for drug administration during	290
drug development and/or after market approval, data from in vivo and in vitro studies should be	291
submitted. Studies to support the compatibility and suitability of the selected vehicle(s), the	292
supporting methodology, and timing of such studies should be discussed with the appropriate	293
review division early in drug development (such as during pre-IND, end-of-phase 2 (EOP2)	294
meetings), or postapproval, as applicable.	295
296
If a liquid or soft food is ultimately recommended as a vehicle(s) for drug administration, patient	297
dosing information should be included in the labeling. For example, this includes the studied	298
vehicle(s), volume of the vehicle(s), frequency of dosing, along with the pharmacokinetic	299
information, if available, which should be included in the Pharmacokinetics subsection of the	300
CLINICAL PHARMACOLOGY section of labeling. For complete information, see section H:	301
Recommendations for Labeling.	302
WG STOPPED	303
Under special circumstances the Agency may request additional studies and in vivo	304
bioavailability data if deemed appropriate (e.g., if there is reason to believe there may be	305
interactions requiring further assessment).	306
307
The in vitro methods described in this document are for selection and qualification of vehicles;	308
they do not replace in vivo food-effect studies.19	
309
310
H. 	Recommendations for Labeling	311
312
If a liquid or soft food is qualified as a vehicle(s) and recommended for the administration of a	313
drug for the target indicated population (or sub-population), such information should be	314
summarized in labeling. The labeling should include sufficient information to ensure that the	315
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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healthcare provider, patient, and/or caregiver has the essential information to use the	316
recommended vehicle(s) to administer the drug safely and effectively and to avoid substitutions	317
that are unacceptable. Labeling should include, as applicable:	318
319
• 	Recommended type(s) of soft food or liquid vehicle(s);	320
321
• 	Detailed vehicle use information, such as the volume and temperature range of the	322
qualified vehicle(s) that are approved for use;	323
324
• 	Recommended critical manipulations, such as emptying capsule contents or crushing a	325
tablet for ease of administration;	326
327
• 	For repeated or multiple use dosing, information concerning the conditions to support	328
preparation of the drug product-vehicle mixture and instructions for its storage between	329
uses;	330
331
• 	Information on compatibility of the recommended vehicle(s) with feeding tube	332
characteristics;	333
334
• 	Information on liquids and soft foods found to be unacceptable, and the rationale for	335
avoiding their use as vehicles.	336
337
A succinct summary of the compatability and suitability study and data that supports the use of	338
liquid or soft food vehicles in the target population as well as relevant data concerning	339
unacceptable vehicles should be discussed in the Pharmacokinetics subsection of the CLINICAL	340
PHARMACOLOGY section.20	
341
342
The DOSAGE AND ADMINISTRATION section should include directions for administering	343
the drug using the recommended liquid or soft food vehicle.22 This section should also include	344
information on the target indicated patient population for delivering the drug using a liquid or	345
soft food vehicle (e.g., pediatric patients, older adults who have difficulty swallowing solid oral	346
dosage forms) as well as the preparation, administration, and storage of the mixed drug product-	347
vehicle. The Instructions for Use should contain detailed patient-appropriate directions for the	348
preparation, administration, and storage of the mixed drug product-vehicle by a patient or	349
caregiver, if applicable.	350
351
A cross-reference to the CLINICAL PHARMACOLOGY section for additional details	352
concerning the liquid or soft food vehicles should be included. See Appendix B for examples for	353
the preparation, administration, and storage of the mixed drug product-vehicle in the DOSAGE	354
AND ADMINISTRATION section.	355
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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IV. 	IN VITRO METHODS RECOMMENDED FOR ASSESSING IMPACT OF A	359
VEHICLE ON PRODUCT QUALITY ATTRIBUTES	360
361
The following approaches are recommended to determine whether a proposed vehicle is	362
compatible and suitable for use with the drug product. Also, see Appendix C (Sample Handling	363
and Qualification Decision Tree) and section IV.B.	364
365
The product quality data generated from the following studies, as applicable for the dosage form,	366
should be included in a report to support qualification of each proposed vehicle and to support	367
that the drug product quality is maintained when the drug product is mixed with the qualified	368
vehicles.	369
370
A. 	Analytical Method	371
372
A validated analytical method should be used to quantify the amount of drug substance in the	373
vehicle mixture for the assessments described in section B below. The drug substance may or	374
may not be exposed to the vehicle depending on the dosage form and sample preparation. If the	375
dosage form remains intact in the vehicle, changes in assay (potency) and drug product	376
performance/integrity are not expected, but the absence of such changes should be verified.	377
378
The analytical method for assay of drug substance in the proposed vehicle should be developed	379
and validated in accordance with the principles outlined in guidances.21,22,23,24 The source of	380
analytical interferences, if observed, between ingredients in liquids or soft foods with the drug	381
substance and the excipients in the dosage forms should be determined.	382
383
B. 	Assessment of the Drug Substance in the “Mixture”	384
385
A series of assessments should be performed to qualify the proposed vehicle for a specific drug	386
product as outlined in the Sample Handling and Qualification decision tree in Appendix C.	387
The following describes the sequence of the assessments in the decision tree:	388
389
1. 	Sample Handling	390
391
A basic screen should be carried out to determine stability of the drug substance in standard GI	392
buffer media and in Fed State Simulated Gastric Fluid (FeSSGF), which is buffer media	393
containing milk. Sample handling processes, depending on the stability of the drug substance in	394
the screening media, or the ability of a drug product coating to prevent exposure to a drug	395
substance that is unstable in the screening media, are described in the decision tree in Appendix	396
C.	397
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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For sample preparation approach B, described in Appendix C, the intact drug product or	399
particulate material containing the drug substance should be separated from the mixture, and	400
integrity and dissolution tests should be performed on the solid particles.	401
402
2. 	Integrity, Potency, Stability, and Homogeneity	403
404
Integrity: A qualified vehicle should be shown to maintain the drug substance quality attributes.	405
If the drug product has a coating and is used intact, the qualified vehicle should have no impact	406
on the coating and as a result, on the integrity of the drug substance within the drug product. In	407
the cases where a coated tablet is to be crushed before mixing and the integrity of the coated	408
tablet is intentionally compromised, or where the drug product dissolves in the vehicle, exposing	409
the drug substance, the potential for the proposed vehicle to impact the integrity of the drug	410
substance (e.g., changes in polymorphic form, loss of bead integrity) should be evaluated.	411
412
Potency (assay): Potency assessment should determine the amount of the drug substance in the	413
drug product-vehicle mixture to support the recommended labeled use time. The testing should	414
be carried out after mixing or dissolving and again two hours after incubating the drug product	415
with the vehicle to support immediate use. If the proposed labeling will include manipulation of	416
the drug product prior to mixing with the vehicle (e.g., emptying capsule contents or crushing a	417
tablet), this should be done prior to the potency assessment. Samples should be collected at	418
predefined time points and assayed for determination of potency. The test should demonstrate a	419
lack of significant change in assay from the original value (where a significant change is defined	420
as no more than five percent of the original value).25	
421
422
When providing mass balance (total recovery) calculations for products where the sample	423
contains particulate material (sample preparation approach B), the amount of drug substance	424
extracted from particulate or intact drug product (such as coated beads, pellets) and the amount	425
of drug substance dissolved/released into the drug product and vehicle mixture should be	426
determined. The recovery data should be consistent with the labeled claim.	427
428
Stability: Stability assessment of the drug product-vehicle mixture should be provided to	429
support labeling instructions for its preparation and labeled use time. To qualify a vehicle for	430
immediate drug administration, a two hour stability assessment (USP controlled room	431
temperature: 20º C-25º C)26 should be conducted in a manner consistent with immediate use of	432
the mixture as described in the labeling. Additionally, stability assessment under refrigerated	433
conditions (USP controlled cold temperature: 2º C-8º C) may be needed.	434
435
If potency testing of the drug product and the vehicle mixture suggests possible interactions (e.g.,	436
a significant loss in the amount of the drug substance is observed), the stability assessment	437
should include testing for degradation products to verify drug substance and drug product	438
integrity, as applicable. Stability-indicating methods should be used to determine the presence of	439
an impurity (in amounts exceeding the accepted threshold) or formation of new degradants as a	440
result of a potential interaction between the multiple components of the drug product and vehicle	441
mixture.	442
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
Homogeneity (dose uniformity): The proposed vehicle(s) should also be suitable for	444
preparation of homogeneous mixtures. The drug product should be thoroughly mixed with the	445
liquid or soft food to ensure a homogeneous mixture. Even though the drug product and vehicle	446
mixture is prepared for immediate use, it is possible that the patient may not ingest all of the	447
mixture immediately. In such cases, the more homogeneous the mixture is, the more reliable the	448
estimate of the ingested dose. To evaluate the homogeneity of the mixture, the drug product and	449
vehicle mixture should be divided into equal portions (n=3 to 6) and tested.	450
451
3. 	Dissolution/Drug Release Testing	452
453
Composition of soft foods or liquids such as added thickeners, sweetening agents, and other	454
ingredients can alter release and delivery of drug substance from the drug product.27 In cases	455
where the drug substance is not immediately dissolved in the liquid or soft food, dissolution/	456
release testing of drug substance from the dosage form mixed with the proposed vehicle should	457
be carried out according to established methods.28 Dissolution testing should be conducted in	458
media typically used for testing solid oral dosage forms and USP Apparatus I or Apparatus II can	459
be used. The following dissolution media are generally recommended: (1) 0.1 N HCl or	460
simulated gastric fluid USP without enzymes; (2) USP buffer at pH 4.5; (3) USP buffer at pH 6.8	461
or simulated intestinal fluid USP with or without enzymes; and (4) FFESSGF.29,30 The sample	462
preparation process should enable assessment of drug dissolution/release patterns for the drug	463
product-vehicle mixture in a manner consistent with drug dissolution/release characteristics and	464
claims for the drug product.	465
466
Typically, 12 individual units of the dosage form are used for dissolution testing of a drug	467
product. This information should be included in the vehicle qualification report or cross-	468
referenced to the drug product information in the submission. For dissolution/release testing of	469
drug substance from the drug product-vehicle mixture, data from six units mixed into the	470
proposed vehicle should be collected at each pre-determined sampling time. A comparison of the	471
dissolution profile for the original product with the drug product mixed with the proposed	472
vehicle should meet the similarity factor (f2) acceptance criteria.31	
473
474
Depending on the targeted patient population, dosage form, and drug substance characteristics,	475
additional in vitro testing may be appropriate to understand the effect of the proposed vehicle(s)	476
on the in vivo dissolution of the drug product.	477
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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4. 	Dosage Form Specific Considerations	480
481
For liquid drug products such as syrups, emulsions, or similar dosage forms, it may be possible	482
to mix the drug product homogenously with the vehicle. In vitro methods for product quality and	483
performance assessments should follow sample preparation and handling, see Appendix C,	484
Approach A of the Decision Tree.	485
486
Dosage form characteristics and composition of the drug product should be considered to ensure	487
that sample preparation and handling approaches are consistent with the intended in vivo	488
performance of the drug product.	489
490
Certain use conditions, such as emergency use, and/or use in a professional healthcare setting,	491
may necessitate other testing approaches that are not discussed in this guidance. We recommend	492
that sponsors consult with the appropriate review division for cases that require unique	493
considerations.	494
495
496
V. 	LOCATION OF DATA IN SUBMISSIONS	497
498
The information supporting selection and qualification of the vehicle to be mixed with the drug	499
should be provided as a separate report in the 3.2.P.2 (Pharmaceutical development) section of a	500
common technical document (CTD)32-formatted application.	501
502
In the proposed labeling portion of a submission, information related to the drug product-vehicle	503
mixture including important preparation and administration instructions should be included in	504
the DOSAGE AND ADMINISTRATION section, and any relevant pharmacokinetic	505
information, if available, should be included in the Pharmacokinetics subsection of the	506
CLINICAL PHARMACOLOGY section of labeling.	507
508
32 See ICH guidance for industry M4Q(R1) Technical Requirements for Registration of Pharmaceuticals for Human
Use.

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APPENDIX A	509
510
Commonly Used Soft Foods and Liquids With Their Approximate pH Range	511
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
Reference, unless otherwise noted,	514
https://www.clemson.edu/extension/hgic/food/pdf/hgic3030.pdf.	515
516 a: Clin. Ther. 2008, 30 (7), 1300-1308.	517 b: National Secondary Drinking Water Regulations (http://www.water-research.net/index.php/standards/secondary-	518 standards).	519 c: Grapefruit juice is not recommended for using as a vehicle	520 (www.health.harvard.edu/fhg/updates/update0206d.shtml). Its inclusion here is for reference purposes only.	521 d: Honey is not recommended for children under age of 12 (Spika JS, N Shaffer, N Hargrett-Bean, S Collin, KL	522 MacDonald, PA Blake, 1989, Risk Factors for Infant Botulism in the United States, Am J Dis Child, 143(7):828-	523 832, and https://www.cdc.gov/dotw/botulism/index.html).	524 e: http://elitepublishing.net/ph_foods.html.	525
526
527

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APPENDIX B	528
529
Examples of Labeling Language	530
531
The following examples illustrate labeling text for the DOSAGE AND ADMINISTRATION	532
section for drug products (as is or in a manipulated form) that can be mixed with liquids or soft	533
foods. The labeling should include specific use information, such as the volume and temperature	534
of the qualified vehicle(s) approved for use.	535
536
• 	Drug X capsules should be swallowed intact with a glass of water. For patients with	537
swallowing difficulties, Drug X capsules can be opened and the contents sprinkled onto	538
a teaspoon (5 mL) or tablespoon (15 mL) of soft food and ingested immediately. Use	539
only foods that do not require chewing, such as apricot, banana, or sweet potato baby	540
food; applesauce; and instant pudding. Contact of the capsule contents with foods such	541
as milk, custard, ice cream, and many other dairy products can dissolve the protective	542
(or enteric) coating and destroy the drug substance.	543
544
• 	Drug Y packet contents can be administered 1) dissolved in 1 teaspoonful (5 mL) of	545
cold or room temperature milk or breast milk, or 2) mixed with a teaspoonful (5 mL)	546
of cold or room temperature applesauce or banana puree. 	Puddings or formula	547
containing soybean flour, and vegetable purees should not be used because the fiber in	548
these foods can bind the drug substance. 	Liquids or other foods can be ingested	549
subsequent to the administration of Drug Y packet contents.	550
551
• 	Once Drug Y packet is opened, the full dose (with or without mixing with milk, breast	552
milk, or the apple and banana puree) must be administered immediately. If all of the	553
mixture is not ingested, discard any unused portion. Any unused contents of Drug Y	554
packet must not be stored for future use.	555
556

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APPENDIX C	557
558
Sample Handling and Qualification Decision Tree	559
560
Approaches for sample preparation and handling are described to support drug product quality	561
assessments to determine whether the selected soft food or liquid qualifies for use as a vehicle.	562
563
564
565
566 * Drug product labeling should describe the qualified vehicle and any studied vehicles that cannot be used.	567
568
Sample handling Approach A (drug substance is completely dissolved and particulate	569
material, if any, is not the drug substance):	570
571
Depending on the type of sample (diluted soft food or liquid), sample preparation may involve a	572
simple filtration step followed by chromatographic separation and analysis of the drug substance;	573
in some cases, an additional extraction step from the soft food or liquid may be required before	574
sample analysis.	575
576
Sample handling Approach B (sample contains particulate material and some of the drug	577
can be in the particulate material):	578
579
a) 	Once the sample is taken from the media (soft food or liquid), the particulate matter is	580
washed and separated for further analysis.	581
582

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b) 	The wash and the remaining soft food or liquid is combined and processed for assaying	583
for the drug substance.	584
585
c) 	The particulate matter (such as pellets) retrieved from the vehicle and washed as in	586
Approach A above should be tested according to the dissolution method to determine	587
release characteristics, as well as the amount of remaining drug substance in the	588
particulate material.	589
590
d) 	Depending on the type of sample (diluted soft food or liquid), sample preparation in	591
Approach B above may involve a simple filtration step followed by chromatographic	592
separation and analysis of the drug substance; in some cases an additional extraction step	593
from the soft food or liquid may be required before sample analysis.	594
595