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

DRAFT GUIDANCEThis guidance document is being distributed for comment purposes only.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publication in the Federal Register of the notice announcing the availability of the draft
guidance.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 writtencomments 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 thedocket number listed in the notice of availability that publishes in the Federal Register.
For questions regarding this draft document, contact (CDER) Mamta Gautam-Basak, 301-7960712.

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 ProductQuality 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

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TABLE OF CONTENTSI.

INTRODUCTION............................................................................................................. 1II.

BACKGROUND ............................................................................................................... 2

III.

GENERAL CONSIDERATIONS AND RECOMMENDATIONS .............................. 3A.

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 ..... 8G.

Information from In Vivo and In Vitro Studies .......................................................................... 8H.

Recommendations for Labeling .................................................................................................... 8IV.

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

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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 1

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This draft guidance, when finalized, will represent the current thinking of the Food and Drug
Administration (FDA or Agency) on this topic. It does not establish any rights for any person and is notbinding on FDA or the public. You can use an alternative approach if it satisfies the requirements of theapplicable statutes and regulations. To discuss an alternative approach, contact the FDA staff responsible
for this guidance as listed on the title page.

I.

INTRODUCTION

This guidance applies to orally administered drug products and provides recommendations tosponsors 2 who will use or recommend use of liquids 3 and/or soft foods as vehicles for drug
administration in investigational new drug applications (INDs), new drug applications (NDAs),
Biologics License Applications (BLAs), as applicable, and in supplements to these applications. 4This guidance addresses the approaches recommended for suitability determination of vehicles
intended for use with specific drug products by providing the following:•Considerations for selection of liquids and/or soft foods as vehicles.

•

Standardized in vitro methodology and data recommendations for drug product quality
assessments to qualify vehicle(s) for drug product administration.

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 andDrug 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 productspecific Agency guidance. With respect to ANDAs and the recommendations contained in this guidance, we notethat immediate-release solid oral dosage forms generally are considered to be products for which formulationdifferences between generic products and their reference listed drug (RLD) would not impact administration withvehicles. The vehicle studies on the RLD would establish the compatibility of the active ingredient with therecommended 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 thisguidance could be used to confirm that the formulation of a generic product is compatible with the vehicles ofadministration in the RLD label. If FDA determined that in vivo data are needed to support use of a vehicle for ageneric 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 productlabeling. If certain foods are found unacceptable, they should also be included in thelabeling.

This guidance and the methods it describes do not replace existing guidance documents that
address food-effect assessments on the drug product 5 or dosage form, or stability testing
conducted to support a shelf-life determination. 6 For those drug products marketed with avehicle for administration (i.e., the vehicle is co-packaged with the drug product), therecommendations regarding selection and methods provided in this guidance are applicable,
but additional considerations and recommendations may also apply.
If a different approach than those recommended in this guidance is used, sponsors areencouraged to discuss the proposed approach with the appropriate FDA quality assessment staff
before conducting the studies.
In general, FDA’s guidance documents do not establish legally enforceable responsibilities.
Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only
as recommendations, unless specific regulatory or statutory requirements are cited. The use of
the word should in Agency guidances means that something is suggested or recommended, but
not required.

II.

BACKGROUND

There are many commercial drug product dosage forms such as granules, pellets, powders, ortablets for which the drug product labeling includes instructions for the optional use of soft foods
or liquids as vehicles for their administration.
In the absence of availability of a dosage form that is appropriate for the targeted patient
population (e.g., pediatric, geriatric), small amounts of liquids and/or soft foods as described in
the FDA-approved product labeling can be used as a suitable vehicle(s) for oral administrationand immediate ingestion of the specific drug product. Generally, drug products mixed in small
amounts of liquids (5 to 15 mL) or soft foods are used in pediatric and other patient populations
who are unable to swallow solid oral dosage forms. Although sponsors are required to develop
age-appropriate formulations as part of a pediatric drug development program 7 occasionally thedevelopment of age-appropriate dosage forms and formulations proves to be exceedingly
complex. The use of a liquid such as infant formula or breast milk and/or soft food as avehicle(s) may be the only option for delivering the drug substance to the targeted patient
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).

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product, and are deemed compatible and suitable for use in the targeted patient populations, areconsidered suitable for use as vehicles with the specific drug product. The drug product-vehicle
mixture is not considered a new dosage form of the existing drug.
To ensure consistency in drug product quality when administered with a vehicle, it is important
to standardize the methodology supporting vehicle selection, and the supportive data to designate
vehicle suitability. Standardization of the preparation and use instructions for the drug productvehicle mixture is also important, as ambiguity in instructions or incomplete information canlead to unintended outcomes, including dosing errors and/or misuse of the drug product.
The methodology described in this guidance is intended to improve consistency in these areas
and applies to potential use of vehicles during different stages of drug development, including
lifecycle management as follows:•

During development (IND stage): to select a vehicle for administering the test drug
product to populations who are unable to swallow solid oral dosage forms (e.g., children,
older adult patients); and for some bioavailability (BA) studies conducted forformulation development and optimization.

•

Prior to marketing application (NDA stage): to propose a vehicle(s) for use of the drug
product for the original or additional condition of use (e.g., a new indication or new
patient population).

•

Postapproval or supplement submission: to propose changes to the drug product or its
labeling that necessitate reassessment of compatibility and suitability of the approved
vehicle.

Considerations and in vitro methods described in this guidance are also applicable for selecting
vehicles out of necessity in unusual circumstances, such as when considering counterterrorism
measures. 8 In such cases, when the benefits outweigh risks and alternate dosage forms areunavailable, liquids and/or soft foods may be used as vehicles for specific drug products.

III.

GENERAL CONSIDERATIONS AND RECOMMENDATIONS

Only those liquids and/or soft foods demonstrated to have no appreciable effect on drug productperformance should be proposed as vehicles. The potential impact of a vehicle on drug productperformance is determined by assessment of drug product quality attributes, including potency(assay), in vitro dissolution/release, and other pertinent attributes when the drug product is usedwith the proposed vehicle(s). In section IV, standardized in vitro methods for evaluatingcompatibility of the proposed liquid and/or soft food are described.

8

Refer to the following:
http://www.fda.gov/Drugs/EmergencyPreparedness/BioterrorismandDrugPreparedness/ucm130996.htm andhttp://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
forms such as granules, pellets, powders, as well as certain specific modified release drug
products such as coated mini-tablets or beads that are labeled to be administered via sprinkling(e.g., capsules or packets containing beads). 9 When a drug product requires handling to make itsuitable for administration in a vehicle, such as crushing a tablet, emptying capsule contents,
making serial dilutions, or mixing syrup into a vehicle, the resultant product is referred to as a“manipulated” drug product in this document. If critical manipulations are needed, such as
emptying capsule contents or crushing a tablet to mix with the vehicle for ease of administration,
the impact of the manipulations should be studied. The preparation and use instructions provided
in labeling should give clear instructions that can be followed by the patient, caregiver, or
healthcare professional in a homecare setting or a healthcare facility. 10
The following are key considerations and recommendations for selection and use of vehicles for
drug product administration and are intended to ensure that any liquid or soft food proposed as avehicle does not compromise drug product performance.
A.

Selection of Liquids and Soft Foods: Compatibility and Suitability

Using liquids and soft foods as vehicles for drug administration can prove to be challenging
because many factors such as seasonal, regional and climate conditions can influence thecomposition of natural food substances. Liquids and soft foods that have relatively small
fluctuations in their composition and characteristics (such as sugar content, acidity, viscosity)
may be better candidates for screening as potentially compatible liquids and/or soft foods withdrug products for further testing. Liquids and/or soft foods should be screened with considerationof the following characteristics: 1) the drug substance, 2) the drug product, 3) the properties ofthe proposed vehicle, such as its acidity/alkalinity and binding/chelating characteristics, and 4)
the target population. For liquid dosage forms, composition of the drug product (including use ofstabilizing, emulsifying, and suspending agents) should be considered when selecting possible
vehicles to mix with the drug product. If possible, sponsors should identify more than one
compatible vehicle to provide options for patients with allergy or intolerance to a single vehicle.
For compatibility assessments, the pH value of proposed liquids and soft foods should beconsidered before further testing for their compatibility with the intact or manipulated drug
product, including products with coatings. For example, for drug products with an intact entericprotective coating suitable for an acidic environment with pH values up to pH 5, the proposed
vehicle should not have a pH value higher than 5, as exposing the coating to higher pH values
will disrupt and remove the coating from the drug product. 11,12 See Appendix A for commonlyused soft foods and liquids with their approximate pH ranges.

9

See guidance for industry Size of Beads in Drug Products Labeled for Sprinkle.
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.
10

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It is important that a comprehensive suitability determination is performed to evaluate potential
use of the proposed vehicle in the targeted patient population. Suitability determinations should
include a composite assessment of multiple factors, such as the patient’s medical condition;
perceptions of the product-vehicle mixture such as flavor, texture, and mouthfeel; and agerelated responses to physical characteristics of the mixture. For example, perception of mouthfeelof the intact or manipulated drug product in the vehicle mixture will vary with the targeted
patient population. Graininess of the drug product and vehicle mixture can trigger chewing inyoung patients.
If a certain liquid or soft food is considered unsuitable for the targeted patient population, even if
the proposed vehicle(s) and the intact or manipulated drug product are chemically compatible,
the indicated soft food or liquid may not be considered an acceptable vehicle for use. For
example, adding a drug product to applesauce or another soft food is inappropriate if the targeted
patient population is infants who are not yet eating solid food. Such data, when available, forliquids and soft foods evaluated and found to be unacceptable should also be submitted,
including the rationale for avoiding their use as vehicles.
B.

Impact of Vehicle on the Drug ProductA direct assessment of the impact of the proposed vehicle on the intact or manipulated drug
product should be conducted to determine the compatibility of the proposed vehicle with thedrug product. Specifically, a liquid or soft food is considered suitable for use as a vehicle fordrug product administration when it has no appreciable effect on drug product stability or
performance. The resulting drug product-vehicle mixture should exhibit no change in potency (asdetermined by assay) over the proposed use time period and no significant change in drug releasecharacteristics. See section IV for recommended methods.
Once combined, the drug product and vehicle mixture should be ingested immediately (or as
directed in the labeling) to avoid dosing errors or inadvertent dosing, and inadvertentcontamination of the drug product-vehicle mixture. When the labeling calls for immediate use of
the mixture, such use should be adequately supported by product quality assessments that are
carried out at pre-determined times over two hours after preparation of the mixture. The twohour assessment period is considered to provide the necessary time window to ensure physicaland chemical stability of the drug product-vehicle mixture. Microbiological testing is not needed
for the drug product-vehicle mixture if it is intended to be used within two hours because the riskof microbial proliferation to harmful levels is miminal. See section IV for recommended test
methods.
C.

Patient Adherence and Acceptance: Palatability and Swallowability13

Adherence is defined as the degree of constancy and accuracy with which a patient takes a drug
product as instructed by his or her healthcare provider, and is a key factor in successful
therapeutic intervention. Factors that impact adherence include: 1) patient acceptance of the13

Thompson CA, Lombardi DP, Sjostedt P, Squires LA, 2013, Industry Survey on Current Practices in theAssessment 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) theability of the caregiver to administer the drug product as intended.
Acceptance of the drug product is determined in part by palatability and swallowability thatwould determine the patient adherence. Palatability is defined as the quality of a drug productthat makes it pleasant or acceptable in terms of taste, after-taste, smell, and texture and is a
critical factor in determining patient acceptance of oral dosage forms. Swallowability may be
defined as the patient being able to take the drug without gagging or choking. Taste sensation
develops early in life and evolves with age. In general, the goal should be to develop drug
formulations with a neutral taste that would be acceptable to the majority of patients. Althoughtaste-masking technology is advancing rapidly, for those drug products where taste-masking is
not possible, alternate approaches such as mixing with appropriate liquids and/or soft foods tomask taste can be employed to improve palatability of a finished dosage form. In cases where thedrug substance dissolves in the vehicle, the drug product and vehicle mixture should be
adequately taste-masked, if necessary for palatability.
Palatability of a drug product mixed with a vehicle can be influenced by factors including, but
not limited to, concomitant disease, condition or medication and targeted patient population (e.g.,pediatric or geriatric). Disease states can also influence a patient’s sensory perceptions and affectthe patient’s ability to swallow certain dosage forms. In addition, cultural aspects such as dietand societal influences can impact a patient’s preference for certain liquids or soft foods asvehicles. Therefore, the palatability and swallowability of the drug product mixed with thevehicle should be determined in the intended population of use.
Methods for quantitative assessments of palatability and swallowability for drug products areadvancing and continue to evolve. 14,15 Sponsors should discuss their planned approach to assess
palatability and swallowability of their drug product with the appropriate review divison. The
assessments should consider relevant patient characteristics (such as age, disease or medical
condition, concomitant medications, etc.), characteristics of the vehicle mixture(s) (such as taste,
flavor, texture, and mouthfeel), and the ability of patients in the targeted population to swallow
the drug product-vehicle mixture.
D.

Drug Product and Vehicle1.

Preparation and Handling Procedures

In the selection of the vehicle, consideration should be given to the complexity of the
preparation, homogeneity of the mixture, and handling procedures as these can result in
decreased accuracy in dose delivery. Mixing drug products (intact or manipulated) with liquids
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 Assessmentof 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 andbeyond, 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
dosing accuracy, as appropriate, an oral syringe or measuring spoon should be included with thedrug product along with clear use instructions. 16
Carrying out dilutions accurately in a homecare setting can be difficult. To enable accurate
dosing, tablet splitting of non-scored tablets or dilutions should be avoided, unless stated in thelabel. Even with functionally scored tablets, there are limitations in accurately dividing a tablet
into dose strengths beyond that provided by the scoring. 17 For example, we recommend against
dividing nonfunctionally scored tablets into smaller doses (such as one-fourth of a tablet),because it can result in crumbling of the tablet and inaccuracy of the recommended dose. For
unscored tablets the manufacture/availability of multiple strengths of the drug product is highly
encouraged.
2.

Dose and Dosing Volume

The suggested volume of the vehicle for mixing with solid oral dosage forms should take into
consideration the age, size, and average consumption of the vehicle by the targeted patient
population. For example, children younger than two years old may not be able or willing toingest large volumes of liquids or soft foods at one time, whereas this volume may be acceptable
for an older child or adult. To ensure administration of the full dose of the drug and to facilitate
swallowing, the smallest volume of vehicle(s) sufficient to provide acceptable taste-masking,roughly 5 to 15 mL, should be used to prepare the drug product and vehicle mixture. In addition,
homogeneous (i.e., uniform) mixing of the drug product in a smaller volume of vehicle isgenerally easier and will facilitate complete administration of the dose. If the homogeneous
mixing of the intact or manipulated drug product with a small volume of the vehicle is difficult
and requires a large volume (e.g., more than 15 mL) of the vehicle for dosing, exploring alternate
vehicles should be considered to avoid incomplete dosing if all of the drug product and vehicle
mixture cannot be readily ingested.
E.

Drug Product and Vehicle Mixtures for Repeated Use or Multiple Users

Generally, use of vehicles for drug administration refers to single use of the preparation where
the drug product, once mixed with the liquid or soft food, is consumed immediately by a single
patient. Under certain circumstances, use of the drug product-vehicle mixture preparation for
multiple doses (e.g., one or more patients) can be considered acceptable (i.e., in a healthcare
facility or in another setting where qualified professionals are responsible for preparing the drug
product-vehicle mixtures and dosing the patients). Adequate characterization of the drug productand vehicle mixture (including adequate in-use stability data and microbiological assessments),
and instructions for preparing the drug product-vehicle mixture, should be included in thesubmission to support such multiple dose labeling statements.

16

We recommend that ANDAs for which the RLD contains these materials submit data and information in theapplication 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
Tubes

In cases where the drug product labeling describes feeding tube administration, orally
administered drug products can be given through a feeding tube (oral or enteral) to pediatric oradult patients who are unable to ingest solid or liquid dosage forms. 18 In addition to therecommended assessments in this guidance, the feasibility and risk of administration of the drug
product-vehicle mixture through a feeding tube should be addressed. For example, if the productmay be administered by feeding tube, then an assessment demonstrating delivery of full volumeof the mixture with no loss of drug product or potency is necessary, and should include thevolume of solution to be used to rinse the feeding tube to ensure complete administration of the
mixture. Similarly, factors that can result in the risk of drug aspiration or blockage of the tube
should be evaluated.
G.

Information from In Vivo and In Vitro Studies

If the sponsor anticipates use of liquid or soft foods as vehicles for drug administration during
drug development and/or after market approval, data from in vivo and in vitro studies should besubmitted. Studies to support the compatibility and suitability of the selected vehicle(s), thesupporting methodology, and timing of such studies should be discussed with the appropriate
review division early in drug development (such as during pre-IND, end-of-phase 2 (EOP2)
meetings), or postapproval, as applicable.
If a liquid or soft food is ultimately recommended as a vehicle(s) for drug administration, patient
dosing information should be included in the labeling. For example, this includes the studied
vehicle(s), volume of the vehicle(s), frequency of dosing, along with the pharmacokinetic
information, if available, which should be included in the Pharmacokinetics subsection of the
CLINICAL PHARMACOLOGY section of labeling. For complete information, see section H:
Recommendations for Labeling.
WG STOPPED
Under special circumstances the Agency may request additional studies and in vivo
bioavailability data if deemed appropriate (e.g., if there is reason to believe there may beinteractions requiring further assessment).
The in vitro methods described in this document are for selection and qualification of vehicles;
they do not replace in vivo food-effect studies. 19
H.

Recommendations for Labeling

If a liquid or soft food is qualified as a vehicle(s) and recommended for the administration of adrug for the target indicated population (or sub-population), such information should besummarized in labeling. The labeling should include sufficient information to ensure that the18

Williams NT, 2008, Medication administration through enteral feeding tubes, Am J Health-Syst Pharm, 65:23472357.
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 therecommended vehicle(s) to administer the drug safely and effectively and to avoid substitutions
that are unacceptable. Labeling should include, as applicable:•

Recommended type(s) of soft food or liquid vehicle(s);•Detailed vehicle use information, such as the volume and temperature range of thequalified vehicle(s) that are approved for use;•

Recommended critical manipulations, such as emptying capsule contents or crushing atablet for ease of administration;•

For repeated or multiple use dosing, information concerning the conditions to support
preparation of the drug product-vehicle mixture and instructions for its storage between
uses;

•

Information on compatibility of the recommended vehicle(s) with feeding tube
characteristics;•

Information on liquids and soft foods found to be unacceptable, and the rationale foravoiding their use as vehicles.

A succinct summary of the compatability and suitability study and data that supports the use of
liquid or soft food vehicles in the target population as well as relevant data concerning
unacceptable vehicles should be discussed in the Pharmacokinetics subsection of the CLINICALPHARMACOLOGY section. 20
The DOSAGE AND ADMINISTRATION section should include directions for administering
the drug using the recommended liquid or soft food vehicle.22 This section should also include
information on the target indicated patient population for delivering the drug using a liquid orsoft food vehicle (e.g., pediatric patients, older adults who have difficulty swallowing solid oral
dosage forms) as well as the preparation, administration, and storage of the mixed drug productvehicle. The Instructions for Use should contain detailed patient-appropriate directions for the
preparation, administration, and storage of the mixed drug product-vehicle by a patient or
caregiver, if applicable.
A cross-reference to the CLINICAL PHARMACOLOGY section for additional details
concerning the liquid or soft food vehicles should be included. See Appendix B for examples forthe preparation, administration, and storage of the mixed drug product-vehicle in the DOSAGE
AND ADMINISTRATION section.

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
VEHICLE ON PRODUCT QUALITY ATTRIBUTESThe following approaches are recommended to determine whether a proposed vehicle iscompatible and suitable for use with the drug product. Also, see Appendix C (Sample Handlingand Qualification Decision Tree) and section IV.B.
The product quality data generated from the following studies, as applicable for the dosage form,should be included in a report to support qualification of each proposed vehicle and to support
that the drug product quality is maintained when the drug product is mixed with the qualified
vehicles.
A.

Analytical Method

A validated analytical method should be used to quantify the amount of drug substance in thevehicle mixture for the assessments described in section B below. The drug substance may or
may not be exposed to the vehicle depending on the dosage form and sample preparation. If thedosage form remains intact in the vehicle, changes in assay (potency) and drug productperformance/integrity are not expected, but the absence of such changes should be verified.
The analytical method for assay of drug substance in the proposed vehicle should be developed
and validated in accordance with the principles outlined in guidances. 21,22,23,24 The source ofanalytical interferences, if observed, between ingredients in liquids or soft foods with the drug
substance and the excipients in the dosage forms should be determined.
B.

Assessment of the Drug Substance in the “Mixture”

A series of assessments should be performed to qualify the proposed vehicle for a specific drug
product as outlined in the Sample Handling and Qualification decision tree in Appendix C.
The following describes the sequence of the assessments in the decision tree:
1.

Sample Handling

A basic screen should be carried out to determine stability of the drug substance in standard GI
buffer media and in Fed State Simulated Gastric Fluid (FeSSGF), which is buffer media
containing milk. Sample handling processes, depending on the stability of the drug substance inthe screening media, or the ability of a drug product coating to prevent exposure to a drug
substance that is unstable in the screening media, are described in the decision tree in Appendix
C.

21

See guidance for industry Analytical Procedures and Methods Validation for Drugs and Biologics.
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.
22

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For sample preparation approach B, described in Appendix C, the intact drug product orparticulate material containing the drug substance should be separated from the mixture, andintegrity and dissolution tests should be performed on the solid particles.
2.

Integrity, Potency, Stability, and Homogeneity

Integrity: A qualified vehicle should be shown to maintain the drug substance quality attributes.
If the drug product has a coating and is used intact, the qualified vehicle should have no impact
on the coating and as a result, on the integrity of the drug substance within the drug product. In
the cases where a coated tablet is to be crushed before mixing and the integrity of the coatedtablet is intentionally compromised, or where the drug product dissolves in the vehicle, exposing
the drug substance, the potential for the proposed vehicle to impact the integrity of the drug
substance (e.g., changes in polymorphic form, loss of bead integrity) should be evaluated.
Potency (assay): Potency assessment should determine the amount of the drug substance in the
drug product-vehicle mixture to support the recommended labeled use time. The testing should
be carried out after mixing or dissolving and again two hours after incubating the drug productwith the vehicle to support immediate use. If the proposed labeling will include manipulation of
the drug product prior to mixing with the vehicle (e.g., emptying capsule contents or crushing atablet), this should be done prior to the potency assessment. Samples should be collected at
predefined time points and assayed for determination of potency. The test should demonstrate alack of significant change in assay from the original value (where a significant change is defined
as no more than five percent of the original value). 25
When providing mass balance (total recovery) calculations for products where the sample
contains particulate material (sample preparation approach B), the amount of drug substance
extracted from particulate or intact drug product (such as coated beads, pellets) and the amountof drug substance dissolved/released into the drug product and vehicle mixture should bedetermined. The recovery data should be consistent with the labeled claim.
Stability: Stability assessment of the drug product-vehicle mixture should be provided tosupport labeling instructions for its preparation and labeled use time. To qualify a vehicle for
immediate drug administration, a two hour stability assessment (USP controlled room
temperature: 20º C-25º C) 26 should be conducted in a manner consistent with immediate use of
the mixture as described in the labeling. Additionally, stability assessment under refrigerated
conditions (USP controlled cold temperature: 2º C-8º C) may be needed.
If potency testing of the drug product and the vehicle mixture suggests possible interactions (e.g.,a significant loss in the amount of the drug substance is observed), the stability assessment
should include testing for degradation products to verify drug substance and drug productintegrity, as applicable. Stability-indicating methods should be used to determine the presence ofan impurity (in amounts exceeding the accepted threshold) or formation of new degradants as aresult of a potential interaction between the multiple components of the drug product and vehicle
mixture.
25
26

See ICH guidance for industry Q1A(R2) Stability Testing of New Drug Substances and Products.
See USP 40-NF 35, General Chapter <659> PACKAGING AND STORAGE REQUIREMENTS.

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Homogeneity (dose uniformity): The proposed vehicle(s) should also be suitable forpreparation of homogeneous mixtures. The drug product should be thoroughly mixed with theliquid or soft food to ensure a homogeneous mixture. Even though the drug product and vehicle
mixture is prepared for immediate use, it is possible that the patient may not ingest all of the
mixture immediately. In such cases, the more homogeneous the mixture is, the more reliable theestimate of the ingested dose. To evaluate the homogeneity of the mixture, the drug product andvehicle mixture should be divided into equal portions (n=3 to 6) and tested.
3.

Dissolution/Drug Release Testing

Composition of soft foods or liquids such as added thickeners, sweetening agents, and otheringredients can alter release and delivery of drug substance from the drug product. 27 In cases
where the drug substance is not immediately dissolved in the liquid or soft food, dissolution/
release testing of drug substance from the dosage form mixed with the proposed vehicle should
be carried out according to established methods. 28 Dissolution testing should be conducted inmedia typically used for testing solid oral dosage forms and USP Apparatus I or Apparatus II canbe used. The following dissolution media are generally recommended: (1) 0.1 N HCl or
simulated gastric fluid USP without enzymes; (2) USP buffer at pH 4.5; (3) USP buffer at pH 6.8
or simulated intestinal fluid USP with or without enzymes; and (4) FFESSGF. 29,30 The sample
preparation process should enable assessment of drug dissolution/release patterns for the drug
product-vehicle mixture in a manner consistent with drug dissolution/release characteristics andclaims for the drug product.
Typically, 12 individual units of the dosage form are used for dissolution testing of a drug
product. This information should be included in the vehicle qualification report or crossreferenced to the drug product information in the submission. For dissolution/release testing ofdrug substance from the drug product-vehicle mixture, data from six units mixed into the
proposed vehicle should be collected at each pre-determined sampling time. A comparison of the
dissolution profile for the original product with the drug product mixed with the proposed
vehicle should meet the similarity factor (f2) acceptance criteria. 31
Depending on the targeted patient population, dosage form, and drug substance characteristics,
additional in vitro testing may be appropriate to understand the effect of the proposed vehicle(s)on the in vivo dissolution of the drug product.

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 Applicationin Dissolution Testing, Dissolution technologies, p 15-28.
31
Ibid.

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4.

Dosage Form Specific Considerations

For liquid drug products such as syrups, emulsions, or similar dosage forms, it may be possible
to mix the drug product homogenously with the vehicle. In vitro methods for product quality andperformance assessments should follow sample preparation and handling, see Appendix C,
Approach A of the Decision Tree.
Dosage form characteristics and composition of the drug product should be considered to ensurethat sample preparation and handling approaches are consistent with the intended in vivo
performance of the drug product.
Certain use conditions, such as emergency use, and/or use in a professional healthcare setting,
may necessitate other testing approaches that are not discussed in this guidance. We recommendthat sponsors consult with the appropriate review division for cases that require uniqueconsiderations.

V.

LOCATION OF DATA IN SUBMISSIONS

The information supporting selection and qualification of the vehicle to be mixed with the drug
should be provided as a separate report in the 3.2.P.2 (Pharmaceutical development) section of acommon technical document (CTD) 32-formatted application.
In the proposed labeling portion of a submission, information related to the drug product-vehicle
mixture including important preparation and administration instructions should be included in
the DOSAGE AND ADMINISTRATION section, and any relevant pharmacokinetic
information, if available, should be included in the Pharmacokinetics subsection of the
CLINICAL PHARMACOLOGY section of labeling.

32

See ICH guidance for industry M4Q(R1) Technical Requirements for Registration of Pharmaceuticals for Human
Use.

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APPENDIX A
Commonly Used Soft Foods and Liquids With Their Approximate pH Range

Apples (puree)Apple juice
Applesauce
Baby food, unstrained
Bananas (puree)
Buttermilk
Carrots (puree)
Chocolate pudding(a)Coconut milk
Cranberry juice
Drinking water (b)Fruit jellies
Fruit jam
Grapefruit juice (c)Honey (d)Infant formula
Maple syrup (e)MilkOrange juice
Orange marmalade
Peanut butter
Pineapple juice
Rice pudding (a)Soybean milk
Strawberries
Strawberry jam
Yogurt
513
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517
518
519
520
521
522
523
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527

pH range
3.34 – 3.90
3.35 – 4.00
3.10 – 3.60
5.95 – 6.05
4.5 – 5.2
4.41 – 4.83
5.88 – 6.40
5.5 – 6.0
6.1 – 7.0
2.30 – 2.52
6.5 – 8.5
3.0 – 3.5
3.5 – 4.5
2.90 – 3.25
3.70 – 4.20
5.7 – 6.0
4.6 – 5.15
6.4 – 6.8
3.30 – 4.19
3.00 – 3.33
6.28
3.30 – 3.60
4–5
7
3.00 – 3.90
3.00 – 3.40
4.4 – 5.0

Reference, unless otherwise noted,
https://www.clemson.edu/extension/hgic/food/pdf/hgic3030.pdf.
a: Clin. Ther. 2008, 30 (7), 1300-1308.
b: National Secondary Drinking Water Regulations (http://www.water-research.net/index.php/standards/secondarystandards).
c: Grapefruit juice is not recommended for using as a vehicle(www.health.harvard.edu/fhg/updates/update0206d.shtml). Its inclusion here is for reference purposes only.
d: Honey is not recommended for children under age of 12 (Spika JS, N Shaffer, N Hargrett-Bean, S Collin, KL
MacDonald, PA Blake, 1989, Risk Factors for Infant Botulism in the United States, Am J Dis Child, 143(7):828832, and https://www.cdc.gov/dotw/botulism/index.html).
e: http://elitepublishing.net/ph_foods.html.

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APPENDIX B
Examples of Labeling Language
The following examples illustrate labeling text for the DOSAGE AND ADMINISTRATION
section for drug products (as is or in a manipulated form) that can be mixed with liquids or soft
foods. The labeling should include specific use information, such as the volume and temperatureof the qualified vehicle(s) approved for use.
•

Drug X capsules should be swallowed intact with a glass of water. For patients with538

swallowing difficulties, Drug X capsules can be opened and the contents sprinkled onto539

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 such542

as milk, custard, ice cream, and many other dairy products can dissolve the protective543(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 formula548

containing soybean flour, and vegetable purees should not be used because the fiber in549

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 the554

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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559
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564

565
566
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569
570
571
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573
574
575
576
577
578
579
580
581
582

APPENDIX C
Sample Handling and Qualification Decision Tree
Approaches for sample preparation and handling are described to support drug product quality
assessments to determine whether the selected soft food or liquid qualifies for use as a vehicle.

* Drug product labeling should describe the qualified vehicle and any studied vehicles that cannot be used.

Sample handling Approach A (drug substance is completely dissolved and particulatematerial, if any, is not the drug substance):
Depending on the type of sample (diluted soft food or liquid), sample preparation may involve a
simple filtration step followed by chromatographic separation and analysis of the drug substance;
in some cases, an additional extraction step from the soft food or liquid may be required before
sample analysis.
Sample handling Approach B (sample contains particulate material and some of the drug
can be in the particulate material):a) Once the sample is taken from the media (soft food or liquid), the particulate matter iswashed and separated for further analysis.

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

17