Guidance for Industry 

Size of Beads in Drug Products 

Labeled for Sprinkle 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 

Food and Drug Administration 

Center for Drug Evaluation and Research (CDER) 

 
May 2012 

CMC 

Rev. 1 

 
 
   
Guidance for Industry 

Size of Beads in Drug Products 

Labeled for Sprinkle 

 
 
 
Additional copies are available from: 

Office of Communications 
 
Division of  Drug Information, WO51, Room  2201 
 
Center for Drug Evaluation  and Research  

Food and  Drug Administration 

10903 New Hampshire Ave. 

Silver Spring, MD 20993-0002 
  
Phone: 301-796-3400;  Fax: 301-847-8714 
 
druginfo@fda.hhs.gov 

 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) 

 
May 2012 

CMC 

Rev. 1 

 
  Contains Nonbinding Recommendations 
 
TABLE OF CONTENTS 

 
 
 
I.  INTRODUCTION.................................................................................................................1
  
II.   BACKGROUND.......................................................................................1   
 
III.  DISCUSSION...........................................................................................2 
A.  Maximum Bead Size for Drug Products Labeled for Sprinkle..................................................2  

B.  Enteral Feeding Tube Administration .........................................................................................3 

C.  Bioavailability/Bioequivalence Recommendations .....................................................................3  

 
  Contains Nonbinding Recommendations 
 
1 
Guidance for Industry  
1 
Size of Beads in Drug Products Labeled for Sprinkle 
2 
 
3 
4   
5  This guidance represents the Food and Drug Administrations (FDAs) current thinking on this topic.  It 
6  does not create or confer any rights for or on any  person and does not operate to bind FDA or the public.  
7  You can use an alternative approach if the approach satisfies the requirements of the applicable statutes 
8  and regulations. If you want to discuss an alternative approach, contact the FDA staff responsible for 
9  implementing this guidance.  If you cannot identify the appropriate FDA staff, call the appropriate 
10  number listed on the title page of this guidance.  
11   
12   
13   
14  I.  INTRODUCTION  
15   
16  This guidance provides applicants preparing or submitting new drug applications (NDAs), 
17  abbreviated new drug applications (ANDAs), and biologics licensing applications (BLAs) the 
18  Center for Drug Evaluation and Researchs current thinking on appropriate size ranges for beads2  
19  in drug products that are labeled to be administered via sprinkling (e.g., capsules or packets 
20  containing beads). 
21   
22  FDAs guidance documents, including this guidance, do not establish legally enforceable 
23  responsibilities. Instead, guidances describe the Agencys current thinking on a topic and should 
24  be viewed only as recommendations, unless specific regulatory or statutory requirements are 
25  cited. The use of the word should in Agency guidances means that something is suggested or 
26  recommended, but not required.  
27   
28  II.  BACKGROUND 
29   
30  Certain drug products that contain beads within a capsule indicate in the labeling that the capsule 
31  can be broken and the internal beads can be sprinkled on soft foods and swallowed without 
32  chewing as an alternative administration technique.  This is particularly common with drug 
33  products designed to have extended- or delayed-release characteristics (i.e., the beads are 
34  manufactured to release the drug product at different rates).  To make certain that the intended 
35  product performance is achievedwhether from a capsule that has been broken or from a packet 
36  containing beadsit is important to have reasonable assurance that the patient will be able to 
37  swallow the beads (uncrushed) with the food with which the beads are mixed without stimulating 
38  the urge to chew. Additional assurances may be needed when the label also includes specific 
39  language concerning alternate administration via an enteral feeding tube.   
40   
41   
                                                 
1  This guidance has been prepared by the Office of Pharmaceutical Science in the Center for Drug Evaluation and 
Research (CDER) at the Food and Drug Administration. 
2 For the purposes of this guidance, the term  beads will be used to describe the component particles in drug products 
labeled for sprinkle (i.e., beads, granules, pellets, sprinkles, particles, mini-tablets). 
 
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  Contains Nonbinding Recommendations 
 
42  III.   DISCUSSION   
43   
44  The recommendations in this guidance are based on literature on chewing and swallowing 
45  particle size  and on Agency experience with NDAs and ANDAs submitted for these dosage 
46  forms.  This guidance provides the following information related to drug products labeled for 
47  sprinkle: (1) appropriate maximum size for the beads, (2) special considerations for sprinkle 
48  drug products that include language in labeling concerning alternate administration via an enteral 
49  feeding tube, and (3) bioavailability or bioequivalence recommendations.  
50   
51  A.  Maximum Bead Size for Drug Products Labeled for Sprinkle 
52   
53  To determine an appropriate maximum bead size, the Agency took two actions.  First, the 
54  Agency reviewed studies of human mastication, which demonstrated that food is chewed to a 
55  median particle size range from 0.82 to 3.04 mm before swallowing.3,4  Second, we examined 
56  currently approved drug products labeled for sprinkle that contain beads up to 2.4 mm and found 
57  no recognized safety risks or loss of efficacy associated with the bead size. 
58   
59  Based on this information, the Agency recommends a target bead size up to 2.5 mm with no 
60  more than 10 percent variation over this size, to a maximum size of 2.8 mm.  The recommended 
61  bead size allowances consider the variability and differing manufacturing processes of beads 
62  (e.g., pellet versus mini-tablet manufacturing).  If the proposed bead size is greater than that 
63  recommended in this guidance, the applicant should provide justification for the proposed bead 
64  size, including studies demonstrating that the bead can be swallowed without chewing using 
65  sprinkle administration in the intended population.   
66   
67  The Agency recognizes the specific importance of a maximum size limit for modified-release 
68  products, where unintentional chewing of beads may lead to pharmacokinetic differences, but 
69  also believes that maintaining a consistent maximum bead size for all drug products labeled for 
70  sprinkle is appropriate. Inadvertently chewing beads labeled for sprinkle may lead to 
71  noncompliance with taking medication because of taste, safety issues, and decreased drug 
72  product efficacy. The target and maximum bead size recommendations thus apply to all drug 
73  products that contain particles that are labeled for sprinkle administration, whether the product 
74  has immediate-, delayed-, or extended-release characteristics.  Target and maximum bead size, 
75  including bead size distribution, can be determined through analytical sieving in accordance with 
76  USP <786>5 or other appropriately validated methods.   
77   
78  The bead size distribution can be provided in the 3.2.P.3.3 (Description of Manufacturing 
79  Process and Process Controls) section or 3.2.P.5.1 (Specification) section, and the maximum 
80  bead size can be provided in the 3.2.P.1 (Description and Composition of the Drug Product) 
81  section or 3.2.P.3.4 (Control of Critical Steps and Intermediates) section of a common technical 
82  document (CTD) formatted application. 
                                                 
3  Jalabert-Malbos, M.L., Mishellany-Dutour, A., Woda, A., and Peyron, M.A., 2007, Particle size distribution in the food bolus 
after mastication of natural foods, Food Quality and Preference, 18, 803-812.  
4  Peyron, M.A., Mishellany, A., and Woda, A., 2004, Particle size distribution of food boluses after mastication of six natural 
foods, Journal of Dental Research, 83(7), 578-582.  
5 See USP <786> Particle Size Distribution Estimation by Analytical Sieving.  
 
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  Contains Nonbinding Recommendations 
 
83  This recommendation applies only to NDAs, ANDAs, and BLAs for products that are not yet 
84  approved.  Sponsors of currently approved NDAs, ANDAs, or BLAs for products that contain 
85  beads that do not meet the recommended limits in this guidance need not modify their product 
86  specifications, unless there is reason to believe that an individual product poses a particular risk 
87  to public health because of its bead size. 
88   
89  An ANDA that references a currently approved reference listed drug (RLD) that exceeds the 
90  recommended limits in this guidance may propose a target and maximum bead size equal to or 
91  less than that used in the currently approved RLD.  If the proposed target and/or maximum bead 
92  size is greater than that used in the currently approved RLD, the applicant should provide 
93  justification for the proposed bead size, as described above.  If the ANDA applicant has data 
94  regarding the RLD bead size variation, then those data should be provided to support the size(s) 
95  of the beads in the ANDA product. This information can be provided in the 3.2.P.2 
96  (Pharmaceutical Development) section or 3.2.P.5.6 (Justification of Specification) section of a 
97  CTD formatted application.   
98   
99    B.  Enteral Feeding Tube Administration 
100   
101  A small number of sprinkle drug products include language in the labeling that specifically 
102  provides for alternative administration via enteral feeding tubes to accommodate patients who 
103  cannot safely swallow or are unable to tolerate oral intake.  Successful delivery of sprinkle drug 
104  products through an enteral feeding tube requires that all of the beads (uncrushed) be able to 
105  safely pass through the feeding tube and not cause tube occlusions. 
106   
107  Drug products that include this alternate administration method should demonstrate that the 
108  entire contents can be adequately administered.  For example, in vitro in-use tests of the sprinkle 
109  drug product with feeding tubes indicated in the labeling can be used to support the product use 
110  with labeled routes of administration.  Such a study or studies, as applicable, are recommended 
111  for NDAs and ANDAs, as bead size may vary or coating may differ between these products, 
112  resulting in varying ability to pass through a feeding tube.  If there are questions about the design 
113  or analysis of such studies, the sponsors and/or applicants should contact the appropriate review 
114  division within the Office of New Drugs or the Office of Generic Drugs. There is no 
115  recommendation for these studies if the labeling does not specify enteral feeding tube 
116  administration.  These studies can be provided in the 3.2.P.2 (Pharmaceutical Development) 
117  section or 3.2.P.5.6 (Justification of Specification) section of a CTD formatted application.  
118   
119    C.  Bioavailability/Bioequivalence Recommendations 
120   
121  The acceptability of bead size and bead size differences from a bioavailability (BA) or 
122  bioequivalence (BE) perspective is directly evaluated in BA/BE studies. 
123   
124  In NDAs, in the case of capsules containing beads, for the labeling to indicate that the beads in 
125  the drug product can be sprinkled on soft foods, additional in vivo relative BA studies may be 
126  needed. This can be accomplished by administering beads that have been sprinkled on one of the 
127  soft foods (e.g., applesauce) that are listed in the labeling (test treatment) and comparing the 
128  sprinkled products BA results to those of the product administered in the intact form (reference 
 
  3
  Contains Nonbinding Recommendations 
 
129  treatment).  Both products should be administered under fasting conditions.6  In addition, the 
130  administration of beads when mixed with soft foods should be evaluated for the ability to take 
131  the product without chewing the beads. If there are questions about the design or analysis of 
132  such BA studies, the sponsors and/or applicants should contact the appropriate review division 
133  within the Office of New Drugs.  
134   
135  In ANDAs, when the labeling for the RLD for a modified-release drug product indicates that the 
136  product may be sprinkled on soft foods, a sprinkle study comparing the test and RLD products 
137  should be performed.  Both treatments should be sprinkled on one of the soft foods that are listed 
138  in the labeling (e.g., applesauce). The BE data should be analyzed using average BE, and the 90-
139  percent confidence interval criteria should be used to evaluate BE.  Specific BE requirements for 
140  individual drug products can be found in the guidance for industry on Bioequivalence 
141  Recommendations for Specific Drug Products.7  
142   
143  In ANDAs, for immediate-release (IR) drug products labeled for sprinkle, it is generally not 
144  necessary to conduct a sprinkle BE study, as the expectation would be that the sprinkles would 
145  behave similarly for the test and RLD IR products.   
146   
147  If there are questions about the design or analysis of specific BE studies, the sponsors and/or 
148  applicants should contact the appropriate review division within the Office of Generic Drugs.  
149  The Agency may request additional BE studies under special circumstances if deemed 
150  appropriate. 
                                                 
6  Information on  BA studies of sprinkled drug products also can be found in the guidance for industry, Food-Effect 
Bioavailability and Fed  Bioequivalence Studies, December 2002.  CDER updates guidances periodically.  To make  sure you have 
the most recent version of a guidance, check the FDA Drugs guidance web page at  
www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.  
7  See www.fda.gov/drugs/guidancecomplianceregulatoryinformation/guidances/ucm075207.htm.   
 
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