Restricted Delivery Systems: 
Flow Restrictors for Oral 
Liquid Drug Products 
 
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DRAFT GUIDANCE 
 
  This guidance document is being distributed for comment purposes only.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publication in the Federal Register of the notice announcing the availability of the draft 
guidance.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 Rhiannon Leutner (CDER) at 240-402- 
5998. 
 
For questions about this document regarding CBER-regulated products, contact the Office of 
Communication, Outreach, and Development (OCOD) at 1-800-835-4709 or 240-402-8010. 
 
 
U.S. Department of Health and Human Services  
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER)  
Center for Biologics Evaluation and Research (CBER)  
Center for Devices and Radiological Health (CDRH)  
Office of Combination Products (OCP) 
 
March 2020 
Drug Safety 
   
Restricted Delivery Systems: 
Flow Restrictors for Oral 
Liquid Drug Products 
 
Guidance for Industry
 
 
Additional copies are available from: 
Office of Communications, Division of Drug Information  
Center for Drug Evaluation and Research 
Food and Drug Administration 
10001 New Hampshire Ave., Hillandale Bldg., 4th Floor  
Silver Spring, MD 20993-0002  
Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353 
Email: druginfo@fda.hhs.gov  
https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs  
and/or 
Office of Communication, Outreach and Development  
Center for Biologics Evaluation and Research 
 Food and Drug Administration 
10903 New Hampshire Ave., Bldg. 71, Room 3128 
Silver Spring, MD 20993-0002 
Phone: 800-835-4709 or 240-402-8010 
Email: ocod@fda.hhs.gov 
https://www.fda.gov/vaccines-blood-biologics/guidance-compliance-regulatory-information-biologics/biologics-guidances     
  and/or 
Office of Policy 
Center for Devices and Radiological Health 
Food and Drug Administration 
10903 New Hampshire Ave., Bldg. 66, Room 5431 
Silver Spring, MD 20993-0002 
Email: CDRH-Guidance@fda.hhs.gov 
https://www.fda.gov/medical-devices/device-advice-comprehensive-regulatory-assistance/guidance-documents-medical-devices-
and-radiation-emitting-products  
 
U.S. Department of Health and Human Services  
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER)  
Center for Biologics Evaluation and Research (CBER)  
Center for Devices and Radiological Health (CDRH)  
Office of Combination Products (OCP) 
 
March 2020 
Drug Safety 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
TABLE OF CONTENTS 
 
 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 2 
III.  DISCUSSION .................................................................................................................... 3 
IV.  GENERAL RECOMMENDATIONS ............................................................................. 5 
A.  Restriction Effects .......................................................................................................................... 5 
B.  Human Factors and Design Considerations ................................................................................ 6 
C.  Directions for Use ........................................................................................................................... 7 
APPENDIX A: PRODUCT-SPECIFIC RECOMMENDED RESTRICTION EFFECTS .... 9 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1    Restricted Delivery Systems: Flow Restrictors for Oral Liquid 
2  Drug Products  
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 provides recommendations regarding the use of restricted delivery systems2,3 to 
17  limit unintentional ingestion4 of oral liquid drug products (e.g., oral solution, oral suspension) by 
18  children.5  The recommendations in this guidance apply broadly to oral liquid drug and 
19  biological products.6,7  Accordingly, this guidance is intended for manufacturers of oral liquid 
20  drug and biological products. In this guidance, the term manufacturer is used broadly to include 
21  firms that market drug products under the Over-the-counter (OTC) Drug Review; holders of new 
                                                 
1 This guidance has been prepared by the Office of Surveillance and Epidemiology, the Division of Nonprescription 
Drug Products, and the Division of Pediatric and Maternal Health in the Center for Drug Evaluation and Research 
(CDER), in collaboration with the Center for Devices and Radiological Health (CDRH), the Center for Biologics 
Evaluation and Research (CBER), and the Office of Combination Products at the Food and Drug Administration. 
2 For the purpose of this guidance, a restricted delivery system is defined as a Packaging system designed or 
constructed to restrict (control) the amount of the drug product that may be delivered in order to limit unintended 
access by children and other similarly vulnerable populations. [. . .]  One component of the Restricted delivery system 
is the flow restrictor,  which is a Packaging component that restricts the flow of liquid.  The flow restrictor may be 
used as part of a Restricted delivery system or as an adaptor to facilitate use of a measuring device for oral medicinal 
liquids. A flow restrictor should not compromise CPSC standards for special packaging [Child-resistant and Senior-
friendly packaging (16 CFR 1700.15 et seq.)]. General Chapter <659> Packaging and Storage  Requirements, 
United States Pharmacopeia (USP) 40-NF 35.  As used in this guidance, the term restricted delivery  system is 
distinct from the term restricted device as defined in 21 CFR 807.3(i). 
3 This guidance provides specific recommendations for flow restrictors and general recommendations that may be 
applicable to a range of restricted delivery systems, including flow restrictors.  FDA acknowledges the potential for 
development of new restricted delivery systems and is including general recommendations for consideration. 
4 Accessing medication without caregiver permission or oversight is also referred to in this guidance as accidental 
exposure, unsupervised ingestion, unsupervised exposure, and accidental ingestion. 
5 The principles in this guidance also apply to other similarly vulnerable populations. 
6 References to drugs and biological products include drugs approved under section 505 of the Federal Food, Drug, 
and Cosmetic Act (21 U.S.C. 355) and biological products licensed under section 351 of the Public Health Service 
Act (42 U.S.C. 262) that are drugs.  For the purposes of this guidance, drug product or drug will be used to refer to 
human prescription drugs and biological products that are regulated as drugs. 
7 Manufacturers should determine whether a restricted delivery system is appropriate for use with  their product.  
Restricted delivery systems may not be appropriate for some products (e.g., activated charcoal  solutions, oral 
glucose solutions, or bulk stock bottles). 
 
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22  drug applications (NDAs), biologics license applications (BLAs), and abbreviated new drug 
23  applications (ANDAs); and firms that manufacture components packaged or labeled for 
24  commercial distribution with oral liquid drug products, including firms that buy product in bulk 
25  to sell under their own label and add a flow restrictor to the product when they fill the bulk 
26  product into direct-to-consumer packaging.   
27   
28  In general, FDAs guidance documents do not establish legally enforceable responsibilities.  
29  Instead, guidances describe the Agencys current thinking on a topic and should be viewed only 
30  as recommendations, unless specific regulatory or statutory requirements are cited.  The use of 
31  the word should in Agency guidances means that something is suggested or recommended, but 
32  not required.  
33   
34   
35  II.  BACKGROUND 
36   
37  In 1970, the Poison Prevention Packaging Act (PPPA) was enacted to protect children (under 5 
38  years of age) from unintentional exposure to certain household substances, including foods, 
39  drugs, and cosmetics.8  Under the Federal Food, Drug, and Cosmetic Act (FD&C Act), a drug 
40  that has packaging or labeling that is in violation of an applicable regulation issued pursuant to 
41  section 3 or 4 of the PPPA is deemed to be misbranded.9  FDA was responsible for enforcing the 
42  PPPA until 1973, when jurisdiction was transferred to the U.S. Consumer Product Safety 
43  Commission (CPSC).10   
44   
45  CPSCs regulations list standards for special packaging11,12 (also referred to in this guidance 
46  as child-resistant packaging (CRP)) for a wide range of household products, including most oral 
47  prescription drugs and many nonprescription drug products.13  There are different ways to make 
48  packaging child-resistant, with the most common forms being a child-resistant closure (e.g., a 
49  safety cap) and certain unit-of-use blister packaging (e.g., puncture-resistant and peel-push 
50  blisters).  However, not all container closures (i.e., packaging components that contain and 
51  protect drug products), including unit-of-use packaging, are child-resistant.  Furthermore, child-
52  resistant should not be equated to child-proof, because CRP is not designed to completely 
53  eliminate the possibility of an accidental pediatric ingestion.  It can only impede access to 
54  harmful products. 
55   
56  CRP is regarded as an important public health safety tool for reducing the incidence of harmful 
57  health outcomes related to unintentional ingestions.14  Many oral liquid drug products are 
                                                 
8 Poison Prevention Packaging Act of 1970 (PPPA) (Pub. L. 91-601, 84 Stat. 1670), enacted December 30, 1970. 
9 See section 502(p) of the FD&C Act (21 U.S.C. 352(p)). 
10 Consumer Product Safety Act (Pub. L. 92-573, 86 Stat. 1207), October 27, 1972, Sec. 30. 
11 See 16 CFR part 1700.  See also definitions in section 2 (4) of the PPPA. 
12 Special packaging and child-resistant packaging are used interchangeably in this guidance. 
13 See 16 CFR part 1700 for substances requiring special packaging and the relevant packaging standards and testing 
procedures. 
14 Early studies in the 1960s demonstrated a nearly a 10-fold reduction in unsupervised pediatric ingestions with 
medicines with special packaging distributed from the Fort Lewis-McChord Air Force Base in Washington.  During 
the years CRP has been used to package drugs, cosmetics, and household chemicals, the number of children who 
 
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58  marketed with CRP features.  However, even with the availability of this safety tool, adverse 
59  events related to unintentional ingestion of drug products, including oral liquid drug products, 
60  continue to be reported.  One analysis of the National Electronic Injury Surveillance System-
61  Cooperative Adverse Drug Event Surveillance (NEISS-CADES)15 data estimated that children 
62  younger than 6 years old account for more than 9,500 annual Emergency Department (ED) visits 
63  attributed to the unintentional ingestion of oral liquid drug products.16  
64   
65  Additional measures should also be considered to help reduce unintentional ingestion of oral 
66  liquid drug products, including safe and secure product storage.17  Exposure-limiting packaging, 
67  such as a restricted delivery system, is one such measure that complements CRP.  Specifically, 
68  restricted delivery systems are intended to restrict the flow of liquid from the opening of a 
69  container.  Restricted delivery systems are not a replacement for CRP and use of restricted 
70  delivery systems should not compromise CRP.  Rather, manufacturers should consider using a 
71  combination of CRP and restricted delivery systems to further reduce unintentional ingestion of 
72  oral liquid drug products. 
73   
74   
75  III.  DISCUSSION OF FLOW RESTRICTORS    
76   
77  An example of a restricted delivery system is a flow restrictor, which can be added to the neck of 
78  a bottle to restrict or control the flow of liquid.  Flow restrictors can be added to a container at 
79  the site of manufacture, or they can be co-packaged with the drug product and added to the 
80  container at the time of use.  Alternatively, the design of the container can be such that the flow 
81  restrictor is molded and integrated into the bottle neck and cannot be separated from the bottle.  
82  Bottles containing a flow restrictor may need a dosing device, such as an oral syringe, to extract 
83  the drug product.  Depending on the design and technology, flow restrictors can be of the open or 
84  closed type. 
85   
86  1.  Closed Flow Restrictors.  In general, a closed flow restrictor limits access to a single-unit 
87  volume at one time.  A closed flow restrictor can be designed with a self-closing valve 
                                                 
have died from ingesting toxic household substances has declined significantly.  See 
https://www.cpsc.gov/Regulations-Laws--Standards/Statutes/Poison-Prevention-Packaging-Act/. 
15 NEISS-CADES is an expansion of the CPSC National Electronic Injury Surveillance System (NEISS), used to 
monitor consumer-product-related injuries. NEISS-CADES collects data on all adverse drug events treated in U.S. 
hospital emergency departments, whether or not associated with consumer products. NEISS data are collected from 
a nationally representative sample of U.S. hospital emergency departments; NEISS-CADES uses a subsample of 
those emergency departments for its data collection. See https://www.cpsc.gov/Research--Statistics/NEISS-Injury-
Data. 
16 Lovegrove MC, Weidle NJ, Budnitz DS. Trends in emergency department visits for unsupervised pediatric 
medication exposures, 2004-2013. Pediatrics 2015 Oct;136(4): e821-829 (annual national estimate in ED visits for 
unsupervised exposures involving oral liquid medication by children younger than 6 years old between 2010 and 
2013). 
17 Safe and secure product storage is a complementary safety measure that is important to keep in mind.  When 
medications are stored in reach and sight of children, children are able to gain access to and defeat CRP or restricted 
delivery systems in some instances, thereby reducing the effectiveness of these packaging measures.  Therefore, 
FDA recommends that all drugs, irrespective of the type of packaging, be stored safely out of the reach and sight of 
children to further the overall public health efforts to address unintentional ingestion of drug products. 
 
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88  that opens when the dosing device is inserted and reseals after removal of the dosing 
89  device.  Closed flow restrictors are designed such that the valve orifice matches a 
90  corresponding dosing device, and in some cases, the design may be so specific that it 
91  includes a lock-and-key mechanism needing a designated dosing device. 
92   
93  2.  Open Flow Restrictors.  An open flow restrictor allows for a continuous, controlled 
94  volume.  When an oral syringe is used, an open flow restrictor does not reseal after 
95  removal of the oral syringe and when the bottle is inverted it permits a slow flow of 
96  liquid from the container. 
97   
98  The efficacy of flow restrictors has been demonstrated in the pediatric population.18,19  Children 
99  age 3 to 4 years are typically able to empty the entire contents of bottles without flow restrictors 
100  within 2 minutes; however, when a bottle was fitted with a flow restrictor, children of the same 
101  age were prevented from completely emptying the bottle contents within a 6-minute period.20  In 
102  cases of unintentional liquid acetaminophen ingestions, the average individual dose was lower in 
103  cases that involved bottles with flow restrictors.21  In general, the incorporation of a flow 
104  restrictor reduces the total volume of liquid children are able to extract from liquid medicine 
105  bottles, which may reduce the risk of harm resulting from unintentional ingestions. 
106   
                                                 
18 Lovegrove MC, Hon S, Geller RJ, Rose KO, Hampton LM, Bradley J, Budnitz DS.  Efficacy of flow restrictors in 
limiting access of liquid medications by young children. Journal of Pediatrics 2013 Oct; 163(4): 1134-1139. 
19 Geller RJ, Hon SL, Reynolds KM, Burnham RI, Badillo R, Ketcham S, Muresan N, Peters ME, Stokkeland KL, 
Green JL.  Do New Child Resistant Closures Reduce Injury Following Accidental Ingestion? 2015 Annual Meeting 
of the North American Congress of Clinical Toxicology (NACCT).  Clinical Toxicology 2015: 53:639-777. 
20 Lovegrove et al. assessed the efficacy of flow restrictors in 110 children age 36 to 59 months in a block 
randomized trial with a convenience sample from five preschools.  The authors noted that flow restrictors on 
uncapped (open) bottles decreased the ability of young children to remove liquid medicine from bottles when 
compared to uncapped or partially opened bottles without flow restrictors.  In this randomized study, 3- and 4-year- 
old children were able to remove the entire contents of nearly all bottles without flow restrictors that were either 
open (96%; 25 out of 26 children) or incompletely closed (82%; 68 out of 83 children) within 2 minutes.  However, 
none of the children emptied a bottle with a flow restrictor in less than 6 minutes, and only 6% (7 out of 110 
children) emptied a bottle with a flow restrictor within the full 10-minute testing period. Furthermore, the maximum 
amount of liquid the youngest children studied (age 36 to 41 months) were able to remove was less than 5 milliliters. 
Overall, the study findings showed that children removed less total liquid from bottles with flow restrictors when 
compared to open or incompletely closed control bottles. 
21 Geller et al. conducted a 6-month poison center phone survey of 1,952 parents of children who had unintentional 
ingestions of liquid drug products that demonstrated the potential efficacy of flow restrictors in children younger 
than 12 years old.  The survey identified 289 cases of single-ingredient unintentional acetaminophen ingestions 
among children of the 528 parents who completed the survey.  The majority (88.1%) of these children were younger 
than 3 years old.  The authors noted that the unintentional ingestions involving liquid acetaminophen with flow 
restrictors resulted in a lower estimated average dose, whereas the unintentional ingestions involving packaging 
without flow restrictors resulted in a 2.5 times larger risk of an estimated exposure greater than 150 milligrams 
(mg)/kilogram (kg), which is the threshold dose used by some poison centers for referral to a health care facility. 
The American Academy of Clinical Toxicology (ACCT) guidelines and POISINDEX recommend 200 mg/kg as the 
threshold dose for which referral to ED is suggested in cases of acetaminophen toxicity. 
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107  IV.  GENERAL RECOMMENDATIONS 
108   
109  Manufacturers should consider the use of a restricted delivery system, such as a flow restrictor, 
110  as an additional measure to further reduce the risk of unintended ingestions of oral liquid drug 
111  products. 
112   
113  As manufacturers seek to develop restricted delivery systems, they are strongly  encouraged to 
114  discuss with FDA any proposed restricted delivery system early in the  development process.22  
115   
116  Standardized test methodologies23,24 for assessing restricted delivery systems for liquid 
117  consumer products are currently being developed.  We recommend that manufacturers consider 
118  general testing methods and parameters that assess product functionality for labeled use and 
119  assess performance necessary to prevent unintentional ingestions.  Manufacturers should also 
120  consider elements such as those discussed below when developing a restricted delivery system 
121  for their oral liquid drug product. 
122   
123  A.  Restriction Effects25 
124   
125  FDA recommends targeted restriction effects to limit the amount of an oral liquid drug product 
126  that may be delivered over a period of time.  The majority of unintended ingestion cases occur 
127  within 5 minutes of access to drug products,26 and an analysis of NEISS-CADES data reports 
128  that 60% of unintentional OTC liquid medication ingestions involve children 2 years old and 
129  younger.27  Accordingly, the recommended targeted restriction effects of the restricted delivery 
130  system should reduce the amount of liquid that flows from a bottle in a 5-minute period based on 
131  the toxic dose of the drug product to a 2-year-old child.28,29 
132   
                                                 
22 For products marketed under the OTC Drug Review, contact the Division of Nonprescription Drug Products in 
CDERs Office of New Drugs.  For products requiring premarket review (i.e.   new drugs under section 201(p) of 
the FD&C Act (21 U.S.C. 321(p)), contact the appropriate review division within FDA. 
23 See ASTM Standard F3375-19 Test Method for Assessing Non-Metered Restricted Delivery Systems for Liquid 
Consumer Products at: https://www.astm.org/Standards/F3375.htm  
24 ASTM News Release, New Standard Aims to Limit Childrens Access to Liquid Medicines, Other Products.  See 
link: https://www.astm.org/cms/drupal-7.51/newsroom/new-standard-aims-limit-children%E2%80%99s-access-
liquid-medicines-other-products 
25 In this guidance, restriction effects are the changes to the amount of liquid drug product that may be delivered 
over a period of time in order to limit access by children and other similarly vulnerable populations. 
26 Ozanne-Smith J, Day L, Parsons B, Tibballs J, and Dobbin M.  Childhood poisoning: Access and prevention. 
Journal of Pediatric Child Health. 2001; 37: 262265. 
27 Lovegrove MC, Weidle NJ, Budnitz DS. Trends in emergency department visits for unsupervised pediatric 
medication exposures, 2004-2013. Pediatrics 2015; 136. 
28 FDA recommends using the 50th percentile weight for age estimates in toxic dose calculations; see CDC growth 
charts at https://www.cdc.gov/growthcharts/. 
29 Lovegrove, Weidle, Budnitz (Pediatrics 2015; 136) also note that children younger than 1 year of age accounted 
for 5% of ED visits for unsupervised ingestions.  The visits for those age 1 and 2 years accounted for the majority of 
visits (this includes visits for unintended ingestion of both oral solid and liquid dosage forms).  However, visits for 
oral OTC liquid medication exposures involved a proportionally greater number of children over the age of 2 years, 
which is one of the reasons why FDA chose 2-year-olds for the recommended targeted restriction effects. 
 
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133  Recommended restriction effects are described in Appendix A for some of the commonly 
134  identified oral liquid drug products that result in ED visits from unintentional ingestion.  The 
135  restriction effects in Appendix A incorporate the recommendation above (regarding a 5-minute 
136  period and a 2-year-old child) and are based on general parameters used by poison center 
137  professionals (e.g., POISINDEX) in determining threshold doses that call for emergency 
138  evaluation, as well as on practice guidelines developed by the American Academy of Clinical 
139  Toxicology (AACT).30,31 
140   
141  The use of a restricted delivery system that limits access to a single-unit volume at one time,  
142  such as a closed flow restrictor, is warranted for drug products with a narrow therapeutic index32 
143  because there is a small difference between therapeutic and toxic doses.  This type of restricted 
144  delivery system should also be considered for oral liquid drug products with significant toxicities 
145  at doses that are close to the therapeutic dose.  For drug-drug combinations, manufacturers 
146  should consider the most toxic agent in the combination as well as the combined toxicity of all 
147  product ingredients in determining the desired restriction effect. 
148   
149  Viscosity of the liquid is another important consideration because it will determine the rate at 
150  which a liquid flows and influence the performance of restricted delivery systems.  Restricted 
151  delivery systems should be suitable for use with a liquid with the viscosity of the particular 
152  formulation so that typical volumes can be reasonably dispensed by the target 
153  consumer/patient/caregiver populations.  Products with high viscosity may be difficult for a 
154  parent or caregiver to extract from some restricted delivery system designs.  Conversely, 
155  products with low viscosity, which flow freely, may benefit from a more restrictive packaging 
156  design. 
157   
158  B.  Human Factors and Design Considerations 
159   
160  In addition to the preceding information, the following design considerations should be taken 
161  into account in selecting the most appropriate restricted delivery system for an oral liquid drug 
162  product: 
163   
164    Restricted delivery systems should be constructed of materials that are safe for oral, skin, 
165  and mucosal contact, as well as compatible with the drug formulation.33 
                                                 
30 Chyka PA, Erdman AR, Manoguerra AS, Christianson G, Booze LL, Nelson LS, Woolf AD, Cobaugh DJ, 
Caravati EM, Scharman EJ, Troutman WD.  Dextromethorphan poisoning: An evidence-based consensus guideline 
for out-of-hospital management.  Clinical Toxicology 2008; 45(6): 662-677, DOI: 10.1080/15563650701606443.     
31 Scharman EJ, Erdman AR, Wax PM, Chyka PA, Caravati EM, Nelson LS, Manoguerra AS, Christianson G, 
Olson KR, Woolf AD, Keyes DC, Booze LL, Troutman WG. Diphenhydramine and dimenhydrinate poisoning: An 
evidence-based consensus guideline for out-of-hospital management. Clinical Toxicology 2008; 44(3): 205-223, 
DOI: 10.1080/15563650600585920. 
32 Narrow therapeutic index drugs are defined as those drugs where small differences in dose or blood concentration 
may lead to serious therapeutic failures and/or adverse drug reactions that are life-threatening or result in persistent 
or significant disability or incapacity.  See: Yu LX, Jiang W, Zhang X, Lionberger R, Makhlouf F, Schuirmann DJ, 
Muldowney L, Chen ML, Davit B, Conner D, Woodcock J. Novel bioequivalence approach for narrow therapeutic 
index drugs. Clinical Pharmacology and Therapies 2015; 97(3): 286-291. 
33 Guidance for Industry, Container Closure Systems for Packaging Human Drugs and Biologics (May 1999).  We 
update guidances periodically.  For the most recent version of a guidance, check the FDA guidance web page at   
https://www.fda.gov/RegulatoryInformation/Guidances/default.htm. 
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166   
167    If a dosing device should be used for the restricted delivery system, a compatible dosing 
168  device should be included in the product packaging. 
169   
170  The following considerations apply specifically to flow restrictors: 
171   
172    Different types of flow restrictors (e.g., open or closed) should be considered and the 
173  optimal flow restrictor should be used. 
174   
175    The flow restrictor should not leak when used. 
176   
177    Performance testing should include testing for the maximum number of doses available in 
178  the liquid drug container multiplied by a factor of 1.5.  For example, a 100 milliliter (mL) 
179  bottle that is intended to deliver 5 mL doses (contains 20 total 5 mL doses), should be 
180  tested 30 times (20 doses available x 1.5 safety margin = 30 performance tests).  These 
181  performance tests should be conducted at all specified orientations or when not specified, 
182  all possible container orientations as defined by the product label.34  Compatibility of the 
183  dosing device (e.g., a calibrated and labeled oral syringe) with the restricted delivery 
184  system should be carefully considered and evaluated during the design process. 
185   
186  When designing or selecting an appropriate restricted delivery system, manufacturers should 
187  balance the degree of restrictiveness with the need to ensure ease of use.  For example, the 
188  restricted delivery system should not be overly burdensome in ways that discourage product use 
189  or that encourage improper use.  In addition, it is vital that the restricted delivery system not be 
190  easily removed or pushed through the neck of the bottle, to avoid contaminating the drug product 
191  or presenting a choking hazard to children. 
192   
193  We encourage working with the appropriate review division at FDA to determine the submission 
194  information and types of studies that may be necessary for products that require premarket 
195  review.  We recommend manufacturers consider human factors principles and usability studies 
196  as part of their development program.35 
197   
198  C.  Directions for Use 
199   
200  Drug products must have labeling that bears adequate directions for use,36 with limited 
201  exceptions;37 when manufacturers choose to use a restricted delivery system for a drug product, 
202  this requirement includes providing adequate directions for using the drug product with the 
                                                 
34 Specified by a compendial test or standardized test by a testing body, such as American Society for Testing and 
Materials (ASTM) or International Organization for Standardization (ISO). 
35 See Guidance for Industry and FDA Staff, Applying Human Factors and Usability Engineering to Optimize 
Medical Device Design (February 2016), and Guidance for Industry, Safety Considerations for Product Design to 
Minimize Medication Errors (April 2016).  See also draft Guidances for Industry and FDA Staff, Applying Human 
Factors and Usability Engineering to Medical Devices (June 2011) and Human Factors Studies and Related 
Clinical Study Considerations in Combination Product Design and Development (February 2016). 
36 Section 502(f)(1) of the FD&C Act.   
37 See, e.g., 21 CFR 201.100 (prescription drugs for human use).  
 
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203  restricted delivery system.38  In addition to meeting the general requirement for the labeling of a 
204  drug product to bear adequate directions for use, the Agency recommends that the labeling of 
205  drug products with a restricted delivery system include a toll-free telephone number or email 
206  address for consumers, patients, or caregivers to obtain replacement parts, when such parts (such 
207  as syringes) are needed to ensure optimal performance of the restricted delivery system. 
208   
209  To include a restricted delivery system in the packaging of drug products undergoing premarket 
210  review, we recommend contacting the appropriate review division staff to discuss the 
211  information to be submitted to the Agency to ensure that the drug products labeling bears 
212  adequate directions for using the drug product with the restricted delivery system.    
213   
214  For oral liquid drug products marketed under the OTC Drug Review, at this time and based on 
215  our current understanding of the risks of these products, FDA does not intend to object to the use 
216  of an appropriate restricted delivery system, provided the labeling includes non-graphical 
217  instructions in the Drug Facts labeling that explain how to appropriately use the restricted 
218  delivery system, as well as applicable OTC drug monograph directions, and provided that the 
219  labeling satisfies all other applicable labeling requirements.39  The additional non-graphical 
220  instructions should be limited to describing how to use the restricted delivery system to deliver 
221  the appropriate dose.  If graphical images are necessary to ensure effective use of the restricted 
222  delivery system, a labeling insert may be included in the packaging to provide the necessary 
223  information to the consumer, patient or caregiver.  If additional language is added to the Drug 
224  Facts labeling or a separate labeling insert is included in the packaging of products marketed 
225  under the OTC Drug Review, we recommend that the manufacturer establish that the target 
226  consumer/patient/caregiver population comprehends the additional language.40 
227     
                                                 
38 Section 502(f)(1) of the FD&C Act.  In addition, as a general matter, an ANDA is required to contain information 
to show that the labeling proposed for the generic drug is the same as the labeling for the reference listed drug 
(RLD), except for changes required because of differences approved under a suitability petition (see section 
505(j)(2)(C) of the FD&C Act and 21 CFR 314.93), or because the generic drug and the RLD are produced or 
distributed by different manufacturers (see section 505(j)(2)(A)(v) of the FD&C Act). See also FDAs Draft 
Guidance entitled Comparative Analyses and Related Comparative Use Human Factors Studies for a Drug-Device 
Combination Product Submitted in an ANDA. 
39 See, e.g., 21 CFR part 201 and 21 CFR 330.1. 
40 See Guidance for Industry, Label Comprehension Studies for Nonprescription Drug Products (August 2010). 
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228 
229   231  APPENDIX A: PRODUCT-SPECIFIC RECOMMENDED RESTRICTION EFFECTS 
230  232     
233  Consider the following flow diagram when considering the use of a restricted delivery system. 
 
 
 
Single ingredient  no Fixed-combination drugs
product
yes
Consider toxicity of product  Consider the most toxic agent in 
to 2 year old child the combination as well as the 
combined toxicity of all 
ingredients to 2 year old child
Narrowi nthdeerxapeutic  yes Utvsheoa lotu flmi ame ri taests  atorcnicceete stdsim  tdoee  al(ie vs.eignr.yg c lsleoy ussetneditm   
no flow restrictor) is warranted
Determine harmful dose to 2 year 
old child (e.g. quantity sufficient to 
require medical care and/or 
observation, POISINDEX/AACT 
Guidelines)
Consider use of restricted delivery 
system that limits the egress of this 
harmful dose (quantity of liquid) in 
no less than 5 minutes
 
 
218   
219  The following drug product examples1 are provided to illustrate the goal of restricting a toxic or 
220  harmful volume of liquid (based on the 50th percentile weight estimate for a 2-year-old)2 
221  accessible to a child within 5 minutes. 
222   
223  Acetaminophen3: Restricted delivery systems for acetaminophen-containing products should 
224  restrict the flow of liquid to a deliverable quantity not to exceed 2,400 milligrams (mg) of 
225  acetaminophen in a 5-minute interval.  Due to the risk of liver failure, consider the use of a 
226  restricted delivery system that limits access to a single-unit volume at one time, such as a closed 
227  flow restrictor. 
228   
                                                 
1 These examples were chosen because 91% of ED visits for OTC liquid medication exposures involved 
acetaminophen, cough and cold remedies, ibuprofen, or diphenhydramine.  See Lovegrove MC, Weidle NJ, Budnitz 
DS.  Trends in emergency department visits for unsupervised pediatric medication exposures, 2004-2013. Pediatrics 
2015;136. 
2 See footnote 27. 
3 Assumes a 200 mg/kg threshold and a12 kg child.  For a 160 mg/5 mL concentration, this results in not to exceed 
(NTE) 75 mL in 5 minutes (min).  Source: 200 mg/kg American Academy of Clinical Toxicology Guidelines (2,400 
mg); 200 mg/kg POISINDEX (2,400 mg). 
 
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  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
229  Dextromethorphan4: Restricted delivery systems for dextromethorphan-containing products 
230  should restrict the flow of liquid to a deliverable quantity not to exceed 90 mg of 
231  dextromethorphan in a 5-minute interval. 
232   
233  Diphenhydramine5: Restricted delivery systems for diphenhydramine-containing products 
234  should restrict the flow of liquid to a deliverable quantity not to exceed 90 mg of 
235  diphenhydramine in a 5-minute interval. 
236   
237  Ibuprofen6: Restricted delivery systems for ibuprofen-containing products should restrict the 
238  flow of liquid to a deliverable quantity not to exceed 2,400 mg of ibuprofen in a 5-minute 
239  interval. 
240   
241  Pseudoephedrine7: Restricted delivery systems for pseudoephedrine-containing products should 
242  restrict the flow of liquid to a deliverable quantity not to exceed 144 mg of pseudoephedrine in a 
243  5-minute interval. 
244   
                                                 
4 Assumes a 7.5 mg/kg threshold and a12 kg child. For a 30 mg/5 mL concentration, this results in NTE 15 mL in 5 
min. For a 15 mg/5 mL concentration, this results in NTE 30 mL in 5 min. Source: 7.5 mg/kg AACT Guidelines (90 
mg); 10 mg/kg POISINDEX (120 mg). 
5 Assumes a 7.5 mg/kg threshold and a12 kg child.  For a 12.5 mg/5 mL concentration, this results in NTE 36 mL in 
5 min. Source: 7.5 mg/kg AACT (90 mg); 7.5 mg/kg POISINDEX (90 mg). 
6 Assumes a 200 mg/kg threshold and a12 kg child.  For a 100 mg/5 mL concentration, this results in NTE 120 mL 
in 5 min.  Source: 200 mg/kg POISINDEX (2400 mg). 
7 Assumes a 12 mg/kg threshold and a12 kg child.  For a 30 mg/5 mL concentration, this results in NTE 24 mL in 5 
min.  Source: 12 mg/kg POISINDEX. 
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