Guidance for Industry 
and FDA Staff: 
 
Technical Considerations for Pen, Jet, 
and Related Injectors Intended for Use 
with  
Drugs and Biological Products 
 
 
Additional copies are available from: 
 
Office of Combination Products 
Office of Special Medical Programs 
Office of the Commissioner 
Food and Drug Administration 
10903 New Hampshire Avenue, WO-32 Hub 5129 
Silver Spring, MD 20993 
(Tel) 301-796-8930 
(Fax) 301-796-8619 
http://www.fda.gov/CombinationProducts/default.htm  
 
This document finalizes the draft guidance issued in April 2009. 
 
For questions regarding this document, contact the Office of Combination Products at 
combination@fda.gov or Patricia Y. Love, MD at 301-796-8933 or patricia.love@fda.hhs.gov 
 
U.S. Department of Health and Human Services  
Food and Drug Administration 
Center for Devices and Radiological Health, 
Center for Drug Evaluation Research,  
Center for Biologics Evaluation and Research, and 
Office of Combination Products in the Office of the Commissioner 
 
June 2013 
  Contains Nonbinding Recommendations 
 
Table of Contents 
 
INTRODUCTION.....................................................................................................................3 
BACKGROUND.......................................................................................................................4 
SECTION I:  SCIENTIFIC AND TECHNICAL CONSIDERATIONS.............................5 
A.  INJECTOR DESCRIPTION.............................................................................................5 
B.  DESIGN FEATURES.........................................................................................................9 
C.  INJECTOR MATERIALS OF CONSTRUCTION AND MANUFACTURE............14 
D.  PERFORMANCE TESTING: GENERAL USE INJECTOR CONSIDERATIONS15 
E.  PERFORMANCE TESTING: INJECTOR AND DRUG/BIOLOGICAL PRODUCT 
CONSIDERATIONS........................................................................................................19 
F.  PERFORMANCE TESTING: CLINICAL CONSIDERATIONS..............................23 
G. STERILIZATION AND STERILITY ASSURANCE...................................................23 
H. LABELING.......................................................................................................................25 
SECTION II:  CONTENT AND FORMAT CONSIDERATIONS...................................28 
SECTION III:  WHERE CAN I FIND ADDITIONAL INFORMATION OR DISCUSS 
MY QUESTIONS?............................................................................................................28 
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Guidance for Industry and FDA Staff  
1
 
Technical Considerations for Pen, Jet, and Related 
Injectors for Use with 
Drugs and Biological Products 
 
This guidance represents the Food and Drug Administration's (FDA's) current thinking 
on this topic.  It does not create or confer any rights for or on any person and does not 
operate to bind FDA or the public.  You can use an alternative approach if the approach 
satisfies the requirements of the applicable statutes and regulations.  If you want to 
discuss an alternative approach, contact the FDA staff responsible for implementing this 
guidance.  If you cannot identify the appropriate FDA staff, call the appropriate number 
listed on the title page of this guidance.  
 
  Introduction    
 
FDA is issuing this guidance document to describe the technical and scientific 
information that FDA expects in a marketing application for a pen, jet, or related injector 
device that is intended to be used with a drug or biological product.2 
 
For purposes of this guidance, the term injector includes, but is not limited to: jet 
injectors, pen injectors, piston syringes, needle-free injectors, mechanically operated 
injectors, and injectors with computerized or electronic elements. 
  
Pen, jet and related injectors may be marketed under different provisions.  For example, 
pen injectors for general use are regulated as class II devices under 21 CFR 880.5860 
(product code NSC) or 21 CFR 880.6920 (product code KZH).3  Jet injectors for general 
use, including needle or needle-free injectors, are regulated as class II devices under 21 
CFR 880.5430 (product code KZE).  Typically such general use injectors are regulated 
by CDRH.  When injectors are combined with, packaged with, or labeled for use with a 
specific drug/biological product they may be combination products.4 
 
                                                 
1 This guidance was prepared by the Office of Combination Products in the Office of the Commissioner in 
conjunction with the Center for Devices and Radiological Health, the Center for Drug Evaluation and 
Research, and the Center for Biologics Evaluation and Research. 
2 Throughout this guidance, we use the terms marketing application and submission interchangeably to 
reference whichever type may be appropriate for your product.  The marketing application includes original 
submissions, amendments, and supplements, as appropriate. 
3 In identifying pen injectors, FDA distinguishes pen injectors from piston syringes and pen injectors with 
manually-inserted needles from pen injectors with automatically-inserted needles.  
4 Combination products are defined at 21 CFR 3.2(e). 
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This guidance does not apply to devices the sole purpose of which is to aid in the 
insertion of a syringe (product code IQG under 21 CFR 890.5050) nor to infusion sets 
(product code FPA under 21 CFR 880.5440).  Also, this guidance does not apply to 
dental surgery gas-powered jet injectors (product code EGQ under 21 CFR 872.4465) or 
dental surgery spring-powered jet injectors (product code EGM under 21 CFR 872.4475).   
 
This guidance supplements other FDA guidance documents that may apply regarding 
specific content requirements of a marketing application and any electronic and software 
components of your product.  See Section III for a list of some additional guidance 
documents that may be useful when developing pen, jet, or related injectors for use with 
drugs and biological products. 
 
FDA's guidance documents, including this guidance, 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.  
 
 
Background 
 
Pen, jet, and related injectors may provide an innovative approach to deliver drugs or 
biological products, and they may enhance safety, improve dosing accuracy, and increase 
patient compliance, particularly in self-administration settings.  For example, these 
injectors are designed to provide an accurate method of injecting a dose of 
drug/biological product contained in a cartridge, reservoir, or syringe through an 
automatically or manually inserted hypodermic needle(s) or through a high velocity jet.  
They are intended for use by a healthcare provider or for self-administration by a patient.  
Injectors may be designed for single use or multiple uses, and may be disposable or 
reusable.  For example, a single use injector may be used in acute intervention for 
treatment or prevention while a multi-dose injector may be used as part of a single patient 
long term treatment regimen. 
 
There are three basic usage groups of injectors.  First, there are general injectors intended 
for use with a wide range of drugs/biological products.  Second, there are injectors 
intended for use with a certain class/family of drugs or biological products, or with a 
specific product line.5  Third, there are injectors intended for use with a specific 
drug/biological product; e.g., a) pre-filled with the drug/biological product, b) co-
packaged with the drug/biological product, or c) separately distributed but labeled for use 
together.  
 
                                                 
5 For purposes of this guidance document, class and family are used interchangeably.  An example of 
an injector to be used with a class or family of product is an injector designed for insulin drug 
formulations.  An example of an injector to be used with a product line is an injector intended to be used 
with all injectable products that a specific company markets. 
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Injectors are subject to different regulatory requirements depending, for example, on their 
intended use, technological characteristics, proposed labeling, and packaging.  For 
instance, as noted above, injectors intended for general use with a wide range of legally 
marketed drugs/biological products (i.e., without a specified drug or biological product) 
generally are regulated as class II medical devices under the premarket notification 
(510(k)) provision.  Likewise, injectors intended for use with a certain class/family of 
drugs/biological products often are regulated as class II medical devices under the 510(k) 
provision.  Injectors intended for use with a specific drug/biological product are typically 
considered combination products under 21 CFR 3.2(e).6  Combination product 
assignment is based on primary mode of action (PMOA).7  Combination products with a 
drug or biological product PMOA are assigned to CDER or CBER for regulation.  For 
combination products comprising an injector and a drug/biological product, one 
marketing application is generally sufficient; this application is usually an NDA or a 
BLA.8 
  
This guidance focuses on the scientific and technical considerations that a manufacturer 
should consider when developing a pen, jet, or related injector and submitting a 
marketing application.  It provides considerations applicable to all injectors described 
above.  It also provides general content and format information for injectors that are 
reviewed under 510(k) submissions as well as injectors reviewed under an NDA or BLA 
submission for the combination product. 
 
 
SECTION I: SCIENTIFIC AND TECHNICAL 
CONSIDERATIONS FOR YOUR PREMARKET 
SUBMISSION 
 
A.  Injector Description 
 
Given the spectrum of injector designs, we recommend that your premarket submission 
includes a comprehensive description of your product, its indication(s) for use, and its 
conditions of use.  Depending on the product, the submission should include the 
following elements, as applicable:  
 
1.  Identification 
The proposed injector should be identified using the following information: 
 
  Trade name or proprietary name of the injector 
  Associated name; e.g., generic or other name of the injector9 
                                                 
6 General information on combination products is available at 
http://www.fda.gov/CombinationProducts/default.htm. 
7 Combination products are assigned to a Center for primary review and regulation based on a 
determination of the products primary mode of action (PMOA); 21 CFR 3.4. 
8 Please see section I.A.4, below, for general information related to the marketing application.  
9 In a 510(k), a classification name relates to the injector characteristics. 21 CFR 807.3(j). 
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  Device classification regulation (e.g., 21 CFR 880.5860) and product code 
(e.g., NSC).10   
 
2.  Indication For Use 
The proposed indication statement should include the following items: 
 
  Patient population (e.g., medical disorder, demographics) 
  Injection site (area on the body where the drug/biological product is 
injected) 
  Intended injection tissue and depth of injection (e.g., subcutaneous, 
intramuscular, intradermal) 
  Type-of-use (e.g., individual patient use as a single, disposable, reusable, 
or refillable injector)  
  Purpose of product use (e.g., for general use or for use with a product 
class, family, product line, or a specifically named drug or biological 
product) 
  Intended user (e.g., patient, caregiver, health care provider) 
 
The following table illustrates some of this information. 
 
 
        Type of Use                                    Description 
Single-use  Entire injector and primary container closure or drug 
container is discarded after a single use 
Disposable  Injector can be used more than once for a single 
patient only with the same primary container closure 
or drug container in place and is discarded after the 
drug container is empty 
Reusable   Injector can be used more than once for a specified 
single patient only with replaceable primary 
container closure or drug container 
Other  Describe any unique type-of-use or intended user 
conditions; 
      Intended User                                  Description 
Personal  For self-administration or by a caregiver  
Professional  For use by a healthcare provider in a healthcare or 
institutional setting for a specified single patient only 
 
 
                                                 
10 The device classification and code only apply for injectors submitted under a 510(k).  
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3.  Description of Conditions of Use11 
 
The discussion of the conditions of use for the injector should include: 
 
  Method of injection (e.g., manual piston, spring load, gas, jet, other) 
  Drug/biological product(s) intended for delivery by the injector 
  Dose capability (e.g., single dose, multiple dose, adjustable dose) 
  Packaging configuration (e.g., as a pre-filled injector-drug/biological 
product, as a co-package containing the injector and drug/biological 
product for assembly, or as a separately distributed injector) 
  Environment of use conditions (e.g., home, school, battlefield) 
  Storage, handling, and other use factors for pre-filled injectors; e.g., 
refrigeration, environmental conditions and/or protection from light, and 
warming to room temperature before injector actuation. 
 
4.  Description of Drug/Biological Product for Injection 
 
As noted above, there are three different usage groups of injectors: (a) injectors 
intended for use with a wide range of legally marketed drugs/biological products 
(general use), (b) injectors intended for use with a specific class or product-line of 
legally marketed drugs/biological products, and (c) injectors intended for use with 
only a specific drug/biological product.  Overall, the descriptive information on the 
drug/biological product should reflect the following considerations as applicable to 
each injector configuration and the drug/biological product intended for injection: 
 
a)  General use injectors: Typically, general use injectors are regulated under 
the 510(k) premarket notification process.  In order for FDA to clear a 
general use injector for marketing, at least one injectable product (e.g., a 
drug or biologic) must already be approved for use in the dose, rate, route, 
configuration, and the method of injection submitted in the 510(k)).12  For 
general use injectors, the description section of your application should 
include the following information, in addition to the information 
recommended by other applicable guidance. 
 
  The name(s) of the drugs/biologic products that are currently approved 
and marketed for the dose, rate, route, and method of injection 
proposed for the general use injector.  Your submission should include 
                                                 
11 Information in the "Conditions of Use" section may also be part of the "Labeling Indications,"  the "Use 
and Handling," or the Dosage and Administration section, as appropriate depending on the type of 
marketing application submitted  (e.g., Structured Product Labeling in an NDA/BLA  see Guidance for 
Industry, Indexing Structured Product Labeling assessable at 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM07231
7.pdf ).  
12 In cases where only one marketed injectable product is available or, if a compatible drug/biological 
product or configuration is in development or pending approval, or if there are drug/biological product-
injector compatibility concerns; FDA recommends that you contact the CDRH review branch or the Office 
of Combination Products to discuss whether general use is appropriate.  
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a copy of the most recent labeling for the representative product(s) of 
the range of approved drug/biological products that are currently 
marketed to be used with your injector.  Specifically, for each 
injectable product and its approved diluent for use in reconstitution, 
the submission should include a copy of the approved labeling of the 
diluent and the approved labeling of the drug/biological product 
proposed for reconstitution.  The approved labeling of the 
drug/biological product should indicate that the product is approved 
for the dose, rate, route, and using the method of injection of the 
proposed injector.  The dose is generally identified as a concentration 
or volume.  The route of injection includes, subcutaneous, intradermal, 
intramuscular, or intravenous.  The rate reflects differences in flow 
rate produced by a manual piston syringe, power, jet or other forces.13 
 
  The characteristics and composition of the drug/biological product that 
are compatible and not compatible with your injector material and 
performance characteristics.  FDA uses this information in part to 
inform final device labeling language.  If identifying incompatible 
drug/biological product characteristics is not feasible, then provide a 
scientific rationale for why the characteristics were not tested.  
Examples of composition considerations include active and inactive 
ingredients, pH, viscosity, preservatives, and osmolarity along with the 
aqueous or oil-based characteristics.  If you are considering submitting 
representative product data for a general use injector (instead of testing 
with specific drugs or biologic products), contact CDRH for discussion 
on whether such representative testing is appropriate for your 
submission.  (For additional information on performance testing for 
general use injectors, see Section I.D.) 
 
b)  Injectors intended for use with a class/family of products, with a specific 
product line, or with a specific drug/biological product: If the injector is 
intended to deliver a specific drug/biological product, a certain product 
line, or a class/family of products,14 your submission should include the 
following.  
 
  The approved product(s) for injection by brand and/or generic name 
and their labeled indication(s) for administration.  In these 
circumstances, FDA intends to consider whether the target product, 
product line, or class/family of products is currently approved for the 
dose, rate, route, and using the method of injection proposed for the 
injector.  We also recommend that your submission includes a copy of 
the most recent product labeling of the approved drug/biological 
product(s) in the family/class to be used with your injector.  For some 
                                                 
13 Generally when the rate or method of injection is not specifically identified in the drug or biological 
product labeling instructions or clinical trials section, the default method is that of a manual piston syringe. 
14 See footnote 5. 
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very narrow product lines with consistent product characteristics, it 
may be acceptable to provide a copy of the labeling for one 
representative drug or biological product within the product line.  (For 
additional information on performance testing for these products, see 
Section I.E.  For additional information on labeling, see Section I.H.) 
 
  Documentation that the drug/biological product is currently approved 
for marketing in the necessary configuration for use in the injector.   
 
If you are proposing your injector for use with an unapproved drug or biological product, 
or for use with an approved drug or biological product but using a new route, dose, rate 
or method of injection, the relevant Centers will identify the necessary data for the 
premarket review of the drug/biological product, and the appropriate type of 
submission(s) for the unapproved product(s) and the injector.15  We recommend that you 
contact the Office of Combination Products for additional information to determine the 
lead center.16   
 
If you are providing injectors to pharmaceutical firms (or entities such as holders of other 
marketing applications) for further manufacturing, pre-filling, or co-packaging, and if 
you wish to maintain certain confidential information regarding your injector, you can 
provide FDA with proprietary information about these injectors in a device master file 
submission to CDRH.  When doing so, you should also provide letters of authorization to 
the other firms/application holders who are performing the additional manufacturing 
steps or are relying on your information.17  These other entities could then reference the 
information in your device master file when they provide their own marketing 
submissions (i.e., NDA/BLA).  For pre-filled injectors and for injectors co-packaged with 
a drug/biological product, the marketing application should identify which application 
holder/manufacturer/supplier will perform the pre-filling, co-packaging, and other 
manufacturing steps to produce the final finished product for marketing.  For additional 
procedural information see Section III. 
 
B.  Design Features 
 
Design features encompass the technical specifications of the injector, the characteristics 
of the injectable product, the injector configuration (e.g., general use, prefilled, or co-
packaged) and the human factors to be considered to ensure safe and effective use of the 
product.  When submitting a general use device under 510(k), the design information in 
section I.B.1-6 below should be compared to the predicate device. 
 
                                                 
15 Changes in the dose, rate route or method of injection may trigger the Pediatric Research Equity Act 
(PREA) (21 U.S.C. 355c).  See FDA Guidance How to Comply with the Pediatric Research Equity Act ; 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM07975
6.pdf. 
16 See http://www.fda.gov/CombinationProducts/default.htm and footnote 7. 
17 For more information on medical device master files (MAFs) and authorized references see 
http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/HowtoMarketYourDevice/PremarketS
ubmissions/PremarketApprovalPMA/ucm142714.htm. 
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1.  Comparison to an Existing Delivery Method 
 
To facilitate the regulatory review of the injector, manufacturers may compare 
various design features of their injector to features in similar legally marketed 
products.  The goal of this comparison differs depending on the injector use and 
regulatory pathway for the injector.   
 
a)  General use injectors (510(k) pathway):  
 
The 510(k) marketing pathway requires demonstration of substantial 
equivalence to a legally marketed predicate injector(s).18  The following 
are examples of comparative information that you should provide in a 
510(k) submission.  For additional information also see Section I.D., 
Performance Testing. 
 
  510(k) number(s) of the predicate(s) 
  Indications for use of the new injector 
  Conditions of use 
  Injection sites 
  Where applicable, depth of needle insertion for route of injection 
  Injector life 
  Compatible cartridges 
  Where applicable, compatible needles 
  Dose, dose accuracy, rate of injection, frequency of injection, and 
precision (including mechanisms to determine the dose) 
  Power source 
  Overall dimensions 
  Weight 
  Design features 
  Materials of construction 
  Performance specifications and profile (e.g., force, pressure) 
  Where applicable, needle lumen and jet injector nozzle orifice size 
  Drug/biological product(s) intended for use with the injector 
 
b)  Prefilled injectors, injectors co-packaged with the drug/biologic, 
or injectors and drug/biologic distributed separately and marketed 
under the NDA/BLA pathway: 
 
  For prefilled injectors, co-packaged injectors, or injectors and 
drug/biologic distributed separately and marketed under the 
NDA/BLA, each premarket submission is reviewed and approved 
for a specific injector with a specific drug/biological product.  In 
most instances, data required in a general use injector 510(k) are 
not sufficient to address the safety or effectiveness questions for 
                                                 
18 See 21 CFR Part 807 Subpart E. 
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the device constituent part of a combination product submitted in 
the NDA/BLA (i.e., to demonstrate safe and effective use with a 
specific drug/biological product for the combination product 
indication).  For example, a general use 510(k) does not contain 
specific safety and effectiveness information on the dedicated 
drug-injector combination, its specific characteristics, or the 
intended patient population.  Therefore, the submission should 
include injector-drug/biological product specific data.  In 
addition, if the injector for the drug/biological product would 
change, for example, the route or method of injection, or other 
characteristics of the approved drug/biological product, then the 
NDA/BLA should include the relevant data (e.g., 
pharmacokinetics or other end-points from oral, intravenous, 
intramuscular, or subcutaneous dosing) in comparison to other 
approved drug/biological product delivery methods as 
appropriate.  Also see section I.D.  
 
2.  Engineering Drawings and Photographs 
 
We recommend that you provide engineering component and assembly drawings for 
your injector which includes the following key functional components: 
  Fluid path and reservoir 
  Power supply  
  Dose-setting mechanism, such as a dial, used to set the desired dose 
 
In addition, you should provide the following: 
  Exploded views and photographs of the injector and illustrations showing 
the drug product delivery stages 
  Engineering drawings with critical dimensions and tolerances 
  List of the components incorporated in the injector 
 
3.  Dose Setting and Administering an Injection 
 
In order for FDA to assess the ability of the injector to reliably and reproducibly 
deliver the desired injection volume of the target drug/biological product(s) into the 
target tissue, and to compare the reliability and reproducibility to those of the 
predicate injector (or other delivery method as appropriate), we recommend you 
provide a description of the procedures for setting and administering the 
drug/biological dose when using the new and predicate injector including (if 
applicable): 
  Assembling the injector at the point of clinical use 
  Loading the drug/biological product 
  Priming the injector 
  Pre-setting the dose 
  Inspecting the drug/biological product 
  Preparing and positioning for an injection 
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  Adjusting the dose 
  Resetting after use 
  Changing and disposing the needle 
 
Likewise, we also recommend that you include, if applicable:  
  A description of the power source for the injector. 
  A description of the controls, such as dose indicators, activation status, 
and reservoir volume. 
  The method and mechanism for ensuring that the drug/biological product 
in the chamber or cartridge is sufficient for the desired volume of delivery. 
  A discussion of the frequency of incomplete or partial dosing, or 
overdosing events, and the actions necessary to remedy these events. 
  The time required for delivery of the drug/biological product. 
  If the injector has a retractable fixed needle, a discussion of how the 
design ensures that the full dose will be delivered prior to needle 
retraction. 
  For jet injectors, a description of the nozzle design (e.g., single orifice, 
multiple nozzles/orifices of different sizes). 
  A description of all of the attachments that are necessary for the proper 
operation of the jet injector, even if they are not part of the injector 
proposed for marketing, or part of a cleared or approved product being 
referenced (e.g., a regulator for compressed air, transfer device, IV luer 
lock needleless connector, needle, and/or needle array). 
  If assembly by the user is required, a detail description of how the injector 
is assembled; if the injector is pre-filled, a detail description of how the 
drug/biological product is contained in the injector. 
 
4.  Graduation Marks and Fill Lines 
 
Graduation marks and fill lines may be used to aid the user in setting the correct dose 
or for verifying the set dose.  We recommend that these markings be included in the 
design of the injector to aid proper dosing in accordance with the approved 
drug/biological product labeling, when:  
 
  The injector is intended to deliver multiple doses of a drug/biological product; 
  The dose can be adjusted by the user; or 
  The injector is intended to deliver a single dose of a specific drug/biological 
product and the risks associated with under- or over-dosing are critical as 
determined by a risk analysis. 
 
When using graduation marks or fill lines, the submission should include validation 
of the accuracy of these markings.  If graduation marks/fill lines are not feasible, then 
the submission should provide an alternative method to alert the user if under or over-
dosing occurs. 
 
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5.   Visual Inspection of the Drug/Biological Product 
 
In some circumstances, the drug/biological product for delivery has labeling 
instructions requiring visual inspection of the product before injection.  (In part this 
ensures compliance with the 21 CFR 201.57(c)(3)(iv) requirement for the Dosage and 
Administration labeling section to include the following verbatim statement for 
parenterals: Parenteral drug products should be inspected visually for particulate 
matter and discoloration prior to administration, whenever solution and container 
permit.'')  As a result, the injector design should allow for appropriate inspection.  
For example, for a pre-filled injector that holds a cartridge for future or repeat dose 
use that cannot be removed once it is placed in the injector, the injector design should 
permit the appropriate visualization of the drug/biological product when it is in the 
injector.  Additionally, the inspection should allow the visualization of the 
drug/biologic name and concentration/strength in order to minimize medication 
errors. 
 
6.  Safety Features 
 
Injectors may have a variety of safety features to ensure accurate dosing and to 
prevent sharps injury.  In addition to graduation/fill marks and visual inspection, these 
features may include audible, visual, and tactile notifications as well as switches and 
mechanical protections.  We recommend that you describe all safety features of the 
injector including alarms, warnings, and switches, their purposes, and their 
instructions for use, and provide testing to demonstrate that the safety features 
perform as intended.  If the injector has a sharps injury prevention feature (e.g., 
retractable needle), we recommend that you address the issues discussed in the 
guidance document Supplementary Guidance on Premarket Notifications for Medical 
Devices with Sharps Injury Prevention Features (Aug. 2005), available at 
http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocum
ents/ucm071663.htm.  See also FDA 2011 communication on Needles and Other 
Sharps - Safe Disposal of Sharps Outside of Health Care Settings at 
http://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/HomeHealthand
Consumer/ConsumerProducts/Sharps/default.htm. 
 
We also recommend that you conduct a risk analysis that considers the overall 
product and includes both the injector and drug/biological product for injection.  
Specifically, you should assess the risk of use of the intended drugs/biological 
products delivered with the injector as related to the human factors characteristics of 
the patient population using the intended drugs/biological products.  For additional 
discussion on human factors see Section I.B.7 below and Section I.F.)   
 
7.   Human Factors Design Considerations 
 
The design of the injector should take into consideration the intended user population, 
the expected indications for use, and the environment of use.  For example, in home 
use populations, these factors should include age, tissue characteristics at site of 
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injection, and any limitations in the perception, strength, mobility, and manual 
dexterity among the user population for whom the injector is intended.19  Injectors 
that are designed for user populations that might have visual impairments or manual 
dexterity limitations might need to have design features that accommodate those 
limitations; e.g., auditory alerts, larger easy grip.  Likewise, injectors intended for use 
by individuals serving in the military should take into account the wide range of 
environmental conditions under which the injectors will be stored and possibly used 
(e.g., in desert or tropical climates or frigid conditions, and at various altitudes, such 
as in an aircraft or in a submarine).  Other factors associated with the environmental 
conditions include ambient lighting, noise, and user physical activity levels.  Careful 
evaluation of how these factors can affect safe and effective use of the injector, and 
how they can be mitigated should be assessed during the design and development of 
the injector.  (See Section I.F for further discussion of human factors). 
 
C. Materials Used in Injector Construction and Manufacture 
 
Your marketing application should identify all known materials that comprise the injector 
as well as the manufacturing materials used in construction of the injector.  For general 
use injectors submitted under a 510(k), for each component of the injector, please specify 
the nature and composition of all materials of construction and identify any differences in 
comparison to the predicate.  The submission should provide the chemical, grade, and 
brand name, and indicate which materials are in or will affect the fluid path.20  It should 
also identify any components or materials that are not identical to those of the predicate 
injector (e.g., plastic stoppers instead of rubber stoppers).  For any new component or 
materials of construction, the submission should include the methods and results of 
testing described in this section. Also, the submission should include a comparison of the 
characteristics of the drug/biological products intended for use with the predicate injector 
versus the drug/biological products intended for use with your proposed injector. 
 
Certain drugs/biological products have different responses to metals and manufacturing 
materials that may be components of an injector (e.g., silica, steel, carbon, polymers).  
Also, some drug or biological products may interact with manufacturing process 
residuals.  The submission should, therefore, include the results of tests that examine the 
interaction between the injector materials of construction, manufacture, and process 
residuals with the drug/biological product.  These tests should evaluate how the injector-
drug/biological product interactions affect each others performance.  The testing should 
include the entire product use cycle functionality testing in the stability program (see 
Section I.D.2 and I.D.3).   
 
                                                 
19  See Draft Guidance for Industry and FDA Staff - Apply Human Factors and Usability Engineering to 
Optimize Medical Device Design (June 2011), available at 
http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm259748.htm. 
When finalized, this guidance will represent the FDAs current thinking on this topic. 
20 For purposes of this guidance, materials that are in or will affect the fluid path are components and 
accessories of the injector that make contact with the drug/biological product, including the needle, dose 
chamber, cartridge, plungers and stoppers, and reservoirs for the drug/biological product. 
14
 
 
  Contains Nonbinding Recommendations 
 
Testing should characterize the components of the injector, the component materials, and 
residuals from the manufacturing process.  For injectors submitted under the NDA/BLA 
the same information should be submitted, but the comparison to a predicate is not 
applicable.  The following list describes specific issues FDA intends to consider in 
reviewing the submission: 
 
  Analysis of  leachables arising from the interaction between the drug/biological 
product and injector (see Section 1.E.3) 
  Analysis of extractables from the injector components using solvents under 
laboratory conditions and providing the extraction profiles (see Section 1.E.3) 
  Analysis of adsorption of drugs/biological products (including preservatives) onto 
injector components   
  Analysis of head-space volatile compounds when the injector is the primary 
containment closure for the drug/biologic  
  Analysis of drug-injector interaction over time for re-useable injectors 
  Analysis of functional materials corrosion from contact with the drug/biologic 
product. 
  Analysis of seal integrity (e.g., lubricity breach of sealing)  
  Identification and analysis of effect of introduced particulates  
 
D. Performance Testing: General Use Injector Considerations  
 
Performance testing for general use injectors should be with the final injector for 
marketing and should take into account the characteristics of the wide range of 
drugs/biological products in their final approved dosing form (including their approved 
diluent for reconstitution) with which your injector is intended to be used.  Also, as 
appropriate for the injector design, the testing should demonstrate the drug/biological 
product composition characteristics that are compatible with the injector and those that 
are not (see Section I.A.4.a).  FDA recognizes that in some general use circumstances, it 
may be acceptable to conduct testing with a range of representative drug/biological 
products.  If such testing is proposed, the submission should provide a detailed 
justification for why it is appropriate and why the chosen product or range of products is 
acceptable.  When conducting performance testing, we recommend that you follow the 
most current version of the standards recognized by FDA which are identified below and 
at http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfStandards/search.cfm.21 
 
  ISO 7886-1: Sterile Hypodermic Syringes for Single Use - Part 1: Syringes for 
Manual Use 
  ISO 10993-1:Biological Evaluation of Medical Devices - Part 1: Evaluation 
and Testing 
  ISO 11608-1:, Pen-Injectors for Medical Use  Part 1:  Pen-injectors  
Requirements and test methods 
                                                 
21 In a 510(k) submission when the data comply with FDA recognized standards, the submission may 
include summary data.  However, full data should be available to provide upon FDA request during review 
process.  Standards documents are available from the authorizing organizations. 
15
 
 
  Contains Nonbinding Recommendations 
 
  ISO 11608-2: Pen-Injectors for Medical Use  Part 2:  Needles  
Requirements and test methods 
  ISO 11608-3:  Pen-Injectors for Medical Use  Part 3:  Finished Cartridge  
Requirements and test methods 
  ISO 11608-4:  Pen-Injectors for Medical Use  Part 4:  Requirements and test 
methods for electronic and electromechanical pen-injectors 
  ISO 21649: Needle-Free Injectors for Medical Use - Requirements and Test 
Methods. 
  ASTM D4169:, Standard Practice for Performance Testing of Shipping 
Containers and Systems 
 
If applicable, FDA also recommends that you conduct software, electrical safety, and 
electromagnetic compatibility testing for your injector.  Guidance on testing these aspects 
of your injector is available from FDA.22 
 
FDA recommends that your submission include results from the performance testing on 
the finished products as follows: 
  
  List the specific bench tests conducted 
  Description of each test protocol 
  Summary of the results 
  Description of your analysis, and 
  Discussion of your conclusions 
 
The description of test protocols should identify the: 
  Objective of the test 
  Test articles used in the test 
  Test methods and procedures (including any specific test conditions) 
  Study endpoint; i.e., the specific parameter measured, and 
  Pre-defined acceptance or pass/fail criteria. 
  Test procedures to demonstrate that the injector connections are compatible 
with other devices necessary for use but are not part of the submission (e.g., 
transfer device, IV luer lock needleless connection, needle, needle array).23 
 
1.  Biocompatibility 
 
For general use injectors, FDA recommends that you conduct biocompatibility testing 
as described in the guidance, Use of International Standard ISO-10993, Biological 
                                                 
22 See General Principles of Software Validation; Final Guidance for Industry and FDA Staff (Jan. 2002); 
http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm085281.htm. 
23 For examples of connectivity concerns, see FDA Safety Communication: Needleless Pre-filled Glass 
Syringes: Stakeholder Advisory - Compatibility Problems with Needleless Intravenous Access Systems; 
http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm2342
19.htm.  Also, see FDA Drug Safety Communication: Connection problems involving certain needleless 
pre-filled glass syringes containing adenosine and amiodarone; 
http://www.fda.gov/Drugs/DrugSafety/ucm254215.htm. 
16
 
 
  Contains Nonbinding Recommendations 
 
Evaluation of Medical Devices Part-1: Evaluation and Testing.24  The 
biocompatibility testing should consider components or materials in contact with the 
patient, including components or materials that are in the fluid path that externally 
communicates with the patient's body (e.g., skin, tissue, blood, bodily fluids).  The 
selected biocompatibility tests should be appropriate for the type and duration of 
contact with your device.  Summaries of biocompatibility testing should include: 
 
  Listing of the specific tests you conducted 
  The details of extraction testing (e.g., whether the entire injector or only a 
small piece of the injector was extracted, whether all the components were 
included in the extraction, whether the extraction was performed on the 
finished injector subject to all processing methods and sterilization) 
  The extracts tested and justification for the choice of extracts (e.g., polar, 
non-polar) 
  The animal model or cell line 
  The extract conditions (e.g., time, temperature, area- or mass-to-volume 
ratio compared to in-use conditions) 
  The test and controls used 
  The end points used  
  As appropriate, toxicity testing of extracts described in the United States 
Pharmacopeia USP<87>, USP<88>, USP<381> and USP<661> as well as 
systemic toxicity, delayed dermal contact sensitization studies, non-
pyrogenicity testing, cytotoxicity testing using red blood cells and mouse 
fibroblasts, and Ames assays.25 
 
Depending on the specific materials in the product and conditions of use, FDA may 
request additional pharmacology-toxicology testing.   
 
2.  Shelf-Life Stability and Expiration Dating 
 
For stability and expiration dating, the testing should consider the general use 
injectors shelf-life/expiration dating before it is actually used and the injector in-use 
life with the drug/biological product.  The test data should include a demonstration 
that at the labeled expiration date the injector can still be reliably and reproducibly 
used for the labeled number of injections with the same dose accuracy.  FDA 
recommends that shelf and in-use life-testing endpoints include: 
 
  Freedom from defects (e.g., displaced parts, cracking, leaking, change in 
injection force) 
  Proper assembly of replacement needles and cartridges 
  Accuracy of delivered dose (see Section I.E.1) 
 
                                                 
24 ISO-10993, Biological Evaluation of Medical Devices Part-1: Evaluation and Testing 
http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm080735.htm. 
25 United States Pharmacopeia information is accessible at http://www.usp.org. 
17
 
 
  Contains Nonbinding Recommendations 
 
As above, the submission should include an analysis and discussion of the physical 
degradation of and changes to the injector before use and during use due to the 
exposure conditions.  For additional information relating to the life of an injector, see 
Section I.E.2. 
 
3.  Environmental Conditions 
 
You should submit data to verify that the injector performance is not adversely 
affected by environmental conditions, such as the following: 
 
  Sterilization 
  Extreme operating temperature environments (i.e., upper and lower ends 
of the specification) 
  Extreme storage temperature environments (i.e., upper and lower ends of 
the specification) 
  Extreme conditions of use testing, when applicable (i.e., upper and lower 
ends of the specification) 
  Packaging 
  Shipping conditions 
 
In addition, for jet injectors, the extent of wear and tear on the nozzle and fluid path 
is of concern.  The high jet stream velocity and pressure may have deleterious effects 
on the fluid path and the nozzle, including erosion, component deformation, and 
structural failure.  These effects should be assessed in relationship to the injector and 
component service life, servicing, or replacement intervals. 
 
4.  Functional Testing 
 
Depending on the type of injector, as appropriate for the injector design, a company 
may be asked to conduct additional bench testing to demonstrate that the injector 
functions as intended.  Testing to assess the functionality of your injector may 
include: 
 
  Flow rate 
  Injection time (i.e., time required to deliver the drug/biological product) 
  Reliability of the mechanism to deliver the drug/biological product 
  Depth of injection  
  Safety features 
  Verification for absence of leakage 
  Verification of non-coring needle (e.g., if the needle is used to puncture a 
septum) 
  Needle dwell time (i.e., amount of time that the needle is in the body) 
  Chemical resistance (i.e., data to ensure that the injector and its label are 
not adversely affected by the recommended cleaning agents) 
  Structural testing at extreme pressure and temperature conditions 
18
 
 
  Contains Nonbinding Recommendations 
 
 
Testing to assess the mechanical specifications of your injector may include: 
 
  Force required for assembly 
  Force required to actuate the injector 
  Force required to defeat the needle shield or other safety mechanism 
  Load testing on individual components 
  Needle bond strength (i.e., force required to pull the needle off the 
injector) 
  Needle penetration force (i.e., force available for needle insertion) 
  Needle deflection angle that causes injector failure (note: this is important 
if the needle retracts after insertion) 
 
The above tests should include testing of all safety features to ensure they perform as 
intended.  Also, for multiple use injectors, the testing should verify the duration of 
repeated use. 
 
E. Performance Testing: Injector and Drug/Biological Product Considerations 
 
For a general use injector, in association with the considerations in Section I.D, the 
submission should include the results from performance testing of the final finished 
injector for final finished dosage form for testing of the drug/biological product dose 
accuracy and for depth and route of injection as described below.  For injectors intended 
for use with a certain class/family or product line or with a specific drug/biological 
product, when developing your plan for performance testing you should begin with the 
considerations described in Section I.D and should then focus on the unique attributes of 
the injectable product class/family or product line, as described below.  Likewise, 
subsequent to the applicable considerations in section I.D, the following testing 
considerations apply to the specific drug/biological product of a combination product. 
 
When conducting performance testing for your injectable product, you should use the 
actual drug/biological product(s) in its final approved dosage form (including its 
approved diluent, if applicable) as intended for injection.  For example, for an injector 
intended for use with a specific drug, you should perform biocompatibility testing with 
that drug (see Section I.D.1).   
 
When conducting performance testing for a class/family or product line, you should 
consider the type of testing necessary to evaluate the expected injector-drug/biological 
product interactions.  For example, if the injector materials are coated with a polymer, 
then the submission should identify which types of drug/biological product characteristics 
were tested to demonstrate an acceptable level of leachable or extractable material into 
the drug/biological product (see Section I.E.3 below).   
 
We recommend that your submission include results from the following performance 
tests, in addition to the tests identified in Section I.D:    
 
19
 
 
  Contains Nonbinding Recommendations 
 
1.  Dose Accuracy 
 
Using your final injector, FDA recommends the following injection dose accuracy 
testing for the drug/biological product in its approved dosage form for injection, 
including the use of the approved diluent as applicable.  If the study is for a device-
drug/biological product pending approval, then the testing should use the final 
combination. 
 
  Testing to demonstrate that the volume/weight of drug/biological product 
expelled through the injector is the same as the set dose 
  Testing to ensure that multi-dose (fixed dose) cartridge injectors are 
designed to accurately deliver the fixed dose each time for the number of 
multi-dose injections specified in the labeling  
  Testing to ensure that multi-dose (variable dose) cartridge injectors are 
designed to accurately deliver each successive randomly set dose 
  Testing to ensure that dose settings/markings correlate with the volume of 
drug/biological product delivered   
 
We recommend, where appropriate, that injectors include an alarm that notifies the 
user when only a partial dose has been delivered.  Performance testing should include 
testing of such alarm(s).  Product labeling should also include information instructing 
the user on what action should be taken in the event of partial dosage.  (In addition, 
see information in Section I.B.4.) 
 
2.  Depth and Route of Injection 
 
Testing should demonstrate that the depth of needle penetration and/or dispersion of 
the drug/biological product in the target tissue are accurate and consistent.  The model 
chosen for this testing should be human skin and any specific tissue layers, or should 
simulate the human target tissue as closely as possible.  If the selected model is a 
simulation of human tissue, the application should include an explanation to justify 
why the model is appropriate.26   
 
Where applicable, provide a statistical comparison and justification for any 
differences between the measurements for the subject injector and those for predicate 
injectors or other delivery methods, as appropriate for the development question 
being addressed.  (See section I.B.1) 
 
Certain drugs or biological products require delivery to a precise tissue plane (e.g., 
intradermal, subcutaneous, intramuscular).  Where applicable, the submission should 
include test results demonstrating reliable and reproducible depth of delivery (e.g., 
amount delivered subcutaneously, intradermally, or intramuscularly).  Also see 
Section I.B.7 and I.F.1. 
                                                 
26 Examples of acceptable depth of penetration testing include, but are not limited to, human, porcine, and 
cadaver models.   
 
20
 
 
  Contains Nonbinding Recommendations 
 
 
For injectors that involve the mechanical actuation and insertion of the hypodermic 
needle, jet injection or needleless injector, we recommend that you perform additional 
testing to examine the following parameters: 
 
  Reliability for the specified depth of insertion throughout the expected 
injector life cycle 
  Injector performance such as the amount of pressure needed to administer 
an injection and the permissible areas of body that may receive successful 
injections  
  How population-specific issues, such as gender, body weight, age, and 
skin disorders, may affect injection safety or effectiveness 
  The presence of blood vessels to avoid intravascular injection (if 
applicable) 
 
For jet injectors, testing should also characterize the fluid dispersion from the 
injection to indicate the percentage of fluid in or at the surface of the muscle and at 
various depth ranges in the subcutaneous region.  The submission should include 
images of injections depicting the distribution of the injected drug/biological product.  
 
3.  Special Testing Considerations 
 
If the injector materials also comprise the container closure system for the specific 
drug/biological product, then you should perform the following in-vitro testing to 
support the performance of your injector with the specific drug/biological product.  In 
some circumstances, similar testing may be appropriate for injectors intended for use 
with a class/family or product line. 
 
  Extractables or Leachables 
 
In addition to the studies identified in Section I.C, you should provide studies 
that evaluate head space volatiles in the cartridge.  Specifically, you should 
demonstrate that any seals or o-rings have the ability to contact different 
method of injection drug/biological products without sloughing or leaching 
material.  Testing should also demonstrate seal integrity.  Other testing that 
may be applicable to identify interaction with the injector and the injector 
manufacturing materials include: 
-  Extractant analysis: e.g., pH shift, turbidity, heavy metals, non-volatile 
residue, residue on ignition, UV absorption, silicone content. 
-  Chromatography: e.g., nucleating agents, cross-linking agents, curing 
agents, antioxidants, acid scavengers, plasticizers. 
-  Impurities and degradation products 
-  Endotoxins 
 
21
 
 
  Contains Nonbinding Recommendations 
 
In addition, data should include the methods and assay sensitivity used to 
determine the acceptable level of device materials leachable or extractable 
into the drug product. 
 
  Adsorpables 
 
Testing should evaluate the presence of drug/biological product or component 
gases, liquids, or solutes that accumulate on a surface of the injection device.  
Data should include the methods and assay sensitivity used to determine the 
acceptable level of drug/biological product adsorpables. 
 
  Drug/Biological Product Container and Closure Integrity 
 
For the configuration in which the injector or its fluid path is in direct contact 
with the drug/biological product, we recommend consideration of the 
principles in the FDA guidance, Container Closure Systems for Packaging 
Human Drugs and Biologics: Chemistry, Manufacturing and Controls 
Documentation (May 1999); available at 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInform
ation/Guidances/UCM070551.pdf. 
 
  Shelf-life and Expiration Dating: Injector-Drug/Biological Product 
 
Applications for injectors intended for use with a specific drug/biologic 
product or for a drug/biological class/family or product line should include 
stability data to establish the shelf-life and expiration dating of the relevant 
fully assembled injector-drug/biological product.  For example, as 
appropriate, tests may assess the shelf life of the assembled product in storage 
conditions before use.  They may also assess stability and expiration dating of 
the final to-be-marketed configuration under expected in-use conditions (e.g., 
rugged use, different environmental conditions).  Where applicable, the tests 
should evaluate the product after reconstitution.  They should assess any 
injectate that remains in the fluid path after injection; e.g., to determine if it 
degrades or contributes to the denaturing of the drug/biological product.  As 
applicable, the in-use life testing should include data to demonstrate that the 
method of injection (e.g., rate, shear force, injection pressure) does not affect 
stability, safety, or effectiveness of the drug or biological product(s).   
When conducting stability and expiration dating tests, the entire injector 
system should be tested; i.e., the drug/biological product in its direct container 
closure (cartridge) plus any surrounding injector materials and packaging.  
Bench testing for container closure and packaging ruggedness should include, 
but is not limited to, mechanical reliability (release specifications), accelerated 
testing, temperature cycling, temperature extremes, pressure changes, 
vibration, etc.  (For information on testing of a general use injector, see 
Section I.D.2.) 
 
22
 
 
  Contains Nonbinding Recommendations 
 
F. Performance Testing: Clinical Considerations 
 
Specific considerations for clinical trial design are beyond the scope of this guidance.  
Human factors studies would evaluate user interactions with the injector and whether the 
intended user population could safely and effectively use the injector with the specified 
drug/biological product.  
 
1.  Human Factors 
 
To demonstrate that the users can safely and effectively use the injector in subsequent 
pivotal clinical studies, you should perform a comprehensive evaluation of all user 
related risks, and as needed, conduct human factors/usability studies with the final 
version of the device to validate users performance with representative users.  
Depending upon the characteristics of the injector, its intended user population, and 
the environment of use, the studies should focus on essential aspects of using the 
product.  These aspects may include, for example, the ability of users: 
 
  To read, understand and follow instructions; 
  To adequately set up the injector; 
  To reconstitute injectable materials, draw up or set the proper dose, prime 
the injector (if required); 
  To perform the injection or self-injection correctly; and  
  To dispose of sharps and other disposable materials safely and properly.   
 
2.  Additional Considerations  
 
FDA may request additional in-use information for critical features of injectors 
intended for use with a specific drug/biological product.  For example, additional 
information may be appropriate for certain lock-out features, complex dose-
adjustment methods, or other high-risk systems.  For such products, we recommend 
that you contact the lead review division to discuss other pre-clinical and clinical data 
requirements. 
 
G. Sterilization and Sterility Assurance 
 
1.  Sterilization 
 
Sterilization incorporates two aspects: the sterility assurance necessary for the injector 
itself and the sterility assurance necessary for the final finished injector-drug/biological 
product as a whole.  For general use injectors intended for use with a wide range of 
marketed drugs/biological products, the submission should include sterilization 
information for the injector, as recommended in the FDA guidance, Submission and 
Review of Sterility Information in Premarket Notification (510(k)) Submissions for 
23
 
 
  Contains Nonbinding Recommendations 
 
Devices Labeled as Sterile (Draft).27  If the injector is provided as sterile, the data 
should demonstrate a probability of a non-sterile unit not greater than 1 x 10-6.  The 
components comprising the fluid pathway should be shown to be non-pyrogenic.  For 
all sterile components, the submission should contain a description of the injector 
packaging, including a list of packaging materials.  In addition, the sterility assurance 
necessary for the injector-drug/biological product in its final finished form the testing 
should be as recommended in the FDA guidance entitled, Guidance for Industry for 
the Submission Documentation for Sterilization Process Validation in Applications for 
Human and Veterinary Drug Products.28 
 
FDA recognizes that the following standards may be useful for determining sterilization 
processes and test methods.  The database of CDRH recognized standards is available 
at http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfStandards/search.cfm 
 
  ANSI/AAMI/ISO 17665-1: 2006, Sterilization of Health Care Products  Moist 
Heat  Part 1: Requirements for the development, validation, and routine control 
of a sterilization process for medical devices 
  ANSI/AAMI/ISO 11135-1:2007,Sterilization of Health Care Products  Ethylene 
oxide  Part 1:  Requirements for development, validation, and routine control of 
a sterilization process for medical device 
  USP 27:2004, Sterility, Biocompatibility, Biological Tests and Assays, Bacterial 
Endotoxin Test (LAL), Pyrogen Test (USP Rabbit Test), or other applicable tests 
related to the drug/biological product and delivery of the drug/biological product 
  AAMI/ANSI/ISO 11737-1:2006, Sterilization of medical devices-microbiological 
methods-Part 1: Determination of the population of microorganisms on product 
  ANSI/AAMI/ISO 11607:2006, Packaging for terminally sterilized medical 
devices 
 
For an injector that will be in a co-package or will be pre-filled with a specific 
drug/biological product, the submission should address the possible effects of the 
method of sterilization on the package (e.g., effects specific to the drug/biological 
product concerning, for example, light stability or oxygen sensitivity; effect on 
stability; effect on performance).  For an injector cartridge that will be in direct 
contact with a drug/biological product, we recommend that you select an appropriate 
method of sterilization for the product and primary packaging material, and that you 
justify your choice of method in your submission.  For example, if terminal 
                                                 
27 Submission and Review of Sterility Information in Premarket Notification (510(k)) Submissions for 
Devices Labeled as Sterile (Draft) available at 
http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm109884.htm.  
When finalized this draft will supersede the FDA 2002 Updated 510(k) Sterility Review Guidance K90-1;   
http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UC
M072790.pdf.  
28 Guidance for Industry for the Submission Documentation for Sterilization Process Validation in 
Applications for Human and Veterinary Drug Products, available at 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM07217
1.pdf 
24
 
 
  Contains Nonbinding Recommendations 
 
sterilization will adversely affect the drug or biological product, you should justify 
the selected method for sterility assurance. 
 
2.  Cross-Contamination Potential 
 
The vast majority of injectors are approved or cleared for single patient use.  In 
general, multi-patient use injectors (e.g., reusable needle-free Multi-Use-Nozzle Jet 
Injectors) raise significant concerns for the risk of blood born pathogen and skin 
contaminant transmission from patient to patient.  For example, there is a potential for 
disease transmission when blood contamination of the fluid path or the injectable 
product occurs during a previous injection.  Contamination can occur on the skin-
contacting surface of the injector or inside the injector from splash-back.  It is also 
possible that the replaceable cap may become contaminated.  In addition, in-between 
use cleaning of any component in or around the fluid path may result in 
contamination.   
 
Sponsors are likely to face challenges in validating methods to evaluate the absence 
of cross-patient contamination.  Initial information on such methodological 
challenges is available in the transcript of the FDA General Hospital and Personal 
Use Devices Advisory Panel meeting.29  FDA strongly encourages sponsors who are 
considering the development of multi-patient use injectors to meet with FDA to 
discuss approaches to validate their testing methods and overall development plans.  
To facilitate discussion, FDA recommends that the sponsor submit a Pre-Submission, 
which should include, at a minimum, information on the use of the most sensitive test 
available, a discussion of test method selection, assumptions, limitations, plans to 
document the accuracy of this method, and a thorough discussion and justification of 
the test method selection. 
 
H. Labeling 
 
Pen, jet, and related injectors are intended for use by health care professionals, caregivers 
or for self-administration by the patient.  We recommend developing labeling that 
carefully considers the end user and is consistent with the labeling of the drug or 
biological product for injection.  (See section I.A.4 for the type of information that should 
be available in the approved labeling for the drug/biological product proposed for 
injection with the injector.)  In some circumstances, it may be appropriate to develop a 
patient package insert or labeling for the patient or caregiver.30  Additional instructions 
may be appropriate for in-service training programs to familiarize users with the features 
of the injector and how to use the injector in a safe and effective manner.   
 
1.  General Labeling Principles 
 
                                                 
29 For more information, see the transcript for the FDA General Hospital and Personal Use Devices Panel 
(August 9, 2005), available at http://www.fda.gov/ohrms/dockets/ac/05/transcripts/2005-4172t1.htm. 
30 See 21 CFR 208.20. 
25
 
 
  Contains Nonbinding Recommendations 
 
In general, the following describes the appropriate elements that should be included 
in the labeling of the injector.  As appropriate for how the injector and the 
corresponding drug/biological product are marketed (e.g., co-packaged, prefilled, or 
separately sold products), the labeling format should be tailored to ensure safe and 
effective use.31  
 
  Injector description, including name 
  Intended use and indications for use 
  Type-of-use for the injector (e.g., personal, professional, single-use, 
reusable, labeled and sold for only one patient) 
a.  Labeling should include appropriate warnings and precautions for the 
use conditions and patient population.  For example, single-patient 
reusable injectors should include a warning to inform the user not to 
share the injector with other patients. 
b.  Labeling on the injector itself should provide for space to allow 
healthcare provider to write the name of the specific patient for whom 
the injector is specified to avoid medication error. 
c.   Labeling should include a prominent statement for single patient use 
only to avoid misuse and cross contamination.  
  Intended patient population 
  For general use injectors and those intended for use with a class/ family or 
a specific product line, sufficient labeling should be provided for the 
health care provider to determine what drug/biological product(s) is 
approved for administration by the injection method.  As appropriate, this 
includes but is not limited to the following:32  
a.  Language stating the readily identifiable characteristics of the 
class, family or product line of drug or biological products 
approved for use with the injector; e.g., characteristics that are in 
the drug/biological product labeling,  
b.  Language referring the user to the approved drug/biological 
labeling to determine if it is specifically approved for use with that 
type of injector and to obtain relevant dosing information, or  
c.  Language indicating that the injector is for use in accordance with 
the approved labeling of the drug/biological product. 
d.  List of brand name or list of name, type, and characteristics of 
drug/biological product that is specifically approved for use with 
the type of injector, method of injection, the dose range for the 
                                                 
31 The labeling format may vary depending upon the type of marketing application.  For example, a general 
use device under 510(k) should provide sufficient information for a user to determine how to select an 
approved drug/biological product to inject using the injector.  (Generally, see 21 CFR Part 801).  For a 
combination product, the language will be specific for the device and drug/biological product.  If the 
combination product is under NDA/BLA the format should be consistent with the Physician Labeling 
requirements available at 
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/LawsActsandRules/ucm085169.ht
m.   
32 In developing final labeling, in addition to the data submitted, FDA considers the information on the 
approved drug label(s) provided in the submission, see Section I.A.4 
26
 
 
  Contains Nonbinding Recommendations 
 
injector, number of doses the injector delivers, single patient use or 
other conditions. 
e.  Drug/biological product capability (e.g., single-dose-disposable, 
repeat dose disposable, single patient reusable or refillable, 
adjustable dose). 
  Contraindications 
  Warnings, limitations, and precautions, including incomplete dosing, 
overdosing, dosing site error (e.g., injection into the incorrect tissue), and 
cross-contamination  
  Safety and effectiveness data accrued with use of the injector 
  Identification of any drug/biological product characteristics that are not 
compatible with the injector, if known  
  Areas of the body appropriate for injection, including depictions with 
diagrams, and appropriate skin preparation prior to injection 
  Target tissue and injection sites, including appropriate warnings for 
intravenous injection of drugs/biological products intended for 
intramuscular or subcutaneous injection 
  Directions for use, user instructions, and diagrams.  As appropriate, this 
should include instructions for use of the injector that is consistent with 
the approved drug labeling instructions 
  Assembly instructions and diagrams (e.g., how the drug/biological product 
is contained in the injector and the method for inserting the 
drug/biological product into the injector) 
  Maintaining sterility during injector assembly 
  Dose setting and administering an injection 
  How to ensure that the full dose is delivered   
  How to ensure that a full dose remains in a reusable prefilled injector 
  Prevention of or remedy for incomplete or partial dosing or overdosing 
events 
  The correct amount of pressure needed for an injection 
  Information about injection depth 
  Labeling recommendations for sharps injury prevention features 
  Environmental conditions of use and storage 
  Reuse, cleaning, servicing 
  Proper safe biomedical sharps waste disposal instructions for the injector, 
cartridge, and needles 
  Troubleshooting 
  Life of the injector and critical components   
 
For injectors intended for use with a specified class/family or product line, FDA may 
request additional labeling information (e.g., expiration dating after insertion of the 
drug/biological cartridge into the injector and/or reconstitution of a drug cartridge, or 
use of nomenclature consistent with that of the drug/biological product).  
 
Injector labeling should include a patient labeling and medication guide as applicable.   
27
 
 
  Contains Nonbinding Recommendations 
 
SECTION II: CONTENT AND FORMAT 
CONSIDERATIONS  
 
FDA recommends a pre-submission meeting with the lead Center to discuss how you 
propose to organize the NDA/BLA Common Technical Document (CTD) submission to 
identify the injector related information.  Similar meetings should be requested when an 
NDA/BLA submission is used along with a separate device submission.  For additional 
information on stand alone 510(k) submissions, see 21 CFR Part 807 Subpart E.  Also for 
process, content, and related information on all submissions see the links in Section III. 
 
It should be noted that product codes are applicable to devices marketed under a 
device submission.  When you include a pen, jet, or related injector in an 
NDA/BLA submission, you may reference the product code of a previously 
cleared injector and any associated information.  As discussed in section 
I.B.1.(b), the reference to a 510(k) generally would not be sufficient, however, to 
address the safety and effectiveness of the device in the context of the use being 
proposed in the NDA/BLA submission (i.e., its use with a specific 
drug/biological product(s)).  
 
 
SECTION III: WHERE CAN I FIND ADDITIONAL 
INFORMATION?  
 
We recommend that you have early discussions with FDA if you are developing an 
injector described in this guidance and if you are uncertain about the type of technical 
and scientific information that may be appropriate or necessary in your submission.  Such 
product-specific advice may be useful for complex delivery systems, for associated 
drugs/biological products, or for technical aspects of the device.  Where appropriate, you 
may request a pre-submission meeting for more detailed discussion.   
 
For injector systems associated with a new route, dose, rate or method of injection for the 
drug or biological product, FDA expects an inter-Center collaboration, as appropriate for 
the type of scientific and technical questions.  If there are Center jurisdiction questions, 
we recommend that you contact the Office of Combination Products for additional 
information. 
 
Additional guidance information is available from the CDRH, General Hospital Devices 
Branch at 301-796-2585 or from the Office of Combination Products by email to 
combination@fda.gov.  General guidance information and links to the different center 
documents are also accessible at http://www.fda.gov/oc/combination/.  For an injector 
intended for use with a specific drug/biological product, additional information is 
available from the CDER or CBER review division. 
 
The following FDA guidance and informational documents may be useful when 
developing injectors intended for use with drugs and biological products. 
28
 
 
  Contains Nonbinding Recommendations 
 
  Draft Guidance for Industry and FDA Staff  Applying Human Factors and 
Usability Engineering to Optimize Medical Device Design  (June 2011); 
http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDo
cuments/ucm259748.htm 
  Guidance for Industry and FDA Staff: Early Development Considerations for 
Innovative Combination Products (Sept. 2006); 
http://www.fda.gov/RegulatoryInformation/Guidances/ucm126050.htm 
  Draft Guidance to Industry and FDA Staff: Current Good Manufacturing 
Practice for Combination Products (Sept. 2004); 
http://www.fda.gov/RegulatoryInformation/Guidances/ucm126198.htm 
  Guidance for Industry and FDA Staff: Format for Traditional and Abbreviated 
510(k)s (August 2005); 
http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDo
cuments/ucm084365.htm 
  The New 510(k) Paradigm - Alternate Approaches to Demonstrating Substantial 
Equivalence in Premarket Notifications - Final Guidance (March 1998); 
http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDo
cuments/ucm080187.htm 
  21 CFR 807.87 -Information Required in a Premarket Notification Submission; 
http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart
=807 
  Guidance on Medical Device Patient Labeling; 
http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDo
cuments/ucm070782.htm 
  Guidance for Industry, Formal Meetings with Sponsors and Applicants for 
PDUFA Products (Feb. 2000); 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformatio
n/Guidances/UCM153222.pdf 
  IND Meetings for Human Drugs and Biologics: Chemistry and Manufacturing 
Controls Information (May 2001); 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformatio
n/Guidances/UCM070568.pdf 
  International Conference on Harmonization Q8(R2) Pharmaceutical 
Development (May 2006); 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformatio
n/Guidances/UCM073507.pdf 
  Device Master File and Authorized Cross Reference Information:  
http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/HowtoMarke
tYourDevice/PremarketSubmissions/PremarketApprovalPMA/ucm142714.htm 
  Labeling for Human Prescription Drug and Biological Products  Implementing 
the New Content and Format Requirements; 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformatio
n/Guidances/UCM075082.pdf 
 
29