Technical Considerations for Demonstrating Reliability of Emergency-Use Injectors Submitted under a BLA, NDA or ANDA: Draft Guidance for Industry and Food and Drug Administration Staff

Administrative draft guidance, not enacted legislation.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

Technical Considerations for
Demonstrating Reliability of
Emergency-Use Injectors Submitted
under a BLA, NDA or ANDA:
Guidance for Industry and Food and
Drug Administration Staff
DRAFT GUIDANCE
This guidance document is being distributed for comment purposes only.
Although you can comment on any guidance at any time (see 21 CFR 10.115(g)(5)), to ensure that the agency
considers your comment on this draft guidance before it begins work on the final version of the guidance, submit
written or electronic comments on the draft guidance within 60 days of publication in the Federal Register of the
notice announcing the availability of the draft guidance. Submit written comments to the Division of Dockets
Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852.
Submit electronic comments to http://www.regulations.gov. All comments should be identified with the docket
number listed in the notice of availability that publishes in the Federal Register.
Additional copies are available from:
Office of Combination Products
Food and Drug Administration
WO32, Hub/Mail Room #5129
10903 New Hampshire Avenue
Silver Spring, MD 20993
(Tel) 301-796-8930
(Fax) 301-847-8619
https://www.fda.gov/combination-products
For questions regarding this document, contact Patricia Love, Office of Combination Products, at 301-796-8930,
patricia.love@fda.hhs.gov or combination@fda.gov.
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Devices and Radiological Health
Center for Drug Evaluation and Research
Center for Biological Evaluation and Research
Office of Combination Products in the Office of the Commissioner
April 2020

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Table of Contents
I. 	INTRODUCTION 	2
II. 	SCOPE 	3
III. 	REGULATORY FRAMEWORK 	4
IV. 	BACKGROUND ON RELIABILITY 	5
V. RELIABILTY REPORT DEVELOPMENT AND CONTENT
RECOMMENDATIONS FOR PREMARKET SUBMISSIONS 	9
VI. 	RELIABILITY REPORT FORMAT CONSIDERATIONS 	17
VII. 	WHERE TO FIND ADDITIONAL INFORMATION 	17
VIII. APPENDIX: FAULT TREE EXAMPLE 	19

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Technical Considerations for Demonstrating Reliability of	1
Emergency-Use Injectors Submitted under a BLA, NDA, or ANDA	2
Guidance for Industry and Food and Drug Administration Staff 1
3
4
This draft guidance, when finalized, will represent the current thinking of the Food and Drug	5
Administration (FDA or Agency) on this topic. It does not establish any rights for any person	6
and is not binding on FDA or the public. You can use an alternative approach if it satisfies the	7
requirements of the applicable statutes and regulations. To discuss an alternative approach,	8
contact the FDA staff responsible for this guidance as listed on the title page.	9
10
11
I. 	INTRODUCTION	12
13
This guidance covers emergency-use injectors submitted under a biologics license application	14
(BLA), new drug application (NDA), or abbreviated new drug application (ANDA). The term	15
“emergency-use injector” means injectors marketed with an emergency-use drug2 as a prefilled	16
single entity combination product under 21 CFR 3.2(e)(1) or as a co-packaged combination	17
product under 21 CFR 3.2(e)(2). Emergency-use injector includes pen injectors, autoinjectors, or	18
on-body-wearable delivery systems for drugs for emergency treatment of conditions such as	19
anaphylaxis, opioid overdose, poisoning, or severe hypoglycemia.	20
21
For injectable drug or biological products that are intended to treat emergent, life-threatening	22
conditions, it is essential to ensure that the emergency-use injector will reliably deliver the drug	23
as intended. Failure of the injector may prevent adequate delivery of a life-saving drug to a	24
patient. In this context, reliability is defined as the probability that the injector will perform as	25
intended, without failure, for a given time interval under specified conditions.3	
26
27
The FDA guidance document, “Technical Considerations for Pen, Jet, and Related Injectors	28
Intended for Use with Drugs and Biological Products” provides general recommendations for	29
the technical and scientific information to be included in marketing applications for a range of	30
injectors for various uses.4 In that document the reliability of the injector in delivering the drug	31
product is listed as one of the functional elements FDA assesses in premarket review. This	32
1 This guidance has been prepared by the Center for Devices and Radiological Health in cooperation with the Center
for Drug Evaluation and Research, the Center for Biologic Evaluation and Research, and the Office of Combination
Products in the Office of Medical Products and Tobacco/ Office of Clinical Policy and Programs/ Office of the
Commissioner at the Food and Drug Administration.
2 For purposes of this guidance, unless otherwise stated, the term drug applies to human drug and biological
products.
3 Reliability definition source: IEC 61078:2016 - Reliability Block Diagrams. Some Agency guidance documents
use the term robustness to convey the reliability concept.
4 The FDA guidance Technical Considerations for Pen, Jet, and Related Injectors Intended for Use with Drugs and
Biological Products is accessible at https://www.fda.gov/regulatory-information/search-fda-guidance-
documents/technical-considerations-pen-jet-and-related-injectors-intended-use-drugs-and-biological-products.

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document describes additional information and data that FDA recommends be included in	33
marketing applications to demonstrate that an emergency-use injector is reliable.	34
35
In general, FDA’s guidance documents do not establish legally enforceable responsibilities.	36
Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only	37
as recommendations, unless specific regulatory or statutory requirements are cited. The use of	38
the word should in Agency guidances means that something is suggested or recommended, but	39
not required.	40
41
II. 	SCOPE	42
43
This guidance’s focus is emergency-use injectors marketed with the emergency-use drug as a	44
prefilled single entity combination product or as a co-packaged combination product.5 The	45
recommendations in this guidance are applicable to combination products intended to treat	46
emergent, life-threatening conditions, when it is essential to ensure that the injector will reliably	47
deliver the drug as intended.6 Such products are marketed as combination products assigned to	48
the Center for Drug Evaluation and Research (CDER) or the Center for Biological Evaluation	49
and Research (CBER) with market authorization under an approved NDA, ANDA, or BLA.7	
50
51
Although this guidance contains specific recommendations of ways to demonstrate the reliability	52
of emergency-use injectors,8 the recommendations would also be useful in considering how to	53
demonstrate the reliability of other emergency-use drug delivery devices; e.g., intranasal sprays,	54
inhalation devices, topical cutaneous sprays, syringes, or transdermal systems. Questions	55
regarding whether these recommendations would apply to a specific emergency-use drug	56
delivery system and proposed methods to demonstrate the reliability should be discussed with	57
the Agency early in the product development process.9	
58
59
5 See 21 CFR part 3. Combination products are comprised of differently regulated articles; i.e., a drug-device,
device-biological product, drug-biological product, or a combination of a drug, device, and biological product. See
21 CFR 3.2(e)(1) and (2) for definitions of single entity and co-packaged combination products.
6 The reliability data discussed within this guidance document is limited to assessing functional performance of the
device and does not address human factors/user interface considerations. For information on human factors see
FDA guidance: Human Factors Studies and Related Clinical Study Considerations in Combination Product Design
and Development, https://www.fda.gov/regulatory-information/search-fda-guidance-documents/human-factors-
studies-and-related-clinical-study-considerations-combination-product-design-and; or FDA guidance Applying
Human Factors and Usability Engineering to Medical Devices, https://www.fda.gov/regulatory-information/search-
fda-guidance-documents/applying-human-factors-and-usability-engineering-medical-devices.
7 See 21 CFR 3.4. Combination Products are assigned to a lead center based on the primary mode of action
(PMOA). In this instance, the drug or biological product is considered to be the PMOA and the combination
products are assigned to CDER or CBER. For additional information contact the Office of Combination Products at
combination@fda.gov.
8 Throughout this document the term emergency-use injector applies to the device constituent part of the
combination product.
9 Applicants developing an emergency-use injector or similar product for an ANDA should request Agency
feedback on the potential applicability of the recommendations in this guidance document.

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III. 	REGULATORY FRAMEWORK	60
61
Combination products are subject to 21 CFR Part 4, which sets forth current good manufacturing	62
practice (CGMP) requirements for combination products. The constituent parts of a combination	63
product retain their regulatory status (as a drug or device, for example) after they are combined.	64
The CGMP requirements that apply to each of the constituent parts apply to the combination	65
product they constitute.	66
67
For single-entity combination products and co-packaged combination products, such as those	68
covered in this guidance, part 4 identifies two ways to demonstrate compliance with CGMP	69
requirements. Under the first option, manufacturers demonstrate compliance with all CGMP	70
regulations applicable to each of the constituent parts included in the combination product.	71
Under the second option, manufacturers implement a streamlined approach for combination	72
products that include both a drug and device by demonstrating compliance with either the drug	73
CGMPs (21 CFR parts 210 and 211) or the device Quality System (QS) regulation (21 CFR part	74
820) and also demonstrating compliance with specified provisions from the other two sets of	75
CGMP requirements.	76
77
Under the streamlined approach described in 21 CFR 4.4(b), manufacturers of drug-led, drug-	78
device combination products,10 such as those that are the subject of this guidance, may meet the	79
requirements of both the drug CGMPs and device QS regulation by designing and implementing	80
a CGMP operating system that demonstrates compliance with the drug CGMPs and the	81
following provisions from the device QS regulation in accordance with 21 CFR 4.4(b)(1) (drug	82
CGMP-based streamlined approach):	83
84
• 	21 CFR 820.20 	Management responsibility	85
• 	21 CFR 820.30 	Design controls	86
• 	21 CFR 820.50 	Purchasing controls	87
• 	21 CFR 820.100 	Corrective and preventive action	88
• 	21 CFR 820.170 	Installation	89
• 	21 CFR 820.200 	Servicing	90
91
As explained in the FDA guidance for “Current Good Manufacturing Practice Requirements for	92
Combination Products, “the core requirements embedded in these regulations provide for	93
systems that assure proper design, monitoring, and control of manufacturing processes and	94
facilities. This includes establishing a strong quality management system, using appropriate	95
quality raw materials, establishing robust manufacturing and control procedures based on sound	96
design principles, and detecting and investigating product quality deviations. In addition, these	97
10 A biological product regulated under section 351 of the Public Health Service Act is also, by definition, a drug or
a device. Accordingly, for combination products that include a biological product, in addition to complying with the
drug CGMP and device QS regulation requirements as applicable in accordance with 21 CFR part 4, manufacturers
of such products must comply with the CGMP requirements in 21 CFR parts 600 through 680 that would apply to
the biological product if it were not part of a combination product. 21 CFR 4.4(b)(3).

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regulations call for ongoing assessment of systems and the implementation of corrective actions	98
where appropriate.”11	
99
100
IV. 	BACKGROUND ON RELIABILITY	101
102
Emergency-use injectors such as those for treatment of anaphylaxis typically are used by the	103
patient, caregiver, or first responder outside of a health care environment. For the patient	104
experiencing the emergency or their assisting lay caregivers, there may be only one opportunity	105
to use the product and for that one opportunity the emergency-use injector needs to successfully	106
inject the drug at that time. Further, because these emergency-use injectors are for a single use,	107
the functional performance cannot be verified before the injector is used. Therefore, to ensure	108
safe and effective use of the emergency-use injector, FDA recommends using the reliability	109
engineering methods described in this guidance to ensure that the injector will function as	110
intended within its expiration date. Designing the combination product to achieve its identified	111
functional performance (reliability) is consistent with the combination product good	112
manufacturing practice design control requirements provisions (see 21 CFR 4.4(b)(1)(ii) and	113
4.4(b)(1)(iv)).	114
115
Although the requirements of both the drug CGMPs and device QS regulation must be met, as	116
described in Section III above, several aspects of the design requirements identified in 21 CFR	117
4.4(b)(1)(ii) are particularly important in the development and reliability of an emergency-use	118
injector. For example,	119
120
• 	21 CFR 820.30(c) states that “[e]ach manufacturer shall establish and maintain	121
procedures to ensure that the design requirements relating to a device are appropriate and	122
address the intended use of the device, including the needs of the user and patient.”	123
124
• 	21 CFR 820.30(d) states that “[e]ach manufacturer shall establish and maintain	125
procedures for defining and documenting design output in terms that allow an adequate	126
evaluation of conformance to design input requirements. Design output procedures shall	127
contain or make reference to acceptance criteria and shall ensure that those design	128
outputs that are essential for the proper functioning of the device are identified.”	129
130
• 	21 CFR 820.30(f) states that “[e]ach manufacturer shall establish and maintain	131
procedures for verifying the device design. Design verification shall confirm that the	132
design output meets the design input requirements. The results of the design verification,	133
including identification of the design, method(s), the date, and the individual(s)	134
performing the verification, shall be documented in the DHF.” Moreover, 21 CFR	135
820.30(g) states that “[e]ach manufacturer shall establish and maintain procedures for	136
validating the device design. Design validation shall be performed under defined	137
operating conditions on initial production units, lots, or batches, or their equivalents.	138
Design validation shall ensure that devices conform to defined user needs and intended	139
11 See Section II.B accessible at https://www.fda.gov/regulatory-information/search-fda-guidance-
documents/current-good-manufacturing-practice-requirements-combination-products.

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uses and shall include testing of production units under actual or simulated use	140
conditions.”	141
142
• 	21 CFR 820.30(h) states that “[e]ach manufacturer shall establish and maintain	143
procedures to ensure that the device design is correctly translated into production	144
specifications.”	145
146
• 	21 CFR 820.30(i) states that “[e]ach manufacturer shall establish and maintain	147
procedures for the identification, documentation, validation or where appropriate	148
verification, review, and approval of design changes before their implementation.”	149
150
• 	21 CFR 820.100 states that “each manufacturer shall establish and maintain procedures	151
for implementing corrective and preventive action.”	152
153
FDA considers that “the needs of the user and patient” (21 CFR 820.30(c)) in an emergency-use	154
context would be that, for the patient experiencing the emergency or his/her assisting lay	155
caregiver, there is only one opportunity to use the product and, thus, FDA has found emergency-	156
use injectors acceptable if they would successfully inject the drug on the first try. In this	157
instance, the design input requirements would provide functional measures for performance	158
characteristics, specifications for how reliably the emergency-use injector functions, and the use	159
condition of the patient or caregiver. This would include identification of a reliability	160
specification that is consistent with the level of risk to the patient if the emergency-use injector	161
does not function (e.g., the morbidity or mortality associated with untreated anaphylactic shock).	162
163
In addition, FDA interprets the requirements under 21 CFR 820.30(f) and (g) to mean that a	164
manufacturer of an emergency-use injector must verify and validate the design of the injector to	165
ensure that it works in “one opportunity” situations. These requirements can be met, for	166
example, if available documentation demonstrates that (1) the emergency-use injector has met its	167
design input requirements within the specified reliability targets at expiry and (2) design	168
validation has been conducted on finished products to ensure reliability targets are met and that	169
test conditions were representative of how the product would be exposed up to expiry.	170
171
The preceding design control requirements are intended to ensure that the emergency-use	172
injector performance is as reliable as possible. Consistent with this purpose, FDA has found	173
emergency-use injectors to be acceptable if they would successfully inject on the first try in “one	174
opportunity” (or emergency) situations. This reliability concept has an inherent feasibility	175
consideration. FDA recommends that emergency-use injectors include design control	176
specifications for successful injection reliability of 99.999% with a 95% level of confidence As	177
FDA has found such specifications to be acceptable under applicable standards. This prospective	178
99.999% target is equivalent to post-market detection of failure to successfully inject in	179
1/100,000 injection attempts. This reliability level was found to balance appropriately the	180
objective of ensuring the emergency-use injector performance is as safe and reliable as possible	181
with considerations on feasibility.	182
183
As part of determining an acceptable level of reliability, FDA has considered available	184
information for risk assessment. Specifically, the FDA-recognized standard, ISO 14791 -	185

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Application of risk management to medical devices, provides insight regarding probabilities of	186
occurrence.12 In the standard, examples are provided for semi-quantitative analysis that	187
identifies probable, remote, and improbable events rates. In the standard, events occurring in the	188
range of 1/10,000 detection rate are considered to be probable. In FDA review experience, this	189
probable failure rate is likely associated with unacceptable rates of adverse events for	190
emergency-use injectors that may result in product recalls. In the standard, events occurring less	191
than a 1/1,000,000 detection rate are considered to be improbable. Although the lowest possible	192
failure rates are desirable, FDA believes that based on the standard rates and current technology,	193
that the improbable rate of less than 1/1,000,000 detection rate could result in drug shortage or	194
delayed product availability. In contrast to both of the preceding rates, events occurring within	195
1/100,000 to 1/1,000,000 detection rate are considered as a remote probability of occurrence.	196
Therefore, based on the ISO standard, FDA believes the detection of failure to successfully inject	197
in 1/100,000 injection attempts is an appropriate risk management target for ensuring successful	198
injection and treatment when there is only one opportunity to inject. Further, FDA review of	199
recent marketing applications demonstrates that the reliability target of 99.999% with a 95%	200
level of confidence (i.e., 1/100,000 failure to successfully inject rate) is achievable for these	201
emergency-use injectors.	202
203
The following information provides the details of an example of what FDA currently believes	204
would be an acceptable approach for the mathematical model, statistics, fault tree analysis, and	205
use of combination product current good manufacturing design control requirements provisions	206
(21 CFR 4.4(b)(1)(ii) and 4.4(b)(1)(iv)) to establish reliability of the emergency-use injector.	207
FDA recognizes that as an alternative to the approach discussed in this guidance, applicants may	208
propose other reliability specifications methodologies. For example, based on considerations	209
such as product design, drug being delivered, for emergent unmet medical needs, counter-	210
terrorism considerations, or conditions of use, alternative reliability specifications may be	211
appropriate. During emergency-use injector development FDA encourages applicants to seek	212
FDA meetings to discuss their proposals and rationale (e.g., context of use, risk/benefit, shortage,	213
and supportive data).	214
215
Establishing reliability	216
217
Establishing reliability is an iterative process in which the design controls should focus on	218
emergency-use injector attributes determined to be essential for achieving the emergency-use	219
injector’s intended use.13 The level of reliability necessary to manufacture a safe and effective	220
combination product directly correlates to the level of risk associated with an unreliable emergency-	221
use injector. Because reliability as a mathematical model is defined as R(t) = 1 – F(t), where F(t)	222
represents the cumulative distribution function of failure, the goal should be to define the point at	223
which that distribution, F(t), is adequately controlled. The reliability specification(s), R(t),	224
represents the probability that the emergency-use injector will perform as intended, without failure,	225
12 ISO 14971:2007/R(2016) Medical Devices - Application of risk management to medical devices; Section 3.4.2
Semi-quantitative analysis.
13 For more information on design controls for a combination product see 21 CFR Part 4 Subpart A, and related
FDA guidance Current Good Manufacturing Practice Requirements for Combination Products accessible at
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/current-good-manufacturing-practice-
requirements-combination-products.

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for a given time interval under specified conditions. This level of risk should be identified in the	226
risk analysis conducted as part of device design controls activities.14	
227
228
This assessment is specific to the combination product’s intended use because the risks are likely	229
to be impacted by the condition being treated, environments of use, emergency-use injector	230
technology, drug, user characteristics, etc. The emergency-use injector reliability analysis, in	231
addition to the traditional development activities, should incorporate the following device design	232
control activities as applicable to the emergency-use injector:	233
234
• 	Identification of the reliability requirements and specifications;	235
• 	Risk analysis;	236
• 	Design verification and validation of the reliability requirements and specifications; and	237
• 	Design transfer of the reliability specification to the correct production specifications.	238
239
As described in Section IV Background on Reliability, after transfer of the design into	240
production, the manufacturing controls must be adequate to produce reliable emergency-use	241
injectors as specified.15 These controls should, among other required activities, include the	242
following to ensure the design specifications and tolerances that must be achieved during	243
production and that all sources of potential quality problems are analyzed:	244
245
• 	Adequate manufacturing in-process controls and release activities to ensure the final	246
finished emergency-use injector conforms to its specifications;	247
• 	Adequately defined acceptance activities for the supplied components to ensure that the	248
manufactured combination product has the required design attributes to ensure the	249
reliability specifications are achieved; and	250
• 	Establish and maintain procedures for implementing corrective and preventive action	251
(CAPA) activities (e.g., post-market complaints) to ensure that all sources of quality data	252
are analyzed and, where necessary, preventive or corrective actions are taken.16	
253
254
In addition to providing assurance of the emergency-use injector reliability, the advantages of a	255
well-constructed reliability analysis include the following life-cycle management benefits in the	256
linkage between the design and manufacturing controls.	257
258
• 	The least reliable design elements or manufacturing controls of an emergency-use	259
injector can be identified prior to commercialization of the combination product. This	260
can further inform potential improvements in manufacturing controls, tracking or	261
trending limits of part rejects, and future investigations of failed combination products;	262
• 	Future changes to either design or manufacturing processes can be evaluated against the	263
reliability analysis to assess the potential impact to the emergency-use injector reliability;	264
• 	Post-market emergency-use injector failure investigations can directly link to the	265
emergency-use injector reliability analysis to readily identify gaps or deficiencies in the	266
emergency-use injector’s design and/or manufacturing controls; and	267
14 See 21 CFR 820.30(g).
15 See 21 CFR 820.30(h).
16 See 21 CFR 820.100.

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• 	Once the results of those specific design elements or manufacturing controls are	268
understood within the context of the overall reliability analysis, if the reliability analysis	269
is implemented early in the development cycle, reliability improvements can be made by	270
making changes to the emergency-use injector design or manufacturing processes or	271
controls.	272
273
Section V below provides an example of an acceptable way to demonstrate the reliability of the	274
emergency-use injector and define failure to successfully inject.	275
276
V. 	RELIABILTY REPORT DEVELOPMENT AND CONTENT	277
RECOMMENDATIONS FOR PREMARKET SUBMISSIONS	278
279
As discussed in Section IV, achieving the necessary reliability specification is based on	280
knowledge of the design, manufacture, and use of the combination product. Generally, the	281
highest risk is failure to successfully inject (e.g., activation and drug delivery functions). This	282
occurs when one or more functional failure modes result in the emergency-use injector failure to	283
deploy the needle to the target site or failure to complete drug delivery as intended. As described	284
in Section IV Background on Reliability, FDA has found emergency-use injectors to be	285
acceptable if they would successfully inject in “one opportunity” (or emergency) situations. As	286
stated above, FDA has found emergency-use injectors to be acceptable under the applicable	287
standards when they include design control specifications for successful injection reliability of	288
99.999% with a 95% level of confidence.	289
290
To establish the emergency-use injector’s safe and effective injection performance, the	291
marketing application should include information to verify and validate that the emergency-use	292
injector achieves its reliability specifications and related information. The following sections	293
identify examples of acceptable activities for developing the verification and validation data. If	294
applicants submit such information, FDA recommends that the applicants provide these data in	295
the form of an emergency-use injector reliability report to facilitate efficient review.17 The	296
following subsections provide examples of the type of information to provide in the reliability	297
report. Section VI of this guidance provides a reliability report format example.	298
299
1. 	Design Inputs and Design Outputs Necessary18 for Ensuring Reliability	300
301
As described in Section IV, specifications for how reliably the emergency-use injector	302
functions and the use condition of the patient or caregiver need to be identified.19 The design	303
inputs necessary for ensuring reliability should be identified and developed into specified	304
design outputs. Selecting design inputs that may not be relevant to the reliable function of	305
the emergency-use injector could result in an inability to meet the manufacturer’s established	306
reliability specifications. To assist in identifying design input requirements, manufacturers	307
should consider the following information:	308
17 Throughout the remainder of this document the term “reliability report” applies to the emergency-use injector
reliability report.
18 See 21 CFR 820.30(c) and 820.30(d).
19 See 21 CFR 820.30(c).

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• 	Intended use and associated risks;	309
• 	Emergency-use injector risk analysis, including the drug constituent part	310
characteristics;	311
• 	Use-related issues to the extent that they could impact the reliability of the	312
combination product, including:	313
o 	Use tasks, which may include unpacking, preparation, administration and disposal	314
of the combination product; and	315
o 	Use conditions and environments of use.	316
• 	Use-condition factors20 to consider include all users of the emergency-use injector,	317
where they are using it, and the possible circumstances under which the emergency-	318
use injector may be used, including:	319
o 	Use environment (e.g., school, work, public transportation vehicle, harsh climates,	320
first responder chaotic conditions) and associated risks to reliability; and	321
o 	User characteristics (e.g., self- injection with cognitive or physical impairment	322
associated with the disorder being treated) and associated risks to reliability.	323
324
Table -1 provides an example of emergency-use injector design considerations for	325
emergency-use injector reliability only.21	
326
327
328
329
(See next page for Table-1.)	330
331
20 The use condition factors discussed within this guidance document are limited to assessing functional
performance of the emergency-use injector and do not address human factors/user interface considerations. For
information on human factors see FDA guidance: Human Factors Studies and Related Clinical Study
Considerations in Combination Product Design and Development (Draft 2016), https://www.fda.gov/regulatory-
information/search-fda-guidance-documents/human-factors-studies-and-related-clinical-study-considerations-
combination-product-design-and; or Applying Human Factors and Usability Engineering to Medical Devices,
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/applying-human-factors-and-usability-
engineering-medical-devices.
21 Other types of input or output considerations for the safe and effective use of the emergency-use injector should
continue to be part of the combination product development. For more information see FDA guidance Technical
Considerations for Pen, Jet, and Related Injectors Intended for Use with Drugs and Biological Products accessible
at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/technical-considerations-pen-jet-
and-related-injectors-intended-use-drugs-and-biological-products.

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Table-1: Emergency-Use Injector Design Reliability Development
Considerations22
Consideration Category 	Examples
Protective Packaging
• 	Packaging ability to prevent emergency-use injector
damage during shipping, daily carry, etc.
• 	Removal from packaging or carrying case (e.g., force
to remove)
Removal / Deactivation of
Safety Mechanisms
• 	Force to remove caps or needle shields
• 	Force to deactivate safety mechanism
Activation Force 	• 	Force to initiate the injection mechanism
Needle Insertion
• 	Needle bevel specifications
• 	Needle material of construction
• 	Needle Insertion Forces (e.g., penetrating clothing,
skin, etc.)
• 	Needle resistance to bending and fracture
Needle Patency 	• 	Particulates
Injection Depth
• 	Target tissue for drug delivery
• 	Body habitus, skin and tissue characteristics
• 	Anatomical location(s) for injection
• 	Types of garments to be injected through
• 	Exposed needle length
Drug Delivery Initiates as
Intended
• 	Needle reaches intended injection depth
• 	Drug delivery begins when needle is at intended
injection depth
• 	Drug fluid properties (e.g., viscosity)
Drug Delivery Stops as
Intended
• 	Needle does not retract before intended dose is
delivered
• 	Audible, visual, or tactile feedback does not
prematurely signal a completed injection
Dose Accuracy • 	Intended dose delivered to intended injection site or
depth
332
The preceding tabular considerations are to assist in identifying the emergency-use injector	333
performance characteristics that inform the design inputs and outputs. Based on such	334
considerations the applicant should develop the design inputs and outputs that are essential	335
for ensuring reliability of the applicant’s proposed product. The reliability report should	336
define all the design inputs and outputs determined to be necessary for achieving reliability.	337
It is important to clearly define the difference between acceptable and unacceptable	338
emergency-use injector performance to determine appropriate design inputs that will inform	339
22 For more information on development design controls for a combination product see 21 CFR Part 4 Subpart A,
and see related FDA guidance Current Good Manufacturing Practice Requirements for Combination Products
accessible at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/current-good-
manufacturing-practice-requirements-combination-products.

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the design outputs. If the design outputs are not correctly defined, then the overall reliability	340
analysis may also be inadequate.	341
342
2. Definition of Emergency-Use Injector Reliability Specifications	343
344
345
346
347
348
349
350
351
352
353
354
355
356
357
358
359
360
361
362
363
364
365
366
367
368
369
370
371
372
373
374
As noted in the preceding discussion on design inputs and outputs, there are multiple design
specifications that should be considered with respect to the reliability of the emergency-use
injector. Using the mathematical expression identified in Section IV, R(t) = 1 – F(t), the
reliability specification is defined as the probability distribution, R(t). An example of
acceptable reliability specifications is those that are developed in accordance with the risk
assessment as described in Section V.3 – Fault Tree Analysis of this document and, through
this analysis, linked to the appropriate manufacturing controls to ensure the reliability of the
final finished combination product. The specifications may be one or two-sided depending
upon the risk associated with the failure (e.g., risk of overdose and under-dose exists for a
two-sided dose-accuracy reliability specification).
For the reliability specification analysis, failure to inject should be the primary endpoint.
This should be the top-level failure mode of the fault tree analysis as described in Section
V.3.23 The reliability analysis and testing should include emergency-use injector
performance requirements based on the assessment of the design (see Section V.1). In
general, FDA recommends that these include dose accuracy, extended needle length,
activation force, and injection time be included as part of emergency-use injector
reliability.24 However, manufacturers should assess the specific emergency-use injector
design to determine if additional performance attributes are considered to be essential for
completing a successful injection. For example, a specific design may have a cap that must
be removed to initiate injection and the manufacturer may determine that cap removal is
essential to completing a successful injection.
3. Fault Tree Analysis
The information described in the preceding sections could be used to develop a model of the
reliability using fault tree analysis. The fault tree analysis would focus on failure to achieve
the reliability specifications. An example of an acceptable analysis is one that also includes
additional fault trees to address other emergency-use injector performance requirements
determined to be essential for reliability (e.g., dose accuracy, extended needle length).
Manufacturers should consider the following for their fault tree analyses:	375
376
• 	Design and manufacturing elements should be considered for the fault tree analysis	377
for the purposes of establishing the reliability of the emergency-use injector to	378
perform as intended, without failure, for a given time interval under specified	379
conditions;	380
23 For more information of fault tree analyses see IEC 61025:2006 – Fault Tree Analysis (FTA); NASA Fault Tree
Handbook with Aerospace Applications, 2006.
24 The acceptance criteria for the performance attributes in Table-2 should be established based on relevance to
clinical performance (i.e., established as design inputs), and not based on manufacturing capability or to facilitate
meeting the reliability target.

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• 	The probability data for each basic event25 should be included in the fault tree;	381
• 	The analysis should consider potential common cause failures and whether	382
assumptions of independence of events are supportable;	383
• 	Any risk analyses (e.g., such as design and process failure modes effects analysis)26	
384
used to support the fault tree analysis should be included in the reliability report;	385
• 	Once the fault tree analyses are completely developed, data should be provided to	386
support that the reliability specification for the top-level failure mode is verified and	387
validated (e.g., the probability data for each basic event should be supported with	388
evidence); and,	389
• 	The basic events in the fault tree analysis should be linked to appropriate design	390
and/or manufacturing controls.	391
392
393
394
395
396
397
398
399
400
401
402
403
404
405
406
407
408
409
410
Based on standard fault tree analysis quantification methods, the reliability of each basic
event within the fault tree analysis should be assessed through a cumulative analysis to
determine whether the reliability specification for the top-level failure mode is adequately
supported. The statistical methods utilized to demonstrate the reliability of each basic event
within the fault tree analysis should inform the test sample size necessary for reliability
testing of the final finished combination product. To assess the potential for the basic event
failure mode of the emergency-use injector, it is important to use a statistical tolerance
interval27 method in which the limits of each individual component are analyzed (e.g.,
dimensions, geometry, material strength, etc.),28 both by itself and in conjunction with its
associated components (i.e., stack-up analysis). To effectively use the tolerance interval
method, the critical measurable elements of each component contributing to the basic event
should be clearly stated and the statistical tolerance limit29 identified. Data to support the
tolerance interval methodology should be provided and may include process validation data
for individual components. The resultant k factor30 for each basic event should be used to
calculate the necessary sample size of the reliability study based on the desired reliability
specification and confidence interval.
An example of acceptable use of the statistical tolerance interval methodology is one
described above.31 An acceptable methodology should evaluate both design and	411
25 The basic event is a failure mode event or state that cannot be further developed; i.e., the lowest level failure mode
that cannot be further subdivided.
26 ISO 14971 Second edition 2007-Medical devices - Application of risk management to medical devices; and
IEC 60812:2006 - Analysis techniques for system reliability - Procedure for failure mode and effects analysis
(FMEA). (FDA recognized standards.)
27 Statistical tolerance interval is an interval determined from a random sample in such a way that one may have a
specified level of confidence that the interval covers at least a specified proportion of the sampled population per
ISO 3534-1:2006. (FDA recognized standards.)
28 ISO 16269-6 Second edition 2014 – Statistical interpretation of data - Determination of statistical tolerance
intervals. (FDA recognized standards.)
29 Statistical tolerance limit is the statistic representing an end-point of a statistic tolerance interval per ISO 3534-
1:2006. (FDA recognized standards.)
30 The k factor is the variable used to determine the limits of a statistical tolerance interval per ISO 16269-6:2014.
31 There are other methods that may also be appropriate to support the fault tree analysis and overall reliability
specifications. If a manufacturer intends to use a method not described in this guidance document, the FDA

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manufacturing risks associated with the emergency-use injector such that the fault tree	412
analysis is assessing reliability of the final, finished combination product. (See Section VIII -	413
Appendix for a fault tree analysis template example.)	414
415
4. Reliability Testing	416
417
FDA recommends that a reliability analysis include verifying and validating the adequacy of	418
the data used to support the reliability specifications, and that the data support the reliability	419
specification over the combination product expiry period. The following subsections	420
describe information recommendations for preconditioning and testing reliability samples.	421
422
a. 	Use Conditions and Preconditioning Recommendations	423
424
To identify the reliability test conditions to ensure achievement of the reliability	425
specification at the end of use-life,32 it is important to define the combination product’s	426
use conditions and preconditioning steps. This ensures that the testing program has	427
adequately challenged the ability of the emergency-use injector to withstand stressors that	428
are likely to occur or to which the product will be exposed during the use-life.	429
Combination product-specific use-life factors to consider for preconditioning steps that	430
influence shelf-life may include the following preconditions:	431
432
• 	Shipping;	433
• 	Aging;	434
• 	Storage orientation and conditions;	435
• 	Vibration;	436
• 	Shock (e.g., resistance to impacts, such as being dropped); and	437
• 	Environmental factors:	438
o 	Temperature (extremes and cyclic);	439
o 	Altitude and pressure effects (e.g., airplane, submarine, or other above/below	440
sea-level effects); and	441
o 	Air particulates (dust/sand).	442
443
444 	FDA recommends that the reliability report include the following information to help
establish the acceptability of the use of accelerated testing to generate supporting data:	445
446
• 	Validation data to ensure that the accelerated methods accurately model the time-	447
dependent failure mechanisms of the emergency-use injector;	448
• 	Results of testing at various time points to identify any trends in emergency-use	449
injector performance; and	450
encourages the manufacturer to request a meeting to discuss the validity of the proposed approach for supporting the
reliability specification.
32 Use-life begins when the product manufacture is complete and ends on the date when the product cannot function
as intended (the expiration date). For the combination product, the expiration date also may be described as shelf
life or end of use-life of the drug-device combination product.

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• 	A statistical justification to ensure that the sample size at the final time point is	451
adequate to support the pre-specified reliability and confidence interval goals.	452
FDA recommends that the tolerance interval method discussed in Section V.3 be	453
used to provide the sample size justification.	454
455
The report should also describe the use conditions that are important for the emergency-	456
use injector’s reliability and should define the bounded specifications for each condition	457
(e.g., a temperature range).	458
459
b. 	Testing	460
461
Reliability verification testing should be conducted on the final finished combination	462
product after considering the appropriate preconditioning and use conditions laid out in	463
Section IV.4.a. A reliability report should include the test protocol with validated test	464
methods.	465
466
The sample size for reliability verification testing should be justified with an appropriate	467
statistical method as discussed in Section V.3 and based on the emergency-use injector	468
reliability specifications described in Section V.2. If multiple test groups are included in	469
the manufacturer’s protocol, such as aged and non-aged test groups, then the sample size	470
should ensure adequate statistical results from each group.	471
472
All test failures should undergo root cause analyses which directly link to the fault tree	473
analysis. The fault tree analysis may need to be updated based on any previously	474
unknown failure modes discovered during reliability verification testing. If there is a	475
failure, the reliability testing may need to be redone depending on the conclusions of the	476
root cause analyses.	477
478
5. Total Product Life Cycle Reliability	479
480
Throughout the life cycle of the combination product, manufacturers may become aware	481
of potential emergency-use injector malfunctions, nonconformance or other related	482
quality problems. In these cases, manufacturers must investigate the potential cause and	483
identify any actions that may be needed to correct and prevent recurrence.33	
484
485
An example of an acceptable reliability report is one that documents the manufacturer’s	486
plan for maintaining emergency-use injector reliability throughout the product life cycle	487
as part of compliance with 21 CFR part 4 current good manufacturing practice	488
requirements for combination products.34 An example of an acceptable plan is a plan that	489
includes the following:	490
491
33 21 CFR 820.100.
34 See 21 CFR Part 4 Subpart A, and related FDA guidance Current Good Manufacturing Practice Requirements for
Combination Products accessible at https://www.fda.gov/regulatory-information/search-fda-guidance-
documents/current-good-manufacturing-practice-requirements-combination-products.

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• 	Procedures that include requirements for analyzing processes, work operations,	492
concessions, quality audit reports, quality records, service records, complaints,	493
returned combination product, and other sources of quality data to identify	494
existing and potential causes of nonconformance, or other quality problems;35	
495
496
• 	As part of defect and/or failure investigations, the procedures use the reliability	497
data and fault tree analysis as part of the root cause analysis;	498
499
• 	Procedures for when, during complaint investigations and related CAPA	500
activities, it is appropriate to image the emergency-use injector internally or	501
physically open the emergency-use injector to inspect, measure, and test	502
assemblies or individual components and compare results with the specifications	503
and data identified in the reliability analysis;	504
505
• 	Appropriate steps for linking the reliability data to the appropriate acceptance	506
activities, including the specific emergency-use injector attributes that are	507
evaluated, evaluation methods, and acceptability criteria that should be considered	508
in the context of the emergency-use injector’s reliability;	509
510
• 	Detailed descriptions of the in-process control and release test sampling plans to	511
ensure that the reliability specification is maintained for each released lot;	512
513
• 	Established action limits for significant increases in rejections of the emergency-	514
use injector and its components due to incoming inspection, in-process control, or	515
release test failures;	516
517
• 	The activities triggered by exceeding an action limit should include 1) the need	518
for implementing CAPA, 2) a root cause investigation, and 3) an associated risk	519
analysis of the failure. The reliability data and fault tree analysis are consulted as	520
part of the root cause investigation;	521
522
• 	Procedures for updating the reliability data when new information is obtained	523
(e.g., previously unidentified failure modes); and	524
525
• 	A section that addresses disposition of non-released emergency-use injector or	526
combination product pending analysis and mitigation of newly identified failures.	527
528
6. Activities when Implementing Emergency-Use Injector Design or Manufacturing	529
Modifications	530
531
An example of an acceptable reliability report is one that includes a plan for the activities	532
to be completed when implementing an emergency-use injector design or manufacturing	533
modification. After completing the initial reliability report, future design changes and	534
35 21 CFR 820.100.

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manufacturing process changes may occur that necessitate re-evaluation of reliability to	535
ensure emergency-use injector reliability.36 To determine when the reliability data may	536
need to be updated, the impact of the change should be evaluated based on the existing	537
reliability model.	538
539
Manufacturers should consider if the change impacts the design output specifications of	540
the emergency-use injector or the basic events of the fault tree analysis. If it is	541
determined that the change does impact these aspects, creates new design outputs, or	542
creates new risks, then the emergency-use injector reliability report should be updated	543
with data regarding the changes and included within your premarket submission.	544
545
VI. 	RELIABILITY REPORT FORMAT CONSIDERATIONS	546
547
To facilitate the data assessment, the reliability report should be provided in the following	548
format:	549
550
Section 	Content
1. 	Combination Product Definition
• 	Drug Type
• 	Indications for Use
• 	Emergency-Use Injector Technical and Functional Description
• 	Design Inputs and Design Outputs Necessary for Reliability
2. 	Emergency-Use Injector Reliability Specifications
3. 	Fault Tree Analysis
4. 	Reliability Test Plan and Data
5. 	Total Product Life Cycle Reliability Plan
7. 	Conclusions
8. 	Appendices Containing Supporting Data Reports or Risk Analyses
551
When submitting this information to an NDA or BLA, we recommend including the information	552
with other device constituent part information located in eCTD module 3.2.P.7.37	
553
554
VII. 	WHERE TO FIND ADDITIONAL INFORMATION	555
556
As noted in Section II, the drug-delivery emergency-use injectors addressed by this guidance are	557
designed as combination products with a CDER or CBER lead. These combination products are	558
submitted under an IND, NDA, ANDA, or BLA pathway (including supplements). To address	559
any uncertainties for the emergency-use injector reliability development process, FDA strongly	560
encourages early development meetings (e.g., Pre-IND or Pre-ANDA to discuss the initial	561
combination product) as well as subsequent IND meetings throughout the development process.	562
36 See 21 CFR 820.30(i) and 820.70(b).
37 See section-5 in the FDA eCTD Technical Conformance Guide: Technical Specifications Document: Guidance
for Industry Providing Regulatory Submissions in Electronic Format -Certain Human Pharmaceutical Product
Applications and Related Submissions Using the eCTD Specifications, December 2019 accessible at
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/ectd-technical-conformance-guide.

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These meetings can include requests for clarification on the reliability information discussed in	563
this document. For applicants with emergency-use delivery systems that are not emergency-use	564
injectors, these meetings could be used for early consideration of the principles identified in this	565
document. All meeting requests should be submitted to the lead center in accordance with its	566
procedures and should identify the requested participants (e.g., the lead center, CDRH, Office of	567
Combination Products). FDA intends to use its Inter-Center Consult Review Process38 for the	568
assessment of the scientific and technical questions described in this document. The following	569
guidance documents provide procedural information on requesting meetings with FDA and	570
general information on combination products.	571
572
• 	Guidance for Industry - Formal Meetings Between the FDA and Sponsors or Applicants	573
of PDUFA Products; https://www.fda.gov/regulatory-information/search-fda-guidance-	574
documents/formal-meetings-between-fda-and-sponsors-or-applicants-pdufa-products-	575
guidance-industry	576
577
• 	Formal Meetings Between FDA and ANDA Applicants of Complex Products Under	578
GDUFA – Guidance for Industry (DRAFT); https://www.fda.gov/regulatory-	579
information/search-fda-guidance-documents/formal-meetings-between-fda-and-anda-	580
applicants-complex-products-under-gdufa-guidance-industry	581
582
• 	Guidance for Industry and FDA Staff - Technical Considerations for Pen, Jet, and	583
Related Injectors Intended for Use with Drugs and Biological Products;	584
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/technical-	585
considerations-pen-jet-and-related-injectors-intended-use-drugs-and-biological-products	586
587
• 	eCTD Technical Conformance Guide: Technical Specifications Document: “Guidance	588
for Industry Providing Regulatory Submissions in Electronic Format —Certain Human	589
Pharmaceutical Product Applications and Related Submissions Using the eCTD	590
Specifications” December 2019 accessible at https://www.fda.gov/regulatory-	591
information/search-fda-guidance-documents/ectd-technical-conformance-guide	592
593
• 	For general information on combination products see	594
https://www.fda.gov/CombinationProducts/default.htm	595
38 For more information on the Inter-Center Consult Review process see
https://www.fda.gov/media/81927/download

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VIII. 	APPENDIX: FAULT TREE EXAMPLE	596
597
The following is a template example of a fault tree analysis for an emergency-use injector. The	598
example uses the following key terms.39	
599
600
• 	Basic Event: A failure mode event or state that cannot be further developed.	601
602
• 	Failure to successfully inject: Failure of an emergency-use injector to successfully inject	603
occurs when one or more functional failure modes result in the emergency-use injector	604
failing to deploy the needle or failing to complete drug delivery when or as intended. This	605
could include circumstances where the emergency-use injector prematurely activates or	606
does not activate when intended.	607
608
• 	Failure Mode: The manner in which a failure occurs.	609
610
Fault Tree Analysis:	611
612
For the emergency-use injector, each final element of the fault tree (e.g. A.1.i.a) should directly	613
link to probability data supporting the overall reliability of the product. The steps for fault tree	614
analysis include the following. See the preceding sections of this document for guidance for	615
information on the completion of these steps, conduct of the analysis, and data submission.	616
617
• 	Definition of the scope of the analysis;	618
• 	Familiarization with the design, functions and operation of the system;	619
• 	Definition of the top event;	620
• 	Construction of the fault tree;	621
• 	Analysis of the fault tree logic; and,	622
• 	Reporting on results of the analysis;	623
624
The template defines the top event as the Failure to Successfully Inject. The fault tree should be	625
broken down into all reasonable, identified faults and failure modes that could lead to a Failure-	626
to-Inject event. The lowest level in the example fault tree illustrates how individual components	627
are incorporated into the fault tree.	628
629
This fault tree example is not prescriptive. The actual number of levels and total amount of	630
failure modes identified in a manufacturer’s fault tree will depend on the specific design and	631
manufacturing of that emergency-use injector.	632
633
634
(See next page for example of flow diagram.)	635
636
39 For a more complete glossary and more information see ISO 61025:2006 – Fault tree analysis and the NASA
Fault Tree Handbook with Aerospace Applications, 2006.

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637