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DRAFT GUIDANCE
 
 
  This guidance document is being distributed for comment purposes only.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considers your comment on this draft guidance before it begins work on the final version of the guidance, submit 
written or electronic comments on the draft guidance within 60 days of publication in the Federal Register of the 
notice announcing the availability of the draft guidance.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  Contains Nonbinding Recommendations 
 
Draft  Not for Implementation 
 
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   
5  This draft guidance, when finalized, will represent the current thinking of the Food and Drug 
6  Administration (FDA or Agency) on this topic.  It does not establish any rights for any person 
7  and is not binding on FDA or the public.  You can use an alternative approach if it satisfies the 
8  requirements of the applicable statutes and regulations.  To discuss an alternative approach, 
9  contact the FDA staff responsible for this guidance as listed on the title page.  
10   
11   
12  I.  INTRODUCTION 
13   
14  This guidance covers emergency-use injectors submitted under a biologics license application 
15  (BLA), new drug application (NDA), or abbreviated new drug application (ANDA).  The term 
16  emergency-use injector means injectors marketed with an emergency-use drug2 as a prefilled 
17  single entity combination product under 21 CFR 3.2(e)(1) or as a co-packaged combination 
18  product under 21 CFR 3.2(e)(2).  Emergency-use injector includes pen injectors, autoinjectors, or 
19  on-body-wearable delivery systems for drugs for emergency treatment of conditions such as 
20  anaphylaxis, opioid overdose, poisoning, or severe hypoglycemia. 
21   
22  For injectable drug or biological products that are intended to treat emergent, life-threatening 
23  conditions, it is essential to ensure that the emergency-use injector will reliably deliver the drug  
24  as intended.  Failure of the injector may prevent adequate delivery of a life-saving drug to a 
25  patient.  In this context, reliability is defined as the probability that the injector will perform as 
26  intended, without failure, for a given time interval under specified conditions.3 
27   
28  The FDA guidance document, Technical Considerations for Pen, Jet, and Related Injectors 
29  Intended for Use with Drugs and Biological Products provides general recommendations for 
30  the technical and scientific information to be included in marketing applications for a range of 
31  injectors for various uses.4  In that document the reliability of the injector in delivering the drug 
32  product is listed as one of the functional elements FDA assesses in premarket review.  This 
                                                           
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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33  document describes additional information and data that FDA recommends be included in 
34  marketing applications to demonstrate that an emergency-use injector is reliable. 
35   
36  In general, FDAs guidance documents do not establish legally enforceable responsibilities.  
37  Instead, guidances describe the Agencys current thinking on a topic and should be viewed only 
38  as recommendations, unless specific regulatory or statutory requirements are cited.  The use of 
39  the word should in Agency guidances means that something is suggested or recommended, but 
40  not required.  
41   
42  II.  SCOPE 
43   
44  This guidances focus is emergency-use injectors marketed with the emergency-use drug as a 
45  prefilled single entity combination product or as a co-packaged combination product.5  The 
46  recommendations in this guidance are applicable to combination products intended to treat 
47  emergent, life-threatening conditions, when it is essential to ensure that the injector will reliably 
48  deliver the drug as intended.6  Such products are marketed as combination products assigned to 
49  the Center for Drug Evaluation and Research (CDER) or the Center for Biological Evaluation 
50  and Research (CBER) with market authorization under an approved NDA, ANDA, or BLA.7  
51   
52  Although this guidance contains specific recommendations of ways to demonstrate the reliability 
53  of emergency-use injectors,8 the recommendations would also be useful in considering how to 
54  demonstrate the reliability of other emergency-use drug delivery devices; e.g., intranasal sprays, 
55  inhalation devices, topical cutaneous sprays, syringes, or transdermal systems.  Questions 
56  regarding whether these recommendations would apply to a specific emergency-use drug 
57  delivery system and proposed methods to demonstrate the reliability should be discussed with 
58  the Agency early in the product development process.9 
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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60  III.  REGULATORY FRAMEWORK 
61   
62  Combination products are subject to 21 CFR Part 4, which sets forth current good manufacturing 
63  practice (CGMP) requirements for combination products.  The constituent parts of a combination 
64  product retain their regulatory status (as a drug or device, for example) after they are combined.  
65  The CGMP requirements that apply to each of the constituent parts apply to the combination 
66  product they constitute. 
67   
68  For single-entity combination products and co-packaged combination products, such as those 
69  covered in this guidance, part 4 identifies two ways to demonstrate compliance with CGMP 
70  requirements.  Under the first option, manufacturers demonstrate compliance with all CGMP 
71  regulations applicable to each of the constituent parts included in the combination product.  
72  Under the second option, manufacturers implement a streamlined approach for combination 
73  products that include both a drug and device by demonstrating compliance with either the drug 
74  CGMPs (21 CFR parts 210 and 211) or the device Quality System (QS) regulation (21 CFR part 
75  820) and also demonstrating compliance with specified provisions from the other two sets of 
76  CGMP requirements. 
77   
78  Under the streamlined approach described in 21 CFR 4.4(b), manufacturers of drug-led, drug-
79  device combination products,10 such as those that are the subject of this guidance, may meet the 
80  requirements of both the drug CGMPs and device QS regulation by designing and implementing 
81  a CGMP operating system that demonstrates compliance with the drug CGMPs and the 
82  following provisions from the device QS regulation in accordance with 21 CFR 4.4(b)(1) (drug 
83  CGMP-based streamlined approach): 
84   
85    21 CFR 820.20  Management responsibility 
86    21 CFR 820.30  Design controls 
87    21 CFR 820.50  Purchasing controls 
88    21 CFR 820.100  Corrective and preventive action 
89    21 CFR 820.170  Installation 
90    21 CFR 820.200  Servicing 
91   
92  As explained in the FDA guidance for Current Good Manufacturing Practice Requirements for 
93  Combination Products, the core requirements embedded in these regulations provide for 
94  systems that assure proper design, monitoring, and control of manufacturing processes and 
95  facilities.  This includes establishing a strong quality management system, using appropriate 
96  quality raw materials, establishing robust manufacturing and control procedures based on sound 
97  design principles, and detecting and investigating product quality deviations.  In addition, these 
                                                           
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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98  regulations call for ongoing assessment of systems and the implementation of corrective actions 
99  where appropriate.11 
100   
101  IV.  BACKGROUND ON RELIABILITY 
102   
103  Emergency-use injectors such as those for treatment of anaphylaxis typically are used by the 
104  patient, caregiver, or first responder outside of a health care environment.  For the patient 
105  experiencing the emergency or their assisting lay caregivers, there may be only one opportunity 
106  to use the product and for that one opportunity the emergency-use injector needs to successfully 
107  inject the drug at that time.  Further, because these emergency-use injectors are for a single use, 
108  the functional performance cannot be verified before the injector is used.  Therefore, to ensure 
109  safe and effective use of the emergency-use injector, FDA recommends using the reliability 
110  engineering methods described in this guidance to ensure that the injector will function as 
111  intended within its expiration date.  Designing the combination product to achieve its identified 
112  functional performance (reliability) is consistent with the combination product good 
113  manufacturing practice design control requirements provisions (see 21 CFR 4.4(b)(1)(ii) and 
114  4.4(b)(1)(iv)).   
115   
116  Although the requirements of both the drug CGMPs and device QS regulation must be met, as 
117  described in Section III above, several aspects of the design requirements identified in 21 CFR 
118  4.4(b)(1)(ii) are particularly important in the development and reliability of an emergency-use 
119  injector.  For example,  
120   
121    21 CFR 820.30(c) states that [e]ach manufacturer shall establish and maintain 
122  procedures to ensure that the design requirements relating to a device are appropriate and 
123  address the intended use of the device, including the needs of the user and patient. 
124   
125    21 CFR 820.30(d) states that [e]ach manufacturer shall establish and maintain 
126  procedures for defining and documenting design output in terms that allow an adequate 
127  evaluation of conformance to design input requirements.  Design output procedures shall 
128  contain or make reference to acceptance criteria and shall ensure that those design 
129  outputs that are essential for the proper functioning of the device are identified. 
130   
131    21 CFR 820.30(f) states that [e]ach manufacturer shall establish and maintain 
132  procedures for verifying the device design. Design verification shall confirm that the 
133  design output meets the design input requirements.  The results of the design verification, 
134  including identification of the design, method(s), the date, and the individual(s) 
135  performing the verification, shall be documented in the DHF.  Moreover, 21 CFR 
136  820.30(g) states that [e]ach manufacturer shall establish and maintain procedures for 
137  validating the device design. Design validation shall be performed under defined 
138  operating conditions on initial production units, lots, or batches, or their equivalents.  
139  Design validation shall ensure that devices conform to defined user needs and intended 
                                                           
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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140  uses and shall include testing of production units under actual or simulated use 
141  conditions. 
142   
143    21 CFR 820.30(h) states that [e]ach manufacturer shall establish and maintain 
144  procedures to ensure that the device design is correctly translated into production 
145  specifications. 
146   
147    21 CFR 820.30(i) states that [e]ach manufacturer shall establish and maintain 
148  procedures for the identification, documentation, validation or where appropriate 
149  verification, review, and approval of design changes before their implementation. 
150   
151    21 CFR 820.100 states that each manufacturer shall establish and maintain procedures 
152  for implementing corrective and preventive action. 
153   
154  FDA considers that the needs of the user and patient (21 CFR 820.30(c)) in an emergency-use 
155  context would be that, for the patient experiencing the emergency or his/her assisting lay 
156  caregiver, there is only one opportunity to use the product and, thus, FDA has found emergency-
157  use injectors acceptable if they would successfully inject the drug on the first try.  In this 
158  instance, the design input requirements would provide functional measures for performance 
159  characteristics, specifications for how reliably the emergency-use injector functions, and the use 
160  condition of the patient or caregiver.  This would include identification of a reliability 
161  specification that is consistent with the level of risk to the patient if the emergency-use injector 
162  does not function (e.g., the morbidity or mortality associated with untreated anaphylactic shock). 
163   
164  In addition, FDA interprets the requirements under 21 CFR 820.30(f) and (g) to mean that a 
165  manufacturer of an emergency-use injector must verify and validate the design of the injector to 
166  ensure that it works in one opportunity situations.  These requirements can be met, for 
167  example, if available documentation demonstrates that (1) the emergency-use injector has met its 
168  design input requirements within the specified reliability targets at expiry and (2) design 
169  validation has been conducted on finished products to ensure reliability targets are met and that 
170  test conditions were representative of how the product would be exposed up to expiry. 
171   
172  The preceding design control requirements are intended to ensure that the emergency-use 
173  injector performance is as reliable as possible.  Consistent with this purpose, FDA has found 
174  emergency-use injectors to be acceptable if they would successfully inject on the first try in one 
175  opportunity (or emergency) situations.  This reliability concept has an inherent feasibility 
176  consideration.  FDA recommends that emergency-use injectors include design control 
177  specifications for successful injection reliability of 99.999% with a 95% level of confidence As 
178  FDA has found such specifications to be acceptable under applicable standards.  This prospective 
179  99.999% target is equivalent to post-market detection of failure to successfully inject in 
180  1/100,000 injection attempts.  This reliability level was found to balance appropriately the 
181  objective of ensuring the emergency-use injector performance is as safe and reliable as possible 
182  with considerations on feasibility.   
183   
184  As part of determining an acceptable level of reliability, FDA has considered available 
185  information for risk assessment.  Specifically, the FDA-recognized standard, ISO 14791 - 
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186  Application of risk management to medical devices, provides insight regarding probabilities of 
187  occurrence.12  In the standard, examples are provided for semi-quantitative analysis that 
188  identifies probable, remote, and improbable events rates.  In the standard, events occurring in the 
189  range of 1/10,000 detection rate are considered to be probable.  In FDA review experience, this 
190  probable failure rate is likely associated with unacceptable rates of adverse events for 
191  emergency-use injectors that may result in product recalls.  In the standard, events occurring less 
192  than a 1/1,000,000 detection rate are considered to be improbable.  Although the lowest possible 
193  failure rates are desirable, FDA believes that based on the standard rates and current technology, 
194  that the improbable rate of less than 1/1,000,000 detection rate could result in drug shortage or 
195  delayed product availability.  In contrast to both of the preceding rates, events occurring within 
196  1/100,000 to 1/1,000,000 detection rate are considered as a remote probability of occurrence.  
197  Therefore, based on the ISO standard, FDA believes the detection of failure to successfully inject 
198  in 1/100,000 injection attempts is an appropriate risk management target for ensuring successful 
199  injection and treatment when there is only one opportunity to inject.  Further, FDA review of 
200  recent marketing applications demonstrates that the reliability target of 99.999% with a 95% 
201  level of confidence (i.e., 1/100,000 failure to successfully inject rate) is achievable for these 
202  emergency-use injectors. 
203   
204  The following information provides the details of an example of what FDA currently believes 
205  would be an acceptable approach for the mathematical model, statistics, fault tree analysis, and 
206  use of combination product current good manufacturing design control requirements provisions 
207  (21 CFR 4.4(b)(1)(ii) and 4.4(b)(1)(iv)) to establish reliability of the emergency-use injector.  
208  FDA recognizes that as an alternative to the approach discussed in this guidance, applicants may 
209  propose other reliability specifications methodologies.  For example, based on considerations 
210  such as product design, drug being delivered, for emergent unmet medical needs, counter-
211  terrorism considerations, or conditions of use, alternative reliability specifications may be 
212  appropriate.  During emergency-use injector development FDA encourages applicants to seek 
213  FDA meetings to discuss their proposals and rationale (e.g., context of use, risk/benefit, shortage, 
214  and supportive data). 
215   
216  Establishing reliability 
217   
218  Establishing reliability is an iterative process in which the design controls should focus on 
219  emergency-use injector attributes determined to be essential for achieving the emergency-use 
220  injectors intended use.13  The level of reliability necessary to manufacture a safe and effective 
221  combination product directly correlates to the level of risk associated with an unreliable emergency-
222  use injector.  Because reliability as a mathematical model is defined as R(t) = 1  F(t), where F(t) 
223  represents the cumulative distribution function of failure, the goal should be to define the point at 
224  which that distribution, F(t), is adequately controlled.  The reliability specification(s), R(t), 
225  represents the probability that the emergency-use injector will perform as intended, without failure, 
                                                           
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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226  for a given time interval under specified conditions.  This level of risk should be identified in the 
227  risk analysis conducted as part of device design controls activities.14  
228   
229  This assessment is specific to the combination products intended use because the risks are likely 
230  to be impacted by the condition being treated, environments of use, emergency-use injector 
231  technology, drug, user characteristics, etc.  The emergency-use injector reliability analysis, in 
232  addition to the traditional development activities, should incorporate the following device design 
233  control activities as applicable to the emergency-use injector: 
234   
235    Identification of the reliability requirements and specifications; 
236    Risk analysis; 
237    Design verification and validation of the reliability requirements and specifications; and 
238    Design transfer of the reliability specification to the correct production specifications. 
239   
240  As described in Section IV Background on Reliability, after transfer of the design into 
241  production, the manufacturing controls must be adequate to produce reliable emergency-use 
242  injectors as specified.15  These controls should, among other required activities, include the 
243  following to ensure the design specifications and tolerances that must be achieved during 
244  production and that all sources of potential quality problems are analyzed: 
245   
246    Adequate manufacturing in-process controls and release activities to ensure the final 
247  finished emergency-use injector conforms to its specifications; 
248    Adequately defined acceptance activities for the supplied components to ensure that the 
249  manufactured combination product has the required design attributes to ensure the 
250  reliability specifications are achieved; and  
251    Establish and maintain procedures for implementing corrective and preventive action 
252  (CAPA) activities (e.g., post-market complaints) to ensure that all sources of quality data 
253  are analyzed and, where necessary, preventive or corrective actions are taken.16 
254   
255  In addition to providing assurance of the emergency-use injector reliability, the advantages of a 
256  well-constructed reliability analysis include the following life-cycle management benefits in the 
257  linkage between the design and manufacturing controls. 
258   
259    The least reliable design elements or manufacturing controls of an emergency-use 
260  injector can be identified prior to commercialization of the combination product.  This 
261  can further inform potential improvements in manufacturing controls, tracking or 
262  trending limits of part rejects, and future investigations of failed combination products; 
263    Future changes to either design or manufacturing processes can be evaluated against the 
264  reliability analysis to assess the potential impact to the emergency-use injector reliability; 
265    Post-market emergency-use injector failure investigations can directly link to the 
266  emergency-use injector reliability analysis to readily identify gaps or deficiencies in the 
267  emergency-use injectors design and/or manufacturing controls; and 
                                                           
14 See 21 CFR 820.30(g). 
15 See 21 CFR 820.30(h). 
16 See 21 CFR 820.100. 
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268    Once the results of those specific design elements or manufacturing controls are 
269  understood within the context of the overall reliability analysis, if the reliability analysis 
270  is implemented early in the development cycle, reliability improvements can be made by 
271  making changes to the emergency-use injector design or manufacturing processes or 
272  controls. 
273   
274  Section V below provides an example of an acceptable way to demonstrate the reliability of the 
275  emergency-use injector and define failure to successfully inject.   
276   
277  V.  RELIABILTY REPORT DEVELOPMENT AND CONTENT 
278  RECOMMENDATIONS FOR PREMARKET SUBMISSIONS 
279   
280  As discussed in Section IV, achieving the necessary reliability specification is based on 
281  knowledge of the design, manufacture, and use of the combination product.  Generally, the 
282  highest risk is failure to successfully inject (e.g., activation and drug delivery functions).  This 
283  occurs when one or more functional failure modes result in the emergency-use injector failure to 
284  deploy the needle to the target site or failure to complete drug delivery as intended.  As described 
285  in Section IV Background on Reliability, FDA has found emergency-use injectors to be 
286  acceptable if they would successfully inject in one opportunity (or emergency) situations.  As 
287  stated above, FDA has found emergency-use injectors to be acceptable under the applicable 
288  standards when they include design control specifications for successful injection reliability of 
289  99.999% with a 95% level of confidence. 
290   
291  To establish the emergency-use injectors safe and effective injection performance, the 
292  marketing application should include information to verify and validate that the emergency-use 
293  injector achieves its reliability specifications and related information.  The following sections 
294  identify examples of acceptable activities for developing the verification and validation data.  If 
295  applicants submit such information, FDA recommends that the applicants provide these data in 
296  the form of an emergency-use injector reliability report to facilitate efficient review.17  The 
297  following subsections provide examples of the type of information to provide in the reliability 
298  report.  Section VI of this guidance provides a reliability report format example. 
299   
300  1.   Design Inputs and Design Outputs Necessary18 for Ensuring Reliability  
301   
302  As described in Section IV, specifications for how reliably the emergency-use injector 
303  functions and the use condition of the patient or caregiver need to be identified.19  The design 
304  inputs necessary for ensuring reliability should be identified and developed into specified 
305  design outputs.  Selecting design inputs that may not be relevant to the reliable function of 
306  the emergency-use injector could result in an inability to meet the manufacturers established 
307  reliability specifications.  To assist in identifying design input requirements, manufacturers 
308  should consider the following information: 
                                                           
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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309    Intended use and associated risks;  
310    Emergency-use injector risk analysis, including the drug constituent part 
311  characteristics; 
312    Use-related issues to the extent that they could impact the reliability of the 
313  combination product, including: 
314  o  Use tasks, which may include unpacking, preparation, administration and disposal 
315  of the combination product; and 
316  o  Use conditions and environments of use. 
317    Use-condition factors20 to consider include all users of the emergency-use injector, 
318  where they are using it, and the possible circumstances under which the emergency-
319  use injector may be used, including: 
320  o  Use environment (e.g., school, work, public transportation vehicle, harsh climates, 
321  first responder chaotic conditions) and associated risks to reliability; and 
322  o  User characteristics (e.g., self- injection with cognitive or physical impairment 
323  associated with the disorder being treated) and associated risks to reliability.  
324   
325  Table -1 provides an example of emergency-use injector design considerations for 
326  emergency-use injector reliability only.21  
327   
328   
329   
330  (See next page for Table-1.) 
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 
  Packaging ability to prevent emergency-use injector 
damage during shipping, daily carry, etc.  
Protective Packaging 
  Removal from packaging or carrying case (e.g., force 
to remove) 
Removal / Deactivation of    Force to remove caps or needle shields 
Safety Mechanisms    Force to deactivate safety mechanism 
Activation Force    Force to initiate the injection mechanism 
  Needle bevel specifications 
  Needle material of construction 
Needle Insertion    Needle Insertion Forces (e.g., penetrating clothing, 
skin, etc.) 
  Needle resistance to bending and fracture 
Needle Patency    Particulates 
  Target tissue for drug delivery 
  Body habitus, skin and tissue characteristics 
Injection Depth    Anatomical location(s) for injection 
  Types of garments to be injected through 
  Exposed needle length 
  Needle reaches intended injection depth 
Drug Delivery Initiates as    Drug delivery begins when needle is at intended 
Intended  injection depth 
  Drug fluid properties (e.g., viscosity) 
  Needle does not retract before intended dose is 
Drug Delivery Stops as  delivered 
Intended     Audible, visual, or tactile feedback does not 
prematurely signal a completed injection 
  Intended dose delivered to intended injection site or 
Dose Accuracy 
depth 
332   
333  The preceding tabular considerations are to assist in identifying the emergency-use injector 
334  performance characteristics that inform the design inputs and outputs.  Based on such 
335  considerations the applicant should develop the design inputs and outputs that are essential 
336  for ensuring reliability of the applicants proposed product.  The reliability report should 
337  define all the design inputs and outputs determined to be necessary for achieving reliability.  
338  It is important to clearly define the difference between acceptable and unacceptable 
339  emergency-use injector performance to determine appropriate design inputs that will inform 
                                                           
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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340  the design outputs.  If the design outputs are not correctly defined, then the overall reliability 
341  analysis may also be inadequate.  
342 
343  2.Definition of Emergency-Use Injector Reliability Specifications
344 
345  As noted in the preceding discussion on design inputs and outputs, there are multiple design 
346  specifications that should be considered with respect to the reliability of the emergency-use 
347  injector.  Using the mathematical expression identified in Section IV, R(t) = 1  F(t), the 
348  reliability specification is defined as the probability distribution, R(t).  An example of 
349  acceptable reliability specifications is those that are developed in accordance with the risk 
350  assessment as described in Section V.3  Fault Tree Analysis of this document and, through 
351  this analysis, linked to the appropriate manufacturing controls to ensure the reliability of the 
352  final finished combination product.  The specifications may be one or two-sided depending 
353  upon the risk associated with the failure (e.g., risk of overdose and under-dose exists for a 
354  two-sided dose-accuracy reliability specification). 
355 
356  For the reliability specification analysis, failure to inject should be the primary endpoint.  
357  This should be the top-level failure mode of the fault tree analysis as described in Section 
358  V.3.23  The reliability analysis and testing should include emergency-use injector 
359  performance requirements based on the assessment of the design (see Section V.1).  In 
360  general, FDA recommends that these include dose accuracy, extended needle length, 
361  activation force, and injection time be included as part of emergency-use injector 
362  reliability.24  However, manufacturers should assess the specific emergency-use injector 
363  design to determine if additional performance attributes are considered to be essential for 
364  completing a successful injection.  For example, a specific design may have a cap that must 
365  be removed to initiate injection and the manufacturer may determine that cap removal is 
366  essential to completing a successful injection.
367 
368  3. Fault Tree Analysis
369 
370  The information described in the preceding sections could be used to develop a model of the 
371  reliability using fault tree analysis.  The fault tree analysis would focus on failure to achieve 
372  the reliability specifications.  An example of an acceptable analysis is one that also includes 
373  additional fault trees to address other emergency-use injector performance requirements 
374  determined to be essential for reliability (e.g., dose accuracy, extended needle length).  
375  Manufacturers should consider the following for their fault tree analyses: 
376 
377   Design and manufacturing elements should be considered for the fault tree analysis
378  for the purposes of establishing the reliability of the emergency-use injector to
379  perform as intended, without failure, for a given time interval under specified
380  conditions;
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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381   The probability data for each basic event25 should be included in the fault tree; 
382   The analysis should consider potential common cause failures and whether
383  assumptions of independence of events are supportable;
384   Any risk analyses (e.g., such as design and process failure modes effects analysis)26
385  used to support the fault tree analysis should be included in the reliability report;
386   Once the fault tree analyses are completely developed, data should be provided to
387  support that the reliability specification for the top-level failure mode is verified and
388  validated (e.g., the probability data for each basic event should be supported with
389  evidence); and,
390   The basic events in the fault tree analysis should be linked to appropriate design
391  and/or manufacturing controls.
392 
393  Based on standard fault tree analysis quantification methods, the reliability of each basic 
394  event within the fault tree analysis should be assessed through a cumulative analysis to 
395  determine whether the reliability specification for the top-level failure mode is adequately 
396  supported.  The statistical methods utilized to demonstrate the reliability of each basic event 
397  within the fault tree analysis should inform the test sample size necessary for reliability 
398  testing of the final finished combination product.  To assess the potential for the basic event 
399  failure mode of the emergency-use injector, it is important to use a statistical tolerance 
400  interval27 method in which the limits of each individual component are analyzed (e.g., 
401  dimensions, geometry, material strength, etc.),28  both by itself and in conjunction with its 
402  associated components (i.e., stack-up analysis).  To effectively use the tolerance interval 
403  method, the critical measurable elements of each component contributing to the basic event 
404  should be clearly stated and the statistical tolerance limit29 identified.  Data to support the 
405  tolerance interval methodology should be provided and may include process validation data 
406  for individual components.  The resultant k factor30 for each basic event should be used to 
407  calculate the necessary sample size of the reliability study based on the desired reliability 
408  specification and confidence interval. 
409 
410  An example of acceptable use of the statistical tolerance interval methodology is one 
411  described above.31  An acceptable methodology should evaluate both design and 
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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412  manufacturing risks associated with the emergency-use injector such that the fault tree 
413  analysis is assessing reliability of the final, finished combination product.  (See Section VIII - 
414  Appendix for a fault tree analysis template example.) 
415 
416  4. Reliability Testing
417 
418  FDA recommends that a reliability analysis include verifying and validating the adequacy of 
419  the data used to support the reliability specifications, and that the data support the reliability 
420  specification over the combination product expiry period.  The following subsections 
421  describe information recommendations for preconditioning and testing reliability samples. 
422 
423  a. Use Conditions and Preconditioning Recommendations
424 
425  To identify the reliability test conditions to ensure achievement of the reliability 
426  specification at the end of use-life,32 it is important to define the combination products 
427  use conditions and preconditioning steps.  This ensures that the testing program has 
428  adequately challenged the ability of the emergency-use injector to withstand stressors that 
429  are likely to occur or to which the product will be exposed during the use-life.  
430  Combination product-specific use-life factors to consider for preconditioning steps that 
431  influence shelf-life may include the following preconditions: 
432 
433   Shipping;
434   Aging;
435   Storage orientation and conditions;
436   Vibration;
437   Shock (e.g., resistance to impacts, such as being dropped); and
438   Environmental factors:
439  o Temperature (extremes and cyclic);
440  o Altitude and pressure effects (e.g., airplane, submarine, or other above/below
441  sea-level effects); and
442  o Air particulates (dust/sand).
443 
444  FDA recommends that the reliability report include the following information to help 
445  establish the acceptability of the use of accelerated testing to generate supporting data: 
446 
447   Validation data to ensure that the accelerated methods accurately model the time-
448  dependent failure mechanisms of the emergency-use injector;
449   Results of testing at various time points to identify any trends in emergency-use
450  injector performance; and
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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451    A statistical justification to ensure that the sample size at the final time point is 
452  adequate to support the pre-specified reliability and confidence interval goals.  
453  FDA recommends that the tolerance interval method discussed in Section V.3 be 
454  used to provide the sample size justification.  
455   
456  The report should also describe the use conditions that are important for the emergency-
457  use injectors reliability and should define the bounded specifications for each condition 
458  (e.g., a temperature range). 
459   
460  b.  Testing 
461   
462  Reliability verification testing should be conducted on the final finished combination 
463  product after considering the appropriate preconditioning and use conditions laid out in 
464  Section IV.4.a.  A reliability report should include the test protocol with validated test 
465  methods. 
466   
467  The sample size for reliability verification testing should be justified with an appropriate 
468  statistical method as discussed in Section V.3 and based on the emergency-use injector 
469  reliability specifications described in Section V.2.  If multiple test groups are included in 
470  the manufacturers protocol, such as aged and non-aged test groups, then the sample size 
471  should ensure adequate statistical results from each group. 
472   
473  All test failures should undergo root cause analyses which directly link to the fault tree 
474  analysis.  The fault tree analysis may need to be updated based on any previously 
475  unknown failure modes discovered during reliability verification testing.  If there is a 
476  failure, the reliability testing may need to be redone depending on the conclusions of the 
477  root cause analyses.  
478   
479  5.  Total Product Life Cycle Reliability 
480   
481  Throughout the life cycle of the combination product, manufacturers may become aware 
482  of potential emergency-use injector malfunctions, nonconformance or other related 
483  quality problems.  In these cases, manufacturers must investigate the potential cause and 
484  identify any actions that may be needed to correct and prevent recurrence.33   
485   
486  An example of an acceptable reliability report is one that documents the manufacturers 
487  plan for maintaining emergency-use injector reliability throughout the product life cycle 
488  as part of compliance with 21 CFR part 4 current good manufacturing practice 
489  requirements for combination products.34  An example of an acceptable plan is a plan that 
490  includes the following: 
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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492    Procedures that include requirements for analyzing processes, work operations, 
493  concessions, quality audit reports, quality records, service records, complaints, 
494  returned combination product, and other sources of quality data to identify 
495  existing and potential causes of nonconformance, or other quality problems;35  
496   
497    As part of defect and/or failure investigations, the procedures use the reliability 
498  data and fault tree analysis as part of the root cause analysis;  
499   
500    Procedures for when, during complaint investigations and related CAPA 
501  activities, it is appropriate to image the emergency-use injector internally or 
502  physically open the emergency-use injector to inspect, measure, and test 
503  assemblies or individual components and compare results with the specifications 
504  and data identified in the reliability analysis; 
505   
506    Appropriate steps for linking the reliability data to the appropriate acceptance 
507  activities, including the specific emergency-use injector attributes that are 
508  evaluated, evaluation methods, and acceptability criteria that should be considered 
509  in the context of the emergency-use injectors reliability;  
510   
511    Detailed descriptions of the in-process control and release test sampling plans to 
512  ensure that the reliability specification is maintained for each released lot; 
513   
514    Established action limits for significant increases in rejections of the emergency-
515  use injector and its components due to incoming inspection, in-process control, or 
516  release test failures; 
517   
518    The activities triggered by exceeding an action limit should include 1) the need 
519  for implementing CAPA, 2) a root cause investigation, and 3) an associated risk 
520  analysis of the failure. The reliability data and fault tree analysis are consulted as 
521  part of the root cause investigation;   
522   
523    Procedures for updating the reliability data when new information is obtained 
524  (e.g., previously unidentified failure modes); and 
525   
526    A section that addresses disposition of non-released emergency-use injector or 
527  combination product pending analysis and mitigation of newly identified failures.  
528   
529  6.  Activities when Implementing Emergency-Use Injector Design or Manufacturing 
530  Modifications 
531   
532  An example of an acceptable reliability report is one that includes a plan for the activities 
533  to be completed when implementing an emergency-use injector design or manufacturing 
534  modification.  After completing the initial reliability report, future design changes and 
                                                           
35 21 CFR 820.100. 
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535  manufacturing process changes may occur that necessitate re-evaluation of reliability to 
536  ensure emergency-use injector reliability.36  To determine when the reliability data may 
537  need to be updated, the impact of the change should be evaluated based on the existing 
538  reliability model.  
539   
540  Manufacturers should consider if the change impacts the design output specifications of 
541  the emergency-use injector or the basic events of the fault tree analysis.  If it is 
542  determined that the change does impact these aspects, creates new design outputs, or 
543  creates new risks, then the emergency-use injector reliability report should be updated 
544  with data regarding the changes and included within your premarket submission. 
545   
546  VI.  RELIABILITY REPORT FORMAT CONSIDERATIONS 
547   
548  To facilitate the data assessment, the reliability report should be provided in the following 
549  format: 
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   
552  When submitting this information to an NDA or BLA, we recommend including the information 
553  with other device constituent part information located in eCTD module 3.2.P.7.37 
554   
555  VII.  WHERE TO FIND ADDITIONAL INFORMATION    
556   
557  As noted in Section II, the drug-delivery emergency-use injectors addressed by this guidance are 
558  designed as combination products with a CDER or CBER lead.  These combination products are 
559  submitted under an IND, NDA, ANDA, or BLA pathway (including supplements).  To address 
560  any uncertainties for the emergency-use injector reliability development process, FDA strongly 
561  encourages early development meetings (e.g., Pre-IND or Pre-ANDA to discuss the initial 
562  combination product) as well as subsequent IND meetings throughout the development process.  
                                                           
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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563  These meetings can include requests for clarification on the reliability information discussed in 
564  this document.  For applicants with emergency-use delivery systems that are not emergency-use 
565  injectors, these meetings could be used for early consideration of the principles identified in this 
566  document.  All meeting requests should be submitted to the lead center in accordance with its 
567  procedures and should identify the requested participants (e.g., the lead center, CDRH, Office of 
568  Combination Products).  FDA intends to use its Inter-Center Consult Review Process38 for the 
569  assessment of the scientific and technical questions described in this document.  The following 
570  guidance documents provide procedural information on requesting meetings with FDA and 
571  general information on combination products. 
572   
573    Guidance for Industry - Formal Meetings Between the FDA and Sponsors or Applicants 
574  of PDUFA Products; https://www.fda.gov/regulatory-information/search-fda-guidance-
575  documents/formal-meetings-between-fda-and-sponsors-or-applicants-pdufa-products-
576  guidance-industry  
577   
578    Formal Meetings Between FDA and ANDA Applicants of Complex Products Under 
579  GDUFA  Guidance for Industry (DRAFT); https://www.fda.gov/regulatory-
580  information/search-fda-guidance-documents/formal-meetings-between-fda-and-anda-
581  applicants-complex-products-under-gdufa-guidance-industry 
582   
583    Guidance for Industry and FDA Staff - Technical Considerations for Pen, Jet, and 
584  Related Injectors Intended for Use with Drugs and Biological Products; 
585  https://www.fda.gov/regulatory-information/search-fda-guidance-documents/technical-
586  considerations-pen-jet-and-related-injectors-intended-use-drugs-and-biological-products    
587   
588    eCTD Technical Conformance Guide: Technical Specifications Document: Guidance 
589  for Industry Providing Regulatory Submissions in Electronic Format Certain Human 
590  Pharmaceutical Product Applications and Related Submissions Using the eCTD 
591  Specifications December 2019 accessible at https://www.fda.gov/regulatory-
592  information/search-fda-guidance-documents/ectd-technical-conformance-guide 
593   
594    For general information on combination products see 
595  https://www.fda.gov/CombinationProducts/default.htm   
                                                           
38 For more information on the Inter-Center Consult Review process see 
https://www.fda.gov/media/81927/download 
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596    APPENDIX:  FAULT TREE EXAMPLE 
597   
598  ThVe IfIoIl.lowing is a template example of a fault tree analysis for an emergency-use injector.  The 
599  example uses the following key terms.39   
600   
601    Basic Event: A failure mode event or state that cannot be further developed. 
602   
603    Failure to successfully inject: Failure of an emergency-use injector to successfully inject 
604  occurs when one or more functional failure modes result in the emergency-use injector 
605  failing to deploy the needle or failing to complete drug delivery when or as intended. This 
606  could include circumstances where the emergency-use injector prematurely activates or 
607  does not activate when intended. 
608   
609    Failure Mode: The manner in which a failure occurs. 
610   
611  Fault Tree Analysis:  
612   
613  For the emergency-use injector, each final element of the fault tree (e.g. A.1.i.a) should directly 
614  link to probability data supporting the overall reliability of the product.  The steps for fault tree 
615  analysis include the following.  See the preceding sections of this document for guidance for 
616  information on the completion of these steps, conduct of the analysis, and data submission. 
617   
618    Definition of the scope of the analysis; 
619    Familiarization with the design, functions and operation of the system; 
620    Definition of the top event; 
621    Construction of the fault tree; 
622    Analysis of the fault tree logic; and,  
623    Reporting on results of the analysis; 
624   
625  The template defines the top event as the Failure to Successfully Inject.  The fault tree should be 
626  broken down into all reasonable, identified faults and failure modes that could lead to a Failure-
627  to-Inject event.  The lowest level in the example fault tree illustrates how individual components 
628  are incorporated into the fault tree.   
629   
630  This fault tree example is not prescriptive.  The actual number of levels and total amount of 
631  failure modes identified in a manufacturers fault tree will depend on the specific design and 
632  manufacturing of that emergency-use injector.  
633      
634   
635  (See next page for example of flow diagram.) 
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   
20