Federal Register / Vol. 83, No. 114 / Wednesday, June 13, 2018 / Notices 27609 

TABLE 1—ESTIMATED ANNUAL REPORTING BURDEN 1—Continued 

Type of information Number of 

respondents 

Number of 

responses per 

respondent 

Total annual 

responses 

Average 

burden per 

response 

(hours) 

Total hours 

Recommended information to be included when firms 

choose to disseminate HCEI materials to payors about 

approved or cleared medical devices.

236 10 2,360 20 ................... 47,200 

Recommended information to be included when firms 

choose to disseminate information about unapproved 

products or unapproved uses of approved or cleared 

products.

717 2 1,434 .5 (30 minutes) 717 

Followup information to payors regarding previously communicated about unapproved products or unapproved 

uses of approved or cleared products.

359 2 718 2 ..................... 1,436 

Total .............................................................................. ........................ ........................ ........................ ........................ 137,353 

1There are no capital costs or operating and maintenance costs associated with this collection of information. 

This guidance also refers to 

previously approved collections of 

information found in FDA regulations. 

The collections of information in 21 

CFR 314.81(b)(3)(i) (Form FDA 2253) 

have been approved under OMB control 

number 0910–0001. 

FDA is issuing this final guidance 

subject to OMB approval of the 

collections of information. Before 

implementing the information 

collection provisions of the guidance, 

FDA will publish a notice in the Federal 

Register announcing OMB’s decision to 

approve, modify, or disapprove the 

collections of information, including 

OMB control number(s) for newly 

approved collections. 

III. Electronic Access 

Persons with access to the internet 

may obtain the guidance at https://

www.fda.gov/Drugs/Guidance

ComplianceRegulatoryInformation/

Guidances/default.htm, https://

www.fda.gov/BiologicsBloodVaccines/

GuidanceComplianceRegulatory

Information/Guidances/default.htm, 

https://www.fda.gov/MedicalDevices/

DeviceRegulationandGuidance/ 

GuidanceDocuments/default.htm, or 

https://www.regulations.gov. 

Dated: June 7, 2018. 

Leslie Kux, 

Associate Commissioner for Policy. 

[FR Doc. 2018–12632 Filed 6–12–18; 8:45 am] 

BILLING CODE 4164–01–P 

DEPARTMENT OF HEALTH AND 

HUMAN SERVICES 

Food and Drug Administration 

[Docket No. FDA–2018–N–2065] 

Alternative or Streamlined 

Mechanisms for Complying With the 

Current Good Manufacturing Practice 

Requirements for Combination 

Products; Proposed List Under the 

21st Century Cures Act 

AGENCY: Food and Drug Administration, 

HHS. 

ACTION: Notice. 

SUMMARY: As required by the 21st 

Century Cures Act (Cures Act), the Food 

and Drug Administration (FDA or 

Agency) is proposing a list of alternative 

or streamlined mechanisms for 

complying with the current good 

manufacturing practice (CGMP) 

requirements for combination products. 

Combination products are products 

composed of two or more different types 

of medical products (drug, device, and/ 

or biological product). 

DATES: Submit either electronic or 

written comments on this notice by 

September 11, 2018 to ensure that the 

Agency considers your comment on this 

proposed list before it begins work on 

the final list. 

ADDRESSES: You may submit comments 

as follows. Please note that late, 

untimely filed comments will not be 

considered. Electronic comments must 

be submitted on or before September 11, 

2018. The https://www.regulations.gov 

electronic filing system will accept 

comments until midnight Eastern Time 

at the end of September 11, 2018. 

Comments received by mail/hand 

delivery/courier (for written/paper 

submissions) will be considered timely 

if they are postmarked or the delivery 

service acceptance receipt is on or 

before that date. 

Electronic Submissions 

Submit electronic comments in the 

following way: 

• Federal eRulemaking Portal: 

https://www.regulations.gov. Follow the 

instructions for submitting comments. 

Comments submitted electronically, 

including attachments, to https://

www.regulations.gov will be posted to 

the docket unchanged. Because your 

comment will be made public, you are 

solely responsible for ensuring that your 

comment does not include any 

confidential information that you or a 

third party may not wish to be posted, 

such as medical information, your or 

anyone else’s Social Security number, or 

confidential business information, such 

as a manufacturing process. Please note 

that if you include your name, contact 

information, or other information that 

identifies you in the body of your 

comments, that information will be 

posted on https://www.regulations.gov. 

• If you want to submit a comment 

with confidential information that you 

do not wish to be made available to the 

public, submit the comment as a 

written/paper submission and in the 

manner detailed (see ‘‘Written/Paper 

Submissions’’ and ‘‘Instructions’’). 

Written/Paper Submissions 

Submit written/paper submissions as 

follows: 

• Mail/Hand delivery/Courier (for 

written/paper submissions): Dockets 

Management Staff (HFA–305), Food and 

Drug Administration, 5630 Fishers 

Lane, Rm. 1061, Rockville, MD 20852. 

• For written/paper comments 

submitted to the Dockets Management 

Staff, FDA will post your comment, as 

well as any attachments, except for 

information submitted, marked and 


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1There are also ‘‘cross-labeled’’ combination 

products (§ 3.2(e)(3) and (4)). With respect to crosslabeled combination products, part 4, subpart A 

was intended to clarify only that the CGMP 

requirements applicable to the drugs, devices, or 

biological products also apply to these types of 

articles when they are constituent parts of such 

combination products. Constituent parts of crosslabeled combination products need only comply 

with the requirements otherwise applicable to that 

type of product (e.g., 21 CFR parts 210 and 211 for 

a drug constituent part or 21 CFR part 820 for a 

device constituent part). The ‘‘streamlined 

approach’’ and related mechanisms described in 

this notice are generally not relevant or applicable 

to cross-labeled combination products. However, to 

the extent that the constituent parts of a crosslabeled combination product are manufactured at 

the same facility, the manufacturing process would 

be akin to when the manufacture of the constituent 

parts of a co-packaged combination product occurs 

at the same facility. Accordingly, as discussed in 

the combination product CGMP guidance (Ref. 1), 

for cross-labeled combination products 

manufactured at the same facility, the Agency does 

not intend to object to the use of a streamlined 

CGMP operating system for the manufacture of the 

combination product rather than distinct systems 

for the manufacture of each constituent part that is 

occurring at that facility. 

identified, as confidential, if submitted 

as detailed in ‘‘Instructions.’’ 

Instructions: All submissions received 

must include the Docket No. FDA– 

2018–N–2065 for ‘‘Alternative or 

Streamlined Mechanisms for Complying 

with Current Good Manufacturing 

Practice (CGMP) Requirements for 

Combination Products.’’ Received 

comments, those filed in a timely 

manner (see ADDRESSES), will be placed 

in the docket and, except for those 

submitted as ‘‘Confidential 

Submissions,’’ publicly viewable at 

https://www.regulations.gov or at the 

Dockets Management Staff between 9 

a.m. and 4 p.m., Monday through 

Friday. 

• Confidential Submissions—To 

submit a comment with confidential 

information that you do not wish to be 

made publicly available, submit your 

comments only as a written/paper 

submission. You should submit two 

copies total. One copy will include the 

information you claim to be confidential 

with a heading or cover note that states 

‘‘THIS DOCUMENT CONTAINS 

CONFIDENTIAL INFORMATION.’’ The 

Agency will review this copy, including 

the claimed confidential information, in 

its consideration of comments. The 

second copy, which will have the 

claimed confidential information 

redacted/blacked out, will be available 

for public viewing and posted on 

https://www.regulations.gov. Submit 

both copies to the Dockets Management 

Staff. If you do not wish your name and 

contact information to be made publicly 

available, you can provide this 

information on the cover sheet and not 

in the body of your comments and you 

must identify this information as 

‘‘confidential.’’ Any information marked 

as ‘‘confidential’’ will not be disclosed 

except in accordance with 21 CFR 10.20 

and other applicable disclosure law. For 

more information about FDA’s posting 

of comments to public dockets, see 80 

FR 56469, September 18, 2015, or access 

the information at: https://www.gpo.gov/ 

fdsys/pkg/FR-2015-09-18/pdf/2015- 

23389.pdf. 

Docket: For access to the docket to 

read background documents or the 

electronic and written/paper comments 

received, go to https://

www.regulations.gov and insert the 

docket number, found in brackets in the 

heading of this document, into the 

‘‘Search’’ box and follow the prompts 

and/or go to the Dockets Management 

Staff, 5630 Fishers Lane, Rm. 1061, 

Rockville, MD 20852. 

FOR FURTHER INFORMATION CONTACT: 

Melissa Burns, Office of Combination 

Products, Food and Drug 

Administration, 10903 New Hampshire 

Ave., Bldg. 32, Rm. 5125, Silver Spring, 

MD 20993, 301–795–5616, 

melissa.burns@fda.hhs.gov. 

SUPPLEMENTARY INFORMATION: 

I. Background 

In December 2016, the Cures Act 

(Pub. L. 114–255) was signed into law. 

Section 3038(c) of the Cures Act 

mandated that FDA publish in the 

Federal Register a list identifying types 

of combination products and 

manufacturing processes for which 

‘‘good manufacturing processes’’ may be 

adopted that vary from the requirements 

set forth in § 4.4 (21 CFR 4.4) or that 

FDA proposes can satisfy the 

requirements in § 4.4 through 

‘‘alternative or streamlined 

mechanisms,’’ and to review this list 

periodically. In accordance with this 

statutory mandate, FDA is publishing a 

proposed list in section II of this 

document, which addresses processes 

for single-entity and co-packaged 

combination products that can satisfy 

requirements in § 4.4 through 

alternative or streamlined mechanisms 

(hereafter ‘‘mechanisms’’). 

On January 22, 2013, FDA issued a 

final rule on CGMP requirements for 

combination products (see 78 FR 4307 

and part 4 (21 CFR part 4, subpart A)). 

Prior to issuance of the final rule, 

although CGMP regulations were in 

place to establish requirements for 

drugs, devices, biological products, and 

human cells, tissues, or cellular or 

tissue-based products (HCT/Ps), there 

were no regulations to clarify and 

explain the application of these CGMP 

requirements to combination products. 

The final rule clarified which CGMP 

requirements apply to combination 

products. It also established a 

transparent and streamlined regulatory 

framework for combination product 

manufacturers to use when 

demonstrating compliance with 

applicable CGMP requirements. 

A combination product is a product 

composed of two or more different types 

of medical products (i.e., a combination 

of a drug, device, and/or biological 

product). The drugs, devices, and 

biological products included in 

combination products are referred to as 

‘‘constituent parts’’ of the combination 

product. Combination products include 

‘‘single-entity’’ combination products 

that are physically, chemically, or 

otherwise combined or mixed and 

produced as a single entity (§ 3.2(e)(1) 

(21 CFR 3.2(e)(1)) (e.g., prefilled 

syringes and drug-eluting stents) and 

‘‘co-packaged’’ combination products 

where two or more separate products 

are packaged together in a single 

package or as a unit and composed of 

drug and device products, device and 

biological products, or biological and 

drug products (§ 3.2(e)(2)) (e.g., a 

surgical or first-aid kit).1 Section 4.4 

outlines how manufacturers of singleentity and co-packaged combination 

products (hereafter ‘‘CP manufacturers’’) 

can demonstrate compliance with 

applicable CGMP requirements, 

including through implementation of a 

streamlined approach to meet the 

requirements of both the drug CGMP 

and the device Quality System (QS) 

regulation by designing and 

implementing a CGMP operating system 

that demonstrates compliance with 

either of the following: 

• The drug CGMP regulations in parts 

210 and 211 (21 CFR parts 210 and 211) 

and the following specified provisions 

from the device QS regulation 

(§ 4.4(b)(1), ‘‘drug CGMP-based 

streamlined approach’’): (1) § 820.20 (21 

CFR 820.20) Management responsibility, 

(2) § 820.30 (21 CFR 820.30) Design 

controls, (3) § 820.50 (21 CFR 820.50) 

Purchasing controls, (4) § 820.100 (21 

CFR 820.100) Corrective and preventive 

action, (5) § 820.170 (21 CFR 820.170) 

Installation, and (6) § 820.200 (21 CFR 

820.200) Servicing; or 

• The device QS regulation in part 

820 (21 CFR part 820) and the following 

specified provisions from the drug 

CGMP regulations (§ 4.4(b)(2), ‘‘device 

QS regulation-based streamlined 

approach’’): (1) § 211.84 (21 CFR 211.84) 

Testing and approval or rejection of 

components, drug product containers, 

and closures; (2) § 211.103 (21 CFR 

211.103) Calculation of yield; (3) 

§ 211.132 (21 CFR 211.132) Tamperevident packaging requirements for 


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2Several drug CGMP mechanisms included in 

this proposed list depend upon use of a more 

broadly defined batch. FDA notes that approaches 

that depend upon broadly defined batches may 

increase the number of distributed products 

implicated when corrective actions are necessary to 

address postmarket issues. 

over-the-counter (OTC) human drug 

products; (4) § 211.137 (21 CFR 211.137) 

Expiration dating; (5) § 211.165 (21 CFR 

211.165) Testing and release for 

distribution; (6) § 211.166 (21 CFR 

211.166) Stability testing; (7) § 211.167 

(21 CFR 211.167) Special testing 

requirements; and (8) § 211.170 (21 CFR 

211.170) Reserve samples. 

If the combination product includes a 

biological product constituent part, the 

CGMP operating system must also 

demonstrate compliance with 

applicable CGMP requirements for 

biological products in parts 600 through 

680 (21 CFR parts 600 through 680), and 

if the combination product includes an 

HCT/P, the CGMP operating system 

must also demonstrate compliance with 

the applicable current good tissue 

practice requirements in part 1271 (21 

CFR part 1271). 

Following publication of the final 

rule, FDA reviewed data and rationales 

provided by manufacturers who 

proposed various means of addressing 

CGMP considerations for combination 

products. FDA also considered feedback 

on its draft guidance on CGMP 

requirements for combination products, 

published in January 2015, in which 

stakeholders requested further guidance 

on circumstances in which flexible 

approaches may be available and how to 

engage with FDA on them. The final 

‘‘Guidance for Industry and FDA Staff: 

Current Good Manufacturing Practice 

Requirements for Combination 

Products’’ includes discussion of 

existing mechanisms to comply with the 

final rule and of circumstances in which 

FDA did not intend to object to 

manufacturers applying practices that 

vary from the requirements set forth in 

the rule (Ref. 1). The Agency continues 

to apply a risk-based approach to 

evaluating methods for ensuring the 

quality of combination products and to 

welcome proposals from manufacturers 

for how to enhance the efficiency of 

development and manufacturing 

activities, while ensuring the safety and 

effectiveness of the combination 

products produced. 

II. Proposed List of Mechanisms for 

Complying With § 4.4 CGMP 

Requirements for Combination 

Products 

A. Introduction 

The following is a proposed list of 

mechanisms for demonstrating 

compliance with relevant combination 

product CGMP requirements, as 

described below. Where applicable, 

reference is made to sections of the 

‘‘Guidance for Industry and FDA Staff: 

Current Good Manufacturing Practice 

Requirements for Combination 

Products’’ for additional information 

(Ref. 1). FDA will continue to evaluate 

this list in light of Agency experience 

and stakeholder input. Manufacturers 

are welcome to propose other 

approaches not described, and FDA 

continues to encourage dialogue with 

the Agency on various means of 

demonstrating CGMP compliance for 

combination products. 

For each mechanism described below, 

CP manufacturers should consider what 

documentation would be sufficient to 

support that the mechanism, including 

the specific approach for implementing 

it, assures appropriate control of the 

manufacture of the combination product 

to ensure safety and effectiveness of the 

product. Appropriate evidence and an 

explanation of the rationale to support 

the approach should be accessible at the 

manufacturing facility for review during 

facility inspections. For additional 

discussion on how to interact with FDA 

regarding the mechanisms described 

below, see section III. 

B. Mechanisms for Complying With 

Drug CGMP Requirements (Part 211) 

Specified in § 4.4 2

FDA interprets the mechanisms 

identified in the sections below as a 

means to demonstrate compliance with 

the specified part 211 requirements 

identified in § 4.4: 

1. Section 211.165 Testing and Release 

for Distribution 

Use of product samples that are not 

finished combination products (but that 

are representative of the finished 

combination product with respect to the 

characteristics and attributes being 

tested) when performing testing required 

by § 211.165 to determine whether the 

drug constituent part meets final 

specifications. To meet the requirements 

of § 211.165, the CP manufacturer 

would need to establish, including 

where appropriate through bridging 

studies and other quantitative means, 

that any differences in the 

manufacturing process for the 

representative samples as compared to 

the finished combination product do not 

affect the drug constituent part. For 

example, as part of product release 

testing, drug-eluting lead manufacturers 

could perform release testing for 

identity, potency, or other quality 

attributes on a representative lead tip 

assembly that contains the drug 

constituent part, but does not contain 

the full electronic and mechanical 

assembly, so long as they can establish 

that the differences in the 

manufacturing process do not impact 

the drug constituent part and the sample 

is representative of the finished 

combination product with respect to the 

quality attributes being tested. 

(See also Section IV.B.5 of Reference 

1 for additional information on testing 

and release for combination products.) 

2. Section 211.166 Stability Testing 

Use of bracketing and matrixing 

approaches to stability studies for 

combination products. Principles for 

bracketing and matrixing approaches to 

meet the requirements of § 211.166 have 

already been addressed by the Agency 

with regard to drug products (Ref. 2), 

and such principles can also be applied 

to combination products. For example, 

when assessing stability for a prefilled 

syringe that is marketed in various fill 

volumes, one of the approaches that a 

CP manufacturer could utilize, if 

appropriate, is bracketing based on the 

smallest and the largest fill volume of 

product configurations. In determining 

the extremes for a bracketing approach 

and/or when justifying the use of a 

matrix design for single-entity 

combination products, it is important 

that the drug-device interactions and 

variations in the manufacturing 

processes are considered. For copackaged combination products, such 

approaches can be applied to the drug 

constituent part of the product. 

Leveraging stability data for an 

already marketed combination product. 

Such mechanisms can be considered 

when the new combination product is a 

modification of an already marketed 

product and the modification does not 

impact the stability of the drug 

constituent part. For example, when 

developing new lengths of a drug-coated 

catheter product for which the catheter 

materials, drug coating, manufacturing 

process, and packaging configurations 

are largely unchanged from existing 

marketed sizes, the CP manufacturer 

would generally be able to leverage 

existing stability data to establish initial 

product shelf life or to support reduced 

stability data requirements, so long as 

characteristics of the product that could 

impact stability (materials, packaging 

configuration, etc.) remain the same. 

However, if the device constituent part 

of a drug-coated catheter includes a new 

material that is in contact with the drug 

coating, for example, new stability 

studies would generally be needed 

under § 211.166. 


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(See also Section IV.B.6 of Reference 

1 for additional information on stability 

requirements for combination products.) 

3. Section 211.167 Special Testing 

Requirements 

Defining ‘‘batch’’ based on the drug 

constituent part rather than the finished 

combination product for purposes of 

special testing requirements for 

pyrogens and endotoxins. For example, 

a manufacturer of a combination 

product that has a sub-assembly coated 

with a drug, which is then incorporated 

into several ‘‘batches’’ or ‘‘lots’’ of the 

overall combination product, may be 

able to define a batch for purposes of 

pyrogen and endotoxin testing as a 

batch of that sub-assembly for purposes 

of meeting the requirements of 

§ 211.167. As with the other 

mechanisms described in this list, this 

mechanism would only potentially be 

available if there would be no impact on 

the drug constituent part from 

subsequent manufacturing processes, 

including when the constituent parts are 

combined to produce the final 

combination product. CP manufacturers 

should consider whether such risks may 

be introduced later in the production 

process (after the batch has been 

defined). This approach will most 

frequently apply for co-packaged 

combination products or single-entity 

combination products for which only a 

component or sub-assembly of the 

overall product is in contact with the 

drug constituent part. 

(See also Section IV.B.7 of Reference 

1 for additional information on special 

testing requirements for combination 

products.) 

4. Section 211.170 Reserve Samples 

Keeping reserve samples that are 

representative of the finished 

combination product. CP manufacturers 

may use validated surrogates as 

representative samples to meet the 

requirements of § 211.170, provided the 

surrogate is appropriate, both in terms 

of the manufacturing process and the 

characteristics of the container closure. 

For example, maintaining only a subassembly of a coated single-entity 

combination product or only the drug 

constituent part of a co-packaged 

combination product as a reserve 

sample would generally be permissible 

under the regulation when: (1) All 

manufacturing process steps after the 

coating step or the fill for the drug 

constituent part are shown not to affect 

the drug constituent part, (2) the 

immediate container closure has 

essentially the same characteristics as 

that for the drug constituent part as 

packaged in the combination product 

for distribution, and (3) the 

representative samples are suitable for 

all required testing of the drug 

constituent part for which the reserve 

samples are being kept. 

Using samples from representative 

lots of a larger batch for retention of 

reserve samples. To meet the 

requirements of § 211.170, CP 

manufacturers may be able to use 

bracketing and matrixing approaches to 

retain reserve samples from certain lots 

to adequately represent the broadly 

defined batch of the combination 

product. For example, CP manufacturers 

might be able to retain reserve samples 

of appropriately varied sizes of a drugcoated combination product from 

within a broadly defined batch that 

includes multiple lots of different sizes. 

(See also Section IV.B.8 of Reference 

1 for additional information on reserve 

sample requirements for combination 

products.) 

C. Mechanisms for Complying With 

Device Quality System Requirements 

(Part 820) Specified in § 4.4 

FDA interprets the mechanisms 

identified in the sections below as a 

means to demonstrate compliance with 

the specified part 820 requirements 

identified in § 4.4: 

1. Section 820.30 Design Controls 

Using existing pharmaceutical 

development practices and 

documentation that align with the 

design control principles and 

requirements of § 820.30. Robust 

pharmaceutical development practices 

would address many design control 

requirements to assure compliance with 

§ 820.30, where applicable. CP 

manufacturers need to demonstrate how 

development processes and terminology 

align with design control principles and 

requirements in § 820.30, when 

required, including, where necessary, 

developing additional design control 

elements. When evaluating the 

adequacy of existing pharmaceutical 

development processes, particular 

attention should be given to postmarket 

management of design changes to the 

combination product and the alignment 

of change control practices with the 

principles and requirements of § 820.30, 

as applicable. 

2. Exemption of Combination Products 

From Device QS Regulation 

Exemption of the combination 

product from all or certain provisions of 

the device QS regulation (part 820) if 

the device constituent part of the 

combination product is itself exempt 

from such requirements and use of the 

device constituent part falls within the 

scope of the relevant exemption, 

including with respect to the device 

constituent part’s intended use. Some 

devices are exempt from all or certain 

provisions of the device QS regulation 

(see, for example, liquid medication 

dispensers such as cups and droppers 

that fall within the scope of § 880.6430 

(21 CFR 880.6430), provided the use of 

the device is not a new intended use or 

does not otherwise raise different safety 

and effectiveness questions (see, for 

example, limitations to the exemption 

under 21 CFR 880.9). Consistent with 

this, for the combination product to be 

exempt from the associated provisions 

of the device QS regulation, we interpret 

this exemption to mean that the use of 

the device in the combination product 

must not be a new intended use or 

otherwise raise different safety and 

effectiveness questions for the device. 

This circumstance will most frequently 

apply to co-packaged combination 

products. For example, an oral dosing 

syringe (a liquid medication dispenser 

under § 880.6430) that is co-packaged 

with a drug may be exempt from certain 

provisions of the device QS regulation 

(and hence the combination product 

may also be exempt from such 

provisions); however, incorporation of 

such a dispenser into a primary 

container closure system or copackaging of such a dispenser with an 

emergency-use product, for example, 

may constitute a new intended use for 

the dispenser or raise different safety 

and effectiveness questions for the 

dispenser, such that the relevant 

exemption would not apply. 

(See also Section III.C.3 of Reference 

1 for additional information on the 

exemption from provisions of the device 

QS regulation for combination 

products.) 

III. Interacting With FDA on 

Mechanisms for Complying With CGMP 

for Combination Products 

1. Process for Interacting With FDA 

In some cases, CP manufacturers may 

interact with FDA to gain approval or 

otherwise notify FDA of a 

manufacturing change. In other cases, 

although a submission or notification is 

not required, CP manufacturers may 

want to discuss potential use of CGMP 

mechanisms with FDA. CP 

manufacturers are encouraged to 

interact early with FDA on 

contemplated CGMP mechanisms. 

• Pre-Submissions and Meeting 

Requests. CP manufacturers who want 

to obtain FDA feedback prior to 

submitting a premarket application or a 

postmarket supplement or who 

otherwise want to obtain feedback on 


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3A combination product is assigned to an Agency 

center (Center for Biologics Evaluation and 

Research, Center for Drug Evaluation and Research, 

or Center for Devices and Radiological Health) that 

will have primary jurisdiction (i.e., the ‘‘lead 

Center’’) for that combination product’s review and 

regulation. Assignment of a combination product to 

a lead Center is based on a determination of which 

constituent part provides the primary mode of 

action of the combination product (21 U.S.C. 

353(g)). 

4When final, this guidance will represent the 

FDA’s current thinking on this topic. 

5When final, this guidance will represent the 

FDA’s current thinking on this topic. 

6Note that when discussing a mechanism for 

complying with CGMP requirements for which the 

CP manufacturer is leveraging information in 

master file(s), the master file holder must submit a 

letter of authorization to permit FDA to review such 

information (see 21 CFR 314.420(d) and 21 CFR 

814.20(c)). The specific information within the 

master file that is being leveraged should be clearly 

identified to FDA. 

7Requirements for postmarket supplements are 

contained, for example, in 21 CFR 314.70 (NDAs), 

21 CFR 601.12 (BLAs), and 21 CFR 814.39 (PMAs). 

Any questions on whether FDA review is required 

for a postmarket CGMP mechanism should be 

directed to the lead Center. 

8With reference to Ref. 8, when final, this 

guidance will represent the FDA’s current thinking 

on this topic. 

their approach may interact with FDA 

via the existing established process 

applicable to the lead Center 3 for the 

combination product. For combination 

products reviewed under a new drug 

application (NDA) or a biologics license 

application (BLA), such interactions 

will generally be through Type C 

meetings (Ref. 3).4 For combination 

products reviewed under an abbreviated 

new drug application (ANDA), these 

interactions will generally be through 

pre-ANDA meetings (Ref. 4).5 For 

combination products reviewed under a 

device premarket submission (e.g., a 

premarket approval application (PMA), 

de novo classification, or premarket 

notification (510(k)), these interactions 

will generally be via the pre-submission 

process (Ref. 5). 

Regardless of the type of submission, 

such interactions should be focused on 

a general discussion of the mechanism 

and CGMP approach the CP 

manufacturer wishes to pursue and 

associated justification to support the 

approach. Only representative data is 

typically appropriate in these 

interactions; complete data should be 

included in the subsequent premarket 

submission or postmarket supplement, 

if required, and/or be maintained at the 

manufacturing facility, as appropriate.6

• Premarket Review. CP 

manufacturers should include in their 

original submission for NDAs, BLAs, 

ANDAs, and PMAs information on any 

mechanisms for complying with CGMP 

requirements. For PMAs, this 

information should be included in the 

manufacturing section of the PMA. For 

information regarding where to place 

information in NDAs, BLAs, or ANDAs, 

refer to ‘‘eCTD Technical Conformance 

Guide’’ (Ref. 6). 

• Postmarket Supplements or 

Notifications to FDA. Postmarket 

changes to implement a combination 

product CGMP mechanism for NDAs, 

ANDAs, BLAs, and PMAs, may require 

submission of a supplement or 

notification to FDA.7 CP manufacturers 

should consult related guidances 

relevant to the type of constituent part 

of the combination product (Refs. 7 to 

9).8 If a CP manufacturer has questions 

on the appropriate submission type or 

the need for a submission, they can 

contact the lead Center for assistance. 

2. Content Suggestions 

When submitting information on a 

CGMP mechanism, along with any 

submission requirements applicable to 

the submission type, the following 

content should be included: 

• Applicable CGMP regulation. 

Identify the CGMP regulation applicable 

to the described mechanism. For 

example, if a submission includes a 

mechanism related to stability testing, 

indicate that § 211.166 is the applicable 

CGMP requirement. 

• Applicable Products. If the 

mechanism is to be applied to multiple 

products and/or product configurations, 

list all related sizes, strengths, etc., as 

well as all related application numbers. 

• Related Interactions with FDA. If 

the CP manufacturer has had previous 

interactions with FDA relevant to the 

proposed mechanism, either for the 

product addressed in the submission or 

for related products, the CP 

manufacturer should provide reference 

to those interactions. Where applicable, 

the CP manufacturer may crossreference previously submitted 

information. 

• Justification and Scientific Data. 

Include a rationale to support that the 

proposed mechanism assures adequate 

manufacturing control to ensure product 

safety and effectiveness. When 

describing a CGMP mechanism in a 

premarket or postmarket submission, 

the description should be accompanied 

by data necessary to support the 

approach. When proposing a change 

from a CGMP approach that was 

reviewed previously by FDA, such 

justification should include analysis of 

how the proposed approach compares to 

the previously reviewed approach as an 

effective manufacturing control, 

including representative data, as 

appropriate, to substantiate the analysis. 

3. FDA Engagement 

CP manufacturers are encouraged to 

discuss combination product CGMP 

mechanisms with FDA. Any questions 

on how to engage FDA in such 

discussions should be directed to the 

lead Center for the product or the Office 

of Combination Products, as needed. 

4. FDA Review 

FDA may review information from a 

CP manufacturer related to a mechanism 

for complying with CGMP requirements 

for combination products in premarket 

applications, postmarket supplements 

or notifications, pre-submissions and 

meetings, and during facility 

inspections. FDA may determine that 

the data and rationale presented by a CP 

manufacturer for a particular 

mechanism are insufficient to 

demonstrate that the mechanism, as 

proposed or implemented, meets the 

applicable CGMP requirement. FDA 

generally will notify the CP 

manufacturer and/or applicant in 

writing of any such determination. 

IV. Other Issues for Consideration 

We have developed this proposed list 

of mechanisms based on information 

submitted to FDA by CP manufacturers 

as well as FDA experience with 

manufacturing processes and CGMP 

compliance approaches that have been 

shown through appropriate data and 

rationales to support the manufacture of 

safe and effective products. FDA 

requests comment from stakeholders 

who believe there are additional types 

of combination products and/or 

manufacturing processes where 

different approaches may be 

appropriate. When providing such 

feedback, the suggested approach 

should be: 

• Applicable to a type or range of 

combination products (e.g., not just a 

single CP manufacturer’s product). 

Commenters should indicate to which 

types of combination products or 

manufacturing processes they believe 

the suggested approach should apply. 

• Supported by adequate data and 

rationales to demonstrate that such an 

approach would continue to support 

manufacturing of safe and effective 

combination products. Commenters 

should summarize the data and 

rationale that support the suggested 

approach. 

Any confidential information submitted 

to FDA via the docket should be 

appropriately identified (see 

Instructions above, in ADDRESSES). 

V. Paperwork Reduction Act 

This notice refers to previously 

approved collections of information 


amozie on DSK3GDR082PROD with NOTICES1
27614 Federal Register / Vol. 83, No. 114 / Wednesday, June 13, 2018 / Notices 

found in FDA regulations. These 

collections of information are subject to 

review by the Office of Management and 

Budget (OMB) under the Paperwork 

Reduction Act of 1995 (44 U.S.C. 3501– 

3520). We note that the information 

collected under the underlying CGMP 

regulations for drugs, devices, and 

biological products, including current 

good tissue practices for HCT/Ps, found 

in parts 211, 820, 600 through 680, and 

1271, have already been approved and 

are in effect. The provisions of part 211 

are approved under the OMB control 

number 0910–0139. The provisions of 

part 820 are approved under OMB 

control number 0910–0073. The 

provisions of parts 606 and 640 are 

approved under OMB control number 

0910–0116. The provisions of part 610 

are approved under OMB control 

number 0910–0116 and OMB control 

number 0910–0338 (also for part 680). 

The provisions of part 1271, subparts C 

and D, are approved under OMB control 

number 0910–0543. 

We note that the information 

collected under the related submission 

types have already been approved and 

are in effect. The collections of 

information regarding formal meetings 

with sponsors and applicants have been 

approved under OMB control number 

0910–0429. The collections of 

information regarding new drug 

approvals (NDA) and abbreviated new 

drug applications (ANDA) have been 

approved under OMB control number 

0910–0001. The collections of 

information regarding pre-ANDAs have 

been approved under OMB control 

number 0910–0797. The collections of 

information regarding pre-submissions 

have been approved under OMB control 

number 0910–0756. The collections of 

information regarding PMAs have been 

approved under OMB control number 

0910–0231. The collections of 

information for premarket notification 

(510(k)) have been approved under 

OMB control number 0910–0120. The 

collections of information for the de 

novo classification process have been 

approved under OMB control number 

0910–0844. The collections of 

information regarding biologics license 

applications have been approved under 

OMB control number 0910–0338. 

VI. References 

The following references are on 

display in the Dockets Management 

Staff (see ADDRESSES) and are available 

for viewing by interested persons 

between 9 a.m. and 4 p.m., Monday 

through Friday; they are also available 

electronically at https://

www.regulations.gov. FDA has verified 

the website addresses, as of the date this 

document publishes in the Federal 

Register, but websites are subject to 

change over time. 

1. ‘‘Guidance for Industry and FDA Staff: 

Current Good Manufacturing Practice 

Requirements for Combination 

Products,’’ January 2017. https://

www.fda.gov/RegulatoryInformation/

Guidances/ucm126198.htm. 

2. ‘‘Guidance for Industry: Q1D Bracketing 

and Matrixing Designs for Stability 

Testing of New Drug Substances and 

Products,’’ January 2003. https://www.

fda.gov/downloads/Drugs/Guidances/

ucm073379.pdf. 

3. ‘‘Draft Guidance for Industry: Formal 

Meetings Between the FDA and Sponsors 

or Applicants of PDUFA Products,’’ 

December 2017. https://www.fda.gov/

downloads/Drugs/GuidanceCompliance

RegulatoryInformation/Guidances/

UCM590547.pdf. 

4. ‘‘Draft Guidance for Industry: Formal 

Meetings Between FDA and ANDA 

Applicants of Complex Products Under 

GDUFA,’’ October 2017. https://

www.fda.gov/downloads/drugs/guidance

complianceregulatoryinformation/

guidances/ucm578366.pdf. 

5. ‘‘Guidance for Industry and Food and Drug 

Administration Staff: Requests for 

Feedback on Medical Device 

Submissions: The Pre-Submission 

Program and Meetings with Food and 

Drug Administration Staff,’’ September 

2017. https://www.fda.gov/downloads/

medicaldevices/deviceregulationand

guidance/guidancedocuments/

ucm311176.pdf. 

6. ‘‘eCTD Technical Conformance Guide,’’ 

November 2017. https://www.fda.gov/

downloads/Drugs/UCM465411.pdf. 

7. ‘‘Guidance for Industry: Changes to an 

Approved NDA or ANDA,’’ April 2004. 

https://www.fda.gov/downloads/drugs/

guidancecomplianceregulatory

information/guidances/ucm077097.pdf. 

8. ‘‘Draft Guidance for Industry: Chemistry, 

Manufacturing, and Controls Changes to 

an Approved Application: Certain 

Biological Products,’’ December 2017. 

https://www.fda.gov/downloads/

BiologicsBloodVaccines/Guidance

ComplianceRegulatoryInformation/

Guidances/General/UCM590118.pdf. 

9. ‘‘Guidance for Industry and FDA Staff: 30- 

Day Notices, 135-Day Premarket 

Approval (PMA) Supplements and 75- 

Day Humanitarian Device Exemption 

(HDE) Supplements for Manufacturing 

Method or Process Changes,’’ April 2011. 

https://www.fda.gov/downloads/Medical

Devices/DeviceRegulationandGuidance/

GuidanceDocuments/UCM080194.pdf. 

Dated: June 7, 2018. 

Leslie Kux, 

Associate Commissioner for Policy. 

[FR Doc. 2018–12634 Filed 6–12–18; 8:45 am] 

BILLING CODE 4164–01–P 

DEPARTMENT OF HEALTH AND 

HUMAN SERVICES 

Food and Drug Administration 

[Docket No. FDA–2014–D–0223] 

Humanitarian Device Exemption 

Program; Draft Guidance for Industry 

and Food and Drug Administration 

Staff; Availability 

AGENCY: Food and Drug Administration, 

HHS. 

ACTION: Notice of availability. 

SUMMARY: The Food and Drug 

Administration (FDA or Agency) is 

announcing the availability of the draft 

guidance entitled ‘‘Humanitarian Device 

Exemption (HDE) Program.’’ This draft 

guidance concerns the HDE program as 

a whole and, among other topics, it 

explains the criteria FDA considers to 

determine if ‘‘probable benefit’’ has 

been demonstrated as part of the 

Agency’s decision-making process 

regarding marketing authorization for a 

humanitarian use device (HUD). The 

draft guidance also incorporates recent 

amendments to the Federal Food, Drug, 

and Cosmetic Act (FD&C Act) that affect 

the HDE program and answers other 

common questions that we receive 

about the program. This draft guidance 

is not final nor is it in effect at this time. 

DATES: Submit either electronic or 

written comments on the draft guidance 

by August 13, 2018 to ensure that the 

Agency considers your comment on this 

draft guidance before it begins work on 

the final version of the guidance. 

ADDRESSES: You may submit comments 

on any guidance at any time as follows: 

Electronic Submissions 

Submit electronic comments in the 

following way: 

• Federal eRulemaking Portal: 

https://www.regulations.gov. Follow the 

instructions for submitting comments. 

Comments submitted electronically, 

including attachments, to https://

www.regulations.gov will be posted to 

the docket unchanged. Because your 

comment will be made public, you are 

solely responsible for ensuring that your 

comment does not include any 

confidential information that you or a 

third party may not wish to be posted, 

such as medical information, your or 

anyone else’s Social Security number, or 

confidential business information, such 

as a manufacturing process. Please note 

that if you include your name, contact 

information, or other information that 

identifies you in the body of your 

comments, that information will be 

posted on https://www.regulations.gov. 


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