This section of the FEDERAL REGISTER

contains notices to the public of the proposed

issuance of rules and regulations. The

purpose of these notices is to give interested

persons an opportunity to participate in the

rule making prior to the adoption of the final

rules.

Proposed Rules Federal Register

48423 

Vol. 74, No. 183 

Wednesday, September 23, 2009 

DEPARTMENT OF AGRICULTURE 

Agricultural Marketing Service 

7 CFR Part 970 

[Docket No. AO–FV–09–0138; AMS–FV–09– 

0029; FV09–970–1E] 

Leafy Green Vegetables Handled in the 

United States; Extension of Time for 

First Session of Hearing on Proposed 

Marketing Agreement No. 970 

AGENCY: Agricultural Marketing Service, 

USDA. 

ACTION: Proposed rule; notice of 

additional time for public hearing on 

proposed national marketing agreement 

for leafy green vegetables. 

SUMMARY: This notice announces that 

the scheduled hearing date for the 

Monterey, California session of a public 

hearing to consider a proposed 

marketing agreement for the handling of 

leafy green vegetables in the United 

States may be extended by one day, if 

deemed necessary by the presiding 

administrative law judge. 

DATES: The Monterey, California session 

for the public hearing is currently 

scheduled for September 22 through 24, 

2009. This hearing session may be 

extended by an additional day, 

September 25, 2009, if deemed 

necessary. As with the other scheduled 

sessions, this session would begin at 

8:30 a.m. and conclude at 5 p.m., or any 

other time as determined by the 

presiding administrative law judge. 

ADDRESSES: The hearing location in 

Monterey is: Hyatt Regency Monterey, 1 

Old Golf Course Road, Monterey, 

California, (831) 372–1234. 

FOR FURTHER INFORMATION CONTACT: 

Antoinette Carter, Marketing Order 

Administration Branch, Fruit and 

Vegetable Programs, AMS, USDA, 1400 

Independence Avenue, SW., Stop 0237, 

Washington, DC 20250–0237; 

Telephone: (202) 720–2491, Fax: (202) 

720–8938, or e-mail: Antoinette.Carter

@ams.usda.gov; or Melissa Schmaedick, 

Marketing Order Administration 

Branch, Fruit and Vegetable Programs, 

Northwest Marketing Field Office, AMS, 

USDA, 1220 SW. Third Avenue, Room 

385, Portland, OR 97204; Telephone: 

(503) 326–2724, Fax: (503) 326–7440, or 

e-mail: Melissa.Schmaedick

@ams.usda.gov. 

SUPPLEMENTARY INFORMATION: 

Prior documents in this proceeding: 

Notice of Hearing issued August 31, 

2009; published September 3, 2009 (74 

FR 45565). 

Notice is hereby given that the 

scheduled hearing date for the 

Monterey, California session of a public 

hearing to consider a proposed 

marketing agreement for the handling of 

leafy green vegetables in the United 

States may be extended by one day, if 

deemed necessary by the presiding 

administrative law judge. 

The Department of Agriculture 

(USDA) previously announced a hearing 

to consider a proposed marketing 

agreement for the handling of leafy 

green produce in the United States. 

Hearing dates have been scheduled for 

various locations throughout the United 

States, including Monterey, California. 

However, an additional day may be 

required to receive testimony and 

evidence in Monterey. This notice 

announces the addition of September 

25, 2009 to the first session, if deemed 

necessary by the presiding 

administrative law judge. 

Information regarding the hearing and 

the proposed marketing agreement is 

contained in the Notice of Hearing, 

which may be viewed at: http://

www.regulations.gov/search/Regs/

home.html#documentDetail?R=

0900006480a1c313. 

List of Subjects in 7 CFR Part 970 

Marketing agreements, Reporting and 

recordkeeping requirements, Vegetables. 

Authority: U.S.C. 601–674. 

Dated: September 18, 2009. 

Rayne Pegg, 

Administrator, Agricultural Marketing 

Service. 

[FR Doc. E9–22992 Filed 9–21–09; 11:15 am] 

BILLING CODE 3410–02–P 

DEPARTMENT OF HEALTH AND 

HUMAN SERVICES 

Food and Drug Administration 

21 CFR Part 4 

[Docket No. FDA–2008–D–0409] 

Current Good Manufacturing Practice 

Requirements for Combination 

Products 

AGENCY: Food and Drug Administration, 

HHS. 

ACTION: Proposed rule. 

SUMMARY: The Food and Drug 

Administration (FDA or agency) 

proposes to codify the current good 

manufacturing practice (cGMP) 

requirements applicable to combination 

products. This proposed rule is 

intended to promote the public health 

by clarifying which cGMP requirements 

apply when drugs, devices, and 

biological products are combined to 

create a combination product. In 

addition, the proposed rule sets forth a 

transparent and streamlined regulatory 

framework for firms to use when 

demonstrating compliance with cGMP 

requirements for ‘‘single-entity’’ and 

‘‘co-packaged’’ combination products. 

DATES: Submit written or electronic 

comments on this proposed rule by 

December 22, 2009. See section IX of 

this document for the proposed effective 

date of a final rule based on this 

document. 

ADDRESSES: You may submit comments, 

identified by Docket No. FDA–2008–D– 

0409 (formerly Docket No. 2004D– 

0431), by any of the following methods: 

Electronic Submissions 

Submit electronic comments in the 

following way: 

• Federal eRulemaking Portal: http:// 

www.regulations.gov. Follow the 

instructions for submitting comments. 

Written Submissions 

Submit written submissions in the 

following ways: 

• FAX: 301–827–6870. 

• Mail/Hand delivery/Courier (for 

paper, disk, or CD–ROM submissions): 

Division of Dockets Management (HFA– 

305), Food and Drug Administration, 

5630 Fishers Lane, rm. 1061, Rockville, 

MD 20852. 

To ensure more timely processing of 

comments, FDA is no longer accepting 

comments submitted to the agency by emstockstill on DSKH9S0YB1PROD with PROPOSALS

48424 Federal Register / Vol. 74, No. 183 / Wednesday, September 23, 2009 / Proposed Rules 

1For purposes of part 3 and this proposed rule, 

a ‘‘biological product’’ means a biological product 

subject to regulation under section 351 of the Public 

Health Service Act (the PHS Act) (42 U.S.C. 262). 

All biological products regulated under the PHS Act 

meet the definitions of drug or device in section 201 

of the Federal Food, Drug, and Cosmetic Act (the 

act) (21 U.S.C. 321). 

2See also 21 U.S.C. 360j(f)(1). 

3See, generally, 21 U.S.C. 351(a)(2)(B) and (h). 

mail. FDA encourages you to continue 

to submit electronic comments by using 

the Federal eRulemaking Portal, as 

described previously, in the ADDRESSES

portion of this document under 

Electronic Submissions. 

Instructions: All submissions received 

must include the agency name and 

docket number for this rulemaking. All 

comments received may be posted 

without change to http:// 

www.regulations.gov, including any 

personal information provided. For 

additional information on submitting 

comments, see the ‘‘Comments’’ heading 

of the SUPPLEMENTARY INFORMATION

section of this document. 

Docket: For access to the docket to 

read background documents or 

comments received, go to http:// 

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 Division of Dockets 

Management, 5630 Fishers Lane, rm. 

1061, Rockville, MD 20852. 

FOR FURTHER INFORMATION CONTACT: John 

Weiner, Office of Combination Products 

(HFG–3), Food and Drug 

Administration, 15800 Crabbs Branch 

Way, suite 200, Rockville, MD 20855, 

301–427–1934. 

SUPPLEMENTARY INFORMATION: 

I. Introduction 

As set forth in part 3 (21 CFR Part 3), 

a combination product is a product 

comprised of any combination of a drug 

and a device; a device and a biological 

product; a biological product and a 

drug; or a drug, a device, and a 

biological product.1 Under § 3.2(e), a 

combination product includes: 

1. A product comprised of two or 

more regulated components, i.e., drug/ 

device, biologic/device, drug/biologic, 

or drug/device/biologic, that are 

physically, chemically, or otherwise 

combined or mixed and produced as a 

single entity (single-entity combination 

products); 

2. Two or more separate products 

packaged together in a single package or 

as a unit and comprised of drug and 

device products, device and biological 

products, or biological and drug 

products (co-packaged combination 

products); 

3. A drug, device, or biological 

product packaged separately that 

according to its investigational plan or 

proposed labeling is intended for use 

only with an approved individually 

specified drug, device, or biological 

product where both are required to 

achieve the intended use, indication, or 

effect and where upon approval of the 

proposed product the labeling of the 

approved product would need to be 

changed, e.g., to reflect a change in 

intended use, dosage form, strength, 

route of administration, or significant 

change in dose; or 

4. Any investigational drug, device, or 

biological product packaged separately 

that according to its proposed labeling 

is for use only with another individually 

specified investigational drug, device, or 

biological product where both are 

required to achieve the intended use, 

indication, or effect. 

The Medical Device User Fee and 

Modernization Act of 2002 (MDUFMA) 

modified section 503(g) of the act) (21 

U.S.C. 353(g)) to require the 

establishment of an Office (Office of 

Combination Products (OCP)) within the 

Office of the Commissioner of FDA. The 

responsibilities of OCP include ensuring 

the prompt assignment of combination 

products to agency components, the 

timely and effective premarket review of 

such products, and the consistent and 

appropriate postmarket regulation of 

like products subject to the same 

statutory requirements to the extent 

permitted by law (21 U.S.C. 353(g)(4)). 

Section 501 of the act (21 U.S.C. 351) 

states circumstances under which drugs 

and devices (including biological 

products, which by definition are also 

drugs or devices, and including human 

cellular and tissue-based products 

(HCT/Ps) that are regulated as drugs, 

devices, and/or biological products) are 

deemed adulterated.2 Adulteration 

includes the failure to manufacture a 

product in accordance with applicable 

cGMP requirements, regardless of 

whether the product appears to meet its 

final specifications.3

The constituent parts of a 

combination product retain their 

regulatory status (as a drug or device, for 

example) even after they are combined. 

Accordingly, the cGMP requirements 

that apply to each of the constituent 

parts continue to apply when they are 

combined to make combination 

products. To date, however, the agency 

has not issued specific regulations 

clarifying the applicability of the cGMP 

requirements to combination products. 

While cGMP regulations are in place 

that establish requirements for drugs, 

devices, biological products, and 

HCT/Ps, there are currently no 

regulations that clarify and explain the 

application of these cGMP requirements 

when these drugs, devices, biological 

products, and HCT/Ps are constituent 

parts of a combination product. 

FDA believes that the absence of clear 

cGMP requirements for combination 

products could result in inconsistent or 

differing application of the various 

cGMP requirements applicable to the 

constituent parts, which could affect 

product safety and the public health. 

In the Federal Register of October 4, 

2004 (69 FR 59239), the agency 

announced the availability of a Draft 

Guidance for Industry and FDA entitled 

‘‘Current Good Manufacturing Practice 

for Combination Products.’’ The agency 

received 15 comments, which were 

largely supportive of the regulatory 

approach described in the draft 

guidance. The agency has carefully 

reviewed these comments and has 

addressed many of them in the 

proposed rule. A common theme that 

emerged from these comments was the 

need to develop a clear regulatory 

framework that takes account of the fact 

that combination products are made up 

of drug, device, and biological product 

constituent parts. At the same time, 

commenters wanted to ensure that the 

framework would not demand 

unnecessary redundancy in the 

operating systems to meet cGMP 

requirements (cGMP operating systems). 

After careful consideration of the 

comments, and of how best to ensure 

that cGMPs for combination products 

are consistent and appropriate, FDA has 

determined that rulemaking is 

warranted. FDA believes that 

rulemaking will best help ensure the 

manufacture of safe and effective 

combination products, by providing a 

clear and transparent regulatory 

roadmap for the application of cGMP 

requirements to these products. The rule 

is being proposed as part of FDA’s 

ongoing effort to improve the 

consistency and appropriateness of the 

regulatory requirements for combination 

products. 

For certain types of combination 

products, the application of current 

good manufacturing practice 

requirements is fairly straightforward. 

Specifically, the constituent parts of a 

combination product are each subject 

only to the cGMP regulations applicable 

to that type of constituent part (e.g., 

drug or device) if the combination 

product consists of constituent parts 

that are packaged separately and 

intended for use only with another 

approved or investigational, 

individually specified drug, device, or 

biological product, as defined in 

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Federal Register / Vol. 74, No. 183 / Wednesday, September 23, 2009 / Proposed Rules 48425 

4As described in the Department of Health and 

Human Services (DHHS) Unified Agenda, 72 FR 

22490 (April 30, 2007), FDA also plans to propose 

regulations on postmarketing safety reporting for 

combination products. FDA proposes to codify 

those requirements in 21 CFR part 4, subpart B. 

5See §§ 210.1(c), 820.1(a), and 1271.45(a). For the 

purposes of this proposed rule, FDA uses the term 

‘‘current good manufacturing practice 

requirements’’ to include all such requirements 

found in the standards in parts 600 through 680 that 

may apply to combination products. See § 211.1(b). 

FDA notes that many of the requirements in parts 

600 through 680 are not considered cGMP 

requirements and are not covered by this proposed 

rule. In addition, FDA notes that biological 

products must comply with all applicable 

requirements in parts 600 through 680. 

§ 3.2(e)(3) and (e)(4). This is because 

these constituent parts, while part of a 

combination product, are separately 

manufactured and packaged. 

Accordingly, they remain separate for 

purposes of applying the cGMP 

regulations. 

Thus, for example, if a combination 

product were to include a separately 

manufactured and packaged drug 

constituent part, the manufacture of that 

constituent part would be subject to the 

cGMP regulations for drugs at parts 210 

and 211 (21 CFR parts 210 and 211) 

(drug cGMPs). Similarly, if a 

combination product were to include a 

separately manufactured and packaged 

device constituent part, the manufacture 

of that constituent part would be subject 

to the quality system (QS) regulation for 

devices at part 820 (21 CFR part 820). 

Likewise, a drug, device, or biological 

constituent part of a combination 

product that is separately packaged for 

investigational use as defined in 

§ 3.2(e)(4) is subject to the cGMP 

requirements that apply to either an 

investigational drug, device, or 

biological product, respectively. For 

example, an investigational drug that 

was labeled for use with a separately 

marketed device would be subject to the 

cGMP requirements that apply to 

investigational drugs under section 

501(a)(2)(B) of the act and part 211. 

Section 4.3 of the proposed rule 

would identify the cGMP regulations 

that apply to the constituent parts of a 

combination product, regardless of 

whether the product is a combination 

product under § 3.2(e)(1), (e)(2), (e)(3), 

or (e)(4). Since each constituent part of 

a combination product as defined in 

§ 3.2(e)(3) and (e)(4) is subject only to 

the cGMP requirements that would 

otherwise apply to that constituent part, 

the agency sees no need to elaborate 

upon the practical application of cGMP 

requirements for these two types of 

combination products. The proposed 

rule would expressly address, however, 

the practical application of cGMP 

requirements to single-entity and copackaged combination products as 

defined at § 3.2(e)(1) and (e)(2). 

The proposed rule recognizes that, in 

most instances, for single-entity and copackaged combination products, a 

cGMP operating system that satisfies the 

cGMP regulations applicable to one 

constituent part will also satisfy most of 

the cGMP requirements applicable to 

the other constituent part. In particular, 

the agency believes that compliance 

with either the drug cGMPs or the QS 

regulation will satisfy most of the cGMP 

requirements applicable to either a drug 

or a device constituent part. The agency 

has reviewed the drug cGMPs and QS 

regulation and identified those specific 

provisions from each that a firm would 

need to satisfy in addition to complying 

with the other of these two sets of cGMP 

regulations. 

Accordingly, the proposed rule at 

§ 4.4(b) would offer two options for 

demonstrating compliance with the 

cGMP requirements applicable to each 

of the constituent parts in a co-packaged 

or single-entity combination product. 

These options would be either: (1) To 

demonstrate compliance with the 

specifics of all cGMP regulations 

applicable to each of the constituent 

parts included in the combination 

product containing, or (2) to 

demonstrate compliance with the 

specifics of either the drug cGMPs or the 

QS regulation, rather than both, when 

the combination contains both a drug 

and a device, under certain conditions. 

These conditions include demonstrating 

compliance with specified provisions 

for the other of these two sets of 

requirements, and with all other cGMP 

requirements applicable to the 

constituent parts (i.e., in parts 600 

through 680 (21 CFR parts 600 through 

680) for biological products or in part 

1271 (21 CFR part 1271) for HCT/Ps). 

The proposed rule would help ensure 

that cGMP requirements that apply to 

single-entity and co-packaged 

combination products are clear and 

consistent, regardless of which agency 

component has lead jurisdiction for the 

combination product, or which type of 

application is submitted for marketing 

authorization. The proposed rule would 

permit practical streamlining by 

providing options for demonstrating 

compliance with cGMP requirements for 

these types of combination products. 

This proposed approach would help 

ensure appropriate implementation of 

these requirements while avoiding 

unnecessary redundancy in cGMP 

operating systems for these products. 

The proposed rule would also help 

ensure that the cGMP operating systems 

for these types of combination products 

are appropriately tailored both to the 

specific constituent parts included in 

the combination product and to the 

specific manufacturing processes being 

used. 

FDA recognizes that timely, 

comprehensive guidance and training is 

important to help ensure consistent and 

appropriate implementation of any final 

rule that may issue based upon this 

proposed rule. FDA intends to issue 

such guidance to industry on the 

implementation of the regulatory 

requirements for use of a streamlined 

cGMP operating system for single-entity 

and co-packaged combination products. 

FDA invites comments on particular 

areas of guidance that would be most 

helpful in designing and implementing 

a cGMP operating system in accordance 

with the proposed rule. 

II. Description of the Proposed Rule 

FDA proposes to create 21 CFR part 

4, subpart A, to codify the cGMP 

requirements that apply to combination 

products.4

A. General Principles 

A combination product is comprised 

of constituent parts, i.e., drug(s), 

device(s), and/or biological product(s) 

(21 U.S.C. 353(g)(1); see also § 3.2(e)). 

These drug, device, and/or biological 

product constituent parts retain their 

regulatory identity as a drug, device 

and/or biological product when they are 

combined to create a combination 

product. Accordingly, when combined 

to create a combination product, each of 

the constituent parts remains subject to 

its respective cGMP requirements. 

Under proposed § 4.3, the cGMP 

requirements in parts 210 and 211 

would apply to combination products 

that include a drug, and those in part 

820 would apply to combination 

products that include a device. All 

biological constituent parts of 

combination products meet the 

definition for device or drug in the act, 

and all HCT/Ps included as constituent 

parts of combination products are 

regulated as drugs, devices, and/or 

biological products (see section C 

below). Accordingly, all constituent 

parts of a combination product would 

be subject either to the drug cGMPs or 

QS regulation. In addition, if a 

constituent part of a combination 

product is also a biological product, the 

cGMP requirements in part 606 for 

blood and blood components, and 

among the requirements (standards) for 

biological products in other sections of 

parts 600 through 680 would be 

applicable.5 Similarly, if a constituent 

part is also an HCT/P, the current good 

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48426 Federal Register / Vol. 74, No. 183 / Wednesday, September 23, 2009 / Proposed Rules 

tissue practice requirements in part 

1271 would be applicable. 

B. CGMP Requirements for Single-Entity 

and Co-Packaged Combination Products 

For single-entity and co-packaged 

combination products, the proposed 

rule would allow firms to demonstrate 

compliance with cGMP requirements by 

implementing and complying with 

either the drug cGMPs or the QS 

regulation, rather than both, under 

certain conditions. These conditions 

include demonstrating that the cGMP 

operating system complies with 

specified provisions from the other of 

these two sets of regulations. In 

addition, this operating system would 

have to be shown to comply with all 

other cGMP regulations applicable to 

the constituent parts (i.e., in parts 600 

through 680 for biological products or in 

part 1271 for HCT/Ps). 

More specifically, if a single-entity or 

co-packaged combination product 

includes both a drug and a device and 

the cGMP operating system is shown to 

comply with the drug cGMP regulations 

at 21 CFR parts 210 and 211, the system 

would also have to be shown to comply 

with the following specific provisions of 

the QS regulation, as described in 

proposed § 4.4(b)(1): 

1. § 820.20. Management 

responsibility. 

2. § 820.30. Design controls. 

3. § 820.50. Purchasing controls. 

4. § 820.100. Corrective and 

preventive action. 

5. § 820.170. Installation. 

6. § 820.200. Servicing. 

In this instance, if a firm demonstrates 

compliance with the drug cGMP 

regulations at parts 210 and 211 and the 

specific QS regulation provisions listed 

above, it would also be considered to be 

in compliance with all other provisions 

of the QS regulation. The firm would 

not have to demonstrate compliance 

with the other provisions of the QS 

regulation. 

If a single-entity or co-packaged 

combination product includes both a 

drug and a device and the cGMP 

operating system is shown to comply 

with the QS regulation requirements at 

part 820, the system would also have to 

be shown to comply with the following 

specific provisions of the drug cGMP 

regulations, as described in proposed 

§ 4.4(b)(2): 

1. § 211.84. Testing and approval or 

rejection of components, drug product 

containers, and closures. 

2. § 211.103. Calculation of yield. 

3. § 211.132. Tamper-evident 

packaging for over-the-counter (OTC) 

human drug products. 

4. § 211.137. Expiration dating. 

5. § 211.165. Testing and release for 

distribution. 

6. § 211.166. Stability testing. 

7. § 211.167. Special testing 

requirements. 

8. § 211.170. Reserve samples. 

In this instance, if a firm demonstrates 

compliance with the QS regulation at 

part 820 and the specific drug cGMP 

regulation provisions listed above, it 

would also be considered to be in 

compliance with all other provisions of 

the drug cGMP regulations. The firm 

would not have to demonstrate 

compliance with the other provisions of 

the drug cGMPs. 

Furthermore, if the combination 

product includes a biological product 

constituent part, in addition to 

demonstrating compliance with either 

the drug cGMPs or the device QS 

regulation, along with the specified 

provisions of the other of these two sets 

of regulations if applicable, the cGMP 

operating system would also have to be 

shown to comply with all additional 

cGMP requirements that apply to that 

constituent part as a biological product 

(see parts 600 through 680). Similarly, if 

the combination product includes an 

HCT/P constituent part, it would also 

have to be shown to comply with the 

requirements of part 1271. For those 

combination products that contain 

biological products and/or HCT/Ps, the 

proposed rule would impose no 

additional burdens and, in many cases, 

would offer the option of streamlining 

related to the drug cGMPs and the 

device QS regulation. 

The applicability of the specific 

provisions identified in proposed 

§ 4.4(b) would, as is the case with all 

cGMP regulations, depend upon the 

characteristics of the constituent part 

and the type of manufacturing activity 

performed. For example, if a 

manufacturer makes an OTC 

combination product that includes a 

drug constituent part, it would need to 

comply with the specific tamper-evident 

packaging requirements of § 211.132. A 

manufacturer who makes a prescription 

combination product would not need to 

comply with that provision. To take 

another example, if a manufacturer 

makes a product that has hardware 

requiring installation and/or servicing, 

it would need to comply with the 

installation and/or servicing provisions 

at §§ 820.170 and 820.200, respectively. 

Similarly, the scope, specificity, and 

complexity of the requirements will 

vary depending on the type of activity 

performed. For example, the cGMP 

requirements for firms that repackage 

articles into certain ‘‘convenience’’ kits 

or package a drug with a disposable 

delivery device will generally be less 

demanding than the more extensive 

requirements associated with the 

manufacture of some other combination 

products, such as drug-coated devices. 

The streamlined option provides for 

the potential to incorporate specific 

requirements from the drug cGMPs into 

the framework of a QS operating system, 

and vice versa. These additional, 

specific requirements should be 

incorporated where most appropriate 

into the operating system. 

Both the QS and drug cGMP 

regulations require that procedures be 

written to assure that the products being 

manufactured, processed, and held meet 

cGMP requirements. Accordingly, the 

written procedures for a streamlined 

system would have to assure that the 

firm could demonstrate compliance 

with the cGMP requirements specified 

in the proposed rule. 

In addition to reducing duplicative 

documentation that would otherwise be 

required if multiple sets of cGMP 

regulations were implemented 

independently, this approach to 

documentation of the procedures would 

help facilitate cGMP inspections, by 

setting forth how the cGMP 

requirements for combination products 

are being met and how this is being 

demonstrated in accordance with the 

streamlined approach. 

C. Requirements for a Combination 

Product That Includes an HCT/P 

Questions have been raised by 

stakeholders concerning the application 

of cGMP requirements to HCT/Ps that 

are constituent parts of combination 

products. The HCT/P regulation at part 

1271 distinguishes between HCT/Ps 

regulated solely under section 361 of the 

PHS Act (42 U.S.C. 264), and those that 

are regulated as drugs, devices, and 

biological products under the PHS Act 

and/or the act. The HCT/P regulation 

provides, among other things, that an 

HCT/P that is combined with another 

article (other than water, crystalloids, or 

a sterilizing, preserving, or storage 

agent) does not meet the criteria for 

regulation solely under section 361 of 

the PHS Act, but rather would be 

regulated under the PHS Act and/or the 

act as a drug, device, and/or biological 

product. (See §§ 1271.10 and 1271.20). 

Thus, by operation of the HCT/P 

regulation, an HCT/P that is a 

constituent part of a combination 

product will be regulated as a drug, 

device, and/or biological product. 

Further, because all biological product 

constituent parts meet the definition of 

drug or device, all HCT/P constituent 

parts of a combination product 

regulated as a biological product also 

meet the definition of drug or device. 

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Federal Register / Vol. 74, No. 183 / Wednesday, September 23, 2009 / Proposed Rules 48427 

6See §§ 210.1(c), 210.2, 211.1(b), 820.1(a), and 

1271.1(b)(2). 

Therefore, if a combination product 

includes an HCT/P constituent part, in 

addition to whatever other cGMP 

requirements may apply due to the 

other constituent parts of the 

combination product, these cGMP 

requirements would apply: 

• Part 1271;6

• Either the drug cGMPs or the QS 

regulation; and 

• If the HCT/P is regulated as a 

biological product, whichever biological 

product cGMP requirements apply, as 

specified in parts 600 through 680. 

As indicated in section II.B of this 

document, a firm could choose the 

streamlining option in proposed 

§ 4.4(b), as applicable, with respect to 

the drug and device cGMP requirements 

for combination products containing 

HCT/Ps. 

D. What Requirements Apply to the 

Constituent Parts of a Combination 

Product Before They Are Combined, or 

Packaged Together? 

FDA recognizes that the manufacture 

of a single-entity or co-packaged 

combination product is a complex 

process. The firm or firms participating 

in the production process may 

manufacture, receive, store, or otherwise 

handle the constituent parts of the 

combination product at various 

facilities, including the facility at which 

the constituent parts are combined to 

make the single-entity or co-packaged 

combination product. The fact that 

many firms and/or facilities may be 

involved raises questions about whether 

and when the proposed streamlined 

approach to cGMP operating systems 

could be used. Proposed § 4.4(c) would 

make clear that when manufacturing of 

a constituent part does not occur at the 

same facility as another type of 

constituent part, the operating system 

must be shown to comply with all of the 

cGMP regulations applicable to that 

constituent part. Proposed § 4.4(d) 

would provide that when two or more 

types of constituent parts are in the 

same facility, the streamlined approach 

may be used. However, proposed 

§ 4.4(d) also clarifies that whenever 

manufacture of a constituent part occurs 

at a separate facility from all other types 

of constituent parts, the manufacture of 

that part must occur under the 

regulations applicable to that part. 

Following are some examples to 

illustrate the situations in which the 

proposed streamlined approach could or 

could not be used. 

Example 1: Drug and device 

constituent parts are manufactured at 

two different facilities. Then a third 

facility combines the constituent parts 

into a single-entity or co-packaged 

combination product. Before the 

constituent parts of a single-entity or copackaged combination product are in 

the same facility for incorporation into 

the combination product, the 

manufacturing processes for the 

constituent parts at their separate 

facilities are distinct. Accordingly, 

under proposed § 4.4(c), each of these 

separate facilities must maintain a 

separate cGMP operating system and 

demonstrate compliance with the cGMP 

regulations applicable to that type of 

constituent part (for example, drug 

cGMPs if the constituent part is a drug). 

Once the constituent parts are brought 

to the third facility, the streamlined 

approach could be used. 

Example 2: The constituent parts are 

manufactured in the same facility, and 

are then sent to another facility to be 

combined into a single-entity or copackaged combination product. 

The streamlined approach could be 

used for the manufacture in both 

facilities. Proposed § 4.4(d) addresses 

this situation. 

Example 3: Facility 1 manufactures a 

drug constituent part. Facility 2 

manufactures a device constituent part. 

The drug constituent part is shipped to 

facility 2. Then both the drug 

constituent part and the device 

constituent part are shipped from 

facility 2 to facility 3. Facility 3 

combines the constituent parts into a 

single-entity or co-packaged 

combination product. 

In this situation, manufacture of the 

drug constituent part at facility 1 must 

be shown to comply with the drug 

cGMP regulations. Manufacture of the 

device at facility 2 must be shown to 

comply with the device QS regulation. 

Proposed § 4.4(c) would make this clear. 

For the drug constituent part while it 

is at facility 2, the streamlined approach 

could be used. That is, the QS operating 

system at facility 2 could be 

supplemented by the applicable, 

additional drug cGMP provisions 

specified in proposed § 4.4(b). Proposed 

§ 4.4(d) addresses this situation. Facility 

3 could use the streamlined approach by 

demonstrating compliance with either 

the drug cGMPs or the QS regulation as 

the cGMP operating system, 

supplemented by the particular 

provisions from the other (drug or 

device) regulations specified in 

proposed § 4.4(b). Proposed § 4.4(d) also 

addresses this situation. 

E. Inspection and Enforcement 

For purposes of enforcing the act, 

section 704 of the act provides that FDA 

can enter any factory, warehouse, or 

establishment in which drugs and 

devices are manufactured, processed, 

packed, or held, for introduction into 

interstate commerce or after such 

introduction, to enter any vehicle being 

used to transport or hold drugs or 

devices in interstate commerce, and to 

inspect such factory, warehouse, 

establishment, or vehicle and all 

pertinent equipment, finished and 

unfinished materials, containers, and 

labeling therein. This inspection 

extends to all records and all things 

bearing on whether the drugs or devices 

are adulterated. 

In the case of combination products, 

if a firm chooses to use the streamlined 

approach outlined in the proposed rule 

at § 4.4(b) by implementing the drug 

cGMPs supplemented by compliance 

with the provisions of the QS regulation 

specified in proposed § 4.4(b)(1), the 

FDA inspection would focus on 

compliance with the drug cGMPs and 

the specified QS provisions. If the firm 

complies with the drug cGMPs and the 

specified QS provisions, the firm would 

be considered to be in compliance with 

the other provisions of the QS 

regulation. Likewise, if the operating 

system satisfies the QS regulation and 

the drug cGMP provisions proposed at 

§ 4.4(b)(2) are also satisfied, a firm 

would be considered to be in 

compliance with all other drug cGMP 

provisions. 

III. Legal Authority 

The agency derives its authority to 

issue the regulations in proposed 21 

CFR part 4, subpart A, from 21 U.S.C. 

321, 331, 351, 352, 353, 355, 360, 360b– 

360f, 360h–360j, 360l, 360hh–360ss, 

360aaa–360bbb, 371(a), 372–374, 379e, 

381, 383, and 394, Federal Food, Drug, 

and Cosmetic Act, and 42 U.S.C. 216, 

262, 263a, 264, and 271, Public Health 

Service Act. Most importantly, the 

provisions at sections 501(a)(2)(B) and 

501(h) of the act (21 U.S.C. 351(a)(2)(B) 

and 351(h)) require drugs and devices to 

be manufactured in accordance with 

cGMPs. Section 520(f) of the act (21 

U.S.C. 360j(f)) specifically authorizes 

the issuance of cGMP regulations for 

devices. 

Section 501 of the act (21 U.S.C. 351) 

states that a drug or device is deemed 

adulterated if it is not manufactured in 

accordance with cGMPs. This provision 

also applies to biological products that 

are constituent parts of combination 

products because these products meet 

the definition of drug or device under 

section 201 of the act (21 U.S.C. 321). 

This provision also applies to HCT/Ps 

that are constituent parts of combination 

products because the HCT/P regulation 

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48428 Federal Register / Vol. 74, No. 183 / Wednesday, September 23, 2009 / Proposed Rules 

provides, among other things, that an 

HCT/P that is combined with another 

article (other than water, crystalloids, or 

a sterilizing, preserving, or storage 

agent) is regulated under the PHS Act 

and/or the act as a drug, device, and/or 

biological product (see §§ 1271.10 and 

1271.20). In addition, section 351 of the 

PHS Act (42 U.S.C. 262) authorizes FDA 

to issue manufacturing standards for 

biological products. Section 361 of the 

PHS Act (42 U.S.C. 264) authorizes the 

issuance of regulations to prevent the 

introduction, transmission, or spread of 

communicable diseases. 

Under applicable statutory provisions, 

the following cGMP regulations were 

previously issued for drugs, devices, 

and biological products that may be 

included as constituent parts of 

combination products: 

• Drug cGMP regulations for finished 

pharmaceuticals or drug products set 

forth at parts 210 and 211). 

Drug products not subject to these 

regulations (e.g., bulk drugs or active 

pharmaceutical ingredients) must still 

meet the current good manufacturing 

practice general standard required by 

the statute. 

• QS regulation for devices set forth 

at part 820. 

• cGMP regulations specific to certain 

types of biological products and/or 

HCT/Ps set forth at parts 600 through 

680 and 1271. 

There is considerable overlap in the 

drug cGMPs and QS regulation, and for 

the most part the overlap is apparent. 

For example, both establish 

requirements for management, 

organization, and personnel; both 

require documentation and record 

keeping; and both allow flexibility in 

their application to the manufacture of 

a particular product. FDA considers the 

drug cGMPs and the QS regulation to be 

similar, and they are meant to achieve 

the same general goals. 

Nevertheless, these two sets of 

regulations differ somewhat because 

each is tailored to the characteristics of 

the types of products for which it was 

designed. For instance, each set of 

regulations contains certain specific 

requirements for various cGMP concepts 

that are only more generally addressed 

in the other regulation. For example, the 

QS regulation has detailed corrective 

and preventive action (CAPA) 

requirements (§ 820.100) while CAPA 

principles are more generally addressed 

in the cGMP regulation as part of 

Production Record Review (§ 211.192). 

The cGMP requirements specific to 

each constituent part of a combination 

product also apply to the combination 

product itself because, by definition, 

combination products consist of drugs, 

devices, and/or biological products. 

These articles do not lose their discrete 

regulatory identity when they become 

constituent parts of a combination 

product. Therefore, all combination 

products are subject to at least two sets 

of cGMP requirements. For example, in 

the case of a drug-device combination 

product, the QS regulation in part 820 

and the drug cGMP regulations in parts 

210 and 211 would apply to the 

combination product. This proposed 

rule is intended to clarify the 

applicability of these requirements to 

combination products and to provide a 

streamlined option for practical 

implementation for co-packaged and 

single-entity combination products. 

Because the drug and device cGMP 

requirements are so similar, when using 

this streamlined approach, 

demonstrating compliance with the 

requirements of one set of regulations 

(e.g., drug cGMPs), along with 

demonstrating compliance with the 

requirements of the specified provisions 

from the other set (e.g., QS regulation), 

would be considered to be 

demonstrating compliance with all 

requirements from the other set (e.g., QS 

regulation). 

Although combination products retain 

the regulatory identities of their 

constituent parts, the act also recognizes 

combination products as a category of 

products that are distinct from products 

that are solely drugs, devices, or 

biological products. For example, 

section 503(g)(4)(A) of the act (21 U.S.C. 

353(g)(4)(A)) requires OCP to 

‘‘designate’’ a product as a combination 

product as well as to ensure ‘‘consistent 

and appropriate postmarket regulation 

of like products subject to the same 

statutory requirements.’’ Further, 

section 563 of the act, (21 U.S.C. 

360bbb–2(a)), governs the 

‘‘classification’’ of products as ‘‘drug, 

biological product, device, or a 

combination product subject to section 

503(g)’’ (emphasis added). In this 

respect, the act identifies a combination 

product as a distinct type of product 

that could be subject to specialized 

regulatory controls. 

Under the preceding authorities and 

section 701(a) of the act (21 U.S.C. 371), 

which authorizes FDA to issue 

regulations for the efficient enforcement 

of the act, FDA has the authority to 

issue regulations clarifying the 

applicability of cGMP requirements to 

combination products. The agency is 

also authorized under these authorities 

to issue regulations specifying how 

compliance with cGMP requirements for 

combination products may be 

demonstrated. 

IV. Environmental Impact 

FDA has determined under 21 CFR 

25.30(a), 25.30(h), 25.30(j), 25.31(a), (c), 

(h), and (j), and 25.34(a) and (d) that this 

action is of a type that does not 

individually or cumulatively have a 

significant effect on the human 

environment. Therefore, neither an 

environmental assessment nor an 

environmental impact statement is 

required. 

V. Paperwork Reduction Act of 1995 

We note that the information 

collected under the underlying cGMP 

regulations for drugs, devices, and 

biological products, including HCT/Ps, 

found at parts 211, 820, 600 through 

680, and 1271 have already been 

approved and are in effect. The 

currently approved burden estimates are 

available in the following links. The 

provisions of part 211 are approved 

under OMB control number 0910–0139, 

which expires November 30, 2011 

(http://www.reginfo.gov/public/do/ 

PRAViewICR?ref_nbr=200809-0910- 

008). The provisions of part 820 are 

approved under OMB control number 

0910–0073, which expires on November 

30, 2010 (http://www.reginfo.gov/ 

public/do/PRAViewICR?ref_nbr=

200709-0910-006). The provisions of 

parts 606, 640, and 660 are approved 

under OMB control number 0910–0116, 

which expires February 29, 2012 (http:// 

www.reginfo.gov/public/do/PRAView

ICR?ref_nbr=200811-0910-006). The 

provisions of part 610 are approved 

under OMB control number 0910–0116, 

which expires February 29, 2012, (link 

already provided in this paragraph) and 

OMB control number 0910–0338, which 

expires on June 10, 2010 (also for part 

680) (http://www.reginfo.gov/public/do/ 

PRAViewICR?ref_nbr=200703-0910- 

017). The provisions of part 1271, 

subparts C and D, are approved under 

OMB control number 0910–0543, which 

expires on May 31, 2010 (http:// 

www.reginfo.gov/public/do/PRAView

ICR?ref_nbr=200705-0910-001). To 

obtain more detailed, itemized estimates 

of the burden associated with particular 

regulatory provisions, please click on 

the link called ‘‘View Supporting 

Statement and Other Documents’’ from 

any of the Reginfo.gov links provided in 

this paragraph. (FDA has verified the 

Web site addresses, but FDA is not 

responsible for any subsequent changes 

to the Web sites after this document 

publishes in the Federal Register.) 

We do not believe that this proposal 

would constitute an additional 

paperwork burden because firms must 

currently comply with the cGMP 

regulations addressed by this proposed 

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Federal Register / Vol. 74, No. 183 / Wednesday, September 23, 2009 / Proposed Rules 48429 

7The proposed rule seeks to clarify which cGMP 

requirements apply when drugs, devices, and 

biological products are used to create combination 

products. The agency notes that there are no 

express preemption provisions of the act applicable 

to prescription drugs or biological products. Section 

521 of the act (21 U.S.C. 360k) contains an express 

preemption provision that applies to devices; 

nonetheless, the Supreme Court concluded in 

Medtronic, Inc. v. Lohr, 581 U.S. 470, 500–01 

(1996), that requirements not applicable to a 

particular device (such as the device good 

manufacturing practice requirements at issue in this 

proposed rule) do not preempt State law under 

section 521 of the act. 

rule: In fact, our intent is to minimize 

burden on respondents by providing a 

more streamlined approach. Therefore, 

burden associated with complying with 

these cGMP regulations represents the 

maximum burden for compliance with 

this proposed rule. We invite comment 

on how many firms might avail 

themselves of the streamlined approach 

presented in this proposed rule for copackaged and single-entity combination 

products and on what the reduction in 

paperwork burden would be. 

VI. Federalism 

FDA has analyzed this proposed rule 

in accordance with the principles set 

forth in Executive Order 13132. Section 

4(a) of the Executive order requires 

agencies to ‘‘construe * * * a Federal 

statute to preempt State law only where 

the statute contains an express 

preemption provision or there is some 

other clear evidence that the Congress 

intended preemption of State law, or 

where the exercise of State authority 

conflicts with the exercise of Federal 

authority under the Federal statute.’’ 

The sole statutory provision giving 

preemptive effect to the proposed rule is 

section 751 of the act (21 U.S.C. 379r), 

which would apply only with respect to 

OTC drug components of combination.7

VII. Analysis of Impacts 

A. Introduction 

FDA has examined the impacts of the 

proposed rule under Executive Order 

12866 and the Regulatory Flexibility Act 

(5 U.S.C. 601–612), and the Unfunded 

Mandates Reform Act of 1995 (Public 

Law 104–4). Executive Order 12866 

directs agencies to assess all costs and 

benefits of available regulatory 

alternatives and, when regulation is 

necessary, to select regulatory 

approaches that maximize net benefits 

(including potential economic, 

environmental, public health and safety, 

and other advantages; distributive 

impacts; and equity). The agency 

believes that this proposed rule is not a 

significant regulatory action as defined 

by the Executive order. 

The Regulatory Flexibility Act 

requires agencies to analyze regulatory 

options that would minimize any 

significant impact of a rule on small 

entities. Because this proposed rule 

explains how requirements that are 

currently in effect apply to combination 

products, the agency does not believe 

that this proposed rule would have a 

significant economic impact on a 

substantial number of small entities. 

FDA requests comment on this issue. 

Section 202(a) of the Unfunded 

Mandates Reform Act of 1995 requires 

that agencies prepare a written 

statement, which includes an 

assessment of anticipated costs and 

benefits, before proposing ‘‘any rule that 

includes any Federal mandate that may 

result in the expenditure by State, local, 

and tribal governments, in the aggregate, 

or by the private sector, of $100,000,000 

or more (adjusted annually for inflation) 

in any one year.’’ The current threshold 

after adjustment for inflation is $130 

million, using the most current (2007) 

Implicit Price Deflator for the Gross 

Domestic Product. FDA does not expect 

this proposed rule to result in any 1- 

year expenditure that would meet or 

exceed this amount. 

B. The Rationale Behind the Proposed 

Rule 

The proposed rule has two related 

purposes. The first is to clarify the 

cGMP requirements that apply to 

combination products, and the second is 

to help ensure the consistent and 

appropriate application and 

enforcement of these requirements. 

Constituent parts and manufacturing 

practices vary among combination 

products; different cGMP requirements 

apply depending upon the constituent 

parts in the combination product and 

what manufacturing practices are used. 

Second, the proposed rule attempts to 

streamline the practical implementation 

of cGMP requirements for co-packaged 

and single-entity combination products. 

C. Impact of Proposed Rule 

FDA estimates that approximately 300 

manufacturers of combination products 

will be affected by the proposed rule. 

These manufacturers of combination 

products should benefit from the greater 

clarity provided regarding which 

regulatory provisions apply to their 

products. For both existing and future 

products, the streamlined approach set 

forth in the proposed rule would help 

ensure that cGMPs for co-packaged and 

single-entity combination products are 

consistent and appropriate, without 

duplicative or otherwise unnecessary 

aspects. This codification of cGMP 

requirements for combination products 

would also help ensure predictability 

and consistency in the application and 

enforcement of these regulatory 

requirements with regard to all 

combination products across FDA. 

Firms must already comply with the 

cGMP regulations for drugs, devices, 

and biological products, including 

HCT/Ps, found at parts 211, 820, 600 

through 680, and 1271, that are 

applicable to the constituent parts of 

their combination products. The cost of 

this proposed rule would be the 

incremental costs to modify or 

streamline existing SOPs. We do not 

know how many firms may choose to 

use the proposed streamlined approach 

for single-entity and co-packaged 

combination products, or for how many 

products; nor do we know how many 

firms are already using such an 

approach in light of the draft guidance. 

Some firms may incur one-time 

incremental costs assessing compliance 

with the proposed rule and perhaps 

altering some standard operating 

procedures. Because this proposed rule 

codifies agency practice that is 

described in current guidance 

documents and because no new cGMP 

requirements are proposed, we believe 

the time required would be small and 

estimate it to be about 25 hours per 

product. This estimate is based on 

numbers we have used in previous rules 

with similar requirements. The amount 

of these compliance assessment costs for 

an individual firm, and the impact of 

any such costs, will depend on the 

number and nature of the products the 

firm produces and how the firm has 

applied current regulations. 

Nonetheless, because the time required 

would be limited, the agency believes 

the impact will not be significant on 

entities considered small based on the 

Small Business Administration’s 

definition of a small entity (500 

employees for device and biological 

product firms and 750 employees for 

drug firms). The agency requests 

comment on the incremental burden 

estimate associated with this rule. 

VIII. Request for Comments 

Interested persons may submit to the 

Division of Dockets Management (see 

ADDRESSES) written or electronic 

comments regarding this proposed rule. 

Submit a single copy of electronic 

comments or two paper copies of any 

mailed comments, except that 

individuals may submit one paper copy. 

Comments are to be identified with the 

docket number found in brackets in the 

heading of this document. Received 

comments may be seen in the Division 

of Dockets Management between 9 a.m. 

and 4 p.m., Monday through Friday. 

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48430 Federal Register / Vol. 74, No. 183 / Wednesday, September 23, 2009 / Proposed Rules 

IX. Proposed Effective Date 

The agency is proposing that any final 

rule that may issue based upon this 

proposed rule become effective 180 days 

after its date of publication in the 

Federal Register. 

List of Subjects in 21 CFR Part 4 

Combination products, Biological 

products, Devices, Drugs, and Human 

cell, Tissue, and cellular and tissuebased products, Regulation of 

combination products. 

Therefore, under the Federal Food, 

Drug, and Cosmetic Act, the Public 

Health Service Act, and under authority 

delegated to the Commissioner of Food 

and Drugs, it is proposed that 21 CFR 

part 4 be added to read as follows: 

PART 4—REGULATION OF 

COMBINATION PRODUCTS 

Subpart A—Current Good Manufacturing 

Practice Requirements for Combination 

Products 

Sec. 

4.1 What is the scope of this subpart? 

4.2 How does FDA define key terms and 

phrases in this subpart? 

4.3 What current good manufacturing 

practice requirements apply to my 

combination product? 

4.4 How can I comply with these current 

good manufacturing practice 

requirements for a co-packaged or singleentity combination product? 

Subpart B [Reserved] 

Authority: 21 U.S.C. 321, 331, 351, 352, 

353, 355, 360, 360b–360f, 360h–360j, 360l, 

360hh–360ss, 360aaa–360bbb, 371(a), 372– 

374, 379e, 381, 383, 394; 42 U.S.C. 216, 262, 

263a, 264, 271. 

Subpart A—Current Good 

Manufacturing Practice Requirements 

for Combination Products 

§ 4.1 What is the scope of this subpart? 

This subpart applies to combination 

products. It establishes which current 

good manufacturing practice 

requirements apply to these products. 

This subpart clarifies the application of 

current good manufacturing practice 

regulations to combination products, 

and provides a regulatory framework for 

designing and implementing the current 

good manufacturing practice operating 

system at facilities that manufacture copackaged or single-entity combination 

product. 

§ 4.2 How does FDA define key terms and 

phrases in this subpart? 

The terms listed in this section have 

the following meanings for purposes of 

this subpart. 

Act means the Federal Food, Drug, 

and Cosmetic Act. 

Agency means the Food and Drug 

Administration. 

Biological product has the meaning 

set forth in § 3.2(d) of this chapter. A 

biological product also meets the 

definitions of either a drug or device as 

these terms are defined under § 4.2. 

Combination product has the meaning 

set forth in § 3.2(e) of this chapter. 

Constituent part is a drug, device, or 

biological product, including an HCT/P, 

that is part of a combination product as 

defined in § 3.2(e) of this chapter. 

Co-packaged combination product 

has the meaning set forth in § 3.2(e)(2) 

of this chapter. 

Current good manufacturing practice 

operating system means the operating 

system within an establishment that is 

designed and implemented to address 

and meet the current good 

manufacturing practice requirements for 

a combination product. 

Current good manufacturing practice 

requirements means the requirements 

set forth under § 4.3(a) through (d). 

Device has the meaning set forth in 

3.2(f) of this chapter. A device that is a 

constituent part of a combination 

product is considered a finished device 

within the meaning of the QS 

regulation. 

Drug has the meaning set forth in 

§ 3.2(g) of this chapter. A drug that is a 

constituent part of a combination 

product is considered a drug product 

within the meaning of the drug cGMPs. 

Drug cGMPs refers to the current good 

manufacturing practice regulations set 

forth in parts 210 and 211 of this 

chapter. 

FDA means the Food and Drug 

Administration. 

HCT/Ps refers to human cell, tissue, 

and cellular and tissue-based products, 

as defined in § 1271.3(d) of this chapter. 

Manufacture includes, but is not 

limited to, designing, fabricating, 

assembling, filling, processing, testing, 

labeling, packaging, repackaging, 

holding, and storage. 

QS regulation refers to the quality 

system regulation in part 820 of this 

chapter. 

Single-entity combination product has 

the meaning set forth in § 3.2(e)(1) of 

this chapter. 

Type of constituent part refers to the 

category of the constituent part, which 

can be either a biological product, a 

device, a drug, or an HCT/P, as these 

terms are defined under this § 4.2. 

§ 4.3 What current good manufacturing 

practice requirements apply to my 

combination product? 

If you manufacture a combination 

product, the current good 

manufacturing practice requirements 

listed in this section apply as follows: 

(a) The current good manufacturing 

practice requirements in parts 210 and 

211 of this chapter apply to a 

combination product that includes a 

drug constituent part; 

(b) The current good manufacturing 

practice requirements in part 820 of this 

chapter apply to a combination product 

that includes a device constituent part; 

(c) The current good manufacturing 

practice requirements in part 606 of this 

chapter for blood and blood components 

and among the requirements (standards) 

for biological products in other sections 

of parts 600 through 680 of this chapter 

apply to a combination product that 

includes a biological product 

constituent part to which those 

requirements would apply if that 

constituent part were not part of a 

combination product; and 

(d) The current good tissue practice 

and donor eligibility requirements for 

HCT/Ps in part 1271 of this chapter 

apply to a combination product that 

includes an HCT/P constituent part to 

which those requirements would apply 

if that constituent part were not part of 

a combination product. 

§ 4.4 How can I comply with these current 

good manufacturing practice requirements 

for a co-packaged or single-entity 

combination product? 

(a) Under this subpart, for singleentity or co-packaged combination 

products, compliance with all 

applicable current good manufacturing 

practice requirements for the 

combination product shall be achieved 

through the design and implementation 

of a current good manufacturing 

practice operating system that is 

demonstrated to comply with: 

(1) The specifics of each set of current 

good manufacturing practice regulations 

listed under § 4.3 as they apply to each 

constituent part included in the 

combination product; or 

(2) Paragraph (b) of this section. 

(b) If you elect to establish a current 

good manufacturing practice operating 

system in accordance with paragraph (b) 

of this section, the following 

requirements apply: 

(1) If the combination product 

includes a device constituent part and a 

drug constituent part, and the current 

good manufacturing practice operating 

system has been shown to comply with 

the drug cGMPs, the following 

provisions of the QS regulation must 

also be shown to have been satisfied; 

upon demonstration that these 

requirements have been satisfied, no 

additional showing of compliance with 

respect to the QS regulation need be 

made: 

(i) § 820.20 of this chapter. 

Management responsibility. 

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Federal Register / Vol. 74, No. 183 / Wednesday, September 23, 2009 / Proposed Rules 48431 

(ii) § 820.30 of this chapter. Design 

controls. 

(iii) § 820.50 of this chapter. 

Purchasing controls. 

(iv) § 820.100 of this chapter. 

Corrective and preventive action. 

(v) § 820.170 of this chapter. 

Installation. 

(vi) § 820.200 of this chapter. 

Servicing. 

(2) If the combination product 

includes a device constituent part and a 

drug constituent part, and the current 

good manufacturing practice operating 

system has been shown to comply with 

the QS regulation, the following 

provisions of the drug cGMPs must also 

be shown to have been satisfied; upon 

demonstration that these requirements 

have been satisfied, no additional 

showing of compliance with respect to 

the drug cGMPs need be made: 

(i) § 211.84 of this chapter. Testing 

and approval or rejection of 

components, drug product containers, 

and closures. 

(ii) § 211.103 of this chapter. 

Calculation of yield. 

(iii) § 211.132 of this chapter. Tamperevident packaging requirements for 

over-the-counter (OTC) human drug 

products. 

(iv) § 211.137 of this chapter. 

Expiration dating. 

(v) § 211.165 of this chapter. Testing 

and release for distribution. 

(vi) § 211.166. of this chapter. 

Stability testing. 

(vii) § 211.167 of this chapter. Special 

testing requirements. 

(viii) § 211.170 of this chapter. 

Reserve samples. 

(3) In addition to being shown to 

comply with the other applicable 

current good manufacturing practice 

requirements listed under § 4.3, if the 

combination product includes a 

biological product constituent part, the 

current good manufacturing practice 

operation system must also be shown to 

implement and comply with all current 

good manufacturing practice 

requirements identified under § 4.3(c) 

that would apply to that biological 

product if that constituent part were not 

part of a combination product. 

(4) In addition to being shown to 

comply with the other applicable 

current good manufacturing practice 

requirements listed under § 4.3, if the 

combination product includes an 

HCT/P, the current good manufacturing 

practice operation system must also be 

shown to implement and comply with 

all current good manufacturing practice 

requirements identified under § 4.3(d) 

that would apply to that HCT/P 

constituent part if that constituent part 

were not part of a combination product. 

(c) During any period in which the 

manufacture of a constituent part to be 

included in a co-packaged or singleentity combination product occurs at a 

separate facility from the other type(s) of 

constituent part(s) to be included in that 

single-entity or co-packaged 

combination product, the current good 

manufacturing practice operating 

system for that constituent part must be 

demonstrated to comply with all current 

good manufacturing practice 

requirements applicable to that type of 

constituent part. 

(d) When two or more types of 

constituent parts to be included in a 

single-entity or co-packaged 

combination product have arrived at the 

same facility, or the manufacture of 

these constituent parts is proceeding at 

the same facility, application of a 

current good manufacturing process 

operating system that complies with 

§ 4.4(b) may begin, except with respect 

to any constituent part that remains or 

becomes subject to § 4.4(c). 

(e) The current good manufacturing 

practice requirements set forth in this 

subpart and in parts 210, 211, 600 

through 680, 820, and 1271 of this 

chapter, supplement, and do not 

supersede, each other unless the 

regulations explicitly provide otherwise. 

In the event of a conflict between 

regulations applicable under this 

subpart to combination products, 

including their constituent parts, the 

regulations most specifically applicable 

to the constituent part in question shall 

supersede the more general. 

Subpart B [Reserved] 

Dated: September 17, 2009. 

David Horowitz, 

Assistant Commissioner for Policy. 

[FR Doc. E9–22850 Filed 9–22–09; 8:45 am] 

BILLING CODE 4160–01–S 

EQUAL EMPLOYMENT OPPORTUNITY 

COMMISSION 

29 CFR Part 1630 

RIN 3046–AA85 

Regulations To Implement the Equal 

Employment Provisions of the 

Americans With Disabilities Act, as 

Amended 

AGENCY: Equal Employment 

Opportunity Commission (EEOC). 

ACTION: Notice of proposed rulemaking. 

SUMMARY: The Equal Employment 

Opportunity Commission (the 

Commission or EEOC) proposes to 

revise its Americans with Disabilities 

Act (ADA) regulations and 

accompanying interpretive guidance in 

order to implement the ADA 

Amendments Act of 2008. The 

Commission is responsible for 

enforcement of title I of the ADA, as 

amended, which prohibits employment 

discrimination on the basis of disability. 

Pursuant to the ADA Amendments Act 

of 2008, EEOC is expressly granted the 

authority to amend these regulations, 

and is expected to do so, in order to 

conform certain provisions contained in 

the regulations to the Amendments Act. 

DATES: Written comments on this 

rulemaking must be submitted on or 

before November 23, 2009. 

ADDRESSES: Written comments should 

be submitted to Stephen Llewellyn, 

Executive Officer, Executive Secretariat, 

Equal Employment Opportunity 

Commission, 131 M Street, NE., Suite 

4NW08R, Room 6NE03F, Washington, 

DC 20507. As a convenience to 

commenters, the Executive Secretariat 

will accept comments transmitted by 

facsimile (‘‘FAX’’) machine. The 

telephone number of the FAX receiver 

is (202) 663–4114. (This is not a toll-free 

number.) Only comments of six or fewer 

pages will be accepted via FAX 

transmittal to ensure access to the 

equipment. Receipt of FAX transmittals 

will not be acknowledged, except that 

the sender may request confirmation of 

receipt by calling the Executive 

Secretariat staff at (202) 663–4070 

(voice) or (202) 663–4074 (TTY). (These 

are not toll-free telephone numbers.) 

You may also submit comments and 

attachments electronically at http:// 

www.regulations.gov, which is the 

Federal eRulemaking Portal. Follow the 

instructions online for submitting 

comments. Copies of comments 

submitted by the public will be 

available for review at the Commission’s 

library, 131 M Street, NE., Suite 

4NW08R, Washington, DC 20507, 

between the hours of 9:30 a.m. and 5 

p.m. or can be reviewed at http:// 

www.regulations.gov. 

FOR FURTHER INFORMATION CONTACT: 

Christopher Kuczynski, Assistant Legal 

Counsel, or Jeanne Goldberg, Senior 

Attorney Advisor, Office of Legal 

Counsel, U.S. Equal Employment 

Opportunity Commission at (202) 663– 

4638 (voice) or (202) 663–7026 (TTY). 

These are not toll-free-telephone 

numbers. This document is also 

available in the following formats: large 

print, Braille, audio tape, and electronic 

file on computer disk. Requests for this 

document in an alternative format 

should be made to the Office of 

Communications and Legislative Affairs 

at (202) 663–4191 (voice) or (202) 663– 

mstockstill on DSKH9S0YB1PROD with PROPOSALS