Guidance for Industry 

and FDA 

Current Good Manufacturing 

Practice for 

Combination Products 

DRAFT GUIDANCE

This guidance document is being distributed for comment purposes only. 

Comments and suggestions regarding this draft document should be submitted within 60 days of 

publication in the Federal Register of the notice announcing the availability of the draft 

guidance. Submit comments to Division of Dockets Management (HFA-305), Food and Drug 

Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. All comments should be 

identified with the docket number listed in the notice of availability that publishes in the Federal 

Register. 

For questions regarding this draft document, contact Patricia Y. Love at 301-427-1934. 

U.S. Department of Health and Human Services 

Food and Drug Administration 

Office of the Commissioner 

Office of Combination Products (OCP) 

September 2004

1
Guidance for Industry 

and FDA 

Current Good Manufacturing 

Practice for 

Combination Products 

Additional copies are available from: 

Office of Combination Products, HFG-3 

Office of the Commissioner 

Food and Drug Administration 

15800 Crabbs Branch Way, Suite 200

Rockville, MD 20855

(Tel) 301-427-1934

(Fax) 301-427-1935

http://www.fda.gov/oc/combination

U.S. Department of Health and Human Services 

Food and Drug Administration 

Office of the Commissioner 

Office of Combination Products (OCP) 

September 2004 
Contains Nonbinding Recommendations 

Draft — Not for Implementation

TABLE OF CONTENTS 

I. INTRODUCTION..............................................................................................................................................1

II. BACKGROUND INFORMATION.............................................................................................................2

A. WHAT IS A COMBINATION PRODUCT? ...............................................................................................................2

B. WHAT IS A CONSTITUENT PART OF A COMBINATION PRODUCT? .......................................................................2

C. HOW ARE COMBINATION PRODUCTS REGULATED? ...........................................................................................3

III. CURRENT GOOD MANUFACTURING PRACTICE.............................................................................3

A. BACKGROUND..................................................................................................................................................3

B. CURRENT GOOD MANUFACTURING PRACTICE FOR COMBINATION PRODUCTS ................................................5

C. CONSIDERATIONS FOR DIFFERENT TYPES OF COMBINATION PRODUCTS............................................................7

IV. COMMUNICATION WITH FDA DURING DEVELOPMENT OF A COMBINATION PRODUCT8

A. WHEN DOES FDA RECOMMEND DISCUSSING CGMP ISSUES WITH THE AGENCY?............................................8

B. WHERE CAN I GET MORE INFORMATION? .........................................................................................................8
Contains Nonbinding Recommendations 

Draft — Not for Implementation

Guidance for Industry1 1 

2 

3 

4 

Current Good Manufacturing Practice for Combination Products

5 

This draft guidance, when finalized, will represent the Food and Drug Administration's (FDA's) current 

thinking on this topic. It does not create or confer any rights for or on any person and does not operate to 

bind FDA or the public. You can use an alternative approach if the approach satisfies the requirements of 

the applicable statutes and regulations. If you want to discuss an alternative approach, contact the FDA 

staff responsible for implementing this guidance. If you cannot identify the appropriate FDA staff, call 

the appropriate number listed on the title page of this guidance. 

6 

7 

8 

9 

10 

11 

12 

13 

14 

15 

16 

17 

18 

19 

20 

21 

22 

23 

24 

25 

26 

27 

 

I. INTRODUCTION 

This document provides guidance to industry and FDA staff on the applicability of current good 

manufacturing practice2 provisions to combination products as defined under 21 CFR 3.2(e). 

Such provisions apply to the manufacture3

 of combination products to ensure that (1) the product 

is not adulterated; (2) the product possesses adequate strength, quality, identity, and purity; and 

(3) the product complies with performance standards as appropriate for the marketed 

combination product. 

This guidance does not address technical manufacturing methods or make recommendations for 

manufacturers'4

 selection of facilities to manufacture products.

 

FDA's guidance documents, including this guidance, do not establish legally enforceable 

responsibilities. Instead, guidances describe the Agency's current thinking on a topic and should 

1 This guidance has been prepared by the Office of Combination Products in the Office of the Commissioner in

cooperation with the Center for Biologics Evaluation and Research (CBER), the Center for Drug Evaluation and 

Research (CDER), and the Center for Devices and Radiological Health (CDRH) at the Food and Drug

Administration. 

2

 For purposes of this guidance document, the term current good manufacturing practice refers to the current good

manufacturing practice regulations for drugs and most biological products under 21 CFR Parts 210 and 211, for

certain biological products under 21 CFR Parts 600-680, and the quality system regulations for devices under 21

CFR Part 820. 

 

3

 For purposes of this document, the term manufacture refers to the methods to be used in, and the facilities and

controls to be used for, the manufacture, processing, packing, or holding of a drug (21 CFR 210.01(a)), and those

used for the design, manufacture, packaging, labeling, storage, installation, and servicing of all finished devices

intended for human use (21 CFR 820.1(a)). In addition, the term manufacture refers to the methods and facilities for 

certain biological products that are considered to supplement, not supercede, the drug provisions, unless the 

regulations explicitly provide otherwise (21 CFR 210.2(a)). 

 

4 For purposes of this guidance document, the term “manufacturer” refers to any person who would be required to

comply with current good manufacturing practice regulatory requirements for drugs, biological products, devices, or

combination products. 

1
Contains Nonbinding Recommendations 

Draft — Not for Implementation

28 

29 

30 

31 

32 

33 

34 

35 

36 

37 

38 

39 

40 

41 

42 

43 

44 

45 

46 

47 

48 

49 

50 

51 

52 

53 

54 

55 

56 

57 

58 

59 

60 

61 

62 

63 

64 

65 

66 

67 

68 

69 

70 

71 

72 

73 

be viewed only as recommendations, unless specific regulatory or statutory requirements are 

cited. The use of the word should in Agency guidances means that something is suggested or 

recommended, but not required. 

II. BACKGROUND INFORMATION 

 A. What is a combination product? 

A combination product is a product composed of any combination of a drug and a device; a 

biological product and a device; a drug and a biological product; or a drug, device, and a 

biological product. Under 21 CFR 3.2 (e), a combination product is defined to include: 

1. A product comprising 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; 

2. Two or more separate products packaged together in a single package or as a unit 

comprising drug and device products, device and biological products, or biological and 

drug 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. 

 

B. What is a constituent part of a combination product? 

For the purposes of this guidance document, a constituent part of a combination product is an 

article in a combination product that can be distinguished by its regulatory identity as a drug, 

device, or biological product, as defined in section 201 of the Federal Food, Drug, and Cosmetic 

Act (the Act) or 351(i) of the Public Health Service Act. For example, a device coated or 

impregnated with a drug has two constituent parts, the device and the drug. For simplicity, the 

concepts in this guidance are described in the context of a combination product composed of two 

constituent parts. These concepts are also relevant for combination products with more than two 

constituent parts. 

2
Contains Nonbinding Recommendations 

Draft — Not for Implementation

74 C. How are combination products regulated? 

75 

76 

77 

78 

79 

80 

81 

82 

83 

84 

85 

86 

87 

88 

89 

90 

91 

92 

93 

94 

95 

96 

97 

98 

99 

100 

101 

102 

103 

104 

105 

106 

107 

108 

109 

110 

 

A combination product is assigned to an Agency center or alternative organizational component 

that will have primary jurisdiction for its premarket review and regulation. Under section 

503(g)(1) of the Act, assignment to a center with primary jurisdiction, or a lead center, is based 

on a determination of the primary mode of action (PMOA) of the combination product.5

 For 

example, if the PMOA of a device-biological combination product is attributable to the 

biological product, the Agency component responsible for premarket review of that biological 

product would have primary jurisdiction for the combination product. The lead center generally 

has responsibility for oversight of the regulation of the combination product, including the 

evaluation of current good manufacturing practice. 

 

Section 503(g)(4)(D) of the Act requires FDA to "ensure the consistency and appropriateness of 

postmarket regulation of like [combination] products." To achieve consistency, FDA will treat 

like combination products similarly. To ensure appropriateness, FDA plans to require that 

manufacturers use the applicable current good manufacturing practice regulations for their 

combination products. In the regulation of a combination product, the application of consistent 

and appropriate current good manufacturing practice should help to ensure that the combination 

product is not adulterated under section 501 of the Act and is manufactured in accordance with 

appropriate regulatory provisions for the combination product and its constituent parts. 

III. CURRENT GOOD MANUFACTURING PRACTICE 

A. Background 

Section 501 of the Act states the circumstances under which a drug or device is deemed 

adulterated and authorizes FDA to establish current good manufacturing practice to avoid 

adulteration.6

 Adulteration includes a failure of the drug, biological product, or device to be 

manufactured in accordance with current good manufacturing practice, regardless of whether the 

product is actually deficient in some respect.7 Current good manufacturing practice regulatory 

provisions are intended to ensure that the drug, biological product, or device is not adulterated; to 

ensure the product possesses adequate strength, quality, identity, and purity of a drug or 

biological product; and to ensure compliance with performance standards for a device. The 

following current good manufacturing practice regulations and other applicable standards are 

codified for products that may be constituent parts of a combination product:8

5

 A proposed rule defining the primary mode of action of a combination product was published in the May 7, 2004,

Federal Register, http://www.fda.gov/oc/combination/default.htm. 

6

 See also section 520(f)(1). 

7

 See generally sections 501(a)(2)(B) and 501(h). 

 

8 FDA has also issued a proposed rule for Good Tissue Practices, Manufacturers of Human Cellular and 

Tissue-Based Products; Inspection and Enforcement (Federal Register Notice, January 8, 2001,Vol 66, No. 5, p

1507-1559). 

3
Contains Nonbinding Recommendations 

Draft — Not for Implementation

 Current good manufacturing practice (CGMP) regulations for finished pharmaceuticals, or 

drug products (21 CFR Parts 210 and 211).9

 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. 

111 

112 

113 

114 

115 

116 

117 

118 

119 

120 

121 

122 

123 

124 

125 

126 

127 

128 

129 

130 

131 

132 

133 

134 •

135 

136 

137 

138 

 

 Quality system (QS) regulation for devices (21 CFR Part 820). 

The biological product regulations, 21 CFR Parts 600-680, may also apply to the manufacture of 

drugs that are also biological products along with the drug CGMP provisions.10 They also may 

apply along with the QS regulations to the manufacture of devices that are also biological 

products.11

There is considerable overlap in the CGMP and QS regulations, 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 

application to the manufacture of particular products.12 FDA considers the CGMP13 and the QS 

regulations to be similar, and they are meant to achieve the same goals. 

Nonetheless, FDA recognizes that each set of regulations is somewhat different because each is 

tailored to the characteristics of the types of products for which they were designed (i.e., CGMP 

for drugs or biological products, QS regulation for devices). Each set of regulations contains 

certain express/specific requirements that may be only more generally described in the other 

regulation. Typically, these express/specific requirements are related to the unique 

characteristics of a drug, device, or biological product. For example: 

Calculating the yield and stability of a drug constituent part: The CGMP regulation has 

specific requirements for the calculation of yield (21 CFR 211.103) and for ensuring 

stability of the drug product (21 CFR 211.166). Under the QS regulation, for a 

combination product with a drug constituent part, yield and stability requirements would 

be incorporated more generally as part of the design validation provisions (21 CFR 

9

 For the purposes of this guidance document, the abbreviation "CGMP" refers only to the drug regulations at 21

CFR Parts 210 and 211, while the phrase "current good manufacturing practice" refers to the various sets of

manufacturing practice regulations (see footnote 2). 

10 See 21 CFR 211.1(b) and 21 CFR 210.2(b). 

11 See 21 CFR 820.1(b). 

12 Each set of regulations also allows either a device or a drug manufacturer who is engaging in only some

operations that are subject to the requirements in either 21 CFR 820 or 21 CFR 210 and 211 to only comply with the 

regulations applicable to the operations in which it is engaged. Therefore, a device manufacturer only has to comply 

with the regulations in 21 CFR 820 that are applicable to the operations in which it is engaged in the manufacture of

the device, and a drug manufacturer only has to comply with the regulations in 21 CFR 210 and 211 that are 

applicable to the operations in which it is engaged in the manufacture of the drug. For example, a drug

manufacturer who is only involved in the issuance of labeling of the product, 21 CFR 211.125, may not need to

comply with regulations related to receipt and storage of untested components, 21 CFR 211.82. 

13 See FDA Guidance, "Quality System Approach to Pharmaceutical Current Good Manufacturing Practice 

Regulations," available at http://www.fda.gov/cder/guidance/index.htm for an explanation of how to implement a 

comprehensive QS model under the CGMPs.

4
Contains Nonbinding Recommendations 

Draft — Not for Implementation

139 

140 

141 •

142 

143 

144 

145 

146 

147 

148 

149 

150 

151 

152 

153 

154 

155 

156 

157 

158 

159 

160 

161 

162 

163 

164 

165 

166 

167 

168 

169 

170 

171 

172 

173 

174 

175 

176 

177 

178 

179 

180 

181 

182 

183 

184 

820.30(g)). 

Corrective and preventive action (CAPA): The QS regulation has detailed CAPA 

requirements (21 CFR 820.100), while CAPA principles are more generally identified in 

the CGMP regulation as part of Production Record Review (21 CFR 211.192). 

B. Current Good Manufacturing Practice for Combination Products 

FDA has not promulgated current good manufacturing practice regulations specifically for 

combination products. Until it does so, each constituent part (i.e., the drug, device, or biological 

product) remains subject only to its governing current good manufacturing practice regulations 

when marketed separately, see 21 CFR 3.2(e)(3) and (4), and when manufactured separately as 

constituent parts of a combination that will later be combined, see 21 CFR 3.2(e)(1) and (2). For 

example, if a drug is marketed that is intended for use only with an approved individually 

specified device that is also marketed separately, the drug constituent must comply only with 21 

CFR Parts 210 and 211, and the device constituent must comply only with 21 CFR Part 820. 

Similarly, during the time of separate manufacture (i.e., before drug and device combination 

products are produced as a single entity or are co-packaged) 21 CFR Parts 210 and 211 apply 

only to the drug constituent, and 21 CFR Part 820 applies only to the device constituent. 

However, for combination products that are produced as a single-entity or are co-packaged, see 

21 CFR 3.2(e)(1) and (2), both sets of current good manufacturing practice regulations are 

applicable during and after joining the constituent parts together. The rest of this section refers 

only to situations when combination products that are produced as a single entity or are copackaged as defined in 21 CFR 3.2(e)(1) and (2) are joined together. 

FDA recognizes that many manufacturing facilities operate under one type of current good 

manufacturing practice system (i.e., either that described by the QS or CGMP regulation). As 

noted above, FDA recognizes that there is considerable overlap between the QS and CGMP 

regulations. It should generally not be necessary for manufacturers who make combination 

products that are produced as a single entity or are co-packaged to maintain two separate 

manufacturing systems to ensure compliance with both sets of regulations during and after 

joining the constituents together. FDA believes that compliance with both sets of regulations 

during and after joining these types of combination products can generally be achieved by using 

either the CGMP or QS regulations, e.g., by using the current good manufacturing practice 

system already operating at a manufacturing facility, as described below. 

During and after joining these types of combination products together, FDA believes that 

compliance with both sets of regulations can generally be achieved by following one set because 

under a more general requirement in one set of regulations, it will be possible to develop and 

implement a practice that complies with a more specific requirement in the other set of 

regulations. To ensure consistent and appropriate current good manufacturing practice, FDA 

recommends that manufacturers of these types of combination products assess how best to 

comply with both sets of regulations, during and after joining the constituent parts together, by 

carefully considering the requirements of the CGMP and QS regulations in relation to the 

constituent parts, and the combination product(s) they manufacture. 

5
Contains Nonbinding Recommendations 

Draft — Not for Implementation

185 

186 

187 

188 

189 

190 

191 

192 

193 

194 

Table 1 identifies key provisions of the CGMP and QS regulations that differ in their specificity. 

FDA recommends manufacturers of combination products that are co-packaged or produced as a 

single entity carefully consider these provisions during and after joining the constituent parts, to 

ensure compliance with both the CGMP and QS regulations. 

Table 1: Key Current Good Manufacturing Practice Provisions to Consider During and 

After Joining Together Co-packaged and Single-Entity Combination Products 

If the Operating Manufacturing Control 

System is Part 820 (QS Regulation) 

If the Operating Manufacturing Control 

System is Part 210/211 (CGMP Regulation) 

Carefully 

Consider 

These Specific 

CGMP 

Requirements 

Title Carefully

Consider 

These Specific 

QS 

Requirements 

Title 

§ 211.84 Testing and approval or 

rejection of components, 

drug product containers, and 

closures 

§ 820.30 Design controls 

§ 211.103 Calculation of yield § 820.50 Purchasing controls 

§ 211.137 Expiration dating § 820.100 Corrective and preventative 

actions

§ 211.165 Testing and release for 

distribution 

§ 211.166 Stability testing 

§ 211.167 Special testing requirements 

§ 211.170 Reserve samples 

* Including all subsections, as appropriate. 

195 

196 

197 

198 

199 

200 

201 

202 

203 

204 

205 

206 

207 

208 

In addition, depending on the particular combination product, it may be important to consider 

other specific requirements to ensure compliance with both the CGMP and QS regulations. 

Examples include aseptic control assurance for drug and biological product constituent parts 

unable to withstand terminal sterilization (21 CFR 211.113(b) and § 211.42)); 21 CFR 606 for 

blood and blood component constituent parts; 21 CFR 211.132 for combination products 

incorporating drug constituent parts that are sold over-the-counter; and any good tissue practice 

regulations that may be promulgated. 

FDA recommends that manufacturers of these types of combination products present information 

to the Agency when the product is being developed (e.g., during Agency meetings or during 

inspections) about how they intend to achieve compliance with each set of regulations during and 

after joining the products together, in particular by showing how they achieve compliance with 

6
Contains Nonbinding Recommendations 

Draft — Not for Implementation

the provisions identified in Table 1 above, as well as any other provisions applicable to the 

combination product being manufactured. 

209 

210 

211 

212 

213 

214 

215 

216 

217 

218 

219 

220 

221 

222 

223 

224 

225 

226 

227 

228 

229 

230 

231 

232 

233 

234 

235 

236 

237 

238 

239 

240 

241 

242 

243 

244 

245 

246 

247 

248 

 

 

If a manufacturer of these types of combination products is concerned about whether application 

of one set of current good manufacturing practice regulations satisfies the requirements of the 

other set(s), FDA encourages the manufacturer to discuss with the appropriate Agency personnel 

when the product is being developed how best to achieve current good manufacturing practice 

compliance. Further, FDA expects that this guidance will be revised as FDA modifies the 

existing CGMP/QS regulations.14 

C. Considerations for different types of combination products 

As described under section I.A, there are four types of combination products. To summarize, the 

following are considerations by type of combination product: 

 

 Combination products with constituent parts that are physically, chemically or otherwise 

combined or mixed and produced as a single entity (21 CFR 3.2(e)(1)), and combination 

products with constituent parts that are packaged together (21 CFR 3.2(e)(2)): 

Before combination or co-packaging, the manufacture of each constituent part is subject 

only to the current good manufacturing practice regulations associated with each 

constituent part. For example, for a drug-coated device, the drug constituent part would 

be subject only to the CGMP regulation (or to Section 501(a)(2)(B) of the Act for a bulk 

drug substance or active pharmaceutical ingredient), while the device constituent part 

would be subject only to the QS regulation. 

Once the product is combined into a single entity or co-packaged, both sets of regulations 

apply to the combination. FDA recommends manufacturers follow the guidance 

described in section III.B above to achieve compliance with all applicable current good 

manufacturing practice regulations. 

 Combination products with constituent parts that are separately marketed but intended to 

be used together (21 CFR 3.2(e)(3) and (e)(4)): 

The manufacture of each constituent part is subject to the current good manufacturing 

practice regulations associated with each constituent part, and is not subject to both sets 

of regulations. For example, for a photodynamic therapy system consisting of a laser and 

a photosensitizing drug that are marketed separately, the laser would be subject to the QS 

regulation while the photosensitizing drug would be subject to the CGMP regulation. 

14 FDA Pharmaceutical GMPs for the 21st Century: A Risk Based Approach, 2nd progress report and

implementation plan, (http://www.fda.gov/cder/gmp/2ndProgressRept_Plan.htm). 

 

7
Contains Nonbinding Recommendations 

Draft — Not for Implementation

8

249 

250 

251 

252 

253 

254 

255 

256 

257 

258 

259 

260 

261 

262 

263 

264 

265 

266 

267 

268 

269 

270 

271 

272 

273 

274 

275 

276 

277 

278 

IV. COMMUNICATION WITH FDA DURING DEVELOPMENT OF A 

COMBINATION PRODUCT 

A. When does FDA recommend discussing CGMP issues with the Agency? 

FDA recommends that manufacturers of combination products discuss with the Agency how 

current good manufacturing practice regulations apply to their products. Manufacturers are 

encouraged to seek FDA comment on their implementation of current good manufacturing 

practice during pre-investigational (pre-IND/IDE) meetings and throughout combination 

product development.15 FDA recommends that these discussions include consideration of the 

risks of the combination product, its technology, and any anticipated postmarket 

development and post approval changes. FDA recommends that the applicant(s) include all 

critical manufacturers in these discussions and include information on critical steps that may 

be conducted at source/contract firms and any special testing. 

FDA staff involved in the discussions about the application of current good manufacturing 

practice regulations to a combination product may include, but are not limited to, reviewers 

in the lead and consulting product review divisions (CBER, CDER, and CDRH); the current 

good manufacturing practice experts in the Offices of Compliance in the lead and consulting 

centers and the district office; Office of Regulatory Affairs national expert advisors, as 

appropriate; and the Office of Combination Products. 16 FDA will document its 

recommendations concerning the manufacturer’s proposal in FDA meeting minutes, letters, 

or other permanent communication records, as appropriate. Also, FDA staff should 

communicate this information to the appropriate District Office. 

B. Where can I get more information? 

The Office of Combination Products is available as a resource to sponsors and review staff 

throughout the lifecycle (development, premarket review and postmarket regulation) of a 

combination product. The Office can be reached at (301) 427-1934 or by email at 

combination@fda.gov. In addition, the Office maintains an updated list of FDA guidance 

documents that sponsors may find helpful in determining the regulatory provisions for their 

products. The guidance is available at the Office’s Internet Website at 

279 

280 

281 

282 http://www.fda.gov/oc/combination (for FDA staff, http://intranet.fda.gov/oc/ocp/index.html). 

283 

284 The Office of Regulatory Affairs Website provides detailed information on inspection 

policies. The Office can be reached at http://www.fda.gov/ora. ORA inspectional guidances 

are located at 

285 

286 http://www.fda.gov/ora/inspect_ref/igs/iglist.html. 

287 

 

15 FDA recommends that manufacturers follow the lead Center’s existing guidances or practices for requesting 

formal meetings with the lead center. 

16 FDA staff should follow the procedures outlined for the intercenter consultative/collaborative review process, 

http://www.fda.gov/oc/combination/consultative.html