Source: https://www.federalregister.gov/articles/2013/01/22/2013-01068/current-good-manufacturing-practice-requirements-for-combination-products
Timestamp: 2015-02-28 23:07:17
Document Index: 739771127

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Federal Register | Current Good Manufacturing Practice Requirements for Combination Products
-4323 (17 pages)
Shorter URL: https://federalregister.gov/a/2013-01068 Related Topics
Current Good Manufacturing Practice Requirements for Combination Products -CLOSED
B. What is the scope of this subpart? (§ 4.1)
C. How does FDA define key terms and phrases in this subpart? (§ 4.2)
D. What current good manufacturing practice requirements apply to my combination product? (§ 4.3)
E. How can I comply with these current good manufacturing practice requirements for a co-packaged or single-entity combination product? (§ 4.4)
E.1. How To Comply With QS Regulation Requirements Under § 4.4(b)(1)
E.2. How To Comply With Drug CGMP Requirements Under § 4.4(b)(2)
E.3. How To Comply With Biological Product and HCT/P Requirements Under § 4.4(b)(3)
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.
Under § 3.2(e), a combination product includes:
The constituent parts of a combination product retain their regulatory status (as a drug or device, for example) 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, and biological products, there are currently no regulations that clarify and explain the application of these CGMP requirements when these drugs, devices, and biological products 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 addition, the absence of clear requirements could lead some manufacturers to develop and document manufacturing practices that are redundant and overly burdensome.
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 Practices for Combination Products.” The Agency received 15 comments, which were largely supportive of the regulatory approach described in the draft guidance. 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 lead to unnecessary redundancy in the operating systems used to meet CGMP requirements (CGMP operating systems).
In developing the proposed rule, the Agency reviewed the drug CGMPs and QS regulation. We identified specific provisions from the drug CGMPs and QS regulation that a firm would need to satisfy in addition to complying with the other of these two sets of CGMP requirements to demonstrate compliance with both of these sets of requirements. Based on this assessment, the proposed rule offered two options for demonstrating compliance with the CGMP requirements applicable to a co-packaged or single-entity combination product. These options were either: (1) To demonstrate compliance with the specifics of all CGMP regulations applicable to each of the constituent parts included in the combination product 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 included demonstrating compliance with specified provisions from the other of these two sets of CGMP requirements. In addition, for a combination product that included a biological product, the CGMPs requirements for biological products in parts 600 through 680 (21 CFR parts 600 through 680) would apply, and, for a combination product that included any human cell, tissue, and cellular and tissue-based products (HCT/Ps), the regulations in part 1271 (21 CFR part 1271) would apply.
We intended for the proposed rule to 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 was also intended to streamline demonstrating compliance with CGMP requirements for these types of combination products and to help ensure appropriate implementation of these requirements while avoiding unnecessary redundancy in CGMP operating systems for these products.
The final rule is largely identical to the proposed rule. It is organized in the same four sections addressing scope (§ 4.1), definitions (§ 4.2), the CGMPs that apply to combination products (§ 4.3), and how to comply with these CGMP requirements for a single-entity or co-packaged combination product (§ 4.4).
Section 4.2. Section 4.2 provides definitions for terms used in the regulation. Some of these definitions are included for convenience, for example, cross-referencing an existing definition (such as for “combination product”) or to establish the meaning for a reference term (such as “drug CGMP”). Other definitions include content specific to the rule. In addition to cross-referencing the definition for “device” in § 3.2(f), the rule states that a device that is a constituent part of a combination product is considered a finished device within the meaning of the QS regulation; and the definition for “drug” cross-references § 3.2(g) and also states that a drug that is a constituent part of a combination product is a drug product within the meaning of the drug CGMPs. The definition for “current good manufacturing practice operating system” states that such a system is the operating system within an establishment that is designed and implemented to address and meet the CGMP requirements for a combination product.
Section 4.3. Section 4.3 lists all of the requirements that may apply to a combination product under this rule, depending on the types of constituent parts the combination product includes. The CGMP requirements listed are those found in parts 210 and 211 for drugs, part 820 for devices, and parts 600 through 680 for biological products, and the current good tissue practices found in part 1271 for HCT/Ps. We have removed the specific reference to part 606 because it is already reflected in the reference to parts 600 through 680.
Section 4.4(a). This subsection states that the CGMP requirements applicable to a combination product can be satisfied in one of two ways. Under § 4.4(a)(1), a manufacturer can demonstrate compliance with each applicable regulation in its entirety (e.g., with all of the drug CGMPs and the QS regulation, for a drug-device combination product). Alternatively, under § 4.4(a)(2), if the combination product is subject to the drug CGMPs and QS regulation, these two sets of requirements can be met by demonstrating compliance with: (1) Either the drug CGMPs or QS regulation and (2) those provisions specified in § 4.4(b) from the other of these two sets of regulations.
Section 4.4(b)(1). This subsection states that if a manufacturer chooses to demonstrate compliance with the drug CGMPs per § 4.4(a)(2), that manufacture must also demonstrate compliance with the following provisions of the QS regulation to demonstrate compliance with both sets of regulations:
§ 820.20. Management responsibility.
§ 820.30. Design controls.
§ 820.50. Purchasing controls.
§ 820.100. Corrective and preventive action.
§ 820.170. Installation.
§ 820.200. Servicing.
Section 4.4(b)(2). This subsection states that if a manufacturer chooses to demonstrate compliance with the QS regulation per § 4.4(a)(2), that manufacturer must also demonstrate compliance with the following provisions of the drug CGMPs to demonstrate compliance with both sets of regulations:
§ 211.84. Testing and approval or rejection of components, drug product containers, and closures.
§ 211.103. Calculation of yield.
§ 211.132. Tamper-evident packaging requirements for over the-counter (OTC) human drug products.
§ 211.137. Expiration dating.
§ 211.165. Testing and release for distribution.
§ 211.166. Stability testing.
§ 211.167. Special testing requirements.
§ 211.170. Reserve samples.
Section 4.4(b)(3). This subsection states that manufacturers must also demonstrate compliance with the CGMPs among the requirements (including standards) for biological products listed in § 4.3(c) if the combination product includes a biological product, and with the requirements for HCT/Ps listed in § 4.3(d) if the combination product includes an HCT/P.
Section 4.4(d). This subsection states that a facility at which two or more types of constituent parts have arrived or continue to be manufactured may apply a CGMP system that complies with § 4.4(b).
(Response) We confirm that the term “demonstrate” is not intended to have a new meaning for purposes of this rule. The Agency intends for it to be interpreted in the same manner as it would be for purposes of the CGMP regulations listed in § 4.3. As the commenters state, depending on the circumstances and requirements at issue, appropriate means by which to demonstrate compliance with these CGMP requirements may include development of written procedures and maintenance of records documenting use and verification of CGMPs.
An investigational drug for use in a phase 1 study is subject to the statutory requirements set forth in 21 U.S.C. 351(a)(2)(B). The production of such a drug is exempt from compliance with the regulations in part 211. This exemption does not apply to an investigational combination product or constituent part of a combination product for use by or for the sponsor in phase 2 or phase 3 studies, or when the drug has been lawfully marketed.
Similarly, while device sponsors must ensure that investigational devices are manufactured under a state of control, 21 CFR 812.1 provides that investigational devices are exempt from part 820 except for design control requirements under § 820.30. (See 21 CFR 812.30(b)(5)(ii)). The Agency considers both these exemptions, from parts 211 and 820 obligations, to apply to combination products and constituent parts of combination products, whether being studied under an approved investigational device exemption (IDE) or an approved investigational new drug application (IND).
The second scenario is where two or more different types of medical products (e.g., a device and a biological product) are used together at the point of care to make another medical product. The medical products used to make the other medical product might comprise a combination product. In such cases, the CGMP requirements applicable under this rule to the type of combination product that they constitute (e.g., cross-labeled or co-packaged) may apply. See §§ 4.3 and 4.4. The Agency has not published general guidance on the issue of when two medical products used at the point of care to make another product constitute a combination product. Accordingly, product sponsors are encouraged to contact the Office of Combination Products (OCP) with any questions on this topic.
Regarding the issue of master files, we note that, as discussed throughout this preamble, this rule is not intended to change existing CGMP requirements established under the regulations listed in § 4.3. Rather, this rule is intended to clarify how to comply with those requirements for a combination product. Accordingly, if the manufacture of an item addressed in a master file would be subject to CGMP requirements under a rule listed in § 4.3, those CGMP requirements must be met under this rule, including as provided in § 4.4. If the manufacture of the item would not be subject to CGMP requirements under a rule listed in § 4.3, then no CGMP requirements apply to the manufacture of that item under this rule. For example, if the item is a component of a device and its manufacture, therefore, would not be subject to the QS regulation, the manufacture of that item is not made subject to the QS regulation by this rule. However, the CGMP requirements for manufacturers of combination products and constituent parts of combination products that include items addressed in master files may include duties with respect to such items (e.g., purchasing control requirements under the QS regulation for a combination product that includes a device).
An important question, however, in responding to this comment is how to define the term “convenience kit.” For purposes of this rule, we define the term to include only kits that solely include products that are: (1) Also legally marketed independently and (2) included in the kit as already packaged for independent marketing and with the same labeling as for independent marketing. This is an important question because no additional CGMP requirements generally would apply to the products in such a “convenience kit” simply because they have been included in the kit. The only additional CGMP requirements that would generally apply to such a convenience kit would be those applicable to the assembly, packaging, labeling, any sterilization, or further processing of the kit itself. In contrast, if any products to be included in a kit are repackaged, relabeled or otherwise modified for purposes of their inclusion in the kit, the kit is not a “convenience kit” for purposes of this rule and all the CGMP requirements applicable under this rule based on any changes made to the constituent parts would apply.
(Response) A combination product must include two or more different types of constituent parts (e.g., a drug and device, or biological product and a drug). The definition of device at section 201(h) of the FD Act (21 U.S.C. 321(h)) includes devices that are an “accessory” to another device. A device and such an accessory to it are, therefore, both devices and when combined would not constitute a combination product.
(Response) The term “manufacture” for purposes of the rule is intended to encompass all activities defined as manufacturing under the drug CGMPs and QS regulation and also under the biological product and HCT/P regulations listed in § 4.3. Both specification developers and contract manufacturers “manufacture” and are considered manufacturers for purposes of these underlying CGMP regulations and are, therefore, subject to this rule if they manufacture combination products or constituent parts of combination products However, an entity that is not considered a manufacturer for purposes of the QS regulation, which manufactures a device component, is not subject to this rule even if that component will be incorporated into a combination product or constituent part of a combination product at some other facility. See Quality System (QS) Regulation/Medical Device Good Manufacturing Practices (http://www.fda.gov/medicaldevices/deviceregulationandguidance/postmarketrequirements/qualitysystemsregulations/default.htm).
(Response) The suggestion that containers and closures are treated as drug components for purposes of CGMPs is incorrect. Components are defined under § 210.3 as “any ingredient intended for use in the manufacture of a drug product, including those that may not appear in such drug product.” It is true that containers and closures are subject to the drug CGMPs rather than the device QS regulation. While some CGMP requirements apply to both drug components and containers/closures, containers/closures are separately addressed in the drug CGMPs, and distinct CGMP requirements apply to them (see § 211.84).
(Response) We have declined to revise the definition of constituent part, or to include a definition of component, in the rule. The current definition of constituent part found in § 4.2 provides a succinct way to identify a drug, device, or biological product as included in a combination product. Such a term of reference is needed not only for this rule but in relation to virtually all regulatory activity for combination products.
The rule does not change the scope of the regulations listed in § 4.3. Rather, it expressly codifies the applicability of these requirements to combination products and clarifies how to comply with these regulations for combination products. Accordingly, articles not otherwise subject to the regulations listed in § 4.3 are not made subject to those regulations by this rule. Therefore, for example, if an article would be considered a device component, and it would not be subject to the QS regulations in the absence of this rule, that device component does not become subject to the QS regulations because of this rule.
In addition, we note that the term component is defined for a drug at § 210.3(b)(3) and for a device at § 820.3(c). The existing definitions appropriately characterize the components of drugs and devices, respectively, and we see no need to develop a distinct definition in relation to combination products.
(Response) The definitions for co-packaged and single-entity combination product are quoted in part I.A. of this preamble and are found in § 3.2(e). This rule merely cross-references those existing definitions. We note, however, that the term “component” as used in the definition for single-entity combination product in § 3.2(e) and this rule, is synonymous with “constituent part” under this rule. We recommend visiting the Web page for OCP on the Agency's Web site at http://www.fda.gov/CombinationProducts/default.htm, for further information relating to these definitions and examples of combination products.
(Response) We have been mindful of this consideration in attempting to make the rule and this preamble as clear as possible, including in the selection and manner of defining key terms in § 4.2.
(Comment 12) One commenter sought clarification of the CGMP requirements applicable to combination products comprised of constituent parts that are manufactured and marketed separately. This commenter proposed revising § 4.3 to address this issue by replacing “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 * * * ” with “The current good manufacturing practice requirements in parts 210 and 211 of this chapter apply to the drug constituent part of a combination product” and parallel changes with respect to device and biologic constituent parts.
(Response) The preamble to the proposed rule discussed in some detail the issue of what CGMP requirements apply to the manufacture of constituent parts that are manufactured and marketed separately from one another (see 74 FR 48423 at 48424 to 48425). We do not see a need to revise § 4.3 to provide further clarity as requested by the commenter. Section 4.3 lists the CGMP regulations applicable to combination products. This rule does not change the requirements of these listed regulations. In § 4.4, this rule addresses how to comply with these requirements for single-entity and co-packaged combination products because of the complexity of applying these requirements to these types of combination products. The rule does not expressly address how to comply with these requirements for separately manufactured and marketed constituent parts of combination products because each of these separately manufactured constituent parts is subject only to the regulations listed in § 4.3 that are applicable to that type of constituent part. We note that we have modified § 4.3(c) for clarity.
(Response) This rule does not alter the regulations listed in § 4.3. All of the CGMP requirements applicable to a combination product or constituent part must be met where and when required.
We agree that not all the provisions of the CGMP regulations listed in § 4.3 as applicable to a class of combination product (e.g., drug-device or biological product-drug combination product) or constituent part (drug, device, or biological product) may be relevant to a specific type of combination product or constituent part. The preamble to the proposed rule addressed this point (see 74 FR 48423 at 48426). For example, only combination products that include an OTC drug must comply with tamper-evident packaging requirements, and only combination products that include a type of device that is installed or serviced must comply with installation and servicing requirements.
Similarly, we agree that not all CGMP requirements may apply at a facility that is performing only certain aspects of the manufacture of a combination product. As §§ 210.2(b) and 820.1(a)(1) reflect, an entity that engages in only some operations subject to the regulations in parts 210, 211, 600 through 680, 820, and 1271, need only comply with the regulations applicable to those operations. In addition, manufacturers retain the ability to demonstrate that a departure from stipulated CGMP requirements is appropriate, to the extent that the CGMP regulations for drugs, devices, biological products, and HCT/Ps permit such showings (see, for example, § 820.1(a)(3), providing manufacturers an opportunity to document justifications for determining that requirements qualified by “where appropriate” in part 820 are not appropriate for the particular product).
Section 4.3 of the rule lists all of the CGMP requirements that may apply to a combination product and its constituent parts. Section 4.4 addresses how manufacturers may comply with these requirements for single-entity and co-packaged combination products. Section 4.4 states that manufacturers may comply with these requirements through the design and implementation of a CGMP operating system that meets all applicable CGMP requirements. Section 4.2 defines CGMP operating system as the operating system within an establishment that is designed and implemented to address and meet the CGMP requirements for a combination product. Accordingly, if the combination product is manufactured at multiple facilities, each facility would need such an operating system, including the facility from which the applicant oversees all of the manufacturing activities and compliance with all CGMP requirements related to the product.
(Comment 14) Some commenters sought clarification of § 4.4(b)(1) and (b)(2) and confirmation of whether the rule requires compliance with both the drug CGMPs and with the QS regulation throughout the entire manufacturing process for combination products and their constituent parts, or only at facilities where constituent parts subject to both of these two sets of requirements are being made. Commenters asserted that applying both sets of requirements throughout the entire manufacturing process of a combination product would result in a more demanding and complex CGMP system than currently expected for non-combination medical products. Other commenters proposed that the rule should be revised to have a “product-based” rather than a “facility-based” approach.
The rule provides that a facility that is manufacturing only one type of constituent part of a co-packaged or single-entity combination product need only comply with the CGMP requirements applicable to that constituent part type (§ 4.4(c)). Facilities that perform manufacturing activities for more than one type of constituent part of such a combination product must comply with the CGMP requirements applicable to each type of constituent part being manufactured at that facility (§ 4.4(d)). The rule permits the use of the streamlined approach to demonstrate compliance with the drug CGMP and device QS regulation requirements when both are applicable to a facility's manufacturing activities for a single-entity or co-packaged combination product (§ 4.4(a) and (b)).
(Comment 15) Some commenters sought clarification of the language of § 4.4(d) that states that a facility where two or more different types of constituent parts have arrived or at which their manufacture is proceeding may apply the streamlined approach provided for under § 4.4(a)(2) and (b). One commenter proposed that this streamlined system should only have to be met once two or more types of constituent parts have been assembled. Some commenters proposed that once initiated, the system should apply on a “forward-looking” basis and should not reach back to manufacturing operations that occurred prior to when the constituent parts begin being manufactured together at the same facility.
Section 4.4(d) concerns the CGMP operating system for a specific facility participating in the manufacture of a single-entity or co-packaged combination product. If a facility manufactures only one type of constituent part of such a combination product, it must comply with the CGMPs for that type of product (e.g., the QS regulation if the constituent part is a device). In contrast, when two or more constituent parts of a combination product are being manufactured at the same facility, the manufacturer must comply with the CGMPs applicable to each type of constituent part (e.g., the drug CGMPs and device QS regulation if the facility is combining or otherwise manufacturing both drug and device constituent parts). Accordingly, § 4.4(d) states that a facility may initiate a CGMP operating system that complies with § 4.4(b) when the manufacture of two or more different types of constituent parts is being conducted at that facility. Section 4.4(d) is intended to clarify that when a facility must comply with the CGMP requirements for more than one type of constituent part, a § 4.4(b)-compliant CGMP operating system is available as a means of demonstrating compliance.
We reject the proposal that the CGMP requirements applicable to a constituent part come into effect only after that constituent part has been formed. Such an approach would be inconsistent with the application of the underlying CGMP regulations listed in § 4.3. The trigger is whether the facility is conducting manufacturing operations that would be subject to the underlying CGMP requirements. For example, if a facility is manufacturing only device components, it might not be subject to CGMP requirements under the QS regulation. However, a facility that is manufacturing a finished device from such components is subject to the QS regulation. Therefore, for example, if a facility is manufacturing a finished combination product, a prefilled syringe for instance, from device components and drug components, that facility is subject to both the QS regulation and drug CGMPs.
(Response) FDA disagrees with this comment. Medical device In Vitro Diagnostic (IVD) product manufacturers routinely perform OOS investigations successfully. OOS investigation is conducted under § 211.192 for drugs and under §§ 820.80(d) and 820.90 for devices. In some cases, as for IVD devices, OOS for a device may be similar to OOS for a drug. In others, the approach may differ. This rule is not intended to alter the scope of such investigations for drugs or devices. Accordingly, whether a combination product manufacturer opts to institute a CGMP operating system that implements the QS regulation plus the called-out provisions from part 211, or one that implements the drug CGMPs plus the specified provisions of the QS regulation, OOS for the combination product should be appropriate to address the considerations articulated in § 211.192 for the drug constituent part and in §§ 820.80(d) and 820.90 for the device constituent part. For example, unexplained discrepancies (or the failure of a batch or any components to meet any specifications) shall be thoroughly investigated as appropriate.
(Comment 17) Some commenters requested that the Agency clarify selection criteria for whether to adopt the approach under § 4.4(b)(1) that calls for implementation of the drug CGMPs plus specified provisions of the QS regulation or the approach under § 4.4(b)(2) that calls for implementation of the QS regulation plus specified provisions of the drug CGMPs. One commenter suggested the primary mode of action of the combination product as one possible basis for selection.
(Response) We do not see a need to limit under what circumstances a manufacturer may or should select the approach under § 4.4(b)(1) or (b)(2). It is appropriate to leave the decision of whether to implement a system in accordance with § 4.4(b)(1) or (b)(2) to the discretion of the manufacturer. Some facilities, for example, may already operate under either the drug CGMPs or QS regulation in manufacturing other products, and may prefer to demonstrate compliance with both sets of regulations by taking the steps necessary to demonstrate compliance with the called out provisions of the regulation under which they do not otherwise operate. Other facilities may have no pre-existing manufacturing approach, for example, and select an option on other grounds. Both the approaches permitted in§ 4.4(b) are permissible under the rule, and neither is considered preferable by the Agency.
(Comment 18) One commenter sought guidance on how to implement a CGMP system in accordance with § 4.4(a)(1), which permits establishment of a system that fully implements all of the CGMP regulations applicable to the combination product under § 4.3. Specifically, this commenter sought guidance on how to resolve conflicts among requirements of the regulations applicable to a combination product if implemented in accordance with § 4.4(a)(1).
(Response) As discussed previously in this document, the requirements of the drug CGMP and QS regulation are similar in many respects. Further, the various regulations listed in § 4.3 are generally compatible with one another. Nonetheless, we appreciate that questions as to how to reconcile them and actual conflicts may arise. Accordingly, regulations listed in § 4.3 and this regulation include provisions addressing how to resolve any conflicts among them. These provisions essentially call for following whichever requirement is more specifically applicable. See §§ 211.1(b), 820.1(b), and 4.4(e) of this rule. This determination may be based on such factors such as which regulation addresses a manufacturing issue most precisely and which requirement arises from the regulation most specifically applicable to the constituent part. Should we become aware of potential conflicts with respect to combination products in general or classes of combination products, we intend to address them in guidance. However, we are not aware of any such potential conflicts at this time.
(Comment 19) One commenter requested that the following language be added to § 4.4(c): “Device components and constituent parts are governed under QSR. The drug components and constituent parts are governed under CGMPs. The components of constituent parts would be governed under the quality system in which they are specified.” A second commenter proposed a similar change to § 4.3(a) to state that drug CGMPs “apply to the drug constituent part of a combination product,” and corresponding changes to § 4.3(b) through (d).
(Response) We have not made either proposed revision because we do not agree that they would clarify the rule, and also because they could cause confusion. Section 4.4(c) provides that all CGMP requirements applicable to a constituent part of a single-entity or co-packaged combination product must be satisfied during any period in which that constituent part is manufactured at a separate facility. In some cases, the CGMPs applicable to that constituent part may arise from only one of the regulations listed in § 4.3. In other cases, the applicable CGMPs may arise from several of these listed regulations. Similarly, as explained in sections E.1 and E.2 of this document, the CGMP requirements listed in § 4.3 apply to the combination product, and compliance with them may involve policies, procedures, and practices applicable to the combination product as a whole or to multiple constituent parts.
(Comment 20) As discussed previously in this document, some commenters sought guidance concerning the applicability of the requirements specified in § 4.4(b) as a general matter. The great majority of comments addressing in particular the application of the QS regulation requirements specified under § 4.4(b)(1) focused on § 820.30 (design controls). Some commenters asked for clarification of how to apply design controls to combination products. Some questioned whether design controls should apply other than to the device constituent part of a combination product. Some asked for guidance regarding how to apply design controls to non-device constituent parts of a combination product, noting that the decision to incorporate such an article into a combination product may occur after that article has already been developed.
(Response) Design controls apply when a device constituent part is used in a combination product. Design controls require the manufacturer of a combination product which includes a device constituent part to establish and maintain procedures to ensure that the design requirements for the combination product are appropriate and address the intended use of the combination product, including the needs of the user and patient. The design control process may rely on existing information for the constituent parts, such as information provided in support of the combination product's marketing authorization.
The design history file for a combination product with device and drug or biological product constituent part must address all design issues resulting from the combination of the constituent parts, regardless of whether the manufacturer chooses to apply a CGMP operating system that implements part 820 plus the provisions of part 211 specified in § 4.4(b)(2) of this rule or implements part 211 plus the provisions of part 820 specified in § 4.4(b)(1) of this rule. For example, with regard to a drug or biologic product constituent part in a combination product, the design history file would document and provide objective evidence that the drug or biologic is appropriate for use with the device (e.g., why the formulation of the drug constituent part is appropriate for use in a drug-eluting stent given the need to ensure controlled elution, resistance to flaking, etc.). Similarly, with regard to a device constituent part in a combination product, the design history file would document and provide objective evidence that the device constituent part is appropriate for use with the drug or biological product (e.g., that a syringe is appropriate for use as a delivery device for a drug by providing assurance that there is no interaction with the drug, that the syringe will deliver the drug properly, and that container closure integrity and shelf life can be maintained, etc.).
The combination product manufacturer is responsible for design and development planning, including the design of processes for the manufacture of the combination product. For products manufactured by multiple manufacturers, the finished combination product manufacturer and the application holder (if they are not the same entity), each are responsible for these duties. The design inputs must ensure that the design requirements are appropriate and address the intended use of the combination product, including the needs of the patient and the user of that combination product. Design output procedures must ensure that those design outputs that are essential for the proper functioning of the combination product are identified. The total finished design output consists of the combination product, its packaging, and its labeling. In addition, design control requirements for review, verification, validation, design changes and design history file apply. If a sponsor wishes to use an existing or off-the-shelf product as a constituent part of a combination product, the design controls must ensure that the existing product meets appropriate design requirements for the combination product to be safe and effective, which may require modification of the existing product for use as part of the combination product. See § 820.30. Further explanation will be provided in the related guidance.
(Comment 21) Some commenters proposed adding the requirements from §§ 211.160 (general requirements) and 211.194 (laboratory records) of the drug CGMP requirements to the list of requirements with which manufacturers must demonstrate compliance under § 4.4(b)(2).
(Response) We do not find that it is necessary to add §§ 211.160 and 211.194 to § 4.4(b)(2). The topics addressed in these sections are adequately addressed in part 820, including, for example, in §§ 820.70 (production and process controls), 820.72 (calibration), 820.80 (acceptance activities), 820.180 (general requirements), and 820.250 (statistical techniques).
Section 211.160 is primarily concerned with the “establishment of * * * specifications, standards, sampling plans, test procedures, or other * * * control mechanisms” with respect to the laboratory. This section also states that these control mechanisms and changes to them shall be drafted by the appropriate organizational unit and reviewed by the quality control unit. These requirements shall be followed and documented, and any deviation shall be recorded and justified. Also, appropriate “instruments, apparatus, gauges, and recording devices” shall be calibrated. While we recognize that pharmaceutical laboratory control is critical to the quality of drug components, in-process materials, and the final product, this section's requirements are broad enough to be comparable to requirements specified in §§ 820.70(a) and (b) (general requirements and changes to production and process controls), 820.80(c) (in-process acceptance activities), 820.250 (statistical techniques), 820.20(a)(1) (responsibility and authority), and 820.72(b) (calibration).
Section 211.194 is primarily concerned with the management and maintenance of official records with respect to the laboratory. This section's requirements are comparable to requirements specified in § 820.180 (general requirements for official records). While § 211.194 specifies some requirements for testing of laboratory samples, “complete records” of all data generated within a laboratory is comparable to “all records” as described in § 820.180. Section 211.194 can be used as a source of information for specific pharmaceutical laboratory testing records needing to be managed and maintained, as well as relevant CGMP guidance with respect to pharmaceutical and microbiological laboratories.
(Comment 22) Some commenters sought clarification of circumstances under which § 211.103 (calculation of yield) should be satisfied and questioned whether determining yield would provide meaningful information beyond what the QS regulation requires regarding whether processes are under control. One sought clarification of whether the requirement applies only to drug constituent parts.
(Response) Section 211.103 states that calculation of yield “shall be determined at the conclusion of each appropriate phase of manufacturing, processing, packaging, or holding” for a drug product. This may provide valuable information and insight to the status of a manufacturing process at significant evaluation points, not just for the final product. In addition, § 211.103 provides an important quality check both for a pharmaceutical production process as a whole and for individual unit operations of the process. It is important to account for any increase or decrease in expected yield of materials during the manufacturing process. When either occurs, it is important to conduct a prompt and thorough investigation. Appropriate manufacturing controls can help prevent deviations from expected process yield, which can be important to the success of manufacturing steps and to ensuring that the final product meets specifications. Any phase of the pharmaceutical process that is subject to potential component, in-process material, or product loss, due to physical or chemical means, should be evaluated with respect to actual and theoretical yield of these materials. Section 211.103 does not apply to device constituent parts of combination products.
(Comment 23) Some commenters sought clarification of the application of § 211.170 (reserve samples). Some argued that reserve sample requirements should apply only to drug constituent parts of combination products and not to device constituent parts or the entire combination product, asserting that keeping samples of devices or complete combination products would be cost prohibitive. Others sought guidance regarding how to comply with reserve sampling requirements for “small lot” products with less than 100 products in a lot, or products that come in multiple sizes and shapes.
(Response) Reserve samples are needed to help ensure the postmarket safety and effectiveness of combination products, as they are for drugs and biological products. They are used, for example, to address certain product complaints, evaluate stability concerns, and assess the causes of adverse events. Under § 211.170, reserve samples must be maintained for each lot of a drug (or biological product) “under conditions consistent with product labeling,” “stored in the same immediate container-closure system in which the drug product is marketed or in one that has essentially the same characteristics,” and must consist of “at least twice the quantity necessary to perform all the required tests, except those for sterility and pyrogens.”
(Comment 24) Some commenters sought guidance on compliance with batch release testing requirements under § 211.165. One asserted that such “testing-in” requirements are in conflict with “design-in” requirements of the QS regulation. Some sought clarification of who is responsible for batch release for drug constituent parts, and whether the release is under a Certificate of Analysis or based on actual approval of the batch records. One asked how “batch” would be defined, specifically whether the batching of the device constituent part or the drug would prevail in determining what is a “batch.” One noted that a different approach might be appropriate for smaller production batches (for example, of less than 100) as opposed to batches that might contain 100,000 units. One asked if the Agency agreed that flexibility in applying the requirements would be appropriate if the combination product has a device primary mode of action. One asked if the Agency would consider testing of selected batches appropriate for small batch, high-cost combination products. One asked whether the Agency would permit combining sub-batches or testing of representative samples of the finished product. One asked, with regard to devices that contain antimicrobials, whether testing of antimicrobial activity could be considered a suitable surrogate endpoint for the determination of strength of the active ingredient.
All proposed testing and sampling plans of drug constituent parts should be conducted in accordance with §§ 211.160 and 211.165. Sampling plans should be designed to assure appropriate statistical quality control criteria are met as a condition for the drug constituent part's approval and release. The acceptance criteria for all sampling and testing of a drug constituent part for product release should be reviewed and approved by the firm's quality unit.
“Release” of pharmaceutical ingredients, excipients, and/or products may mean different things depending on where in the manufacturing process the materials are being tested. Incoming ingredients, excipients, and supplies from suppliers must be tested, controlled, and documented in accordance with § 211.84. Reliance on reports of analysis and certificates of testing may be permitted under certain circumstances as provided at § 211.84(d) so long as at least one specific identity test is conducted for each component of a drug constituent part. Acceptable materials can be “released” into the drug constituent part or combination product production system. Finished drug constituent parts or combination products must also be tested, controlled, and documented before they can be “released” for distribution to other clients or the market.
(Comment 25) Some commenters sought clarification of how to comply with §§ 211.166 (stability testing) and 211.137 (expiration dating) requirements. Two comments sought clarification of stability testing and expiration testing for kits, and one questioned the practicality of annual stability testing for each “size and shape” of a combination product.
(Response) Combination products that include drug constituent parts must comply with § 211.166. A written testing program must be established to verify the stability of the drug constituent part. These stability testing programs are critical in determining appropriate storage conditions and expiration dating. Any drug product manufactured for commercial distribution should be subjected to stability testing, including each type of drug constituent part included in a kit. Among other considerations, this testing must enable evaluation of any effects of storage in a container closure system, which may be a device constituent part, on the stability of the drug. See § 211.166(a)(4). As stated in § 211.137, expiration dating must comply with 21 CFR 201.17. We plan to provide additional information on how to comply with the requirements of §§ 211.166 and 211.137 in the related guidance for this rule.
(Response) As noted previously in this document, and stated in the definition for biological product at § 4.2, a biological product is also by definition a drug or a device. Accordingly, a biological product is always either subject to the drug CGMP regulations described in parts 210 and 211, or to the QS regulation described in part 820, as appropriate, regardless of whether the biological product is a constituent part of a combination product. Furthermore, biological products, including those that are constituent parts of combination products, must comply with all applicable requirements in parts 600 through 680. To the extent that requirements in parts 600 through 680 pertain to manufacturing for biological products, these requirements apply in conjunction with the CGMP regulations in parts 210, 211, and 820 and do not create a separate CGMP operating system. Therefore, the additional requirements that pertain to manufacturing for biological products in parts 600 through 680 that would otherwise apply to a biological product if it were not part of a combination product must still be met when that biological product is a constituent part of a combination product.
As noted in the preamble to the proposed rule, many requirements in parts 600 through 680 are not considered CGMP requirements. Moreover, many requirements in parts 600 through 680 are applicable only to certain types of biological products. For example, blood and blood components are subject to the CGMP requirements for such products under part 606. Additionally, a vaccine manufactured using a spore-forming microorganism would be subject to § 600.11(e)(3) (work with Spore-forming microorganisms). As a result, the specific requirements in parts 600 through 680 that apply will depend on the type of biological product.
An HCT/P that is not regulated solely under section 361 of the PHS Act (42 U.S.C. 264) is regulated as a drug, device, and/or biological product (see §§ 1271.10 and 1271.20).
The requirements for HCT/Ps under part 1271 are designed to prevent the introduction, transmission, and spread of communicable diseases. These requirements must be met for HCT/Ps, and are essential to protecting the public health. However, the Agency recognizes that there are some sections of part 1271 that overlap with the requirements under the drug CGMPs and the QS regulation, and has addressed these overlaps in draft guidance. See “Guidance for Industry; Current Good Tissue Practice (CGTP) and Additional Requirements for Manufacturers of Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps)” (http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Tissue/UCM285223.pdf).
(Response) Based on experience to date, the Agency believes that conflicts are unlikely to occur between the HCT/Ps manufacturing requirements listed in § 4.3(d) and the drug CGMPs or device QS regulation. Further, as discussed in response to Comment 18 of this document, the rule includes a provision at § 4.4(e) on how to resolve conflicts between CGMP requirements. Accordingly, we do not see a need to revise the rule in respect to this issue or to address it in guidance at this time. Regarding the issue of xenotransplantation products, we note that the Agency has already addressed this topic in guidance (see “Guidance for Industry: Source Animal, Product, Preclinical, and Clinical Issues Concerning the Use of Xenotransplantation Products in Humans,” (http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Xenotransplantation/ucm074354.htm).
(Response) This final rule serves to clarify options for manufacturers to comply with the sets of CGMPS applicable to their combination product. As stated in the preamble to the proposed rule, manufacturers are responsible for compliance with the CGMP requirements that apply to each constituent part of their combination products (74 FR 48423 at 48424). This rule does not establish any new requirements. Accordingly, we see no reason to delay its effective date, and consistent with the plan described in the proposed rule, we are issuing this rule to be effective in 180 days. The Agency wants to move forward in providing greater assurance that the streamlined approach outlined in the 2004 draft guidance and codified in § 4.4(b) of this rule may be used to demonstrate compliance with CGMPs for combination products. As noted throughout this notice, we are preparing companion guidance to provide further, general information regarding our expectations for compliance with CGMPs for combination products, and we remain available to work with manufacturers to resolve product-specific questions. We intend to continue to apply a risk-based approach to facility inspection and, consistent with ensuring protection of the public health and in light of the specific circumstances, to offer manufacturers a reasonable opportunity to correct deficiencies before taking further compliance or enforcement actions.
(Comment 30) Several commenters requested that FDA issue companion guidance for this rule. Some requested that such guidance include relevant case studies or descriptions of what would constitute a demonstration of compliance with requirements for examples of combination products and manufacturing activities. One proposed that the guidance address the application of provisions of the drug CGMPs and QS regulation that are not specified in the rule and their compatibility with those provisions that are specified in § 4.4(b) from the other of these two regulations. One commenter proposed guidance on the application of CGMP requirements for combination products in relation to master files. One commenter proposed a need for a table of key CGMP considerations for developing a streamlined system and for audit instructions and inspection check lists. Some emphasized the need to address what actions existing facilities should take to come into compliance. One encouraged harmonization with international efforts where possible. One stated that FDA should provide additional guidance on how the rule will affect Agency policy on CGMP requirements for investigational device constituent parts in combination products for which the Center for Biologics Evaluation and Research or the Center for Drug Evaluation and Research has the lead. One requested that guidance provide for the opportunity to discuss CGMP issues with the Agency. Some requested that such guidance issue prior to the final rule. One commenter advised that we review existing guidance to ensure its consistency with this rule.
(Comment 31) Some commenters recommended using the term “hybrid” rather than “streamlined” in reference to the compliance option under § 4.4(b) for single-entity and co-packaged combination products. One commenter suggested that the rule does not reduce the burden of compliance with both the drug CGMPs and QS regulation. Some commenters argued that the term streamlined might suggest a relaxation of requirements when § 4.4(b), in fact, does not relax CGMP requirements for such products.
(Response) We appreciate the concerns raised by these commenters. However, we disagree with the conclusion that § 4.4(b) does not provide a means to streamline compliance with the drug CGMPs and device QS regulations for single-entity and co-packaged combination products. The alternative to the approach permitted under § 4.4(b) is that of § 4.4(a), under which a facility would need to demonstrate compliance with all applicable requirements under both of these regulations. Section 4.4(b), in contrast, reflects the Agency's judgment that many provisions of these two regulations are similar to one another and that demonstrating compliance with most requirements of one of these sets of regulations suffices to demonstrate compliance with similar provisions of the other set.
Most importantly, the provisions at sections 501(a)(2)(B) and (h) of the FD Act (21 U.S.C. 351(a)(2)(B) and (h)) require drugs and devices to be manufactured in accordance with CGMPs. Section 520(f) of the FD Act (21 U.S.C. 360j(f)) specifically authorizes the issuance of CGMP regulations for devices. Section 501 of the FD Act states that a drug or device is deemed adulterated if it is not manufactured in accordance with CGMPs. This provision applies to biological products including those that are constituent parts of combination products because these products meet the definition of drug or device under section 201 of the FD Act. This provision also applies to HCT/Ps that do not meet the criteria for regulation solely as HCT/Ps under section 361 of the PHS Act, because they meet the definition of a drug, or device under section 201 of the FD Act. 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 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, biological products, and HCT/Ps that may be included in combination products:
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. 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 CAPA requirements (§ 820.100) while CAPA principles are currently more generally addressed in the drug CGMP regulation as part of Subpart J, Records and Reports, specifically at §§ 211.180(e) and 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. (See § 3.2(e)). 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.
Although combination products retain the regulatory identities of their constituent parts, the FD 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 FD 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(a) of the FD 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 FD 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 FD Act (21 U.S.C. 371), which authorizes FDA to issue regulations for the efficient enforcement of the FD 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.
FDA disagrees with these comments. The Agency has made its views clear that all manufacturers are already responsible for compliance with the CGMP requirements that apply to each constituent part of their combination products. This final rule clarifies and codifies this view. The CGMPs for drugs, devices, and biological products all require periodic review and update to the systems to ensure they remain current with advances in technology and regulatory practice. Those manufacturers who choose to streamline their systems for legacy products that are in compliance with current practice, do so voluntarily, and it is assumed would only do so if the private benefits of doing it out-weigh the private costs. Because the final rule clarifies and codifies Agency practice on the application of existing CGMP regulations to combination products, it will make it simpler and less burdensome for all manufacturers to apply the regulations when developing new products. It could even shorten approval times for some products by reducing delays caused by lack of systems in place to comply with all applicable CGMP requirements.
VII. Executive Order 13132: Federalism Back to Top
FDA has analyzed this final rule in accordance with the principles set forth in Executive Order 13132. FDA has determined that the rule does not contain policies that have substantial direct effects on the States, on the relationship between the National Government and the States, or on the distribution of power and responsibilities among the various levels of government. Accordingly, the Agency has concluded that the rule does not contain policies that have federalism implications as defined in the Executive order and, consequently, a federalism summary impact statement is not required. The sole statutory provision giving preemptive effect to this rule is section 751 of the FD Act (21 U.S.C. 379r), which would apply only with respect to OTC drug constituent parts of combination products.
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 single-entity combination product?
Subpart A—Current Good Manufacturing Practice Requirements for Combination Products Back to Top
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 this section.
Co-packaged combination product has the meaning set forth in § 3.2(e)(2) of this chapter.
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.
HCT/Ps refers to human cell, tissue, and cellular and tissue-based products, as defined in § 1271.3(d) of this chapter. An HCT/P that is not solely regulated under section 361 of the Public Health Service Act may be a constituent part of a combination product. Such an HCT/P is subject to part 1271 of this chapter and is also regulated as a drug, device, and/or biological product.
Single-entity combination product has the meaning set forth in § 3.2(e)(1) of this chapter.
(3) In addition to being shown to comply with the other applicable manufacturing requirements listed under § 4.3, if the combination product includes a biological product constituent part, the current good manufacturing practice operating system must also be shown to implement and comply with all manufacturing 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 operating system must also be shown to implement and comply with all current good tissue practice requirements identified under § 4.3(d) that would apply to that HCT/P if it were not part of a combination product.
(e) The requirements set forth in this subpart and in parts 210, 211, 820, 600 through 680, and 1271 of this chapter listed in § 4.3, 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.
1. For purposes of part 3 and this 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 FD Act) (21 U.S.C. 321).
2. Section 501 of the FD Act (21 U.S.C. 351) states circumstances under which drugs and devices (including biological products, which also meet the definition of either drug or device) are deemed adulterated. 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. See, generally, 21 U.S.C. 351(a)(2)(B) and (h).
3. For the purposes of this rule, FDA uses the term “CGMP requirements” to include all such requirements found in the standards in parts 600 through 680 that may apply to biological products. FDA notes that biological products, including biological product constituent parts of combination products, must comply with all applicable requirements in parts 600 through 680, but many of the requirements in parts 600 through 680 are not considered CGMP requirements and are therefore not covered by this rule.
4. See § 210.2(c).
5. 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/or biological products under the PHS Act. The HCT/P regulation provides that an HCT/P that is combined with another article (other than water, crytalloids, or a sterilizing, preserving or storage agent) does not meet the criteria for regulation solely under section 361 of the PHS Act, but would be regulated as a drug, device and/or biological product. Refer to §§ 1271.10 and 1271.20 when considering what regulations apply to a combination product with an HCT/P constituent part.