21 CFR Part 4 - CGMP for Combination Products
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21 CFR Part 4 - CGMP for Combination Products
- 1. 21 CFR Part 4 Current Good Manufacturing Practice Requirements for Combination Products Docket No. FDA-2009-N-0435 FINAL RULE Jasmin NUHIC April 2013 THIS RULE IS EFFECTIVE 22 JULY 2013
- 2. OBJECTIVE • To understand, through development, implementation and feedback, the 21 CFR Part 4 rule and how it applies to you 21 CFR Part 4 THIS RULE IS EFFECTIVE 22 JULY 2013 2
- 3. TOPICS • Rationale for the final rule • Examples of combination products • Proposed rule • Legal authorities • Assessment and impacts • The final rule • Comments and responses • References and credits 21 CFR Part 4 THIS RULE IS EFFECTIVE 22 JULY 2013 3
- 4. RATIONALE FOR FINAL RULE • The final rule has two related purposes: – To clarify the cGMP requirements that apply to combination products, – To help ensure the consistent and appropriate application and enforcement of these requirements. • The Food and Drug Administration (FDA) is issuing this regulation on the current good manufacturing practice (cGMP) requirements applicable to combination products. • This rule is intended to promote the public health by clarifying which cGMP requirements apply when drugs, devices, and biological products are combined to create combination products. • In addition, the rule sets forth a transparent and streamlined regulatory framework for firms to use when demonstrating compliance with cGMP requirements for ``single-entity'' and ``co- packaged'' combination products. 21 CFR Part 4 4 THIS RULE IS EFFECTIVE 22 JULY 2013
- 5. EXAMPLES OF COMBO PRODUCTS 21 CFR Part 4 THIS RULE IS EFFECTIVE 22 JULY 2013 5 An epinephrine autoinjector by Phillips-Medisize Corp. Drug Eluting Balloon by Medtonic, Inc PolyCap ™ System by MicroeDoseTheraupeutx Insulin pump by Medtronic, Inc Image curtesy of Food and Drug Administration
- 6. PROPOSED RULE RULES TITLE APPLIES TO 21 CFR Part 210 cGMP In Manufacturing, Processing, Packing, Or Holding Of Drugs; General Drugs 21 CFR Part 211 cGMP Finished Pharmaceuticals Pharmaceuticals 21 CFR Part 600 cGMP Biological Products: General Biologics 21 CFR Part 601 cGMP Biological Products: Licencing Licencing (biologics) 21 CFR Part 606* cGMP For Blood And Blood Components Blood 21 CFR Part 607 cGMP Establishment Registration And Product Listing For Manufacturers Of Human Blood And Blood Products Registration (blood) 21 CFR Part 610 cGMP General Biological Products Standards General (biologics) 21 CFR Part 630 cGMP General Requirements For Blood, Blood Components, And Blood Derivatives General (blood) 21 CFR Part 640 cGMP Additional Standards For Human Blood And Blood Products Additional (blood) 21 CFR Part 660 cGMP Additional Standards For Diagnostic Substances For Laboratory Tests Additional (labs) 21 CFR Part 680 cGMP Additional Standards For Miscellaneous Products Additional (misc) 21 CFR Part 820 cGMP Quality System Regulation Devices 21 CFR Part 1271 cGMP Human Cells, Tissues, And Cellular And Tissue-based Products Tissue 21 CFR Part 4 THIS RULE IS EFFECTIVE 22 JULY 2013 6 *NOTE: 21 CFR Part 606 removed as references from 21 CFR Part 4; applicable elements already included in 21 CFR Part 600-680
- 7. LEGAL AUTHORITIES • USA – FDA with Food, Drug and Cosmetic Act • Europe (most EU countries and not EU countries) – Medical Device Directive MDD 93/42/EEC – Medicinal Product Directive 2001/83/EC (as amended by 2004/27/EC) • Other – Indian – Ireland – Etc. 21 CFR Part 4 THIS RULE IS EFFECTIVE 22 JULY 2013 7
- 8. ASSESSMENTS AND IMPACTS • Economic Impact • Environemental Impact • Paperwork Reducation Act 21 CFR Part 4 THIS RULE IS EFFECTIVE 22 JULY 2013 8
- 9. THE FINAL RULE • The final rule is largely identical to the proposed rule. • It is organized in four sections: – Addressing scope (Sec. 4.1), – Definitions (Sec. 4.2), – The cGMPs that apply to combination products (Sec. 4.3), and – How to comply with these cGMP requirements for a single-entity or co- packaged combination product (Sec. 4.4). 21 CFR Part 4 THIS RULE IS EFFECTIVE 22 JULY 2013 9
- 10. THE FINAL RULE (cont`d) • Subpart A – 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 B – [Reserved] 21 CFR Part 4 THIS RULE IS EFFECTIVE 22 JULY 2013 10
- 11. THE FINAL RULE (cont`d) • Amendments to the rule: – On August 9, 2012, NIGC published a final rule amending its enforcement regulation to include a graduated pre-enforcement process for voluntary compliance. – That rule referenced a rule that was later withdrawn and also incorrectly referenced an internal citation. – The final rule corrects the error and makes technical amendments to reference the Commission’s recently finalized appeal rules contained in a new subchapter. 21 CFR Part 4 THIS RULE IS EFFECTIVE 22 JULY 2013 11
- 12. COMMENTS AND RESPONSES • FDA received 25 sets of comments – «demostrate»? – Manufacturing? R&D? Investigational product? – cGMP that apply? – Packaging and co-packaging? – Efforcement and effective date? – Guidance? Aletrnative approaches? – Other 21 CFR Part 4 THIS RULE IS EFFECTIVE 22 JULY 2013 12 TEN (10) PAGES OF COMMENTS AND RESPONSES
- 13. REFERENCES • USA Govenment Printing Office (21 CFR Part 4) – Rule: http://www.gpo.gov/fdsys/pkg/FR-2013-01-22/html/2013-01068.htm • Food and Drug Adminisration (FDA) – Combination products: http://www.fda.gov/CombinationProducts/default.htm 21 CFR Part 4 THIS RULE IS EFFECTIVE 22 JULY 2013 13 • THANKS TO: – Food and Drug Administration (FDA), Medtronic, Inc (MDT), Phillips-Medisize Corp., MicroeDoseTheraupeutx, TranSystems
- 14. 21 CFR Part 4 THIS RULE IS EFFECTIVE 22 JULY 2013 14
Editor's Notes
- [Federal Register Volume 78, Number 14 (Tuesday, January 22, 2013)][Rules and Regulations][Pages 4307-4323]From the Federal Register Online via the Government Printing Office [www.gpo.gov][FR Doc No: 2013-01068]=======================================================================-----------------------------------------------------------------------DEPARTMENT OF HEALTH AND HUMAN SERVICESFood and Drug Administration21 CFR Part 4[Docket No. FDA-2009-N-0435]Current Good Manufacturing Practice Requirements for Combination ProductsAGENCY: Food and Drug Administration, HHS.ACTION: Final rule.
- As set forth in part 3 (21 CFR part 3), a combination product is a product comprised of any combination of a drug and a device; a device and a biological product; a biological product and a drug; or a drug, a device, and a biological product.\\1\\ Under Sec. 3.2(e), a combination product includes:--------------------------------------------------------------------------- \\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&C Act) (21 U.S.C. 321).--------------------------------------------------------------------------- 1. A product comprised of two or more regulated components, i.e., drug/device, biologic/device, drug/biologic, or drug/device/biologic, that are physically, chemically, or otherwise combined or mixed and produced as a single entity (single-entity combination products); 2. Two or more separate products packaged together in a single package or as a unit and comprised of drug and device products, device and biological products, or biological and drug products (co-packaged combination products); 3. A drug, device, or biological product packaged separately that according to its investigational plan or proposed labeling is intended for use only with an approved individually specified drug, device, or biological product where both are required to achieve the intended use, indication, or effect and where upon approval of the proposed product the labeling of the approved product would need to be changed, e.g., to reflect a change in intended use, dosage form, strength, route of administration, or significant change in dose (a type of cross-labeled combination product); 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 (another type of cross-labeled combination product).
- Examples from the audience?What do they make?
- The proposed rule addressed CGMP requirements for all combination products. However, for certain types of combination products, the application of CGMP requirements is fairly straightforward. Specifically, the constituent parts of a combination product are each subject only to the CGMP regulations applicable to that type of constituent part (e.g., drug or device) if the constituent parts are manufactured and marketed separately, as may be the case for constituent parts of cross-labeled combination products. Because these constituent parts, while part of a combination product, are separately manufactured and marketed, they remain separate for purposes of applying the CGMP regulations. Therefore, the proposed rule merely provided that all such constituent parts must be manufactured in accordance with the CGMP requirements that would apply to them if they were not part of a combination product.========================================================================The application of CGMP requirements to single-entity and co- packaged combination products is less straightforward. Consequently, the proposed rule expressly addressed the practical application of CGMP requirements to these two categories of combination products.========================================================================The application of CGMP requirements to single-entity and co- packaged combination products is less straightforward. Consequently, the proposed rule expressly addressed the practical application of CGMP requirements to these two categories of combination products. The proposed rule reflected Agency recognition that, in most instances, for single-entity and co-packaged combination products, a CGMP operating system that satisfies the CGMP regulations applicable to one constituent part will also satisfy most of the CGMP requirements applicable to the other constituent part. In particular, we explained that compliance with either the CGMP regulations for drugs at parts 210 and 211 (21 CFR parts 210 and 211) (drug CGMPs) or the quality system (QS) regulation for devices at part 820 (21 CFR part 820) will satisfy many, though not all, of the CGMP requirements applicable to both drug and device constituent parts. 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.\\3\\ --------------------------------------------------------------------------- \\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. --------------------------------------------------------------------------- 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. After publication of the proposed rule, to facilitate development of comments on the rule, FDA co-sponsored a workshop in January 2010. At this workshop, the Agency provided a summary of the proposed rule and stakeholders then worked in groups to identify issues on which it might be helpful to develop comments.
- III. Legal Authority The Agency derives its authority to issue the regulations in 21 CFR part 4, subpart A, from 21 U.S.C. 321, 331, 351, 352, 353, 355, 360, 360b–360f, 360h– 360j, 360l, 360hh–360ss, 360aaa– 360bbb, 371(a), 372–374, 379e, 381, 383, and 394, Federal Food, Drug, and Cosmetic Act, and 42 U.S.C. 216, 262, 263a, 264, and 271, Public Health Service Act. Most importantly, the provisions at sections 501(a)(2)(B) and (h) of the FD&C 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&C Act (21 U.S.C. 360j(f)) specifically authorizes the issuance of CGMP regulations for devices. Section 501 of the FD&C 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&C 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&C 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: • Drug CGMP regulations for finished pharmaceuticals or drug products set forth at parts 210 and 211). Drug products not subject to these regulations (e.g., bulk drugs or active pharmaceutical ingredients) must still meet the current good manufacturing practice general standard required by the statute. • QS regulation for devices set forth at part 820. • Requirements that pertain to manufacturing within the requirements (including standards) for biological products in parts 600 through 680. • Current good tissue practices for HCT/Ps set forth in part 1271. There is considerable overlap in the drug CGMPs and QS regulation, and for the most part the overlap is clear. For example, both establish requirements for management, organization, and personnel; both require documentation and recordkeeping; and both allow flexibility in their application to the manufacture of a particular product. FDA considers the drug CGMPs and the QS regulation to be similar, and they are meant to achieve the same general goals. Nevertheless, these two sets of regulations differ somewhat because each is tailored to the characteristics of the types of products for which it was designed. 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). This rule clarifies the applicability of these two regulations to combination products and provides a streamlined option for practical implementation for co-packaged and single-entity combination products. Because the drug and device CGMP requirements are so similar, when using this streamlined approach, demonstrating compliance with the requirements of one of these two set of regulations (e.g., drug CGMPs), along with demonstrating compliance with the requirements of the specified provisions from the other set (e.g., QS regulation), would be considered to be demonstrating compliance with all requirements from both. 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&C 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&C 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&C 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&C 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&C Act (21 U.S.C. 371), which authorizes FDA to issue regulations for the efficient enforcement of the FD&C Act, FDA has the authority to issue regulations clarifying the applicability of CGMP requirements to combination products. The Agency is also authorized under these authorities to issue regulations specifying how compliance with CGMP requirements for combination products may be demonstrated.
- IV. Analysis of Economic Impacts A. Introduction FDA has examined the impacts of the final rule under Executive Order 12866, Executive Order 13563, the Regulatory Flexibility Act (5 U.S.C. 601–612), and the Unfunded Mandates Reform Act of 1995 (Pub. L. 104–4). Executive Orders 12866 and 13563 direct Agencies to assess all costs and benefits of available regulatory alternatives and, when regulation is necessary, to select regulatory approaches that maximize net benefits (including potential economic, environmental, public health and safety, and other advantages; distributive impacts; and equity). FDA believes that this final rule is not a significant regulatory action under Executive Order 12866. The Regulatory Flexibility Act requires Agencies to analyze regulatory options that would minimize any significant impact of a rule on small entities. Because the final rule codifies what is currently in effect, the Agency certifies that the final rule will not have a significant economic impact on a substantial number of small entities. Section 202(a) of the Unfunded Mandates Reform Act of 1995 requires that Agencies prepare a written statement, which includes an assessment of anticipated costs and benefits, before proposing ‘‘any rule that includes any Federal mandate that may result in the expenditure by State, local, and tribal governments, in the aggregate, or by the private sector, of $100,000,000 or more (adjusted annually for inflation) in any one year.’’ The current threshold after adjustment for inflation is $139 million, using the most current (2011) Implicit Price Deflator for the Gross Domestic Product. FDA does not expect this final rule to result in any 1-year expenditure that would meet or exceed this amount. B. Rationale for Final Rule The final rule has two related purposes. The first is to clarify the CGMP requirements that apply to combination products, and the second is to help ensure the consistent and appropriate application and enforcement of these requirements. Constituent parts and manufacturing practices vary among combination products; different CGMP requirements apply depending upon the constituent parts in the combination product and what manufacturing practices are used. The final rule attempts to streamline the practical implementation of CGMP requirements for co-packaged and single-entity combination products. C. Response to Comments A number of comments suggested that the regulatory impact analysis of the proposed rule underestimated the incremental cost to comply with this rule; however they did not suggest alternative estimates or methodologies. There were divergent views as to whether the burden of compliance would be greater for legacy products or for small firms and those new to manufacturing combination products. One comment suggested the rule, as proposed, would inhibit innovation. 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. D. Impact of Final Rule FDA estimates that approximately 300 manufacturers of combination products will be affected by the final rule. These manufacturers of combination products should benefit from the greater clarity provided regarding what regulatory provisions apply to their products and how they may comply with them. For both existing and future products, the streamlined approach set forth in the final rule will help ensure that CGMP requirements for co-packaged and single-entity combination products are consistent and appropriate, without duplicative or otherwise unnecessary aspects. This codification of CGMP requirements for combination products will also help ensure predictability and consistency in the application and enforcement of these regulatory requirements with regard to all combination products across FDA. Firms must already comply with the CGMP regulations for drugs, devices, and biological products, including the current good tissue practice regulations for HCT/Ps, found at parts 211, 820, 600 through 680, and 1271, that are applicable to the constituent parts of their combination products. The cost of this final rule would be the incremental costs to modify or streamline existing standard operating systems. Because this final rule is codifying our current practice, any firms that choose to streamline or modify existing SOPs are doing so because the private benefits are greater than the private costs. If some firms choose to modify their SOPs as a result of this final rule, the net benefits of the rule will be greater than the costs. Some firms may incur one-time incremental costs reassessing compliance with the final rule. Because this final rule codifies Agency practice that is described in current guidance documents and because no new CGMP requirements are proposed, we believe the time required would be small and estimate it to be about 25 hours per product. The amount of these compliance assessment costs for an individual firm, and the impact of any such costs, will depend on the number and nature of the products the firm produces and how the firm has applied current regulations. Nonetheless, because the time required would be limited, the Agency believes the impact will not be significant on entities considered small based on the Small Business Administration’s definition of a small entity (500 employees for device and biological product firms and 750 employees for drug firms).V. Environmental Impact FDA has determined under 21 CFR 25.30(a), 25.30(h), 25.30(j), 25.31(a), (c), (h), and (j), and 25.34(a) and (d) that this action is of a type that does not individually or cumulatively have a significant effect on the human environment. Therefore, neither an environmental assessment nor an environmental impact statement is required.VI. Paperwork Reduction Act of 1995 We note that the information collected under the underlying CGMP regulations for drugs, devices, and biological products, including current good tissue practices for HCT/Ps, found at parts 211, 820, 600 through 680, and 1271, have already been approved and are in effect. The provisions of part 211 are approved under the Office of Management and Budget (OMB) control number 0910–0139. The provisions of part 820 are approved under OMB control number 0910–0073. The provisions of parts 606, 640, and 660 are approved under OMB control number 0910–0116. The provisions of part 610 are approved under OMB control number 0910–0116 and OMB control number 0910–0338 (also for part 680). The provisions of part 1271, subparts C and D, are approved under OMB control number 0910–0543. This final rule contains no new collections of information. Therefore, clearance by OMB under the Paperwork Reduction Act of 1995 is not required. VII. Executive Order 13132: Federalism 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&C Act (21 U.S.C. 379r), which would apply only with respect to OTC drug constituent parts of combination products.
- Section 4.1. Section 4.1 states that the rule establishes which CGMP requirements apply to combination products, clarifies the application of these requirements, and provides a regulatory framework for designing and implementing CGMP operating systems at facilities that manufacture copackaged or single-entity combination products. 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 Sec. 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 Sec. 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.Section 4.4 addresses how to comply with these CGMP requirements for co-packaged and single-entity combination products, as summarized in the subsections that follow. 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 Sec. 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 Sec. 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 Sec. 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 Sec. 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: Sec. 820.20. Management responsibility. Sec. 820.30. Design controls. Sec. 820.50. Purchasing controls. Sec. 820.100. Corrective and preventive action. Sec. 820.170. Installation. Sec. 820.200. Servicing. Section 4.4(b)(2). This subsection states that if a manufacturer chooses to demonstrate compliance with the QS regulation per Sec. 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: Sec. 211.84. Testing and approval or rejection of components, drug product containers, and closures. Sec. 211.103. Calculation of yield. Sec. 211.132. Tamper-evident packaging requirements for over the-counter (OTC) human drug products. Sec. 211.137. Expiration dating. Sec. 211.165. Testing and release for distribution. Sec. 211.166. Stability testing. Sec. 211.167. Special testing requirements. Sec. 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 Sec. 4.3(c) if the combination product includes a biological product, and with the requirements for HCT/Ps listed in Sec. 4.3(d) if the combination product includes an HCT/P. Section 4.4(c). This subsection states that a facility at which a single type of constituent part is manufactured must demonstrate compliance with the CGMP requirements applicable to that type of constituent part. 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 Sec. 4.4(b). Section 4.4(e). This subsection states that, in the event of a conflict between CGMP requirements applicable to a combination product, the regulations most specifically applicable to the constituent part at issue shall prevail.
- PART 4—REGULATION OFCOMBINATION PRODUCTSSubpart A—Current Good ManufacturingPractice Requirements for CombinationProductsSec.4.1 What is the scope of this subpart?4.2 How does FDA define key terms andphrases in this subpart?4.3 What current good manufacturingpractice requirements apply to mycombination product?4.4 How can I comply with these currentgood manufacturing practicerequirements for a co-packaged or singleentitycombination product?Subpart B [Reserved]Authority: 21 U.S.C. 321, 331, 351, 352,353, 355, 360, 360b–360f, 360h–360j, 360l,360hh–360ss, 360aaa–360bbb, 371(a), 372–374, 379e, 381, 383, 394; 42 U.S.C. 216, 262,263a, 264, 271.Subpart A—Current GoodManufacturing Practice Requirementsfor Combination Products§ 4.1 What is the scope of this subpart?This subpart applies to combinationproducts. It establishes which currentgood manufacturing practice requirements apply to these products.This subpart clarifies the application ofcurrent good manufacturing practiceregulations to combination products,and provides a regulatory framework fordesigning and implementing the currentgood manufacturing practice operatingsystem at facilities that manufacture copackagedor single-entity combinationproducts.§ 4.2 How does FDA define key terms andphrases in this subpart?The terms listed in this section havethe following meanings for purposes ofthis subpart:Biological product has the meaningset forth in § 3.2(d) of this chapter. Abiological product also meets thedefinitions of either a drug or device asthese terms are defined under thissection.Combination product has the meaningset forth in § 3.2(e) of this chapter.Constituent part is a drug, device, orbiological product that is part of acombination product.Co-packaged combination producthas the meaning set forth in § 3.2(e)(2)of this chapter.Current good manufacturing practiceoperating system means the operatingsystem within an establishment that isdesigned and implemented to addressand meet the current goodmanufacturing practice requirements fora combination product.Current good manufacturing practicerequirements means the requirementsset forth under § 4.3(a) through (d).Device has the meaning set forth in§ 3.2(f) of this chapter. A device that isa constituent part of a combinationproduct is considered a finished devicewithin the meaning of the QSregulation.Drug has the meaning set forth in§ 3.2(g) of this chapter. A drug that is aconstituent part of a combinationproduct is considered a drug productwithin the meaning of the drug CGMPs.Drug CGMPs refers to the current goodmanufacturing practice regulations setforth in parts 210 and 211 of thischapter.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 regulatedunder section 361 of the Public HealthService Act may be a constituent part ofa combination product. Such an HCT/Pis subject to part 1271 of this chapterand is also regulated as a drug, device,and/or biological product.Manufacture includes, but is notlimited to, designing, fabricating,assembling, filling, processing, testing,labeling, packaging, repackaging,holding, and storage.QS regulation refers to the qualitysystem regulation in part 820 of thischapter.Single-entity combination product hasthe meaning set forth in § 3.2(e)(1) ofthis chapter.Type of constituent part refers to thecategory of the constituent part, whichcan be either a biological product, adevice, or a drug, as these terms aredefined under this section.§ 4.3 What current good manufacturingpractice requirements apply to mycombination product?If you manufacture a combinationproduct, the requirements listed in thissection apply as follows:(a) The current good manufacturingpractice requirements in parts 210 and211 of this chapter apply to acombination product that includes adrug constituent part;(b) The current good manufacturingpractice requirements in part 820 of thischapter apply to a combination productthat includes a device constituent part;(c) The current good manufacturingpractice requirements among therequirements (including standards) forbiological products in parts 600 through680 of this chapter apply to acombination product that includes abiological product constituent part towhich those requirements would applyif that constituent part were not part ofa combination product; and(d) The current good tissue practicerequirements including donor eligibilityrequirements for HCT/Ps in part 1271 ofthis chapter apply to a combinationproduct that includes an HCT/P.§ 4.4 How can I comply with these currentgood manufacturing practice requirementsfor a co-packaged or single-entitycombination product?(a) Under this subpart, for singleentity or co-packaged combinationproducts, compliance with allapplicable current good manufacturingpractice requirements for thecombination product shall be achievedthrough the design and implementationof a current good manufacturingpractice operating system that isdemonstrated to comply with:(1) The specifics of each set of currentgood manufacturing practice regulationslisted under § 4.3 as they apply to eachconstituent part included in thecombination product; or(2) Paragraph (b) of this section.(b) If you elect to establish a currentgood manufacturing practice operatingsystem in accordance with paragraph (b)of this section, the followingrequirements apply:(1) If the combination productincludes a device constituent part and adrug constituent part, and the currentgood manufacturing practice operatingsystem has been shown to comply withthe drug CGMPs, the followingprovisions of the QS regulation mustalso be shown to have been satisfied;upon demonstration that theserequirements have been satisfied, noadditional showing of compliance withrespect to the QS regulation need bemade:(i) Section 820.20 of this chapter.Management responsibility.(ii) Section 820.30 of this chapter.Design controls.(iii) Section 820.50 of this chapter.Purchasing controls.(iv) Section 820.100 of this chapter.Corrective and preventive action.(v) Section 820.170 of this chapter.Installation.(vi) Section 820.200 of this chapter.Servicing.(2) If the combination productincludes a device constituent part and adrug constituent part, and the currentgood manufacturing practice operatingsystem has been shown to comply withthe QS regulation, the followingprovisions of the drug CGMPs must alsobe shown to have been satisfied; upondemonstration that these requirementshave been satisfied, no additionalshowing of compliance with respect tothe drug CGMPs need be made:(i) Section 211.84 of this chapter.Testing and approval or rejection ofcomponents, drug product containers, and closures.(ii) Section 211.103 of this chapter.Calculation of yield.(iii) Section 211.132 of this chapter.Tamper-evident packaging requirementsfor over-the-counter (OTC) human drugproducts.(iv) Section 211.137 of this chapter.Expiration dating.(v) Section 211.165 of this chapter.Testing and release for distribution.(vi) Section 211.166 of this chapter.Stability testing.(vii) Section 211.167 of this chapter.Special testing requirements.(viii) Section 211.170 of this chapter.Reserve samples.(3) In addition to being shown tocomply with the other applicablemanufacturing requirements listedunder § 4.3, if the combination productincludes a biological productconstituent part, the current goodmanufacturing practice operatingsystem must also be shown toimplement and comply with allmanufacturing requirements identifiedunder § 4.3(c) that would apply to thatbiological product if that constituentpart were not part of a combinationproduct. (4) In addition to being shown tocomply with the other applicablecurrent good manufacturing practicerequirements listed under § 4.3, if thecombination product includes an HCT/P, the current good manufacturingpractice operating system must also beshown to implement and comply withall current good tissue practicerequirements identified under § 4.3(d)that would apply to that HCT/P if itwere not part of a combination product.(c) During any period in which themanufacture of a constituent part to beincluded in a co-packaged or singleentity combination product occurs at aseparate facility from the otherconstituent part(s) to be included in thatsingle-entity or co-packagedcombination product, the current goodmanufacturing practice operatingsystem for that constituent part at thatfacility must be demonstrated to complywith all current good manufacturingpractice requirements applicable to thattype of constituent part.(d) When two or more types ofconstituent parts to be included in asingle-entity or co-packagedcombination product have arrived at thesame facility, or the manufacture ofthese constituent parts is proceeding atthe same facility, application of acurrent good manufacturing processoperating system that complies withparagraph (b) of this section may begin.(e) The requirements set forth in thissubpart and in parts 210, 211, 820, 600through 680, and 1271 of this chapterlisted in § 4.3, supplement, and do notsupersede, each other unless theregulations explicitly provide otherwise.In the event of a conflict betweenregulations applicable under thissubpart to combination products,including their constituent parts, theregulations most specifically applicableto the constituent part in question shallsupersede the more general.Subpart B [Reserved]
- PART 4—REGULATION OFCOMBINATION PRODUCTSSubpart A—Current Good ManufacturingPractice Requirements for CombinationProductsSec.4.1 What is the scope of this subpart?4.2 How does FDA define key terms andphrases in this subpart?4.3 What current good manufacturingpractice requirements apply to mycombination product?4.4 How can I comply with these currentgood manufacturing practicerequirements for a co-packaged or singleentitycombination product?Subpart B [Reserved]Authority: 21 U.S.C. 321, 331, 351, 352,353, 355, 360, 360b–360f, 360h–360j, 360l,360hh–360ss, 360aaa–360bbb, 371(a), 372–374, 379e, 381, 383, 394; 42 U.S.C. 216, 262,263a, 264, 271.Subpart A—Current GoodManufacturing Practice Requirementsfor Combination Products§ 4.1 What is the scope of this subpart?This subpart applies to combinationproducts. It establishes which currentgood manufacturing practice requirements apply to these products.This subpart clarifies the application ofcurrent good manufacturing practiceregulations to combination products,and provides a regulatory framework fordesigning and implementing the currentgood manufacturing practice operatingsystem at facilities that manufacture copackagedor single-entity combinationproducts.§ 4.2 How does FDA define key terms andphrases in this subpart?The terms listed in this section havethe following meanings for purposes ofthis subpart:Biological product has the meaningset forth in § 3.2(d) of this chapter. Abiological product also meets thedefinitions of either a drug or device asthese terms are defined under thissection.Combination product has the meaningset forth in § 3.2(e) of this chapter.Constituent part is a drug, device, orbiological product that is part of acombination product.Co-packaged combination producthas the meaning set forth in § 3.2(e)(2)of this chapter.Current good manufacturing practiceoperating system means the operatingsystem within an establishment that isdesigned and implemented to addressand meet the current goodmanufacturing practice requirements fora combination product.Current good manufacturing practicerequirements means the requirementsset forth under § 4.3(a) through (d).Device has the meaning set forth in§ 3.2(f) of this chapter. A device that isa constituent part of a combinationproduct is considered a finished devicewithin the meaning of the QSregulation.Drug has the meaning set forth in§ 3.2(g) of this chapter. A drug that is aconstituent part of a combinationproduct is considered a drug productwithin the meaning of the drug CGMPs.Drug CGMPs refers to the current goodmanufacturing practice regulations setforth in parts 210 and 211 of thischapter.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 regulatedunder section 361 of the Public HealthService Act may be a constituent part ofa combination product. Such an HCT/Pis subject to part 1271 of this chapterand is also regulated as a drug, device,and/or biological product.Manufacture includes, but is notlimited to, designing, fabricating,assembling, filling, processing, testing,labeling, packaging, repackaging,holding, and storage.QS regulation refers to the qualitysystem regulation in part 820 of thischapter.Single-entity combination product hasthe meaning set forth in § 3.2(e)(1) ofthis chapter.Type of constituent part refers to thecategory of the constituent part, whichcan be either a biological product, adevice, or a drug, as these terms aredefined under this section.§ 4.3 What current good manufacturingpractice requirements apply to mycombination product?If you manufacture a combinationproduct, the requirements listed in thissection apply as follows:(a) The current good manufacturingpractice requirements in parts 210 and211 of this chapter apply to acombination product that includes adrug constituent part;(b) The current good manufacturingpractice requirements in part 820 of thischapter apply to a combination productthat includes a device constituent part;(c) The current good manufacturingpractice requirements among therequirements (including standards) forbiological products in parts 600 through680 of this chapter apply to acombination product that includes abiological product constituent part towhich those requirements would applyif that constituent part were not part ofa combination product; and(d) The current good tissue practicerequirements including donor eligibilityrequirements for HCT/Ps in part 1271 ofthis chapter apply to a combinationproduct that includes an HCT/P.§ 4.4 How can I comply with these currentgood manufacturing practice requirementsfor a co-packaged or single-entitycombination product?(a) Under this subpart, for singleentity or co-packaged combinationproducts, compliance with allapplicable current good manufacturingpractice requirements for thecombination product shall be achievedthrough the design and implementationof a current good manufacturingpractice operating system that isdemonstrated to comply with:(1) The specifics of each set of currentgood manufacturing practice regulationslisted under § 4.3 as they apply to eachconstituent part included in thecombination product; or(2) Paragraph (b) of this section.(b) If you elect to establish a currentgood manufacturing practice operatingsystem in accordance with paragraph (b)of this section, the followingrequirements apply:(1) If the combination productincludes a device constituent part and adrug constituent part, and the currentgood manufacturing practice operatingsystem has been shown to comply withthe drug CGMPs, the followingprovisions of the QS regulation mustalso be shown to have been satisfied;upon demonstration that theserequirements have been satisfied, noadditional showing of compliance withrespect to the QS regulation need bemade:(i) Section 820.20 of this chapter.Management responsibility.(ii) Section 820.30 of this chapter.Design controls.(iii) Section 820.50 of this chapter.Purchasing controls.(iv) Section 820.100 of this chapter.Corrective and preventive action.(v) Section 820.170 of this chapter.Installation.(vi) Section 820.200 of this chapter.Servicing.(2) If the combination productincludes a device constituent part and adrug constituent part, and the currentgood manufacturing practice operatingsystem has been shown to comply withthe QS regulation, the followingprovisions of the drug CGMPs must alsobe shown to have been satisfied; upondemonstration that these requirementshave been satisfied, no additionalshowing of compliance with respect tothe drug CGMPs need be made:(i) Section 211.84 of this chapter.Testing and approval or rejection ofcomponents, drug product containers, and closures.(ii) Section 211.103 of this chapter.Calculation of yield.(iii) Section 211.132 of this chapter.Tamper-evident packaging requirementsfor over-the-counter (OTC) human drugproducts.(iv) Section 211.137 of this chapter.Expiration dating.(v) Section 211.165 of this chapter.Testing and release for distribution.(vi) Section 211.166 of this chapter.Stability testing.(vii) Section 211.167 of this chapter.Special testing requirements.(viii) Section 211.170 of this chapter.Reserve samples.(3) In addition to being shown tocomply with the other applicablemanufacturing requirements listedunder § 4.3, if the combination productincludes a biological productconstituent part, the current goodmanufacturing practice operatingsystem must also be shown toimplement and comply with allmanufacturing requirements identifiedunder § 4.3(c) that would apply to thatbiological product if that constituentpart were not part of a combinationproduct. (4) In addition to being shown tocomply with the other applicablecurrent good manufacturing practicerequirements listed under § 4.3, if thecombination product includes an HCT/P, the current good manufacturingpractice operating system must also beshown to implement and comply withall current good tissue practicerequirements identified under § 4.3(d)that would apply to that HCT/P if itwere not part of a combination product.(c) During any period in which themanufacture of a constituent part to beincluded in a co-packaged or singleentity combination product occurs at aseparate facility from the otherconstituent part(s) to be included in thatsingle-entity or co-packagedcombination product, the current goodmanufacturing practice operatingsystem for that constituent part at thatfacility must be demonstrated to complywith all current good manufacturingpractice requirements applicable to thattype of constituent part.(d) When two or more types ofconstituent parts to be included in asingle-entity or co-packagedcombination product have arrived at thesame facility, or the manufacture ofthese constituent parts is proceeding atthe same facility, application of acurrent good manufacturing processoperating system that complies withparagraph (b) of this section may begin.(e) The requirements set forth in thissubpart and in parts 210, 211, 820, 600through 680, and 1271 of this chapterlisted in § 4.3, supplement, and do notsupersede, each other unless theregulations explicitly provide otherwise.In the event of a conflict betweenregulations applicable under thissubpart to combination products,including their constituent parts, theregulations most specifically applicableto the constituent part in question shallsupersede the more general.Subpart B [Reserved]
- II. Comments on the Proposed RuleFDA received 25 sets of commentsfrom regulated entities, tradeassociations, and individuals. To makeit easier to identify comments and ourresponses, the word ‘‘Comment’’appears before the comment’sdescription, and the word ‘‘Response’’appears before our response. We havealso numbered the comments to helpdistinguish among them. The numberassigned to each comment is purely fororganizational purposes and does notsignify the comment’s value orimportance or the order in which it wasreceived. Certain comments weregrouped together under a single numberbecause the subject matter of thecomments was similar.A. General(Comment 1) Some commenterssought clarification of whatmanufacturers must do to‘‘demonstrate’’ compliance for purposesof this rule. Commenters proposed thatthe Agency confirm that ‘‘demonstrate’’is used in this rule as ‘‘it always hasbeen with respect to GMPs.’’Specifically, commenters stated that therequirements for firms to demonstratecompliance are set forth in the rules andinclude, for example, theimplementation of written procedures,internal auditing and otherrequirements. Commenters noted that ’’’demonstrate’ also encompassesdemonstrating and justifying thatspecific provisions are inapplicable to afacility.’’(Response) We confirm that the term‘‘demonstrate’’ is not intended to havea new meaning for purposes of this rule.The Agency intends for it to beinterpreted in the same manner as itwould be for purposes of the CGMPregulations listed in § 4.3. As thecommenters state, depending on thecircumstances and requirements atissue, appropriate means by which todemonstrate compliance with theseCGMP requirements may includedevelopment of written procedures andmaintenance of records documentinguse and verification of CGMPs.B. What is the scope of this subpart?(§ 4.1)(Comment 2) Some comments statedthat the rule is unclear as to whether itapplies only to commercial productionor also during product development andto investigational products. Onecommenter proposed includinginformation on the stages of a product’slife cycle during which the rule applies.Another requested further guidance onthis issue.(Response) Section 4.3 lists all of theCGMP regulations that apply to acombination product under the rule.The rule does not modify theseregulations; rather it addresses how tocomply with them for a combinationproduct.An investigational drug for use in aphase 1 study is subject to the statutoryrequirements set forth in 21 U.S.C.351(a)(2)(B). The production of such adrug is exempt from compliance withthe regulations in part 211. Thisexemption does not apply to aninvestigational combination product orconstituent part of a combinationproduct for use by or for the sponsor inphase 2 or phase 3 studies, or when thedrug has been lawfully marketed.4Similarly, while device sponsors mustensure that investigational devices aremanufactured under a state of control,21 CFR 812.1 provides thatinvestigational devices are exempt frompart 820 except for design controlrequirements under § 820.30. (See 21CFR 812.30(b)(5)(ii)). The Agencyconsiders both these exemptions, fromparts 211 and 820 obligations, to applyto combination products andconstituent parts of combinationproducts, whether being studied underan approved investigational deviceexemption (IDE) or an approvedinvestigational new drug application(IND).(Comment 3) One comment noted thatthe rule does not address products thatproduce another product on site at thepoint of care, which the commenternotes are typically devices that producea drug. The commenter requests that thefinal rule clarify that the manufactureris subject only to the CGMPrequirements applicable to the productthat makes the other product on site.(Response) This rule applies tocombination products. Accordingly,questions regarding CGMPs for noncombinationproducts are beyond itsscope. However, this comment raisesthe question of whether medicalproducts that make other medicalproducts at the point of care areregulated as combination products and,therefore, subject to this rule.There are two potential scenarios toconsider. The first is where a singlemedical product (e.g., a device) makesanother medical product (e.g., a drug) atthe point of care. In this case, themedical product that makes the othermedical product at the point of care andthe medical product manufactured atthe point of care would not be regulatedas a combination product. Rather, themedical product that makes the othermedical product would be regulated inaccordance with its own classificationand, therefore, subject to the CGMPrequirements applicable to that type ofarticle. For example, if the product thatmakes the other product is a device, itwould be subject to the QS regulation.The second scenario is where two ormore different types of medicalproducts (e.g., a device and a biologicalproduct) are used together at the pointof care to make another medicalproduct. The medical products used tomake the other medical product mightcomprise a combination product. Insuch cases, the CGMP requirementsapplicable under this rule to the type ofcombination product that theyconstitute (e.g., cross-labeled or copackaged)may apply. See §§ 4.3 and4.4. The Agency has not publishedgeneral guidance on the issue of whentwo medical products used at the pointof care to make another productconstitute a combination product.Accordingly, product sponsors areencouraged to contact the Office ofCombination Products (OCP) with anyquestions on this topic.(Comment 4) One commenter askedfor Agency guidance on whetherproducts on the market prior to theestablishment of OCP are consideredcombination products by the Agencyand, therefore, subject to the rule.Several commenters stated that theproposed rule did not clearly address itsapplicability to approved productsalready being marketed. Commentersrequested that the Agency limitapplication of the rule to new productsand to existing products only when adesign change, or significant designchange, is made to the product, and notbe applied retroactively to existingproducts. One commenter stated thatexisting manufacturers should beexempt from pre-manufacturing designcontrol requirements. One commenterstated there was a need for guidanceregarding how the rule would affectCGMP requirements for productsaddressed in master files. One statedthat the Agency should identify whichcurrently marketed products are subjectto this rule.(Response) This rule does not createnew CGMP requirements, but ratherattempts to clarify how to apply them tocombination products. Compliance withall applicable CGMP requirements isrequired for all products andappropriate to ensure consistentmanufacture of products that meet thesafety and effectiveness and qualitystandards that form the basis for productmarketing authorization, regardless ofwhen a product was first marketed orapproved.As noted elsewhere in this document,we intend to provide furtherinformation in related guidance, on howto comply with this rule and theunderlying regulations to which itrefers, including with respect to cominginto compliance with pre-manufacturingdesign control requirements forproducts currently being marketed.Regarding the issue of master files, wenote that, as discussed throughout thispreamble, this rule is not intended tochange existing CGMP requirementsestablished under the regulations listedin § 4.3. Rather, this rule is intended toclarify how to comply with thoserequirements for a combination product.Accordingly, if the manufacture of anitem addressed in a master file would besubject to CGMP requirements under arule listed in § 4.3, those CGMPrequirements must be met under thisrule, including as provided in § 4.4. Ifthe manufacture of the item would notbe subject to CGMP requirements undera rule listed in § 4.3, then no CGMPrequirements apply to the manufactureof that item under this rule. Forexample, if the item is a component ofa device and its manufacture, therefore,would not be subject to the QSregulation, the manufacture of that itemis not made subject to the QS regulationby this rule. However, the CGMPrequirements for manufacturers ofcombination products and constituentparts of combination products thatinclude items addressed in master filesmay include duties with respect to suchitems (e.g., purchasing controlrequirements under the QS regulationfor a combination product that includesa device).(Comment 5) Some commentersraised concerns regarding application ofthe rule to co-packaged combinationproducts, arguing that the rule aswritten would be overly burdensome forthese products. One commenterproposed that ‘‘Convenience kits thatcontain device(s) and drugs or biologicswould be governed under 21 CFR 4 onlyif the device(s) included in the kit areClass II or III.’’ The commenter offeredas a rationale for this change thatapplication of the approach in theproposed rule to such products wouldrepresent ‘‘an unnecessarilyburdensome approach to the industryand in most instances will not providegreater protection of the public health.’’Other commenters asked for guidanceon the application of CGMPrequirements to a drug manufacturerwho purchases a finished, ‘‘off-theshelf’’medical device to include in akit. A commenter stated that the control,packaging and release of kits can beadequately handled by current parts210, 211, and 600 CGMP regulations,and that existing guidance andsupplement approval requirements(design verification testing for containerclosure) are adequate to address anyadditional considerations necessitatedby the packaging and labeling of a kit.(Response) We do not agree that therule represents an unnecessarilyburdensome approach to CGMPcompliance for ‘‘convenience kits’’ orother kits and do not find it necessaryto alter the application of the rule to‘‘convenience kits.’’This rule is not intended to createnew CGMP requirements, and insteadseeks to clarify how to apply them tocombination products. A kit thatincludes two or more types of medicalproducts (e.g., a device and a drug), isa combination product and subject tothis rule. Accordingly, the manufactureof the products in the kit would also besubject to this rule.An important question, however, inresponding to this comment is how todefine the term ‘‘convenience kit.’’ Forpurposes of this rule, we define the termto include only kits that solely includeproducts that are: (1) Also legallymarketed independently and (2)included in the kit as already packagedfor independent marketing and with thesame labeling as for independentmarketing. This is an importantquestion because no additional CGMPrequirements generally would apply tothe products in such a ‘‘conveniencekit’’ simply because they have beenincluded in the kit. The only additionalCGMP requirements that wouldgenerally apply to such a conveniencekit would be those applicable to theassembly, packaging, labeling, anysterilization, or further processing of thekit itself. In contrast, if any products tobe included in a kit are repackaged,relabeled or otherwise modified forpurposes of their inclusion in the kit,the kit is not a ‘‘convenience kit’’ forpurposes of this rule and all the CGMPrequirements applicable under this rulebased on any changes made to theconstituent parts would apply.Accordingly, no additional CGMPrequirements would apply to an ‘‘offthe-shelf’’ device that is packaged andlabeled in accordance with its existingmarketing authorization for theindependent sale solely because of itsinclusion in a convenience kit.However, if an off-the-shelf device isincluded in a co-packaged combinationproduct for an intended use that differsfrom the intended use for which thatdevice is marketed separately,additional CGMP requirements mayapply, including design controls toensure that the device is appropriate forthe specific use to which it is put in thecombination product.C. How does FDA define key terms andphrases in this subpart? (§ 4.2)(Comment 6) One commenter askedwhether a device combined with amedical device accessory would beconsidered a combination product.(Response) A combination productmust include two or more differenttypes of constituent parts (e.g., a drugand device, or biological product and adrug). The definition of device atsection 201(h) of the FD&C Act (21U.S.C. 321(h)) includes devices that arean ‘‘accessory’’ to another device. Adevice and such an accessory to it are,therefore, both devices and whencombined would not constitute acombination product.(Comment 7) One commenterrequested clarification relating to thedefinition of the term ‘‘manufacture.’’This commenter sought confirmationthat the rule is intended to encompassthe types of activities included in thedefinition of manufacture under drugCGMPs and the QS regulation, and tocover the entities undertaking theseactivities. This commenter also soughtclarification of what parties must do tocomply with CGMPs, for example, if themanufacture of a combination productinvolves a specification developer,contract manufacturer, and componentmanufacturer. This commenterproposed that the responsibility forensuring that all requirements are metshould fall to the manufacturer whoholds the marketing application.(Response) The term ‘‘manufacture’’for purposes of the rule is intended toencompass all activities defined asmanufacturing under the drug CGMPsand QS regulation and also under thebiological product and HCT/Pregulations listed in § 4.3. Bothspecification developers and contractmanufacturers ‘‘manufacture’’ and areconsidered manufacturers for purposesof these underlying CGMP regulationsand are, therefore, subject to this rule ifthey manufacture combination productsor constituent parts of combinationproducts However, an entity that is notconsidered a manufacturer for purposesof the QS regulation, whichmanufactures a device component, isnot subject to this rule even if thatcomponent will be incorporated into acombination product or constituent partof a combination product at some otherfacility. See Quality System (QS)Regulation/Medical Device GoodManufacturing Practices (http://www.fda.gov/medicaldevices/deviceregulationandguidance/postmarketrequirements/qualitysystemsregulations/default.htm).As discussed in response toComments 13 and 14 of this document,the CGMP requirements applicable to aparticular manufacturer for the workdone at its facility may vary based uponthe type or types of constituent partsbeing manufactured and the aspects oftheir manufacture that are beingperformed. Where multiple facilitiesbear responsibility for various aspects ofthe manufacturing process, only theholder of the application or clearancefor the product (hereafter referred to asthe applicant for purposes of thepreamble to this rule) is responsible forcompliance with all aspects of theCGMP requirements applicable to theentire manufacturing process and acrossall facilities.(Comment 8) Some commenterssought confirmation that containers andclosures, which they asserted arecurrently treated as drug components,would continue to be treated as such.Some commenters sought guidance onwhether a prefilled syringe would beconsidered a combination product.(Response) The suggestion thatcontainers and closures are treated asdrug components for purposes ofCGMPs is incorrect. Components aredefined under § 210.3 as ‘‘anyingredient intended for use in themanufacture of a drug product,including those that may not appear insuch drug product.’’ It is true thatcontainers and closures are subject tothe drug CGMPs rather than the deviceQS regulation. While some CGMPrequirements apply to both drugcomponents and containers/closures,containers/closures are separatelyaddressed in the drug CGMPs, anddistinct CGMP requirements apply tothem (see § 211.84).The Agency will continue to regulatedrug containers and closures inaccordance with parts 210 and 211. Asyringe, however, is not a merecontainer/closure. A syringe is a deviceused to deliver another medical product(e.g., a drug) (see, e.g., 21 CFR880.5860). Accordingly, a prefilledsyringe is a combination product andsubject to this rule. See also response toComment 15 of this documentdistinguishing complete syringeconstituent parts from components ofsyringes. We plan to addressdistinctions between devices andcontainers/closures in further detail inlater guidance.(Comment 9) Several commentersasked that the Agency revise and clarifythe term ‘‘constituent part,’’ arguing thatits interpretation is important tounderstanding the scope of the rule.Some commenters proposed inclusionof a definition for component orlanguage in the codified regarding howmanufacturers should addresscomponents in their CGMP systems.These and other commenters soughtclarification of how the rule might applyto components of devices andingredients for drugs and biologicalproducts. Some commenters also soughtclarification of how the definition ofconstituent part might relate to whetheran article should be considered a drugcomponent as opposed to a device,citing container closures as an example.Some commenters also asked that theAgency provide guidance, includingexamples, of articles the Agencyconsiders constituent parts and articlesthat we consider components.(Response) We have declined to revisethe definition of constituent part, or toinclude a definition of component, inthe rule. The current definition ofconstituent part found in § 4.2 providesa succinct way to identify a drug,device, or biological product asincluded in a combination product.Such a term of reference is needed notonly for this rule but in relation tovirtually all regulatory activity forcombination products.The rule does not change the scope ofthe regulations listed in § 4.3. Rather, itexpressly codifies the applicability ofthese requirements to combinationproducts and clarifies how to complywith these regulations for combinationproducts. Accordingly, articles nototherwise subject to the regulationslisted in § 4.3 are not made subject tothose regulations by this rule. Therefore,for example, if an article would beconsidered a device component, and itwould not be subject to the QSregulations in the absence of this rule,that device component does not becomesubject to the QS regulations because ofthis rule.In addition, we note that the termcomponent is defined for a drug at§ 210.3(b)(3) and for a device at§ 820.3(c). The existing definitionsappropriately characterize thecomponents of drugs and devices,respectively, and we see no need todevelop a distinct definition in relationto combination products.The Agency appreciates the value ofguidance to ensure understanding ofthis rule by both industry and FDA staff.The Agency is developing guidance onthe application of the rule, includingexamples to illustrate these and otherconcepts addressed.(Comment 10) One commenter soughtclarification of the definitions for ‘‘copackaged’’and ‘‘single-entity’’combination products. This commenteralso requested a list of examples toclarify these definitions.(Response) The definitions for copackagedand single-entity combinationproduct are quoted in part I.A. of thispreamble and are found in § 3.2(e). Thisrule merely cross-references thoseexisting definitions. We note, however,that the term ‘‘component’’ as used inthe definition for single-entitycombination product in § 3.2(e) and thisrule, is synonymous with ‘‘constituentpart’’ under this rule. We recommendvisiting the Web page for OCP on theAgency’s Web site at http://www.fda.gov/CombinationProducts/default.htm, for further informationrelating to these definitions andexamples of combination products.(Comment 11) One commenter urgedthe Agency to take care to ensure thatstakeholders understand theterminology being used in the rule andits preamble.(Response) We have been mindful ofthis consideration in attempting to makethe rule and this preamble as clear aspossible, including in the selection andmanner of defining key terms in § 4.2.D. What current good manufacturingpractice requirements apply to mycombination product? (§ 4.3)(Comment 12) One commenter soughtclarification of the CGMP requirementsapplicable to combination productscomprised of constituent parts that aremanufactured and marketed separately.This commenter proposed revising § 4.3to address this issue by replacing ‘‘Thecurrent good manufacturing practicerequirements in parts 210 and 211 ofthis chapter apply to a combinationproduct that includes a drug constituentpart * * * ’’ with ‘‘The current goodmanufacturing practice requirements inparts 210 and 211 of this chapter applyto the drug constituent part of acombination product’’ and parallelchanges with respect to device andbiologic constituent parts.(Response) The preamble to theproposed rule discussed in some detailthe issue of what CGMP requirementsapply to the manufacture of constituentparts that are manufactured andmarketed separately from one another(see 74 FR 48423 at 48424 to 48425). Wedo not see a need to revise § 4.3 toprovide further clarity as requested bythe commenter. Section 4.3 lists theCGMP regulations applicable tocombination products. This rule doesnot change the requirements of theselisted regulations. In § 4.4, this ruleaddresses how to comply with theserequirements for single-entity and copackagedcombination products becauseof the complexity of applying theserequirements to these types ofcombination products. The rule doesnot expressly address how to complywith these requirements for separatelymanufactured and marketed constituentparts of combination products becauseeach of these separately manufacturedconstituent parts is subject only to theregulations listed in § 4.3 that areapplicable to that type of constituentpart. We note that we have modified§ 4.3(c) for clarity.E. How can I comply with these currentgood manufacturing practicerequirements for a co-packaged orsingle-entity combination product?(§ 4.4)(Comment 13) Some commentersnoted that not all requirements of theCGMP regulations applicable tocombination products may be relevantto a particular product or to when andwhere particular aspects of themanufacturing process are undertaken.Commenters offered recommendationsfor addressing this variation in guidanceor through revision of the rule.(Response) This rule does not alter theregulations listed in § 4.3. All of theCGMP requirements applicable to acombination product or constituent partmust be met where and when required.We agree that not all the provisions ofthe CGMP regulations listed in § 4.3 asapplicable to a class of combinationproduct (e.g., drug-device or biologicalproduct-drug combination product) orconstituent part (drug, device, orbiological product) may be relevant to aspecific type of combination product orconstituent part. The preamble to theproposed rule addressed this point (see74 FR 48423 at 48426). For example,only combination products that includean OTC drug must comply with tamperevidentpackaging requirements, andonly combination products that includea type of device that is installed orserviced must comply with installationand servicing requirements.Similarly, we agree that not all CGMPrequirements may apply at a facility thatis performing only certain aspects of themanufacture of a combination product.As §§ 210.2(b) and 820.1(a)(1) reflect, anentity that engages in only someoperations subject to the regulations inparts 210, 211, 600 through 680, 820,and 1271, need only comply with theregulations applicable to thoseoperations. In addition, manufacturersretain the ability to demonstrate that adeparture from stipulated CGMPrequirements is appropriate, to theextent that the CGMP regulations fordrugs, devices, biological products, andHCT/Ps permit such showings (see, forexample, § 820.1(a)(3), providingmanufacturers an opportunity todocument justifications for determiningthat requirements qualified by ‘‘whereappropriate’’ in part 820 are notappropriate for the particular product).Many, but not all, CGMPrequirements are facility specific.Examples of such requirements includerequirements for testing of the productby a facility or controls over thesupplies brought into the facility. Otherrequirements, however, are not facilityspecific.For example, some concern theproduct as a whole, such as designcontrols, and some concern overarchingduties for the manufacturing process asa whole, such as Corrective andPreventive Action (CAPA) andmanagement responsibility. Dutiesassociated with such cross-cuttingCGMP requirements may be shared byseveral facilities.All manufacturers are responsible forensuring compliance with all CGMPrequirements applicable to themanufacturing activities at theirfacilities. In addition, the applicant isresponsible for ensuring compliancewith all of the CGMP requirementsapplicable to the product, taking intoaccount all of the activities occurring atall facilities involved with themanufacturing process.Section 4.3 of the rule lists all of theCGMP requirements that may apply toa combination product and itsconstituent parts. Section 4.4 addresseshow manufacturers may comply withthese requirements for single-entity andco-packaged combination products.Section 4.4 states that manufacturersmay comply with these requirementsthrough the design and implementationof a CGMP operating system that meetsall applicable CGMP requirements.Section 4.2 defines CGMP operatingsystem as the operating system withinan establishment that is designed andimplemented to address and meet theCGMP requirements for a combinationproduct. Accordingly, if thecombination product is manufactured atmultiple facilities, each facility wouldneed such an operating system,including the facility from which theapplicant oversees all of themanufacturing activities andcompliance with all CGMPrequirements related to the product.The issues raised in these commentsare not peculiar to combinationproducts or their constituent parts,though addressing them may presentsome added complexity because of thenumber of sets of regulations that mayapply to a combination product, therelatively complex nature of theseproducts, and the multiple Agencycomponents that may have an interest inensuring compliance with CGMPrequirements for these products.Examples and clarification to aidcompliance will be provided insubsequent guidance.(Comment 14) Some commenterssought clarification of § 4.4(b)(1) and(b)(2) and confirmation of whether therule requires compliance with both thedrug CGMPs and with the QS regulationthroughout the entire manufacturingprocess for combination products andtheir constituent parts, or only atfacilities where constituent parts subjectto both of these two sets of requirementsare being made. Commenters assertedthat applying both sets of requirementsthroughout the entire manufacturingprocess of a combination product wouldresult in a more demanding andcomplex CGMP system than currentlyexpected for non-combination medicalproducts. Other commenters proposedthat the rule should be revised to havea ‘‘product-based’’ rather than a‘‘facility-based’’ approach.(Response) As discussed in responseto Comment 13 of this document, theapplicability of some CGMPrequirements will vary depending onthe circumstances, including whataspect of a product’s manufacture takesplace at a facility and whether multiplefacilities are involved in themanufacture of a combination product.Accordingly, we do not agree that therule should be either ‘‘product-based’’or ‘‘facility-based.’’ A manufacturermust comply with the requirementsapplicable to the activities undertakenat its facility, including applicableaspects of requirements that apply tomultiple facilities or the overallmanufacturing process for the product,and a product applicant must ensurecompliance with all CGMPrequirements for its product.The rule provides that a facility thatis manufacturing only one type ofconstituent part of a co-packaged orsingle-entity combination product needonly comply with the CGMPrequirements applicable to thatconstituent part type (§ 4.4(c)). Facilitiesthat perform manufacturing activitiesfor more than one type of constituentpart of such a combination productmust comply with the CGMPrequirements applicable to each type ofconstituent part being manufactured atthat facility (§ 4.4(d)). The rule permitsthe use of the streamlined approach todemonstrate compliance with the drugCGMP and device QS regulationrequirements when both are applicableto a facility’s manufacturing activitiesfor a single-entity or co-packagedcombination product (§ 4.4(a) and (b)).With regard to CAPA requirementsand the parallel requirements of thedrug CGMPs, for example, the applicantand any other manufacturer(s) for asingle-entity or co-packagedcombination product must ensure thatan appropriately comprehensive reviewof activities is undertaken at whateverfacilities may be relevant to determinethe root cause of manufacturingproblems, deviations, ornonconformities. These requirementsalso call for corrective actions andpreventive measures to be taken withregard to all relevant manufacturingsteps at all relevant facilities, so that theproblem is corrected and potentialproblems will be prevented or mitigatedgoing forward. In the case of the productapplicant these duties arecomprehensive, applying to all relevantfacilities and all appropriate measuresfor the product. For products withmultiple manufacturers, the scope of theduties for each manufacturer parallelsand depends upon the scope of theactivity undertaken at thatmanufacturer’s facility. The relatedguidance for this rule will address theseissues further.(Comment 15) Some commenterssought clarification of the language of§ 4.4(d) that states that a facility wheretwo or more different types ofconstituent parts have arrived or atwhich their manufacture is proceedingmay apply the streamlined approachprovided for under § 4.4(a)(2) and (b).One commenter proposed that thisstreamlined system should only have tobe met once two or more types ofconstituent parts have been assembled.Some commenters proposed that onceinitiated, the system should apply on a‘‘forward-looking’’ basis and should notreach back to manufacturing operationsthat occurred prior to when theconstituent parts begin beingmanufactured together at the samefacility.(Response) As discussed previously inresponse to Comment 13 of thisdocument, there are various types ofCGMP requirements, some of which arefacility-specific, and some that apply tomultiple facilities or the overallmanufacturing process for the product.All of these requirements must be metfor a combination product. As thesecomments suggest, the requirementsapplicable to a particular manufacturerdepend on the activities undertaken atthe facility or facilities thatmanufacturer operates, with theapplicant having responsibilities forcompliance with all CGMPrequirements for its product.Section 4.4(d) concerns the CGMPoperating system for a specific facilityparticipating in the manufacture of asingle-entity or co-packagedcombination product. If a facilitymanufactures only one type ofconstituent part of such a combinationproduct, it must comply with theCGMPs for that type of product (e.g., theQS regulation if the constituent part isa device). In contrast, when two or moreconstituent parts of a combinationproduct are being manufactured at thesame facility, the manufacturer mustcomply with the CGMPs applicable toeach type of constituent part (e.g., thedrug CGMPs and device QS regulationif the facility is combining or otherwisemanufacturing both drug and deviceconstituent parts). Accordingly, § 4.4(d)states that a facility may initiate a CGMPoperating system that complies with§ 4.4(b) when the manufacture of two ormore different types of constituent partsis being conducted at that facility.Section 4.4(d) is intended to clarify thatwhen a facility must comply with theCGMP requirements for more than onetype of constituent part, a § 4.4(b)-compliant CGMP operating system isavailable as a means of demonstratingcompliance.We reject the proposal that the CGMPrequirements applicable to a constituentpart come into effect only after thatconstituent part has been formed. Suchan approach would be inconsistent withthe application of the underlying CGMPregulations listed in § 4.3. The trigger iswhether the facility is conductingmanufacturing operations that would besubject to the underlying CGMPrequirements. For example, if a facilityis manufacturing only devicecomponents, it might not be subject toCGMP requirements under the QSregulation. However, a facility that ismanufacturing a finished device fromsuch components is subject to the QSregulation. Therefore, for example, if afacility is manufacturing a finishedcombination product, a prefilled syringefor instance, from device componentsand drug components, that facility issubject to both the QS regulation anddrug CGMPs.(Comment 16) One commenterasserted that due to ambiguitiesassociated with an out-of-specification(OOS) investigation, excessive workmay be involved if there is a need toperform a device component review.(Response) FDA disagrees with thiscomment. Medical device In VitroDiagnostic (IVD) product manufacturersroutinely perform OOS investigationssuccessfully. OOS investigation isconducted under § 211.192 for drugsand under §§ 820.80(d) and 820.90 fordevices. In some cases, as for IVDdevices, OOS for a device may besimilar to OOS for a drug. In others, theapproach may differ. This rule is notintended to alter the scope of suchinvestigations for drugs or devices.Accordingly, whether a combinationproduct manufacturer opts to institute aCGMP operating system thatimplements the QS regulation plus thecalled-out provisions from part 211, orone that implements the drug CGMPsplus the specified provisions of the QSregulation, OOS for the combinationproduct should be appropriate toaddress the considerations articulated in§ 211.192 for the drug constituent partand in §§ 820.80(d) and 820.90 for thedevice constituent part. For example,unexplained discrepancies (or thefailure of a batch or any components tomeet any specifications) shall bethoroughly investigated as appropriate.(Comment 17) Some commentersrequested that the Agency clarifyselection criteria for whether to adoptthe approach under § 4.4(b)(1) that callsfor implementation of the drug CGMPsplus specified provisions of the QSregulation or the approach under§ 4.4(b)(2) that calls for implementationof the QS regulation plus specifiedprovisions of the drug CGMPs. Onecommenter suggested the primary modeof action of the combination product asone possible basis for selection.(Response) We do not see a need tolimit under what circumstances amanufacturer may or should select theapproach under § 4.4(b)(1) or (b)(2). It isappropriate to leave the decision ofwhether to implement a system inaccordance with § 4.4(b)(1) or (b)(2) tothe discretion of the manufacturer.Some facilities, for example, mayalready operate under either the drugCGMPs or QS regulation inmanufacturing other products, and mayprefer to demonstrate compliance withboth sets of regulations by taking thesteps necessary to demonstratecompliance with the called outprovisions of the regulation underwhich they do not otherwise operate.Other facilities may have no pre-existingmanufacturing 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 bythe Agency.(Comment 18) One commenter soughtguidance on how to implement a CGMPsystem in accordance with § 4.4(a)(1),which permits establishment of asystem that fully implements all of theCGMP regulations applicable to thecombination product under § 4.3.Specifically, this commenter soughtguidance on how to resolve conflictsamong requirements of the regulationsapplicable to a combination product ifimplemented in accordance with§ 4.4(a)(1).(Response) As discussed previously inthis document, the requirements of thedrug CGMP and QS regulation aresimilar in many respects. Further, thevarious regulations listed in § 4.3 aregenerally compatible with one another.Nonetheless, we appreciate thatquestions as to how to reconcile themand actual conflicts may arise.Accordingly, regulations listed in § 4.3and this regulation include provisionsaddressing how to resolve any conflictsamong them. These provisionsessentially call for following whicheverrequirement is more specificallyapplicable. See §§ 211.1(b), 820.1(b),and 4.4(e) of this rule. Thisdetermination may be based on suchfactors such as which regulationaddresses a manufacturing issue mostprecisely and which requirement arisesfrom the regulation most specificallyapplicable to the constituent part.Should we become aware of potentialconflicts with respect to combinationproducts in general or classes ofcombination products, we intend toaddress them in guidance. However, weare not aware of any such potentialconflicts at this time.(Comment 19) One commenterrequested that the following language beadded to § 4.4(c): ‘‘Device componentsand constituent parts are governedunder QSR. The drug components andconstituent parts are governed underCGMPs. The components of constituentparts would be governed under thequality system in which they arespecified.’’ A second commenterproposed a similar change to § 4.3(a) tostate that drug CGMPs ‘‘apply to thedrug constituent part of a combinationproduct,’’ and corresponding changes to§ 4.3(b) through (d).(Response) We have not made eitherproposed revision because we do notagree that they would clarify the rule,and also because they could causeconfusion. Section 4.4(c) provides thatall CGMP requirements applicable to aconstituent part of a single-entity or copackagedcombination product must besatisfied during any period in whichthat constituent part is manufactured ata separate facility. In some cases, theCGMPs applicable to that constituentpart may arise from only one of theregulations listed in § 4.3. In other cases,the applicable CGMPs may arise fromseveral of these listed regulations.Similarly, as explained in sections E.1and E.2 of this document, the CGMPrequirements listed in § 4.3 apply to thecombination product, and compliancewith them may involve policies,procedures, and practices applicable tothe combination product as a whole orto multiple constituent parts.E.1. How To Comply With QSRegulation Requirements Under§ 4.4(b)(1)(Comment 20) As discussedpreviously in this document, somecommenters sought guidanceconcerning the applicability of therequirements specified in § 4.4(b) as ageneral matter. The great majority ofcomments addressing in particular theapplication of the QS regulationrequirements specified under § 4.4(b)(1)focused on § 820.30 (design controls).Some commenters asked forclarification of how to apply designcontrols to combination products. Somequestioned whether design controlsshould apply other than to the deviceconstituent part of a combinationproduct. Some asked for guidanceregarding how to apply design controlsto non-device constituent parts of acombination product, noting that thedecision to incorporate such an articleinto a combination product may occurafter that article has already beendeveloped.(Response) Design controls applywhen a device constituent part is usedin a combination product. Designcontrols require the manufacturer of acombination product which includes adevice constituent part to establish andmaintain procedures to ensure that thedesign requirements for the combinationproduct are appropriate and address theintended use of the combinationproduct, including the needs of the userand patient. The design control processmay rely on existing information for theconstituent parts, such as informationprovided in support of the combinationproduct’s marketing authorization.The design history file for acombination product with device anddrug or biological product constituentpart must address all design issuesresulting from the combination of theconstituent parts, regardless of whetherthe manufacturer chooses to apply aCGMP operating system thatimplements part 820 plus the provisionsof part 211 specified in § 4.4(b)(2) of thisrule or implements part 211 plus theprovisions of part 820 specified in§ 4.4(b)(1) of this rule. For example,with regard to a drug or biologic productconstituent part in a combinationproduct, the design history file woulddocument and provide objectiveevidence that the drug or biologic isappropriate for use with the device (e.g.,why the formulation of the drugconstituent part is appropriate for use ina drug-eluting stent given the need toensure controlled elution, resistance toflaking, etc.). Similarly, with regard to adevice constituent part in a combinationproduct, the design history file woulddocument and provide objectiveevidence that the device constituentpart is appropriate for use with the drugor biological product (e.g., that a syringeis appropriate for use as a deliverydevice for a drug by providing assurancethat there is no interaction with thedrug, that the syringe will deliver thedrug properly, and that containerclosure integrity and shelf life can bemaintained, etc.).The combination productmanufacturer is responsible for designand development planning, includingthe design of processes for themanufacture of the combinationproduct. For products manufactured bymultiple manufacturers, the finishedcombination product manufacturer andthe application holder (if they are notthe same entity), each are responsiblefor these duties. The design inputs mustensure that the design requirements areappropriate and address the intendeduse of the combination product,including the needs of the patient andthe user of that combination product.Design output procedures must ensurethat those design outputs that areessential for the proper functioning ofthe combination product are identified.The total finished design outputconsists of the combination product, itspackaging, and its labeling. In addition,design control requirements for review,verification, validation, design changesand design history file apply. If asponsor wishes to use an existing or offthe-shelf product as a constituent part ofa combination product, the designcontrols must ensure that the existingproduct meets appropriate designrequirements for the combinationproduct to be safe and effective, whichmay require modification of the existingproduct for use as part of thecombination product. See § 820.30.Further explanation will be provided inthe related guidance.E.2. How To Comply With Drug CGMPRequirements Under § 4.4(b)(2)(Comment 21) Some commentersproposed adding the requirements from§§ 211.160 (general requirements) and211.194 (laboratory records) of the drugCGMP requirements to the list ofrequirements with which manufacturersmust demonstrate compliance under§ 4.4(b)(2).(Response) We do not find that it isnecessary to add §§ 211.160 and 211.194to § 4.4(b)(2). The topics addressed inthese sections are adequately addressedin part 820, including, for example, in§§ 820.70 (production and processcontrols), 820.72 (calibration), 820.80(acceptance activities), 820.180 (generalrequirements), and 820.250 (statisticaltechniques).Section 211.160 is primarilyconcerned with the ‘‘establishment of* * * specifications, standards,sampling plans, test procedures, orother * * * control mechanisms’’ withrespect to the laboratory. This sectionalso states that these controlmechanisms and changes to them shallbe drafted by the appropriateorganizational unit and reviewed by thequality control unit. These requirementsshall be followed and documented, andany deviation shall be recorded andjustified. Also, appropriate‘‘instruments, apparatus, gauges, andrecording devices’’ shall be calibrated.While we recognize that pharmaceuticallaboratory control is critical to thequality of drug components, in-processmaterials, and the final product, thissection’s requirements are broad enoughto be comparable to requirementsspecified in §§ 820.70(a) and (b) (generalrequirements and changes to productionand process controls), 820.80(c) (inprocessacceptance activities), 820.250(statistical techniques), 820.20(a)(1)(responsibility and authority), and820.72(b) (calibration).Section 211.194 is primarilyconcerned with the management andmaintenance of official records withrespect to the laboratory. This section’srequirements are comparable torequirements specified in § 820.180(general requirements for officialrecords). While § 211.194 specifies somerequirements for testing of laboratorysamples, ‘‘complete records’’ of all datagenerated within a laboratory iscomparable to ‘‘all records’’ as describedin § 820.180. Section 211.194 can beused as a source of information forspecific pharmaceutical laboratorytesting records needing to be managedand maintained, as well as relevantCGMP guidance with respect topharmaceutical and microbiologicallaboratories.(Comment 22) Some commenterssought clarification of circumstancesunder which § 211.103 (calculation ofyield) should be satisfied andquestioned whether determining yieldwould provide meaningful informationbeyond what the QS regulation requiresregarding whether processes are undercontrol. One sought clarification ofwhether the requirement applies only todrug constituent parts.(Response) Section 211.103 states thatcalculation of yield ‘‘shall bedetermined at the conclusion of eachappropriate phase of manufacturing,processing, packaging, or holding’’ for adrug product. This may providevaluable information and insight to thestatus of a manufacturing process atsignificant evaluation points, not just forthe final product. In addition, § 211.103provides an important quality checkboth for a pharmaceutical productionprocess as a whole and for individualunit operations of the process. It isimportant to account for any increase ordecrease in expected yield of materialsduring the manufacturing process.When either occurs, it is important toconduct a prompt and thoroughinvestigation. Appropriatemanufacturing controls can helpprevent deviations from expectedprocess yield, which can be importantto the success of manufacturing stepsand to ensuring that the final productmeets specifications. Any phase of thepharmaceutical process that is subject topotential component, in-processmaterial, or product loss, due tophysical or chemical means, should beevaluated with respect to actual andtheoretical yield of these materials.Section 211.103 does not apply todevice constituent parts of combinationproducts.(Comment 23) Some commenterssought clarification of the application of§ 211.170 (reserve samples). Someargued that reserve sample requirementsshould apply only to drug constituentparts of combination products and notto device constituent parts or the entirecombination product, asserting thatkeeping samples of devices or completecombination products would be costprohibitive. Others sought guidanceregarding how to comply with reservesampling requirements for ‘‘small lot’’products with less than 100 products ina lot, or products that come in multiplesizes and shapes.(Response) Reserve samples areneeded to help ensure the postmarketsafety and effectiveness of combinationproducts, as they are for drugs andbiological products. They are used, forexample, to address certain productcomplaints, evaluate stability concerns,and assess the causes of adverse events.Under § 211.170, reserve samples mustbe maintained for each lot of a drug (orbiological product) ‘‘under conditionsconsistent with product labeling,’’‘‘stored in the same immediatecontainer-closure system in which thedrug product is marketed or in one thathas essentially the samecharacteristics,’’ and must consist of ‘‘atleast twice the quantity necessary toperform all the required tests, exceptthose for sterility and pyrogens.’’For a single-entity combinationproduct, such as a prefilled syringe ora drug-eluting disc or stent, it would beappropriate to retain samples of thecomplete product from each lot and, inany event, the samples should includethe drug and all device components thatcome into direct contact with the drug.For co-packaged and cross-labeledcombination products, it generallyshould be sufficient to maintain samplesof each lot of the drug or biologicalproduct in the immediate container/closure in which it is marketed. Specificquestions or concerns about reservesamples should be discussed with thelead review center for the combinationproduct. We will provide furtherinformation regarding how to complywith sample retention requirements forcombination products in relatedguidance for this rule.(Comment 24) Some commenterssought guidance on compliance withbatch release testing requirements under§ 211.165. One asserted that such‘‘testing-in’’ requirements are in conflictwith ‘‘design-in’’ requirements of the QSregulation. Some sought clarification ofwho is responsible for batch release fordrug constituent parts, and whether therelease is under a Certificate of Analysisor based on actual approval of the batchrecords. One asked how ‘‘batch’’ wouldbe defined, specifically whether thebatching of the device constituent partor the drug would prevail indetermining what is a ‘‘batch.’’ Onenoted that a different approach might beappropriate for smaller productionbatches (for example, of less than 100)as opposed to batches that mightcontain 100,000 units. One asked if theAgency agreed that flexibility inapplying the requirements would beappropriate if the combination producthas a device primary mode of action.One asked if the Agency would considertesting of selected batches appropriatefor small batch, high-cost combinationproducts. One asked whether theAgency would permit combining subbatchesor testing of representativesamples of the finished product. Oneasked, with regard to devices thatcontain antimicrobials, whether testingof antimicrobial activity could beconsidered a suitable surrogate endpointfor the determination of strength of theactive ingredient.(Response) Section 4.4 applies tosingle-entity and co-packagedcombination products. Testing andrelease for distribution of finishedpharmaceuticals is a critical step in drugproduct manufacture and qualitycontrol. This applies to all single entityand co-packaged combination productsthat contain a drug constituent part.Such testing requirements do notconflict with design-based controls.Rather, the two work hand-in-hand toensure appropriate manufacture andproduct performance.Each combination productmanufacturer should establishprocedures defining ‘‘a batch’’ in allphases of production, and describe allbatch numbering systems used forincoming material, in-process material,and finished products. Theseprocedures allow the manufacturer toconnect specific lots of constituentparts, components and in-processmaterial to the specific lot ofcombination product in which theywere used as well as provide traceabilityof sampling and testing, packaging andlabeling activities. Master productionand control records should be designedto enable this traceability. Batchdefinition, control, and trackingprocedures should be explained inproduct applications and available forreview on inspection.All proposed testing and samplingplans of drug constituent parts shouldbe conducted in accordance with§§ 211.160 and 211.165. Sampling plansshould be designed to assureappropriate statistical quality controlcriteria are met as a condition for thedrug constituent part’s approval andrelease. The acceptance criteria for allsampling and testing of a drugconstituent part for product releaseshould be reviewed and approved bythe firm’s quality unit.‘‘Release’’ of pharmaceuticalingredients, excipients, and/or productsmay mean different things depending onwhere in the manufacturing process thematerials are being tested. Incomingingredients, excipients, and suppliesfrom suppliers must be tested,controlled, and documented inaccordance with § 211.84. Reliance onreports of analysis and certificates oftesting may be permitted under certaincircumstances as provided at § 211.84(d)so long as at least one specific identitytest is conducted for each component ofa drug constituent part. Acceptablematerials can be ‘‘released’’ into thedrug constituent part or combinationproduct production system. Finisheddrug constituent parts or combinationproducts must also be tested, controlled,and documented before they can be‘‘released’’ for distribution to otherclients or the market.Regarding the issue of whetherverification and testing of antimicrobialactivity could be a suitable surrogate forthe determination of strength, we notethat it would not be appropriate to usea qualitative activity determination(such as a determination of generalantimicrobial activity) in place of aquantitative determination of biologicalactivity (such as a determination ofmicrobial inhibitory concentration(MIC)). Further, what type of test toconduct can depend on the purpose ofthe antimicrobial. For example, if adevice is coated with an antimicrobialdrug, and the intended use of thecombination product involvesdissemination of the drug to produce apharmacologic effect, then ‘‘strength’’could be determined by chemicalanalysis (reflecting chemical content) orby MIC (reflecting biological activity).However, if the antimicrobial coatingserves only to inhibit or preventmicrobial colonization of the device,then an antimicrobial preservativeeffectiveness test might be moreappropriate.We plan to discuss batch releasetesting further in the related guidancefor this rule.(Comment 25) Some commenterssought clarification of how to complywith §§ 211.166 (stability testing) and211.137 (expiration dating)requirements. Two comments soughtclarification of stability testing andexpiration testing for kits, and onequestioned the practicality of annualstability testing for each ‘‘size andshape’’ of a combination product.(Response) Combination products thatinclude drug constituent parts mustcomply with § 211.166. A writtentesting program must be established toverify the stability of the drugconstituent part. These stability testingprograms are critical in determiningappropriate storage conditions and5 The HCT/P regulation at part 1271 distinguishesbetween HCT/Ps regulated solely under section 361of the PHS Act (42 U.S.C. 264) and those that areregulated as drugs, devices and/or biologicalproducts under the PHS Act. The HCT/P regulationprovides that an HCT/P that is combined withanother article (other than water, crytalloids, or asterilizing, preserving or storage agent) does notmeet the criteria for regulation solely under section361 of the PHS Act, but would be regulated as adrug, device and/or biological product. Refer to§§ 1271.10 and 1271.20 when considering whatregulations apply to a combination product with anHCT/P constituent part.expiration dating. Any drug productmanufactured for commercialdistribution should be subjected tostability testing, including each type ofdrug constituent part included in a kit.Among other considerations, this testingmust enable evaluation of any effects ofstorage 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 21CFR 201.17. We plan to provideadditional information on how tocomply with the requirements of§§ 211.166 and 211.137 in the relatedguidance for this rule.E.3. How To Comply With BiologicalProduct and HCT/P RequirementsUnder § 4.4(b)(3)(Comment 26) Some commenterssought clarification of which CGMPrequirements for biological productsand HCT/Ps might apply to acombination product. Some noted thatthe proposed rule provided thatmanufacturers of drug-devicecombination products coulddemonstrate compliance with both thedrug CGMPs and device QS regulationby demonstrating compliance with oneof these regulations in its entirety andwith specified provisions of the otherregulation. In contrast, they noted, theproposed rule stated that manufacturersof combination products that include abiological product or HCT/P mustdemonstrate compliance with all of theCGMP requirements applicable to abiological product or HCT/P,respectively. Commenters askedwhether the Agency could specifybiological product and HCT/P CGMPrequirements with which compliancemust be demonstrated if a manufacturerhas demonstrated compliance with thedrug CGMPs or device QS regulation.(Response) As noted previously inthis document, and stated in thedefinition for biological product at § 4.2,a biological product is also by definitiona drug or a device. Accordingly, abiological product is always eithersubject to the drug CGMP regulationsdescribed in parts 210 and 211, or to theQS regulation described in part 820, asappropriate, regardless of whether thebiological product is a constituent partof a combination product. Furthermore,biological products, including those thatare constituent parts of combinationproducts, must comply with allapplicable requirements in parts 600through 680. To the extent thatrequirements in parts 600 through 680pertain to manufacturing for biologicalproducts, these requirements apply inconjunction with the CGMP regulationsin parts 210, 211, and 820 and do notcreate a separate CGMP operatingsystem. Therefore, the additionalrequirements that pertain tomanufacturing for biological products inparts 600 through 680 that wouldotherwise apply to a biological productif it were not part of a combinationproduct must still be met when thatbiological product is a constituent partof a combination product.As noted in the preamble to theproposed rule, many requirements inparts 600 through 680 are notconsidered CGMP requirements.Moreover, many requirements in parts600 through 680 are applicable only tocertain types of biological products. Forexample, blood and blood componentsare subject to the CGMP requirementsfor such products under part 606.Additionally, a vaccine manufacturedusing a spore-forming microorganismwould be subject to § 600.11(e)(3) (workwith Spore-forming microorganisms).As a result, the specific requirements inparts 600 through 680 that apply willdepend on the type of biologicalproduct.An HCT/P that is not regulated solelyunder section 361 of the PHS Act (42U.S.C. 264) is regulated as a drug,device, and/or biological product (see§§ 1271.10 and 1271.20).5 Therequirements for HCT/Ps under part1271 are designed to prevent theintroduction, transmission, and spreadof communicable diseases. Theserequirements must be met for HCT/Ps,and are essential to protecting thepublic health. However, the Agencyrecognizes that there are some sectionsof part 1271 that overlap with therequirements under the drug CGMPsand the QS regulation, and hasaddressed these overlaps in draftguidance. See ‘‘Guidance for Industry;Current Good Tissue Practice (CGTP)and Additional Requirements forManufacturers of Human Cells, Tissues,and Cellular and Tissue-Based Products(HCT/Ps)’’ (http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Tissue/UCM285223.pdf).(Comment 27) One commenter soughtclarification of how to reconcileconflicts between HCT/P manufacturingrequirements and drug CGMP and QSregulation requirements. Thiscommenter stated that some HCT/Ps arealso considered xenotransplantationproducts due to their exposure toanimal materials (mouse, insects) duringmanufacturing and that FDA shouldconsider addressing this topic in thefinal rule and/or associated guidance.(Response) Based on experience todate, the Agency believes that conflictsare unlikely to occur between the HCT/Ps manufacturing requirements listed in§ 4.3(d) and the drug CGMPs or deviceQS regulation. Further, as discussed inresponse to Comment 18 of thisdocument, the rule includes a provisionat § 4.4(e) on how to resolve conflictsbetween CGMP requirements.Accordingly, we do not see a need torevise the rule in respect to this issue orto address it in guidance at this time.Regarding the issue ofxenotransplantation products, we notethat the Agency has already addressedthis topic in guidance (see ‘‘Guidancefor Industry: Source Animal, Product,Preclinical, and Clinical IssuesConcerning the Use ofXenotransplantation Products inHumans,’’ (http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Xenotransplantation/ucm074354.htm).F. Enforcement and Effective Date(Comment 28) Several commentersrecommended delaying the effectivedate, in most cases to 1 year afterpublication of this rule. Some noted aneed to coordinate various functionsand conduct extensive communicationsand analyses in developing a compliantsystem. Others noted the time theAgency provided for implementation ofaspects of other rules, such as the designcontrol requirements of the QSregulation. Some addressed the timeand financial costs of making suchchanges, arguing that the Agency hassubstantially underestimated the costsof implementing this rule, and shouldextend the effective date in light of thegreater costs they believe will beincurred.(Response) This final rule serves toclarify options for manufacturers tocomply with the sets of CGMPSapplicable to their combination product.As stated in the preamble to theproposed rule, manufacturers areresponsible for compliance with theCGMP requirements that apply to eachconstituent part of their combinationproducts (74 FR 48423 at 48424). Thisrule does not establish any newrequirements. Accordingly, we see noreason to delay its effective date, andconsistent with the plan described inthe proposed rule, we are issuing thisrule to be effective in 180 days. TheAgency wants to move forward inproviding greater assurance that thestreamlined approach outlined in the2004 draft guidance and codified in§ 4.4(b) of this rule may be used todemonstrate compliance with CGMPsfor combination products. As notedthroughout this notice, we are preparingcompanion guidance to provide further,general information regarding ourexpectations for compliance withCGMPs for combination products, andwe remain available to work withmanufacturers to resolve productspecificquestions. We intend tocontinue to apply a risk-based approachto facility inspection and, consistentwith ensuring protection of the publichealth and in light of the specificcircumstances, to offer manufacturers areasonable opportunity to correctdeficiencies before taking furthercompliance or enforcement actions.G. Alternate Approaches(Comment 29) Some commentersproposed alternate approaches,suggesting a more ‘‘unified’’ approachwould be preferable or arguing that thedrug CGMPs and device QS regulationare not well-suited for application toproducts including devices and drugs,respectively. Some encouraged relianceon guidance instead.(Response) As discussed in thepreamble to the proposed rule andsummarized in section I.A of thisdocument, the Agency undertook anextensive evaluation of the drug CGMPs,device QS regulation, and biologicalproduct and HCT/P requirements indeveloping this rule. This processincluded consideration of commentsreceived on the draft guidance thatproposed an approach much the same asthe approach offered in the proposedrule and adopted in this final rule. Thecomments received on that draftguidance and on the proposed rule werelargely supportive of this approach, andthe Agency believes that this approachoffers an efficient and effective means toensure that combination products aremanufactured in accordance with allappropriate CGMP requirements.We see no reason to develop anentirely new regime for combinationproducts, but rather find that it isappropriate to utilize the wellestablishedand understood CGMPrequirements that already exist for theconstituent parts of which combinationproducts are comprised. At the sametime, it is important to establish withclarity and certainty the CGMPrequirements that apply to combinationproducts, to ensure effective complianceand consistent, appropriate regulation.Accordingly, we determined that arulemaking rather than reliance onguidance alone is appropriate to achievethese goals. As discussed throughoutthis preamble and in the preamble to theproposed rule, we understand thatguidance is important to the effectiveimplementation of this rule, and areissuing companion guidance for thisreason.H. Guidance(Comment 30) Several commentersrequested that FDA issue companionguidance for this rule. Some requestedthat such guidance include relevant casestudies or descriptions of what wouldconstitute a demonstration ofcompliance with requirements forexamples of combination products andmanufacturing activities. One proposedthat the guidance address theapplication of provisions of the drugCGMPs and QS regulation that are notspecified in the rule and theircompatibility with those provisions thatare specified in § 4.4(b) from the otherof these two regulations. Onecommenter proposed guidance on theapplication of CGMP requirements forcombination products in relation tomaster files. One commenter proposed aneed for a table of key CGMPconsiderations for developing astreamlined system and for auditinstructions and inspection check lists.Some emphasized the need to addresswhat actions existing facilities shouldtake to come into compliance. Oneencouraged harmonization withinternational efforts where possible.One stated that FDA should provideadditional guidance on how the rulewill affect Agency policy on CGMPrequirements for investigational deviceconstituent parts in combinationproducts for which the Center forBiologics Evaluation and Research orthe Center for Drug Evaluation andResearch has the lead. One requestedthat guidance provide for theopportunity to discuss CGMP issueswith the Agency. Some requested thatsuch guidance issue prior to the finalrule. One commenter advised that wereview existing guidance to ensure itsconsistency with this rule.(Response) As noted in the proposedrulemaking, FDA recognizes that timely,comprehensive guidance is important tohelp ensure consistent and appropriateimplementation of this rule. FDAintends to issue such guidance toindustry and staff, focusing on theimplementation of the regulatoryrequirements for use of a streamlinedCGMP operating system for single-entityand co-packaged combination products.We welcome the comments received onthis issue and look forward to furtherfeedback in response to the guidance weissue. With regard to the requests thatwe issue draft guidance prior toissuance of this final rule, we did notbelieve it would be appropriate toanticipate the content of this rule bypublishing guidance concerning itscontent prior to its finalization.We remain committed to internationalharmonization efforts, including thoserelated to CGMP requirements forcombination products. A practicalchallenge for combination products inparticular is that internationalcollaboration and harmonization effortsare at an early stage for these products.At the same time, there is a current needto clarify and rationalize our domesticCGMP requirements for this rapidlygrowing class of products. We havetaken an approach that integratesunderlying CGMP approaches for drugs,devices, and biological products, whichhave each benefited in various respectsfrom substantial internationalharmonization efforts. The approachadopted in this rule will facilitateimplementation of streamlined CGMPoperating systems for combinationproducts that will integrate as readily aspossible with these existing and ongoingharmonization efforts. We arecommitted to continuing to work withour foreign counterparts on CGMPs andother issues for combination products,and to pursuing domestic regulatoryapproaches in the United States thatwill enable such efforts to the extentpracticable and appropriate consistentwith meeting our domestic regulatoryneeds.With regard to the commentconcerning review of existing guidancefor consistency with this rule, we notethat any prior guidance must be read inlight of subsequent changes to legalrequirements, whether through newstatutory law or issuance of newregulations. The Agency will continueto review all guidance to ensure itscontinued utility and accuracy.I. Other(Comment 31) Some commentersrecommended using the term ‘‘hybrid’’rather than ‘‘streamlined’’ in referenceto the compliance option under § 4.4(b)for single-entity and co-packagedcombination products. One commentersuggested that the rule does not reducethe burden of compliance with both thedrug CGMPs and QS regulation. Somecommenters argued that the termstreamlined might suggest a relaxationof requirements when § 4.4(b), in fact,does not relax CGMP requirements forsuch products.(Response) We appreciate theconcerns raised by these commenters.However, we disagree with theconclusion that § 4.4(b) does notprovide a means to streamlinecompliance with the drug CGMPs anddevice QS regulations for single-entityand co-packaged combination products.The alternative to the approachpermitted under § 4.4(b) is that of§ 4.4(a), under which a facility wouldneed to demonstrate compliance withall applicable requirements under bothof these regulations. Section 4.4(b), incontrast, reflects the Agency’s judgmentthat many provisions of these tworegulations are similar to one anotherand that demonstrating compliance withmost requirements of one of these setsof regulations suffices to demonstratecompliance with similar provisions ofthe other set.We also disagree that use of the term‘‘streamlined,’’ which is consistent withthe rule’s removal of redundantrequirements for compliance withsimilar provisions of the drug CGMPsand QS regulation, implies a relaxationof CGMP requirements. Rather, itreflects the provision of a more efficientmeans to satisfy them.(Comment 32) Some commentersraised issues concerning training ofcompliance staff, inspection standards,coordination and allocation ofresponsibilities among Agency staff, andtracking and oversight for complianceactivities within the Agency.(Response) The Agency recognizes theimportance of effective and appropriatetraining, oversight, and standards forCGMP inspection, and for efficient,effective coordination among staff. Weintend to address such matters throughappropriate inspectional standards,training, and other mechanisms used inrelation to other CGMP inspectionalactivities. However, these issues arematters of internal Agency operationoutside the scope of this rulemaking andwe do not address them further here.(Comment 33) Some commentersstated that the Agency should addresshow to ensure appropriate changecontrols for combination products, withone comment highlighting the issuewith respect to cross-labeledcombination products. Somecommenters proposed that the Agencyconsider requiring constituent partmanufacturers to notify one anotherbefore making changes to theconstituent part. Some commenters alsoaddressed the question of which postapprovalchange requirements shouldapply under what circumstances,proposing that the submissionrequirements for the change be thoseapplicable to the constituent part beingchanged, or the most stringentrequirement applicable to any of theconstituent parts being changed if achange is being made to more than one.(Response) We agree that coordinationwith regard to changes amongmanufacturers participating in themanufacture of a combination productis an important CGMP issue. It is notunique to combination productshowever, and we do not see a need toestablish additional requirementsspecifically for combination products.Where constituent parts of single-entityor co-packaged combination productsare being made by one entity andsupplied to another’s facility where thefinished combination product is made,compliance with purchasing controlrequirements, for example, wouldnecessitate tracking of changes andconfirmation that the change will notprevent the combination product frommeeting its specifications.Similarly, the manufacturers ofseparately manufactured and marketedconstituent parts of cross-labeledcombination products are subject to theCGMP requirements applicable to thetype of constituent part they aremanufacturing. They must ensure thatthe manufacture of their constituent partcomplies with the specificationsestablished to ensure the safe andeffective use of that constituent part incombination with the other constituentparts for the combination product’sintended use(s). Appropriatecoordination among manufacturers withrespect to CGMP compliance forchanges to constituent parts ofcombination products will be furtheraddressed in later guidance.The requirements for reporting postmarketingchanges to the Agency or forobtaining Agency review of postmarketingchanges, when making a postmarketchange to a combination productor a constituent part of a cross-labeledcombination product, are beyond thescope of this rule. The issue of whattype of submission to make to theAgency for a post-approval change to acombination product is also beyond thescope of this rule. However, we notethat we intend to issue guidanceaddressing post-marketing changesubmission requirements.(Comment 34) One commenter raisedan issue regarding reporting of adverseevents for ‘‘cross-labeled’’ combinationproducts. One commenter asked forguidance on labeling requirements forcombination products. Anotherproposed that the Agency develop anew master file category forcombination product constituent partsand components to address applicationand quality requirements for these partsof combination products. Anotherrequested that planned guidance for therule address establishment registrationand product listing for manufacturersand importers of combination products.Another commenter proposeddevelopment of a new export certificateprogram for combination product CGMPcompliance. Another sought guidanceon needle registration, labeling, andtesting.(Response) We appreciate thesecomments, which raise issues that wemay address in other contexts. However,these issues are beyond the scope of thisrule and, therefore, we are not offeringsubstantive responses to them here.
- 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)Office of Combination ProductsFood and Drug AdministrationWO32, Hub/Mail Room #512910903 New Hampshire AvenueSilver Spring, MD 20993301-796-8930Fax:301-847-8619combination@fda.gov