Docket No. FDA-2015-D-0198: Current Good Manufacturing Practice Requirements for Combination Products.

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1 701 Pennsylvania Avenue, Ste. 800 Washington, DC Tel: Fax: April 29, 2015 Division of Dockets Management (HFA-305) Food and Drug Administration 5630 Fishers Lane, Room 1061 Rockville, MD Re: Docket No. FDA-2015-D-0198: Current Good Manufacturing Practice Requirements for Combination Products. Dear Sir or Madam: The Advanced Medical Technology Association ( AdvaMed ) is pleased to provide comments on FDA s draft guidance Current Good Manufacturing Practice Requirements for Combination Products. AdvaMed represents manufacturers of medical devices, diagnostic products, and health information systems that are transforming health care through earlier disease detection, less invasive procedures, and more effective treatment. Our members range from the smallest to the largest medical technology innovators. Generally speaking, industry is encouraged that FDA devised a streamlined program intended to assist manufacturers in complying with 21 C.F.R. Part 4. We have, however, a number of significant issues with the guidance and, importantly, the draft guidance does not sufficiently answer many questions concerning how best manufacturers can comply with this regulation. Our specific comments on the draft guidance are provided in the attachment. We also attached a line-numbered version of the draft guidance to facilitate your review. General thoughts about the draft guidance are provided below. The guidance should make clear that Part 4.4. (e) is intended to apply exclusively to the dual system and that for a streamlined system, companies should incorporate the streamlined provisions required and then determine for themselves how to ensure that the underlying SOPs in place appropriately address the quality requirements for drug or device constituent part, rather than seeking the most stringent regulation cited in either Part 820 or part 211. This is supported by section Part 4.4. (e) of the final rule, which states that,... in the event of a conflict between regulations applicable under this subpart to combination products, including their constituent parts, the regulations most specifically applicable to the constituent part in question shall supersede the more general. This provision is discussed in the preamble only in the context of a system that

2 Docket No. FDA-2009-N-0435 April 29, 2015 Page 2 of 20 incorporates both drug and device CGMPs [ Specifically, this commenter sought guidance on how to resolve conflicts among requirements of the regulations applicable to a combination product if implemented in accordance with 4.4(a)(1). ] and should be included in the text of the guidance document. The draft guidance states that this discussion is not meant to be a comprehensive analysis and then essentially repeats the regulations almost verbatim (in terms of the QS regulation-based streamlining approach Section IV.B). It would be helpful if the guidance provided a more comprehensive discussion on interpretation of specified additional provisions under the streamlined approach, including flexibility in interpretation and acceptable documentation of compliance. Some of the comments in the attached table identify additions or clarifications to the guidance that could inform manufacturer s routes to compliance. The draft guidance, in section IV.B.6 Stability Testing, only mentions a written testing program; however, it fails to discuss the differences and requirements for primary stability programs designed to meet registration expectations and annual stability programs designed to monitor the stability of the drug product over its commercial lifetime. More guidance to this point is needed. Thank you for the opportunity to submit comments on this draft guidance document. Respectfully submitted, /s/ Sharon A. Segal, Ph.D. Vice President Technology and Regulatory Affairs Attachment 2

3 Strikeout = deleted text Underline = suggested new text & 67 Revise to add the following at the end of this sentence: The final rule does not establish any new requirements as to further inform Editorial change Instead, this guidance describes Editorial change (Footnote 2) Add the page range to incorporate entire content of FR notice but is not required Editorial change Specify whether there can be an accessory to a combination product and how it would be regulated.... streamlined approach, demonstrating full compliance with either the drug CGMPs.... The complete drug and the following provisions from the QS regulation in accordance... The complete QS regulation and the following provisions from the drug CGMPs in accordance Include the CGMP regulation for Biologics/HCT/P) Regardless, manufacturers should consider how to manage internal documentation need to demonstrate compliance with all any applicable CGMP requirements of the constituents (Device, drug) and should consider how to manage internal documentation to demonstrate compliance. To ensure the reader understands that there are no new regulatory requirements being added for Combinations Products, i.e., as stated by Federal Register Vol 78(14), January 22, 2013, p.4318, Comment 28 Response To ensure the reader understands all of the FDA viewpoints in comment/ FDA response.. The guidance provides no discussion on accessories of the specific constituent devices or accessories to the combination product (CP) itself. consistent with 21 CFR 4.4(b)(1) consistent with 21 CFR 4.4(b)(2) Revision for clarity as drugs and devices are mentioned, but not biologics etc., and the last sentence of this paragraph mentions 21 CRF 4.4(b). As written, this can be interpreted to mean that only the 6 device sections or only the 8 drug sections listed in lines need to be implemented for the streamlined approach. Discussions with FDA have indicated there is an expectation that the base quality system must already address those CGMP sections not listed. For example, while CAPA is not listed, a drug manufacturer is expected to have a compliance CAPA system already in place as part of their base quality system. 3

4 To facilitate efficient inspection, the agency recommends that manufacturers who choose to operate under a streamlined approach clearly identify in their premarket submissions and at the initiation of an inspection whether they are operating under the drug CGMP-based or QS regulation-based streamlining approach. For products for which the premarket submissions were made prior to promulgation of 21 CFR part 4, such manufacturers should clearly identify at the initiation of an inspection whether they are operating under the drug CGMPbased or QS regulation-based streamlining approach. Specify where this information should be provided in a Common Technical Document (CTD) dossier and/or Standard Technical Document (STED). Recommend that this be provided as a stand-alone Module 1 or Regional CTD that can then be provided during an audit. Similarly this approach could be taken within the format of a DMF or appropriate submission. Further clarify Primary Mode of Action (PMOA): criteria and responsibilities for determination; responsibilities and process for resolving discrepancies between the sponsor and the Agency regarding PMOA. Manufacturers must demonstrate that each applicable CGMP requirement is complied with for the corresponding constituent parts and the combination product, if appropriate. If a streamlined approach is used, the manufacturer must demonstrate compliance with all of the relevant provisions of either the drug CGMPs or QS regulation, and the provisions specified in 21 CFR 4.4(b) for the other set(s) of CGMP requirements applicable to its product. A manufacturer that chooses to use the streamlined approach is not required to comply with the other specific GMP/QSR requirements, beyond those specified in 21 CFR 4.4(b). The draft generally does not give much guidance about legacy products. In this sentence, it does not take into account that indicating the use of a streamlined approach in a premarket submission is not possible for a legacy product.. on the PMOA and how it is determined for a new type of combination product would be helpful in this section applicable to its the product It should be emphasized that all other requirements as stated in the QSR/CGMPs rule do not need to be followed in a streamlined approach. [Federal Register Vol 78(14), January 22, 2013, p , I. Background, (B) The Proposed Rule and (C) The Final Rule]. Although the examples are helpful, the current draft does not state clearly enough that the provisions in 21 CFR 4.4(b) would be sufficient to achieve compliance and additional requirements of the other QSR/CGMP do not apply. A manufacturer would have to consider whether other requirements of the drug GMP are also applicable. 4

5 Section C.4.2 Definitions Section C.4.2 Definitions Add the following definition to this section: Reserve Sample [ ]: An appropriately identified reserve sample that is representative of each lot in each shipment of each active ingredient shall be retained. [ (a)] An appropriately identified reserve sample that is representative of each lot or batch of drug product shall be retained and stored under conditions consistent with product labeling. The reserve sample shall be stored in the same immediate container-closure system in which the drug product is marketed or in one that has essentially the same characteristics. [ (b)] Reserve samples are needed to help ensure the postmarket safety and effectiveness of combination products. They are used, for example, to address certain product complaints, evaluate stability concerns, and assess the causes of adverse events. Add the following definition to this section: Retained Sample[ (d)]: A representative sample of each lot of (bulk drug) component [ (1)] A representative sample of the Final Combination Product (Drug product) per appropriate (representative sample) criteria [ (2)] Representative Sample/Surrogates A representative sample of a combination product which has a PMOA as a device, does not have to be an actual finished device. The manufacturer may develop a surrogate product that would meet the intent of the regulations. to help ensure the postmarket safety and effectiveness of combination products. They are used, for example, to address certain product complaints, evaluate stability concerns, and assess the causes of adverse events. Examples of potential surrogates include but are not Reserve and Retained Sample terminology is confusing and contradictory. As the FDA guidance s purpose stipulates it is to help device manufacturers, this is an important concept FDA Guidance line ; This discussion is not meant to be a comprehensive analysis, but rather to help manufacturers particularly device manufacturers, who may be less familiar with the drug CGMPs understand the purpose and basic content of the specified provisions of the drug CGMPs, as well as where to find additional guidance. Reserve and Retained Sample terminology is confusing and contradictory. As the FDA guidance s purpose stipulates it is to help device manufacturers, this is an important concept FDA Guidance line ; This discussion is not meant to be a comprehensive analysis, but rather to help manufacturers particularly device manufacturers, who may be less familiar with the drug CGMPs understand the purpose and basic content of the specified provisions of the drug CGMPs, as well as where to find additional guidance. 5

6 limited to: o o Sections of a catheter that was extruded, coated and packaged in the same manner as the finished product Extruded catheters without electronics included. When using a surrogate sample, the manufacturer must maintain documentation demonstrating that the surrogate will meet the intent of the regulation, to help ensure the postmarket safety and effectiveness of combination products. They are used, for example, to address certain product complaints, evaluate stability concerns, and assess the causes of adverse events. Manufacturers are encouraged to use the least burdensome method necessary to demonstrate compliance with this section of the regulation. Note that as a Reserve Sample will be retained, a Retained Sample may be reserved, i.e., 21 CFR and may fulfill the same function [21 CFR (b); 21 CFR ]. Add the following to the Manufacturer definition: CFR 134.1(b) Country of origin. Country of origin means the country of manufacture, production, or growth of any article of foreign origin entering the United States. Further work or material added to an article in another country must effect a substantial transformation in order to render such other country the country of origin within the meaning of this part; however, for a good of a NAFTA country, the NAFTA Marking Rules will determine the country of origin. A sentence stating that the final rule does not alter existing requirements for establishment registration should be added. For example, implementing Design Controls related to the device constituent of a drug-device or biologic-device Combination Product at an existing drug establishment (or any other facility owned by a drug or biologic manufacturer / sponsor) should not impose a requirement to also register those facilities as device establishments (specification developers) 6 FDA Manufacturer definition does not incorporate a reference to US Customs 19 CFR 134 manufacturer definition in relation to Country of Origin In consideration of package labeling and potential Combination Products components from outside the USA, Customs definition takes priority, i.e.,: 19 CFR , Requirements of other agencies; Nothing in this subpart shall be construed as excepting any article (or its container) from the particular requirements of marking provided for in any other provision of any law, such as those of the Federal Trade Commission, Food and Drug Administration, and other agencies. The lines referenced state that any facility that conducts design activities is a manufacturing facility. While this statement appears to be consistent with the definition of manufacture as provided within 21 CFR Part 4, there is a concern that that this statement could be misinterpreted to imply that a facility registered as a drug establishment is now also required to register as a device establishment if that facility implements Design Controls related to the device constituent of a

7 because they are not designing finished medical devices for distribution. Rather, they are designing medical device constituents to be incorporated into a drug-device or biologicdevice Combination Product. Regarding the specific case of design centers that are remotely located from a drug manufacturer s registered drug establishment they would, heretofore, not have been required to register as a drug establishment. Therefore, the guidance should be clear that the new rule does not impose a new requirement that they now register as device establishment(s).....device component (not a finished device) per 21 CFR Part 820.3(c) and is not otherwise subject to the QS regulation for a combination product solely because of 21 CFR Part 4. demonstrate compliance with both the drug CGMPs and QS regulation per applicability of Sec 4.4. The guidance addresses Class I liquid medication dispensers appropriately (as non-drug contacting and drug contacting), however there are Class II/Class III devices that are similarly packaged (e.g., disposable pre-packaged, pre-sterilized syringes in their manufacturer s packaging). The guidance is not clear if these devices would be considered convenience kit devices not subject to additional CGMPs by the kit manufacturer (e.g., for a vial packaged with a packaged syringe and needle) The guidance should state additional conditions or examples including Class II/Class III devices. If such a liquid medication dispenser is co-packaged with a drug as a convenience kit (see III.C.4 below), generally speaking no additional CGMP requirements would apply to that dispenser or to the combination product under part 820 simply because that dispenser is included in the kit. Note, however, that a device constituent part incorporated into a drug container Combination Product. Similarly, there is concern that any facility that a drug manufacturer might use to support the design and development of the device constituent in a drug-device or biologic-device Combination Product (e.g., headquarter facility, satellite design center, laboratory etc.) is required to register that facility as a device establishment (specification developer). If the agency is of the view that the publication of the final rule somehow alters requirements with respect to facility registration for manufacturers of a Combination Product, it should revise existing laws and rules related to device, drug, biologic or Human Cellular Tissue Products (HCT/P) for establishment registration. Failing that, the guidance should be explicit as to what the requirements are so as to avoid industry confusion.. Provided reference from regulation to define a component.. Suggestions to bring clarity to the overall statement regarding simple low risk devices. The Agency is urged to consider providing additional definition regarding simple devices. The combinations suggested to be added are simple, much like an oral dosing cup; however, in many cases, they are not classified or they are components until the point in time where they are combined with the 7

8 raises additional considerations. For example, when establishing batch testing and release and product stability testing criteria under 21 CFR and , a dropper incorporated into a drug container s cap would need to be addressed as part of the drug container because it would come into contact with the drug product. Similarly, when such a dropper is used in conjunction with the drug, the dropper may need to meet certain specifications for dosing of the specific drug product or for maintaining its integrity while in contact with the drug product, for example. As a result, design controls specific to the use of the dropper and its contact with the drug product may be needed and apply under 21 CFR It is understood that appropriate quality controls must be applied to a class 1 device constituent part incorporated into a drug container according to the intended use. For example, Under 21 CFR and , a dropper incorporated into a drug container s cap that is part of the primary container closure system during product release testing and within the packaged product stability program. Measuring devices (i.e. droppers, design cups, etc.) used in conjunction with drugs, should be calibrated to assure dose accuracy. Measuring devices (i.e. droppers, design cups, etc.) used in conjunction with drugs must be evaluated to assure safety, suitability, compatibility with the product. As a result of the above, design controls specific to the use of the dropper and its contact with the drug product are not needed and do not apply under 21 CFR , since other controls are in place to assure quality. It is recommended that the Guidance include discussion and examples for other simple devices that may be used in combination, such as an integrated spray nozzle or pump for OTC nasal products, pumps that deliver topical drug products, pads or sponges that are used to apply cosmetics that contain a sunscreen, etc... a kit that includes two or more different types of medical products container closure of the drug to create the combination product. These are traditionally low risk and should follow a similar logic as defined for the liquid medication dispensers described in lines of the guidance document. The Agency should consider appropriate risk analyses in making these recommendations. 8

9 Footnote 14 ( ; ) ) included in the kit as already offered as a finished device or packaged for independent marketing and with the same labeling as required for independent marketing Reference the Convenience Kits Interim Regulatory Guidance. Add a sentence that stresses that a sponsor (manufacturer of CP) should assess every constituent of the CP (for QS based approach and/or Drug CGMP approach) independently and see what CGMP requirements apply to the constituent if separately marketed (e.g., servicing, installation, cleanroom and other QSR regulations that may not be applicable to the device constituent). Add the following to the end of this section: Furthermore, the preamble to the final rule addressed the requirement differences based on antimicrobial-antibiotic related combination products intended use, e.g., verification and quantitative testing of antimicrobial activity could be a suitable surrogate for the determination of strength if the antimicrobial coating serves only to inhibit or prevent microbial colonization of the device, but qualitative testing would not be appropriate. Clarify designation of Legal Manufacturer, place of manufacture on the labeling, and also for custom and import/export purposes. Add additional information regarding post market data/complaint data into the applicable CGMP systems operated at different facilities. The combination product sponsor 17 is responsible for ensuring that the manufacturing activities for its product occurring at all facilities, including facilities operated by third parties, are in compliance with CGMP requirements. This responsibility is fulfilled by the medical product manufacturer through traditional Some Class 1 devices for oral drug delivery or other devices do not always require secondary packaging and may be packed in a convenience kit with only their surfaces appropriately labeled. Secondary packaging for these devices should not be a necessary condition for them to meet the definition of a convenience kit. nce/guidancedocuments/ucm htm Federal Register Vol 78(14), January 22, 2013, p.4316, Comment 24 Response Maybe an oversight of FTC, not FDA; but need to reach a common ground. Place of substantial transformation vs PMOA. Although the manner in which a manufacturer might exercise control over a third party is covered later in the draft, there is no explicit indication that these controls constitute the full extent of the manufacturer s responsibility. In other words, the application holder is responsible for the CGMP/QSR compliance and the 3 rd party manufacturer is responsible for complying with the 9

10 means, such as quality agreements and audits, as outlined below. This Guidance does not intend to create additional means of supplier quality controls other than those already required by CGMPs and the QSR. Even if a facility is manufacturing only one type of constituent part for a combination product, the CGMP operating system should take into consideration the combination product as a whole, as appropriate. However, if the constituent part is intended for general purpose use or a specific indication it is not the obligation of the combination product manufacturer to include another manufacturer s use in the development in that constituent part. Clarify whether testing refers to the combination product or the constituent.... that might arise from changes to the product or any constituent part of the product : The manufacturer should also establish procedures for acceptance of components, containers/closures, and constituent parts to ensure both detection and evaluation of any changes that are critical to the safety and effectiveness of the combination product prior to incorporating them into the finished combination product. All such controls should be designed to reduce, eliminate, or ideally, prevent qualify nonconformities ensure quality of the finished product As specified in the final rule, design controls apply to any combination product that includes a device constituent part, unless exempted under the appropriate classification regulations. application holder s quality agreement. This does not seem necessary. For example, a device component manufacturer does not typically have the experience to include inputs related to drugs/biologics. They rely on the combination product manufacturer for guidance. of what is being tested Manufacturers need to have agreements in place with contractors regarding change notification. This is covered in previous lines. However, it is not always possible to inspect components, containers/closures and constituent parts to detect and evaluate changes that are critical to the safety and effectiveness of the product. For example, a material change to a closure or component that is not readily observed unless conducting physical property tests. By keeping this sentence more generic, it eliminates confusion between the CGMP requirements and other processes such as lean six sigma functions. On Lines , the guidance states that certain Class I devices are exempt from certain device GMPS including design controls 10

11 Guidance for industry on pharmaceutical development addresses product design and development procedures, reflecting quality by design principles. An approved, documented International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) Q8 Quality by Design system that is supplemented by the relevant sections of Design Control is an acceptable approach to meet the Design Control requirements. Compliance with Q8 is acceptable as meeting the Design Control requirements for the drug constituent of a combination product. For many Combination Products where the PMOA is Drug, the device constituent design control requirements can be addressed by ICH Q8 with appropriate additions from 21 CFR ICH Q8 was design to meet the intended uses of the product Add reference to (c). Reference Design Inputs from 21 CFR Part Revise to read as follows and expected product users needs of product users and patients Include additional detail regarding approvals for its intended use, under actual or simulated use conditions. Add additional information regarding design inputs, design outputs, verification and validation procedures in a consistent manner regarding design reviews and approvals to stay consistent between paragraphs.... requires that the manufacturer complete perform risk analysis.... Per (c), (d), (e), (f), etc. The approval, including the date and signature of the individual(s) approving the requirements, shall be documented. Clarity for Verification vs. Validation See 21 CFR 820.3(aa) (f) Provide correct reference See 21 CFR 820.3(z)(2) (g) Provide correct reference Footnote Number 32 needs to be made into a superscript Editorial change Include reference to FDA guidance on software validation This paragraph mentions Design Transfer for the first time. Include reference to Design Transfer (21 CFR (h) in the reference as a footnote.. Make the paragraphs regarding design input, output, verification, validation follow a consistent explanation of approvals, documentation in the DHFs, etc.. Risk Analysis is a continuous process. nce/guidancedocuments/ucm htm 11

12 Revise to read: should address all the design issues Footnote In addition, the combination product manufacturer must assess the impact of design changes and comply with design control requirements for any modifications that need to be made to a constituent part for use in the combination product (e.g., new formulation of the drug or new features of a device) under 21 CFR (i). Include reference to ISO for risk. 21 CFR details describes how to sample, test, examine... Revise to read: All discrepancies in yyield discrepancies outside of expected documented variation should be investigated. Clarify whether/how automated equipment must be validated and cite Reference Process validation guidance. The term all is too inclusive and implies potentially exhaustive theoretical issues. There are many instances where a minor change to the device or the drug does not affect the safety or the efficacy of the constituents nor the combination product. There are many modifications to drugs that would not affect the combination, so a design control for drug modifications that do not affect the device or the combination product is not necessary. 21 CFR does not detail these processes, it merely describes them. Current text is too restrictive and implies that any yield calculation that is not exactly the same will require investigation. There is always some amount of normal expected variation in yield. df Yield determinations must be made at the conclusion of each appropriate phase of manufacturing, processing, packaging, and holding for the drug constituent part(s) and for the combination product as a whole. The device constituent parts before incorporation into the combination product are not required to yield determinations. Accordingly, calculation of yield should be determined at each phase at which component, in-process material, or product loss may occur, during the formulation of the drug prior to incorporation into the combination product, during incorporation (e.g., filling or coating), and during the packaging process. Revise to read:... and the data generated for the yield calculation in a manufacturing or production record should be documented along with the expected yield variation. Clarify when yield determinations begin to apply to the device constituent. Also, require clarification as to whether the yield determinations of the device constituent parts are required before they are incorporated into the combination product. Need to introduce the concept of normal variation for yield. This concept was discussed and agreed to during the May 21, 2014 meeting between FDA and AdvaMed. 12

13 (Footnote 54) tamper-evident packaging and labeling alerting to alert customers regarding potential compromises to the product packaging. Clarify that the co-packaged entity retains its own expiration dating within its labeling inside the packaged CP. Laboratory testing must be performed on every batch of a single-entity combination product or surrogates and of the drug constituent part(s) of a copackaged combination product, See 21 CFR 4.3, 4.4, and In addition, under the design control requirements, testing must be performed to demonstrate that the device functionality (i.e., mechanical performance of the device constituent part) is maintained until the specified expiration date. See 21 CFR This device functionality testing can be demonstrated during development only, if adequately studied and justified. Add a discussion that a single entity combination product, not pyrogen-labeled but provided sterile, and that is sterilized via a validated sterilization cycle within the device quality systems (21 CFR 820), may be the more applicable requirement. Specifically, 21 CFR (a) requires appropriate laboratory testing of drug products purporting to be sterile. Depending on the development, validation and control of these processes, appropriate laboratory testing for each batch might include reading dosimeters or recovery of biological indicators. For example, a single entity product that is terminally sterilized via a validated sterilization process according to recognized international standards do not require product testing for Alert is for potential breaches/compromised packaging and not to protect the features as such. For individualized serialized combination products, such as cardiac rhythm management leads, single-entity combination product batches do not exist. Therefore, surrogate testing of the drug product is essential to assure that each batch of drug product meets the appropriate acceptance criteria and specifications. Clarify whether testing of the device functionality requires realtime testing for each lot put on annual stability, or if the testing to demonstrate device functionality until expiry can be demonstrated during development of the combination product rather than on each lot of the combination product put on stability in the stability program. For combination product families with large drug portfolios, the amount of repetitive motion required for technicians to test these products throughout a typical ICH drug product stability program would be excessive and unnecessary if well designed studies were performed to support the device throughout the shelf life of the combination product platform. See: Federal Register Vol 78(14), January 22, 2013, p.4314, Comment 18 Response. Additionally, this modified text links to the proposed updates for lines Sterility test such as that described in USP <71> is not appropriate and not recommended for products that are terminally sterilized. Manufacturing processes controlled per the cgmps and achievement of critical validated sterilization process parameters will demonstrate achievement of the defined sterility assurance level. 13

14 release. Dosimeters placed during irradiation or biological indicators placed during ethylene oxide or steam sterilization may be used to release the product after terminal sterilization. Special testing may be required for the drug constituent part, or the combination product as a whole, depending on the product. With respect to 21 CFR (a), batch testing requirements would apply both to the drug constituent part and to the finished combination product for a single-entity combination product (such as a prefilled syringe) to ensure the combination product is sterile and pyrogen-free when distributed. For terminally sterilized products, sterility test requirements may be met utilizing dosimetric and parametric release (e.g. sterilization validation). The requirements related to sterility and non-pyrogenicity of the empty syringe would be addressed through compliance with process controls under 21 CFR part 211 and the provisions of 21 CFR part 820 specified in 21 CFR part 4 (for example, design control requirements under 21 CFR and purchasing control requirements under 21 CFR ), rather than batch testing under 21 CFR (a). 56 Additionally, for a single entity combination product, which is labeled sterile but which is not labeled pyrogen-free, and the combination product is sterilized via a validated sterilization cycle within the device quality systems (21 CFR 820), this validated sterilization cycle testing may be considered the appropriate laboratory testing required by 21 CFR (a). Devices and drugs have a long history of effectively applying Sterile Parametric practices. This option should be considered/ USP <1222> acknowledges the limits of sterility testing and the process for utilizing parametric release for drug products. Similarly this is covered for devices under ISO 11135, ISO & -2, ISO , and ISO It might also be recommended that the guidance include as a reference USP 38 <1222> Terminally Sterilized Pharmaceutical Products Parametric Release This is an Agency accepted practice under 21 CFR for the elimination of batch-specific sterility testing. As described in Federal Register [Vol 78(14), January 22, 2013, p.4314, Comment 18 Response], i.e., FDA specifically states that... these provisions essentially call for following whichever requirement is more specifically applicable [4.4e]..... which regulation addresses a manufacturing issue most precisely and which requirement arises from the regulation most specifically applicable to the constituent part..... (FDA) intend to address them in guidance. Thus, for single entity combination product, which is labeled sterile but which is not labeled pyrogen-free, and the combination product is sterilized via a validated sterilization cycle within the device quality systems (21 CFR 820), this validated sterilization cycle testing may be considered: The appropriate laboratory testing required by 21 CFR (a), and The more specifically applicable regulation, and The requirement most specifically applicable. Thus, this particular situation should be addressed in the FDA guidance 14

15 , 1180, 1595 Accordingly, as explained below, for co-packaged combination products, manufacturers should maintain samples of the drug constituent part, and for single-entity combination products, they should maintain samples that include the device constituent part or components thereof as appropriate. When choosing components or equivalent from a device constituent as the reserve samples containing the drug constituent part, a scientific rationale must be included. Reserve Samples Separate the text s discussion (and requirements for) the two different items: First discuss Active Ingredient (AI) requirements [21 CFR211.84(d)(1)], and then Separately discuss the Drug Product requirements [21 CFR211.84(d)(2)] (Add after L1180): Section D, an antibiotic coated catheter (ACC) example, which utilizes antimicrobial coating to only inhibit or prevent microbial colonization of the device (i.e., not intended to treat infections), focuses on how to comply with the drug CGMP provisions specified in 21 CFR 4.4(b)(2), for example, 21 CFR Yield Calculations to highlight an issue not raised in the previous examples. Considering that the antimicrobial inhibitory function is intended only to inhibit or prevent microbial colonization of the device (i.e., not intended to treat infections), Yield Calculations may be conducted utilizing different measurement techniques. As Yield is a measure of the active ingredients inhibitory strength, and 21 CFR 210(a)(16) defines Strength as: (i) The concentration of the drug substance (for example, weight/weight, weight/volume, or unit dose/volume basis), and/or (ii) The potency, that is, the therapeutic activity of the drug product as indicated by appropriate laboratory tests or by adequately developed and controlled clinical data There are many devices where a Retain Sample of the entire combination could be cost prohibitive and unnecessary to achieve the intent, however when only considering a part of the combination product, a rationale for this should be generated. Provide clarity and reduce confusion between the two distinct reserve sample types. Additionally, the 21 CFR (d) separates these two requirements into (1) and (2), demonstrating their differences. Add an additional Combination Product example where an inhibitory antibiotic coating products antimicrobial activity s verification and quantitative testing is utilized as a suitable surrogate for the strength determination, i.e., a specific CGMP consideration relating to CGMP provisions specified in 21 CFR 4.4(b). The current Drug Coated Mesh Example only describes drug which treats infections, it does not cover the common Combination Product where an antimicrobial coating/ combination product serves only to inhibit or prevent microbial colonization of the device. Based on 21 CFR Yield Calculation related subsections, the yield calculation: May provide valuable information and insight to the status of a manufacturing process at significant evaluation points, not just for the final product. Provides an important quality check both for a pharmaceutical production process as a whole and for individual unit operations of the process. Requires a prompt and thorough investigation when any increase or decrease in expected yield occurs. 15

16 , 1180, 1595 (expressed, for example, in terms of units by reference to a standard). Potency measures the functional antimicrobial activity by utilizing an appropriate quantitative zone of inhibition (ZOI) measurement technique. Thus, the Yield Calculations, including Theoretical Yield [ 210(a)(17)], Actual Yield [ 210(a)(18)], Percentage of theoretical yield [ 210(a)(19)], may utilize quantitative zone of inhibition data for their calculation. One acceptable zone of inhibition (ZOI) test method which can be conducted utilizing the actual antibiotic treated material, is Performance Standards for Antimicrobial Disk Susceptibility Tests; Approved Standard Eleventh Edition. M02-A11, Vol 32(1), Clinical and Laboratory Standards Institute, January 2012 However, an appropriate zone of inhibition (ZOI) test method can be conducted utilizing the actual antibiotic treated material, e.g., Performance Standards for Antimicrobial Disk Susceptibility Tests; Approved Standard Eleventh Edition. M02-A11, Vol 32(1), Clinical and Laboratory Standards Institute, January 2012 As the FDA Guidance [line 1167] stated, examples are to focus on specific CGMP considerations relating to CGMP provisions specified in 21 CFR 4.4(b)., and.... [Line 1181] intended to highlight only certain issues that a combination product might raise, and considerations for addressing them, relating to the CGMP provisions specified in 21 CFR 4.4(b). The FDA Federal Register Notice clearly describes cgmp differences for antimicrobial coatings which serve only to inhibit or prevent microbial colonization, a function which is significantly different from the current Drug Coated Mesh example treating infections, [Federal Register Vol 78(14), January 22, 2013, p.4316, Comment 24 Response] Based on 21 CFR Yield Calculation related subsections, the yield calculation: May provide valuable information and insight to the status of a manufacturing process at significant evaluation points, not just for the final product. Provides an important quality check both for a pharmaceutical production process as a whole and for individual unit operations of the process. Requires a prompt and thorough investigation when any increase or decrease in expected yield occurs The Federal Register Vol 78(14), January 22, 2013, p.4316, Comment 24 Response stipulates that: (R)egarding the issue of whether verification and testing of antimicrobial activity could be a suitable surrogate for the determination of strength, we note that it would not be appropriate to use a qualitative activity determination (such as a determination of general antimicrobial activity) in place 16

17 , 1180, , 1180, 1595 Add Text (Add after L1595): D. Antibiotic-coated catheter (ACC) 1. Scenario Description Manufacturer A develops an antibiotic coated catheter (ACC) which utilizes antimicrobial coating to only inhibit or prevent microbial colonization of the device (i.e., not intended to treat infections). The primary mode of action is that of a device. This example focuses on how to comply with the drug CGMP provisions specified in 21 CFR 4.4(b)(2), for example, 21 CFR Yield Calculations to highlight an issue not raised in the previous examples. 2. Compliance with drug CGMP requirements different from those described in previous examples; The ACC is a single-entity combination product as defined in 21 CFR 3.2(e)(1) and, therefore, is subject to both the drug CGMPs and device QS regulation. As a device manufacturer, Manufacturer A already has a CGMP operating system designed to comply with the QS regulation and has elected to establish a QS regulation-based CGMP operating system for of a quantitative determination of biological activity (such as a determination of microbial inhibitory concentration (MIC)..... if the antimicrobial coating serves only to inhibit or prevent microbial colonization of the device, then an antimicrobial preservative effectiveness test might be more appropriate Considering that Minimum Inhibitory Concentration (MIC) testing is utilized for varying doses of drug solutions, it would not be appropriate for antimicrobial coated devices. However, an appropriate zone of inhibition (ZOI) test method can be conducted utilizing the actual antibiotic treated material, e.g., Performance Standards for Antimicrobial Disk Susceptibility Tests; Approved Standard Eleventh Edition. M02-A11, Vol 32(1), Clinical and Laboratory Standards Institute, January 2012 The Federal Register Vol 78(14), January 22, 2013, p.4316, Comment 24 Response stipulates that: (R)egarding the issue of whether verification and testing of antimicrobial activity could be a suitable surrogate for the determination of strength, we note that it would not be appropriate to use a qualitative activity determination (such as a determination of general antimicrobial activity) in place of a quantitative determination of biological activity (such as a determination of microbial inhibitory concentration (MIC)..... if the antimicrobial coating serves only to inhibit or prevent microbial colonization of the device, then an antimicrobial preservative effectiveness test might be more appropriate Considering that Minimum Inhibitory Concentration (MIC) testing is utilized for varying doses of drug solutions, it would not be appropriate for antimicrobial coated devices. [line 1167] This section specifies that While each of these types of combination products is subject both to the drug CGMPs and to the QS regulation, each example is used to focus on specific CGMP considerations relating to CGMP provisions specified in 21 CFR 4.4(b)., and.... [Line 1181] This discussion is intended to highlight only certain issues that a combination product might raise, and considerations for addressing them, relating to the CGMP provisions specified in 21 CFR 4.4(b). 17

18 the ACC in accordance with 21 CFR 4.4(b)(2). While Manufacturer A must ensure that this operating system complies with the QS regulation, taking into account all of the issues raised by inclusion of the drug constituent part, this example focuses on considerations for complying with the drug CGMP provisions specified in 21 CFR 4.4(b)(2) which are different from those described in previous examples. Considering that the antimicrobial inhibitory function to inhibit bacterial growth.... a. 21 CFR Yield Calculations For the various yield calculations, overall yield is As Yield is also a measure of the active ingredients strength, and 21 CFR 210(a)(16) defines Strength as: (i) The concentration of the drug substance (for example, weight/weight, weight/volume, or unit dose/volume basis), and/or (ii) The potency, that is, the therapeutic activity of the drug product as indicated by appropriate laboratory tests or by adequately developed and controlled clinical data (expressed, for example, in terms of units by reference to a standard). As Potency is defined as the therapeutic activity of the drug product, measuring the IZ related functional antimicrobial activity by utilizing the ZOI test is an appropriate measurement technique. As the Theoretical and Actual Yield s concentration and potency are measured by the drug concentration sufficient for quantifiable functional Zone of Inhibition (ZOI) activity, the IZ Solution s antimicrobial drug concentration may be used as a surrogate (or alternative) method to measure the device s IZ level as well as the corresponding ZOI functionality FDA clearly describes cgmp differences for antimicrobial coatings which serve only to inhibit or prevent microbial colonization of the device [Federal Register Vol 78(14), January 22, 2013, p.4316, Comment 24 Response], which is significantly different than the Drug Coated Mesh example which treats infections. This difference clearly needs to be described and explained in the guidance document FDA states 1 that the calculation of yield: (S)hall be determined at the conclusion of each appropriate phase of manufacturing, processing, packaging, or holding'' for a drug product. This may provide valuable information and insight to the status of a manufacturing process at significant evaluation points, not just for the final product. In addition, (21 CFR) provides an important quality check both for a pharmaceutical production process as a whole and for individual unit operations of the process. It is important to account for any increase or decrease in expected yield of materials during the manufacturing process. When either occurs, it is important to conduct a prompt and thorough investigation. Appropriate manufacturing controls can help prevent deviations from expected process yield, which can be important to the success of manufacturing steps and to ensuring that the final product meets specifications. Any phase of the pharmaceutical process that is subject to potential component, in-process material, or product loss, due to physical or chemical means, should be evaluated with respect to actual and theoretical yield of these materials. Section does not apply to device constituent parts of combination products. Yield Calculations [21 CFR ] means actual yields and percentages of theoretical yield shall be determined at the 1 Federal Register Vol 78(14), January 22, 2013, p.4315, Comment 22 Response. 18

19 , Section Clarify how the approach adopted would be documented and how it can be confirmed with the Agency. Address the impact of the situation when the manufacturer of the syringe components does not have design controls for the components or won t share them Because no changes are to be made to the drug other than being prefilled into the syringe, design considerations for the drug should serve as inputs for controlling the design of the syringe to ensure its design reflects adequate consideration of the drug s characteristics, as indicated below. It is not expected that the approved drug formulation or aspects of its labeling that are subject to the requirements of CFR 314 or Compendial requirements are subject to design controls as long as there is no change in the indications of the drug product. During review of the drug product, FDA almost always asks for revisions to the labeling. Additionally RLD updates and changes 19 conclusion of each appropriate phase of manufacturing, processing, packaging, or holding of the drug product. Such calculations shall either be performed by one person and independently verified by a second person, or, if the yield is calculated by automated equipment under , be independently verified by one person. Theoretical yield [21 CFR 210(a)(17)] means the quantity that would be produced at any appropriate phase of manufacture, processing, or packing of a particular drug product, based upon the quantity of components to be used, in the absence of any loss or error in actual production. Actual yield [21 CFR 210(a)(18)] means the quantity that is actually produced at any appropriate phase of manufacture, processing, or packing of a particular drug product. Percentage of theoretical yield [21 CFR 210(a)(19)] means the ratio of the actual yield (at any appropriate phase of manufacture, processing, or packing of a particular drug product) to the theoretical yield (at the same phase), stated as a percentage. The approved drug product should not be subject to design controls, as there already is a regulated pathway to ensure that the drug product and its labeling are of acceptable quality. This is consistent with the information provided in lines of the proposed guidance. Additionally, drug product labeling is subject to frequent modification due to regulation (e.g., minor changes to the Reference Listed Drug package insert) and changes in regulatory expectations (e.g., the use of Single Use vs Single Dose). This level of documentation is too granular for the design inputs and outputs, as these frequent changes would result in unnecessary churn of the Design History File.