AdvaMed Comments on Combination Product Current Good ... · the drug CGMP-based or QS...

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April 29, 2015

Division of Dockets Management (HFA-305)

Food and Drug Administration

5630 Fishers Lane, Room 1061

Rockville, MD 20852

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comments on FDA’s draft guidance “Current Good Manufacturing Practice Requirements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number of significant issues with the guidance and, importantly, the draft guidance does not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 Our specific comments on the draft guidance are provided in the attachment.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also attached a line-numbered version of the draft guidance to facilitate your review.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thoughts about the draft guidance are provided below.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

Docket No. FDA-2009-N-0435

April 29, 2015

Page 2 of 20

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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

ADVAMED COMMENTS Good Manufacturing Practice Requirements for Combination Products

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Strikeout = deleted text Underline = suggested new text

Line # Change Reason

1. 66 & 67 Revise to add the following at the end of this sentence: “The final rule does not establish any new requirements.”

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

2. 76 Revise to read as follows: “as to further inform” Editorial change

3. 79 Revise to read as follows: “Instead, this guidance describes” Editorial change

4. 84

(Footnote 2) Add the page range to incorporate entire content of FR notice.

To ensure the reader understands all of the FDA viewpoints in comment/ FDA response.

5. 89 Revise to read as follows: “but is not required” Editorial change

6. 106-114 Specify whether there can be an accessory to a combination product and how it would be regulated.

Clarification. The guidance provides no discussion on accessories of the specific constituent devices or accessories to the combination product (CP) itself.

7. 148 Revise to read as follows: “. . . streamlined approach, demonstrating full compliance with either the drug CGMPs . . . .”

Clarification

8. 175 Revise to read as follows: “The complete drug and the following provisions from the QS regulation in accordance . . .”

Clarification consistent with 21 CFR 4.4(b)(1)

9. 184 Revise to read as follows: “The complete QS regulation and the following provisions from the drug CGMPs in accordance . . .”

Clarification consistent with 21 CFR 4.4(b)(2)

10. 199 Include the CGMP regulation for Biologics/HCT/P). 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).

11. 211-213

Revise to read as follows:

“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.

As written, this can be interpreted to mean that only the 6 device sections or only the 8 drug sections listed in lines 177-195 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.


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12. 216-220


“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 CGMP-based or QS regulation-based streamlining approach.”

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.

13. 216-220

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.

Clarification.

14. 223

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.

Clarification on the PMOA and how it is determined for a new type of combination product would be helpful in this section.

15. 262

Revise to read as follows: “Manufacturers must demonstrate that each applicable CGMP requirement is complied with for the corresponding constituent parts and the combination product, if appropriate.”

Clarification.

16. 263-265


“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).”

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.4308-9, 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.

17. 265 Revise to read as follows: “. . . applicable to its the product” Clarification


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18.

Section C.4.2

Definitions

306-401

Add the following definition to this section:

“Reserve Sample [§211.170]:

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.”

“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 807-810; “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.”

19.

Section C.4.2

Definitions

306-401

Add the following definition to this section:

“Retained Sample[§211.84(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 807-810; “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.”


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limited to:

o Sections of a catheter that was extruded, coated and packaged in the same manner as the finished product

o 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 211.170 and may fulfill the same function [21 CFR 211.84(b); 21 CFR 211.170].”

20. 312-330

Add the following to the Manufacturer definition:

“. . . . 19 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.”

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 134.31, 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.

21. 313 - 330

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)

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


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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 biologic-device 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).

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.

22. 346-347 Revise to read as follows: “. . . .device component (not a finished device) per 21 CFR Part 820.3(c) and is not otherwise subject to the QS regulation . . .”

Clarification. Provided reference from regulation to define a “component.”

23. 348 Revise to read as follows: “ . . . for a combination product solely because of 21 CFR Part 4.”

Clarification

24. 369 Revise to read as follows: “demonstrate compliance with both the drug CGMPs and QS regulation per applicability of Sec 4.4.

Clarification

25. 370-385

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.

Clarification.

26. 373-385


“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

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


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raises additional considerations. For example, when establishing batch testing and release and product stability testing criteria under 21 CFR 211.165 and 211.166, 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 820.30.

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 211.165 and 211.166, 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 820.30, 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…

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 370-385 of the guidance document. The Agency should consider appropriate risk analyses in making these recommendations.

27. 387 Revise to read as follows: “. . . a kit that includes two or more different types of medical products”

Clarification


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28. 392-393

Revise to read as follows: “2) 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…”

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.

29.

Footnote 14

(402-405; 440-443)

Reference the “Convenience Kits Interim Regulatory Guidance.”

Clarification

http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm080216.htm

30. 415

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).

Clarification

31. 415-426

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.”

Federal Register Vol 78(14), January 22, 2013, p.4316, Comment 24 Response

32. 467-468 Clarify designation of “Legal Manufacturer,” place of manufacture on the labeling, and also for custom and import/export purposes.

Maybe an oversight of FTC, not FDA; but need to reach a common ground. “Place of substantial transformation vs PMOA.”

33. 467-527 Add additional information regarding post market data/complaint data into the applicable CGMP systems operated at different facilities.

Clarification

34. 469-471


“The combination product sponsor17

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

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




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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.

application holder’s quality agreement.

35. 478-494


“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.

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.

36. 512 Clarify whether “testing” refers to the combination product or the constituent.

Clarification of what is being tested

37. 535 Revise to read as follows: “. . . that might arise from changes to the product or any constituent part of the product”

Clarification

38. 537-540

Revise to read as follows::

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.

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.

39. 591-592 Revise to read as follows: “All such controls should be designed to reduce, eliminate, or ideally, prevent qualify nonconformities ensure quality of the finished product”

By keeping this sentence more generic, it eliminates confusion between the CGMP requirements and other processes such as lean six sigma functions.

40. 640-641


“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.”

On Lines 370-376, the guidance states that certain Class I devices are exempt from certain device GMPS including design controls


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41. 641- 643


“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 820.30. ICH Q8 was design to meet the intended uses of the product.

42. 663 Add reference to 820.30(c). Reference Design Inputs from 21 CFR Part 820.

43. 664-665 Revise to read as follows “…and expected product users needs of product users and patients.”

Clarification.

44. 670 Include additional detail regarding approvals. Per 820.30(c), (d), (e), (f), etc. “The approval, including the date and signature of the individual(s) approving the requirements, shall be documented.”

45. 675 Revise to read as follows: “for its intended use, under actual or simulated use conditions.

Clarity for Verification vs. Validation.

46. 671-684

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.

Clarification. Make the paragraphs regarding design input, output, verification, validation follow a consistent explanation of approvals, documentation in the DHFs, etc.

47. 685 Revise to read as follows: “. . . requires that the manufacturer complete perform risk analysis. . . “

Clarification. Risk Analysis is a continuous process.

48. 696 See 21 CFR 820.3(aa). 820.320(f) Provide correct reference.

49. 697 See 21 CFR 820.3(z)(2). 820.320(g) Provide correct reference.

50. 698 Footnote Number “32” needs to be made into a superscript Editorial change

51. 700 Include reference to FDA guidance on software validation. Clarification http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm085281.htm

52. 709 This paragraph mentions Design Transfer for the first time. Include reference to Design Transfer (21 CFR 820.320(h) in the reference as a footnote.

Clarification




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53. 713 Revise to read: “should address all the design issues . . .” The term “all” is too inclusive and implies potentially exhaustive theoretical issues.

54. 722-725

Revise to read as follows: “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 820.30(i).”

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.

55. 738-743

Footnote 33 Include reference to ISO 14971 for risk. Clarification

56. 844 Revise to read as follows: “21 CFR 211.84 details describes how to sample, test, examine . . .”

21 CFR 211.84 does not detail these processes, it merely describes them.

57. 880 Revise to read: “All discrepancies in yYield discrepancies outside of expected documented variation should be investigated.”

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.

58. 888 Clarify whether/how automated equipment must be validated and cite Reference Process validation guidance.

Clarification http://www.fda.gov/downloads/Drugs/Guidances/UCM070336.pdf

59. 881-886


“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.”

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.

60. 891-892 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.”

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.

http://www.fda.gov/downloads/Drugs/Guidances/UCM070336.pdf

http://www.fda.gov/downloads/Drugs/Guidances/UCM070336.pdf


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61. 902 Revise to read as follows: “tamper-evident packaging and labeling alerting to alert customers regarding potential compromises to the product packaging.”

Clarification

Alert is for potential breaches/compromised packaging and not to protect the features as such.

62. 926-933 Clarify that the co-packaged entity retains its own expiration dating within its labeling inside the packaged CP.

Clarification

63. 950-951

Revise to read as follows: “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 co-packaged combination product,”

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.

64.

989-991

(Footnote 54)

Revise to read as follows: “See 21 CFR 4.3, 4.4, and 211.166. 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 820.30. This device functionality testing can be demonstrated during development only, if adequately studied and justified.”

Clarify whether testing of the device functionality requires real-time 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.

65. 996

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.

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 1013-1018.

66. 998-999


“Specifically, 21 CFR 211.167(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

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.


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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.”

67. 1006-1012


“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 211.167(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).”

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 11137-1 & -2, ISO 17665-1, and ISO 20857.

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 211.167 for the elimination of batch-specific sterility testing.

68. 1013-1018


“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 820.30 and purchasing control requirements under 21 CFR 820.50), rather than batch testing under 21 CFR 211.167(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 211.167(a).”

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

211.167(a), and

The more specifically applicable regulation, and

The requirement most specifically applicable.

Thus, this particular situation should be “addressed in the FDA guidance”


15


69. 1037-1040


“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.”

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.

70. 1041-1054

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)]

Provide clarity and reduce confusion between the two distinct reserve sample types. Additionally, the 21 CFR § 211.84(d) separates these two requirements into § (1) and (2), demonstrating their differences.

71. 1167, 1180,

1595

(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 211.103 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

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 211.103 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.


16


(expressed, for example, in terms of units by reference to a standard).”

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

72. 1167, 1180,

1595

“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”

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 211.103 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


17


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

73. 1167, 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 211.103 Yield Calculations to highlight an issue not raised in the previous examples.”

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.

74. 1167, 1180,

1595

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

[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).


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 211.103 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 states1 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) 211.103 provides an important quality check both for a pharmaceutical production process as a whole and for individual unit operations of the process. It is important to account for any increase or decrease in expected yield of materials during the manufacturing process. When either occurs, it is important to conduct a prompt and thorough investigation.

Appropriate manufacturing controls can help prevent deviations from expected process yield, which can be important to the success of manufacturing steps and to ensuring that the final product meets specifications. Any phase of the pharmaceutical process that is subject to potential component, in-process material, or product loss, due to physical or chemical means, should be evaluated with respect to actual and theoretical yield of these materials. Section 211.103 does not apply to device constituent parts of combination products.”

Yield Calculations [21 CFR 211.103] 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.


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 211.68, 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.

75. 1193,

Section 1.

Clarify how the approach adopted would be documented and how it can be confirmed with the Agency.

Clarification

76. 1233-1240 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.

Clarification

77.

1242 - 1245 Revise to read as follows:

“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.”

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 713 – 725 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.

78. 1251-1263 During review of the drug product, FDA almost always asks for revisions to the labeling. Additionally RLD updates and changes

Clarification


20


in labeling standards result in additional labeling changes. Provide guidance on the level of detail that should be included in the DHF for labeling so that these changes would not result in unnecessary churn of the DHF.

79. 1252-1263 Provide separate verification description and examples from validation description.

Clarification

80. 1267 Revise to read as follows: “reduce or mitigate any unacceptable risk (s) to acceptable levels.

Clarification

81. 1273-1283

Specify whether it is sufficient to have this information kept within the pharmaceutical quality system as is currently done, or whether all of these requirements become design outputs and go through the 820 requirements. Specify also whether the DHF can have broad pointers or individual pointers to the pharma quality system for those items that have historically been handled within the drug CFR.

Clarification. This is very important for legacy products; particularly those that are part of a syringe system platform, which has not had DHF.

82. 1588 Revise to read as follows: “..stents to that use that particular lot of the bulk drug . . .”

Clarification

January 2015

Guidance for Industry and 1

FDA Staff: 2

Current Good Manufacturing Practice 3

Requirements for Combination Products 4

DRAFT GUIDANCE 5

This guidance document is being distributed for comment purposes only. 6

Comments and suggestions regarding this draft document should be submitted within 60 days of 7

publication in the Federal Register of the notice announcing the availability of the draft guidance. 8

Submit written comments to the Division of Dockets Management (HFA-305), Food and Drug 9

Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. Submit electronic comments to 10

http://www.regulations.gov. All comments should be identified with the docket number listed in the 11

notice of availability that publishes in the Federal Register. 12

Additional copies are available from: 13

Office of Combination Products 14

Food and Drug Administration 15

WO32, Hub/Mail Room #5129 16

10903 New Hampshire Avenue 17

Silver Spring, MD 20993 18

(Tel) 301-796-8930 19

(Fax) 301-847-8619 20

http://www.fda.gov/oc/combination 21

For questions regarding this document, contact John Barlow Weiner, Associate Director for 22

Policy, Office of Combination Products, at 301-796-8930 or [email protected]. 23

U.S. Department of Health and Human Services 24

Food and Drug Administration 25

Office of Combination Products (OCP) in the Office of the Commissioner 26

Center for Biologics Evaluation and Research (CBER) 27

Center for Drug Evaluation and Research (CDER) 28

Center for Devices and Radiological Health (CDRH) 29

Office of Regulatory Affairs (ORA) 30

http://www.regulations.gov/

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

mailto:[email protected]

TABLE OF CONTENTS 31

I. Introduction ................................................................................................................................ 3 32

II. Background ............................................................................................................................... 4 33

A. Definition of a combination product ........................................................................................... 4 34

B. Overview of the final rule ............................................................................................................. 5 35

C. The role of the lead center and other agency components ........................................................ 7 36

III. General Considerations for CGMP Compliance .................................................................... 8 37

A. Demonstrating compliance........................................................................................................... 8 38

B. Investigational products ............................................................................................................... 8 39

C. 4.2 Definitions ................................................................................................................................ 9 40

D. What CGMP requirements apply to a product or facility? .................................................... 12 41

E. Control of changes to a combination product .......................................................................... 15 42

IV. What do I need to know about the CGMP requirements specified in 21 CFR 4.4(b)? . 15 43

A. Provisions from the QS regulation specified in 21 CFR 4.4(b)(1) .......................................... 15 44

B. Provisions from the drug CGMPs specified in 21 CFR 4.4(b)(2) ........................................... 21 45

C. Combination products that include biological products and HCT/Ps ................................... 28 46

V. Application of CGMP requirements to specific types of combination products ................... 30 47

A. Prefilled syringe .......................................................................................................................... 31 48

B. Drug-coated mesh ....................................................................................................................... 35 49

C. Drug Eluting Stent (DES)........................................................................................................... 39 50

VI. Contact Us .............................................................................................................................. 43 51

VII. References ............................................................................................................................. 44 52

3

Contains Nonbinding Recommendations 53 Draft — Not for Implementation 54

Guidance for Industry and FDA Staff: 55

Current Good Manufacturing Practice Requirements for Combination 56

Products1 57

This draft guidance, when finalized, will represent the Food and Drug Administration’s

(FDA’s) current thinking on this topic. It does not create or confer any rights for or on any

person and does not operate to bind FDA or the public. You can use an alternative approach if

the approach satisfies the requirements of the applicable statutes and regulations. If you want

to discuss an alternative approach, contact the FDA staff responsible for implementing this

guidance. If you cannot identify the appropriate FDA staff, call the appropriate number listed

on the title page of this guidance.

58

I. Introduction 59

This guidance describes and explains the final rule on CGMP requirements for 60

combination products (final rule as codified in 21 CFR part 4) that FDA issued on January 22, 61

2013.2 Prior to issuance of the final rule, although CGMP regulations were in place to establish 62

requirements for drugs, devices, biological products, and Human Cells, Tissues, and Cellular and 63

Tissue-Based Products (HCT/Ps), there were no regulations to clarify and explain the application 64

of these CGMP requirements to combination products. The final rule was intended to provide 65

such clarification and specify how compliance with applicable CGMP requirements may be 66

demonstrated. 67

Section II of this document provides the definition of a combination product, an 68

overview of the final rule, and the role of the lead center and other agency components with 69

respect to combination product CGMP issues. Section III addresses certain general 70

considerations for CGMP compliance for combination products, and Section IV presents the 71

purpose and content of specific CGMP requirements addressed in the final rule, and Section V 72

analyzes hypothetical scenarios intended to clarify how to comply with certain CGMP 73

requirements addressed in the final rule. Throughout this guidance, the agency also refers to 74

existing guidance and additional sources of information that address CGMP requirements for 75

drugs, devices, biological products, and HCT/Ps, as further inform combination product 76

manufacturers on how to comply with CGMP requirements. 77

FDA’s guidance documents, including this guidance, do not establish legally enforceable 78

responsibilities. Instead, guidance describe the agency’s current thinking on a topic and should 79

be viewed only as recommendations, unless specific regulatory or statutory requirements are 80

1 This guidance was prepared by the Office of Combination Products in the Office of the Commissioner in 81 conjunction with the Center for Biologics Evaluation and Research, Center for Drug Evaluation and Research, 82 Center for Devices and Radiological Health, and the Office of Regulatory Affairs. 83 2 See the Current Good Manufacturing Practice Requirements for Combination Products, 78 FR 4307 (January 22, 84 2013). 85

4


cited. The use of the word should in agency guidance means that something is suggested or 88

recommended, but not required. 89

II. Background 90

A. Definition of a combination product 91

As set forth in 21 CFR part 3, a combination product is a product composed of any 92

combination of a drug, device, or biological product.3 The drugs, devices, and biological 93

products included in combination products are referred to as “constituent parts” of the 94

combination product. 95

Under 21 CFR 3.2(e), a combination product includes: 96

A product comprised of two or more regulated components, i.e., drug/device, 97

biologic/device, drug/biologic, or drug/device/biologic, that are physically, 98

chemically, or otherwise combined or mixed and produced as a single entity (a 99

“single entity” combination product, such as a prefilled syringe or drug-eluting 100

stent); 101

Two or more separate products packaged together in a single package or as a 102

unit and comprised of drug and device products, device and biological products, 103

or biological and drug products (a “co-packaged” combination product, such as a 104

surgical or first-aid kit); 105

A drug, device, or biological product packaged separately that according to its 106

investigational plan or proposed labeling is intended for use only with an 107

approved, individually specified drug, device, or biological product where both 108

are required to achieve the intended use, indication, or effect and where upon 109

approval of the proposed product the labeling of the approved product would need 110

to be changed (e.g., to reflect a change in intended use, dosage form, strength, 111

route of administration, or significant change in dose) (a “cross-labeled” 112

combination product, as might be the case for a light-emitting device and a light-113

activated drug); or 114

3 For purposes of 21 CFR part 3 and the CGMP rule for combination products, a “biological product” means a 115 biological product subject to regulation under section 351 of the Public Health Service Act (the PHS Act, 42 116 U.S.C. 262). All biological products regulated under the PHS Act meet the definitions of drug or device in section 117 201 of the Federal Food, Drug, and Cosmetic Act (the FD&C Act, 21 U.S.C. 321). Any reference in this guidance 118 to CGMP requirements as applicable to a combination product that includes a drug constituent part should be 119 understood to refer as well to any combination product that includes a biological product constituent part that is 120 also subject to regulation under the FD&C Act as a drug, and any reference to CGMP requirements as applicable 121 to a combination product that includes a device constituent part should be understood to refer as well to 122 combination products that include a biological product constituent part that is also subject to regulation as a device 123 under the FD&C Act. 124

5


Any investigational drug, device, or biological product packaged separately that 127

according to its proposed labeling is for use only with another individually 128

specified investigational drug, device, or biological product where both are 129

required to achieve the intended use, indication, or effect (another type of cross-130

labeled combination product). 131

B. Overview of the final rule 132

As stated in the final rule, the constituent parts of a combination product retain their 133

regulatory status (as a drug or device, for example) after they are combined. The final rule 134

clarifies that the CGMP requirements that apply to each of the constituent parts apply to 135

the combination product they constitute. 136

The final rule on CGMP requirements for combination products applies to all 137

combination products. As stated in the preamble to the final rule, the CGMP requirements for 138

constituent parts of cross-labeled combination products that are manufactured separately and not 139

co-packaged are the same as those that would apply if these constituent parts were not part of a 140

combination product (e.g., for a drug/device combination product, 21 CFR parts 210 and 211 141

would apply to the manufacture of the drug constituent part(s) of the cross-labeled combination 142

product, and 21 CFR part 820 would apply to the device constituent part(s)). 143

For single-entity and co-packaged combination products, part 4 offers two ways to 144

demonstrate compliance with CGMP requirements. Under the first option, manufacturers 145

demonstrate compliance with all CGMP regulations applicable to each of the constituent parts 146

included in the combination product.4 Under the second option, manufacturers implement a 147

streamlined approach, demonstrating compliance with either the drug CGMPs (21 CFR part 148

211) or the quality system (QS) regulation (21 CFR part 820) rather than demonstrating full 149

compliance with both, when the combination product contains both a drug and a device, under 150

certain conditions.5 These conditions include demonstrating compliance with specified 151

provisions from the other of these two sets of CGMP requirements. In addition, for a 152

combination product that includes a biological product, the CGMP requirements for biological 153

products in parts 600 through 680 (21 CFR parts 600 through 680) would apply, and, for a 154

combination product that includes any HCT/Ps, the regulations in part 1271 (21 CFR part 155

1271)—including the current good tissue practice (CGTP) requirements and donor eligibility 156

requirements—would apply.6,7, 8 157

4 See 21 CFR 4.4(a) 158 5 See 21 CFR 4.4(b). 159 6 See 21 CFR 4.4(a) and (b). 160 7 As discussed later in section IV.C, an HCT/P may be a “constituent part” of a combination product when the 161 HCT/P is not regulated solely under section 361 of the PHS Act because it fails to meet one or more of the criteria in 162 21 CFR 1271.10 and is regulated as a drug, device, and/or biological product. See also 21 CFR 1271.20. 163

8 For the purposes of part 4, FDA uses the term “CGMP requirements” to include all such requirements found in the 164 standards in parts 600 through 680 that may apply to biological products. We note that biological products and 165 combination products that include biological product constituent parts must comply with all applicable requirements 166 in parts 600 through 680. Because many of the requirements in parts 600 through 680 are not considered CGMP 167 requirements, such requirements are not covered by the final rule and are not a focus of this guidance. 168

6


Specifically, the streamlined approach under 21 CFR 4.4(b) provides that combination 171

product manufacturers may meet the requirements of both the drug CGMPs and device QS 172

regulation by designing and implementing a CGMP operating system that is demonstrated to 173

comply with either of the following: 174

The drug CGMPs and the following provisions from the QS regulation in accordance 175

with 21 CFR 4.4(b)(1) (considered a drug CGMP-based streamlining approach): 176

(i) 21 CFR 820.20. Management responsibility 177

(ii) 21 CFR 820.30. Design controls 178

(iii) 21 CFR 820.50. Purchasing controls 179

(iv) 21 CFR 820.100. Corrective and preventive action 180

(v) 21 CFR 820.170. Installation 181

(vi) 21 CFR 820.200. Servicing 182

OR 183

The QS regulation and the following provisions from the drug CGMPs in accordance 184

with 21 CFR 4.4(b)(2) (considered a QS regulation-based streamlining approach): 185

(i) 21 CFR 211.84. Testing and approval or rejection of components, drug 186

product containers, and closures 187

(ii) 21 CFR 211.103. Calculation of yield 188

(iii) 21 CFR 211.132. Tamper-evident packaging requirements for over-the- 189

counter (OTC) human drug products 190

(iv) 21 CFR 211.137. Expiration dating 191

(v) 21 CFR 211.165. Testing and release for distribution 192

(vi) 21 CFR 211.166. Stability testing 193

(vii) 21 CFR 211.167. Special testing requirements 194

(viii) 21 CFR 211.170. Reserve samples 195

21 CFR 4.4(c) provides that if a facility manufactures only a constituent part of a co-196

packaged or single-entity combination product, that facility is subject only to the CGMP 197

regulations applicable to that constituent part (e.g., 21 CFR part 211 for a drug or 21 CFR part 198

820 for a device). 21 CFR 4.4(d) provides that when two or more types of constituent parts to be 199

included in a single-entity or co-packaged combination product have arrived at the same facility, 200

or the manufacture of these constituent parts is occurring at the same facility, that facility must 201

comply with all CGMP requirements described in 21 CFR part 4 applicable to the 202

manufacturing activities at that facility, and a streamlined approach under 21 CFR 4.4(b) may be 203

used to demonstrate compliance with these requirements. 204

7


As described above, facilities subject to section 4.4(d) may opt to implement a 207

streamlined approach under 21 CFR 4.4(b) by either adopting a drug CGMP-based or QS 208

regulation-based streamlining approach. A manufacturer may prefer one approach over the other 209

based, for example, on the details of the manufacturing process used at the facility or in light of 210

other manufacturing activities undertaken at the facility. Regardless, manufacturers should 211

consider how to manage internal documentation to demonstrate compliance with all applicable 212

CGMP requirements. 213

The agency intends to apply the same policies when inspecting combination product 214

manufacturers regardless of whether the manufacturer chooses to adopt a streamlined approach or 215

to implement both the drug CGMPs and the device QS regulation in their entirety. To facilitate 216

efficient inspection, the agency recommends that manufacturers who choose to operate under a 217

streamlined approach clearly identify in their premarket submissions and at the initiation of an 218

inspection whether they are operating under the drug CGMP-based or QS regulation-based 219

streamlining approach. Manufacturers using either a streamlined approach or opting to implement 220

all applicable CGMP requirements should be able to identify and readily access for FDA 221

inspection all documentation needed to demonstrate compliance with 21 CFR part 4. 222

C. The role of the lead center and other agency components 223

A combination product is assigned to an agency center that will have primary jurisdiction 224

(i.e., the lead) for that combination product’s premarket review and regulation. Under section 225

503(g)(1) of the FD&C Act, assignment of a combination product to a center with primary 226

jurisdiction is based on a determination of which constituent part provides the primary mode of 227

action (PMOA) of the combination product.9 228

If the PMOA of a device-biological product combination product is attributable to the 229

biological product, for example, the agency component responsible for premarket review of that 230

biological product would have primary jurisdiction for the regulation of the combination product. The 231

lead center for premarket review of the combination product also has the lead for ensuring 232

compliance with CGMP regulatory requirements. Regardless of the PMOA, agency components will 233

coordinate as appropriate to enable efficient, effective CGMP regulatory oversight, including 234

appropriate CGMP inspections. 235

It is important to note that if a manufacturer adopts a streamlined approach, the manufacturer 236

is not required to choose the CGMP regulations associated with the constituent part that provides the 237

PMOA of the combination product as the base system. For example, if the drug constituent part of a 238

drug-device combination product provides the product’s PMOA, the manufacturer of that 239

combination product may choose to adopt the QS regulation-based streamlining approach. 240

For a combination product, the lead center is a manufacturer’s primary point of contact. 241

Manufacturers may also contact the Office of Combination Products (OCP) for assistance as needed, 242

9 The “primary mode of action” of a combination product is the single mode of action (drug, device, or biological 243 product) that provides the most important therapeutic action of the combination product. The most important 244 therapeutic action is the mode of action expected to make the greatest contribution to the overall intended 245 therapeutic effects of the combination product. See 21 CFR 3.2(k) and (m). 246

8


to identify appropriate contact points, help resolve substantive issues, or otherwise facilitate 249

interactions with the agency for combination products. 250

III. General Considerations for CGMP Compliance 251

As described above and in the final rule, a combination product must comply with all 252

applicable CGMP regulations. This section addresses some general considerations for CGMP 253

compliance for combination products. 254

A. Demonstrating compliance 255

As discussed in section II above, the final rule offers two ways for co-packaged and 256

single-entity combination product manufacturers to demonstrate compliance with applicable 257

CGMP requirements. As noted in the preamble to the final rule, the term “demonstrate” is not 258

intended to have a new meaning for purposes of part 4. The agency intends for it to be 259

interpreted in the same manner as it would be for purposes of the CGMP regulations listed in 21 260

CFR 4.3. Manufacturers must demonstrate that each applicable CGMP requirement is complied 261

with for constituent parts and the combination product, if appropriate.10

262

If a streamlined approach is used, the manufacturer must demonstrate compliance with 263

all of the relevant provisions of either the drug CGMPs or QS regulation, and the provisions 264

specified in 21 CFR 4.4(b) for the other set(s) of CGMP requirements applicable to its product. 265

Further guidance on how to demonstrate compliance with the other constituent part’s 266

regulations specified in 21 CFR 4.4(b) is provided in section IV of this guidance. As that 267

discussion explains, some of these specified provisions address issues focusing on one type of 268

constituent part (e.g., reserve sampling). Others address issues that may concern multiple 269

constituent parts or the combination product as a whole (e.g., design controls or corrective and 270

preventive action (CAPA)). 271

This guidance does not focus on how to demonstrate compliance with the provisions of 272

the drug CGMPs and device QS regulation that are not specified in 21 CFR 4.4(b)). Such 273

provisions address a variety of manufacturing considerations regarding, for example, in-process 274

materials, facility and equipment, record-keeping, labeling, personnel, inputs, testing, and 275

distribution. 276

B. Investigational products 277

Part 4 does not alter the scope of the underlying CGMP regulations for drugs, devices, 278

biological products, and HCT/Ps. In particular, part 4 does not alter the applicability of these 279

CGMP regulations to investigational products. 280

An investigational drug for use in a phase 1 study is subject to the statutory requirements 281

set forth in 21 U.S.C. 351(a)(2)(B). The production of such a drug is generally exempt from 282

10 21 CFR part 4. 283

9


compliance with the regulations in 21 CFR parts 210 and 21111

and, therefore, so is an 286

investigational combination product that includes a drug constituent part for use in a phase 1 287

study. This exemption does not apply to an investigational combination product or drug 288

constituent part, however, once it has been made available for use by or for the sponsor in phase 289

2 or phase 3 studies, nor does the exemption apply to a drug product that has been lawfully 290

marketed. 291

Under 21 CFR 812.1, investigational devices are exempt from part 820 except for design 292

control requirements under 21 CFR 820.30.12

This exemption also applies to investigational 293

combination products that include an investigational device constituent part. 294

The agency considers these exemptions from requirements under parts 211 and 820 295

applicable to combination products and constituent parts of combination products, whether being 296

studied under an investigational device exemption (IDE) or an investigational new drug 297

application (IND). Even when these regulatory CGMP exemptions apply, however, methods, 298

facilities, and manufacturing controls that are appropriate for the investigational products should be 299

used. When applying appropriate manufacturing practices, the agency recommends that the hazards 300

and associated risks from the manufacturing environment that might adversely affect an 301

investigational combination product be considered. 302

For further information on CGMP for investigational products, see 21 CFR 210.2(c), 21 CFR 303

820.1, and 61 FR 52,616-52,617, and the Guidance for Industry on CGMP for Phase 1 304

Investigational Drugs (July 2008). 305

C. 4.2 Definitions 306

Unless part 4 expressly states otherwise, terms used have the same meaning as when used 307

in the underlying, referenced regulations. This section addresses the meaning and significance for 308

combination products of the terms “manufacture” and “manufacturer,” “constituent part,” 309

“component,” “device,” and drug “container” and “closure.” It also addresses the meaning of 310

“convenience kit” as a type of combination product. 311

1. “Manufacture” and “manufacturer” 312

The definition of the term “manufacture” in 21 CFR 4 is intended to include all of the 313

activities considered within the scope of manufacturing for drugs, devices, biological products, 314

and HCT/Ps. Accordingly, the definition of “manufacture” in 21 CFR 4.2 includes, but is not 315

limited to, designing, fabricating, assembling, filling, processing, testing, labeling, packaging, 316

repackaging, holding, and storage. Therefore, an entity that undertakes any of these activities for 317

11 See 21 CFR 210.2(c). 318 12 The preamble to the QS regulation (61 FR 52602) provides additional detail on when design controls apply for 319 products early in the design life-cycle: “The design control requirements are not intended to apply to the 320 development of concepts and feasibility studies. However, once it is decided that a design will be developed, a plan 321 must be established to determine the adequacy of the design requirements and to ensure that the design that will 322 eventually be released to production meets the approved requirements.” (61 FR 52616, Comment 62) 323

10


a combination product is a manufacturer under 21 CFR part 4. For example, if a company 326

designs a drug-device combination product, that activity constitutes the manufacture of that 327

product, thus the facility at which the design work occurs is a manufacturing facility and that 328

entity is a manufacturer, even if all other aspects of the combination product’s manufacture (e.g., 329

fabricating, labeling, or packaging) are performed by a third-party contractor. 330

2. “Constituent part” versus “component” 331

As discussed in the preamble to the final rule, the term “constituent part” is used by the 332

agency as a succinct way to identify a drug, device, or biological product included in a 333

combination product. Under the drug CGMPs (21 CFR 210.3), “component” is defined as “any 334

ingredient intended for use in the manufacture of a drug product, including those that may not 335

appear in such drug product.” Under the QS regulation (21 CFR 820.3(c)), the term 336

“component” is defined as “any raw material, substance, piece, part, software, firmware, 337

labeling, or assembly which is intended to be included as part of the finished, packaged, and 338

labeled device.” 339

In short, the terms “constituent part” in 21 CFR part 4 and “component” in the CGMP 340

regulations serve different regulatory purposes. The use of the term “constituent part” in part 4 to 341

refer to drugs, devices, and biological products included in combination products does not alter 342

the meaning of the term “component” or alter the applicability of the regulations listed in 21 CFR 343

4.3 to components. 344

Accordingly, if a facility is solely manufacturing an article that would be considered a 345

device component (not a finished device) and is not otherwise subject to the QS regulation (see 346

21 CFR 820.1(a)), it is not subject to the QS regulation for the manufacture of that component 347

solely because of 21 CFR part 4. 348

3. Drug containers and closures versus delivery devices 349

The agency draws a distinction between drug containers and closures and delivery 350

devices. The essential distinction is whether the article is designed to deliver the drug it contains 351

or merely to hold it. 352

If the article merely holds the drug, it is only subject to drug CGMPs as a container or 353

closure. A container closure system is the sum of packaging components that together contain 354

and protect the drug product. This includes primary and secondary packaging components if the 355

latter are intended to provide additional protection to the drug product.13

A packaging system 356

may be considered a container closure system. A packaging component is any single part of a 357

container closure system. Examples of packaging components are containers, ampules, vials, 358

screw caps, stoppers, and stopper overseals. 359

13 See the Guidance for Industry on Container Closure Systems for Packaging Human Drugs and Biologics: 360 Chemistry, Manufacturing, and Controls Documentation (May 1999). 361

11


An article that does not merely hold or contain the drug, but also delivers it, is not merely 364

a container or closure and may also be subject to the QS regulation. A piston syringe, for 365

example, is not only a container or closure. A piston syringe is a device used to deliver another 366

medical product, as described in 21 CFR 880.5860, and is subject to the QS regulation. 367

Accordingly, a syringe filled with a drug, for example, is a combination product and must 368

demonstrate compliance with both the drug CGMPs and QS regulation. 369

There are other delivery devices, such as simple liquid medication dispensing devices 370

regulated under 21 CFR 880.6430, that are Class I devices exempt from the QS regulation except 371

for the requirements of 21 CFR 820.180 (general requirements for records) and 21 CFR 820.198 372

(complaint files), neither of which is a specified provision under 21 CFR 4.4(b)(1). If such a 373

liquid medication dispenser is co-packaged with a drug as a “convenience kit” (see III.C.4 374

below), generally speaking no additional CGMP requirements would apply to that dispenser or to 375

the combination product under part 820 simply because that dispenser is included in the kit. 376

Note, however, that a device constituent part incorporated into a drug container raises additional 377

considerations. For example, when establishing batch testing and release and product stability 378

testing criteria under 21 CFR 211.165 and 211.166, a dropper incorporated into a drug 379

container’s cap would need to be addressed as part of the drug container because it would come 380

into contact with the drug product. Similarly, when such a dropper is used in conjunction with 381

the drug, the dropper may need to meet certain specifications for dosing of the specific drug 382

product or for maintaining its integrity while in contact with the drug product, for example. As a 383

result, design controls specific to the use of the dropper and its contact with the drug product may 384

be needed and apply under 21 CFR 820.30. 385

4. Convenience kits 386

As explained in the preamble to the final rule, a kit that includes two or more types of 387

medical products (e.g., a device and a drug) is a co-packaged combination product and, 388

therefore, the manufacture of the kit is subject to part 4. The CGMP requirements applicable to 389

a kit manufacturer depend on what products are included in the kit. The preamble to the final 390

rule also states that if the kit includes only products that are 1) also legally marketed 391

independently and 2) included in the kit as already packaged for independent marketing and 392

with the same labeling as required for independent marketing, it is a “convenience kit,” and the 393

only manufacturing steps for the combination product would be the assembly, packaging, 394

labeling, any sterilization, or further processing of the kit itself. Accordingly, the kit 395

manufacturer would only have to demonstrate compliance with CGMP requirements with 396

respect to those manufacturing activities. However, if a kit includes any products that are 397

repackaged, relabeled, or otherwise modified for purposes of their inclusion in the kit, these 398

activities for the constituent parts would be additional aspects of the manufacture of the 399

combination product, thus the kit manufacturer would also have to demonstrate compliance with 400

CGMP requirements with respect to these manufacturing steps.14

401

14 Co-packaged combination product manufacturers, including manufacturers of kits, should carefully consider the 402 impact of any sterilization process on the items in the co-package. For example, a constituent part may be sensitive to 403 further processing, as may be the case for surgical sutures. Similarly, some sterilization methods suitable for devices, 404 such as irradiation, are not suitable for many drugs. Also, additional verification to confirm no degradation 405

12


D. What CGMP requirements apply to a product or facility? 408

While combination product manufacturers must demonstrate compliance with all of 409

the CGMP regulations applicable to their combination product under 21 CFR 4.3, as discussed 410

above, they may demonstrate compliance with the drug CGMPs and device QS regulation 411

requirements through one of the streamlined approaches under 21 CFR 4.4(b). Further, not all 412

the provisions of the CGMP regulations listed in 21 CFR 4.3 may be applicable to a specific 413

combination product or constituent part. 414

1. Are all CGMP regulations applicable to a product? 415

The preamble to the proposed rule addressed which CGMP requirements apply to which 416

combination products (see 74 FR at 48426), noting, for example, that only an over-the-counter 417

(OTC) combination product must comply with the tamper-evident packaging requirements in 418

the drug CGMPs and only combination products that include a type of device constituent part 419

that is installed or serviced must comply with installation and servicing requirements in the QS 420

regulation. The preamble to the final rule addressed similar considerations for combination 421

products that include a biological product constituent part, explaining that many of the 422

requirements for biological products are applicable only to certain types of biological products. 423

For example, blood and blood components are subject to the CGMP requirements for such 424

products under part 606. In addition, a vaccine manufactured using a spore-forming 425

microorganism would be subject to 21 CFR 600.11(e)(3). 426

Similarly, not all CGMP requirements may apply at a facility that performs only certain 427

aspects of the manufacture of a combination product. As 21 CFR 210.2(b) and 820.1(a)(1) 428

describe, an entity that engages in only some operations subject to the regulations in parts 210, 429

211, 600 through 680, 820, and 1271, need only comply with the regulations applicable to those 430

operations. For example, a facility that manufactures a co-packaged combination product that 431

includes a finished, packaged drug manufactured under the drug CGMPs and received from 432

another facility need not calculate yield for that drug constituent part. 433

2. What is the meaning of “where appropriate” in the CGMP, QS, and 434

CGTP regulations? 435

Firms must demonstrate compliance with all regulations applicable to their product or 436

facility under part 4. However, the drug CGMPs, QS regulation, and CGTPs for HCT/Ps use the 437

term “where appropriate” and similar language to acknowledge that certain measures may not be 438

necessary under certain circumstances. Such language indicates that firms have the opportunity 439

in safety and effectiveness after any re-sterilization may be necessary. Furthermore additional sterilization issues may 440 need to be considered, including complete validation of the sterilization process to insure sterility for each constituent 441 part within the kit, and evaluation of the impact of the sterilization process on the constituent parts. See, for example, 442 the Guidance for Industry on Sterilized Convenience Kits for Clinical and Surgical Use (January 2002). 443

444

445

13


to document justifications for determining that such a measure or approach is not appropriate for 448

a particular product or the specific manufacturing activity they are undertaking.15

449

For instance, 21 CFR 820.30(i) stipulates that each manufacturer establishes16

and 450

maintains procedures for the identification, documentation, validation, or—where appropriate— 451

verification, review, and approval of design changes before their implementation. Design 452

changes may include both modifications to the product itself and changes to the process used to 453

manufacture the product. Changes to the design, such as changes to properties of the material or 454

dimensional specifications that can be verified through appropriate measurement and test 455

methods, may not need to be validated. However, changes that could impact user needs, such as 456

changes to the user interface, may require validation. 457

Also, in some cases not expressly identified in the final rule, CGMP requirements in 458

different regulations may be similar, and actions sufficient to demonstrate compliance with one 459

may be sufficient to demonstrate compliance in whole or in part with the other. For example, 21 460

CFR 211.192 and associated provisions of part 211 require thorough investigation of any 461

unexplained discrepancy or the failure of a batch or any of its components to meet any of its 462

specifications, and then taking appropriate action to address any such discrepancy or failure. 463

Similarly, 21 CFR 820.100 in the QS regulation requires each manufacturer to establish and 464

maintain procedures for implementing corrective and preventive action, including investigating 465

the cause of nonconformities relating to the product, processes, or quality system. 466

3. What CGMP responsibilities apply to specific manufacturers and facilities, and 467

how should CGMP compliance be coordinated across facilities? 468

The combination product sponsor17

is responsible for ensuring that the manufacturing 469

activities for its product occurring at all facilities, including facilities operated by third parties, 470

are in compliance with CGMP requirements. Each of these manufacturing facilities must be in 471

full compliance with the CGMP requirements applicable to each manufacturing process that 472

occurs at that specific facility. 473

A facility that manufactures only a finished device intended to be a constituent part of a 474

combination product (i.e., does not engage in any other manufacturing of the combination 475

product) must comply only with the QS regulation. Similarly, a facility that manufactures only a 476

drug intended to be a constituent part of a combination product (i.e., does not engage in any other 477

manufacturing of the combination product), must comply only with the drug CGMPs. Even if a 478

facility is manufacturing only one type of constituent part for a combination product, the CGMP 479

15 Under both 21 CFR 820.1(a)(3) and 1271.150(e), a requirement that is qualified by “where appropriate,” is 480 “appropriate” if, for example, non-implementation of the requirement could reasonably be expected to result in the 481 product not meeting its specified requirements. In the case of an HCT/P, these may be requirements related to 482 prevention of introduction, transmission, or spread of communicable diseases, or a manufacturers inability to carry 483 out any necessary corrective action. Under both provisions, a requirement is deemed to be appropriate unless the 484 manufacturer can document justification that it is not. 485 16 Per 21 CRF 820.3(k), “Establish means define, document (in writing or electronically), and implement.” 486 17 For purposes of this guidance, “sponsor” means the entity that holds the marketing authorization for a co-487 packaged or single entity combination product. 488

14


operating system should take into consideration the combination product as a whole, as 491

appropriate. For example, the design controls for a device constituent part may include inputs to 492

address design characteristics to ensure that the combination product as a whole meets specified 493

requirements. 494

Some CGMP requirements may concern the combination product as a whole, such as 495

design controls, and some may concern overarching responsibilities for the quality system as a 496

whole, such as CAPA requirements. Take, for example, a manufacturing facility collecting 497

nonconformance data that are trended as an input to the CAPA system for a combination 498

product. If a problem is detected that requires a product or process design change, the expertise 499

to develop and implement the change may reside at a different facility. To address such 500

circumstances, a sponsor may have a CAPA system that is shared between facilities, or facility-501

specific CAPA systems with established links between them to handle issues requiring multi-502

facility collaboration. 503

Manufacturing activities that occur at multiple facilities and associated CGMP operating 504

systems should be coordinated appropriately. Each manufacturing facility for a combination 505

product should have documentation specifying its respective responsibilities, and the 506

manufacturer of the finished combination product should have access to this documentation. For 507

example, if a combination product manufacturer uses a specification developer to design the 508

finished product, the manufacturer of the combination product should have the design control 509

records or have access to them if they are held by the specification developer. In addition, the 510

manufacturer should have assurances that the specification developer maintained an adequate 511

design control system. To give another example, if product testing occurs at a contract testing 512

facility, the manufacturer of the combination product should have documentation of the testing 513

conducted and controls applied at the contract facility or have access to the documentation if held 514

at the contract facility. Accordingly, manufacturers should address access to such records among 515

other issues as part of supplier evaluation and oversight. 516

Measures the sponsor might take to ensure CGMP compliance at all manufacturing 517

facilities for the combination product include auditing and other oversight activities. For example, 518

when multiple facilities participate in the manufacturing process, the sponsor may facilitate 519

CGMP compliance by coordinating interactions among the facilities. A sponsor can enter into 520

comprehensive quality agreements with the various facilities and suppliers involved and 521

coordinate development of such agreements among these entities. These quality agreements may, 522

for instance, specify expectations as to which facility will perform what activities and develop and 523

maintain what documentation needed to demonstrate compliance with which CGMP requirements 524

(based, for example, on which aspects of manufacture each facility conducts). These agreements 525

may also detail what measures a facility will take to ensure compliance with CGMP requirements 526

and any other relevant duties established by the sponsor for that facility. 527

15


E. Control of changes to a combination product 530

As discussed in the preamble to the final rule, while not an issue unique to combination 531

products, coordination of changes among manufacturers participating in the manufacture of a 532

combination product is an important CGMP issue. The manufacturer of a co-packaged or single-533

entity combination product should ensure appropriate consideration of any implications for the 534

safety or effectiveness of its combination product that might arise from changes to it, including to 535

any constituent part of it. Therefore, the manufacturer should establish arrangements with its 536

suppliers to receive notice of changes. The manufacturer should also establish procedures for 537

acceptance of components, containers/closures, and constituent parts to ensure both detection and 538

evaluation of any changes that are critical to the safety and effectiveness of the combination 539

product prior to incorporating them into the finished combination product. 540

Similarly, if one entity manufactures one constituent part of a cross-labeled combination 541

product and another entity manufactures the other constituent part, both should have procedures 542

in place to inform one another of changes that may affect the safety or effectiveness of the 543

combination product, and to confirm that the specifications for the respective constituent parts 544

remain appropriate or are updated as needed to ensure that the combination product remains safe 545

and effective. For example, a change to the drug constituent part of a cross-labeled combination 546

product might require a design change to the device constituent part for the combination product 547

to remain safe and effective. Accordingly, awareness and assessment of drug changes to 548

determine whether they require, in this example, a change to the device constituent part(s) may be 549

important to compliance with design control requirements for the device under 21 CFR 820.30. 550

Similarly, a change to a device constituent part of a cross-labeled combination product may 551

necessitate a change to a drug constituent part that would then need to be reflected in the 552

chemistry, manufacturing, and controls specifications and testing procedures for the drug. 553

IV. What do I need to know about the CGMP requirements 554

specified in 21 CFR 4.4(b)? 555

A. Provisions from the QS regulation specified in 21 CFR 4.4(b)(1) 556

This section provides summary descriptions of the provisions from the QS regulation 557

with which manufacturers must demonstrate compliance when using the drug CGMP-based 558

streamlining approach established under section 4.4(b)(1). This discussion is not meant to 559

provide a comprehensive analysis, but rather to help manufacturers—particularly drug and 560

biological product manufacturers who may be less familiar with the QS regulation—understand 561

the purpose and basic content of the specified QS regulation provisions. This section also 562

includes references to some additional guidance documents that may be helpful.18

Section V 563

18 This section does not address 21 CFR 4.4(b)(1)(v) and (vi) , which require manufacturers to demonstrate 564 compliance with installation and servicing requirements under 21 CFR 820.170 and 820.200, respectively. These 565 requirements are included in section 4.4(b)(1) to ensure manufacturers comply with them when applicable to a 566 single-entity or co-packaged combination product. However, the agency anticipates that installed and serviced 567

16


presents hypothetical examples offering additional guidance on how to address these 570

provisions for a combination product. 571

1. Management responsibility (21 CFR 820.20) 572

Statutory CGMP provisions, as well as the drug CGMP regulations, establish 573

requirements relating to management responsibility.19

While there are specific requirements in 574

21 CFR 820.20 that are not explicitly addressed in 21 CFR part 211, section 501(a)(2)(B) of the 575

FD&C Act requires oversight and controls to ensure product quality, including to manage risks 576

and establish the safety of raw materials, in-process materials, and the finished drug product. In 577

addition, guidance documents for drug manufacturers describe how to use quality systems to 578

comply with drug CGMPs.20

A manufacturer of a combination product that includes a device 579

constituent part must ensure that the elements required under 21 CFR 820.20 are satisfied. 580

For example, among other requirements, a manufacturer must establish the appropriate 581

responsibility, authority, and interrelation of all personnel who manage, perform, and assess 582

work affecting quality; provide adequate resources for management, performance of work, and 583

assessment activities; and appoint a management member who is responsible for ensuring that 584

quality system requirements are effectively established and maintained, and for reporting on the 585

performance of the quality system to management with executive responsibility.21

A 586

manufacturer must establish and maintain an adequate organizational structure to ensure that 587

the product is designed and produced in conformance with CGMP requirements.22

The 588

technical, administrative, and human resources functions affecting the quality of the product 589

should be controlled, whether these functions involve hardware, software, equipment, 590

processed materials, product components, or services. All such controls should be designed to 591

reduce, eliminate, or, ideally, prevent quality nonconformities. 592

devices will rarely be constituent parts of such combination products. They are more likely to be separately 593 manufactured and marketed constituent parts of cross-labeled combination products. In such cases, as discussed at 594 78 FR 4308, each such constituent part would be subject to the CGMP requirements associated with that product. 595 Accordingly, the device constituent part of such a cross-labeled combination product would be subject to installation 596 and servicing requirements. 597 19 See, for example, 21 USC 351 (establishing that “current good manufacturing practice” includes management 598 oversight of manufacturing and control to ensure quality and lifecycle risk management); 21 CFR 211.22, 211.25, 599 and 211.180; the Guidance for Industry on Q10 Pharmaceutical Quality System (April 2009); and the Guidance for 600 Industry on Quality Systems Approach to Pharmaceutical CGMP Regulations (September 2006). 601 20 See the Guidances for Industry on Q10 Pharmaceutical Quality System and Quality Systems Approach to 602 Pharmaceutical CGMP Regulations. 603

21 “Management with executive responsibility is that level of management that has the authority to establish and 604 make changes to the company quality policy. The establishment of quality objectives, the translation of such 605 objectives into actual methods and procedures, and the implementation of the quality system may be delegated. The 606 regulation does not prohibit the delegation. However, it is the responsibility of the highest level of management to 607 establish the quality policy and to ensure that it is followed ... It is without question management’s responsibility to 608 undertake appropriate actions to ensure that employees understand management’s policies and objectives. 609 Understanding is a learning process achieved through training and reinforcement. Management reinforces 610 understanding of policies and objectives by demonstrating a commitment to the quality system visibly and actively 611 on a continuous basis. Such commitment can be demonstrated by providing adequate resources and training to 612 support quality system development and implementation.” (61 FR. 52602 at 52612) 613 22 See 21 CFR 820.20(b). 614

17


21 CFR 820.20 requires that a manufacturer establish and maintain management 617

responsibility for product quality. Management with executive responsibility must establish its 618

policy and objectives for and commitment to quality, pursuant to 21 CFR 820.20(a). 619

Manufacturers are also responsible for establishing a quality plan and quality system procedures 620

in accordance with 21 CFR 820.20(d) and (e). The quality plan must define the quality practices, 621

resources, and activities relevant to the combination product that is being designed and 622

manufactured and must establish how the quality requirements will be met. The plan can either 623

be an independent document, or it can reference elements of the manufacturer’s quality system. 624

The quality system procedures should ensure compliance with each aspect of the CGMPs 625

applicable to the combination product. Accordingly, under a drug CGMP-based streamlining 626

approach, these procedures and instructions should address the drug CGMPs and those 627

provisions from the QS regulation identified in 21 CFR 4.4(b)(1). The number, complexity, and 628

structure of the manufacturer’s procedures and instructions may vary depending on factors such 629

as the size of the manufacturer, organizational structure, and type of combination product being 630

manufactured. Drug manufacturers may already have some of these procedures in place as part of 631

the requirements for a quality control unit under 21 CFR 211.22 and can reference these 632

procedures and augment them as needed to meet the requirements of 21 CFR 820.20. 633

Management with executive responsibility must review the suitability and effectiveness 634

of the quality system, in accordance with 21 CFR 820.20(c), including to ensure that the quality 635

system satisfies the established quality policy and objectives. These reviews must be conducted 636

at defined intervals and with sufficient frequency. 637

2. Design controls (21 CFR 820.30) 638

The preamble to the proposed rule discusses design control requirements for combination 639

products at some length.23

As specified in the final rule, design controls apply to any combination 640

product that includes a device constituent part. Guidance for industry on pharmaceutical 641

development addresses product design and development procedures, reflecting “quality by 642

design” principles.24

The QS regulation includes requirements for design development with 643

which compliance must be demonstrated (21 CFR 820.30(b)). The following is a description of 644

design control requirements and the documentation that must be maintained for co-packaged and 645

single-entity combination products.25

646

Design control procedures apply to activities undertaken during product development and 647

premarket assessment, as well as to postmarket changes to the design or manufacturing process. 648

Accordingly, in some cases, the activities described below may be conducted as part of 649

23 See 78 FR 4314-4315. 650 24 See the Guidance for Industry on Q8(R2) Pharmaceutical Development (November 2009). 651 25 While outside the scope of 21 CFR 4.4(b)(1), it bears noting that the design control process and design history file 652 for the device constituent parts of cross-labeled combination products should address the suitability of the device for 653 use as part of the combination product, including the interactions and interrelationships between it and other 654 constituent parts of the combination product. 655

18

656


premarket development and the marketing authorization process. As noted above, regardless of 659

when the activity occurs or where related records may reside, the CGMP operating system 660

should include appropriate documentation or reference it, to ensure readily available access to 661

this documentation for FDA inspection.26

662

Design input requirements for the combination product should include considerations 663

such as performance characteristics, safety and reliability requirements, and expected product 664

users. Once the design inputs have been established, the design outputs (e.g., specifications and 665

engineering drawings) must be developed based on those inputs.27

Once design outputs have 666

been established for all design inputs, design verification and validation activities must be 667

performed to ensure that the combination product design output meets design input requirements, 668

including user needs and intended uses. These activities must be documented in the design 669

history file28

and must be subjected to design reviews.29

670

Verification means confirmation by examination and provision of objective evidence that 671

specified requirements have been fulfilled.30

Design verification is demonstrating that a 672

manufacturer has designed the product it intended to; such testing confirms that the product 673

developed is consistent with the assumptions made by the design team when developing design 674

inputs, but does not necessarily confirm that the product is safe and effective for its intended use. 675

Design verification activities may include, for example, performance tests, safety tests, or visual 676

inspections. 677

Design validation means establishing by objective evidence that product specifications 678

conform to user needs and intended use(s).31

Design validation ensures that the product is 679

designed correctly to achieve its intended purposes. Specifically, design validation must ensure 680

that the product conforms to defined user needs and intended uses and includes testing of 681

production units under actual or simulated use conditions. Design validation activities, for 682

example, may include simulated use testing or clinical/nonclinical evaluations, including 683

human factors testing and software validation.32

684

In addition, 21 CFR 820.30(g) requires that the manufacturer complete risk analysis, 685

where appropriate, which should begin early in the design process and continue throughout the 686

lifecycle for the product. Risk analysis influences other aspects of design control and additional 687

activities including purchasing controls. Risk analysis should be completed on the combination 688

product as a whole to identify risks associated with its design, manufacturing processes, and 689

intended uses. Some risks may be identifiable during initial design development and addressed 690

in design inputs, while others may become apparent based on postmarket experience (including 691

26 See 21 CFR 820.30(j), 820.180, and 211.180 692 27 See 21 CFR 820.30(d). 693 28 See 21 CFR 820.30(j). 694 29 See 21 CFR 820.30(e). 695 30 See 21 CFR 820.3(aa). 696 31 See 21 CFR 820.3(z)(2). 697

32 For further information about human factor considerations and testing, see FDA’s Human Factors and Medical 698 Devices web page at 699 http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/HumanFactors/default.htm. 700

http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/HumanFactors/default.htm.

19


adverse event reporting) and used to determine whether any aspect of the design should be 703

adjusted or revised. Any unacceptable risk(s) should be reduced or mitigated. 704

In accordance with 21 CFR 820.30(i), manufacturers are also required to have procedures 705

to ensure that any changes to design requirements are identified, documented, validated or verified 706

where appropriate, reviewed, and approved prior to implementation. A change control process is 707

essential to incorporate design changes appropriately both during the original design process for 708

the combination product and after the design has been transferred to manufacturing. The records 709

of these changes must be maintained as part of the design history file. They create a history of the 710

evolution of the design, which can be important when investigating failures or evaluating the 711

appropriateness of proposed modifications or changes to the product. 712

The design history file for a combination product should address all design issues 713

relating to the combined use of the constituent parts. The design history file may not need to 714

document design and development planning for established characteristics of the individual 715

constituent parts, such as the safety and effectiveness of a drug constituent part of a co-packaged 716

combination product if that drug constituent part was previously approved for the same 717

indication. If a finished device, drug, or biological product is purchased, the combination 718

product manufacturer is not required to retrospectively “design” that constituent part with 719

respect to such previously reviewed characteristics. Rather, the combination product 720

manufacturer should understand the constituent part’s existing design specifications thoroughly 721

in order to perform design controls properly for its use in the combination product.33

In addition, 722

the combination product manufacturer must comply with design control requirements for any 723

modifications that need to be made to a constituent part for use in the combination product (e.g., 724

new formulation of the drug or new features of a device) under 21 CFR 820.30(i). 725

It is appropriate to leverage existing data in developing a design history file for a 726

combination product that may not have been developed under design controls. For example, 727

existing specifications may become part of the required design output documentation. Similarly, 728

testing performed prior to distribution of the combination product may be included as 729

documentation of design verification and validation. The combination product manufacturer is 730

responsible for assembling available information and assessing what, if any, additional 731

information and evidence may be needed, such as additional testing or documentation of the 732

design control activities, to address all aspects of design control that are needed to support the 733

manufacture of the product as currently marketed, ensure its safety and effectiveness, and support 734

any future changes to that product. However, manufacturers do not need to prepare a 735

development plan or conduct design review meetings for the product as currently marketed 736

because the development stages that these activities would support have already occurred. 737

33 Similarly, if a combination product manufacturer is purchasing device components for inclusion in a combination 738 product, and the device component supplier is manufacturing a finished device from the same or similar components 739 and is therefore subject to the QS regulation, the combination product manufacturer may be able to leverage 740 elements of that supplier’s design controls in developing the overall design controls for the combination product. If 741 the component supplier does not manufacture a related finished device, the combination product manufacturer’s 742 design control activities for the device constituent part will likely need to be more extensive. 743

20


FDA encourages combination product manufacturers to direct specific questions on 746

the adequacy of their design control measures and documentation to the lead center for their 747

products, or OCP as needed, for assistance. For further information on design controls, see the 748

preamble for the final QS regulation.34

749

3. Purchasing controls (21 CFR 820.50) 750

Combination product manufacturers must control purchased products35

and services as 751

described in 21 CFR 820.50. They must establish such controls for products received at their 752

facility for use in the manufacture of the combination product, for all suppliers of these products, 753

and for suppliers of services obtained (such as terminal sterilization conducted by an outside 754

entity). Facilities that have previously manufactured only drugs, rather than devices or 755

combination products, likely will have relevant procedures in place in accordance with 21 CFR 756

part 211, subpart E, but these procedures may need to be augmented to demonstrate compliance 757

with the specific requirements of 21 CFR 820.50. 758

Manufacturers must evaluate potential suppliers and define the type and extent of control 759

to be exercised over them based on the evaluation results.36

They may conduct such evaluations 760

based on factors such as the risks associated with the supplied product or service and complexity 761

of the specifications for it. They must establish and maintain records of acceptable suppliers for 762

purchased products and services, pursuant to 21 CFR 820.50(a)(3), and establish and maintain 763

data that clearly describe or reference the specified requirements for received products (e.g., 764

contracts with relevant terms) pursuant to 21 CFR 820.50(b). 765

One mechanism by which to facilitate purchasing control is the careful structuring of 766

purchasing agreements with suppliers. Where possible, such agreements must be used to ensure 767

that the manufacturer is notified of changes to the products or services being provided.37

Such 768

notice of changes facilitates compliance not only with purchasing control duties, but potentially 769

other regulatory requirements as well, including design control obligations to complete 770

additional design verification testing (e.g., to ensure that the purity and stability of a drug 771

constituent part is maintained). If it is not possible to obtain such notice, the combination 772

product manufacturer should implement additional controls to ensure that changes are identified 773

and appropriate measures are taken.38

774

34 See Medical Devices; Current Good Manufacturing Practice (CGMP) Final Rule; Quality System Regulation, 61 775 FR 52602-52662 (October 7, 1996). 776 35 Under 21 CFR 820.3(r), The term “product” includes components and manufacturing materials, in addition to in- 777 process and finished articles. 778 36 See 21 CFR 820.50(a)(2). 779 37 See 21 CFR 820.50(b). 780 38 While beyond the scope of this guidance, it bears noting that product sponsors may be obligated to notify the 781 agency of changes or seek agency approval prior to making them, depending upon the nature of the change. See, for 782 example, 21 CFR 314.70, 601.12, and 814.39. Accordingly, controlling changes to the materials included in the 783 combination product and the processes and facilities used for their manufacture can be important to ensure 784 compliance with other regulatory duties (in addition to CGMP requirements). 785

21


4. Corrective and Preventive Actions (21 CFR 820.100) 788

Sponsors for co-packaged or single-entity combination products that have a device 789

constituent part must establish and maintain procedures for implementing CAPA, in accordance 790

with 21 CFR 820.100. Relevant requirements in the drug CGMPs include 21 CFR 211.192 and 791

21 CFR 211.180(e). 792

The sponsor should ensure that an appropriately comprehensive review of activities is 793

undertaken at whatever facilities may be relevant to determine the cause of existing or potential 794

problems, which could include manufacturing problems, deviations, or nonconformities for the 795

combination product. The sponsor must identify the action(s) needed to correct and prevent 796

recurrence, then implement such changes. The sponsor should take appropriate measures, which 797

may include CAPAs, with regard to all relevant manufacturing steps at all relevant facilities so 798

that the problem is corrected and problems will be prevented or mitigated going forward. 799

Manufacturers of the combination product must undertake CAPA measures, when required, for 800

issues arising at their facilities. All relevant manufacturers should participate in cross-facility 801

efforts, as appropriate, to determine the cause of problems and the appropriate measures to 802

correct and prevent such problems, as well as document these activities.39

803

B. Provisions from the drug CGMPs specified in 21 CFR 4.4(b)(2) 804

This section provides a brief description of the provisions from the drug CGMPs with 805

which manufacturers must demonstrate compliance when using the QS regulation-based 806

streamlining approach established under 21 CFR 4.4(b)(2). This discussion is not meant to be a 807

comprehensive analysis, but rather to help manufacturers—particularly device manufacturers, 808

who may be less familiar with the drug CGMPs—understand the purpose and basic content of 809

the specified provisions of the drug CGMPs, as well as where to find additional guidance. 810

The specified provisions of the drug CGMPs include requirements for testing and other 811

verification procedures for batches or lots, whether of drug components, drug containers and 812

closures, drug constituent parts, or the whole combination product. As discussed in the preamble 813

to the final rule, combination product manufacturers should establish procedures defining a 814

“batch” or “lot” in all phases of production and describe all batch and lot numbering systems 815

used for incoming material, in-process material, and finished products. These procedures allow 816

manufacturers to connect specific lots or batches of constituent parts, components, and in-process 817

material to the specific batches or lots of the combination product for which they are used. These 818

procedures also enable traceability of sampling and testing, packaging, and labeling activities. 819

Master production and control records should be designed to enable this traceability. An 820

explanation of batch and lot definitions, controls, and tracking should be available for review on 821

inspection. 822

39 For further guidance, see the preamble to the QS regulation at 61 Fed. Reg. at 52633-52635, Comments 158-166, 823 and the Guidances for Industry on Q10 Pharmaceutical Quality System and Quality Systems Approach to 824 Pharmaceutical CGMP Regulations. 825

22


1. Testing and approval or rejection of drug product components, containers, and 828

closures (21 CFR 211.84) 829

Drug product components, containers, and closures must be tested in accordance with 21 830

CFR 211.84. A drug component is any ingredient intended for use in the manufacture of a drug 831

product, including those that may not appear in the drug product.40

As explained in section 832

III.C.3, a container closure system is the sum of packaging components that together contain and 833

protect the drug product. Combination product manufacturers would not need to demonstrate 834

compliance with this provision for device constituent parts or materials used in the manufacture 835

of a device constituent part, except if the device constituent part or component thereof is also a 836

drug component or constitutes the drug container or closure or a part thereof. For CGMP 837

operating systems established in accordance with 21 CFR 4.4(b)(2) (QS regulation-based 838

streamlining approach), if materials are used solely for manufacture of a device constituent part 839

that is not part of the drug container or closure (e.g., a co-packaged device), the manufacturer 840

need only demonstrate compliance with applicable provisions of 21 CFR part 820 to show 841

appropriate control of such materials for that device constituent part (including 21 CFR 820.30, 842

820.50, 820.80, and 820.86). 843

21 CFR 211.84 details how to sample, test, examine, and accept or reject drug product 844

components, containers, and closures from other facilities, including other facilities owned or 845

controlled by the manufacturer. In lieu of such testing, 21 CFR 211.84 allows for some reliance 846

on a supplier’s written analysis, provided that certain identity testing is conducted and that the 847

reliability of the supplier’s analysis is established by the manufacturer through appropriate 848

validation of the testing results at appropriate intervals. These duties augment and elaborate 849

upon acceptance activities requirements expressly established under 21 CFR 820.80. 850

Accordingly, if a facility already has 820.80-based acceptance procedures, it would be 851

appropriate to provide for compliance with 21 CFR 211.84 requirements by augmenting these 852

existing procedures as needed to incorporate 21 CFR 211.84 compliance measures. 853

Each lot of drug components, containers, and closures must be withheld from use until it 854

has been sampled, tested, or examined, as appropriate, and released for use by the quality control 855

unit.41

The samples collected for each lot must be representative of the entire lot.42

These 856

representative samples must be collected and tested or examined in accordance with the 857

procedures specified in 21 CFR 211.84. These procedures require, among other things, 858

appropriate sampling technique to prevent the introduction of contaminants into the sampled 859

component and contamination across multiple sampled components.43

In addition, the number of 860

containers to sample and the amount of material to be taken from each container must be based 861

on appropriate criteria (e.g., component variability, confidence levels, degree of precision 862

desired, past quality history of the supplier, and the quantity needed for analysis).44

863

40 See 21 CFR 210.3(b)(3). 864 41 See 21 CFR 211.84(a). 865 42 See 21 CFR 211.84(b). 866 43 See 21 CFR 211.84(c). 867 44 See 21 CFR 211.84(b). 868

23


Some references that may be useful for sampling by variables and sampling by attributes 871

include “ASTM Standard E2709, Standard Practice for Demonstrating Capability to Comply 872

with an Acceptance Procedure” and “ASTM Standard E2334, Standard Practice for Setting an 873

Upper Confidence Bound For a Fraction or Number of Non-conforming Items, or a Rate of 874

Occurrence for Non-conformities, Using Attribute Data, When there is a Zero Response in the 875

Sample,” respectively. 876

2. Calculation of Yield (21 CFR 211.103) 877

Actual yields and percentages of theoretical yield for the drug constituent part(s) of a 878

combination product must be determined as described in 21 CFR 211.103. Excess or low yields 879

suggest errors in the production process. All discrepancies in yield should be investigated. 880

Yield determinations must be made at the conclusion of each appropriate phase of 881

manufacturing, processing, packaging, and holding for the drug constituent part(s) and for the 882

combination product as a whole.45

Accordingly, calculation of yield should be determined at each 883

phase at which component, in-process material, or product loss may occur, during the 884

formulation of the drug prior to incorporation into the combination product, during incorporation 885

(e.g., filling or coating), and during the packaging process. These calculations must be performed 886

by one person and independently verified by a second person, unless the yield is calculated by 887

automated equipment in accordance with section 21 CFR 211.68, in which case it must be 888

independently verified by one person.46

889

For each appropriate phase of the manufacturing process performed, the formula used and 890

the data generated for the yield calculation in a manufacturing or production record should be 891

documented. These records should include actual yields and percentages of theoretical yields for 892

the drug product, including as it is processed and combined with the other constituent part(s) of 893

the combination product. If a third party is manufacturing the drug for the combination product, 894

that manufacturer is responsible for complying with the calculation of yield requirement at the 895

appropriate phases of the drug manufacturing process it performs, but the combination product 896

manufacturer is responsible for ensuring that the supplier satisfies these requirements as a part of 897

the purchasing controls for its combination product in accordance with 21 CFR 820.50. 898

3. Tamper-evident packaging requirements for over-the-counter human 899

drug products (21 CFR 211.132) 900

Manufacturers of OTC combination products must comply with the requirements of 21 901

CFR 211.132. The required controls include tamper-evident packaging and labeling alerting 902

customers to these protective features of the product’s packaging. These controls are important 903

to help improve the security of OTC combination product packaging and help ensure the safety 904

and effectiveness of OTC combination products. 905

45 See 21 CFR 211.103. 906 46 See 21 CFR 211.103. 907

24


For single-entity combination products, tamper-evident packaging requirements apply to 910

the packaging for the combination product as a whole. For co-packaged combination products, 911

these requirements can be met through appropriate packaging of the drug constituent part(s) 912

within the larger co-package so long as such an approach is otherwise permissible under the 913

packaging and labeling requirements applicable to that combination product. 914

An exemption from tamper-evident packaging and labeling requirements for an OTC 915

combination product, may be requested in accordance with 21 CFR 211.132(d). If the 916

manufacturer makes changes to packaging and labeling of an approved OTC product to comply 917

with the requirements of 21 CFR 211.132, it must notify the lead center for the combination 918

product before distributing it.47

919

4. Expiration dating (21 CFR 211.137) 920

Section 211.137 helps assure that drug products (drug constituent parts in the case of 921

combination products) meet applicable standards of identity, strength, quality, and purity at 922

the time of use by requiring that the product labeling bear an expiration date. This date must 923

take into account any storage conditions stated in the labeling and be based on appropriate 924

stability testing as described in 21 CFR 211.166.48

925

The expiration dating for a combination product also should take into account any other 926

applicable shelf-life considerations (e.g., for a product that is to be provided sterile, the length of 927

time that its packaging material can be assured to retain its integrity and, thereby, maintain a 928

sterile barrier). The expiration date for a combination product may be shorter than the expiration 929

date or shelf life for its drug constituent part(s) if marketed independently. Reasons for a shorter 930

expiration period could include interactions between the constituent parts when combined, the 931

effects of additional manufacturing steps, or other differences arising from the combination of 932

the constituent parts. 933

5. Testing and release for distribution (21 CFR 211.165) 934

Testing and release for distribution are critical in drug product manufacture and quality 935

control. Section 211.165 requires that an appropriate laboratory determination of satisfactory 936

conformance to final specifications (including the identity and strength of each active ingredient) 937

is made for each batch of drug product prior to release. Section 211.165 also requires 938

appropriate laboratory testing, as necessary, of each batch of a drug product required to be free of 939

objectionable microorganisms. In addition, sampling and testing plans must be described by 940

written procedures.49

941

Accordingly, manufacturers must test each batch of their combination product to 942

determine satisfactory conformance to final written specifications for the drug constituent part.50

943

47 See 21 CFR 211.132(e). 944 48 See 21 CFR 211.137(b). 945 49 See 21 CFR 211.165(c). 946 50 See 21 CFR211.165(a). 947

25


Laboratory testing must be performed on every batch of a single-entity combination product and 950

of the drug constituent part(s) of a co-packaged combination product, to ensure that all batches 951

meet appropriate specifications for their approval and release.51

A detailed listing of all the tests 952

performed and the acceptance criteria should be maintained and available for inspection.52

953

If one facility is manufacturing a drug product as a constituent part to be supplied to 954

another facility or manufacturer for inclusion in a co-packaged combination product, appropriate 955

and adequate laboratory testing should be conducted by the drug product manufacturing facility 956

prior to release of the drug constituent part(s) for distribution in accordance with 21 CFR 957

211.165. Appropriate testing or examination (such as visual inspection) should also be conducted 958

throughout the remaining manufacture of the finished co-packaged combination product to ensure 959

that the drug constituent part(s) continues to conform to its final specifications. 960

6. Stability testing (21 CFR 211.166) 961

Section 211.166 requires a written testing program designed to assess the stability 962

characteristics of drug products. Furthermore, 21 CFR 211.166 sets forth required elements of 963

the testing program, including elements concerning sample size, storage conditions for samples 964

retained for testing, and other elements related to testing methodology and frequency. 965

Manufacturers are responsible for establishing and managing the stability program. 966

Stability testing is performed to determine appropriate storage conditions and expiration 967

dates (see section IV.B.4). Among other considerations, this testing must enable evaluation of 968

any effects on the stability of the drug due to storage in a container closure system, which may 969

be a device constituent part (or component of the device constituent part).53

For a single-entity 970

combination product, testing must be performed on the drug constituent part in the finished 971

combination product.54

972

If a combination product manufacturer purchases a drug product manufactured by a third-973

party manufacturer for inclusion in its co-packaged combination product, that third-party 974

manufacturer is responsible for stability testing for that drug product. The combination product 975

manufacturer is responsible for ensuring the stability of the drug product as marketed in the co- 976

51 See 21 CFR 211.165(a), (b). 977 52 21 CFR 211.165 addresses testing and release for “drug products”; appropriate controls for intermediate stages 978 (e.g., in process materials) in the manufacture of combination products are addressed under separate provisions of 979 the drug CGMPs and QS regulation that are not specified in 21 CFR part 4. Accordingly, if the manufacturer 980 operates under a streamlined approach under 21 CFR 4.4(b), it should take into consideration the materials and 981 manufacturing steps for the combination product as a whole in determining how to demonstrate compliance with 982 obligations for in-process materials, and may find it helpful to refer to the corresponding requirements of the other 983 regulation. For example, if the facility operates under a QS regulation-based streamlining approach, in determining 984 how to comply with duties under 21 CFR 820.70, 820.80, and 820.86 for the combination product as a whole, 985 reference to 21 CFR 211.110 and guidance relating to it may facilitate appropriate consideration of issues related to 986 such materials for drug constituent parts. 987 53 See 21 CFR 211.166(a)(4). 988 54 See 21 CFR 4.3, 4.4, and 211.166. In addition, under the design control requirements, testing must be performed 989 to demonstrate that the device functionality (i.e., mechanical performance of the device constituent part) is 990 maintained until the specified expiration date. See 21 CFR 820.30. 991

26


package through appropriate mechanisms, such as purchasing controls or conducting additional 994

stability testing. Documentation of such oversight should be included in the CGMP records.55

995

7. Special testing requirements (21 CFR 211.167) 996

21 CFR 211.167 establishes requirements for batch testing applicable to drug products 997

having particular characteristics. Specifically, 21 CFR 211.167(a) requires appropriate 998

laboratory testing of drug products purporting to be sterile and/or pyrogen-free to determine 999

conformance with such requirements; 21 CFR 211.167(b) requires appropriate testing of 1000

ophthalmic ointments to determine conformance to specifications regarding the presence of 1001

foreign particles and harsh or abrasive substances; and 21 CFR 211.167(c) requires appropriate 1002

laboratory testing of controlled-release dosage forms to determine conformance to the 1003

specifications for the rate of release of each active ingredient. A special testing requirement 1004

specified in 21 CFR 211.167 applies to a combination product only if the combination product 1005

or a drug constituent part of it falls into one or more of these three categories. Special testing 1006

may be required for the drug constituent part, or the combination product as a whole, 1007

depending on the product. 1008

With respect to 21 CFR 211.167(a), batch testing requirements would apply both to the 1009

drug constituent part and to the finished combination product for a single-entity combination 1010

product (such as a prefilled syringe) to ensure the combination product is sterile and pyrogen-1011

free when distributed. In contrast, if a vial of a vaccine were co-packaged with an empty 1012

syringe, the requirements in 21 CFR 211.167(a) would apply only to the vial of vaccine. The 1013

requirements related to sterility and non-pyrogenicity of the empty syringe would be addressed 1014

through compliance with process controls under 21 CFR part 211 and the provisions of 21 CFR 1015

part 820 specified in 21 CFR part 4 (for example, design control requirements under 21 CFR 1016

820.30 and purchasing control requirements under 21 CFR 820.50), rather than batch testing 1017

under 21 CFR 211.167(a).56

A similar analysis would apply for compliance with 21 CFR 1018

211.167(b) for a single-entity versus a co-packaged combination product that includes an 1019

ophthalmic ointment. 21 CFR 211.167(c) would apply to a controlled release drug constituent 1020

part of a co-packaged combination product and also to a controlled release single-entity 1021

combination product, to confirm rate of release of the active ingredient. For example, a 1022

transdermal drug patch or drug-eluting disc or stent would be subject to 21 CFR 211.167(c). 1023

8. Reserve samples (21 CFR 211.170) 1024

Reserve samples are needed to help ensure the postmarket safety and effectiveness of 1025

combination products, as they are for drugs and biological products. They are used, for example, 1026

to address certain product complaints, evaluate stability concerns, and assess the causes of 1027

adverse events. The reserve sampling requirements of 21 CFR 211.170 must be met to ensure 1028

appropriate sampling systems for the drug constituent parts of combination products. 1029

55 For further information on stability testing considerations, see, for example,, the Guidance for Industry on 1030 Q1A(R2) Stability Testing of New Drug Substances and Products (November 2003). 1031 56 1032

For additional information on pyrogen and endotoxin testing, see the Guidance for Industry on Pyrogen and 1033 Endotoxins Testing: Questions and Answers (June 2012). 1034

27


Accordingly, as explained below, for co-packaged combination products, manufacturers should 1037

maintain samples of the drug constituent part, and for single-entity combination products, they 1038

should maintain samples that include the device constituent part or components thereof as 1039

appropriate. 1040

Under 21 CFR 211.170, reserve samples must be kept that are representative of each lot 1041

of the active ingredient and of each lot or batch of the drug product. Furthermore, reserve 1042

samples of drug products must be retained and stored under conditions consistent with product 1043

labeling and stored in the same immediate container-closure system in which the drug product is 1044

marketed or in one that has essentially the same characteristics.57

All reserve samples must 1045

consist of at least twice the quantity necessary to perform all the required tests, except those for 1046

sterility and pyrogens.58

Manufacturers must examine drug product samples for deterioration, 1047

investigate evidence of deterioration, and record and maintain the results of such examination.59

1048

Drug product reserve samples generally must be maintained for 1 year after the expiration date 1049

for the drug product; different time periods apply to certain radioactive and OTC products.60

1050

Active ingredient samples generally must be kept for 1 year after the expiration date for the last 1051

lot of the combination product containing the active ingredient.61

Accordingly, manufacturers 1052

should retain samples from each lot of the bulk drug substance for 1 year after the expiration date 1053

of the last lot of the combination product to use that lot of the active ingredient. 1054

For co-packaged combination products, it is generally sufficient to maintain the 1055

appropriate number of samples from each lot of the active ingredient and from each lot of the 1056

drug product in the immediate container/closure in which it is marketed. For single-entity 1057

combination products, manufacturers also should maintain reserve samples of the active 1058

ingredient and of the drug product within its container/closure. In some cases, the 1059

container/closure may be the entire device constituent part. In others, it may be a part of the 1060

device or distinct from the device constituent part. For a drug-eluting stent or disc, or a prefilled 1061

syringe, for example, reserve samples should be kept of the entire combination product. In 1062

contrast, if, for example, the combination product consists of an injector system (device 1063

constituent part) into which the user inserts cartridges containing the drug reserve samples of the 1064

filled cartridge alone would suffice to comply with drug product sample retention duties. A 1065

complete injector system may be needed to conduct testing of the samples. 1066

Manufacturers with questions regarding their duties under section 211.170, including 1067

what may constitute a representative sample or a sufficient number of samples to keep, may 1068

contact the lead center for their combination product, as well as OCP as needed, for assistance. 1069

57 See 21 CFR 211.170(b). 1070 58 See 21 CFR 211.170(a) and (b). 1071 59 See 21 CFR 211.170(b). 1072 60 See 21 CFR 211.170(b). Active ingredient samples generally must be kept for 1 year after the expiration date for 1073 the last lot of the combination product containing the active ingredient. See 21 CFR 211.170(a). 1074 61 See 21 CFR 211.170(a). 1075

28


C. Combination products that include biological products and HCT/Ps 1078

In addition to all other CGMP requirements applicable to the combination product under 1079

21 CFR 4.3 and 4.4, a manufacturer of a combination product that contains a biological product 1080

or an HCT/P must comply with the requirements that would apply to the biological product or 1081

HCT/P if it were not part of a combination product. 1082

1. Complying with CGMP requirements for biological products 1083

It is important to remember that a biological product is also by definition a drug or a 1084

device. Accordingly, in addition to the requirements in 21 CFR parts 600 through 680, a 1085

biological product is always either subject to the drug CGMPs or the QS regulation, regardless of 1086

whether the biological product is a constituent part of a combination product. The CGMP 1087

requirements for biological products in 21 CFR parts 600 through 680 augment the drug CGMPs 1088

and QS regulation to ensure adequate consideration of issues for biological products. The CGMP 1089

requirements for biological products in 21 CFR parts 600 through 680 address the particular 1090

challenges biological products pose, including challenges arising from their relative complexity. 1091

For biological products, consistency of manufacturing procedures can, in fact, be a primary 1092

means by which to ensure the safety, purity, and potency of the product. 1093

The CGMP requirements for biological products in 21 CFR parts 600 through 680 1094

augment the drug and device CGMPs and must be satisfied if a combination product includes a 1095

biological product constituent part. However, as noted in the preamble to the final rule, many 1096

requirements in parts 600 through 680 are applicable only to certain types of biological products. 1097

For example, while part 600 facially addresses biological products in general, only products 1098

manufactured using a spore-forming microorganism would be subject to 21 CFR 600.11(e)(3) 1099

(Work with Spore-forming microorganisms). Similarly, only blood and blood components are 1100

subject to the CGMP requirements for such products under part 606. In addition, the CGMP 1101

requirements for biological products applicable to a given product can vary based on product-1102

specific considerations. 1103

In short, the specific requirements in 21 CFR parts 600 through 680 that must be met to 1104

comply with 21 CFR 4.3 and 4.4(c) for a particular combination product that includes a 1105

biological product constituent part will depend on the type of biological product it includes. The 1106

agency welcomes the opportunity to discuss these requirements with manufacturers to ensure 1107

sound, effective CGMP operating systems. If manufacturers have questions regarding these 1108

requirements, they may contact the lead center for the combination product, as well as OCP as 1109

needed, for assistance. 1110

29


2. Complying with CGMPs for HCT/Ps 1113

An HCT/P that is not regulated solely under section 361 of the PHS Act is also regulated 1114

as a drug, device, and/or biological product.62

As explained in the preamble to the final rule, the 1115

drug CGMPs, QS regulation, and the requirements in 21 CFR parts 600 through 680 may apply 1116

to an HCT/P depending on whether the product is regulated as a drug, device, or biological 1117

product.63

The current CGTPs, including donor eligibility requirements for HCT/Ps in part 1118

1271, apply to a combination product that includes an HCT/P. 1119

These CGMPs and the CGTPs supplement one another for such products and do not 1120

supersede each other unless the regulation specifically provides otherwise. In the event that a 1121

regulation in 21 CFR part 1271 is in conflict with a requirement in 21 CFR parts 210, 211, 600 1122

through 680, or 820, the regulations more specifically applicable to the product in question will 1123

supersede the more general.64

1124

The requirements for the manufacture of HCT/Ps under part 1271 are designed to prevent 1125

the introduction, transmission, and spread of communicable diseases, and thereby are essential to 1126

protecting the public health. However, requirements under some sections of part 1271 overlap 1127

with the requirements under the drug CGMPs and the QS regulation. The agency has addressed 1128

these overlaps in part 1271 and in the Guidance for Industry on Current Good Tissue Practice 1129

(CGTP) and Additional Requirements for Manufacturers of Human Cells, Tissues, and Cellular 1130

and Tissue-Based Products (HCT/Ps) (CGTP Guidance). 1131

21 CFR 1271.150(d) explains, in part, that for HCT/Ps regulated as biological products, 1132

drugs or devices, the procedures contained in subpart D and in subpart C of part 1271 and the 1133

procedures contained in 21 CFR parts 210, 211, and 820, supplement one another. As a 1134

consequence, compliance with certain provisions of 21 CFR part 211 or 820 may also constitute 1135

partial or complete compliance with certain provisions of 21 CFR part 1271. However, for 1136

certain CGTP requirements, the CGTP requirements would require additional manufacturing 1137

practices because the CGTP requirements would not be partly or completely covered by a 1138

corresponding CGMP or QS regulation requiring the same practice. Accordingly, the 1139

adjustments that might need to be made to an existing CGMP operating system to be fully 1140

compliant with the 21 CFR part 1271 CGTP requirements for a combination product that 1141

includes an HCT/P may differ if the system being augmented is a drug manufacturing system 1142

62 The HCT/P regulations at part 1271 distinguish between HCT/Ps regulated solely under section 361 of the PHS 1143 Act (42 U.S.C. 264) and those that are also regulated as drugs, devices, and/or biological products. Section 1271.10 1144 provides that an HCT/P that is more than minimally manipulated or that is combined with another article (other than 1145 water, crystalloids, or a sterilizing, preserving, or storage agent) does not meet the criteria for regulation solely under 1146 section 361 of the PHS Act. Refer to 21 CFR 3.2(e), 1271.10, 1271.15, and 1271.20, to determine whether an HCT/P 1147 is regulated as a drug, device, or biological product constituent part of a combination product or is excepted from the 1148 requirements in part 1271. 1149 63 See 78 FR 4317. 1150 64 See 21 CFR 1271.150(d). Also see the Guidance for Industry on Current Good Tissue Practice (CGTP) and 1151 Additional Requirements for Manufacturers of Human Cells, Tissues, and Cellular and Tissue-Based Products 1152 (HCT/Ps) (December 2011). 1153

30


under 21 CFR part 211, a device manufacturing system under 21 CFR part 820, or a combination 1156

product manufacturing system that demonstrates compliance with 21 CFR part 211 and 21 CFR 1157

part 820 in accordance with 21 CFR 4.4(a)(1), 4.4(b)(1), or 4.4(b)(2). 1158

For further information, see the CGTP Guidance. FDA understands the complexity of 1159

manufacturing considerations and duties for combination products that contain an HCT/P that is 1160

a biological product (or drug or device) constituent part. Accordingly, the agency encourage 1161

manufacturers to contact the lead center for your product, or OCP as needed, if manufacturers 1162

have questions about how to comply with CGMP requirements for their particular product. 1163

V. Application of CGMP requirements to specific types of 1164

combination products 1165

The hypothetical scenarios addressed in this section focus on three types of combination 1166

products. While each of these types of combination products is subject both to the drug CGMPs 1167

and to the QS regulation, each example is used to focus on specific CGMP considerations 1168

relating to CGMP provisions specified in 21 CFR 4.4(b). Specifically: 1169

Section A, a prefilled syringe example, focuses on how to comply with the QS regulation 1170

provisions specified in 21 CFR 4.4(b)(1) if a manufacturer adopts a drug CGMP-based 1171

streamlining approach for its CGMP operating system (by demonstrating compliance with 1172

the drug CGMPs and with the specified provisions from the QS regulation). 1173

Section B, a drug-coated mesh example, focuses on specific provisions of the QS 1174

regulation specified in 21 CFR 4.4(b)(1) to highlight some additional issues not raised in 1175

the prefilled syringe scenario. 1176

Section C, a drug-eluting stent (DES) example, focuses on how to comply with the drug 1177

CGMP provisions specified in 21 CFR 4.4(b)(2) if a manufacturer adopts a QS 1178

regulation-based streamlining approach for its CGMP operating system (demonstrating 1179

compliance with the QS regulation and the specified provisions from the drug CGMPs). 1180

This discussion is intended to highlight only certain issues that a combination product 1181

might raise, and considerations for addressing them, relating to the CGMP provisions specified 1182

in 21 CFR 4.4(b). This discussion is not intended to reflect a complete analysis of the CGMP 1183

issues that need to be addressed for such products, whether under the specific CGMP provisions 1184

discussed or any other CGMP requirements also applicable to such products. In addition, 1185

specific products may raise distinct issues that are not taken into account in the hypothetical 1186

scenarios presented below. If manufacturers have specific questions relating to their particular 1187

products, the agency recommends that they contact the lead center for the product, as well as 1188

OCP as needed, for assistance. 1189

31


A. Prefilled syringe 1192

1. Scenario Description 1193

A drug manufacturer (Manufacturer A) plans to sell a drug in a prefilled syringe 1194

presentation. Manufacturer A already has marketing approval for the drug product and would 1195

apply for the marketing approval for this prefilled syringe presentation. No other changes to the 1196

drug will be made. Manufacturer A will buy off-the-shelf syringe components from a supplier 1197

(Manufacturer B) who also manufactures finished syringes using the same components. 1198

Manufacturer A will assemble the syringe components, prefill the syringe at a facility it 1199

operates, and then package, label, and distribute the prefilled syringe from this facility. 1200

Manufacturer A’s facility has an existing drug CGMP operating system. As the prefilled 1201

syringe is a single-entity combination product under 21 CFR 3.2(e)(1), Manufacturer A must 1202

demonstrate compliance with both the drug CGMPs and device QS regulation.65

To do so, 1203

Manufacturer A opts to establish a CGMP operating system using the drug CGMP-based 1204

streamlining approach in accordance with 21 CFR 4.4(b)(1). While Manufacturer A must ensure 1205

that its operating system fully complies with the drug CGMPs for this product, taking into 1206

account all of the issues raised by inclusion of the device constituent part, this example focuses 1207

on considerations for demonstrating compliance with the provisions from the QS regulation 1208

specified in 21 CFR 4.4(b)(1). 1209

2. Compliance with QS regulation requirements 1210

Having chosen to use the drug CGMP-based streamlining approach, under 21 CFR 1211

4.4(b)(1), in addition to demonstrating compliance with the drug CGMPs, Manufacturer A must 1212

comply with the applicable specified provisions of the Quality System (QS) regulation as 1213

discussed below. For each such provision, this discussion offers exemplary considerations and 1214

activities for the combination product manufacturer to meet the QS regulation requirements. 1215

a) 820.20, Management Responsibility 1216

While 21 CFR 211.22, 211.25, and 211.180 establish requirements relevant to 1217

management responsibility, Manufacturer A must ensure that its CGMP operating system 1218

demonstrates compliance with the specific requirements in 21 CFR 820.20 (discussed in greater 1219

detail in section IV.A.1). 1220

Manufacturer A should, for example, review its existing CGMP operating system to 1221

determine how to demonstrate compliance with these requirements. Management with executive 1222

responsibility for Manufacturer A should review the facility’s quality policy and develop and 1223

implement appropriate oversight procedures, if such procedures are not already in place, to 1224

ensure both the policy and oversight are adequate. The oversight procedures should include 1225

65 See 21 CFR 4.4. 1226

32


clear delineation of the personnel to whom management with executive responsibility is 1229

delegating responsibility for implementing the quality policy (including translation into 1230

methods and procedures) and for implementation of the CGMP operating system for this 1231

product at the facility. 1232

b) 820.30, Design Controls 1233

Manufacturer A is responsible for establishing and maintaining procedures for design 1234

control activities for the combination product. In this scenario, Manufacturer A is the product 1235

sponsor and is manufacturing the prefilled syringe. Accordingly, Manufacturer A is responsible 1236

for the design control activities for the syringe as part of the combination product, as well as for 1237

the combination product. However, Manufacturer A is buying the syringe components from 1238

Manufacturer B, another manufacturer, which uses the same components to manufacture finished 1239

syringes. As a result, Manufacturer A may be able to leverage syringe-specific design control 1240

activities, procedures, and documentation from the design controls Manufacturer B uses for its 1241

finished syringes. Because no changes are to be made to the drug other than being prefilled into 1242

the syringe, design considerations for the drug should serve as inputs for controlling the design of 1243

the syringe to ensure its design reflects adequate consideration of the drug’s characteristics, as 1244

indicated below. 1245

i. Design inputs and outputs 1246

The table below includes illustrative examples of design inputs and user needs and 1247

related design outputs for this prefilled syringe. 1248

Design Input/User Needs Design Output

Required minimum/maximum

delivery dose for drug

Drawing/specification for syringe

minimum/maximum volume

Drug viscosity and

desired/required delivery rate

Drawing/specification for needle

bore, glide force, for example

Expected use condition (e.g., expected

user experience/education level)

Content, reading level, for example,

for the prefilled syringe’s labeling

Maximum allowable temperature of

drug

Packaging/labeling specifications for

the prefilled syringe

No degradation of drug or syringe

over the expected shelf-life as a

result of contact with one another

Specifications for drug-contacting

syringe materials

Expected shipping method and

appropriate storage conditions

Design drawings/specifications for

primary and secondary packaging

Drug delivery method (e.g., needle

or needleless delivery)

Drawing/specification for needle and/or

other associated syringe components

33


ii. Design verification and validation 1251

Once Manufacturer A has established design outputs for all design inputs, it must 1252

perform design verification and validation activities to ensure that the combination product 1253

meets design input requirements, including user needs and intended uses.66

Examples of 1254

appropriate testing of the prefilled syringe include: bench testing of the delivery of the drug 1255

from the syringe to ensure repeatable and accurate drug delivery; shock and vibration testing of 1256

the packaged prefilled syringe to ensure no damage or loss of integrity in shipping; validation 1257

that expected users can adequately follow the instructions for use; other human factors studies; 1258

biocompatibility testing; drug and syringe compatibility studies; leachables and extractables 1259

testing; and verification that the prefilled syringe works with all expected delivery methods 1260

(i.e., needle, needleless). These activities would be documented in the design history file 1261

pursuant to 21 CFR 820.30(j) and would be subject to design change and review requirements 1262

pursuant to 21 CFR 820.30(e and (i). 1263

iii. Risk Analysis 1264

Under the risk analysis requirement of 21 CFR 820.30(g), Manufacturer A must identify 1265

risks associated with the prefilled syringe design, its manufacturing processes and intended 1266

uses, and reduce or mitigate any unacceptable risk(s). The table below lists some potential risks 1267

associated with prefilled syringes and potential mitigations for these risks. 1268

Risk Mitigation

Syringe filled with incorrect drug dose In-process acceptance testing,

process validation

Loss of sterility Container/closure integrity testing,

packaging validation/testing

Drug contamination from materials

contained in syringe

Purchasing controls (including

receiving acceptance activities with

syringe component manufacturer), in-

process and finished product testing to

ensure no introduction of

contaminants during manufacture and

over the product shelf-life

Syringe failure during use Design verification testing on syringe,

purchasing controls over syringe

component manufacturer 1269

66 See 21 CFR 820.30(f) and (g). 1270

34


iv. Design changes 1273

Manufacturer A must also have procedures in place to ensure that any changes to design 1274

requirements are identified, documented, validated and/or verified, reviewed, and approved prior 1275

to implementation in accordance with 21 CFR 820.30(i). Activities should include review of the 1276

original risk analysis, review and approval of the revised design inputs and outputs, and review 1277

and approval of the design change. For example, before changing the material used in the 1278

syringe that comes into contact with the drug, Manufacturer A should repeat verification 1279

activities that were originally performed to ensure that no degradation of the drug or device 1280

performance characteristics will occur before the expiration date for the combination product as 1281

a result of the change of materials. All of this information would need to become a part of the 1282

design history file in accordance with 21 CFR 820.30(j). 1283

c) 820.50, Purchasing Controls 1284

Manufacturer A is required to control its purchasing activities for the syringe components 1285

in accordance with 21 CFR 820.50. 1286

For example, if the syringe barrel and plunger material is critical to ensuring that there is 1287

no adverse reaction with the drug, Manufacturer A should structure purchasing agreements with 1288

Manufacturer B to ensure that Manufacturer A is notified of any changes in design or materials 1289

for any components prior to implementation. In addition, because the device constituent part 1290

(syringe) is also a container/closure for the drug, Manufacturer A must perform acceptance 1291

testing of the syringe components in accordance with 21 CFR 211.84. Similarly, if Manufacturer 1292

A uses an outside facility for terminal sterilization of the prefilled syringe, for example, 1293

Manufacturer A must also have appropriate controls over that sterilization service provider in 1294

accordance with section 820.50. 1295

d) 820.100, Corrective and Preventive Actions 1296

Manufacturer A is required to establish and maintain CAPA procedures related to the 1297

combination product as discussed above in section IV.A.4. Following are two examples of 1298

issues that might arise and exemplary steps for addressing them. 1299

Example 1: Manufacturer A has implemented in-process manufacturing verifications that 1300

the syringe is being filled with the correct drug dose, and the data from this process are analyzed 1301

for potential nonconformities. Manufacturer A notes an increase in nonconformities relating to 1302

the volume of drug being placed in the syringe and in turn opens a CAPA to investigate the 1303

problem. Upon investigation of the cause of the improper fill volume, Manufacturer A 1304

determines that maintenance procedures on the filling equipment are the cause of the incorrect fill 1305

volume. These procedures are updated, and verification testing performed to confirm that the 1306

changes correct the problem. 1307

35


Example 2: Manufacturer A begins receiving an increased number of customer 1310

complaints related to holes or damage to the syringe sterile package and opens a CAPA to 1311

investigate the issue. The CAPA reveals that Manufacturer B has made changes to a syringe 1312

component such that there are sharp edges that can damage the sterile pouch during shipping. 1313

Manufacturer A works with Manufacturer B to eliminate the sharp edge or finds a new supplier. 1314

Manufacturer A also augments purchasing specifications and acceptance test steps to perform 1315

visual inspection of the syringe components. Manufacturer A repeats related design verification 1316

testing to ensure that the new syringe meets all design requirements and does not result in pouch 1317

damage during shipping. 1318

e) 820.170, Installation and 820.200, Servicing 1319

Installation and servicing requirements would not apply to the prefilled syringe because 1320

the product does not require installation or servicing activities. 1321

B. Drug-coated mesh 1322


Manufacturer A plans to sell a synthetic surgical mesh coated with a drug. Manufacturer 1324

A has a marketing authorization to sell the uncoated mesh. Manufacturer A wants to coat the 1325

mesh with the drug to treat infection at the site of the product’s implantation. Manufacturer B 1326

has an approval to market the drug for local administration treat infection at the site of 1327

implantation of this class of device, but not in a formulation suitable for coating onto the mesh. 1328

Manufacturer A has established a business relationship with Manufacturer B to use the drug and 1329

develop the data needed to support Manufacturer A’s marketing authorization for the coated 1330

mesh. Manufacturer B will manufacture the drug formulation for spraying onto the mesh, and 1331

Manufacturer A will manufacture the finished drug-coated mesh combination product. 1332

2. Compliance with QS regulation requirements 1333

The coated mesh product is a single-entity combination product under 21 CFR 3.2(e)(1). 1334

Manufacturer A is subject both to the drug CGMPs and the QS regulation for this combination 1335

product. Therefore, Manufacturer A must ensure that its CGMP operating system complies with 1336

both the QS regulation and drug CGMPs, in accordance with one of the approaches permitted 1337

under 21 CFR 4.4, taking into account all of the issues raised by inclusion of the drug constituent 1338

part. This discussion, however, focuses on design control and purchasing control considerations 1339

arising from inclusion of the drug constituent part in the product. 1340

a) 820.30, Design Controls 1341

All of the design control activities required by 21 CFR 820.30, as summarized in IV.A.2 1342

above, must be addressed in the design history file for the drug-coated mesh. Design control 1343

considerations likely would be addressed as part of premarket review of this combination 1344

product (e.g., regarding the suitability of the drug formulation and the compatibility of the mesh 1345

with the drug). Accordingly, much of the information that needs to be included in the design 1346

36


history file would be developed and submitted as part of the premarket review process. 1349

Manufacturer A may opt to incorporate such information by cross-reference to such premarket 1350

submissions. Whatever approach Manufacturer A selects must ensure that all required design 1351

history information is readily available to FDA for review. 1352

The design history file for the surgical mesh must include design input, output, 1353

verification and validation data, and the results of design reviews for the combination product. 1354

In developing the design controls related to the drug constituent part, Manufacturer A may rely 1355

on the safety, efficacy, quality and in situ dose data for the drug as marketed. These existing 1356

data that supported approval of the drug would be available as a reference for the combination 1357

product design history file to enable development of design inputs for the drug constituent part 1358

and the combination product as a whole, and otherwise facilitate its development process. 1359

A focus of the design control process for the drug constituent part of the combination 1360

product is to ensure that the drug-coated mesh will be safe and effective for treating infection 1361

at the site of implantation. Accordingly, if the necessary dose of the drug for effective 1362

prevention of infection, for example, is already known, it would be an input (if the precise dose 1363

is not yet known, then an input would be that the product elute a safe and effective dose); 1364

design outputs and validation and verification would need to be established to ensure that this 1365

required dose is provided when the drug elutes from the mesh.67

In addition, risk analysis must 1366

be conducted to identify any risks associated with the design, manufacturing, and use of the 1367

mesh.68

Also, mitigation measures should be identified and performed to address any identified 1368

risks. Design reviews should incorporate these and other related design considerations for the 1369

product and relevant personnel with expertise in both the drug- and device-specific issues (as 1370

well as an individual independent from the design stage being reviewed). The transfer of the 1371

product design into production specifications should incorporate all important aspects of the 1372

drug constituent part for use in the combination product. 1373

i. Design inputs and outputs 1374

The table below includes illustrative examples of design inputs, including user needs, and 1375

related design outputs that may need to be considered in light of the inclusion of the drug 1376

constituent part. 1377

67 See 21 CFR 820.30(d), (f), and (g). 1378 68 See 21 CFR 820.30(g). 1379

37


Design Input/User Needs Design Output

Required delivery dose and delivery

rate for the drug

Drug formulation and concentration,

coating thickness, uniformity of

coating, manufacturing process

requirements, allowable storage

conditions, drug delivery rate

Expected use condition (e.g.,

anatomical location of use, surgical

technique)

Labeling (instructions for use),

Material/drug composition to ensure no

damage to mesh or coating during

surgical placement

Maximum allowable temperature

during transportation, handling, and

storage for the combination product

Packaging/labeling specifications for

the combination product

No unacceptable degradation of the drug over the expected shelf-life

Specifications for the drug-contacting materials, shelf-life labeling

No degradation of the surgical mesh

over the expected shelf-life

Specifications for mesh material and

drug formulation, shelf-life labeling 1382

ii. Design verification and validation 1383

Several examples of design verification and validation activities are described below: 1384

- One intended use is that the drug-coated mesh will reduce infections. Manufacturer A 1385

must perform a clinical trial (design validation) to ensure that the drug, when 1386

combined with the mesh, is effective in preventing infection and does not raise safety 1387

concerns.69

Design outputs from this study would include the drug concentration in 1388

the coating formulation to be specified in purchasing controls over Manufacturer B 1389

and the coating thickness as specified in process controls over the application of the 1390

coating by Manufacturer A. 1391

A user need is that a physician be able to use the mesh product as labeled without 1392

damaging the drug coating or the mesh material. Manufacturer A would also have to 1393

verify that the mechanical properties of the coated mesh are such that the product can 1394

withstand the stresses anticipated during the surgical procedure and still perform as 1395

intended.70

The results would be used to define and develop the design outputs for the 1396

product, including final instructions for use, as well as mechanical product 1397

specifications and related in-process acceptance testing criteria.1398

Another input to the design process is that the product has a shelf-life consistent with 1399

the stability of the drug formulation and the mesh. Manufacturer A would perform1400

69 See 21 CFR 820.30(g). 1401 70 See 21 CFR 820.30(f). 1402

38


design verification testing such as bench testing after accelerated aging to confirm that 1405

the critical performance properties of the mesh material are not degraded during 1406

storage or as a result of contact with the drug coating and stability studies71

to ensure 1407

that the properties of the drug are not degraded over the expected shelf life. The 1408

design outputs arising from this process would include the labeled expiration date and 1409

storage conditions of the combination product and packaging design specifications. 1410

iii. Risk analysis and mitigation 1411

The table below lists some potential risks associated with a surgical mesh coated with 1412

a drug, and potential mitigations for these risks. 1413

Risk Mitigation

Drug concentration in coating not

sufficient to treat infection (e.g.,

due to insufficient thickness,

inappropriate delivery rate, or

non-uniformity of coating)

In-process acceptance testing,

process validation

Mesh erodes or drug degrades

during use or storage

Design verification testing (bench), clinical

testing, labeling (instructions for use),

purchasing controls over drug supplier,

specifications and other process controls 1414

b) 820.50, Purchasing Controls 1415

Manufacturer A may already have established procedures for controlling 1416

purchasing/supplier activities pursuant to 21 CFR 820.50. Manufacturer A must ensure that 1417

appropriate purchasing controls for Manufacturer B are established and maintained. In particular, 1418

based on the risk associated with the drug and supplier, Manufacturer A must evaluate 1419

Manufacturer B as a potential supplier of the drug and establish the type and extent of control to 1420

be exercised over Manufacturer B as a selected supplier.72

1421

Purchasing controls (and acceptance activities under 21 CFR part 211) should focus on 1422

ensuring that Manufacturer B can supply the drug that meets the specifications that Manufacturer 1423

A has established during the design control process. Manufacturer A should establish purchasing 1424

agreements with Manufacturer B to ensure that Manufacturer A is notified of any changes that 1425

may affect the performance of the combination product prior to their implementation. The 1426

notifications should address issues including changes to the composition, manufacturing process 1427

or facility, or design of the drug component. 1428

Such proposed changes may require that Manufacturer A complete additional design 1429

verification and/or validation. For example, verification testing may be necessary to confirm that 1430

71 See the Guidance for Industry on Q1A(R2) Stability Testing of New Drug Substances and Products (November 1431 2003). 1432 72 See 21 CFR 820.50(a)(2). 1433

39


the purity and stability of the drug is maintained, pursuant to the requirements of section 1436

820.30(i)73

1437

C. Drug Eluting Stent (DES) 1438


In this scenario, Manufacturer A is the sponsor and manufacturer for a drug-eluting stent 1440

(DES) composed of a stent coated with a drug. Manufacturer B manufactures the active 1441

pharmaceutical ingredient (API or bulk drug substance), Manufacturer C manufactures a 1442

polymer with which the bulk drug substance will be combined for coating onto the stent, and 1443

Manufacturer D manufactures the materials used for the product’s packaging. Manufacturer A 1444

purchases the bulk drug substance from Manufacturer B and the polymer from Manufacturer C, 1445

then formulates the drug coating solution and uses it to coat the stent in its own facility. At the 1446

same facility, Manufacturer A packages the DES using the primary packaging materials it 1447

purchases from Manufacturer D. 1448

2. Compliance with drug CGMP requirements 1449

The DES is a single-entity combination product as defined in 21 CFR 3.2(e)(1) and, 1450

therefore, is subject to both the drug CGMPs and device QS regulation. As a device 1451

manufacturer, Manufacturer A already has a CGMP operating system designed to comply with 1452

the QS regulation and has elected to establish a QS regulation-based CGMP operating system for 1453

the DES in accordance with 21 CFR 4.4(b)(2). While Manufacturer A must ensure that this 1454

operating system complies with the QS regulation, taking into account all of the issues raised by 1455

inclusion of the drug constituent part, this example focuses on considerations for complying with 1456

the drug CGMP provisions specified in 21 CFR 4.4(b)(2).74

1457

a) 21 CFR 211.84, Testing and approval or rejection of components, drug product 1458

containers, and closures 1459

As part of its existing CGMP operating system, Manufacturer A has already implemented 1460

21 CFR 820.30, 820.50, 820.80, and 820.86. Accordingly, Manufacturer A has controls in place 1461

to evaluate suppliers, contractors, and consultants based on their ability to meet quality and 1462

specified requirements. Manufacturer A’s purchasing controls for the DES must include 1463

evaluation of Manufacturer B as the supplier of the bulk drug substance, Manufacturer C as the 1464

supplier of the polymer for the coating, and Manufacturer D as the supplier of the packaging 1465

materials in conformance with 21 CFR 820.50(a)(1). Supplier approval should include an 1466

evaluation that provides adequate evidence (e.g., past quality history) that the entity can 1467

consistently provide material meeting specifications. In addition, under its CGMP operating 1468

system for the facility, Manufacturer A has controls to identify the acceptance status of 1469

73 As the sponsor for the drug-coated mesh, Manufacturer A would also have postmarket duties to notify the agency of 1470 such changes and, in some cases, to obtain agency approval of the change depending on the nature of the change. 1471 74 Control of the device constituent part (i.e., the bare stent) would be undertaken in accordance with the QS 1472 regulation. 1473

4 0


manufactured products. Manufacturer A’s duties under 21 CFR 211.84 relate to these various 1476

obligations and controls arising from the QS regulation. Under 21 CFR 4.4(b)(2), Manufacturer 1477

A must augment its existing CGMP operating system as needed to satisfy the requirements of 21 1478

CFR 211.84 for the DES. 1479

In accordance with 21 CFR 211.84, the bulk drug substance, polymer, and packaging 1480

materials supplied by manufacturers B, C, and D must be sampled, tested, or examined, as 1481

appropriate, by Manufacturer A to determine if they should be approved or rejected for use. 1482

Each lot of these incoming materials must be withheld from use until it is determined that it 1483

meets appropriate written specifications of identity, strength, quality, and purity and related 1484

tests, under 21 CFR 211.84. Designated areas for disposition and sampling of components and 1485

materials should be controlled to ensure that all incoming lots are evaluated and not 1486

contaminated. Representative samples from each lot must be taken in accordance with 21 CFR 1487

211.84(b) and (c) to make a determination of the quality of the lot. 1488

The packaging materials should be visually inspected to ensure the correct, specified 1489

materials have been received from Manufacturer D. The bulk drug substance and polymer each 1490

must be tested by Manufacturer A for conformity with all appropriate written specifications for 1491

purity and quality, and for strength of the bulk drug substance, unless a report of analysis is 1492

appropriately relied on (as described in the paragraph below).75

Samples used for testing must 1493

be representative of the lot of material being assessed.76

Sampling methods should specify the 1494

number of containers to be sampled, which part of the container to sample, and the amount of 1495

material to be taken from each container. The number of containers to sample and the sample 1496

size should be based on a statistically valid sampling plan that takes into consideration the 1497

material type, degree of precision required, material variability, past quality history of the 1498

supplier, and the quantity needed for analysis. Sampling should be conducted at defined 1499

locations and by procedures designed to prevent contamination of the material sampled and 1500

contamination of other materials. 1501

Under certain circumstances, Manufacturer A may rely on a report of analysis from a 1502

supplier in lieu of conducting some of its own testing. If, for example, Manufacturer B performs 1503

conformity testing for the bulk drug substance (testing to ensure the material meets appropriate 1504

purity, strength, and quality specifications) just prior to the shipment of material to Manufacturer 1505

A, then a report of analysis may be accepted by Manufacturer A in lieu of testing for these 1506

characteristics by Manufacturer A, if certain conditions are met. Specifically, Manufacturer A is 1507

still responsible for the performance of at least one specific identity test upon receipt of a lot of 1508

the bulk drug substance, even if a comprehensive report of analysis accompanies the lot. 1509

Reliance on reports of analyses is also contingent on Manufacturer A establishing the reliability 1510

of the supplier’s analyses through appropriate validation of the test results at appropriate 1511

intervals.77

The supplier can be evaluated through initial purchasing controls and at suitable, 1512

subsequent intervals. A similar analysis would apply if Manufacturer C were to conduct 1513

conformity testing for the polymer it supplies to Manufacturer A. 1514

75 See 21 CFR 211.84(d)(2). 1515 76 See 21 CFR 211.84(b). 1516 77 See 21 CFR 211.84(d)(2). 1517

41


Incoming testing by Manufacturer A (and receipt of a report of analysis with respect to 1520

the materials obtained from Manufacturer B, C, or D if tested by them) must occur prior to 1521

formulation at Manufacturer A of the finished DES.78

Due to the nature and intended use of 1522

sterile drug eluting stents, testing must include microbiological testing of the bulk drug substance 1523

and polymer.79

1524

b) 21 CFR 211.103, Calculation of yield 1525

Manufacturer A is responsible for the calculation of yield at appropriate phases throughout 1526

the entire manufacturing process of the drug constituent part, including its application to the DES, 1527

and the packaging of the DES. The calculation of yield should be determined during appropriate 1528

steps in the manufacturing process, including the formulation of the drug constituent part and 1529

polymer prior to and after the coating of the stent. The formula used and the data generated for the 1530

calculation should be maintained in a manufacturing and/or production record. 1531

c) 21 CFR 211.132, Tamper-evident packaging requirements for over-the-counter 1532

(OTC) human drug products 1533

This regulatory requirement is not applicable to drug-eluting stents, as they are not OTC 1534

products. 1535

d) 21 CFR 211.137, Expiration dating 1536

As the manufacturer of the combination product, Manufacturer A is responsible for 1537

establishing the expiration date on the labeling of the finished combination product. The 1538

expiration date must be established based on the data from the stability studies on the finished 1539

packaged DES and should also take into account other shelf-life considerations as required under 1540

design control. These considerations include the functionality of the stent and polymer and the 1541

integrity of the coating and the packaging.80

1542

e) 21 CFR 211.165, Testing and release for distribution 1543

Manufacturer A must test each batch of the finished combination product to determine 1544

conformance with final written specifications of the product. A detailed listing of all the tests 1545

performed on the DES and the acceptance criteria should be incorporated into the documentation 1546

for the manufacturing, production, and laboratory systems. A description of each analytical test 1547

should be developed and documented in standard operating procedures. A general list of tests for 1548

drug-eluting stents is provided below. Additional information on drug-eluting stents is provided 1549

in the draft Guidance for Industry on Coronary Drug-Eluting Stents–Nonclinical and Clinical 1550

Studies –(March 2008).81

1551

78 See 21 CFR 211.84(a). 1552 79 See 21 CFR 211.84(c)(3) and (d)(6). 1553 80 See 21 CFR 211.137(a) and (b). 1554 81 When finalized, this guidance will represent FDA’s current thinking on DES. 1555

42

1556


Appearance 1559

Identification 1560

Assay 1561

Impurities and Degradation Products 1562

Content Uniformity 1563

Drug Release Rate (immediate and/or extended release rates) 1564

Package Integrity and Sterility 1565

Endotoxins 1566

Particulate Matter 1567

Additional Testing, when applicable (including testing for polymer molecular weight, 1568

residual monomers, catalysts, and other additives) 1569

f) 21 CFR 211.166, Stability testing 1570

Stability testing for the final DES product should address the following considerations: 1571

appearance, assay/drug content, impurities/degradation products, rate of drug release, particulate 1572

matter, sterility, and package integrity. Methods used for batch release under 21 CFR 211.165 1573

may also be suitable for stability testing. Analytical procedures for stability testing should be 1574

fully validated as suitable to demonstrate stability. 1575

g) 21 CFR 211.167, Special testing requirements 1576

Manufacturer A must conduct or contract to conduct conformity testing of the DES in 1577

accordance with 21 CFR 211.167(a) because this class of product is purported to be sterile and 1578

pyrogen-free. In addition, testing in accordance with 21 CFR 211.167(c) must be conducted 1579

because the DES constitutes a controlled-release dosage form. 1580

h) 21 CFR 211.170, Reserve samples 1581

Manufacturer A must maintain reserve samples representative of each lot of the bulk 1582

drug substance used in the combination product and of each lot or batch of the finished 1583

packaged DES.82

Reserve samples must consist of at least twice the quantity necessary to 1584

perform all tests required for the bulk drug substance and the finished DES, excluding sterility 1585

and pyrogen testing.83

The reserve samples must be kept for the time periods required by 21 1586

CFR 211.170. The samples of the bulk drug substance should be kept for 1 year past the 1587

expiration date of the last lot of finished drug-eluting stents to use that lot of the bulk drug 1588

substance.84

The samples for each lot of the finished DES must be kept for 1 year after the 1589

expiration date for the product.85

1590

82 See 21 CFR 211.170(a) and (b). 1591 83 See 21 CFR 211.170(a) and (b). 1592 84 See 21 CFR 211.170(a)(1). 1593 85 See 21 CFR 211.170(b)(1). 1594

43


VI. Contact Us 1597

If you have questions regarding compliance with CGMP requirements for combination 1598

products after reviewing this guidance and the other guidance documents cited in this 1599

document, we encourage you to contact us. We recommend you contact the lead center for your 1600

product in the first instance. However, you may also contact OCP for assistance. Below are 1601

contact points for each center and OCP. 1602

1. CBER 1603

Mail: Office of Communication, Outreach and Development (OCOD) 1604


Building 71, Room 3103 Silver 1606

Spring, MD 20993 Rockville, 1607

MD 20852-1448 1608

Phone: 1-800-835-4709 or 240-402-8010 1609

Email: [email protected] 1610

2. CDER 1611

Mail: Division of Drug Information (DDI) 1612

Hillandale Building 1613


Silver Spring, MD 20993 1615

Phone: 1-855-543-3784 or 301-796-3400 1616


3. CDRH 1618

Mail: Division of Industry and Consumer Education (DICE) 1619


Building 66, Room 4621 Silver 1621

Spring, MD 20993 1622

Phone: 1-800-638-2041 or 301-796-7100 1623


4. OCP 1625

Mail: Office of Combination Products, Food and Drug Administration 1626


Building 32, Hub/Mail Room 1628

#5129 Silver Spring, MD 20993 1629

Phone: 301-796-8930 1630

Fax: 301-847-8619 1631






4 4


VII. References 1635

Device 1636

1. Design Control Guidance for Medical Device Manufacturers, Guidance for Industry (March 1637

1997) 1638

(http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/Guidanc 1639

eDocuments/ucm070642.pdf) 1640

2. Sterilized Convenience Kits for Clinical and Surgical Use, Guidance for Industry (Jan. 1641

2002) 1642



3. Quality System Information for Certain Premarket Application Reviews, Guidance for 1645

Industry and FDA Staff (Feb. 3, 2003) 1646



4. Glass Syringes for Delivering Drug and Biological Products: Technical Information to 1649

Supplement International Organization for Standardization (ISO) Standard 11040-4 - 1650

Draft Guidance for Industry and FDA Staff (April 2013) 1651

(http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM346181.pdf) 1652

5. Human Factors and Medical 1653

Devices(http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/HumanFact 1654

ors/default.htm) 1655

Drugs 1656

6. Container Closure Systems for Packaging Human Drugs and Biologics: Chemistry, 1657

Manufacturing, and Controls Documentation, Guidance for Industry, (May 1999) 1658

(http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid 1659

ances/UCM070551.pdf) 1660

7. Q7A Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients, 1661

Guidance for Industry (Aug 2001) 1662

(http://www.fda.gov/ICECI/ComplianceManuals/CompliancePolicyGuidanceManual/uc 1663

m200364.htm) 1664

8. Q1A(R2) Stability Testing of New Drug Substances and Products, Guidance for Industry 1665

(Nov. 2003) 1666



http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/Guidanc



http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM346181.pdf)

http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/HumanFact

http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid

http://www.fda.gov/ICECI/ComplianceManuals/CompliancePolicyGuidanceManual/uc


45


9. Sterile Drug Products Produced by Aseptic Processing — Current Good Manufacturing 1671

Practice, Guidance for Industry (Sept. 2004) 1672



10. Quality Systems Approach to Pharmaceutical CGMP Regulations, Guidance for Industry 1675

(Sept. 2006) 1676



11. Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical Production, 1679

Guidance for Industry (Oct. 2006) 1680



12. CGMP for Phase 1 Investigational Drugs, Guidance for Industry (July 2008) 1683



13. Q10 Pharmaceutical Quality System, Guidance for Industry (April 2009) 1686



14. Process Validation: General Principles and Practices, Guidance for Industry (Jan. 2011) 1689



15. Pyrogen and Endotoxins Testing: Questions and Answers, Guidance for Industry (June 1692

2012) 1693



Biological Products 1696

16. Cooperative Manufacturing Arrangements for Licensed Biologics, Guidance for Industry 1697

(Nov. 2008) 1698

(http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulator 1699

yInformation/Guidances/General/UCM069908.pdf) 1700

17. Contact Manufacturing Arrangement for Drugs Quality Agreement, Guidance for 1701

Industry (May 2013) 1702

(http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidan 1703

ces/ucm353925.pdf) 1704








http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulator

http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidan

4 6


HCT/Ps 1707

18. Current Good Tissue Practice (CGTP) and Additional Requirements for Manufacturers of 1708

Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps), Guidance for 1709

Industry (Dec. 2011) 1710

(http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulator 1711

yInformation/Guidances/Tissue/UCM285223.pdf) 1712

Combination Products 1713

19. Coronary Drug-Eluting Stents – Nonclinical and Clinical Studies, Draft Guidance for 1714

Industry (March 2008) 1715



http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulator


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