Combination products Updates Final FDA Guidance

Transcription

1 Compliance Seminars Combination products Updates Final FDA Guidance Presented by Anna Lundén Webinar, March 8, 2017

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3 Compliance Seminars Our international course program for GMP professionals in the European industry. The instructors are leading GMP specialists in their areas and have long experience of training. The courses are arranged several times a year around Europe. Program and registration: Some of the topics covered in the program: Auditing & Inspections Batch Record Review Biopharmaceuticals & Biotechnology CAPA (Medical Device) Cleanrooms, Contamination control, Cleaning & Cleaning validation Clinical Trial Materials Design Control (Medical Device) Distribution & Cold Chain (GDP) Engineering (GEP) Laboratory Operation Quality System Requirements (Medical Device) Risk Management Sterile Pharmaceuticals Validation and Qualification Play4GMP board game The GMP board game that tests and improves your GMP compliance, knowledge, attitude and awareness! Pharmaceutical and Medical Device editions. Play4GMP is a fun, challenging, and interactive learning game for team members with diverse GMP experience and knowledge. The game tasks and challenges reflect ordinary day-by-day GMP compliance realities. Play4GMP will reveal all you know, and don t know about GMP, and in the end all participants has gained knowledge that improves the team attitude and awareness, necessary for GMP compliance. Your free document library and search tool Find your way in regulations and guide documents. We have gathered all the important GMP documents for you - on-line Document library and search tool Speed up your search for regulatory texts and guidance documents related to International GMPs, Quality system regulations and warning letters! Search - Open - Print Glossary - Abbreviations and terminology Compliance links and event calendar Our Glossary contains hundreds of those words commonly used within the GMP arena. Find links to authorities and organisations within the GMP/QSR field. Check out the calendar for courses and events. See our short presentation video and register at:

4 Literature GMP and QSR handbooks Anna Lundén have gathered the most important GMP and QSR facts in these books. Get basic knowledge about GMP/QSR in a clear and easy to read style. Suitable for self studies and as reference. GMP collections Relevant GMP s collected in handy booklets: - Pharmaceutical Production - Sterile production - Combination products Also available as E-books for your mobile phone, tablet or computer. Guides and self study courses Guide documents with comments and references. Course material suitable for self studies and/or in-house training. GMP/GDP translations in pocket size format Very handy and the original text in parallel. Swedish, French and Danish. Quality awareness posters Make people aware of the 12 most common human factors elements that may impact the ability to perform effectively and safely - The Dirty Dozen 12 posters that describe each of the human factors and give advice on how to prevent them. Includes study booklet for training sessions. Consulting Use our worldwide Network of GMP specialists Even though we are specialized in developing and presenting compliance training related to current US GMP regulations and FDA requirements, we do offer consultancy in different levels. Consultants can either be our own training specialists or consultants from our partners or affiliates. Depending of the scoop of the consultancy assignment, availability of consultants, Training in local languages We offer GMP and QSR training in several languages. FR SE IT DK Visit our web site for local course programs level of expertise and time frame, we will be able to propose a proper solution for your company. For more information, specify your needs and contact us. Ideas and knowledge to share? To be able to keep our top position as one of Europe s leading Compliance training and consultancy organizations we are constantly looking for new ideas, topics, and partners. So if you have an idea we are always interested to listen. Key2Compliance AB Tjädervägen Lidingö Tel: info@key2compliance.com BL0135d

5 Combination products Updates Final FDA Guidance 2017 Key2Compliance AB 1 Content Background and Definitions 21 CFR 4, CGMP for Combination products FDA s Final Guidance for Industry Highlights Q & A 2017 Key2Compliance AB Key2Compliance AB Page 1

6 Background and Definitions 2017 Key2Compliance AB 3 Transdermal Patch for treatment of ADHD Insulin inhalator Bone cement with anti biotics Pre filled Adrenalin Auto injector 2017 Key2Compliance AB Key2Compliance AB Page 2

7 Background FDA Food and Drug Administration CFR Code of Federal Regulations 21 CFR 210/211 CGMP for Drugs 21 CFR 820 CGMP/QS Regulation for Medical Devices Etc. 21 CFR 3 Definition of Combination products 21 CFR 4 Combination products Subpart A Current Good Manufacturing Practice Subpart B Postmarketing Safety Reporting 2017 Key2Compliance AB 5 Background CDRH Center for Devices and Radiological Health CDER Center for Drug Evaluation and Research CBER Center for Biologics Evaluation and Research OCP Office of Combination Products Key2Compliance AB Key2Compliance AB Page 3

8 Definitions Defined in 21 CFR 3.2(e) A product comprised of two or more regulated components, i.e., drug/device, biologic/device, drug/biologic, or drug/device/biologic, that are physically, chemically, or otherwise combined or mixed and produced as a single entity Example: Pre filled syringe, inhaler with drug Two or more separate products packaged together in a single package or as a unit and comprised of drug and device products, device and biological products, or biological and drug products Example: Surgical tray with instruments and lidocain Plus 2 more: Labelled to be used together 2017 Key2Compliance AB 7 Definitions Single entity Copacked Crosslabelled 2017 Key2Compliance AB Key2Compliance AB Page 4

9 Definitions PMOA Primary Mode of Action the single mode of action of a combination product that provides the most important therapeutic action of the combination product. Will guide which Center shall take the lead for review of an application Ref: FDA Guidance for Industry, CGMP Requirements for Combination Products, 01/ Key2Compliance AB 9 Manufacture Definitions Includes, but is not limited to, designing, fabricating, assembling, filling, processing, testing, labeling, packaging, repackaging, holding and storage Ref: FDA Guidance for Industry, CGMP Requirements for Combination Products, 01/ Key2Compliance AB Key2Compliance AB Page 5

10 Definitions Constituent part Used by FDA to identify a drug, device or biologic in a combination product Component Defined slightly different in drug CGMPs compared to device CGMPs/QS CGMP/QS applies different to Device Components and Drug Components! Ref: FDA Guidance for Industry, CGMP Requirements for Combination Products, 01/ Key2Compliance AB 11 Definitions Facility that manufacture only a device components Not subject to QS Regulations (21 CFR 820) Facility that manufacture only a drug API Not subject to CGMP as per 21 CFR 210/211 But the Device Manufacturer may request compliance in part! But FDA expects compliance with ICH Q7 Ref: FDA Guidance for Industry, CGMP Requirements for Combination Products, 01/ Key2Compliance AB Key2Compliance AB Page 6

11 Definitions Facility that manufacture a drug device combination formed from components is subject to 21 CFR 211 and 21 CFR 820 Ref: FDA Guidance for Industry, CGMP Requirements for Combination Products, 01/ Key2Compliance AB 13 Definitions Device or container/closure for the drug? The Agency will continue to regulate drug containers and closures in accordance with parts 210 and 211. A syringe, however, is not a mere container/closure. A syringe is a device used to deliver another medical product (e.g., a drug) (see, e.g., 21 CFR ). Accordingly, a prefilled syringe is a combination product and subject to this rule. 21 CFR 4 Preamble comment # Key2Compliance AB Key2Compliance AB Page 7

12 Definitions Device or container/closure for the drug? The essential difference is generally whether the article is designed to deliver the drug it contains or merely hold it. Ref: FDA Guidance for Industry, CGMP Requirements for Combination Products, 01/ Key2Compliance AB 15 Definitions Container closure system Includes primary and secondary packaging components if latter intended to provide additional protection Elements of container closure system that are device constituent parts: Piston syringes, metered dose inhalers, IV bags and IV container Ref: FDA Guidance for Industry, CGMP Requirements for Combination Products, 01/ Key2Compliance AB Key2Compliance AB Page 8

13 Definitions Convenience Kit For purposes of this rule, we define the term to include only kits that solely include products that are: (1) Also legally marketed independently and (2) included in the kit as already packaged for independent marketing and with the same labeling as for independent marketing. This is an important question because no additional CGMP requirements generally would apply to the products in such a convenience kit simply because they have been included in the kit. The only additional CGMP requirements that would generally apply to such a convenience kit would be those applicable to the assembly, packaging, labeling, any sterilization, or further processing of the kit itself. 21 CFR 4 Preamble comment # Key2Compliance AB 17 Convenience Kit Definitions Accordingly, no additional CGMP requirements would apply to an off the shelf device that is packaged and labeled in accordance with its existing marketing authorization for the independent sale solely because of its inclusion in a convenience kit. 21 CFR 4 Preamble comment # Key2Compliance AB Key2Compliance AB Page 9

14 Convenience Kit Definitions In contrast, if any products to be included in a kit are repackaged, relabeled or otherwise modified for purposes of their inclusion in the kit, the kit is not a convenience kit for purposes of this rule and all the CGMP requirements applicable under this rule based on any changes made to the constituent parts would apply. 21 CFR 4 Preamble comment # Key2Compliance AB 19 Convenience Kit Definitions if an off the shelf device is included in a co packaged combination product for an intended use that differs from the intended use for which that device is marketed separately, additional CGMP requirements may apply, including design controls to ensure that the device is appropriate for the specific use to which it is put in the combination product. 21 CFR 4 Preamble comment # Key2Compliance AB Key2Compliance AB Page 10

15 21 CFR 4 CGMP for Combination products 2017 Key2Compliance AB CFR 4 21 CFR 4 Combination products First proposal 23 September 2009 Final text published 22 January 2013 Became effective 22 July 2013 Subpart A Current Good Manufacturing Practice Additional text effective January Subpart B Postmarketing Saftey reporting for Combination products 2017 Key2Compliance AB Key2Compliance AB Page 11

16 Streamlined approach 21 CFR 4 21 CCFR 4.4 alternatives for CGMP compliance 4.4(a)(1) Comply with all GMP requirements for both parts 4.4(b)(1) Comply with Drug GMP and the streamlined approach for Device GMP 4.4(c)(1) Comply with Device GMP and streamlined approach for Drug GMP 4.4(b)(3) Comply with additional requirements for Biological products and HTC/P products 2017 Key2Compliance AB CFR 4 A Quality system based on 21CFR210/211: Add following requirements from 21 CFR Management responsibility Design Controls Purchasing controls Corrective and preventive actions Installation Service 2017 Key2Compliance AB Key2Compliance AB Page 12

17 21 CFR 4 A quality system based on 21CFR820: Add following requirements from 21 CFR 211 (1 of 2) Test.. of component, containers, closures Calculation of yield Tamper evident packaging Expiration dating Testing and release for distribution 2017 Key2Compliance AB CFR 4 A quality system based on 21CFR820: Add following requirements from 21 CFR 211 (2 of 2) Stability testing Special testing requirements Reserve samples 2017 Key2Compliance AB Key2Compliance AB Page 13

18 Design Control 21 CFR 4 Design controls require the manufacturer of a combination product which includes a device constituent part to establish and maintain procedures to ensure that the design requirements for the combination product are appropriate and address the intended use of the combination product, including the needs of the user and patient. Preamble comment # Key2Compliance AB CFR 4 Design History File (DHF) The design history file for a combination product with device and drug or biological product constituent part must address all design issues resulting from the combination of the constituent parts, regardless of whether the manufacturer chooses to apply a CGMP operating system that implements part 820 plus the provisions of part 211 specified in Sec. 4.4(b)(2) of this rule or implements part 211 plus the provisions of part 820 specified in Sec. 4.4(b)(1) of this rule. Preamble comment # Key2Compliance AB Key2Compliance AB Page 14

19 21 CFR 4 Design History File (DHF) with regard to a drug or biologic product constituent part in a combination product, the design history file would document and provide objective evidence that the drug or biologic is appropriate for use with the device (e.g., why the formulation of the drug constituent part is appropriate for use in a drug eluting stent given the need to ensure controlled elution, resistance to flaking, etc.). Preamble comment # Key2Compliance AB CFR 4 Design History File (DHF) with regard to a device constituent part in a combination product, the design history file would document and provide objective evidence that the device constituent part is appropriate for use with the drug or biological product (e.g., that a syringe is appropriate for use as a delivery device for a drug by providing assurance that there is no interaction with the drug, that the syringe will deliver the drug properly, and that container closure integrity and shelf life can be maintained, etc.) Preamble comment # Key2Compliance AB Key2Compliance AB Page 15

20 21 CFR 4 Yield Calculation for Device Constituent Section does not apply to device constituent parts of combination products Preamble comment # Key2Compliance AB 31 Reserve Samples 21 CFR 4 For co packaged and cross labeled combination products, it generally should be sufficient to maintain samples of each lot of the drug or biological product in the immediate container/closure in which it is marketed. Preamble comment # Key2Compliance AB Key2Compliance AB Page 16

21 21 CFR 210/ CFR 4 Facility A drug Pick 21 CFR 210/211 or 21 CFR 820 plus streamlined approach Facility C Combination Facility B device 21 CFR Key2Compliance AB CFR 4 Pick 21 CFR 210/211 or 21 CFR 820 plus streamlined approach Facility A Drug and device Facility B Combination 2017 Key2Compliance AB Key2Compliance AB Page 17

22 21 CFR 4 21 CFR 210/ CFR 820 and streamlined approach for the drug while in plant Pick 21 CFR 210/211 or 21 CFR 820 plus streamlined approach Facility A drug Facility B device Facility C Combination Drug sent to B Drug and device sent to C 2017 Key2Compliance AB 35 FDA s Final Guidance for Industry CGMP Requirements for Combination Products Published January 2017 Highlights 2017 Key2Compliance AB Key2Compliance AB Page 18

23 Legacy products Highlights Although products developed prior to promulgation of part 4 are frequently termed legacy combination products, FDA deliberately does not use this terminology in this guidance because it could be inappropriately interpreted to indicate that products developed prior to promulgation of part 4 are therefore subject to fewer CGMP obligations than products developed after promulgation of part Key2Compliance AB 37 Highlights Documentation of CGMP approach It is always the manufacturers responsibility to ensure compliance with all applicable CGMP requirements The Quality System documentation should identify the CGMP operating system Share this with investigators at initiation of inspection If discussions during premarket review: Identify if streamlined approach is used CGMP approach for each facility 2017 Key2Compliance AB Key2Compliance AB Page 19

24 Highlights Cross references in the regulations (Reserve samples) reference (Production record review) (Calculation of yield) reference (Automatic, mechanical, and electronic equipment) definition of design output mentions device master record ( ) 2017 Key2Compliance AB Production record review would be sufficiently covered by Analyzing data sources Automatic..equipment is covered in (i) Automated processes Master records in 211 and 820 aligned Master Production and Control Records 2017 Key2Compliance AB Key2Compliance AB Page 20

25 Highlights Investigational products drugs Drug for Phase I study generally exempted from 21CFR210/211 Applies also to investigational combination product for Phase I Not if drug has been used earlier in another Phase II or III study Not if drug has been lawfully marketed 2017 Key2Compliance AB 41 Highlights Investigational products devices Exempt from 21CFR820 except for Design controls in Design controls may also be exempted for certain devices Most devices in Class I (low risk) are exempted from Design controls Design controls should start early, when company has determined that product appears to have clinical utility and management has committed to further development Even though exemptions apply, FDA recommends hazards and risks related to production to be considered for all investigational products 2017 Key2Compliance AB Key2Compliance AB Page 21

26 Highlights Low risk devices exempted from certain requirements Most devices in Class I are exempted from Design controls Some devices in Class I are exempted from all requirements in 820 except (General requirements, records) and (Complaint files) 21 CFR Liquid medication dispensers (cups, droppers etc.) 2017 Key2Compliance AB 43 Highlights However, if a device that would ordinarily be exempt from all or certain provisions in part 820 is incorporated into a container closure system, for example if a dropper is incorporated into the cap of a bottle of a drug, this may be a new use of the device such that the exemptions from part 820 may not be applicable. In any event, when incorporated into a container closure system, the device must be addressed as part of the container closure system for purposes of part 211. Compliance with 21CFR211 may be enough 2017 Key2Compliance AB Key2Compliance AB Page 22

27 Highlights Documented evaluation If you believe a container closure system with delivery attributes is not a device If you believe device constituent part exempt from parts of QS (21CFR820) In doubt or questions? Discuss with Lead center or OCP 2017 Key2Compliance AB 45 Highlights Application of requirements Certain requirements relates to the product as a whole Changes in production of a constituent part may affect the other constituent part Design Controls and CAPA system investigations Make sure adequate flow of information between facilities and manufacturers Key2Compliance AB Key2Compliance AB Page 23

28 Highlights Section A System based on Drug CGMPs 21 CFR 210/211 Section B System based on Device QS 21 CFR Key2Compliance AB 47 Design Controls Highlights A Pharmaceutical development may focus on drug considerations Principles in ICH Q8(R2) for Quality by Design can be leveraged and built upon Integrate interaction with the device constituent part Combined use shall be a safe and effective product that performs as intended Terminology may differ, make sure communication is clear! 2017 Key2Compliance AB Key2Compliance AB Page 24

29 Design Controls DHF Highlights A Can leverage and cross reference drug development data Data to support safety and efficacy of the drug in a copacked combination product If already approved for the same indication If modified additional activities performed and documented in the DHF 2017 Key2Compliance AB 49 Highlights A Design controls for Combination products already on the market FDA expects evaluation design controls and documentation adequate? Review pre market submissions, product risk profile and postmarket experience Additional testing and documentation required? 2017 Key2Compliance AB Key2Compliance AB Page 25

30 Purchasing controls Highlights A Documented supplier evaluation and records of approved suppliers Data with specified requirements for products and services E.g. Contracts and Quality Agreements Change notification If not possible to obtain implement additional controls 2017 Key2Compliance AB 51 Highlights A Corrective and preventive actions Cover activities at all involved facilities Root cause investigation and appropriate measures Consider implications of corrective and preventive actions for all constituent parts and for product as a whole Drug references: (e) FDA OOS Guidance ICH Q10 Pharmaceutical Quality System 2017 Key2Compliance AB Key2Compliance AB Page 26

31 Batch/lot definitions Highlights B Procedures to define batch or lot in all phases of production Incoming material, in process material, finished product Master production and control records designed to enable traceability 2017 Key2Compliance AB 53 Calculation of yield Highlights B For drug constituent part High or low yield may suggest a problem early detection system If outside established and documented allowable variation investigate 2017 Key2Compliance AB Key2Compliance AB Page 27

32 Calculation of yield Highlights B Data for device constituent parts and components may be necessary to control the manufacturing process although yield calculation not required for device constituent Problems with device may affect drug yield Prefilled syringes rejected due to nonconformity of needle Yield calculations for each appropriate phase 2017 Key2Compliance AB 55 Highlights B Calculation of yield at each phase at which component, in process material, or product loss may occur Formulation of the drug Incorporation of drug into the combination product Packaging process E.g. filling, coating Documented in Device History Record (DHR) 2017 Key2Compliance AB Key2Compliance AB Page 28

33 Highlights B Testing and release for distribution Single entity laboratory testing of each batch Co packed on every batch of the drug constituent part Test of in process material More details in and guidance about inprocess testing for drugs 2017 Key2Compliance AB 57 Highlights B Testing and release for distribution May be OK to test samples that are not finished combination products Needs to be representative Bridging studies to show that additional manufacturing steps do not affect the drug constituent part 2017 Key2Compliance AB Key2Compliance AB Page 29

34 Highlights B Stability testing Matrix and bracketing approaches can be used Adequately justified and where applicable, reviewed by the FDA Expiration date for new combination, modification of existing product Leverage stability data for existing product if modification does not impact the stability of the drug Example: Changing catheter length without changing drug coated balloon 2017 Key2Compliance AB 59 Stability testing Highlights B Need for new studies should be evaluated for changes to any constituent part Manufacturing process Size or shape of device constituent part holding/in contact with the drug Material changes of device constituent part 2017 Key2Compliance AB Key2Compliance AB Page 30

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40 Key2Compliance AB Tjädervägen 10 SE Lidingö, Sweden info@key2compliance.com