21 CFR Part 4 - CGMP for Combination Products

To understand, through development, implementation and feedback, the 21 CFR Part 4 rule and how it applies to you

1. 21 CFR Part 4 Current Good Manufacturing Practice Requirements for Combination Products Docket No. FDA-2009-N-0435 FINAL RULE Jasmin NUHIC April 2013 THIS RULE IS EFFECTIVE 22 JULY 2013

2. OBJECTIVE To understand, through development, implementation and feedback, the 21 CFR Part 4 rule and how it applies to you 21 CFR Part 4 THIS RULE IS EFFECTIVE 22 JULY 2013 2

3. TOPICS Rationale for the final rule Examples of combination products Proposed rule Legal authorities Assessment and impacts The final rule Comments and responses References and credits 21 CFR Part 4 THIS RULE IS EFFECTIVE 22 JULY 2013 3

4. RATIONALE FOR FINAL RULE The final rule has two related purposes: To clarify the cGMP requirements that apply to combination products, To help ensure the consistent and appropriate application and enforcement of these requirements. The Food and Drug Administration (FDA) is issuing this regulation on the current good manufacturing practice ( cGMP ) requirements applicable to combination products . This rule is intended to promote the public health by clarifying which cGMP requirements apply when drugs, devices, and biological products are combined to create combination products. In addition, the rule sets forth a transparent and streamlined regulatory framework for firms to use when demonstrating compliance with cGMP requirements for ``single-entity'' and ``co-packaged'' combination products. 21 CFR Part 4 4 THIS RULE IS EFFECTIVE 22 JULY 2013

5. EXAMPLES OF COMBO PRODUCTS 21 CFR Part 4 THIS RULE IS EFFECTIVE 22 JULY 2013 5 An epinephrine autoinjector by Phillips- Medisize Corp. Drug Eluting Balloon by Medtonic, Inc PolyCap ™ System by MicroeDoseTheraupeutx Insulin pump by Medtronic, Inc Image curtesy of Food and Drug Administration

6. PROPOSED RULE RULES TITLE APPLIES TO 21 CFR Part 210 cGMP In Manufacturing, Processing, Packing, Or Holding Of Drugs; General Drugs 21 CFR Part 211 cGMP Finished Pharmaceuticals Pharmaceuticals 21 CFR Part 600 cGMP Biological Products: General Biologics 21 CFR Part 601 cGMP Biological Products: Licencing Licencing (biologics) 21 CFR Part 606* cGMP For Blood And Blood Components Blood 21 CFR Part 607 cGMP Establishment Registration And Product Listing For Manufacturers Of Human Blood And Blood Products Registration (blood) 21 CFR Part 610 cGMP General Biological Products Standards General (biologics) 21 CFR Part 630 cGMP General Requirements For Blood, Blood Components, And Blood Derivatives General (blood) 21 CFR Part 640 cGMP Additional Standards For Human Blood And Blood Products Additional (blood) 21 CFR Part 660 cGMP Additional Standards For Diagnostic Substances For Laboratory Tests Additional (labs) 21 CFR Part 680 cGMP Additional Standards For Miscellaneous Products Additional (misc) 21 CFR Part 820 cGMP Quality System Regulation Devices 21 CFR Part 1271 cGMP Human Cells, Tissues, And Cellular And Tissue-based Products Tissue 21 CFR Part 4 THIS RULE IS EFFECTIVE 22 JULY 2013 6 *NOTE: 21 CFR Part 606 removed as references from 21 CFR Part 4; applicable elements already included in 21 CFR Part 600-680

7. LEGAL AUTHORITIES USA FDA with Food, Drug and Cosmetic Act Europe (most EU countries and not EU countries) Medical Device Directive MDD 93/42/EEC Medicinal Product Directive 2001/83/EC (as amended by 2004/27/EC) Other Indian Ireland Etc. 21 CFR Part 4 THIS RULE IS EFFECTIVE 22 JULY 2013 7

8. ASSESSMENTS AND IMPACTS Economic Impact Environemental Impact Paperwork Reducation Act 21 CFR Part 4 THIS RULE IS EFFECTIVE 22 JULY 2013 8

9. THE FINAL RULE The final rule is largely identical to the proposed rule. It is organized in four sections: Addressing scope (Sec. 4.1), Definitions (Sec. 4.2), The cGMPs that apply to combination products (Sec. 4.3), and How to comply with these cGMP requirements for a single-entity or co-packaged combination product (Sec. 4.4). 21 CFR Part 4 THIS RULE IS EFFECTIVE 22 JULY 2013 9

10. THE FINAL RULE (cont`d) Subpart A 4.1 What is the scope of this subpart ? 4.2 How does FDA define key terms and phrases in this subpart ? 4.3 What current good manufacturing practice requirements apply to my combination product ? 4.4 How can I comply with these current good manufacturing practice requirements for a co-packaged or single-entity combination product? Subpart B [Reserved] 21 CFR Part 4 THIS RULE IS EFFECTIVE 22 JULY 2013 10

11. THE FINAL RULE (cont`d) Amendments to the rule: On August 9, 2012, NIGC published a final rule amending its enforcement regulation to include a graduated pre-enforcement process for voluntary compliance. That rule referenced a rule that was later withdrawn and also incorrectly referenced an internal citation. The final rule corrects the error and makes technical amendments to reference the Commission’s recently finalized appeal rules contained in a new subchapter. 21 CFR Part 4 THIS RULE IS EFFECTIVE 22 JULY 2013 11

12. COMMENTS AND RESPONSES FDA received 25 sets of comments «demostrate»? Manufacturing? R&D? Investigational product? cGMP that apply? Packaging and co-packaging? Efforcement and effective date? Guidance? Aletrnative approaches? Other 21 CFR Part 4 THIS RULE IS EFFECTIVE 22 JULY 2013 12 TEN (10) PAGES OF COMMENTS AND RESPONSES

13. REFERENCES USA Govenment Printing Office (21 CFR Part 4) Rule: http://www.gpo.gov/fdsys/pkg/FR-2013-01-22/html/2013-01068.htm Food and Drug Adminisration (FDA) Combination products: http://www.fda.gov/CombinationProducts/default.htm 21 CFR Part 4 THIS RULE IS EFFECTIVE 22 JULY 2013 13 THANKS TO: Food and Drug Administration (FDA), Medtronic , Inc (MDT), Phillips- Medisize Corp ., MicroeDoseTheraupeutx , TranSystems

14. 21 CFR Part 4 THIS RULE IS EFFECTIVE 22 JULY 2013 14