CGMP and Postmarketing Safety Reporting Requirements for Combination Products GMP by the Sea August 29, 2017 Mark D. Kramer Regulatory Strategies, Inc. 1
Definition of a Combination Product A combination of a drug, device and/or biological product: Single entity physically/chemically combined prefilled syringe cells on scaffold drug-coated device drug-biologic conjugate) Co-packages of devices, drugs and/or biologics Cross labeled products 2
The CGMP Regulation 21 CFR 4 Effective July 22, 2013 3
Legal Theory: Combination = Sum of Parts Drugs, devices and biologics retain their regulatory identities in the combination product Both drug and device requirements apply to a drugdevice combination product The CGMP and postmarket safety reporting requirements that apply to each of the constituent parts continue to apply in the combination product 4
Underlying CGMP Requirements For medical devices: 21 CFR 820 (Quality System Regulation) For drugs: 21 CFR 210/211 (Drug CGMPs) For biological products: Either 21 CFR 210/211 or 21 CFR 820 21 CFR 600-680 (as applicable) 21 CFR 1271 (for HCT/Ps) 5
Two Options to Demonstrate Compliance Fully implement both sets of CGMP regulations (211 AND 820) OR Streamlined approach : Fully comply with a primary set of requirements (211 OR 820) AND Comply with specific requirements of the other set of regulations that are unique to that type of article and would be lost if not required 21 CFR Part 4 Final Rule Available at: http://www.gpo.gov/fdsys/pkg/fr-2013-01-22/pdf/2013-01068.pdf 6
Streamlined Approach Requirements Unique to Drug GMPs (21 CFR 211) Common Elements Requirements Unique to Device GMPs (21 CFR 820) 7
Choice of Base CGMP Operating System At manufacturer s discretion Most facilities will already operate under one approach and it is easier to incorporate the add-on provisions New facilities may have no pre-existing approach and can select the option best suited for the product as a whole Both approaches are permissible and neither is considered preferable by FDA This flexibility only applies to combination products If the facility also manufacturers drugs or devices, they must be fully compliant with 211 and/or 820 8
210/211 Base Device Add-on s 820.20 Management responsibility 820.30 Design controls 820.50 Purchasing controls 820.100 Corrective and preventive action 820.170 Installation 820.200 Servicing Design controls will likely be the main gap for most drug/biologic sponsors the above requirements apply to the device constituent part and the combination product as a whole 9
820 Base Drug Add-on s 211.84 Testing and approval or rejection of components, drug product containers, and closures 211.103 Calculation of yield 211.132 Tamper-evident packaging (for OTC drug products) 211.137 Expiration dating 211.165 Testing and release for distribution 211.166 Stability testing 211.167 Special testing requirements 211.170 Reserve samples All can be gaps for device companies, to varying degrees 10
Eligibility to Apply Streamlined Approach Sites that manufacture more than one type of constituent part of a combination product: Different types of constituent parts have arrived at or manufacture of different constituent parts is proceeding at a facility Single entity and co-packaged combination products only Cross labeled products are separately manufactured and don t require special treatment for CGMPs, HOWEVER 2017 FDA guidance allows streamlined approach if both constituent parts manufactured at same facility 11
Real-World Activities Demonstrate compliance with 21 CFR 4 in marketing applications for new combination products Expect PAI s to address these requirements Routine inspections.perhaps less so (?) Also ensure compliance for legacy combination products Remediation may be necessary to address design controls Component acceptance, yield, stability and retention for device companies A product is a combination product and subject to the CGMP rule if it meets the definition even if FDA has not identified the product as a combination product 12
The PMSR Regulation 21 CFR 4 Effective January 19, 2017 13
Underlying Postmarketing Safety Reporting Reqts. For medical devices: 21 CFR 803 (Medical Device Reporting) 21 CFR 806 (Corrections & Removals Reporting) For drugs: 21 CFR 314 (Drug Adverse Experience Reporting ) 21 CFR 314 (Field Alert Reporting) For biological products: 21 CFR 600 (Biological Product Adverse Experience Reporting) 21 CFR 600.14 (Biological Product Deviation Reporting) 21 CFR 606 (CGMPs for Blood/Blood Components) 14
Overall Approach Common Elements: Drug/Biologic Alert, Field Alert and BPDR Reporting Reporting of Death and Serious Injuries Device Malfunction, 5-Day and Corrections/Removals Reporting 15
Applicability of New Requirements Final rule applies only to combination product and constituent part applicants (application holders) Constituent part applicant: reporting requirements apply only to its constituent part Combination product applicant: reporting requirements apply to its combination product as a whole 16
Overall Reporting Scheme Dictated by Application Type If the combination product or device constituent part received marketing authorization under a device application, comply with 21 CFR 803 and 806 If the combination product or drug constituent part received marketing authorization under an NDA or ANDA, comply with 21 CFR 314 If the combination product or biological product constituent part received marketing authorization under a BLA, comply with 21 CFR 600 and 606 17
Additional Requirements for Combo Applicants Devices If the combination product was approved under BLA, NDA or ANDA and includes a device constituent part, also submit: 5-day reports (21 CFR 803.3/803.53) Malfunction reports (21 CFR 803.50) Correction and removal reports (21 CFR 806.10) 18
Additional Requirements for Combo Applicants - Drugs If the combination product was approved under a BLA or device application and includes a drug constituent part, also submit: Field alert reports (21 CFR 314.81) 15-day reports (21 CFR 314.80) however the regulation permits reporting within 30 calendar days instead of 15 calendar days if the product was approved/cleared under a device application 19
Additional Requirements for Combo Applicants - Biologics If the combination product was approved under NDA, ANDA or a device application and includes a biological product constituent part, also submit: Biological product deviation reports (21 600.14/ 606.171) 15-day reports (21 CFR 600.80) (with the same 30 calendar day allowance stated above if the product was approved/cleared under a device application) 20
Periodic Safety Reporting Requirements for Combination Product Applicants NDA, ANDA or BLA holders with combination products including a device constituent part must include a summary and analysis of their malfunction and 5-day reports in their periodic safety reports, in addition to the standard content of these periodic reports Device application holders may be required by FDA to submit additional postmarketing safety events (such as periodic reports) and will be notified by Agency in writing if applicable 21
Information Sharing (Constituent Part Applicants) Upon receipt of information involving a death or serious injury (as defined in the MDR regulation) or adverse experience (as defined in the NDA or BLA regulations) associated with the combination product, the applicant: Must provide the information to the other constituent part applicant(s) within 5 calendar days of its receipt of the information Maintain records of what was shared, the date received, the date provided, and the name and contact information of the person to whom the information was provided Preamble: Party sharing information is not required to analyze, investigate or take any action beyond forwarding to the other party nor are they required to share follow-up information 22
How and Where to Submit Reports Constituent part applicants: follow reporting regulation applicable to the type of application (e.g., device application follow MDR instructions) Combination product applicants: Individual case study reports (15-day, malfunction, death/ serious injury, 5-day reports) reported as per application type assures review by lead Center Correction/removal and NDA field alert reports District Office as usual BPDRs CDER or CBER 23
Summary: Where and When Reports are Submitted Type of Report Where Submitted Timeframe (Days) 5-Day Report Lead Center 5 days Malfunction Report Lead Center 30 days Correction/ Removal Report District Office 10 days 15-Day Alert Report Lead Center 15 days (30 days if approved/cleared under device application) NDA Field Alert Report District Office 3 days Biological Product Deviation Report CDER or CBER 45 days Death or Serious Injury CDRH (only applies if approved under device application) 30 days 24
Compliance Timeframes Currently in effect as of January 19, 2017: Existing reporting requirements per application type July 19, 2018 (18 months after the effective date) for the new requirements: Additional reporting provisions specific to the additional constituent part Device events in drug/biologic periodic safety reports Information sharing for constituent part applicants Recordkeeping requirements 25
Real World Activities Applies to legacy combination products meeting the definition as well as newly approved products, whether specifically identified as combination products or not Ensure PMSR procedures are developed and implemented and reflective of regulation by compliance date Don t need to wait until July 2018 to implement the new requirements; use narrative sections to describe events until forms are changed Additional FDA guidance expected to address several practical aspects of rule, such as MedWatch form completion, assignment of codes, etc. 26
Questions? Mark D. Kramer Regulatory Strategies, Inc. 414.731.4257 kramer@regulatorystrategies.net 27