cgmp and postmarketing safety reporting requirements for...
TRANSCRIPT
CGMP and Postmarketing Safety Reporting Requirements for Combination Products
GMP by the SeaAugust 29, 2017
Mark D. KramerRegulatory Strategies, Inc.
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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
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The CGMP Regulation
21 CFR 4
Effective July 22, 2013
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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 drug-device combination product
▪ The CGMP and postmarket safety reporting requirements that apply to each of the constituent parts continue to apply in the combination product
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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)
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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
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Streamlined Approach
“Common” Elements
Requirements Unique to Drug
GMPs (21 CFR 211)
Requirements Unique to Device
GMPs (21 CFR 820)
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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
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This flexibility only applies to combination productsIf the facility also manufacturers drugs or devices, they
must be fully compliant with 211 and/or 820
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
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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
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All can be gaps for device companies, to varying degrees
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
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“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
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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
The PMSR Regulation
21 CFR 4
Effective January 19, 2017
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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)
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Overall Approach
Common Elements:
Reporting of Death and
Serious Injuries
Drug/Biologic Alert, Field Alert
and BPDR Reporting
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
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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
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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)
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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
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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)
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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
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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
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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
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Summary: Where and When Reports are Submitted
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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
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
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“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.
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