Transcript Slides

Streamlined cGMP Requirements
Combination
Products
Workshop: A
Comprehensive
Overview
Washington,
DC
December
17, 2015
Mary Getz, Vice President, Quality Systems and Compliance, NSF
Health Sciences
Sonali Gunawardhana, Of Counsel, Wiley Rein LLP
Moderated by David Elder, Vice President, PAREXEL Consulting
Combination Products
General Overview of 21 CFR Part
4 Requirements
Mary C Getz, PhD
VP, Quality – NSF Medical Device
Consulting
Background
• Office of Combination Products (OCP) established
December 24, 2002
• In the Federal Register of October 4, 2004 FDA
announced Draft Guidance – “Current Good
Manufacturing Practices for Combination Products”
– The Agency received 15 comments, which were largely supportive
– A common theme – combination products are made up of drug, device, and
biological product constituent parts
– FDA determined that rulemaking was warranted
• The Agency published a proposed rule in the Federal
Register of September 23, 2009
• Final rule became effective July 22, 2013
3
The Final Rule
• Established minimum requirements to
assure the safety, identity, strength, quality,
and purity, as applicable, of drugs, devices,
biological products, and HCT/Ps
• The new regulation does not introduce any
new regulations, it just clarifies how existing
regulations are expected to be implemented
• No products are grandfathered – all
combination products, regardless of
introduction date, are expected to be
compliant with the regulations
CONFIDENTIAL
4
21 CFR 3.2(e) Combination
Product Definition
• Types of Combination products are defined as follows:
(1) Single Entity: 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
Examples of single-entity products
– Prefilled syringe
– Transdermal patch
– Drug-eluting stents
NOTE: a drug packaged as part of container/closure, such as
a vial, would not be considered a combo product
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21 CFR 3.2(e) Combination
Product Definition (continued)
• Types of Combination products are defined as follows:
(2) Co-packaged: 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
Examples of Co-packaged products
– Drug with delivery mechanism i.e., nebulizer, inhaler,
dropper or syringe
– Convenience kits (first aid kits or surgery kits)
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21 CFR 3.2(e) Combination
Product Definition (continued)
• Types of Combination products are defined as follows:
(3) Cross-labeled: A drug, device, or biological product packaged
separately that according to its investigational plan or proposed
labeling is
– intended for use only with an approved individually specified drug,
device, or biological product where both are required to achieve the
intended use, indication, or effect and
– where upon approval of the proposed product the labeling of the
approved product would need to be changed, e.g., to reflect a change
in intended use, dosage form, strength, route of administration, or
significant change in dose
Examples of Cross-labeled products
– Light-emitting devices which specify a certain antibiotic or protein
solutions to be used in a medical procedure
– Drug with specific applications for delivery mechanism
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So how does the final ruling impact each
type of combination product relative to
GMPs compliance strategy?
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Constituent Parts Establish the
GMP Regulations
• The constituent parts* of a combination product retain
their regulatory status (as a drug or device, for
example) after they are combined
• Allow the Primary Mode of Action (PMOA) to
influence the direction and strategy
– In particular, compliance with either the cGMP regulations
for drugs 21 CFR 210 and 211 or the quality system (QS)
regulation for devices 21 CFR 820 will satisfy many,
though not all, of the cGMP requirements applicable to
both drug and device constituent parts
– However, the PMOA does not dictate the Compliance
strategy, the company does
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Driver of cGMP
• Constituent Part(s)* establish GMP Regulations
– The constituent parts of a combination product retain
their regulatory status (as a drug or device, for
example) after they are combined
– Accordingly, the cGMP requirements that apply to
each of the constituent parts continue to apply when
they are combined to make combination products
*Definition: Constituent part is a drug, device, or
biological product that is part of a combination product
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cGMP Requirements to Meet Combo
Products Regs 21 CFR 4.4(e)
• …In the event of a conflict between cGMP
requirements applicable to a combination product, the
regulations most specifically applicable to the
constituent part at issue shall prevail…
– “constituent part at issue shall prevail”
Translation: Given what the constituent part in question is,
the regulations for that part shall be applied as a priority
•
Example – If the needle component (constituent part is a device)
is being evaluated in response to complaints and it was
determined that unknown mold cavity changes were made at the
vendor, while 21 CFR 210, 211 does not have specific
Purchase Controls regarding notification of changes, since the
constituent part is a device, 21 CFR 820.50(b) would apply
requiring the supplier to notify prior to making any changes, as
well as 820.30(f) to assure verification of those changes
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cGMP Compliance Options
• The final rule offers several approaches to
selecting the cGMP operating requirements
applicable to a co-packaged or single-entity
combination product.
• These options are:
(1) Non-streamlined approach – demonstrate
compliance with the specifics of both cGMP regulations
applicable to each of the constituent parts included in
the combination product
(2)(a) Demonstrate compliance using the streamline
approached based on the CFR 210/211 drug cGMPs
(2)(b) Demonstrate compliance using the streamlined
approached based on the CFR 820 QS regulation
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How Industry Can Apply the
Regulation
The drug constituent must
follow applicable sections
of the cGMP’s
The device constituent
must follow applicable
sections of the QSR’s
The biologic constituent
must follow applicable
sections of the cGMP’s
[Parts 210 and 211]
[Part 820]
[Parts 600 - 680]
Drug / Device
Combination Product
Biologic / Device
Combination Product
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cGMP Requirements to Meet Combo Products
Regs 21 CFR 4.4(b)(1) and 21 CFR 4.4(b)(2)
If the Operating Manufacturing Control System is
Part 820 (QS Regulation)
If the Operating Manufacturing Control System is
Part 210/211 (CGMP Regulation)
CGMP Requirements
Title
Carefully Consider These
Specific QS Requirements
Title
§ 211.84
Testing and approval or
rejection of components, drug
product containers, and
closures
§ 820.20
Management responsibilities
§ 211.103
Calculation of yield
§ 820.30
Design controls
Tamper-evident packaging
requirements for over-thecounter (OTC) human drug
products
§ 820.50
Purchasing controls
§ 211.137
Expiration dating
§ 820.100
Corrective and preventative
actions
211.165
Testing and release for
distribution
§ 820.170
§ 211.166
Stability testing
§ 820.200
§ 211.167
Special testing requirements
§ 211.170
Reserve samples
§ 211.132
Installation
Servicing
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Overview of Regulatory Strategy
Considerations for Combo Product
• Primary Mode of Action (PMOA)
– “Most important therapeutic action of a
combination product”
– Determines Center for product’s review
• OCP does not review submissions
• OCP’s purpose is to provide expertise/guidance to
sponsors and the Agency, and facilitate timely reviews
and consistency in the application of policies
– Sometimes PMOA is not clear
• FDA will look to past precedent, primary safety
concerns, and Agency expertise
CONFIDENTIAL
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Overview of Regulatory Strategy
Considerations for Combo Product
• PMOA / Product Jurisdiction Determination
– Legally determines assignment
– Request for Designation (RFD)
• 15 page limited document with rationale for Sponsor’s
suggested PMOA / classification
• FDA’s formal response within 60 days (binding
decision). If deadline is missed, then the requestor’s
recommendation applies
– Indication for use (overall therapeutic effect) and
primary mode of action are critical elements in
jurisdictional determination
CONFIDENTIAL
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Considerations for
Combination Products
• Evaluate products to determine if the final
product meets the definition of a “combination
product” to establish the appropriate quality
system for the product. This determination
shall be documented
• Product must meet the combination product
requirements from “cradle-to-grave” or design
development (prior to use in humans) to
discontinuation
– NOTE: The product must comply with regulatory
requirements in the market(s) registered
CONFIDENTIAL
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Key Takeaway
• Important point is that during this process
neither PMOA nor OCP determines or
dictates the cGMP Part 4 compliance
approach (i.e., streamlined or not), that is
the company’s decision
Regulatory Considerations for
Medical Device-based GMPs –
Choosing the Streamline
Approach
Mary C Getz, PhD
VP, Quality – NSF Medical Device
Consulting
cGMP Requirements to Meet Combo Products
Regs 21 CFR 4.4(b)(1) and 21 CFR 4.4(b)(2)
If the Operating Manufacturing Control System is Part 820 (QS Regulation)
CGMP Requirements
Title
§ 211.84
Testing and approval or rejection of components, drug product containers,
and closures
§ 211.103
Calculation of yield
§ 211.132
Tamper-evident packaging requirements for over-the-counter (OTC) human
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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21 CFR 210/211 Requirements
• Calculation of yield (211.103)
– Excess or low yields suggest error. Conduct at
each phase at which loss may occur, from drug
formulation through combination product
packaging as applicable/appropriate
• Stability testing (211.166)
– Must be conducted for the drug constituent part
as incorporated into the combination product
3
21 CFR 210/211 Requirements
(continued)
• Special testing (211.167)
– Sterility, pyrogenicity, ophthalmic ointment specs,
controlled release
– Controlled release combination products include
drug-eluting stents and transdermal patches
• Reserve samples (211.170)
– Representative samples from each lot of
combination product
– Must include container/closure, which may be
device constituent part (prefilled syringe) or be
distinct from the device (drug in cartridge for use
in auto-injector)
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Device PMOA: Case Study
• Drug-Eluting Stent
– Amount of data required in submission
depends upon existing information on the drug
used (existing IND or is it an NDA) and the
similarities in exposure/dose
– New drugs – full characterization of safety to
understand clinical pharmacology issues
• In vitro studies > PK study > clinical trial with DES
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Regulatory Considerations for Med Device
based GMPs Choosing Streamline Approach
• If pursuing the streamlined approached
based on CFR 820, the following aspects of
210/211 need to be addressed:
– When do I Introduce the API into the Design
Control process?
– Sourcing of the API
– Stability – not only the 2 separate but also the
drug/device combination
– If it is will be sold over-the-counter, then tamperevident packaging is required
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Regulatory Considerations for Med Device
based GMPs Choosing Streamline Approach
• Retain Sampling – the challenge for medical device
companies is the sample size. What if I am not able
to gather 2X? Rationale/justification for why not –
document!
• Laboratory Controls – methods validation is key
• Process Validation – focused on drug – content
uniformity
• Yield Calculations
• Special testing – such as sterility or pyrogen testing,
if required
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Overall GMP Compliance Strategy
• Build-in the regulatory expectations upfront in
order to make both the Regulatory and Quality
pathways efficient and effective
• Establish procedures that meet the both aspects
of CFR 210/211 and CFR 820. For those that are
unique to just one regulation, be clear in the
“SCOPE” on how they apply. If opting out of a
particular activity, then justify and document
rationale.
• Cultivate relationships with OCP and the
reviewing/approval agency – transparency and
openness are key
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Business Processes and
Impact on the Compliance
Strategy
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Business Processes Which
Influence the Compliance Strategy
• Several Business processes which can have a
direct impact which combination products
compliance approach to pursue. They are:
– Product Development Process (PDP) – looks at new
product introduction to market – typically companies
are focused on EITHER Drug or Device but not the
combination until much later downstream
– Strategic Planning – 3 to 5 years to review product
pipeline and manage their portfolio
– Sales & Ops Planning – resources planning as well as
discussions regarding internal vs. external sourcing
(manufacturing, packaging)
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Product Development Process
• Product Development Process (PDP) – new product
introductions and line extensions as well as potential new
product platforms
• Critical Inputs that can impact your Compliance Strategy
– Complexity of products – drug/device delivery
– Product Safety and Performance Risks – is the product high risk
or low risk, and does the combination of the drug/device impact
the risk status? – implantable device or chemotherapeutic drugs
– Line extensions – are you looking at new markets, different
demographics that would require a dosing change or device
modification?
– Novel approach – new drug or device entities
– Acquisition of products – impact on pipeline development and
sourcing (external manufacturing)
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Strategic Planning
• A company should, at minimum, spend time
at their Strategy Planning meeting(s) to
determine the following:
– Are they a combination products manufacturer
and document as such
– If so, how to address the product pipeline (future)
as well as legacy products
– If not, but intend to be there, plan a strategy to
address the combination production regulations
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Sales & Ops Planning
• Sourcing Decisions which can and will impact
Compliance Strategy
– Is Manufacturing being done onsite or outsourced?
– The complexity of drug/device as well as the
associated Manufacturing processes
– Size and complexity of manufacturing facility
– Supplier Selection: Does the Manufacturer have GMP
processes in place to support combination products?
• Resource Planning
– Skills and experience of personnel
– Training program
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Part 4 Implementation
Challenges
• Organizations have struggled in their approach to
addressing the Regulations as seen below:
– During the past 2 years, some companies have had a
“knee jerk” reaction to the Part 4 regulations – fire,
aim, ready
– Lets do it ALL at once, instead of a systematic
approach – what makes sense based on the direction
the company is headed
– Head in the sand – “we have always done it this way,
why change, it is TOO much $$ – we will wait for a
regulatory action to change”
– We aren’t a combo product so these requirements
don’t apply to us (repackagers)
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Conclusion and Summary
• cGMP Compliance Roadmap – streamline or not
– Product type and positioning (PMOA)
– Regulatory approach (cGMP compliance focus,
where are your strength(s) and experience?)
– Product complexity and risk profile
– Strategic planning (supply chain, product pipeline)
– Relationship with Agency – work with them
throughout the process – NO SURPRISES!
• FINALLY – it is YOUR CALL – make whatever you
decide work for you
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The Food and Drug Law Institute
Presents:
Combination Products: A
Comprehensive Overview
Thursday, December 17, 2015
Sonali P. Gunawardhana
Contents of Quality Systems
Regulation/ Medical Devices
Quality Systems (QS) Regulation contained in Title 21 Part 820 CFR
QS Regulation covers:
• – Quality Management and Organization
• – Device design
• – Buildings
• – Equipment
• – Purchase and handling of components
• – Production and process controls
• – Packaging and labeling control
• – Device evaluation
• – Distribution
• – Installation
• – Complaint handling
• – Servicing
• – Records
Background
• Effective June 1, 1997, replacing the 1978
GMP for medical devices
• Preamble to the 1997 regulation Important
• Requirements are not prescriptive
• Provides framework of basic requirements
for manufacturers to follow
GMP Regulation/ Requirements
Good Manufacturing Practice (GMP) requirements set forth in QS Regulation are
promulgated under section 520 of the FD&C Act
GMP require that domestic or foreign manufacturers have a quality system for the
design, manufacture, packaging, labeling, storage installation, servicing
of medical devices intended for commercial distribution in the U.S.
The GMP regulation requires:
• that various specifications and controls be established for devices
• that devices be designed under a quality system to meet these specifications
• that devices be manufactured under a quality system
• that finished devices meet these specifications
• that devices be correctly installed, checked, and serviced
• that quality data be analyzed to identify and correct quality problems
• that complaints be processed
Quality Management System
• A manufacturer must develop a Quality
Management System (QMS)
commensurate with:
– risk presented by the device
– complexity of device and manufacturing
processes
– size and complexity of organization
Establishments That Must Adhere to GMP
•
•
•
•
•
Remanufacturers
Custom Device Manufacturers
Contract Manufacturers
Contract Testing Labs
Repackagers, Relabelers, and
Specification Developers
• Manufacturers of Accessories
• Initial Distributors
Quality Management
Subsystems
Management Subsystem
• 820.20 Management Responsibility
• 820.22 Quality Audits
• 820.25 Training
Design and Development
Subsystem
• 820.30 Design Controls
• 820.70 Production and Process Changes
• 820.181 Device Master Record
• 820.250 Statistical Techniques
Production and Process
Controls Subsystem
•
•
•
•
•
820.50 Purchasing Controls
820.60 Identification
820.65 Traceability
820.70 Production and Process Controls
820.72 Inspection, measuring, and test
equipment
• 820.75 Process Validation
Production and Process
Controls Subsystem
• 820.80 Receiving, in-process, and finished
device acceptance
• 820.86 Acceptance Status
• 820.120 Device labeling
• 820.140 Handling
• 820.150 Storage
• 820.160 Distribution
• 820.170 Installation
Corrective and Preventive
Actions (CAPA) Subsystem
•
•
•
•
•
820.100 CAPA
820.90 Nonconforming Product
820.198 Complaints
820.200 Servicing
820.250 Statistical Techniques
Questions?
Contact Information
Sonali P. Gunawardhana
1776 K Street, NW
Washington, DC 20006
(202) 719- 7454
[email protected]
http://www.wileyrein.com/professionals.cfm?sp=bio&id=1624