Combination Products

Workshop: A Comprehensiv

e Overview

Washington, DC

December 17, 2015

Streamlined cGMP Requirements

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• In the Federal Register of October 4, 2004 FDA announced Draft Guidance – “Current Good Manufacturing Practices for Combination Products”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

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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 theGMP 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

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The drug constituent must

follow applicable sections of the

cGMP’s

[Parts 210 and 211]

The drug constituent must

follow applicable sections of the

cGMP’s

[Parts 210 and 211]

The device constituent must

follow applicable sections of the

QSR’s

[Part 820]

The device constituent must

follow applicable sections of the

QSR’s

[Part 820]

The biologic constituent must

follow applicable sections of the

cGMP’s

[Parts 600 - 680]

The biologic constituent must

follow applicable sections of the

cGMP’s

[Parts 600 - 680]

Drug / Device

Combination Product

Drug / Device

Combination Product

Biologic / Device

Combination Product

Biologic / Device

Combination Product

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 TitleCarefully 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

§ 211.132Tamper-evident packaging requirements for over-the-counter (OTC) human drug

products

§ 820.50 Purchasing controls

§ 211.137 Expiration dating § 820.100Corrective and preventative

actions

211.165Testing and release for

distribution§ 820.170

 Installation 

§ 211.166 Stability testing  § 820.200 Servicing 

§ 211.167 Special testing requirements

§ 211.170 Reserve samples

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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 15

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 16

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 17

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

§ 211.84Testing 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

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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 tamper-

evident packaging is required

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• 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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Regulatory Considerations for Med Device based GMPs Choosing Streamline Approach

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/ RequirementsGood 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

sgunawardhana@wileyrein.comhttp://www.wileyrein.com/professionals.cfm?sp=bio&id=1624