Produced by: FOI Services, Inc. 704 Quince Orchard Road • Suite 275 Gaithersburg MD 20878-1770 USA

Phone: 1-800-654-1147 or +1-301-975-9400Fax: 301-975-0702Email: infofoi@foiservices.comwww.foiservices.com

TC140515

FDA’s Former Director of the Office of Combination Products Looks at the Effects of the New GMP Requirements on Combination Products

by Mark �ramerMark �ramer President, Regulatory Strategies, Inc.

Date: Thursday, May 15, 2014Time: 1:00pm – 2:30pm Eastern Daylight Time (GMT/UT 1700)

12:00pm – 1:30pm Central Time 11:00am – 12:30pm Mountain Time 10:00am – 11:30am Pacific Time

Teleconference Course MaterialsYou may duplicate this for each person attending the conference.

Call-In: Dial 1-888-848-0354 approximately 10-15 minutes prior to the start time. When prompted, enter the PIN code followed by the # key: 8815460# Outside the U.S. & Canada, you will receive special instructions by email. If you become disconnected and cannot reconnect through the number above, you can also call in on +1-801-853-0800.

At the conclusion of the conference, an audio file will be made available for order. Attendees receive a special reduced price of $225. To order go to www.foiservices.com/newgmp5460.htm or call 301-975-9400.

Important NoticeThe information provided in this course by the instructor is his/her personal opinion and does not necessarily

represent the opinions of FOI, Inc. or its staff. Companies relying on the information do so at their own risk and assume the risk and any subsequent liability that results from relying on the information.

The information provided does not constitute legal advice.

FDA’s Former Director of the Office of Combination Products Looks at the Effects of the New GMP Requirements on Combination Products:

FDA Enforcement & the Changes Firms (Should) Have Made

Speaker Mark Kramer, Regulatory Strategies, Inc.

Panelists

John Smith, Allergan Joe Maliszewski, CareFusion

Moderator

Nancy Singer, Compliance- Alliance, LLC

An FOI Services Teleconferences • May 2014

GMP Requirements for Combination Products

Mark D. Kramer

Regulatory Strategies, Inc.

2

Outline Definitions and Types of Combination Products

Background and Overview of the Regulation

Deeper Dive into Key Aspects of Regulation

Implementation, Enforcement and Recommendations

3

Definitions & Types of Combination Products

4

Definition of a Combination Product A combination of a drug, device

and/or biological product: Drug-device

Drug-biologic

Device-biologic

Drug-device-biologic

Not drug-drug, device-device, biologic-biologic

Not combinations with foods or cosmetics

5

Three ways that articles can be combined to create a combination product: Physically combined

Co-packaged

cross labeled

Today’s Focus

Physically Combined (“Single Entity”)

A product comprised of two or more regulated components that are physically, chemically or otherwise combined or mixed as a single entity – 21 CFR 3.2(e)(1)

Examples: Prefilled syringes or auto-injectors

Antimicrobial or other drug-coated catheters/stents

Chemotherapeutic drug-monoclonal antibody (biologic) conjugate

6

Co-Packaged (or Kit)

Two or more separate products packaged together (e.g., co-package of a drug and a device) – 21 CFR 3.2(e)(2)

Examples:

Drug or biological product packaged with applicator, empty syringe, or injector pen

Kit with catheter, gloves and antimicrobial wipes or lidocaine jelly

7

Cross Labeled Products provided/packaged separately but intended for use

together where both are required to achieve the intended use, and where mutually conforming labeling is needed -- 21 CFR 3.2(e)(3) [and (e)(4) for investigational cross labeled products]

Examples: Photodynamic therapy drug and light source

Drug and auto-injector

Drug and companion diagnostic (IVD)

8

Background & Overview of the Regulation

9

Legal Theory: Combination = Sum of Parts

Drugs, devices and biologics retain their “regulatory identities” in the combination product

Legally, both drug and device requirements fully apply to the combination product

The GMP requirements that apply to each of the constituent parts continue to apply in the combination product

10

Underlying CGMP Requirements

For medical devices:

21 CFR 820 (Quality System Regulation)

For drugs:

21 CFR 210/211 (Drug CGMPs)

11

For biological products:

Either 21 CFR 210/211 or 21 CFR 820

21 CFR 600-680 (as applicable)

21 CFR 1271 (for HCT/Ps)

A drug-device combination product is subject to both 21 CFR 820 and 21 CFR 210/211

Commonalities Differences Drug and device CGMPs are

intended to achieve the same general goals

Each has controls for management, organization, personnel, testing, documentation, recordkeeping

Each provides flexibility to tailor to particular product or actual activities performed at a facility

12

General/Philosophical Differences: Drug approach is more

prescriptive, “test-in” Device approach is more

modern, quality system focused, “design in”

Specific Differences:

Tailored to type of product for which each rule was written

No notion of design controls for drugs or calculation of yield for devices

CGMP Regulations

13

Common Elements

Requirements Unique to Drug

GMPs (21 CFR 211)

Requirements Unique to Device

GMPs (21 CFR 820)

Driving Force for Regulation Development

Recognize the similarities while avoiding the duplication required to fully implement both sets of GMP regulations

2004 draft guidance established FDA’s current thinking into CGMP requirements for combination products

Regulation ensures requirements are enforceable

14

Compromise to Duplicative Requirements Fully comply with all applicable sets of GMP requirements OR

“Streamlined approach” - Consider a combination product to be compliant with both sets of regulations as long as: It fully complies with a primary set of requirements (“umbrella system”) AND It complies with specified requirements of the “other” set of regulations

unique to that type of article and would be lost if not required

Ensure unique requirements are preserved regardless of how the combination product is regulated

15

21 CFR Part 4 – Final Rule Available at: www.gpo.gov/fdsys/pkg/FR-2013-01-22/pdf/2013-01068.pdf

Streamlined Approach

16

Common Elements:

Follow Either 820 or 211

Requirements Unique to Drug

GMPs (21 CFR 211)

Requirements Unique to Device

GMPs (21 CFR 820)

Choice of Umbrella Operating System

At manufacturer’s discretion

Some facilities may already operate under one approach and it is easier to incorporate the “add-on” provisions

Other facilities may have no pre-existing approach and may select the umbrella best suited for the product as a whole

Both approaches are permissible and neither is considered preferable by FDA

Caveat: There are restrictions on when the streamlined approach can be used

17

210/211 Umbrella – Device “Add-ons” (i) Section 820.20 Management responsibility.

(ii) Section 820.30 Design controls.

(iii) Section 820.50 Purchasing controls.

(iv) Section 820.100 Corrective and preventive action.

(v) Section 820.170 Installation.

(vi) Section 820.200 Servicing.

18

In the context of a modern, compliant pharmaceutical quality system, design controls will likely be the

main gap for most pharmaceutical sponsors.

820 Umbrella – Drug “Add-ons” (i) Section 211.84 Testing and approval or rejection of components, drug product containers, and closures.

(ii) Section 211.103 Calculation of yield.

(iii) Section 211.132 Tamper-evident packaging requirements for OTC human drug products.

(iv) Section 211.137 Expiration dating.

(v) Section 211.165 Testing and release for distribution.

(vi) Section 211.166 Stability testing.

(vii) Section 211.167 Special testing requirements.

(viii) Section 211.170 Reserve samples.

19

Focus on the “test-in” elements of drug GMPs.

Single Entity & Co-Packaged Combinations

Subject to both drug and device CGMP regulations

Two options to demonstrate compliance: Comply with the specifics of all CGMP regulations applicable to the constituent

parts OR

Comply with the specifics of either drug or device GMPs, rather than both provided that specified additional provisions from the ‘other’ set of requirements are also met

20

Cross Labeled Combination Products Constituent parts that are manufactured and marketed

separately remain separate for GMP purposes

Each constituent part is subject only to the GMP regulations applicable to that type of constituent part if it was not part of a combination product

Device = 21 CFR 820

Drug = 21 CFR 210/211

Biologic = 21 CFR 820 or 210/211 and 600-680 (and 1271)

21

Deeper Dive into Key Aspects of Regulation

22

Components vs. Finished Products 21 CFR 210/211 and 21 CFR 820 apply to finished

pharmaceuticals and devices, not components

However, for combination products: A device constituent part is considered a finished device within the meaning

of 21 CFR 820…and therefore must comply with GMPs

A drug constituent part (e.g., an API) is considered a drug product within the meaning of 21 CFR 210/211…and therefore must comply with GMPs

23

This interpretation – now formalized by regulation – gives FDA the authority to subject constituent parts

(essentially components) to the underlying CGMP requirements of devices and drugs.

§4.3 Applicable CGMP Requirements - Drugs and Devices

If you manufacture a combination product, the requirements listed in this section apply as follows:

(a) The CGMP requirements in parts 210 and 211 of this chapter apply to a combination product that includes a drug constituent part

(b) The CGMP requirements in part 820 of this chapter apply to a combination product that includes a device constituent part

24

Both 21 CFR 210/211 and 21 CFR 820 apply to a drug-device combination product.

The “add-on” requirements apply to the combination product, not just the individual constituent part which ‘contributes’ them. Examples: Design Controls, Calculation of Yield

§4.3 Applicable CGMP Requirements – Biologics and HCT/Ps

(c) The CGMP requirements among the requirements (including standards) for biological products in parts 600 through 680 of this chapter apply to a combination product that includes a biological product constituent part to which those requirements would apply if that constituent part were not part of a combination product; and

(d) The current good tissue practice requirements including donor eligibility requirements for HCT/Ps in part 1271 of this chapter apply to a combination product that includes an HCT/P.

25

Any requirement that would apply from 21 CFR 600-680 and/or 21 CFR 1271 to the biologic or HCT/P alone

also applies to the combination product.

§4.3 Biologic Requirements – Examples

Chemotherapy-Monoclonal Antibody Conjugate Subject to 210/211 plus any requirements under 21 CFR 600-680 applicable

to the biologic

Live Virus Vaccine in Prefilled Syringe Subject to 21 CFR 210/211 and 820

21 CFR 610.30 Test for Mycoplasma for Live Virus Vaccines applies as well as any other applicable 21 CFR 600-680 standards

26

§4.3 HCT/P Requirements – Examples

Harvested Tendon Combined with Suture

Tendon is HCT/P but structural in nature so likely would be considered device

Device + device = Not a combination product

Subject to 21 CFR 820 + 21 CFR 1271 (as for all HCT/Ps)

Cell Therapy Combined with Polymer Device

Cell Therapy is chemical/metabolic HCT/P so biological drug

21 CFR 210/211, 820 and 1271 apply to the combination product, plus any additional applicable standards from 21 CFR 600-680

27

Facility Requirements: Single vs. Multiple Types of Constituent Parts

Facility manufacturing only one type of constituent part of a single entity or co-packaged combination product need only comply with the GMP requirements applicable to that type of constituent part

Facility performing manufacturing activities for more than one type of constituent part of the combination product (“have arrived at or proceeding”) must:

Comply with the GMP requirements for each type of constituent part being manufactured at that facility

Achieve this by fully complying with both sets of regulations OR implementing the streamlined approach

Cannot mix/match constituent parts of different combination products

28

Design Controls

Design controls apply when a device constituent part is used in a combination product

Design controls apply to the combination product, not just the device

Manufacturer required to ensure that the design requirements for the combination product as a whole: are appropriate address the intended use of the combination product address patient and user needs

29

Design Controls (continued)

Must address all design issues resulting from the combination of the constituent parts

Examples: Why drug formulation is appropriate for coating on a device given the intended

use of the combination product (e.g., elution time, resistance to flaking, etc.)

Why a given syringe design is appropriate for use as delivery device for the drug (material compatibility with drug, accuracy of drug delivery, markings, container closure integrity, etc.)

Need design control documentation for the device constituent part and the combination product as a whole

30

Stability Testing/Reserve Samples

Stability/expiration dating: Generally more rigorous than shelf life testing expectations for devices and data

will usually be more heavily scrutinized by FDA premarket

Reserve Samples: Retained samples from each lot of active ingredients and drug products

[combination product]

Must retain at least 2x the quantity necessary to determine whether active ingredient and final product meets established specifications

To be held for 1 year after expiration date of the last lot of the drug product [combination product] containing the active ingredient

31

Reserve Samples – FDA Preamble Clarification

For single-entity combinations, retain samples of the complete product from each lot which should include the drug and all device components that come into direct contact with the drug

Prefilled syringe or drug-coated device: will require samples of the complete combination product

Auto-injector with cartridge: retain samples of cartridge containing the drug, but don’t need to retain injector

For co-packaged combinations, retain samples of each lot of drug in the immediate container/closure in which it is marketed (presumes separately packaged)

32

Other Drug Add-Ons

Testing and approval/rejection of components, drug product containers and closures: Must have specific procedures for testing/release of components, containers

and closures

Must at least verify drug identity even if it has a Certificate of Acceptance

Calculation of yield: Must assess actual and percentage of theoretical yield at each appropriate

phase of manufacturing and storage

FDA Preamble clarification: Does not apply to device constituent parts, but does apply to the drug constituent part and the combination product as a whole

33

Other Drug Add-Ons (continued)

Testing and release for distribution: Must verify final conformance to specifications of each batch of drug

[combination] product, including microbiological

Special testing: Must have laboratory testing to verify product is sterile and/or pyrogen-free

(if so labeled)

Rate of release of active ingredients (for controlled-release dosage forms)

Tamper-evident packaging (for OTC products): Must have one or more indicators or barriers to entry

34

Applicability to Investigational Products

Rule does not modify applicability of GMPs to investigational products

Investigational drugs in Phase I study are subject to statutory requirements in 501(a)(2)(B) of Act but production is exempt from 21 CFR 211 Drugs in Phase 2 and Phase 3 studies are subject to 210/211

Investigational devices (regardless of Phase) are exempt from 21 CFR 820 except for design controls (820.30)

Agency considers both these exemptions to apply to combination products and their constituent parts, regardless of whether being studied under IDE or IND

35

Implementation, Enforcement & Recommendations

36

Implementation

FDA: rule does not establish any new requirements

2004 draft guidance has been FDA’s “current thinking”

FDA to apply risk-based approach to facility inspection and enforcement, if the circumstances support

Expect both drug/device investigators for significant combination products

“Demonstrate compliance” in same manner as for the underlying CGMP regulations; i.e., written procedures, maintenance of records documenting use

37

Effective July 22, 2013…applies to all legacy and new single entity and co-packaged combination products.

Manufacturer Responsibility

Design and implement a CGMP operating system that meets all CGMP requirements applicable to the product

Take into account all of the activities occurring at all facilities involved with the manufacturing process

Each facility needs a CGMP operating system relevant to its operations (e.g., testing, design control, CAPA, etc.) Including the facility from which the applicant oversees all of the

manufacturing activities and compliance with all GMP requirements related to the product

38

Enforcement Has Begun…

39

Amgen Warning Letter Inspection occurred June 2013, prior to Part 4 effective date

Prefilled syringes and auto injectors are identified as combination products

Device constituent parts adulterated: not in conformance with 21 CFR 820

Failure to establish/maintain design validation procedures to ensure devices conform to defined user needs and intended uses

Failure to establish/maintain procedures concerning design changes prior to their implementation

Failure to establish/maintain purchasing controls (example: service providers conducting preventive maintenance of x-ray equipment used in manufacturing)

Required to have DHFs for the combination products under 21 CFR 820.30(j)

40

Key Areas to Demonstrate Compliance Ensure procedures implemented and reflective of regulation

Do worry about legacy products

Maintain documentation that demonstrates compliance for each combination product at each facility

Prepare a matrix for each combination product that clearly identifies: Umbrella operating system at that facility Description of manufacturing activities conducted and constituent parts

at each facility How the “add-on” provisions have been implemented (e.g., could have

pointers to other procedures)

Pay special attention to design controls, purchasing controls, CAPA, stability, reserve samples, calculation of yield and testing/approval of components

41

Topics for Future FDA Guidance Document How to comply with the rule, e.g., legacy products

Examples to help illustrate the rule

Design control application

Distinctions between devices and container/closures

Clarify sample retention, batch release and stability requirements

Coordination among manufacturers and purchasing controls

FDA open to additional topics warranting guidance

Agency to issue inspectional standards, training and other mechanisms to ensure consistency

42

Other Key Areas of Combination Product Regulation

Unique Device Identifier…first deadline 9/24/14

Postmarket Reporting…final rule expected soon

Product Jurisdiction/Assignment

Premarket Review Policies

Registration and Listing

Post-approval changes guidance

43

…at some point, all key regulatory differences between devices and drugs will need to be clarified…

Thank You!

44

Mark D. Kramer Regulatory Strategies, Inc.

+1-414-731-4257 kramer@regulatorystrategies.net

Panel Remarks

45

Industry Experience

John Smith Director, Global Regulatory Affairs

Allergan

46

Combination Product Requirements

More clarity than before, further changes expected

– US: Final Rule (21 CFR 4) published and effective No formal FDA guidance yet, but it’s on the way

– EU: Medical Device Regulation coming sometime soon Among other things, the new regulation clarifies review and approval of

“combination” products in the EU

– Other: Many countries consulting with U.S. FDA about approaches to combination product regulation

47

Reactions & Plans

No FDA combination product inspections (yet) Preparation:

– Issued a combination product SOP to define: Decision tree – when is it a combination product? GMP requirements

– Simplified Design Control procedure and increased its flexibility to cover devices and combination products of varying complexity and risk

– Trained development teams to apply Design Control and Risk Management tools to combination products

– Anticipating changes in post market surveillance/AE reporting

48

Reactions & Plans (continued)

Planning to expand scope of ISO 13485 certification to cover combination product design and manufacture – Anticipating EU Competent Authority requests for Notified Body

consultations

Evaluate product pipeline and legacy products – Identify gaps, plans to close them

Applying changes globally (requirements must be met

regardless of intended market)

49

Bottom Line

Changes don’t happen overnight – Plan for bumps in the road – Learn from observation and feedback – Be patient and keep an open mind

50

Joe Maliszewski Sr. Design Assurance Engineer

CareFusion

51

Industry Experience

Recent Experience – General Comments

Background: Device business with limited drug experience

Major revisions to design control (ICH Q8 vs 21 CFR 820.30) and risk management (ICH Q9 vs ISO 14971)

Manufacturing compliance requirements are site and product specific

52

Recent Experience – Compliance Efforts Site-specific compliance is key

53

21 CFR 210 / 211 21 CFR 820 211.84 – Testing and Approval or Rejection of Components, Drug Product Containers, and Closures

820.20 – Management Responsibility

211.103 – Calculation of Yield 820.30 – Design Controls

211.132 – Tamper Evident Packaging Requirements for Over-the-Counter (OTC) Human Drug Products.

820.50 – Purchasing Controls

211.137 – Expiration Dating 820.100 – Corrective and Preventive Actions

211.165 – Testing and Release of Distribution 820.170 – Installation

211.166 – Stability Testing 820.200 - Servicing

211.167 – Special Testing Requirements

211.170 – Reserve Samples

Recent Experience – Compliance Efforts

Site-specific compliance is key

54

21 CFR 210 / 211 21 CFR 820 211.84 – Testing and Approval or Rejection of Components, Drug Product Containers, and Closures

820.20 – Management Responsibility

211.103 – Calculation of Yield 820.30 – Design Controls

211.132 – Tamper Evident Packaging Requirements for Over-the-Counter (OTC) Human Drug Products.

820.50 – Purchasing Controls

211.137 – Expiration Dating 820.100 – Corrective and Preventive Actions

211.165 – Testing and Release of Distribution 820.170 – Installation

211.166 – Stability Testing 820.200 - Servicing

211.167 – Special Testing Requirements

211.170 – Reserve Samples

Recent Experience – Compliance Efforts

Manufacturing site

55

21 CFR 210 / 211 21 CFR 820 211.84 – Testing and Approval or Rejection of Components, Drug Product Containers, and Closures

820.20 – Management Responsibility

211.103 – Calculation of Yield 820.30 – Design Controls

211.132 – Tamper Evident Packaging Requirements for Over-the-Counter (OTC) Human Drug Products.

820.50 – Purchasing Controls

211.137 – Expiration Dating 820.100 – Corrective and Preventive Actions

211.165 – Testing and Release of Distribution 820.170 – Installation

211.166 – Stability Testing 820.200 - Servicing

211.167 – Special Testing Requirements

211.170 – Reserve Samples

Speakers Mark D. Kramer spent five years as FDA’s Director of Combination Products; his 17 years at the Agency also included various positions in CDRH. Currently, Mark is President of Regulatory Strategies, Inc., a regulatory consultancy specializing in medical devices and combination products. From 2007-2010, Mark was Vice President, Regulatory Affairs and Chief Regulatory Strategist at GE Healthcare, where he had executive responsibility for U.S., Canadian and Latin American regulatory affairs for the firm’s medical device business. Contact Mark at kramer@regulatorystrategies.net or phone +1-414-731-4257.

Joe Maliszewski is a Senior Design Assurance Engineer at CareFusion, a manufacturer of medication management systems, respiratory care technologies, surgical instruments and other medical devices. He has many years of experience in product development quality roles and has participated in multiple FDA inspections. An ASQ Certified Quality Engineer, Joe holds a BSE in Biomedical Engineering.

John Smith has over 20 years of experience in medical device and pharmaceutical regulatory affairs and quality assurance, accumulated in a variety of companies, small and large. Before joining Allergan in 2011, John was responsible for global post-market safety for Abbott Medical Optics. Prior to that he held senior RA/QA positions responsible for ISO 9001/13485 quality systems in several medical device companies. John has a bachelor’s degree in Mechanical Engineering from MIT and an MBA from the University of Florida.

Nancy Singer spent over 14 years as AdvaMed’s Special Counsel for FDA compliance and enforcement matters. In this role, Nancy represented regulated industry on the working group that conceived and validated the procedures for the Quality System Inspection Technique (QSIT). While working on QSIT, Nancy received Vice President Gore’s Reinventing Government Hammer Award and the FDA Commissioner’s Special Citation. Nancy began her career as an attorney with the United States Department of Justice where she did litigation for the Food and Drug Administration. Email Nancy at nancy@compliance-alliance.com

56

Thank You! Questions?

To ask a question. The operator will explain how you can ask a question. For privacy reasons, each question will be announced only by the first name of the person reported at dial-in, but anyone in your group may ask the question(s). Please try to avoid using a speakerphone while asking your question. If you have a question later or would like to arrange a private discussion, contact information for Mark Kramer and Nancy Singer is included on page 56. To contact the panelists, please email Nancy Singer, who will forward your inquiry. We value your feedback. Please return the evaluation at the end of this handout to enter a prize drawing for a $100 amazon.com gift card and/or arrange to receive a certificate of attendance verifying your participation in this 1.5 hour educational session. Additional information. These slides and instructions for ordering the audio recording of this presentation at the 50% attendee discount are available at www.foiservices.com/newgmp5460.htm

57

Training Evaluation Form FDA’s Former Director of the Office of Combination Products Looks at the Effects of the New GMP Requirements on Combination ProductsMark Kramer, Presenter – May 15, 2014

Win a $100 Amazon.com Gift Certificate from FOI!Just complete this form and fax it to +1-301-569-7506 by May 22, 2014 and you will be entered in a drawing for an Amazon.com Gift Certificate

Please indicate your primary job responsibility (circle one):

Regulatory Affairs QA/QC Statistics Medical Writing Electronic Submissions General Management

Other (please specify):____________________________________

Please rate various aspects of this course (1 = Poor; 2=Fair; 3=Good; 4=Very Good; 5=Excellent – please circle your answers)

What is your overall rating of the course? 1 2 3 4 5

How do you rate the content of the course? 1 2 3 4 5

Were course materials clear and understandable? 1 2 3 4 5

Was the length of the course adequate to cover the content? 1 2 3 4 5

Was the instructor knowledgeable about the subject matter? 1 2 3 4 5

How would you rate the instructor overall? 1 2 3 4 5

Other comments: Please feel free to comment on any aspect of this course, including the instructor, content, and technical arrangements:

TC140515

By providing the information below and faxing this page to +1-301-569-7506 by Thursday, May 22, 2014 you will be entered in a drawing for a $100 Amazon.com Gift Certificate from FOI.

Your Name: _______________________________________________________________________

Company Name: ___________________________________________________________________

Email Address: ____________________________________________________________

Check here to receive a Certification of Attendance verifying your 1.5 training contact hours for this educational session. Please provide your legibly printed name with your signature next to it, email address, and fax this form to the number below. Your certificate will be emailed to you.