Introduction - cdn.ymaws.com€¦ · development that is fully executed for the combination product...

Introduction

•  Development of drug + device combination products requires the understanding of the different regulations for drugs and devices

–  Mindset differences between staff that develop drugs and devices –  Product teams need to understand both

•  Integration and alignment of development processes for drugs and devices facilitates robust combination product development

–  Ensures clarity and consistency of approach for the combination product as a system

–  Enables efficiency and meeting development timelines

A quick review of the development process for devices

Intended Use User Requirement Spec (URS) “easy to push”

Design Input Requirements (DIR) “Force ≤ 25N”

Verify product meets design input requirements (DIR) ✔ “Force ≤ 25N”

Verify product meets user requirements (URS) ✔ “easy to push”

Risk Management: Use, Design and Process Risk Assessments (FMEAs)

Device design, characterizaLon and opLmizaLon

Human Factors Assessments and TesLng

Guidance for Industry and FDA Staff:

Technical Considerations for Pen, Jet, and Related Injectors Intended for Use

with Drugs and Biological Products

Additional copies are available from:

Office of Combination Products Office of Special Medical Programs

Office of the Commissioner Food and Drug Administration

10903 New Hampshire Avenue, WO-32 Hub 5129 Silver Spring, MD 20993

(Tel) 301-796-8930 (Fax) 301-796-8619

http://www.fda.gov/CombinationProducts/default.htm

This document finalizes the draft guidance issued in April 2009.

For questions regarding this document, contact the Office of Combination Products at [email protected] or Patricia Y. Love, MD at 301-796-8933 or [email protected]

U.S. Department of Health and Human Services

Food and Drug Administration Center for Devices and Radiological Health,

Center for Drug Evaluation Research, Center for Biologics Evaluation and Research, and

Office of Combination Products in the Office of the Commissioner

June 2013

Roche is assessing the best means to meet the requirements of new and emerging regulation/guidance

•  21 CFR Part 4 bridges requirements between drug and device regulation in the U.S.

–  21 CFR Parts 210 & 211 –  Part 820 (QSRs)

•  Pharma company basing its quality system on cGMPs is required to demonstrate compliance with specified provisions of the QSR

–  Design Controls –  Purchasing Controls –  CAPA –  Management responsibility

•  FDA companion guidance on how to comply to be issued to provide further clarification of requirements

•  New EMA Draft Guidance on Use Errors and pending FDA Draft Guidance on Human Factors for Combination Products

Contains Nonbinding Recommendations

Draft - Not for Implementation

Draft Guidance for Industry and

Food and Drug Administration Staff

Applying Human Factors and

Usability Engineering to Optimize

Medical Device Design

DRAFT GUIDANCE

This guidance document is being distributed for comment purposes only.

Document issued on: June 22, 2011

You should submit comments and suggestions regarding this draft document within 90 days

of publication in the Federal Register of the notice announcing the availability of the draft

guidance. Submit written comments to the Division of Dockets Management (HFA-305),

Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. Submit

electronic comments to http://www.regulations.gov. Identify all comments with the docket

number listed in the notice of availability that publishes in the Federal Register.

For questions regarding this document, contact Ron Kaye at [email protected] or (301)

796-6289, or Molly Story at [email protected] or (301) 796-1456.

When final, this document will supersede Medical Device Use-Safety: Incorporating

Human Factors Engineering into Risk Management

(Issued July 18, 2000).


Food and Drug Administration

Center for Devices and Radiological Health

Office of Device Evaluation

Guidance for Industry and FDA Staff:

Submissions for Postapproval Modifications

to a Combination Product Approved Under a

BLA, NDA, or PMA

DRAFT GUIDANCE


Comments and suggestions regarding this draft document should be submitted within 90 days of

publication in the Federal Register of the notice announcing the availability of the draft

guidance. Submit written comments to the Division of Dockets Management (HFA-305), Food

and Drug Administration, 5630 Fishers Lane, Room 1061, Rockville, MD 20852. Submit

electronic comments to http://www.regulations.gov. All comments should be identified with the

docket number listed in the notice of availability that publishes in the Federal Register.

Additional copies are available from:

Office of Combination Products


WO32, Hub/Mail Room #5129

10903 New Hampshire Avenue

Silver Spring, MD 20993

(Tel) 301-796-8930

(Fax) 301-847-8619

http://www.fda.gov/CombinationProducts/default.htm.

For questions regarding this draft document contact the Office of Combination Products, Office

of Special Medical Programs in the Office of the Commissioner, Dr. Patricia Love, 301-796-

8933 or [email protected].



Office of Combination Products

Office of Special Medical Programs

Office of the Commissioner

January 2013 1

Contains Nonbinding Recommendations Draft - Not for Implementation

1

Draft Guidance for Industry and

Food and Drug Administration Staff

Design Considerations for Devices

Intended for Home Use DRAFT GUIDANCE


Document issued on: December 12, 2012

You should submit comments and suggestions regarding this draft document within 90 days of


guidance. Submit written comments to the Division of Dockets Management (HFA-305),

Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. Submit

electronic comments to http://www.regulations.gov. Identify all comments with the docket

number listed in the notice of availability that publishes in the Federal Register.

For questions for the Center for Devices and Radiological Health regarding this document,

contact Mary Brady at 301-796-6089 or by e-mail at [email protected]. For questions

for the Center for Biologics Evaluation and Research, contact the Office of Communication,

Outreach, and Development at 800-835-4709 or 301-827-1800.

Department of Health and Human Services


Center for Devices and Radiological Health

Center for Biologics Evaluation and Research

Guidance for Industry

Safety Considerations for Product

Design to Minimize Medication Errors

DRAFT GUIDANCE


Comments and suggestions regarding this draft document should be submitted within 60 days of


guidance. Submit electronic comments to http://www.regulations.gov/ Submit written

comments to the Division of Dockets Management (HFA-305), Food and Drug Administration,

5630 Fishers Lane, rm. 1061, Rockville, MD 20852. All comments should be identified with

the docket number listed in the notice of availability that publishes in the Federal Register.

For questions regarding this draft document contact (CDER), Office of Surveillance and

Epidemiology, Division of Medication Error Prevention and Analysis, Carol Holquist at 301-

796-0171.



Center for Drug Evaluation and Research (CDER)

December 2012 Drug Safety

4307

Federal Register / Vol. 78, No. 14 / Tuesday, January 22, 2013 / Rules and Regulations

1 For purposes of part 3 and this rule, a

‘‘biological product’’’ means a biological product

subject to regulation under section 351 of the Public

Health Service Act (the PHS Act) (42 U.S.C. 262).

All biological products regulated under the PHS Act

meet the definitions of drug or device in section 201

of the Federal Food, Drug, and Cosmetic Act (the

FD&C Act) (21 U.S.C. 321).

2 Section 501 of the FD&C Act (21 U.S.C. 351)

states circumstances under which drugs and

devices (including biological products, which also

meet the definition of either drug or device) are

deemed adulterated. Adulteration includes the

failure to manufacture a product in accordance with

applicable CGMP requirements, regardless of

whether the product appears to meet its final

specifications. See, generally, 21 U.S.C. 351(a)(2)(B)

and (h).

Issued in Seattle, Washington, on

December 19, 2012.

Clark Desing,

Manager, Operations Support Group, Western

Service Center.

[FR Doc. 2013–01071 Filed 1–18–13; 8:45 am]

BILLING CODE 4910–13–P

DEPARTMENT OF HEALTH AND

HUMAN SERVICES


21 CFR Part 4

[Docket No. FDA–2009–N–0435]

Current Good Manufacturing Practice

Requirements for Combination

Products

AGENCY: Food and Drug Administration,

HHS.

ACTION: Final rule.

SUMMARY: The Food and Drug

Administration (FDA or Agency) is

issuing this regulation on the current

good manufacturing practice (CGMP)

requirements applicable to combination

products. This rule is intended to

promote the public health by clarifying

which CGMP requirements apply when

drugs, devices, and biological products

are combined to create combination

products. In addition, the rule sets forth

a transparent and streamlined regulatory

framework for firms to use when

demonstrating compliance with CGMP

requirements for ‘‘single-entity’’ and

‘‘co-packaged’’ combination products.

DATES: This rule is effective July 22,

2013.

FOR FURTHER INFORMATION CONTACT: John

Barlow Weiner, Office of Combination

Products, Food and Drug

Administration, 10903 New Hampshire

Ave., Bldg. 32, Rm. 5130, Silver Spring,

MD 20993, 301–796–8930.

SUPPLEMENTARY INFORMATION:

Table of Contents

I. Background

A. Rationale for the Rulemaking

B. The Proposed Rule

C. The Final Rule

II. Comments on the Proposed Rule

A. General

B. What is the scope of this subpart? (§ 4.1)

C. How does FDA define key terms and

phrases in this subpart? (§ 4.2)

D. What current good manufacturing

practice requirements apply to my

combination product? (§ 4.3)

E. How can I comply with these current

good manufacturing practice

requirements for a co-packaged or single-

entity combination product? (§ 4.4)

E.1. How To Comply With QS Regulation

Requirements Under § 4.4(b)(1)

E.2. How To Comply With Drug CGMP

Requirements Under § 4.4(b)(2)

E.3. How To Comply With Biological

Product and HCT/P Requirements Under

§ 4.4(b)(3)

F. Enforcement and Effective Date

G. Alternate Approaches

H. Guidance

I. Other

III. Legal Authority

IV. Analysis of Economic Impacts

A. Introduction

B. Rationale for Final Rule

C. Response to Comments

D. Impact of Final Rule

V. Environmental Impact

VI. Paperwork Reduction Act of 1995

VII. Executive Order 13132: Federalism

I. Background

A. Rationale for the Rulemaking

As set forth in part 3 (21 CFR part 3),

a combination product is a product

comprised of any combination of a drug

and a device; a device and a biological

product; a biological product and a

drug; or a drug, a device, and a

biological product.1 Under § 3.2(e), a

combination product includes:

1. 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 (single-entity combination

products);

2. 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 (co-packaged combination

products);

3. 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 (a type of cross-labeled

combination product); or

4. Any investigational drug, device, or

biological product packaged separately

that according to its proposed labeling

is for use only with another individually

specified investigational drug, device, or

biological product where both are

required to achieve the intended use,

indication, or effect (another type of

cross-labeled combination product).

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.2 To date, however, the

Agency has not issued specific

regulations clarifying the applicability

of the CGMP requirements to

combination products. While CGMP

regulations are in place that establish

requirements for drugs, devices, and

biological products, there are currently

no regulations that clarify and explain

the application of these CGMP

requirements when these drugs, devices,

and biological products are constituent

parts of a combination product. FDA

believes that the absence of clear CGMP

requirements for combination products

could result in inconsistent or differing

application of the various CGMP

requirements applicable to the

constituent parts, which could affect

product safety and the public health. In

addition, the absence of clear

requirements could lead some

manufacturers to develop and document

manufacturing practices that are

redundant and overly burdensome.

In the Federal Register of October 4,

2004 (69 FR 59239), the Agency

announced the availability of a Draft

Guidance for Industry and FDA entitled

‘‘Current Good Manufacturing Practices

for Combination Products.’’ The Agency

received 15 comments, which were

largely supportive of the regulatory

approach described in the draft

guidance. A common theme that

emerged from these comments was the

need to develop a clear regulatory

framework that takes account of the fact

that combination products are made up

of drug, device, and biological product

constituent parts. At the same time,

commenters wanted to ensure that the

framework would not lead to

unnecessary redundancy in the

operating systems used to meet CGMP

VerDate Mar<15>2010 17:36 Jan 18, 2013 Jkt 229001 PO 00000 Frm 00003 Fmt 4700 Sfmt 4700 E:\FR\FM\22JAR1.SGM 22JAR1

tkel

ley

on D

SK3S

PTVN

1PR

OD

with

The development approach must vary based on the type of product and the level of ownership of the device design

Device Association with Drug

Label Reference

One-Way 510K Cleared & Commercially

Marketed

Two-Way (Cross-Labeled)

510K Cleared

Co-Packaged

Commercially Marketed

(510K Cleared)

Roche-Specific Design

Integrated

Commercially Marketed (with

other drugs) Roche-Specific

Design

Device Example

Drug in a vial with reference to a specific device (e.g. syringe, nebulizer)

Drug in a vial or cartridge with cross-references to a delivery device by brand (e.g. reusable pen)

Product packaged with a commercially marketed device for convenience (e.g. needle)

Product packaged with a custom device (e.g. custom reconstitution device not marketed elsewhere)

Prefilled auto-injectors, pens and other systems

Supplier Controls

None; confirm alignment with intended use in 510K

Contractual agreement for development, supply and/or quality

Contractual agreements for supply and quality

Contractual agreements for development, quality and supply

Contractual agreements for development, quality and supply

Device Functionality Assessment

•  Technical testing for drug-device compatibility and dose delivery

•  Reference 510K


•  Reference 510K •  May choose to use

design control tools


•  Reference 510K

•  Design Verification conducted

•  Design Controls on combination

•  Design Verification conducted •  Design Controls on combination

Human Factors

None Risk-dependent human factors assessment

None or risk-dependent human factors assessment

Full human factors program, including risk analyses, formative and summative testing

Full human factors program, including risk analyses, formative and summative testing

A current challenge is ensuring health authority expectations are met for one-way, cross-labeled and convenience kit products

•  Ambiguity of requirements - health authority information requests vary across products, use scenarios, and product complexity

•  Technical assessments are not identical to design verification, although both have the same objectives

•  Growing expectation that some drugs will require a human factors assessment even if they are not combination products

–  Not typical aspect of drug development

•  Early health authority feedback is needed –  Ensure expectations can be met –  Avoid inefficiency and timeline delays

Phase1 Phase 2 Phase 3 Phase 4

Device Strategy Design & Development Plan

Design Verification for Clinical & Scale-Up Readiness

Launch Design Verification for Commercial, Validated Device Design, Regulatory Submission,

Commercial Mfg. Readiness

Prepare to Launch Industrialize

Prepare to Launch Design &

Develop Industrialize Device Strategy

~ 6 mo ~ 12 mo 12 to 18 mo

~ 9 to 24 mo

~ 9 to 30 mo

~ 9 to 12 mo

~ 9 to 12 mo

Plan Evaluate Concept

Design & Development Plan

Design Verification for Clinical & Scale- up

Readiness

Launch Validated & Verified Commercial Design, Regulatory Submission,


Monitor & Improve

Monitor & Improve

Prefilled Syringe

(Assumes first clinical introduction is Phase 3 start)

Injection Device (e.g. auto-injector) (Assumes first clinical introduction is a bridging study during Phase 3)

Timing of initiation of combination product development depends on the type of device and when it is introduced into the clinic

•  Assumption is that the technology platform is clinically ready and development is primarily the customization of the device for the drug

•  Timing depends on device complexity

•  Device development will be initiated •  Earlier if needed for Phase 1 or Phase 2 clinical trials (e.g. inhalation product) •  Later for post-launch life cycle management

Plan Design & Develop

~ 6 mo up to 12 mo ~ 18 mo

Evaluate Concept

Launch

Phase1 Phase 2 Phase 3 Phase 4

Device Strategy Design & Development Plan

Design Verification for Clinical & Scale-Up Readiness

Launch Design Verification for Commercial, Validated Device Design, Regulatory Submission,


Prepare to Launch Industrialize

Prepare to Launch Design &

Develop Industrialize ~ 12 mo 12 to 18 mo

~ 9 to 24 mo

~ 9 to 30 mo

~ 9 to 12 mo

~ 9 to 12 mo

Plan Design &

Development Plan Design Verification for

Clinical & Scale- up Readiness

Launch Verified & Validated Commercial Design, Regulatory Submission,


Monitor & Improve

Monitor & Improve

Prefilled Syringe

(Assumes first clinical introduction is Phase 3 start)

Injection Device (e.g. auto-injector) (Assumes first clinical introduction is a bridging study during Phase 3)

Plan Design & Develop

~ 6 mo up to 12 mo ~ 18 mo

Evaluate Concept

Launch

Ample time must be provided to develop the device technology before it is combined with the drug

Device Technology Development

Concept à Clinical Readiness

•  License-in mature device technology or start new technical development early

•  Development of a platform (multiple drug applications) or product-specific

•  Strategy for evolving Target Product Profile must be considered - user population and drug formulation properties not fully defined early in the drug development process

1 – 5 years

Other key factors that need consideration with respect to integration of the drug and device development processes…

•  Timing of initiation of Design Controls and Design History File –  Formally implemented once a decision has been made to develop the combination product

vs. the technology platform? –  Potential solution to create baseline “platform” design control documentation for technology

development that is fully executed for the combination product

•  Early understanding of drug properties for consideration with device selection/design –  TPP, formulation viscosity and volume, filling process to ensure device technology is suitable –  Plan for a range of changes in product team strategy (dose, etc.)

•  Timing of completion of Design Validation – cannot be prior to Phase 3 clinical testing –  Final packaging, labeling and branding colors not available –  Commercially representative devices (launch scale) not typically available

•  Appropriately scoping design transfer based on drug clinical phase –  Clinical manufacturing has controls (not same level of design control documentation as

commercial)

Development of combination product control strategy: Linking the elements of Design Controls and QbD

21 CFR 820.30, Design Controls /ISO 13485, Cl.

7.3, Design and Development

ISO 14971 Risk Management

21 CFR 820, Quality System Requirements/ISO 13485,

Quality Management Systems

•  Design Controls and QbD have common principles: both begin with pre-defined objectives, emphasize product and process understanding and control, and are based on risk management

•  Our approach aligned processes to assess potential patient harm to ensure consistency in the development of the control strategy for the combination product

PharmaceuLcal Device

CombinaLon Product Source: Nasr, Moheb. (2011, FDA). Implementa?on of Quality by Design (QbD) – Current Perspec?ves on Opportuni?es and Challenges Topic Introduc?on and ICH Update

Roche Design Control tools were aligned to our QbD approach to ensure consistent development of the control strategy for the combination product

1.) CQA Identification Using Risk Ranking &

Filtering Tool

3.) Assess Process Impact/Stability Impact

4.) Attribute Testing Strategy based on CQA and Process

Impact Knowledge

2.) Determine CQA Acceptance Criteria

5.) Overall Control

Strategy

Critical Quality Attributes Process Control

Ø Design Outputs (e.g. specifications) to control the product design and process

Ø Hazard Assessment Ø User Requirements Ø  “Easy to push” Ø Hazard is “worsening of disease

symptoms” due to incomplete dose

Ø Design Inputs Requirements Ø Use FMEA Ø  “Injection force ≤ 25N”

Ø Design and process FMEAs: iterative process of assessing and reducing risk of the design and process

Ø Device characterization/verification and assembly process validation

Ø  Combination product stability data Ø  “Siliconization can impact injection

force”

Control Strategy

Ø Overall manufacturing capability assessment Ø  Level of control determined and type of testing

and points of control Ø  “Manufacturer CofA, test injection force of

syringe at incoming inspection”

Alignment of drug QbD safety and device hazard assessment scoring ensures functionality is included in the assessment and that harms are assessed in the same way

Hazard Assessment Scoring Criteria

Device Severity Score ( QbD CQA Impact

Score)

Effects may cause serious adverse health consequences, permanent disability, or death

10 (20)

Effects may cause a significant impact to patient health (e.g. temporary or medically reversible health problems or disability)

8 (16)

Effects are noticeable by user and may make product unusable; requires medical intervention

6 (12)

Effects are noticeable by user and may make product difficult to use; does not require any medical intervention

4 (4)

Effects will have negligible to no impact to patient health

2 (2)

11

Drug QbD Approach Device Approach

(based on ISO 14971)

The control strategy is determined by assessing the impact of the device design and process variability on the CQAs •  CQA identified by association to a high severity harm •  Material variability or process parameter linked to high severity (harm) is assessed for its

impact on the CQA (e.g. device/process characterization, monte carlo simulation, etc.) •  Severity and probability of occurrence drive actions to reduce risk to an acceptable level •  The level of impact of the material variability or process parameter on the CQA determines

the control strategy (incoming inspection, IPCs, CofA and/or stability testing) –  Material or process parameter with meaningful

impact on CQAs are considered critical process or design (e.g. dimension) parameter

12

Example: Prefilled Syringe Design Risk Assessment (FMEA)

Concluding Remarks

•  Alignment of the drug and device processes enables clarity and consistency in development approach for the overall drug + device system

•  Proactively, rather than reactively, address alignment of drug – device requirements

–  Avoids project delays during development –  Best ensures regulatory compliance

Acknowledgements

Ivy Lin Shelley Luciak Chin-Wei Soo Sherri Biondi Lee Wood Jennifer Mercer Amanda Roden Andrew Kosky Paul Villaneuva

Judith Svarczkopf

Introduction - cdn.ymaws.com€¦ · development that is fully executed for the combination product...

Documents

Transcript of Introduction - cdn.ymaws.com€¦ · development that is fully executed for the combination product...