Regulatory CMC and Design Control Considerations for Pre ...

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Regulatory CMC and Design Control

Considerations for Pre-filled

Syringes – Industry Perspective

5th Annual Pre-filled Syringes Summit, San Diego, CA, 25 June 2015

SUZETTE ROAN

Regulatory Affairs CMC, Combination Products & Medical Devices


• US and EU regulatory framework

• US – 21 CFR Parts 3&4

• EU – drug-delivery products regulated as medicinal products

• Design control and risk management approaches for PFS

• Suggestions for US and EU submission content

OVERVIEW


US and EU Regulatory FrameworkPre-filled Syringes


REGULATION OF COMBINATION PRODUCTSUS and EU Approach

US EU

• Combination Product defined in

statute (21CFR3)

• Any combination of medical

device, biologic, and drug

• Must meet requirements for all

constituents

• Approval path determined by

“primary mode of action” (i.e., BLA,

NDA, 510(k), PMA)

• No formal “combination product”

statute

• Drug-Device Combination: Drug is

primary and device is only for

delivery.

• Medicinal Product Directive

(2001/83/EC) drives approval through

medicinal competent authority

• Device-Drug Combination: Drug

only serves ancillary purpose

• Medical Device Directive (93/42/EEC)

drives CE marking through notified body

with consultation to medicines

competent authority for safety and

usefulness of medicinal substance


DEFINITION OF COMBINATION PRODUCT

• Simply defined – any combination of any two of the “big three” regulated medical products:

drugs, biologics, or devices.

• Drug-Device

• Biologic-Device

• Drug-Biologic

• Drug-Device-Biologic

• Each product in a combination product (i.e., drug, device, and biologic) is called a “constituent”

• Constituent part retains its legal status when its combined in a combination product –

regulatory requirements travel with the constituent part

• Manner of combination

• Single-entity (e.g., prefilled pen injector, pre-filled syringe, drug-eluting stent)

• Co-packaged (e.g., kit containing injector with drug cartridge)

• Cross- labeled (e.g., injector labeling says that injector is to be used with a specific-named

drug and vice versa)


• Device Components – individual syringe components (e.g., barrel, needle

shield, plunger, backstop, plunger rod)

• Drug Constituent – formulation plus the primary packaging

• Device Constituent – fully assembled/functional pre-filled syringe

presentation

• Add-on finished devices (e.g., needle safety device) are also considered device

constituents

• Combination Product - fully assembled/functional pre-filled syringe

presentation

SOME TERMINOLOGY


• Piston Syringes historically regulated as devices

• Product Code – FMF

• 21 CFR 880.5860, Class II

• Pre-filled Syringes were historically registered as container closure systems

for the drug product contained therein

• 21 CFR 4 clarified intention to enforce pre-filled syringes as combination

products subject to CGMPs.

• “syringe is a device used to deliver another medical

product…Accordingly, a prefilled syringe is a combination product and

subject to this rule” (preamble)

PRE-FILLED SYRINGE AS A COMBINATION

PRODUCT


• Final Rule Effective July 22, 2013

• Manufacture of single-entity or co-packaged combination products shall:

• Comply with all applicable CGMP requirements for the constituents contained

within the combination product, OR

• Adopt a streamlined approach, as follows:

• Select the base system for the manufacturer (e.g., Drug GMP, Device

QSR), and then show compliance with additional provisions:

21 CFR PART 4 –CGMP REQUIREMENTS

FOR COMBINATION PRODUCTS

Drug GMP Streamlining Approach:

• 820.20 Management Responsibility

• 820.30 Design Controls

• 820.100 CAPA

• 820.170 Installation

• 820.200 Servicing

Device QSR Streamlining Approach:

• 211.84 Testing and approval or rejection of

components, drug product containers, and closures

• 211.132 Tamper-evident packaging requirements for

the OTC human drug products

• 211.137 Expiration dating

• 211.165 Testing and Release for distribution

• 211.167 Special Testing Requirements

• 211.170 Reserve Samples

Note – a facility that manufactures only one type of constituent part and not combination products only

needs to comply with CGMP requirements for the constituent part


• Draft issued January 2015

• Some highlights:

• Explains impact to investigational products

• Clarifies terminology – manufacturer, component vs. constituent part, drug

container vs. delivery devices

• Robust sections on how to implement the specified CGMP requirements for

streamlining approaches

• Note – useful insights for both Drug CGMP and Device QSR based

systems, so be sure to carefully read through all

• Includes Agency thinking for products which may not have been

developed under design controls

• Case Studies - including a PFS

CGMP REQUIREMENTS FOR COMBINATION

PRODUCTS DRAFT GUIDANCE


• Principal mode of action of the product is the determinant for which Directive

applies

• Medical Device Directive (MDD, 93/42/EEC):

• “single integral product which is intended exclusively for use in the given

combination and which is not reusable…governed by Directive

2001/83/EC. The relevant essential requirements of Annex I to this

Directive shall apply as far as safety and performance-related device

features are concerned”

DRUG-DEVICE COMBINATION –

REGULATORY FRAMEWORK


• MEDDEV on Borderline Products (2.1/3 rev 3) - drug-delivery products

regulated as medicinal products

• According to the MDD, this single product is governed by the MPD but

the relevant essential requirements of Annex I to the MDD shall apply as

far as the safety and performance-related device features are

concerned

• Pre-filled Syringe listed as an example of a drug-delivery product

regulated as a medicinal product

• MHRA Guidance on Borderline Products – “Syringe marketed pre-filled with

a drug” – covered by MPD, but essential requirements of MDD apply with

respect to safety and performance features of the device

PRE-FILLED SYRINGES


• Medical Device Directive is currently being revised and will include changes

which affect drug-device combinations

• 2012 MDD draft revision text – conformity assessment requirement

proposed:

• Applicant to submit evidence (e.g. an EU declaration of conformity or

a certificate issued by a notified body) that the device part is in

conformity with the applicable general safety and performance

requirements of the future Regulation on medical devices.

• We understand that this requirement would apply to PFS as well as

other delivery devices

• Stay tuned as the MDD revisions are finalized.

FUTURE CHANGES


• Most global markets either follow EU approach or treat PFS as a container

closure system

• Continue to work with local affiliates/networks to understand if there are any

changes forthcoming for how to submit applications for PFS

GLOBAL MARKETS


Design Control & Risk

ManagementApplication to Pre-filled Syringes


DESIGN CONTROL WATERFALL


DEVICE CONSTITUENT VS. COMBINATION PRODUCT

DESIGN CONTROL WATERFALL INTERPRETATION


DEVICE COMPONENT VS. COMBINATION PRODUCT

DESIGN CONTROL WATERFALL INTERPRETATION

Purchased device

components may have

some verification

activities completed by

the supplier which

support their selection

for the combination

product


DEVICE DEVELOPMENT PHASES

Regulatory Affairs Role

Planning Design Verify Validate TransferPost-

Marketing

•User Needs

•Intended

Use

•Design

Inputs

•Hazard

Analysis

•Regulatory

Strategy

•FMEAs

•Product

Specs

•Engineering

Drawings

•Supplier

Selection

•DVT

•ISO testing

•Biocompat.

Testing

•Stability

Studies

•Transport

Studies

•Formative

HF

•Summative

HF

•Clinical

Study

•Risk Benefit

Report

•Device

Master

Record

•Process

Validation

•Regulatory

Submission

•Complaints

•AEs

•CAPAs

•Continuous

Improv./

Next

Generation

Change Management

Risk Management, Design Reviews, Change Control throughout development


• Design controls need to be in place for both the device constituent parts and

the combination product for the PFS

• How to implement? How is this different from standard container/closure

suitability assessments?

→ NOT THAT DIFFERENT!

• Many of the same assessments are performed

• Much of the same data is used to satisfy container/closure

requirements as are used to satisfy design control considerations

• Design controls provide for a standardized, systematic, prospective,

iterative model for device design and development to ensure that the

device is safe and effective

DESIGN CONTROL IMPACT OF 21 CFR 4

ON PRE-FILLED SYRINGES


COMPARISON OF DESIGN CONTROLS TO TRADITIONAL

CONTAINER CLOSURE DEVELOPMENT

Design Control

Element

Traditional Drug Development Design Control Approach

Design & Development

Planning

Master project plan D&D Plan

Design Input Target Product Profile,

Regulations/Guidance Documents

User Requirements, Design Input

Requirements

Design Output Specification, Drawings, MBR Specification, Drawings,

MBR/DMR

Design Review Development Go/No Go decision

points

Formal Design Reviews,

Independent Reviewer

Design Verification Characterization studies, suitability

studies

DVT, functionality assessment

Design Validation Use in clinical studies Actual or Simulated (Human

Factors) Use Testing

Design Transfer Tech Transfer Tech Transfer/DMR

Design Changes Change control Change control

Design History File Drug development project files DHF


DESIGN INPUTS - PFS

• Physical and performance requirements of a device that are used as a

basis for device design:

– User Requirements – ease of use, environment of use, essential requirements (EU

MDD Annex 1)

– Technical/Functional Requirements - Syringe volume, material type, Needle gauge,

needle type, cover, shield, Plunger material, plunger rod, Seal integrity, sterility,

stability, compatibility, tungsten, silicone

– Safety Requirements - safety device, leachables, biocompability, latex free,

BSE/TSE free

– Regulatory Inputs – relevant guidances/standards which product should conform

– Business Requirements – supply considerations, use of existing

facilities/equipment, platform considerations

• When developing Input Requirements for a PFS, be mindful of the

possible additional presentations: is an autoinjector planned?


DESIGN INPUTS

Finding the Regulatory Sources

• FDA (CDRH) website – can use product

codes to look up recognized standards,

guidance documents, etc. applicable to a

given device type

• Standards and guidance documents

reference other guidance documents and

standards

• Adverse events and Medical Device

Reports

• MEDDEV guidances


FAMILIAR CONTAINER CLOSURE PFS

REQUIREMENT SOURCES

• Device is suitable for intended use (e.g., protects, compatible, safe, performs, etc.)

FDA Guidance – Container Closure Systems for Packaging

Human Drugs & Biologics

• <1> Injections, <381> Elastomeric Closures, <660> Containers, <1031> Biocompatibility, <1207> PkgIntegrity

USP General Chapters

• Suitability of container closure device (e.g., materials, protection, compatibility, safety, performance, etc.)

ICH M4Q – CTD (Quality)

• Functionality tests for dose delivery systemICH Q1A(R2) - Stability

• Test procedures and acceptance criteria related to functionality of delivery system

ICH Q6A - Specifications

• Demonstration of reproducible and accurate dose delivery

ICH Q8(R2) – Pharmaceutical Development


SOME PFS REQUIREMENT SOURCES

• 10993: Series on Biocompatibility

• 11040-4: Prefilled Syringes – Part 4: Glass barrels

• 11040-5: Prefilled Syringes – Part 5: Plunger stoppers

• 11608: Series on injection systems

• 14971: Medical Devices – Application of risk management to medical devices

• 23908: Sharps Injury Protection – Requirements and test methods

ISO

• Medical Devices with Sharps Injury Prevention Features

• Applying Human Factors and usability engineering to Optimize Medical Device Design (Draft)

• Glass Syringes for Delivering Drug and Biological Products: Technical Information to Supplement International Organization for Standardization (ISO) Standard 11040-4 (Draft)

• Technical Considerations for Pen, Jet, and Related Injectors Intended for Use with Drugs and Biologics

• Design Considerations for Devices Intended for Home Use

Guidance Documents


DESIGN VERIFICATION

• Verification that the Outputs meet the Inputs → Did I make the product right?

• Confirmation via studies, tests, inspections, and analyses

• Bench tests

• Dimensional verification

• Comparison to established product

• May leverage results on components to

demonstrate that the combination product

meets the requirement (e.g., biocompatiblity)


DESIGN VALIDATION

• Objective evidence that the device meets the user needs and intended uses

→ Did I make the right product?

• Confirmation via

• User/human factors studies with testing of IFU

• Performed under actual or simulated use


RISK MANAGEMENT

• Integrated throughout the design process to systematically identify and, as

necessary, mitigate risk

• Product hazard analysis at start of design phase

• Series of Failure Modes and Effects Analyses throughout design process

(iterative) – System FMEA, User FMEA, Process FMEA, etc.

• Early phases – assess based upon theoretical risk based upon the type

of product / similar products already on the market

• Further in development – can use experience gained to date from

clinical and user studies to understand the potential failure modes

• Incorporate experience from other similar products in company’s portfolio into

Risk Management process


PURCHASING CONTROLS

• Vital for combination products, as most include purchased

materials/components/device assemblies

• Design only as good as the purchasing controls

without strong purchasing controls, design can change without you even

knowing

• Supply agreements:

• Customers and suppliers should agree on notification and approval of changes

and include these terms in agreements

• Suppliers should ensure that THEIR suppliers have adequate change control

programs in place


US and EU Submission ContentPre-filled Syringes


• PFS presented BOTH as a container closure system and as a combination

product

• Typical C/C content presented in 3.2.P.2.4. (Pharmaceutical Development:

Container Closure System) and 3.2.P.7 (Container Closure System) according

to ICH recommendations

• Supplement 3.2.P.2.4 with summary of combination product design and

development:

• Summary of design inputs, outputs, verification plan and results, design

validation summary and HF report

• Overview of design of product and operating principles (if applicable)

• Supplement 3.2.P.3 or 3.2.P.7 with combination product manufacturing and

controls

SUBMISSION APPROACH


• Details on biocompatibility studies to support safety of the PFS

• PFS Functionality

• Break loose and extrusion forces – over time and batch to batch

• Silicone interaction studies

• Tungsten compatibility

• QSR procedures (requests commonly reference “Quality System Information

for Certain Premarket Application Reviews” Guidance)

COMMONLY REQUESTED DATA


• PFS presented as a container closure system

• Typical C/C content presented in 3.2.P.2.4. (Pharmaceutical

Development: Container Closure System) and 3.2.P.7 (Container Closure

System) according to ICH recommendations

• Usability summary included to support safe use of the drug-device delivery

system

SUBMISSION APPROACH


SUMMARY

• Regulatory requirements for combination products in the US

and EU are different and evolving

Know the requirements of each market during

development

• Design controls are required for pre-filled syringe

combination products

Additional requirements build on currently performed

container closure development activities

• Submission content can be customized for the region


ACKNOWLEDGEMENTS

Tony Watson - RA CMC, Combination Products & Medical Devices, Biogen

Gretchen Vandal - RA CMC, Combination Products & Medical Devices, Biogen

Steve Dew - RA CMC, EU & Combination Products & Medical Devices, Biogen


Questions?

Thank You!

Roan, Drug Delivery Partnerships 2015, pg. 35


USEFUL LINKS – FDA

• Safety Considerations for Product Design to Minimize Medication Errors (Draft Dec 2012) -

http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM331810.pdf

• Safety Considerations for Container Labels and Carton Labeling Design to Minimize Medication Errors (Draft April 2013) -


• Medical Devices with Sharps Injury Prevention Features (Aug 2005) -

http://www.fda.gov/medicaldevices/deviceregulationandguidance/guidancedocuments/ucm071663.htm

• Use of International Standard ISO-10993, "Biological Evaluation of Medical Devices Part 1: Evaluation and Testing“ (Draft, Apr 2013) -

http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM348890.pdf

• Technical Considerations for Pen, Jet and Related Injectors Intended for Use with Drugs and Biological Products (June 2013) -

http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM147095.pdf

• Applying Human Factors and Usability Engineering to Optimize Medical Device Design (Draft, June 2011) -


• Medical Device Use-Safety: Incorporating Human Factors Engineering into Risk Management (June 2000) -

http://www.fda.gov/downloads/MedicalDevices/.../ucm094461.pdf

• Glass Syringes for Delivering Drug and Biological Products: Technical Information to Supplement International Organization for

Standardization (ISO) Standard 11040-4 (Draft, Apr 2013) -


• Guidance on the Content of Premarket Notification [510(K)] Submissions for Piston Syringes (Apr 1993) -

http://www.fda.gov/RegulatoryInformation/Guidances/ucm081324.htm







http://www.fda.gov/downloads/MedicalDevices/.../ucm094461.pdf




USEFUL LINKS – FDA (CONT’D)

• CDRH Product Classification Database -http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfPCD/PCDSimpleSearch.cfm

• Design Considerations for Devices Intended for Home Use (Nov 2014) -


• Early Development Considerations for Innovation Combination Products (Sept 2006) -


• Federal Register, Vol 78, No. 14, 21 CFR Part 4 Final Rule (January 22, 2013) - http://www.gpo.gov/fdsys/pkg/FR-2013-01-22/pdf/2013-

01068.pdf

• Current Good Manufacturing Practice Requirements for Combination Products (Draft, Jan 2015) -


http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfPCD/PCDSimpleSearch.cfm



http://www.gpo.gov/fdsys/pkg/FR-2013-01-22/pdf/2013-01068.pdf



EC Guidance MEDDEV 2.1/3 Rev 3: Medical Devices: Borderline products, drug-delivery products and medical devices

incorporating, as an integral part, an ancillary medicinal substance or an ancillary human blood derivative -

http://ec.europa.eu/health/medical-devices/files/meddev/2_1_3_rev_3-12_2009_en.pdf

MHRA Guidance – Borderlines between Medical Devices and Medicinal Products (June 2013) -

http://webarchive.nationalarchives.gov.uk/20141205150130/http://www.mhra.gov.uk/home/groups/dts-bs/documents/publication/con286964.pdf

Medical Devices Expert Group on Borderline and Classification, Manual on borderline and classification in the Community

Regulatory framework for medical devices (referred to as the ‘manual of decisions’) - http://ec.europa.eu/health/medical-

devices/files/wg_minutes_member_lists/borderline_manual_ol_en.pdf

EC Proposal on medical devices, and amending Directive 2001/83/EC, Regulation (EC) No 178/2002 and Regulation

(EC) No 1223/2009 (Sept 2012) http://ec.europa.eu/health/medical-devices/files/revision_docs/proposal_2012_542_en.pdf

CHMP/CVMP Guideline on Plastic Immediate Packaging Materials (Dec 2005) -

http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003448.pdf

ICH Topic M 4 Q, Location issues for Common Technical Document for the Registration of Pharmaceuticals for Human

Use – Quality Questions and Answers


USEFUL LINKS – EU

http://ec.europa.eu/health/medical-devices/files/meddev/2_1_3_rev_3-12_2009_en.pdf

http://webarchive.nationalarchives.gov.uk/20141205150130/http:/www.mhra.gov.uk/home/groups/dts-bs/documents/publication/con286964.pdf

http://ec.europa.eu/health/medical-devices/files/wg_minutes_member_lists/borderline_manual_ol_en.pdf

http://ec.europa.eu/health/medical-devices/files/revision_docs/proposal_2012_542_en.pdf




ICH REFERENCES

ICH M4Q - Container Closure: “The suitability of the container closure… “reproducibility of the

dose delivery from the device when presented as part of the drug product.”

ICH Q6A Specifications: Test Procedures and Acceptance Criteria: “…parenteral formulations

packaged in pre-filled syringes, autoinjector cartridges, or the equivalent should have test

procedures and acceptance criteria related to the functionality of the delivery system.”

ICH Q1A (R2) Stability Testing: including “functionality tests (e.g., for a dose delivery system)”

ICH Q8(R2) Pharmaceutical Development: “Critical Quality Attributes (CQA)…..“Drug Product

Container Closure System: If a dosing device is used (e.g., dropper pipette, pen injection device,

dry powder inhaler; demonstrate that a reproducible and accurate dose is delivered under testing

conditions that, as far as possible, simulate the use of the product.”

http://www.ich.org/home.html

http://www.ich.org/home.html

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