Global Regulatory Affairs · • EU: MDD 93/42/EEC as amended and MEDDEV 2.1/3 rev 5.1 – Typically addressed with a CE Mark or by demonstrating conformance Global Regulatory Affairs

Global Regulatory Affairs

Perspectives on the Development and Commercialization of Combination ProductsCommercialization of Combination Products

Regulatory Requirements and Functionality Tests for P fill d S i d A t i j tPre-filled Syringes and Auto-injectors

Presented by: Douglass MeadDirector, RA-CMC, Medical Devices & Combination ProductsJanssen Research & Development LLCJanssen Research & Development, LLC

WCBP 2012January 23 2012 January 23, 2012

Disclosures: • The following presentation includes the personal views of the presenter and do


• The following presentation includes the personal views of the presenter and do not necessarily represent the official views of Janssen R&D, LLC.

• Data presented should not be associated with any specific biological product.• Regulatory requirements presented may differ from actual regulatory

requirements imposed by Health Authorities for specific combination products.

Topicsp• A summary of regulatory requirements for functionality of

prefilled syringes and autoinjectors

• The fundamentals of Design Controls under the proposed rule for cGMPs for Combination Products

• The principles of functionality characterization - with examples

• The use of Design Inputs in justifying release specifications

• Assessment of usability in human factors studies and in clinical trials

• Strategies for delivery device post-approval changes – when and how

Global Regulatory Affairs 2

Historical Regulatory Requirements for Drug Delivery Device FunctionalityDevice Functionality

• FDA Guidance: Container Closure Systems for Packaging Human Drugs and Biologics (May 1999)– “Suitability for the Intended Use: Every proposed packaging system should

be shown to be suitable for its intended use: it should adequately protect the dosage form; it should be compatible with the dosage form; and it should be composed of materials that are considered safe for ; puse with the dosage form and the route of administration. If the packaging system has a performance feature in addition to containing the product, the assembled container closure system should be shown to function properly.” (emphasis added)p p y ( p )

• ICH M4Q Common Technical Document for the Registration of Pharmaceuticals for Human Use – Quality (2003/2001)

“The suitability of the container closure system discussion should consider – The suitability of the container closure system…discussion should consider, for example… reproducibility of the dose delivery from the device when presented as part of the drug product.”


Historical Regulatory Requirements for Drug Delivery Device Functionalityy• ICH Q6A Specifications: Test Procedures and Acceptance Criteria for New

Drug Substances and New Drug Products: Chemical Substances (1999)– “…parenteral formulations packaged in pre-filled syringes, autoinjectorp p g p y g , j

cartridges, or the equivalent should have test procedures and acceptance criteria related to the functionality of the delivery system.”

• ICH Q1A (R2) Stability Testing of New Drug Substances (2003) – “Stability studies should include testing of those attributes of the drug product that Stability studies should include testing of those attributes of the drug product that

are susceptible to change during storage and are likely to influence quality, safety, and/or efficacy. The testing should cover, as appropriate, the physical, chemical, biological, and microbiological attributes, preservative content (e.g., antioxidant, antimicrobial preservative), and functionality tests (e.g., for a dose delivery

) ”system).”

• For a PFS, Health Authorities have expected information on:– Syringe piston (stopper) break loose and travel forces from multiple lots

Confirmation of expelled volume– Confirmation of expelled volume– Silicone content (associated with glide)– Elastomer and tungsten interactions with protein formulations– DMF for additional design, manufacturing, and quality information


– Container closure integrity

4

Historical Regulatory Requirements for Drug Delivery Device Functionality – Autoinjectors and Pre-filled Pensy j

• ISO 11608:2000 Pen-injectors for medical use; Part 1: Pen-injectors, Part 2: Needles, Part 3: Finished cartridges, Part 4 (2006): [Electronic functions] - Requirements and test methods( ) [ ] q– Intended primarily for insulin pens but portions relevant to autoinjectors

were assessed.

• FDA Draft Guidance: Technical Considerations for Pen, Jet, and R l t d I j t I t d d f U ith D d Bi l i l Related Injectors Intended for Use with Drugs and Biological Products (2009)– Drug/device compatibility if in direct product contact

Suggested tests: dose accuracy flow rate injection time functional – Suggested tests: dose accuracy, flow rate, injection time, functional reliability, depth of injection, functionality of the safety mechanism, verification for absence of leakage, chemical resistance, structural testing, actuation force, force to defeat needle safety feature, needle penetration force cap/shield removal force functional stability penetration force, cap/shield removal force, functional stability, human factors/usability, etc.

• EU: MDD 93/42/EEC as amended and MEDDEV 2.1/3 rev 5.1– Typically addressed with a CE Mark or by demonstrating conformance


Typically addressed with a CE Mark or by demonstrating conformance to Annex 1 – Essential Requirements - of the Medical Device Directive

5

The New Paradigm in Regulatory Requirements• FDA Combination Products Regulations

– 21 CFR Part 3 (1991) – Product Jurisdiction Rules - Definitions• Integral (single-entity) delivery devices (pre-filled) [21CFR 3(e)(1)]• Kitted (co-packaged) products [21CFR 3(e)(2)]

C l b l d d t [21CFR 3( )(3)] [ l i ti ti l 21CFR 3( )(4)]• Cross-labeled products [21CFR 3(e)(3)] [plus investigational – 21CFR 3(e)(4)]

– Proposed 21 CFR Part 4 – Regulation of Combination Products (2009) Subpart A (4.1-4.4)—Current Good Manufacturing Practice Requirements for Combination Products Requirements for Combination Products • Applies to integral and kitted combination products• Product development impact is: Design Controls (21 CFR 820.30)• Not yet a final rule.

• New ISO Standards - ISO/FDIS 11608 Needle-based injection systems for medical use - Requirements and test methods (near final)

Part 1: Needle based injection systems – Part 1: Needle-based injection systems – Part 2: Needles– Part 3: Finished containers – Part 5: Automated functions

A d ISO 23908 2011 Sh i j t ti R i t d t t th d


– And ISO 23908:2011- Sharps injury protection -- Requirements and test methods

6

Key Elements of 21CFR 820.30 - Design controls• Design and Development Planning (Device/Combination Product • Design and Development Planning (Device/Combination Product

Development Plan)• Design Inputs (What does the user require of the device? What

technical and “suitability” characteristics are required of the device? a a d u ab y a a a qu d o dHow is a biological drug a design input?)

• Design Outputs (design phase - performance acceptance criteria, specifications, drawings) May be used to specify off-the-shelf products. Biological drug specification ≅ Design Output

• Design Verification [bench performance tests to confirm specifications (Outputs) are met] Confirmation that the specific d i ( ) i bl i h ifi bi l i l ddevice(s) are suitable with a specific biological drug.

• Design Validation [Establishing by objective evidence that the device(s) meets user needs and intended uses (Design Inputs); user/clinical studies and testing of the IFU process validation user/clinical studies and testing of the IFU, process validation, functional stability] Tested with the target population (and biological drug, where necessary).


Examples of Functionality Characterization - PFSPlot of Viscosity and Average Piston Travel Force vs Glycerin/WFIPlot of Viscosity and Average Piston Travel Force vs Glycerin/WFI

concentration (N=24)

18

20

11

12

9.0212

14

16

18

orce

(N)

8

9

10

11

emat

ic

cS)

Measured Piston Travel Force

5.42

6

8

10

Pist

on T

rave

l Fo

5

6

7

Mea

sure

d K

ine

Visc

osity

(c

Viscosity (cS)

X Lit t l

3.462.98

2.630

2

4

25 30 35 40 45 50 55 60 652

3

4Viscosity of mAb formulation of interest

X = Literature values

% Glycerin in WFI

• 27 Gauge, ½ inch needle• Plot of kinematic viscosity (cS) vs piston travel force was linear


Examples of Functionality Characterization Autoinjector Delivery Time vs ViscosityAutoinjector Delivery Time vs Viscosity

administration time vs glycerin conc

16Autoinjector Delivery Time

10.58

10

12

14

time

[N]

yspecification = 15 seconds

7.46

4.92 6.08

4

6

8

adm

inis

tratio

n t

MeanSpecification

0

2

20 30 40 50 60 70

glycerin conc [%]

Expon. (Mean)glycerin% N Mean StDev Median

30 24 4.92 0.65 540 24 6.08 0.50 650 24 7.46 0.66 760 24 10.58 0.65 11

glycerin conc [%]

• 27 Gauge, ½ inch needle, 1.0 mL volume PFS• Conclusion: Main spring drive force should be sufficient for most mAb


formulations up to about 9+ cS.

9

Autoinjector spring force characterizationNeedle insertion & syringe plunger force as a function of spring extensionF

orcce

Spring force (F) available for complete PFS delivery

• Autoinjector design principles suggested that PFS Glide VelocityAutoinjector design principles suggested that PFS Glide Velocitywas an important parameter of interest for characterization– In addition to glide forces measured at an arbitrary fixed plunger drive

velocity plunger Glide Velocity at a fixed force (F) will be assessed velocity, plunger Glide Velocity at a fixed force (F) will be assessed

– Plunger travel distance (for 1.0 mL fill) ÷ max specified Delivery Time determined Glide Velocity acceptance criteria


Glide Force and Glide Velocity Characterization• Fixed piston speeds to measure glide forces are not standardized, and forces p p g

are highly dependent on test velocityAverage Piston Travel ForceTrendline: y = 0.0274x + 0.5872

R2 = 0.996114

16

6

8

10

12

Forc

e [N

]

Representative mAb with viscosity ~ 1.2 cP

Influence of test velocity on piston travelforce

Average Piston Release ForceTrendline: y = -4E-05x + 4.1513

R2 = 0.00330

2

4

0 50 100 150 200 250 300 350 400 450 5000 50 100 150 200 250 300 350 400 450 500

Velocity [mm / min]

Typical mAb glide velocity curve

B eeakloose Effect of PFS bubblemm/sec

Typical mAb glide force curve

Force (N)

Breeakloose force


Piston travel distance Piston travel distance

The Device Design Controls Paradigm for a PFS

• Health Authorities have treated piston break loose and travel• Health Authorities have treated piston break loose and travel forces like biochemical release specifications.– Registered force specifications for commercial release may be restricted to

test res lts on clinical trial lotstest results on clinical trial lots • Should a device Design Controls approach be considered in setting

specifications?– Users can accommodate a wide range of forces by varying injection speed.– PFS plunger thumb rest diameter and finger flange design are as important

to usability as PFS injection forces– Separate human factors studies* can establish user requirements and

justify force specifications– Dermal/tissue fillers approved by FDA (CDRH) have much higher injection

forces than typical mAb solutions (e g Artecoll® Coaptite® forces than typical mAb solutions. (e.g., Artecoll®, Coaptite®, Radiesse®)

* Example: Cilurzo F et al. Injectability Evaluation: An Open Issue, AAPS PharmSciTech Vol 12 No 2 June 2011


AAPS PharmSciTech, Vol. 12, No. 2, June 2011

mAb characterization study - two formulations (PFS)- Glide Velocity assessment- Needle gauges - 26 vs 27 g g- Two temperatures 10°C vs 30°C

Target minimum glide velocities

Red (30°C) and Blue (10°C) results suggested a benefit to the a benefit to the nominal formulation and 26 ga needle

mAb Formulation Description 20°C Viscosity (cP) 10°C Viscosity (cP)i l / i i d i i


Nominal 104 mg/mL optimized excipients 5 to 6 7 to 9Maximized (Worst case) 113 mg/mL enhanced excipients 8 to 11 13 to 19

mAb characterization study – two formulations (AI) - Autoinjector Delivery Time assessment- Needle gauges - 26 vs 27 - Two temperatures 10°C vs 30°C

Red (30°C) and Blue (10°C) results suggested a slight benefit to a slight benefit to the nominal mAb formulation and 26 ga needle

mAb Formulation Description 20°C Viscosity (cP) 10°C Viscosity (cP)Nominal 104 mg/mL optimized excipients 5 to 6 7 to 9


Nominal 104 mg/mL optimized excipients 5 to 6 7 to 9Maximized (Worst case) 113 mg/mL enhanced excipients 8 to 11 13 to 19

Autoinjector functional stability challenges specific to protein (mAb) solutions

• PFS glide forces can increase as product ages affecting autoinjector delivery time and other performance attributes. Potential root causes include:– Protein aggregation on PFS barrel walls causes increased friction.

Potential for aggregation on surfaces may be linked to potential for particle formation.*

PFS glide force (mAb aged >12mos @ 25°C) (worst case)

PFS glide velocity(mAb aged >12mos @ 25°C) (worst case)

Force (N)

Nominal

Velocity (mm/s)

)

*B JS R d l h TW C t JF Eff t f S f d L h bl


*Bee JS, Randolph TW, Carpenter JF, Effects of Surfaces and Leachables on the Stability of Biopharmaceuticals. J Pharm Sci. Vol. 100 No. 10 (2011)

Autoinjector functional stability challenges specific to protein (mAb) solutions

• PFS glide forces can increase as product ages affecting autoinjector delivery time and other performance attributes. Potential root causes include:– Silicone lubrication quantity and distribution on syringe barrel

and the potential for silicone migration*

PFS Silicone layer thickness (e.g., RapID)

Marginal gsilicone distribution

*Cairns, A PDA 2008 poster: The Impact of Therapeutic Protein Adsorption on the Mechanical


, _ p p p pPerformance of Pre-Filled Syringes and Auto-Injectors

Parameters that may affect autoinjectorfunctionality and stability with an mAb

Design of Experiments Studies• Assessed parameters (32 parameter combinations, 160 samples,

320 datapoints; T=0 and 3 mos.):– Polysorbate concentration - minimal vs 2.5 X concentration – Particle content (pooled with product of known protein particle content)(p p p p )– Silicone content (solvent wash to various levels vs nominal specification)– Silicone distribution (silicone wash/spiked into empty barrel vs nominal characteristics)– Initial stopper position ±2 mm– Spring forces (lower vs nominal)

Results:

– Autoinjector component’s age (youngest vs oldest)– Storage orientation horizontal storage vertical storage– Time at room temperature before testing

• Results:– Polysorbate concentration – High concentration reduced particles but increased friction

in 3 samples (vertical storage) – uncertain root cause (potential washing effect).– Silicone content and distribution - affected stopper friction. (solvent wash to various

levels vs nominal specification)levels vs nominal specification)– Initial stopper position ±2 mm – marginal effect?– Spring forces - no impact– Autoinjector component’s age (youngest vs oldest) - no impact– Storage orientation - horizontal storage preferred


g g p– Time at room temperature before testing – no effect

Parameters that may affect autoinjectorfunctionality and stability

Design of Experiments Studies• Implications:

Selection of type and quantity of surfactant

Compensated for by adeq ate silicone Improved

glide &Delivery time stability

Surfactant quantity

adequate silicone quantity or distribution?

Surfactant quantity Surfactant quantity

Silicone quantity or distribution may be critical

Increasing surfactant may reduce protein aggregation on PFS barrel walls

q y

Increasing surfactant may wash silicone from barrel walls

Suggests an ideal surfactant quantity that may be assessed by PFS glide studies

• Unresolved question: We don’t know if protein is binding to bare glass in PFS barrel areas without sufficient silicone or if

PFS barrel walls glide studies

gthere are protein-silicone complexes on glass that reduce silicone’s lubricity or increase piston/stopper stiction.


Functionality assessed in human factors studies• CDER may now require formal summative human factors studies* for• CDER may now require formal, summative human factors studies for

delivery devices and request that protocols be submitted for FDA (CDRH) review prior to initiating them. Protocols should include a final draft IFUs and a User Risk Analysis including critical tasks. Thisdraft IFUs and a User Risk Analysis including critical tasks. This activity is an essential element of Design Validation that FDA is implementing right now.– Prepare a Task Analysis based on the IFU – identify critical tasksp y y– Conduct formative studies (intervention) and a summative study (no intervention)– Population (groups) categories should be justified; 15-25 subjects per group– Actual field experience will magnify results; expect that use complaints may be higher

than rates for product defects; IFU and design changes can help; Human behavior (e.g., startle reactions) isn’t always predictable. Autoinjector trainer devices can help.

• CDER is moving to requiring final to-be-marketed presentations to be used in Phase 3 trials Usability should be assessed Comparability of drug deliveryPhase 3 trials. Usability should be assessed. Comparability of drug delivery with different delivery devices may be a question. (Potential for bioequivalence or PK studies)

*FDA Draft Guidance - Applying Human Factors and Usability Engineering to Optimize Medical


Device Design (June 22, 2011)

Functionality specifications for combination products

• Functional device specifications can be derived from Design • Functional device specifications can be derived from Design Inputs (user requirements and technical design requirements) which are then verified and validated. This is in contrast to biological drug product specifications that are determined by the production process, studied in clinical trials, and then registered.

Autoinjector examples:Autoinjector examples:– Delivery time: 15 seconds – based on market research; a 510(k)

cleared predicate autoinjector has a 20 second maximum delivery time

– Injection depth: determined by user requirements and dermal thickness data

– Actuation forces: determined by human factors studies in intended population population.

• The eCTD Justification of Specifications module (32P56) should include a discussion of user requirements in the context establishing specifications.


g p

20

Post-approval delivery device changes

• Motivations– Design improvements to enhance usability– New technology available over the biologic product life-cycle.gy g y

• FDA’s Office of Combination Products is finalizing a guidance on submission requirements for post-approval changes. There is currently no clear guidance other than to follow the respective center y g p(drug) requirements. FDA/OCP is recommending (March 2011) pre-market discussions of potential changes, post-market comparability assessment strategies (e.g., bench tests, HFS, clinical studies), and inventory planning sufficient to allow for FDA approval of changes prior to implementation.

• CDRH guidances may be a useful metric*

*Guidance for Industry and FDA Staff - 510(k) Device Modifications: Deciding When to Submit a 510(k) for a Change to an Existing Device (July 27, 2011)

Draft Guidance for Industry and Food and Drug Administration Staff - The 510(k) Program:


Draft Guidance for Industry and Food and Drug Administration Staff - The 510(k) Program: Evaluating Substantial Equivalence in Premarket Notifications [510(k)] (December 27, 2011)

Conclusions

• Patients are prescribed a biologic drug – but they see and use a medical device; Usable delivery devices are a key component of personalized medicine and are a significant benefit to patients (e.g., hand-impaired patients)

• Formulations can be optimized for drug delivery; devices can be optimized for the formulations (Design Inputs).

• Combination product regulations and Health Authority expectations are evolving and vary in different markets; frequent interactions, adequate justifications, and flexibility in development programs are necessary

• Design Controls do not necessarily increase the tests required and can be an effective tool for development and justification of

f b d h l f b hspecifications. Combination products require the application of both drug and device regulations and principles. Device and combination product competencies and experience are essential for success.


Acknowledgementsg

Tom Hogan

Tony Lubiniecki

Nishant Bhasin

R S hRene Spycher

Jasminka Kovac

Christian BraunChristian Braun


Global Regulatory Affairs · • EU: MDD 93/42/EEC as amended and MEDDEV 2.1/3 rev 5.1 – Typically addressed with a CE Mark or by demonstrating conformance Global Regulatory Affairs

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