Applying Pharmaceutical QbD concepts to Medical … · Applying Pharmaceutical QbD concepts to Medical Device Stability Studies Laure L. Larkin M.Sci., CPP . ... Medical Devices?

Applying Pharmaceutical QbD concepts to Medical Device Stability Studies Laure L. Larkin M.Sci., CPP Manager – Package Qualification Management

L. Larkin 03/04/14 – DJ13174 Rev B

MEDICAL DEVICE RELEASE CRITERIA

Medical device regulations relating to stability, both in the US and oUS, are concerned with design review.

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• The short list for Design Review: • Quality Systems Requirements • ISO 13485 Requirements • ISO 9000 Requirements

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US MEDICAL DEVICE REGULATIONS

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• FDA - QSR 21 CFR Subpart K--Labeling and Packaging Control

• Sec. 820.120 Device labeling. Each manufacturer shall establish and maintain procedures to control labeling activities. (a) Label integrity. Labels shall be printed and applied so as to remain legible and affixed during the customary conditions of processing, storage, handling, distribution, and where appropriate use.

• Sec. 820.130 Device packaging. Each manufacturer shall ensure that

device packaging and shipping containers are designed and constructed to protect the device from alteration or damage during the customary conditions of processing, storage, handling, and distribution.

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oUS MEDICAL DEVICE REGULATIONS

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ISO 13485:2003(E) 7.5.5 Preservation of product The organization shall establish documented procedures or documented work instructions for preserving the conformity of product during internal processing and delivery to the intended destination. This preservation shall include identification, handling, packaging, storage and protection. Preservation shall also apply to the constituent parts of a product.

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US & oUS CONSENSUS STANDARDS

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ISO 11607-1:2006(E) 6.4 Stability testing 6.4.1 Stability testing shall demonstrate that the sterile barrier system maintains integrity over time. 6.4.2 Stability testing shall be performed using real-time aging. 6.4.3 Stability testing, using accelerated aging protocols, shall be regarded as sufficient evidence for claimed expiry dates until data from real-time aging studies are available.

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US & oUS CONSENSUS STANDARDS

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ISO 11607-1:2006(E) 6.4 Stability testing continued 6.4.4 Real-time and accelerated aging tests should begin simultaneously. 6.4.5 When expiry dates are based upon product performance, stability testing for expiry dating should be conducted along with package stability testing.

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When Do We Start Evaluating a Device for Stability Testing?

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• Testing strategies should be identified while the project is still in the concept stage.

• Waiting can be catastrophic to timelines.

– All sterile parts! – Non-sterile items? For

example batteries and oils experience performance degradation over time

– What about raw materials, manufacturing materials, components? (ex. HDPE granules, sterile gloves, temperature indicating labels)

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How Do We Decide What To Do For Device Stability Testing?

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• Strategic Testing • Early Risk Assessments • Stability Families • QbD Concepts

• Forced Degradation Studies • Understand The Product • Understand The Risks

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Quality by Design (QbD)

• The foundation of Quality by Design is to establish process understanding and link it to product reproducibility.

• How do we apply this to Medical Devices?

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How Does QbD Fit into the Stability Validation?

Plant Operations

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DEFINE • What are the unknowns?

– Chemical Degradation – Physical Degradation – Microbial Degradation – Therapeutic Degradation – Toxicological Degradation

• We must understand the risks! • What is the desired design space?

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DESIGN • What is the product quality

profile? • What are the Critical

Material & Quality Attributes (CMA’s & CQA’s)?

• How do we prevent? – Chemical Degradation – Physical Degradation – Microbial Degradation – Therapeutic Degradation – Toxicological Degradation

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Forced Degradation / Stress Testing

• Borrow tool from Pharmaceuticals to apply to Devices • Forced decomposition using extreme conditions

– Temperature • heat • freeze/thaw

– Chemical • pH • high oxygen tension • hydrogen peroxide oxidation • ozone oxidation

– Sterilization Methods – Humidity

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• Is a well controlled or understood production process required?

• What are the Critical Process Parameters (CPP’s)? –Equipment Requirements –Process Requirements –Environmental Requirements

CONTROL

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IDENTIFY • Determine what to control (worst cases) in the

protocol?

• Product related

• Process/equipment related

• Environmental related

• Package related

• Distribution/storage related

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A design window large enough to fly a Pterodactyl through!

• Checklists

• Up front testing

• Forced Degradation Studies

• Lots of well characterized:

• Materials

• Processes

• Packages

• Defendable sampling and testing plan during stability protocol – NLT 95% Confidence & 95% Probability

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CMA/CPP/CQA in medical devices

• Risk Tables

• Tiered risk assessment approach

• Raw Materials

• Equipment/Processes

• Distribution/Storage

• Patient Impact

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Known Unknowns?

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How to Identify Unknowns • Develop a checklist based on FDA CDRH device

guidance • www.fda.gov/downloads/medicaldevices/deviceregulationandguidance/guidancedocuments/ucm081366.pdf

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Use Information From Other Sources

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The article includes a nice set of references!

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Understanding Risk!

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• Which activity has a higher risk? • Conducting full scale stability testing

Expensive Resource intensive Possible late stage failures Missed launch dates

• Approving a Stability Adoption Cheap Fast Failure is not an option Launch date is a slam dunk!

HC SVNT DRACONES

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Risk vs. Gambling

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• Deciding to limit stability testing when…

• Data on sample/testing cost is available

• Data on environmental sensitivities is limited

• Data on production processes is limited

• Data on test methods is limited

• Data on interactions is limited

• Data on materials is limited

• Scientist/Engineer Opinion

• = “Bet the farm on Red 7”

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Resisting the pressure to gamble

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• High cost of samples and testing • Long duration • Complexity of the testing • Lack of onsite testing facilities and expertise • C-Suite psychology

• “Overconfidence is a powerful source of illusions, primarily determined by the quality and coherence of the story that you can construct, not by its validity. If people can construct a simple and coherent story, they will feel confident regardless of how well grounded it is in reality.”

McKinsey Quarterly 2010

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It is imperative that we understand our products

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• If it is not our companies knowledge (IP) it will eventually be some ones:

• Patients • Doctors • Competitors • Regulating Agencies • News Agencies • Lawyers

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Final Message? • It is our responsibility to

make sure we don’t misunderstand our medical device stability risk!

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THANK YOU FOR YOUR ATTENTION

• Thanks to my team! • Matt Zagorski • Lynne Fulton

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