A B O U T R & Q

Regulatory and Quality Solutions (R&Q) provides industry-leading regulatory and quality engineering services throughout the entire product lifecycle.

A B O U T I U V O B I O S C I E N C E

iuvo BioScience is a contract research organization serving the pharmaceutical and medical device industries. With a focus on safety and biocompatibility, iuvo

provides assistance through the full product development life cycle, from research to release, in the areas of GLP-compliant toxicology, microbiology and

analytical chemistry testing laboratories along with contract ethylene oxide sterilization.

A B O U T T O D A Y ’ S S P E A K E R S

Focused on the product development lifecycle

CAPA and complaint systems, design control processes, and International approval(510k, PMA, CE)

Auditing quality systems against ISO and QSR regulations

Christine Santagate, RAC, Client Solutions Advisor

A B O U T T O D A Y ’ S S P E A K E R S

Director of Analytical Chemistry at iuvo BioScience with analytical development experience at Pharmacia, Pfizer, and Bausch + Lomb

15 years’ experience in design, execution, interpretation, and registration of E&L studies

Member of the PQRI Working Group on E&L in Parenteral and Ophthalmic Drug Products

Chris Houston, PhD, Director of Analytical Chemistry

A G E N D A

Device Definition

Material Selection

Test Selection Considerations

Test Construct

Design Changes

Excluded Devices

Combination Products

M E D I C A L D E V I C E D E F I N I T I O N

"an instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or other similar or related article, including a component part, or accessory which is:

recognized in the official National Formulary, or the United States Pharmacopoeia, or any supplement to them,

intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment, or prevention of disease, in man or other animals, or

intended to affect the structure or any function of the body of man or other animals, and which does not achieve its primary intended purposes through chemical action within or on the body of man or other animals and which is not dependent upon being metabolized for the achievement of any of its primary intended purposes."

B I O C O M P A T I B I L I T Y

Biocompatibility answers two fundamental questions:

Is the material safe?

Does it have the necessary physical and mechanical properties for its proposed function

The extent to which a material needs to be characterized depends on :

Type of Material

End use of the device

Function of the material within the device

Availability of existing data on the material

M A T E R I A L S E L E C T I O N

Biocompatibility is ultimately a function of a completed device, so it encompasses all of its components, assembly processes and overall design and must be considered at design onset.

Use known biocompatible materials

Individual components as well as overall packaging must be considered.

Material testing is performed to determine toxicity of the material, leachable substances and degradation products.

When selecting materials, ask if the manufacturer has performed component level biocompatibility.

Thoughtful material selection can help ensure the overall biocompatibility of a finished product.

E&L Overview - Pharma

• Nuts and boltso Pharma definitions – focus on packagingo Plastic additiveso Beginning with the end in mind

Guidelines, working group outputs, etc.• Experimental considerations

o Special caseso Case studies

Definitions in the Pharma Space

• Extractable: A chemical species that can be removed from an individual packaging component by force (solvents). Extractables are potential drug product impurities.o Simulation studies generate extractables using realistic mimics of drug

products – analogous to leachables in the medical device space.• Leachable: An extractable that migrates into drug product under nominal

conditions. Leachables are generally a practical subset of extractables –they are the substances that affect quality, safety, and/or efficacy.

• Migrants: Extractables that cross a physical barrier to enter the drug product (e.g., those from secondary packaging).

• Primary Packaging: Make direct contact with thedrug product.

• Secondary Packaging: Do not make directcontact w/ product.

Extractables

Leachables

Plastic Additives – Why?

• Antimicrobials

• Antistats

• Colorants / opacifiers

• UV blockers

• Optical brighteners

• Light stabilizers

• Slip agents: e.g., glycerol monostearate

• Plasticizers: e.g., diethylhexyl phthalate (DEHP)

• Antioxidants

o Primary: e.g., hindered phenols as free radical scavengers, long term stabilization (BHT, Irganox 1010, 1076, 3114)

o Secondary: e.g., trivalent phosphorus compounds, hydroperoxidescavengers, sacrificial process stabilization (Irgafos 126, 168)

Additives allow the material to perform as required

Pharma E&L Concerns – Where It All Began

• Late 1980s and into the 1990so Replacement of chlorofluorocarbons (CFCs) in metered dose inhalers (MDIs)

with hydrofluorocarbons (HFCs)o CFC and HFC propellants are strong organic extraction solventso In the MDI world, “all extractables are leachables”

• Orally inhaled and nasal drug product (OINDP) concerns based on agents present in elastomeric gasket/valve componentso Polyaromatic hydrocarbons (PAHs) / polynuclear aromatics (PNAs)

In carbon black used as a filler in sulfur-cured elastomerso N-nitrosamines

Derived from curing agents for vulcanized componentso 2-mercaptobenzothiozole (2-MBT)

Elastomeric curing agento All substances recognized as genotoxic at low levels

• Concern: compounds efficiently leached by MDI formulations and dosed directly to the diseased organs of a sensitive patient population

Norwood, Nagao, Stults. PDA J Pharm Sci and Tech 2013, 67 413-429

FDA Guidelines – Focus on OINDP

• Metered Dose Inhaler (MDI) and Dry PowderInhaler (DPI) Drug Products (DRAFT, 1998)o Still in draft state

• Container Closure Systems for PackagingHuman Drugs and Biologics (May 1999)o Introduces concept of risk based on dosage form and route of administration

(next slide)o Focus on OINDP, few specifics for other routes of administration

• Nasal Spray and Inhalation Solution, Suspension, and Spray Drug Products (July 2002)

• Inhalation Drug Products Packaged in Semipermeable Container Closure Systems (DRAFT, July 2002)o Concern over label components migrating into DP through LDPE

• None of these documents provide practical guidelines on how low to test for leachables: this is a critical question for analytical chemists

chris.houston@iuvobioscience.com

Thank you!

csantagate@rqteam.com

RQTeam.com iuvobioscience.com