Safe Handling of ADCs in R&D and Manufacturing

36 Pages·2013·8.65 MB·English

Safe Handling of Antibody-Drug
Conjugates in R&D and Manufacturing

Antibody Drug Con jugate Workshop

26 June, 2013
Cambridge, U.K.

Justin Mason-Home
Managing Director

SafeBridge Europe, Limited

Mountain View, CA  New York, NY  Liverpool, UK
www.safebridge.com
SafeBridge Consultants, Inc.
Scientific Solutions to Safety Challenges
 Global leaders in potent compound safety
 Experts in risk assessment for product protection
 Group of environmental health and safety
professionals with expertise in:
 Toxicology
 Industrial hygiene (occupational hygiene)
 Analytical chemistry
 Safety
 Occupational medicine
Occupational Health and Safety in
ADC Facilities Design
 ADCs are (bio)pharmaceutically active
substances, the components of which
are hazardous substances
 The principles used in pharmaceutical
occupational health and safety can be
applied directly to ADCs
Handling (Bio)Pharmaceutical
Compounds is a RISKY business!
 Handling potent pharmaceuticals is a risky
business
 Consequences of mishandling can be
severe
 There are no SENSORS to measure for
potent compounds
 Contrast extensive product quality data
versus often limited or no exposure control
data – Why?
Elements of a Comprehensive Occupational
Health Program
 Compound occupational health hazard category
linked to control
 General and specific handling guidance
 Primary importance of engineering controls
 Occupational Exposure Limits (OELs)
 Sensitive OH analytical methods
 Design to Contain and Control
 OH exposure and control performance testing
 Training and Medical Surveillance
Occupational Exposure Limit (OEL)
 An acceptable level for an 8-hour day and 40-
hour work week; similar to OSHA PEL or
ACGIH TLV
 OEL is developed to protect even sensitive
subgroups, e.g., women of child bearing
capacity
 Developed when a drug reaches significant
manufacturing amounts or critical FDA stage
 Simultaneous development of sensitive
analytical method for occupational hygiene
monitoring
Examples of OELs
Drug/Material OEL
Naproxen (NSAID) 5,000 g/m3
Nicardipine (cardiac drug) 400 g/m3
Isotretinoin (Accutane for acne) 5 g/m3
Paclitaxel 0.8 – 10 g/m3
Fentanyl (synthetic opiod) 0.5 g/m3
17β-estradiol (natural estrogen) 0.1 g/m3
Flunisolide (corticosteroid) 0.07 g/m3
Ethinyl estradiol (synthetic estrogen) 0.035 g/m3
Camptothecin (anti-cancer) 0.03 g/m3
Nafarelin (peptide hormone) 0.001 g/m3
ADC Payload OELs?

 Doxorubicin and derivatives
 Duocarmycin
 Maytansinoids
 Auristatins
 Calicheamicin
 CC-1065
 PBDs

Seattle Genetics – “Our auristatins, a class of microtubule-
disrupting agents, are 100- to 1,000-fold more potent than
traditional chemotherapy drugs in preclinical models”

Benchmark OELs – 0.005 – 0.1 µg/m3
Occupational Potency and Toxicity of
Biologics
Originally thought to be reasonably safe to handle

large molecules

Dermal = poor

Ingestion = poor

Inhalation ??

Injection ?? (Needlestick?)

Target organ toxicity

Irritation potential

Sensitization potential

Sensitization Potential of mAb
 Is this really an immune response?
 The immunogenicity of a mAb varies with the amount
of murine material it has
 As more “humanized” and “fully human” mAbs are
developed will this continue to be a concern?
 Phage display technology produces a molecule with
neither non-human components nor artificially fused
human sequences – ie all human components