Developing and Maintaining Safe Working Environments...
Transcript of Developing and Maintaining Safe Working Environments...
Developing and Maintaining Safe Working Environments in
ADC Facilities
Justin Mason-Home, FRSCManaging Director
SafeBridge Europe, Limited.Mountain View, CA • New York, NY • Europe (UK)
www.safebridge.com
SafeBridge Consultants, Inc. Group of environmental, health and safety
professionals with expertise in: toxicology safety occupational hygiene analytical chemistry occupational medicine developing programs to recognise, evaluate and
control occupational exposures to potent pharmaceuticals
Expertise is in pharmaceutical safety and health consulting (150 person-years experience) Offices in SF Bay Area, New York City & Europe
(Liverpool, UK)
Two SafeBridge Offices in the U.S.
Mountain View, CA New York, NY
SafeBridge Europe, Ltd.Liverpool, England
Developing and Maintaining Safe Working Environments in ADC
Facilities
ADCs are (bio)pharmaceutical substances, the components of which are hazardous substances
The principles used in pharmaceutical occupational health and safety can be applied directly to ADCs
Format
Presented material - Interactive Hazard Assessment Exposure Risk Assessments Facility Design Matters
Potent Compound Safety Video Conceptual Design Practical Exercise in Groups
Handling (Bio)Pharmaceutical Compounds is a RISKY business!
Handling potent pharmaceuticals is a riskybusiness
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?
Are EH&S Considerations Important to Product Development?
Managing Liability and Productivity
Effect on Speed-To-Market
Competitive Advantage
Third Party Relationships
People, Ethics and Compliance
Current BiopharmaceuticalBusiness Climate
Many “start-ups” with new technologies and new compounds push for “speed to market”
Many “alliance” partnerships between big and small firms
Outsourcing of services Contract development organisations Contract manufacturing
Team Approaches to Projects/Products Environmental Health and Safety (EH&S) not usually included as members Lean Organisations - less EH&S staff per employee
Current Product Development Trends in Biopharmaceuticals
Many products are chemical structures closely related to compounds which naturally occur in the body
Potential exposure to highly active drugs - most therapeutic doses in microgram quantities
Structures have been altered so they have the following biological effects: more active than naturally occurring compounds longer duration of action in the body than the naturally
occurring compound Support products (diagnostics, screening devices,
analytical) may involve handling of potent compounds
What Does it Look Like When it Goes Right?
The manufacturer of the product understands the nature of the product and its hazards
The manufacturer has the knowledge and capability to handle the product safely
The manufacturer takes appropriate control measures
Product is delivered on-time, on-budget and with high quality to specifications
No employee incidents, exposures or accidents No environmental impairment No liability or regulatory issues
What Does It Look Like When It Goes Wrong?
Production delays Over budget Poor quality and off specification HSE, EPA, FDA involvement Worker health effects and/or concerns Accidents Environmental impact Resultant legal action, citations, insurance claims Third party issues Lost competitive advantage and market share
How do you Manage EH&S in theProduct Process?
Develop a systematic approach Integrate EH&S matters into projects
Effective technology transfer Use technical professionals knowledgeable in the areas
of occupational hygiene, occupational toxicology, safety engineering, analytical chemistry and related disciplines
Recognise the business benefits of this type of approach and train your management organisation productivity competitive advantage quality professionalism
Elements of a Comprehensive Occupational Health Program for Potent Compounds
• General and specific safe handling guidance• Primary importance of engineering controls
• Development of Occupational Exposure Limits (OELs)• Occupational Health Categorisation for early stage
molecules• Develop sensitive analytical techniques for high
potency compounds• OH exposure assessment• Improve exposure controls based on data• Verification of controls• Medical surveillance• Training and SOPs• Risk communication
Business Advantages of a Comprehensive Program
Prevention of occupational illnesses “No surprises” to divert management attention Increase speed to market
Anticipate environmental regulatory data requirements
Reduced reliance on personal protective equipment Fewer employee issues Support of third parties Reduced vulnerability to regulatory citations
Potential of Pharmaceutical Substances to Cause Occupational Illness
Historical Examples Sex Hormones Opiates Antibiotics Prostaglandins “Cytotoxic” Drugs NCEs
Hazard Assessments
Small molecule cytotoxic compound mAb Other biologically active biomolecules Linker hazard
Small Molecule “Cytotoxic” Hazard
Occupational Exposure Limits (OELs)
An acceptable level for a 40-hour work week or short term exposure; similar to UK WEL, OSHA PEL or ACGIH TLV
OEL is sometimes developed to protect even sensitive subgroups, e.g., women of child bearing age
Developed when a drug reaches significant manufacturing amounts or critical FDA stage
Simultaneous development of sensitive analytical method for occupational hygiene monitoring
Traditional Formula for Establishing OELs Using Uncertainty Factors
OEL = NOAEL x BWUF1,2,… x PK x V
where:NOAEL = No Observed Adverse Effect LevelBW = Body WeightUF 1,2,…= Uncertainty FactorsPK = Adjustment for pharmacokineticsV = Volume of air inhaled in an 8-hour day (10 m3)
Examples of Small Molecule OELsDrug/Material OEL Naproxen (NSAID) 5,000 µg/m3
Nicardipine (cardiac drug) 400 µg/m3
Isotretinoin (Accutane for acne) 5 µg/m3
Paclitaxel (anti-cancer) 0.8 – 10 µg/m3
Fentanyl (synthetic opiod) 0.7 µg/m3
Thalidomide 0.25 µg/m3
17β estradiol (natural estrogen) 0.1 µg/m3
Ethinyl estradiol (synthetic estrogen) 0.035 µg/m3
Camptothecin (anti-cancer) 0.03 µg/m3
Leuprolide (peptide hormone) 0.02 µg/m3
Nafarelin (peptide hormone) 0.001 µg/m3
ADC Payload OELs?
• Doxorubicin + derivatives• Duocarmycin• Maytansinoids• Auristatins• Calicheamicin• CC-1065• PBDs• IBDs
• Adozelsin• Carzelesin• Bizelesin• SJG-136• TP004
SeaGen – “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 => 5 – 100 ng/m3
Early Stage Molecule Hazard
Occupational Health Categorisation and Handling Practice System
A systematic means to group materials by their HAZARD and RISK OF EXPOSURE so that suitable CONTROL can be defined and applied where traditional tools (OELs, monitoring methods) are unavailable
Created by Pharmaceutical Safety Group (PSG) subgroup on potent compound handling
Used to communicate risks and to establish consistent control approaches within an organisation
Similar systems are common in pharma industry
Where do you get Hazard Information?
The Safety Data Sheet (SDS) R and S phrases in the past H and P phrases now
The Regulator The supplier! A Toxicologist
Anticipated mechanism of action
Anticipated or current therapeutic indication
Anticipated or current dose
Toxicology data – critical endpoints are “CMRs”
Drugs that may be comparable – similar structure or mechanism of action
Most Critical Data for Determining which Category or “Band”
Toxicity/Potency Categorisation of Chemicals (SafeBridge System)
Category 1: Low ToxicityOEL >0.5 mg/m3 (aspirin)
Category 2: Intermediate ToxicityOEL 10 µg/m3 - 0.5 mg/m3 (insulin, oxycodone)
Category 3: Potent (default)OEL 30 ng/m3 - 10 µg/m3 (estradiol 17-β, paclitaxel)
Category 4: Highly potentOEL < 30 ng/m3 (nafarelin, leuprolide, sufentanyl)
1 2 3 4BAND
OELContinuum of Potency
1 2 3 4BAND
OELContinuum of Potency
1 2 3 4BAND
OELContinuum of Potency
1 2 3 4BAND
OELContinuum of Potency
1 2 3 4BAND
OELContinuum of Potency
Gatekeeping
“Category 3” – What system? The base data on which to form risk assessments
and drive processesOften poorly practised; frequently not translated
effectively into control SDS or NDDS?Get the right data early – technology transferMake safety part of the process and even part of the
contract
Biological Molecule Hazard
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
Concern for Sensitization Potential
HMW proteins Food allergies
Eggs Peanuts
Environmental allergens Latex Pollens Dust mites Animal dander
Risk Assessment Methodology
Toxicologists are still miles away from recommending OELs for respiratory allergens based on animal studies
The presence of dose-response relationship and NOELs in sensitized and challenged animals suggest that assessment of safe levels of exposure is feasible
Clinical Reactions with Infliximab
Acute infusion reactions seen in 5% When rate of infusion decreased, fewer
reactions If it occurs at first infusion, cannot be allergy No objective evidence of allergic response
No wheezingNo elevated IgE serum levels
Very few patients develop delayed reactions Arthralgias, myalgias, fever all resolve without
treatment
Clinical Reactions with Infliximab
Dose = 5 mg/kg 250-350 mg/dose Not potent by most criteria However, MW = 150 kDa Consider number of molecules (0.2% of
equivalent weight of penicillin) ie 1/500th dose?
Sensitization potential of other drugs Penicillin 10% (of hospitalized patients) Procainamide 15-30% Vancomycin 50-90%
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? Newer technologies available to produce
molecules with neither non-human components nor artificially fused human sequences – ie all human components
Clinical v. Occupational Allergy
If clinical use leads to the induction of a true allergic response, can occupational exposure lead to subsequent reaction?
Can occupational exposure lead to induction of a true allergic response on its own?
Biological Molecule OELsMaterial OEL Insulin 100 µg/m3
mAbs 1 - >100 µg/m3
Payloads (for comparison) 0.005 – 0.1 µg/m3
Nafarelin (peptide hormone) 0.001 µg/m3
Don’t forget the conjugate itself!
Exposure Risk Assessments
Hierarchy of Control
Elimination Substitution Engineering controls (“hardware”) Administrative controls (“software”) Personal Protective Equipment
PPE RPE
Factors Leading to Significant Exposures
Physical form of the material Labour intensive steps
manual transfer of materials weighing active materials
High energy operations milling, sizing, fluidising, spraying over-pressurisation
Poor work practices carelessness or lack of awareness
Cleaning and maintenance operations
Routes of Occupational Exposure(Small Molecule)
Inhalation Dermal Absorption Ingestion Inadvertent Contact with Skin & Mucous Membranes
Exposure PathwaysSource – Pathway – Target
Source
Pathway
Target
“MASS TRANSPORT”
Handling Practice Guidelines
For each Category (1-4), a handling practice should be developed based on experience of the type of technology available and exposure for different working environments:
Laboratory Operations
Pilot Plant and Production Operations
Laboratory Handling Practices Category 3
Work Environment A designated area for handling compounds Work surfaces are to be cleaned daily; if absorbent paper is
used it should be changed daily No open handling of powders should be a priority; powder
handling should be done in a powders weighing hood, a glove box or other approved ventilation system
Solutions can be handled outside a containment system or without local exhaust ventilation during procedures with no potential for aerosolisation
PPE Appropriate gloves, lab coat, safety glasses Respirator selection appropriate to task
Laboratory Handling PracticesCategory 4
Work Environment A designated area for handling compounds required Work surfaces are to be cleaned daily; if absorbent paper is
used it should be changed daily No open handling of powders; work only to be done in
isolators, gloveboxes or approved ventilated enclosures Powder should be put into solution or tightly capped
container for transfer Local exhaust not required for solutions containing <100
mg if no potential for aerosolisation PPE
Appropriate gloves, lab coat, safety glasses Air purifying respirators must be worn by all personnel in
the immediate area if engineering controls are unavailable
Production/Pilot Plant Handling Practices Category 3
Work Environment High degree of process containment, enclosure, local
exhaust ventilation, and/or isolation/barrier technology
Negative/positive air and buffer zones required Closed material transfer, no open handling Production change areas Controlled access
PPE Category 1 plus: PAPR or air-supplied respirator with loose fitting
facepiece specifically selected chemical protective clothing
Production/Pilot Plant Handling Practices Category 4
Work Environment Total process containment/isolation Separated/dedicated work areas Secured and restricted access Highly specialised ventilation system Failure protection Clean in place; automation emphasis
PPE Category 3 for exposure situations
Break
ADC Facility Design Matters
Define Control Objectives (Examples) Process emissions are to maintained at or below a
limit value “x” µg/m3 through the use of effective engineering controls.
All routine potential exposures will be controlled to below the OEL (or fraction of the OEL).
Actual exposures will be controlled to within the assigned protection factor of respiratory protective equipment used.
Time weighting will not be used to achieve the control objective.
Migration of material out of processing rooms will be prevented
What Control or Containment at What Point?
• Know the hazard• Identify potential exposure points• Identify exposure risk factors
• Quantities• Physical Form• Frequency• Operational matters (mass transport drivers)
• Select containment for higher risk, higher hazard activities
• Select other types of control for lower risk activities
• Verify that control or containment is effective
ADC Facility Design Elements
Smooth and logical material and personnel flows Access, Ingress and Egress arrangements Negative differential air pressure in processing
rooms relative to surrounding areas. Room air locks/anterooms are recommended
• Provide an air pressurisation barrier• Serve as a gown/degown area• One-way personnel traffic
Recirculation of air into non-production areas is not permitted
HEPA filtered room air exhaust not be recirculated
Facility Design Elements (2)
• Specify appropriate control devices• Designated areas should be posted with
appropriate notification and hazard warning• Controlled access to the work area is required.
• Locker rooms and showers contiguous with processing/work areas are recommended for manufacturing suites.
• Air showers are not recommended• Mist/water showers are preferred and
recommended.
Traditional Engineering Controls Approaches
Ventilation engineered local exhaust
• at emissions points• effective to 100 µg/m3
laminar flow (hoods) directionalised laminar flow (booths)
• may be effective to 50 µg/m3 for less dusty operations
Other enclosures of specific parts and containers vacuum transfer
Articulating Arm Connections
Supports the hood
Provides ability to move hood into position and out of the way
Advanced Engineering Control Approaches
Process containment barriers/isolators (equipped with RTPs) bag techniques (bag w/in a bag) specialised connectors and valves (SBVs)
Closed transfer systems Low energy transfer systems CIP/WIP Systems
Ventilated enclosures Powder handling enclosures Enclosures for subdividing, filling, sizing
IsolatorsWeighing and Dispensing, Solution Make-Up, Product
Charging
Design Features - Transfer Systems- Airlock
- Bag in/Bag out Port- Rapid Transfer Port (DPTE®)
Potent Compound Charging
Charge Vessels Handling active materials
safely around the plant Handling lubricants and
additives Providing viewing access Access for sampling or
cleaning Suitable for automated
docking Incorporate VibroflowTM
discharge aide
Reactor
Charge drum
Active
Passive
Ventilated Balance Safety Enclosure®
Ventilated Enclosure for Drying, Sampling, Weighing and/or Subdividing
Administrative Controls “Software”
“Software” in this context is how you operate the “hardware”
PEOPLE
TRAININGSOPs
CULTURE
TECHNIQUE
MANAGEMENT SYSTEMS
Personal Protective Equipment
Powered air purifying respirators (PAPRs)
• With combination cartridges
• Hood covering
Skin protection
• Tyvek® coveralls and sleeve covers
• Booties
• Double gloves
Workplace Testing
Analytical Methods
Requires sensitive air (and wipe) sampling analytical methodologies
Requires very sensitive analytical methods RIA ELISA HPLC LC/MS/MS
Data analysis calculate and compare to CPT or OEL Statistics and confidence levels
Report and Recommendations Periodic reassessment
Analytical Targets
Preferred 10% of the OEL/CPT in a 15 minute sample
Acceptable 20% of the OEL/CPT in a 60 minute sample
Minimum 50% of the OEL/CPT in a 240 minute
sample
Analytical Method Validation
Must have all standard validation parameters Detection limit, precision specificity Extraction, collection, retention efficiencies Storage effects
Plus Recovery studies at various flow rates for air
monitoring methods
Recovery studies off of different materials of construction for surface methods
Method Development
Analytical Procedure Sampling Procedure Effects of Storage Overall Quantitation Limit (eg 75% recovery;
precision of ±25% )
Need: Certified standard Any method information eg out of QA Description of HPLC or other method used by QA or QC lab; Physico-chemical properties Impurity information
Containment (or Control) Performance Testing
Objective To evaluate the containment performance of a
containment device against a containment performance target (CPT)
Method API: or Simulated use of the containment device using a
surrogate material FAT and SAT
Containment Performance Target (CPT)
Containment testing against a CPT should not be confused with occupational exposure limit (OEL) compliance testing.
Containment performance testing evaluates device performance, not operator exposure and is based on concentration over the period of contained operation, not an 8-hour exposure.
ISPE Guidelines
ISPE Good Practice Guide:
“Assessing the Particulate Containment Performance of Pharmaceutical Equipment.”
Surrogate Containment Performance Testing
Imitate the operation as closely as possible using surrogate. Normal usage conditions Usual quantities of material Imitate operations conducted
Measure at likely leakage points Evaluate at least three times.
try to use three different operators.
Surrogate Materials
Lactose Naproxen sodium Mannitol Paracetamol (Acetaminophen)
Occupational Hygiene Exposure Assessment
Develop a sampling strategy ISPE guide for device testing
Personal and area monitoring Identify representative and maximal case exposures Compare results to OEL or CPT Recommend improvements Communicate results
Communicate the Results
In the UK it is a regulatory requirement (COSHH Reg. 12) to communicate the results of any personal monitoring, especially if an OEL has been exceeded
Risk communication is in itself a risky business!
Results are all OK…..When do I test Again?
Good question! Start somewhere and keep going Use data obtained to inform frequency of testing Share data internally and externally Determine control performance in your hands
Other techniques Have the process “drive” the control strategy – not
the other way round Use a range of other techniques:
Excellent training Excellent SOPs Develop a “risk aware” workforce Medical surveillance
Developing a Systematic Process to Handling Chemicals
Identify hazard potential of incoming via compound questionnaire, SDS, Literature review, etc.
Develop occupational health categorisation for compounds
Institute control measures based on category/experience
Develop written SOPs for handling & disposal Implement employee training program in safe
handling Develop OEL and air monitoring method to verify
control measures and work practices
Developing a Systematic Process to Handling Chemicals (continued)
Verify process through: Periodic assessment Air monitoring and control implementation Health surveillance Maintenance and testing of controls
Summary
Biopharmaceutical companies are developing more potent/novel drug products
Incoming compounds and products present unknown risks
Business success may hinge on EH&S aspects A comprehensive and innovative program to control
exposures to these products has many elements. Systematically involve EH&S early in the process
and implement EH&S recommendations Make informed choices about risk acceptance Build into your entire business culture - the most
successful companies do!