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!