Potent Compound Awareness Training

Transcription

1 Potent Compound Awareness Training Lillian Fry, CSP Sr. Industrial Hygiene and Safety Consultant Southborough, MA SafeBridge Consultants, Inc. Mountain View, CA New York, NY Europe, UK A TRINITY CONSULTANTS COMPANY

2 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

3 Trinity Consultants, Inc.

4 Objectives To discuss the nature of potent compound and understand their potential hazards To explain how exposure potential is determined To understand safe handling procedures To discuss control options for working safely with potent compounds To answer your questions and address your concerns

5 Physiological Adverse Effects Pharmaceutical molecules are developed for their biological activity Pharmacological effect of the drug is considered adverse in workers Biological effect may be different in disease-state patients and non-disease state workers Handling potent pharmaceuticals is a risky business No real-time detectors unable to use senses

6 Pharmaceutical Substances Can Cause Occupational Illness Historical Examples Sex Hormones Opiates Antibiotics Prostaglandins Cytotoxic Drugs

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8 Comprehensive Occupational Health Program for Drug Substances Compound categorization scheme General and specific safe handling guidance Implementation of controls Occupational Exposure Limits (OELs) Sensitive IH analytical methods IH exposure assessment Verification of control performance Improve control based on data Training Medical surveillance

9 Occupational Exposure Limits (OELs) An acceptable level of airborne exposure for a 40-hour work week; similar to PEL or ACGIH TLV OEL is usually developed for healthy workers but can consider sensitive subgroups (e.g., women of child bearing age, asthmatics, etc.) Developed when a drug reaches significant manufacturing amounts or critical FDA stage Simultaneous develop sensitive analytical method for industrial hygiene monitoring

10 Traditional Formula for Establishing OELs OEL = where: NOEL TD BW UF C PK Using Uncertainty Factors NOEL x BW UF C x PK x V = No Observed Effect Level = Therapeutic Dose = Body Weight or = Uncertainty Factors TD UF C x PK x V = Adjustment for pharmacokinetics V = Volume inhaled in 8-hour day (10 m 3 )

11 Examples of OELs Drug/Material OEL Naproxen (NSAID) 5,000 µg/m 3 Nicardipine (cardiac drug) 400 µg/m 3 Cyclosporin A (transplant rejection) 20 µg/m 3 Ganciclovir (genotoxic antiviral) 5 µg/m 3 Paclitaxel (genotoxic anticancer) µg/m 3 Thalidomide µg/m 3 Tamoxifen (genotoxic anticancer) µg/m 3 Cisplatin (genotoxic anticancer) µg/m 3 Ethinyl estradiol (estrogen) µg/m 3 Campothecin (genotoxic anticancer) µg/m 3 Nafarelin (peptide hormone) µg/m 3

12 IH Sampling and Analytical Methods Develop analytical method Both air and surface measurements HPLC, LC/MS or ELISA Need to be very sensitive with some detection levels in the sub-nanogram range. Develop a sampling strategy Identify representative and maximal cases Careful observation of controls and work practices Compare to OEL Recommend improvements Communicate results

13 Air Monitoring Survey

14 Occupational Health Categorization and Handling Practice System Created by Pharmaceutical Safety Group (PSG) subgroup on potent compound handling Systematically addresses exposure situations where traditional tools (OELs, monitoring methods) are unavailable Toxicity and potency characteristics linked to safe work environments Used to communicate risks and to establish consistent control approaches within an organization

15 Compound Categorization Pharmaceutical companies place compounds into categories based on their hazard profile Category 1: Low Toxicity / Potency Category 2: Intermediate Toxicity / Potency Category 3: Potent / Toxic Category 4: Highly Potent / Highly Toxic

16 Category 1 of 4 Material Hazard Criteria* Most Important Factors Irritants Low acute/chronic systemic effects (reversible) Low potency No CMRs Pharmacological mechanism of action Other Considerations Immediate onset of symptoms (minutes to hours) Good warning properties * One or more of the above criteria may place a material into this category

17 Category 2 of 4 Material Hazard Criteria* Most Important Factors Moderate to high acute toxicity / Moderate chronic toxicity Reversible systemic effects / Low severity No CMRs Pharmacological mechanism of action Other Considerations Includes corrosives and up to moderate sensitizers Poor or no warning properties Onset of symptoms immediate or delayed Moderate degree of medical intervention required * One or more of the above criteria may place a material into this category

18 Category 3 of 4 (default category) Most Important Factors Material Hazard Criteria* Pharmacological mechanism of action Serious acute / chronic / irreversible systemic effects Potency ( 1 mg/kg/day in animals; 10 mg clinical dose) CMRs Potent sensitizers Other Considerations Poor or no warning properties High degree of medical intervention required Immediate and delayed onset of symptoms Well absorbed by one or more route * One or more of the above criteria may place a material into this category

19 Category 4 of 4 Material Hazard Criteria* Most Important Factors Pharmacological mechanism of action Severe acute / chronic / irreversible effects Super potent ( 70 µg/day dose clinically; 10 µg/kg/day in animals) CMRs May affect sensitive subpopulations (e.g. asthmatics) Other Considerations Poor or no warning properties High degree of medical intervention required Immediate and delayed onset of symptoms * One or more of the above criteria may place a material into this category

20 Compound Examples Non-steroidal anti-inflammatory (NSAID) Low acute oral toxicity Irritant Gastrointestinal, kidney effects at high doses Not a CMR Category 1 OEL = 5 mg/m 3 Cardiac Drug Irritant Affects heart rate Reversible kidney effects, hypotension Not a CMR Category 2 OEL = 50 µg/m 3

21 Compound Examples Steroid hormone In women - may cause deepening of voice, acne, increased facial hair, infertility In men - may cause gynecomastia, decreased libido, testicular effects Category 3 OEL = µg/m 3 (industry range) Prostaglandin Affects GI motility Abortifacient (causes miscarriage) Affects asthmatics; Category 4 OEL = µg/m 3

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23 Medical Surveillance Screening for at risk health conditions (e.g., blood disorders, liver, pregnancy) Early detection of adverse health effects from drugs handled Prevent or limit adverse health effects Another layer of protection Should target anticipated effects in the workforce Report and intervene early

24 Continuum of Potency OEL BAND

25 Continuum of Potency OEL BAND

26 Classical Risk Assessment Source Pathway Target Pathway Source Target

27 Routes of Occupational Exposure Inhalation Dermal absorption Inadvertent contact with skin & mucous membranes Ingestion Accidental injection

28 Factors Leading to Significant Exposures Physical form of the material Labor intensive steps manual transfer of materials weighing active materials High energy operations milling, sizing, fluidizing, spraying over-pressurization Poor work practices carelessness or lack of awareness Cleaning and maintenance operations

29 Control and Handling Guidance Pre-assign safe handling procedures for each operation based on its exposure potential (handling matrix) Control recommendations were based on success with compounds having similar characteristics Work environments, process controls, techniques, PPE Based on experience and air monitoring data Guidance will vary depending on scale of operation (laboratory, kilo, pilot plant, commercial)

30 Laboratory Handling Practices - Category 3 Work Environment PPE 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 aerosolization Use good lab practices Appropriate gloves, lab coat, safety glasses Respirator selection appropriate to task

31 Laboratory Handling Practices - Category 4 Work Environment PPE 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 aerosolization Appropriate gloves, lab coat, safety glasses Air purifying respirators must be worn by all personnel in the immediate area if engineering controls are unavailable

32 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

33 Production/Pilot Plant Handling Practices - Category 4 Work Environment Total process containment/isolation Separated/dedicated work areas Secured and restricted access Highly specialized ventilation system Failure protection Clean in place; automation emphasis PPE Category 3 for exposure situations

34 Engineering Controls Facility Process Administrative Controls Hierarchy of Control Work practices and procedures Worker education and training Job rotation Personal Protective Equipment (PPE) Various levels of respiratory equipment Protective clothing, gloves, eyewear

35 Ventilation Traditional Engineering Controls Engineered local exhaust At emissions points Can be effective to 100 µg/m 3 Laminar flow (hoods) Other Enclosures of specific parts and containers Vacuum transfer

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37 Floor to-ceiling Hood

38 Labconco Biological Safety Cabinet

39 Advanced Engineering Control Approaches Process containment barriers/isolators (equipped with RTPs) bag techniques (bag w/in a bag) Closed transfer systems vertical process trains intermediate bulk containers (IBCs) specialized connectors and valves (SBVs) Ventilated enclosures powders weighing hoods enclosures for subdividing, filling, sizing

40 Ventilated Balance Enclosures (VBEs) Flow Sciences a1-safetech

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42 Drying Oven Integrated Into Ventilated Enclosure

43 Bulk Powder Handling Flow Sciences Labconco

44 Flexible Containment Weighing & Dispensing Slide courtesy of ILC Dover

45 Isolators Weighing and Dispensing Product Charging

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47 Administrative Controls Safety culture Rotation of workers Well defined procedures Safe work practices

48 Personal Protective Equipment (PPE) Respiratory protection (RPE) Airline respirator Powered Air Purifying Respirator (PAPR) Tight fitting cartridge respirator Disposable filtering facepiece (dust/mist) respirator Skin protection chemical protective clothing (Tyvek) gloves Eye protection

49 Things to Think About All substances can be handled safely Care must be taken with potent compounds Safe handling procedures are determined by the exposure potential of the task and potency of the material Think the process through to minimize exposures Consider all routes of exposure Utilize engineering controls and PPE properly Utilize the information resources available to you Report any negative experiences You have the greatest amount of control over your exposure potential