Exposure Risk Assessment Challenges

1. Exposure Risk Assessment Challenges:Occupational Hygiene in the Pharmaceuticaland Chemical Industries Maharshi Mehta, CSP, CIH President International Safety Systems, Inc., Washingtonville New York, USA www.issehs.com Samson Ponselvan Head, Corporate EHS Shasun Pharmaceuticals Limited, Chennai, India AIHA 2013 Asia Pacific OH Conference, Singapore

2. Agenda: Two Part PresentationPart 1: Maharshi Mehta • Growing need for sustainable Industrial hygiene and process safety in Emerging Economies • Introduction to potential health and process safety risk • Risk Assessment and Risk Controls • Challenges Encountered • Approaches adopted • Lessons Learned ©International Safety Systems, Inc. www.issehs.com

3. Part-2 : Samson - Agenda • Background /Introduction • Why is this important ? • HSE Trends in Asian countries • IH in Pharma and Chemical industries • Challenges in managing potential health risks and solutions • Hierarchy of controls • - At Source / At Path / At Work • IH Management System Models • Integration of IH and handling of potent APIs • Conclusion

4. Introduction Pharmaceutical manufacturing is growing 8% to 12% per year in emerging economies India is the world’s largest producer of bulk drugs Supply chain, third party manufacturing are increasing rapidly Outsourcing expected to exceed $53B More than 100 FDA-approved pharmaceutical facilities are in India- the largest number in any country outside the U.S

5. Infrastructure Pharma Manufacturing EHS • Over 450 colleges/departments offering degree and other education programs in pharmaceutical science • More than 50,000 students graduates/year • Manufacturing equipment, containment technologies • R&D centers , laboratories • Two colleges offering Master in Industrial Hygiene Program • 150 Industrial Hygienists for all companies in India total • 5 CIHs • Safety professionals or occupational physicians practicing IH • No Accredited Lab for API/Surrogate

6. Introduction-Pharmaceutical and Chemical Industries • Active Pharmaceutical Ingredient (API) Manufacturing similar to typical chemical industries • Bulk drug is manufactured • Potential process safety risk and chemical exposure risk is high • Large volume potential solid exposure risk is high after solid liquid separation • Formulation or Dosage Form • Solids and liquid pharmaceuticals are made • Potential solid API exposure risk is high ©International Safety Systems, Inc. www.issehs.com

7. API/Chemical Manufacturing –Process Safety – The highest priority • Low flash points solvent. Most commonly used: • Toluene, Methanol, Dimethyl Formamide, Acetonitrile • Unit operations • Tanker unloading and tank farm, barrel transfer • Reactor vessel charging and cleaning • Solid liquid separation, distillation • Most common Contributory factors • Open handling of solvents • Validation of inerting • Non-conductive container handling • Effectiveness of grounding and bonding • “Explosion Proof” lighting ©International Safety Systems, Inc. www.issehs.com

8. Example of Process Safety Incident A massive explosion and fire gutted a pharmaceutical supply plant, killing at least three people and injuring more than two dozen others -- about 12 of them critically. Authorities recommended residents within a mile radius around the plant to evacuate A volatile mix of air and suspended dust caused the explosion The explosion was so powerful it blew doors open on houses more than a mile away and sent debris flying, with some pieces landing more than two miles away

9. Process Safety - Most common recommendations • Process safety risk is manageable • Awareness and Risk Assessment (HAZOP) • Storage tank integrity, flame arrestor breather valves, dyking • Validation of inerting-flow rate, volume, O2<4%. Inerting of not just process vessels – Centrifuge • Static electricity controls • Painted surfaces • Continuity, resistance and earthing • Conductive containers • Specifics on intrinsically safe lighting ©International Safety Systems, Inc. www.issehs.com

10. Industrial Hygiene Hazard Anticipation - Hazards likely to be present? Hazard Recognition - What are health hazards? Risk Evaluation - Exposed to health hazard? How much? Risk Control - How can exposure be reduced? So that…Health risk is minimized And potential for occupational illnesses, material loss are reduced and the company liability minimized

11. Hazards – Exposures – Controls - and Risk: example…Low Risk Compression Activity Health Hazard: API Enclosed compression machine Potential for exposure from fugitive emission Reduced risk due to effective use of airline respirator

12. Industrial Hygiene - Methodology(Compression) • Health Hazard Identification • Obtain hazard data for API from MSDS and label • Exposure/Risk Assessment • How frequently and how long compression machine is running? • How frequently compression machine is cleaned? • Are exposure controls effective in reducing exposure? • Are recommended RPE/PPEs used? • Is exposure monitoring conducted? • Is the exposure below OEG?

13. Hierarchy of Controls • Elimination – Avoid Compression? • Substitution – Use of low potency compound? • Process Changes – Vacuum transfer blend in compression hopper? • Not feasible due to business constraints e.g., product validation and registration process • Engineering Controls – Complete enclosure of compression machine and tablet container? • Administrative Controls – Reducing or restricting exposure duration? • Personal Protective Equipment and Respiratory Protective Equipment – Eye Protection, cleaning disinfecting respirator, storing respirator in a zip lock plastic bag?

14. API Chemical Plants: Health Hazards - Solvents • Toluene and DMF • Potential reproductive hazards • Acetonitrile • CN formation • Tetrahydrofuran (also peroxide forming agent) • Isopropanol • Small Volume Highly Toxic compounds • Aniline • Iodine ©International Safety Systems, Inc. www.issehs.com

15. API/Chemical Plants: Solvent Exposure Potential to Exceed OEL Solid liquid separation – Centrifuge - Manual digging Short term exposure – Tanker/barrel QC Sample taking, tanker hose disconnecting, residual tanker solvent collecting Reactor, vessel cleaning Distillation residue collection ©International Safety Systems, Inc. www.issehs.com

16. API/Chemical Plants: Solvent Exposure Controls • Agitated Nutche Filter/Filter Dryer in place of Centrifuge • Tanker QC sample from bottom nozzle and not by opening dome • Nitrogen for pushing solvents before opening hose after tanker unloading • Local Exhaust Ventilation ©International Safety Systems, Inc. www.issehs.com

17. Acute Pharmacological Effects Health effects described in this and subsequent slides potentially could occur from overexposure when effective exposure controls are not in place. Pharma compound Exposure Incident: An operator working on the manufacture of a product containing Barbiturates was admitted to hospital in hypoglycaemic coma and the report of a study by the Pharma company found that operators absorbed through skin significant levels of Barbiturates. ©International Safety Systems, Inc. www.issehs.com

18. Hormones Overexposure to hormone during manufacturing, development and testing may result in elevated levels of hormone in the body and affect the normal functions of the related endocrine gland. ©International Safety Systems, Inc. www.issehs.com

19. Steroids – Health Effects • Male Employees: • Gynecomastia (excessive development of the mammary glands), decreased libido, reduced testicular size, increased pigmentation of the nipple area, nipple sensitivity, dysspermia (the occurrence of pain during ejaculation), weight loss, and headaches • Female Employees: • Menstrual disorders (such as increased flow or intermenstrual spotting), nausea, headaches, breast pain, leukorrhea (vaginal discharge), and swollen ankles • Adverse effect on skin such as acne and erythema ©International Safety Systems, Inc. www.issehs.com

20. Antibiotics - Health Effects • Allergic reactions: • Itching and redness of eyes, runny nose, skin rashes, asthma, anaphylaxis • Vitamin deficiency: • Workers with repeated exposure to antibiotics experience change in number and type of bacteria which are normally present in intestines which break down and absorb vitamins in intestines • Fungal infections: • Daily exposure to antibiotic dust can lead to fungal infections of the skin and nails. • Women workers may develop vaginal yeast infections following exposure to antibiotics ©International Safety Systems, Inc. www.issehs.com

21. Antineoplastic - Health Effects • Acute effects: severe soft-tissue damage, fetotoxicity, headaches, lightheadedness, dizziness, nausea and allergic reactions • Effect on growth and reproduction of the normal cells as Cytotoxic drugs may not distinguish between normal and cancerous cells • Other secondary malignancies, such as bladder cancer and lymphoma • Chromosomal damage (e.g., Chlorambucil) • Testicular and ovarian dysfunction, including sterility • Biological effects (even at very low levels of absorption) ©International Safety Systems, Inc. www.issehs.com

22. OELs Exposure limits are not a fine line between safe and dangerous concentrations Occupational Exposure Limits (OELs) Airborne concentration limit of a substance to which it is believed that a worker may be exposed, without adverse health effects, expressed as an average concentration. The time weighted average concentration for 8 hr work-day, 40 hour work-week , to which nearly all workers may be repeatedly exposed, day after day, without adverse effect. An OEL is substance-specific and is a level at which workplace exposure is expected to be without detectable pharmacological or toxicological effect in occupational circumstances. Industrial Hygienists conduct personal exposure monitoring to assess employees’ exposure relative to these levels.

23. Adjusted Occupational Exposure Limits (AOEL)* *AOEL = AM X OEL-TWA (basis ACGIH Excursion Limits) ©International Safety Systems, Inc. www.issehs.com

24. Occupational Exposure Bands (OEBs) – Categorization 5000 • OEB 1 • 5000- 1000 ug/m3 Increasing Toxicity and/or Potency Not harmful, not irritating, low pharmacological activity e.g. predicted therapeutic dose >100mg/day, Examples – many excipients 1000 • OEB 2 • 1000 - 100 ug/m3 Harmful, may be irritant, Moderate pharmacological activity, predicted therapeutic dose >10 - 100mg/day, Examples – Loratadine 100 Moderate toxic and /or high pharmacological activity, predicted therapeutic dose >1–10mg/day, Respiratory sensitizers and potent dermal sensitizers, Severe irritants and corrosives, also default category, Examples – many penicillin & cephalosporin antibiotics • OEB 3 • 100 - 10 ug/m3 10 Toxic Serious irreversible effects, Carcinogens, Mutagens, Reproductive and Developmental Toxins, Potent respiratory sensitisers, predicted therapeutic dose  1mg/day, Examples –Corticosteroids, some oncology drugs • OEB 4 • 10 - 1 ug/m3 ≤1 • OEB 5 • ≤1 ug/m3 Extremely toxic and or extremely high pharmacological activity predicted therapeutic dose  1mg/day, Serious irreversible effects, Potent Carcinogens, Mutagens, Reproductive and Developmental Toxins, Examples - potent hormones or hormone effectors, select anti-cancer drugs ©International Safety Systems, Inc. www.issehs.com

25. Risk Assessment Model Risk Ranking Criteria are summarized in next 3 slides • Most model considers • Potency • Frequency duration of exposure • Air-borne Potential • Exposure Controls • Formulation • Small volume, less frequency/duration high potent compounds considerations • Potential skin and ingestion risks are also critical ©International Safety Systems, Inc. www.issehs.com

26. High Potent Compound in Chemical Industries Beryllium - OEL 2 ug/m3 Hex chrome – OEL 5 ug/m3 Ni Carbonyl – OEL 50 ppb Chloromethylisothiazolone – Kethon – very low OEL used as biocide Bischloromethyl ether OEL 1 ppb ©International Safety Systems, Inc. www.issehs.com

29. Final Risk Ranking Criteria ©International Safety Systems, Inc. www.issehs.com

30. Quantitative Exposure Monitoring Sampling media Sampling pump Calibrator Sampling media

31. Important Considerations • What to sample? • Contaminants with higher degree of toxicity with potential for exposure identified during qualitative exposure assessment • Whom to sample? • Personnel potentially exposed to identified contaminants • Are all personnel required to be sampled? • No, sample few from those having similar exposures known as Similar Exposure Group (SEG) (e.g., charging personnel, Dispensing personnel)

32. Important Considerations • How many samples to be collected? • 6 (minimum) for each contaminant in SEG • Additional samples need to be collected for high potent compounds or when variability in exposure results is significant • Where to sample? • Areas/activities/operations with potential for exposures defined during Industrial Hygiene Risk Assessment • When should the sampling be done? • Representative sampling in all shifts • Different operators, different shifts ©International Safety Systems, Inc. www.issehs.com

33. Challenges in API Exposure Monitoring • OELs are not available for large number of APIs and intermediates • Validated methods are not available for large number of API analysis • Potent compounds require meticulous handling of samples to avoid cross contamination • Limited accredited laboratories are available in USA for APIs • Each API employee and swab sampling method validation include sensitivity (LOQ lower than high API), desorption efficiency, number of spike samples and other critical parameters ©International Safety Systems, Inc. www.issehs.com

34. Addressing Challenges API Exposure Monitoring Implement Established Exposure Controls following Control Banding Approach Use validated methods and accredited lab with API analysis experience especially for highly potent APIs as employee health depends on the results Follow rigorous validated sampling methods to avoid sample contamination (disposal powder free gloves, plastic Ziplock bag for every sample) Use surrogate monitoring if API validated methods are not available ©International Safety Systems, Inc. www.issehs.com

35. Surrogate Monitoring Good Practices Guidelines - ISPE • International Society for Pharmaceutical Engineering (ISPE) • Standardized Measurement of Equipment Particulate Airborne Concentration (SMEPAC) Committee • ISPE Good Practice Guide: Assessing the Particulate Containment Performance of Pharmaceutical Equipment • Standardized method of measuring • Performance of containment systems against specific challenge • Establish an agreed and valid method that can be used to meet the requirements of practitioners and supplier organizations

36. Example of Laminar Flow Booth Surrogate Monitoring at LFB

37. API/Chemical Plants: Exposure Controls: Reactor Charging • Potential for exposure during: • Manual charging of solids • Handling of empty bags/super-sacks – (major source of exposure) Very effective: Charging booth Empty bags collected in plastic bag from inside of glove box Effective: Reactor Charging with LEV

38. API/Chemical Plants: Exposure Controls: Tanker Unloading Nitrogen – pushing residual chemical Secured connections with arrangement to rinse piping before disconnecting

39. API/Chemical Plants: Exposure Controls: Tanker Unloading Barrel Transfer of Chemicals Potential for exposure during transfer with left in hose A barrel decanting unit reduces leaks, spills and exposures Never to use air pressure

40. Dispensing and Weighing of Solids - Small Volume Not Effective: LFB are nt effective in reducing exposure below about 50 ug/m3 Dispense cell, isolator for high potent compounds

41. Solid Discharging Fully Contained Discharge Through Weigh Isolator

42. Ventilated Balance Safety Enclosure (VBSE)® – For High Potent Compounds in laboratory • Face velocity • Not too high • Not too low • 50 fpm to 70 fpm • HEPA filtration • Ducted • Size of opening for weighing - adjustable • Air flow monitor and alarm • Can be customized ©International Safety Systems, Inc. www.issehs.com

43. Efficient LEV design

44. Principles of General Ventilation System • Maintain always negative air pressure in the contamination generating room with respect to rest of the building • Replace exhaust air by make-up air • Do not install an exhaust fan near an intake opening or window (e.g., contaminated air will be pulled back into building rather than exhausted) • Ensure contaminated air does not pass through breathing zone

45. Efficient Local Exhaust Ventilation (LEV) • Inefficient ventilation system design is one of the most common walkthrough findings • The designing contractors are often not knowledgeable of design principles • Adequate capture efficiency has not been accomplished despite money spent in energy consumption • Knowing basic principles of ventilation system helps in (a) modifying existing ventilation systems and (b) in guiding designing contractors towards efficient ventilation system design In an efficient LEV, energy consumption is minimum and contaminant removal from operator’s breathing zone is maximum

46. Hood Provide a flange or hood at the air inlet. 25% more energy is required to capture contaminates from the front, when a flange or hood is not provided Air is drawn from back side also Air drawn from front only Locate hood closed to contaminant generation Preferred Reduce distance if feasible

47. Hood Tapered hood are more efficient than right angle hoods Enclose sides as much as feasible Locate hood so that contaminants do not pass through the breathing zone of an operator

48. Duct Straight duct is more efficient than a duct with many bends and elbows. Smaller duct length and smoother duct surface improves efficiency Examples of inefficient ducts Abrupt change in duct diameter and branch entry reduce the efficiency • For most of LEVs, round duct is preferred over rectangular duct • Prevents accumulation of solids • Makes less noise • Durable

49. Application of LEV Empty bags are placed in this large bag Solid charging Solid filling in drums Barrel decanting Glove box for highly toxic compounds Portable extractor

50. Ventilation measurements • Velocity measurement on the face of the hood is best indicator of efficiency • Depending on the face area, measure air velocity at several points on the face and determine average face velocity • The face velocity to capture most of the contaminants is 100 f/min (0.5 m/sec) Instruments used to measure face and duct velocities