David Miedinger MD PhD Disclosure DM is a full-time employee at F. - - PDF document

Occupational Health in the Biotechnology Industry

David Miedinger MD PhD

Disclosure

• DM is a full-time employee at F. Hoffmann-La Roche Ltd and owns

stocks and stock options of this organization

• DM is a former employee of Suva and has received research grants

from this organization

• DM is a lecturer at the University of Basel

Definition

• Biotechnology according to Merriam-Webster:

– the manipulation (as through genetic engineering) of living

• rganisms or their components to produce useful usually

commercial products (such as pest resistant crops, new bacterial strains, or novel pharmaceuticals)

Biotechnology research & development

• Integration of various disciplines

– Molecular and cellular biology – Chemistry – Bio-chemistry – Genetics – Biochemical engineering – Process engineering – Computer science

• Hazards

– Recombinant and nonrecombinant micororganisms – Active pharmaceutical ingredients (APIs) – Chemicals – Physical hazards

Lee SB & Ryan LJ, Am Ind Hyg Ass J, 1996

Good Manufacturing Practice – GMP

• Regulations promulgated by the US FDA, EMA
• Require that manufacturers, processors, and packagers of drugs,

medical devices, some food, and blood take proactive steps to ensure that their products are safe, pure, and effective

• Protects the consumer from purchasing a product which is not effective
• r even dangerous or eliminate instances of contamination, mixups,

and errors

• Failure of firms to comply with GMP regulations can result in very

serious consequences

www.ispe.org

Human factors and Ergonomics (I)

• Limited evidence that job rotation reduces the exposure of physical

risk factors. Positive correlation between job rotation and higher job

• satisfaction. Worker training is a crucial component of a successful job

rotation program

• Participatory ergonomics: Actively involving workers in developing

and implementing workplace changes – Reduction of MSK injury risks, improved information flow, improved meningfulness of work, more rapid technological and organisational change, enhanced performance – Greater «ownership» by those affected leading to greater commitment to change – But: mixed nature of health effect evaluations, diversity of program designs, variety of organisational characteristics and contexts

Simprini Paula R et al, Applied Ergonomics, 2017 Burgess-Limerick R, Applied Ergonomics, 2017

Occupational contact dermatitis (OCD)

• Prevalence rates for OCD range

from 19% to 50% depending on profession and source

• Workers in pharmaceutical

manufacturing are in contact with reactive intermediates and drugs

• OCD to intermediates occurs

almost exclusively in employees working in drug development and manufacturing plants

Winkler GC et al, Regul Toxicol Pharmacol, 2015 Antonov D et al; Bircher AJ; Diepgen, TL and Coenraads PJ all in Kanerva’s Occupational Dermatology, 2. Ed., 2012 By James Heilman, MD - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=94449 17

Occupational dermatitis in the pharmaceutical industry

• Dermatology clinic in Ireland
• 73 patients seen in a 15 year period
• 2/3 contact dermatitis, 1/3 irritant contact dermatitis
• Primary site was the face in 66% of contact dermatitis patients
• Hand dermatitis more commonly due to irritants
• Causes for PPE associated allergies:

– Thiurams (Latex gloves) – Tetramethylthiuram monosulfide (Rubber face mask) – Nickel (Metal clasp) – Uncertain (Nitrile gloves and boots)

Bennet MF et al, Br J Dermatol, 2016

Non-glove personal protective equipment- related occupational dermatoses

• EPIDERM (UK-wide surveillance sheme) 1993-2013
• 0.84% of all occupational skin disease
• at body sites less commonly associated with occupational skin disease
• 194 (9.2%) of PPE-related cases
• diagnosed as: allergic contact dermatitis (47%), irritant contact

dermatitis (16%), friction (11%), occlusion (11%), unspecified dermatitis (9%), acne (3%), infections (2), and contact urticaria (1%)

• industries most associated: manufacturing (19%), public administration

and defence (17%), health and social work (16%), and transport, storage, and communication (10%)

Bhoyrul B et al, Contact Dermatitis, 2018

Sharp Injury/Needlestick- What to do? Biosafety

• All used instruments are potentially infectious

Everybody working with potentially infectious material must be vaccinated aginst hepatitis B Correct use of PPE

• Instruments must be prepared and labbeled for transport according to

the regulations

• Instruments and parts must be decontaminated before they are shipped

Decontamination certificate must be attached

• Decontaminated instruments are still potentially infectious (only

to a lesser degree) – must be disposed of in a safe way

Handling of instruments Biosafety in Biotechnology Research Operations

• Laboratory-Acquired Infections (LAIs) seem to be rare
• US Report of Theft, Loss or Release of Select Agents and Toxins (TLR

incident report) 2004-2010 – 11 LAIs associated with biological select agent and toxin (annual rate of 1,6 per 10’000 authorized workers) – All unrecognized and/or unreported exposures (aerosols?) – No fatalities and no secondary transmission to other humans

• But:

– Lack of systematic reporting very likely (fear of reprisal or embarrassment) – Difficult to identify subclinical infections – Atypical incubation periods and routes of infection

Henkel RD et al., Applied Biosafety, 2012 Singh K, Clin Inf Dis, 2009

Advancement of Biotechnology

• First generation: Recombinant DNA technology

– transfer of already existing genes from one cell to another

• Second generation: Synthetic Biology

– Design, assembly, synthesis, or manufacture of new genomes, biological pathways, devices or organisms not found in nature – Re-designing of existing genes, cells or organisms for the purpose

• f gene therapy

Howard J et al., 2017 https://blogs.cdc.gov/niosh-science-blog/2017/01/24/synthetic-biology/

Risks of Lentivirus Vectors (LVVs) and Transgene Exposures

• LVVs can cause clonal expansion and may cause oncogenesis through

insertional mutagenesis

– SCID treated with retrovirus developed leukemia – X-linked chronic granulomatous disease treated with retrovirus developed myelodysplasia or acute myeloid leukemia – Beta-thalassemia treated with retrovirus developed nonmalignant clonal expansion of erythroblasts

• LVV-infected genes can become cancerous through activation of
• ncogenes or inactivation of tumor suppressor genes
• Recombination unintentionally reconstitutes a replication-competent

and pathogenic virus

Schlimgen R et al. JOEM 2016 Cavazzana-Calvo M et al, Science 2000 Hacein-Bey-Abina S et al, Science 2003 Howe SJ et al J Clin Invest 2008 Stein S et al, Nat Med 2010 Cavazzana-Calvo M et al Nature 2010

There is a potential risk of accidental insertional mutagenesis for an individual inadvertently exposed to LVV engineered for research purposes!

Risk for transmission

• Clinically relevant exposures

– Parenteral inoculation – Mucous membranes of the eyes, nose or mouth – Direct contact with nonintact skin

• Aerosol exposures through droplet transmission

– Eg. Centrifuging or pipetting can generate droplets 5-10 µm diameter

• Replacement of HIV envelope with VSV-G

– Entire mucosal membrane of tracheobronchial region can potentially be infected

• Authors recommend PEP after clinically relevant LVV exposure

Schlimgen R et al. JOEM 2016

Biosafety Levels: Risk Management Levels

• Company directive: Defines standards for the protection of employees,

environment and general public from adverse effects due to exposure of biological material produced or handled in Roche facilities or under the responsibility of Roche

• Risk calculation:

– Exposure management defined by work practices and infrastructure – No measurements necessary – Biosafety rules and standards are well harmonized

• Binding for all companies of the Roche Group

Risk = x Hazard Exposure Risk Group 1-4 difficult to measure Biosafety Level 1-4 Risk and Risk Managment

Primary and Secondary Prevention in the Biosafety Lab – Preplacement and Periodic Medical Evaluations

• Primary prevention

– Vaccination (HBV, …) – Review previous and ongoing medical problems (defective immune system skin disorders), medications (immunosuppressants) and allergies

• Secondary prevention

– Health surveillance (limited value)

• Small size of groups under study
• Variability in individual exposures
• Potentially long induction-latency period
• Subclinical disease, uncertainty as to the adverse effect
• Lack of sensitivity or specificity of screening tests
• Uncertainty as to the connection between

exposure and effect

Biosafety in Microbiological and Biomedical Laboratories 5th Editio Goldman RH, Occupational Medicine, 1991

CME Question 1

• Which findings related to the workplace are most frequently

encountered during medical health surveillance exams in the biotechnology industy? a. Asbestos-related lung disease (eg. Asbestosis, pleural plaques, …) b. Repetitive stress related musculo-skeletal disorders (WRULD, RSI, …) c. Heat or cold burns related to extreme temperature during production processes d. PPE related contact dermatitis

CME Question 2

• Which statement regarding non-glove personal protective equipment

related occupational dermatoses is incorrect a. Are more frequently encountered than glove-related occupational dermatoses b. Thiurams, Tetramethylthiuram monosulfide and Nickel are possible allergens c. Often occur at body sites less commonly associated with occupational skin disease d. They may be a result of GMP requirements to produce medicines that are safe, pure, and effective

CME Question 3

• Which statement regarding Lentiviruses (LVVs) is false

a. LVVs can integrate a siginificant amount of viral cDNA into DNA of host cells and can even infect non-dividing cells b. LVVs with VSV-G envelope can potentially infect the mucosal membrane of the tracheobronchial region of the worker c. Aerosol exposures through droplet transmission is a rare but potential

• ccupational exposure

d. PEP for LVVs exposure is evidence based