Practical Considerations for the Use of - PowerPoint Presentation

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Practical Considerations for the Use of In Vivo AAV-Based Gene Therapies Chris JenkinsPrincipal Partner & Chief Gene Therapy Biosafety Officer Clinical Biosafety Services, USA

MEDWEB-US-00035

Slide2

Disclosures

Chris

Jenkins

, PhD, MPH, RBP, CHMM

Founder of a for-profit clinical research organization supporting gene and cell therapy

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Points to CoverAAV, adeno-associated virus.

Overview of

gene therapy

Overview of biological risk in the context of gene therapies

Review of the risks and containment practices when working with

AAV vectors

Slide4

OVERVIEW OF GENE THERAPY

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Gene Therapy: A Novel Treatment Option

Gene therapy is the therapeutic modification of genetic material or its expression in order to treat disease

1,2

Developments in gene delivery techniques

have improved safety and efficacy

3,4

Now, viral gene therapy products have achieved regulatory approval in the US and EU

5–10

Number of Gene Therapy Clinical Trials

Approved Worldwide, 1989–2018

Updated December 2018

Image adapted from The Journal of Gene Medicine, 2018. Available at: http://www.abedia.com/wiley/years.php. Accessed November 27, 2019.

1. Mayo Clinic. Gene therapy. Available at: www.mayoclinic.org/testsprocedures/gene-therapy/about/pac-20384619. Accessed November 27, 2019; 2. U.S. FDA. What is gene therapy? Available at: https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/what-gene-therapy. Accessed November 27, 2019; 3. Naso MF. BioDrugs 2017;31:317–334; 4. Thomas CE, et al. Nat Rev Genet 2003;4(5):346–358; 5. Hoggatt J. Cell 2016;166(2):263; 6. U.S. FDA. News release. August 30, 2017. Available at: https://www.fda.gov/drugs/informationondrugs/approveddrugs/ucm574154.htm.

Accessed November 27, 2019; 7. U.S. FDA. News release. October 18, 2017. Available at: www.fda.gov/drugs/informationondrugs/approveddrugs/ucm581296.htm. Accessed November 27, 2019; 8. U.S. FDA. News release. December 18, 2017. Available at: https://www.fda.gov/news-events/press-announcements/fda-approves-novel-gene-therapy-treat-patients-rare-form-inherited-vision-loss. Accessed November 27, 2019; 9. U.S. FDA. News release. May 24, 2019. Available at: www.fda.gov/news-events/press-announcements/fda-approves-innovative-gene-therapy-treat-pediatric-patients-spinal-muscular-atrophy-rare-disease. Accessed November 27, 2019; 10. Bluebird bio. Press release. June 3, 2019. Available at: http://investor.bluebirdbio.com/news-releases/news-release-details/bluebird-bio-announces-eu-conditional-marketing-authorization. Accessed November 27, 2019.

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Gene Therapy: Current State in the US

The number of IND applications for gene therapy products submitted to the FDA has been steadily increasing since 2011,

with an all-time high achieved in 2018

1

Prior to clinical testing in human subjects,

an IND application is submitted to the FDA

for authorization to administer an

investigational drug to humans

1

All New IND Applications for

Gene Therapy Products by Year

*1,2

Year

Number of IND applications

for gene therapy

*Data adapted with permission from Lorrie McNeill, Director, FDA Office of Communications. Data in graph are from Marks P. 20182, except 2018 data from Eisenman D. 20191. FDA, U.S. Food and Drug Administration; IND, investigational new drug.1. Eisenman D. Applied Biosafety: J ABSA International 2019;24(3):147–152; 2. Marks P. Presented at CASSS Cell & Gene Therapy Symposium 2018, Rockville, MD, USA.

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Delivery Methods for Gene Therapy

Ex vivo

Cells are extracted from the patient, modified with the therapeutic gene, and injected back into the patient

In vivo

The therapeutic gene is transferred directly to

target cells in the body

... and injected into

the patient

Therapeutic

transgene

The therapeutic transgene

is packaged into a delivery vehicle such as a virus

The genetically modified cells

(e.g. stem cells or T cells

2

)

are multiplied in the laboratory

The therapeutic transgene is introduced into a delivery cell such as a stem cell that is often derived from the patient

...and re-administeredto the patientTherapeutictransgene

The therapeutic transgeneis packaged into a delivery vehicle such as a virus

Figure adapted from Figure 1 in

Collins M, Thrasher A. 2015

1

.

1. Collins M, Thrasher A.

Proc Biol Sci

2015;282:20143003; 2.

Kymriah

®

[package insert]. 2018.

Available at: https://www.pharma.us.novartis.com/sites/www.pharma.us.novartis.com/files/kymriah.pdf. Accessed November 27, 2019.

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Introduction to Viral Vectors

Approximately

70%

of gene therapy trials and all approved agents use viral vectors to deliver the therapeutic gene

1–8

Viral vectors are

naturally

occurring

viruses

that have had their original viral genes replaced with the desired transgene

9,10

Removal of replication components within the viral genome means

that they

no longer replicate compared with their wild-type counterpart10,111. The Journal of Gene Medicine. Gene Therapy Clinical Trials Worldwide, August 2018. Available at: http://www.abedia.com/wiley/vectors.php. Accessed November 27, 2019; 2. Kymriah® [package insert]. 2018. Available at: https://www.pharma.us.novartis.com/sites/www.pharma.us.novartis.com/files/kymriah.pdf. Accessed November 27, 2019; 3. Luxturna™ [package insert]. 2017. Available at: http://sparktx.com/LUXTURNA_US_Prescribing_Information.pdf. Accessed November 27, 2019; 4. Strimvelis® [summary of product characteristics]. 2016. Available at: https://www.ema.europa.eu/en/documents/product-information/strimvelis-epar-product-information_en.pdf. Accessed November 27, 2019; 5. BioPharm. The genesis of gendicine: The story behind the first gene therapy. Available at: http://www.biopharminternational.com/genesis-gendicine-story-behind-first-gene-therapy. Accessed November 27, 2019; 6. Yescarta

® [package insert]. 2019. Available at: https://www.yescarta.com/files/yescarta-pi.pdf. Accessed November 27, 2019; 7. U.S. FDA. News release. May 24, 2019. Available at: https://www.fda.gov/news-events/press-announcements/fda-approves-innovative-gene-therapy-treat-pediatric-patients-spinal-muscular-atrophy-rare-disease. Accessed November 27, 2019; 8. Bluebird Bio. Press release. June 3, 2019. Available at: http://investor.bluebirdbio.com/news-releases/news-release-details/bluebird-bio-announces-eu-conditional-marketing-authorization. Accessed November 27, 2019; 9. Lukashev AN, Zamyatnin AA Jr. Biochemistry (Mosc) 2016;81(7):700–708; 10. Nayak S, Herzog RW. Gene Ther 2010;17(3):295–304; 11. Nayerossadat N, et al. Adv Biomed Res 2012;1:27.

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Persist in the cell nucleus predominantly as extrachromosomal episomes

1,2

Generally

non-integrating

1

Genomes integrate into the host genome

1

Integrating

1

Types of Viral Vectors

Adeno-associated virus (AAV)

Retrovirus

Lentivirus*

*Lentiviral vectors are derived from the retroviral class of viruses3.1. Lukashev AN, Zamyatnin Jr AA. Biochemistry (Mosc) 2016;81(7):700–708; 2. Naso MF, et al. BioDrugs 2017;31:317–334; 3. Chira S, et al. Oncotarget 2015;6:30675–30703.

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OVERVIEW OF BIOLOGICAL RISK IN CONTEXT OF GENE THERAPIES

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The appropriate containment for gene therapy agents is based on:

Physical containment

Work handling practices

The risk of gene therapy agents is based on:

Risk of parental (wild-type) delivery vector

Nature of genetic modifications

Nature of manufacturing and formulation

Nature of administration (dosing)

Resources for establishing risk and containment worldwide include:

The NIH (

NIH guidelines

)

1

The CDC (

Biosafety in Microbiological and Biomedical Laboratories

)

2

The World Health Organization (Laboratory Safety Manual)3European Association of Hospital Pharmacists (Guidance on the Pharmacy Handling of Gene Medicines)4

Overview

CDC, Centers for Disease Control and Prevention; NIH, National Institutes of Health. 1. NIH. NIH guidelines for research involving recombinant or synthetic nucleic acid molecules. April 2019. Available at:

https://osp.od.nih.gov/wp-content/uploads/NIH_Guidelines.html

. Accessed November 27, 2019; 2.

U.S. Department of Health and Human Services. Biosafety in Microbiological and Biomedical Laboratories – 5th Edition. December 2009. Available at: https://www.cdc.gov/labs/pdf/CDC-BiosafetyMicrobiologicalBiomedicalLaboratories-2009-P.PDF. Accessed November 27, 2019

; 3. World Health Organization. Laboratory Biosafety Manual – Third Edition. 2004. Available at: http://www.who.int/csr/delibepidemics/WHO_CDS_CSR_LYO_2004_11/en/. Accessed November 27, 2019; 4. Vulto AG, et al.

EJHP Pract

2007;13:29–39.

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The NIH guidelines and WHO categorize wild-type infectious agents into risk groups:

Group 1

Group 2

Group 3

Group 4

Agents that are not associated with disease in healthy adult humans

Agents that are associated with human disease that

is rarely serious and for

which preventive or

therapeutic interventions

are

often

availableAgents that are associated with serious or lethal human disease for which preventive or therapeutic interventions may be available (high individual risk but low community risk)Agents that are likely to cause serious or lethal human disease for which preventive or therapeutic interventions are not usually available (high individual risk and high community risk)

Lowest riskHighest riskRisk Groups (1)

NIH, National Institutes of Health; WHO, World Health Organization.

1. NIH. NIH guidelines for research involving recombinant or synthetic nucleic acid molecules. April 2019. Available at: https://osp.od.nih.gov/wp-content/uploads/2013/06/NIH_Guidelines.pdf. Accessed November 27, 2019; 2.

U.S. Department of Health and Human Services. Biosafety in Microbiological and Biomedical Laboratories – 5th Edition. December 2009. Available at: https://www.cdc.gov/labs/pdf/CDC-BiosafetyMicrobiologicalBiomedicalLaboratories-2009-P.PDF. Accessed November 27, 2019.

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Appendix B of the NIH guidelines provides an extensive list of infectious agents for each risk group

The CDC BMBL provides information on high-risk pathogens but not low-risk

infectious agents – they refer to the NIH guidelines for recombinant agents

The WHO LBM provides limited information on specific infectious agents

The Public Health Agency of Canada has published Pathogen Safety Data Sheets

(PSDS) that provide risk group information on a wide variety of microorganisms

Risk Groups (2)

BMBL, Biosafety in Microbiological and Biomedical Laboratories; CDC, Centers for Disease Control and Prevention; LBM, Laboratory Biosafety Manual;

NIH, National Institutes of Health; WHO, World Health Organization.

1. NIH. NIH Guidelines. Available at: https://osp.od.nih.gov/biotechnology/nih-guidelines/. Accessed November 27, 2019; 2. Public Health Agency of Canada. Pathogen Safety Data Sheets. July 2018. Available at: https://www.canada.ca/en/public-health/services/laboratory-biosafety-biosecurity/pathogen-safety-data-sheets-risk-assessment.html. Accessed November 27, 2019.

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BSL-4

High-risk

biological agents

Low-risk

biological

agents

Biosafety levels established worldwide by WHO and CDC

Ensures safe handling of biological agents

Includes facilities, practices, and engineering controls

Levels progress from the lowest risk biological agents to the highest risk biological agents

Levels build on the precautions and containment

equipment of the previous level plus any

additional precautions needed for

the higher risk biological agent

Biosafety Levels (BSLs)

CDC, Centers for Disease Control and Prevention; WHO, World Health Organization.

World Health Organization. Laboratory Biosafety Manual – Third Edition. 2004. Available at: http://www.who.int/csr/delibepidemics/WHO_CDS_CSR_LYO_2004_11/en/. Accessed November 27, 2019.

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BSL-1

BSL-2

BSL-3

BSL-4

Microbes that are not known to cause disease in healthy adults

Examples: E.coli, AAV

Practices

Standard microbiological practices

Open bench or table

permitted

Laboratory personnel have specific training

Laboratory supervised by scientist with appropriate training

Standard lab practices for food, drink, smoking, etc. apply

Equipment

Lab coat and glovesFacilitiesSink for washing hands Means for controlling access (e.g. door)

Microbes that pose moderate risk to workers and environmentExample: Staphylococcus aureusPracticesAccess to work area limited when work is conductedEquipment

PPE includes mask and eye

protection of face shieldBSC for procedures that may cause exposure to aerosol or splashesAccess to autoclaveWork area includes self-closing doors and access to eye wash stationMicrobes that can cause serious or potentially lethal disease

Example: Mycobacterium tuberculosis (tuberculosis)PracticesReceive immunization for microbes usedAccess restricted at all timesEquipmentBSC (preferably Class II or III) for all open proceduresFacilitiesExhausted air cannot be recirculatedTwo sets of self-closing locked doors for entranceImmediate access

to autoclaveHand washing sink near lab exitMethod of decontaminating all lab waste

Very few labs in the worldMost exotic and dangerous microbesExample: Ebola virusPracticesDedicated lab clothingShower upon exitEquipment

Class III BSC or full-body, air-supplied suitFacilitiesSeparate building or isolated zoneDedicated air supply and processed exhaust

Biosafety Levels 1–4

AAV, adeno-associated virus; BSC, biological safety cabinet; BSL, Biosafety Level; PPE, personal protective equipment.

U.S. Department of Health and Human Services. Biosafety in Microbiological and Biomedical Laboratories – 5th Edition. December 2009.

Available at: https://www.cdc.gov/labs/pdf/CDC-BiosafetyMicrobiologicalBiomedicalLaboratories-2009-P.PDF. Accessed November 27, 2019

.

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Biosafety Level 1 (BSL-1)

Criteria for inclusion

Agents not known to consistently cause disease in healthy adults

Laboratory practices

Standard microbiological practices

Safety equipment

No primary barriers required

PPE includes laboratory coat and gloves

Facilities

Doors for access control

Benches able to support loads and use, and easy to clean

Sink for hand washing

PPE, personal protective equipment.

U.S. Department of Health and Human Services. Biosafety in Microbiological and Biomedical Laboratories – 5th Edition. December 2009.

Available at: https://www.cdc.gov/labs/pdf/CDC-BiosafetyMicrobiologicalBiomedicalLaboratories-2009-P.PDF. Accessed November 27, 2019.BSL-4

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Biosafety Level 2 (BSL-2)

Criteria for inclusion

Agents of moderate hazard associated with human disease that can be transmitted via percutaneous injury, ingestion, or mucous membrane exposure

Laboratory practices

BSL-1 practices plus

Limited access to laboratory

Biohazard warning signs

Safety equipment

BSL-1 equipment plus

PPE includes laboratory coat, gloves, face and eye protection

BSC for procedures that may cause exposure to aerosol or

splashes

FacilitiesSelf-closing doorsSink for hand washingReadily available eye wash stationAvailable autoclaveBSL-4

BSC, biological safety cabinet; PPE, personal protective equipment. U.S. Department of Health and Human Services. Biosafety in Microbiological and Biomedical Laboratories – 5th Edition. December 2009. Available at: https://www.cdc.gov/labs/pdf/CDC-BiosafetyMicrobiologicalBiomedicalLaboratories-2009-P.PDF. Accessed November 27, 2019.

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Non-viable rDNA (plasmids, liposomes)

Transgene is toxic

or oncogenic

Transgene is NOT

toxic nor oncogenic

Consider the risk group

of the transgene

BSL-1

Replication

competent

Replication

incompetent

Does NOT

generally integrateinto genomeIntegrates into genome

Does NOT generally integrateinto genomeIntegrates intogenomeTransgene is toxic or oncogenic

Transgene is NOTtoxic nor oncogenicTransgene is toxic

or oncogenic

Transgene is NOTtoxic nor oncogenicConsider the risk group of the organism and transgeneConsider the riskgroup of the organism

Consider the risk groupof the transgeneConsider the risk group of the organism and transgeneBSL-1Consider the risk group of the organism and transgeneViable bacteria,

yeasts, viruses

Decision Tree for Handling of Gene Therapy Products

BSL, biosafety level; rDNA, recombinant DNA.

Petrich J, et al.

J Pharm Pract

2019. doi: 10.1177

/0897190019854962 [Epub ahead of print].

Gene therapy product

Replication competency

Genomic integration

Oncogenicity potential

Handling

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Decision Tree for Handling of Gene Therapy Products

BSL, biosafety level; rDNA, recombinant DNA.

Petrich J, et al.

J Pharm Pract

2019. doi: 10.1177

/0897190019854962 [Epub ahead of print].

Non-viable rDNA (plasmids, liposomes)

Transgene is toxic

or oncogenic

Transgene is NOT

toxic nor oncogenicConsider the risk group

of the transgeneBSL-1

ReplicationcompetentReplicationincompetentDoes NOT generally integrateinto genome

Integrates into genomeDoes NOT generally integrateinto genomeIntegrates intogenome

Transgene is toxic or oncogenic

Transgene is NOT

toxic nor oncogenicTransgene is toxic or oncogenicTransgene is NOTtoxic nor oncogenicConsider the risk group of the organism and transgene

Consider the riskgroup of the organismConsider the risk groupof the transgeneConsider the risk group of the organism and transgeneBSL-1

Consider the risk group of the organism and transgeneViable bacteria, yeasts, viruses

Gene therapy product

Replication competency

Genomic integration

Oncogenicity potential

Handling

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PREPARATION OF INSTITUTIONS FOR AAV-BASED GENE THERAPIES

Slide21

AAV is a member of the

parvovirus family

of

single-stranded small DNA viruses

1

AAV

requires a helper virus

such as adenovirus or herpes simplex virus

for replication

1

AAV has

several serotypes that impact tropism

(susceptible tissues), but all appear to be

non-pathogenic

2

AAV-based vectors typically exist as extrachromosomal episomes

1

AAV can

efficiently infect both non-dividing and dividing cells

1

AAV is typically

transmitted by respiratory and gastrointestinal routes

2,3

Biological Properties of AAV

AAV, adeno-associated virus.

1. Deyle DR, Russell DW.

Curr Opin Mol Ther

2009;11(4):442–447; 2. Gonçalves MAFV.

Virol J

2005;2:43; 3. Biosafety in Microbiological and Biomedical Laboratories (BMBL) 5th Edition. October 2018. Available at: https://www.cdc.gov/labs/BMBL.html. Accessed November 27, 2019.

Slide22

Safety Features of AAV Vectors

Native (wild-type) AAV is considered a Risk Group 1 microorganism

– contact with AAV

is

not associated

with human illness

1

AAV vectors are replication

incompetent

(non-infectious)

by design

1,2

Absent hazardous transgenes, AAV vectors can be handled at BSL-1 containment (BSL-2 containment may be considered for genes of unknown significance)AAV vectors are susceptible to common disinfectants approved for bloodborne pathogens (e.g. EPA Lists B, D, and E)3

AAV, adeno-associated virus; BSL, Biosafety Level; EPA, Environmental Protection Agency.

1. Gonçalves MAFV.

Virol J

2005;2:43; 2. Deyle DR, Russell DW.

Curr Opin Mol Ther

2009;11(4):442–444; 3. United States Environmental Protection Agency.

Selected EPA-registered Disinfectants. Available at: https://www.epa.gov/pesticide-registration/selected-epa-registered-disinfectants. Accessed November 27, 2019.

Slide23

Safety Considerations of AAV Vectors

AAV vectors are biologically active and efficient at one-time gene transfer

1

AAV vectors can be easily transmitted by aerosols

2

– special care is needed to minimize and protect against aerosols

Therapeutic genes present in AAV vectors may have varied properties

3

Exposure to AAV vectors can result in seroconversion

3,4

✘

AAV, adeno-associated virus.

1. Foust KD, et al.

Nat Biotechnol

2010;28(3):271–274; 2. Deyle DR, Russell DW.

Curr Opin Mol Ther

2009;11(4):442–447; 3. Tenenbaum L, et al.

Curr Gene Ther

2003;3:545–565; 4. Nayak S, et al.

Gene Ther

2010;17(3):295–304.

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Safety Considerations of AAV Vectors: Shedding

Diverse AAV vectors are shed by different routes and warrant different considerations and handling, based on the individual product in question

1,2

Potential routes of shedding include tears, stool, saliva, urine, and semen

1,2

Shed AAV-based vectors are not expected to be infectious

2

Product-specific studies should always inform handling instructions

AAV, adeno-associated virus.

1. Le Guiner C, et al.

Methods Mol Biol

 2011;807:339–359; 2. Swedish Medical Products Agency 2. Summary notification information format for the release of genetically modified organisms other than higher plants in accordance with Article 11 of Directive, 2001/18/EC. Available at: https://lakemedelsverket.se/upload/halso-och-sjukvard/kliniska-provningar/SNIF%20201797435.pdf. Accessed November 27, 2019.

Determining the AAV vector biodistribution and shedding is central for the safety assessment of proposed early-phase clinical trials

1

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Guidance on Handling of Gene Therapies

In North America, no formal guidance on handling of gene therapies currently exists

General guidance has been published on the handling

of gene therapies

Main aims include

1,2

:

Development of institutional r

eadiness for gene

therapies

Standardizing practices of storage, transportation, preparation, dispensing, administration, waste disposal, decontamination, and accidental exposure

1. Armitstead JA, et al.

Hospital Pharmacy

2001;36(1):56–66; 2.

Petrich J, et al.

J Pharm Pract

2019. doi: 10.1177/0897190019854962 [

Epub ahead of print].

Slide26

Biosafety Considerations for Pharmacy Staff –

Storage

Wear suitable disposable personal protective equipment

when removing gene therapies from container in which

it was delivered

Store at a suitable temperature,

according to

product information

Gene therapy storage areas should be

labeled

to alert employees of possible hazard

The shipping container should be

appropriately inspected

by a pharmacist to ensure safe transit

Armitstead JA, et al.

Hospital Pharmacy

2001;36(1):56–66.

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Biosafety Considerations for Pharmacy Staff – Handling and Preparation

Wear suitable protective clothing

to minimize risk of microbiological contamination during preparation

Use of a Class II

biological safety cabinet

or pharmaceutical grade isolator (compliant with NSF49 standard)

Ensure

decontamination of work surface areas

with appropriate disinfectant and biohazard disposal

Gene therapy should be drawn up using

‘double-glove’ technique

Use appropriate personal protection equipment

–

coat and gloves

Armitstead JA, et al.

Hospital Pharmacy

2001;36(1):56–66.

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Biosafety Considerations for Pharmacy Staff – Dispensing

All gene therapies should

be

prepared in a

Class II hood

Gene therapy prescription should be checked

according to the normal pharmacy procedure

The pharmacist must

document dispensing specifics

such as time, concentration volume, and lot number

All preparations must be

double checked

by another pharmacist

Personal protective clothing standard

for pharmacy should be worn as recommended

Armitstead JA, et al.

Hospital Pharmacy

2001;36(1):56–66.

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Biosafety Considerations for Clinical Staff – Accidental Exposure

A spillage kit

must be made available

in the event of accidental exposure

Areas must be immediately decontaminated following spillage

Decontamination

should be carried out according to local organizational guidelines

Infection Control should be notified of the spillage

Spillages must be contained

by closing off the area in which the spillage has occurred

Armitstead JA, et al.

Hospital Pharmacy

2001;36(1):56–66.

Slide30

Biosafety Considerations for Clinical and Pharmacy Staff – Disposal

Disposable materials and personal protective equipment used in dispensing should be

sealed in a biohazard waste container

and incinerated

Any sharps used should be

placed into a sharps container

Spillage on clothes

should be contained before leaving any spillage site and the cloth should be discarded into a bag and then placed into an autoclave

The waste container must be

clearly labeled and

display a

biohazard symbol

Armitstead JA, et al.

Hospital Pharmacy

2001;36(1):56–66.

Slide31

Guidance on handling of gene therapies has been set out by NIH/CDC

1,2

The biological risks from working with AAV vectors are considered very low

AAV vectors can be handled at BSL-1, the lowest biosafety level

Formal staff training is imperative for the safe and effective handling of

gene therapies

Institutional readiness will enable quick and safe uptake of novel

gene therapies

Conclusions

AAV, adeno-associated virus; BSL, Biosafety Level; CDC, Centers for Disease Control and Prevention; NIH, National Institutes of Health.

1. NIH. NIH guidelines for research involving recombinant or synthetic nucleic acid molecules. April 2016. Available at: https://osp.od.nih.gov/wp-content/uploads/2013/06/NIH_Guidelines.pdf. Accessed November 27, 2019; 2. Biosafety in Microbiological and Biomedical Laboratories (BMBL) 5th Edition. October 2018. Available at: https://www.cdc.gov/labs/BMBL.html. Accessed November 27, 2019.

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THANK YOU