Biosafety PDF

SIT Internal Biosafety Process safety Dr. Joy Pang PHE 3019 / TCE 3012 Biosafety 1  SIT Internal Importance of biosafety Protection of personnel working in a lab setting or “biologic...

SIT Internal Biosafety Process safety Dr. Joy Pang PHE 3019 / TCE 3012 Biosafety 1  SIT Internal Importance of biosafety Protection of personnel working in a lab setting or “biological” environment Protection of members of the public Protection of the environment Direction, resources and training required for the safe handling of hazardous biologicals 2 PHE 3019 / TCE 3012 Biosafety  SIT Internal Importance of biosafety Cool stuff Safety Training Time PHE 3019 TCE 3012 Biosafety 3 Learning objectives SIT Internal You should: Have knowledge of international and national biosafety regulations Have knowledge of common viral vectors Be able to describe potential hazards from viral vectors Be able to describe biosafety considerations in Biopharma Be able to explain viral contamination scenarios during Biomanufacturing PHE 3019 TCE 3012 Biosafety 4  SIT Internal International and national biosafety standards and regulations PHE 3019 TCE 3012 Biosafety International legislation, regulation and SIT Internal guidelines PHE 3019 TCE 3012 Biosafety 6  SIT Internal Laboratory biosafety manual (WHO) PHE 3019 Biosafety 7  SIT Internal Laboratory biosafety manual (WHO) Provides practical guidance on biosafety techniques for use in laboratories at all biosafety levels (BSL-1 to BSL-4) Recommends the codes of practice, equipment, laboratory design and facilities, and health and medical surveillance required for the safe handling of infectious substances at BSL-1 to BSL-4 Addresses risk assessment and the safe use of recombinant DNA technology Provides an overview of good microbiological techniques and laboratory equipment Introduces biosecurity concepts Provides guidelines for the commissioning and certification of laboratories PHE 3019 TCE 3012 Biosafety 8 International legislation, regulation and SIT Internal guidelines PHE 3019 TCE 3012 Biosafety 9  SIT Internal Laboratory biosecurity guidance (WHO) PHE 3019 Biosafety 10  SIT Internal Laboratory biosecurity guidance (WHO) Expands on the laboratory biosecurity concepts introduced in the WHO Laboratory Biosafety Manual Address the safekeeping of all Valuable Biological Materials (VBM), including not only pathogens and toxins, but also scientifically, historically and economically important biological materials Covers the following key areas: Relationship between biosecurity and biosafety; Biorisk management; Countering biorisks (e.g. accountability, potential misuse) Laboratory biosecurity programmes PHE 3019 TCE 3012 Biosafety 11 Singapore legislation, regulation and SIT Internal guidelines PHE 3019 TCE 3012 Biosafety 12 Local legislation, regulation and SIT Internal guidelines PHE 3019 TCE 3012 Biosafety 13  SIT Internal Biological agents and toxin act (BATA) PHE 3019 Biosafety 14  SIT Internal Role of biosafety in Biopharma Ensures safety during development, production, and distribution of biological drugs and therapies Maintains product quality and efficacy by preventing contamination in biopharmaceutical processes Plays a key role in worker safety, protecting employees from exposure to potentially harmful biological materials Ensures environmental protection by preventing the unintentional release of genetically modified organisms (GMOs) and hazardous materials Ensures regulatory compliance with agencies such as FDA and EMA for product approval and market access PHE 3019 TCE 3012 Biosafety  SIT Internal Components of biosafety in Biopharma Research and Development: Biosafety measures are essential for protecting researchers, especially when working with novel biological entities and genetic engineering techniques. Containment and Control: Different levels of containment, known as Biosafety Levels (BSL), are used based on the potential hazards. Quality Assurance: Biosafety is a key aspect of quality control, preventing contamination and maintaining product integrity. Environmental Responsibility: Preventing the release of GMOs and hazardous materials into the environment is crucial for ecological protection. Public Trust: Commitment to biosafety helps maintain public trust in the biopharmaceutical industry by demonstrating safety and ethical practices PHE 3019 TCE 3012 Biosafety  SIT Internal Safety terminology in pharma PHE 3019 TCE 3012 Biosafety Singapore Biorisk code of conduct  SIT Internal Safety terminology in pharma Singapore Biorisk code of conduct  SIT Internal Safety terminology in pharma Singapore Biorisk code of conduct  SIT Internal Viral vectors PHE 3019 TCE 3012 Biosafety  SIT Internal Viral vectors Commonly used as gene delivery systems Can also be used for human gene therapy As genetic engineering research increases, viral vectors are becoming an important safety issue Prokaryotic or Eukaryotic viruses: Recombinant prokaryotic viruses (bacteriophages) Eukaryotic viruses PHE 3019 TCE 3012 Biosafety 21 SIT Internal  SIT Internal Common eukaryotic Viral Vectors Narrow or wide host range Flexibility in the type of transgene that is delivered Easily produced in the laboratory Common eukaryotic viral vectors:  Adeno-associated Virus  Adenovirus  Retrovirus  Herpes Virus  Vaccinia Virus PHE 3019 TCE 3012 Biosafety 23 Credit: UMDNJ Emergency management & occupational health & safety  SIT Internal Risk assessment of viral vectors Following factors must be considered: PHE 3019 TCE 3012 Biosafety 24 Credit: University of Cincinnati Biosafety office  SIT Internal Viral vector risk group Viral vector has genes removed from genome of wild-type parent to create space for gene of interest and to increase safety Viral vector may regain deleted genes and revert to its original form Important to be aware of risk group classification of parent virus from which the vector originated PHE 3019 TCE 3012 Biosafety 25 Credit: University of Cincinnati Biosafety office  SIT Internal Viral vector risk group Infectious agents are categorized in different risk groups (1-4) based on their relative risk to healthy adult humans PHE 3019 Biosafety 26 Credit: University of Cincinnati Biosafety office  SIT Internal Risk group vs biosafety level PHE 3019 Biosafety 27 Credit: University of Cincinnati Biosafety office  SIT Internal Cell tropism Note: Special care should be taken while working with pantropic or amphotropic viruses which can infect human cells PHE 3019 TCE 3012 Biosafety 28 Credit: University of Cincinnati Biosafety office  SIT Internal Nature of transgene Replication incompetent viral vectors still present risks Even if a viral vector particle does not replicate, it may still infect the individual’s cells and have its transgene expressed Any gene that can significantly alter the cell cycle when over-expressed is a gene of concern Viral vector may contain oligonucleotides intended to inhibit target genes of host Nature of transgene (or gene to be inhibited) is the most important factor to consider while performing risk assessment involving viral vectors PHE 3019 TCE 3012 Biosafety 29 Credit: University of Cincinnati Biosafety office  SIT Internal Reversion prevention Viral vectors are frequently modified to minimize risk of handling Involves deletion of part of viral genome critical for viral replication Replication incompetent vectors can gain back deleted genes required for replication (referred to as replication-competent virus, RCV breakthroughs) Design vectors in a way to decrease chances of RCV breakthrough PHE 3019 TCE 3012 Biosafety 30 Credit: University of Cincinnati Biosafety office  SIT Internal Case study of viral contamination during biologics manufacture Dr. Joy Pang PHE 3019 / TCE 3012 Biosafety 31 Viral contamination during biologics SIT Internal manufacturing Recombinant protein therapeutics, vaccines, and plasma products have a long record of safety. Use of cell culture to produce recombinant proteins is still susceptible to contamination with viruses. These contaminations cost millions of dollars to recover from, can lead to patients not receiving therapies, and are very rare, which makes learning from past events difficult. Case studies provide insights into the most common viral contaminants, the source of those contaminants, the cell lines affected, corrective actions, as well as the impact of such events. Have implications for the safe and effective production of not just current products, but also emerging cell and gene therapies which have shown much therapeutic promise. PHE 3019 TCE 3012 Biosafety Nature Biotechnology | VOL 38 | May 2020 | 563–572 | www.nature.com/naturebiotechnology  SIT Internal History of viral contamination Despite damaging consequences from virus contamination, learning from previous contamination events is a challenge. These events are rare; with only 26 virus contaminations over the past 36 years PHE 3019 TCE 3012 Biosafety Nature Biotechnology | VOL 38 | May 2020 | 563–572 | www.nature.com/naturebiotechnology  SIT Internal Types of contaminating viruses PHE 3019 / TCE 3012 Biosafety Nature Biotechnology | VOL 38 | May 2020 | 563–572 | www.nature.com/naturebiotechnology  SIT Internal Biopharma contamination risks Different host cells, different risks: -67% of reported contaminations involved Chinese hamster ovary (CHO) cells. -33% of events implicated human or primate cell lines. Contamination occurred at various stages: -3 events during preclinical non-cGMP manufacture. -2 during clinical cGMP manufacture. -13 during commercial manufacture. Potential reasons for cGMP contaminations: -Greater scale and media volumes in cGMP production. -Lack of mandatory viral testing in non-cGMP manufacturing. Source of contamination differs: -CHO cell culture: Raw materials or medium components. -Human or primate cell culture: Manufacturing operators or cell line itself. Nature Biotechnology | VOL 38 | May 2020 | 563–572 | www.nature.com/naturebiotechnology Virus Contamination Risks in Therapeutic SIT Internal Production Three Main Risks: 1. Cell Sources 2. Materials Used in Cell Culture 3. Exposure of Process Stream to Operator or Environment PHE 3019 / TCE 3012 Biosafety Nature Biotechnology | VOL 38 | May 2020 | 563–572 | www.nature.com/naturebiotechnology  SIT Internal Risk 1: Cell sources Risks of Animal- and Human-Derived Cell Sources: Use increases viral contamination risk. Strategies include amplification or concentration to detect viruses. Treatment options like gamma irradiation have been considered. Higher safety risk associated with viral contamination in human or primate cell lines due to susceptibility to human-pathogenic viruses PHE 3019 TCE 3012 Biosafety Nature Biotechnology | VOL 38 | May 2020 | 563–572 | www.nature.com/naturebiotechnology  SIT Internal Risk 2: Materials Used in Cell Culture Animal-Derived Raw Materials (ADRM) risks such as serum pose a high risk of virus contamination Industry trends favor the replacement of ADRMs Three of four viruses contaminating CHO cell culture were suspected or confirmed to originate from serum Notably, removal of ADRMs does not eliminate contamination risks. Filter sterilization is common but sometimes not robust enough to keep out viruses PHE 3019 / TCE 3012 Biosafety Nature Biotechnology | VOL 38 | May 2020 | 563–572 | www.nature.com/naturebiotechnology  SIT Internal Risk 3: Exposure of Process Stream to Operator or Environment Exposure to Environment: Potential virus contamination from operators and the environment, especially during open manufacturing steps. Traditional biopharmaceutical processes follow a well-controlled, operationally closed approach. Advanced therapy and medicinal products (ATMP) manufacturing often relies on open cell culture transfers, increasing virus contamination risk. Environmental Contamination Prevention: Use of functionally closed systems with disposable equipment. Closed transfer systems or HEPA-filtered hoods for open transfers. PHE 3019 / TCE 3012 Biosafety Nature Biotechnology | VOL 38 | May 2020 | 563–572 | www.nature.com/naturebiotechnology Challenges in viral detection during SIT Internal biomanufacturing Viruses may persist in the environment and raw materials. Testing of raw materials does not consistently detect contaminating viruses. In only 3 events, viral contaminants were directly detected in the suspect raw material. Amplification or concentration of the raw material was necessary to achieve detectable viral loads PHE 3019 / TCE 3012 Biosafety Nature Biotechnology | VOL 38 | May 2020 | 563–572 | www.nature.com/naturebiotechnology  SIT Internal Impact of contamination events in Biopharma Investigation Duration: Severity determines investigation duration (may last a few months). Financial Costs: Reported investigation costs range from $1 million to $10 million. Worst cases may exceed hundreds of millions. Competitive Disadvantage: Contamination events can lead to a competitive disadvantage for products. Manufacturing Interruptions: Viral contaminations result in plant downtime (~1 - 2 months). Financial Consequences: Loss of revenue, discarded batches, and lawsuits. Decreased company reputation and stock value. Delays in Product Development: Contaminations lead to significant delays in product development. Impact on Patients: Patients may experience modified treatment regimens. Some patients may not receive adequate drug levels until manufacturing operations are restored. PHE 3019 / TCE 3012 Biosafety Nature Biotechnology | VOL 38 | May 2020 | 563–572 | www.nature.com/naturebiotechnology  SIT Internal Manufacturing shutdown PHE 3019 / TCE 3012 Biosafety Nature Biotechnology | VOL 38 | May 2020 | 563–572 | www.nature.com/naturebiotechnology  SIT Internal Virus Risk-Mitigation Strategies Viral-Vectored Gene Therapy: Plasmids used in biologics production should be virus-free. Master virus banks characterized for adventitious viruses. Testing for viruses: Difficult to test for adventitious viruses in recombinant viral stocks. New detection technologies like high-throughput sequencing explored Raw Material Control: Direct testing of raw materials had limited value. Some biopharmaceutical manufacturers treat media to inactivate or remove potential viruses. PHE 3019 TCE 3012 Biosafety Nature Biotechnology | VOL 38 | May 2020 | 563–572 | www.nature.com/naturebiotechnology  SIT Internal Virus Risk-Mitigation Strategies Three Complementary Approaches: Prevention of Virus Entry: Selection of low-risk starting and raw materials. Manufacturing controls to reduce virus risk. Testing of In-Process Materials: Ensuring materials are virus-free and enabling lot rejection. Clearance of Virus: Virus inactivation and/or removal. Extraordinary importance in reducing the risk of virus contamination. PHE 3019 TCE 3012 Biosafety Nature Biotechnology | VOL 38 | May 2020 | 563–572 | www.nature.com/naturebiotechnology  SIT Internal Common viral clearance methods PHE 3019 TCE 3012 Biosafety Nature Biotechnology | VOL 38 | May 2020 | 563–572 | www.nature.com/naturebiotechnology Implications for Cell and Gene Therapy SIT Internal Manufacturers Expanding Landscape:  Increasing regulatory approvals for several cell and gene therapies Patient-Centric Approach:  Autologous cell-based products often as last-line treatments.  Contamination-related delays have severe consequences for patients Challenges and Resources:  Practical steps to reduce virus contamination risk are challenging.  Organizations without established viral safety practices and limited resources face unique hurdles. PHE 3019 TCE 3012 Biosafety Nature Biotechnology | VOL 38 | May 2020 | 563–572 | www.nature.com/naturebiotechnology