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Frequently Asked Questions about viral vectors
Biopharmaceuticals

Frequently Asked Questions about viral vectors

 

[Viral vectors] General questions about viral vectors

Viruses have evolved over millions of years to reach and enter specific target cells where they seize the cellular machinery to express viral genes and assemble progeny particles. Hence, viral vectors represent the most effective means of gene transfer to modify specific cell types or tissues and can be manipulated to express genes of therapeutic interest.

Viral vectors are usually derived from parental wild type viruses whose viral genes (essential for replication & virulence) have been replaced with the genes of interest. They can be used as in vitro or in vivo tools for biomolecular and gene functional studies, but also to transfer therapeutic genes in patients in order to treat genetic disorders, fight cancer, muscular or CNS degeneration, or elicit immunological responses against infectious pathogens (vectorized vaccines).

Viral vectors can be used as in vitro or in vivo tools for biomolecular and gene functional studies, but also to transfer therapeutic genes in patients to treat genetic disorders, fight cancer, muscular or CNS degeneration, or elicit immunological responses against infectious pathogens (vectorized vaccines).

Viral vectors can be injected directly into a specific tissue in the body (eyes, liver, CNS, tumor...), where it is taken up by individual cells (in vivo gene therapy). Alternately, a sample of the patient's cells (such as haematopoïetic stem cells) can be removed, genetically modified by a viral vector in a laboratory setting and then returned to the patient (ex vivo gene therapy).

Vectors based on lentivirus, adenovirus and adeno-associated viruses (AAV) are the main viruses currently being used in gene therapy. There is no universal vector suitable for all applications, instead each vector has its own characteristics with specific advantages & drawbacks (see question 4).

Lentivectors infect both actively dividing and non-dividing cells. They can stably integrate their genetic material into human chromosomal DNA and can thus express their therapeutic gene for long-term.

Adenoviral vectors infect both actively dividing and non-dividing cells. In contrast with Lentivectors, they don't integrate their genome into host cell’s DNA. Hence, they express the transgene transiently, which is a desirable property for expressing genes whose biological activity doesn't require a stable expression, as it is the case for vaccines or cancer gene therapy.

AAV vectors infect both actively dividing and non-dividing cells. Upon infection, their genome is maintained as extrachromosomal episomes, allowing stable transgene expression in non-dividing cells (episomes being progressively diluted in dividing cells).

- AAV vectors 

Benefits     Drawbacks

> Parental virus is apathogenic
> Long-term expression of the transgene
> Episomal vector
> Low immunogenicity
> Transduce non-dividing & dividing cells
> Numerous serotypes with different tropisms

> Low DNA packaging capacity (4.5kb)
> Empty vector particles generated during the manufacturing process
> Pre-existing immunity
> Highly resistant vector particles

 

- Adenovirus vectors 

Benefits Drawbacks

> Ensure high level of transgene expression
> Transduce non-dividing & dividing cells
> Larger cloning capacity
> Tumor-targeted replication of specifically
designed oncolytic adenovectors
> Vector particles produced at high titer

> Highly immunogenic
> The vector genome does not integrate into the host cell genome
> Transient transgene expression only
> Pre-existing immunity (AdV5)
> Risk of inflammatory response

 

- Lentivirus vectors

Benefits Drawbacks

> Long-term expression of the transgene
> The vector genome integrates into host cell genome
> Low immunogenicity
> Transduce non-dividing & dividing cells
> VSV-G pseudotyped LV have a broad host-cell
range and confer a high particle stability

> DNA packaging capacity relatively limited (10kb)
> Possible insertional mutagenesis
> Enveloped particles are poorly resistant,
which makes their storage, production and purification difficult
> Few pseudotypes available (mainly VSV-G)

The latest generations of viral vectors are designed so that they are unable to replicate autonomously and do not generate competent viruses by recombination. They contain only the minimal viral sequences required for their efficient production and vector function while potential toxic/virulence genes have been eliminated.

Therapeutic genes carried by last generation viral vectors are not considered as toxic and do not question the biosafety risk of the vector. Viral vectors production and purification are performed under biosafety level two (BSL2).

 

[Viral vectors] Track record in viral vector manufacturing

For more than 20 years, Novasep provides process development and manufacturing services for viral vectors from pre-clinical supply to commercial manufacturing.

To learn more about the number of viral vector projects we transferred/performed over the last five years:

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Find out how many viral vector batches we have produced and released in the last five years:

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To learn more about our experience in late-stage programs: 

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To learn more about our experience in viral vector process validation and commercial manufacturing:

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[Viral vectors] Development services

Novasep offers both analytical & process development services for viral vectors. Regarding the process development, Novasep can develop/adapt/optimize upstream and downstream processes.

Novasep also offers scale-up services up to 48CS10/30HS36 in adherence culture mode, and up to 1,000L or 2,000L in suspension culture mode, for clinical or commercial supply, respectively.

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Yes, Novasep has accumulated a substantial experience in the development of manufacturing processes for a large variety of viral vectors. A significant number of processes have been fully developed and successfully transferred to GMP manufacturing for phase I/II to late clinical development stages.

To discover the types of manufacturing processes used to produce & purify the different viral vectors:

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Viral vector production in adherence is convenient for the supply of clinical material destined to a limited number of patients, typically for orphan drug applications, and when the cell population targeted by the gene transfer is reduced (e.g., the retina). Advantages of this approach include the relative ease & speed of implementation and the limited cost of this technology. Numerous clinical phase biotech companies opt for this strategy for their proof-of-concept studies. However, this mode of production is limited in its scalability.

In contrast, when the clinical application concerns a large population of patients (such as cancer therapies) and/or when the cell population targeted by the gene transfer is large (such as the liver cells), it is mandatory to develop from the outset a well scalable manufacturing process. The production in suspension mode is more desirable for this later approach.

Yes, Novasep is very experienced in the transfer of manufacturing processes from lab-scale to well developed or validated processes either in R&D or directly in GMP facilities for early & late clinical development stages.

Find out more about the estimated timeline for a process development project:

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[Viral vectors] Manufacturing services

Our two Novasep sites in Belgium, located in Gosselies and Seneffe, offer viral vectors manufacturing services. They are located 40 km south of Brussels, near Brussels South Airport.

To learn more about the estimated timeline for a clinical viral vector manufacturing project:

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Taking into account the usual timelines required to select a CDMO then to initiate the project until the clinical manufacturing, it is recommended to anticipate the outsourcing of viral vector manufacturing as well as all related activities at least one year before the estimated start of the clinical manufacturing.

The technology transfer is planned and managed by Novasep Manufacturing Sciences and Technology team (MSAT) in charge of process transfers.

Novasep regularly produces viral vectors for clinical supply up to phase III and commercial launch.

Yes, Novasep has 2 state-of-the-art commercial facilities on its Seneffe site: Senrise-IV is a multi-USP/DSP clean room facility with two independent manufacturing lines allowing to produce Drug Substances up to the USP scale of 2,000L. Senefill is a Fill & Finish facility for the production of commercial Drug Products with a capacity to produce up to 10,000 vials made in resin or glass, with a wide range of vial sizes.

Yes, Novasep offers stand-alone Fill & Finish services for various biologics such as recombinant proteins, plasmids, biological extracts, vaccines, living GMOs and viral vectors. Novasep can handle GMO & biologic products up to BSL2.

To learn more about viral vector products storage: 

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[Viral vectors] Analytical services

To discover Novasep's analytical capabilities for viral vectors:

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Novasep can take in charge the development, pre-validation, transfer & validation of analytical methods for viral vectors from early to late clinical development stages in order to support process development, characterization, validation or commercial manufacturing.

Novasep is used to transfer analytical methods for early to late clinical development stages. The analytical transfer from the CRO or customer to the Novasep analytical development or QC team is duly planned and performed through a stepwise process compliant with EMA & USP/FDA guidelines.

Analytical assays are submitted to a technical review in order to decide the best way to internalize it. Usually, assays are implemented in the Analytical Development laboratory (AD) to support process development/transfer. These methods are then pre-validated before being transferred to the Quality control laboratory (QC) when a "fit for purpose" status is demonstrated. QC then performs a formal validation if the clinical development stage of the program requires it.

Each step is documented by protocol and report.

Novasep will typically either partially or fully validate analytical methods for early to late clinical development stages. AD laboratory classically pre-validates the method to demonstrate the "fit for purpose" status, while QC laboratory performs a formal validation according to ICH Q2 R1 guidance.

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Discover which type of stability studies Novasep can perform:

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[Viral vectors] Equipment and scale-up for viral vectors manufacturing

Discover Novasep’s capabilities in terms of R&D, clinical and commercial cGMP facilities for viral vectors:

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To learn more:

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[Viral vectors] Quality and Regulatory Affairs

Our sites in Belgium have recently been successfully inspected by the Belgian Authorities (FAMHP - Federal Agency for Medicines and Health Products) "representing" the EMA:
> Our Gosselies site has been inspected in 2018
> Our Seneffe site has been inspected in 2020

Our QA system is also assessed and improved periodically through Novasep self-inspections and customer audits.

Yes, Novasep can provide, in the frame of the project, the support for the supply of documents or information necessary for the customer to make its BLA.

Procedures are in place to guarantee a good segregation between batches to avoid any risk of cross-contamination

This segregation concerns particularly the type of activity, flows of personnel, material, waste, intermediate or finished products, but also the aspects of cleaning, decontamination, environmental monitoring, classification of premises, pressure cascades, etc...

Yes, Novasep has Qualified Persons on site to ensure the release of viral vector drug products.

 

[Viral vectors] Project Management

At Novasep, we consider Project Managers to be central for the success of a project. The Project Managers act as single points of contact for the customer, interfacing with Novasep teams (R&D, Production, Supply chain, QA, QC, Finance). The Project Manager will be key in the definition of the scope of work, work packages and associated budget and timelines. The Project Manager is responsible to set regular meetings, internally with Novasep teams to ensure milestones are being met, and with the customer to share any project update.

To find out how Novasep's team handle scope changes:

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Downloads
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