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Vaccine Production

Vaccine Production

Securing process quality with flexible manufacturing solutions for all vaccine platforms

 

From the first inspiration in the late 18th century to gene-based DNA and RNA vaccines and novel cancer immunotherapies  vaccines teach the body’s natural defences to target unwanted bacterial, viral and cellular threats. The antigens that have been used to form the foundation of this instruction include whole bacteria or virus, and sub-units such as polysaccharides or proteins, and these may be conjugated to additional proteins or combined with other adjuvants to enhance the immune response.

 

This diversity in the type of vaccine antigen, along with the inherent variation in the targets, have created challenges for vaccine manufacturers when compared to a relatively small number of platform processes that exist for other biotherapeutic production processes. Smaller batches and facilities configured for multi-product  manufacturing require responsive production systems to reduce lead times and production costs. Accelerating vaccine development and manufacturing by coupling research advances in vaccine technology with systems that support agility through a Quality by Design approach is critical to deliver life-saving immunizations to those in need globally.

 

Antigens can be generated ex-vivo, directly from the target cell or virus, or indirectly via recombinant expression systems.  Increasingly research looks to ways to generate antigens in-vivo via the genetic modification of cells. This genetic modification can be achieved using DNA or RNA which are themselves generated via an expression process (pDNA production) or chemically synthesized (mRNA ). 

 

Each class of vaccine presents specific process development and manufacturing challenges, and the scale of production varies depending upon the targeted disease. As a result, there is no single vaccine manufacturing approach. There are, however, flexible technologies that can meet each of the challenges during process development and at GMP scale. These customizable technologies can be applied separately but can also be combined to design robust, integrated, flexible platforms that support rapid process development and safeguard the quality of life-protecting vaccines, where closed-systems and aseptic processing is essential.

 

Pall’s innovative  process technologies have been an important contributor to the success of many vaccine production processes, and we are constantly working with the industry to enhance our solutions to meet new vaccine development and manufacturing challenges. Our Scientific and Laboratory Services (SLS) teams are available to work with you to create a platform configuration which meets your specific vaccine production needs.

 

Contact us to discuss how we can help you to get up and running quickly or drive efficiencies in your current processes.

 

 

 

Vaccine Type

Antigen

Typical Process

Nucleic Acid Vaccines

Plasmid DNA (pDNA)

Messenger RNA (mRNA)

Recombinant vector vaccines

Fermentation

Chemical synthesis

Cell culture

Recombinant Vaccines

Recombinant protein

Recombinant virus

Cell culture

Sub-Unit Vaccines

Recombinant protein

Polysaccharides & Peptides

Conjugates

Cell culture (mammalian / insect)

Fermentation (bacterial / yeast)

Bacterial Toxoid Vaccines

Toxoid proteins

Fermentation

Whole Cell Vaccines

Live attenuated virus

Live attenuated bacteria

Mammalian cell culture

Microbial cell culture

Inactivated bacteria

Inactivated virus

Microbial cell culture

Egg based / Mammalian cell culture

Nucleic Acid Vaccines

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Together with recombinant vaccines, nucleic acid vaccines represent the fastest growing class and are particularly suited to rapid vaccine development in response to emerging viral threats.  The genetic material may be DNA or mRNA and is encoded to produce the targeted antigen in-situ. Delivery of the genetic material to the target tissues can use several vectors including lipid nanoparticles (LNP), viral vectors and plasmid DNA, or the uptake enhanced using techniques such as electroporation.

mRNA Vaccines

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Chemically synthesized and encoded to directly generate specific disease antigens, this new class of vaccine can be quickly developed and scaled rapidly to make clinical material available for trials and commercialization.  They also hold promise for the prevention and treatment of various cancers by targeting tumor-associated antigens.

 

The synthetic nature of this class of vaccine simplifies the manufacturing challenges compared to more complex biological processes and is generally perceived as having a strong and predictable safety profile as a result. Despite these apparent advantages, challenges relating to the stabilization and delivery of the genetic material to the target cells exist and may provide particular challenges throughout the generation of drug substance and the final formulation and filling processes.

 

Specifically, the use of lipid nanoparticles (LNP) is being investigated as a delivery mechanism, however, it is known that these complex formulations can be susceptible to the low throughput of some sterilizing grade filters and carry increased risk of bacterial penetration without careful filter selection and validation.

 

Purification

 

Ultrafiltration membranes used during diafiltration and product concentration stages may be applied for size-based purification.

 

Anion exchange membrane chromatography may be applied for endotoxin control and change-based contaminant removal.

 

Filtration

 

Complex formulations, can create unique filtration challenges and careful filter selection is required to maintain high yields.

 

High throughput capsules reduce filter size-related product loses and maintain high yields.

 

Fluid Handling

 

Maintaining the cleanliness of manufacturing processes is a central element of manufacturing in accordance with cGMP.  The use of single-use systems can vary from the collection and transfer of process components in bioprocessing bags to complete integrated and automated single-use manufacturing processes.  These support closed manufacturing processes that assist with multi-product manufacturing to deliver cost effective, responsive and agile processes. 

DNA Vaccines – Plasmid Vectors

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Vaccines using plasmid DNA to transfect cells cause the intracellular expression of one or several antigens relating to target pathogens or cancerous cells.  While the plasmid may code for different changes, these are similar to some stages during the production of viral vectors used for gene therapy applications.  The scale will vary depending upon the target disease however the production processes are essentially the same.

 

Plasmid DNA Production

 

Plasmid production processes, common with gene therapy applications can be found here

 

Single-Use Processing

 

From media preparation to cell culture and purification, the use of single-use systems and bioreactors, coupled by sterile connectors and disconnectors, helps maintain the safety at all stages of the production process, final formulations and filling.  These intrinsically closed processing solutions also support rapid turnaround of different processes in multi-product facilities.

DNA Vaccines – Viral Vectors

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Viral vector DNA vaccines use harmless viruses such as poxvirus and adeno-associated virus (AAV) to deliver eingineered genetic instructions to the target tissue.  These sequences are encoded to cause these tissues to produce the desired anitgens which, in turn, then stimulate the immune system to generate antibodies.

 

These processes are shared with gene therapy applications and leverage the same technology, especially supporting industrial scale solutions for the adherent and suspension cell culture that multiply these viruses.  When coupled with platform purification processes, thsese vaccines can be developed and industrialized rapidly.

 

Viral Vector Production

 

Viral vector production is widely used in gene therapy process and relevant technology can be found here

 

Single-Use Processing

 

From media preparation to cell culture and purification, the use of single-use systems and bioreactors, coupled by sterile connectors and disconnectors, helps maintain the safety at all stages of the production process, final formulations and filling.

Recombinant Virus Vaccines

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Viruses, engineered to look like a wild virus strain to a body’s immune system, but without the undesirable effects, hold much promise as platform vaccines.  The manufacturing processes share similar technologies with both gene therapy and monoclonal antibody production depending upon the producer cell-line.

 

Upstream

 

Single-use bioreactors to support both suspension and adherent cell cultures 

Sterilizing grade gas filtration

Sterilizing grade liquid filtration for media filtration and sterile additions

 

Harvest and Clarification

 

Maintaining a high virus yield while separating the virus from the host cells requires careful optimization.  The use of single-use depth filtration platforms simplify the clarification and the choice of the right grades will ensure recovery is optimized.

 

Media Preparation

 

Solutions for buffer and media preparation to support upstream processing include mixing applications, storage and transport.  Additional operations such as sterile filtration can be integrated with mixing technologies to create robust automated solutions

 

Purification

 

Concentration and diafiltration for size-based separation of contaminant using ultrafiltration cassettes.

 

Anion exchange membrane chromatography simplifies the removal of endotoxin and change-based contaminant removal such as host cell DNA, proteins and endotoxin.  It may also be applied for bind-elute operations to purify and concentrate virus without high shear ultrafiltration.

 

For processes including mammalian cell cultures viral safety is an important consideration and can be managed with orthogonal controls such as inactivation and virus filtration.

Recombinant Vaccines

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Yeast, bacterial, mammalian and insect cell lines may be used depending on the complexity of the antigen being produced and several may be combined (conjugated) to illicit the desired immune response.  When using mammalian cell lines, these processes share the upstream challenges of monoclonal antibody production and leverage the range of cost-effective solutions available for the development and manufacture of these vaccines.

Upstream

 

Maintaining a monoseptic environment is essential for a successful production process.  This can be supported with the use of single-use technology integrating filtration and single-use bioreactors.

Sterilizing grade gas filtration

Sterilizing grade liquid filtration for media filtration and sterile additions

 

Harvest and Clarification

 

Partnered with centrifugation or used on its own, the removal of whole cells and cellar debris can be easily achieved using single-use depth filtration systems optimized for throughput and yield.

 

Stax single-use depth filtration platforms support the simple clarification of post-centrifugation and low turbidity cell cultures

 

For mammalian and insect cell cultures the Stax mAx clarification platform provides a simple, scalable solution even for high turbidity harvest.

 

For challenging bacterial lysates the PallSep Biotech MF system provides a robust solution for low volume <500 L processes.

 

Media Preparation

 

Solutions for buffer and media preparation to support upstream processing include mixing applications, storage and transport.  Additional operations such as sterile filtration can be integrated with mixing technologies to create robust automated solutions

 

Purification

 

Concentration and diafiltration for size-based separation of contaminant using Delta ultrafiltration cassettes.

 

Mustang XT Anion exchange membrane chromatography for endotoxin control and change-based contaminant removal such as hot cell DNA, proteins and endotoxin.

 

For processes including mammalian cell cultures viral safety is an important consideration and can be managed with orthogonal controls such as inactivation and virus filtration.

 

Fluid Handling

 

Maintaining the cleanliness of manufacturing processes is a central element of manufacturing in accordance with cGMP.  The use of single-use systems can include unit operations such as the collection and transfer of process components in bioprocessing bags to complete integrated and automated single-use manufacturing processes.  These support closed manufacturing processes that assist with the rapid turn around and multi-product manufacturing to deliver responsive and agile processes.

Bacterial Toxoid Protein Vaccines

Read more

Using inactivated bacterial toxins (toxoids) as the antigen, these vaccines protect against certain bacterial threats such as diphtheria and tetanus.

 

Upstream

 

Maintaining a monoseptic environment is essential for a successful production process.  This can be supported with the use of single-use technology and maintained with filtration.

 

Single-use bioreactors

Sterilizing grade gas filtration

Sterilizing grade liquid filtration for media filtration and sterile additions

 

Harvest and Clarification

 

Partnered with centrifugation or used on its own, the removal of whole cells and cellar debris can be easily achieved using single-use depth filtration systems optimized for throughput and yield.

 

Stax single-use depth filtration (e.g grade K100P)

 

Media Preparation

 

Mixing solutions for buffer and media preparation to support upstream processing and formulation

 

Sterile filtration

 

Purification

 

Concentration and diafiltration can achieve the size-based separation of contaminants using ultrafiltration cassettes.

 

Anion exchange membrane chromatography may be used for endotoxin control and the removal of contaminants through charge based interactions.

 

Fluid Handling

 

Kleenpak® Presto sterile connectors and Kleenpak sterile disconnectors control risks associated with the connection and disconnection of fluid paths to safeguard operators, quality and simplify processing when using single-use manufacturing technology.  Such solutions are perfect for the aseptic formulation of multivalent vaccines where sterile filtration may not be possible after the addition of some adjuvants.

Live Attenuated Vaccines

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First generation vaccines, include the majority of influenza vaccines and use attenuated or inactivated virus. In the case of influenza vaccines these are historically produced from the inoculation of embryonic chicken eggs.  Recent developments using mammalian cell-based cultures such as human embryonic kidney (HEK)-293 cells or Manin-Darby canine kidney (MDCK) cells have the potential to improve the effectiveness of the vaccine and permit greater process flexibility.

 

Maintaining sterility throughout a series of large-scale manufacturing and formulation steps requires careful process design. The need for strict controls increases with the addition of some adjuvants which make the addition of sterilizing grade filtration impractical due to the removal of these adjuvants by the filtration process.  To meet these challenges, aseptic conditions need to be maintained throughout the process and can be simplified through the use of single-use closed processes.

 

Harvest and Clarification

 

Solutions vary depending upon the cell culture process.  For cell-based vaccines, these also depend on the cell-line however single-use depth filtration is a strong 

 

For processes such as egg-based cultures the use of polymeric depth filters work well in conjunction with centrifugation to remove solid contaminants ready for further purification and formulation.

 

Fluid Handling

 

Kleenpak® Presto sterile connectors and Kleenpak sterile disconnectors help to maintain the sterility during the connection and disconnection of fluid paths throughout the process.  When combined with bioprocessing bags and tubing transfer sets these single-use fluid flowpaths can be used to combine multiple strains of vaccine to simplify the processing while safeguarding quality.