A vaccine is a biological product that provides active acquired immunity to a particular disease. It contains an agent that is weakened or killed forms of the microbe or viruses, or resembles disease-causing microorganisms. This agent stimulates the body’s immune system to destroy a particular disease. Vaccination is one of the greatest achievements of medical biotechnology sector. When compared to the pre-vaccine era, humans had few defense against infectious disease 12. Despite this, vaccines have been used as protective agents against 12 major infectious disease, such as diphteria, tetanus, yellow fever, smallpox, pertussis, poliomyelitis, Haemophilus influenzae type b disease, measles, mumps, rubella, rabies and typhoid 42. In the current era, vaccines also be used as effective tools against the emergence of infectious disease in the world, such as cervical cancer that caused by Human papillomavirus, influenza, rotavirus, etc. The more than 1 billion doses of vaccines manufactured worldwide are given to people each year. The vaccine manufacturing is one of the most monitored, rigorously designed, and compliant products manufactured today (Gomez, et.al, 2008).
However, behind the success of vaccination, there are some controversies among parents. These controversies could be affected the vaccine distribution to targeted populations. Most public health experts recommend 95% of the population should be vaccinated to achieve herd immunity and minimize the possibility of resurgence of deadly infections 45. The controversies and dilemma in vaccine distribution could influence parents for not vaccinating their children. It will be a huge threat of immunization program. Although vaccine manufacturers have developed very effective and great vaccines, it come non sense when the targeted populations do not have themselves vaccinated.
Bacterial antigen vaccines
There are numbers of bacterial antigen vaccines, such as tetanus, pertussis and diphteria toxoid vaccines that have similar process for vaccine production. The production of toxoid vaccine starts with the growth of organism based on the products that will be produced, for instance Clostridium tetani for tetanus toxoid vaccine, Bordetella pertussis for pertussis toxoid vaccine, and Corynebacterium diphteriae for diphteria toxoid vaccine.
The selected culture of the organism then being obtained, expanded and frozen in order to create a master seed for the future production. To start individual batches of product, this master seed should be expanded to make working seeds. Viable cell density then should be obtained to achieve sufficient amount to inoculate the production bioreactor. The culture is harvested after the organism expands in the bioreactor. This product then called as single harvest. The toxin recovers from the cells after centrifugation or filtration process. The centrifugation and/or filtration is a process to remove cells to harvest the toxin from it. Then, the toxin is treated with chemical agents such as formaldehyde, which causes the toxin molecules to cross-link eliminating the toxicity, but retaining the protein structure needed to elicit a protective immune response. This process result called as toxoid.
The toxoid is purified by a variety of methods which may include ultrafiltration (separation of the toxoid from impurities based on size differences), chromatography (separation of toxoid from impurities based on differences of charge and/or size), fractionation and precipitation (addition of a salt to cause the toxoid or impurities to selectively precipitate and to be removed from the solution). The toxoid is tested for appearance, sterility, antigen purity, specific toxicity, reversion to toxicity, test for residual free detoxifying agent/ formaldehyde content and potency prior to formulation into the final vaccine.
Toxoid may be mixed with an adjuvant to increase the immune response. For instance, tetanus toxoid is adjuvated with aluminum salts (natrium phosphate, aluminum hydroxide, aluminum phosphate, etc.). It can be administered as a monovalent vaccine or mixed with other toxoids, as well as other antigens, in a combination vaccine. The toxoid generally stable in this form without any special processing or additional component as a stabilizer. However, the final product may be mixed with preservative and buffer for maintaining its quality during storage condition. Within all the process, the environment should be monitored for humidity, temperature, number of particle, and number of microorganisms. The environment monitoring (EM) is to prevent the culture contamination.
In some cases, the antigen needs to be extracted from the cell paste following the bioreactor harvest (polysaccharide-based vaccine processes for Haemophilus influenzae type B; meningitis types A, C, W135, and Y; and pneumococcal vaccines, recover the polysaccharide from the cell wall). In some cases the purified product is not stable and needs to be lyophilized. Lyophilization, also known as freeze-drying, is a process that allows the removal of water at low temperatures to maintain potency during the manufacturing process and providing greater stability of the final drug product during storage and distribution to the end user.
Live Virus Vaccine
Live virus vaccine is the most effective means of developing a robust and protective response, often with a low vaccine dose. LVVs is made by the inoculation of a replication competent virus. The viruses used in production are altered from wild-type viruses to weaken, or “attenuate” them such that a robust protective response is obtained without severe disease. In some cases, the virus may not replicate in the human host (cowpox used to protect from smallpox) or be altered genetically such that it does not replicate. Similarly, the live virus may be innocuous but used as a viral vector vaccine to deliver other antigens (an approach being tested for Ebola vaccine). LVVs use a serial passage of pathogenic virus tissue culture or animal hosts.
Since LVV is using virus, so it adds more complex to the process. Viruses need a living organism to amplify and make a viral expansion in a cell culture. The cell culture system is needed for the viral axpansion. For example in live-attenuated polio vaccine manufacturing process, it strats with the growth in fertile mmonkey kidney cells. The target virus is injected to the the kidney cell and then infects the cell and after several days, they will be replicated and the virus is harvested from the kidney cell. After that, the purification process and formulation will be conducted to create a final vaccine. The LVVs use monkey kidney cells that are passed the quality control test, such as sterility and test for adventitious agents (WHO, 2014). Live-attenuated influenza vaccine has similar manufacturing process, but it uses chicken embryo to replicate the viruses.
Many LVVs use an immortalized cell line which has been thoroughly tested and certified to be free of adventitious agents that would have a deleterious effect on the manufacturing process or vaccine safety. These cell lines, similar to the master seeds for the bacterial products, are specific for each product and are frozen into master and working cell banks allowing long-term availability and viability of the cells and manufacturing processes they support. Many cell lines require an attached surface to multiply and to be viable through the manufacturing process (eg, Vero cells, MRC-5 cells); this requires special equipment and processing to support the virus expansion.
The most popular options for this production are roller bottles (bottles slowly turning to allow nutrients to wash over growing cells, while controlling temperature and dissolved gas concentration), flat plate reactors (which have multiple parallel plates for cell culture attachment and growth, pumping nutrients through the device), or microcarriers (small beads in suspension in a bioreactor allowing a surface for growth and bioreactor mixing for nutrient replacement). In each case, as the cells expand and need to be transferred to a large-scale device, they must be detached, typically with addition of an enzyme like trypsin, then reattached to the new surface (by removal/dilution of trypsin and addition of other nutrients).
With these processes being done in a sterile environment, the equipment costs and complexity is high, often requiring robotics and clean room operations to reduce risk of failure. Once the expansion of the culture is complete, which could take several weeks, the culture is infected and the viral production is generally fairly fast (several days). When infection is complete, the virus may be collected from the culture media (if secreted) or purified from the disrupted cells.
Unit operations in this case are similar to those described in bacterial antigen production. Because a virus needs a living cell to expand, once the cells are removed, the virus may have limited stability. The processing times are strictly controlled to limit degradation of potency and often the material is frozen to −20 or −70°C to preserve potency between manufacturing steps. Most LVVs are ultimately freeze-dried (MMR, varicella) or may be delivered frozen (live attenuated influenza vaccine). Some need to be frozen until use even after lyophilization to prolong shelf life. There are exceptions like rotavirus vaccine which is stable at 2–8°C for 2 years.
Inactivated virus vaccine
The Inactivated virus vaccine would produce the viral antigen similar to the processes described for LVVs, but the virus is inactivated by chemical means to render it noninfectious. The exposure to the viral proteins, without an active infection, can produce protection against the disease in many viral diseases. The inactivation may take place before or after purification. The best examples of inactivated virus vaccines include inactivated polio vaccine which largely grown in monkey kidney cell culture, where the virus is inactivated with formaldehyde or BPL (b-propiolactone); inactivated poliovirus vaccine, grown in Vero cells on microcarriers in large bioreactors, inactivated with formaldehyde; and hepatitis A vaccine, grown in MRC-5 cells on flat plate reactors and inactivated with formaldehyde.
The production of several vaccine antigens without using the native infectious organism is available to do today because of the advances of genetic engineering.
Advances in genetic engineering have allowed the production of several vaccine antigens without use of the native infectious organism. In this case, a yeast culture, such as Saccharomyces cerevisiae can be altered to produce a vaccine antigen such as the hepatitis B surface antigen (HBsAg), which protects against hepatitis B infection. In this case the process resembles the bacterial antigen process. At the end of the fermentation process, the HBsAg is harvested by lysing the yeast cells. It is separated by hydrophobic interaction and size-exclusion chromatography. The resulting HBsAg is assembled into 22-nm diameter lipoprotein particles. The HBsAg is purified to greater than 99% for protein by a series of physical and chemical methods. The purified protein is treated in phosphate buffer with formaldehyde, sterile filtered, and then coprecipitated with alum (potassium aluminum sulfate) to form bulk vaccine adjuvated with amorphous aluminum hydroxy phosphate sulfate. The vaccine contains no de- tectable yeast DNA but may not contain more than 1% yeast protein (Parkman, 1999; Mahoney % Kane, 1999; CDC, 2000) Similar approaches are used to make human papillomavirus (HPV) vaccines.
THE PROCESS OF VACCINE MANUFACTURING AND DISTRIBUTION
This section outlines some key considerations in developing, licensing, and maintaining a vaccine for safe, consistent, and reliable supply. It should not be considered a complete list of requirements or considerations, but is used to illustrate the complexity and challenges of development and manufacturing vaccines for people not in the vaccine manufacturing industry. The section is divided into methods of manufacturing (including starting materials), manufacturing components, supply chain, supporting systems, facilities, process development and validation, analytical development and validation, characterization, and quality systems.
Methods of manufacturing
There are two key points worth repeating from the opening of this chapter— vaccines are generally given to healthy people to reduce the future risk of disease, hence, it is important that they do not cause any harm to the patient. Besides the obvious impact to the patient, a vaccine considered to be unsafe would risk low acceptance and compliance with vaccination recommendations and therefore increase the risk of disease outbreaks in the greater population. Second, the starting materials are a critical resource and need to be fully characterized, shown to be safe, performant, and stable, and made available in sufficient quantities to support long-term supply. The safety database is generated in clinical trials using the starting materials of early development and manufacturing and they are the foundation of the safety profile. Changes to the vaccine starting materials (or any element of the vaccine manufacturing process) may result in unanticipated changes to the vaccine performance and safety and are strictly regulated to ensure safety and effectiveness.
The master cell bank needs to be of a certified source (eg, from a previously licensed cell bank), or fully documented to show the source of the cells and the materials used to produce/expand the cells that are free of risks to the patient. These risks include adventitious viral agents in the cell bank from the original source material or from the media and reagents used to expand the cell bank, tumorigenicity of the cell line, genetic stability of the cell line, and long-term viability of the cell line (ability to freeze, thaw, and use for many years or de- cades). Points to consider have been published by FDA for characterization and certification of cell lines for use in biological manufacturing and are updated based on growing experience and advancement of analytical methods.
The first step in manufacturing is the establishment of a “master seed.” This is a collection of vialed cells which form the starting material for all future production. It is extensively characterized for performance, stability, and the absence of any adventitious agents. For viral production, the master seed includes a “master cell bank” and a “master virus.” From this bank, working cell banks are prepared, which are used as the routine starting culture for production lots. The final vaccine is a direct function of its starting materials, and a change in this seed can be as complicated as initiating a new product development altogether. Hence, manufacturers are advised to make sufficient master seed materials to support the full life-cycle of production, which can be several decades for vaccines.
Similar to cell banks, the source of virus for the viral master seed and the culture for the master seed of microbial and recombinant products needs to be carefully documented, reagents used certified to be safe-sourced and/or tested to be free of adventitious agents, and stable for long-term use in manufacturing. For recombinant products, the seeds need to show genetic stability such that the genes inserted to produce the target molecule do not change over time from what was tested in clinical studies used to license the product.
With starting material secured, the raw materials used to expand the seeds, produce, purify, and inactivate the products must be likewise shown to be safe, stable, and readily available for long periods of time without substantial change in composition. A significant challenge in vaccine manufacturing is that many raw materials are of biological origin (extracts of animal, plant, or microbial origin) and are subject to significant, sometimes undetectable, variability in normal raw material release testing.
The variability in the raw materials adds to the inherent variability of the biological manufacturing process creating a challenge for the reliable supply of the product. Ideally, complex, biologically sourced raw materials are replaced with chemically well-defined entities with less variability and higher purity profiles. In many cases, these materials are not readily defined, available, or cost-effective such that the cost of manufacturing can be below what most markets can afford to pay for the vaccine. Typically the variability is accepted, but can cause supply disruptions if careful raw material characterization or screening cannot be developed to support the process control.
Further, raw materials of animal origin (eg, calf serum often used in cell culture, enzymes used in cell culture and purification) are subject to considerable testing burden to confirm the source of the material to be safe and/or the viral clearance steps used to process the raw material and/or the vaccine itself are adequate to eliminate or greatly reduce any risk of deleterious effect. Manufacturers must “validate” that the process is reducing these risks to an acceptable level on a consistent basis.
Again, it is ideal to develop a medium free of any animal-sourced ingredients to minimize the challenges of testing and sourcing the raw materials. Vendors supplying raw materials for biological production are subject to the same good manufacturing and documentation practices of vaccine manufacturers. Raw materials must be tested and released for use against prescribed specifications. Animal-sourced materials must be certified to be safe sourced. Vendors are subject to audit or qualification of the manufacturer for compliance with good manufacturing practices, including change control documentation and notification. Ultimately, the manufacturer is responsible for the quality of the product, even for steps managed prior to its receipt of the materials and the control of these processes are key for long-term success in manufacturing.
A key element of process control beyond the starting and raw materials are the batch records and standard operating procedures that detail the manufacturing process to ensure consistent production of vaccine relative to what was proven safe and effective in the clinic. Manufacturers are required to manage the “recipe” for making vaccines such that each lot is made following the process prescribed in the license. This includes following detailed standard operating procedures documented such that as new people are hired to make the product, they are able, through adequate training and following the prescribed procedures, to make the product in a way identical to the original batches and/or following changes approved by regulators to those processes or procedures.
In addition to following the procedures, analytical tests are completed during and after the production of a batch are need to demonstrate that they are within an allowed variability as specified in the product license. This includes product- specific tests (antigen content, potency, etc.) as well as nonspecific tests (pH, bio-burden, etc.). Trending these data over time is a key element of vaccine manufacturing to be able to identify variability in the process that may not be obvious in individual batch testing with respect to process drift or an undetected change in raw material quality.
Formulation and filling
After the active ingredients are ready, they will be formulated and filled into the packaging f the final product. The drug substance is further processed through formulation and filling, labeling and packaging to become drug product ready for use by the patient. The formulation of the vaccine is designed to maximize the stability of the vaccine while delivering it in a format that allows efficient distribution and preferred clinical delivery of the product. The formulated vaccine may include an adjuvant to enhance the immune response, stabilizers to prolong shelf life, and/ or preservatives to allow multidose vials to be delivered (Gomez, et.al, 2008).
After formulation, the product is filled into vials or syringes under strictly controlled conditions to prevent introduction of any viable or nonviable contamination, and sealed to ensure container closure integrity during shelf life. Filled vials may be lyophilized in order to increase stability; in this case, the vials are fitted with special stoppers that are partially inserted during drying to allow moisture to escape, and fully inserted and capped after drying. Quality control (QC) testing at this stage usually consists of safety, potency, purity, sterility, and another assays specific to the product.
Similar to raw material sourcing, the components used in the manufacture of the product, and in particular the components that contact the product during processing, are subject to strict control and are an important element of the overall process control and quality systems governing the production process. In addition to composition testing to confirm appropriate materials of construction, components are testing to confirm they do not alter the product during processing. Whereas many traditional vaccine manufacturing processes used glass and stainless steel equipment, where the product contact equipment is largely inert (ie, not additive to the product), more recent processes use polymer-based components and even disposable equipment (use once and discard) to reduce manufacturing time, improve worker safety (handling glass), reduce risk of cross-contamination (and equipment cleaning requirements), ease sterilization of manufacturing equipment, and to allow closure of manufacturing systems from the external environment.
Although there are many benefits of the new approaches, they bring new complexities. Extractables and leachables (E&L) are the elements of the product-contact components that could contaminate a product stream during processing and each polymer/component must be tested in your manufacturing environment to confirm that the components are not additive to the process with your specific product. (Standard testing approaches are being sought to replace testing of every component/product combination explicitly.) There is also a need for strict change control at the manufacturer (and their suppliers) to identify significant changes of source materials or process changes that could alter the E&L profile and require additional confirmatory testing to permit a change. These changes may be process improvements by the vendor or necessary changes due to availability of raw materials. Qualified substitutes for every product contact component are recommended to secure supply performance, but it is difficult due to many proprietary resins and de- signs that are not interchangeable
Validation is demonstrating that the process performs as expected and that the desired outcome is reliably delivered when the process is executed according to approved procedures (author’s definition). The need to validate the process exists with all modern regulators, but the requirements vary. Key performance characteristics that need to be validated, other than product meeting obvious specified attributes (eg, potency, purity, sterility), include viral clearance (product and potentially raw materials), container closure integrity (product not exposed to external environment during manufacturing or shipping/storage), product stable/performing during full range of process hold times or process durations, process performant at extreme of boundary conditions established for process control.
Analysis method validation
For analytics, rigorous validation requirements are also well known and guidance from FDA (Guidance for Industry Analytical Procedures and Methods Validation for Drugs and Biologics—Feb 2014) is readily available as draft, nonbinding guidance. “Parameters that may be evaluated during method development are specificity, linearity, limits of detection (LOD) and quantitation limits (LOQ), range, accuracy, and precision.” Validation is often completed in the final product matrix and revalidation may be required if manufacturing process changes warrant it.
Supporting systems and facility requirements
In addition to the manufacture, release, distribution, and control of vaccine manufacturing noted, one must also consider the rigor of the support systems of any industrial operation. Site and management controls; environmental, health, and safety practices and controls; and waste management (in particular potential hazardous or infectious waste) are all technical systems that need to be man- aged in addition to the manufacturing and analytics themselves. These systems can be more intense than at a nonbiological facility due to the handling of bio- logical agents and inactivating agents that cannot be released in an uncontrolled manner. Additionally, systems for process automation, process control, material control, material ordering, and movement within the facility are essential com- plications of biological manufacturing that are not often discussed and will not be discussed in detail in this chapter.
From a facilities perspective, one must focus on protecting the product during manufacture from conditions that can lead to product failure. Temperature control during operation and storage is one example, essential to support product potency and stability. In addition, providing the proper air quality for each process step requires strict control of air supply volume, temperature, humidity, and particle burden, especially if the product is exposed to the processing room environment. For this case, the strictest controls of air quality and people gowning and movement are essential to maintain a high probability of sterility of the process. Excursions to these quality requirements must be investigated and confirmed to have no product impact; otherwise batches of product may be discarded. Likewise, containment of the biological organisms is managed to re- duce any risk of environmental contamination or cross-contamination of products or batches. For facilities that produce multiple products, many procedures and engineering controls are necessary to maintain segregation of products and between critical process steps within a batch. Facilities and equipment also need to be validated to show they reliable perform the operations intended, but also to show they can be thoroughly cleaned and sterilized between uses.
Quality systems and regulatory
A foundational element of successful product manufacturing and release are the supporting quality systems that govern material handling, management of documents, change control, employee training and qualification, process trending, product investigations, and ultimately batch release in conformance with the product license. The quality organization, typically responsible for all analytical testing as well, can be 20–40% of the total operating organization. The focus of this organization is confirmation that required procedures are executed using qualified/release raw materials, components, and batch records; the execution of the batch was successful with respect to the batch meeting all specifications outlined in the analytical release; all equipment and facilities performed as designed and outlined in the product license; and any deviations from the currently approved licensed process are investigated and confirmed to have no impact of potency, safety, stability, or efficacy, and are conformant to the license.
The quality organization is required to audit manufacturing and analytical processes routinely to confirm compliance with current good manufacturing practice (cGMP). The quality organization is likewise accountable for the quality of incoming raw materials and audits or qualifies vendors of all critical manufacturing and testing material as well as the organizations responsible for distributing the product to the final user. Trending of internal and external product quality attributes is routine. Quality must investigate any customer complaints and facilitate continuous process improvement based on the root cause assessment of complaints, process failures, and findings during routine and for-cause audits. Whereas this is written such that the quality is accountable for the ultimate product, it should be clearly understood that all members of the organization that are involved in procurement of goods and services, manufacturing and release of product, and distribution to the final customer are accountable for the product quality.
Quality systems are designed to assure quality, but the old ad- age that quality must be built in at every step, by following approved procedures without deviation, and with the full focus and objective of every employee is very true. You cannot test in quality. The FDA Code of Federal Regulations outlines the full requirements of the quality organization.
FDA and other global regulatory agencies routinely audit the facilities and processes of every manufacture on an annual or biennial basis, depending on the products produced. Firms showing the best compliance performance, lowest customer complaints, and consistent continuous improvement can be inspected less frequently by exception.
In the United States, current authority for the regulation of vaccines resides primarily in Section 351 of the Public Health Service Act and specific sections of the Federal Food, Drug and Cosmetic Act.10,11 Section 351 of the Public Health Service Act gives the federal government the authority to license biologic products and the establishments where they are produced.6 In the European Union, animal and human vaccines are regulated by the European Medicines Agency (EMA), whose main responsibility is the promotion of public and animal health. The EMA’s Committee on Medicinal Products for Human Use through its Vaccine Working Party has oversight for human vaccines. Vaccines are licensed through a centralized procedure that allows for simultaneous licensure within all countries within the European Union.
Harmonization of licensing and regulating procedures for vaccines worldwide has obvious benefits in rapidly delivering safe and effective vaccines to the market. Impediments to harmonization include lack of standardized regulatory procedures and mutual recognition of licenses and inspections between countries and world- wide regulatory agencies. Harmonization of regulation continues to progress as joint FDA–EMA establishment inspections programs have become reality and adherence to harmonized International Conference on Harmonisation (ICH) guidance expected.5
ICH Q9, Quality Risk Management, was approved or adopted by the European Union, United States, and Japan in 2005. This guidance provides for a systematic approach to identify and control potential quality issues arising during development and manufacturing of pharmaceuticals, biotechnology products and biologics, improves quality decision making, and provide regulators with a higher degree of confidence in a firm’s ability to address potential quality risks.
The guiding principles of quality risk management are that the evaluation of risk to quality is based on scientific knowledge and patient protection and that the level of evaluation is commensurate with the quality risk identified. It is expected that the concepts of quality risk management be embedded within all systems and processes throughout the product lifecycle.
The targeted outcome of process development is a fit for use, well-understood manufacturing, and release process for the vaccine. In very simple terms, you want a process that is easy to execute consistently, by multiple people, for a long period of time, with multiple sources of equipment and raw materials, without interruption or failure. To define the true robustness of a process, one must understand the desired outcome and the edges of process control that lead to failure, such that the process and failure modes are understood and can be controlled such to avoid failure.
Given enough time and energy, this outcome is possible. Using “Quality by Design” (QbD), ideally one identifies the most likely process failure modes and sets specifications for inputs to the process that ensure successful outputs. By controlling the variability of the inputs and executing the standard process, you increase the success rate of the process regardless of people, raw material source, equipment change, and so on, provided you stay within the “design space.” Likewise, once this is “validated” or demonstrated over a sustained period, there is the potential added benefit of reduced release testing (parametric release, provided input conditions are met one may be permitted to reduce final product testing). Operating in this mode can provide high first-time quality and low operating costs.
The investment in science and technology and understanding is high, but most of all, the investment in time is often the obstacle that prevents this ideal state. In the “race” of getting a new product to market to have impact on a disease that is taking lives or reducing quality of life, one tends to make many risk-based decisions and accepts a less-than-perfect process for the sake of responsiveness. Unfortunately, once the vaccine is licensed with a “sub- optimal” process, with the high obstacles to change noted throughout this chapter, the willingness to reinvest in the ideal process is generally lower than the need to take on the next vaccine product development challenge. Rigorous monitoring and control, as well as documenting failure investigations and building a database and design space through experience can allow a firm to get nearer to this optimal process leveraging QbD principles in a retrospective manner to build a design space over time.
Analytical procedures capable of confirming that the process has performed as designed and that the product meets requirements established during clinical safety and efficacy testing is a key element of the manufacturing process. The effort to develop these processes can be more challenging than developing the manufacturing process itself as you essentially test to confirm the presence of the “biologically active product” and excipients in the right concentrations, as well as the absence of nearly every component used in the manufacturing process (raw materials, E&L, etc.), particularly during validation.
Beyond analytics that support release, methods that “characterize” the product, critical for future change control, are often required. These may include protein sequencing, particle size, isoelectric point, typical residuals profile, among others. Further, the analytics are often required to develop the process in the first place, before the product is truly defined, making this an iterative process as well, as the product and methods are refined in parallel.
One complexity of the development process often missed by people outside the industry is that you are always trying to bridge your process data from earliest preclinical lots through all clinical steps, to the current manufacturing process, while the raw materials, process, and analytics are in considerable flux. Ultimately, the analytics must be considered part of the manufacturing process as it is impossible to separate the impact of either individually. They stand as one. To that effect, every challenge noted previously with respect to manufacturing processes also stands for the complex supporting analytical processes.
Vaccine distribution and supply chain
The current condition of vaccine distribution in Indonesia
Vaccine supply chain
The supply chain supporting a manufacturing process and delivery is a key to long-term success. The complexity of making a single lot with respect to raw materials and components is outlined previously. A similar complexity exists for raw materials and components used in the analytical release processes (eg, test reagents, test equipment, disposable components) that support the manufacturing process. Further, the raw materials and components have their own supply chains; vendors providing raw materials often purchase starting materials from their suppliers and so on. For components, the manufacturer may purchase from an assembler, who purchases components from multiple suppliers, who purchase the resins from still another supplier. Traceability on changes in manufacturing processes and resins is very challenging in these complex supply chains, yet this is the norm, not the exception.
In addition to sourcing the materials in the appropriate quantities at the right time, within the specified quality and license requirements, one must also allow for increases in demand with short notice, position inventory for supply interruptions, manage contracts for ongoing supply and quality, all while controlling costs. In addition, the materials that are prepared and released must be stored at the appropriate temperature, and delivered while maintaining the cold chain control to many markets around the world. (These markets may have different regulatory requirements and the supply chain needs to ensure that the products made of each market go only to that market.) Backup suppliers for every key raw material and component are recommended and can only really be considered backup if used with some frequency (dual suppliers) and with sufficient capacity to assume all supply if the alternate supplier fails (often with little or no notice). Inventory is a solution to this challenge, but it adds cost and if a quality defect is found, a higher amount of inventory is at risk of discard. The challenges noted are easily as complex and impactful as the technical aspects of manufacturing vaccines and the systems and controls need to be equally rigorous to those noted in the technical production challenges.
VACCINE CHALLENGES FROM THE INDUSTRY PERSPECTIVES
This section outlines some challenges specific to the vaccine industry from an informal survey of industry associates across three continents. Many challenges are highlighted previously in this chapter and will not be repeated. Others may provide an interesting perspective to people unfamiliar with the manufacturing experience.
Vaccine life cycle
Vaccines, unlike many other innovative products, can have long life cycle (compared to novel pharmaceuticals that can be copied and produced generically after patents expire). This is largely due to the complexity and lack of characterization of the relatively variable biological processes and the inability to make a “true copy” or generic version of the product. This attribute makes manufacturing challenging as noted, but also worth the investment of good controls and continuous improvement. The historical approval timing of today’s vaccines are as follows (partial list):
- 1950s: Yellow fever, polio vaccines
- 1960s: DTwcP (discontinued in the United States in 2002)
- 1970s: MMR
- 1980s: HIB, Hep B
- 1990s: DTacP, varicella, Pn-Cj (7)
- 2000s: Rotavirus, HPV, zoster, MMRV, Pn-Cj (13)
Many of these products are produced by methods similar to those outlined in the original license (MMR, HIB), others have been replaced by second generation processes using newer technologies (yellow fever, inactivated polio). Regardless, the vaccines have a long life (40+ years), yet facilities useful life is generally 30 years, and equipment useful life is less than 20 years. Over this 40+ year life cycle, the equipment used for the original license is no longer the state of the industry, yet a change in equipment could require new clinical studies and at least full repeat of process validation. While equipment and technology is advancing, so are the regulatory requirements. This is an added challenge to keeping a product “current” when the life cycle is so long. This is clearly a challenge unique to vaccine manufacturing.
Vaccine supply chain
Facility and system assets and maintenance cost
Costs for new facilities for vaccines have been publicly noted and have ranged from 150 to >600M USD, for example, for egg-based and cell culture–based influenza facilities in the United States, respectively, in the last 10 years. The costs are high due high levels of automation and fixed equipment, which must be cleaned and sterilized in place between batches, coupled with low yields and the need for a high number of doses in a short time each year. For higher- yielding processes, single-use equipment has been shown to reduce capital costs as the product contact components are used one time, are available in presterilized ready-to-use format, and do not have to be cleaned as they are disposed after use. In exchange for the lower capital costs, firms may see higher operating costs and the challenges managing the complex component supply chains and E&L validation challenges mentioned earlier. These advances have been largely made in the last 10 years and although progress continues to be made, the investment in large fixed equipment continues as a lower-risk option for many suppliers.
The emergence of global disease complexity
On the issue of global demand complexity, the industry must tackle the diversity of regulatory requirements (where harmonization is yet to be achieved) for the various markets, competition for the market share within each market, and the practice of many international markets, which operate on a tender-purchase order. On a regular basis, companies compete for business based on cost and either earns all or none of the business from specific countries for 1–3 years (and the product may be specifically made for that market and not useable else- where). This is an effective way for governments to manage limited health- care budgets and increasing buying power and it is good business practice. It also incents companies to continually improve processes and decrease costs of manufacture, without reducing safety or effectiveness of the vaccines.
The challenge comes in the area of planning production. Lead times for vaccines is typically 4–16 months from initial batch start to completion of final drug product released for distribution (longer lead times are associated with more complex or multivalent products). Managing the long lead times and uncertainty in demand makes manufacturing planning a challenge. As vaccines have limited shelf life (18–36 months) and customers generally want 12+ months of shelf life on receipt, the risk of obsolescence of product made and released prior to sale is high and discards of the product result. Higher discards increases aver- age cost of goods and makes a firm less competitive in tender business.
Purity versus cost
In general, one would expect that the purest form of a vaccine antigen would be the safest by means of fewer adverse reactions to residual production process components in the final vaccine. Increased purity generally comes at the cost of lower product yield and hence increases cost of production, cost and size of facilities, and either batch size or batch frequency, increasing the cost risk of any individual batch or the number of batches produced with some finite failure rate. At the same time, the increased safety of purer product may be hypothetical rather than proven through clinical safety evaluation. Evaluating various purity levels to optimize the cost without increasing adverse events is rarely done due to the time and clinical cost required to do so. The ultimate specification on purity is determined based on process capability and confirmation of safety in the clinic at that level versus a true optimization. Lower cost of goods and affordability for more markets could be the outcome of a more targeted approach.
Central versus distributed manufacturing
“Economies of scale” has historically led to the development of a number of large central manufacturing facilities for vaccines around the world. These central facilities have the capability of lower costs of goods by producing a high number of doses from a single, albeit large, investment. However, product distributed from these central facilities are required to meet the regulatory requirements of every market served. As these requirements are not yet fully harmonized, the complexity of the operation and supply chains for the facilities are increased, as are the number of regulatory audits the facilities receives. Alternatively, smaller, regionally distributed facilities could meet the local regulatory requirements and operate with simpler supply chains and distribution challenges. (Some countries are now requiring some local value-added production commitments in order to adopt the vaccines in their populations.
This is positive for the country as it can lead to self-sufficiency during a period of vaccine shortages elsewhere and as it creates a capability.) The challenge for manufacturers is the ability to maintain consistent change control and uniformity of process across such a diverse set of facilities and process scales, the ability to leverage or react to local customer complaints or adverse events when processes may have drifted from the licensed process, and the ability to leverage market supply/demand variability globally instead of “every country for itself.” Finally, in order to support transfer of manufacturing processes to the distributed manufacturers, loss of intellectual property is an added challenge of the innovator.
Timing of investments
The final dilemma of note in this text is that of the timing of investments in manufacturing that is necessary to ensure ample supply on launch for multiple markets against the uncertainty of final approval of the product in all markets. Facility construction, commissioning, demonstration of production, validation of production, and validation of methods typically requires 3–5 years for a large-scale sterile facility. It is ideal to make the consistency lots for the clinical trial in the ultimate manufacturing facility to reduce bridging studies and reduce risk of a process change on scale-up or final facility/process fit that requires additional or prolonged clinical studies to support approval. Yet this timing re- quires the investment in the production facility during Phase 1 or Phase 2 clinical development when the risk of failure is still rather high.
Weighing the risk of product failure against the risk of licensing complexities is a routine dilemma of every manufacturer. The risk can be reduced or diversified if the firm leverages platform processes (a facility that could make product A or product B), so if one fails, the facility is still available for the alternate. Unfortunately, this is rarely done and the risk is often managed through use of launch facilities, followed by scale-up or additional construction after license approval with the modest risk that future facilities may not be identical to the original and additional clinical development could be needed.
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