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An integrated focus on product design, development, operation, and control.
Maciej Frolow/Getty ImagesPharmaceutical product development activities are highly inter-connected in nature. For parenteral drug products, the prefilled syringe is generally considered a challenging container closure system, particularly in the case of vaccines with complex product design requirements. The product design phase involves integration of prefilled syringe as a crucial part of the target product profile (TPP) when considering the complex health policy and user requirements imposed by different global geographic regions and regulatory authorities. The product development phase focuses on the prefilled syringe as an integral part of the vaccine drug product. Particular attention needs to focus on multiple syringe component attributes such as silicone oil and tungsten that may create potential interactions with the diverse molecular properties of antigens. Emphasis of the product operation phase is to link prefilled syringes to the product performance per design requirements and supplier process capability and quality control. Lastly, processing and supplier quality control must be implemented within regulatory compliance framework to ensure delivery of quality vaccine product to patients.
The goal of pharmaceutical product development is to design and establish the formulation composition and its manufacturing process to consistently deliver a drug product with all the appropriate quality attributes required for its intended efficacy and safety profile. A systematic approach according to the quality-by-design (QbD) concept is applied to achieve both the information and material deliverables during the product development lifecycle (1). Before work begins on the development of a new product, it is crucial to clearly define the quality attributes of the product with consideration of the end user's needs in mind, commonly referred to as the target product profile (TPP) in the pharmaceutical industry. A TPP can be used to facilitate discussions with regulators regarding the anticipated label claims for a product (2). It can also be used for the private sector market, to help determine competition and associated pricing strategies (3, 4). Alternatively in the case of vaccines, a TPP can be used as a tool to engage and align with public health policy organization by working together to achieve the intended health impact (4, 5).
The definition of TPP according to the target disease/health policy and user requirement drives the design of the dosage form with selection of the primary container-closure system as an integral aspect to meet the delivery requirement. Drug products packaged in prefilled syringes essentially remove the withdrawal step from another container, such as a vial or ampoule, prior to administration. As a result, prefilled syringes offer a more convenient alternative to vials for the preparation and administration of injectable drugs. This results in improved provider/patient convenience and compliance, as well as product differentiation when combined with auto-injector delivery devices.
There are many drivers and good reasons to have vaccines in the prefilled syringe presentation. First and foremost vaccines are complex biological entities; therefore, they must be administered by injection due to the lack of significant advance in alternative delivery technologies. From the technical point of view, one can imagine it is absolutely crucial to reduce the risk of wrong dose and also better dose precision; therefore, one can see the advantages of prefilled syringe as compared to vials. From a practical point of view, vaccines are sometimes driven by public health outbreaks because many doses could be given in a crowded setting, allowing simple administration with limited manipulation. This provides for less probability of handling errors in a prefilled syringe presentation, which is preferred. Lastly, there is a different economic factor than for example biologics and is driven by key stakeholders in the public health sector. The minimal overfill in a prefilled syringe as opposed to vial can also provide an economic advantage, because costs per unit must be low. In summary, there are clear scientific, practical, and economical drivers for developing vaccines products in prefilled syringes.
Vaccine product development is complex in many aspects. First, vaccine products are prophylactic as opposed to therapeutic, and more often than not, the target population is children and pregnant women, so the regulatory standard is high. Second, the product types are diverse such as recombinant proteins, glycoconjugates, virus-like particles, attenuated viruses, and live viruses. The dosing requirement is also challenging, in that doses are typically very small. Multiple antigens are often combined to reduce the number of injections, and adjuvants are added in some cases to boost the immune response. Lastly, the complex properties and interaction with prefilled syringe results in an acute challenge to vaccine manufacturers.
The prefilled syringe is a complex system where the component characteristics often depend on the material of construction and processing conditions, which results in variability of the component attributes such as silicone oil level and distribution, as well as residual tungsten. Specifically, silicone oil and tungsten has been implicated in the induction of protein aggregation (6). It is also important to understand whether aggregation is a prerequisite for a cascade phenomenon leading to the visible particulate formation, which is not acceptable for a parenteral product. Not only does this create stability issues, proteinaceous aggregates presented in a highly arrayed structure of sub-visible size range, such as might be found in large non-denatured aggregate species, have been known to potentially interact with the immune system to enhance immune responses (7, 8). This interaction causes great concern and has been critically scrutinized by the regulatory bodies for therapeutic proteins. However, this should not be falsely perceived as a "hand waving favorable" immunogenicity risk assessment for vaccine products. It is categorically essential to ensure that product quality attributes including aggregate species, must be under strict control to demonstrate the intended immune response of the vaccine for the target disease and patient population. As stated earlier, the prophylactic nature of vaccine products impose a higher and more rigorous regulatory standard.
In particular, the glass syringe barrel contains silicone oil for functionality purposes, which could migrate into the drug product solution during shelf-life storage. When protein interacts with silicone oil, there are potentially two phenomena that could lead to visible particulates formation. First, hydrophobic interaction could enhance protein aggregation as a prerequisite for visible particulates formation (6). On the other hand, the dispersed silicone oil droplets, although at low level, may be charged dependent on the formulation condition. The charge effect could lead to colloidal instability and flocculation of the silicone oil emulsion together with the protein, which has been reported in literature (9). The protein and silicone oil droplets are quite different in size microscopically, which can be characterized by a recently developed new technique of suspended microchannel resonator (SMR) (10). Silicone oil droplets are charged particles where surface properties have a large effect on emulsion stability. Both the concentration (i.e., quantity) and total surface area (i.e., number and size of oil droplets) are critical attributes to understand the protein silicone interaction phenomenon. Depending on the isoelectric point of the protein and pH of formulation, protein adsorption can change the surface charge properties, and therefore, kinetic instability of the silicone oil emulsion. As a result, the flocculation and coalescence of protein adsorbed silicone oil droplets can lead to the formation of visible particulates. This potential mechanism of action is illustrated in Figure 1.
Figure 1: Silicone interaction and formation of visible particulates. (ALL FIGURES COURTESY OF AUTHORS)
These concepts are also highly relevant in the case of a complex vaccine product, for example, glycoconjugates. Effective immunization against encapsulated bacteria can be achieved by a type of vaccine based on oligosaccharide conjugated to a carrier protein, for example CRM197, a non-toxic mutant of diphtheria toxin (11). For a particular target disease, different serotypes with different polysaccharides would be needed to achieve majority coverage of the population. For example, serogroups A, B, C, W135, Y, and recently X account for the majority of meningococcal disease in humans (12). Bacterial polysaccharides are high molecular weight and mostly negative-charged carbohydrate molecules. Semi-synthetic glycoconjugates are complex molecules composed of protein and carbohydrate moieties linked together by chemical reactions. The conjugation reactions involve different chemistry and, therefore, different linking sites on the surface of the protein and along the saccharide chain. Moreover, the polysaccharides are high molecular weight carbohydrate moieties with some degree of polydispersion, which increases the heterogeneity of the resulting glycoconjugates.
The polysaccharides are mostly negatively charged, and there is also significant charge heterogeneity of these glycoconjugate vaccines. Figure 2 shows an example of the charge heterogeneity of three glycoconjugate vaccines as compared to the carrier protein measured by pI. The pI is a well-defined single band for the carrier protein but there is a significant dispersion of isoelectic point (pI) representing charge heterogeneity for the three different glycoconjugates. Each of these highly charge heterogeneous molecules are expected to interact with silicone in a different manner both individually in a monovalent and collectively in a trivalent formulation, which could lead to decrease colloidal stability of the low concentration silicone oil emulsion in a prefilled syringe. It is likely that visible particulates form when the silicone oil droplets associated with these glycoconjugates coalescence.
Figure 2: Charge heterogeneity of three glycoconjugates A, B, C and carrier protein as control measured by isoelectric focusing gel.
At present, there is little reported in the literature on systematic and comprehensive characterization of silicone glycoconjugate interactions under a variety of formulation conditions to support the successful development of these types of important vaccine products. On the other hand, it is also important to consider the silicone variability associated with the prefilled syringe components, such as the intra- and inter-batch variability plus the migration during storage before product is filled. After the product is filled, product storage, handling, shipment, agitation, and excursion all contribute to potential significant intra- and inter-batch variability.
In summary, a vaccine product such as glycoconjugate has additional complexity and challenges for prefilled syringe development when compared to therapeutic proteins. It is logical and reasonable to recognize that a large part of development effort should focus on understanding the components, and a standardized toolbox can help build such understanding and a better strategy to control the variability.
Successful development of a vaccine product in prefilled syringes requires careful evaluation of the interaction between the formulation and primary packaging components. In support of each vaccine, a QbD approach will be used to design systematic product and process development studies and ensure a comprehensive data package. It is, therefore, crucial that a platform approach for these development efforts be implemented, in which there is detailed characterization and fundamental understanding of the various component attributes and associated variability within the platform prefilled syringe systems. In addition, the prefilled syringe system selected for the platform approach must also fit well with the existing manufacturing and production capability. To achieve a robust and flexible prefilled syringe platform, it is also beneficial to form a strategic alliance with a reliable supplier that has a good reputation of quality control. Processing and quality control compliance are vital for a successful vaccine product development and subsequent licensure. In summary, we propose a holistic and integrated approach to focus on the linkage of prefilled syringe in the following areas:
It is important to recognize there is significant interdependence between these areas, where an integrated platform toolbox is warranted and these six aspects are connected into the four phases of product design, development, operation, and control (Figure 3). The product design phase involves integration of the prefilled syringe as a crucial part when considering the complex health policy and user requirements imposed by different global geographic regions as well as private market competition. The product development phase focuses on the prefilled syringe as an integral part of the vaccine product due to the multiple contacts and potential interactions with the diverse molecular properties of antigens. In particular, particles characterization pertinent to silicone interactions is crucial because vaccines are prophylactic treatment to elicit an immune response before sick.
Figure 3: Integrated platform toolbox approach for vaccine product development in prefilled syringe.
The emphasis of product operation phase is to link the prefilled syringe to the product performance per design requirements and supplier process capability and quality control. As a result, a key focus will be on supplier collaboration to understand their process capability and improvements. Lastly, quality control of supplier with respect to incoming components, as well as manufacturing process with respect to both site and equipment, must be implemented with periodic review mechanism within the regulatory compliance framework to assure quality vaccine products delivered to the patients.
In addition, the six areas are divided into nine categories with detail attributes under each category based on technical considerations, prior project experience, and learning. These attributes can be summarized in a fishbone diagram, as shown in Figure 4, to form the basis of risk assessment to select and implement different feasible options for a standard toolbox approach. In summary, the standard work stream, when combined with a toolbox approach, will drive down the development risk with information that allows plug and play, as well as supply of standardized component material that result in lower cost of goods. Furthermore, the platform approach can be improved and is expandable with accumulated product experience in the future after joint efforts with a formulation group and suppliers.
Figure 4: Fishbone diagram of detail attributes as basis for risk assessment for selection and implementation of prefilled syringe toolbox.
The benefit of using a standard set of prefilled syringe components consistently for a variety of products is that a solid and robust data package can be established to support licensure application. These categories of information include:
This is important because it's expected to provide all of this information in a submission as summarized in Table I.
Table I: General submission information requirement.
A holistic and integrated prefilled syringe platform toolbox approach will streamline development with higher probability of success even in the complex and challenging case of vaccine products. More importantly, such an approach is not only beneficial to technical challenges, but also provides economic benefits. We sincerely hope that the cost of innovation for a new prefilled syringe system is not so prohibitive that vaccine products cannot afford to achieve the intended health impact to society.
We like to thank Anna Coslovi and Francesca Beccai for their preliminary results to characterize the charge heterogeneity of glycoconjugate vaccines.
Kingman Ng is head, Ronald Malone is principal scientist, Changyun Xiong is scientist II, and Xuefeng Yi is senior scientific associate, all at Pharmaceutical Sciences, Novartis Vaccines and Diagnostics, Inc., firstname.lastname@example.org.
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Article submitted: March 5, 2013. Article accepted: May 1, 2013