By Natasha Van Rutten, Product Development Director, Catalent Biologics
Due to advances in technology and increased development of parenteral drugs, one of the fastest growing choices for drug delivery in the pharmaceutical industry is the prefilled syringe (PFS).1 Not only can PFSs help cut manufacturing and product costs for pharmaceutical companies, but they also offer significant benefits to the physician and patient. However, before taking advantage of these benefits, it is important to understand how formulation development for a PFS affects manufacturing. Doing so can drive the industry toward optimizing delivery of injectable products and, ultimately, improving patient care.
Why Would a Company Transition from a Vial to a PFS?
A vial-to-PFS switch could be a planned (or unplanned) strategic decision based on the patient needs and/or healthcare worker requirement for existing therapeutic indications or for new therapeutic indications. Reasons for switching could include:
- Change in the route of administration (intravenous in Phase 1 and 2 to subcutaneous route for Phase 3 and commercialization).
- Increase the dose and the preference to administer as large a dose as possible in lower volumes.
- Preference to administer very low doses of the active ingredient as accurately as possible in lowest achievable volumes with minimum waste. This is common with flu vaccines as well as therapeutics that contain low concentration active ingredients with a small therapeutic window.
- Preference for a final market presentation in an auto-injector or needle safety device.
- Preference for transition to an integrated combination product, as opposed to use of multiple non-integrated components (e.g., a vial with lyophilized product, that has to be reconstituted before injection) for parenteral administration.
In addition, vials could be overfilled by up to 30% to ensure the full dose could be retrieved for administration to the patient.2 This is not necessary with a PFS, as the PFS design, components (including stopper), and functionality improve dosing control, thereby significantly reducing drug product waste. As a result, PFSs have lower manufacturing costs, despite the higher cost of goods versus vials. For healthcare providers, PFSs simplify administration to the patient, and more importantly, their ease of use allows medications to be administered at home by the patient. This could have a major impact on patient compliance, which is a long-standing problem in healthcare today.3
Beginning The Transition From a Vial to a PFS
If the choice is made to switch from a vial to a PFS, there are key pieces of information needed to provide to the formulation team. This includes the target product profile (TPP), the product’s critical quality attributes (CQAs), and available risk assessments and drug product (DP) development reports. Many departments (e.g., product development, quality assurance, clinical groups) will be involved throughout the development process, so collaboration and effective communication is imperative for all parties. A gap assessment and gap analysis based on available information should be implemented thereafter.
Before beginning formulation development, identify the most appropriate container closure for the DP and, of course, from which vendor it will be purchased. The standard pharmaceutical requirement for a PFS is that it is made from type I borosilicate, which is used to make a variety of sizes. It is important to know which sizes a prospective development and manufacturing partner can accommodate and to determine if an autoinjector could be used or not, as this limits the type of syringes to be used. The most used pharmaceutical stoppers are made of either bromobutyl or chlorobutyl rubber. USP chapter 381 classifies “elastomeric components” into Type I and Type II. The difference between them is primarily in their mechanical properties. For example, Type II can be used in multiple piercing applications. Regulatory authorities require specific information at the time of filing about the PFS that was selected. This includes a list of materials of construct, vendor compatibility statements, specifications, and a drawing for each component of the PFS, such as the glass barrel, the stopper, and the plunger.
Key Formulation Development Considerations
Changing from a vial to a PFS requires a formulation strategy that considers several important factors. The first is how a PFS impacts the CQAs and stability of the active ingredient(s). To determine this, formulation experts must complete stability studies to establish comparability between a vial and the PFS. The formulation strategy will also be driven by the protein’ intrinsic properties, such as molecular weight, isoelectric point, and potential hotspots for chemical and physical degradation, as well as the achievable protein concentration.
Protein concentration is a critical attribute of any injectable drug product. The protein’s solubility dictates the concentration that can be used in the formulation, as proteins can form aggregates at higher concentrations leading to an increase in turbidity. Protein concentration is also critical in determining the viscosity of the solution, which increases exponentially with rising protein concentrations. It is important to control DP viscosity throughout development and manufacture, as viscosity can limit the final dose concentration, manufacturability/processability (e.g., filterability, filling), administration device, and in-use (clinical/patient) administration (notably, syringeability). Excipients, such as amino acids, may need to be added to control the viscosity of the formulation.
In cases where a reduction in viscosity (or increase in solubility) cannot be achieved by authority-approved (e.g., FDA) formulation excipients, the molecule may need to return to R&D for modifications in primary structure in order to achieve target viscosity and/or solubility while maintaining desired activity. Product volume in the final container is also a key consideration. How low of a volume can be achieved for a “lower volume parenteral” depends on achievable protein concentration, desired dosing, and the resulting volume to be administered from the PFS.
Keeping product attributes in mind during formulation development can help achieve DP stabilization during three important stages. The first is during manufacturing where the molecule goes through different unit operations that impart physical and shear stresses on the protein. The second is during administration to the patient, ensuring no losses or degradation occur during administration while having the minimal volume injected. And third is when determining the overall stability of the DP in the PFS versus the vial so that optimum protein stability can be maintained in the container closure at different storage temperatures over the course of its intended shelf life.
Core Formulation Development Activities
It is possible a formulation or protein concentration will not need to change when transitioning from a vial to a PFS (to be confirmed through a comparability stability study between the two containers). The chances of success could potentially increase if the same material of construct is used for both the PFS and the vial (this applies for both the container and rubber stopper formulation) as well as representative drug substance (DS) material (in cases where the same DS is not used for later stage development in PFSs). Note that this is not a guaranteed approach due to additional components in PFSs not present in glass vials that may affect product stability (e.g., silicone oil needed for syringe lubrication and tungsten residues in a glass PFS with staked-in needles).
If a client prefers the earlier “vial formulation” be used in the future PFS, it is strongly recommended to combine the comparability stability study (PFS vs. vial) with an excipient screening study. This is a risk mitigation and timeline-saving strategy used when PFS stability is found to be inferior to that in the vial. The excipient screening study could be a truncated version with best guess “platform” type formulations (using sugar and/or amino acid stabilizers with a surfactant, all of which are commonly used in current commercial products at the optimum pH/buffer for molecule stability – provided that information is thoroughly understood). The diligent approach is one that starts with a pH/buffer/salt screening study, followed by an excipient screening study focusing on the effect of various stabilizer types and concentrations. This includes sugars (sucrose and trehalose are the most widely used and effective stabilizers), amino acids (such as arginine or proline), or a mixture of any of these stabilizers. A surfactant screening study could be performed separately or combined with the excipient screening study. One can implement a design of experiment (DoE) approach during the excipient and surfactant screening studies.
An alternative risk mitigation strategy (especially if material is limited) is to perform high-throughput screening (HTS) studies using a DoE approach, and skip the traditional formulation screening. Based on the HTS study outcome, a few select "promising” formulations would be put on a longer-term stability study in the PFS. An HTS campaign could be a time-saving tool during the pH/buffer/salt screening stage by eliminating buffers, extreme pHs, and/or salt concentrations at which the active ingredient shows significant instability (using end points, such as protein melting temperature, fluorescence, etc.). Care should be taken not to apply many variables when designing an HTS study. It is also not advisable to rely heavily on an approach that does not provide much kinetic (long-term stability) information during a formulation screening aimed at achieving a commercial formulation, thus potentially overlooking great formulations that provide long-term storage stability.
Traditional HTS studies also risk not covering process (manufacturing) stresses, administration related stresses, and container closure related stresses (e.g., destabilizing effects of silicone oil, tungsten, polymers in the case of polymer PFSs). Thereby, one could potentially overlook specific formulation ingredients needed to overcome process (manufacturing) stresses or administration-related issues, or that stabilize the molecule against container closure aspects (including adsorption).
Other important considerations during formulation development for a PFS include:
- Do not use buffers known to cause injection site pain (e.g., citrate) in the formulation
- Ensure formulation osmolarity meets allowable pharmacopeial ranges for the route of administration
- If viscosity is defined in the TPP and/or defined as a CQA, make sure the formulation meets those requirements (upper limit could differ depending on company strategy, but ranges from 10-15N)
- Try to incorporate commonly used surfactants approved for parenteral administration of biologics (e.g., polysorbate-80, PS20, and Pluronic F68)
- Toxicological/clinical safety assessments are needed to confirm that the levels of excipients used in the formulation do not exceed the maximum amount per daily doses
- Include hyaluronidase enzyme in the DP formulation to enable subcutaneous administration of higher volumes of the DP.
After formulation lock, the team will need to complete additional formulation development activities. These include establishing storage conditions and conditions of use during DP administration as well as performing forced degradation studies (per ICH guidelines) for characterizing the product impurities in the representative container closure. In addition, because silicone oil is used as a lubricant on the glass area to reduce friction between the glass and the rubber stopper, consideration needs to be given to its behavior during processing. For example, glass tubes are heated to extreme temperatures (up to 1,200°C) so that rollers can form a cone shape at one end of the syringe. To keep the bore open and define its interior diameter, a tungsten pin is inserted into the syringe.4 As a result, silicon oil and tungsten spiking studies should be conducted to determine product sensitivity to each of these materials and, subsequently, define the acceptable ranges that need to be maintained in the PFS.
Finally, the team will need to conduct a formulation robustness study to confirm that slight changes in levels of key formulation ingredients (including pH) will not impact the long-term storage stability of the DP in the PFS of choice. At this stage of development, there are fewer variables to consider, so it is highly recommended to use DoE when selecting the formulations.
It is also important to determine the extractable and leachables (E&L) profile for each of the PFS components. Some vendors provide data outlining which extractables could potentially leach over the lifetime of the product once it is in the PFS. A leachables profile, determined using the formulation buffer, is desirable to understand the risk of E&L materials contaminating the DP during storage. If there is interaction between any of the formulation buffer ingredients (e.g., polysorbates) and assay/column, consider alternate methods or systems permitted by health authorities to conduct a leachables study (e.g., using alternative solvents, such as 25% ethanol for deriving leachables). It must also be determined if the leachables impact DP storage stability. A toxicological assessment is needed once the leachables profile is established. Finally, if an isolator filling line that is sterilized or cleaned using vaporized hydrogen peroxide is going to be used, or if a molecule is sensitive to oxidation, then vaporized hydrogen peroxide spiking studies must also be performed.
How Does Formulation Development Affect Manufacturing?
When switching from a vial to a PFS, the manufacturing process parameters of existing unit operations for vials have to be adapted to those needed for PFSs, especially when there are changes to the formulation and/or protein concentration. Therefore, process development and process characterization studies should be implemented as soon as the lead formulation is identified from the screening studies, but prior to technical runs to facilitate technical DP transfer and subsequent clinical batches, registration batches, and process performance qualification runs. Some parameters that will need to be established or optimized, especially when increasing viscosity, include (but are not limited to):
- Tangential flow filtration (TFF) – The process whereby the more dilute DS from the downstream purification process is concentrated is one of the most stressful unit operations in DS/DP manufacture. Unless the process is properly developed, characterized, optimized, and controlled (i.e., consideration given to filter type, filter holder, flux, flow rate, transmembrane pressure, Donnan effect, etc.), it could result in significant physical damage to the protein in the DS.
- Freeze-Thaw – Minimum temperature for freezing the DS (more critical if higher protein concentrations are to be used in PFS manufacture versus in vials) should be established. It is strongly advisable to freeze DS at temperatures lower than the glass transition temperature of the freeze concentrate to avoid instability during cold temperature storage. Acceptable rates of freeze and thaw of the DS that would not result in DS physical instabilities during the process should also be established.
- Mixing – Scaled down mixing studies should be performed to establish probable revolutions per minute (and mixing times) needed for mixing of DS at higher concentrations and/or larger volumes with formulation buffer(s) for PFS manufacture vs. vial manufacture for scale-up purposes. Any stresses that could result in protein instabilities during processing from higher mixing speeds should be determined. In-process controls analysis performed during manufacturing should also be established to determine mixing time.
- Filtration – Develop and characterize the microbial filtration for the buffer as well as the DS and then the sterile filtration for the formulated product.
- Filling – Types of pumps used for filling PFSs may differ from those used for filling vials; therefore, identify the impact of the pump type on the critical quality attributes. Filling parameters as well as the filling and overfill volumes should also be established. This is important for assessing product yield and potential losses for the unit operation and from the overall manufacturing process itself.
In addition to adjusting existing unit operations, new ones may need to be added, such as TFF (if there is a need to concentrate the protein in the DS), artwork and labeling, assembly process and lines (due to the introduction of the needle safety device or autoinjector), and packaging process and lines. Critical process parameters (CPPs), the failure mode and effects analysis (FMEA), and the control strategy should then be documented.
Once the formulation is developed and optimized in the laboratory, data and knowledge collected during the process development is provided to the technical transfer and manufacturing teams. They will confirm several key factors prior to a technical transfer run. For example, if new formats, such as a new syringe or stopper, have been introduced into the manufacturing line, they should be tested using either empty PFSs or some filled with either water or buffer. Any changes should be updated in the CPPs, FMEA, and control strategy documents.
Additionally, transport validation studies should be planned for the finished product in its representative final packaging (secondary and tertiary). This should be performed in conjunction with the medical device group so that they can confirm whether the essential performance requirements of the medical device are met. The analytical group is also a critical part of transitioning from a vial to a PFS, with many activities completed in conjunction with the formulation group. This includes, but is not limited to, completing forced degradation studies, establishing the E&L profile and product specifications, and assessing comparability from a structural characterization perspective.
The last step in transitioning from a vial to a PFS is implementing design control for combination product development. These activities run parallel to formulation and process development as phase 3 enabling activities. Phases are namely design input, design output, design verification, design transfer and design validation (i.e., human factor) studies. It is important to work with a knowledgeable and experienced development and manufacturing partner that can navigate and satisfy the regulatory requirements for your PFS.
Expertise and Experience Matter
With so many complex formulation and manufacturing activities required to transition from a vial to a PFS, it is imperative a drug manufacturer has the capabilities to be successful. Those companies without the full expertise and experience to do so may choose to work with a contract development and manufacturing partner who can see the project through to the end. Look for a partner that has a wide range of experience rather than a specialized area of focus and can apply existing knowledge based on the unique needs of a company.
The process should begin with the collection of vital information about a product, its target market, and other pertinent information as well as any potential constraints. Once a partner has a better understanding about a project and its goals, they should be able to address any knowledge gaps that exist and what must be done to fill those gaps. It is also important they provide a clear picture of the potential risks in the path to market and what measures they will take to address those threats.
Success is based on two main parts: a pharmaceutical company defining a clear strategy for its DP (what is the quality target product profile, target market, final container, etc.), and a partner ― internal or external ― having the ability and knowledge to guide the research team towards a successful scale-up, submission, and commercial launch. A ‘'Patient First” focus during the entire process will help to not only treat patients safely and reliably but also to do so in the most efficient and comfortable way.
About The Author
Natasha Van Rutten, Director, Product Development, at Catalent Biologics. Natasha has more than two decades of experience in the pharmaceutical industry. In her current role Natasha is responsible for new product introduction into Catalent’s flagship European syringe filling site in Brussels, Belgium. Prior to working for Catalent, Natasha was the Head of Strategy & Operations for Cenexi and spent over 16 years at GSK within its Engineering and Vaccine R&D groups. Natasha holds a degree in Civil and Mechanical Engineering from Université catholique de Louvain and an Executive Master of Business Administration from Vlerick Business School. In addition, she has received her Project Management Professional certification.
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