The number of seasonal influenza vaccine doses in the U.S. has increased 10-fold since 1980 (Table 1) with 169.1 million doses distributed in the U.S. during the 2018-2019 season.¹ The development of seasonal influenza vaccines is a carefully choreographed effort beginning with a meeting by an FDA advisory committee in March² to decide which strains to include in the next season’s vaccine, followed by production of potency standards—in parallel with manufacturers’ preparations—for the new campaign. Seasonal influenza vaccines are unique as their limited time span from strain selection to distribution requires most vaccine producers to rely on outsourcing partners to mitigate risk and ensure timely production. Demand for contract manufacturing organizations (CMOs) support for seasonal influenza vaccines is expected to increase as the seasonal influenza vaccine market is projected to reach more than $4 billion by the end of 2022.³ 

While many CMOs claim vaccine fill-finish experience,⁴ seasonal campaigns present logistical challenges that few outsourcing partners are prepared to accommodate. Successful contract manufacturing of seasonal vaccine products requires the right facility, culture, and expectations to help ensure quality and on-time delivery. What should sponsors look for when evaluating contract manufacturing services for a new seasonal vaccine program? 


Facility and technical capabilities
Sponsors of seasonal vaccines should seek a partner with extensive experience in the production of pre-filled syringe (PFS) products as well as experience with vaccines and suspensions. An experienced partner can work with the product owner to understand their vaccine’s critical quality attributes (CQAs) and, by leveraging their experience with other suspension products, will be able to readily identify the critical process parameters (CPPs) within their control that may impact the CQAs. Examples of potential CPPs include recirculation, pumping mechanism, and temperature control. Suspension products may require intermittent or constant recirculation to ensure homogeneity of product potency throughout the filling process and the manufacturer should have the experience to make a recommendation of recirculation parameters and mixing speed of the tank to ensure adequate dispersion of suspended solids. In addition, studies are needed to understand the impact of solution level in the tank and mixing speed on the acceptability of the suspension remaining in the tank near the end of the process. To ensure optimization of mixing and recirculation processes, manufacturers must be experienced and proficient at monitoring in-process homogeneity of filled units within the production process using turbidimetric and spectroscopic techniques. 

The fill mechanism itself may impact product quality. PFS filling lines were historically equipped with rotary piston pumps, but concern over protein aggregation has resulted in an increase in utilization of peristaltic pumps for biologic products. Generally, piston pumps offer greater accuracy and speed, but advances in peristaltic pump head design, drive motors, and calibration algorithms have narrowed differences in performance for all but the most viscous formulations.⁵ As high throughput is critical for seasonal vaccine manufacturing, lines equipped with modern rotary piston pumps capable of filling 500 units/minute are preferred, but the availability of alternative fill mechanisms may be beneficial if development studies indicate that shear impacts product quality. 

Ideally, flexibility should extend beyond filling mechanism. Vaccine producers may wish to ship formulated vaccine as a sterile bulk suspension, with no sterile filtration intended prior to filling. In this scenario, the CMO’s experience performing aseptic connections should be scrutinized. Alternatively, sterile filtration of formulated vaccine may be required.  While disposable product contact equipment may be an option, durable equipment is more commonly used in seasonal vaccine production to reduce cost. The proposed new USP chapter <665> Plastic Materials, Components, and Systems Used in the Manufacturing of Pharmaceutical Drug Products and Biopharmaceutical Drug Substances and Products⁶ will increase the testing required to demonstrate compatibility with disposable bags and may create additional barriers to the use of plastic single use materials for vaccine production. The CMO should have a robust cleaning validation program to support the use of durable equipment and have the scientific knowledge to be able to apply a risk-based approach to cleaning validation. Additionally, the CMO should be able to develop a residue detection method, and the method validation should include recovery from surfaces using sample coupons of surface materials using the sampling methods utilized in manufacturing. For example, once a residue detection method and cleaning validation process are developed and validated, they may not require revalidation for subsequent campaigns. An evaluation of strain and formulation changes, in collaboration with the sponsor, should be performed to determine change management for validated processes.

While the formulation and filling process tends to receive the greatest scrutiny in the evaluation of potential manufacturing partners, sponsors should evaluate the technical capabilities in the inspection, labeling, and packaging process as well. The high-throughput and speed required for production of a seasonal vaccine will require the use of automated inspection systems. Automated inspection processes must be validated specifically for each product, though revalidation would not be required for subsequent campaigns if the product change is limited to strain substitution. Vaccine developers should seek a service provider with strong experience in automated inspection of PFS and experience validating automated inspection of semi-transparent fluids. Parameters to be evaluated during development of the inspection process should include temperature of the product as this can have a significant effect on the rejection of syringes during automated inspection of some products. Inspection soon after removal of the filled units from 2-8°C storage can result in precipitation of formulation components which can lead to rejects. The precipitated particles would dissolve as the product temperature approached RT resulting in acceptable units.

The Drug Supply Chain Security Act⁷ (passed as part of the Drug Quality and Security Act) requires serialization of product units. While serialization is straightforward when only one product manufacturing site is utilized, the volume of units required by major seasonal vaccine manufacturers will require that vaccine sponsors utilize any internal capacity as well as one or more CMOs. While all CMOs should now be prepared to meet serialization requirements, it is critical that the information technology systems supporting serialization can communicate with the sponsor’s system to ensure that the serial numbers applied are unique and traceable across the network of product manufacturing sites utilized.

Lastly, because of the time-critical nature of seasonal vaccine production, sponsors should evaluate redundancy at their potential CMO. Redundant filling lines, supplied with separate water and HVAC systems, can provide the ultimate assurance of delivery, though sponsors should balance their desire for risk reduction with the cost of performing process validation on a second line. Implementation of a second redundant packaging line has less of a validation barrier, and can provide risk mitigation as well as increased capacity, particularly in cases when an inventory of filled units has been built and stored.

Culture of speed and execution
Strong experience and technical capabilities are critical to success of any project, but the unique time constraints associated with seasonal products require a culture of speed and focus on execution. One area where planning and execution are critical is in supply chain logistics. The potential CMO should be able to articulate and have demonstrated best practices in supplier planning. These include having redundant suppliers for PFS components qualified in their supplier quality system with these redundant components qualified to run on automated filling and inspection lines. The CMO should build strong communication channels with vendors, and these suppliers should be queued and prepared to react and deliver quickly. For example, packaging artwork requires FDA approval, creating a stage gate for the start of automated inspection and packaging campaigns. Strong vendor relationships and preparation can shrink the time required for delivery of printed labels and packaging material after artwork approval from weeks to several days. Ample cold storage capacity can provide logistical advantages as well. Sufficient cold storage can allow for pre-shipment of bulk vaccine by the sponsor and staging of initial supplies at the fill facility. Additionally, capacity for cold storage of work-in-progress (WIP) materials can allow for inventory build-up of filled units while awaiting artwork approval.  Upon approval, the pre-produced inventory of filled units can be inspected, labeled, and packaged using redundant automated lines to expedite delivery.

The quality team must also demonstrate the culture of execution while maintaining focus on compliance and product quality. Having individuals from the incoming Quality Control team present at the fill facility can result in expedited active pharmaceutical ingredient (API) and material release for supplies received just in time. Other best practices include having a dedicated team of consistent reviewers who can expedite review and release of documentation. This dedicated team should develop a collaborative relationship with the sponsor to ensure rapid closures of any investigations and non-conformance reviews (NCR) which would otherwise delay batch release. 

Having on-site technical experts from R&D can also expedite investigation closures. One example of a competency that sponsors should evaluate at potential partners is the ability to rapidly identify particles using technologies such as digital microscopy, FTIR microscopy, Scanning-Electron Microscopy (SEM) and Elemental Dispersive Spectroscopy (EDS). Immediate on-site particle identification can determine if they are intrinsic or foreign and speed closure of investigations to meet batch release targets.

Lastly, the facility should have a plan to staff seasonal campaigns quickly and shift resources as project demand moves from filling to packaging. Ideally, this is accomplished through cross-training so that experienced personnel familiar with the product can move seamlessly between manufacturing tasks to best meet product resource demands. A facility accustomed to year-around 24/7 operations can maximize equipment utilization to offer efficient production. 

Expectations and continuous improvement
A successful long-term collaboration with a CMO requires clear, mutually agreed upon expectations as well as a shared culture of continuous improvement. Clear expectations start in the contracting process, and an experienced service provider will have a contract team and a project management team experienced with seasonal products and their unique requirements. One example of a contractual term that is unique to seasonal products is the inclusion of provisions for a flexible start window for filling and packaging operations. Proactive facility capacity management within the flexible start window can allow for dynamic scheduling by the project management team, resulting in manufacturing start within 48 hours of notice by the vaccine sponsor.

An experienced CMO understands that seasonal vaccine manufacturing is a full-year process. While it may be possible to muscle through a campaign, consistent success and on time delivery requires year-round planning. For example, the facility change control management process must be monitored, and changes to the lines or facility during the seasonal campaign season that could result in a CBE-30 must be avoided. The project management team should work closely with the facility maintenance and regulatory affairs teams to ensure that upgrades and changes be planned proactively to avoid any delays in approval of the annual vaccine product. Maintenance of filling and packaging lines used for a seasonal campaign product should be proactively performed during the season prior to the campaign to avoid any preventable service interruptions. Additionally, during the annual planning period the CMO can prepare for the next campaign by assessing any changes to the vaccine and the impact this may have on any validated processes such as product contact equipment cleaning, communicating with vendors to ensure supply of components, updating and validating any API release testing procedures, and conducting product specific training for manufacturing operators and laboratory analysts.

Each campaign should end with a collaborative review by the sponsor and the CMO of what went well, what didn’t go well and areas for improvement. Any lessons learned can be incorporated by the CMO during the planning process for the following campaign. 


Conclusion
Seasonal vaccine products place unique demands on CMOs. When seeking an external manufacturing partner, vaccine developers should look beyond the manufacturing capabilities visible on a tour and probe specific knowledge about risk analysis and redundancy of equipment as well as ability to comply with serialization requirements for a product manufactured at multiple facilities. Even more important and difficult to assess is the service provider’s culture. Does the CMO have strong component and vendor supplier relationships and do they have a culture of planning that allows for rapid execution on short notice? Does the CMO offer the flexibility of start time and resource staffing to meet changing demands? Lastly, does the CMO work collaboratively with the customer, embracing lessons learned sessions and constructive feedback that can be incorporated into future campaigns? A culture of execution and continuous improvement is a critical factor in meeting the requirements for speed and reliability required by modern high-volume seasonal vaccine campaigns.

References

1. https://www.cdc.gov/flu/about/qa/index.htm, accessed March 29, 2019.
2. FDA’s Critical Role in Ensuring Supply of Influenza Vaccine https://www.fda.gov/ForConsumers/ConsumerUpdates/ucm336267.htm,  accessed March 29, 2019
3. https://www.medgadget.com/2018/07/seasonal-influenza-vaccine-market-to-reach-more-than-us-4-billion-in-7mm-country-outlook-vaccination-analysis-pipeline-insights-to-2022.html, accessed March 29, 2019.
4. https://www.contractpharma.com/csd/contract-services-directory/manufacturing-vaccines/, accessed March 29, 2019. 
5. Lambert P, “Dispensing Biopharmaceuticals with Piston and Peristaltic Pumps”.  Pharmaceutical Technology, http://www.pharmtech.com/dispensing-biopharmaceuticals-piston-and-peristaltic-pumps, September 2008, accessed March 29, 2019.
6. USP Proposed Chapter (665) Plastic Materials, Components, and Systems Used in the Manufacturing of Pharmaceutical Drug Products and Biopharmaceutical Drug Substances and Products, PF 43(3) [May–June 2017].
7. https://www.fda.gov/Drugs/DrugSafety/DrugIntegrityandSupplyChainSecurity/DrugSupplyChainSecurityAct/ucm376829.htm, accessed April 1, 2019.