Case Study: Brazil Fill/Finish The Role of CMOs in Supporting Global Vaccine Production Needs
This year’s 5th Annual Advanced Aseptic Processing Technologies Tour features a case study of an Advanced Aseptic Processing facility for the production of lyophilized and liquid dos-age form vaccines and biopharmaceutical products. This state-of-the-art greenfield facility will be located in Brazil, and is slated for completion on or about 2Q 2016. The program is structured to provide an outstanding overview of the pharmaceutical facility design process, featuring the role of top tier equipment vendors in developing and supplying “Best Available Technology” to address technical challenges throughout the project. Persons engaged in a pharmaceutical design activity or supporting role will find the presentation and tour to be of great value.
The tour commences with a brief project overview, provided by Jason Collins and Robert Roy from IPS. Jason and Rob have been involved with the project since the concept phase, and will speak to IPS’ unique project development approach, which focuses on risk mitigation through separation and automation (QbD) to ensure product quality while meeting the projected production capacity requirements.
From the onset, the customer has been committed to sustain-able global regulatory compliance for the facility. This is best achieved through a primary reliance on engineering and architectural controls to ensure product quality, or in other words by building quality into the process. Use of administrative controls (SOPs) in place of either engineering or architectural controls is strongly discouraged at all design phases.
The role of equipment vendors in achieving the objectives of sustainable compliance + production efficiency can hardly be overstated. Top tier equipment vendors design and fabricate a large number of fill finish lines each year. Their design groups therefore serve as repositories of the “best thinking” in the pharmaceutical industry on how to approach various problems. Their real-world experience in manufacturing, testing and operating these systems provides the best possible feedback with respect to which systems and features are cost effective, reliable and user friendly. These systems and features then become, by definition, the “Best Available Technology”. Through close collaboration with these equipment vendors, a number of Advance Aseptic Processing technologies have been selected for inclusion in the facility design basis. These include, but are not limited to, the following:
- Barrier Isolation technology for aseptic formulation and fill/finish operations, including lyophilizer loading and unloading. Barrier isolators are widely regarded as providing the highest level of sterility assurance for the product, while at the same time protecting the operators from exposure to the product. Previous difficulties with isolator validation, turn around, etc. have been overcome as is demonstrated by the large number of successful, approved installations worldwide.
- Single Use Disposable Systems (SUDS) for selected formulation, filtration/ transfer, buffer storage, and filling applications. Single Use Disposable systems greatly reduce or eliminate product cross contamination and batch-to-batch carryover risk. The design basis for this facility incorporates Single Use Disposable fluid paths for all filling machines, a specification made possible by recent improvements in vendors peristaltic filling systems and development of SUD positive displacement filling systems. Other unit operations are under investigation for application of SUDS, for example stabilizer prep, filtration and storage, vaccine pooling and formulation, bulk product sampling, etc.
- 100% Non-Destructive Checkweigh systems to ensure vial filling accuracy. This Process Analytical Technology (PAT) has seen recent improvements in accuracy and speed; 100% checkweighing can now be realized at line throughputs of up to 400 vials per minute (vpm). Use of this technology ensures correct dosing for all containers under all processing conditions, including for example filler starting and stopping. This technology also eliminates the need for isolator provisions to segregate vials in the event of a bad checkweigh.
- In-line automated inspection for liquid products, to ensure product quality and to minimize reject generation. Direct coupling of the inspection machines to the liquid fillers is included in the design basis. Advances in inspection technology allow for automated high speed inspection for a variety of quality attributes including for example absence of visible particulate, cosmetic defects to the vials/ caps, headspace analysis, etc. Direct coupling of the line for liquid filling means that these attributes are inspected in real-time with respect to manufacturing; in the event defect generation rate exceeds pre-established parameters the line can be stopped to investigate and/or correct the root cause.
- Advanced Stopper Processing Systems, for cost effective in-house processing of serum and lyo stoppers. The stopper processing systems under consideration offer secure and reproducible stopper processing, to include washing, siliconization, sterilization and drying. The delivery systems provide secure storage and transport of stoppers from the component prep area to the isolated filling line, and secure transfer of stoppers into the filling isolator for processing.
- Raised/missing stopper inspection, monitoring of capping parameters, and post-capping crimp quality inspection – compliance with EU Annex 1 requirements for vial sealing. Recent changes in regulatory requirements for this unit operation have introduced new requirements and considerably design complexity into this once straightforward operation. Questions to be answered now include whether to cap inside the isolator or in a RABS; requirements for a “Grade A Air Supply” when RABS is selected, whether or not to include raised/missing stopper inspect/reject capability, whether to monitor capping parameters (head pressure and vial rotation) during sealing, use of in-process testing to demonstrate Container Closure Integrity (CCI). The current design basis includes stoppering in a RABS enclosure immediately outside the barrier isolator, with gloveport access at all point upstream of the vial sealing stations. This design avoids having to sterilize overseals during routine processing, but necessitates installation and qualification of raised stopper inspection equipment to comply with FDA expectations. We have also included monitoring of capping parameters during sealing, and use of in-process testing (e.g. Residual Seal Force monitoring) to ensure container closure integrity. Due to the potential impact of this unit operation of overall reject rates and production efficiencies, we are also focusing on component quality, and are investigating the feasibility of post capping crimp quality inspection via camera-based systems.
Read the full article in the INTERPHEX 2012 Pharmaceutical Processing supplement.
Jason S. Collins, AIA
Director of Process Architecture
Sterling G. Kline, RA
Aseptic Subject Matter Expert
Robert Roy, PE
Director, Aseptic Technology