Pharmaceutical Validation

Saturday, March 10, 2018

Scaling Down of Biopharmaceutical Unit Operations — Part 1: Fermentation

The fermentation process can be challenging to scale down and several factors must be evaluated for each step.

Mar 01, 2005

BioPharm International

Volume 18, Issue 3

Anurag Rathore

Creation and qualification of scale-down models are essential for performing several critical activities that support process validation and commercial manufacturing. As shown in Figure 1, these activities include process characterization and production support studies that are performed to evaluate column and membrane lifetimes, demonstrate clearance of host-cell impurities and viruses, and troubleshoot manufacturing issues. While the underlying fundamentals are relatively the same as those when scaling up, some unique considerations should be taken when scaling unit operations down.^1-4 The goal when scaling down is to create a small-scale or lab-scale system that mimics the performance of its large-scale (pilot or manufacturing) counterpart, when both the process parameters are varied within their operating ranges and also when a process parameter deviates outside its operating range. Before it can be used for lab studies, the scale-down model needs to be qualified and its equivalence to large-scale examined. Data from an inaccurate scale-down model could result in conclusions that may not be applicable to large-scale, resulting in an unsuccessful process-validation campaign or continued lot failures in a manufacturing campaign.

This article is divided into two segments. The first part focuses on an upstream unit operation — fermentation. The next segment will cover two downstream unit operations — chromatography and filtration. The combined article is the fifth in the "Elements of Biopharmaceutical Production" series.

Figure 1. Scale-down Models are Best Utilized for Process Characterization and Production Support

HARDWARE SCALE-DOWN GUIDELINES
Fermentation processes often involve several scales of operation, encompassing inoculum development, seed expansion, and production fermentation. The differences in volumes between the steps in a single fermentation process can be 10X to 100X for the pilot scale, and 1,000 to 100,000X for the production scale. This may cause the fermentation processes to be challenging to scale down and the specific process parameters, vessel geometries, and operational control strategies must be evaluated for each step. Some general guidelines to consider in developing a representative scale-down model follow.

Practitioners use the terms "similar reactor" or "similar vessel geometries" to describe optimal conditions for a scale-down strategy. However, similarity in vessel geometry does not necessarily imply identical systems, although this would be the most attractive option. Instead, geometric similarity means that the overall aspect ratios of each vessel (small vs. large) are close enough to not impact performance. More importantly, the impeller and sparger designs and placements within the vessel are nearly identical.

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Technology Improvements Drive Capacity Gains for Biologics Fill/Finish

Until recently, the handling of sterile liquids in the pharmaceutical industry has relied on decades-old techniques and technologies. During the past 10 years, however, biologics have taken a prominent role in the drug-development pipeline. The value of these drugs, sometimes measured in tens of thousands of dollars per dose, has put greater pressure on biologics downstream fill and finish operations. The increased scrutiny from regulators and the greater product value have initiated industry improvements so that quality, safety, and cost-efficiency remain high at this crucial late stage in manufacturing.

BioPlan recently prepared a white paper identifying trends among in-house fill and finish operations for recombinant therapeutics (1). This research excluded outsourced operations and CMOs. BioPlan found significant differences between industry capacity and capacity use for these large-molecule facilities, compared with the constraints currently being experienced in small-molecule fill and finish, which have in some cases even led to drug shortages at the hospital level.

In biologics in-house operations, BioPlan found trends that include the increased use of isolator technologies, more high-speed operations, and other innovative approaches. Findings regarding capacity use indicate that in-house manufacturers, on average, continue to have additional available fill-and-finish vialing, pre-filled device, and lyophilization capacity:

Utilization averaged 55% for lyophilization

58% for pre-filled devices

70% for vialing.

At present, there is sufficient capacity, even without adding shifts or additional equipment. This finding is in contrast to the situation with small molecules, where some facilities are working at near-capacity, and facility consolidation, regulatory actions, closures, and the use of less efficient legacy equipment have created bottlenecks and even serious drug shortages at the hospital level.

The state of in-house fill/finish capacity
BioPlan’s in-house biologics fill/finish market analysis evaluated the capacity for recombinant biologics and compiled information from 89 candidate facilities in the US and Europe. More than 50 industry participants were surveyed at facilities, equipment suppliers, and consulting groups.

Regarding vialing, capacity utilization averaged 70%; this figure represents the average for biopharmaceutical in-house manufacturers, which generally produce at most a few products at each facility. While this indicates that a relatively large flex or expansion vialing capacity may be available among current primary manufacturers, in-house facilities are not designed for, nor are they capable of, running at maximum capacity, due to down-time, maintenance, and cleaning/validation.

For pre-filled devices and syringes (PFS), an even greater amount of flex capacity was found. Pre-filled syringe and cartridges fill-finish capacity averaged 6.75 million per shift; the average PFS fill/finish capacity utilization was 55%, suggesting considerable expansion capacity potential among those facilities doing in-house PFS fill-finish.

Finally, with regards to lyophilization capacity, which averaged 760 square feet among those facilities with these data available, utilization averaged 58%, again indicating room for expanding manufacturing output.

Overall, the largest scale manufacturing operations tend to be concentrated among just a few companies, with this the case for in-house fill/finish. Most of those largest-capacity facilities are based in Europe.

Activities outsourced by biomanufacturers
Although BioPlan’s white paper analysis focused on in-house fill-finish capacity, other BioPlan research found that eight in 10 biopharmaceutical manufacturers worldwide outsource at least some fill/finish operations today, up from 6 in 10 in 2010 (2). In fact, fill/finish operations are one of the most commonly outsourced activities, behind only toxicity testing (86.8% outsourcing to some degree) and analytical testing of other bioassays (89% outsourcing).

The results of BioPlan’s annual report also show that, in volume terms, fill/finish operations are one of the most heavily outsourced activities: Respondents estimated outsourcing (on average) 37.9% of the fill/finish operations at their facilities, ahead of areas like toxicity testing (35.4%) and validation services (19.9%) (see Figure 1).

Figure 1: Top five activities outsourced to some degree by biomanufacturers.

Available in-house capacity implications
The excess capacity available to in-house manufacturers of biologics may allow expansion of in-house fill/finish operations without adding shifts or equipment. Capacity, however, is commonly misrepresented as being related to machine speed or lyophilizer chamber capacity in vials. In-house fill/finish operators also note that equipment turnaround time, cleaning, and sterilization (in situ and ex situ) also need to be considered when calculating efficiencies. In this analysis, capacity utilization was defined as the “typical estimated usage of fill/finish capacity per shift”/“maximum capacity per shift”, using current number of shifts, and production equipment. As noted, a facility could significantly increase capacity by adding shifts, if needed.

Future trends
The fill/finish industry will likely depend on ramp-up of technologies and capabilities both in-house and at CMOs. Future trends will include:

Fill and finish CMOs are becoming larger, through mergers and acquisitions.

CMOs will continue to install state-of-the-art fill/finish equipment, mostly to support clinical manufacturing. Biopharmaceutical CMOs will do less sub-contracting of their fill and finish to specialized CMOs.

Fill-Finish CMOs in India and rapidly developing countries are handling increasing amounts of biopharmaceutical products, mostly for domestic and lesser-regulated international commerce.

Conclusion
In-house biologics fill/finish operations are unique from contract manufacturers’ business strategies. In addition, comparing small molecule in-house vs large molecule/recombinant biologics leads to significantly different conclusions. The lower capacity use rates for biologics can be partly explained by the more recent installation of higher technology equipment, RABS/isolators, and automation. The effect of end-product value is likely also a factor.

Newer technology adoption will impact utilization rates at both in-house and outsourced service providers (CMOs) as legacy equipment is replaced; however, this area requires further research. Fill/finish operations represent one of the top activities projected to be outsourced at significantly greater levels in the future. In fact, nearly 28% of global industry respondents to BioPlan’s annual study indicate they will be outsourcing more of their fill/finish projects over the next 24 months.

Decisions in this area are likely to be based on efficiency, cost effectiveness, and capacity availability as the industry makes critical in-house vs outsource decisions. For CMOs to compete for fill/finish business, data indicate that it’s increasingly important that they position themselves as having state-of-the art equipment, especially in fill/finish services.

References
1. BioPlan Associates, Trends in Aseptic Bioprocessing Capacity for the Fill and Finish of Recombinant Biologics: An Analysis of US and European In-house Capacity and Capacity Utilization (BioPlan Associates, December 2014).
2. BioPlan Associates, 11th Annual Report and Survey of Biopharmaceutical Manufacturing Capacity and Production (Rockville, MD, April 2014), www.bioplanassociates.com/11th.

Article Details
Pharmaceutical Technology
Vol. 39, Issue 1
Pages: 66-68
Citation: When referring to this article, please cite it as E. Langer, "Fill/Finish Capacity Use for Biologics," Pharmaceutical Technology 39 (1) 2015.

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FDA Publishes Revised Process-Validation Guidance

FDA published its long-awaited guidance titled Process Validation: General Principles and Practices this week. The document, which revises and replaces the 1987 guidance titled Guideline on General Principles of Process Validation, explains the components of process validation for the manufacture of human and animal drug and biological products, including active pharmaceutical ingredients. The guidance emphasizes the importance of risk-based decision making and recommends that the degree of control over attributes be commensurate with their risk to the process or output.

The new guidance categorizes process-validation activities into three stages.
During Stage 1, process design, a company defines the commercial process based on what it has learned throughout development and scale-up activities. The document recommends that companies use design-of-experiment studies and risk-analysis tools to understand process variables. In Stage 1, a company should develop strategies to control processes by reducing the variation of inputs, adjusting equipment to compensate for input variation, or both tactics. Process design must be based in science, and decisions about design should be documented, according to the guidance.

During Stage 2, process qualification, a company should evaluate its process design. This evaluation should include an examination of the facility and the qualification of equipment and utilities, according to the guidance. In addition, personnel should carry out process-performance qualification (PPQ) to confirm the process design and demonstrate that the commercial manufacturing process performs as expected. “The approach to PPQ should be based on sound science and the manufacturer’s overall level of product and process understanding and demonstrable control,” according to the document. PPQ requires a written protocol that describes items, such as manufacturing conditions, data to be collected, tests to be performed, and the sampling plan. The ultimate decision to begin commercial distribution should be supported by data from commercial-scale batches, according to the guidance.

Stage 3, continued process verification, provides ongoing assurance during routine production that the process remains in a state of control. This goal requires a system for detecting deviations from the process. “Adherence to the CGMP [current good manufacturing practice] requirements, specifically, the collection and evaluation of information and data about the performance of the process, will allow detection of undesired process variability” and help personnel determine whether action must be taken to correct, anticipate, and prevent problems so that the process remains in control, according to the guidance.

During this stage, a company should establish an ongoing program to collect and analyze product and process data that relate to product quality. Trained personnel should statistically trend and review the data, and the information collected should verify that the quality attributes are appropriately controlled throughout the process, according to the guidance.

See related Pharm Tech articles:

The Importance of Equivalence in the Execution and Maintenance of Validation Activities (Pharm Tech)

The New FDA Process Validation Guideline (Pharm Tech)

Is FDA's Draft Process-Validation Guidance a Mixed Blessing? (Equipment & Processing Report)

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Fill/Finish Capacity Use for Biologics

Utilization averaged 55% for lyophilization

58% for pre-filled devices

70% for vialing.

Figure 1: Top five activities outsourced to some degree by biomanufacturers.

Future trends
The fill/finish industry will likely depend on ramp-up of technologies and capabilities both in-house and at CMOs. Future trends will include:

Fill and finish CMOs are becoming larger, through mergers and acquisitions.

CMOs will continue to install state-of-the-art fill/finish equipment, mostly to support clinical manufacturing. Biopharmaceutical CMOs will do less sub-contracting of their fill and finish to specialized CMOs.

Fill-Finish CMOs in India and rapidly developing countries are handling increasing amounts of biopharmaceutical products, mostly for domestic and lesser-regulated international commerce.

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Is FDA's Draft Process-Validation Guidance a Mixed Blessing?

The US Food and Drug Administration’s Draft Guidance for Industry—Process Validation: General Principles and Practices provides a life-cycle approach for validating pharmaceutical processes and aims to help pharmaceutical companies achieve consistently high product quality. The document includes several concepts that are familiar to the industry but also contains ambiguities and recommendations that might be difficult for some drugmakers to follow.

The draft guidance suggests manufacturers establish links from their clinical process to their commercial-manufacturing process. This approach is similar to the one FDA has used in its preapproval inspections. If the guidance becomes final as it currently stands, manufacturers may be expected to use the data that they gain during formulation and development to define a product’s critical attributes, which would be the basis for the manufacturing-process parameters.

The agency points out that development and formulation data can improve a company’s understanding of its processes during scale-up and commercial manufacturing. This understanding would help companies control variability and increase product quality, says Chris Ames, director of global validation at Catalent Pharma Solutions (Somerset, NJ). Companies would submit these data to FDA to establish links between clinical and commercial processes.

But the draft guidance does not advise manufacturers about how to identify the most important characteristics of its product or manufacturing process, or about how to demonstrate links from the clinical to commercial process. “They’ve left it completely open to interpretation as to what data you provide and what format you use,” says Jim Agalloco, president of Agalloco and Associates. This ambiguity would suit Big Pharma because it frees companies to use their experience and discretion in deciding how to follow the guidance, says Agalloco. Small and emerging drugmakers, however, would likely be confused because they don’t have the depth of knowledge that would help them define critical attributes.

Some elements of the draft guidance resemble a Six Sigma approach to manufacturing, which is familiar to the pharmaceutical industry. The main similarity is the draft guidance’s recommendation of a statistical link that demonstrates that variability remains constant from the clinical through the commercial manufacturing stages. The statistical link is intended to confirm that processes are the same throughout all phases.

Although the draft guidance suggests statistical analysis, it leaves industry with only a broad understanding of what that means. FDA does not explicitly suggest that manufacturers use particular statistical tools, the agency simply recommends that companies apply good statistics to establish the links, says Agalloco.

The draft guidance suggests manufacturers define a process that can be measured, analyzed, improved, and controlled, and this approach is closely related to Six Sigma. The benefit of the Six Sigma technique is that it provides a mechanism for scientific review of a process, for assessing variability, and for identifying improvements, says Ames.

On the other hand, it is unclear whether the draft guidance recommends a product be refined in the way that a Six Sigma approach would. “To me, Six Sigma implies an acceptance by FDA that you might not have done a sufficient job in development and scale-up and are allowed to improve product and process while it is in operation,” says Agalloco. Patients’ experiences with a product might persuade a manufacturer that it should adjust one of the drug’s parameters to improve it. Six Sigma would allow postcommercialization changes to a product, but the draft guidance may not be compatible with them, Agalloco says.

Before it could submit a regulatory filing, a company would have to spend a great deal of time and money to better understand its ingredients, its product, its manufacturing process, its material handling, and associated variables. Pharmaceutical companies might object to the draft guidance’s approach because it suggests this expensive work be completed before commercialization, but the costs would not be recoverable before commercial-scale manufacturing began.

Although it is based on good science, if the final guidance is approved as drafted, it could easily increase drug-development time by one or two years, thus costing a manufacturer millions of dollars, says Warren Charlton, a consultant at WHC Bio Pharma Technical Services. Manufacturers would need to use smart strategies to shorten development time, but not knowing how much data regulators expect in a submission would make this strategy difficult.

The draft guidance inspired a huge volume of comments that will likely take FDA a long time to review, says Agalloco. Even though the guidance might not be final for at least a year, manufacturers would be wise to study it now and seek advice about interpreting it. In this difficult time for the pharmaceutical industry, no company can afford to ignore regulators’ recommendations, and advance preparation would be to a manufacturer’s benefit.

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