BIOPROCESSING: BRIDGING THE GAP FROM BATCH TO CONTINUOUS PRODUCTION

For years, traditional batch manufacturing has dominated the biopharma industry. Recently, however, continuous bioprocessing has gained traction among biopharma manufacturers. Below is a look at some of the key differences between these two types of bioprocessing and the resources required for each. Finally, this paper will examine the ways that industry regulations have adapted to the advent of continuous bioprocessing and the ways that continuous production has impacted the single-use market.

 OVERVIEW

Batch Bioprocessing: An Industry Tradition

Batch bioprocessing is well-known throughout the biopharma industry. As the dominant force in the processing arena, batch bioprocessing remains the most popular type of processing because it "works well and is familiar." The critical elements of batch bioprocessing are as follows:

  • Individual drug components are combined over time through a multi-step process
  • The current batch must be completed before the next batch can be processed
  • In many cases, there may be up to seven or more steps required before bioprocessing is completed
  • Batch bioprocessing often requires six or seven different pieces of equipment to complete a product

Continuous Bioprocessing: Powerful Non-Stop Production

As manufacturing has evolved over the years, so has product processing. Along with the increased demand for heightened productivity and quality manufacturers of automobiles, consumer goods, petroleum products, and foods began making the shift to continuous processing decades ago. 

In recent years the biopharma industry has begun to follow a similar path, though the adoption of continuous production has been more gradual among biopharma manufacturers compared to manufacturers in other industries. 

The Key Difference Between Batch and Continuous Bioprocessing

The key difference between batch processing and continuous processing lies in the seamlessness of the production process. In the case of batch processing, production typically stops following the completion of each step of the drug's manufacturing process. The hallmark of continuous processing, on the other hand, is a seamless production cycle without interruptions after each step of the production process.  

BATCH BIOPROCESSING

Advantages

The advantages of batch processing have combined to sustain its popularity among biopharma companies. Even after the introduction of continuous bioprocessing, batch bioprocessing remains an industry favorite due to its familiarity and low failure rate. Here is a look at some of the critical advantages of batch bioprocessing: 

Biopharma companies are highly familiar with batch bioprocessing 

Familiarity with batch processing is a top reason why the majority of biopharma companies use batch bioprocessing. According to Eric Langer, batch bioprocessing "works well and is familiar," whereas continuous bioprocessing is viewed as "more complex and susceptible to problems."

Batch bioprocessing has a relatively low failure rate

In addition to being highly prevalent, batch bioprocessing yields a surprisingly low failure rate. Batch failures occur less than twice per year on average, making it an attractive option for many biopharma companies. This low failure rate does little to propel biopharma companies to consider a move to continuous bioprocessing.

Lower costs on equipment and resources

Some biopharma companies choose to stick with batch bioprocessing because the cost of procuring and maintaining processing equipment is lower compared to equipment costs associated with continuous bioprocessing. Additionally, batch bioprocessing does not require the ongoing monitoring that continuous bioprocessing requires.

Disadvantages

While batch bioprocessing remains an industry standby, it is flawed in several respects. In general, the shortcomings of batch bioprocessing relate to inefficiency and production speed, though opportunities for improvement also exist in other areas. Here is a look at some of the top disadvantages of batch bioprocessing.

Heightened inefficiency and waste

Inefficiency is the most common disadvantage of batch processing. Because batches are often produced at separate facilities, batch processing requires the complete cessation of production while ingredients are prepared and shipped from different warehouses across the globe. 

Manual handling can result in a higher rate of human error

The high number of steps and locations involved with batch processing means that humans handle products with greater frequency compared to continuous bioprocessing. This increased handling, in turn, means that the likelihood of human error is higher. 

Prototype mistakes can be costly

While batch bioprocessing's failure rate is relatively low, the cost of processing errors can be high, especially if there is an error in the prototype. A large batch of products could feasibly it all the way to the end of the processing cycle before a mistake is detected, resulting in defects in the entire batch. With continuous processing, the error would be detected during the production of the very first drug, resulting in less product waste. 

CONTINUOUS BIOPROCESSING

Advantages

Continuous bioprocessing (CBP) is a logical alternative to batch bioprocessing and is slowly beginning to gain traction within the biopharma field. A growing number of companies recognize the benefits of CBP, especially following FDA approval Janssen Products' transition from batch to continuous bioprocessing. Below are the top advantages of continuous processing:

Improved efficiency

The ability to manufacture a product from start to finish without halting productivity is CBP's most impressive benefit. In contrast to batch bioprocessing, which requires cessation of operations to transfer products from one room or another to complete the next processing phase, CBP significantly reduces overall processing time.

Lower operating costs

While CBP's use of automation may initially require investment in more costly equipment, the long-term savings offered by CBP are compelling. Siemens estimates cost savings of 10 to 20% over batch processing, pointing out that CBP facilities cost less to build while 100% of facility space is used. Transportation costs are also eliminated because batches do not have to be transported to a lab for analysis. 

Faster product releases

Confining CBP to a single location expedites production time, significantly reducing the time required for a product to reach patients. This shorter time to market is a major selling point for stakeholders in the biopharma industry who value healthy cash flow and seek a shorter sales cycle. 

Reduced energy consumption

Biopharma companies across the globe are tightening their focus on energy efficiency and protecting the environment. CBP reduces biopharma products' environmental exposure and promotes the maximization of production space.  

Why are some reluctant to adopt continuous bioprocessing?

As outlined above, there are many reasons to consider a transition to continuous bioprocessing. However, there is still a pervasive reluctance to adopt CBP within the biopharma industry. For the most part, these reservations are related to a lack of familiarity with CBP and the equipment required to make the move to CBP. Some biopharma companies perceive CBP as being too complicated or sophisticated for their needs, while others are reluctant to adopt CBP because there are relatively few companies that have taken the plunge to adopt CBP. Finally, some companies lack the capital required to invest in specialized CBP equipment and a larger facility.

Equipment Investment

The transition from batch to continuous bioprocessing requires the addition of sophisticated equipment as well as highly trained technicians who can oversee the production process and screen for processing flaws. Here are some of the types of equipment required for a company to move toward continuous production at the commercial scale:  

  • Cell retention equipment
  • Perfusion bioreactors
  • Purification technology
  • Filtration devices
  • Surge tanks

Notably, while equipment adjustments are required to move toward continuous production, the transition often results in an overall decrease in floor space requirements that results when unit operations are downsized to a single facility that hosts a fully connected production process.  

Process Changes

As outlined by industry experts Ronald Rader and Eric Langer, the biopharma industry continues to lag behind other industries in the adoption of continuous production. Very few manufacturers have invested in the necessary equipment required for CBP, and they lack the resources to transition to continuous production. Some of the key process changes needed to move to continuous production include the following:

  • A real-time in-line monitoring system
  • Introduction of new reactor technologies
  • A restructured facility layout that accommodates CBP
  • More robust training for production engineers
  • A more rigorous quality control system

In addition to these process changes, manufacturers must be prepared to meet increasingly demanding regulatory requirements for product quality. The prospect of adapting to new regulations, along with a reluctance to adapt to modern equipment and processes, combine to deter many biopharma companies from embracing continuous production.

Overcoming Operational Challenges 

As outlined previously, many biopharma companies are hesitant to make the transition from batch processing to continuous processing. Ronald A. Rader, Senior Director of Technical Research with BioPlan Associates, outlines the following challenges presented by continuous bioprocessing:

  • Contamination risks
  • Process operational complexities
  • Upstream development and characterization time
  • Process development control barriers 

These challenges have contributed to the increase in hybrid bioprocessing, which mitigates these challenges while propelling manufacturers toward the adoption of a fully continuous approach. 

Continuous Production and Single-Use

Single-use technologies account for a growing percentage of manufacturing technologies within the biopharma industry. With the single-use bioprocessing market expected to increase by more than 17% over a five-year period, the biopharma industry will continue its shift toward continuous bioprocessing. Some notable trends related to bioprocessing and the single-use market include the following:

  • Currently, there are only a few key players in the single-use market
  • The market leader is Thermo Fisher, who accounts for over half of the market share
  • GE Healthcare, Pall Corporation, Sartorius Stedim, and EMD Millipore account for more a more modest market share

HYBRID SYSTEMS

A system is considered to be a hybrid if it features some process elements that run continuously and other elements that operate in batch mode. Hybrid systems typically feature a combination of reusable stainless steel equipment and single-use equipment. Todd Andrews, with CPC, outlines some of the specific applications for hybrid systems, which include the following:

  • Employing single-use bioreactors at the start of a seed train then switching to stainless steel bioreactors to accommodate larger volumes
  • Using single-use bags to make additions to reusable stainless equipment
  • Employing single-use tubes to obtain samples from a reusable stainless bioreactor

Hybrid systems are growing in popularity, as they offer the familiarity of batch processing in addition to some of the efficiencies of CBP. Most importantly, hybrid systems offer efficiency and enable products to reach the market faster compared to traditional batch bioprocessing systems. Two of the unique benefits offered by hybrid systems include the following:

Hybrid systems help bolster confidence in single-use systems

As today's facilities seek improved efficiency, they are gradually beginning to introduce single-use systems for select processing phases. A hybrid system allows a facility to achieve desired production goals while boosting the manufacturer's confidence in single-use systems. In most cases, this involves the implementation of a few single-use systems for some processes to bolster efficiency within a stainless steel plant.

Hybrid systems demonstrate superior performance

Researchers who compare the effectiveness of batch, continuous, and hybrid strategies often deduce that hybrid strategies are superior in terms of their economic and operational performance. Hybrid systems were often deemed to offer superiority across all phases of the product's lifestyle from preclinical to commercial manufacture. 

    REGULATION

    Historically, regulatory agencies have been slow to endorse single-use devices, making it more difficult for continuous bioprocessing to gain rapid traction. As a result, many existing regulations are written for manufacturers who use batch processing.

    At the heart of this lack of regulatory acceptance of continuous bioprocessing is concern regarding the use of certain plastics that are frequently used to construct single-use equipment. Specifically, skeptics worry that these plastics and polymers were approved using old or outdated testing standards. In particular, there is a focus on ensuring that harmful compounds are not released from the bags. The release of such compounds could impede production and cause risk to patients.  

    Given these concerns, the FDA and other regulatory agencies continue to proceed with caution as they update regulatory standards. However, in recent years, the FDA has shown increasing support for the adoption of continuous bioprocessing through the following measures:

    • The introduction of three grants totaling approximately $6,000,000 to study and recommend improvements in continuous bioprocessing
    • The establishment of an Emerging Technologies Program to advance processing and product quality 
    • Approval of a manufacturer's (Janssen Products, LP's) change from batch to continuous bioprocessing 

    These measures illustrate the FDA's recognition of the benefits of continuous processing and the agency's commitment to advancing research and technologies. Acceptance and support of continuous bioprocessing by the FDA and other regulatory agencies is expected to continue in the future.

    A Glimpse Into the Future of Continuous Bioprocessing

    As more companies focus on optimizing space and resources, the biopharma industry is expected to continue to move toward continuous bioprocessing. For instance, organizations such as the National Institute for Bioprocessing Research and Training are embracing continuous bioprocessing because of its ability to enhance plant flexibility and curb manufacturing expenses. 

    This trend has already prompted some biopharma manufacturers to begin developing their own CBP equipment and technologies. Biomanufacturers such as Hemispherx Biopharma have introduced modulators and technologies that foster a transition to CBP and minimize the need for monitoring staff. More manufacturers are expected to follow suit by designing cutting-edge CBP equipment that addresses their specific needs. 

    SUMMARY

    The transition to continuous bioprocessing has been gradual but is gaining traction as biopharma companies increase their focus on efficiency and swift results. Hybrid systems represent a growing trend in biopharma to gradually migrate toward continuous bioprocessing systems in an effort to boost efficiency. In response to these industry developments, the FDA and other regulatory agencies have begun to adjust their controls to reflect their support of modern and efficient processing systems. In light of these trends, the future appears to be bright for continuous bioprocessing and the single-use market. 

     

     

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