The pharmaceutical industry loses about $50 billion due to the shortcomings of batch processing. It's mainly because of time requirements, delivery mishaps, damage, or the cost of a review. A potential solution for this issue is continuous manufacturing.
The transition to continuous manufacturing has taken place. It is due to factors like Brexit, COVID-19, and a push for sustainability. The easiest way to describe continuous manufacturing is as a series of procedures that maximize drug production to maintain a steady stream of medications.
This is in contrast to batch manufacturing. Batch manufacturing comprises complex operations carried out globally. Here products are manufactured in huge batches as opposed to continuously.
There are many other production sectors that have been utilizing the continuous manufacturing method for years, yet the pharmaceutical sector stands out. It is because, without any wait times, the complete process happens in a single location.
We'll examine the ins and outs of continuous manufacturing in this article. The definition, history, benefits, and challenges of continuous manufacturing will be discussed. Following are the topics covered:
- What is Continuous Manufacturing?
- What Are the Types of Continuous Manufacturing Systems?
- How to Set up a Continuous Manufacturing System?
- Driving Forces of Continuous Manufacturing
- Difference Between Batch and Continuous Manufacturing
- Advantages and Disadvantages of Continuous Manufacturing
- Sector Overview
- Key Takeaways
What is Continuous Manufacturing?
A number of unit operations are combined in continuous manufacturing (CM). It continuously processes raw materials to create the finished product. There is no agreed-upon definition of continuous manufacturing (CM).
The terms "continuous manufacturing," "continuous production," and "continuous processing" are used. But because they have different connotations, these phrases cannot be used interchangeably.
The term "continuous production," as its name implies, describes a production plan that runs continuously for a full seven days a week. The term "continuous processing,", describes a single-unit operation. Here raw materials are continuously loaded, processed, and discharged without interruption.
- Continuous manufacturing consists of a sequence of more than one unit operation.
- Continuous manufacturing involves integrating discrete continuous unit operations with process analytical technology (PAT).
- It keeps track of and regulates crucial process parameters (CPPs), crucial material attributes (CMAs), and crucial quality parameters (CQAs).
- Continuous manufacturing also simplifies manufacturing procedures by getting rid of work-up unit operations.
- Continuous manufacturing hardware is frequently smaller and situated in a single building.
On the other hand, batch manufacturing (BM) uses discrete unit operations with offline quality testing and storage between each stage. Additionally, batch manufacturing entails transporting intermediates between facilities.
Continuous processes carry out all testing, feeding, and processing in line. But batch, manufacturing necessitates transporting, testing, and re-feeding materials from one process to the next. High-tech process analytical technologies guarantee quality as it is being produced.
History of Continuous Manufacturing
Many sectors have now embraced this continuous manufacturing technology. Continuous manufacturing got its beginnings in the eighteenth century during the first Industrial Revolution. But the continuous manufacturing of pharmaceuticals has recently gone from being a trendy idea to a reality.
- Continuous manufacturing is not new, but it is novel in the pharmaceutical manufacturing industry.
- In several industries, continuous processes have been standard practice for close to a century.
- In iron manufacturing, where equipment can run for years, continuous manufacturing has a long history.
- In some food and beverage processing as well as the petrochemical industry, it is standard practice.
- Despite the delayed acceptance of continuous manufacturing, the FDA is in favor of more widespread use of these technologies.
Given that the number of continuous manufacturing facilities under review has quadrupled in the last five years. Continuous manufacturing appears to play a significant role in the years to come.
What Are the Types of Continuous Manufacturing Systems?
Assembling items on assembly lines using sub-assemblies is a manufacturing process. It is used in repetitive manufacturing and discrete manufacturing. Continuous manufacturing incorporates these procedures, which makes it distinct from continuous manufacturing.
Yet, continuous manufacturing can make use of two different types of continuous manufacturing. Which are:
Manufacturing a standardized product in huge quantities is known as mass production. The main elements of continuous manufacturing include process, materials, equipment, and an unbroken flow of materials.
Mass and flow production is when many units of a product are produced at once and stored in a warehouse while waiting to be sold. A manufacturing run may be carried out on a single machine or on many machines that are organized according to the sequence of activities.
The product is in constant and high demand during manufacture. At various phases of the production process, the materials can create various products. This can be kerosene, gasoline, etc., like in an oil refinery. Because only one product can be produced, these factories have very little flexibility.
These types of workflow production include
- Analytical Process of Production- The division of raw materials into various products.
- Synthetic Process of Production- This method of the production process involves combining two or more elements.
How to Set up a Continuous Manufacturing System?
Planning and preparation are essential. It is due to the capital intensity and complexity of large continuous manufacturing plants.
Yet, even a small to medium-sized business looking to switch from jobbing or batch manufacturing to continuous manufacturing will need to put some significant thought into it. For such a situation, starting a project mindset is helpful.
Phase 1: Feasibility
An organization-wide feasibility phase should be designed. It should be supported under the direction of someone with extensive manufacturing knowledge.
Production, engineering & maintenance, financial, quality, and safety staff would all play important roles in the planning stage.
Phase 2: Planning
The decisions that must be made will start with the production philosophy that determines the equipment to be used. High-volume production of standardized goods enables the fabrication or selection of specialized or single-task equipment
- Is there a place where extra or backup equipment with several roles can be used?
- How likely is it that a client's or a product's requirements will change?
These choices sometimes entail making a trade-off between current capital expenses and possible operational expenses in the future.
In continuous manufacturing, maintaining quality within an operational line allows for prompt action from alarms or advisories. It helps ensure consistent in-spec output, control, and monitoring systems.
Each choice will influence decisions on technology and staff. This will result in reducing the danger of producing non-conforming goods.
Phase 3: Implementation
The "only" thing left to do when everything has been planned out is to start moving forward. Keep a close eye on how linked your technology and equipment are during the implementation period. The production process can be optimized by having the capacity to create, store, track, and check asset data.
The following need to be integrated:
- Predictive analytics
- Asset status
- Performance data
- Maintenance software
Outcomes from pre-maintenance shutdown strategy:
- Balancing the burden
- Identifying the necessary skills
- Locating spare parts
- Scheduling maintenance
- Upgrade tasks
Why Do Process Plants Use Continuous Manufacturing?
Continuous manufacturing is the only strategy that provides enough product supplies. It makes effective use of the machinery available for particular verticals. Energy production or water treatment are some examples. Other industries, like batch-manufacturing medicines, food, and beverage, are realizing the benefits of continuous manufacturing.
It is used to scale up output, raise quality standards, and lower the possibility of human mistakes. Compared to batch manufacturing, continuous manufacturing demands a larger initial investment. Yet, constant production efficiency improvements make continuous manufacturing more viable in the long run.
- Employees are less involved in continuous manufacturing to track procedures and guarantee quality.
- This rendered it unsuitable until recently for products that need frequent customization.
- Cutting-edge AI-based solutions are enabling facilities to use continuous manufacturing while still custom-designing the product.
- Manufacturers used batch numbers to track items and, if required, recall them by creating a paper trail for them.
- Yet, continuous manufacturing plants can define products by different criteria.
- This involves utilizing big data from IIoT sensors and smart devices, allowing businesses to track batches more, recall fewer items, and so cut down on waste.
For example, the FDA now advises continuous manufacturing of medications. It helps boost plant productivity, increase quality, and lessen shortages.
Why Does the Production Method Your Company Employs Matter?
Your company's ability to succeed or fail depends on choosing the proper manufacturing method. This begins with an analysis of the factors that go into making your products.
The complicated manufacturing process depends on a number of inputs, including the following four production factors:
- Capital- Refers to assets like factories and equipment that are employed in the manufacture of other items.
- Land- This includes all occurring resources, both renewable and non-renewable, that can be used to provide supply.
- Entrepreneurship- The person or group who assumes the financial risk to combine the other three variables of production.
- Labor- Any activity that employees engage in that contributes to the production.
It is critical to match your production method to the kind of product you're manufacturing, consumer demand, your industry's competition, and your budget. Utilizing the ideal production procedure helps your company run smoothly, which in turn boosts profits.
What Are the Best Ways for Process Plants to Use Continuous Manufacturing?
It is now possible to build a smart factory that applies continuous manufacturing even to customized goods and products. And those that need a high level of traceability thanks to smart machinery that combines AI and machine learning (ML) with data from IIoT sensors.
By doing this, factories can improve their bottom line by becoming more productive, competitive, and lucrative.
Driving Forces of Continuous Manufacturing
The batch manufacturing method is characterized by the sequential arrangement of large tanks. These are managed individually for each process.
- It has traditionally been used in the pharmaceutical and fine chemical industries. It is the primary method of production.
- Continuous manufacturing, like that seen in large plants for manufacturing chemical products, has not been widely adopted.
- Continuous manufacturing is a flow production technique that uses continuous raw material delivery.
- While the manufacturing process is in progress to produce or process goods without interruption.
Since manufacturers want to maximize profits, their main incentive for using continuous manufacturing is its potential to reduce manufacturing costs.
The need for breakthrough therapies to reach the market is growing. Continuous manufacturing can improve product development. It helps enable faster delivery of patients' access to life-saving medications without sacrificing product quality.
The production of customized medicines is a new trend in the pharmaceutical business. It is replacing the mass manufacture of bestselling medications in the pharmaceutical business. This necessitates a switch from the current batch manufacturing system to the flexible, volume-output continuous manufacturing system.
The current batch manufacturing system is a product-variety continuous manufacturing system. The creation of tailored medications benefits from this capability.
There is competition from producers of generic and biosimilar pharmaceuticals. Other factors like rising research and development expenses, the anticipated low growth rate in developed nations, and growing patient demand for affordable drugs also exist.
Due to these factors, pharmaceutical companies are facing a threat to their revenues. Manufacturers are thus investigating the usage of continuous manufacturing. Continuous manufacturing has been shown to lower operational costs and capital expenditures.
In the upcoming years, environmental protection will be a controversial subject. It will put more external pressure on manufacturers.
- The popularity of continuous manufacturing is fueled by the fact that it is a viable alternative to traditional manufacturing methods. Continuous manufacturing promotes environment-friendly operations.
- It has a smaller environmental impact, besides its many appealing advantages.
- The switch from batch to continuous manufacturing has not yet gained traction in the pharmaceutical business.
- This is due to the fact that batch methods can assure enough profits in the high-value-added pharmaceuticals area.
- It is negating the need to transition. This would need further capital investment. Provided there are no issues with the product's quality or the production process.
Yet, in the middle of the 1990s, a problem with product quality surfaced in the US. Faulty medications from batch production were placed on the market and became a topic of public discussion.
- The inability of batch manufacturing to alter production volume has been cited as a drawback.
- This has spurred the trend toward a continuous manufacturing system.
- It enables the production of the requisite volume as needed.
In its national strategy from 2018 the US Food and Drug Administration (FDA) mentioned the adoption of continuous manufacturing by the pharmaceutical and fine chemical industries. The FDA mentioned continuous manufacturing as a key issue.
The FDA's industry guidance from 2004 included recommendations for the use of continuous manufacturing for pharmaceuticals. The guidance also included recommendations for the use of continuous manufacturing for pharmaceuticals.
Difference Between Batch and Continuous Manufacturing
The several parts of medicine are combined in a batch process in the pharmaceutical industry. The current batch must complete processing before the next batch can be processed as the materials move from step to step.
Before a product is manufactured, there may be upwards of six or seven steps in the process that are finished with six or seven pieces of equipment.
- A medicine is produced continuously in a pharmaceutical facility.
- It starts with the raw materials and continues all the way to the finished product.
- Thus, there is no need to turn off machinery, and there is no downtime while the product is being made.
In short, batch processing must stop between each phase of the creative process. But, continuous processing can continue creating a product indefinitely. Depending on your objectives, either process is a completely solid way to generate a great finished product. Each has advantages and disadvantages for the producer.
Pharmaceutical companies have produced their products in batches for many years. A "batch" is a particular amount of medicine created using a multi-step procedure in batch manufacturing. Batch production is a tried-and-true manufacturing technique. But, the transitions between the phases can be cumbersome and ineffective.
Manufacturers are starting to incorporate continuous manufacturing technology into the pharmaceutical production process. This is to streamline production. Batch production has the following advantages:
- Less expensive than other processing techniques
- Pausing between batches causes downtime
- Inherently flexible, allowing manufacturers to produce different batches of new products
- Perfect for short production runs and seasonal items
- Reduces inventory
- For short production runs, batch production works best.
Advantages of Batch Production
The fact that set-up costs are initially lower is arguably batch production's most significant benefit. Additionally, it is simpler to make each batch distinct. Finally, due to their composition or formula, some goods and materials need to be produced in batches.
Drug businesses can use batch production to create particular quantities of a given product. Later on, they can change their manufacturing priorities in response to shifting market demands. The oldest of the two techniques is batch processing.
In batch processing, all the components for a particular product are combined in a sizeable tank or vat. The finished product is packaged and shipped out for distribution once the desired composition has been achieved. This method's key benefit is that it is quite easy to understand and regulate.
Additionally, because everything is combined at once, it is simple to make sure that everything is well-mixed. The finished product satisfies all requirements for quality.
Lessening the Possibility of Contamination
If all the ingredients are combined at once, there is a reduced possibility that they may become contaminated while being prepared.
More Control over the Quality
Since all materials are combined at once, it is simple to guarantee that they are all thoroughly incorporated. It also proves that the finished product satisfies all requirements for quality.
Because it is simpler to alter the composition or procedure in the middle of a batch. Batch processing is more adaptable than continuous processing. If you need to update the product for quality or safety concerns, this can be useful.
Batch processing facilitates product tracing to the original batch. It is useful for quality assurance or product recall.
Lower Capital Expenditure
Because batch processing uses simpler equipment than continuous processing. Batch processing has a lower capital expenditure. For small enterprises or startups with limited funding, this might be a huge advantage.
Challenges with Batch Processing
There are tonnes of benefits to using a batch process. It does, yet, face certain difficulties. The following are some drawbacks of batch processing:
Each step must be finished before the next can start since batches proceed sequentially. The waiting times can build up if the complete manufacturing stream has six or seven processes. Low utilization rates and challenging process scheduling may result from this.
The industrial standard is batch production, and its shortcomings are widely known. as well as its benefits. There are ongoing issues with supply chain risks, human error, and manufacturing timelines. This has made continuous processes an interesting alternative for both manufacturers and regulators.
Greater Storage Space
Because the materials must be combined in batches and held until they are needed. Batch processing necessitates more storage space.
Difficulties in the Supply Chain
This entails shipping to a new facility. Material can decay and threaten a batch if there are any supply chain problems or if the required holding conditions aren't satisfied.
Drug recalls have increased in recent years as a result of supply chain disruptions. It includes particularly those involving global pharmaceutical supply networks.
Batch processing typically takes longer than continuous processing. Each batch needs to be mixed, processed, and stored before the next batch. Multiple stages are involved in batch manufacturing.
Materials are tested in a reputable lab between each stage. When quality has been established, the majority of the ongoing work is stored before materials are passed on to the following phase. Long manufacturing cycles are a result of the accumulation of these "hold times."
Greater Waste and Production Costs
If a batch of products does not meet quality standards, the entire batch may need to be scrapped. This results in greater waste and higher production costs.
Continuous Manufacturing Vs Batch Production
Continuous manufacturing merges the whole manufacturing stream into a single, completely integrated flow. Whereas, batch production requires the sequential processing and testing of material over distinct phases.
By eliminating built-in production gaps, this "continuous" production can reduce manufacturing timelines from months to days.
Advantages and Disadvantages of Continuous Manufacturing
Businesses can reduce hold times. They can use all their production lines' capacity. They can integrate quality testing by implementing continuous manufacturing. Manufacturers can respond to changes in demand more quickly with the aid of continuous manufacturing. A continuous line enables producers to react more quickly to shifting markets.
This can be done by processing both larger and lower dosages of medicine as needed. Additionally, it makes recipes conceivable that conventional batch procedures cannot. The advantages of continuous manufacturing are:
- Flexible batch sizes
- High accuracy from using machinery
- Simplified scaling
- Increased control over important process parameters
- Ease and simplicity of organization of this type of process
- Lower energy consumption, improved utilization
- Cheaper labor rates because production will rely more on machinery than any other resource
- Reduce waste
- Remove the need for off-line testing and storage
- Improve schedule adherence
- Lower manufacturing costs
- High returns on investments
- Increase the usage of automated production and predictive maintenance
- Speed up production.
Continuous manufacturing is also a more adaptable method. It makes scaling up production much simpler. For instance, scaling up just entails extending the continuous manufacturing process.
In other words, compared to batch manufacturing, continuous manufacturing is more efficient. Continuous manufacturing makes it easier to adjust supply to demand. As a result, it is possible to create smaller batches, which results in less waste when a batch contains errors.
The following are some crucial areas where an ERP or MRP (Material Requirements Planning) system can be helpful in:
- Monitor carrying costs
- Control production
- Evaluate work-in-progress costs
These solutions allow you to quickly view your manufacturing and material expenses. This simplifies your selling price computation in the end.
- Can suffer a significant loss if demand declines or drops over time.
- Constant machinery and equipment inspection and maintenance
- There is no chance for customers to modify their purchases
- Difficult to adapt to new circumstances and requirements.
- Shutdowns and reconfiguration can be time-consuming and expensive.
Again, a more hands-on worker might not find continuous manufacturing to be very useful. Besides, it doesn't harm to be aware of the opposition and manufacturing in general.
Why not investigate the various manufacturing techniques to choose which is best for you? Regardless of the workflow you choose, our ERP for Pharmaceutical Industry and MRP article can assist you in organizing and setting up your company to operate as efficiently as possible.
Challenges in Continuous Manufacturing
Processes used in continuous manufacturing are not without difficulties.
Continuous manufacturing systems offer obvious benefits for manufacturing. But, the pharmaceutical industry's economics have been difficult to navigate. Manufacturers are always worried about the returns on any investment in continuous manufacturing technology.
This takes into account costs for new equipment and closing down old capacity. It also estimates the lifetime profitability of a particular therapy.
One is the complexity and length of time required to perform changeovers on continuous manufacturing lines. This can exceed a week.
- There are hundreds of parts in continuous manufacturing systems that need to be cleaned, replaced, and tested.
- Even expert operators may find changeovers to be time-consuming.
- This happens because they are very manual operations (one that is facilitated by digital SOPs).
- The question of whether frequent changeovers can be carried out to permit short-duration runs and tiny batches is still unanswered.
- While switching over should be able to be done in less than a day, present lines can take up to a week. This is because of the lengthy disassembly, cleaning, and reassembling process.
The lack of a globally unified regulatory framework on continuous manufacturing has been cited as a constraint. It serves as the main obstacle to the implementation of continuous manufacturing.
- Harmonization is essential because, without it, producers would have to get permission from many RAs to sell their goods abroad.
- In the past, RAs frequently concealed changes to drug products made after approval.
- This involved imprinting the production philosophies of manufacturers with a fixed mindset of batch procedures.
- The adoption of continuous manufacturing by manufacturers has also been hampered by concerns over regulatory delays.
- Besides, governmental backing for continuous manufacturing has increased lately.
- Specialized teams have been established by the FDA, EMA, and PMDA to encourage the use of continuous manufacturing.
- The FDA Emerging Technology Program (ETP), was established in 2014. It was created to aid manufacturers in overcoming implementation difficulties.
- To help implementation, regulatory recommendations on crucial conditions for continuous manufacturing have been developed.
- The definition of a "batch," process validation, continuous process verification, and PAT are among the rules.
A lot of training is needed to operate machinery for continuous manufacturing. Everyone engaged must have enough exposure to and understanding of the system. This should be done to ensure proper usage due to the complexity of the equipment and the possibility of errors.
High Upfront Costs for Investments
Due to the usage of PAT and automation software, developing continuous processes is expensive. The high initial cost is another significant barrier for firms to put in place continuous manufacturing.
There exists a difficulty in making the case for new equipment while existing batch equipment is still working. So, for the majority of manufacturers, investing in continuous manufacturing is not a top priority.
- This is a huge challenge for generics producers who have thin profit margins.
- High demand for generic medications would discourage a generic firm from making an investment in continuous manufacturing.
- Manufacturers might expect financial rewards. This is despite the large initial capital expenditure needed for continuous manufacturing equipment. This is particularly true with high-volume production.
- Continuous manufacturing has been shown in many trials to save production costs.
A Novartis-MIT Center for Continuous Manufacturing investigation revealed a sizeable decrease in labor costs. The study also revealed a decrease in in-process inventory and energy consumption. This led to further significant cost savings.
Continuous manufacture of antibodies proves that the hybrid technique is more helpful economically than end-to-end continuous manufacturing. Yet, the greatest cost savings are possible with continuous processes.
The complexity of a wide range of parameters involved in the development of biopharmaceuticals may be to blame for the discrepancies in findings. Yet, most economic evaluations argue that batch manufacturing is the least helpful technique economically.
According to research, the initial high cost of implementation can be outweighed by the cost reductions. As a result, firms can achieve long-term profits through continuous manufacturing.
Equipment Limitations and Technological Issues
There is currently a lack of equipment for continuous manufacturing. Smaller firms without these capabilities are forced to outsource their manufacturing to a small pool of CMOs equipped for continuous manufacturing. When working with CMOs, manufacturers should also take data security.
The possibility of material cross-contamination was also taken into account. As a result, pharmaceutical companies were forced to make equipment modifications at the last minute. This further delayed the adoption of continuous manufacturing.
- The pace of innovation among equipment providers has slowed down. This is due to the pharmaceutical industry's delayed deployment.
- Batch unit operations use discrete equipment that can be changed to support many manufacturing pathways.
- Discrete batch unit processes, yet, result in less productive machinery and plants.
- 'Plug-and-play' continuous equipment made up of distinct reconfigurable unit processes is being created. This is despite the fact that continuous manufacturing is currently less versatile in this regard.
As a result, this difficulty should no longer be a barrier. Pharmaceutical businesses' interest in continuous manufacturing is growing, encouraging increased participation in the innovation process.
To develop novel continuous manufacturing techniques for biopharmaceuticals, equipment vendors and biopharmaceutical manufacturers are working together.
Challenges in Business, Operations, and Culture
Ideally, continuous manufacturing should be used in the initial stages of drug development to remove the need to demonstrate regulatory equivalence to batch technologies now in use. This is a key consideration in drug development.
In the same way, implementing continuous manufacturing throughout the clinical stages is more efficient for biopharmaceuticals than changing current batch procedures. The resulting product is more efficient than changing current batch procedures. This is due to the intrinsic complexity and high process dependence of biopharmaceuticals.
- A new medicine product's high learning curve for continuous manufacturing, however, can complicate a short launch window.
- As a result, it will be difficult to match a manufacturing breakthrough with a clinical trial timeframe. This may call for organizational adjustments.
- The industry has developed a conservative culture as a result of regulatory uncertainty. This has slowed the adoption of innovative technologies.
- For the pharmaceutical sector to adapt its batch processing-based production philosophy, attitude and cultural adjustments are required.
- Additionally, before becoming extensively adopted in the pharmaceutical industry, new technologies must have large, proven benefits.
Therefore, it is crucial for international organizations to share examples of continuous manufacturing success. This is to inspire manufacturers.
Technical, Safety, and Quality Issues
The characterization of raw materials and intermediate qualities is more complicated in continuous manufacturing. Hence, material traceability is a major quality problem.
In continuous manufacturing operations, it can be challenging to determine when a batch of products begins and ends.
A large number of excipients are utilized. this is particularly difficult for low-volume and low-dose medicinal formulations. The amount of time the material spends moving through each unit activity can be tracked. Thus, RTD monitored by PAT may be a way to get around this problem and assure material traceability.
- Effective process control strategies are essential for continuous manufacturing.
- This would help ensure process performance and product quality.
- There are fewer transition steps in continuous manufacturing than there are in batch manufacturing. Yet, it still raises important safety issues.
- The overfilling of material, excessive system pressure and other possible risks not present in batch manufacturing must all be avoided by manufacturers.
- These technological concerns about continuous manufacturing have been covered in some publications in recent years.
Besides, many equipment producers are working with the pharmaceutical sector. They are working to find technical solutions for continuous manufacturing. Technical difficulties are thus not always significant barriers for producers.
Skills and Knowledge Gap
Continual manufacturing technology development and implementation demand qualified employees. The pharmaceutical business is still developing continuous manufacturing. Thus there is a shortage of workers with the necessary expertise.
- This presents a challenge to both manufacturers and regulators. Continuous systems need staff with statistical training.
- Despite the fact that training has been provided, closing the knowledge gap would need increased multidisciplinary cooperation and dedication from all pertinent stakeholders.
- Continuous manufacturing will lead to certain manual tasks being redundant due to automation.
- Yet, continuous manufacturing offers a chance to create new opportunities in research and development and testing. This is because there is a need for qualified employees.
- Reduced labor intensity will also result in fewer mistakes made by people.
As a result, there would be an increase in new positions available that required highly skilled individuals.
Examples of Continuous Manufacturing
Operations that can fully benefit from continuous manufacturing flow use continuous production systems. Here are a few specific instances.
Genomics, food production, pharmaceuticals, and biofuels are a few of the items that biotechnology produces. These are items that biotechnology produces using living things and molecular biology.
Automobile manufacturers are better recognized for process production. The facilities, which consist of three integrated units, operate as a single unit to cast, stamp, make engines, assemble vehicles, and pack metal. This is a long and complex example of continuous manufacturing application.
Metals and Mining
Continuous manufacturing are used in the mining and metals sectors to extract and convert raw materials. A leader in the manufacture of aluminum mines the mineral bauxite and converts it into alumina. Bauxite is an essential component of aluminum. It is delivered to aluminum smelters to be transformed into metal.
Batch processing was well recognized in the pharmaceutical industry. Yet, a lot of people are beginning to switch to manufacturing. The manufacturing process creates coated tablets in a continuous manufacturing stream from raw powders.
It enables the provision of tailored solutions to client's needs. It is a continuous stream of roll compaction or wet granulation. Following a $95 million investment, GlaxoSmithKline inaugurated two new continuous manufacturing facilities in Singapore. The company also enlarged the third.
Recommendations and Prospective Outcomes
Even though the adoption of continuous manufacturing methods has been slow, an increasing number of facilities are adopting these methods when launching a new product. Additionally, authorities continue to reduce concerns in the sector about delays in drug approval for products made utilizing continuous manufacturing methods.
The advantages of continuous manufacturing are also too compelling to ignore. Continuous manufacturing is the way of the future for the pharmaceutical business, at least for new medicines and new facilities.
Despite the difficulties experienced by manufacturers and regulators, it is clear that the switch to continuous manufacturing is progressing. Key suggestions are made in this part to make it easier to adopt continuous manufacturing.
Given the many obstacles, implementing the entire end-to-end continuum of continuous manufacturing might represent a quantum leap for manufacturers. Manufacturers can use hybrid ways to deploy continuous manufacturing. They can also use step-by-step to get around this obstacle.
Manufacturers can use hybrid processes to boost output and gain experience with continuous unit operations. Manufacturers can also generate money to cover the high initial cost by combining the benefits of batch and continuous processes. The manufacture of antibodies can benefit economically from hybrid techniques as well.
By using this strategy, manufacturers can evaluate the advantages of continuous processes and move toward end-to-end continuous manufacturing. This allows manufacturers to gain all the advantages of continuous manufacturing for both small-molecule medications and biopharmaceuticals.
The industry's existing regulatory uncertainties must be resolved, and regulatory harmonization is essential. Without harmonization, regulatory agencies' efforts to comprehend new continuous manufacturing technologies will result in a slowdown in implementation.
- The adoption of continuous manufacturing would proceed more quickly. It would proceed under consistent regulatory review and supervision.
- The advantages of harmonized regulations include process enhancements and the creation of new manufacturing techniques to create novel compounds. Ultimately, harmonized regulations result in an improvement in patient access to medications.
- Since manufacturers will have a better understanding of the regulatory requirements with global regulatory harmonization, continuous manufacturing would become more prevalent.
Availability of Equipment
While expanding a process might appear to be fairly simple, actually finding the right equipment might be challenging. Some companies even need switching suppliers. To avoid modifying any of the parameters, which can make sourcing commercial equipment more challenging. It is ideal to use commercial equipment produced from the same material as your POC equipment.
Silicon carbide is one possibility, yet not all manufacturers produce small-scale versions of this material. So more raw material is needed in the beginning.
Value of Quality
As a result of batch manufacturing, which has been used by the pharmaceutical sector for many years. Manufacturing organizations have developed a limited perspective and a conservative mentality.
- The hardest part of adopting continuous manufacturing is changing organizational mindsets.
- The adoption of pharmaceutical quality systems (PQS) is essential for continuous manufacturing. The adoption of PQS has increased in recent years as manufacturers become more open to the concept.
- Yet, PQS has inherent limitations because good decisions are what lead to good results.
- To develop quality products through continuous production, manufacturers must adopt a culture of quality.
- Organizations can also implement the ideas of Kaizen or Lean Six Sigma to create cross-functional quality improvement processes.
Financial Risk Management
To reduce investment risk, global consortia and other pre-competitive industry-wide initiatives could be created. Additionally, the investment risk will be reduced by continuous manufacturing technology that may be used for many different goods.
- It is also crucial to carry out a thorough review of the uses, expenses, and advantages of new technology.
- The majority of economic assessments are now conducted on finished pharmaceutical products but not on APIs.
- Thus, creating a business case for the continual manufacture of APIs is still necessary.
- The government's ongoing financial contributions will also lower the hefty initial cost.
- In the past, tax and regulatory incentives have sparked improvements across the board.
- Pharmaceutical manufacturing clusters were able to flourish because of tax benefits, particularly in Ireland, Singapore, and Puerto Rico.
- Governments should offer tax incentives for continuous manufacturing as it will help patients with better access to medications.
- Government support for the technique of continuous manufacturing is rising nowadays.
To speed up the clearance process and grant a patent exclusivity period for medicines produced by continuous manufacturing, regulators should also take into account offering regulatory incentives to manufacturers for using continuous manufacturing.
Given the chance to break even more quickly and increase revenues, these incentives would encourage firms to switch to continuous manufacturing.
Time and Expense
Continuous manufacturing allow for continuous operation until the project is finished, minimizing the manpower and financial costs associated with starting and stopping production between batches. This results in a shorter manufacturing time for the entire project volume.
Other elements that could affect project timing must also be taken into account. While your customer's time to market may very well be shortened, you must clean your continuous reactors after a project is finished to prevent cross-contamination.
- Cleaning a flow reactor is rather a complicated procedure because it involves a network of pipes with different lengths and diameters.
- This might affect internal turnaround times and delay the start of new projects.
- Continuous manufacturing can maximize throughput, as well as lessen the possibility of expensive batch dumping should something go wrong, all while saving money.
Only a little amount of product would be wasted in the event of a pipe collapse because reactions occur on a much smaller scale, which might save a significant sum of money and raw materials.
Building Capacity, Working Together, and Publishing
To overcome the shortage of skilled workers in continuous manufacturing technologies, training programs must be held. Various organizations, such as ISPE, C-SOPS, and the United States Pharmacopoeia, now host training programs (USP).
To modify the processes for their products, the pharmaceutical industry can also learn from other sectors of the economy that have already adopted continuous manufacturing. Cross-departmental cooperation and institutional alliances are also necessary for the implementation of continuous manufacturing.
- Manufacturers should stay in close contact with authorities and business leaders.
- Cornerstones for promoting collaboration to advance innovation are international conferences like ISCMP and national programs like the "Pharma Innovation Program Singapore."
- Furthermore, the dissemination of continuous manufacturing success stories and obstacles would boost industry confidence and set standards for best practices.
- To guarantee that the industry has the information and skills required to undertake continuous manufacturing, training programs and publications are both essential.
Fit for the Product
Certain API types work better with flow reactor pipes. Solids frequently produce clogs in the network of pipes used to ensure appropriate mixing, forcing operators to disassemble their equipment should a solution precipitate out.
To accommodate the manufacturing of solids, continuous equipment with bigger pipes is available. Such machinery vibrates while in use to keep the materials inside moving constantly.
If you choose to use continuous manufacturing to create solid APIs, this method works well, but the machinery must be bolted in place and is more expensive than the standard kit.
Pharma 4.0 and Industry 4.0
Currently, the pharmaceutical business has a staggering amount of data that is not being well exploited, and data integrity is still a major problem. A rise in data collection from systems like PAT would make these problems worse in continuous manufacturing.
Although using this kind of technology could have many advantages, it is not without difficulties. When deciding whether continuous processing is appropriate, businesses must evaluate both sides.
It is true that adopting continuous processing has certain economic advantages, especially when you consider the effect of having to discard a batch of high-value APIs if something goes wrong. Despite this, the price of production machinery for continuous manufacturing is significant; even small-scale machinery costs businesses more than £30K.
So, the business case for adoption rests on the potential to make money. Furthermore, it is simple to doubt the adaptability of this pricey equipment. Since lab equipment is built of stainless steel, managing acidic compositions can be challenging owing to possible corrosion.
This restricts the reactions that can be carried out, especially during proof-of-concept (POC) work, unless you spend extra money on a non-reactive metal kit. Batch reactors are more accessible in comparison.
Maintenance Needs for Plants with Continuous Manufacturing
Given the complexity, importance, and 24/7 nature of continuous manufacturing, much thought must be given to plant and process design, maintenance philosophies, strategies, tactics, and operational interventions.
Concerns for Safety
All maintenance interventions must focus on safety, but maintenance shutdowns for continuous manufacturing plants demand extra preparation.
- Commercial pressures are created by the economic pressures of breaching planned shut dates when there are stringent time limits.
- What do failures of equipment and safety accidents have in common? They are both brought about by human error.
- And when you're rushing, mistakes like that are more likely to occur.
- A continuous manufacturing system will need many trades to work together or close to one another during a planned maintenance shutdown.
- To prevent exposure to moving machinery, electricity, or stored energy, testing by one maintenance crew must be coordinated with others in the area.
- Workers must adhere to Lockout / Tagout rules and other safety practices at all times.
Factors for Facility Design
After the facility has been constructed and operational personnel hired, the aforementioned considerations come into play.
- Engineering and maintenance assessments ought to take place while the manufacturing asset or facility is still being designed to increase its maintainability.
- The in-service dependability of each piece of equipment should be taken into account when determining the total cost of ownership (TCO), which guides purchasing advice with maintenance interventions planned at most annually.
- Similarly, FMECA analyses of process flows should be used to inform decisions on factory architecture, equipment redundancy evaluations, and spare inventory.
Modern computerized maintenance management system (CMMS) systems can be used by businesses to manage condition and performance data from continuous manufacturing assets instead of specialized software. Before that, assets must be properly upgraded with sensor equipment or already have it.
- A CMMS lowers the need for reactive maintenance interventions, which can have prohibitive cost consequences in a continuous manufacturing system by providing insight into the maintenance function.
- Users of CMMSs can use deterioration trends in conjunction with predictive maintenance analytics to determine when an asset will fail.
In this method, which is very helpful in the context of continuous manufacturing, maintenance planners and managers have plenty of time to allocate the required resources and schedule maintenance.
Factors for Maintenance Philosophies
The maintenance philosophy will need to be considered. Before choosing one or a combination of maintenance strategies and technologies, reliability-centred maintenance is advised.
- Manufacturers may also want to consider business-focused maintenance and total productive maintenance.
- Both of them provide a variety of intriguing methods, some of which may be a good fit for your operational requirements.
- Reactive, preventive, condition-based, and predictive maintenance strategies will often be determined by a maintenance philosophy.
- Preventative maintenance takes place in parallel operations to provide system redundancy in continuous manufacturing facilities.
- Given how rarely maintenance shutdowns occur, condition-based maintenance techniques will make up the majority of the plan.
- The assets that suffer high costs from downtime or repair will be the focus of predictive and prescriptive maintenance.
Considerations for Operations
The length of these shutdowns are subject to intense time pressure, and planned downtimes are spaced very far apart. The choices about maintenance employment could become very difficult as a result.
Should you outsource all maintenance or maintain it in-house? The cost and accessibility of competent contractors will be major factors. This is a crucial choice since it affects how many spare parts you have on hand, how you gain access to specialized equipment, and how you organize other internal resources.
Last but not least, it's important to give serious thought to equipment upgrades and technology obsolescence so that they can be planned, resourced, and scheduled.
Initiatives in Various Countries
The EU, the US, Australia, and Japan, in particular, are pursuing the development of catalysts, machinery, and prototypes that will enable the replacement of batch manufacturing with continuous manufacturing among national projects in Japan and other nations, as part of policies for strengthening industrial competitiveness.
For its ambitious goal of achieving continuous and automated operation of all processes from raw material inputs through the production of medicinal tablets, the Pharmacy on Demand project in the US stood out among the others.
- The Flow Science & Technology Consortium (FlowST Consortium) was founded in Japan in 2015 with the help of businesses, academia, and the government.
- The consortium's development efforts have received backing from the Ministry of Economy, Trade, and Industry and the New Energy and Industrial Technology Development Organization (NEDO).
From raw material input to product output, every process is automated, and the necessary area would only be about the size of a convenience shop. Additionally, a solution is being suggested for equipment storage in containers and truck transportation, enabling simple on-site pharmaceutical manufacturing.
- Pharmaceutical companies use continuous manufacturing, which is found in businesses in Europe and the US.
- US pharmaceutical giants Eli Lilly and Pfizer, who were among the first to respond, have already moved several of the products they generated via continuous manufacturing into commercial production after receiving FDA approval.
- Based on the findings of their collaborative study with MIT, Novartis (Switzerland) launched CONTINUUS Pharmaceuticals to offer designing services for machinery used in continuous manufacturing.
- By leveraging its technological prowess in catalyst and process development developed in the petrochemical industry and applying it to the continuous manufacturing of medicines, South Korea's SK biotek has established continuous manufacturing systems to replace numerous batch processes.
Pharmaceutical Sector Overview
Currently, businesses are starting to use continuous manufacturing techniques to create various pharmaceutical items. Also being investigated are hybrid production systems that combine batch and continuous operations.
This technique combines two systems, such as, for instance, a batch system used for traditional reactions and refinements (processing of medication components) with a continuous manufacturing system used for crystallization and tablet processing (pharmaceutical formulation).
- Future developments in sensing technologies, such as those for soft sensors, are anticipated to enable the implementation of full continuous manufacturing, which integrates the entire manufacturing process and to further encourages hybrid-type systems.
- The use of such a system will enable the pharmaceutical producer that owns the equipment to manage all the pharmaceutical operations since, once the raw ingredients are input, one production facility is required to generate the tablet medicine in one go.
As a result, continuous manufacturing has the ability to completely transform the value chain, which up until now has consisted of labor agreements between major pharmaceutical producers and intermediate manufacturers.
- Over the past ten years, the pharmaceutical sector has shifted toward continuous manufacturing.
- The complex manufacturing processes employed in the production of pharmaceuticals are now supported by advanced manufacturing technology.
- Sensors and analytical techniques have been developed to align quality control.
- Additionally, the legislative and financial climate supported manufacturers' pursuit of innovation.
- The FDA recognized that continuous manufacturing had the ability to raise quality, meet customer demand, and enhance medical care, and they have expressed their support.
Vertex Pharmaceuticals made history in 2015 when it became the first company to receive FDA approval for a medicine produced on a continuous line. Each of the following three years saw the approval of manufactured products for Janssen, Eli Lilly, and Novartis.
Fine Chemicals Sector Overview
Many products in the fine chemicals sector of the chemical industry, such as organic compounds, synthetic resins, and agrochemicals, are produced utilizing the batch process.
In the future, it is anticipated that the implementation of continuous manufacturing for these fine compounds would gain momentum to lessen operator workload, improve safety, and reduce equipment requirements.
For instance, there has been a recent development in the adoption of continuous manufacturing processes through industry-academia collaboration, even for the production of agrochemicals, whose unit price is lower than that of pharmaceutical products.
- These initiatives are being made as part of the research and development platform of the National Agriculture and Food Research Organization (NARO), which aims to create inventive production methods for the realization of inexpensive agricultural chemicals.
- Some believe that because the laws for medicines are more strict, the implementation of continuous manufacturing in the fine chemicals industry will happen first.
- In such a situation, the business environment of the engineering and equipment manufacturers engaged in continuous manufacturing is likewise anticipated to be affected by such a development.
How can Deskera Assist with Continuous Manufacturing?
As a business owner, it is crucial that you stay on top of your processes and resource management. To achieve this, you need to manage production cycles, resource allocations and a lot more. Deskera MRP is the one tool that lets you do all the above.
Deskera allows you to:
- Manage and track inventory
- Control production schedules
- Create custom dashboards
- Maintain bill of materials
- Optimize resource allocations
- Generate detailed reports
One of the primary ways to produce is continuous manufacturing, also known as flow manufacturing. It denotes that a product is manufactured, without any breaks or gap between batches.
Traditional applications of continuous manufacturing include the production of high-volume, non-customizable goods in the petrochemical, oil and gas, paper and pulp, and water treatment industries, as well as the production of goods that are consumed, such as electricity generation and water treatment facilities.
- Batch production is in contrast to continuous manufacturing.
- With continuous manufacturing, machines and equipment are in use and the method to make various items hardly ever varies.
- While batch processing is the simplest and most straightforward type of processing, continuous processing can assist remove production bottlenecks and boost product quality and quantity.
- With laborers around the clock and materials moving continuously through a series of activities, stoppages need careful planning and management since they increase costs, cause problems with quality, and waste products.
The design of a thorough maintenance strategy, supported by targeted data collection and analysis using a contemporary computerized maintenance management system, are the minimum requirements needed to create a sustainable continuous manufacturing system, with equipment downtime limited to infrequent maintenance shutdowns.
- Continual production has evident advantages for the pharmaceutical business, despite the low implementation rates. Expect to see wider use of continuous production as advanced manufacturing becomes the standard in the life sciences manufacturing industry.
- The continuous manufacturing flow's aim is to create a flow in which materials are continuously manufactured, produced, or processed.
- Continuous manufacturing increases the flexibility of track and trace, allowing you to define a drug's batch quantity based on factors like the amount created or the length of time rather than the equipment used to make it.
- The correct equipment must be supported by reliable and scalable chemistry, systematic process design, and effective process analytical technology (PAT) for continuous processing to be successful, making a talented team essential.