Advances in mAbs Technologies with Changing Business Environment
Rajesh Gupta
Subject Matter Expert / Director, Process
NNE Pharmaplan India Ltd
Gaurav Abhishek
Process Engineer, Biotech
NNE Pharmaplan India Ltd
Niharika Ruhela
Process Engineer, Biotech
NNE Pharmaplan India Ltd
Tushar Sukhdevrao Shende
Process Engineer, Biotech
NNE Pharmaplan India Ltd

Monoclonal antibodies (mAbs) are currently being used as the leading therapeutics for several diseases across the globe and are being used for treatment of cancer, immune disorders, and infections. This article discusses how the patent expiry is impacting the mAbs manufacturing business framework and is being influenced by the design drivers - to be the first in the market.

Monoclonal antibodies (mAbs) contribute almost 60% of market revenue among the top ten bestseller drugs worldwide. Growth of biosimilar market isdriven by the numbers of patents getting expired in the coming years, regulations and guidelines for manufacturing of different class of biosimilars and potential demand of these products. Although, a few new mAbs that have gained regulatory approval in last few years, it is expected to have 70 mAbs product in global market by 2020.

With more number of new mABs, coupled with the expiry of the patents and more affordability is expected to generate the overall sales of nearly US$125 billion in next 4-5 years. [1]

The patent of some of the 1st generation mAbs have expired and few more are expected to expire in coming years and this has triggered the development of mAbBiosimilars in the estimated time frame [3]. The patent of drugs such as Rituximab/MabThera, Remicade, Herceptin, Humira, Avastin, Synagis, Erbitux, and Lucentis are due to expire in the coming years and the manufacturers are in no mood to let this opportunity go.







Market for mAbs is expected to grow in near future due to, patent expiry of few block buster drugs and newproducts in pipeline. European and US market is wide open due to the patent expiry which influence the Asian drug makers. [3]It is expected that the emerging biosimilar market, especially in China, India and Brazil will record high growth rate driven by cost-effectiveness of biosimilars and the growing awareness supported by growing healthcare infrastructure in these countries.

MANUFACTURING INITIATIVES

The common and robust manufacturing platform for mAbs are key for the commercial manufacturer and success for the product. The advent of Biosimilars is driving a desire to achieve lower cost of goods and globalize biologics manufacturing. Biosimilars are the major advantage to reduce the cost and globalize the manufacturing.







Outsourcing

Assembling biosimilars needs particular capacities, fastidious arranging, critical budgetary interest in hardware, exceptionally talented staff, innovation, work force, and materials. The intricacy and costs required in biosimilar advancement keep on rising till they accomplish economies of scale, hampering the underlying achievement of biosimilars production. Subsequently, numerous merchants are progressively deciding on contract fabricating associations and contract examine associations with set up proficiency in the field of assembling biosimilars. These associations are creating and approving explanatory strategies to enable pharmaceutical organizations to stay focused and monetarily feasible in the market. Additionally, producing biosimilars in creating nations, for example, India and China has lessened the imperative venture by around 40%, making India and China a centre for outsourced biosimilar fabrication. Outsourcing the manufacturing process for biosimilars to developing nation will help the supplier to new products in the market in more efficient and cost effective manner. [2]

New Technologies

Additionally; new trends and technologies are coming in the manufacturing of mAbs like Single use technology, Continuous manufacturing etc which are providing pace to the mAbsbiosimilar manufacturing.

These mABs based drugs are used for treatment of Cancer, immune disorders, and infections. mAbs manufacturing market is induced by numerous drivers, like cost effective treatment, growing number of patent expiry, favourable regulatory requirement. [3]

Development of biosimilar in comparison to the reference product will consume potentially less time and revenue, since there is no requirement to carry out the process at R&D scale and few stages at clinical trial can also be saved.

Due to the fastest growth and profit in mAb business, the new era of the mAb manufacturing facility requires agility, dynamics and flexibility. Introduction and adaptation of Single use and continuous manufacturing technology is giving pace and flexibility to the mAb business. Continuous manufacturing facilities are most cost effective as one can produce faster with smallerfootprint requirement of the facility, less manual intervention, and investment. Single facility can be used to manufacture multi product by opting combination of single use technology as the product change over time will be less and chance of cross contamination will be nullified. The continuous operating facilities are expected to be more efficient (in terms of productivity, less changeover time for cleaning and validations) compared to a batch bioprocessing facility.

At present, we see a merging of these two correlative techniques as manufacturers try to coordinate single-utilize frameworks into a nonstop generation stage. This speaks to an outlook change in how biotherapeutics are fabricated, and it offers promising advantages for the two producers and customers. [6]

Characteristics of continuous manufacturing

Continuous production is used under the following circumstances:
  • Dedicated equipment with zero flexibility.
  • Process handling is fully automated.
  • Component materials cannot be readily identified with final product.
  • Planning and scheduling is a routine action.
Challenges of continuous manufacturing

  • One major challenge is the existing batch infrastructure that many companies already have in place. When this occurs, companies are reluctant to invest in novel machinery and technologies.
  • Another challenge is the pervasive mindset of the industry that pharmaceuticals should be produced via outdated methodology simply because that is the way it has always been done.
  • Also, there is a lack of experience in continuous manufacturing at most pharmaceutical companies, which is a result of decades of batch manufacturing. [5]
This is reinforced by the notion that regulators will balk at approving novel processes. We consider this belief erroneous, based on actions taken by the U.S. FDA and other regulatory agencies (e.g. the FDA has approved drugs produced in a continuous fashion).

Benefits to continuous manufacturing

There are many pros of continuous bioprocessing, many of these similar and complementing those of single-use systems.
  • Reduced time to market: One identical platform for product development and market launch.
  • Process cycle time reduction
  • Reduced CAPEX and OPEX costs
  • Closed system without hold
  • Smaller facility footprint requirement
  • Easy scale up
  • Increased productivity
  • Improved quality
  • Optimum utilization of resource
  • Increased flexibility
Limitations to continuous manufacturing[4]

Flexibility to accommodate and process number of products does not exist.
  • Very high investment for setting flow lines.
  • Product differentiation is limited.
  • If contamination occurs, huge volumes of product may be lost
  • PAT implementation
  • Required Intensive Planning: To prepare for the change-over, substantial work is necessary regarding detailed design, preparation, project planning, scheduling, and plans for ongoing maintenance and improvements.
  • Costs Significantly to Implement up Front: Purchasing or adapting machinery to be more flexible is costly.
Regulatory Challenges

The continuous manufacturing is an upcoming technology and it comes with its own package of challenges at the operational level. As mentioned earlier; the continuous manufacturing system is quite complicated, requiring more skilled labour and more expansive technological expertise. An extensive network of software and hardware must work together well consistently.

Some of the regulatory challenges faced by the industry exploring in to continues manufacturing includes:
  • Batch/ lot definition,
  • Process dynamics,
  • Bioburden management
  • Deviation management and Lot traceability
  • Definition of design space for continuous manufacturing
Defining the Batch

Defining a batch in continuous manufacturing platform is important aspect so as to be able to investigate in case of any deviation, recall the product or if anything goes wrong.

Batch - a specific quantity of a drug or other material that is intended to have uniform character and quality, within specified limits, and is produced according to a single manufacturing order during the same cycle of manufacture

Batch refers to the quantity of material and does not specify the mode of manufacture

Lot - a batch, or a specific identified portion of a batch, having uniform character and quality within specified limits; or, in the case of a drug product produced by continuous process, it is a specific identified amount produced in a unit of time or quantity in a manner that assures its having uniform character and quality within specified limits.

Definitions for both "batch" and "lot" are applicable to continuous processes

Batch Definition for CPP could be based on the specific time period or/and amount of product produced. Within specified time period, the product uniformity/ consistency must be maintained and it should be within the critical process parameters. Control strategy can be implemented to do the same. Material traceability is an important requirement to identify deviation or nonconformity which includes raw material used, Media/buffer used etc.

Process Dynamics

Intensive studies are required to understand the process dynamics at the development stage and suitability of materials throughout the process as well as the impact of variations in feed, media and buffer at Continuous Process platform.

Bioburden Management

Opting single use system, closed process and filter arrangement at appropriate intermediate process steps will help to control the bioburden. Filter sizing and filter change frequency is the challenge for bioburden control in continuous manufacturing and it can be resolved by proper risk assessment and characterising the intermediate product.

Deviation Management and Lot Traceability

To guarantee batch/ lot in term of quality, residence time distribution model can be used. This will help to identify deviations/ non-conformity throughout the batch/ lot. This model will help to have complete visibility and control over any deviation, and manufacturer will have the option to discard the affected lot or portion of batch.

Design Space of Continuous Bioprocessing

Concept for the design space used for batch processing can be utilized for continuous process platform. Critical process parameter for individual unit operation can be linked to the critical quality attributes and each unit operation altogether links into a controlled strategy.

Way Forward

The biopharma industry is highly regulated one and the regulators should be fully convinced that the there is no compromise done with the drug quality and safety as far as the patients are concerned.

For molecules already in manufacturing; it is difficult to switch over to the continuous mode because of the regulatory pathway. However, for manufacturers which are in early stage of development of biosimilar - post patent expiry in vision; it is much easier to adopt to the new technology.

To support this; there is a significant regulatory push in the direction of continuous manufacturing, especially from US FDA and other agencies which are in favour of the advanced control strategies associated with continuous manufacturing. The updated European regulations on e.g. process validation and other GMP aspects are enabling this direction and it is becoming increasingly clear that industry is pushing on an open door when it comes to regulatory endorsement towards continuous manufacturing.

References:

1. Why Monoclonal antibodies (mAbs) are the Future of Medicine; Yale Books Unbound. August 2015.
2. Top 4 Trends Impacting the Global mAb Biosimilars Market Through 2020; Technavio. October 2016.
3. Sample Report - Global Mab Biosimilars Market.
4. What is holding Industry back from Implementing Continuous Processing: Can Asia Adopt More Quickly?; Eric Langer, Managing Partner, BioPlan Associates, Inc. Rockville, MD USA. December 2015.
5. An exclusive Q&A with CONTINUUS Pharmaceuticals on continuous manufacturing operational best practices and trends for 2017; Meg LaTorre-Snyder. December 2016.
6. Single-Use Continuous Manufacturing: The New Paradigm In Biopharmaceutical Processing; Jerry Martin. October 2016.

Contact: SDVE@nne.com