The biopharmaceutical market is growing rapidly and is expected to continue on this upward track.1 Seven of the top 10 best-selling drugs in 2013 were biologics.2 Pharmaceutical innovators are investing more in the development of biopharmaceuticals because biologics have certain advantages over more traditional small molecule therapies. Biologic medicines such as proteins, antibodies, siRNA and other natural products have higher specificity compared with small molecule drugs. This means they are more targeted and therefore induce fewer side effects, which can increase patient compliance.
Targeted therapies are useful in the treatment of diseases such as cancer because the molecules can be directed specifically to the tumour and can avoid attacking normal healthy cells.3 One of the major limitations of some biologic medicines is their short half-life in the body. They can also be attacked by the immune system or degraded by proteolytic enzymes, all of which can reduce the bioavailability of the biologic entity.
The addition of an mPEG can reduce the activity of the drug but this is compensated for by the increased bioavailability of the molecule
At present, the gold standard solution for increasing the half-life of biologics is the use of methoxy polyethylene glycol (mPEG) chains. These can be attached to the biological molecule via a process known as PEGylation. This has the effect of increasing the hydrodynamic radius of the biologic, thus reducing the renal clearance in the kidneys. It also shields it from attack by the immune system and degradation enzymes, which has the overall effect of increasing the bioavailability of the compound. The addition of an mPEG can, however, reduce the activity of the drug but this is compensated for by the increased bioavailability of the molecule.
The manufacture of activated mPEGs for PEGylation is not a core activity for pharma companies. The increased adoption of PEGylation has resulted in a rise in the number of pharma companies that outsource the development and manufacture of mPEGs for conjugation to their biologic compounds. Currently mPEGs are manufactured for a number of drugs, both commercialised and in clinical development, and for biosimilars.
Outsourcing activated mPEG manufacture
A preferred contract business partner will have global reach, state-of-the-art facilities, and a wealth of expertise and capabilities to meet the needs of biopharmaceutical innovators. Innovator companies typically look for an outsourcing partner that can offer quality, reliability and security of supply of mPEGs from preclinical through to commercial scale. These attributes may come with experience and the use of the appropriate control measures and analytical techniques. The reliability of an outsourcing partner might be assessed by looking at a company’s track record, and supply security can be supported by choosing a supplier able to handle all aspects of product development and manufacture at various scales.
A drug developer will determine the required mPEG early in the development of the biologic, and the outsourcing partner will work with the innovator to develop the mPEG. Therefore, it would be of benefit to an innovator if a manufacturer has the experience of making a wide variety of mPEGs and can manufacture them at scale. Production at large scale can bring cost advantages to the manufacturer, which can be passed on to the innovator.
Figure 1: mPEG-OH is the key raw material for the manufacture of activated mPEGs
To be able to offer the supply of PEGs at scale, a supplier will require facilities suitable for the manufacture of grams to metric tonnes of product. An innovator would expect the facilities to be GMP compliant and US FDA approved, and to have an excellent inspection history.
Dr. Reddy’s Custom Pharmaceutical Services (CPS), for example, a contract development and manufacturing organisation (CDMO) with experience of producing a wide range of mPEGs at various scales and at three different GMP manufacturing facilities, has improved the manufacturing processes, making them shorter, more efficient and giving a higher purity product. Improvement of manufacturing processes is an example of how outsourcing can give the customer access to innovation.
Another offering that would be desirable to innovator companies would be the back integration from the activated mPEG to mPEG-OH, the critical raw material in the manufacture. This back integration gives supply chain security and ensures that the quality of the final activated mPEG can be controlled by the CDMO throughout the manufacturing process.
Analysis of large polymeric molecules such as mPEGs can be a challenge, but knowing the quality and purity of the mPEG is crucial
The quality of the mPEG can be assessed using a variety of analytical techniques. Analysis of large polymeric molecules such as mPEGs can be a challenge, but knowing the quality and purity of the mPEG is crucial. Therefore, a customer would want to have confidence in a manufacturer to perform and understand a range of analytical techniques. High quality mPEGs ought to have high levels of activation, narrow polydispersity and low diol content.
Methods used for analysis of mPEGs include NMR, HPLC, GC and MS. The manufacturer should be able to develop the methods according to the mPEG that the customer requires. Analytical techniques can be used to assess critical parameters, such as levels of activation and diol content. Diol is an impurity that can cause the formation of bi-functionally activated molecules, capable of cross reactivity. Some CDMOs have developed analytical techniques that can separate diol and diol-derived impurities from one another, based on functionality. This eliminates interference caused by molecules with different molecular weights.
mPEGs can be custom made to different chain lengths. This level of flexibility for customisation is allowed only if a supplier is able to offer back integration to mPEG-OH, and has the synthetic skill and manufacturing expertise to convert through to the activated form. Outsourcing the manufacture of mPEGs gives the customer the opportunity to use the skills and experience of the outsourcing partner, which can potentially accelerate project time-lines.
Understanding customer needs
An mPEG supplier will need a dedicated team able to understand the needs of the customer. A close working customer relationship will help ensure that projects are run smoothly, to time and in a cost-efficient manner. From a regulatory point of view it is also useful if an outsourcing partner is able to offer advice and information to the customer about filing Drug Master Files (DMFs). Some contract businesses will have DMF files for mPEGs and this will help give the innovator company confidence that regulatory measures are followed and are up-to-date. Expertise in regulatory matters, including the filing of DMFs and assistance with questions from the authorities, is invaluable for customers.
Mark Pearson
mPEGs are likely to remain the dominant half-life extension technology for biologics because they are FDA-approved and well accepted by the industry. Activated mPEGs are used in several launched drugs including PEG-INTRON for the treatment of Hepatitis C, Oncaspar for treatment of acute lymphoblastic leukaemia and Neulasta and the Dr. Reddy’s biosimilar Peg-grafeel for treatment of neutropenia during chemotherapy. The market for PEGylated biopharmaceuticals continues to grow because of their benefits, low side-effects and ideal pharmacokinetic behaviour.
Many of the new PEGylated drugs that are coming through clinical development are for chronic indications. When an indication is chronic, a patient will receive a greater quantity of drug over a longer period of time and thus a greater volume of mPEG will be required. It is important that an outsourcing partner has the capabilities and facilities for the scale up of the mPEG to meet the needs of the innovator company as it brings its new PEGylated drug to market.
In summary, the need for innovator companies to outsource the manufacture and scale-up of activated mPEGs is expected to increase with the growth of the biopharmaceuticals market. PEGylation remains an efficient tool for the improvement of the pharmacokinetics and drug performance of biologics. Manufacturers of mPEGs will need global reach, first class facilities, capabilities and expertise to meet the growing demand from innovator companies.
A good CDMO will satisfy these needs and will be at the cutting-edge of mPEG technology. Many more applications of activated mPEGs are expected in the future that will require tailor-made products. The application of mPEGs also has the potential to revive some failed drug substances by increasing their bioavailability in a safe, efficacious manner. Placing trust in a reliable CDMO for the manufacture of activated mPEGs can bring many benefits, while reducing the associated risks.
References
1. Downey, W. Chimica Oggi – Chemistry Today. 2013. 31(1): 19–24.
2. King, S. Pharma’s 50 biggest selling drugs: AbbVie’s Humira joins the $10 billion club. First Word Pharma. 2014. http://www.firstwordpharma.com/node/1194000#axzz3C5FoSLqr
3. Guillarme, D. Analytical Scientist. 2014. 13(214): 22–23.
