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With Start-Up Biotechs, First-in-Human Trumps Quality by Design (QbD)

Tuesday Aug 18, 2015

By Susan Dana Jones  (sjonesatbptcdotcom)  

According to the 2011 FDA Guidance for Industry on process validation and 2012 EMA process validation guideline, process design and understanding should begin as soon as a lead molecule is identified and process development begins. However, is this always the best strategy?

The product’s critical quality attributes (CQA), those features of the product that impact clinical safety or efficacy, should be defined and controlled. To do so requires understanding which process parameters are essential to producing a product with the intended CQA. Contrast these recommended approaches with the reality of a start-up biotechnology company developing a potentially life-saving, disease-ameliorating biopharmaceutical product that may or may not actually succeed in the clinic. Let’s look at the reality of a hypothetical biopharmaceutical company, BioX. BioX is developing a cutting-edge product with potential for treating an aggressive and incurable cancer. Undoubtedly, they will be competing with other companies for access to physicians and centers to enroll patients in their trials. If successful, BioX will encounter competition in the market.

BioX has raised money to move their product from the conceptual stage to the IND/IMPD or equivalent stage, and has promised investors that the initial human trials will commence within 12 – 18 months following program initiation. BioX and its investors are highly motivated to manufacture a product that meets all safety requirements so patient safety is not compromised. However, BioX is not very motivated to define CQA or to invest time and resources into understand the manufacturing process at the level specified in the guidance documents at this initial stage. In my experience, speed to clinic trumps extra time in early process development for these small companies every time. So what process design and development activities should BioX invest in prior to first in human trials? Also, what steps can be taken to reduce future process risk without adding unnecessary delays in the product development timeline?

An obvious choice in my opinion, is investing in an MAA/BLA enabling production cell line. By using current technologies coupled with robust, well-characterized parental cell lines, it is feasible to obtain multiple stable, high producing microbial or mammalian cell lines within relatively short timeframes. A strategy of using Multiple Master Cell Banks (MMCB) allows more than one clone can be pushed through the initial development activities. The final testing to ensure that the selected production cell line meets commercial requirements is postponed until later. This approach reduces the risk of cell line failure during lengthy stability testing. Multiple Master Cell Banks can be produced at relatively low cost if the testing is deferred until final clone selection so that only one MCB needs to be tested. By moving 3 to 4 clones forward at this stage, reduces the risk of failure due to clonality or genetic stability issues. Without “back-up” cell lines, companies like BioX lose precious time to clinic, a situation that can be fatal to a small company.

Product produced at a smaller scale than the intended cGMP process, even product produced in a development laboratory, can supply IND-enabling GLP toxicology studies, enabling completion of these studies well in advance of the availability of full scale GMP material. These time-saving, low-risk approaches to initial development are often applied by companies such as BioX. Further, such approaches are routinely meet with regulatory approval provided sufficient data supporting the comparability of the GMP clinical trial material to the product used for the toxicology studies is provided. Upon successful completion of early clinical trials and an indication of efficacy that warrants further development, BioX can then turn its attention towards full process understanding, defining CQA and critical process parameters, and entering into the activities that are expected and anticipated per the guidance documents mentioned above. This paradigm is the reality for many companies and provides BioX and others with a route to the clinic and, hopefully, the market in a manner that is beneficial to patients, physicians, and the market.


Will Two-Phase Purification Replace Protein A?

Tuesday Aug 4, 2015

Reconsider using aqueous two-phase systems (ATPS) in purification processes

By: Frank Riske  (friskeatbptcdotcom)  

Aqueous two-phase systems (ATPS) for protein separation and purification was a program theme at the Biopartitioning and Purification Conference 2015 (BPP 2015) held on June 7-10, 2015 in Vienna, Austria. This process, often involving polyethylene glycol, (PEG) and a phosphate, sulfate or citrate buffer for example, are based on partitioning a molecule between two phases. The rekindling of interest in ATPS has come about as the biopharmaceutical industry begins to look beyond Protein-A (PA) for monoclonal antibody (MAb) purification as titers continue to increase and immunotherapeutic molecules evolve.

For conventional MAbs processes, ATPS can effectively remove cells and other debris, reducing both the process volume and the burden on the clarification filters. As the harvest titer increases, the percentage of process impurities decreases, and the recovery and purity of the target molecule with ATPS increases. High titer, relatively large hydrophobic molecules (which include MAb), are ideal targets for a platform process utilizing ATPS and potentially crystallization. ATPS may also be a good choice for MAb or MAb-like molecules that are poorly suited to the Protein-A platform. For example, those antibodies that may dimerize or fragment at the low pH used to elute them from PA.

Although MAbs will continue to be an important part of the drug development pipeline for many years, there is a potential shift underway in the immunotherapy landscape to antibody-like molecules (e.g. FAb, Fab2, single chain antibodies, dimeric single chain antibodies, nanobodies, BiTES, etc.). The number of viral gene therapies, VLP’s and recombinant proteins emerging from discovery into development also appears to be increasing. These molecules are not amenable to a PA platform, but may be good candidates for ATPS, either for protein separation or for crystallography. Viruses and VLP are especially attractive candidates due to their large size and high partitioning coefficients.

Where can ATPS help? The BPP 2015 meeting discussed ATPS, crystallography, formulation and other subjects related to the understanding of protein separation, stability and solubilization. ATPS is especially useful for hydrophobic proteins such as IGF-1 and TPA and shows promise for the continuous refolding of GCSF. ATPS can improve protein solubility and protein separations, plus may modify both protein solubility and resin selectivity. Abraham Lenhoff, Professor of Chemical Engineering at the University of Delaware, reported that the insoluble material formed at high protein concentrations has structure. Using Newtonian light scattering, he observed that these colloidal gels have a bicontinuous structure. This finding has implications for the separation of many molecules that are loaded at high concentrations on resins and then eluted with a steep step gradient. The elution profile may represent a series of precipitations and solubilizations as the protein concentration changes on its transit through the resin. Dariusch Hekmat, Staff Scientist at the Technical University of Munich (TUM), described the crystallization from crude solutions of a MAb having a genetically modified backbone to enhance crystallization. Understanding the Constant sequences that need to be changed and evaluating if these are acceptable changes from an immunological viewpoint, will be important moving forward. In conclusion, it’s my opinion that, ATPS, and the polymers used for ATPS, should be (re)considered in the purification, precipitation, resolubilization and stabilization of recombinant proteins (including MAbs) viruses and VLPs.


The BioProcessing Summit

Tuesday Jul 21, 2015

BPTC Senior Consultants, Drs. Sheila G. Magil and Frank Riske, will be leading CHI’s Introduction to Bioprocessing training seminar during its annual BioProcessing Summit  held from August 3-7, 2015 in Boston, MA. The 1.5 day seminar, held on August 3-4, offers a comprehensive survey of the steps needed to product today’s complex biopharmaceuticals, from early development through commercial manufacturing. The seminar begins with a brief introduction to biologic drugs and the aspects of protein science that drive the intricate progression of analytical and process steps that follows. They then step through the stages of bioprocessing, beginning with the development of cell lines and ending at scaling up for commercial production. They will also explore emerging process technologies, facility design considerations, and the regulatory and quality standards that govern our industry throughout development. The important roles of analytical methods at all stages of development as well as formulation and stability assessments in developing and gaining approval for a biopharmaceutical are also examined. This class is directed to attendees working in any aspect of industry, including scientific, technical, business, marketing, or support functions who would benefit from a detailed overview of this field.


How To Take Charge of Your COGS

Monday Jul 13, 2015

By Rick Stock  (rstockatbptcdotcom)  

In my last blog, I wrote about all the gory details describing expenses that can go into cost of goods sold (COGS) for biopharmaceuticals. However, I did not describe why COGS are so important to model in the first place. The simple answer is that a good model allows you to forecast COGS based on information from development runs at scales that are very different from the intended commercial scale. For drug substance, this may be in the form of cost per gram. For drug products, this is often in the form cost per dose, whether this be a vial, pre-filled syringe or other delivery device.

Routinely the most important COGS related calculation is the cost per dose. A good model will calculate accurate costs that are a critical factor in determining whether your product will be economically viable at the anticipated selling price. Of course, the selling price is generally determined by what the market can support. For many products, there is also a trade-off between price and sales volume; as prices are lowered, sales volume increases. Similarly, there is a relationship between production volume and COGS, which can be forecast with a good model. Having an accurate COGS model as early as possible in the development process is extremely useful to assist companies in determining appropriate investment, sales and marketing strategies that will guide future product development activities. Just take a look at these top ten disastrous launches. In many of these cases, failure to set a reasonable market price and manage COGS contributed to the unsuccessful product launches.

A current area that is hot for applying COGS modeling is biosimilars. Many of the blockbuster biologics have or will soon experience patent expirations. This will introduce competition into the market for many biopharmaceuticals, causing many big pharma companies to take a hard look at reducing price to ensure market share with potential biosimilar competition. Historical data from these well-known processes are useful in constructing a very accurate cost model, which can aid in developing strategies for innovator product firms. On the other end of this spectrum are the biosimilar companies. These companies are applying COGS modeling very early in the development stages to determine which target molecules are worth manufacturing for the biosimilars market and to establish COGS targets for these products.

Finally, COGS models can aid in determining the costly portions of the manufacturing process for all companies manufacturing biologics. Results from these models drive manufactures to remove “economic bottlenecks” by heading back to process development to increase titers and purification yields, reducing labor with new technology or outsourcing activities in order to reduce COGS. A COGS model developed early in the product life cycle will allow you to identify the key cost drivers in your manufacturing process at all stages of development. This approach will provide the insight required to inform critical manufacturing decisions that significantly impact the success of your product(s).


Big, bigger, but will they be the biggest? The past, present and future of MAbs in the market place

Monday Jun 15, 2015

By Dawn M. Ecker  (deckeratbptcdotcom)  

The modern biotechnology era began in 1982 with the approval of Humulin in 1982[a], the first recombinant product. Throughout its 32 years of existence, the biopharma industry has grown tremendously, launching over 200 biopharmaceuticals. As indicated in Figure 1, the 182 currently marketed products have generated an unprecedented $152B in global sales[b] in 2014. When the current number of pipeline products in development are coupled with discoveries and technological advances in the biopharmaceutical sciences, product revenues for the biopharmaceutical industry can only continue to grow.

For a third consecutive year, Humira is the world’s best-selling biologic and for the last two years, sales of Humira have exceeded $10B. The first biologic to break the $10B barrier in 2013, Humira sold $12.5B in 2014, recording the highest sales for a recombinant product since the beginning of the modern biotechnology era. Table 1 displays the remaining top ten biopharmaceuticals of 2014, which include a cytokine, two insulins and seven antibody-based products. The antibody product Lucentis, which has made its initial debut in the top ten in 2014, has the distinction of being the first commercialized antibody fragment product produced using a microbial system.

Looking back a decade to 2004, when biopharma was in its twenties – total sales for the then 88 approved products didn’t quite reach $50B. The top ten selling biopharmaceuticals back then were slightly more diverse, with four hormones, three antibody products, two cytokines and an insulin. Interestingly, in both 2004 and 2014, the top ten selling products comprised nearly half of all biopharmaceutical sales and four of the top ten products in 2004 have remained on the top ten list for 2014: Enbrel, Remicade, Rituxan/Mabthera, and Neulasta/Neupogen. Gone from the 2004 top ten list are the four epoetin-based hormones, the human insulin and the cytokine, replaced with insulin analogs, and more antibody products.

Ten years ago, monoclonal antibodies were beginning to make their presence known, and now, MAbs are a formidable portion of today’s biopharma landscape. Surveying the overall recombinant biopharmaceutical pipeline, it is clear from our bioTRAK® database, that antibody products dominate the development pipeline. Of the nearly 400 products in late stage development (Phase 2 through BLA/MAA/NDA application), over 80% are antibody related products. Looking closer at the antibody products and fragments in development, nearly 10% of these antibody products are produced in microbial systems. With several companies developing single chain, domain fragments and some full-length antibodies in non-mammalian systems, potential exists in the next decade for the additional commercialization of these microbial-based antibody products.




Slide2As the development and commercialization of antibody products continue to forge ahead with no slowdown in sight, we can be assured antibodies will remain the cornerstone of the biopharmaceutical market for the foreseeable future. When looking forward to 2025, does the past decade suggest that Enbrel, Remicade, Rituxan/Mabthera, and Neulasta/Neupogen will continue to be amongst the top 10? Will microbial manufactured antibodies and fragments be “the next big thing”? Only time will tell, but we can’t wait to see.