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Protein A: Extending this Platform Process Paradigm

Friday Apr 15, 2016

by: Frank Riske, Ph.D.  (friskeatbptcdotcom)  

The use of affinity resins for recombinant protein purification has the potential to revolutionize downstream manufacturing processes. Such platform processes, based around affinity chromatography, will accomplish what Protein-A (PA) resin has done for monoclonal antibody therapeutics (MAb’s), a $85 billion market. For non-MAb recombinant proteins the use of affinity approaches will substantially reduce process development time and bring new products to market more quickly. Although a unique affinity resin will likely be needed for each protein of interest, the benefits of affinity resin development will outweigh the development requirements of time and cost.

Protein A works because IgG monoclonal antibodies have similar Fc regions, which bind to a specific Protein A domain. Non-antibody therapeutic proteins do not share common binding regions. The challenge becomes identifying a specific affinity ligand around which to develop a capture resin. Such a unique affinity ligand/resin system, one that binds the target with nM to pM affinity, can often yield a highly pure target protein with high recovery. The ligand should specifically bind the target in culture broth or other crude post-upstream streams and release the target under conditions that maintain the target protein’s biological activity.

What would the process look like? An additional two to three columns would likely be used to polish the target material post the affinity capture column. The second column, in a bind elute mode, would be specific for removing the major impurity(s) in the product, such as aggregates, fragments, or improperly glycosylated or phosphate forms, etc. The third column, in a flow through mode, might be an anion membrane used to reduce residual materials such as DNA, endotoxin (if from E. coli culture) and host cell proteins.

Affinity ligands include affimers, aptamers, peptides, dyes and other small molecules. The discovery and initial development of any of these ligands can take several months and producing a custom commercial resin will take additional time. An approach, to reduce the development and implementation time, would involve applying rational design, and/or high throughput screening, during the research phase when the therapeutic protein is being characterized. The ligand identification would be completed as efficacy is determined in the appropriate animal model. The purpose would be to obtain an appropriate ligand (in-house or external) for Phase I downstream development. Small batches of resin from the resin manufacturer would be used to develop the process. At the completion of process development sufficient affinity resin would be available from the resin vendor for early clinical studies. The ability to produce commercial lots would be established during Phase II. A well established, large scale, resin manufacturer would be charged with developing a robust reproducible manufacturing process at the appropriate scale for the client’s needs and to keep sufficient inventory at hand.

The use of affinity chromatography simplifies development and condenses the development timeline for commercial implementation. Combining affinity capture with scaling- out (adding a second production line when additional commercial capacity is needed) should simplify facility design as well.


American Biomanufacturing Summit 2016

Monday Apr 4, 2016

On May 10th, BPTC’s Senior Consultant, Patti Seymour, will be part of a panel discussion entitled: Examining Planning and Modeling Techniques to Achieve Effective Capacity Management in Your Biomanufacturing Network. The panel will focus on:

  • Discussing strategic capacity issues when building a global network
  • Planning for variability in market demand for both mature and a growing products
  • Optimizing internal and external networks to increase speed to market
  • Developing flexible models to take the guesswork out of capacity planning

The other panelists are:

Lance Minor, VP, Global Biologics Operations Network Strategy and Performance, MedImmune

Stephen Muldoon, VP Manufacturing and Engineering Services, AbbVie

Ray Kaczmarek, VP, Commercial Manufacturing and Supply Operations, Pacira Pharmaceuticals

Mike Storan, Vice President, IDA Ireland – Moderator 

On May 11th, Patti will be giving a Breakfast Briefing entitled: Global Biomanufacturing Trends, Capacity, and Technology Drivers. As the number of commercial products and pipeline candidates grows, a crucial issue facing the industry is the current and future state of biomanufacturing capacity, the availability of that capacity, and the technologies impacting upstream and downstream bioprocessing. Patti will present BPTC’s capacity model and its implications for pharmaceutical and biopharmaceutical companies and contract manufacturing organizations (CMOs) for aligning their strategies to not only address capacity but to address greater complexity in supplier risk, the competitive forces of innovator biologics and biosimilars, and the adoption of advanced biomanufacturing technologies.


Biobetters Need a Definition!

Tuesday Mar 29, 2016

By: Joe Siemiatkoski  (jsiemiatkoskiatbptcdotcom)  

The Biosimilars Clinical Studies & Analytical Similarity Summit held in Boston from March 21-23, 2016 covered a broad range of topics ranging from assay considerations to clinical study design and regulatory filing strategies. One topic that came up in virtually every presentation or discussion forum was the concept of “biobetters”. There is no formal definition of the term “biobetter” in either the FDA or EMA guidance or regulations for biosimilars. Various groups in the biopharmaceutical industry have crafted their own definitions of what would constitute a biobetter, and there is very little agreement across these proposed definitions. The range of elements proposed, which could make a biosimilar into a biobetter included:

· Changes to drug product formulation to improve stability

· Changing the administration route to improve patient acceptance or ease of use

· Improvement to the glyco-profile or sialylation

Some of the elements proposed would still “fit” into the existing biosimilar filing pathways. For example, changes in amounts of excipients, or switching to another commonly used excipient (e.g., substituting citrate for phosphate as the buffering salt) would generally be allowed as long as pharmacokinetic behavior was comparable. However, using a novel excipient would not be allowed under the EMA biosimilar filing pathway.

Changes to protein isoform distribution is another area where non-impactful changes could be allowed. For instance, if the biosimilar sponsor can demonstrate there is no potency or pharmacokinetic behavioral difference in a molecule with ½ the deamidation present in the innovator molecule, this change would generally not preclude a biosimilar filing pathway. The “totality of evidence” must be in favor of the molecule being considered highly similar to the innovator with no clinically relevant differences.

However, if a sponsor proposed filing a biosimilar application for a molecule with increased sialylation – and consequently a measureable difference in pharmacokinetic behavior, the EMA could not accept the filing according to the requirements of the biosimilar regulations. The difference in pharmacokinetic behavior cannot be compensated for by simply adjusting dose level, the molecule would not be considered a biosimilar because patient exposure is not comparable. There would be at least a theoretical advantage in being able to reduce dosing of a biopharmaceutical while maintaining therapeutic effect, so this situation could be viewed as an unintended negative outcome of the regulation, and should be further discussed in an appropriate forum.

By the end of the conference, it was very clear that the concept of “deliberate biobetters” does not fit into the current biosimilar regulatory pathways. The proper approval mechanism for a molecule, which demonstrates greater potency, better pharmacokinetic behavior, or other clinically relevant differences, is the standard new molecular entity approval pathway. Clearly, the definition of what constitutes a “biobetter” is a topic that requires discussion in an appropriate forum.


Biosimilars, Clinical Studies and Analytical Similarity Summit

Friday Mar 18, 2016

Joseph Siemiatkoski, Consultant will be attending Biosimilars, Clinical Studies and Analytical Similarity Summit to be held at the Hyatt Regency Boston from March 21-23, 2016. If you’re interested in setting up a meeting while at the conference, please send me an email. Click here  (jsiemiatkoskiatbptcdotcom)   to email Joe.


Raw Material Testing: When is Enough, Enough?

Thursday Mar 17, 2016

by: Joe Siemiatkoski  (jsiemiatkoskiatbptcdotcom)  

The CaSSS WCBP (Well-Characterized BioPharmaceutical) conference focusses on addressing issues at the interface of analytical development and global regulatory for biotechnology derived health intervention products. The goal of this symposium series is to provide a forum for discussing the latest challenges in biopharmaceutical development, as well as to consider practical approaches to address these challenges. Round Table discussions are a symposium format where a small group (12 to 15 participants) discuss industry practices, and regulatory experience with specific topics or issues. The Round Table discussion topic “Raw Material Testing, Enough is Enough, or Is It?”, took on the challenge of developing and managing a cGMP raw material testing program.

The group agreed that some form of stratification of raw materials was essential to establishing a manageable, effective testing program. Gone are the days of accepting raw materials based on Certificate of Analysis (CoA) and a compendial identity test. A full-on risk assessment for all the raw materials used in a biotech process is generally run by the Quality Control group with input from QA, Regulatory Affairs, and the relevant Process Development groups. There are no current guidance documents on how to do these risk assessments, but most companies evolve their processes over time as additional knowledge is gained across multiple programs. The first step is to define the categories for the materials based on the potential for the material to impact product CQAs and patient safety, followed by the more formal FMEA ranking of the individual materials.

The risk assessment is only the beginning, Quality Agreements and Vendor Qualification programs are two pillars of a successful raw material management effort. The utility of a solid Quality Agreement was highlighted by the group as a way of managing not only the raw material vendor, but also for sub-vendors. Notification of changes at a sub-vendor for a critical raw material should be relayed through the primary vendor so that the sponsor can ascertain whether the change will impact the raw material. Robust Vendor Qualification programs should be rigorous in order to assure CoA testing, and reduce redundant testing upon receipt. On-going verification of CoA results should be part of a vendor qualification program, along with periodic audits of systems and facilities.

Overall, the scope and complexity of raw material management has significantly evolved in response to better understanding of the impact of raw material changes to Quality Target Product Profiles (QTPPs) and patient safety. Raw materials risk assessments, robust Quality Agreements, and a comprehensive Vendor Qualification program are combined to manage complex raw material supply chains. Since the biopharmaceutical sponsor is responsible for all raw material testing, whether it is performed in-house or at a vendor or subcontractor; the criticality of developing solid systems cannot be over stated.