BioProcess Blog

FDA Takes Big Step Forward in Biosimilar Regulatory Pathway

Julia Dishman Adam — Wed, 15 Feb 2012 15:29:00 +0000

By Patti Seymour (pseymourbptccom) and Howard Levine (hlevinebptccom)

Nearly two years after the Biologics Price Competition and Innovation (BPCI) Act was passed, FDA has finally taken the big step towards defining a regulatory pathway for biosimilars in the US. On February 9, 2012 FDA issued three draft guidance documents, Scientific Considerations in Demonstrating Biosimilarity to a Reference Product and Quality Considerations in Demonstrating Biosimilarity to a Reference Protein Product, along with a Q&A summary of these documents, Biosimilars: Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009, describing the Agency’s interpretation of the Act’s requirements for biosimilar product licensure.

These guidances reflect the broad framework that FDA officials have spent months outlining and are consistent with their August 2011 New England Journal of Medicine article, stating that FDA will take a “totality of evidence” approach to biosimilar approval and require extensive characterization of the biosimilar product using state of the art analytical techniques. Even with this detailed characterization, animal and human clinical studies will still be mandated for the foreseeable future. Consistent with EMA’s approach to biosimilar approval, the detailed and extensive analytical characterization will allow a reduction in the scope and extent of animal and/or human studies required.

While the guidances cover many issues important to the overall development of biosimilars, we are encouraged by several points that are especially relevant for the CMC development of biosimilars. The current draft guidances do allow for differences in the formulation of a biosimilar product compared to its reference product. For example, FDA indicates that it may be possible for a biosimilar product formulated without human serum albumin to be considered similar to a reference product formulated with human serum albumin. We applaud this rationale and sensible position of allowing biosimilar developers to move away from potentially dangerous raw materials used in the innovator products and implement technical advances in formulation development without losing the biosimilar status of the product. We also support allowing biosimilar products to use different delivery devices or container closure systems from that used in the reference product making it possible, for example, for a biosimilar product to be approved in a pre-filled syringe or auto-injector device while the reference product may be in a conventional vial presentation.

As you may recall from our previous post on this topic, we are in favor of allowing data generated using a non-US licensed reference products in support of a biosimilar application in the US. FDA agrees with this approach and will consider the use of a non-US licensed reference product in certain studies to support biosimilarity. Since most biologic products today are sourced from a single manufacturing location, but sold globally, FDA will require the relationship between the license holder for the non-US licensed product and BLA holder for the US licensed reference product to be disclosed, including whether the non-US licensed product is manufactured in the same facility(ies) as the US-licensed reference product and whether the facility(ies) are licensed and inspected by a regulatory authority that has similar scientific and regulatory standards as FDA. Even if non-US licensed reference product data can be used, analytical characterization and at least one clinical pharmacokinetic (PK) study and, if appropriate, at least one pharmacodynamic (PD) study must directly compare the biosimilar product with the US licensed reference product.

To help companies with the design of acceptable biosimilar development plans, FDA is encouraging them to meet with the Agency to discuss their detailed plans and share manufacturing information and preliminary comparative analytical data so that the Agency and the Sponsor can agree on the type and amount of animal and clinical data needed to support eventual licensure of the biosimilar product. According to Theresa Mullin, director of FDA’s Office of Planning and Informatics, FDA has received 31 requests for such meetings and had held 21 of these meetings as of December 2011.

These guidances are an important and meaningful first step toward full implementation of the BPCI Act. Overall, the guidances do not contain any surprises although we are pleased to find them more open to permissible deviations from the reference product than expected. The Agency is accepting public comment on the draft guidances for the next 60 days and will, hopefully issue its final guidances shortly thereafter. Now that these general guidances for biosimilar development have been published we hope FDA will turn its attention to product specific guidances as has already been done in Europe to ensure a clear and meaningful roadmap for the development and approval of biosimilar products in the US.

Industry-wide capacity utilization to increase by 50%

Julia Dishman Adam — Tue, 31 Jan 2012 15:06:00 +0000

by Howard Levine (hlevinebptccom)

With the continued growth in sales and number of products, the biopharmaceutical industry is rapidly becoming the driver for the overall pharmaceutical industry. In this fully documented and referenced report we draw from our proprietary Biopharmaceutical Product database to analyze the continued growth of biopharmaceutical sales. We review the production methods used for these products and analyze the impact of those produced in mammalian cell culture on global manufacturing capacity. Despite the continued growth in sales of biopharmaceutical products and the associated requirement for increasing mammalian cell culture capacity to meet this market demand, we find that overall capacity utilization rates have remained low and forecast that average industry-wide capacity utilization will increase approximately 50% from 2011 to 2016 as construction of new capacity slows and more products reach the market.

The impact of this increasing utilization rate on biomanufacturing capacity and the current concentration of this capacity in a small number of companies may limit some companies’ ability to access capacity in a timely manner. While the five product companies controlling the majority of cell culture manufacturing capacity have more than enough capacity to accommodate their anticipated future needs and keep their own utilization rates low, many of the remaining companies, which either have smaller-scale manufacturing capacity or are relying on CMOs, may find a need for additional capacity by 2016 suggesting that CMOs and smaller biopharmaceutical companies may announce the installation of new capacity in the coming years.

The 150-page State of Mammalian Cell Culture Biomanufacturing report provides a comprehensive analysis of the current and future supply and demand for mammalian cell culture capacity, including the geographic distribution of manufacturing capacity, the impact of facility utilization rates on overall capacity requirements, and the influence of emerging technologies on manufacturing facility design and utilization. With detailed figures, graphs, and tables highlighting including a comprehensive list of sales data and bulk product requirements for all biopharmaceutical products produced in mammalian cell culture currently on the market, Unlike other qualitative surveys or unreferenced articles on biomanufacturing, The State of Mammalian Cell Culture Biomanufacturing provides detailed, data-driven insight into the mammalian cell culture manufacturing market to inform senior executives and program managers with the essential and timely information needed to fully understand the mammalian cell culture manufacturing landscape and to stay competitive.

Supply Chain Risk Management in an Era of Drug Shortages

Julia Dishman Adam — Thu, 05 Jan 2012 15:56:00 +0000

By Patti Seymour (pseymourbptccom)

With shortages of life saving medicines making headlines recently, President Obama signed an Executive Order on October 31 to ease pressure on health care providers and reverse this dangerous trend. Drug shortages, primarily involving generic sterile injectables, have been increasing in frequency and severity in recent years with roughly half of the approximately 80 manufacturers experiencing shortages in 2011.

FDA has reacted to this situation by issuing “A Review of FDA’s Approach to Medical Product Shortages,” detailing the existing drug shortage, summarizing actions FDA is taking both to prevent and respond to drug shortages, and the unique drivers causing these shortages. While the problem is complex and caused by a variety of contributing factors, quality issues at the drug manufacturing facilities seem to be a leading cause of the drug shortages, accounting for 43% of all shortages. As discussed in my previous post on this topic, FDA is focused on identifying and correcting supplier performance as part of their overall risk-based approach to inspections, which has translated into numerous 483 citations at sterile product contract manufacturers. The expectation is that Sponsors will be more proactive in managing these suppliers to ensure product quality, but clearly this is not happening. A leading manufacturer of sterile injectable oncology products, Ben Venue Laboratories, announced in August that the company was exiting the contract manufacturing business while it dealt with multiple FDA 483s at their manufacturing facility in Bedford, Ohio. Unfortunately for Sponsors and patients relying on medicines manufactured there, Ben Venue temporarily suspended all drug manufacture and distribution just before Thanksgiving, putting further pressure on already stressed supply chains.

Unfortunately, Ben Venue is not an isolated case. When using a CMO for any part of your supply chain, it is important to ensure that the CMO is operating in full compliance of all cGMP regulations to avoid supply disruptions. This diligence begins with the initial selection of the CMO but should continue through periodic GMP compliance audits. Without question, any quality issues identified either during a Sponsor audit or a regulatory inspection should routinely be addressed immediately and the CMO monitored to ensure appropriate corrective actions have been implemented and compliance is maintained or restored. Proactive supply chain monitoring can provide early warning signs of potential supply chain issues, enabling Sponsors to implement risk-mitigation plans to head-off potential catastrophes. For all links in the supply chains, a risk-management plan which identifies all elements that could contribute to a breakdown in supply and outlines risk-mitigation strategies, such as second source manufacturing for key links in the supply chain, that will ensure continuity of supply.

While some of the current drug shortages could not have been predicted, many of them could have merely by connecting the dots through vigilant supply chain oversight and robust risk-management plans. It’s not too late to thoroughly analyze your supply chain and inspect it for any chinks or weak links that could disrupt continuity of supply. Make this your New Year’s resolution.

10th Biosimilars Americas

Julia Dishman Adam — Tue, 03 Jan 2012 20:50:26 +0000

Join Patti Seymour, Senior Consultant, at the10th Biosimilars Americas conference, to be held March 13-15, 2012 in Boston, MA to learn more about manufacturing strategies for biologics, biosimilars and novel therapies. To pre-arrange a meeting with Ms. Seymour at the conference, please click here (pseymourbptccom) .

Biosimilars Congregation 2012

Julia Dishman Adam — Sun, 01 Jan 2012 22:01:25 +0000

With the global market for biosimilars forecast to exceed $4 billion by 2015, there is intense focus on the development and commercialization of these products as a means of bringing cost-effective biologic theapeutics to patients worldwide. Join Dr. Howard L. Levine (hlevinebptccom) , Principal Consultant, and Dr. Susan Dana Jones (sjonesbptccom) , Senior Consultant, at the Biosimilars Congregation 2012 on February 24, 2012 at the Thistle Marble Arch, London, UK. This exciting conference will unite industry leaders to analyze commercial developments and identify successful management strategies for biosimilars worldwide. Drs. Levine and Jones look forward to seeing you in London. To schedule time with either of them to discuss your CMC needs, click here (sjonesbptccom) .

BPI Europe 2012

Julia Dishman Adam — Mon, 26 Dec 2011 15:52:41 +0000

Join Dr. Howard L. Levine (hlevinebptccom) , President and Principal Consultant, at the Eight Annual BioProcess International European Conference, April 18-19, 2012 in Prague to learn more about manufacturing strategies for biologics, biosimilars and novel therapies. Drawing from BPTC’s proprietary Biopharmaceutical Product database and recently published report “The State of Mammalian Cell Culture Biomanufacturing,” Dr. Levine will speak on the “Global Demand and Utilization of Mammalian Cell Culture Manufacturing Capacity. His presentation will highlight the expected 50% growth in industry-wide capacity utilization between now and 2016 as well as the impact of recent technological advances in manufacturing processes, improvements in expression levels, widespread acceptance of single-use bioreactors, and the increased interest in biosimilars throughout the world. As with its sister event, the BioProcess International Conference held last October in Long Beach, CA, BPTC is pleased to be a part of BPI Europe. To pre-arrange a meeting with Dr. Levine at the conference, please click here (hlevinebptccom) .

Increasing interest in ADCs

Julia Dishman Adam — Wed, 14 Dec 2011 17:26:00 +0000

By Tom Ransohoff (transohoffbptccom)

BPTC’s inaugural bioPULSE^TM survey focused on perceptions and trends in the development of antibody-drug conjugates (ADCs). The responses to three of the survey questions foreshadow significant growth in the ADC field. First, a vast majority of respondents (83%) expect to see a significant increase in the number of ADCs entering the biopharmaceutical pipeline in the coming five years. Second, as many respondents (24%) indicated that their company is not currently developing ADCs but planned to do so in the future as those indicating that their company is already developing ADCs (also 24%). Finally, an overwhelming number of respondents expect this field to be very large (95% selecting either “massive – as big as MAbs” or “important – but not as large as MAbs”) compared to only 5% who felt that ADCs would be limited to niche markets only. Although we recognized ADCs as an important emerging class of biopharmaceutical products, we were honestly surprised at the strength of opinions from respondents related to the potential of this area.

Along with the optimism for growth in the ADC area, the survey indicated some concerns related to remaining CMC development hurdles and the adequate availability of critical outsourcing services to support development and supply of these products. The results of the survey clearly indicated that conjugation technology and linker chemistries were among the greatest CMC development hurdles for these products. Additionally, a number of potential areas likely to experience increasing demand for service providers, such as CMOs with the ability to handle biologic-cytotoxic conjugates, were identified by survey participants. It will be interesting to see how the CMO/CRO world responds to the increasing demand for services to support ADC products.

The objective of all bioPULSE^TM surveys is to obtain relevant and focused feedback on topics of interest to the biologics manufacturing community. The web-based surveys are quick, short, and rewarding (everyone who participates will be emailed a summary and analysis of the aggregate results). The topic of the second bioPULSE survey, which is currently open and accessible at www.bptc.com/biopulse, focuses on vaccine manufacturing and supply. Your input is encouraged, appreciated and rewarded!

Cell Culture World Congress 2012

Julia Dishman Adam — Sat, 10 Dec 2011 15:17:54 +0000

Join Dr. Susan Dana Jones (sjonesbptccom) at the second annual Cell Culture World Congress to be held in Munich, Germany from February 28 to March 1. At the conference, Dr. Jones will provide insights into the benefits of focusing on product quality early in cell line development in her talk entitled, “Enabling cost-effective product quality focus in early biopharmaceutical development.” Email (sjonesbptccom) Dr. Jones to set up a meeting.

Biosimilars and Biobetters

Julia Dishman Adam — Tue, 06 Dec 2011 15:24:24 +0000

Patti Seymour (pseymourbptccom) , Senior Consultant, will be presenting a talk entitled, “Biomanufacturing Capacity for Biosimilars: Is there enough?” at CHI’s inaugural Biosimilars and Biobetters conference to be co-located with the third annual Biotherapeutics Analytical Summit in Baltimore, Maryland from March 19-20, 2012. To pre-arrange a meeting with Patti to learn how BPTC can help develop your company’s biosimilar or biobetter strategy from clone to commercial, click here. (pseymourbptccom)

EMA Still Not Supporting Biosimilar Interchangeability

Howard Levine — Sun, 30 Oct 2011 14:00:00 +0000

Howard Levine (hlevinebptccom) , Sheila Magil (smagilbptccom) , and Alex Kanarek (akanarekbptccom)

The EMEA (now EMA) issued its first guideline for similar biological medicinal products in 2005, followed by detailed guidelines for specific products in subsequent years. Citing such issues as the development of biosimilar monoclonal antibodies, The WHO Guidelines on Evaluation of Similar Biotherapeutic Products, and EMA’s emphasis on the 3 R principles (replacement, reduction and refinement) in animal testing, EMA issued a few weeks ago a concept paper on revising their 2005 guideline to bring it more in line with these newer guidances. Recognizing that repeat dose toxicity studies in non-human primates recommended in it’s the earlier guidelines are of little relevance, the concept paper recommends that a risk-based approach for the design of non-clinical studies be used which takes into account the results of biochemical comparability studies, the availability of sensitive in vitro functional assays which are predictive of in vivo pharmacodynamics, and the feasibility and relevance of in vivo testing in a relevant species. With regards to human clinical trials, the concept paper recommends that the biosimilar guidelines should be revised to address the need for pharmacodynamic markers in Phase 1 studies and whether or not a biosimilar product can proceed to pivotal Phase 3 clinical trials if similarity to selected PK parameters have been met but relevant pharmacodynamics markers are not available. The concept paper also recommends updating the guideline to include examples of acceptable surrogate endpoints already recommended in guidelines for specific classes of biosimilar products, defining considerations for acceptance of pharmacodynamics markers for demonstration of clinical similarity, and the possibility of using a non-inferiority design for certain Phase 3 studies.

Given the technical advancements in the development of biosimilars over the past couple of years, it is encouraging to see EMA acknowledging this rapidly changing environment and embracing the idea of updating its original guidelines. The clarification on non-clinical requirements, especially the importance of defining reliable PK/PD markers for biosimilarity, and the possibility of using non-inferiority as an end-point for clinical trials should help accelerate the development and introduction of biosimilar products. The use of non-inferiority as a criterion for approval should allow faster, smaller, and less expensive clinical trials but comes with the disadvantage that such trials may make it more difficult to demonstrate interchangeability of a biosimilar product with the original innovator product. Neither the original guideline nor the current concept paper addresses what criteria would be necessary to establish interchangeability, the holy grail of biosimilars. Our reading of the concept paper and other recent activities and announcements from EMA, as well as the US FDA, suggest we are not likely to see any meaningful pathway towards interchangeability in the US or Europe anytime soon. This is a shame since the true potential for biosimilars will not be met until we have established guidelines for using these products completely interchangeably with the original innovator product as is currently the case for small molecule generic drugs.