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News for the Biologics Industry

WuXi AppTec periodically sends out an e-newsletter to our contacts in the biologics industry. To access previous issues, click here.

If you are not currently receiving the newsletter and would like to be on our mailing list, please email us at: info@wuxiapptec.com. Please put "Biologics News" in the subject line.

For questions about any of these items or other information on WuXi AppTec’s services, please contact a WuXi AppTec representative.

August 2011

INDUSTRY NEWS

FDA’s Proposed Changes to GLP Regulations Draw Industry Comments
In December 2010 the FDA issued an Advanced Notice of Proposed Rulemaking for changes to the Good Laboratory Practice (GLP) regulations for non-clinical laboratory studies (21 CFR Part 58). A 60-day comment period set at the time was later extended to March 31, 2011, and many companies – including WuXi AppTec – submitted comments.

Following are brief descriptions of the proposed changes:

• GLP Quality System: Integrating certain basic elements of a quality system (such as ISO 9001) in the GLP quality system.
• Multi-Site Studies: Specifying the person responsible for each site of a multi-site study.
• Electronic/Computerized Systems: Updating the regulations to include the use of electronic computerized systems.
• Sponsor Responsibilities: Specifying additional sponsor responsibilities, such as the development/approval of study protocols.
• Animal Welfare: Including a way to evaluate compliance with animal welfare regulations.
• Information on QA Inspection Findings: Requiring yearly summaries of general inspection findings that are not study-specific.
• Process-Based Systems Inspection: Permitting a combination of systems inspections and study-based inspections.
• Test & Control Article Information: Considering additional requirements for test and control article characterization.
• Sample Storage Container Retention: Eliminating the requirement for test article storage containers for the duration of the study.

 

Comments from industry companies were varied, but, in general, most of the proposed changes are being viewed as improvements.  Indeed, many will not have a significant impact on the industry, and several are changes that are needed for harmonization with other industry standards and regulations. However, one that bears watching is the proposal to include additional specific responsibilities for the sponsor of studies, particularly in the area of sponsor involvement in the development and approval of protocols. WuXi AppTec submitted a comment specifically addressing the point that the additional regulations would need to be worded carefully to avoid confusion between the sponsor and testing facility as to the extent of sponsor involvement, particularly in the protocol development area.

The technical experts at WuXi AppTec are not only involved in commenting on these proposed changes, but also diligent about staying on top of everything that concerns GLP studies and FDA expectations. We are committed to keeping our clients informed of all such regulations and the potential impact of any changes.

For more information or to speak with one of our experts regarding GLP testing, contact your WuXi AppTec Account Manager.

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FDA’s Proposed Amendments to the Sterility Test Requirements for Biological Products
On June 21, 2011 the FDA issued a proposal to amend the sterility test requirements for biological products (21 CFR Parts 600, 610 and 680).  A 90-day comment period was set, with comments to be submitted by September 19, 2011.  The proposed rule is intended to do two things: provide greater flexibility to manufacturers of biological products and encourage the use of potentially more appropriate state-of-the-art test methods.

The following are brief descriptions of the most significant proposed changes:

▪     Elimination of specified sterility test methods, culture media formulae and culture media test requirements
The proposal is to expand the acceptable sterility test to both culture-based and non-culture-based methods.  This provides the manufacturer the flexibility to take advantage of suitable new test methods in keeping with scientific advances.  In this case, the current requirements for certain culture media, test methods/procedures, incubation conditions and definitions of a lot of culture medium will potentially be affected.  However, any alternate test method must be validated in accordance with established protocols.

The proposal states “FDA considers the established USP compendial sterility test methods to already have been validated using as established validation protocol, so their accuracy, specificity, and reproducibility need not be re-established to fulfill the proposed validation requirement.”

▪     Elimination of specified membrane filtration procedure requirement for certain products
CFR 610.12(f) specifies that a membrane filtration test should be used in the sterility test.  The proposal is to require that the sterility test must be appropriate to the material being tested (such that the material does not interfere with the test) thereby allowing more flexibility in the method chosen.

▪     Elimination of the requirement for testing culture media
The proposal is to eliminate the specification for certain test organisms to be used, as well as the number of organisms to be used, in demonstrating the “growth-promoting qualities” of the media.  This is based on the option of using non-growth-based methods.  In conjunction with this, the current term “growth-promoting qualities” will be replaced with “growth-promoting properties.”

▪     Modification of the repeat sterility test requirements
The FDA is proposing to modify the repeat sterility test so that repeat tests would occur only once for each lot.  Additionally, they propose to eliminate repeat testing of bulk material, since they are proposing to not require a sterility test on bulk material.

▪     Replacement of the storage and maintenance requirements for cultures of test organisms used to determine the “growth-promoting qualities” of culture media
In light of the option for using non-culture-based methods, the FDA is proposing to require that the validation, at a minimum:  include samples of the final material; incorporate appropriate viable contaminating micro-organisms; and demonstrate the test’s growth-promoting properties and the method’s detection system capabilities, including aerobic and anaerobic organisms and organisms that grow at different rates.

▪     Replacement of the sample size/amount requirement
Due to the variety of products covered under 610.12, the FDA is proposing to eliminate the sample number requirement and instead require that the sample be appropriate to the material being tested, based on a) the size/volume of the final lot, b) the duration of manufacturing, c) the final container configuration and size, and d) the quantities/concentration of inhibitors.

▪     Replacement of the interpretation of test results under 610.12(c)
The FDA proposes to replace the requirement for interpretation of the sterility test with a requirement that manufacturers establish, implement, and follow written procedures for sterility testing, which will include all steps for initial and repeat testing.  However, the proposal will stay consistent with USP <71> in that an investigation should be performed, and if the microbial presence can be ascribed to lab error or faulty materials, the test may be repeated once.

▪     Simplification of the Exceptions paragraph under 610.12(c)
The proposal is to maintain the current exceptions to the sterility test, which are whole blood, cryoprecipitated AHF, platelets, red blood cells, plasma, smallpox vaccine, AHG, and Blood Grouping Reagents.  It will also make modifications to the exception for biologics where the special nature of the product precludes or does not require a sterility test, or the sterility of the lot is not necessary to assure its safety, purity or potency.

In general, most of the proposed changes are improvements in that the requirements are not as prescriptive and allow for methods and procedures to be used that are more suitable for the product itself.  However, with elimination or relaxation of certain requirements, the burden of proof of those “new” methods becomes more onerous on the manufacturer if they develop certain tests/parameters that differ significantly from those to which the industry has been accustomed.

WuXi AppTec intends to submit comments addressing several of the proposed rules, mostly in support of the modifications.  The technical experts at WuXi AppTec will stay current with all developments concerning sterility testing of biologics and FDA requirements.  We are committed to keeping our clients informed of all such regulations and the potential impact of any changes.

For more information or to speak with one of our experts regarding these proposed rules and the potential impact, please contact your WuXi AppTec Account Manager.

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FDA Withdraws 1987 LAL/BET Guidelines
In our April Biologics Newsletter, WuXi AppTec alerted readers to the FDA’s plans to withdraw the 1987 LAL/BET Guidelines.  Last month the FDA did, in fact, withdraw the guidelines.  Following, for our readers’ convenience, we repeat our analysis of the impact on the biologics industry.

The FDA withdrew the guideline it established in 1987 concerning bacterial endotoxins testing. That FDA guideline – entitled Guideline on validation of the Limulus amebocyte lysate test as an end-product endotoxin test for human and animal parenteral drugs, biological products and medical devices (commonly known as the 1987 LAL Guidelines) – had been one of the leading U.S. documents used by the biopharmaceutical and medical device industry for sampling, validation and performance of the bacterial endotoxins test.

At the time the 1987 LAL Guidelines were developed, there were no other comprehensive documents that covered the subject of endotoxin testing, other than a section in the U.S. Pharmacopeia. Since that time, AAMI (Association for the Advancement of Medical Instruments) published a standard called ST 72:2002, Bacterial endotoxins – Test methodologies, routine monitoring, and alternatives to batch testing, and the worldwide Pharmacopeia harmonized their LAL endotoxin testing protocols. The AAMI standard included information from both the 1987 LAL Guidelines and the USP, but clarified and expanded on that information with sections about sampling criteria, testing techniques, product families, qualification/validation, test parameters, change control and alternatives to batch testing. With the withdrawal of the 1987 LAL Guidelines, the AAMI ST 72 standard can be used as a reference concerning bacterial endotoxins testing, since it is on the FDA consensus standard list. A revision of ST 72 is in the final stages of approval and should be published in August 2011. In addition, the harmonized USP/EP/JP sections on detection of endotoxins can also be referenced.

What does this mean for industry? The immediate impact will be to documents such as SOPs or internal protocols that reference the 1987 LAL Guidelines for testing criteria and endotoxin limits. But there are other possible issues for manufacturers and testing laboratories as they consider other reference documents such as the AAMI ST 72 or the Pharmacopeia versus the 1987 LAL Guidelines.

WuXi AppTec’s technical experts – two of whom serve on the AAMI Sterilization Standards Committee and have established a wide range of endotoxin assays based on worldwide pharmacopeia testing protocols – are ready to answer any questions you may have about bacterial endotoxin testing in general as well as specifically address the differences between the FDA, worldwide pharmacopeia/compendial protocols, and AAMI documents.

To speak with one of our experts or for information regarding our endotoxin testing services, contact your WuXi AppTec representative.

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WUXI APPTEC NEWS / LAB UPDATES

 

Process Development Support Provided Through Database Mining

Process Development Support Provided Through Database Mining

Process Development Support Provided Through Database Mining

Process Development Support Provided Through Database Mining

Process Development Support Provided Through Database Mining
Significant costs are associated with process development activities particularly for the viral clearance evaluation aspects.  These costs could be higher than anticipated due to the following situations:

• The need to evaluate additional or alternative process steps because existing steps evaluated were ineffective or unable to reach the target log reduction value.
• The need to remediate or potentially re-design a given step due to complications associated with viral and protein loads
• The use of process run parameters (e.g., pH, conductivity, flow rates, flux, etc.) not optimally suited for virus removal or inactivation.

Not only might your costs be increased due to the need to repeat studies or evaluate other processing steps, but there might also be potential delays to your IND or BLA filings.

To help mitigate these costs and delays, WuXi AppTec has taken 20 years worth of viral clearance studies and amassed a searchable database to assist clients in determining proactively if certain process steps or process run parameters will be appropriate for evaluating viral clearance or inactivation. Likewise, an entire process could be evaluated to determine if your process can achieve the appropriate retroviral clearance typically requested by the regulatory agencies.  Information can also be provided that could assist in streamlining your process scale-down efforts.

The database – which is continually updated – contains over 10,000 data points including:  type of process step (e.g., Protein A or Anion Exchange Column Chromatography, Nanofiltration); type of virus evaluated (xMuLV, PPV, MVM); type of product evaluated (monoclonal antibody, animal-derived raw material, viral gene therapy, virucide); concentration of virus and protein/product load; and individual process step run parameters (pH, time, temperature, conductivity, flow rates, flux).  All of these parameters can be searched internally by senior scientists trained in viral clearance at WuXi AppTec and a report will be generated for your evaluation and assessment. 

For more information on this new service,  contact your WuXi AppTec Account Manager.  And be sure to sign-up for our upcoming free technical webinar on September 21 to learn more on this topic.  Click here to register.

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Dramatically Increase Viral Clearance Log Reduction Values Utilizing WuXi AppTec’s Ultrapure Viral Stocks

Dramatically Increase Viral Clearance Log Reduction Values Utilizing WuXi AppTec’s Ultrapure Viral Stocks

 

Dramatically Increase Viral Clearance Log Reduction Values Utilizing WuXi AppTec’s Ultrapure Viral Stocks
The inclusion of nanofilters in the purification process for most biologics has proven to be one of the most robust steps that companies can rely on to help obtain high virus log reduction values (LRVs) during viral clearance studies.  These filters are specifically designed for the removal of viruses and have demonstrated the capacity to remove multiple virus types, including the smallest viruses.  However, this processing step can also suffer from some difficult performance issues especially during viral clearance studies.  The performance of scale-downed nanofiltration steps during viral clearance studies has often proven difficult after the addition of virus spikes.  A key factor in these performance issues?   The use of viral stocks that have significant levels of residual cellular debris left over after viral harvest and/or the presence of media components in the final virus lots. 

Because of this issue, WuXi AppTec has worked to develop high titer ultrapure viral stocks, with the goal of:  (1) ensuring that the performance of the filtration process is not drastically altered by the addition of the virus to the protein matrix, and (2) increasing the concentration of the virus without contaminants so that higher percent spike levels can add to the total log reduction values (LRVs) achieved from this step.     

Through WuXi AppTec’s R&D efforts, we have created a unique virus purification process that can be applied to several viruses.  Among the first virus families to which we applied the process were the Parvoviruses, including Minute Virus of Mice (MMV) and Porcine Parvovirus (PPV).  These new ultrapure Parvovirus stocks have been shown to contain fewer contaminants (i.e., residual nucleic acid and protein) than other grades of purified virus.  Assessments with Dynamic Light Scattering instrumentation also demonstrated less aggregation in these new ultrapure preparations.

In addition, through evaluation of the new Parvovirus stocks, and in collaboration with the manufacturers of several nanofilters, WuXi AppTec has shown a dramatic improvement in the filtration performance compared to other grades of purified Parvoviruses similarly evaluated.  The new ultrapure viruses have shown minimal or no changes to the flux or overall protein throughput capabilities of these nanofilters during virus spiking studies – even at high percentage virus spike levels.  Thus a higher percent spike level can be evaluated resulting in dramatic increases in LRVs for nanofiltration steps.   

For more information on these new ultrapure virus stocks and their use in viral clearance studies, contact your WuXi AppTec Account Manager.  

And be sure to sign-up for our upcoming free technical webinar on September 21 to learn more and see the compelling LRV data on these unique virus stock preparations Click here to register.

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New Technical Staff Spotlight:
Alan Moore • Vice President, Testing and Cell Services
Thirty-year biopharmaceutical industry expert Alan Moore joined the WuXi AppTec Philadelphia technical team in June.  He will contribute to the biopharmaceutical safety center of excellence in Philadelphia with responsibility for specific testing laboratories and the contract manufacturing services for biological product and cell therapies.  Mr. Moore brings over thirty years of experience in the biopharmaceutical and biologics contract services industry to an already experienced technical staff.  Prior to joining WuXi AppTec, he provided regulatory and product development consulting services through the independent consultancy Enfilade Advisors.   Previously he served as Executive Vice President and Chief Business Officer of Althea Technologies, Inc., which provided development, API manufacturing and aseptic filling services.  Prior to joining Althea, he was General Manager of Biopharmaceutical Development Services at Charles River Laboratories in Rockville, Maryland, after the acquisition of Primedica Corporation, where he was Vice President of Biopharmaceutical Development Services.  He was President of Genzyme Transgenics Washington Laboratories, a Genzyme subsidiary, and concurrently served as a Senior Regulatory Advisor to Genzyme Corporation supporting a broad range of cell-based biological products. He also served in roles of increasing responsibility over 16 years at Microbiological Associates (BioReliance) where he was Director of Business Development, after previously serving as Director of the Biotechnology Services Division.  His experience includes development of corporate and business systems to accommodate efficient performance in the regulated services industries, developing and maintaining key client and strategic partnering agreements, and establishing strong international client relationships.  Mr. Moore has interacted extensively with international regulatory bodies in the areas of cell line characterization and quality control for biological products; participated in the development of regulatory agency guidance documents; and made presentations at regulatory-agency-sponsored meetings in the U.S., Canada, Europe, Japan and Australia.

 

WuXi AppTec

WuXi AppTec is a leading global pharmaceutical, biopharmaceutical and medical device outsourcing company with operations in China and the United States. Research-driven and customer-focused, WuXi AppTec provides a broad and integrated portfolio of laboratory and manufacturing services across the discovery-to-commercialization spectrum. Our services are designed to assist our customers worldwide in shortening the time and lowering the cost of drug and medical device R&D by providing cost-effective and efficient outsourcing solutions.

www.wuxiapptec.com