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News for the Biologics Industry

WuXi AppTec sends out a periodic 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 more information on WuXi AppTec’s broad spectrum of services for biologics, please click here, contact your Wuxi AppTec Account Manager, or email us at: info@wuxiapptec.com.

May 2010

INDUSTRY NEWS
Renewed Focus on Prevention and Detection of Adventitious Agents

Introduction
Recent, well-documented and publicly announced virus contamination events at Genzyme and GlaxoSmithKline emphasizes the need to continue to define, refine and expand programs to detect and prevent a contamination event through appropriate biosafety testing programs, cleaning procedures and environmental monitoring programs.

With patient safety and public well-being as the primary driver for the development of any biosafety program, and in consideration of other factors – such as the cost of cleaning facilities post-event, the impact of potential lost commercial revenue or delays into the clinic, potential drops in public valuation (stock price) and decreased public or patient confidence – the need for comprehensive biosafety programs becomes paramount. This newsletter is dedicated to providing a brief overview of biologics biosafety testing, as well as other preventative measures such as supply chain assessment and cleaning validations. We are also pleased to offer sources of assistance from WuXi AppTec should an event occur in your facility.

For more information on any of the following, contact a WuXi AppTec representative.

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Raw materials screening / supply chain assessment: The first line of defense
The 1993 U.S. FDA Points to Consider guidance document for the characterization of cell lines used for the production of biologicals outlined a three-tiered biosafety testing program for biopharmaceuticals aimed at detecting and preventing potential adventitious agents during product development and through the manufacturing process. The three-tiers as described in the document include:

1. Production, identification and characterization of cell substrates and starting materials
2. Validation of the manufacturing process for removal or inactivation of adventitious agents
3. Testing of the bulk and final product

Based on industry GMP standards or common industry practices, the first tier includes the assessment and analysis of all raw materials used in the production of the therapeutic for the introduction of potential microbial or viral contaminants. As many viral contamination events can be traced to a specific raw material, the need to perform a thorough analysis of all raw materials and processing points in the supply chain should be examined. This analysis becomes even more critical if any animal-derived components or reagents are used in production. While many biopharmaceutical companies have moved away from direct use of animal-derived products in their media and excipients, there may well be other potential contaminations from the growth and processing steps of plant-derived or other commonly sourced ‘natural’ materials that should be considered. WuXi AppTec is available to assist in the assessment of your entire raw materials program and the design of testing programs to mitigate contamination risks or the writing of appropriate risk assessment documents.

Click here to access a PDF with additional details on WuXi AppTec’s supply chain assessment capabilities.

For more information, contact a WuXi AppTec representative.

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Cleaning validations: Minimizing your risks

Virus Cleaning Validation Plans
Recent industry viral contamination events have increased awareness and the need to assess the potential of viral contaminants from a wide variety of sources and to establish the appropriate cleaning procedures. Establishing and validating virus cleaning procedures for both GMP facilities and manufacturing suites, as well as product purification process equipment and chromatography resins, follow similar guidelines and procedures to the more standard microbial cleaning programs. Virus spiking studies onto common facility and equipment construction materials – including stainless steel equipment, flooring, walls, and other plastic or glass surfaces – are typically evaluated using representative samples from the manufacturers (coupons) with common virucidal agents being assessed for overall viral kill and kinetics of kill. Mimicking exact spraying and cleaning processes at small scale is critical to ensure that the larger-scale cleaning procedures will provide the same results as in the validation program.

WuXi AppTec has a wide variety of viruses that can be utilized in virus cleaning studies, including MMV, Vesivirus (the 2117 strain), and other models of viruses that demonstrate different levels of chemical resistance. Current trends in the industry have seen an increase in the number of biopharmaceutical manufacturers who are performing “pre-event” cleaning validations with some of the most resistant viruses as a risk management tool to avoid long delays should a contamination occur in one of their facilities.

In addition, if the manufacturing process includes reuse of resins, assessing both new and used resins is also common practice during late-stage development of the purification process. WuXi AppTec can help you with cleaning validation programs for facilities, equipment and resins.

Microbial Cleaning Validation Programs
In aseptic manufacturing facilities and in controlled environments where microbial contamination is a potential concern, the establishment and validation of cleaning and/or sanitizing procedures for the effective removal/reduction of microbial contaminants is strongly recommended and often required by the FDA and EU. Guidelines for such validations can be found in various guidance documents, including those from the American Standards for Testing and Materials (ASTM) and the Association of Official Analytical Chemists (now AOAC International), among others.

Validation of these procedures is often accomplished through the application of the selected cleaner or sanitizer to inoculated coupon materials, representative of surfaces found in the controlled areas that will be cleaned or sanitized by these procedures, in a manner which replicates, as closely as possible, the actual cleaning or sanitizing method. Mimicking these procedures, on a small scale, is critical to ensure that the larger-scale procedures, routinely performed in the manufacturing or processing environment, will provide similar results as those observed during the validation.

Ideally, facility-specific environmental microbial isolates would be used for the inoculations, but, due to the frequent instability of wild-type microorganism populations, standardized strains of the same species from the American Type Culture Collection (ATCC) are often substituted. Selection criteria for the challenge microorganism(s) for this type of validation should include, but not be limited to: the relative expected resistance of the organism(s) to the cleaning/sanitizing agent being used; the frequency of occurrence in the controlled environment; the potential impact of the organism(s) on the product; and whether the organism(s) would be considered objectionable under typical company policy or product end-use.

To learn more about sanitizer or cleaning efficacy validation programs and environmental monitoring practices for your manufacturing facilities, contact a WuXi AppTec representative.

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Vesivirus and Mycoplasma: Cutting-edge detection technology for cleaning validations and lot release

Vesivirus qPCR and Cell-Based Assays
Vesivirus (Strain 2117) was identified as the viral contaminant in the well-documented contamination event at Genzyme. Vesivirus is a 32-40 nm non-enveloped RNA virus in the Calicivirus family. The impact of this event to the biopharmaceutical industry as a whole is still to be determined. It is conceivable that future regulatory or industry recommendations in response to this event will require a definitive evaluation of mammalian-derived products, the raw materials that are employed, facility, suite and equipment cleaning, and purification processes for Vesivirus detection, inactivation or removal. To assist companies in this evaluation (should it be needed), Wuxi AppTec has developed and validated a qPCR assay for detection of Vesivirus 2117. In addition, the 2117 Vesivirus strain has been tested in several cells lines in the typical In Vitro Virus Contamination Test. The virus was readily detected in CHO cells, but not in many other common cells lines that are used for cell substrate, raw material or unprocessed bulk harvest testing. In addition, WuXi AppTec has developed a high titer and pure stock of the 2117 vesivirus as well as a feline calicivirus model that can be used to evaluate the capability of purification processes to remove or inactivate this potential viral contaminant or for spiking studies in cleaning validation programs.

TD-PCR for Mycoplasma Detection
WuXi AppTec offers a validated PCR assay to detect Mycoplasma DNA. The method – based on the touchdown method published by Eldering et al, 2004. Biologicals. 32, 183-193 – is compliant with EP 5.8 Section 2.6.7. and the new draft section in the USP. The assay has been accepted as a lot release assay in Europe, but has yet to be fully accepted by the U.S. FDA for lot release. Many clients have started to evaluate this method as a potential replacement for the standard culture method used in the typical unprocessed bulk product lot release programs, raw material testing programs, or as a lot release test for products such as cell therapies that have a limited shelf-life. Furthermore the method could be effectively used in mycoplasma cleaning validation programs due to its greater sensitivity.

The potential benefits include a rapid turnaround time (< 4 Days), greater sensitivity than culture-based methods, more cost-effectiveness, and standardization to an international reference (EDQM). WuXi AppTec can perform this method either GLP or, once a test article-dependent qualification is completed, GMP.

For more information on vesivirus and mycoplasma testing, contact a WuXi AppTec representative.

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Viral clearance and process validation studies: Knowing when – and how – to evaluate critical purification steps
Viral clearance and inactivation process validation studies are required throughout the development cycle of all biologic products produced from mammalian cell culture or animal and human tissues. However, even with several regulatory guidance documents that address how and when to perform these programs, the case-by-case nature of biologic development still raises some unanswered questions such as:

• How much clearance/inactivation will this particular process step provide?
• How much clearance is required for a given process?
• What critical process parameters could I change to get better clearance/inactivation?
• What are robust viral clearance/inactivation steps and can they be used in this process?
• Which type of virus(es) should be used in the studies?
• Are the regulations the same around the world?
• Are there different requirements between IND and BLA filings?
• Do I need to do viral clearance studies in-between the IND and BLA filings?

WuXi AppTec has been collecting data generated through 20 years and 2000 viral clearance studies to help you answer these critical questions. A summary of these findings that can help answer these questions and more can be provided and tailored to answer your process specific needs.

For more information, contact a WuXi AppTec representative.

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WuXi AppTec offers expert response teams for contamination events
Should you have a contamination event in your process development and/or manufacturing activities, WuXi AppTec has a team of experts to help you identify the contaminant and to help review or establish raw materials screening and cleaning procedures should that be required. In addition, if you have questions about performing an up-front risk assessment for adventitious agent control, or designing facility cleaning programs, raw materials control and environmental monitoring programs, the Biosafety Response Team at WuXi AppTec – along with a team of respected industry consultants – is available to assess and develop implementable programs.

For more information, contact a WuXi AppTec representative.

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WUXI APPTEC NEWS
Charles River Laboratories to Acquire WuXi AppTec

On Monday, April 26, 2010, WuXi PharmaTech (Cayman) Inc. [the parent company of WuXi AppTec] and Charles River Laboratories International, Inc., announced that their respective boards had reached an agreement for Charles River Laboratories International, Inc. to purchase all the outstanding shares of WuXi PharmaTech (Cayman) Inc. for cash and stock valued at approximately $1.6 billion.

Following is a letter to our customers providing more information.

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UPCOMING MEETINGS

Expert representatives from WuXi AppTec will be at the following conferences and we look forward to seeing you there. If you would like to schedule a meeting for a particular show, click here

• International Society of Cellular Therapies (ISCT)
  May 23-26 in Philadelphia
  Philadelphia is home to our cellular therapeutics manufacturing and testing facility. If you would like to make arrangements to tour the facility (located in the historic Navy Yard, about 10 minutes from the convention site), please click here
• Viral Safety for Biologics
  June 8-10 in Cologne, Germany
• ILSI BioMed
  June 13-17 in Tel Aviv, Israel
• IBC Cell Line Development and Engineering Conference
  June 22-24 in San Francisco
• Cambridge Healthtech ImVac – The Immunotherapeutics & Vaccine Summitt
  August 17-19 in Cambridge, Massachusetts

For more information on WuXi AppTec’s broad spectrum of services for biologics, please click here, contact your Wuxi AppTec representative, or email us at: info@wuxiapptec.com

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