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News for the Biologics Industry

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WuXi AppTec representative.

July 2012

Contents [click on links for full story]


US FDA Issues Three Guidances for Industry Draft Documents for Biosimilar Products
Recently, the US FDA issued three Guidances for Industry draft documents that outline the agency’s current thinking regarding the steps necessary to demonstrate biosimilarity.

EMA Releases Draft Guideline on Process Validation
The EMA has provided to industry a Draft Guideline on Process Validation for comment.

USP Updates 232/233 Elemental Impurities Chapters
The U.S. Pharmacopeia has recently announced the latest update to heavy metals testing.

ICH Q11 Drug Substance Guideline Finalized
ICH officially released guideline Q11. What will be the impact / changes to the industry?

US FDA Issues Final Rule to Amend Sterility Test Requirements for Biological Products
The US FDA has issued a proposal to amend the sterility test requirements for biological products (21 CFR Parts 600, 610 and 680).


New DNA Sequencing Services – from Gene to Genome!
WuXi AppTec can provide sequencing services to support genetic stability studies or for cloning confirmation and other applications. State-of-the art next generation high throughput DNA sequencing is now available, including whole genome and transcriptome analysis.

Comprehensive Product Characterization Services
Broad analytical method offering for product comparability or reference standard characterization can be provided in either the U.S. or China.

Single-Source, Fully-Integrated Protein/Monoclonal Antibody Development and Manufacturing
Utilizing facilities in both China and the U.S., WuXi AppTec can provide single-source services from discovery to clinical trial GMP manufacture and lot release.

U.S.-Based Bioanalytical Laboratory
WuXi AppTec’s Philadelphia facility now provides bioanalytical support of discovery, preclinical safety, and efficacy and clinical trial programs.

NHP Toxicology Programs
Many recombinant proteins or monoclonal antibodies require non-human primates as part of the preclinical safety assessment package.


US FDA Issues Three Guidances for Industry Draft Documents for Biosimilar Products Biosimilar products are complex biologically-derived therapeutics that are highly similar – but not necessarily identical – to a licensed brand name (reference product) counterpart. The United States Biologics Price Competition and Innovation Act of 2009 permits an applicant to rely in part on existing scientific knowledge about the safety and efficacy profile of the approved reference product in order to follow an abbreviated pathway to licensure for a biosimilar product. Section 351(k) of the United States Public Health Service (PHS) Act details the requirements for application for licensure of a proposed biosimilar product.

Recently, the US FDA issued three guidances for Industry draft documents that outline the agency’s current thinking regarding the steps necessary to demonstrate the biosimilarity of a proposed therapeutic protein product to a US FDA-licensed reference product. Two of the guidance documents provide information regarding the scientific considerations and quality attributes required to achieve that goal, whereas the third document, which utilizes a “question and answer” format, offers guidance for the development of biosimilars (as originally provided in the US Biologics Price Competition and Innovation Act of 2009).

The “Guidance for Industry: Scientific Considerations in Demonstrating Biosimilarity to a Reference Product" recommends that sponsors take a step-wise approach to demonstrating that the proposed therapeutic protein product is highly similar to a reference product. The document outlines the scientific principles to be used in that step-wise approach, and presents a totality-of-the-evidence review standard for license applications under section 351(k) of the US Public Health Service (PHS) Act. The initial and critical step on the path to determine biosimilarity consists of a comprehensive and comparative structural and functional characterization of the proposed biosimilar with the reference product. It is the results of these initial studies that will inform and guide the considerations and content of the rest of the biosimilar development program. The document then outlines the general considerations for (1) the role of animal toxicity, PK/PD, and immunogenicity studies, (2) the design of relevant comparative human PK/PD and clinical immunogenicity studies and the use of data generated from such studies, and (3) the potential inclusion and use of comparative clinical efficacy and safety studies. Finally, the document addresses the considerations of a post-market safety surveillance plan.

The “Guidance for Industry: Quality Considerations in Demonstrating Biosimilarity to a Reference Protein Product” describes the step-wise approach introduced in the “Scientific Considerations” document to determine whether a proposed product meets the threshold of biosimlarity to a reference product, including the quality attributes to be assessed and the analytical studies that should be considered for the determination of biosimilarity. The document addresses key elements for the proposed biosimilar product and reference product comparability studies, such as assessments of the manufacturing process and the product expression system; characterization of the physicochemical properties (i.e., primary, secondary, and higher order structure); functional properties, receptor binding and immunochemical properties; and product-related and process-related impurity profiles. Product specification comparisons, and comparative stability data – including product degradation kinetics, and product degradent profile comparisons – are also described. The document makes it clear that in addition to the required reference product comparability data, a full quality data package for product characterization, biosafety (i.e., cell bank characterization, viral clearance studies, lot release testing), process validation, product and process specification, and product stability that normally comprises the chemistry, manufacturing, and controls (CMC) section for any biologics regulatory submission is also required for the regulatory submission for a biosimilar, and cannot be abbreviated.

These draft guidance documents are similar in principle and scope to biosimilar guidance documents issued by the European Medicines Agency (EMA), Health Canada (where biosimilars are termed Subsequent Entry Biologics), and the World Health Organization (WHO). It should be noted that the EMA intends to issue a new guidance document specific for biosimilar monoclonal antibodies, and is re-evaluating and revising the existing biosimilar guidances based on experience with biosimilars that have come on the market, and because of the advent of more complex biosimilar products.

WuXi AppTec’s technical staff are ready to answer any questions you may have about biosimilar products in general as well as specifically address the testing recommended to meet the quality attributes for your proposed biosimilar product. To speak with one of our staff on this topic or for information regarding our comprehensive menu of services for biosimilar products, please contact your WuXi AppTec Account Manager.

EMA Issues Draft Guideline on Process Validation
The European Medicines Agency has issued for comment a draft guideline for process validation. The document outlines considerations for assuring/measuring that a manufacturing process performs reliably to produce a product with defined quality attributes and specifications. This document also introduces the concepts of (1) Continuous Process Verification (CPV), an ongoing real-time assessment of manufacturing process performance; (2) a hybrid process validation and CPV approach in cases where the sole application of PV or CPV is not practical, desirable, or feasible; and (3) the use of CPV as a post-process validation activity to be employed during the life cycle of a commercialized product. CPV is a science and risk-based approach that consists of continuous and timely monitoring of relevant process parameters and product quality. While CPV can be used as an alternative approach to process validation, it can also be used in certain circumstances in conjunction with process validation. The document offers that CPV can be introduced at any time in the life cycle of the product for purposes such as process validation protocol design or the revalidation of existing products where process changes or improvements are implemented. Although not discussed in the document, the benefits of this approach to the biopharmaceutical industry could be significant. In-line real-time monitoring for adventitious agents could be utilized in circumstances where the performance of viral clearance studies are impractical, used as part of a strategy to accelerate product development timelines, or used as part of the product life cycle monitoring program.

To speak with one of our staff on this topic or for information regarding our comprehensive menu of process development and validation services, please contact your WuXi AppTec Account Manager.

USP Updates 232/233 Elemental Impurities Chapters
The U.S. Pharmacopeia recently announced the latest update to heavy metals testing. USP General Chapters <232> Elemental Impurities—Limits and <233> Elemental Impurities—Procedures are complementary guidelines that explain the risk-based approach to program design and provide instructions for the execution of tests. Although the guidance does not become mandatory until May 1, 2014, these documents will be officially released December 1, 2012. Considering these documents now in program planning is important to avoid unnecessary changes and revalidations later.

The USP update was initiated to better address the safety concerns of all elemental impurities – not just heavy metals – and allows for the use of modern, more sensitive techniques. Chapter <232> gives guidance on how to design the elemental impurities program as well as how to interpret the results. Chapter <233> provides guidance on test design.

Moving from the traditional heavy metals test to more efficient and sensitive methods, such as Inductively Coupled Plasma Mass Spectrophotometry (ICPMS), provides for low-detection limits, control of interferences, and thorough risk assessments.

To help manufacturers stay on top of the latest product and process analytical challenges and techniques, WuXi AppTec has further expanded its chemistry program in St. Paul with testing services in support of these new guidelines, including the newest ICPMS technology, along with microwave-assisted digestion.

With years of elemental preparation and analysis experience, state-of-the-art equipment and trained toxicologists, we are well positioned to meet the needs of manufacturers in assessing the levels of potential impurities in biologic products. Please contact your WuXi AppTec Account Manager to learn more.

ICH Q11 Drug Substance Guideline Finalized
A new ICH Document has been approved by the Steering Committee under Step 4 and recommended for adoption to the three ICH regulatory bodies: Q11 “Development and Manufacture of Drug Substances (Chemical and Biotechnological/Biologic Entities).”

ICH Q11 focuses on approaches for the development, implementation, and monitoring of drug substance manufacturing processes. Traditional, enhanced, and combination approaches to drug substance development, as well as design space considerations for the manufacturing process, are discussed. Common to all approaches is the need to identify an appropriate manufacturing process, the critical quality attributes associated with the drug substance that impact drug product quality, and a well-defined control program to ensure appropriate process performance and product quality is maintained. A critical step in the development program is the identification of key materials and process parameters that need to be monitored and controlled.

WuXi AppTec can assist you by providing risk assessments and safety studies regarding potential adventitious agent and other impurities as potential critical quality attributes for drug substances, and the ability of the manufacturing process to clear such impurities. To learn more, please contact your WuXi AppTec Account Manager.

US FDA Issues Final Rule to Amend Sterility Test Requirements for Biological Products
The US FDA issued a final rule, effective June 4, 2012, to amend the sterility test requirements for biological products (21 CFR Parts 600, 610 and 680).

The rule does two things:

  • Provides greater flexibility to manufacturers of biological products.
  • Encourages the use of potentially more appropriate state-of-the-art test methods.

In general, most of the changes are improvements because the requirements are not as prescriptive and allow for methods/procedures to be used that are more suitable for the product itself. However, the burden of proof for “new” methods becomes more onerous for the manufacturer, especially if they use parameters that differ significantly from those to which the industry has been accustomed.

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

Following is a brief summary of some of the more significant changes:

Changes associated with the sterility test itself
The rule expands the acceptable sterility test to both culture-based and non-culture-based methods (new or rapid methods). The FDA is requiring that the test validation include samples of the final material, incorporate appropriate viable contaminating micro-organisms, and demonstrate the test’s growth-promoting properties as well as the method’s detection system capabilities, including aerobic and anaerobic organisms and organisms that grow at different rates. Because of this, the specification has been eliminated 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.

The rule eliminates the requirement for a membrane filtration test and simply states that the sterility test must be appropriate to the material being tested, such that the material does not interfere with the test, and thereby allowing more flexibility in the method chosen. Therefore the direct inoculation (immersion) procedure will not be considered an exception.

The FDA has replaced 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. The FDA is modifying the repeat sterility test so that repeat tests would occur only once for each lot.

Changes associated with sampling
The FDA has determined that, in most cases, the most appropriate test material for the sterility test is the final container material. However, due to the nature of some biological products, testing the final container may not be appropriate, so the rule requires a sterility test on either the final container or other material (e.g., bulk or API) prior to release of the product. The FDA is eliminating the sample number requirement and instead is requiring 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. The rule maintains the exceptions to the sterility test: whole blood, cryoprecipitated AHF, platelets, red blood cells, plasma, smallpox vaccine, AHG, and Blood Grouping Reagents. It makes 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.

To learn more, please contact your WuXi AppTec Account Manager.


By leveraging expertise and facilities in both the U.S. and China, WuXi AppTec can expedite your timelines and reduce your costs into clinical trials and beyond. Expanded service offerings in key drug development program areas include the following.

New DNA Sequencing Services Available – from Gene to Genome!
By leveraging laboratories in both the US (Philadelphia, PA) and China (Shanghai), WuXi offers its clients comprehensive small- and large-scale DNA sequencing services for a variety of applications critical to bioteherapeutic and vaccine product development.

WuXi AppTec’s Philadelphia facility offers essential R&D and GLP/GMP DNA sequencing services from early-stage development (e.g., confirming identity and integrity of genes after cloning) to GMP lot release of clinical and commercial viral or plasmid-based products.

DNA sequencing is also an essential tool in cell line genetic stability studies. Along with the other critical assays for genetic stability studies, such as Southern & Northern Blotting and qPCR for Copy Number Determination, WuXi AppTec provides a seamless and simple alternative to using multiple sourcing vendors.

By providing industry-leading quality, GLP and GMP oversight, and technical expertise, WuXi AppTec’s DNA sequencing services offer our clients the assurance needed for critical development and lot release testing programs.

The WuXi AppTec Genome Center in Shanghai, China is staffed by industry leaders with more than 10 years of experience developing and designing technologies and applications for the study of genomics in healthcare. Their mission is to provide an effective integration of genomic technologies to advance drug discovery, clinical development, and personalized medicine, offering complete solutions to tackle biological and clinical problems by applying genomic, bioinformatics and disease domain knowledge.

Utilizing state-of-the-art, high-throughput methodologies, the Genome Center’s capabilities include: Whole Genome, Exome, Transciptome, Target Capture, Epigenetics, Amplicon, miRNA, Metagenome, and ChIP Sequencing.


Comprehensive Product Characterization Services

WuXi AppTec provides a comprehensive range of analytical testing services to characterize complex biological vaccines, and biotherapeutic proteins and antibodies to ensure product quality and consistency during all stages of biopharmaceutical development. Analytical, cell and molecular biology laboratories in both China and the U.S. can provide the vast array of characterization assays for complex biologics that include glycan composition, peptide mapping and sequencing and extinction coefficient determination.

Services include the battery of regulatory-compliant tests needed for reference standard characterization, detection and estimation of process-related impurities (e.g., host cell DNA and protein assays), along with a host of biosafety tests that include sterility, endotoxin (LAL), mycoplasma and bioburden analysis.

Some of the methods offered by WuXi AppTec:
• HPLC (SEC, RP and IEX) • Mass Spectrometry (LC/MS/MS) • HPAEC-PAD • SDS PAGE • Western Blotting • Flow Cytometry • ELISA / Immunoassays • PCR and qPCR • FTIR • GC • cIEF and CGE • ICP • UV Spectrophotometry • Circular Dichroism • Cell-Based Potency Assays • Custom In-Vitro and In-Vivo Methodologies

Whether the product is in the discovery, development, clinical trials, or commercialization stage, WuXi AppTec can provide the high-quality analysis and characterization expertise required for your programs. Assays can be transferred, developed, verified, qualified or validated at WuXi AppTec and can be run under R&D, GLP or GMP protocols.


Single-Source, Fully-Integrated Protein/Monoclonal Antibody Development and Manufacturing

WuXi AppTec’s strategic investment in our bio-derived/biologics platform is designed to offer a complete R&D and GMP service portfolio from discovery and development all the way to commercialization for products submitted to regulatory agencies around the world.

In the last two years, WuXi has made significant additions to our biologics platform through expanded capabilities in Shanghai and a new manufacturing facility in Wuxi city, where speed and cost-competitive efficiency are maximized. Adding these to the long-established and respected capabilities of our Philadelphia site, we offer our clients a leading and comprehensive, quality-based platform.

Along with our comprehensive R&D platform, we provide global regulatory experience plus local manufacturing in China that arms our clients with unprecedented access to a fast-growing market. This access can foster a rapid proof-of-concept with potentially lower costs which can lead to successful commercialization around the globe faster than traditional routes.

Capabilities include non-GMP, 50-200L cell culture capacity in Shanghai as well as complete discovery and development services:

  • MAb Discovery & Screening
  • Cell Line Engineering and Construction
  • Bioprocess Development (upstream and downstream)
  • Analytical Development and Protein Characterization
  • Manufacturing (non-GMP)

The newly constructed facility in Wuxi city complies with worldwide cGMP regulations, features 500L and 1000L bioreactors for mammalian cell culture production, and uses state-of the-art disposable technologies, including the following services to our expanded biologics platform:

  • cGMP Cell Banking
  • Recombinant Protein and Monoclonal Antibody Manufacture (cGMP / non-GMP)
  • Stability Studies
  • Formulation, Fill & Finish

In addition, supporting services such as GMP cell banking, cell line characterization and viral clearance validation can be provided by our industry-leading technical teams in our U.S. facilities.


U.S.-Based Bioanalytical Laboratory

WuXi AppTec has established a bioanalytical laboratory in our 75,000-square-foot R&D, testing and manufacturing facility in Philadelphia, complementing our US FDA-certified bioanalytical lab in Shanghai. Leveraging over 25 years’ of group management industry experience, WuXi AppTec offers comprehensive and FDA/OECD/SFDA GLP-compliant bioanalysis services to support drug discovery, ADME/DMPK programs, and preclinical and clinical development of pharmaceuticals, biomarkers, antibodies and other biological products.

With our team of technical experts, an established system of sharing SOPs and protocols across all worldwide sites, and utilization of high-throughput sample analysis, we can provide substantial cost savings and expedited timelines to our clients.

Services provided include:

  • GLP and non-GLP sample analysis for both small and large molecules
  • PK/TK/PD analysis for preclinical and clinical studies
  • Antibody immunogenicity assays
  • Generic drug BE studies (pilot and pivotal)
  • Method transfer, development and validation
  • High-throughput LC/MS/MS, UPLC/TOMTEC sample analysis
  • Incurred sample reanalysis for each conducted study
  • Stability testing
  • Metabolite identification and elucidation
  • Synthesis of commercially non-available internal standards and metabolites


NHP Toxicology Programs – Center of Excellence for Toxicology

WuXi AppTec’s preclinical toxicology testing offers seamless integration with our drug discovery and development services, accelerated timelines for candidate selection, and a cost advantage that yields one of the best values in the industry. Our 314,000 ft2 facility in Suzhou is one of Asia’s largest, offering high quality preclinical services meeting FDA, OECD and SFDA GLP Standards. The China facilities increase the capabilities and capacity of the in-life laboratories established in the U.S. to support medical device, pharmaceutical/biopharmaceutical and combination products.

Non-human primates are supplied primarily from Jingang (Hainan, China) with over 20,000 NHP on site, and experience exporting SPF animals to the U.S. since 2005. Our preclinical studies for biologics are customized for each product and designed to generate meaningful results through the performance of thorough scientific and regulatory-compliant programs (FDA, OECD, SFDA Good Laboratory Practice).

Complete range of studies:

  • General Toxicology
  • Genetic Toxicology
  • Safety Pharmacology
  • Immunology
  • Developmental and Reproductive Toxicology
  • ISO-10993 Studies
  • Pharmacokinetics

Guidance for preclinical safety assessment of biotechnology-derived pharmaceuticals was updated in June 2011, with the revised ICH S6 (R1) reaching Step 4. At WuXi AppTec, our integrated services platform for biologics development includes extensive capabilities to meet the requirements of this guidance, in line with our goal to help our worldwide customers shorten the time and lower the cost of R&D through cost-effective and efficient outsourcing solutions.



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.