outsourcing analytical testing for …...outsourcing analytical testing for biologics - a cro’s...

OUTSOURCING ANALYTICAL TESTING FOR BIOLOGICS - A CRO’S PERSPECTIVE

December 11, 2017

Min Zhao, Ph.D.Director, Analytical Services Biologic Product - CMC Services

Dongmei Wang, Ph.D.Executive Vice President and General Manager, CMC Services

Kang Wang, Ph.D. VP, Analytical Services

TABLE OF CONTENTS

Introduction............................................................................................................................. 3

The Nature of Proteins..................................................................................................... 3

In-Depth Structural Elucidation/Physicochemical Characterization of Biological

Molecules................................................................................................................................. 4

Importance to Manufacturers.................................................................................... 4

Regulatory Requirements............................................................................................. 5

The Analytical Process................................................................................................. 5

Batch-Release Testing........................................................................................................... 8

Table 1: GMP API Release and Stability Tests................................................................. 9

Glossary.................................................................................................................................. 10

Stability Testing...................................................................................................................... 11

Working With Your Analytics Partner...................................................................................... 12

Conclusion.............................................................................................................................. 12

© 2017 Frontage Laboratories, Inc.VISIT US AT: frontagelab.com2.

IntroductionBiologics are complex large molecules derived from living organisms or manufactured from cells, and they have inherent structural heterogeneity. Indeed, proteins, given their chemistry, are the “most structurally complex and functionally sophisticated molecules known.”1

Thus, the analytical testing required to support Chemical, Manufacturing, and Controls (CMC) activities of

biologics is highly sophisticated, and is becoming more so as the modalities of biologics grow more complex (with antibody drug conjugates, conjugate vaccines, PEGylated proteins, fusion proteins, gene therapies, and cell-based therapies).

In this environment, biopharmaceutical companies have increasingly outsourced analytical testing of biologics to Contract Research Organizations (CROs). Today, the paradigm has shifted from CROs being mere “extra hands” in the process to being professional problem solvers tasked with finding innovative and creative solutions. This market demand is driving CROs to hire top-tier scientists to provide their expertise in developing a detailed understanding of the quality attributes of biologics, including in-depth structural elucidation, post-translational modification, and degradation pathways. At the same time, CROs are investing in cutting-edge instrumentation to modernize their analytical capabilities for supporting clients with release and stability testing as well as to solve the most challenging analytical problems for large molecules.The following paper provides an overview of how CROs can support biologics’ analysis with an emphasis on in-depth structural elucidation, product release requirements, and stability testing (including degradation pathway studies).

The Nature of ProteinsProteins are fascinating to researchers because of their complexity and heterogeneity. To characterize a protein properly, one must understand its primary, secondary, and tertiary structures, as defined in the sidebar, “Three Levels of Protein Structural Architecture.” The knowledge gained through this characterization exercise will be applied in release and stability studies. A protein molecule consists of a long chain of amino acids that are connected by covalent peptide bonds. (Hence, proteins are also called polypeptides.) Proteins come in a wide variety of shapes, and generally contain from 50 to 2000 amino acids in their chains. The sequence of amino acids in the chain—which is unique to each protein—is the molecule’s primary structure. The repeating sequence of atoms along the core of the polypeptide chain is referred to as the polypeptide backbone. Attached to this repetitive chain are side chains, those portions of the amino acids that are not involved in making a peptide bond. These side chains, of which there are 20 different types, give each amino acid its unique properties. Some are nonpolar and hydrophobic (“water-fearing”), others are negatively or positively charged, some are reactive, and so on.

1Alberts, Bruce et al, Molecular Biology of the Cell, 4th Ed., Garland Science, 2002


CROs HAVE BECOME PROFESSIONAL

PROBLEM-SOLVERS FINDING INNOVATIVE &

CREATIVE SOLUTIONS


Three Levels of Protein Structural Architecture

Primary Structure: The amino acid sequence derived from cDNA

Secondary Structure: The folding of the polypeptide chains, e.g., α-helix and β-sheet

Tertiary Structure: The spatial conformation of the protein, which impacts the functional region, e.g., complementarity determining region (CDR) of an antibody

Figure 1 is a graphic representation of the structure of an Immunoglobulin G (IgG) molecule. It consists of a heterodimer of two heavy chains and two light chains with 16 pairs of disulfides. The IgG contains defined functional sites (domains), including antigen binding, compliment binding, and macrophage binding.

Figure 1: Primary Structure of an Immunoglobulin Molecule

The protein’s internal chemical-physical properties allow its long, flexible polypeptide chains to fold over on themselves in many ways, forming certain configurations (α-helices, β-sheets, and random coils). This is the molecule’s secondary structure.The order in which amino acids line up in the chain determines the protein’s full, three-dimensional shape, which is referred to as the protein’s tertiary structure. This higher-order structure ultimately affects the way that the protein functions, for example by providing catalytic sites for enzymes or complementarity determining regions (CDRs) for antibodies.

The job of elucidating a protein’s structure is further complicated by the fact that the side chains can be chemically modified to perform other functions in what is called post-translational modification (PTM). Some modifications can occur in vivo as a result of biological actions, such as disulfide bond formation, phosphorylation, glycosylation (one of the most widely occurring and functionally important), SUMOylation, and lipidation, among others. Other chemical modifications, or PTMs, can take place on the side chains or ends of the polypeptide during various stages of manufacture, such as purification, formulation, and storage. Such modifications are considered a degradation of the protein. For example, the heavy chain (HC) of antibodies can lose its lysine at the C-terminal end or become pyroglutaminated at the N-terminal end. The side chains of asparagine can undergo deamidation via the formation of a cyclic succinimide intermediate and converted to aspartate or iso-aspartate, especially at the NG (pair of asparagine-glycine) hotspot. Methionine can become oxidized to methionine sulfoxide by reactive oxygen species. These types of chemical degradation can happen at various sites at different levels in the protein, potentially impacting its activity and stability. For instance, deamidation occurring in the variable region of the HC of an antibody, which constitutes the CDR, has been shown to affect the antigen-binding affinity, thus impacting the biological function of the product.

In-Depth Structural Elucidation/Physicochemical Characterization of Biological MoleculesImportance to ManufacturersUnderstanding the structural features of a protein is an essential first step in designing sound release and stability programs for two primary reasons. First, there is interplay between the structure of a protein and its three main quality attributes: charge variants, size variants, and glycans in glycoproteins. Specifically, electrostatic charges are very important to selected protein-to-protein



interactions and affect product purity; dimers and higher-order aggregates are associated with immunogenicity in patients; and the N-linked glycans within antibodies affect biological functions. Second, changes to proteins resulting from PTM can, in altering the protein structure, play a role in the protein’s activity and can cause immunogenicity. Indeed, “the possibility of a safety-related issue being traced back to inadequate analytical characterization of a product is very real.”2 Thus, it is critical that proteins undergo a thorough analysis to elucidate their structure and characterize their physiochemical properties prior to product approval and release of production batches into the market. History gives us several examples of situations in which the structure and/or physiochemical characteristics of a biologic were directly responsible for issues with a product’s safety/efficacy. In 1998, there was an observed increase in the incidence of pure red cell aplasia (PRCA) associated with the subcutaneous (s.c.) injection of Eprex® (epoetin alfa) for the treatment of symptomatic anaemia. An extensive analytical investigation revealed that the dimers and aggregates of the product increased when it was exposed to tungsten leachate found in the prefilled syringes, and that soluble polytungstate seemed to have a strong denaturing effect on the protein.3

Another case involved interferon-β (IFNβ), which is used to treat multiple sclerosis (MS). In clinical studies, Rebif® (IFNβ-1b, a recombinant IFNβ manufactured from Escherichia coli cells, that doesn’t contain glycans) was shown to be less active but significantly more immunogenic than Avonex® (IFNβ-1a, a recombinant IFNβ manufactured in Chinese hamster ovary cells that contains glycans). Analytical studies showed that Rebif had a higher level of aggregates, presumably due to the lack of glycosylation which is needed to prevent

a hydrophobic region of IFNβ-1b from interacting with other proteins. The exposed hydrophobic region increases aggregation of IFNβ-1b while the secluded hydrophobic region decreases aggregation of IFNβ-1a.4

Regulatory RequirementsAll regulatory agencies in advanced markets have specific expectations around the analytical testing that is required as part of the New Drug Application (NDA) process and as a final step in production. According to the International Conference on Harmonization (ICH), characterization studies should be performed in development and following significant process changes; characterization includes the determination of physicochemical properties, biological activity, immunochemical properties, purity, and impurities.5

The US Food & Drug Administration (FDA) requires that manufacturers include a section in all Investigational New Drug (IND) applications providing “sufficient CMC information to assure the proper identification, quality, purity and strength of the investigational drug.”6 In its guidance, “Points to Consider in the Manufacture and testing of Monoclonal Antibody Products for Human Use,” the FDA states that “a precise and thorough characterization of antibody structural integrity, specificity, and potency should be conducted and described in the IND.”7

Providing a robust package of analytical data may also limit the scope of animal toxicity data required by the FDA in assessing a biosimilar. The agency states, “if comparative structural and functional data using the proposed product provide strong support for analytical similarity to a reference product, then limited animal toxicity data may be sufficient to support initial clinical use of the proposed product”.8

The Analytical ProcessThe first step in the process is to develop an analytical

2Berkowitz, Steven A., et al., “Analytical tools for characterizing biopharmaceuticals and the implications for biosimilars,” Nat Rev Drug Discov, 11(7): 527-5403 http://www.nature.com/nbt/journal/v24/n6/full/nbt0606-613.html?foxtrotcallback=true4http://journals.sagepub.com/doi/10.1177/17562856124692645https://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q2_R1/Step4Q2_R1_Guideline.pdf6https://www.fda.gov/downloads/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/UCM301050.pdf7https://www.fda.gov/downloads/biologicsbloodvaccines/guidancecomplianceregulatoryinformation/otherrecommendationsformanufacturers/ucm153182.pdf8https://www.fda.gov/downloads/drugs/guidances/ucm291128.pdf



plan that will incorporate what is already known about the molecule from previous research and the discovery process and address what still needs to be understood or confirmed in the manufacturing process. Typically, the structural analyses are conducted in advance of preparing the Investigational New Drug (IND) Application, so the protein is quite well understood with respect to primary, secondary, and tertiary structures. The goal of elucidating the structural degradation and characterizing the physicochemical properties of the protein at this point is to correlate the quality attributes with manufacturing experience as well as clinical impact. For example, aggregates of protein are known to cause immunogenic reactions in clinical practice, and thus are considered critical quality attributes for the manufacturing process. Because each protein molecule is unique, the analytical plan must be created on a case-by-case basis according to the clinical significance of the target product’s quality attributes. Characterization can often involve 10-20 different methods, each used to understand a different aspect of the molecule and each requiring special instruments and technical knowledge to interpret the findings.

• Structural ElucidationWith a protein composed of polypeptide chains, the conceptual approaches start with the three levels of structural characterization: primary, secondary, and tertiary. Tests need not be done in a particular order. Elucidating primary structures often involves a “bottom-up” analytical approach using peptide mapping (a.k.a., peptide mass fingerprinting or protein fingerprinting). In this method, the polypeptide chain is cleaved at specific peptide bonds using an endopeptidase, such as trypsin, chymotrypsin, or Glu-C. If the protein contains disulfide bonds, it is first reduced and alkylated prior to the enzymatic digestion to generate the peptides, which are then separated by reversed-phase chromatography, or capillary-zone electrophoresis, and detected by ultraviolet absorbance. The separated peptides are then ionized by electrospray ionization (ESI) and further

selected by a time-of-flight (TOF), quadrupole, or ion-trap mass spectrometer before their m/z values (atomic mass number/charge number) are detected. Additional analysis of the peptides can be performed by tandem mass spectrometry (MS/MS) based on further fragmentation of the peptide ions. The information, taken together, can be used to produce de novo sequencing of the polypeptides. Often, the post-translational modification or degradation such as disulfides, oxidation, or deamidation of the amino acid side chains can be detected by this bottom-up approach.With the advent of high-resolution mass spectrometry (e.g., QTof Triple TOF instrument), the top-down approach becomes more practical for analyzing the heterogeneous structures of the large molecule, such as the intact mass, glycosylation, or antibody drug conjugate. This approach provides a direct method for measuring the m/z values without digestion, which sometimes can create artifacts in the modification of the molecule.A middle-up/down approach takes advantage of the high-resolution detection of the protein species, while reducing the artifacts from sample preparation from a bottom-up approach. One example is to use a recently discovered immunoglobulin-degrading cysteine protease from Streptococcus pyogenes (IdeS) to specifically digest the hinge region of IgG, producing F(ab’)2 fragment and Fc fragments, which can be separated using organic size exclusion chromatography before being analyzed by ESI-TOF mass spectrometry.

• Characterization of Physiochemical Properties With a combination of the bottom-up, middle-up/down and top-down approaches, the primary structures, PTMs, and heterogeneity of the polypeptide chains can be readily elucidated. However, the spatial arrangement and folding of the polypeptide, or its higher-order structure, remains to be deciphered, which is usually related to the protein’s physical/chemical properties. The higher-order structures of the protein are very important quality attributes and have significant



manufacturing and clinical impact on the product safety, purity, and efficacy.Circular dichroism is a technique for determining the relative content of the secondary structure (in the far UV region), such as α-helix or β-sheet, and tertiary structure (in the near UV region), based on the characteristic spectral profiles of the protein. In addition, intrinsic fluorescence arising from tryptophan, tyrosine, or cysteine residues reflects the chemical environments surrounding these side chains, and thus is used to determine the tertiary structures. Further, differential scanning calorimetry can measure the absorption of heat by the protein as it undergoes the endothermic phase transition, which is considered as the melting of the secondary structure into molten states. More advanced techniques for understanding the tertiary structure include two-dimensional nuclear magnetic resonance spectroscopy (2-D NMR), attenuated total reflection Fourier transform infrared spectroscopy (ATR-FTIR), and X-ray crystallography. Hydrogen–deuterium exchange experiments are often performed to investigate the solvation of exchangeable protons such as those in hydroxyl or amine group. Aggregates of protein are often considered as the culprit for immunogenicity, and thus dimers and aggregates must be characterized using a variety of methods, including size exclusion chromatography (SEC), often with a light scattering detector to determine the absolute mass of the molecule; capillary gel electrophoresis with SDS (CE-SDS); analytical ultracentrifugation (AUC); and field-flow fractionation (FFF).Since the electrostatic potential of a protein in solution plays an important role in protein-protein interaction and stability, this critical quality attribute is characterized by ionic exchange chromatography (IEX) and capillary isoelectric focusing (cIEF).With IgG molecules, or other glycoproteins, the glycans are critical quality attributes. The N-linked glycans (complex, hybrid, or high mannose) in IgG can be released by cleavage of the innermost

GlcNAc and asparagine residue in the Fc region of IgG using an enzyme, namely peptide-N4-(N-acetyl-beta-glucosaminyl) asparagine amidase (PNGase F). The free glycans are then labeled with a fluorescent probe such as 2-Aminobenzoic acid (2-AA), or the newly created, dual probe, RapiFluor-MS™, for both fluorescence and mass detection. Proteins are functional biomolecules with binding receptors that elicit specific biological responses after the binding event. A number of methods are available to determine the binding potency, e.g., the affinity of IgG to bind to its antigen can be detected by enzyme-linked immunosorbent assay (ELISA). In addition, the kinetic binding events of the protein to the receptor can be determined for the on-rate and off-rate (i.e., association rate constant and dissociation rate constant) using techniques such as surface plasmon resonance (SPR) and bio-layer interferometry (BLI).The functional potency of the protein is often determined by cell-based assays, which measure the dose-response curves of the specific cellular event elicited by the presence of the molecule. The dose-response curves are often fitted to a model-independent, four-parameter function to calculate the EC50 values.Residual host-cell proteins (HCPs), can often be co-purified with the product in downstream chromatographic steps. The HCPs can be detected with the ELISA method, using the primary detection antibodies generated against the specific Null culture without the product DNA of interest inserted in the plasmid. Commercial kits are available for different cell lines, such as E. coli and CHO cells, but often one must generate primary antibodies using the specific cell culture and downstream process when the product is close to entering the clinical phase. This requirement poses a big challenge when the specific cell culture and manufacturing process is not available. This could be the case, for example, when the manufacturing steps of the innovator product in biosimilarity assessment remain a trade secret. In this situation, it would not



be possible for biosimilar sponsors to obtain the primary antibody of the innovator cell culture. Advances in CESI-MS and 2-D LC-MS meet the challenge of providing a semi-quantitative method using the signature peptides from the HCPs. Similar to HCP, residual host-cell DNA can be quantified using quantitative polymerase chain reaction (qPCR), which allows scientists to detect a specific DNA sequence in host cells and simultaneously determine the actual copy number of this sequence relative to a standard.Other impurities from the cell culture or from a downstream process include antifoam, antibiotics, EDTA, etc., and can be measured for clearance using methods such as HPLC, LC-MS/MS, and ICP-OES or ICP-MS. Particulate matters in sub-visible and micron size are of particular concern due to a potential immunogenic reaction. Although a large volume of molecules is needed to apply the light obscuration method, current advances in micro-flow imaging (MFI) allow high sensitivity in detecting and imaging transparent, fragile, and unstable protein particles.

Batch-Release TestingThe primary goal of release testing is to prevent substandard lots from reaching the public. Thus, Current Good Manufacturing Practices (CGMP) and regulatory guidance require that manufacturers test the drug substance and drug product to ensure its identity, strength, quality, purity, and potency prior to clinical trial and commercial distribution. The FDA’s expectations for release testing of biologics are outlined in its guidance document, “Analytical Procedures and Methods Validation for Drugs and Biologics.” The agency reviews the analytical methods that the manufacturer used as well as the test data package in order to “establish that the analytical procedures used in testing meet proper standards of accuracy, sensitivity, specificity,

and reproducibility and are suitable for their intended purpose.”9

Thus, release tests cover four areas: • The identity of the drug substance and its distinction

from other closely related products. This can be established using methods that are specific for the product, such as Western blotting and protein fingerprinting.

• Purity, a measure of the amount of Active Pharmaceutical Ingredient (API) compared to impurities and residual solvents. This can be measured using a variety of chromatographic methods (including SEC, IEX or RP methods), or electrophoretic methods (including SDS-PAGE, CE-SDS, IEF and cIEF), which enables product- or process-related impurities to be separated from the API.

• Potency, or the biological function of the molecule in terms of binding affinity to the receptor or the cellular response to increasing dose of the product. Potency can be tested via methods for the binding affinity, including ELISA, SPR, BLI, or functional potency, often by using cell-based assays.

• The general physical properties of the molecule to include its visual appearance (color, opacity), pH, and viscosity.

The panel of release methods should be based on an in-depth understanding of the product’s critical quality attributes, and selecting and performing the tests will require experience in analysis, manufacturing, and clinical development. Table 1 lists common test methodologies used both for release testing and stability testing, discussed below.



9“Guidance for Industry: Analytical Procedures and Methods Validation for Drugs and Biologics,” FDA, July 2015. https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM386366.pdf

Table 1: GMP API Release and Stability Tests



TESTING PURPOSE TEST METHOD INSTRUMENT

CHARGE VARIANTS* CIEF CE

CE-SDS (REDUCED AND NON-REDUCED)* CE-SDS CE

HMW/LMW SPECIES* SEC HPLC HPLC

PROTEIN PURITY* RP HPLC HPLC

ANTIBIOTICS CONTENT LC-MS/MS LC, CE-MS

PEPTIDE MAPPING* LC-MS/MS LC, CE-MS

GLYCAN PROFILE BY PNGASE F RAPIFLUOR HILIC/QDA LC-MS

HOST CELL PROTEIN ELISA MICROPLATE READER

PROTEIN A ELISA MICROPLATE READER

BINDING POTENCY ELISA MICROPLATE READER

FUNCTIONAL POTENCY* CELL BASED ASSAY MICROPLATE READER

APPEARANCE, COLOR AND CLARITY* VISUAL NA

PH* USP <791> PH METER

RESIDUAL DNA QPCR QPCR

WESTERN BLOTTING WESTERN BLOT WESTERN BLOTTING

*used for stability testing



GLOSSARY

AAA AMINO ACID ANALYSIS

ATR-FTIR ATTENUATED TOTAL REFLECTION FOURIER TRANSFORM INFRARED SPECTROSCOPY

AUC ANALYTICAL ULTRACENTRIFUGATION

BLA BIOLOGICS LICENSE APPLICATION

BLI BIO-LAYER INTERFEROMETRY

CE CAPILLARY ELECTROPHORESIS

CE-SDS SDS-GEL CAPILLARY ELECTROPHORESIS

CESI CAPILLARY ELECTROSPRAY IONIZATION

CEX CATION EXCHANGE CHROMATOGRAPHY

CHO CHINESE HAMSTER OVARY CELL

CIEF CAPILLARY ISOELECTRIC FOCUSING

EC50 HALF MAXIMAL EFFECTIVE CONCENTRATION

ELISA ENZYME-LINKED IMMUNOSORBENT ASSAY

FFF FIELD FLOW FRACTIONATION

HCP HOST CELL PROTEIN

HPLC HIGH PERFORMANCE LIQUID CHROMATOGRAPHY

IEX ION EXCHANGE CHROMATOGRAPHY

IND INVESTIGATIONAL NEW DRUG



GLOSSARY (continued)

LC LIQUID CHROMATOGRAPHY

MS MASS SPECTROMETRY

MS/MS TANDEM MASS SPECTROMETRY

NMR NUCLEAR MAGNETIC RESONANCE SPECTROSCOPY

QPCR QUANTITATIVE POLYMERASE CHAIN REACTION

RP REVERSED-PHASE CHROMATOGRAPHY

SEC SIZE EXCLUSION CHROMATOGRAPHY

SPR SURFACE PLASMON RESONANCE

UV ULTRA VIOLET

VPE VARIABLE PATHLENGTH SYSTEM, SLOPE SPECTROSCOPYTM

Stability Testing “Biological products are particularly sensitive to environmental factors such as temperature changes, oxidation, light, ionic content, and shear.”10 These factors can cause structural degradation which can impact their quality, safety, efficacy, and shelf life. The most common types of degradation in biologics are deamidation, oxidation, aggregation, and glycation. Regulators, therefore, require manufacturers to adopt a long-term stability program that ensures that the product will be protected from changes to its identity, purity and potency. Stability testing should “provide evidence on how the quality of a drug substance or

drug product varies with time under the influence of a variety of environmental factors, such as temperature, humidity, and light, and to establish a retest period for the drug substance or a shelf life for the drug product and recommended storage conditions.”11

In general, stability testing should:• Cover any external condition that affects potency

(the ability of a product to achieve its intended effect), purity, and quality. ICH Q5C states, “When the intended use of a product is linked to a definable and measurable biological activity, testing for potency should be part of the stability studies. The same guidance explains, “The absolute purity of a

10“Quality of Biotechnological Products: Stability Testing of Biotechnological/Biological Products Q5C,” 11ICH Harmonised Tripartite Guideline, November 30, 1995 “Guidance for Industry Q1A (R2) Stability Testing of New Drug Substances and Products,” FDA, November 2003



biotechnological/biological product is extremely difficult to determine. Thus, the purity of a biotechnological/biological product should be typically assessed by more than one method, and the purity value derived is method-dependent. For the purpose of stability testing, tests for purity should focus on methods for determination of degradation products.”

• Evaluate the product’s integrity in normal conditions as well as in stress conditions (such as UV stress, sheering and vortexing, freeze and thaw cycles, acid and base treatment, and heating). Forced degradation studies—studies that subject the drug substance or product to extreme conditions—provide a better understanding of the degradation pathway, or its physical and chemical modifications under stress. That information can be extrapolated to understand the effect of storage in the long term.

• Explore short-term, long-term, and accelerated storage conditions. For new drug substances and products, the FDA requires six months of accelerated stability data and a minimum 12 months of long-term stability data on at least three batches as part of the data package for approval of a new drug.

Stability testing to support shelf life claims may involve complex methodologies, which are a subset of those types of tests performed prior to release. The tests in Table 1 identified with an asterisk support stability testing. There is no single stability-indicating assay or parameter that profiles the stability characteristics of a biotechnological/biological product, as the appropriate tests depend on the characteristics and properties of the drug substance. Very often, the stability-indicating methodologies involve the monitoring of product-related impurities, which may be the degradation species generated during storage, such as aggregates, charge variants, chemically modified side chains, including

oxidized, deamidated, and glycated side chains. Working with Your Analytics Partner The need for outsourcing analytical testing for biologics is expected to increase substantially in the next decades or so. To meet the demand from biologics development companies, a CRO should not only be equipped with cutting-edge technologies, instruments and state of art facilities, but also staffed with experienced scientists. The following four areas of expertise are essential for contract testing services of biologics:

• Extensive experience with analytical testing services to enable IND and BLA filing for biologics and biosimilars

• A strong team with comprehensive technical skills to help the customer overcome challenging problems

• A track record of regulatory inspection and compliance to ensure delivery of high quality data and projects

• Project management skills in scientists/project leaders to streamline effective and efficient communication to save time and costs, as well as to deliver results in a timely manner for clients

ConclusionIn outsourcing analytical testing to a CRO, small and start-up companies have a tremendous opportunity to take advantage of their partner’s technical strength and regulatory experiences in biologics product development. A CRO that offers fully integrated services can take over the entirety of testing for product release and the stability program as well as satisfy the need for reference standard qualification, product characterization, comparability, biosimilarity and forced degradation studies. Medium-sized and large biopharmaceutical companies often have special needs for testing of impurities, such as process impurities or leachable and extractable, that can be outsourced to a CRO.

Frontage Laboratories, Inc. is a CRO providing integrated, scientifically-driven research, analytical and development services throughout the drug discovery and development process to enable biopharmaceutical companies to achieve their drug development goals. We offer our clients comprehensive services in analytical testing and formulation development, drug metabolism and pharmacokinetics (DMPK), bioanalysis, preclinical safety and toxicology and early phase clinical studies. We have enabled many innovator, generic and consumer health companies of all sizes to file IND, NDA, ANDA, BLA and 505(b)(2) submissions in global markets allowing for successful development of important therapies and products for patients. We have successfully assisted clients to advance hundreds of molecules through development to commercial launch in global markets. We are committed to providing rigorous scientific expertise to ensure the highest quality and compliance.

outsourcing analytical testing for …...outsourcing analytical testing for biologics - a cro’s...

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