The structure and activity of complex biotherapeutic molecules require sensitive analytical technologies that can characterize these complicated protein structures and observe their pharmacokinetic activity, elements fundamental to biotherapeutic drug development and production. Relevant technologies are needed to make detailed analytical assessments of structure, function, and purity, and further innovation is needed to address the continued challenge faced by the industry, including approaches to analytical method development and multiple analytical assays.

s July 2021 Biopharmaceutical Analysis eBook

Feliza Mirasol is the science editor for 

When referring to this article, please cite it as F. Mirasol, “Complex Biomolecules Require Analytical Evolution," 

BioPharm International Biopharmaceutical Analysis

Articles

The ever-increasing complexity of biotherapeutic molecules presents unique analytical challenges for developers.

Complex Biomolecules Require Analytical Evolution

A critical element in all drug development—from early clinical trials to final form and dose of a drug—is the qualification and validation of analytical methods and bioassays. 

This paper identifies the relevant International Council for Harmonisation (ICH) and 

) guidelines and suggests appropriate and efficient study designs, method of analysis, and acceptance criteria. All study designs suggested are the minimum number of determinations needed to qualify or validate a method.

BioPharm International’s July 2021 Biopharmaceutical Analysis 

Thomas A. Little*, PhD, drlittle@bioassaysciences.com, is president of Bioassay Sciences.

*To whom all correspondence should be addressed

When referring to this article, please cite it as T.A. Little, “Best Practices for Analytical Method Validation: Study Design, Analysis, and Acceptance Criteria," 

Developing analytical methods and bioassays is necessary from early on in the drug development life cycle.

Best Practices for Analytical Method Validation: Study Design, Analysis, and Acceptance Criteria

This article summarizes a pharmaceutical industry consensus viewpoint of the current regulations regarding data integrity as applied to analytical test data generated to support regulatory activities. In particular, the focus is on data generated by external personnel (e.g., a third-party laboratory or instrument service technician), referred to as vendors. 

Analytical instrumentation used in the pharmaceutical industry generates data not only during analytical sample analysis but also during routine or preventive maintenance, such as instrument calibration or qualification, and during troubleshooting associated with repairs. The various scenarios under which outsourced data may be generated and managed are discussed.

Thomas Cullen*, thomas.f.cullen@abbvie.com, and Cliff Mitchell work in Analytical Research and Development at AbbVie Inc. (North Chicago, IL); Julie Lippke and Joseph Mongillo both work in Analytical Research and Development at Pfizer Inc. (Groton, CT); Koottala S. Ramaswamy works in Global Development Quality at Merck & Co., Inc. (West Point, PA); and Thomas Purdue works in Quality at Boehringer Ingelheim Pharmaceuticals Inc. (Ridgefield, CT); all authors are members of the IQ Consortium.

When referring to this article, please cite it as T. Cullen, C. Mitchell, J. Lippke, J. Mongillo, K.S. Ramaswamy, and T. Purdue, “Data Integrity Considerations for Vendor-Generated Data Associated with Analytical Testing," 

Data Integrity

Sponsors should consider best practices for maintaining data generated during sample analysis and instrument maintenance.

Data Integrity Considerations for Vendor-Generated Data Associated with Analytical Testing

In biopharmaceutical products, residual host cell proteins (HCP) are inevitable impurities.

Viral vector-based gene therapy products, however, present additional HCP control challenges, especially those intended for severe indications and placed on an accelerated development pathway. Time-to-market pressures may conflict with the timelines required to develop a product-specific immunoassay.

HCP content is a critical quality attribute highly relevant to the safety of a gene therapy product. The authors present a holistic approach to ensure that the analytical methods used in process development and quality control are suitable for their intended use by providing accurate results.

The points that should be considered for a risk mitigation strategy are presented, including a discussion on the use of generic immunoassay kits versus project-specific assays.

Olaf Stamm, PhD, is scientific advisor, biologics testing; Andrew Hanneman, PhD, is scientific advisor, biologics testing; Art Cansizoglu, PhD, is senior scientist, and Thorsten Strahl is supervisor protein and scientific officer, all with Charles River.

When referring to this article, please cite it as O. Stamm, et. al., “Detecting Residual HCPs Demands a Holistic Approach," 

Gene therapy products present a unique set of challenges for the control of host cell protein impurities.

Detecting Residual HCPs Demands a Holistic Approach

Biopharmaceutical products, the demand for which has grown significantly over the past decade, are synthesized by living cells. During the purification process, the substrates for growth, host cell components, and product variants must be removed. These impurities can be classified into three categories: product-related impurities (variants that differ from the desired product), process-related impurities (materials added to the process and cellular components), and contaminants (e.g., microorganisms).

Biopharmaceutical proteins are produced in cellular expression systems using a host cell organism. Impurities in such a biotherapeutic product are proteins derived from the proteome of the host cell. Removing host cell proteins (HCPs) from biologic products is vital for protecting drug efficacy, stability, and safety, but low-level residual HCPs may remain after purification. Detecting and quantifying these residual impurities is therefore essential for biopharmaceutical manufacturers.

Although the ‘gold standard’ technique for HCP analysis, immunoassays have long lead times and can be expensive to set up. Mass spectrometry (MS) is now recognized as an ideal complementary method to immunoassays, with faster set-up times and the ability to quantify and identify individual HCPs, reliably and accurately.

Stuart Pengelley is the senior scientist, Biopharma Application Development for Bruker Daltonics.

When referring to this article, please cite it as S. Pengelley, “Increasing the Depth and Reliability of HCP Analysis Using TIMS-MS,” 

Sophisticated analytical technologies are complementing traditional approaches in the identification of residual process-related impurities of biotherapeutics.

Increasing the Depth and Reliability of HCP Analysis Using TIMS-MS

Over the past two decades, the biopharmaceutical industry, along with the associated regulatory authorities and analytical instrument suppliers, have progressed toward clearer identification of the attributes that are critical for ensuring the quality of biopharmaceuticals and how to measure them efficiently. 

The need to understand and predict these molecules’ behavior drives a requirement for new informational insights. This article puts the spotlight on infrared spectroscopy and recent innovations, including the introduction of Microfluidic Modulation Spectroscopy.

Holly Lombardo*, HLombardo@redshiftbio.com, is product manager, and Matthew McGann is marketing manager; both are at RedShiftBio.

*To whom all correspondence should be addressed.

When referring to this article, please cite it as H. Lombardo and M. McGann, “Improving IR Spectroscopy as a Tool for Biopharmaceutical Analysis," 

Microfluidic Modulation Spectroscopy is a recent innovation in infrared spectroscopy techniques that improves elucidation of secondary protein structure.

Improving IR Spectroscopy as a Tool for Biopharmaceutical Analysis

While the importance of cleaning procedures in bio/pharmaceutical facilities are well-known, recent regulatory citations suggest that pharmaceutical manufacturers and contract manufacturing and development organizations (CDMOs) may take cleaning and cleaning validation for granted. Multiproduct facilities, and particularly biopharmaceutical facilities, pose several cleaning validation challenges.

Risk-based standards for cleaning validation, established in recent years, have established a more scientific basis for cleaning practices. Taking cleaning and sanitization validation programs for granted, however, puts facilities and people at risk and increases the likelihood of costly noncompliance.

Agnes Shanley is former senior editor to 

When referring to this article, please cite it as A. Shanley, “Prioritizing Cleaning Validation," 

As recent COVID-19 vaccine facility citations make clear, failure to meet cleaning and sanitization requirements puts patients, facilities, and operators at risk. 