After 5 years of the draft document under consideration, the USFDA released the final guidance on Bioanalytical Methods and Validations (BMV) on 24 May 2018. Ever since the release, CROs, sponsors and researchers have been on their toes preparing gap analysis documents to check alignment of their current practices with the latest recommendations. The guidelines are pivotal to laboratories who are new to large molecules and lack frequent interaction with regulators. While the USFDA terms this guidance to be a current thinking and recommendation, Bioanalytical laboratories across the globe are busy incorporating them into studies, in their effort to bring out safe therapeutics.

What does the guidance hold for Ligand Binding Assay (LBA) Laboratories?

Compared to the 2001 or the 2013 draft guidance, the 2018 version is much more descriptive and takes into consideration the complex nature of immunoassays in support of biologics development. The finer points of the new guidance are as follows:

The USFDA’s Bioanalytical Method Validation Guidance for Industry 2018What does it hold for Ligand Binding Assay laboratories?

By Dr. Kakali Dhar and Dr. Aparna Kasinath Regulated Large Molecule Bioanalytical Laboratory, Syngene International Limited, Bangalore, India

Summary of tables for

Validation and Bioanalytical study reports

Tabular representation of requirements for small molecules

and large molecules validation

Validation and sample analysis for regulated

Pharmacokinetic assays

Ambivalent aspects of LBA

method development

addressed

2018 Guidance

Best practices for

Biomarkers and repurposed

Diagnostic Kit assays

Bridging data from multiple

Bioanalytical techniques as well as dried blood spot

analysis

Putting Science to Work

While there are helpful clarifications on typical quality assurance questions like the COA not being available for USP reference standards, extent of evaluation of critical reagent lot-to-lot changes under partial validation have been added.

Few other noteworthy parts of the revised guideline, for conduct of validation parameters, are as follows-

ULOQ and LLOQ concentrations

Standard and quality control preparations

Drift Evaluation

Accuracy and Precision evaluation

Preparation of standard curve and quality controls in the same matrix

Selectivity and Specificity

Stability Assessment

Cross Validation

Studies designed with repeated measures from individual subjects

Incurred Sample Reanalysis (ISR)

25% bias criterion

Use of same stock solutions allowed (case to case basis based on assay performance)

Assessment of drift of a method has been included

Evaluation of fresh standards and quality controls in method validation accuracy and precision runs

An allowance for justification for use of surrogate matrix for studies supporting rare diseases has been given

Includes hemolyzed samples, lipemic samples, or samples from special populations. Selectivity evaluation at HQC and LLOQ levels have been recommended

Requires use of freshly prepared standard curve and quality controls. However, frozen standard curves and quality controls may be used with adequate justification

Use of pooled incurred samples; when insufficient volume of study sample exists

All study samples from one subject to be analyzed in a single run to minimize variability

Recommended for all pivotal studies; regardless of the matrix- example ISR requirement for all in vivo human BE studies in ANDAs or pivotal PK, PD and Biomarker studies. For non-clinical studies this consideration has been per method per species

Practice 2018 Guidance

About the Authors

Ph.D. Senior Principal Scientist and Functional Head, Regulated Large Molecule Bioanalytical Laboratory Kakali is proficiently trained in GLP, GCP, GCLP, ICH, EMEA, FDA regulations and laboratory SOPs.She is an authority on writing, reviewing and approval of SOPs, test methods, validation protocols and validation reports, sample analysis protocol and sample analysis reports.

Dr. Kakali Dhar

Ph.D. Head and GLP Test Facility Management, Regulated Large Molecule Bioanalytical LaboratoryAparna is responsible for laboratory operations, technical data conformance to global expectations, GLP compliant processes including data integrity, 21 CFR Part 11 adherence of data acquisition software, skill enhancement trainings, resourcing & staffing, timely execution of all contracted programs and client relationships.

Dr. Aparna Kasinath

In conclusion, while there are a few recommendations that are open to interpretation and few that are a revision from current LBA practices, the overall 2018 USFDA guidance document is comprehensive for LBA requirements.

The industry in its endeavor to make safe medicines is striving to implement these requirements to the best of their abilities. Syngene, which adheres to industry leading best practices has already taken efforts to align its practices with the latest guidance to the satisfaction of its clients and regulators. While on one hand the guidance remains a milestone achievement, on the other it has triggered further discussion and a healthy debate among the bioanalytical community.

About SyngeneSyngene International Limited, is one of the largest and fastest growing Contract Research Organizations in the world. The Company provides integrated discovery and development services across multiple technology platforms including small molecules, large molecules, Antibody-Drug Conjugates and Oligonucleotides under an environment of high regulatory compliance and safety. Syngene has served over 300 clients in the pharma, biotechnology, nutrition, animal health, consumer goods and specialty chemicals industries, including 8 of the top 10 global pharma companies.

For more details or to see how Syngene can support your innovation, visit www.syngeneintl.com or contact us at bdc@syngeneintl.com