Today’s market is rapidly adapting to accommodate new drug types and generics, and there is a growing demand for improved quality assurance methods. Drug developers struggle to ensure both analytical accuracy and compliance in the face of evolving regulatory standards, which are often ambiguous and complex. However, simply meeting regulatory compliance standards falls short in most cases, and the traditional "good enough" approach is proving inadequate. Industry leaders recognize that genuine success now requires striving for the highest level of precision possible through the application of robust techniques. Minimizing variability during method development is the secret to achieving robustness. In this article, we introduce a timely and evidence-supported strategy for reducing variability to optimize accuracy, sensitivity, and confidence. Our approach, elucidated through a comprehensive quality control checklist, aims to bolster regulatory compliance and enhance healthcare outcomes.
The Real Cost of Traditional Methods
Drug developers strive to bring safe and effective pharmaceuticals to market, yet navigating the path to clinical success is fraught with bioanalytical challenges. Ensuring both analytical accuracy and compliance amid evolving, ambiguous regulatory standards remains a formidable task. Moreover, merely meeting these standards often fails to instill confidence in a drug’s safety and efficacy.
Despite these challenges, many labs persist in using traditional methods like ELISA, assuming these techniques streamline the regulatory review process because regulatory reviewers are familiar with them. However, these same reviewers actively advocate for high-resolution methods due to the superior data they generate, enabling more confident assessments of a drug's safety and efficacy.
Cost presents another hurdle. Laboratories contend with limited resources and often weigh the perceived value of investing in high-resolution methods against traditional ones deemed "good enough" for compliance. Yet, this cost-benefit analysis overlooks the potential for regulatory delays, increased costs, and compromised drug efficacy associated with less precise methods.
This article underscores the critical importance of precise bioanalytical methods, not just for meeting regulatory criteria but also for providing robust data that facilitates swift regulatory reviews.
Why "Good Enough" Is No Longer Good Enough
In the fast-paced realm of pharmaceutical development, regulatory standards are the cornerstone of drug approval and market acceptance, ensuring the safety and efficacy of new medications. However, today’s regulatory landscape demands more than mere compliance; precision in data demonstrating drug safety and efficacy is increasingly paramount, particularly for novel drugs and bioequivalent formulations. Calibration Curves (CCs) and Quality Controls (QCs) play a pivotal role in achieving the precise data regulators require. These often-overlooked components are essential for validating bioanalytical accuracy and reliability, crucial for successful drug development.
Moreover, simple yet strategic method adjustments can significantly enhance precision. Techniques that strip endogenous molecules, for instance, heighten sensitivity by eliminating background interference. Similarly, methods overcoming physical challenges like residue buildup in chromatographic columns ensure consistent and reliable results. By minimizing variability through such methods, pharmaceutical developers not only meet regulatory standards but also provide robust data that accelerates regulatory approvals and enhances market readiness. The following innovative methods not only meet regulatory demands but also enhance the efficacy and safety assessments critical for clinical success.
Minimizing Variability Triumphs Over Endogenous Complexity
Thromboxane B2 (TXB2) is a critical biomarker for cardiovascular diseases. Accurately differentiating endogenous and exogenous TXB2 in human serum is a formidable challenge. Our lab developed a method using a charcoal matrix to strip endogenous TXB2 from serum before analysis, thereby removing endogenous sources of variability. This method, coupled with liquid chromatography (LC), achieved up to 80% recovery of TXB2. With an accuracy of 97.5- 100.9% and inter-assay precision of ≤5.1%, this method not only met ISR acceptance criteria but provided confidence well over traditional techniques.
Ultra-sensitive methods are Crucial for Proving Bioequivalence
Fluticasone propionate and salmeterol, key components of asthma and COPD medications, require ultra-sensitive measurement due to their minimal systemic absorption. Our challenge was to detect picogram concentrations of these drugs in human plasma. Employing a solid phase extraction method, we achieved sensitivity thresholds of >2.8 picograms for fluticasone and >1.0 picograms for salmeterol. This method successfully demonstrated bioequivalence and provided precise clinical data for review.
Overcoming Physical Limitations
Liraglutide, a large peptide used to treat diabetes and obesity, posed another challenge. Traditional ELISA techniques often yielded false positives, while chromatographic methods suffered from residue buildup. With this knowledge, our team developed a mass spectrometry/mass spectrometry (MS/MS) technique capable of achieving an accuracy of 102.6-104.6% and inter-assay precision of ≤6.7%. This method, approved by EU regulatory officials, overcame previous obstacles to ensuring reliable results.
A Crisis of Faith
Accurate, sensitive, and reliable drug products are crucial milestones in pharmaceutical development today. Yet, one significant hurdle remains: the cost associated with developing in-house methods. Partnering with a contract research organization (CRO) can facilitate access to advanced bioanalytical techniques and expertise, crucial for navigating complex regulatory environments and accelerating market entry.
Unfortunately, many small companies hesitate to outsource because they fear losing control over essential analytical testing processes. Developing bioanalytical methods requires iterative R&D experimentation, data analysis, and optimization. Boutique CROs are adept at navigating this iterative process, employing a discovery-oriented mindset and implementing accumulated cross-study learnings to solve challenges. They not only meet current standards but also anticipate and adapt to future regulatory changes and scientific advancements.
Digital Transformation Spells Success
Fortunately, the contract research landscape is expanding, offering both affordable access to advanced methodologies and the digital means to effect dynamic communication. Although bioanalytical support services are still scarce, they are on the rise, along with methodologies that deliver the scientific rigor that reviewers require.
By adopting precise bioanalytical methods and leveraging outsourcing options effectively, drug developers can simultaneously achieve robust regulatory compliance and improve healthcare outcomes. These strategies are essential for staying competitive in the dynamic pharmaceutical market and meeting the increasing demands for safety, efficacy, and quality assurance.
Quality Control Checklist
By adhering to these guidelines, drug developers can meet existing regulatory standards with confidence and future-proof their studies. This approach ensures the highest level of precision, minimizes variability, and delivers accurate, sensitive, and reliable results:
1. Conditions for a Robust Study
- Address variability in pharmacokinetic (PK) parameters among individuals.
- Consider genetic differences, age, sex, and other factors.
- Ensure sensitivity and accuracy of analytical methods to detect small differences.
- Design studies with appropriate sample sizes, statistical analysis, and relevant PK parameters.
- Evaluate internal method development versus externalization to a proficient CRO.
2. Use Appropriate Spiking Solutions or Stock Solutions
- Verify the accuracy of stock solutions before spiking. The percentage difference should not exceed 5%.
- Verify accuracy post-dilution before matrix spiking.
3. Prepare Comprehensive Calibration Curves
- At least six non-zero standards were prepared by serial dilution.
- For narrow analysis ranges, add additional QCs reflecting relevant concentrations.
4. Implement Reference Solutions
- Reflect the lowest calibration standard concentration for LLOQ.
- Use additional QCs if >50% of Cmax values fall between middle QC (MQC) and lowest QC (LQC).
- Revise the calibration curve if >50% of Cmax values are below LQC.
5. Conduct Replicate Analyses
- Use replicates for experimental design to ensure confidence and QC.
- Two replicates for up to 120 samples; four replicates for >120 samples.
- Reject internal standards with values below 50% or above 150% of the mean.
6. Training and Quality Assurance
- Ensure all staff members are trained to follow established criteria.
- Implement compliance checks by a qualified quality assurance group.
- Support adherence to standards through management oversight.
Reference
- DiMasi, J.A., Grabowski, H.G., & Hansen, R.W. (2014). Innovation in the pharmaceutical industry: New estimates of R&D costs. Journal of Health Economics, 47, 20-33. doi: 10.1016/j.jhealeco.2016.01.012.
Author Details
Shukla Antriksh Pushpakbhai- Team Lead, Sannova Analytical
Shukla Antriksh Pushpakbhai, a Team Lead at Sannova Analytical, started his career as a research scientist and has about two decades of experience in bioanalytical method development and scientific review of study and validation results. Antriksh is a subject matter expert in instruments like LC/MS/MS and HPLCs, performing IQ, OQ, and PQs. He has also trained and mentored various junior scientists, contributing significantly to their professional growth and the success of bioanalytical research projects.
Publication Details
This article appeared in Pharmaceutical Outsourcing:Vol. 25, No.4 Oct/Nov/Dec 2024Pages: 11-13