Optimising analytical chemistry to improve speed to market

Analytical chemistry’s role in drug development is to provide assurance of the quality, safety, and efficacy of new medicines. The effectiveness with which these analytical requirements are carried out can also have a marked impact on the speed that a product is ready for market. In a bid to bring more innovative approaches to their drug development programmes, increasing numbers of developers are turning to contract development and manufacturing organisations (CDMOs) for support in optimising the way that they confront analytical chemistry. Recipharm’s Sr. Director of analytical development, Ramesh Jagadeesan, discusses how CDMOs are supporting customers in bringing innovation to analytical testing and how these advances have a part to play in fast-tracking development programmes. 

Bringing innovation to analytical testing
The outsourcing market for analytical testing has seen considerable growth, with many drug developers now realising the benefits that working with a CDMO can bring in terms of time-efficiency and being able to redirect in-house resource to focus on core activities. Stricter obligations from regulatory agencies that call for more analytical information on medicines and process development are contributing to the need for improved analytical strategies. Below are some of the innovations in analytical chemistry that are helping to advance drug products to market more rapidly and efficiently. 

Automating analytical instrumentation
Manual instrumentation, such as manual injection and integrators, have long analytical runs to be supervised by an analyst, creating an onerous and time-heavy process at each stage of product development. The introduction of systematic approaches is now enabling analytical instrumentation to be automated. This means that while the volume of data being generated may be increasing, the level of resource necessary to achieve this level of data is reducing, creating huge time and cost savings for pharmaceutical companies. For example, the automation of titrimetric analysis is now enabling the analysis of three times as many samples in comparison to a manual approach, while also reviewing raw data and granting approval electronically.

New analytical techniques
Modern analytical techniques are replacing traditional elemental analysis, such as heavy metal tests and limits of arsenic. The increasing use of raman spectroscopy, inductively coupled plasma - Inductively coupled plasma (ICP-OES), ultra-performance liquid chromatography (ULPC), inductively coupled plasma mass spectrometry (ICP-MS) and nuclear magnetic resonance (NMR), are helping to reduce timelines for identification testing. 

Stability testing has also been subject to advancements, including the application of simulating chambers for freeze thaw, photostability testing and chambers for all temperature zones. 

Looking for the unexpected
Effective approaches to analytical testing should consider and estimate both the ‘expected’ and the ‘unexpected’. Traditionally, analyses have been carried out to determine what has been added to formulations, such as assays. Innovation has now brought the ability to estimate unexpected additions in formulations. For example, ICP-OES and ICP-MS make it possible to quantitate elemental impurities (generated through manufacturing vessels and reactants) at parts per billion levels, ultimately ensuring the safety of patients. 

Supporting R&D
Analytical techniques can be used to determine the most compatible excipients to overcome solubility challenges. Drug-excipient compatibility studies using differential scanning calorimetry and thermogravimetric analysis is also providing valuable information to assist with the selection of excipients.

In the development of oral solid dosage forms, automatic dissolution apparatus can provide the in-vitro co-relation regarding successful formulations in comparison to reference listed product. Various detectors, such as refractive index detectors, fluorescence detectors, evaporative light scattering detectors (ELSD) and QDa mass detectors, are also being used during method development to provide assurance of product safety and efficacy. This provides substantial data for regulatory authorities. Additionally, orthogonal analytical techniques are providing better understanding of product composition in terms of compliance towards Q1 (qualitatively) and Q2 (quantitatively).  

Alleviating regulatory challenges
Advanced analytical testing is also helping to optimise the provision of data to demonstrate regulatory compliance. Extractables and leachables (E&L) testing is improving the process of selecting compliant packaging materials and the compatibility testing of materials. The identification and quantification of unknown impurities above the allowed thresholds is a regulatory requirement, and HPLCs coupled with MS-MS detectors and GCs coupled with MS-MS detectors are now providing greater sensitivity in identifying these. New technology is also helping the industry to meet guidelines such as Quality by Design (QbD), elemental impurities and data integrity requirements. All these innovations together are making significant steps forward in reducing regulatory burden and lessening time-to-market, while also contributing enhancements in patient safety.

Testing considerations during drug development and manufacturing
Knowledge of formulation development and manufacturing plays a considerable role in determining analytical and QC testing methods. Several considerations are key to successful method selection. 

First, the chosen method must be stability indicating and sensitive enough to detect and quantitate in line with current regulations. Robustness is a further crucial consideration and any method must be transferrable from a development lab environment to a highly efficient LEAN oriented environment in a QC lab. The development of analytical methods for genotoxic impurities should also be considered as this will be critically reviewed by regulatory agencies. 

Case study: HPLC method
In the below example, a single method has been produced as an alternative to the use of three separate HPLC methods, incorporating the necessary pre-determined reproducibility and resolution. This has enabled time and cost savings to be achieved during each stability run. Table 1 provides an overview of the method results. 


 Table 1 – Method development case study results 

Method validation
Product speed to market is reliant on validation documents being completed to a high standard. The quality of these documents can affect the speed at which queries can be responded to, thereby influencing a product’s timelines. By ensuring the validation protocols are based on current regulatory guidelines and that the execution of method validations is in line with the relevant protocols it is possible to avoid many of the queries from the agencies. 

The implementation of a strict GMP environment, custom field calculation and the capability for electronic data back-ups, can help ensure error-free data is achieved. At the same time, QbD-based method validations can provide a better understanding of the critical parameters of the analytical method and can help to provide trouble-free methods throughout the product life cycle.

Summary
Innovative analytical chemistry plays a vital role in pharmaceutical development, paving the way for better understanding of a drug product and ensuring that development programmes produce precise and reliable data that meets the requirements of regulatory guidelines. New methodologies, state-of-the-art instrumentation and automated systems are all helping to ensure robust testing, while also reducing timelines and providing substantial data in support of regulatory submissions. By incorporating these advanced analytical methods into their programmes, development teams have a huge opportunity to ensure they have the best strategy in place to speed the process of getting their medicines to market. 

Author Biography 
Dr. Ramesh Jagadeesan, Ph.D, Sr. Director, Analytical Development, Recipharm
Ramesh Jagadeesan, Ph.D in Pharmaceutical Analysis is currently heading the Analytical Excellence Centre at Recipharm, Bangalore, India. He has 20 years of experience in analytical research and development. He has authored numerous research publications in the areas of analytical development, controlled release technology and stability studies. He is an expert in stability studies for NCE, ANDA, commercial and clinical stability.