Analytical testing plays a key role in the pharma and biopharmaceutical industry, providing quantitative and qualitative evidence that a treatment is safe for patient use. Interwoven throughout the development and manufacturing pipeline, analytics provide insight into product safety, potency, efficacy, and quality. In this highly regulated industry, these attributes are vital to successfully bringing a therapeutic to market. Harnessed for continuous monitoring, analytics confirm that a compound meets the critical quality attributes as defined by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH).

The analytic technique chosen can differ depending on the molecule at hand and the stage within the development and manufacturing process. It is important to identify and implement the best possible analytic technique for your product. In addition to producing high-quality and high-yield products, strategically placed analytics also help to streamline the process by highlighting opportunities for optimization.

The information gained, including molecule characteristics, stability, and response to environmental and chemical modifications, must be collated, and included in the investigational new drug (IND) filing application.

This article explores how analytics can be leveraged throughout development and manufacture, highlighting a strategy for analytical success.

The right technique at the right time

Utilizing different analytical methods ensures product quality throughout development, manufacturing, and all the way through to fill. However, it is important to identify techniques that provide the specific information required, securing its use at the best time within production for optimum results. Failure to perform analytics at the correct step could result in repeating analytics, increasing production costs and timelines. Some key analytical steps include:

Characterization
Analytics must first be used to fully characterize and understand the active pharmaceutical ingredient (API) that will form the basis of the final drug product. This includes determining critical compound attributes, such as the structure and activity, which can be applied to determine the mechanism of action and predict how the drug will behave within the body. This should be done before any new components are added; it can help identify which excipients can provide additional support to improve compound characteristics such as solubility.

Excipient compatibility
Selecting suitable excipients for product formulation ensures the active compound has the right bioavailability, solubility, release, and other key attributes. Incorporated at the pre-formulation stage, compatibility testing measures the drug substance’s response to different product formulations, including positive or negative impacts on active ingredient functionality, stability, and bioavailability.

In addition to its necessity as part of preformulation testing, the information generated during this testing stage is also required by regulatory agencies, such as the U.S. Food and Drug Administration (FDA), as part of the drug approval process.

Release testing
Determining the final drug formulation release timings and distribution ensures adequate dosage reaches the target site. These can be modified by changing the chosen excipients or method of delivery, such as coatings or capsules. The formulation should be adjusted to reach regulatory requirements for product safety and efficacy standards.

Stability studies
Ensuring a product is stable throughout its lifecycle is essential, with loss of functionality or degradation over time posing a risk to patients. Stability testing can be divided into the following studies:

• Long-term: Testing the drug for degradation at intervals over an extended period.
• Intermediate: Moderately increasing the rate of degradation by altering exposure levels, providing a picture of stability between long-term and accelerated conditions.
• Accelerated: Pharmaceuticals held under exaggerated stress conditions over a timeframe and monitored at intervals to accelerate the rate of decomposition.
• Freeze-thaw: Impact of freezing and then melting on product stability.

Specialized chambers and equipment are used throughout stability analyses to simulate several environmental conditions—such as temperature, humidity, and lighting conditions—while monitoring the impact on the drug product over time. For example, when exposed to different levels of light, the effect on the product is monitored to see at what exposure the product begins to degrade. These tests are key to determining the storage conditions to maintain product stability, which can differ depending on the product. In addition to establishing product lifetime, the data is also essential for determining stability conditions for storage and defining the expiration date, which is placed on drug product packaging.

Purity
Specific techniques, such as high-performance liquid chromatography (HPLC), can be woven throughout development and manufacture to test the purity of the product. Identifying contaminants and impurities after a given step is especially vital throughout downstream processing, where the removal of impurities leaves the active drug substance.

These steps illustrate the importance of analytics and how they need to be used collaboratively throughout production to develop safe and effective treatments for patients.

Advances in analytics meet changing regulations

There has been an increasing focus on ensuring regulatory compliance throughout drug development and manufacture. Advancements in technology, and subsequently equipment, have aided this and opened new possibilities for more in-depth testing during drug development. When using equipment such as mass spectrometry (MS), high-resolution imaging and others to support drug development programs, there is a growing demand for specialized, comprehensive, and innovative analytical development. This changing landscape sets the standard for the customized development of analytics.

Problems can arise during analytical method development and implementation. This can include challenges with sample preparation, reproducibility, and tech transfer, such as changes in laboratory environment or equipment. Failure to overcome these challenges can hinder analytic results, leading to illegible chromatographic profiles, shifts in retention time and poor signal-to-noise ratio. By following a robust strategy for designing a fit-for-purpose analytical method, these problems can be resolved. In addition, potential hazards are identified early, helping to mitigate risk to ensure a pharmaceutical product meets safety standards.

A six-step strategy for analytical success

There are several different analytical techniques that provide varied information regarding a particular molecule or formulation. Not only must analytics be carefully selected, but they must also be reliable and reproducible to ensure product continuity and purity from batch to batch. This takes robust method development and optimization, often tailored to a specific product. The following strategy should be adopted to successfully select and weave these methods into production:

1.  Literature search: Investigate published analytical works to identify tests that provide the required information about a drug substance or product.
2.  Characterizing the compound: Using standard techniques, fully characterize a molecule, including chemical structure, pKa, solubility and formulation; this data can be used to determine compatible analytic techniques, for example, for an ultraviolet (UV)-detector-based analytic system, the drug compound must be UV active.
3.  Selecting the analytical technique: Choose an appropriate analytical method for the characteristic or functional information required, such as liquid chromatography (HPLC/UPLC with UV/RI/ELSD) or MS-based techniques (LC-MS, ICP-MS).
4.  Defining the analytical target profile: Determine method parameters such as the system suitability criteria (such as sensitivity, selectivity, and precision), resolution between the peaks, interference limits, target run time, limit of detection and limit of quantification, robustness, and reproducibility.
5.  Identifying the critical method parameters: Perform a risk assessment on the instrument, material, methods, measurements, and laboratory environment and pinpoint any potential opportunities for human error. These parameters have a significant impact on the performance, accuracy and reliability of the method and must be altered and optimized to better suit the molecule at hand and ensure the validity of analytical results.
6.  Method verification and finalization: Validate the optimized analytics through specificity (interference check), solution stability, accuracy, method precision and robustness testing. This is key to confirming reliability and reproducibility and ensuring the method adheres to regulations.

By following these six steps, a reliable, reproducible, and customized technique fostering high-quality batch-to-batch production can be formed—crucial to ensuring a product is safe for patient use.

Validation for regulatory compliance

Forming part of the six steps to success and according to regulations, analytical methods used throughout drug manufacture must be validated, taking into account regulatory guidelines for method performance, reliability and consistency. This is an important measure for ensuring use meets regulatory guidelines (such as the FDA, ICH, USP, and others), easing the IND filing process.

After validation, analytical methods are suitable for quality control release testing and eventually can be used for the intended purpose. Any changes made to improve a test require revalidation to ensure they do not negatively impact product quality.

Analytics are the key to generics

Analytics can also be leveraged to determine generic characteristics and prove product bioequivalence. To maintain market revenue growth, a generics company must secure a continuous flow of high-quality small-molecule products at speed to take to market. For this, it is essential to have a thorough understanding of the molecule composition and activity.

Reverse engineering or de-formulation use analytics to break down a drug product or material to determine the identity, quantity, and morphology of its components. Generics tend to be tablets or capsules and contain several excipients that, although not pharmacologically active, play an important role in tailoring and influencing drug performance. After determining the API structure, analytics can also be utilized to identify formulation compositions for generic formulations.

Ensuring speed while doing this is essential as there are a number of generic companies competing for market share.

Analytics are an essential part of drug production

Analytics play an important role in drug development and manufacture to ensure a product meets regulatory requirements. Developing a technique for the product at hand is essential, working to fully characterize and understand the composition, activity, and formulation for desired functionality.

By following the six-step strategy, a method to adequately identify, design and implement analytics that are fit for purpose is clearly set out, resulting in the production of a safe and efficacious drug product to treat patients.

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Ramesh Jagadeesan, Ph.D. in Pharmaceutical Analysis, is currently heading the Analytical Center of Excellence at Recipharm, Bangalore, India. He has 24 years of experience in analytical research and development. He has authored numerous research publications in the areas of analytical development, analytical validation, controlled release technology, and stability studies. He is an expert in stability studies for NCE, ANDA, commercial, and clinical stability.