Analytical Method Development in API Manufacturing: The Key to Successful Commercialization

Five Questions to Ask to Ensure You Pick the Right CDMO for the Job

Given the high costs, regulatory hurdles and competitive marketplace when bringing new drugs to market, drug sponsors are increasingly focused on accelerating development cycles, while ensuring the most effective and sure route to commercialization.

Because of this, analytical method development holds the key, helping to create the optimum environment and conditions to create new molecules and prove that that methods are acceptable  for their intended purpose. In essence, method development ensures that laboratory resources are optimized, and that the methods meet the objectives of each stage of drug development.

Most APIs require a method for their assay, purity profile and residual solvent and each process also requires a method for release of its raw materials and in-process control (IPC) samples.

Creating an analytical method development process

Developing a specific analytical method development process requires key steps, beginning with determining thetype of method being developed. There’s a difference so it’s important to determine whether the method being developed is for assay or purity, for residual solvent or particle size, etc.  You also need to determine the nature of the compound (active pharmaceutical ingredient, excipient, etc.), and select the technique. For example, you must determine if it will be high performance liquid chromatography (HPLC) or gas chromatography (GC), and assess and evaluate the physio-characteristics of the analytes, such as:

  • Solubility
  • Reactivity
  • pH
  • Stability in media
  • Sensitivity to air, heat, humidity, and light

It’s also important to understand the polarity of the molecule and its impurities,  not only in the process samples, but also in final product and for stability testing.

Optimizing the method and the system

Once the analytical method has been developed, then the method is optimized. Each analytical method has to be suitable for its intended use and phase.

More specifically, below are some of the key factors needing consideration during method development:

  • Separation: The biggest issue while developing any purity method. The main two factors in the separation of compounds are selection of column (C8, C18, etc.) and mobile phase.
  • Sensitivity: is the method sensitive enough to detect lower level of impurities (i.e. 0.05%)?
  • Selection of detector (UV, RID, FID, etc.).
  • Selection of mobile phase (organic, aqueous, etc.). Optimized the strength of mobile phase.
  • Determine if the molecule has a genotoxic compound.

Validating the analytical method

Once a method is develop and optimized then the most important task is validation of the analytical method, looking at the molecule comprehensively. Understanding and implementing such a method is key to small molecule and API success. It’s important to determine without a shadow of a doubt that the method is scientifically sound and follows current Good Manufacturing Processes (cGMP). The goal is to have a successful, robust method that works day in and day out.


Selecting the right CDMO for the job

Analytical method development is a fine science and just may be the most critical step in API manufacturing. Not only does it require senior-level expertise, but the FDA is always raising the bar on regulatory requirements, and strong analytical capabilities is a key differentiator. Given this, it’s important to carefully consider the best CDMO to carry it out. Below are five questions to ask before selecting one:

  1. Does the analytical department have expertise and know-how for testing and releasing cGMP materials?
  2. Does the analytical department fully understand the latest regulatory guidelines. If not, this can cause delays or the need to redevelop methods or cause costly revalidation.
  3. Can the analytical department advise you with methods suitable for the intended purpose?
  4. Does the analytical team develop methods for process R&D? Scientists need an understanding of how a method should be developed and to how to make it stability indicating.
  5. Is the CDMO a one-stop-shop for analytics, well-equipped and staffed to handle all stages? Too much outsourcing to separate organizations can impact the cost as well as project timelines. 

Analytical method development is a skill honed by years of experience, lessons learned and strategic thinking backed by sound scientific processes. Yet, carefully developed methods can reduce overall turnaround times from preclinical to commercial release and ensure a smoother pathway from API production to finished drug product. As a fine-tuned science, it pays to select the right CDMO for the job.