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It’s important to put heavy emphasis on analytical chemistry in Active Pharmaceutical Ingredient (API) manufacturing – why? There’s a simple,straightforward answer: if you can’t measure it and assure the integrity of your data, you can’t monitor and/or optimize the process.

A manufacturing process requires accurate sample testing every step of the way. As we have always stressed, it begins with assessment of the raw materials.  An API is only as valuable as its purity.  But there’s more reason to measure and then measure some more: the FDA and other regulatory agencies will look closely at how impurities were assessed while the API was being developed. They will ask about controls.

Ah yes, impurities. Characterizing and controlling them in APIs under development can present four significant challenges to manufacturing for several reasons:

  1. Impurities can arise naturally within the source material.
  2. Impurities can arise as part of a product’s synthesis.
  3. Impurities can occur inadvertently during processing and manufacturing.
  4. Impurities can form during the shelf life of a product, and the process or the packaging may need to be re-engineered to control them.

This article will focus on the importance of, and methods for, a full evaluation of each of the following:

  • Raw materials
  • Potential synthetic route
  • Reagents
  • In-process control (IPC) samples
  • Finished product
  • Stability study samples

Are your specifications scientifically sound?

Identifying, quantifying and diligently monitoring each of the materials and its impurities is key to successful manufacturing. Only step-by-step sample testing can assure impurities are within an acceptable range. The process for every step must have a set of well-defined and meaningful, scientifically sound specifications that can be supported with well thought-out methods that are tailored to the API’s purpose. 

As well, each method must be phase appropriate, validated and be user-friendly.

What is a cookie cutter approach and why it no longer works

A cookie cutter approach for setting specifications for a product, or for developing or validating a method for a material, is no longer a viable approach for successful product manufacturing.

For example, a poorly designed analytical chemistry and process chemistry approach, one which releases the raw materials almost at their face value, followed by running just a couple of chemistry reactions and moving on to manufacturing the final product, is destined for failure.   We refer to this type of process design as the cookie cutter approach (and often the conventional way).

That approach would not work at PCI Synthesis. That’s because my esteemed colleague, Dr. Rajesh Shukla, Vice President of Research and Development, with decades of experience, will say to me, “Hey Mehdi, this impurity needs to be less than 1%, or else the molecule will be hydrolyzed, and we’ll wind up with too much of an unwanted impurity.” Therefore, it is critical to understand where in the process these critical impurities can be controlled and be removed from the process.

In the cookie cutter scenario,a sponsor might not be interested in the concept of having a detailed road map of the process and its impurities due to time and cost, which unfortunately later on it may cause the process to be abandoned, or be re-engineered due to surprises that come from lack of knowledge of the process and /or inadequate analytical method. If, instead, a holistic approach that included careful measurement at every step had been employed, a viable drug candidate might have resulted, not a failed one.

Because of the complexity of today’s molecules and the FDA’s closer scrutiny, you want to avoid moving forward to the next step until you are fairly certain no unwanted impurity that can’t be controlled is lurking.  At the end of the day, the FDA will ask: What controls do you have over raw materials? Over processes? Over the final product?

Questions to ask

Rather than the cookie cutter approach, one has to think way ahead and begin from the end: what needs to be done that will be in line with the FDA’s requirements? What will regulatory bodies ask about this API? Have we been thorough enough and have we measured enough to make our submission solid?

As well, it’s important to notate why the analytical methods and processes developed are appropriate for the product’s intended use.

There are many, many ways to make mistakes along the way. But the good news is that asking the right questions will help avoid many of them. You can  read about the “right first time” questions to ask here.

Insert plenty of checks and balances

Measuring is important, but it stands to reason that in itself that is not enough. There need to be checks and balances in place to support the integrity of the data. Therefore, it is crucial that the right methods, and very specific methods, be developed. These also need to be qualified for the specific sample and be quite precise, and all be supported with 100% data integrity, and an audit trail.

For example, when we develop a process, or we manufacture a product and the assay spec is, say, not less than 98%, it’s incumbent on the analytical team to make sure this number has a high degree of accuracy. That means we know its actual content is 98 %, and not 97%.  Obtaining a high degree of accuracy begins with well trained and qualified staff; well qualified and maintained equipment; well detailed validated method, procedures, documentation, and recording processes; an experienced peer reviewer and final approval reviewer.  

Therefore, in  order to assure data integrity we have to track everything we do by placing checks and balances at each and every step of the analytical task, from checking the staff  training records, sample weighing, sample dilution, setting up the instrument, obtaining data, calculating the results, compiling all data and the results, to checking the overall profile of the results and their meaningfulness.  Do the overall results make sense against the set of specifications?  If so we then have assurance that the assay result is within the specification (not less than 98 %).

It’s no wonder that about a third of the cost of developing a drug is spent in the early stages, in developing and manufacturing the API that will ultimately become a therapeutic agent that is safe and effective for human or veterinary consumption.  It boils down to measuring and checking, again and again, and in a variety of ways, so that every process along the long and convoluted road to an API is optimized.