When Raw Materials Don’t Meet Specs


The very essence of any new drug substance being developed is the materials that comprise it.  So, it’s no wonder that sourcing the highest quality raw materials whenever possible, is a critical concern of Contract Manufacturing Organizations (CMOs) everywhere.

This article provides an overview of how important specs are for determining whether or not you can use raw materials. It also provides some best practices.

What can go wrong with raw materials?

Yet even with the most diligent sourcing and closest supplier alliances, there are many things that can go wrong. You could find foreign matter in the raw materials – in fact, we once found blue ceramic pieces in some raw material, (that we were able to eliminate) yet not before it did some major damage to our reactors.

What happens more often, however, is that the raw materials contain a level of impurities that exceeds the amounts set out in our protocols, or specifications. This is where Good Manufacturing Practices (GMP) come into play.  Here at PCI Synthesis, our GMP guidelines dictate how many samples we are going to take  and what our specifications will be for each one – and we cannot use raw materials that exceed those thresholds.

So what happens when you find raw materials out of spec?

Once we determine the level of impurities in certain raw materials, we need to make a decision to justify if we can use it or not and if it is within GMP guidelines.  The questions that we ask as part of this process are:

  • How close is the material to the final product?
  • What is the issue?
  • What is the corrective action?
  • How can it impact the final product?

Sometimes these questions are out of hands.  For example, if we determine that a sample does not meet the specifications set forth in our DMF for a raw material, then it does not pass inspection – even if we are confident that the impurity-level would not impact in any way the final product.

For example, one of the raw materials that we use is extracted from a root harvested in China. The impurity profile is always changing depending on variables such as how much rain it gets, etc.  We had a batch come in with its profile slightly off, but we took some of it and made a small batch.  We determined that its variable impurities would have no impact on the final product, yet in order to avoid a Form 483, which is a violation for out-of-spec materials, we still could not use it. A good lesson here is that there’s no use in second-guessing agreed-upon specifications, regardless of how confident you might be in the end-result.

How can you ensure the highest quality raw materials?

While by their very nature, raw materials will have some impurity levels, how can a CMO make sure they source the highest quality and prevent problems? Below are key ways:

Properly vet your suppliers.  In an earlier blog, we shared tips on properly vetting suppliers. This may include having each supplier complete a self-evaluation questionnaire, perform on-site evaluations and quality audits.  It also is a good thing to speak to other customers of the supplier and hear about their experiences first-hand.

Ensure redundancy. It pays to have a good back-up plan when working with suppliers of raw materials. At PCI Synthesis we work with two different types of suppliers:  ones that make commodity raw materials that may be common; and those that are made specifically for us, and not sold to other manufacturers.

Establish strong relationships.  Once we find a good supplier, we work to make it a long-lasting one. Providing mutual respect, paying on-time and communicating regularly about any issues that crop up can go a long way to making the process a good one for both parties.

Don’t be penny-wise and pound foolish.  While it’s always good to shop around and source the best raw materials at the best prices, don’t be swayed by price alone. Cutting corners can end up being much costlier in the long run, when products need to be disposed of or when it means failed inspections or long delays.

So where do bad raw materials go?

When there are problems with raw materials, because of impurities or foreign matter or for other reasons, there really are two routes to recouping as much of the cost of the raw materials as possible.

One option is to simply send it back and ask for a refund, but that’s not as easy as it sounds.  There are many regulations around receiving raw materials – especially if the product was sourced from foreign countries, such as India or China. There are strict importing regulations in some of these countries that make it much more difficult for us, or anyone in the U.S. to send it back to them, than it was for them to ship it to the U.S.

The more common scenario is for the supplier to refund costs, without taking back the raw materials.  It’s then up to the CMO to destroy the raw materials so they are not able to be used, whatever the reason.

Raw materials are really the lifeblood of the Active Pharmaceutical Ingredient (API) manufacturing  process.  Ensuring that those materials are of the highest quality and free of as many impurities as possible is key to successful product commercialization and safety.