What Does API Manufacturing Entail?

It seems simple enough: a CDMO is chosen to manufacture an API, takes the chemistry right into the manufacturing suite, adjusts the equipment and begins to produce the drug substance in a process no more complicated than making children’s plastic beach shovels. 

Not exactly.  If that were the case, drug substance manufacturing would be faster and far less expensive.  Making a drug substance that is meant to become a therapeutic for humans (or their pets), one that will undergo rigorous Phase 1, Phase 2 and Phase 3 clinical trials to assess safety and efficacy, is a far more cumbersome and time-consuming process than manufacturing widgets.  It’s more akin to building a jet that can safely fly people across the globe, requiring the specialized expertise, quality control and problem-solving acumen inherent in all complex endeavors.


As we previously discussed, API manufacturing begins with selecting the right CDMO for the project.  Once such considerations as the size of the project, equipment, history of regulatory approvals, and profitability have been taken into account and the CDMO is in position, preparation for API manufacturing begins.

What API manufacturing entails

Chemistry can be fickle, and processes that worked well in the R&D lab may not be as compliant when scaled up to larger quantities. There are many hoops to jump through before the API is manufactured and made ready for shipping to a clinical trial site or, in the case of a commercial product, to a fill/finish facility.

These are three of the steps in API manufacturing, each of which has multiple layers, all of which must be documented for regulatory submission.

  1. Technology transfer
    Whether from an R&D lab to the manufacturing suite, or from an outside organization to the CDMO, technology transfer is the first step in API manufacturing.  A proven technology transfer protocol is necessary.  It assures that comprehensive information about the chemistry—including all materials, processes, and analyticals—are passed along to the API manufacturer.

    The project manager must then obtain the raw materials from the same vendor or another trustworthy source in quantities sufficient for the project, depending on whether it is a preclinical, Phase 1, Phase 2, Phase 3 or commercial project. 
  2. Small batches for process optimization
    To check whether processes can scale to larger quantities, small batches will first need to be made.  Like a master chef creating a recipe for a complex signature dish, these small batches will determine which processes and ingredients need to be adjusted, and the best preparation method, temperature, equipment, etc. create the best product most efficiently.  Constant checking as the process develops is also required. 

    This preparation phase is particularly important if the chemistry came from an overseas lab that may have been operating with different equipment and different regulatory requirements.  Ideally, the chemists who developed the process, who are intimately familiar with the chemistry, would travel to the manufacturing plant and work side by side with the API manufacturer to assure processes can be successfully replicated and scaled.  

    Process optimization, which is frequently tweaked during development and manufacturing, is central to API manufacturing.
  3. Scale-up begins in the kilo lab
    Once the familiarization and process optimization phases of drug substance development are completed, Critical Process Parameters (CPPs) and the key variables that will affect the production process are better understood but not yet assured. The next step is the kilo lab.

    Kilo labs, which do not need to be GMP compliant, can carry out any procedure that has been done in a conventional lab. They can be used to prepare materials for a variety of applications, including:
  • Manufacturing APIs for non-clinical use
  • Preparing regulatory starting materials for GMP synthesis
  • Producing key building blocks to support medicinal chemistry programs at larger scale
  • Carrying out runs of modified processes to demonstrate new procedures on a larger scale prior to being used in the more expensive cGMP suites
  • Producing relatively small amounts (1-20 Kg) of non-GMP compounds to address customer needs in a timely manner.

Inside the GMP manufacturing suite

Before transferring processes and substances into cGMP manufacturing, it is wise to review the specifications and assure the processes meet all specifications. This presents an opportunity for the sponsor’s team and the CDMO team to get comfortable working together.

GMP manufacturing cannot begin until the equipment is thoroughly cleaned. We have developed Standard Operating Procedures (SOPs) that validate the equipment is clean. This critical process can take three days in our facility.  We have heard of CMOs taking up to two weeks to prepare the equipment.

When the drug substance is nearing the end of the pre-GMP work, the CDMO should assign a GMP engineer to observe that work in order to facilitate the transfer of the technology to GMP.  Until then, non-GMP work processes are typically written in a notebook. The GMP engineer should write the Master Batch Record so that it’s ready by the time the cleaning and validating of large-scale fixed equipment has been completed.

Preparation to begin GMP manufacturing also involves the QA team, which validates the raw materials, specifications, and purification levels as well as the step-by-step approach to the manufacturing to ensure consistency across batches.  Every document has to be reviewed and approved by the QA team.

The manufacturing suite is staffed 24/7 so that processes can be constantly scrutinized, and no batches are lost.  Sponsors, patients, and the environment also benefit when a watchful CDMO continuously monitors and adjusts the manufacturing process to streamline production processes and assure that critical quality attributes (CQAs) are achieved. The goal is to improve yield.  The more efficient the process, the lower the API cost and the greater the reduction in waste. 

Master Batch Records are the key to success of GMP manufacturing

The Master Batch Record is the single most important part of GMP manufacturing.
You can find a good MBR guide here


Unlike manufacturing children’s beach shovels, you can’t sell a bad API batch to a discount store.  Ultimately the final API needs to work for its intended therapeutic purpose as verified by stringent regulatory review and approval.  Many factors can impact cGMP manufacturing. Best practices require careful, thorough preparation by the most qualified CDMO, one that also continuously tweaks processes during manufacturing to optimize yield and minimize costs.