There is no manual for achieving best practices in API manufacturing. It has taken us decades of experience and a commitment to constant optimization of every process to drill down to the six essential, common issues it behooves us to pay most attention to in API manufacturing.
Before we get to best practices, we need to know what it is that CMOs intend to achieve for their sponsors. A CMO’s overall goal is to efficiently manufacture high quality APIs at a reasonable cost of goods. In order to do that, the CDMO should:
- Be capable of developing robust processes that achieve critical quality attributes (CQAs).
- Have process controls in place that reduce impurities to acceptable levels in line with ICH’s quality guidelines.
- Have process controls in place that can achieve product consistency controlling for such properties as particle size and moisture content.
- Have a reliable supply chain capable of ensuring long-term and timely delivery of high-quality raw materials.
- Have the equipment necessary to seamlessly transition from lab to commercial manufacturing.
- Continuously focus on process improvements that streamline production and improve yield.
- Have strong project managers, who are an essential—and often overlooked factor—throughout the API development and manufacturing processes.
- Be focused on speed to market.
- Be able to handle and properly dispose of hazardous waste, particularly at commercial scale manufacturing.
- Have received numerous and varied industry awards as validation of the CMO’s expertise, and productivity.
The 6 best practices in API manufacturing
Having chosen a CDMO with the above attributes, most sophisticated sponsors, like
many of us who have been in the New Chemical Entity (NCE) business for a long time, know that one misstep in the process can cascade into weeks of extra work trying to rectify an error, be it a poor choice of raw materials or failure to notate early experiments that didn’t work.
Having built a stellar scientific staff, expertise, experience, and equipment for optimal API manufacturing, we at Seqens North America have distilled the myriad components of the API manufacturing process to the following key internal procedures that are essential for eliminating or mitigating costly errors.
- Raw materials
Be relentless in acquiring and assuring the availability and quality of raw materials. Push early on and quickly for the Bill of Materials. If raw materials have a long lead time or must be custom manufactured, monitor outside vendors closely. Stay in contact with the suppliers to make sure the materials are available and delivered on time, and in sufficient quantities to produce additional material should clinical trials proceed from early to late phases and commercialization.
- Train 3rd shift staff in analytical methods and in all process methods
In order to file a substance for commercialization with the FDA, a manufacturer must include a full description of the manufacturing process, including the analytical procedures that prove the manufactured product meets prescribed standards. Any errors results will cause costly delays in manufacturing—and in regulatory approvals. Therefore, even third shift analysts need to be trained so they are capable of troubleshooting.
Also be alert to analytical errors being masked as equipment failure. If batches are stalled, it may be an analytical issue. An analyst who is not fully trained and in charge of a night shift may be the cause of delays due to lack of knowledge of systems. Make sure the in-process methods are all set, ready to go, and that analysts can solve any problems that arise any time of the day or night.
- Keep manufacturing plant equipment in good repair
Not only is it necessary to have a variety of equipment to accommodate diverse projects and quantities of material, but it must be in good repair. That requires a robust preventive maintenance schedule that allows the plant to be up and running with an absolute minimum of down time. When equipment is upgraded, as for example adding a new agitator, standard operating procedures (SOPs) for the equipment need to be followed, and staff trained, to make sure no delays will result.
As well, any new, specialized equipment must have its installation qualifications completed before use.
- Operator training and expansive batch records
This is so critically important to avoiding plant delays that it bears repeating. With a 24/7 operation, we don’t know which shift will be responsible for an operation. Therefore, everyone on staff must be thoroughly trained in all processes. Additionally, to minimize errors and mistakes, put a lot of time into batch records. Ours are very long and expansive so that operators have all the information they need when they need it. Such detailed procedures help minimize process problems in the plant.
There is one exception: when a scale-up impurity rears its head. Some of our biggest process challenges result from such scaleup impurities, which do occur on occasion. Many times there’s not much you can do other than stop, go back to the lab and tweak the procedure mid-stream before moving ahead.
- When excessive loss of material occurs, find the cause
We have to anticipate that after certain processes, such as filtration, the amount of material produced will be lower. But if 50 kg of material is reduced to 25 kg, it behooves us to determine what happened to the rest of it and whether any of it can be recovered. For that we turn to our engineering experts, who have methodology in place to do investigations to determine such things as what caused the material to be in filtrates. They can decide if a mass balance on the equipment is in order, and if so, whether it is early enough in development process for the batch to be salvageable without it triggering regulatory questions.
- Plan ahead for testing pre-shipping
Once a product is made and the material placed in drums, releasing it as quickly as possible is desirable. However, the product is not ready for shipping until it undergoes testing and the test results reviewed by the QA team. Some of the longest delays can occur as a result of outside testing. After months of work, the inability to ship because of a delayed test is like climbing to within 18 inches of the summit of Mount Everest and not being able to reach the top. It’s extremely frustrating, but until you have verification that the material is within specifications, the material can’t be shipped.
To reach the acme—i.e. ship the material as quickly as possible—plan ahead and incorporate testing such as x-ray diffraction, NMR, metal analysis or other specialized tests into batch records. Also make sure you have batches dedicated for testing ready to send to outside labs.
At the end of the day, sponsors come to a CMO to synthesize high quality material that meets regulatory specifications and deliver that material for its intended purpose. It is critically important not only that material is manufactured, but manufactured properly in accordance with sound scientific principles. Following these six best practices helps assure drug substances are manufactured efficiently and delivered on time and within budget.