October 30, 1935 went down in aviation history as a day the world would never forget. Boeing was set to launch the Model 299, also known as the Boeing B-17 Flying Fortress, the most sophisticated airplane of its time. Yet, soon after take-off, the plane crashed, killing two people on board. An investigation found the airplane to be in perfect condition, but the cause of the crash was most likely that the flight crew had simply forgotten to release the flight control gust locks. After the crash, Boeing made the checklist an unwavering standard operating procedure, a practice which is still in use today by pilots, as well as flight attendants, maintenance specialists and all others involved with the safety of aircraft and its travelers.
This tragic incident proves the critical role of the checklist not only in aviation, but also in Active Pharmaceutical Ingredient (API) manufacturing, where quality and safety is paramount. Here at SEQENS North America, checklists are a core part of our standard operating procedures in our warehouse, manufacturing plant and Quality Control (QC) lab. They help us not only ensure that no aspect of safety or quality is overlooked, but they also give us a paper-trail of compliance to our own internally specified requirements.
In addition to our own quality control, checklists provide us with documentation for customer or Food & Drug Administration (FDA) audits and help to make sure that last-minute fire drills aren’t needed, which can consume valuable time away from production operations.
While neither the FDA, nor Good Manufacturing Practice (GMP) guidelines, require the use of checklists, the FDA does use them when conducting their own audits of facilities. Some of its checklist procedures include the following:
- The checklist is to be used with a notebook into which detailed entries can be made during the audit.
- At least three production batches should be selected for thorough analysis to include: (a) traceability of all components or materials used in the subject batches, (b) documentation of raw material or component, in-process, and finished goods testing for the subject product batches, (c) warehousing and distribution records as they would relate to a possible recall.
- Responses entered on the checklist should be consistent. “X” is recommended for “NO”; a checkmark for “YES”; “n/a” for not applicable to questions that do not apply.
- The notebook used should be a laboratory-type notebook with bound pages.
The checklist holds a key place in the FDA auditing process, as it does in Contract Development and Manufacturing Organization (CDMO) facilities, and it’s interesting to see that, in an online world, it works most efficiently when it’s pretty basic – requiring pen and paper.
Yet, the checklists for specific areas of API manufacturing can be much more complex and specific. They include itemized activities that must be performed and checked off daily, weekly, monthly and yearly. Typically, supervisors are responsible for signing off on checklists, but they are the ultimate responsibility of the QC team. So what exactly does a checklist look like for specific operations? Here are three samples, below:
The warehouse of an API manufacturing plant is a complex place with many moving parts. It can be filled with racks of cylinders, and other types of containers specially designed for chemicals. Workers are often using forklifts, or wearing various forms of protective equipment, and different classes of chemicals must be kept separate – flammables need to be stored in a different zone than oxidizers, corrosives, and other chemicals. And, flammable chemicals need to have a designated room that contains a sprinkler system and wide aisles.
In addition to safety of chemicals, floors must be clean, temperature and humidity must be controlled and the site must be designed to ensure waste streams are contained in case of an accident. The checklist would ensure that maintenance and management is regularly performed on all of these items to maintain quality standards, as well as safety.
The Manufacturing Plant
it’s essential that the operation of critical utilities in the manufacturing plant are monitored regularly to ensure reliability of the process equipment, and ultimately the safety and efficacy of the drugs that are developed.
This is addressed through preventive maintenance, a system of procedures and series of tests performed on production equipment to ensure it runs reliably during the manufacturing process. The checklist would encompass all of these procedures, and ensure that utilities, including Electric Power, purified water systems and thermal energy utilities are properly maintained. It also would ensure that regular cleaning of equipment takes place, safety systems are online, and that all vessels, dryers, and environmental control systems are clean and properly functioning.
The Quality Control Lab
The QC lab is designed to detect, reduce, and correct deficiencies in molecules developed. A key requirement is to ensure that analytical equipment is properly calibrated regularly. Stability chambers must be checked to make sure they are operating properly and that the right temperature, humidity and other environmental factors are being properly addressed. The QC lab at SEQENS North America is a fully compliance GMP suite, so it’s important that it adheres to the standards of cleanliness, orderliness and that equipment is operating at optimal levels each day.
The checklist is of critical importance in the QC lab where critical stability testing is performed to ensure the safety and efficacy of chemicals produced.
Checklists can seem like the most basic of operating procedures, used in much the same way that they have for decades, but their importance cannot be under-estimated. In complex industries with lots of moving parts, like API manufacturing, they provide that re-assurance that every aspect of quality assurance is being met. As Boeing learned the hard way, not following them can be disastrous.
For more information on standard operating procedures, check out: 4 Questions to Ask Your CMO about Standard Operating Procedures; Addressing Quality From All Angles in API Manufacturing, or This API Method Development Checklist Helps Avoid Common Mistakes.
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