By the time your drug candidate is ready to be introduced into cGMP manufacturing a significant investment in both time and money has been expended. Manufacturing is like the final act of a big production. All the effort up to this point has been expended to get to this stage. Whether it’s preparing the Active Pharmaceutical Ingredient (API) for a critical clinical trial or for commercial launch, everything has been geared toward making this final step as smooth and successful as possible.
Still, the jump to cGMP manufacturing is never simple or easy. Producing complex molecules within specification the first time in cGMP is fraught with potential peril at every turn. As they say, the devil is in the details and that is particularly true in the manufacturing suite where numerous details need to be managed closely.
At the same time, unexpected challenges will undoubtedly arise. Your CMO needs to be able to manage them in real time so critical timelines can still be met.
Consequently, in evaluating a CMO’s cGMP manufacturing capabilities it’s critical that you examine these seven facets of their operation to ensure that they have these capabilities.
Your CMO should have a standard protocol for ensuring that processes are scalable and ready to go to manufacturing. In the kilo lab, the processes developed are run to determine whether they work on a larger scale prior to being used in the more expensive cGMP suites or scaled up further into a cGMP manufacturing plant.
Why is the kilo lab phase important during process development? Because it can often minimize unpleasant surprises when the process is executed in the cGMP kilo suites or plant for the first time. Going into cGMP directly from the R&D lab is extremely risky and fails more often than not. No one wants to do process development in a cGMP environment. The costs and loss of time can be significant.
The CMO’s team should have both the equipment and the experience to fully execute this step before moving onto cGMP.
Take a tour of your prospective CMO’s cGMP labs and facilities. Remember that they are functioning and working manufacturing facilities. They should be clean and orderly.
Ask for their general cleaning regimen. You want to see what the facility most likely looks like on any given day and not just on the day you decide to tour.
There should be systems in place for pest control, which is very important.
Most equipment should be either in use, being cleaned, or out of service for preventive maintenance.
Operators should be wearing personnel protective equipment suitable for the operation being conducted. Operator uniforms should appear fresh and applicable to the functions being undertaken.
The plant should have a mix of equipment with reactors of different sizes and materials of construction.
They should also have different types of equipment to filter and dry your product.
The plant’s utilities need to reliably deliver a wide range of temperatures and pressures.
This variety of equipment and utilities is important because you want to ensure that whatever process comes out of the development phase of the project, the plant will be able to handle it. Initially, it may be hard to predict what might be needed so having many different options is essential.
Does the facility have a scheduled preventive maintenance program? Ask for it as it should be readily available.
Is the preventive maintenance program being followed to assure that a facility’s equipment uptime is as high as possible? There is nothing worse than being ready to go into cGMP and find that a key piece of equipment or utility is out of service. While no piece of equipment or utility is immune from a periodic breakdown, a good preventive maintenance program keeps the equipment running at an optimum level on an ongoing basis.
Are the facilities personnel properly trained? Training should not only include process specific training to prevent mistakes in manufacturing, but equipment and operational specific training as well. There should be a training matrix (for every employee and job function) and it should all be documented. Mistakes happen, that’s the real world. But just as with preventive maintenance, proper and continuous training programs can eliminate mistakes that can adversely affect your product.
The Master Batch Record (MBR) is the most important part of GMP manufacturing. Cutting corners here is a big mistake. The MBR is the document that describes and details the manufacturing activities for each intermediate and the final API.
The MBR is part of the required documentation for compliance with Good Manufacturing Practices that conform to the ICH’s “Guidance for Industry, Q7 Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients.”
Master batch records must be well written, with clear, concise and accurate language that conveys the technical and procedural information necessary to ensure consistent manufacturing of drug substance that meets all safety, efficacy and quality requirements.
Writing the Master Batch Record truly requires teamwork. If you cut corners or have a sloppy MBR, you will wind up with other, bigger problems. Ask your CMO to give you an example of an MBR they have approved internally. Review it and make sure they are doing things appropriately.
In multi-purpose facilities where there is always the potential for cross contamination, it is critical that extreme caution is taken to clean equipment. Preventing cross contamination, which can be harmful to your product, is essential.
In the production of pharmaceutical ingredients, cleaning the manufacturing equipment not only makes good sense, but it’s also a strictly regulated aspect of drug substance manufacturing, according to Good Manufacturing Practice (GMP) regulations. This regulatory requirement mandates that cleaning procedures and the analytical methods used for analysis of their samples are demonstrated to be effective and repeatable. This is known as validation of cleaning procedures and analytical methods.
The effectiveness of a cleaning procedure is demonstrated by analyzing rinse and swab samples taken from equipment.
Ask about the CMO’s cleaning validations and review them to make sure they are robust, complete, and the protocols are being used on an ongoing basis.
Where does the CMO do its final product isolation and packaging? While equipment qualification and preventative maintenance are designed to prevent equipment malfunctions that would jeopardize product safety and quality, and proper cleaning changeover from one process to another prevents cross-contamination between processes, one area that is often overlooked for potential microbial or particulate contamination source is the packaging environment. To control this contamination, especially in final packaging and sensitive processes, cleanroom environments are often used.
Take a tour of the CMO’s warehouse and storage facilities. You can tell a lot about an organization by just walking around and asking a few basic questions. The warehouse should be very clean and well organized. Are there temperature and humidity controls appropriate for what is being stored? Materials should be segregated by their status within the quality system. Everything in the facility should be labeled and dispositioned.
How do they sample raw materials? This should be in a segregated area free of any outside contamination.
How are the raw materials transported from the warehouse to the manufacturing environment? Many raw materials will come into facilities on wooden pallets and could have pests. Do they only allow plastic pallets into the cGMP areas for example? At this stage of an evaluation you just want to make sure that the systems are in place and are being adhered to.
The manufacturing team should be a well-staffed group consisting of Production Management, Process Chemists, Engineers, Chemical Operators, and QA personnel.
It takes a well-managed and well integrated group to carry out cGMP manufacturing operations successfully. It can be difficult to determine but try to get a sense of the reporting structure and who is responsible for what, especially when things don’t go right.
Do the people on the floor have the ability to make reasonable decisions when needed or do they have to wait until the next day for management? Delays in decision making can be detrimental to the project and unnecessarily so.
Is technical oversight available 24/7 or on site during critical operations? There should be no compromise on this as it’s crucial for success. Meet the team and by asking just some basic questions you can get a good idea about the groups experience and how they operate.
Once you have completed your evaluation focusing on these factors, you can then make a more informed decision. However, there is one overriding factor you should never discount. Is there a mutual feeling of trust between both parties? Is this an organization you can trust to be transparent throughout the engagement?
Our best client projects are marked by trust and collaboration between our team and the sponsor’s working together in partnership. That’s the way to help insure that your cGMP manufacturing project has a high chance for success.
Do you have questions? Talk to Ed.