While biotech in general is doing well, there’s always pressure on biotechs to use their funds more efficiently and productively. Here at PCI Synthesis, we take pride in providing our clients with objective, honest counsel, including smart ways to keep costs down – but we’ve seen prospective clients whose main priority seems to be to cut costs. They tend to cut corners that are counterproductive and result in additional costs and delays – the opposite of what they had intended.
This situation turns into the perfect storm when it occurs along with ongoing regulatory scrutiny, limited funding, and inexperienced leadership. After a couple of bad experiences, we now walk away from prospective clients who are penny wise and pound foolish. This blog post is part of an effort to educate prospective clients on how to follow good manufacturing processes (GMPs) during pharmaceutical manufacturing, general best practices, and how to make smart decisions about budget.
Our best client projects are marked by trust and collaboration between our team and the sponsor – working together in partnership. On the other hand, the worst projects usually stem from a lack of trust: from sponsors who don’t trust their outsourcing partner, and from our team not trusting the sponsor to make the right decisions. A lack of trust makes a complex project even more challenging.
Our scientists typically work on more projects in one year than many sponsors work on in several years. This level of experience can help us determine issues before they explode into huge problems – and to identify solutions. Sponsors who don’t like to take advice and counsel often end up costing themselves more by trying to cut the wrong corners or pursuing the wrong solutions.
If you feel like you can’t trust your outsourcing partner, you should identify concrete examples of why you don’t trust them. Then you should schedule a meeting with them to determine possible solutions to those issues. If the problem is intractable or if the outsourcer is unwilling to make changes then it might be time to make a change.
There’s a lot of pressure for companies with limited funding, especially those run by business people, to try to save money at every step of the way – perhaps by going with the cheapest bid or skimping on some prep work or analytics. In fact, since GMP manufacturing can cost $75,000 per week, we understand the feeling that cutting back on some assessments may seem like a good way to save a substantial amount of money.
But this strategy most often back-fires. To ensure that everything meets with FDA approval, we must test and validate each substance and process to make sure they work. Without solid, analytical methods, you can’t determine if what you have is good or bad – but sometimes people try to cut back on analytics. The Costs of GMP: Cutting the Wrong Corners, Mistakes & Sloppy Master Batch Records Page 2 of 3
Jumping right to production before validating the processes opens us to having to fix something that should have been addressed earlier – when it would have been easier, faster and less costly.
For example, a client once came to us with a substance that had been developed in another lab. Because they had a tight budget, they asked us to just put it into GMP production with very minimal assessment. However, we found that as the substance scaled up, it picked up an impurity. When it turned out that their material didn’t meet regulatory standards, our Quality Assurance (QA) team would not release the material — which is the right decision — and we had to go back and do additional work just to get the material ready to be released. That took an additional six weeks, and resulted in a lower yield – at a cost of more than $200,000.
What they don’t often appreciate is that GMP manufacturing is like a rocket ship. Each unnecessary week spent to address issues that prevent QA from signing off and releasing substances can quickly add up. And the delays often have a cascading effect on other aspects of development. And contrary to what might be expected, we don’t like it when we have to bill the sponsor more. We would much rather use the time allotted efficiently, and move on to the next project. So we now have a rule: Nothing goes into GMP until we test it for all specifications. It’s cheaper in the long run.
The main different between small-scale and large-scale GMP manufacturing is the equipment used. Small-scale manufacturing uses new glassware, which is cheaper to replace than to clean; while large- scale uses fixed equipment that can hold up to 2,000 gallons, which is cheaper to clean than to replace, even when factoring in time to test that the fixed equipment is demonstrably clean.
We have developed Standard Operating Procedures (SOPs) that validate the equipment is clean. This can take three days, yet we’ve heard some other CMOs can spend two weeks to clean and validate fixed equipment.
One cost-savings tip is: before you transfer the processes and substances into large-scale GMP manufacturing, make sure you understand your specifications and that your processes meet all specifications. This is an opportunity for the sponsor’s team and the CMO team to get comfortable working together.
When your substance is in GMP, don’t try to rush to meet unrealistic timelines. Deadline pressure can cause people to miss steps or cut corners. For example, for really large-scale GMP, we like to make a 100-liter test batch to make sure everything works as intended, sometimes two or three batches to make sure the Master Batch Record (for more, see below) is accurate and consistent. We’ve seen some projects that, during the scaling-up period, find impurities that were not present in smaller quantities.
While your substance is near the end of the non-GMP work, your CMO 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 MBR so that it’s ready by the time the cleaning and validating of large-scale fixed equipment has been completed.
In addition to the engineer, our QA team validates the raw materials, specifications, and purification levels as well as the step-by- step approach to the manufacturing to ensure consistency across different batches before it can go into the GMP manufacturing lab. Every document has to be reviewed and approved by QA.
The Costs of GMP: Cutting the Wrong Corners, Mistakes & Sloppy Master Batch Records Page 3 of 3
The Master Batch Record (MBR) is the most important part of GMP manufacturing – and 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 active pharmaceutical ingredient (API). The MBR is part of the required documentation for compliance with Good manufacturing practices in order to conform to the ICH “Guidance for Industry, Q7 Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients” as well as EudraLex – Volume 4 Good manufacturing practice (GMP) Guidelines for the European Union.
The MBR lists all the equipment that is to be used with safeguards to ensure the equipment is suitable for use. It contains detailed, stepwise, processing instructions [e.g. checks on materials, pre- treatments, sequence for adding materials, critical process parameters (time, temp etc.) that are needed for the manufacture of the intermediate or API.
Those detailed steps include dates and times for starting and completing each significant step, including weighing of all raw materials and intermediates; identification (initials) of the operator(s) who performed each step and the name of the person who checked and verified these operations.
The MBR also includes any in-process controls (with their limits) and records the actual results (when executed) as well as any sampling with test results recorded; all packaging materials, labeling and storage conditions are defined and listed; the expected yield of relevant intermediates and the final product; and the actual product yield obtained; and any deviation from the instructions is noted and recorded.
Finally, 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. This can only be done with the input of Research & Development, Safety & Environmental, Manufacturing, Engineering, Quality Control and Quality Assurance.
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.
GMP guidelines were developed for good reason and ensure that sound and efficient processes are followed for the success of a pharmaceutical project, as well as to ensure its efficacy and safety. Before and during GMP manufacturing is never the time to cut corners to save costs, because that strategy often comes with a heavy price. For other articles about GMP manufacturing check out “Coming Clean on Quality in the Chemical Manufacturing Lab” and other articles on our blog.