To ensure the highest level of quality and minimize any risk to patient safety, any facility where active pharmaceutical ingredients (APIs) are manufactured needs to be run according to strict adherence to cGMP requirements, so that the APIs are free from contamination. Great care must be taken when a manufacturing facility is operated to produce a dedicated product, but for the type of multipurpose facility typically used by a contract manufacturing organization (CMO), where multiple products and their intermediates are synthesized in the same vessels and equipment, the requirements are significantly higher.

At multipurpose facilities, CMOs could have varying manufacturing demands including custom synthesis of a molecule, where volume demands could be met by a single campaign each year, or far more frequent batches; as well as one-off intermediates for investigative studies needed for regulatory purposes or development. A CMO may also maintain an inventory of in-house molecules such as a generic API portfolio. All of these projects could be run using the same assets, and obviously the most important aspect from an operational point of view is to ensure, that where switches between products are frequent, the cleaning procedures are properly executed and verified. This will enable products to be changed over quickly in the plant, while also protecting customers’ products from cross-contamination.

Contamination control
One of the first activities that is undertaken when a new process is transferred into a plant—whether it be a multipurpose facility or not—is to establish an effective cleaning methodology.

When developing a process in the laboratory before it reaches plant-scale, the chemical development group should document how they cleaned their reactors and other equipment. The use of semi-fixed equipment within development, which cannot easily be disassembled for cleaning, means that clean-in-place procedures must be used. For internal projects, or projects that have been transferred where data may not be available, this step and the use of fixed equipment offers the opportunity to hone a cleaning regime early on in the process. This can reduce delay in the scale-up phase of manufacturing.

The chemical development group should also make a qualitative assessment of the target compound’s solubility in a number of different solvents, and this solubility data can be used to aid the development of both an equipment cleaning procedure and to define a rinsate for the cleaning verification analytical method. Determining solubility in a number of solvents allows the production team to choose a cleaning solvent for scale-up activities based on cost, disposal needs (and their associated costs), availability, and ease of handling.

It is important that the analytical method is in place in advance of a new process being undertaken because it is not possible to demonstrate cleanliness after the campaign without it. The goal of a cleanout method is to ensure that the material evaluated is accurately quantitated in order to ensure cleanliness of the equipment. Clean-out methods are typically developed for both the rinsate and swab sample analyses.

As there is always a possibility that the project will be moved to another work center in future, it is important to demonstrate that the cleaning method is good for all materials of construction. This ensures that it will still be appropriate, regardless of whether the equipment is made from glass, stainless steel, Hastelloy or Teflon. This allows the process to be flexible and moved into a different material of construction at a point in the future, the analytical cleaning method will remain valid, and there will be no last-minute requirements to validate a new analytical cleaning methodology.

Having full and complete control over cleaning is crucial when changing over from one process to the next. A Cleaning Residue Limits Determination (CRLD) calculation is performed to determine the maximum allowable carryover from a previous process, and considers the therapeutic data of the last material handled within the equipment, and the dosing of the next API to be made in the facility.
The allowable carryover is typically as low as 50 ppm for reactors and tanks and lower still—maybe 10 ppm—for solids handling equipment, however, depending on the results of the CRLD calculation, this figure could be much less. Only when it has been proven analytically that the equipment is clean and a visual inspection of the equipment has been performed is the next process initiated.

The thorough nature of the cleaning means it is not quick, and operationally there is always a balance to be sought between effective cleaning and downtime on a vessel or manufacturing train—especially if the equipment is key for another project that may be delayed. Typically, cleaning after a manufacturing campaign could take two to three days, however, it is important not to rush it as ineffective activity can mean the duplication of work leading to time delays and potentially economic penalties while plant sits idle; and ultimately the consequences of cross-contamination can be potentially disastrous.

Plant operation staffing
In terms of the day-to-day running of the processes, from an operations point of view the number of operators required for a multipurpose plant is broadly similar to the number needed for a dedicated facility.

However, on the engineering side, it is inevitably going to be a little more resource-heavy to run a plant with varying needs and flexibility to handle multiple projects. Each new process entering the facility will require new batch records to be drafted. A series of production review meetings must also take place, including those covering hazards and operability, as well as walking through the process once the equipment has been set up. With all the production changes, the engineers will have to be involved in all these additional activities, which would not be required for a dedicated facility.

“It is important that the analytical method is in place in advance of a new process being undertaken because it is not possible to demonstrate cleanliness after the campaign without it.”

Further resources will also be required in both chemical and analytical development to support these new processes as they move into production. This is more labor-intensive than it would be in a dedicated plant, where a couple of chemists to act as trouble-shooters when production problems arise should suffice.

When a new process is being transferred into production, chemists and engineers will provide additional coverage for that campaign, and will be present with the operators round-the-clock. This is not because they are required to tell the operators what to do, but more that their role is to ensure that the operators understand what is written in the batch record, and that its instructions are clear and unambiguous.

Once a project becomes established in the plant, it will usually be validated in multiple work centers as this increases the operational flexibility, and allows a plant to remain active—and therefore generating income, as there will be a validated process that can be run there at all times. This is of particular importance for companies that maintain an inventory of generic product lines, for which there is always demand, and the more that can be made, the more revenue can be generated. Empty assets do not make money.

Project management steps
When a CMO receives a request for proposal from a customer, there are a number of steps that require input from development teams and project management specialists to ensure that projects will be suitable for the assets that are available, and that the project is a good fit for a site’s capabilities. Before a contract is drafted, it is important to estimate how much chemical and analytical effort will be required to get the process into production, as well as the cost of running the process campaign itself. Occasionally, proposals are received from customers for processes that contain reagents that are unsuitable for a site due to safety concerns, such as anhydrous hydrazine or phosgene. In these instances, studies are often proposed to investigate the feasibility of alternative reagents or chemistries to affect the same chemical transformation. Ultimately, it is the customer’s decision if they can tolerate changes to their process.

Once a contract has been signed, typically a kick-off meeting will take place with the customer that includes full discussion of the process and analytical methods, and then work will begin in both the chemical and analytical development laboratories to prepare the project for transfer into production.

Some projects may arrive fairly fully formed and with significant supporting material, but it is not unusual for it to be at a very early stage of development, with the process poorly defined. In these cases, there is a lot of flexibility to alter the process to make it more amenable to large-scale operation.

At the other end of the scale, a customer may have already filed the NDA, and are looking for a CMO to be a back-up supplier for an API. As the NDA is fixed, there is little scope for change to those processes. Here, chemical development work will be limited to demonstrating that the process can be successfully carried out at laboratory scale to get a handle on the chemistry, and then getting it ready to move into production.

Similarly, the CMO’s analytical development group will be tasked with transferring and validating the analytical methods, with the amount of work required dependent on the phase of development of the molecule. In the very early phase, all that is required is a simple transfer in and demonstration that methods can be run and are comparable. In late phase development projects, the analytical methods will require formal validation.

Concurrently with this work, team meetings will take place, including representatives from chemical development, analytical development, quality assurance and process engineering. In cases where there may be regulatory needs, other representatives will also be included, for example a site’s controlled substance officer.

Once the process and analytical methods are ready, process engineers will write batch records, and to do this, they work very closely with the process development chemists while they run a scale-up batch. Typically, this may be at a 10–20 liter scale. The engineer will be present in the laboratory, watching the chemist run the process to get an idea of how it looks and behaves before it goes into full production. At this stage, it is advantageous to carry out the work in glassware, as this makes it easy to visualize the process, giving guidance when writing the batch records. This process works best when it is interactive, with the engineers and chemists bouncing ideas off each other to develop a process that might be easier to run on a production scale. With the batch records in hand, production can start.

Another factor that must be addressed early on is purchasing. While there will already be specifications and potentially suppliers in place for common solvents and reagents, many APIs will require less common ingredients to be sourced. Sometimes customers will provide the starting materials, but often it is the responsibility of a CMO’s purchasing department to source suitable vendors. This process can take some time, and therefore engaging with the purchasing team early on is essential so that delays due to raw material availability do not hold up production.

Once the campaign has been run in the plant, the material will be packaged and samples taken for release testing. For APIs, there is typically a long list of tests that must be run by the quality control group to ensure the material meets the customer’s exact specification. The analytical development and quality control personnel work closely together, in the same way as the chemists and engineers, with the analytical development chemist present in the lab alongside the Quality Control (QC) analysts at the outset to ensure the instructions in the method are clear and unambiguous.

The results of the specification tests should be reviewed within the QC department, and then passed on to Quality Assurance (QA). It is common for the customer to want to review all the analytical data and sign off that it meets their requirements before it is also signed off by a QA department, and then the certificate of analysis for the batch is generated ahead of shipping.

Effective management to ensure successful operations
Good communication between all the groups at a facility involved in operations and production is essential. All the necessary analytical methods must be in place before the process moves into production, with the process transfer document written by the chemical development group, and all the necessary raw materials on hand and released. The batch record must be ready, and all the pre-production review meetings complete.

Scheduling is an ongoing task and without tight management can cause delays and production issues. Regular meetings between cross-disciplinary teams at a facility are vital to discuss any necessary changes. Without these, incidents such as a raw material being delayed have a significant impact not only on the project it is destined for, but knock-on effects for the rest of the schedule, and future projects.