In the first of this series of three blog posts on CMO risk mitigation, we discussed ways to establish an effective working relationship with your Contract Manufacturing Organization. Your next objective is to identify Critical Process Parameters (CPPs) – the key variables in a production process that affect Critical Quality Attributes.
In sterile product manufacture, CPPs fall into two main categories:
- Formulation– Generally reliant on the sponsoring company’s expertise; and
- Fill/Finish – Elements of the CMO’s experience and expertise.
Formulation characteristics need to be documented and shared in detail with the CMO’s technical team. They will include:
- Active pharmaceutical ingredient (API) attributes (e.g. – bulk density, purity, solubility )
- Excipient quality/grade
- Order of addition
- Heating/cooling rates/temperatures
- Mixing techniques (type of mixer, speeds, duration)
- Equipment (vessel design, materials of construction)
- External factors, such as heat, light, oxidation and pH
- Filtration type and rate
There is a good deal of complexity here, and it is frequently not realistic to conduct an exhaustive CPP study particularly for an early phase clinical project. Work closely with your CMO to identify a manageable number of critical parameters that merit exploration and focus on those. There is no point in becoming preoccupied with factors that cannot be changed (e.g., API impurity profile) or are unlikely to impact the process. Remember: The FDA does not expect you to explore every possible variable – only those likely to impact product quality.
The goal is to identify and demonstrate a process capable of repeatedly and robustly delivering bulk drug product of the required quality and quantity. You’ll need to develop a set of in-process control specifications to track and verify product quality throughout the process. You’ll need to document process limits (i.e., how long can the process run before quality begins to suffer?
From a fill/finish perspective, there are a separate set of issues to deal with. These include:
- Materials compatibility with the formulation (e.g., tubing, fill needles, etc.)
- Sensitivity to manufacturing environment (clean room or isolator), including temperature, light, oxygen levels and residual sterilant levels
- Closure system (vial/syringe, stopper, seal)
- Filling – Speed, duration of fill, seal force and headspace content.
Your CMO knows its facility better than you do. It can only help you to take advantage of this expertise and allow them to follow their standard process.
The simpler the process, the fewer things can go wrong. Pharmaceutical manufacturing is inherently complex. It is, of course, highly regulated. Process changes and deviations are likely to carry significant consequences. You’ll want to work closely with your CMO to identify CPPs and, ultimately, to reduce and eliminate process variables.
Whenever possible, utilize formulation procedures that are familiar to your CMO – try not to insist on procedures that are markedly different than what they are familiar with unless it is absolutely necessary. Don’t require them to reinvent the wheel just for you.
Use standardized batch records and operating procedures whenever possible. The best reason to stick with these standards is that the people doing the work already are familiar with them. People who are operating a familiar process are less prone to error. If you must employ unique and different methods, make sure they are well-understood and flagged as non-standard to all concerned.
Use of validated procedures ensures the highest degree of regulatory compliance (e.g. – use of pre-sterilized manufacturing supplies from qualified, validated processes). Any significant deviation from validated process may require a time-consuming and expensive re-validation.
Use standardized equipment whenever possible – the machines, instruments and consumables originally used in the process you had validated, and to the extent possible, disposables with a history of adoption in the pharmaceutical industry. The disposables used in your process should:
- Be pre-sterilized using a validated process
- Require minimal assembly; and
- Have established and documented performance characteristics (e.g. – mixing rates).
Take advantage of automation whenever possible. The single most prevalent source of deviations in drug product manufacturing is human error. A good example of effective automation in drug manufacturing is automated/robotic filling, which eliminates most human interaction with critical components.
Once you have a lab-scale process you can rely on, the final challenge is to bridge the gap from lab scale to manufacturing scale. The third and final post in this series will address how effective collaboration between the drug company and the CMO helps in making the jump to GMP manufacturing.