12-14 September 2023
It's a frequent question what GMP-compliant equipment design is or how a system has to be made up in order to be GMP compliant and suitable for the manufacturing of medicinal products/APIs. The short answer is: the system has to be qualifiable.
Since this requires some clarification, here comes a more elaborate answer. To be clear from the start, though, there is no regulatory document or general GMP certification for equipment. This is simply impossible as pharmaceutical manufacturing processes are quite different: dry granulation, tableting, fermentation, sterile filling and others, for example. And if you add manufacturing processes of the classic (chemical) API production, there are clearly more. Even the product itself can pose various requirements for the production equipment. It makes a big difference for the design of a system whether or not the manufactured product has to be sterile or whether the product is temperature or oxygen sensitive. This certainly has an impact on the system design as well. But even though these requirements are quite diverse, there are some general specifications that apply to every GMP compliant equipment design in the GMP regulations:
These 4 points are still so vague that further explanation is in order.
The system may not influence the product quality in a negative way. This simply means that there may no negative interaction between product-contact surfaces and the product. Neither may the system emit substances, nor may components of the product be absorbed. Also, there may be no chemical reactions on the surface.
The system must be easy to clean. This generally applicable sentence can be found in almost every GMP guidance of every country or authority. Behind it there are two objectives: for one, all surfaces (in most cases the product-contact inner surfaces) should be smooth. Cleaning the system by wiping or rinsing is a lot easier with smooth surfaces than with surfaces showing score marks. In these score marks, bacteria could survive the cleaning or disinfection, for one; what's more, product residues could also remain there and merge into a subsequent product. This is called cross contamination.
Even worse than rough surfaces in a system are spots which are hard to reach. Most feared are so-called dead spots; places in a system which aren't wetted by the cleaning agent or which the cleaning agent cannot reach at all. In system construction, these are referred to as dead legs. Dead legs are flooded worse or not at all; they are thus harder to clean, and in the thermal sanitisation these "branches" take longer to reach the required temperature.
This requirement also applies to equipment like packaging lines. These machines also have to be easily cleanable, so that remaining product but also leaflets and labels can be seen and removed during line clearance.
The system has to comply with applicable technical rules. Legally binding GMP regulations are quite vague, especially when it comes to technical matters. Therefore, the question is: which technical rules have to be followed? This of course depends on the nature of the equipment. In some cases, pharmacopoeias or authority guidelines can be helpful. Also, it's always good to know the respective ISO standards or VDI guidelines (in Germany). Documents with further information are frequently published by associations such as the ECA, ISPE, PDA or VDMA, for example. It's important to know here that those rules are rarely binding. Nevertheless, they are very often used to prove that one's own procedure is compliant with or better than the official rules.
The system must be suitable for its purpose. This is one of the most important and at the same time hardest to generalize specifications. It simply means that the product the system is manufactured with has to satisfy the predetermined quality requirements and therefore has the effect the patient requires. This point pretty much covers all the other mentioned points, as well.
The suitability of a system is proven by its qualification. Here too, the qualification depends on the product. A system which is qualified for product A isn't necessarily suitable for product B, as well. The qualification process begins with the user requirement specification (URS) and continues in the phases DQ, IQ, OQ and PQ. And this is also the reason, why GMP-compliance of a system or equipment can only be achieved together with the user.