Regulations that control the construction of facilities and equipment for medical-product manufacturing require qualification
of the facilities and equipment. The International Conference on Harmonization of Technical Requirements for Registration
of Pharmaceuticals for Human Use defines the common principles of the qualification of ingredients, formulations, and packaging
(1). However, it does not clearly define the methods for determining what must be qualified or for performing qualification.
In its guideline on commissioning and qualification (C&Q), the International Society for Pharmaceutical Engineering (ISPE)
states that qualification practices are required after commissioning to provide supplementary assurance that good engineering
practices (GEP) have been followed (2).
ISPE says that a system-impact assessment should be performed first to identify the systems that have a direct effect on the
quality of the product. The components or devices of the direct-impact systems should then be classified as critical components,
which have a direct effect on the quality of the product, and noncritical components, which do not. Qualification practices
should only be applied to the critical components. Adherence to GEP is sufficient for indirect-impact systems and noncritical
ISPE's C&Q document, however, mentions an exceptionally broad range of criteria for identifying critical components. The document
does not describe in detail how to determine which critical components must be qualified or how to qualify them. For these
reasons, various methods for selecting targets and performing qualification have emerged. In many cases, components are qualified
even when they are not required to be.
The Good Manufacturing Practice (GMP) Committee of the Japan Society of Pharmaceutical Machinery and Engineering has studied
qualification practices for systems used in solid-dosage-form facilities, including pan-coating systems, blister-filling and
packaging systems, and pillow-packaging systems (3, 4). On the basis of these studies, this article proposes a new approach
to target selection and qualification and shows how the approach can be applied to blister-filling and packaging systems.
Selecting the targets of qualification
ICH's Q7 Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients states that appropriate qualification of critical equipment and ancillary systems should be completed before starting process-validation
activities. This section will explain which components of the critical equipment and ancillary systems should be selected
as targets of qualification.
Medical-product manufacturing systems have various functions that are performed by the systems' mechanism, shape, and material.
Using a certain system to manufacture medical products entails executing the system's functions under prescribed, controlled
conditions. In ordinary manufacturing processes, some system functions have a direct effect on the quality of the products
and others have an indirect effect.
The authors believe that qualification of critical equipment and ancillary systems should be interpreted as qualification
of system functions that have a direct effect on product quality. The article will apply this principle to qualification-target
selection, using blister-filling and packaging systems as an example. First, the quality of the products should be explained.
The quality of blister products can be defined in terms of protecting their contents (e.g., tablets) and display or identification.
This article focuses on the former function. The authors define the thickness of the blister pocket web as a critical factor
that directly affects product protection.
Blister-filling and packaging systems are direct-impact systems because they directly affect the quality of blister-package
products. An examination of the systems' operating principles shows that the forming function and the speed-control function
directly affect the thickness of the blister pocket web. Furthermore, a close examination of the system devices that affect
the forming function shows that the heating device and the forming device directly affect the thickness of the blister pocket
Parts of the heating and the forming devices directly affect web thickness, and the functions of these critical parts should
be identified. For example, manufacturers should determine the function of the heating device's heating plate and that of
the forming device's forming die. In this case, the required function is that of assigning the appropriate quantity of heat
or shape and size to the plastic film. Because the quantity of heat is usually difficult to measure or control, however, the
temperature of the heating plate should be measured and controlled instead.
The temperature of the heating plate and the shape and size of the forming die are called direct factors. Qualification should be restricted to these direct factors.