UTILITIES AND EQUIPMENT
The installation and operation of all utilities should be qualified before use in the process through commissioning, design
qualification (DQ), installation qualification (IQ), and operational qualification (OQ) studies. When the actual process is
transferred to production, a detailed engineering review ensures that all of the processing ranges are specified in the user
requirements, commissioning documents, and those qualified during the IQ and OQ studies. Acceptability of utility performance
through points of use should be confirmed through performance qualification (PQ) studies. Although changes are made throughout
the course of development and process optimization, documentation reviews can be continually performed as part of the change
control program to ensure the process is operated in the previously qualified ranges.
All processing equipment should have the appropriate level of installation and operational qualification performed. All processing
ranges are verified to be in the qualified ranges of the equipment and all contact surfaces are compatible with product or
process solutions.4 Documentation reviews can be continually performed as changes are made to ensure the process is operated in the previously
qualified ranges. During process validation (or sooner if resources allow) PQ studies on critical pieces of equipment are
performed to ensure the equipment is appropriate for the specific product being manufactured.
The activities related to utility and equipment qualification can be summarized in a high-level list of utilities and equipment
specific to the manufacturing process, which includes references to equipment and system numbers, calibration, and preventive
maintenance schedules and qualification reports. As with facility prevalidation, this list can be used for regulatory submissions
and used as references during PAI readiness and the PAI.
Multicompendial grades for raw materials should be used and in-house specifications should be put in place as early as possible
in the development process. Raw materials should be sourced from approved vendors or testing should be performed according
to the Certificate of Analysis (C of A) until vendor qualification is complete.5 Animal-derived materials should not be used. For critical raw materials, it is beneficial to qualify two sources to ensure
supply, unless these materials are commonly used and readily available.
The details of all raw material qualifications are summarized in tables that include: where the raw materials are used in
the manufacturing process, criticality, grade requirements, vendor information, and in-house specification references. This
list can facilitate the generation of information included in the chemistry, manufacturing, and controls (CMC) section of
the submission documents.
Although the development of analytical methods usually parallels process development, methods should be qualified (e.g., linearity,
accuracy, precision) as early as possible to ensure the validity of results obtained during process optimization studies.6 Understanding concentration and purity or impurity methods, such as ultra violet (UV) and high performance liquid chromatography
(HPLC) at an early stage is important so that variability can be taken into account during the analysis of data from development
Although not necessary, analytical methods used in critical parameter determination studies such as design of experiments
(DOE) and one-factor-at-a-time (OFAT) should be validated.7 At a minimum, these methods need to be qualified to ensure the data generated is meaningful for making decisions on the
criticality of parameters. As mentioned above, this will give greater assurance in the results, and can sometimes reduce the
amount of replicates needed during range-finding experiments. Similarly, these methods can also be used during many of the
Stage 1 (Figure 2) supporting validation activities such as the in-process hold time study.
Once analytical method qualification and validation are complete, all changes are assessed for effect on the respective method
as part of the change control program, and revalidation is performed as needed. A list of methods and qualification and validation
report references is a useful tool that can be used during drafting of the submission.