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.

RAW MATERIALS

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.

ANALYTICAL METHODS

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 studies.

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.