Manufacturing commercial process validation

A process or facility fit assessment needs to be performed and involves translating the transferring site s process into a fit-for-purpose process within the manufacturing facility (Worsham, 2010). A comprehensive appraisal of the process requirements versus facility capabilities should be performed. This can help avoid unanticipated issues, which could lead to either unexpected delays and/or hidden costs at a later stage. Any changes to the process to accommodate the needs of the facility could result in additional process validation requirements. Therefore, changes should be constrained to the absolute minimum, but may be still required to facilitate a commercially viable process. 

FDA inspectors are instructed to look for any differences between the process filed in the application and the process used to manufacturer the bio/clinical batch. Furthermore, one of the main requirements of a manufacturing process is that the process will yield a product that is equivalent to the substance on which the biostudy or pivotal clinical study was conducted. Validation of the process development and scale-up should include sufficient documentation so that a link between the bio/clinical batches and the commercial process can be established. If the process is different after scale-up, the company has to demonstrate that the product produced by a modified process will be equivalent, using data such as granulation studies, finished product test results, and dissolution profiles. 

In prospective process validation, an experimental plan called the validation protocol is executed (following completion of the qualification trials) before the process is put into commercial use. Most validation efforts require some degree of prospective experimentation to generate validation support data. This particular type of process validation is normally carried out in connection with the introduction of new drug products and their manufacturing processes. The formalized process validation program should never be undertaken unless and until the following operations and procedures have been completed satisfactorily ... 

As we know, a critical step within the development cycle of any new product or process is the scale-up step. At this particular point, it is very important that adequate communications have occurred between the group responsible for the product development and the group charged with process validation. Actually, in many organizations, the process/product development department shoulders the responsibility for product scale-up and then transfers the technology to manufacturing for product commercialization [6],... 

In order to assess the state of SPC, a sufficient number of pilot- or commercial-scale batches should be manufactured (at least 10% of anticipated commercial scale) using the same process anticipated for the scaled-up product. When the formulation is finalized, the critical in-process and final product control specifications will be challenged through process validation studies on at least three full- or pilot-scale batches. 

A registration application should include documented evidence that the analytical procedures are validated and suitable for the detection and quantification of impurities (see ICH Q2A and Q2B on Analytical Validation). Technical factors (e.g., manufacturing capability and control methodology) can be considered as part of the justification for selection of alternative thresholds based on manufacturing experience with the proposed commercial process. The use of two decimal places for thresholds does not necessarily reflect the precision of the analytical procedure used for routine quality control purposes. Thus, the use of lower precision techniques (e.g., thin-layer chromatography) can be appropriate where justified and appropriately validated. Differences in the analytical procedures used during development and those proposed for the commercial product should be discussed... 

Finally, the validation work may be performed for this process. This would most likely consist of repeating the 2 full-factorial design mentioned earlier along with three process validation runs at nominal conditions for all factors. The process validation runs would essentially be confirmation runs of the actual process to be used in future commercial manufacturing. Of course, all of these experiments would be based on an approved protocol and would have to yield acceptable data compared with the product specifications. 

Equipment used to produce biotech products should be qualified for design, installation, operation, and performance [15]. The aging and continued performance of re-used process materials such as column resins is an important consideration during the validation of a biotech process. Demonstration of microbial control during processing is also a critical component of process validation, particularly in difficult to clean equipment such as alBnity columns or ultrafiltration membranes. Finally, consistent and reasonable step yield of individual unit operations can be verified during consistency and commercial product manufacturing. 

Process characterization defines process capability and facilitates prospective process validation at the production scale [40]. Full process characterization is valuable in maintaining smooth manufacturing operations and minimizing lost batches, and it provides supporting information for lot release justification for atypical batches [15]. Its goals are to identify key operating and performance parameters, define control limits for key process parameters, demonstrate robustness of the commercial process, and provide technical information about the process [68]. The steps involved in process characterization include risk assess-... 

Process validation would not be expected until commercial batches are produced but information on process boundaries and critical parameters should be obtained at this stage. It should also be pointed out that if the pivotal stability studies to be listed in the final registration (on the drug product or API) are performed on pilot batches, then this data certainly could become subject to inspection. It is becoming inaeasingly common in Europe and the USA for R D facilities to be audited as well as the commercial facility before approval of a manufacturing licence, even though the R D facility has not manufactured any commercial supplies. 

Process analytical technology (PAT) can be developed early in development with a line of sight to commercial process control (ICH Qll 2011a). Easily integrated into the process equipment, as shown in Fig. 7.1, the application of in-line probes can provide unique opportunities to monitor processes in line. Spectroscopic techniques such as ultraviolet/visible (UV/VIS), near-infrared (NIR), and Raman can be utilized in line at the extmder die to ensure critical quality attributes (CQAs) such as composition and amorphous conversion of the API. Validation of these techniques at the pilot scale and transfer to the commercial scale allow for efficient manufacture of commercial material in a continuous manner and the implementation of a process control strategy that enables material outside the design space to be diverted to waste... 

While a non-GMP plant is ready for operation directly after completion of commissioning, for a GMP plant it will take another 6-12 months to establish operational readiness due to facility and equipment qualification and process validation requirements. In addition, for commercial GMP manufacture, and depending on the target markets, the facility needs to be approved by national and international health authorities. 

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