Process Qualifications

Validations fall into two types prospective and retrospective. In prospective validation (see flow chart in Figure 2) the validation is done in a sequential manner, involving installation qualification and operational qualification (IQ/OQ) of equipment (e.g., chromatography instrumentation or column hardware). Appropriate calibrations accompany the IQ/OQ. Process qualification, or PQ, involves formal review and approval of a PQ protocol, execution of this protocol, and issuance of a formal PQ report which includes data analysis and recommendations (i.e., approval/certification of the process). If the process is not approved, the report may recommend a redesign or redoing of the validation protocol and, in some cases, a return of the process to process development for further optimization. 

Indeed, the need for capital investment in a CMO may not have been originally anticipated or planned for and may impact on the whole decision making process. Additional costs and time need to be set aside for training and equipment validation, e.g. PQ/IQ/OQ (process qualification/ installation qualification/ operational qualification), and if this includes equipment with radically different operating principles than currently available on site then additional costs will be required for equipment-specific operating personnel and training. 

Process qualification, including the establishment and locations and values of minimum and maximum doses... 

Processes a) Formula change (addition, deietion, excess) b) Equipment change c) Procedure/direction change Process Qualification QA + Concerned dept, managers... 

When new equipment is purchased or there is a change in the manufacturing site, qualification exercises are performed as part of the validation process. Qualification (installation qualification, operation qualification, and performance qualification) for any equipment or facility is an extreme process which involves testing, verification, and documentation to assure that the particular equipment or facility is per the specification and meets the appropriate standards as defined by vendor and required by manufacturing and engineering personnel [14]. 

Process demonstration formerly called process qualification, represents the actual studies or trials conducted to show that all systems, subsystems, or unit operations of a manufacturing process perform as intended that all critical process parameters operate within their assigned control limits and that such studies and trials, which form the basis of process capability design and testing, are verifiable and certifiable through appropriate documentation. 

A validated manufacturing process is one which has been proved to do what it purports or is represented to do. The proof of validation is obtained through the collection and evaluation of data, preferably, beginning from the process development phase and continuing through the production phase. Validation necessarily includes process qualification (the qualification of materials, equipment, systems, buildings, personnel), but it also includes the control on the entire process for repeated batches or runs. 

Given the fact that the ranging studies have been successfully completed, attention is focused on the next process qualification step—Scale-up studies, demonstrations, and Trials. 

Qualification Verification. Again, the process validation protocol should reference all items that support the validation the procedures, personnel, methods, and equipment. This section therefore lists and summarizes the various installation, operational, and performance/process qualifications completed for the equipment used in the process validation. These qualifications should list each by equipment name and number and qualification and type. A typical verification section is illustrated below. 

Equipment Equipment number Equipment qualification Performance/process qualification ... 

There is much confusion as to what process validation is and what constitutes validation documentation. We use the term validation generically to cover the entire spectrum of CGMP concerns, most of which are essentially facility, equipment, component, methods, and process qualification. The specific term process validation should be reserved for the final stages of the development and product scale-up sequence. 

Performance qualification—those activities that center on the actual product or process being considered. There are other terms, such as process qualification, process validation, product qualification, and product validation, that are sometimes used to narrow the scope of this effort. Here again, semantics have gotten in the way of more important issues. If you desire to use different terminology, go right ahead. Provided all involved understand the intent, the specific title chosen is clearly arbitrary, but the principles are the same. (See Sec. 3.1)... 

Process Qualification FDA (1995) Establishing confidence that a process is effective and reproducible. 

To conclude this section, it is worth noting that the process qualification based on liquid samples, although necessary, is not sufficient to qualify all aspects of the stability of the formulated solution. For example, it may happen that the formulated solution has to be stored in the filling tank for a few hours longer than usual. The behavior of the solution during this extra time cannot be safely predicted from the above in-process data. In order to release the batch produced, it is necessary to have a documented study about the stability of the filling solution at different temperatures, over an adequate period of time, e.g., 24 hours. 

Validation is described as proof that the system performs as stated. As an engineering control, the LAF system must demonstrably support the intended aseptic or controlled process. Validation of the aseptic manufacturing process and the LAF systems that support terminal sterilization in pharmaceutical manufacturing applications should be carried out in accordance with industry standards. Such validation should be accomplished in three phases, consisting of installation qualification (IQ), operational qualification (OQ), and process qualification (PQ), with full and detailed documentation of all activities and... 

Additional Large Scale Process Qualification Studies Product Transfer Document Issued Product Acceptance by Manufacturing Validation Protocols Written Pre-approval Inspection Task Force Initiated Manufacturing Site Preparation Pre-approval Inspection by FDA... 

In a well-designed validation program, most of the effort should be spent on facilities, equipment, components, methods, and process qualification. In such a program, the formalized, final three-batch validation sequence provides only the necessary process validation documentation required by the FDA to show product reproducibility and a manufacturing process in a state of control. Such a strategy is consistent with the FDA preapproval inspection program directive. ... 

Process characterization Process optimization Process qualification Process qualification lOOX... 

Process development (process qualification) or process capability studies are normally started in this important stage II of the scale-up sequence. The scope of stage-II process development consists essentially of product optimization and process characterization studies. Product Optimization ... 

Process qualification (prevalidation batches) determine process capability, challenge in-process control limits... 

The creation of a separate pilot plant or process development unit has been favored in recent years because it is ideally suited to carry out key process qualification and/or process validation studies in a timely manner. ... 

Where in the chain of unit operations (chemical process) does API validation start As long as key intermediates are made in the plant, they and their reaction and processing steps should be subjected to an appropriate cGMP and process qualification-validation program. A key intermediate is defined as an intermediate in which an essential molecular characteristic, usually related to stereochemical configuration, is introduced into the final API structure (moeity). 

---