Purpose of Process Validation in Pharmaceuticals

The kind of effort expended for Process Validation is largely determined by organizational structure. Whether Process Validation is managed by a department, a consultant, or a committee, the criteria for the program are still the same. These criteria will be examined by the responsible individuals so that the program will be tailored to the character of the process under study. The following questions are recommended in developing a suitable validation protocol or plan.

1. What is being validated?

The answer to this question is important because it is essential that the objectives of the validation activity be clearly stated. This understanding will enable the responsible group to plan the protocol and the test program needed to carry out the validation program. Quality assurance requires that the total Process Validation document include the following:

• Data on the IQ for the facility and equipment
• Data on the OQ for the facility and equipment

• An account of the understanding of each process step’s capability
• Data generated during the processing activity and after its completion
• Documentation approval of the validation activity

Documentation of the IQ is important for QA so that the information will be available for future reviews by QA or the FDA inspector. There are three possible approaches that may be followed. First, the IQ information may be compiled as a stand-alone document to which other parts of the validation document would refer. The advantage of this approach is that the IQ doesn’t get tied to a specific process or product validation. The second approach would have each validation document stand alone, which would mean that the IQ information on the equipment and facility would be repeated for every validation report. The third approach would combine the other two approaches; namely, that the facility IQ would remain generic and the equipment IQ would be a part of the process/product validation document. Whatever approach is followed, the overall validation report must provide an effective QA tool. Quality assurance will thus strive to get the entire validation program documented in order to achieve it's short- and long-term needs.

The Process Validation of a new facility must be documented in such a way to ensure that the facility’s design and the operations within it are fully covered. An outline of such activities is listed in Table 4. For example, the validation of a new facility makes it necessary to document the equipment performance under relevant conditions. All process (or facility) equipment will undergo IQ testing to make sure that each piece of equipment operates as it was designed to do. The technologist will determine how the equipment’s performance will vary without the influence of the process material (OQ). This information will form the basis for the remainder of the validation report. From a QA viewpoint, it should also be noted that this information might be useful if it is compared against the parameter measurements under load conditions. Since this information is more properly included in the performance qualification (as process optimization), however, it should not become a part of the validation protocol

On the other hand, if the process must be validated in an existing facility, existing IQ and OQ information may be adequate. In this case, the validation protocol might merely refer to the data rather than require its regeneration, especially when a credible calibration/audit program had been performed for the facility and equipment after the initial IQ and OQ were performed. This part of the validation work thus might merely be referenced in the validation document.

The next concern raised by the question is the determination of whether prospective or concurrent validation is appropriate. This decision should be based on the nature of the PV activity. For a new facility, there is only one possible decision; namely, prospective validation. When certain process changes are made, however, it may be appropriate to choose the concurrent validation approach.

2. Why Should the Process Be Validated?

Personnel involved in the validation function will determine not only what will be in the validation protocol but also why the process will be validated. If a validation committee is responsible for the function, it will include personnel having varied backgrounds, such as production, engineering, process development, QA, and regulatory affairs. Likewise, the PV function would include personnel with these backgrounds or those who interact well with such individuals.

It is important to avoid using a routine, predetermined menu when planning a validation protocol. In the ideal situation, the process development activities would dictate what tests would be included in the protocol and what ought to be the specification limits of the test results. Such activities form the basis for the data gathering because a large number of development batches, including the qualification and optimization trials, would clearly indicate why the specific parameters are being measured and why they indicate that the process is under control. When the validation protocol is the product of a multi-disciplined team, it should thus not become a self-serving exercise of any single function.

For example, the QA function might accept the principles of testing for content uniformity, but then it might also introduce the concept that it wants all the test data to be within the product’s release limits so that the product’s shelf life stability would be ensured. This would thus give the group a broader reason for proceeding with this validation test, rather than merely looking for conformance to the USP content uniformity testing.

3. How Will the Process Be Validated?

The answer to this question determines the detailed activities of the validation protocol. It will state what tests will be used to determine if the process is under control. Furthermore, it will answer other questions, such as: How precise must the test results be before the specification limits will indicate when the process is reliable?

Should the worst-case scenario (e.g., a deliberate failure such as being at a level of 20% over the equipment’s working capacity) be included to ensure the validation of the process? How many batches must be manufactured before the committee will consider the process validated? Will the initial production batch be considered the final optimization or the initial validation batch?

In addition to data gathering, QA will want the validation batches made entirely by the production department. When this stipulation is satisfied, it will be demonstrated that the process control is independent of the technical background of the operating personnel. This kind of approach demonstrates that the manufacturing process will support the soon-to-be-marketed product’s volume demands. This approach also allows QA to have a baseline activity with which it can compare future audit activities.

Also see: Non-sterile Process Validation in Pharmaceuticals

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