Process validation for continuous manufacturing processes

Although some aspects of process validation for continuous processes are the same as those for traditional batch processes, there are some unique considerations. Gretchen Allison, senior director and team leader for Global Quality Validation, Pfizer Global Supply, spoke with Pharmaceutical Technology about these issues.

PharmTech: What are the key considerations for validating a continuous manufacturing process?

Allison (Pfizer): Key considerations for validating a continuous manufacturing process rely on many of the established principles of basic pharmaceutical process development, guides, and standards that the pharmaceutical industry generally applies to validating traditional batch processes—for example, the establishment of critical quality attributes (CQAs), critical process parameters (CPPs), and corresponding acceptance criteria for a given product and process. Other process validation considerations that apply to both traditional batch manufacturing and continuous manufacturing are the use of quantitative statistical methods (as appropriate) to evaluate the validation data and the evaluation of intra-batch and inter-batch variation.

System qualification of commercial equipment and other supporting systems, including process analytical technology and/or automation, is also necessary when validating a continuous manufacturing process, and it may be especially critical if some systems are providing real-time monitoring and control.

Considerations for continuous manufacturing process validation should demonstrate that the process is under control and can achieve expected performance. These include start-up and shutdown of the process, process run-time evaluation, and the ability to detect process excursions. Demonstration that the process-control system can reach and detect when acceptable product is produced may include a set of start-up and shutdown activities. The number of start-ups and shutdowns could be determined based on a risk analysis and the unique critical considerations for that process; examples may include process robustness, process flow rate and residence time, and the number and inter-relationship of CPPs/CQAs.  Process validation activities should consider both the optimum process run time and worst case (e.g., longest) process run time to determine if the system can reach and maintain the intended process conditions over the entire process. The ability to detect excursions from the target CPP or CQA values that may require the diversion of non-conforming material should be evaluated. How changes in the process production rate and/or equipment scale impact the process dynamics and whether the process remains in a state of control during commercial manufacture should also be evaluated.

Continuous process verification (per the International Conference on Harmonisation Q8) as an alternative validation approach can use in-line, on-line, or at-line monitoring or controls to evaluate process performance. This approach may be particularly well suited to the evaluation of continuous manufacturing processes and may enable the use of real-time release testing. Monitoring can be combined with dynamic control systems to adjust the process to maintain output quality. This capability also provides the advantage of enhanced assurance of intra-batch uniformity.  Using this approach, data from production batches can essentially support validation with each manufacturing batch, replacing a conventional process validation approach (e.g., three-batch validation at set-point) that was historically used.

PharmTech: Can you share any best practices around defining a batch/lot in practice?

Allison (Pfizer): Per the FDA Code of Federal Regulations, a batch/lot of material may be defined by a unit of time or quantity. It is typically defined by a unit of time that corresponds to known flow rate and residence time within the given unit operations of the manufacturing line. Clearly defined criteria are necessary to describe the state of control operation and to establish the lot product and process data (e.g., raw materials and processing conditions used) and material traceability.

PharmTech: Is real-time release testing able to be implemented at this stage? What are the challenges?

Allison (Pfizer): Pfizer has developed real-time release testing for some marketed products produced in specific manufacturing facilities. The application of real-time release testing is typically product/process specific and is often specific to given manufacturing facilities. Depending upon the specific process, there may be some challenges in the application of real-time release testing that impact the ability of sites to implement real-time release. Examples include:

• The ability to perform real-time monitoring, evaluation, and trending of some of the critical attributes and/or CPPs applicable to that product may present some technical challenges if robust selective analytical technologies are not yet developed.  

• Ensuring an adequately high sampling frequency for processes with high throughput and low mass/potency to detect potential perturbations that may impact product quality in a real-time manner.

• Ensuring that primary sensors are robust and accurate over the duration of the run, considering, for example, the potential for sensor fouling/buildup of product or sensor failure.

Other reasons why real-time release testing may be challenging include the up-front costs to develop and implement the technology and the limited number of users who have expertise with currently available tools.