Process Validation – Developing a Robust Strategy

Developing a comprehensive process validation strategy early in clinical development is critical to the execution of a successful validation program. Development and process support activities leading up to Process Validation require the allocation of dedicated internal and external resources. Due to the changing nature of validation requirements, partnering with external resources like BioTechLogic, who are experts in the area of Process Validation, can prove to be an important decision in completing the validation program successfully. Time and budgetary constraints do not allow for repeating required activities, so all resources need to be proven in their experience. Development of the validation strategy, a major portion of which is through definition of the process to be validated, will help define the development path, focus the resources to execute the key studies, and drive the validation exercise.

The first stage of the validation strategy defines the process parameters and activities related to each stage of production process. Using the FDA’s Quality by Design initiative as a basis, Process Definition activities are identified which define the exact process to be validated. The process parameters included in the manufacturing instructions should be examined to establish operating ranges based on experimental or manufacturing data. The analytical methods which will be used to define the process need to be qualified and validated. The quality of the starting materials and raw materials should be defined, and the capability of the operators, facility, equipment, and utilities should be examined using historical data, deviations, and planned experiments during clinical batches. Finally, the strategy for product specific cleaning has to be designed.

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. Understanding concentration and purity/impurity methods, such as UV and HPLC, at an early stage is important so variability can be taken into account during the analysis of data from development studies. Analytical methods used in critical parameter determination studies (e.g., DOE, OFAT) should, at a minimum, be qualified to ensure the data generated is meaningful for making decisions on the criticality of parameters. This will give greater assurance to the results, and can sometimes reduce the amount of replicates needed during range-finding experiments.

Once analytical method qualification and validation are complete, all changes are assessed for impact to the respective method as part of the change control program and re-validation is performed as needed.

Multi-compendial grades for raw materials should be used and in-house specifications established as early as possible in the development process. Raw materials should be sourced from approved vendors or full testing according to the Certificate of Analysis (C of A) should be performed until vendor qualification is complete. Every effort should be made to avoid use of animal derived materials. 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 materials should be evaluated based on where the raw materials are used in the manufacturing process, criticality, regulatory grade requirements, vendor information, and in-house specification references.

The facility should be qualified for manufacturing the intended product. Procedures need to be in place for quality systems management such as facility cleaning, gowning, personnel/equipment/material flow, environmental monitoring, calibration, change control, and preventive maintenance. A strategy for open and closed processing steps should be developed so appropriate environmental and process controls can be established. More stringent environmental requirements are implemented as the product moves from the fermentation/cell culture area through isolation and purification. These facility pre-validation activities are documented in reports and outlined in facility flow diagrams that can be used to show control of the environment, product, personnel, material and contamination. A comprehensive list of supporting information related to facility control can be used for regulatory submissions and used as references during pre-approval inspection (PAI) readiness activities and the PAI.

The installation and operation of all utilities should be qualified prior to use in the process through commissioning, design qualification (DQ), installation qualification (IQ) and operational qualification (OQ) studies. When the actual process is performed, specifications ensure that all processing ranges are within the ranges specified in the user requirements, commissioning documents and those qualified during the IQ and OQ. Acceptability of utility performance through points of use should be confirmed through performance qualifications (PQ). While 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 within 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 within the qualified ranges of the equipment, and all contact surfaces are compatible with product/process solutions. As with utility systems, documentation reviews can be continually performed as changes are made to ensure the process is operated within the previously qualified ranges. During process validation, or sooner if resources allow, performance qualification studies on critical pieces of equipment are performed to ensure the equipment is appropriate for the specific product being manufactured. Equipment qualification packages also provide reference to equipment/system numbers, calibration and preventive maintenance schedules and qualification reports.

Cleaning is also a critical aspect of process definition. The same approach can be taken for cleaning equipment and reusable components (e.g., resins, membranes) that is taken with cleaning of areas within the facility (i.e., floors, walls, ceilings). The cleaning agents used should be assessed for both compatibility and effectiveness. To assess compatibility, studies to show the cleaning method does not adversely affect the contact surfaces should be performed. To evaluate cleaning effectiveness, the cleaning method should be challenged with various types of organisms (e.g., gram-negative, gram-positive, yeast, spore former, etc.) – preferably environmental isolates – to show the objective of cleaning is met. Since it is practical to perform cleaning validation during the Manufacturing Qualification batches, it is important to ensure that all cleaning methods are appropriate for use and qualified to appropriate limits.

The second stage of the validation strategy is validating the large scale manufacturing process. There are three phases of Process Validation. Phase 1 is comprised of Pre-Qualification activities which generate the list of critical process parameters used in the Manufacturing Qualification Protocol. Phase 2 is the execution of the Manufacturing Qualification during a minimum of three batches to demonstrate the critical parameters can be adequately controlled, and all in-process controls and specifications are met. Phase 3 is ongoing process monitoring through Life-Cycle Qualification to ensure the quality attributes of the process are not trending negatively within a specification range.

Pre-Qualification is comprised of performing process understanding studies to establish the design space for all process parameters, determining which parameters are critical, and executing supporting validation studies. Because the Pre-Qualification activities involve the evaluation of process parameters and their ranges, the manufacturing instructions need to be finalized prior to starting this activity. The key to meaningful pre-qualification studies is a process pre-qualification plan that is based on a well-defined manufacturing process. This is completed by a thorough analysis of the potential study and how it relates to the desired quality attributes of the product at that stage of the process. For example, chromatography resin re-use (lifetime) studies should only begin when the complete chromatography cycle (sanitization, equilibration, loading, elution, regeneration, cleaning and storage) and the procedure for the manufacture of the starting material (i.e. load) is defined.

Risk assessment and range-finding studies should begin when a complete list of parameter ranges from the manufacturing instructions is compiled. Each parameter is assessed for its potential to affect (positively or negatively) the applicable process controls or quality attributes. Each parameter is given a numerical rating based on the likelihood and potential magnitude of impact (e.g., FMEA), which often includes an evaluation based on scientific rationale of the control mechanism. The parameters that have the highest likelihood and potential to affect the process undergo range-finding studies (e.g., DOE, OFAT) and the outcome for each studied parameter is the relationship between its normal operating range (control space) and its proven acceptable range (design space). The normal operating range is the range at which the parameter is typically controlled during routine operations and is usually the range found in the manufacturing instructions. It takes into account the minimum and maximum values tested during initial development and a review of process history which shows the capability of the operators, facility, equipment, and utilities. The proven acceptable range is defined by the minimum and maximum values for each parameter found during the range-finding studies. Range-finding studies are often designed such that the ranges studied are at least two times (2X) the normal operating range.

The criticality of each process parameter is determined by analyzing the relationship between the operating range, acceptable range and the failure limits. In general, if the acceptable range is approximately 2X the operating range, then the parameter is considered non-critical. This designation implies the parameter can be controlled by the operator or automation system, and even a significant deviation from the setpoint would not impact the manufacturing process. Conversely, if a parameter’s operating range is close to its acceptable range, this indicates that a deviation to the normal operating range would likely result in a failure to an in-process control, in-process specification, or the batch. This parameter would be deemed critical. This analysis is continued until the criticality of all parameters is evaluated, and their potential to impact the process has been determined.

The Pre-Qualification phase is also when most supporting validations are performed because they define parameter ranges of the process. However, not all supporting validation studies are able to be completed in this phase of the Process Validation. For example, during shipping validation, the product packaging and shipping procedures are defined, qualified and validated. These studies, nonetheless, could be performed any time prior to the pre-approval inspection and utilize the shipments of the material produced during the manufacturing process qualification to confirm shipping conditions. In this example, the packing configuration, procedures, laboratory simulations and study design would be completed during the Pre-Qualification, but the actual shipment verification could be performed at a later time.

The Manufacturing Qualification entails the performance of three, consecutive runs at the intended commercial scale. The manufacturing process qualification is performed under a prospective protocol using the appropriate output and results from the Pre-Qualification studies (e.g., critical parameters), in-process controls and specifications, and any additional criteria specific to the process. Critical to this phase is demonstrating the operators can perform processing according to the manufacturing instructions, and that the processing steps remove the process and product related impurities during at least three consecutive batches. Limits and specifications for the Manufacturing Qualification are defined during the Pre-Qualification phase.

The last phase is the ongoing assessment of process performance through Life Cycle Qualification, and management of process changes. Criteria are outlined in a prospective life-cycle qualification protocol and appropriate standard statistical process control (SPC) techniques (control charts, ANOVA, Western Electric Tests, etc.) are used to confirm ongoing acceptability of process performance. Critical parameters are monitored routinely during batch release and compiled with the SPC data for Annual Reporting. After validation, all changes made to manufacturing procedures are assessed for impact to the validated process, and re-validation is performed as needed.

A robust process validation strategy early in clinical development is critical to the execution of a successful validation program. The magnitude of activities leading up to the qualification batches requires resources and expertise which exceeds those in place for routine development and production. If a sound strategy is developed for the Process Definition stage and completion of the Process Validation phases, the risk of repeating the validation exercise is greatly reduced. Additionally, with the proper resources and comprehensive strategy established, the validation exercise will generate a complete and thorough list of documents, reports, flow diagrams and references which will facilitate regulatory submission writing and PAI readiness activities.