Are Your Validation Efforts Based on Sound Process Design?

Process design is the key to effective validation

By Parveen Bhandola, Ph.D.

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Validating any pharmaceutical manufacturing process is a legally enforceable regulatory requirement required by current good manufacturing practices (cGMP) to ensure that drug products are made with the highest possible assurance that all quality attributes are met.

Validation establishes scientific evidence by collecting and evaluating data, to provide assurance that a process is capable of consistently delivering quality products within the commercial manufacturing conditions.

Beyond being a regulatory requirement, process validation makes good business sense, a point to which most experienced pharmaceutical industry professionals can attest. It prevents process failures and allows manufacturers to ensure, consistently, the quality of their products.

We see the results of insufficient validation in process failures, which often result in huge economic losses due to lost materials, time and manpower. In addition, the investigations and documentation associated with these failures can entail huge cost. Longer term, poor validation can have an impact on manufacturer reputation and lead to lost business opportunities. Above all, there is the risk of major regulatory action, such as consent decrees.

Effective and compliance process validation is thus critical to both regulatory requirements and business expectations. However, pharmaceutical manufacturers need to go beyond the minimum requirements and understand regulators’ expectations in light of evolving industry standards. This article reviews FDA’s most recent draft guidance, and emphasizes its tie in with good process design.

Last year, the FDA issued new guidance [1], which was consistent with its previous guidance [2] on validation. However, the newer guidance offers a much more elaborate and detailed description, describing validation as a continuous process consisting of distinct stages, each aligned with the product lifecycle stage, as outlined in FDA/ICH’s guidances “Q 8(R2) Pharmaceutical Development” [3]“Q 9 Quality Risk Management”[4]and “Q10 Pharmaceutical Quality Systems [5].

The revised guidance greatly emphasizes the need for pharmaceutical manufacturers to adopt a science and risk-based approach to validation, fully supported by sound statistical analysis of the process performance data. The guidance expects each manufacturer to strive to develop product and process understanding throughout the product lifecycle in order to improve quality, safety and efficacy.

The lifecycle approach requires starting the Process Validation activities at the Process Design stage and continuing these activities throughout commercial production. FDA’s latest guidance breaks down process validation into three stages:

Stage 1: Process Design
Stage 2: Process Qualification
Stage 3: Continued Process Verification

All stages of Process Validation should be scientifically designed and well-documented. Adequate documentation during all three stages of Process Validation is a regulatory requirement, and this should form the basis of making data-based decisions regarding the process performance at various stages of the product lifecycle. Regulatory expectation for documentation is obviously higher at Stage 2 and Stage 3 as compared to Stage 1 of Process Validation because the first stage is fundamentally a development stage, whereas the last two stages are performed under strict CGMP conditions.

Stage 1 (Process Design) involves generating process knowledge and understanding through well-designed and documented studies for the purpose of developing a strategy for process control for each stage of manufacturing to provide assurance for the overall process to remain in a state of control.

Process Design activities should guide the development of master production and control records. An effective Process Design is essential for developing a process that is capable of reliably and reproducibly producing the product with the intended attributes in routine manufacturing.

Stage 2 (Process Qualification) consists of the following two elements:

a) Design and qualification of the process equipment, utilities and facility
b) Process Performance Qualification

Process Qualification activities begin with the selection of the design for the process equipment, utilities and facility and verification of the selected design for its suitability for the intended process within the complete range of operating conditions. The Process Performance Qualification (PPQ) is somewhat synonymous with what had been, until recently, termed as Process Validation. It is performed under cGMP conditions, and it involves demonstrating controls over the commercial manufacturing process.

PPQ is performed under commercial manufacturing conditions by the personnel trained in commercial manufacturing process according to the controls established through master production and control records. It is important to understand the significance of “commercial manufacturing conditions,” which means that the demonstration of controls should include variability that may be caused by operator-to-operator, shift-to-shift and equipment-to-equipment (for similar equipment).

It should also include potential impact of shift changeovers as well as the effects of breaks or time lags during various stages of the manufacturing process. The equipment, utilities and facility used for PPQ must be qualified, and the raw materials/components must conform to the pre-defined specifications. The product cannot be commercialized before the successful completion of PPQ. The number of batches to be manufactured during PPQ depends on the risk associated with the process and the extent of process data generated during the Process Design stage.

Stage 3 (Continued Process Verification) involves the monitoring of critical process parameters and quality attributes during routine manufacturing to provide ongoing assurance that the manufacturing process continues to remain under the state of control. Continued process verification is extremely crucial as it helps in detecting process drifts and evaluating the unplanned and unexpected process variability that almost invariably creeps into the system in spite of having well-developed change control systems in place. Timely action based on the detection and evaluation of such variabilities can help keep the process in a state of validation.  

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