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 This article reviews FDA’s most recent draft guidance, and emphasizes its tie in with good process design.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 , which was consistent with its previous guidance  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” “Q 9 Quality Risk Management”and “Q10 Pharmaceutical Quality Systems .
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.
The key to accomplishing effective and compliant Process Validation is to ensure that all three stages of Process Validation are performed effectively in a compliant manner. Though all stages of Process Validation are important, Stage 1 (Process Design) is the foundation of the overall Process Validation as subsequent stages (Stage 2: Process Qualification and Stage 3: Continued Process verification) are built on Stage 1.
Process Validation based on the lifecycle concept is like a multi-level building with Stage 1 (Process Design) being the foundation of the building, supporting not only the subsequent stages of Process Validation, but the Process Validation in entirety. Similar to the necessity of a strong foundation for supporting a strong building, a strong Process Design is necessary for supporting a strong Process Validation.
During Stage 1 of Process Validation, process development and scale-up activities are performed to establish scientific knowledge and data to define the commercial process with the overall objective of accomplishing the Process Design. The process knowledge and information gained at this stage help in developing the control strategy for routine production. During the Process Design stage, it is expected to understand the sources of variability, detect the presence, degree, and impact of variations on the manufacturing process. Strategy for controlling the variations should be developed on the basis of the assessment of the impact of variations on the product quality attributes.
Process variations may be caused by materials, equipment, production environment and manufacturing procedures changes. Since a manufacturing process must remain in a state of control over the process lifecycle even as the materials, equipment, production environment and manufacturing procedures change, the role of Process Design becomes crucial as it involves understanding, detection, impact assessment and control of the process variations that may ultimately impact the product quality attributes.
The revised guidance greatly emphasizes the significance of process variability, and Process Design mainly involves detection, impact assessment and controlling variations. Since Process Design is developed specifically for a particular process, it is not possible to discuss all sources of variability that may be applicable to all the processes. The following section attempts to present some examples of the sources of process variability that may help in addressing variations in general.
For example, variability in physical characteristics of raw materials can significantly impact the dry-blending process. Hence, it is important to consider the extent of controls exercised through the raw materials specifications to provide assurance that the process will continue to perform at the expected level. If the specifications for some critical raw materials permit wide ranges for the parameters like particle size distribution, bulk density, tap density and moisture content, it can cause significant variation in the process performance even when all raw materials meet the specifications. A sound Process Design should question the basis for developing the raw materials specifications and establish how the variation within the specifications for certain critical parameters may impact the process performance.
Selection of equipment design suitable for a manufacturing process is extremely important, and the impact of the variability originating from the equipment must be established at the Process Design stage. For example, a manufacturing process may allow the use of two alternative pieces having similar design and working principles, but the changeover from one piece of equipment to the other may cause process variability, and the impact of such variability on the process performance should be considered at the Process Design stage. Secondly, the performance of some equipment parameters may vary over a period of time causing variation in the process performance. For example, variation in the force of shaking the filter bags of a Fluid Bed Drier may cause a variation in the extent of dislodging fines from the filter bag. Such variation is generally not easy to detect, but it may cause significant variation of the Fluid Bed Drying process, thus causing variation in the quality attributes of the processed product.
In spite of proper training of the operators, some variations may be caused as there may be a difference in the performance of experienced operators and newly trained operators. Also, the operators working during night shifts may not be as alert as the operators working during day shift, and this difference may also cause process variations.
A strong interdisciplinary approach and systematic brainstorming sessions can prove very beneficial during the Process Design stage. It is important to involve operators in Process Validation activities, starting at the Process Design stage and continuing throughout the process lifecycle. Most manufacturing managers are well aware of the fact that the operators are like the eyes and ears of the process, and operators are generally the first to observe any abnormal process trends. Hence, it is important to have an open dialogue with the operators regarding their observations about the process and equipment performance on a regular basis throughout the product lifecycle. Most success stories about significant process improvements would not have been possible without operators sharing first-hand information and getting fully involved in the process improvement projects.
The overall approach to Process Validation provided in FDA’s revised guidance is holistic. The recommendations made in the revised Process Validation guidance are well-aligned with the FDA’s “Pharmaceutical CGMPs for the 21st Century – A Risk-based Approach” initiative. With the introduction of the lifecycle approach and emphasis on inter-disciplinary team efforts, the validation activities should cut across the boundaries of Validation departments and spread across the whole organization in order to make the Process Validation really effective and compliant. The revised guidance facilitates the adoption of the constantly evolving technological advancements and innovations. A clear understanding and widespread implementation of the revised guidance should provide a relief to the FDA-regulated industry that is generally perceived as rigid, adamant and reluctant to adopt new technologies. Since flexibility and change are the precursors to improvement, the revised Process Validation guidance will facilitate continuous improvement in the FDA-regulated industry.
1. “Process Validation: General Principles and Practices”, FDA’s Guidance for Industry (January 2011)
2. “Guideline for General Principles of Process Validation”, FDA’s Guidance for Industry (May 1987)
3. “Q 8(R2) Pharmaceutical Development”, FDA/ICH Guidance for Industry
4. “Q 9 Quality Risk Management”, FDA/ICH Guidance for Industry
5. “Q 10 Pharmaceutical Quality Systems”, FDA/ICH Guidance for Industry
Disclaimer: The views expressed in this article are the author’s own views and these do not necessarily represent any organization’s views. All questions should be directed to the author at [email protected].