“Life cycle Approach to Process Validation” -Current Regulatory perspective & It’s Benefits

“Quality has to be built-in into the process and cannot be relied on the testing of final product”

“Process Validation (PV)” concept in pharmaceutical industry was first proposed by USFDA officials, namely, Ted Byers and Bud Loftus in mid-1970, who believed that, introduction of PV will help to improve the quality of pharmaceutical products. Though, initial proposal was in direct response to several problems in the sterility of large volume parenteral market and first validation activities were focused on the processes involved in manufacturing these products, which subsequently expanded to associated processes including environmental control, media fill, equipment  sanitization, purified water production, process equipments software, methods and processes etc.

 First USFDA draft guidance document on “PV” came into existence in 1987. The objective of the guidance was to bring awareness among the pharmaceutical sphere in describing the agency’s thinking so as to produce safe and consistent quality of medicines to patients. As the new concepts of “Quality by Design/(QbD) ” emerge with the inception of ICH guidelines namely, Q8, Q9, Q10 & Q11 , which led to introduction of enhanced approach of validation as “Life Cycle Approach to Process Validation” explicitly outlined in the PV guideline released by USFDA in January 2011.

 PROCESS VALIDATION – LIFE CYCLE APPROACH: 4 STAGE PROCESS:

The current life cycle approach to “Process Validation” divulges that PV is a journey and not a one-off event of just completing the 3 PV runs. All phases in the life of a product from the initial development through marketing until the product’s discontinuation is called life cycle approach to PV.

Enhanced PV model is a science and risk based approach aligning with the principles of “Quality by Design” articulated in ICH guidelines Q8, Q9, Q10 & Q11. A lifecycle approach is applied linking product and process development, validation of the commercial manufacturing process, and management of the process within the change management system to make sure maintenance of the process in a state of control during routine commercial production” is defined below:

Stage-1 : Process Design : The commercial manufacturing process is defined during this stage based on knowledge gained through development and scale-up activities.

Stage-2 : Process Performance Qualification (PPQ) : The process design is evaluated to determine if the process is capable of reproducing commercial manufacturing.

Stage-3 : Continued/Ongoing Process Verification (CPV/OPV): Ongoing assurance gained during routine production that the process remains in a state of control.

Stage-4: Change Management and Re-validation : Ongoing assessment of the process as part of change management system to ensure the revalidation and maintain continuum validated state of control.

STAGE-1: PROCESS DESIGN - APPROACH TO PROCESS DEVELOPMENT: 3 STEPS

The approach to, and extent of developmental study can vary, however the intent is to apply systematic approach to evaluating, understanding and refining the manufacturing process, including but not limited to as following:

Step-1: Establishing Critical Quality Attributes (CQAs):

A CQA is a physical, chemical, biological, or microbiological property or characteristic ensured to design to be within an appropriate limit, range, or distribution to ensure the desired product quality.

Identifying, through e.g., prior knowledge, laboratory experimentation and risk assessment, the material attributes (e.g., of raw materials, starting materials, reagents, solvents, process aids, intermediates) and process parameters that can have an effect on final product CQAs.

Final Product CQAs typically include those properties or characteristics that affect identity, purity, biological activity and stability. When physical properties are important with respect to drug product manufacture or performance, these can be designated as CQAs for example, particle size, bulk density etc.

Impurities are an important class of potential final product CQAs because of their potential impact on drug product safety. For chemical entities, impurities can include organic impurities and residual solvents and their limits can be defined in-line with the ICH Q3A and Q3C respectively.

Step-2: Linking Critical Material Attributes (CMAs) & Critical Process Parameters (CPPs) to Critical Quality Attributes (CQAs):

Material attributes and process parameters with the potential for having an effect on final product CQAs can be evaluated as part of quality risk assessment and those found to be critical to the process should be linked to process control strategy.

For Chemical entity development, a major focus is knowledge and control of impurities. It is important to understand the genesis of the impurity, fate (whether the impurity reacts and changes its chemical structure), and purge (whether the impurity is removed via washing, crystallization etc.) as well as their relationship to the resulting impurities that end up in the drug substance as CQAs.

For example; Any individual impurity is controlled at starting material stage and washed out during the crystallization process, however two dimensional process parameters can play an important role to purge out the impurity effectively i.e. crystallization time versus temperature. The process should be evaluated with the multivariate experimental design study (QbD/Design space) to establish appropriate controls for such impurity so as to put adequate control strategy.

Step-3: Establishing an appropriate process control strategy:

Using the enhanced approach in combination with QRM (ICH Q9) to establish an appropriate control strategy which can include a proposal for a design space(s).

A control strategy is a planned set of controls, derived from current product and process understanding that assures process performance and product quality (ICH Q10). Every manufacturing process, whether developed through a traditional or an enhanced approach (or some combination thereof), has an associated control strategy.

A control strategy can include, but is not limited to, the following:

• Controls on material attributes (including raw materials- starting materials, reactive reagents and /or solvents, intermediates, primary packaging materials for the packaging of final product etc.).
• Controls implicit in the design of the manufacturing process (e.g., sequence of purification steps or order of addition of reagents [chemical entities]).
• In-process controls (including in-process tests and process parameters), Controls on drug substance (e.g., release testing). 

STAGE-2: PROCESS PERFROMANCE QUALIFICATION (PPQ) :

“Determining if the Process Design is Capable of Reproducible Commercial  Manufacturing”

Prerequisite to PPQ?

Based on the process design and control strategy outlined as part of product development document, cross functional teams identifies the execution strategy for the PPQ batches, below are the prerequisite being ensured by the team prior to start with the PPQ batches:

• Verification of the Process design to meet the requirements such as identification of Critical quality attributes, critical material attributes, critical process and in-process parameters requirements and control strategy for the process.
• Qualification and suitability state of the equipments against the process design range intended for the batch processing such as reactor, filtration, dryers etc.
• Qualification and suitability state of the “utilities or ancillary support systems against the process design range such as; HVAC, Water system, Air, Nitrogen, clean room areas etc.
• Qualification and suitability state of the measuring devices against the process design range such as Temperature gauge, pressure gauge, flow meter etc.
• Qualification of Vendors related to Key starting materials and packaging materials.  
• Applicable Standard Operating Procedures (SOPs) are approved.
• Applicable Master Batch Processing Record and cleaning records are approved.
• Approved specifications and testing methods for the raw materials, in-process controls / checks, intermediates and final product.
• Method validation status of the testing procedures intended for the release/stability of the product.

Execution and Evaluation:

Process qualification runs are executed on the pre-approved plan defined by multi-disciplinary team, followings (but not limited to) are suggested to ensure as per new approach to PPQ:  

• Background of the PPQ batches with explicit reason for the study.
• Approach to PPQ to be used, either “Prospective or Concurrent”, with justification as applicable.
• Number of process qualification runs and /or selection of batches (if more or less than three with scientific rationale), fixed/throughput /variable batch size.
• Brief description of the manufacturing process, Synthetic scheme, and Process flow diagram and critical steps highlighted with control strategy.
• Monitoring and collection of data on the Critical Process Parameters (CPPs) and In-process parameters.
• Descriptive sampling plan with the explicit requirement on defining the location, sampling quantity, methodology of sampling with responsibility, testing plan for in-process parameters, Intermediates, and final product.
• Additional testing proposed for the PQP batches, in-process /unit operation steps, intermediates or final product.
• Monitoring and collection of data on the Critical Quality attributes & yield of Intermediate(s) and/or final product.
• Recording of on-line observations such as non-obvious observations, delays, down time, coloration, crystallization pattern, time etc.
• Acceptance criteria for each of the process parameters, in-process parameters, critical quality attributes, yield attributes etc.
• Guidance on the data gathering from the sources, their compilation and evaluation.
• Guidance for the actions needed in case of Change / Deviation / Failure/outlier/aberrant results.
• Requirement and justification for the initiation of Holding time /stability study.
• Training of personnel to be involved into the PPQ Batches.

Successful outcome of PPQ batches and learning have been should be regularized as part of recommendations/CAPAs so as to include the detailed process control strategy for routine commercial manufacturing.

CONTINUED/ONGOING PROCESS VERIFICATION (CPV/OPV):

CPV/OPV is an ongoing program to collect and analyze the data in order to assure that, process remains in state of control or qualified state throughout the commercial manufacturing. The data collected should include relevant process trends and quality of incoming materials or components, in-process material, and finished products, such as but not limited to as below:

• CMAs for key critical materials.
• Critical process parameters (CQA) identified such as, temperature, pressure, flow rate, addition time, time limits, processing steps/limits.
• Reactions conversion, mass balance on crude unit operations, in-process & intermediates.
• Critical quality attributes (CQA) of Intermediates and final product.
• Inter and intra batch variance to determine the influencing cause of variance.
• Trend assessment on Out of Specification (OOS)/out of trend (OOT) investigations, customer Complaint rates with their criticality.
• Trending on deviations, change controls and Corrective and preventive actions (CAPA).
• Statistical trend assessment to determine the normality tests, measure of spread in terms of mean, mode and median to understand the behavior of data.
• Evaluation of process capability to determine to determine the sigma band/Cpk.
• Overall assessment & conclusion on Continued/Ongoing process verification (CPV/OPV).

STAGE-4: CHANGE MANAGEMENT AND REVALIDATION:

Change management system is an ongoing tool used from stage-2 onwards through commercial stage to assess the potential impact of changes, their adequate implementation and closure with effectiveness check to make sure that, the process is maintained in state of control throughout the process life cycle. The extent of changes which can warrant the existing qualification state and pose a high risk to quality, regulatory, GMP, patients should be evaluated with the greater extent and thorough assessment. Revalidation exercise may be necessary , where appropriate (but not limited to) as below:

• Changes to the manufacturing process, such as process parameters, gradients input ratio, route of synthesis etc.
• Change in batch size, manufacturing equipment at the same /different blocks /different site (Equipment with similar or different design).
• Change in the source of starting materials/intermediates vendors other than the registered one.
• Change in the specifications, analytical procedures of starting materials, intermediates, final product.
• Online trending based on reoccurring events such as investigations (customer complaints/OOS/Outliers) or significant variations observed during the PQ and/or CPV review and /or APR/PQR.

SUMMARY AND CONCLUSION : - POSITIVE ASPECTS OF LIFE CYCLE APPROACH:

New life cycle validation model is a science and risk based approach and consistent with the “Quality by Design” approach that is articulated in ICH guidelines Q-8, Q-9, Q-10 & Q11, positive aspects of the new approach are as follows:

• Robust process validation approach will lead to consistent and reliable quality of product.
• Reduction in cost of quality, time and energy.
• Ongoing statistical evaluation of data will detect the trending at early stage to avoid potential failures at later stages.
• Right first time solutions can be offered in avoiding reduction in rejections/recycles.
• Continuous improvement overtime rather than incidental based such as failures/oos.
• Increased into the machine efficiency in enhancing the productivity outlet.
• Implementation of real time release testing in lieu of end product testing based on statistical evaluation.
• Relief in drug application approval process and reduction/fast approval in post approval changes.