Guideline for Process Validation
To define the procedure for exhibit batch monitoring and process validation of drug products for meeting all the predefined attributes and the process is capable of consistently delivering quality products. This involves the collection and evaluation of data from the process design stage through commercial production to establish scientific evidence that the process is capable of consistently delivering quality product with process performance qualification approach.
Scope of Guideline for Process Validation
This Guideline shall be applicable to manufacturing process of the Drug Products manufactured .
- To prepare the SOP.
- To prepare and review process validation protocol and report.
- To execute as well as ensure of process as defined in the batch record and protocol and relevant operating procedures.
- To ensure the different stage sampling as per validation protocol.
- To comply and review process validation report.
- Investigating any deviations from defined manufacturing process and identifying CAPA.
- Training regarding defined procedure under approved protocol, BMR, BPR etc.
- To check and verify the process parameters and data in process tests.
- To perform the sampling as per the approved sampling plan.
- Execution of validation activity as per protocol.
- Update the batch records as per conclusion of validation results.
Quality Control Department:
- To analyze the process validation Samples.
- To provide the data for process validation reports.
Quality Assurance Head/Quality (QA/QC) Head:
- To ensure implementation of the defined system.
To approve & authorize the process validation protocol as well as reports
- To ensure implementation of the defined system.
- To facilitate for execution of the activity.
Research and Development (R&D):
- Provide Manufacturing formula to the site containing list of CPPs, CRITICAL QUALITY ATTRIBUTES and risk assessment.
- Provide specification for input materials, semi-finished and finished product.
- Provide support to Production & QC in process related & analytical related issues.
- Stages of Process Validation : Process Design.
- Process Qualification. Continuous Process Verification.
This is define as transforming of starting materials into finished product through a single operation or a sequence of operation involving processing equipment under suitable environmental controls. This procedure describe the life cycle approach linking the product and process development validation of the commercial manufacturing process and maintenance of the process in a state of control during commercial production.
The objective of this is to develop process control and design a process suitable for routine commercial process that can consistency deliver a product meeting the product quality attributes. This stage cover all the activities related to product research and development, formulation, scales-up/pilot batch studies and final transfer of technology to
Manufacturing site. Product shall be developed as per QbD approach and the commercial manufacturing process shall be define by formulation and development department.
During this stage, the designed process is evaluated to determine if it is capable of reproducible commercial manufacturing. This stage has two elements.
During the facility and qualification of equipment and utilities: The facility, equipment and utilities should be qualified before use.
Process performance qualification involve completion of prerequisite qualification checks for facility, equipment, utilities and personnel, followed by performance qualification of the process to confirm whether it is capable of reproducible yielding quality product at commercial scale.
Organizing and Planning for Process Validation:
The first stage of process validation, which is process deigns, shall be completed at R&D and based on this master formula card (MFC), shall be issued to the plant. Plant shall prepare its manufacturing documentation based on MFC. The document issued by R&D should contain the critical process parameters and the critical quality attributes since these will form the basis of the process validation and process control at the plant. The product development record can be maintained at R&D, however a copy should be available for reference at the plant when requested.
The first element of the second stage of process validation (Process Qualification), which is design / qualification of facilities / equipment shall be completed and be signed off. The second element, which is process validation, will then follow. At the time of commencing the process validation, all qualification record should be approved and singed off and should be available for reference.
Continuous Process Verification (CPV):
The third stage is continuous process verification that the process remains in a state of control during commercial manufacturing. A system for detecting unplanned departures from the process as designed is essential to accomplish this goal.
The data collected should include relevant process trends and quality of incoming materials of component, in-process materials and finish products. The data should be statistically trended and reviewed by trained personnel. The information collected should verify that the quality attributes are being appropriately controlled throughout the process. The continuous monitoring and sampling of process parameter and quality attributes at the level established during the process qualification stage until sufficient data are available to generate significant variability estimates.
Data gathered during this stage might suggest ways to improve and / or optimize the process by altering some aspect of the process of product, such as the operating condition, process controls, and component or in- process material characteristics.
The procedure starts with collection of the data from first batch (CRITICAL QUALITY ATTR1BUTES, CPP & OCL).During second batch manufacturing all CRITICAL QUALITY ATTRIBUTES s, OCLs &CPP will online verified with pervious recorded batch data. This routine will be repeated with every batch. Collected data will be maintained in validated excel sheet. If any deviation observed then handled with approved handling procedure for deviation. It will help us to give continuous quality product.
- For existing batches, CPV monitoring Plan shall be started after data availability of at least 30 commercial batches or commercial batches manufactured in last two years,
CPV monitoring Plan shall include the following points but not limited to:
Evaluation of Post PPQ Batches: Batches manufactured post PPQ process shall be evaluated to get assurance of the process / product robustness so that any drifts from the PPQ batches may be addressed immediately.
Annual Product Review (APR) – APQR SOP shall be referred during APR preparation and approval.
Assessment and identification of drug Product CMAs, CRITICAL QUALITY ATTRIBUTES s and CPPs and setting of Statistical control Limit for CRITICAL QUALITY ATTRIBUTES s, CPPs and CMAs.
Product data shall be collected to evaluate process stability and capability, and scrutiny of inter-batch and intra-batch variation shall be carried out using appropriate statistical techniques.
Based on the evaluation, ways to improve and / or optimize the process by altering some aspect of the process or product, such as the operating conditions (ranges and set-points), process controls, component/ in-process material characteristics, etc. shall be checked out.
Based on the assessed data, Limit of UCL and LCL product wise shall be defined in excel sheet and after implementation of CPV every batch data shall be recorded in that excel sheet. In case variation/change in process it will reflect and If changes are mandated as a conclusion of the CPV process, a well-justified rationale for change, an implementation plan and QA approval before implementation must be documented. Depending on how the proposed change might affect product quality, additional process design and Process Qualification activities could be warranted.
Note: For existing Product – CPPs and CMAs shall be collected from retrospective commercial batches and for New (QbD) product CPPs and CMAs shall be referred from development report, Process qualification report, and PV report. Failed batches shall be excluded during data assessment.
The validation should cover all manufacturing strength of the product. Validation conducted on at least three batches. The validation may need to supplemented with further data obtained from subsequent batches as a part of an on/going a process verification exercise. However number of validation batches may be reduced based on scientific justification and risk assessment.
The validation study should cover entire ranges of variable manufacturing process parameters. During the manufacturing of scale up/down studies i.e. exhibit batches full
ranges of variable process parameters should be challenged to assess the risk on critical quality attributes. Based upon the outcome, MFC to be revise to set the target range with operation ranges.
During commercialization of the product, if there is no change in batch size, final ranges (operational ranges) given in MFC to be validated with target set parameters. However, if during commercialization of the product, batch size different from the exhibit batch, then based on the Quality Risk Assessment ,R&D shall provide the revised MFC for the proposed variable process parameters and accordingly final ranges( operational ranges) given in the MFC to be validated with target set parameters.
Different strength may be validated individually or a bracketing approach may be acceptable for different strength, batch sizes and pack sizes. Bracketing approach shall be governed through adequate scientific Quality Risk Assessment Process.
Where multiple batch sizes are available for a product, process validation shall be performed for each batch size .However validation sampling can be restricted to only those until process that have impact due to difference of batch size
As part of process validation life cycle, some process validation studies may be conducted on pilot scale batches. If the process has not yet been scaled up to production scale. It should be noted that pilot batch size should correspond to at least 10% of the product scale (i.e. such that the multiplication factor from the scale up does not exceed 10.For solid oral dosage forms this size should generally be 10% of the maximum production scale or1,00,000 units whichever is greater. Where the intended batch size is less the 1, 00,000 units, predictive value of the pilot batches may be limited and a justified approach should be followed. However batches manufactured for process validation should be the same as the intended commercial scale batches and the use of any other batch sizes should be justified.
If any product is planned for manufacturing and number of batch of product is one, then in this case verification shall be performed in that batch.
Hold Time Study of the validation batches shall be performed on intermediate stages of products (Semi-finished product).Test to be performed during hold time study shall be as per hold time study protocol of respective products.
The outcome of process validation activities shall be integrated into routine production operation by revising applicable documents (SOP/BPR etc.) through a change control.
For example: There could be instances wherein certain process parameters may be confirmed after validation batches are manufactured. These parameters shall be included into the batch production record to be followed for subsequent batches.
Analytical methods used for the input materials, semi-finished product analysis and analytical method used for analysis of cleaning validation samples shall be validated before taking validation batches.
Releasing Validation Batches:
Batches under process validation shall be released for distribution after successful completion of the validation exercise and review, approval of validation report with supporting raw data.
In exceptional circumstances, where there is a strong benefit- risk ratio for the patient, batch can be released to market on the basis of result for composite or pooled sample of finished product, before compilation of validation report. In such case, Concurrent validation could be used. However, the decision to carry out to Concurrent validation must be justified through scientific ORM process by authorized personnel.
Validation batches can be released for distribution in case of urgent market requirement or if the product ls In short supply. In such case, release of batches should be based on a detailed risk assessment which should be adequately documented and approved. The risk assessment should consider the formulation, the result of process control checks, results of finished products testing.
The suppliers of raw materials (API & excipients) and packaging materials should be qualified prior to the manufacturing of the validation batches. If qualification not completed, a justification based on application of quality risk management principles should be documented.
Note: For process validation batches, personnel from production, R&D or other site transfer be also be involved.
Process Validation Protocol:
Process Validation Protocol should include, but should not be limited to:
A short description of process and reference to the respective Batch Production Record, MFC, Semi -finished and finished product specification.
Explanation: The commercial manufacturing procedure should be followed and batches should be manufactured under normal condition by the personnel routinely expected to perform each step of each unit operation under process. Process validation should not exceed the process parameters defined, unless recommended by R&D.
Functions and responsibilities of individual/ departments.
Summary of Critical Quality Attributes to be investigated.
Explanation: CRITICAL QUALITY ATTRIBUTES is a physical, chemical or microbiological property or characteristic that should be within an approved limit, range or distribution to ensure the desire product quality. The CRITICAL QUALITY ATTRIBUTES should be investigated, decided based on the development report, detailed risk assessment and this should be a part of Master Formula ,issued by R&D. This should form the basis for the validation and should be a part of the protocol. Once validation completed, the risk assessment should be repeated and based on the observed result it should be determine if the risk has been mitigated. This should be documented in Validation Report. If risk has not been mitigated then appropriate action shall be taken based on extent on risk failure.
Summary of Critical Process Parameter (CPPs) and their associated limit.
Explanation: A critical process parameters is a process parameter whose variability has an impact on a critical quality attributes and therefore should be monitored and controlled to ensure the process produces the desired quality. The CPPs to be monitored should be decides based on the development report and a details risk assessment and this should be a· part of MFC issued by R&D. This should form the basis for the validation and should be a part of protocol. Once validation is completed, the risk assessment performed initially
should be reviewed and based on the observed result it should be determined if the risk has been mitigated. This should be documented in the validation report. If the risk has not be mitigated then appropriate action shall be taken based on extent of risk failure.
Summary of Operating Control Limit (OCL).
Explanation: An Operating Control Limit (OCL) is a process parameter whose variability has no impact on quality attributes but shall be monitored for process control ensuring
the process produces the desired quality products The OCLs shall be decided based on the development report and a detailed risk assessment by R&D.
Summary of other (Non-Critical) attributes and parameters which will be investigated or monitored during the validation activity and the reason for their inclusion.
List of equipment/facilities to be used (including measuring/monitoring/recording equipment) the rather with the calibration and qualification status.
In process controls with acceptance criteria and the reasons why each in process control is
selected (if provided by R&D).
Additional testing (If any) to be carried out with acceptance criteria.
Sampling plan with acceptance criteria and the rationale behind it.
Quality Risk Assessment:
A detail risk assessment should be perform to decide on the extent of validation to be perform and the parameters to be investigated. The parameters to be investigated should always include the CRITICAL QUALITY ATTRIBUTES and CPPs as minimum. Anything in addition to these can be included based on the nature of the product. During Validation any deviation observed should be handled through approved deviation handling procedure.
Excluding process parameters specified in the MFC is not advised unless recommended by R&D. A product subjected to stress testing should be released for distribution only after a detailed risk assessment.
Report shall be prepared after completion of activity and analysis of samples. The validation report shall include but not be limited to:
Batch Numbers of validation batches.
Details of input materials (Raw & Packing).
List of equipment’s used.
Summary of CPPs &CRITICAL QUALITY ATTRIBUTES.
Evaluation of analytical data against the acceptance criteria.
Incident/deviation if any.
Recommendation of the validation study and summary/conclusion of validation study.
In most cases PPQ will have a higher level of sampling, additional testing, and greater of process performance than would be typical of routine commercial production.
The level of monitoring and testing should be sufficient to confirm uniform product quality through the batch.
The increased level of scrutiny, testing, and sampling should continue through the process verification stage as appropriate, to establish levels and frequency of routine sampling and monitoring for the particular product and process. Considerations for the duration of the heightened sampling and monitoring period could include, but are not limited to, volume of production, process complexity, level of process, understanding and experience with similar products and process.
Note: The sample quantity must X to 3X in triplicates for blend uniformity and duplicate for representative sample for other stage. For sampling Methodology, Attachment V could be used for reference purpose to design the sampling plan but not restricted .The sampling and location should be as per product requirement, feasibility and regulatory requirements. A schematic diagram will be used to sampling location wherever possible.
The basic need for packaging validation is to enables packaging process to meet the Product, consumer and market requirement i.e. quality attributes in cost effective and consistency efficient, process.
Packaging operation shall be validated as below mentioned (but not limited) Speed
Pack Sealing Temperature (For Example: In case of tablet, Low speed & Temp. high description & RS testing must be done.)
Control on feeding quality/quantity
Container closure system
Challenge tests for rejection mechanism
Integrity of sealing
Challenge tests for detection of missing units. (e.g. Camera Challenge test)
Power Intensity (In case of induction sealers)
Packaging validation shall be performed as per the respective protocol to ensure its quality, identity and safety.
Stability Study of Validation batches:
The validation batches shall be subjected to stability study in their packs to generate data on stability of the product manufactured using the validated process However number of batches to be charged on stability depends upon the risk assessment and change control evaluation.
Any 00S/OOT observed for the stability sample be promptly evaluated for necessary corrective and preventive actions.
Handing of any deviation/incident/non-conformance during validation:
Deviation/incident/non-conformance observed during validation shall be investigated through its respective approved procedure.
Documentation at each stage of the process validation lifecycle is essential for effective communication in complex, lengthy, and multidisciplinary projects. Documentation is important so that knowledge gained about a product and process is accessible and comprehensible to others involved in each stage of the lifecycle. Information transparency and accessibility are fundamental tenets of the scientific method. They are also essential to enabling organizational units responsible and accountable for the process to make informed, science-based decisions that ultimately support the release of a product to commerce.
CGMP documents for commercial manufacturing (i.e. the initial commercial master batch production and control record and supporting procedures) are key outputs output of process design
The diagram of process flow for the full-scale process. Process flow diagrams should describe each unit operation, its placement in the overall process, monitoring and control points, and the component, as well as other processing material inputs (e.g., processing aids) and expected outputs (i.e., in-process materials and finished product).
It is also useful to generate and preserve process flow diagrams of the various scales as the process design progresses to facilitate comparison and decision making about their comparability
Reason for Conducting Validation/Revalidation:
Reason for Process validation/Revalidation of a manufacturing process shall be following (But not Limited to):
New Product Introduction.
Change in equipment train of the existing product.
Change in part of existing equipment.
Change in process/process chemistry of existing product.
Change in composition or component of existing product.
As any other change to process, that needs to evaluate the impact and monitor of change parameter I before implementation.
Changes in the batch size.
Periodic evaluation of validated process.
Based on product evaluation recommendation.
Change in the API/Excipient vendor/source.
Validation in case of change in material grade.
Change initiated due to Market Complaints, any deviation, any failure of stability study etc.
Any changes in regulatory requirements.
Changes in the source of raw materials.
Change in packing material. (Primary container/colure system)
Failure to meet product and process specification in batches would also require process revalidation.
Change(s) in actual process operating parameters of an existing process, component or item of equipment that may affect Quality or its validation status.
Change in batch size.
Change in batch formula.
Change in manufacturing location.
Abnormal trends in quality parameters observed in the APQR based or based on recommendation CPK.
Repeated 00S, OOT and manufacturing failure observed in such cases the decision
for revalidation shall be based on the outcome of investigation of the 00S, OOT and process failure.
Re-validation can include the entire process or part of the process that is impacted base on risk assessment/change control evaluation.
Note: Need of validation in case of change in excipient vendor shall always be based on the impact assessment. A minimum of three batches shall be chosen for revalidation.
Process validation is defined as Collection and evaluation of data, from the process design stage through Commercial production, which establishes scientific evidence that a process is Capable of consistently delivering quality products. Process validation activities performed in three stages such as, Process design, Process Qualification and Continued Process Verification.
This is the activity of defining the commercial manufacturing process that will be reflected in planned master production and control records. The goal of this stage is to design a suitable process for routine commercial manufacturing to consistently deliver a product that meets its quality attributes.
Releasing for distribution a lot of finished product, manufactured following a qualification protocol, but before the entire study protocol has been executed.
Process qualification is the qualification of manufacturing and production processes to confirm they are able to operate at a certain standard during sustained commercial manufacturing. Data covering critical process parameters must be recorded and analyzed to ensure critical quality attributes can be guaranteed throughout production.
Continuous Process Verification (CPV): •
Ongoing assurance from data evaluation of routine production that the process remains in state of control.
Reprocess validation carried out following change to the process/equipment input of materials etc. which will impact the product quality. Revalidation involves of sampling and testing that was employed during the initial validation. It may however be restricted to only particular process stages/steps that are impacted by change.
All phases in the life of product from the initial development through marketing until the products discontinuation.
Manufacturing process are the steps through which raw materials are transformed into a final product.
State of Control:
A condition in which the set of controls consistently provides to assurance of continued process performance and product quality.
Critical Material Attributes (CMA):
A material attributes whose variability has an impact on a critical quality attribute of a product and therefore needs to be monitored or controlled to ensure the process produces for desired product quality.
Critical Process Parameters (CPP): A process parameter whose variability has an impact on a critical quality attribute and, therefore, should be monitored or controlled to ensure the process produces for desired product quality.
Critical Quality Attributes:
A physical, chemical, biological, or microbiological property or characteristic that should be within an appropriate limit, range, or distribution to ensure the desired product quality.
Capability of Process
Ability of the process to produce a product that will fulfill the requirements of that product. The process capability can also be defined in statistical terms.
CPP: Critical Process Parameters CPV: Continuous Process Verification QA: Quality Assurance
QC: Quality Control
PPQ: Process Performance Qualification PV: Process Validation
SOP: Standard Operating Procedure CMA: Critical Material Attributes APQR: Annual Product Quality Report. OCL: Operating Control Limit.
21 CFR Part 210 &211
WHO Annex 3 TRS No. 961, 2011.
Process Va1idation: General Principles and Process Revision -1: January-2011 USFOA.