Standard Operating Procedure (SOP) & Guideline for Continued Process Verification. It is the exercise for assuring that during routine production the process remains in a state of control.
Procedure for Continued Process Verification
1.0 Purpose :
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- To define procedure for the Continued Process Verification.
2.0 Scope :
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- This guideline is applicable for Continued Process Verification of all the dosage forms which are commercialized for the United States of America (USA) and Europe market.
3.0 Responsibilities :
| Quality Control department |
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| Production Department |
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| Quality Assurance department |
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4.0 Definition of terms & abbreviations – Continued Process Verification:
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Definition of terms:
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- Process Validation
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- 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.
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- Critical Process Parameters
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- A process input that, when varied beyond a limited range, has a direct and significant influence on a CQA.
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- Continued Process Verification
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- Assuring that during routine production the process remains in a state of control.
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- Critical Quality Attributes (CQA)
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- 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.
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- State of control
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- A condition in which the set of controls consistently provides assurance of continued process performance and product quality.
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- Control Strategy
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- A planned set of controls, derived from current product and process understanding that ensures process performance and product quality.
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- The controls can include parameters and attributes related to drug substance and drug product materials and components, facility and equipment operating conditions, in-process controls, finished product specifications, and the associated methods and frequency of monitoring and control.
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Abbreviations :
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| APR | : | Annual Product Review | |
| cGMP | : | Current Good Manufacturing Practice. | |
| CPP | : | Critical Process Parameter | |
| CQ | : | Corporate Quality | |
| CQA | : | Critical Quality Attribute | |
| FDD | : | Formulation Development Department | |
| ICH | : | International Conference for Harmonization | |
| LCL | : | Lower Control Limit | |
| PQ | : | Process Qualification | |
| PPQ | : | Process Performance Qualification | |
| PQR | : | Product Quality Review | |
| QA | : | Quality Assurance | |
| QC | : | Quality Control | |
| SOP | : | Standard Operating Procedure | |
| UCL | : | Upper Control Limit | |
| US | : | United States |
5.0 Procedure – Continued Process Verification
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Process Validation shall be performed in three stages as :
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- First Stage (Stage -1) : Process Design
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- Second Stage (Stage -2): Process Qualification
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- Third Stage (Stage -3): Continued Process Verification
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Stage 1: Process Design
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- The commercial manufacturing process shall be defined during this stage based on knowledge gained through development and scale-up activities.
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- The goal of this stage is to design a process suitable for routine commercial manufacturing that can consistently deliver a product that meets its quality attributes.
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Site Transfer Products
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- For site transfer product, Product development report, risk assessment from R&D based on product development report/data and risk assessment report prepared by manufacturing location shall be procured from the parent site.
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- Manufacturing location shall prepare risk assessment report based on risk assessment report provided by parent site.
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- After exhibit batch manufacturing risk assessment report for scale up parameters shall be prepared by location before scale up batches.
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- For the existing commercialized products in the location this stage is not applicable.
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New Product
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- Product development report shall be prepared by formulation development department.
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- Risk Assessment based on product development report/data shall be prepared by formulation development department and provided to manufacturing location.
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- Manufacturing location shall prepare their own risk assessment report (Based on their equipment capabilities, facility and systems, etc.) by referring the risk assessment report provided by formulation development department.
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- After exhibit batch manufacturing risk assessment report for scale up parameters shall be prepared by manufacturing location before scale up batches.
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- Technology transfer procedure shall be done as per corporate guideline “Technology transfer of Drug Products”.
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- For Risk Assessment corporate guideline “Quality Risk Management and Risk-Based Manufacture of Pharmaceutical Products” shall be referred.
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- Trial batches and/or Characterization batches manufactured shall be part of Process Design phase.
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Stage 2: Process Qualification
- During this stage, the process design is evaluated to determine if the process is capable of reproducible commercial manufacturing.
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- Processes for new as well as existing products shall be qualified.
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- Process qualification shall run according to approved protocol detailing sampling, timing, locations, procedures along with analytical tests and acceptance criteria.
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- During the process qualification (PQ) stage of process validation, the process design shall be evaluated to determine if it is capable of reproducing commercial manufacturing.
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- This stage shall be done in two parts:
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Part-1: Design of the facility and qualification of the equipment and utilities.
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- Qualification of utilities and equipment shall be covered under individual plans or as part of an overall project plan.
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- The details of the same shall be mentioned in the Protocol.
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- Qualification activities must be completed prior to start up of Process Performance Qualification (PPQ) stage.
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- Suitability and capabilities of equipment and utilities must be documented in accordance with the process requirements in all the anticipated operating ranges.
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Part-2: Process performance qualification (PPQ).
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- During Stage 2 & onwards, cGMP-compliant procedures must be followed.
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- Successful completion of Stage 2 is necessary before commercial distribution.
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- Need of training shall be assessed prior to start up of PPQ batches.
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- Processes for new as well as existing products shall be qualified based on current version of Process Validation Master Plan of the location.
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Stage 3: Continued Process Verification
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- During this stage continuous monitoring of process parameters and quality attributes at the level established during the process qualification stage shall be done.
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- Ongoing assurance gained during routine production that the process remains in a state of control.
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- This stage is applicable for all commercial drug products in US and Europe.
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- The goal of the third validation stage is continual assurance that the process remains in a state of control (the validated state) during commercial manufacture.
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- Stage 3, Continued Process Verification shall be performed in steps as given below.
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- Identification of CPP and CQA for Continued Process Verification
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- Continued Process Verification throughout the life cycle of the drug product
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- Annual Product Review/Product Quality Review (SOP for APQR)
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Identification of CPPs and CQAs for Continued Process Verification:
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- In case of new drug products, in Process Qualification report parameters for Continued Process Verification shall be summarized and tool/methodology to be followed for each parameter throughout the product life cycle shall be given.
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- In case of existing commercialized drug products in Continued Process Verification parameters protocol (Attachment no. 01) parameters for Continued Process Verification and tool/methodology to be followed for each parameter throughout the product life cycle shall be given.
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- Variable numerical Critical Process Parameters and variable numerical Critical Quality Attributes of the drug product which are identified based on,
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- Risk assessment done by FDD based on product development report/data ,
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- Based on risk assessment done by location (Stage-1) ,
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- Based on Process Qualification (Stage-II) report shall be monitored in Continued Process Verification.
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- For Risk Assessment refer guideline “Quality Risk Management and Risk-Based Manufacture of Pharmaceutical Products”.
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- In Continued Process Verification monitoring of following parameters shall be performed.
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- In-process analysis tests. (QC test)
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- Finished Product analysis tests
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- In-process analysis test. (Performed by production during manufacturing of the batch)
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- Critical Process Parameters during manufacturing of the batch.
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- Yield trend
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Continued Process Verification throughout the life cycle of the drug product:
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- The CPPs and CQAs identified in Continued Process Verification Protocol shall be trended and verified on an ongoing basis during the manufacture of commercial batches.
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- The limits for continued process verification shall be finalized after minimum 20 commercial batches by studying the trend and applying scientific rational.
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- For existing products last minimum 20 commercial batches shall be considered in deciding parameters for Continued Process Verification.
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- Production personnel shall enter the values of critical process parameters where as Quality control personnel shall enter the values of critical quality attributes in worksheet.
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- Note : Critical quality attributes includes quantifiable results of all test items as per final specification.
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- Quality Assurance shall co-ordinate with Production and QC for compilation of data.
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- Data shall be trended using Minitab software.
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- Batch release shall include verification that no out of trend results were observed.
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- QA shall ensure that CPP and CQA values are within control limits prior to release of batch.
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- This shall be documented in batch release check list
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- Excursion from the trends (Out of Trend results) / limits shall be reviewed and investigated as per Event and Investigation procedure (Refer Guideline – Investigation) before taking batch release decision and necessary action shall be taken by QA in consultation with concerned departments.
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Annual Product Review/Product Quality Review
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- During APR/PQR preparation data from all the batches manufactured throughout the year shall be re-evaluated to ensure the manufacturing process is operating in a repeatable, reliable fashion and in a state of control.
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- During APR/PQR preparation, appropriateness of the current approved control strategy will be confirmed so as to highlight any trends and identify the need for product and/or process improvements where such need exists.
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- Data gathered during this stage shall be used to improve and/or optimize the process by altering some aspect of the process or product.
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- Based on the data trends, control limits for yields and critical quality attributes may be re-defined with scientific rational by taking change control.
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- Note: Control limits can be redefined in case of major changes in process or equipment. Such need shall be identified in change control form.
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Continued Process Verification Tools
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- Continued Process Verification can be done by many tools and methodologies.
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- Some of them are listed below.
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- Control charts
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- Process Capability indices calculation.
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- The process capability analysis assesses the process performance relative to the product specification.
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Control charts
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- Control charts (Shewhart charts) are tools used to determine whether a manufacturing or business process is in a state of statistical control.
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- It shows the value of the quality characteristic versus the sample number or versus time.
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- In general, the chart contains a center line that represents mean value for the process or limit.
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- Two horizontal lines, called the upper control limit (UCL) and the lower control limit (LCL).
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Process Capability indices calculation : Process shifted index i.e. Process capability index (Cpk)
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CpK= MIN ( Upper Specification Limit – mean)/ 3 X Standard Deviation, ( mean – Lower Specification Limit)/ 3 X Standard Deviation.
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- Cpk value more than 1.33 or higher is a capable process.
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Folder structure for Continued Process Verification
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- Create separate drive to store the Continued Process Verification Minitab worksheets which shall be access controlled.
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- Each drive shall have two separate folders named as QC and QA. In QC folder QC data shall be stored and in QA folder QA data shall be stored.
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- In software “Project” shall be created. The name of the project shall be product name.
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- In project for each parameter “Worksheet” shall prepare.
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- After preparation of APR/PQR new project shall prepare.
6.0 Reference, and Attachments:
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References :
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- Guidance for Industry, Process Validation: General Principles and Practices, USFDA, January 2011, Revision 1.
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- Guideline on Process Validation, European Medicines Agency, Draft, March 2012.
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- Technical report no. 59, Utilization of Statistical Methods for Production Monitoring, 2012.
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- Encyclopedia of Pharmaceutical Technology, Edited by James Swarbrick, Third Edition, Volume 6 , Page no. 3499 to 3511.
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- Pharmaceutical Technology, By Richard Kettlewell and etl, January/February 2011, Page no. 18 to 26.
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- Pharmaceutical Development, ICH Q8(R2), August 2009.
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- SOP for Quality Risk Management (QRM).
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- Guideline for Technology transfer of drug products
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- SOP for Annual Product Review of Drug products (APQR).
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- Guideline for Change Control Management.
Attachment – 1 : An example for Continued Process Verification Parameters protocol.
| Product | Metformin Hydrochloride Tablets USP, 500 mg |
| Label Claim | |
| Protocol No. |
| 1.0 | Objective | The objective of this protocol is to design the strategy to establish continuous assurance that the process remains in a state of control (the validated state) during commercial manufacture of Metformin Hydrochloride Tablets USP 500 mg. |
The objectives of this protocol are also to address;
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| 2.0 |
Procedure |
In Continued Process Verification monitoring of following parameters shall be done. |
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| In Continued Process Verification only Critical Quality Attributes and variable numerical Critical Process Parameters shall be monitored. | ||
2.1 |
In-process analysis tests. ( QC test) |
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| Metformin Hydrochloride tablets don’t have any in-process specification. | ||
| Hence no test will be monitored for Continued Process Verification. | ||
| 2.2 |
Finished Product Specification |
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| Metformin Hydrochloride tablets finished product specification | ||
| Following test shall be monitored as a part of Continued Process Verification. |
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Sr. no. |
Name of Test | Tool/Methodology for Continued Process Verification |
Limit |
| 1 | Assay |
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| 2 | Content Uniformity | I chart for AV value | 3 sigma or more than 12 AV value. |
| 3 | Dissolution testing | Line plot | Out of trend results shall be monitored. |
| 4 | Related Substances Test | Trend Analysis by plotting graph | 3 sigma or more than 80% of limit whichever is stringent |
| 2.3 |
In-process analysis test. ( Performed by production during manufacturing of the batch) |
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Metformin Hydrochloride tablets Master BMR no. is
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| Following test shall be monitored as a part of Continued Process Verification. |
| Sr. no. | Name of Test | Tool/Methodology for Continued Process Verification | Limit |
| 1 | Individual weight variation | Line plot | Minimum and maximum value shall be plotted. Limit shall be as given in BMR. |
| 2 | Weight of 10 tablets | Line plot | Minimum and maximum value shall be plotted. Limit shall be as given in BMR. |
| 3 | Hardness | Line plot | Minimum and maximum value shall be plotted. Limit shall be as given in BMR. |
| 2.4 |
Critical Process Parameters during manufacturing of the batch. |
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Metformin Hydrochloride tablets Master BMR no. is,
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Following Critical Process Parameters shall be monitored as a part of Continued Process Verification
| Sr. no. | Equipment ID | Critical Process Parameters | Tool/Methodology for Continued PV | Limit |
| 1 | Granulation | Granulation end point , Amperage value | Line Plot | As given in BMR |
| 2 | Drying of granules | LOD ( Limit: 1.25%-1.75% w/w) | Line Plot | As given in BMR |
| Total drying time (Limit:Not more than 20 minutes) | Line Plot | As given in BMR | ||
| 3 | Blending | LOD (For information only) | Line Plot | As given in BMR |
| 4 | Tablet Curing | % Moisture loss (Between 0.5 to 2.5%) | Line Plot | As given in BMR |
| 2.5 | Yield trend | |
| Yield at following stages of manufacturing shall be monitored. |
