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Continued Process Verification Guideline & SOP

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. 

Continued Process Verification

Procedure for Continued Process Verification

1.0   Purpose :

    • To define procedure for the Continued Process Verification.

2.0   Scope : 

    • 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
  • To do Continued Process Verification of-
    • In-process analysis tests ( QC test)
    • Finished Product analysis tests
  • Approval of protocol for Continued Process Verification parameters in case of existing commercialized drug products.
  • Investigation if any out of trend observation during Continued Process Verification.
Production Department
  • Performing Continued Process Verification of
    • In-process analysis test.(Performed by production during manufacturing of batch)
    • Critical Process Parameters during manufacturing of the batch.
    • Yield trend
  • Approval of protocol for Continued Process Verification parameters in case of existing commercialized drug products.
  • Investigation if any out of trend observation during Continued Process Verification.
Quality Assurance department
  • Investigation if any out of trend observation during Continued Process Verification.
  • Review the data trends before release of the batch
  • Approval of protocol for Continued Process Verification parameters in case of existing commercialized drug products.
  • Ensure this guideline is implementation.

4.0   Definition of terms & abbreviations – Continued Process Verification:

    • Definition of terms:

    • Process Validation
    • 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.
    • Critical Process Parameters
    • A process input that, when varied beyond a limited range, has a direct and significant influence on a CQA.
    • Continued Process Verification
    • Assuring that during routine production the process remains in a state of control.
    • Critical Quality Attributes (CQA)
    • 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.
    • State of control
    • A condition in which the set of controls consistently provides assurance of continued process performance and product quality.
    • Control Strategy
    • A planned set of controls, derived from current product and process understanding that ensures process performance and product quality.
    • 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.

    • Abbreviations :

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

  • Process Validation shall be performed in three stages as :

    • First Stage (Stage -1) : Process Design
    • Second Stage (Stage -2): Process Qualification
    • Third Stage (Stage -3): Continued Process Verification

  • Stage 1: Process Design

    • The commercial manufacturing process shall be defined during this stage based on knowledge gained through development and scale-up activities.
    • 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.

    • Site Transfer Products

    • 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.
    • Manufacturing location shall prepare risk assessment report based on risk assessment report provided by parent site.
    • After exhibit batch manufacturing risk assessment report for scale up parameters shall be prepared by location before scale up batches.
      • For the existing commercialized products in the location this stage is not applicable.

    • New Product

    • Product development report shall be prepared by formulation development department.
    • Risk Assessment based on product development report/data shall be prepared by formulation development department and provided to manufacturing location.
    • 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.
    • After exhibit batch manufacturing risk assessment report for scale up parameters shall be prepared by manufacturing location before scale up batches.
    • For Risk Assessment corporate guideline “Quality Risk Management and Risk-Based Manufacture of Pharmaceutical Products” shall be referred.
    • Trial batches and/or Characterization batches manufactured shall be part of Process Design phase.

  • Stage 2: Process Qualification

    • During this stage, the process design is evaluated to determine if the process is capable of reproducible commercial manufacturing.
    • Processes for new as well as existing products shall be qualified.
    • Process qualification shall run according to approved protocol detailing sampling, timing, locations, procedures along with analytical tests and acceptance criteria.
    • 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.
    • This stage shall be done in two parts:

    • Part-1: Design of the facility and qualification of the equipment and utilities.

    • Qualification of utilities and equipment shall be covered under individual plans or as part of an overall project plan.
    • The details of the same shall be mentioned in the Protocol.
    • Qualification activities must be completed prior to start up of Process Performance Qualification (PPQ) stage.
    • Suitability and capabilities of equipment and utilities must be documented in accordance with the process requirements in all the anticipated operating ranges.

    • Part-2: Process performance qualification (PPQ).

    • During Stage 2 & onwards, cGMP-compliant procedures must be followed.
    • Successful completion of Stage 2 is necessary before commercial distribution.
    • Need of training shall be assessed prior to start up of PPQ batches.
    • Processes for new as well as existing products shall be qualified based on current version of Process Validation Master Plan of the location.

  • Stage 3: Continued Process Verification

    • During this stage continuous monitoring of process parameters and quality attributes at the level established during the process qualification stage shall be done.
    • Ongoing assurance gained during routine production that the process remains in a state of control.
    • This stage is applicable for all commercial drug products in US and Europe.
    • 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.
    • Stage 3, Continued Process Verification shall be performed in steps as given below.
      • Identification of CPP and CQA for Continued Process Verification
      • Continued Process Verification throughout the life cycle of the drug product

    • Identification of CPPs and CQAs for Continued Process Verification:

    • 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.
    • 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. 
    • Variable numerical Critical Process Parameters and variable numerical Critical Quality Attributes of the drug product which are identified based on,
      • Risk assessment done by FDD based on product development report/data ,
      • Based on risk assessment done by location (Stage-1) ,
      • Based on Process Qualification (Stage-II) report shall be monitored in Continued Process Verification.
    • For Risk Assessment refer guideline “Quality Risk Management and Risk-Based Manufacture of Pharmaceutical Products”.
    • In Continued Process Verification monitoring of following parameters shall be performed.
    • In-process analysis tests. (QC test)
    • Finished Product analysis tests
    • In-process analysis test. (Performed by production during manufacturing of the batch)
    • Critical Process Parameters during manufacturing of the batch.
    • Yield trend

  • Continued Process Verification throughout the life cycle of the drug product:

    • 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.
    • The limits for continued process verification shall be finalized after minimum 20 commercial batches by studying the trend and applying scientific rational.
    • For existing products last minimum 20 commercial batches shall be considered in deciding parameters for Continued Process Verification.
    • 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.
    • Note : Critical quality attributes includes quantifiable results of all test items as per final specification.
    • Quality Assurance shall co-ordinate with Production and QC for compilation of data.
    • Data shall be trended using Minitab software.
    • Batch release shall include verification that no out of trend results were observed.
    • QA shall ensure that CPP and CQA values are within control limits prior to release of batch.
    • This shall be documented in batch release check list
    • 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.

    • Annual Product Review/Product Quality Review

    • 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.
    • 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.
    • Data gathered during this stage shall be used to improve and/or optimize the process by altering some aspect of the process or product.
    • Based on the data trends, control limits for yields and critical quality attributes may be re-defined with scientific rational by taking change control.
    • Note: Control limits can be redefined in case of major changes in process or equipment. Such need shall be identified in change control form. 

    • Continued Process Verification Tools

    • Continued Process Verification can be done by many tools and methodologies.
    • Some of them are listed below.
    • Control charts
    • Process Capability indices calculation.
    • The process capability analysis assesses the process performance relative to the product specification.

    • Control charts

    • Control charts (Shewhart charts) are tools used to determine whether a manufacturing or business process is in a state of statistical control.
    • It shows the value of the quality characteristic versus the sample number or versus time.
    • In general, the chart contains a center line that represents mean value for the process or limit.
    • Two horizontal lines, called the upper control limit (UCL) and the lower control limit (LCL).

    • Process Capability indices calculation : Process shifted index i.e. Process capability index (Cpk)

    • It is calculated as,

CpK= MIN ( Upper Specification Limit – mean)/ 3 X Standard Deviation, ( mean – Lower Specification Limit)/ 3 X Standard Deviation.

    • Cpk value more than 1.33 or higher is a capable process.

    • Folder structure for Continued Process Verification

    • Create separate drive to store the Continued Process Verification Minitab worksheets which shall be access controlled.
    • 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.
    • In software “Project” shall be created. The name of the project shall be product name.
    • In project for each parameter “Worksheet” shall prepare.
    • After preparation of APR/PQR new project shall prepare.

6.0   Reference, and Attachments:

    • References :

    • Guidance for Industry, Process Validation: General Principles and Practices, USFDA, January 2011, Revision 1.
    • Guideline on Process Validation, European Medicines Agency, Draft, March 2012.
    • Technical report no. 59, Utilization of Statistical Methods for Production Monitoring, 2012.
    • Encyclopedia of Pharmaceutical Technology, Edited by James Swarbrick, Third Edition, Volume 6 , Page no. 3499 to 3511.
    • Pharmaceutical Technology, By Richard Kettlewell and etl, January/February 2011, Page no. 18 to 26.
    • Pharmaceutical Development, ICH Q8(R2), August 2009.
    • SOP for Quality Risk Management (QRM).
    • SOP for Annual Product Review of Drug products (APQR).

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;

  • Collection and evaluation of  information and data about the performance of the process.
  • System (s) for detecting unplanned departures from the process as designed which is essential to accomplish the goal of Continued Process Verification.
2.0

Procedure

 In Continued Process Verification monitoring of following parameters shall be done.
 
  • In-process analysis tests. ( QC test)
 
  • Finished Product analysis tests.
 
  • In-process analysis test. ( Performed by production during manufacturing of the batch)
 
  • Critical Process Parameters during manufacturing of the batch.
 
  • Yield trends
  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)
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
Metformin Hydrochloride tablets finished product specification
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 Assay
  •  I Chart
  • In APR/PQR process capability shall be calculated.
  • Specification: 95-105
  • 3 sigma limit or outside 96-104% whichever is stringent.
  • Cpk: 1.33.
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)
Metformin Hydrochloride tablets Master BMR no. is

  • Ready to compress granules for Metformin HCl tablets USP, ______________.
  • Metformin HCl tablets USP, 500 mg : MBMR no. is _______.
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.
Metformin Hydrochloride tablets Master BMR no. is,

  • Ready to compress granules for Metformin Hcl tablets USP,  _________.
  • Metformin HCl tablets USP, 500 mg : MBMR no. is _________ .

  • 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.

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Janki Singh is experienced in Pharmaceuticals, author and founder of Pharma Beginners, an ultimate pharmaceutical blogging platform. Email: [email protected]

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