SOP for Continued Process Verification

Purpose

To define the procedure for the Continued Process Verification.

Scope

This guideline is applicable for Continued Process Verification of all the dosage forms that are commercialized for the United States of America (USA) and Europe market.

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 of 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 of any out-of-trend observation during ContinuedProcess Verification.

Quality Assurance department

• Investigation of any out-of-trend observation during Continued Process Verification.
• Review the data trends before releasing the batch
• Approval of protocol for Continued Process Verification parameters in case of existing commercialized drug products.
• Ensure this guideline is implemented.

Definition

Process Validation

Process Validation is defined as the 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.

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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 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.

Procedure

Process Validation shall be performed in three stages as

1. Process Design
2. Process Qualification
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 products, Product development reports, risk assessment from R&D based on product development reports/data, and risk assessment reports prepared by manufacturing locations shall be procured from the parent site.
• The manufacturing location shall prepare a risk assessment report based on the risk assessment report provided by the 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

• The product development report shall be prepared by the formulation development department.
• Risk Assessment based on product development report/data shall be prepared by the formulation development department and provided to the manufacturing location.
• Manufacturing location shall prepare their own risk assessment report (Based on their equipment capabilities, facility, systems, etc.) by referring to the risk assessment report provided by the formulation development department.
• After the exhibit batch manufacturing risk assessment report for scale-up parameters shall be prepared by the manufacturing location before scale-up batches.

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• The technology transfer procedure shall be done as per the corporate guideline “Technology transfer of Drug Products”.
• For Risk Assessment corporate guideline “Quality Risk Management and Risk-Based Manufacture of Pharmaceutical Products” shall be referred to.
• Trial batches and/or Characterization batches manufactured shall be part of the 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 the approved protocol detailing sampling, timing, locations, and 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 the start-up of the Process Performance Qualification (PPQ) stage.
• The 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.
• The need for training shall be assessed prior to the start-up of PPQ batches.
• Processes for new as well as existing products shall be qualified based on the current version of the 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 to all commercial drug products in the 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.
• Continued Process Verification shall be performed in steps as given below.

1. Identification of CPP and CQA for Continued Process Verification
2. Continued Process Verification throughout the life cycle of the drug product
3. Annual Product Review/Product Quality Review (SOP for APQR)

Identification of CPPs and CQAs for Continued Process Verification

• In the case of new drug products, in the Process Qualification report parameters for continued Process Verification shall be summarized and the tool/methodology to be followed for each parameter throughout the product life cycle shall be given.
• In the case of existing commercialized drug products in the Continued Process Verification parameters protocol 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 CriticalQuality Attributes of the drug product are identified based on, Risk assessment done by FDD based on product development report/data,

1. Based on risk assessment done by location (Stage-1),
2. Based on the Process Qualification (Stage-II) report
3. 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 the following parameters shall be performed.

1. In-process analysis tests. (QC test)
2. Finished Product analysis tests
3. In-process analysis test. (Performed by production during manufacturing of the batch)
4. Critical Process Parameters during manufacturing of the batch.
5. Yield trend

Continued Process Verification throughout the life cycle of the drug product

• The CPPs and CQAs identified in the Continued Process Verification Protocol shall be trend and verified on an ongoing basis during the manufacture of commercial batches.
• The limits for continued process verification shall be finalized after a minimum of 20 commercial batches by studying the trend and applying scientific rationale.
• For existing products, the last minimum of 20 commercial batches shall be considered in deciding parameters for Continued Process Verification.
• Production personnel shall enter the values of critical process parameters whereas Quality control personnel shall enter the values of critical quality attributes in the worksheet.
• Note: Critical quality attributes include quantifiable results of all test items as per final specification.
• Quality Assurance shall coordinate with Production and QC for the compilation of data.
• Data shall be trended using the software.
• The 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 before the release of the batch.
• This shall be documented in a batch-release checklist
• Excursion from the trends (Out of Trend results) / limits shall be reviewed and investigated as per the Event and Investigation procedure 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, the appropriateness of the currently approved control strategy will be confirmed so as to highlight any trends and identify the need for product and/or process improvements where such a 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 a scientific rationale by taking change control.
• Note: Control limits can be redefined in case of major changes in process or equipment. Such needs shall be identified in the change control form.

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Continued Process Verification Tools

Continued Process Verification can be done by many tools and methodologies.

Some of them are listed below.

1. Control charts
2. Process Capability indices calculation.
3. The process capability analysis assesses the process performance relative to the product specification.

1.  Control charts

• Control 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 centerline that represents the mean value for the process or limit.
• Two horizontal lines are called the upper control limit (UCL) and the lower control limit (LCL).

2.  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 of more than 1.33 or higher is a capable process.

3.  Folder structure for Continued Process Verification

• Create a separate drive to store the Continued Process Verification, which shall be access-controlled.
• Each drive shall have two separate folders named QC and QA. In the QC folder, QC data shall be stored and in the QA folder, QA data shall be stored.
• In software “Project” shall be created. The name of the project shall be the product name.
• In a project for each parameter “Worksheet” shall prepared.
• After the preparation of APR/PQR new project shall prepared.

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

Revision History

Nil

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