SOP ON INVESTIGATIONS

PURPOSE

This Standard Operating Procedure (SOP) defines the requirements for reporting, documenting, investigating, evaluating, managing, resolving and approving closure of investigations from cGxPs, approved specifications and/or procedures.

SCOPE

This standard applies to Investigations related to quality related events that occur from cGxPs, approved specifications, and/or procedures including but not limited to Protocols, Master Batch Records (MBR), Batch Packaging Records (BPR), breakdowns, facilities, storage, distribution, manufacturing, testing, packaging, warehouse and distribution of drug products.

CROSS REFERENCE DOCUMENTS

• Document(s) and Data Control Procedure.
• SOP on Handling of Out of Specification (OOS).
• Corrective and Preventive Action.
• Quality Risk Management (QRM).
• SOP on Handling of Out of Calibration (OOC).
• Product Recall and Mock Recall Procedure.
• SOP on Handling of Out- of Trend (OOT).
• Self-Inspection Programmed.
• Preparation and Review Procedure of Annual Product Quality Review (APQR)/ Product Quality Review (PQR).
• Handling of External Audit and Its Compliance.

ATTACHMENTS

• Investigation Report Template
• Monitoring Mechanism for Investigation CFT
• Investigation Initiation Form
• Investigation Log
• Tool for Root Cause Analysis
• Investigation Extension Request
• Work Flow for Investigation

DEFINITIONS

• Acceptance Criteria: The product specifications and acceptance/rejection criteria, such as acceptable quality level and unacceptable quality level, with an associated sampling plan, that are necessary for making a decision to accept or reject a lot or batch (or any other convenient subgroups of manufactured units). The criteria, a system or process must attain to satisfy a test or other requirements.
• Assessment: The act or process, of evaluating (e.g. extent, magnitude, position, impact or compliance level) of a process, system, project, action or activity.
• Corrective and Preventive Action: A concept with current Good Manufacturing Practice (cGMP) that focuses on the systematic investigation of root causes of unexpected incidences to prevent their recurrence (corrective action) or to prevent their occurrence (preventive action).
• Corrective Action: Action taken to eliminate the causes of an existing non-conformity, defect or other undesirable situation, in order to prevent recurrence.
• Preventative Action: Action taken to eliminate the cause of a potential nonconformity, defect or other undesirable situation, in order to prevent occurrence.
• Cross Functional Team: Diverse team members (SME) typically comprised of heads from Quality, Manufacturing, Qualified Person, Regulatory, Laboratory or their qualified designees used to review and provide a disposition for the proposed deviation.
• cGxP: cGxP is a general term that stands for current Good “x” Practice (x = Clinical, Engineering, Laboratory, Manufacturing, Documentation, Pharmaceutical, etc.). The titles of these Good “x” Practice guidelines usually begin with “Good” andend in “Practice”. cGxP represents the abbreviations of these titles where “x” a common symbol for a variable, represents the specific descriptor.
• Correction: Immediate action taken to resolve finding/issue.
• Critical Classification: Any departure from established standards that has caused or has high probability of causing adverse impact on product safety, quality, identity, potency or purity.
• Major Classification: Any departure from established standards which may have an impact on safety, quality, identity, potency or purity physical characteristics and efficacy of the product or process ( e.g. use of different type of equipment).
• Minor Classification: Any departure from established standards which may not have an impact on safety, quality, identity, potency or purity physical characteristics and efficacy of the product or process.
• Deviation: Any departure from approved procedures or records, including, but not limited to Standard Operating Procedure, Master Production Record, Batch Production Record, Standard Testing Procedure or the failure of a batch or any of its components to meet any of its specifications shall be documented and explained. Potential product quality impacting events shall be investigated and the investigation and its conclusions shall be documented.
• Elimination: Errors eliminate the possibility of error. This can be accomplished by eliminating the task. For example, eliminate mixing errors by purchasing pre-mixed materials. Eliminate recording errors by directly linking the measurement device to a printer.
• Event: Any unforeseen happening or unexpected occurrence.
• Investigation: A documented logical and/or scientific review of data related to all quality events that leads to the identification of the root cause and corrective and preventive action.
• Market Action: An action required to resolve a situation for a marketed product. General reference embracing a notification, potential recall, market withdrawal, or field correction.
• Nonconforming Material: Material that does not meet specified acceptance criteria.
• Product Quality Complaint: Any written, electronic or oral communication reported by Customers, Physicians, Pharmacists, Hospitals, Regulatory Agencies, Health Authorities, Government Laboratories, MA Holders, Retailers, Distributors, etc., that alleges deficiencies related to the safety, identity, strength, quality, purity reliability, and/or efficacy of a product after it is distributed beyond the control area of this company quality systems.
• Root Cause: The underlying (fundamental) reason for a detected quality issue/failure (non-conformity, defect or other undesirable situation), which, if eliminated or corrected, will prevent recurrence of the problem for the same reason.
• Task: Any activity identified as a part of executing a ‘Temporary Change’ or ‘Planned Deviation’. Tasks can be of two types, i.e., pre-require (to be completed before execution of the temporary change or planned deviation) and non-pre-require (can be completed concurrently with execution of the temporary change or planned deviation).

RESPONSIBILITY

Originating department/Person shall be responsible:

To report non-Conformance to a concern supervisor or department head & initiator person.

Head of Originating department/designee shall be responsible for:

To assign the responsibility to department representative to perform the investigation.

To ensure that investigation of any non-conformance/ Deviation or any other QMS documents wherever investigation required shall initiated through CAPA along with investigation is reported to QA within specified time.

To review investigation report.

To monitor the Corrective action and Preventive action (CAPA).

Manufacturing head/designee shall be responsible for ensuring all manufacturing deviations/incidents are reported to QA on the day of discovery, but not later than end of next working day.

Manufacturing head/designee shall be responsible for ensuring all manufacturing deviations/incidents are reported to QA on the day of discovery, but not later than end of next working day.

Quality control head /designee shall be responsible for ensuring all deviations/incidents, non-conformances, failures and/or events in the laboratory are reported to the QA on the day of discovery, but not later than end of next working day.

Head Quality Assurance department shall be responsible for:

Quality Head/Designee shall be responsible for the oversight and assessment of the investigation.

Quality Head/Designee shall be responsible for reviewing and approving the investigation plan, report and timely resolution of all investigation.

Quality Head/Designee shall be responsible for assuring timely implementation of corrective actions and ensuring corrective actions are effective.

Quality Assurance (QA) Head/Designee shall be responsible for providing assistance in performing investigation.

QA Head/Designee shall be responsible for reviewing and approving the investigation reports.

QA Head/Designee shall be responsible for disposition of impacted products / batches and/or releases other controls, based upon investigation conclusions and associated corrections.

Head – Quality Assurance/ Designee shall be responsible for:

To review and approve the investigation report.

To ensure implementation of the defined system.

Plant Head shall be responsible for:

To review and approve the investigation report.

To ensure implementation of the defined system.

PROCEDURE:

Investigation Requirements.

An investigation may be required in order to determine root cause(s) for any of the following situations, but not limited to:

Deviations/ Incidents/ Non-conformances/Failures/ Events.

Product Quality Complaints

Product Recalls, recovery, withdrawal or return of goods.

Internal/external audit or inspection findings.

Periodic Product Quality Reviews.

Ineffective Corrective and Preventive Actions (CAPA).

Any other product quality or patient safety-related issues or review findings.

Initiation of investigations:

An investigation record may be initiated by a responsible person from any department (referred to as “Initiator” hereafter) intending to investigate an identified quality issue.

QA shall assign the investigation report number and make the necessary entry in investigation number allocation log.

QA shall assign the investigation number as given below,

The Investigation number shall be alphanumeric i.e. PC/IR/XXX/YYYY/ZZZ.

Where, PC : Location code.

IR : Investigation Report

XXX : Department Code as per SOP

YYYY  : Stand for year. Four digit of year shall be 2025 for Year 25,

ZZZ     : Stand for serial no. of investigation which runs continuously irrespective of the change in department code.

Every year 3 digit serial number shall start from 001.

The Initiator shall initiate an investigation record and log the investigation number.

The investigation record shall be submitted to the Responsible Person for further execution.

Investigation plan:

The Responsible Person shall acknowledge and complete the hypotheses, investigation plan and approach, and obtain required resources (Materials, Equipment, Facilities and Personnel) and required data (existing) and intended analytical techniques.

The Responsible Person shall attach supporting documents, if applicable.

The Responsible Person shall identify the cross functional investigation team comprised of individuals from affected or other sites, resources external or Subject Matter Expert(s) in area(s) relevant to the investigation.

The Responsible Person shall submit the investigation plan for approval to QA

QA may ask for additional information and/or request changes to the investigation plan.

On satisfactory review of the investigation plan, QA and Quality head shall approve the investigation plan.

The cross functional investigation team shall propose hypothesis to identify the root cause(s) and consider the following elements during hypothesis development: environmental monitoring excursions, raw material non-conformance appropriateness, process deviations – effectiveness, equipment- instrument failure, material or product mishandling, storage condition excursion, calibration excursions and non-conformances, test method failure, cGxP non-compliances, significant changes in historical frequency/trending of similar issues and prior actions taken.

The investigation team / cross functional team shall use appropriate investigative techniques to determine the root cause(s) as a part of the investigative approach. A list of potential techniques along with their applicability is provided in Table 1. This list is not meant to be exhaustive. See Annexure-1 for additional details for these tools.

Table 1: Investigation Technique 

Analysis objective	Possible Analysis Methods/Tools	Primary Use/Applicability
Issue Analysis	Affinity Diagram	A means to creatively generate a large number of ideas/issues and then organize and summarize them into natural groupings in order to understand the essence of a problem and breakthrough solutions.
	Brainstorming	To creatively and efficiently generate a high volume of ideas on any topic.
	Prioritization Matrices	To narrow down options through a systematic approach of comparing choices by selecting, weighting, and applying criteria.
Trend Analysis	Check Sheet	To systematically record and compile data from historical sources, or observations as they occur, so that patterns and trends can be clearly detected and shown.
	Control Charts	To monitor, control, and improve process performance over time by studying variation and its source.
	Process Capability	To determine if a process, given its natural variation, is capable of meeting established customer requirements or specifications.
	Run Chart	To study observed performance data for trends or patterns over a specified period of time.

Analysis objective	Possible Analysis Methods/Tools	Primary Use/Applicability
PatternAnalysis	Check Sheet	To systematically record and compile data from historical sources, or observations as they occur, so that patterns and trends can be clearly detected and shown.
	Flow Charts	To identify the actual flow or sequence of events in a process and to show the complexity, problem areas, redundancy, unnecessary loops, and places where simplification/standardization is possible
	Histograms	To summarize process data that has been collected over a period of time and to graphically present its frequency distribution in bar form.
	Matrix Diagram	To systematically identify, analyze, and rate the presence and strength of relationships between two or more sets of data.
	Normal Test Plots	To investigate whether process data exhibit the standard normal “bell curve” or Gaussian distribution. (Also, known as Normal Probability Plots, Normal Quartile Plots.)
	Pareto Charts	To focus efforts on the problems that offers the greatest potential for improvement by showing their relative frequency or size in a descending bar graph.
	Radar Chart	To visually show in one graphic the size of gaps among a number of both current organization performance areas and ideal performance areas.
Cause/ Effect or Linkage Analysis	Activity Network Diagram	To find both the most efficient path and a realistic schedule for the completion of any project.
	Cause & Effect/Fishbone Diagram	To identify, explore, and graphically display, in increasing detail, all of the possible causes related to a problem and to discover its root cause(s).

Analysis objective	Possible Analysis Methods/Tools	Primary Use/Applicability
Cause/Effect or Linkage Analysis	Fault Tree Analysis or Failure Mode Effect Analysis	To analyze the effects of operating conditions on design reliability and safety.
	Flow Charts	To identify the actual flow or sequence of events in a process and to show the complexity, problem areas, redundancy, unnecessary loops, and places where simplification/standardization is possible.
	Forced Field Analysis	To identify the forces and factors in place that support or work against the solution of a problem, so that the positives can be reinforced and/or the negatives eliminated or reduced.
	Relations Diagram (or Interrelationship Digraph)	To systematically identify, analyze, and classify the cause and effect relationships that exist among all critical issues, so that key drivers or outcomes can become the center of an effective solution
	Scatter Diagram	To study and identify the possible relationships between the changes observed in two different sets of variables.
	Tree Diagram	To graphically represent an implementation by taking a broad goal and breaking it into increasing levels of detailed actions that must be done to achieve the stated goals.
	5-Why’s	To quickly separate symptoms from causes and identify the root cause of a problem.

Note: Refer to Attachment-V on “Tools for Root Cause Analysis” for more details

The following program management-related activities shall be used during the investigation:

Drive the investigation to the timeline in the plan; update the plan, as required, and maintain communication with functional management and other stakeholders on progress and issues.

Identify and obtain resources from respective functional heads, as needed, to complete thorough and effective investigation.

3.11.1. Escalate issues and roadblocks to management, as needed, when:

3.11.2. Technical obstacles result in revisions to approach or timeline.

3.11.3. Resources are not available to execute the plan.

3.11.4. Functional alignment is not achieved on priorities.

Investigation Execution:

Investigation team/CFT shall collect, organize and document the data needed to perform a root-cause analysis.

Data may come from a variety of sources, including, but not limited to the following, as given in Table 2:

Table 2: Possible Data Sources 

Potential Source of Issue	Possible Data Sources
General sources	Historical trends, including previous associated investigations, if applicable Interview of associated personnel Annual Product Quality Reviews Recalls/return goods
Environmental monitoring excursions	Microbiological test data Temperature and Humidity Monitoring data
Raw material non-conformance/ appropriateness	Raw material receiving logs and records Raw material test procedure Raw material test reports
Process deviations/ effectiveness	Validation records Batch manufacturing records of affected batches and previously manufactured batches using the same equipment/room, Change control history and log, Stability data, Package, On-line data, at-line manufacturing & monitoring/recording Systems, On-line cameras
Equipment/instrument failure	Preventive Maintenance and breakdown record Equipment/Instrument usage log Equipment/Instrument data printouts
Material/product mishandling	Packaging record(s) Shipping record(s)
Storage condition excursion	Storage facility/chamber monitoring record
Calibration excursions and non-conformance	Calibration records
Test method failure	Analytical test data Analytical method validation/verification report
GMP non-compliances	Personnel training records Deviation record

Conduct any additional experiments or tests, as required by the investigation plan to supplement data collected from existing sources.

If the investigation is for any findings of contaminant, physical, biological or chemical in nature, it shall be confirmed by analysis for its nature and the extent of impact shall be determined with detailed investigation.

The suspected causes or hypothesis shall be verified with adequate experiments, simulation processes or backed up with strong, supporting scientific rationale to assign as the root cause.

Identify other investigations that were similar in nature and review the investigation approach and results of those investigations as a rationale to assign root cause.

Perform an impact assessment and extend the investigation to other batches and other products of all the markets, which could have been possibly affected. The investigation may include additional testing of the involved batches or components.

Analysis and conclusion:

The investigation team/CFT shall assess the data collected during the investigation and document the root cause(s). An appropriate investigative technique, as listed in Table 1, may be used for analysis, if needed.

Evaluation shall be performed as indicated below.

Note: That the steps listed below are indicative of the types of questions to ask; these do not constitute a comprehensive list. Attach the supporting data, if any.

Evaluation of GMP Compliance

Confirm processes were followed (i.e., no operator error was found).

Confirm process expectations were understood (i.e., no subjectivity exists as part of the process; operator understand what to do at each stage of the process).

Review completed documentation, Batch Record, logbooks, etc., to confirm appropriate data was captured/analyzed by operator.

Evaluation of Equipment and Facilities. Determine how equipment usage may have contributed to the issue.

Review qualified parameters to determine if running at process extremes may have contributed to the issue.

Confirm set-up, shut-down and cleaning processes were followed.

Review maintenance records to determine if recent maintenance may have contributed to issue.

Review calibration requirements and record to confirm machine is current calibrated.

Review spare parts / interchangeable parts to determine if parts failure may have contributed to issue.

Consult with machine vendors/equipment manufacturers/technical experts, as appropriate.

Evaluation of Process:

Determine if process was properly validated.

Determine whether the process is fully and clearly documented to facilitate unambiguous understanding and interpretation by intended user.

Assess the possibility of any weakness (lack of robustness) or errors in the process.

Ensure that process documentation forms, including batch process records are correct and complete.

Evaluation of Analytical/Microbiological Method:

Determine if the method was properly validated/verified.

Verify that the method is fully and clearly documented to facilitate unambiguous understanding and interpretation by the intended user.

Assess the possibility of any weaknesses (lack of robustness) or errors in the method.

Assess the possibility of ambiguity or error in data analysis associated with the method.

Evaluation of Storage/Handling:

Determine whether documented storage and handling requirements are appropriate and have been met.

Assess whether other batches were subjected to the same storage and handling conditions and whether adverse effects were identified on other batches also.

Evaluation of Material:

Review incoming material test data; confirm raw material specifications have been met.

Identify if material lot/batch was used on other products, identify if adverse effects were identified on other product batches.

Confirm material identification.

Consult with vendor/material manufacturer, as appropriate.

Others:

Determine if abnormal manufacturing variations or deviations or incidents occurred on the line, such as (but not limited to) power spikes or outages; extreme environmental conditions, accidents, spills, or safety incidents.

The investigation team/CFT shall conclude the investigation based on the data analysis and categorize the root cause(s) into one of the categories in Table 3:

Table 3: Root-Cause Categories

• Lab Instrument Inadequacy
• Lab Instrument Malfunctioning
• Lab Instrument Maintenance
• Lab Instrument Software
• Lab Testing Method
• Equipment Malfunctioning
• Facility/Utility Malfunctioning
• Equipment Inadequacy
• Facility/Utility Inadequacy
• Facility/Utility Software
• Equipment Software
• Equipment Maintenance
• Facility Maintenance
• Utility Maintenance
• Inadequate Document Control
• Product Development
• Packaging Development
• Labeling
• Manufacturing Process Validation
• Raw Material
• Procedural Inadequacy
• Packaging Material
• Procedural Non-Compliance
• Storage
• Specification/Standard Test Procedure (STP) Inadequacy
• Transportation & Handling
• Planning
• Ineffective Training Program
• Sampling
• Sample Handling
• Others – specify in the “Root Cause Summary”

Upon completion of the investigation, if the root cause(s) cannot be identified, then most probable cause(s) shall be provided by investigation team/CFT.

Details of the investigation and the analysis performed shall be documented.

All raw data and supporting investigation files shall be archived, as per applicable procedure in accordance with the current version of the respective SOP.

Investigation reports shall have the following content, but not limited to as per Attachment-I:

Cover Page: The cover page shall include Title, Location, Unique Investigation Number, Page number, and Company Logo. This information shall be reflected on all the pages of the investigation report.

Table of Contents Page: The table of contents page shall include the content of the investigation with respective page number.

Approval Page: The approval page shall include “prepared by”, “reviewed     by” and “approved by” signatory columns. The report shall be prepared by the Investigation Owner in coordination with cross functional team of investigation. The report shall be reviewed by the cross functional team or QA and finally approved by Head QA/designee and Quality Head.

Objective: The objective shall include the reason for investigation, assessment of impact/risk, and explore the CAPA to mitigate the risk.

Background: The background shall constitute short summary concerning initiating the investigation based on the master document.

Scope: The scope shall include reference to product name and reference number of the Deviation/Incident/Market compliant/Product recall of respective product.

Responsibility: The Responsibility shall cover name of individual(s) involved in the cross functional investigation team/CFT and their responsibility during investigation.

Investigation Results and Discussion: Summary observations, data ranges, defects, deviations or incidents shall be included in this section, and all investigation results shall be summarized.

Additional Experimental Data: The data of additional experiments conducted shall be included and a conclusion documented.

Root Cause/Most Probable Root Cause: List the root cause by providing the reference documents’ numbers which support sound scientific principles. List the most probable root-cause when an investigation is not conclusive. Describe the specific basis for ruling out possible root causes along with reference numbers to supporting documents.

Impact Assessment: List all the batches/products/ systems/ procedures impacted by the failure(s). Impact Assessment shall be assessed with respect to patient safety, product quality, other batches/product, regulatory commitments and business.

Risk Assessment: List the risk identified and proposal for reduction or elimination of the risk.

CAPA: Provide CAPA details.

Conclusion: List the conclusion. The conclusion shall be supported by documented evidence based on sound scientific principles, logic, experimental data and all other relevant factors.

List of Annexure: Provide the annexure number for each of the supporting documents referred to as a part of the investigation.

Investigation closure:

Complete the investigation summary:

Recommended CAPAs; potential controls to assess, mitigate, and reduce the risk of recurrence.

Include potential risks identified as an outcome of the investigation.

Provide the process for communicating risk to impacted areas.

Include the proposed plan for monitoring risk moving forward.

Ensure any open commitments that cannot be completed before the investigation is closed are being regularly tracked to ensure they are completed by their respective deadline(s).

Investigations shall be completed within thirty (30) calendar days from the time that the quality event is first discovered.

If an investigation cannot be completed within the required time frames, the Responsible person shall request an extension from QA with the proposed new timeline and justification for the extension request. The request for extension shall also include an impact assessment to evaluate the effect on activities still to be completed through completion of the investigation. This assessment shall determine if additional controls are needed to avoid issues during the interim. This justification for extension of timelines shall be reviewed and approved by QA prior to implementation as per Attachment-VI.

If an investigation cannot be completed within the required time frames, the Responsible Person must submit an interim report at least every 30 days for the same.

The investigation record shall be submitted to the QA and as applicable, to determine adequacy, completeness, and approval of remedial actions required.

QA as applicable may ask for additional information and/or ask to perform additional work as a part of the investigation.

On satisfactory completion of the investigation record, QA shall complete a risk classification (Critical, MAKor, and Minor) along with documentation of the issue that led to the investigation and finally close the record.

Each investigation report shall be approved by the Head QA/designee and Quality Head.

QA shall inform Quality head, Regional Quality Head and Corporate Quality Compliance Head or respective designees of any deviation/ incident, non-conformance, failure or an event that may potentially require market action (refer to the current version of respective SOP.

Types of Investigations that may require escalation to the Management in accordance with the written procedures as per the current version of the respective SOP.

Investigations “OPEN” for more than 30 calendar days.

Investigations for which there is no assignable root cause but only a most probable root cause.

Investigations concluding into product stoppage / manufacturing hold,

Investigation concluding into product / batch recall

QA shall disposition impacted products/batches and/or releases other controls, based upon investigation conclusions and associated corrections.

After closure of investigation, if further investigation is required (e.g. due to request by QA, discovery of new information/data, internal/external audit observations or management review), closed investigations shall be re-opened by the Quality Head/designee or Responsible Person to perform and document further investigation.

The implementation and effectiveness of CAPA shall be monitored as per written procedures.

Requirements:

Each employee is responsible for the identification of deviation/incident/non- conformance/failures/events at the time it occurs and reporting to the supervisor immediately.

Site shall establish and maintain a system to assure the investigation is conducted by a Responsible Person (RP) in conjunction with QA Head or designee and other involved functions, as required. The investigation shall include the following information:

Description shall include an objective, factual description based in science of what happened and when.

Immediate action taken, the decisions made about the process and product affected shall be documented.

Scope shall include an assessment concerning when the process, equipment, facility, utility, or other source was last working properly.

All known concerns, not limited to the following, shall be included in the report:

Patient or worker safety.

Out-of-Specification and Out-of-Trend observations.

Compliance with cGxPs, compliance with registration, deviation/incident from process validation.

Impact on product safety or efficacy.

Product stability impact.

Effectiveness of previous root cause corrective actions.

Notification requirements.

The gravity of the concern(s) shall be determined by assessing how significant the impact is.

Any additional concern(s) identified during the course of the investigation shall be documented.

The resolution of each concern shall be described, and any unresolved concerns shall be clearly identified.

Impact on the status of the lot shall be described.

The monitoring mechanism for investigations by the CFT shall be developed, refer to Attachment-II for a schematic diagram.

Root cause investigation:

The most probable cause of the deviation/ incident/ non-conformance/failure/ event and what was done to confirm the true cause shall be described.

The investigation shall include the causes that were specifically eliminated as the root cause and supporting rationale for that judgment shall be documented.

The basis of the cause shall be described.

Corrective actions taken to address the issue shall be described.

Corrective and Preventive Actions (CAPA) taken and planned shall be described and tracked through completion.

Lot Corrective Action: A description of the corrective action for the lot (e.g. reprocessing, rework, inspection, destruction, restriction) and similar incident history shall be provided, if applicable.

Material Disposition:

A summary of the concerns not resolved and how the concern(s) influence the disposition of the lot(s), product(s), and process(s) associated with the deviation/incident/non-conformance/failure/event shall be provided. The recommended disposition shall be documented (e.g. release, rejected, rework/reprocess, other).

The rationale for the disposition decision shall be summarized, documented and approved by Head QA as applicable.

Deviation Control

OBJECTIVE:

To lay down the procedure to describe the steps to be followed in case of planned/unplanned deviation from the standardized activity, or standard procedure.

PROCEDURE :

Deviations are of two types: Planned & Unplanned.

Planned Deviation: Any Deviation in the procedure, process, equipment, or standard batch size which is planned, documented, assessed for its impact on product quality, and authorized in advance, with the agreement of all concerned is termed as planned deviation.

Unplanned Deviations (Unforeseen Deviations): While carrying out day-to-day activities, there are chances of unplanned deviations and events to occur. These deviations are unforeseen, accidental and shall occur due to several reasons:

• Equipment failure/breakdowns/malfunctioning
• Power Supply failures / Interruption
• Accident/ Mishap in the plant.
• Breakdown in support services/ utilities
• Any other unforeseen situation (e.g: Production process parameters, HVAC system, Water system, equipment/instrument calibration, environment control, storage conditions, analytical test procedures, etc.)

Any deviation needs to be authorized by Head QA in writing.

For any deviation, intimate QA with an intimation slip for issuance of the Deviation Control Form.

QA to issue the form with a serial number as DV/XX/YYY, where

• DV- denotes Deviation,
• XX – two last digits of the year,
• YYY – Serial number.

The initiating department has to write the description of the deviation. QA should give immediate action to be taken on the deviation. The initiator department should give the root cause for the deviation & justification of the same.

The form has to be forwarded to QA where the Head of QA looks into it through risk assessment to evaluate the impact of deviation on the quality of other products.

The QA Head also looks into the regulatory aspect of it & based on it gives acceptance to the deviation.

The QA Head should discuss with the initiator department’s head the requirement of any CAPA to avoid the recurrence of the same and decision for disposition to be taken.

All of the above has to be recorded in the Deviation Control form with respective signatures.

The investigation of the deviations shall be completed within 30 calendar days. If not completed, then an interim report justifying the delay is to be prepared every 30 days until the investigation is closed.

The original Deviation Control form remains with QA & a copy was given to the initiator department to attach it with the concerned records (if required).

OBJECTIVE:

To lay down the procedure for Change Control System.

PROCEDURE:

If anybody wants to make a change in the existing system and feels that the change will be fruitful in terms of productivity, and quality; he/she should discuss it with his / her department head.

If the department head feels that it is required, then they should initiate the change through the Change control form.

Note: The ownership of the change is with the head of the originating department who is responsible for initiating the change.

The initiating department shall request to QA for issuance of a “Change Control Form” through the “Document Requisition Form.

The change control form consists of the following parts

• Part-I: Initiation of Change Control
• Part II (A): Change control consent and review
• Part-II (B): Change control assessment by QA
• Part III: Final approval of change control by Head QA
• Part IV: Verification of implementation and closing of change control

Part I: Initiation of change control

After receiving of request from the initiator department, QA shall start the issuance of the change control form as per the following procedure.

Take a photocopy of the change control form and make a control copy of the change control form.

QA allocates the change control number in change control form as given below:

CCF-XX-YYY

• CCF    Change control form
• XX      Last two digits of the running calendar year
• YYY   Serial number (000 to 999)

After the change control number allocation, QA writes the date of initiation in the change control form.

Record the change control detail with the change control number in the change control logbook.

Note: All the change control shall be recorded and maintained in the “Change control Logbook” year-wise.

After login, QA shall issue the change control form to the initiator department for execution of the proposed change.

The initiator department selects the “Initiator department”.

The initiator department selects the “Change requested for”.

Initiating department shall write the “Details of change (proposed)”.

Initiating department shall write the reason for the change(s). Attach supporting documents as applicable based on which change is proposed.

The initiating department shall mention the documents’ details that will be affected by the change.

All changes proposed shall be signed by the initiator in the “Change initiated by” column.

The Head of initiating department shall approve the proposed change and shall sign in the “Approved by” column.

Part II A: Change control consent and review

Initiating department shall forward the proposed change to all concerned departments, if required and wherever applicable.

The Head of the concerned departments shall review the proposed change, record the review comments, approve/not approve the change, name sign, and date.

After receiving the comments from all concerned departments, the initiating department shall submit the “Change Control Form” to Quality Assurance.

Part II B: Change control assessment by QA

 QA shall assess the level of change as follows:

• Type-A: A minor change: A change that has minimal potential to have an adverse effect on the identity, strength, quality, and potency of the product as they may relate to the safety or effectiveness of the product.
• Type-B: A major change: A change that has a moderate potential to have an adverse effect on the identity, strength, quality, and potency of the product as they may relate to the safety or effectiveness of the product.
• Type-C: A critical change: A change that has a substantial potential to have an adverse effect on the identity, strength, quality, and potency of a product as they may relate to the safety or effectiveness of the product.

QA shall also perform a risk assessment and review the impact of change on related documents, and write comments.

QA shall recommend the action to be carried out for the proposed change and documents, write the comments and sign in the “Change evaluated by”.

In case approval from any specific regulatory agency is required, QA shall forward the filled scanned Change Control Form to the Regulatory Affairs Department by e-mail and RA shall co-ordinate with concerned regulatory authorities and shall give the comments/approval as per their comments on scanned Change Control Form and send back to QA by e-mail or the hard copy and same will be attached with the original Change Control Form.

Regulatory affairs shall review the effect of the proposed change against the submitted dossiers.

Part III: Final approval of change control by Head

Head QA / designee shall evaluate the proposed change against the checklist.

Head QA / designee shall evaluate the action points mentioned.

Finally, the Head QA / designee shall approve the proposed change, write his comments, and shall sign with the date.

After approval of change control from the QA Head, QA personnel shall send the approved Change Control Form to all concerned department Heads/designees for executing the proposed change through electronic means of communication or photocopy of the approved Change Control Form.

Note: If a Change Control is pending approval for more than 30 working days from the date of login, it is the discretion of the QA Head or designee to approve or reject the change control.

Part IV: Verification of implementation & closing of change control

On the approval of change control, it is the responsibility of Quality Assurance to verify whether the change is implemented or not as per the proposal and verification shall be documented as per the approval checklist. Only after satisfactory implementation of the change and all documents or activity mentioned in the change control form is properly closed, then only QA personnel shall close the change control by signing and putting the date in the “Change monitored by” column.

Then the Change Control Form is forwarded to Head-QA for the closing of the change control. Finally, Head-QA shall close the Change control by signing in the “Change closed by” column.

After the Head-QA signs, QA shall close the change control, put the closing date, and keep the completed change control form in the QA department. And QA shall update the logbook.

Note: In case of a change in the Manufacturing Process or a new vendor, trial batches with proposed changes should be taken & kept on stability to see that the proposed change does not affect the product during its shelf life. After getting the results, the proposed change can be incorporated.

Product Quality Review

OBJECTIVE:

To lay down the Procedure for preparation of Product Quality Review.

PROCEDURE :

Product Quality Review (PQR) is a mechanism to ensure that data captured by the Pharmaceutical Quality System (PQS) is reviewed for trends. This tool can support a continuous improvement environment. PQRs are designed for the purpose of identifying and implementing recommendations for required improvements

Content of PQR

Summary of  Product Quality Review

A brief summary of the PQR should be made for the batches manufactured in the current year even if only one batch was manufactured.

Batches manufactured

A review and number of all batches manufactured including failed batches/rejections during the review period for a specific product should be listed in the PQR. Gaps in batch numbering, e.g. due to validation lots pending approval or orders being canceled before any production commenced, should be explained in detail.

Raw materials from new sources (e.g. API, excipients, and packaging materials)

Raw materials (e.g. API, excipients, and packaging materials) should be listed if purchased from a new source for the manufacturing of the product concerned.

Analytical results (Critical in-process control results & critical analytical test results of finished products)

The comparison of the particularly applicable specifications and initial analysis results of all or of a representative number of batches that were produced during the defined review time frame should be included. These data should include all the critical quality parameters for a specific product and are to be reviewed.

Quality parameters examples for drug products are:

Critical In-process control result

Critical In-process control results should be collected from the Batch manufacturing record and Batch packing record during the following stages of manufacturing as applicable.

Granulation: 

LOD, Blend Assay, and Yield at different stages of manufacturing of the product..

Compression/Encapsulation:

Average weight, Uniformity of weight, Hardness, Thickness, Disintegration Time, Friability, Dissolution ( if applicable ), Assay & Yield of compressed tablets or filled capsules.

Coating:

Average weight, Thickness, Disintegration Time, Dissolution, Assay, and Yield of coated tablets.

Liquid Orals

• pH
• Density
• Related Substances
• Assay (Active, Preservatives)
• Microbial Counts (Total Bacterial; Total Fungal, Pathogens)
• Batch yield

Critical analytical test results of the finished product

Critical analytical test results of the finished product should be collected from the Certificate of Quality as per product specification. This data may include as applicable.

Description, Average weight, Uniformity of weight, , Hardness, Thickness, Disintegration Time,Friability, and Dissolution of finished products.

• Assay
• Impurities (HPLC & GC)
• Content uniformity
• Microbial results
• Other critical parameters.

Deviations and Out of Specification:

A review of all investigations related to deviations and OOS should be performed including a review of the adequacy of previous corrective actions.

Change controls (Change of specifications and process revisions):

All change controls raised should be listed in the PQR. This list should include details of changes made in of specifications, manufacturing, and/or packing process revisions.

Review of any changes to the equipment used during manufacturing and packing of the product.

All information regarding the change of any equipment that was used during the manufacturing or packaging process of the particular product should be included in the PQR.

Stability review:

A summary of stability data of all batches on stability (follow-up stability program), which represents the manufactured batches for distribution. These data should be reviewed and compared with data from the previous year’s review to assure that no negative trend has developed and no stability failures occurred and that the expiry period is still appropriate.

Customer complaints

Any customer complaints received from the respective market during the time frame of the review should be listed in the PQR. The list should include the following details:

1. Product Name & Batch Number.
2. Nature of complaint
3. Root cause.
4. The conclusion made as a result of the investigation

Market Withdrawals, Recalls, and Regulatory Alerts

Any batches withdrawn or recalled, or regulatory alerts made from the respective markets during the time frame of the PQR should be listed along with the reason for the recall or withdrawal.

Returned / Salvaged drug products

A listing of any returned/salvaged drug products should be included. This should include the batch number and the reason for returning. If investigations were performed the result and the decision on the final use should also be listed.

Any returned products that are considered complaints should be evaluated as stated under the point of customer complaints.

Review of an annual visual examination of retained samples

Representative retention samples should be visually examined once a year.

Qualification status of relevant equipment and utilities (HVAC system, Water system, and Compressed air system)

Changes/ deviations to the qualification status of relevant equipment and utilities should be summarized.

Review of contractual arrangements

A review of contractual arrangements with contractors or suppliers should be included to confirm the agreements are up-to-date.

 Trend analysis evaluation and graphical representation of analytical data

Statistical analysis should be performed to assess the batch uniformity and integrity of drug products. Since the process evaluation is performed, a graphical representation of parameters (i.e. Control and Acceptance criteria, etc.) will be useful to study the historical behavior patterns of the process and aid in the visual evaluation of out-of-specification values and/or trends that may translate into abnormal variations. Individual trends shall be analyzed and a conclusion shall be written.

Recommendations and conclusion

All data should be evaluated as a whole and these data should be summarized and recommendations for actions provided. The responsibility for coordination and supervision of follow-up measures is with the QA.

All batches manufactured in the calendar year or review period (January to December) should be included in the preparation of PQR.

All batches manufactured including rejected batches during the review period should be included in the PQR.

All PQRs should be conducted with the objective of verifying the consistency of process parameters and highlighting any trends.

The timeline for completion should not be longer than 3 months past the end of the calendar year.

Release of finished products

OBJECTIVE:

To lay down the procedure for the release of finished products.

PROCEDURE :

Ensure that the Batch Manufacturing Record has been reviewed and audited by Production in all aspects. The reconciliation of the materials and product yield is carried out at the respective stages of the operation.

Ensure that the Production Manager has reviewed the completed BMR before it is submitted to Quality Assurance for final audit and release of the Finished Product for distribution.

QA personnel shall review & verify the following points before preparing the release order.

• Review the Batch Manufacturing Record as per the respective SOP.
• Verify that the product has been approved by Quality control with respect to its testing as per the Product release specification.
• Finished product COA is attached with the BMR.

Verify the Quantity being released from quantity transferred to Finished Goods Store on ‘Product Transfer Note’ and attached with the BMR.

After verification QA personnel shall prepare a ‘RELEASE ORDER’ in duplicate, giving the details of Product Name, Batch details, Analytical Reference Number, Break-up of packed quantity, and total quantity released for sale on basis of the Batch manufacturing.

A serial no. shall allocate to the release order and the signature with the date shall be done by QA personnel.

The signed Release order along with the Batch Manufacturing Records shall submit to the QA Head or his designee for the final release of the Finished Product.

QA Head shall final review the BMR & put his sign with the date on BMR and release order.

QA Head shall forward BMR & release the order to QA personnel.

QA personnel shall send the Second copy of the ‘RELEASE ORDER’ (Green carbon copy) to the Finished Goods Store so that the dispatch of Finished Products shall be planned.

The First copy (Green copy) of the release order shall be attached to the batch manufacturing record and QA personnel shall finally archive the BMR in the documentation cell.

In case a batch has to be released partially, the BMR shall be completed up to that stage & reviewed by Production and QA.

After review of BMRs, if QA personnel shall found all the specifications of the product meeting with the finished product specification till stage then a ‘PARTIAL RELEASE NOTE’ shall be prepared for a partial quantity of batch by QA personnel and shall be approved by QA Head or his designee.

In cases of other than the bifurcated batch, the partial Release status shall be mentioned in BMR, while in case of the bifurcated batch, the final release status shall be mentioned in BMR.

If all bifurcated quantity is being released on the same date, then ‘RELEASE ORDER’ shall be prepared only, no need to prepare ‘PARTIAL RELEASE NOTE’.

For the tests, which take a longer time for completion e.g. Sterility test, Microbial limit test, and Suspension stability analysis, to save the time of transportation, a ‘PROVISIONAL RELEASE’ shall be given for dispatch of the products up to the Distributors.

Dispatched products through provisional release shall meet finished product specifications except e.g. Sterility test, Microbial limit test, and Suspension stability analysis, and further dispatch to market, the product shall be upon confirmation of product final release.

The final release for further sale shall be given only after completion of the above-referred tests e.g. Sterility test, Microbial limit test, and Suspension stability analysis, by preparing a ‘RELEASE ORDER’  in a green copy of the release order and forwarding to Finished Goods Store personnel and distributions for the final release.

QA allocates the release order number in the release of finished products, as given below:

FRN/XX/YYY

FRN    –       Finished Goods Release Number

XX      –       Last two digits of the running calendar year

YYY   –       Serial number (0001 to 9999)

The final release order shall attach with Batch manufacturing Records and hand over to the Documentation Officer/Executive.

Records the release of the finished product in the Logbook for batch release of finished products.

SOP ON PRODUCT RECALL AND MOCK RECALL PROCEDURE

PURPOSE :  To define the procedure for drug product recall and mock recall.

SCOPE  : This SOP shall be applicable to,

Hold and/ or recall of drug products from distribution or market due to certain non- confirmatory aspects or instruction from regulatory agency.

Hold and/ or recall of drug products sold in domestic and/ or export market.

REFERENCE(S)

WHO Technical report series No. 908 (2003), Annexure-4

PIC/s SOP: “Procedure for handling rapid alerts and recalls arising from quality defects”. 1^st July 2004.

Drug and Cosmetics Act, 1940, Schedule-M

CROSS REFERENCE DOCUMENTS

• Change Control Management
• Corrective and Preventive Action (CAPA)
• Quality Risk Management (QRM)
• Handling, Management and investigation of Deviation
• SOP On Investigation

Attachment 

• Product recall classification and associated actions with timelines.
• Format of product recall register (To be maintained at location.).
• Format of product recall register (To be maintained at CQA.)
• Format of product recall register (To be maintained at Logistics).
• Format of product hold and recall authorization request.
• Format for preparation of rationale for product recall.
• Format of letter to be used for Type A recall by logistics.
• Format of letter to be used for Type B recall by logistics.
• Format of recall effectiveness check letter to consignee.
• Format of recall effectiveness check response (Letter / e-mail method).
• Format of recall effectiveness check response (Telephone & personal visit method).
• Format of product recall periodic status / final report.
• Format of mock product recall audit report.

DEFINITIONS

Complaint: A market / consumer complaint is notification that a product in commercial distribution (which also includes physician sample).

May be in violation of the laws or regulations administered by the FDA (Drug Control Authority)

May have caused an illness, injury or death.

Is alleged to have caused problems not covered by the above.

Product Recall: A product recall may be defined as the retrieval from the marketplace of a batch (es) of a medicinal product as a result of a quality defect or other issue being identified with the batch (es) which resulted in the batch (est.) not to be in compliance with the terms of the product marketing authorization. In addition, a product recall may be warranted due to the emergence of new safety information relating to a product or class of products.

Correction: Repair, modification, adjustment, relabeling or inspection of product without physical removal.

Recalling firm / manufacturing location /Location: The firm who has produced /       manufactured / marketed the product (under distribution or in use) being recalled.

Consignee (C & F agent / Distribution depot / Stockist)  : Anyone who receives and further distributes the product.

Market withdrawal: A firms removal or correction of a distributed product which involves a minor violation that would not be subject to legal action by the food and drugs administration or which involves no violation, e.g. Normal stock rotation practices, routine equipment adjustments/repairs etc.

Stock recovery: A firm’s removal or correction of a product that has not been marketed or that has not left the direct control of the firm, i.e. The product is located on premises owned by or under the control of the firm and no portion of the lot has been released for sale/use.

RESPONSIBILITY

Quality Assurance:

To recommend product recall.

To arrange for destruction of recalled product as per relevant SOP of location.

To ensure proper documentation of all the activities.

QA Head:

To authorize the hold and /or destruction authorization request and sent to CQA.

To monitor the activity as per product recall and any other relevant SOP.

To monitor implementation of CAPA as per the recommendation(s).

Plant Head :

To authorize hold and /or destruction authorization request.

To monitor the activity as per SOP.

To monitor implementation of CAPA as per the recommendation(s).

Corporate Quality Assurance(Marketing company):

To provide hold &/or recall registration number.

To review hold &/or recall authorization form.

To intimate logistics /international marketing for retrieval of product from market.

To monitor implementation of CAPA as per the recommendation(s).

Head Corporate Quality Assurance(Marketing company::

To decide on product recall request.

To ensure intimation to respective regulatory agencies.

To get verified the recalled quantity against the distributed quantity and reconciled with the quantity dispatched.

To communicate to R & D, if required.

To get mock recall performed for evaluation of effectiveness of the product recall procedure.

Logistics(Marketing company):

To hold the stock for further distribution at respective consignee.

To provide the stock available at respective consignee.

To retrieve the hold product at company’s depot / any other destruction location.

To intimate corporate quality assurance about retrieval.

Regulatory Affairs(Marketing company):

To provide guidance to location / international marketing for the recall of the exported product.

To get the recall process completed through international marketing for export

To communicate with regulatory agency regarding product recall and its progress for domestic recall.

International Marketing(Marketing company)::

Is a bridge between location / regulatory affairs and regulatory agency of the respective country.

To provide the product distribution &/or stock status information to location as and when requested.

To communicate to regulatory agency of the respective country to hold & / or recall of the product.

PROCEDURE:

Recall initiation:

Initiation of a product recall may be voluntary or Drug Control Authority requested or mandated.

Product hold and recall may trigger due to any of the below reasons:

On confirmation of quality complaint which may be from customer/ patient/ doctor/ regulatory agency /external sources or agencies. Examples of such complaints are following but not limited to:

• Melt back of lyophilized cake.
• Foreign matter.
• Colour change.
• Change in physical form of tablets, solution, and suspension.
• Adverse drug reaction/event.
• Product stability failure.
• Mislabeling observed.
• Counterfeit products.

Product recall classification:

Type A (PIC/s class I & II): Recall from consumer/ retailer / pharmacy / medical user / stockiest level where there is a risk to patient’s health. 

PIC/s Class-I: defects are potentially life threatening or could cause a serious risk to health. A rapid alert notification must be sent to all parties, parties irrespective of whether or not the batch was exported to that country.

Examples of PIC/s-class I defects include following but not limited to.

• Wrong product (label and contents are different products).
• Correct product but wrong strength, with serious medical consequences.
• Microbial contamination of sterile injectable or ophthalmic product
• Chemical contamination with serious medical consequences
• Mix-up of some products with more than one container involved
• Wrong active ingredient in a multi-component product, with serious medical consequences.

PIC/s Class-II: Defects could cause illness or mistreatment, but are not class I. A rapid alert notification should be sent only to those parties to which it is known, or believed, that the batch has been distributed. In the case of parallel exports where there is difficulty in establishing the traceability of batches, consideration should be given to notifying all parties by the rapid alert system.

Examples of PIC/s-class II defects include following but not limited to:

• Mislabeling, e.g. wrong or missing text or figures.
• Missing or incorrect information (leaflets or inserts)
• Microbial contamination of non-injectable, non-ophthalmic sterile product with medical consequences.
• Chemical/physical contamination (significant impurities, cross-contamination, particulates).
• Mix up of products in containers.
• Non-compliance with specification (e.g. assay, stability, fill/weight).
• Insecure closure with serious medical consequences (e.g. cytotoxic, child resistant containers, potent products).

Type B (PIC/s class III): Recall from stockiest where there is no risk to patient’s

PIC/s class-III: Defects may not pose a significant hazard to health, but withdrawal may be initiated for other reasons. If deemed relevant by the issuing authority, the rapid alert system may be used.

Examples of class III defects include following but not limited to:

• Faulty packaging, e.g. wrong or missing batch number or expiry date.
• Faulty closure.
• Contamination, e.g. microbial spoilage, dirt or detritus, particulate matter.

Timelines and actions associated with recalls:

The timelines and actions associated with the above classes of recalls are summarized in Attachment-I.

Hold, recall and destruction procedure for domestic products:

In case of product failure which may be due to any of the reasons, QA person shall make necessary entries in product recall register  and shall inform to CQA through e-mail and shall collect product hold & recall registration number from CQA.

CQA shall make necessary entries in product hold & recall register.

Hold & recall registration number at CQA shall be defined as CHR/25/01 where CHR stands for hold and recall, 25 for year 2025 and 01 is serial number.

QA person shall send approved copy of “Product hold and recall authorization request” to CQA as per Attachment-V along with the rationale  or investigation report containing rationale for hold/recall.

Note: investigation report must include Impact analysis: Inspection / analysis of  samples of other batches and CAPA.

CQA shall review the request and shall take approval from head CQA for further actions depending upon the nature of the problem. Further actions may include following but not limited to:

Holding of the further distribution of the product batch.

Inspection / analysis of samples of different distribution locations.

Withdrawal of stock

Refusal of hold &/or recall request.

Head CQA shall comment / suggest / approve the recall authorization request.

Copy of the approved / commented request shall be sent to location QA department with copy to management, regulatory affairs and logistics.

If recommendations/comments given through mail, copy of the same shall be attached withhold & recall authorization request.

In case of approval of the hold and recall authorization request, CQA shall instruct logistics (with copy to regulatory affairs and Management though e-mail & phone if required) to hold and/or recall the batch(es) and to provide the stock status through e-mail, if required.

Logistics shall provide the stock status available at respective stockiest / C & Fs on the same day and make necessary entry in the product recall register..

CQA shall arrange to collect samples from different stockiest/C& Fs and shall send them to respective location for the inspection / testing (for critical quality parameters) if recommended in hold & recall request.

If required, a representative from concerned location may visit the respective Consignee(s) within 02 working days after receipt of stock status and withdraw the samples and arrange for analysis for further investigation.

In case of type B recall, if CQA has recommended sampling, inspection, analysis of samples of different distribution locations (Stockiest/C&Fs) , location shall take actions accordingly and shall send report to CQA having action taken, analysis results, impact analysis etc. within 03 working days after receipt of the samples at location (except products where biological assay is involved).

In case of rejecting the hold and recall authorization of the batch/es, proper justification shall be included by CQA head.

CQA head shall give instruction to logistics where to recall and destroy the batch in question.

In case of type A recall, logistics shall instruct different C&F /stockiest to recall the batch up to Stock list as well as dealers, distributors, wholesalers and retailer level through mail.

Logistics shall send the proofs of such communications & acknowledgments of the same received from dealers, distributors, wholesalers and retailer to concerned location with copy to CQA.

In case of type A recall rapid alerts to consumer level shall be given through television, radio, newspapers etc. in consultation with respective regulatory agency, if required.

In case of type B recall, Logistics shall instruct different C&F /stockiest to recall the batch up to Stockist level through mail . Copy of the e-mail or proofs of such communications shall be sent to concerned location with copy to

QA person shall ensure hold and recall of the product as per timelines.

QA person shall ensure that recalled product is stored at the designated area ensuring product security, storage condition and segregation.

QA person shall verify the quantity of recalled/recovered stock against hold stock status & shall make necessary entries in hold & recall register.

QA person shall arrange destruction of the batch as per relevant location SOP in the presence of QA. Destruction procedure followed shall be documented as per location SOP.

In case if the recall & destruction is recommended at any other destruction location, the same shall be done in presence of QA representative and necessary destruction details/procedure shall be recorded by location representative as per Attachment-II and relevant SOP.

Incase if recall is due to product complaint /nonconformity received from regulatory agency, CQA shall recommend necessary actions in consultation with regulatory affairs department. Any further communication to regulatory agency regarding investigation, product hold and/recall shall be done through regulatory affairs.

CQA shall monitor that hold and recall actions are taken as mentioned..

Hold, recall and destruction procedure for export products:

Procedure up to recall authorization approval by CQA head for the exported products shall be same as for domestic products.

CQA shall provide the relevant details to regulatory affairs for hold / Recall of the product in the impacted country (ies).

The recall information shall be submitted by Regulatory Affairs to respective country as per rules prevailing in respective country through international marketing.

Regulatory Affairs shall arrange for product hold and recall through international marketing with copy to location (recalling firm), CQA & Management.

The timelines for product hold and recall shall be as per Attachment-I.

Assessing Recall Effectiveness:

The purpose of effectiveness checks is to verify that all consignees have receive notification about the recall and have taken appropriate action. The method for contacting consignees may be accomplished by personal visits, telephone calls, letters, mails or a combination there of.

CQA shall evaluate the effectiveness of the product recall procedure from the actual product recall or by performing mock recall and prepare the evaluation report.

Mock recall(s) shall be performed once in a year ± 1 month.

Procedure for mock product recall:

CQA shall collect following information /batch detail through mail for at least three products from more than one location.

• Product name & strength.
• Batch number.
• Manufacturing and expiry dates.
• Pack presentation.
• Total quantity of batch dispatched.
• Date of dispatch.
• Dispatched to.

Locations shall provide the requested batch details to CQA.

CQA shall inform to the head logistics to hold the stock of the selected products requesting the stock status at various Consignee (distribution depots and C & Fs).

Logistics shall hold the stock of the products and shall provide stock status at various Consignee (distribution depots and C & Fs).

CQA shall visit the two or three Consignee (distribution depots and /or C & Fs) and shall verify the stock of the product/s against stock status received from logistics head along with product storage condition and security of the hold product. The details of audit shall be recorded.

CQA shall prepare the mock product recall report and conclude the effectiveness of the recall.

CQA shall circulate the report to logistics as well as locations for record.

Procedure for effectiveness check of actual product recall:

Location shall perform recall effectiveness in consultation with either logistics department head or international marketing department head & regulatory affairs.

In conducting a recall effectiveness check, there are certain basic questions that consignees shall be asked either through letter/e-mail/ telephonically/ personal visit.

The purpose of these questions is to determine whether: the recall notification was received, the product involved was handled as instructed in the recall notification, the product was further distributed by the consignee before receipt of the recall notification, and if so, were these additional consignees notified. Other questions may need to be asked depending upon the nature of the recall. Also the design and format of the questionnaire may vary depending upon which method of contact is to be used.

Elements of these methods include following.

A letter to consignee.

An envelope prominently inscribed with “IMPORTANT RECALL INFORMATION INSIDE,”

A questionnaire, and

A self-addressed stamped envelope for the consignee to return the completed questionnaire.

The letter/ mail to the consignee shall state exactly the reason for the recall, a complete description of the product being recalled or corrected, and instructions as to disposition of the recalled product, and a request for cooperation in completing and returning the questionnaire.

Upon receipt of the completed questionnaires, a master file shall be prepared to identify responding consignees by their unique identification number and to record their answers to the questions.

Recall effectiveness check shall be completed within 35 working days of product recall at location.

Recall status reports/Recall final report:

Periodic status reports shall be prepared by the recalling firm on the progress of the recall effectiveness checks at biweekly intervals. These recall status reports shall contain following information:

Number of consignees notified of the recall, and date and method of notification.

Number of consignees responding to the recall communication and quantity of products on hand at the time it was received.

Number of consignees that did not respond.

Number of products returned or corrected by each consignee contacted and the quantity of products accounted for.

Number of consignees contacted as per level and results of effectiveness checks that were made.

Estimated time frames for completion of the recall.

Corrective action plan.

In case of domestic product, these periodic status reports should be addressed to CQA & Management

In case of export product, these periodic status reports should be addressed to the respective regulatory agency, Regulatory Affairs, CQA & Management.

A final report on product recall shall be prepared including reconciliation between the delivered and recovered quantities of the products.

The report shall be sent to CQA for recall termination within 35 working days after product recall at location. The final report should include CAPA.

Correction and preventive Action Plan (CAPA) should include following

• Product description
• Consignee list (foreign and domestic).
• Description of the defect (including all reports, documents, memos, etc., of meetings, technical reviews, etc., which pertain to the analysis of the problem).
• Proposed steps to be taken to correct the product in the field and steps taken to prevent future occurrences.
• Proposed effectiveness checks to be conducted.
• Proposed date of completion and appropriate interim dates for implementation of the correction.
• Any and all injury/death investigations or reports.

Pertinent complaints on file.

If product recall is due to stability failure CQA shall intimate R & D and co-ordinate in resolving the product problem.

The recalling firm shall issue CAPA to concerned for the same.

Recall termination:

Termination of a domestic product recall: Type A / Type B

Upon receipt of the final recall report, CQA shall evaluate the same with respect to efforts put to recover the product; quantity delivered v/s quantity recovered and shall approve the recall within 03 working days after receipt of the report.

In case of type B recall, recall shall be terminated after ensuring recall of 100% quantity of the stock from consignee to location.

Termination of a export product recall:

Recall termination procedure shall be as per rule / law /guideline of the regulatory agency of the respective country.

Product destruction/corrections:

The recalling firm and customers shall keep adequate documentation of product destruction as per defined procedures.

Field corrections, (e.g. product relabeling), should be performed by recalling firm representatives, or under their supervision and control at a decided location.

Destruction Procedure of Recalled Product

The product returned from the market, shall be removed from its primary and secondary packing and recovered product shall be collected in SS container. Add sufficient volume of water with this recovered product and after getting it completely dissolved, check the pH, which should be more than 8 (If required use 1M NaOH to set the pH).Transfer this slurry in collection tank of ETP system.

SOP ON JOB RESPONSIBILITIES

OBJECTIVE

To lay down the Procedure for preparation of Job Responsibilities.

PROCEDURE

To maintain a satisfactory system of Quality Assurance and manufacturing of drug products, as per cGMP requirements. Total operation is divided into various functions, called Departments. The following are the departments :

• Warehouse
• Production
• Engineering & Utility
• Quality Control
• Quality Assurance
• Personnel & Administration

Each department shall be provided with defined responsibility to perform the task manufacturing of tablets, capsules, oral Liquid, and dry syrup to meet cGMP requirements.

The duties of each department are defined but not necessarily limited to as follows.

Warehouse

• Preparation and review of the instruction for describing the receipt, identification, quarantine, storage and handling of raw materials/ Packing materials/Finished product.
• Receipt, identification, quarantine, storage and handling of material / product according to pre approved instructions.
• Environmental monitoring of the area as per predefined procedures.
• Making sure that any deviation is reported and investigated properly.
• Making sure that storage area is cleaned.
• Inventory control.

Production

• Preparing and reviewing the instructions for the production of products according to written procedures.
• Producing products according to pre-approved instructions.
• Reviewing all production batch records and ensuring that are completed and signed.
• Making sure that all production deviations are reported and evaluated and that critical deviations are investigated and conclusions are recorded.
• Make sure that production facilities are clean and disinfected when appropriate.
• Making sure that the necessary calibrations are performed and recorded in respective areas.
• Making sure that the premises and equipment are maintained and recorded in respective areas.
• Evaluation of proposed changes in product, process or equipment.
• Making sure that new and when appropriate, modified facilities and equipment are qualified.

Engineering & Utility

• Preparation and review of the instruction for describing the procedure for preventive maintenance, and breakdown maintenance.
• Evaluating any change in equipment, and machinery.
• Operation of all Utilities like Water, HVAC, Boiler, Compressed Air, etc.
• Execution of Installation and Operational Qualification of equipment as per approved protocol.

Quality Control

• Approve / Reject raw material / Packing Material/Finished Product.
• In process Control of product quality.
• Making sure that critical deviations are investigated and resolved.
• Out of Specification Investigation.
• Preparation and Standardization of volumetric solutions and reagents.
• Inventory control of chemicals / Glassware etc.
• Preparation and review of all SOP’s related to department, Specification and test procedures.
• Initiation and review of any change related to the department.
• Preparation and execution of validation protocol for method validation.
• Making sure that materials are appropriately tested and results are reported.
• To conduct Stability Studies.
• Calibration of instruments used in the Laboratories.
• Handling of Reference standard and Working standard and qualification of working standard.
• Quality control department shall be responsible for issue, control, review and retrieval of worksheets.

Quality Assurance

To formulate systems for the implementation of cGMP and to ensure the preparation, approval, and implementation  of  Standard   Operating   Procedures, Standard  Cleaning Procedures, Specifications, Standard Test Procedures, Cleaning validation protocols, stability protocols, Master Batch Production records, etc.,

To evaluate and qualification of vendors of raw materials and packaging materials.

The quality Assurance department shall be responsible for sampling the in-process materials, finished products, and stability samples.

The quality Assurance department shall be responsible to review and approve validation protocols, to review changes in product processes, equipment, or any other changes as per SOP “Change Control”.

The quality Assurance department shall be responsible to check dispensing of materials and for in-process quality control.

The quality Assurance department shall be responsible to release the batch after reviewing the Batch Production records to assure that the batch has been manufactured as per the Master Batch Production Record and there are no deviations, if any, are recorded and authorized.

The quality Assurance department shall be responsible for auditing methods, results, systems, and processes and for performing the trend analysis and preparation of the annual review of drug product quality.

The quality Assurance department shall be responsible to release the finished products and to maintain the reserve samples of finished products and batch production and control records.

The quality Assurance department shall be responsible to investigate market complaints and to maintain market complaints investigation records.

The quality Assurance department shall be responsible for the disposition of Incidents/OOS and approval of deviations.

The quality Assurance department shall be responsible for the monitoring of stability studies.

Quality Assurance personnel shall be trained as per the SOP “Training of Employees”

Personnel & Administration

• To prepare procedures for personnel hygiene medical checkup, housekeeping.
• Employee Welfare.
• To coordinate for training to all employees.
• To conduct regular medical checkups and housekeeping.

The department head shall ensure that an adequate number of personnel with the necessary qualifications and experience are provided to complete the departmental responsibility.

An Organogram for each department shall be prepared by the department head/or his designee and approved by the Head of the Department and QA Head.

The individual employee profile shall be prepared and approved by the Head of the Department as per Attachment-II and revised after two years.

The individual job responsibilities shall be prepared by Department Head and shall be approved by Head-QA as per Attachment-III and revised after two years or hen job responsibilities are revised.