HANDLING OF MARKET COMPLAINTS

To provide the procedure for handling of market complaints and to ensure that all complaints related to drug products are recorded and investigated promptly with the aim of addressing them in a timely manner to satisfy the complainant, adhere to compliance requirements as well as to prevent future occurrences.

SCOPE:

This procedure is applicable at all manufacturing sites comprises volumes of markets. Exclusions from this SOP are the issues reported prior to distribution of the product beyond the control area of Organization quality systems.

RESPONSIBILITY:

Corporate Quality & Compliance:

To receive & log the market complaint at CQC.

To collect the adequate information required for complaint investigation.

To forward the complaint to the concern manufacturing sites for the investigation.

To review Preliminary Investigation Report (PIR) or Final Investigation Report (FIR) received from the sites.

To send the final reply to the complainant.

Quality

To log in the complaint at site.

To perform investigation and prepare investigation report (PIR and/or FIR).

To perform periodic review of the complaints & ensure CAPA implementation, as applicable.

Quality Control Department:

To analyze complaint sample, any another sample in relation to the complaint investigation or control sample.

To provide analytical results or any other data with conclusion.

Production Head:

To cooperate QA in the process of complaint investigation.

To review the complaint investigation report.

Head – Quality Assurance / Quality Control:

To receive complaint from CQC or any other source and forward to QA for investigation.

To provide guidance for the investigation of market complaint.

To approve the complaint investigation report.

Head – Manufacturing site:

To provide guidance for the investigation of market complaint.

To approve the complaint investigation report. 

DEFINITIONS:

Complainant:

Any source from whom the complaint information is received is called the Complainant. E.g. patients, prescribers, pharmacists, nurses, hospitals, retailers, distributors, Regulatory Authority etc.

Complaint:

Any written, electronic or oral communication reported by Customers, Hospitals, Regulatory Agencies, Government laboratories, Retailers, Distributors, etc., that alleges deficiencies related to the identity, quality, reliability, safety and/or efficacy of a product after it is distributed beyond the control area of quality systems shall be considered as a Complaint.

Risk Assessment:

A systematic process of organizing information to support a risk decision is termed as Risk Assessment. It consists of identification of hazards and the analysis and evaluation of risk associated with exposure to those hazards.

Adverse Drug Event:

It refers to any injury occurring at the time a medication or drug product is used, whether or not it is identified as a cause of the injury.

Adverse Drug Reaction:

All harmful and unintended responses to a medicinal product related to any dose should be considered adverse drug reactions.

PROCEDURE:

Receipt & Registration:

On the receipt of the complaint from CQC, CQC should update details and site representative should make necessary entries in the

Market complaint log as per respective site procedure.

If adequate information is not available to relate the complaint as valid, sufficient follow-ups shall be carried out with the complainant through phone, e-mail, written communication, facsimile, etc. If such follow-ups fail to yield this information, non-availability of the information shall be recorded and complaint shall be marked as invalid.

If complaint is Medical in nature, adverse drug reaction reporting form shall be forwarded to complainant for complaints related to ADR / LOE or efficacy issue.

After receiving all the necessary details, CQC shall log the complaint and allocate the complaint registration number. The complaint registration number should be allotted as per respective site SOP.

Complaint shall be recorded and forwarded to manufacturing unit preferably within one working day of receipt of necessary details.

If site receives the complaint from any source other than CQC, copy of complaint shall be forwarded to CQC immediately after receipt. CQC shall log the complaint for tracking at corporate level.

Market complaints shall be comprising of Quality related discrepancy, packing related discrepancy and shortage related discrepancy, but not limited to.

Risk Assessment of Complaint:

For all valid complaints a Risk Assessment shall be conducted by the manufacturing site to classify the risk category of the complaint so as to facilitate Prioritization of investigations and Assessment for the need for Product Recall.

All critical complaint shall be targeted to respond within 2 working days after its initial classification along with PIR or final report.

The following three factors shall be used to identify the level of risk based on nature of the complaint:

Assessment of Severity:

Impact of complaint on product quality and patient safety, Severity is possible consequence of Hazard. Severity (S) refers to an assessment of the seriousness of a failure as it affects the end user.

Having determined that the complaint may represent a risk to the safety, identity, strength, purity and/or quality of the product, the Manufacturing site shall assign a risk rating as per Table A below:

Table A: Severity of Complaint – Rating and Criteria

Risk Rating	Criteria
Low	No impact on product identity, strength, purity and quality Minor GMP non-compliance ,No impact on patient safety (defects which may not pose any significant hazard to health)(Explanation: A lesser deviation from the requirements which calls for moderate action)
Medium	Likely impact on product identity, strength, purity and quality• Major GMP non-compliance• Potential impact on patient safety (defects which could cause illness or mistreatment but are not life-threatening or serious ones but medically reversible)(Explanation: Noticeable impact on product quality/patient safety, but is recoverable. A deviation from the requirements which calls for strong action)• Direct impact on product identity,
High	Direct impact on product identity, strength, purity and quality• Critical GMP non-compliance – this has direct impact on product quality Critical impact on patient safety (defects which are potentially life-threatening or could cause serious risk to health)(Explanation: Definite impact on product quality/patient safety. Affect to the patient in some way.)

Assessment of Probability of Occurrence of the cause(s) of Complaint: 

The cause of a complaint shall be reviewed to determine the ‘Probability of Occurrence’ of the complaint in future. Occurrence refers to the probability that a specific cause will result in a specific failure mode. The term failure in this case refers to the probability of the specific failure mode occurring. The manufacturing site shall assign a rating for the Probability of Occurrence as per Table B below:

Table B: Probability of Occurrence – Rating and Criteria

Table	Criteria
Low	The quality related event is unlikely to occur (i.e. it has not occurred in the past)
Medium	The quality related event may occur (i.e. it has occurred infrequently in the past)
High	The quality related event is likely to occur (i.e. it has occurred in the past on a frequent basis)

Where, the terminologies related to Low, Medium & High could be elaborated as below:

Risk Rating	Criteria
Low	Low probability of failure (same or similar process). Failure only seen once or twice in same or similar process. One occurrence every six months to one year or one occurrence in 10000 events.
Medium	Moderate probability of failure (same or similar process). Failure Potential has been noted in some product lots and or in more than one products of similar process. One occurrence every three months or three occurrences in 1000 events.
High	High probability of failure (same or similar process). Failure / Failure potential has noted in several lots or many Products of similar process. One occurrence in every month or a probability of 3 occurrences in 100 events.

Assigning Level of Risk Based on ‘Severity’ and ‘Probability of Occurrence:

Upon assessing the ‘Severity’ and ‘Probability of Occurrence’ of the complaint, the manufacturing site shall assign risk level as shown in Table C. It may be noted that Severity (i.e. the impact on the patient/product quality) carries a higher weightage than Probability of Occurrence:

Table C: Risk Level based on Severity & Probability of Occurrence

		Risk Rating based on Probability of Occurrence
		Low	Medium	High
Severity	High	Level ONE	Level ONE	Level ONE
	Medium	Level TWO	Level TWO	Level ONE
	Low	Level THREE	Level THREE	Level TWO

 

Assessment of the ‘Probability of Detection (‘State of Control’) of the Complaint:

The purpose of this stage in the risk assessment process is to identify whether there are sufficient controls to ensure that the complaint can be recognized or detected in the system and prevented from recurrence.

The manufacturing site shall assess the state of controls surrounding complaint and assign the rating as per Table D below:

Table D: Probability of Detection (State of Controls) – Rating and Criteria

Rating	Criteria
WEAK	The system has either ‘weak’ or ‘no’ controls to detect the quality related event after its occurrence
MEDIUM	The system has controls and will possibly detect the quality related event after its occurrence
STRONG	The system has multiple controls and is very likely to detect the quality related event after its occurrence

 

Final Risk Classification:

Using the results of the Risk Assessment process as described in the earlier section to identify the level of risk based on the Severity and Probability of Occurrence of the quality issue and corresponding State of Controls, the Manufacturing site shall assess the risk and classify the same as Critical /Major/ Minor based on Table E:

Table E: Final Risk Classification

		State of Controls I Probability of Detection
		Strong	Medium	Weak
Risk Level	Level One	Major	Critical	Critical
	Level Two	Minor	Major	Critical
	Level Three	Minor	Minor	Major

Note:

The risk level calculated through this matrix may be upgraded to a higher level, if needed, based on a case-to-case evaluation by QA.

Based on the validity assessment of the complaint and the Risk Assessment, impacted batches may be blocked/Hold, if required.

If the complaint risk is assessed to be ‘Critical’, the due date for complaint closure shall be calculated as below.

Preliminary investigation report shall be submitted within two working days and Final Investigation report within 10 working days.

If the investigation exceeds 10 days, reason for the same shall be documented & prior justification from QA/QC head shall be taken.

If the complaint Risk is assessed to be ‘Major’ or ‘Minor’, the due date for complaint closure shall 30 working days from date received.

If the investigation exceeds 40 days, reason for the same shall be documented & prior justification from QA/QC head shall be taken.

The complaint risk management action plan shall be dependent on the risk category and in line with SOP on Quality Risk Management.

Based on Risk Assessment, if needed, the Manufacturing site may initiate a Recall Proposal for the affected batches of the product as per SOP on Product Recall. Complaints, assessed to be ‘Critical’ in terms of patient safety, shall be specifically reviewed for the need to initiate product recall proposal. Final approval on product recall shall be taken by Head CQC.

Note: Attach separate report for initial categorization of Complaint based on Risk Assessment.

Investigation of the complaint:

Each complaint shall be investigated mandatorily to identify the root cause by referring site investigation SOP and using necessary scientific tools.

In case of critical complaint where investigation may take time, site QA shall prepare PIR & forward to CQC within 2 working days of

The receipt of Complaint (PIR may include but not limited to review of BMR / BPR / Control sample / Product literature / Trends depending on nature of complaints).

CQC shall send initial reply to the complainant if required, with or without replacement.

Site QA shall attach the PIR with the complaint, which shall be the part of market complaint investigation report.

QA shall conduct the investigation with the help of concern departments.

QA shall arrange for the physical inspection of control sample if required & prepare report of the same, which shall be part of the investigation report.

QA shall provide required quantity of control sample to QC for analysis if required.

QA shall provide required batch manufacturing documents to production or QC for review & data collection.

Production & QC shall provide required information to QA for the preparation of investigation report.

QA shall prepare FIR & shall get it reviewed and approved by the concerned persons.

QA shall send copy of the final investigation report to CQC along with necessary attachments like control sample physical inspection report, batch report, quality control analytical data (in process trend, FP trend, stability data, complaint sample analytical results, control sample analytical results, batch results), training record or any other data.

On receipt of FIR, CQC shall send final reply to the complainant, as required.

Examples of market complaint with suggested investigation is mentioned in below for reference purpose. The examples are limited and

Investigation may vary depending on the nature of compliant and type of formulations and associated factors.

 

Final Classification of Complaint:

Based on the nature of complaint, risk assessment and investigation findings, each complaint shall be classified into one of the following

Categories:

Critical: Complaints related to drug product(s) having potentially life threatening consequences shall be termed as ‘Critical’.

For Example:

Quality Defect which is likely to cause AE/ Efficacy issues which may have life-threatening consequences (based on case-to-case evaluation), any extraneous matter in injectable products, extraneous matter in non-injectable with life-threatening consequences (like metal, glass, etc.), wrong product (label and contents are different), correct product but wrong strength with serious medical consequences, product mix-ups.

Major: Complaints related to drug product(s) having consequences that could cause illness or mistreatment are termed as ‘Major’.

For Example:

Quality defects which are likely to cause AE / efficacy issues which are, however not life threatening, or serious ones, or are medically reversible, wrong / missing text or figures which may affect the product identity/ usage instructions (e.g. missing or incorrect  manufacturing / expiry date, missing leaflets or leaflets with incorrect information), significant shortages, etc.

Minor: Complaints related to drug product(s) having consequences that may not pose a significant hazard to health are termed as ‘Minor’.

For Example:

Faulty closure that will not cause any medical consequences, insignificant shortages, faulty secondary or tertiary packaging, that will not

However, affect the product quality, poor/ improper presentation of product containers, quality defects which are likely to cause efficacy issues, but will not cause any significant hazard to health.

Adverse Drug Event: An adverse event occurring in the course of the use of a drug in professional practice; an adverse event occurring from drug overdose whether accidental or intentional; an adverse event occurring from drug abuse; an adverse event occurring from drug withdrawal; and any failure of expected pharmacological action.

Unclassified: Alleged Lack of Effect (LOE) (due to customer perception, etc.),

The following risk management action plan table can be used for taking a corrective action:

Complaint final Classification	Action
Minor	Requires training for enforcement of procedure /policies / Process instructions etc.
Major	Requires an effective control (i.e. enhanced monitoring & additional check points in the System /Procedure/Process) and Training. Requires remediation and/or automated system based control and or Procedural controls.
Critical	Assessment for impact on batches in manufacturing (work in progress) and batches in distribution shall be done and based on impact assessment following action shall be carried out, as applicable like Immediate suspension of manufacturing activity, Product Recall, information to impacted Manufacturing site(s) / Vendor. Requires development/ modification and revalidation (i.e. Process mapping, process analysis, Investigation, Root cause Analysis, development and validation) and or high degree of training and evaluation. Procedural controls (i.e. quarantining of a batch, Rejection etc.)

Reply to complainant:

In case of critical complaint, CQC head shall send initial reply to the complainant, if required.

Subsequently, CQC shall send copy of initial reply to the concern site for the record.

After receipt of FIR, CQC shall send final reply to the complainant.

Copy of reply shall be send to Manufacturing site & Regulatory affairs department.

Complaint shall be considered closed, if no query received within 30 days of sending reply to complainant.

Six monthly review of complaints:

Quality review of complaints shall be done after every six months by manufacturing site, conclusion shall be drawn & CAPA shall be

Implemented by each site. The date of implementation of CAPA & effective B. No. shall be informed to CQC & the record shall be kept by CQC.

ABBREVIATIONS:

ADE: Adverse Event

ADR: Adverse Drug Reaction

CAPA: Corrective and Preventive Action

CQC : Corporate Quality &Compliance

FDA: Food & Drug Administration

FIR: Final Investigation Report

FP: Finished Product

PIR: Preliminary Investigation Report

ANNEXURES:

Annexure 1 : Flow Chart for handling of Market complaints

Annexure 2: Format of market complaint log

Annexure 3: Template for Market Complaint Preliminary Investigation Report

Annexure 4: Examples of market complaints-guideline for investigation

Annexure 5: Template for Market Complaint Final Investigation Report

Annexure 6: ADR Reporting Form

EXAMPLES OF MARKET COMLAINTS- GUIDELINE FOR INVESTIGATION

Example of Complaint –

1. Ineffectiveness/poor quality/Inadequate response of the drug.

Suggested Investigation

History of the product.

Physical inspection of complaint & control sample.

Review of batch document for,

• Active RM (Raw Material) calculation.
• added of active & inactive RM against bill of material.
• Source of material.
• Dispensing precautions: e.g. API dispensing & storage in the black/ light resistant bag or container.
• Processing precautions: e.g. dissolved oxygen, safe light, and nitrogen flushing or any other.
• Dose control record.
• Processing parameters.
• In process checks by production & QA.
• Daily quality observation record.
• Any deviation, which has direct or indirect impact on product quality.

In process quality control data.

Review of FP analytical report & trend.

Review of stability data.

Complaint & control sample analysis for (as applicable),

• Volume variation.
• Content uniformity.
• Degradation
• Related Substance.
• Moisture content.

Biological assay, where required.

Storage condition.

Audit of C & F agent or retailer if required.

2.Less content in capsules/ tablet/vial/ ampoule/bottle.

Suggested Investigation

Physical inspection of complaint & control sample,

• For minor crack.
• Improper sealing.
• Condition of container label & / or show box to eliminate possibility of leakage.

Review of batch mfg. record for,

• Active RM calculation.
• added of active & inactive RM against bill of material.
• In process checks by production & QA.
• Visual inspection record.
• Leak test record.
• Yield & reconciliation of the batch.

In process & FP quality control data.

Trend of yield.

Sequential log of filling or compression or capsule filing machine for breakdown or any other problem observed during processing.

Daily quality observation record.

Complaint & control sample analysis for as applicable,

• Content uniformity.
• Degradation.
• Related Substance
• Volume variation

3.Budging of strip pockets.

Suggested Investigation

History of the product.

Physical inspection of control & complaint sample.

Improper storage condition.

Review of stability data.

Analysis of complaint &/or control sample for as applicable,

• Related substance
• Moisture content

4.Presence of foreign matter

Suggested Investigation

History of the product.

Physical inspection of complaint & control sample for,

• Minor crack.
• Improper sealing.

Daily quality observation record.

pH trend.

Precipitation.

Physical inspection of particular AR No. used for mfg. of the batch.

Review of batch mfg. record for,

• Primary Packing Material
• Use of pre-treated ampoules (e.g. acid treated amps).
• Empty primary Pkg. material washing & sterilization in record.
• Cleaning record of mfg., filtration & filling equipment’s & area .
• Sterilization record of filtration & filling equipment’s.
• Filter integrity test results (Pre & post filtration).
• Leak test record.
• Terminal sterilization record.

Sequential log of washing machine.

Environmental monitoring data.

Quality/compatibility of closure and primary packing material.

Analysis of complaint sample/ control sample for,

• Identification of preservative.
• Content of preservative.
• Related substance

Microbiological analysis of complaint sample/control sample.

Training record of visual inspectors.

5.Adverse event /Adverse drug reactions (e.g. Vomiting, severe cramps/Rashes)

Suggested Investigation

History of the product.

Microbiological analysis of complaint sample/control sample.

Pharmacology of the API & related formulations.

6.Discoloration of solution or tab/cap/liquid.

Suggested Investigation

History of the product.

Physical inspection of complaint & control sample for,

• Minor crack.
• Improper sealing.

Review of batch mfg. record for,

• Special precautions required during processing e.g. Dissolved oxygen, low light, nitrogen flushing or any other.
• Cleaning record of mfg., filtration & filling equipment’s & area.
• Leak test record.

Daily quality observation record.

Recovery procedure.

In-process checks by production & QA during mfg. & packing.

Analysis of control &/or complaint sample for as applicable,

• Related substance
• Stability data.
• Storage condition.

7.Damaged/broken/leaking capsule/ampoule/vial.

Suggested Investigation

Physical inspection of complaint & control sample.

• Review of batch mfg. record for,
• Visual inspection record.
• & humidity conditions.
• Filling machine setting parameters.
• In process checks during mfg. & packing by QA & production.

Vendor of empty capsule/ampoule/vial.

Sequential log of capsule filling machine for breakdown.

Training of the visual checkers.

Compatibility study of empty hard gelatin cap/ampoule/vial with excipients.

Monitoring of de-foiling & repacking activity.

8.Melt back (of lyophilized cake).

Suggested Investigation

History of the product.

Physical inspection of control & complaint sample.

Review of batch document for,

• Filling in process checks by production & QA
• Lyophilization menu.
• Visual inspection record.
• Hold time at different stages.
• & humidity conditions at different stages.

Review of trend of processing, in-process & FP parameters.

Daily quality observation record.

Review of stability data.

Analysis of complaint &/or control sample for,

• Moisture content.
• Degradation.

Training record of visual inspectors.

9.Broken tab.

Suggested Investigation

History of the product.

Physical inspection of complaint & control sample.

Review of batch mfg. record for,

• In process checks by production & QA during mfg. & packing.
• Visual inspection record.
• NFD checking of cracking

Review of trend of processing, in process & FP parameters.

Daily quality observation record.

Handling of the bulk product and hold time.

Training record of the visual checkers & strip packing machine operators.

Analysis of control &/or complaint sample for,

• Hardness

Monitoring of de-foiling & repacking activity.

10.Product or batch mix-up.

Suggested Investigation

Physical inspection of control & complaint sample for physical appearance of primary pkg. material of two products under question.

System followed to ensure proper segregation product at different stages.

Sequential log of machine at every stage to know the previous or next product taken on the same machine & to ensure absence of same /similar product in the surrounding area.

Other products packed on the same day on the nearby labelling machine or packing line of product under question.

Review of batch mfg. record for,

• Machine & line clearance record at different stages.
• Reconciliation of packaging materials.
• Reconciliation of bulk & FP.

Analysis of control &/or complaint sample for,

• Identification test of two products under question.
• Identification test of preservative.

Wrong labelling/ packing.

Daily quality observation record.

Monitoring of de-foiling & repacking activity.

Training record of packers.

Repacking if done at any C& F location.

11.Poor quality of cap (Dropper/Dispenser).

Suggested Investigation

History of the product.

Physical inspection of Control or complaint sample.

Vendor of pkg. (cap or dropper) material.

Compatibility study.

Review of stability data.

12.Fake product.

Suggested Investigation

History of the product.

Comparison of complaint sample with control sample for appearance of strip/ label (font size of letters, printed text matter, size of the pocket, gap between the two pockets, knurling pattern, logo of the company, movement of tab or cap in the pocket etc.).

Comparison of complaint sample with control sample for appearance of tablet or capsule (size or dimensions, color, imprint, embossing, edge type etc.).

Comparison of primary packaging material (Vial/ampoule/strip/blister/bottle) for shape & size, sealing, height, type of seal, logo on the seal, color of the seal, type of rubber stopper etc.

Analysis of complaint & / or control sample.

14.Empty primary container (Vial /ampoule / bottle /pocket of strip or blister)

Suggested Investigation

Physical inspection of control &/or complaint sample.

Sequential log off-line striping or blistering machine for breakdown or any other problem.

Review of batch document for,

• In process checks by production & QA during filling.
• Leak test record,
• NFD challenge & working.
• Visual inspection record.
• In process checks by production & QA during packing (e.g. On line compressed air flow or any other system followed to Remove empty plastic container or empty pocket in strip or blister).
• Yield & reconciliation of the batch & comparison with trend.

Balance performance & calibration check record.

Weight variation record of packed show boxes & I or shippers.

Proper segregation of packed & empty boxes.

Daily quality observation report.

Training record of the visual inspectors.

Vendor of primary container (as cause of empty container may be hair line cracks due to weak MOC of container).

 14.Receipt of product in different show box/ having different label.

Suggested Investigation

Complaint sample observation.

Physical inspection of control sample.

Previous & next product packed on the same machine.

Appearance of packing material of two products under question.

Review of batch document for,

• Line clearance (by packing & QA) record.
• Reconciliation of packing material.
• Machine & line clearance record.
• In process checks by packing & QA.
• Product packed on adjacent lines/nearby area.
• Daily quality observation record.
• Storage of packing material in the store & in pkg. Dept.
• Procedure to be followed for the left over pkg. Material after completion of packing.
• Monitoring bf de-labelling & re-labelling/ repacking activity.
• Inspection of reaming stock of PM of the products under question.
• PM vendor audit.
• Training of Packers
• Repacking if done at any C &F location/depot.

15.Strip Short in mono-carton/ Carton short in shipper

Suggested Investigation

Physical evaluation of complaint / control sample

• Physical evaluation of complaint / control sample
• Review of batch document for,
• In process checks by packing & QA.
• Visual Inspection record
• Sealing of mono-carton & shipper by proper cello tape /BOPP tape.

Balance and check ware system performance & Calibration check records.

Weight variation record of packed show boxes (mono-cartons) & I or shippers.

Proper segregation of packed & empty boxes.

In case of loose shippers, sealing of shipper as per SOP.

Product complaints SOP