SOP on the Self-Inspection/Internal Audit in the pharmaceutical industry. One of the best quality tool for Quality improvement which helps to identify the gap between the existing procedure and cGMP. Also, check for the compliance of regulatory guidelines. We are discussing Self-Inspection/Internal audit definition, internal audit report, Self-Inspection/Internal audit, and cGMP requirement.

SOP on Self-Inspection/Internal Audit

1.0 PURPOSE: 

The purpose of this SOP for performing Self-inspection/Internal Audit periodically so as to evaluate the quality system is effective and comply to cGMP and to suggest corrective and preventive action (CAPA) for quality improvements.

2.0 SCOPE: 

Applicable to the operations, quality system, process, a procedure which are directly or indirectly connected with all departments i.e. production, store, dispensing, packing, quality control, engineering, environment health and safety (EHS), HR and admin, Quality Assurance etc.

3.0 RESPONSIBILITY: 

3.1 Quality Assurance:

3.1.1 Preparation and approval of annual audit schedule, list of audit team members.

3.1.2 Ensure planning and execution of local internal audit program per established procedures.

3.1.3 Ensuring regular independent review of the quality audit system.

3.1.4 Ensuring the quality audit is effectively implemented.

3.1.5 Impact evaluation of the non-conformance with the auditee department.

3.1.6 Evaluation and approval of new auditor audit report and certify the new auditor.

3.1.7 Updation of the checklist as per regulatory requirement.

3.1.8 Approval of investigation report and check for the closure of the investigation report.

3.2 Audit Team:

3.2.1 Perform Self Inspection/Internal audits of sites, systems, facility, process, etc.

3.2.2 Preparation of non-conformance report.

3.2.3 Review proposed actions for audit observation.

3.2.3 Identification and evaluation of the new auditor.

3.3 Auditee:

3.3.1 Representing the department and provide necessary support and resources to the auditor.

3.3.2 Respond to audit observations with an investigation plan.

4.0 DEFINITION:

4.1. Self-inspection/Internal Audit:

A systematic examination to control and evaluate quality-related activities and their results should comply with documented system and verify the existing system are effectively implemented and are suitable for achieving the quality of the product.

4.2 Auditor:

The person or team of person who conduct an audit and verify the compliance of the facility, system, process, etc.

4.3 Auditee:

The person or team of person who faces the audit and responsible for the compliance of the facility, system, process etc.

4.4 Action plan:

It is a set of actions taken to improve a situation and to fix, or correct a non-conformance.

5.0 PROCEDURE: 

5.1 The Self-inspection/Internal Audit evaluates the compliance with cGMPs in all respects of the facility, system, process, etc. and related to the quality management system.

5.2 The Self-inspection/Internal Audit observations and investigation reports should be treated as confidential. Not for any external agency or regulatory bodies.

5.3 Preparation of audit Plan /schedule of Audit

5.3.1 Prepare Self-inspection/Internal Audit schedule for one year in such way that all departments should be covered.

5.3.2 Schedule is prepared on the monthly basis E.g. QC in Jan-2020, Production in Feb-2020 likewise.

5.3.3 All the department should be covered under Self-inspection/Internal Audit at least twice a year. E.g. QC in Jan-2020 and Jul-2020 likewise.

5.3.4 Schedule should be prepared and approved by QA before the start of the new year.

5.3.5 QA person should be prepared a list of qualified audit team members annually and update the list whenever required for in addition or deletion of qualified members. Approve the list of audit team by Head QA.

5.3.6 Audit should be conducted by cross-functional department.

E.g. In case audit of the Quality Assurance department (auditee) then never choose an audit team member (auditor) of the same department.

See the below table for better clarification:

Sr. No.	Auditee	Auditor	Cross-Functional	Acceptable/ Not Acceptable
1	Quality Assurance (QA)	QC/ production/ store etc.	Yes	Acceptable
		Quality Assurance	No	Not Acceptable
2	Quality Control (QC)	Quality Control (QC)	No	Not Acceptable
		QA/ production/ store etc.	Yes	Acceptable

5.3.7 The members of the audit team should be expert in their own fields and familiar with cGMP.

5.4 Identification & Evaluation of new Auditor

5.4.1 Person should be evaluated and certified based on experience, knowledge, and qualification.

5.4.2 Person having a minimum of 7 years of experience should be eligible for the auditor after evaluation. If a person has more than 15 years’ experience then the person should be considered as an auditor, no need for evaluation.

5.4.3 Evaluation should be done in 3 Stages: 

5.4.3.1 Stage -I: As an observer

5.4.3.1.1 New person should participate in the Self-inspection/Internal Audit as an observer. The certified auditor should guide about activities and the procedures to be carried out during Self-inspection/Internal Audit to a new person. A new person should observe and understand the activity performed by the Self-inspection/Internal Audit team.

5.4.3.1.2 New person should prepare report on his/her own observations and the same should be evaluated by the certified auditor.

5.4.3.1.3 New person should be evaluated by the certified auditor.

5.4.3.2 Stage – II: As a supporter

5.4.3.2.1 New person should support the Self-inspection/Internal Audit team in carrying out self-inspection.

5.4.3.2.2 New person should prepare a report on his/her own observations and same should be evaluated by the certified auditor.

5.4.3.2.3 New person should discuss the observations with the Self-inspection/Internal Audit team and should be involved in report writing. The capability of a new person to analyze the situation, explain the observation and reporting skill should be evaluated by a certified auditor.

5.4.3.2.4 New person should be evaluated by the certified auditor only.

5.4.3.2.5 If the evaluation of stage I and stage II is not satisfactory then repeat stage I and stage II for retrained the new person.

5.4.3.3 Stage III- As Auditor

5.4.3.3.1 If the evaluation of stage I and stage II is satisfactory, New person should be evaluated as per stage III. A new person should be allowed to conduct a Self-inspection/Internal Audit under the observation of team members.

5.4.3.3.2 During this stage New person should be able to evaluate and analyze the situation given by the certified inspector.

5.4.3.3.3 Certified inspector should observe and review the activity performed by a new person and should ensure that inspection is performed in accordance with SOP/cGMP. The certified inspector should evaluate the ability of a new person to gap finding, compliance of guidelines, analyze the situation, provide an explanation of findings and categorizing and reporting of non-conformance.

5.4.3.3.4 New person should prepare a report on observations and the same should be evaluated by a certified inspector.

5.4.3.3.5 Final Self-inspection/Internal audit report should be made by the New person and certified inspector jointly and should be submitted to the inspected department.

5.4.4 If a new person qualifies for all above criteria then should be certificates.

5.4.5 Evaluation should be done for each department separately.

5.4.6 Only after successful evaluation of a new person certified by head QA to conduct audit independently.

5.4.7 Audit agenda and notification send 7 days before to the auditee department.

5.5 Checkpoints to be cover during the audit but not limited: 

5.5.1 Production Department: Master manufacturing Formula, Batch manufacturing record, cGMP, process validation, cleaning validation, control on prevention of mix-up and cross-contamination, material receiving and handling procedure, Change control procedures, deviation reporting, man-material movement flow, Line Clearance Procedure,  limited access to a restricted area, equipment qualification, calibration of equipment and balances, equipment cleaning procedure, status labeling, online batch records, current SOPs in use, segregation of batches in quarantine, availability of Personal Protective Equipment (PPE), Risk Management and Root Cause Analysis, equipment logbooks, etc.

5.5.2 Labelling Control and Artwork verification: verify labeling control i.e. issuance, reconciliation, controls to prevent mix up and to provide proper identification of drug product labels. Storage, testing of labels, Coding types of labels, Printed matter, Label counting Machine (Label Counter), counting machine validation, available stocks, label destruction procedure, barcode system, Label requirement as per country, etc.

5.5.3 Equipment: Handling of electrical appliances/items, MOC for product contact and non-contact parts, equipment design, qualification/validation /calibration records. Annual maintenance/calibration records of equipment by an outside party, Cleaning validation of equipment, Lubricant used for equipment, adequate services, fixed pipes, service pipes labeling, risk of cross-contamination, Requirement of pre filters and terminal HEPA filters, Proper coloring of service piping and devices, drawings of critical equipment’s, range and precision balances and measuring equipment, sufficient space for equipment, Safety guards for moving parts of equipment, Water pipes sanitization, Defective equipment labeling requirement, Qualification, and validation of computerized systems including software used by Stores, Production, Quality Control, and Quality Assurance

5.5.4 Validation & revalidation program: Validation master plan (VMP), process validation, cleaning validation, performance verification, and qualification protocols and reports for the qualification of equipment’s and requalification.

5.5.5 Calibration of instruments or measurement systems: All the equipment and instruments used should be calibrated. Traceability of calibration certificates, calibration records, certificates for the Instruments calibrated by external agencies.

5.5.6 Warehouse/Store Department: Check for storage of raw materials, packing materials and finished products, segregation of material, procedure to avoid mix up, Control storage and handling of material returned/rejected material and logical material flow should avoid cross-contamination, Storage conditions and environmental controls, labeling procedure, FIFO system, area cleaning procedure, access of restricted area, an inspection of material dispensing and sampling booth for material handling and cleaning, material dispatch procedure, etc.

5.5.7 Quality control: Activities such as sampling, chemical analysis, and microbiological analysis, QC organogram/organization chart, and personnel, Analyst Qualification/validation, Instrument qualification, analytical method validation, list of equipment and instrumentation, Calibration, procedure for Out of specification (OOS) and Out of Trend (OOT), preparation of working standard, test standard, and reference standard. Documentation related to QC such as specifications, procedures, reports, change control procedure, deviation, and records, Laboratory Incident report (LIR), Good Laboratory Practices (GLP), Good Documentation Practices (GDP), adaptation of ALCOA+, Handling of audit trail, Pharmacopoeia compliance, status labeling, stability testing documents, and stability analysis as per the procedure etc., verify for the regulatory compliance, Instruments and equipment logbooks etc.

5.5.8 Quality Assurance: Quality system and documented quality policy, Quality management, quality manual, site master file, SOPs handling procedure, Batch record, and Analytical Test results in review, documents control procedure i.e. issuance, review, approval, archival procedures, Master Manufacturing Formula (MMF), Line Clearance Procedure,  batch release procedure, list of authorized batch release persons, Annual product quality review (APQR), Deviations, Change Controls, Investigations, Vendor qualification and Laboratory Quality Assurance Systems, Market Complaint, Product Recall, Deviation, Out of Specification, Training Procedure, and its record, etc.

5.5.9 Complaints Handling: Clearly defined procedure for handling of the complaint, reports of investigations, Complaint log for recording complaints.

5.5.10 Recall Procedure:Clearly defined procedure for handling recall, investigation report for product recall, if any, Mock (fake) recall validation procedure and report.

5.5.11 Regulatory affairs: Dossier Preparation, Technical Agreement Preparation.

5.5.12 Documentation: Documents such as SOPs, daily, weekly and monthly reports, bound books, stock records, daily monitoring records, Training reports, BMRs, BPRs, usage logs, machine logs, machine history file, environmental control records, filter cleaning records and other records etc.

5.5.13 Environment Health and Safety (EHS): Procedures for sanitization and/or cleaning of premises, a procedure for safety practices, periodic medical check-up, effluent treatment plant, Disposal of materials as per the procedure, deactivation of materials and their records, Solvent disposal, Approval for disposal of high-value items etc.

5.5.14 Contract laboratory and manufacture: Responsibilities of the contract giver and contract acceptor are defined, cGMP compliance of contract acceptor,

5.5.15 Engineering/Technical: Air compressors, Boilers, HVAC qualification, utilities, preventive maintenance records, drawing, etc.

5.5.16 HR and Personnel Department: Check for record of employment and record of professional qualification, Induction training, Job responsibility of an employee, Organogram / Organizational Chart, etc.

5.5.17 HK department: Pest control and laundry activity, factory clothing system, area cleaning procedure, scrap handling procedure, etc.

5.5.18 Details of Personnel of various departments: Qualification, experience, and responsibilities of the key personnel properly defined and documented, training reports, health requirements of personnel engaged in production including personal hygiene and clothing.

5.5.19 Building and Maintenance: SOP related to Cleanliness of building/premises, building layout, Proper segregation, design and location for storage, manufacturing, planned the preventive maintenance program, Physical appearance of the facility and building etc.

5.5.20 General Point applicable to all departments: ALCOA+, Good Documentation Practices (GDP), cGMP, follow up of last 6 months Quality Management System (change control, deviation, Complaints), Control on electronic systems, a backup system for an electronic device, an audit trail (if applicable), Trackability of data, document and data control system etc.

5.6 Execution of Self-inspection:

5.6.1 Before starting self-inspection, the Auditor shall conduct a formal opening meeting in presence of the auditee. The agenda and flow of Self-inspection/Internal audit can be discussed in this meeting.

5.6.2 The Self-inspection/Internal Audit team should inspect individual departments like Stores, Quality Control, Production, Engineering, Quality Assurance, Personnel and Safety as per the checklist (cover all above checkpoints) available with Quality Assurance. The focus of Self-inspection/Internal Audit should be to identify deviations, to check the procedures for their revisions and update, identify the implementation of cGMP and regulatory requirements to recommend the necessary corrective and preventive action.

5.6.3 Self Inspection should be carried out from the flow point of operation.

5.6.4 Based on the Annual schedule, the Self-inspection/Internal Audit schedule in a particular month should be informed to all concerned Self-inspection/Internal Audit team members in advance.

5.6.5 The Self-inspection/Internal Audit checklist should be updated/reviewed as per cGMP requirements and regulatory requirements.

5.6.7 Focus on corrective actions stated in the previous Self-inspection/Internal Audit reports and audit reports are implemented, Significant changes noted currently like SOPs, equipment, specification, procedure, process, etc.

5.6.8 Ask questions to the auditee and the integrity of data produced in facilities as per ALCOA+ principles and Good Documentation Practices (GDP).

5.6.9 The auditors shall discuss the potential observations with the supervisor to confirm the non-compliance or the risk. During the audit, auditors should interact with the operators to ensure the awareness of operators.

5.6.10 The audit report should contain clear, concise description of the observation made, with all the necessary details.

5.7 Observation Reporting system: 

5.7.1 The non-conformances noticed during the Self-inspection/Internal Audit should be categorized into “Critical”, “Major” and “Minor”.

5.7.2 Critical non-conformance: Non-conformances, which have direct impact on the identity, purity, strength, safety, accuracy, quality of the product.

5.7.3 Major non-conformance: Non-conformances which may have indirect impact on identity, purity, strength, safety, accuracy, quality of the product.

5.7.4 Minor non-conformance: Non-conformances which may not have impact on quality identity, purity, strength, safety, accuracy, quality of the product.

5.7.5 After completion of the audit, a closing meeting with the auditee should be conducted and summarize the audit observations. The auditee will receive an internal audit report as well as timelines for the submission of audit response with investigation.

5.7.6 The non-conformances report submitted within 2 days to the concerned department Head.

5.8 Investigation of non-conformances (deviation): 

5.8.1 Department head of the respective department which was inspected should investigate the non-conformances.

5.8.2 Department Head along with Quality Assurance should check the impact on any other batches/products/ items/ systems.

5.8.3 Root cause analysis should be done for the non-conformances having an impact on the product quality, wherever required, the risk assessment should be performed.

5.8.4 Once the root cause has been established, an action plan should be carried out. If the action plan is not satisfactory or not completed within specified close time, corrective and preventive action should be logged.

5.8.5 If critical non-conformance is related to a specific batch, then that batch should be released only after complete investigation and impact assessment.

5.8.7 Compliance of critical non-conformance should be submitted within 24 hours and major and minor non-conformance should be submitted within 15 days to the Self-inspection/Internal Audit team after Self-inspection/Internal Audit report is received by concerned department.

5.8.8 A compliance report prepared by Department Head with the corrective action planned/taken should be submitted to the Self-inspection/Internal Audit team.

5.8.9 After review of the Self-inspection/Internal audit report, the investigation report should be reviewed and approved by Quality Assurance Head.

5.8.10 After approval, Quality Assurance should check the investigation report for final closure.

5.8.11 Closure of Self-inspection/Internal Audit should be done within 30 days period based on root cause identification and after implementation of the action plan.

5.8.12 If close out of Self-inspection/Internal Audit is not completed within 30 days, justification should be given for the same.

5.8.13 Self-inspection/Internal Audit log should be reviewed within the first week of every month for the closure of the pending non-conformances of self-inspection.

5.9 Follow up of previous observation to take necessary action: 

5.9.1 Hot topic (most observations) of Self-inspection/Internal Audit non-conformances of last six months considering all observations of the department.

5.9.2 Quality Assurance verifies this observation to help continuous improvement and prepare trend for last 6-month hot topic observation.

5.9.3 These trends should be compared with trends of the previous six months and data should be reviewed and conclusions should be drawn. If required, suitable CAPA should be planned.

 6.0 ABBREVIATIONS

SOP – Standard Operating Procedure

CAPA – Corrective and preventive action

cGMP- current Good Manufacturing Practices

QC – Quality Control

QA- Quality Assurance

HVAC – Heating ventilation and Air Conditioning.

7.0 REFERENCES

7.1 EU GMP Chapter 9-Self Inspection

7.2 ISO 9001:2015 -Quality Management Systems- requirement (9.2Internal Audit)

7.3 PIC/S – Guide to GMP for Medicinal Products Part I, Chapter 9-SelfInspection.

7.4 WHO GMP & Inspections “Quality Assurance of Pharmaceuticals” Volume 2, section 8

7.5 Medicine & Healthcare Products Regulatory Agency, ‘GXP’ Data integrity Guidance and Definitions, MHRA

7.6 ICH Q7: Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients (Section 2: Quality Management).

7.7 Canadian GMPs (C.02.012): Health products and food branch inspectorate: Good Manufacturing Practices (GMP) Guidelines.

7.8 Guidance for Industry, Quality System Approach to Pharmaceutical cGMP Regulations, USFDA

7.9 Schedule M (Section 15) of Drug & Cosmetic Act 1940.

8.0 HISTORY

Not Applicable

9.0 ANNEXURES

Not Applicable

FAQ: