PIC/S GMP --- Product quality review system

Product quality review systemProduct quality reviewCorrective and Preventive Action CAPAPIC/S GMP

Product quality review systemProduct quality reviewCorrective and Preventive Action CAPA

QualityISO EC/

PIC/SQuality SystemCAPAProduct Quality review

QualityThe holder of a manufacturing authorizationmust ensure their products:Fit for their intended use, comply with the requirements of the marketing authorization Do not place patients at risk due to inadequate safety, quality or efficacy

How to achieve the Quality Requirement

To achieve the quality requirement:There must be a comprehensively designed and correctly implemented Quality system

Quality System Trend2000 ISO 9001:2000 Quality Management System

2002.8 FDA:Pharmaceutical Current Good Manufacturing Practices (CGMPs) for the 21st Century

Quality System Trend2003.7

ICH Q8 Pharmaceutical Development ( Status : Step 5, November 2005 ) ICH Q9 Quality Risk Management ( Status : Step 5, November 2005 ) ICH Q10 Pharmaceutical Quality System ( Status : Step 5, June 2008 )

Quality System Trend2006.1 PIC/S,Guide to GMP for Medicinal Products/ Revision of Chapter 1 Quality Management---1.5 Basic requirements of product quality review

2006.9 FDA,Guidance for Industry Quality Systems Approach to Pharmaceutical CGMP Regulations

GMP77

ISO 9000ISO 10013 ISO 8402:1994ISO 9000:2000(TQM) (Customer focused organization) (Leadership) (Involvement of people) (Process approach) (System approach to management) (Continual improvement) (Factual approach to decision making) (Mutual beneficial supplier relationship)

Quality System (FDA)This system assures overall compliance with cGMP and internal procedures and specifications.The system includes the quality control unit and all of its review and approval duties (e.g., change control, reprocessing, batch release, annual record review, validation protocols, and reports, etc.)It includes all product defect evaluations and evaluation of returned and salvage drug products.

Commission Directive 2003/94/ECPharmaceutical Quality assurance means the total sum of the organized arrangements made with the object of ensuring that medicinal products or the investigational medicinal products are the quality required for their intended use.Good Manufacturing Practice means the part of quality assurance are consistently produced and controlled in accordance with the quality standards appropriate to their intended use.

Quality assurance (PIC/S GMP)Quality assurance is the sum total of the organized arrangements made with the object of ensuring that medicinal products are the quality required for their intended use.Quality assurance incorporates GMP plus other factors.

Quality System Model

An ICH visionThe future Pharmaceutical Quality Systems Risk from Manufacturing Risk form Product / Process DevelopmentHighLowHighLowQ10 Pharm. Quality SystemsQ8 Pharmaceutical DevelopmentQuality Risk Management Q9 Continual Improvement

Quality Assurance SystemQuality Management --- PIC/SGMP(Facilities, Production,QC, Distribution,)Product Development

Product Quality Review(2006.1)

ManagementResponsibility

CLIENT

ResourceManagement RequirementInputProduct /ServiceRealizationProduct

CLIENT

SatisfactionMeasurement,Analysis andImprovementContinuous improvement of theQuality Management SystemOutputQuality Management System - ISO 9001:2000

Management ResponsibilitiesManufacturingResourcesEvaluation ActivitiesQuality System Model --- FDA Guidance for Industry Quality Systems Approach to Pharmaceutical CGMP Regulations, FDA, 2006.9

PIC/S GMP Quality Management System

Quality Management System (Finished product)Senior ManagementSupplierQAQCProductionStorageDistributionQuality UnitReview and Approval of Documentation & Change Control.Ensuring Availability of Validation ResourcesMonitoring implementation of GMPBatch Review/Audit and release (Authorized person)Ensuring proper Storage, Distribution & HandlingComplaint Handling & Product RecallsContract Production & AnalysisMonitoring Personnel TrainingVender Qualification, Approval & AuditSelf-Inspection, Quality audit, and Trend EvaluationEnsuring Proper Documentation Control & ManagementProduct Review ProductR & D1.QA Policy, Regulation, Standard, MA 2.Validation/Revalidation

3.QA compliance

4.Documentation Control / Management

5.Corrective and Preventive Actions

6.Management Review

API GMPQuality management Quality should be the responsibility of all persons involved in manufacturing. Manufacturer should establish, document and implement an effective system for management quality. Active participation of management and appropriate manufacturing personnel.The system for management quality should encompass the organizational structure, procedures, processes and resources, as well as actives confidence that the API will meet its intended specifications for quality purity.

API GMPQuality management There should be a quality unit (s) that is independent of production and that fulfills both quality assurance (QA) and quality control (QC) responsibilities. Persons authorized to release intermediates and APIs should be specified. Responsibilities of the Quality Unit (s) should be specified. Responsibility for Production Activities should be specified. Internal Audits (Self inspection, Audit findings and related Corrective and Preventive actions) to verify GMP compliance. Product Quality Review, at least annually, to verify process consistency.

Quality Management System (API)ManagementReceiptQAQCProductionStorageDistributionQuality UnitOrganization, Procedures, Processes, & Resources.Validation of Manufacturing Resources & Change Control.Authorizes Persons to release intermediates & APIs.Documentation & Records Control/Management.Internal Audit.Product Quality Review.Complaint & Recall Handling.Contract Manufacturing & Analysis

Product Quality Review

81 113

Product Quality Review (PIC/S GMP1.5)1.A review of staring materials and packaging materials used for the product, especially those from new sources. ()2.A review of critical in-process controls and finished product results. 3.A review of all batches that failed to meet established specification (s) and their investigation. 4.A review of all significant deviations or non-conformances, their related investigations, and the effectiveness of resultant corrective and preventive actions taken. 5.A review of all changes carried out to the processes or analytical methods.

Product Quality Review6.A review of Marketing Authorization variations submitted/granted/refused, including those for third country (export only) dossiers. 7.A review of the results of the stability monitoring programmed and any adverse trends. 8. A review of all quality-related returns, complaints and recalls and the investigations performed at the time. ()9. A review of adequacy of any other previous product process or equipment corrective action 10.For new marketing authorizations and variations to marketing authorizations, a review of post-marketing commitments.

Product Quality Review11. The qualification status of relevant equipment and utilities, e.g. HVAC, Water, compressed gases etc. 12. A review of Technical agreements to ensure that they are up to date.

Product Quality Review

1.A review of staring materials and packaging materials used for the product, especially those from new sources. ()2.A review of critical in-process controls and finished product results.1.A review of critical in-process control and critical API test results.3.A review of all batches that failed to meet established specification (s)and their investigation.2.A review of all batches that failed to meet established specification (s).4.A review of all significant deviations or non-conformances, their related investigations, and the effectiveness of resultant corrective and preventive actions taken.3.A review of all critical deviations or nonconformance and related investigations.5.A review of all changes carried out to the processes or analytical methods.4.A review of any changes carried out to the processes or analytical methods.6.A review of Marketing Authorization variations submitted/granted/refused, including those for third country (export only) dossiers.7.A review of the results of the stability monitoring programmed and any adverse trends.5.A review of results of the stability monitoring program.8.A review of all quality-related returns, complaints and recalls and the investigations performed at the time.()6.A review of all quality-related returns, complaints and recalls.9.A review of adequacy of any other previous product process or equipment corrective action7.A review of adequacy of corrective actions.10.For new marketing authorizations and variations to marketing authorizations, a review of post-marketing commitments.11.The qualification status of relevant equipment and utilities, e.g. HVAC, Water, compressed gases etc.12.A review of Technical agreements to ensure that they are up to date.

Corrective and Preventive Action CAPA

(ISO 9000) a)b)c)d)

(ISO 9000)a)b)c)d)

Quality System Requirements for Pharmaceutical Inspectorates (PIC/S)14.2 Corrective/ Preventive action14.2.1 The Pharmaceutical Inspectorate should establish and maintain a procedure for investigation of non-compliances with the quality system which are identified through internal or external audit of its activities. The procedure should include the prescribing, implementation and verification of corrective action. The procedure should cover also corrective actions arising from the investigation of complaints and other observations relating to the activities of the inspectorate.14.2.2 The system should include a description of the steps to be taken in assessing the need for quality improvement and preventive action.14.2.3 Corrective and preventive actions should be documented and records should be retained for a defined period.

Corrective and Preventive Actions Any of the Quality Related Complaints and/or Recalls, the deficiencies observed in internal audits and quality audits, and problems noted in trend analysis, must lead to an investigation of the root causes, corrective actions and preventions actions, and followed by monitoring of the effectiveness of the corrective action, and possibly an additional internal audit to assure that the change have remained effective. There must have policies and procedures, and designated staff to implement corrective and preventive actions when necessary. Root cause analysis can be the most difficult part of the corrective and preventive procedures. All possible causes must be investigated,. Deeper analysis is needed to determine whether the root cause was inadequate training, confusing forms, or other type of mistakes.

Guidance for IndustryQuality Systems Approach to Pharmaceutical CGMP Regulations (FDA)CAPA (Corrective and Preventive Action) CAPA is a well-known CGMP regulatory concept that focuses on investigating, understanding, and correcting discrepancies while attempting to prevent their recurrence. Quality system models discuss CAPA as three separate concepts, all of which are used in this guidance.Remedial corrections of an identified problem Root cause analysis with corrective action to help understand the cause of the deviation and potentially prevent recurrence of a similar problem Preventive action to avert recurrence of a similar potential problem

Root cause analysis()

Corrective Action /

Preventive Action

CAPAFDAinvestigating, understanding, and correcting

Investigating 3

Understanding ()

Correcting

Corrective and Preventive Action (CAPA) ProcessAction PlansInvestigateIdentify/EvaluateTrend of DataIntra/Inter Data

CAPA case IXXX()QC lab(Assay)!!CAPA??

CAPA case IIXXX(2)

1st: 2nd: coatingCAPA? ?

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PIC/S GMP(On going stability testing)

(On going stability testing)

PIC/S Part 1 ( 2003.09.01 ) (6.1~6.22 On going stability programme) //

PIC/S Part 1()2007.09.01 Chapter 6 On going stability programme6.23~8.336.24 The purpose .., within specifications under the labelled storage conditions.6.25 in the package in which it is sold, but .the programme of bulk product.6.27 description of the conditions of storage( standardized ICH conditions for long terms testing, consistence with the product labeling, should be used )6.29 .Unless otherwise justified, at least one batch per year of product manufacturing.

PIC/S Part 2123456789/1011(11.5)1213141516/()1718/19

PIC/S 11.50 .....11.51 11.52 ..:...11.53 ......11.54 .()...11.55 .: /.....().11.56 .ICH.

On going stability testing

(Holding time)///()

PIC/S GMP4315

()()()(ICH)

ICH

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(Bracketing design)

Strength50 mg75 mg100 mgBatch123123123

Container size15 mLTTTTTT100 mL500 mLTTTTTT

Matrixing design One-Half Reduction One-Third Reduction

Time point (months)036912182436StrengthS1Batch 1TTTTTTBatch 2TTTTTTBatch 3TTTTTS2Batch 1TTTTTBatch 2TTTTTTBatch 3TTTTT

Time point (months)036912182436StrengthS1Batch 1TTTTTTBatch 2TTTTTTBatch 3TTTTTTTS2Batch 1TTTTTTTBatch 2TTTTTTBatch 3TTTTTT

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Chapter 4PIC/S GMP///

GMP64

82*

Chapter 9.

GMP77

Annex 15Design Qualification Annex 15, 9 GMP Annex 15, 10 3.4DQ3.15/DQ3.19DQ3.27DQ3.34DQ 4.2DQ /4.17 .DQ ()4.18.DQ (/)Worst caseAnnex 1514.b

Annex 8 N1 v.s. each containerGMPPIC/S GMP..

Supplier auditAnnex 8GMP()

GMP78 1PIC/S GMPReference samples(Part 1, 6.12)Reference samples (Part 1, 6.14)Reserve/ Retention Samples (Part 2, 11.7)(Part 1 )2(Part 1 )12 (Part 1 )13 (Part 2 )

Annex 19 1.1 reference samples of starting materials, packaging materials or finished products and retention samples of finished products. (2.1) Reference sample Retention sample/(3.1~3.2)/PIC/S (4.1)

V.S.

Reference sampleRetention sample/

ISO 9000: "Quality Management Systems"-- fundamentals and vocabulary ISO 9001: 2000: "Quality Management Systems"-- requirements ISO 9004: "Quality Management Systems" -- guidelines for performance improvements Eudralex Volume 4: "Medicinal Product for Human and Veterinary Use: Good Manufacturing Practice" PIC/S GMPUS FDA: "Guidance for Industry Quality Systems Approach to Pharmaceutical CGMP Regulations" ICH: ICH Q8, ICH Q9, ICH Q10 PIC/S GMP93.11.26Reference