inspection of active pharmaceutical ingredients

8/9/2019 inspection of active pharmaceutical ingredients

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PHARMACEUTICAL INSPECTION CONVENTION

PHARMACEUTICAL INSPECTION CO-OPERATION SCHEME

PI 030-113 January 2009

AIDE-MEMOIRE

INSPECTION OF ACTIVEPHARMACEUTICAL INGREDIENTS

© PIC/S January 2009Reproduction prohibited for commercial purposes.

Reproduction for internal use is authorised,provided that the source is acknowledged .

Editor: PIC/S Secretariat

e-mail: [email protected] web site: http://www.picscheme.org


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TABLE OF CONTENTS

Page

1. Document History .......................................................................................... 2

2. Introduction.................................................................................................... 23. Purpose ......................................................................................................... 2

4. Scope............................................................................................................ 2

5. Aide-Memoire ................................................................................................ 4

6. Revision History........................................................................................... 23

1. DOCUMENT HISTORY

Adoption by Committee 12.11.2009

Entry into force of PI 030-1 01.03.2009

2. INTRODUCTION

2.1 The adoption of ICH Q7 as the first truly harmonised GMP guideline for activepharmaceutical ingredients (APIs) and the associated development ofregulatory frameworks to implement the guideline as a regulatory standardmark the beginning of a new era of regulation for medicines.

2.2 The adoption of ICH Q7 by PIC/S occurred in May 2001 with the current versionof the guideline having been available since 1 September 2007 as GMPPE 009 (Part II).

2.3 The primary objective for implementing ICH Q7 is the reduction of the risksassociated with the manufacturing quality of APIs and this cannot be achievedwithout an effective inspection system which addresses the specific aspects ofthe global API industry.

3. PURPOSE

3.1 It is recognised that due to their background and experience the majority ofGMP inspectors are more familiar with the inspection of finished products.Therefore, to assist inspectors not specialised in the inspection of APImanufacturers this document has been developed to provide training andguidance for the preparation and performance of such inspections.

3.2 This Aide-Memoire should also contribute to a harmonised approach forinspections of API manufacturers between the different PIC/S Members .

4. SCOPE

4.1 At the time of issue, this document reflected the current state of the art. It is notintended to be a barrier to technical innovation or the pursuit of excellence.


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4.2 This Aide-Memoire focuses on the preparation for inspections and chaptersand/or sections of GMP PE 009 (Part II) which are specific to the inspection of

API manufacturers or critical for the quality of APIs. For sections which includerequirements similar to those in GMP Guide Part I devoted to Finished Productssuch as personnel, documentation, etc., please refer directly to GMP PE 009(Part II).

___________


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5. AIDE MEMOIRE

1. Preparation of API inspection

InspectionElement Workflow

Supportingdocuments

Inspectionhistory

Review the reports of any recent inspections carried out andthe outcome

Inspection reports

If appropriate, contact the inspectorate that conducted the lastinspection to verify the information

Basicinformationrelated to the

APIs

Determine the number of different APIs produced at the site Products QualityReview(s) (PQR)

Determine the classification of the APIs (antibiotics, hormones,cytostatics etc.)

Determine the intended use of the APIs (topic, oral, injectable,inhalation, etc.)

For each API, establish;- grade (freeze dried, micronised, sterile, etc.);- batch size; and- number of batches produced per year

Basicinformationrelated to thesite

Determine if the facilities are multipurpose or dedicated Site Master File

If APIs are potent or highly toxic determine the containmentmeasuresReview a list of manufacturing equipment

Review a list of SOPs

Review the flow of personnel and materials through finishingareas

If manufacturing operations, products or services, areoutsourced establish the name and address of thesubcontractors

SMF

Basicinformationrelated toprocesses

Review:- API specifications and test methods;- Process flow charts;- Detailed description of the process;- Stability studies results;- Impurity profile;- API starting materials definition etc.

Pharmacopoeia; CEP; ASMF (previouslyDMF), CTD part 3.2;Batch ManufacturingRecord if appropriate

If appropriate, contact assessors of the dossiers

Review validation status Validation MasterPlan; list of activitiesscheduled

Changes Review recent major changes (new product, equipment,

building renovation or extension etc.)Review scheduled major changes


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2. Quality Management System

Area ofoperations /

itemsNotes Crucial questions/Show me Supportingdocuments

Internal audits

(Selfinspections)

Approved and

documented schedule,which covers all GMPactivities available

Are internal audits being performed

as scheduled? Can they besubstituted by third party audits?How is the frequency of internalaudits determined?

2.40

Composition of theteam appropriate

Is the composition of the audit teamdetermined according to an SOP?Has consideration been given to:

- Conflict of interest- Code of conduct- Qualifications- Independence from the area

being audited (e.g. Whoinspects the QA function)

Qualification of anyexternal auditors

How is the suitability of externalauditors assessed?

2.40, 3.30

Effectiveness of thesystem to plan thecorrective andpreventive actions

Verification of thecompletion of an action

How does the company ensure thatcorrective actions are effective andare completed in a timely manner?

How do they check the effectivenessof preventive actions?

2.41

The flow of information

is effective

How is the responsible management

informed about the results of theaudits?

2.41, 2.18

Product QualityReview (PQR)

Regular PQRsperformed in a timelymanner (e.g. withinthree months from theend of the period beingevaluated).

Data from in-processcontrols, batch releaseanalysis and other key

quality indicators eincluded

Is the data evaluated for thepresence of trends, and are theseacted upon?

Are complaint, out-of-specification(OOS) and deviation investigations,reported, considered and evaluatedin the PQRs?

Are the PQR results used to re-

evaluate the expected monitoringranges in Batch ManufacturingRecords?

2.50, 2.51


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Area ofoperations /


A review of OOS,

critical IPC and API testresults, deviations,complaints, returns andrecalls, nonconformances andrelated investigations,including theeffectiveness of thecorrective andpreventive actionsconducted

A review of changesconductedStability program dataverified

Are required changes highlighted in

the PQRs implemented through thechange control system?

2.5, 6.61, 6.72, 8.36,

11.15

Based upon the review,the validation status ofa manufacturingprocess is evaluatedand recorded

2.5, 12.60

Complaints All quality relatedcomplaints recordedand investigatedaccording to a writtenprocedure

How are complaints reported,including orally, recorded andinvestigated?

15.10

Complaint recordsinclude all relevantdetails (date andsource of thecomplaint, nature of thecomplaint, referencesto batch number andproduction date)

Is the nature of the complaintcorrectly reported – i.e. is it possibleto establish if there is a recurringproblem?

15.11

The complaintinvestigation reportidentifies correctiveactions and follow

up/preventive actions

Has the impact of this complaint onother batches been considered?

15.11

The final reportspecifies the kind ofresponse provided tothe originator of thecomplaint and thedecision on the statusof the product

Does the corrective action correctlyaddress the problem, or it is focusedon “customer satisfaction”? (i.e. thecompany looked for the root cause ofthe problem, or simply “reimbursed”the originator of the complaint?)

Was source of the complaintremoved in an effective mannerthrough preventive actions?

15.11


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Area ofoperations /


Complaint records and

reports are evaluated inthe PQRs in order toidentify trends, productrelated frequencies,and severity

Are complaints correctly evaluated in

PQRs? (i.e. is there any evaluation ofreoccurrence and trends?) Are corrective/preventive actionsmanaged through the change controlsystem?

13.12-13, 15.12

Recalls The “recalls SOP”specifies the threshold(by way of examplecases, or other means)for which a recall shallbe consideredThe “recalls SOP”

specifies who caninitiate a recall, andhow the recall processshall be managed. (i.e.who is to be informed,and how recalled goodsare to be treated andstored)

Is the recall process clearlydocumented and easy to follow?

15.13, 15.14

The recall procedureclearly defines how toinform the regulatoryauthorities in the caseof recall related to aserious problem

Is there a requirement to inform theauthorities, and request cooperation(in terms of advices and/or actions),in cases where the recall is related toa potentially life-threateningsituation?

15.15

3. Personnel

Area ofoperations /


Cf. Scope 4.2 3.

4. Building and facilities

Area of

operations /items

Notes Crucial questions/Show meSupportingdocuments

General Product protectionincreases from earlythrough to finalmanufacturing steps

Have procedures been implementedto protect the API fromcontamination during the finalstages of manufacture? (e.g.sieving, milling and packaging)

4.10

The level of productprotection is dependentupon the product typeand the expected timeof exposure to the

environment

Have procedures been implementedto protect the API when exposed toeach stage of the manufacturingenvironment (sampling, loading,unloading, etc.)?

4.10


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Area ofoperations /


APIs with

microbiologicalspecifications requireadditional controls

What are the additional controls? 4.10

Have controls been implemented toensure that the activities insurrounding areas/neighbourhoodare not an actual source ofcontamination?

SMF

Have controls been implemented toensure that highly toxic nonpharmaceutical materials(herbicides, pesticides, etc.) are not

manufactured in the samebuilding/equipment as used for APIs.

4.43

APIs specificareas /activities

Tank farms Are the general condition of tanksand ancillary equipment (pumps,pipes, vents, etc.) appropriate fortheir intended use?

Are all tanks and associated pipesappropriately labelled and secure?

7.21, 7.22

Solvent recovery plant See recovery chapter

Washing rooms Are washing areas appropriatelymanaged andcontrolled?(equipment flow, storageof dirty and clean equipment,labelling)

4.10, 4.11

Control rooms Have computerised systems beenvalidated?Have the backup systems beenverified?

Are procedures in place for theanalysis of data?

5.4

Compressed air /nitrogen / other utilities

PIC/S Aide-Memoire onUtilities (PI 009)

Sewage and refuse Is waste effectively removed fromproduction areas (e.g. using closedsystems like containers or plasticbags to prevent contamination ofother areas)?

4.60

Are all waste disposal systemscorrectly identified?

4.60

HVAC Does the HVAC system provide anappropriate environment forfinishing areas where APIs areexposed?

4.21, 4.22


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Area ofoperations /


Water Drinking (potable)

water acceptable ifsuitable for intendeduse

Are records of CoA available?

Has testing at an appropriatefrequency been conducted?Does potable water meet at theminimum WHO guidelines (e.g. freefrom chemicals such ascarcinogens, toxic substances,metals, organochlorine pesticides,lindane, DDT, organic compounds,etc; radiologicals and micro-organisms)

4.30, 4.31, PIC/S Aide-

Memoire on Utilities (PI009)WHO Guidelines fordrinking-water quality

If water sourced from river, wells,etc. and treated by the

manufacturer, has the treatmentprocess been validated?Have the affects of seasonalvariation and human activity on thewater quality been addressed? Isthe process monitored?

4.33

Non-sterile APIintended to be used ina sterile drug

Is the water used in the finalisolation and purification stepsmonitored and controlled formicrobial counts, objectionableorganisms and endotoxins?

4.34

Design Defined areas or other

control system fordifferent activities(storage, sampling,quarantine, production,etc.)

4.14, SMF

Potential contaminationand cross-contamination hasbeen prevented by thelocation and placementof equipment

4.11

Flow of

materials andpersonnel

Are the flow of materials and

personnel appropriate for theprocesses? Are appropriate indicationsdisplayed in critical areas (gowninginstructions, labelling forclean/unclean areas,incoming/outcoming materials, etc.)

4.13

Containment Design of themultipurpose usecontainment area

Has the containment area beenqualified for multipurpose use?

If HVAC is not dedicated, whatcontrols are in place to prevent

cross-contamination?

4.22


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Area ofoperations /


Penicillins and

cephalosporins

Are they produced in dedicated

areas?

4.40

Other highlysensitizing, toxic,potent materials

Are sensitizing, toxic and potentmaterials either produced indedicated areas or are validatedinactivation and/or cleaningprocedures established andmaintained.

4.41

Controls to preventcross-contamination

Have procedures to prevent cross-contamination been established?Is the performance of theseprocedures being monitored?

Are staffs exhibiting appropriatebehaviour and personal gowningtechniques to prevent crosscontamination?

4.42

Are measures in place to ensurethat cross-contamination fromequipment, materials and personnelmoving from one dedicated area toanother area is avoided?

4.42

5. Process equipment

Area of

operations /items Notes Crucial questions/Show meSupportingdocuments

This section is to bedeveloped at the nextrevision of the Aide-Memoire

5.

6. Documentation and records

Area ofoperations /


Cf. Scope 4.2 6.

7. Materials management

Area ofoperations /


Suppliersqualification

Critical materials andtheir suppliers

Have supplier control proceduresbeen defined and implemented?

7.11


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Area ofoperations /


Supplier evaluation Have the following been considered

in supplier control procedures?- a review of the history of supplier- completion of a questionnaire bythe supplier including informationabout quality system, qualitycertifications, third party audits, sitemaster file etc…- a supplier audit including QC labs(considered for critical materials)- evaluation of samples (for newsuppliers)

7.31

Approved suppliers list Does the list include the name and

address of the manufacturer (notonly trader)?Is it an updated and controlleddocument?Is it available for people in charge ofreceiving goods?

7.12, 7.13

7.20

Startingmaterial fromanimal originwith TSE risk

Additional records - Origin of raw materials: country,supply chain, veterinary inspection /certificates, age of animals- Type of tissue used, collectionmethod, risk of cross contaminationduring the collection

- Manufacturing process: overviewof the process, reduction of the TSErisk (validation), risk of crosscontamination, cleaning validation- Traceability: supply chain,availability of the information back tothe slaughterhouses / animals

National or internationalguidance documents(e.g. EP generalmonograph 5.2.8)

Change control Changes are effectivelymanaged through thechange control system

Is the Change Control system usedto manage changes to materialsand suppliers?

7.14, 13.

Storage Transportation andstorage for raw

materials, andintermediates requiringspecial handling

What systems are in place toensure appropriate transport and

storage conditions have beenmaintained?

7.20

Validated electronicsystems for materialstatus control areacceptable. In suchcases, physicalsegregation may not berequired

Where status control of material isby physical location are thelocations well marked?Is access to these locationsrestricted to designated personnel?Where status control of material isby electronic means, is access tothe electronic system restricted todesignated personnel?

10.11, 5.40, 7.20


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Area ofoperations /


Bulk materials Non dedicated tankers Does the cleaning procedure, and

certificate of cleaning, for non-dedicated tankers cover accessoryparts, including transfer hoses?

7.22

Note: Section 7.22 isapplicable to reusablecontainers

If non dedicated reusable containersare used, is there evidence that theyare properly cleaned?

7.22, 8.51

Sampling Sampling plan Are sampling plans appropriate foreach type of raw material beingselected for testing?Does each sampling plan include arationale for the selected method?

7.33

Sampling environmentsappropriate for thematerials beingsampled

Has consideration been given to thesampling environment for eachmaterial being sampled?Does the plan take into account thematerial type, its susceptibility tomicrobial contamination, its use in aparticular manufacturing step andthe final dosage form?

7.34

Analysis Identity testing Is each batch identity tested? 7.30

Extent and frequencyof testing

If reduced testing performed, howwas the supplier approved?

At what intervals is full testingconducted?

7.31


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8. Production and in process controls

Area ofoperations /


Generalconsiderationson theproductionoperations andon facilities

All the productionoperations verified forcompliance with theproduction documentsspecified in 6.2, 6.3,6.4, 6.5 of the GMPGuide, and the processdescribed in the ASMFor module 3, part 3.2.1of CTD or as describedby ICH M4Q

Are production operations actuallyperformed in dedicated ormultipurpose facilities?

Are the critical parameters recordedand controlled?Do formal procedures describingthe production process exist?Do production operationscorrespond with the definedprocess?Is the facility monitored to ensureappropriate conditions are

maintained?Has the method of monitoring beenverified?Is an appropriate level of protectiongiven to centrifuges, filters, ovens,etc?Does the monitoring of the quality ofwater demonstrate that thespecification has been met

Are the critical parameters trended?

8.PIC/S Aide-Memoire onthe Inspection ofBiotechnologymanufactures (1.4)

Compliance toregistered file

and generalconsistency

Do the parameters stated in theregistered file relate to the

operations documented in theBatch Record?- Process parameters,- IPC,- Specifications for intermediatesand finished product

Does the facility have the capabilityto manufacture the batch size of the

APIs produced?Is the inspected site’s addressconsistent with the registered file?

Are all production areas declared inthe registered file?

1.1 § 4 Registered file

ProductionOperations

Raw materials:Dispensing areasurfaces, equipmentand environment

Are dispensing areas andequipment fit for purpose? 8.10, 6.52

Are containers suitable andappropriately labelled?Is material status controlled?

8.11

Critical weighingactivities independentlyconfirmed and verified

Are all critical activities witnessed orsubject to equivalent controls?Do production personnel verify that

materials are correct prior to use?

8.12, 8.13


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Area ofoperations /


Yield within expected

range

Have appropriate yield ranges been

set?Is the batch yield within range?For critical process steps, aredeviations in yield investigated?

8.14

Deviations documentedand investigated

Are deviations documented andexplained?Has an investigation beenperformed for critical deviationsand, if necessary, corrective actionsimplemented?

8.15

Process statusindicated

For each major unit of equipment isthe processing status identified?

8.16

Reprocessing andReworkingappropriately controlled

What systems are in place to trackmaterials for rework, orreprocessing, and to preventunauthorised use?

8.17, 14.2; 14.3

Time Limits Time limits for processoperations, and for thestorage ofintermediates

Where time limits have been set,are these being met?

Are deviations documented andevaluated?

8.20, 8.21

In-processSampling andControls

Written Proceduresavailable for themonitoring and control

of production process

Do written procedures exist tomonitor and control the productionprocess?

Are the procedures based upondevelopment / historicalinformation?

8.30

Acceptance Criteriaappropriate to processstep / stage

Do the in-process controls andacceptance criteria become morestringent for the later processingsteps?

8.31

Critical in-processcontrols aredocumented andapproved by the QualityUnit

Has the Quality Unit given approvalfor in-process controls?

8.32

In-process controlsperformed anddocumented byqualified staff

Are qualified staffs performing in-process controls?

Are adjustments made to processesin accordance with pre-establishedand validated limits?

Are IPC results documented in thebatch record?

8.33

Sampling Proceduresdocumented andscientifically sound

Are there written samplingprocedures which are scientificallysound?

8.34


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Area ofoperations /


In process sampling :

Prevention ofcontamination andassurance of theintegrity of the sample

Are sampling procedures designed

to prevent contamination andensure the integrity of the sample?

8.35

BlendingBatches ofIntermediatesor APIs

Blending of batchesdefined and controlled

Does the company blend batchesand is this process defined andcontrolled?

8.40

Only batches meetingapproved specificationsmay be blended

Have all input batches beenmanufactured by the same process,been individually tested and meetspecification?

8.40

Is the blended batch tested forconformance with specification?

8.43

Traceability of materialused in a blended batch

Is it possible to identify all the inputbatches that make up the blendedbatch?

8.44

Validation of thehomogeneity of theblended batch

Is the blending operation validatedto show homogeneity of thecombined batch where physicalattributes of API’s are critical in thedosage form?

8.45

Impact of blendingprocess on productstability

Does the blending operationadversely affect product stability? Ifso have further stability tests beenperformed.

8.46

Expiry / Retest datedetermination

Is the expiry/retest date of theblended batch based upon theexpiry/retest date of the oldestbatch in the blend?

8.47

ContaminationControl

Prevention ofcontamination ofbatches by carry overfrom a previous batch

Is the carryover of degradants andmicrobial contamination, that couldimpact upon the established APIimpurity profile, prevented?Consider:

- Frequency of inter batchcleaning.- Environmental controls- Open processing

operations

8.45, 8.50, 8.51, 8.52

9. Packaging and identification labelling of APIs and Intermediates

Area ofoperations /


Packaging and

labelling

Impact of packaging

materials on productquality

Do Packaging materials alter the

quality of the API or intermediate?

9.21


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9. Packaging and identification labelling of APIs and Intermediates

Area ofoperations /


Representative label Does the BMR include a

representative label?

9.36

Prevention of crosscontamination ifcontainers reused

Are there appropriate procedures toavoid mix-up and crosscontamination?Consider:

- cleaning- removal of labels

9.22

The issue of labels mustbe controlled

Is there an effective system for theissuing of labels?

9.3

The labelling of an APImust ensure traceability

and provided instructionon any special transportor storage requirements

If and API is transferred outside thecontrol of the manufacturer is the

name and address of themanufacturer incorporated into thelabel.If required, are special storageconditions incorporated into thelabel.

9.43, 10.22

Effectiveness of thesealing system

Has the sealing system beenvalidated?

9.46

10. Storage and distribution

Area ofoperations /

itemsNotes Crucial questions/Show me Supporting

documents

Storage anddistribution

Appropriate storageareas

Is there adequate space includingspecific areas for returned, rejected,quarantined materials?

4.11, 10.10

Have the specified storage conditionsbeen fulfilled?

10.10

Are FEFO / FIFO rules met? 7.42

Controls of transfersunder quarantine

If quarantined material is to betransferred, are there effective controlsand documentation in place to preventuse before formal release by themanufacturer?

10.20

Transport methods andconditions

Has the responsibility for the transportbeen assigned?Is the assignment appropriate?

How are the specified storageconditions maintained duringtransport?

10.21


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10. Storage and distribution

Area ofoperations /


Is the level of control over the

contractor for transportationadequate?Consider:

- audits by the APImanufacturer

- agreements- questionnaire, etc.

10.23

The traceability ofmaterials and productsextends to the point offirst supply

Is there a system in place for productrecall?

10.24

11. Laboratory controls

Area ofoperations /


See PIC/S AideMemoire PI-023

11.

12. Validation

Area ofoperations /

items

Notes Crucial questions/Show me Supportingdocuments

ValidationPolicy

Is the company's validation policydocumented?

12.10, 12.11

Are all critical manufacturing stepsvalidated?

12.12

ValidationDocumentation

Validation protocolestablished andapproved by the QualityUnit

Is the validation protocol compliantwith the company’s validation policy?

12.20

Critical steps thatrequire validation andacceptance criteriaspecified

Has the rationale for identifyingcertain manufacturing steps andoperating parameters as critical, beendocumented?

12.21

The validationapproach adopteddefined anddocumented

What is the validation approachadopted?Consider :

- prospective, concurrent, orretrospective

- the number of process runs

12.10,12.4

The results of validationmust be documented

Any identifieddeficiencies evaluatedand documented

Are variations from the protocoldocumented and justified?

12.22, 12.23


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12. Validation

Area ofoperations /

items


Any corrective actions

implemented anddocumented

Qualification Qualification (DQ, IQ,OQ, PQ) conducted forcritical equipment andancillary systems (bothnew and existing), forintended process, asappropriate

Have all qualification activities beencompleted before process validationbegins?

12.30

Approach toProcessValidation

All operationsdetermined critical tothe quality and purity of

the API are to bevalidated

12.12, 12.40

If prospective validation has not beenperformed, has the validationapproach taken been justified?

12.41

ProspectiveValidation

Prospective validationconsisting of at leastthree consecutivesuccessful batchesmust have beencompleted beforecommercial distributionof the API

12.42, 12.50

ConcurrentValidation

Where only a limitednumber of API batchesare manufactured, orwhere manufacture isinfrequent, concurrentvalidation of at leastthree consecutivesuccessful batches isacceptable

Are batches released for commercialdistribution, before completion ofconcurrent validation, subjected to athorough monitoring and testingprogramme?

12.43, 12.50

RetrospectiveValidation

The number of processruns selected forretrospective validationshould be sufficient todemonstrate processconsistency. In general,data from ten to thirtyconsecutive batchesshould be examinedTest results fromretained samples canbe tested to obtain datafor retrospectivevalidation

Are batches selected for retrospectivevalidation representative of allbatches made during the reviewperiod?

12.45, 12.50

Impurity Profile Process validation

should confirm that theimpurity profile of each

12.52


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12. Validation

Area ofoperations /

items


API is within the limits

specifiedPeriodicReview

There should be aperiodic review ofsystems and processeswith respect tovalidation status

Are Product Quality Reviews used toconfirm that the process under reviewremains validated?

12.60, 2.5

Cleaningvalidation

Focus: multi purposefacilities and finalmanufacturing steps

Are cleaning procedure validated? Ifnot, is there any justification?Is cleaning validation directed tosituations that poses the greatestrisk?

Rational behind the useof either validated ornon validated cleaningmethods for equipmentused at different stagesof production

Are documents available regardingrisk assessment which consider:-characteristics of contaminants (e.g.toxicity, solubility, potency andstability)-equipment (product contact materialand relative surface area, placesdifficult to clean)-process flow (purification steps, bulksize, product change over)-at the minimum, selection ofproduct(s) which represent(s) theworst case scenario (product change-

over, maximum acceptable residuelimit, etc.)

Cleaning proceduresare to be validated

Are the cleaning procedures routinelyused in production the same as thoseused in the validation studies?

Are the cleaning methods applied inproduction the same methods asthose used in the validation studies?Is cleaning routinely performed afterthe manufacture of the same numberof batches?

12.71

Sampling methodsinvolving rinse/swab,with an acceptablerecovery, validated(including sampling formicrobiologicalassessment)

Are personnel performing samplingproperly trained and assessed?Is the sampling method used tomonitor cleaning procedures thesame method used in the validationstudies?

12.73

12.76

Analytical test methodsappropriately validated

Is the analytical test methodsufficiently sensitive related to theestablished residue limits?

12.74

Microbiological aspects Has inhibition of microbial growth byresidue been considered during testmethod validation?

When processes andequipment including

Has the effectiveness ofcleaning/sanitization procedures been

12.75, 5.21, 5.23


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14. Rejection and re-use of materials

Area ofoperations /


Reworking Is an investigation performed before a

decision to rework is carried out?

14.30

Have reworked batches beensubjected to:

- appropriate evaluation- stability testing- a review to show equivalency

to original process?Is validation performed if more thanone batch is affected?Is a report issued if only one batch isaffected?

14.31

The impurity profile of areworked batch shall becomparable to routineproduction batches

Are the impurity profiles of reworkedbatches similar to routine productionbatches?

14.32

Additional testing andtest methods if routinetest methods are foundto be inadequate

Are routine analytical methodsadequate for the analysis of reworkedbatches?Will the methods detect additionaldegradants or other impurities?

14.32

Returns Policy on returnsdocumented

If the company accepts returns, arethe returned APIs and intermediatesidentified as returns and subsequently

quarantined?

14.50

Records of returnsmaintained

Does the procedure for handlingreturned product require the reasonfor returning the product to beidentified?Do the company’s records allowidentification of the transportation andstorage history of the product, whilstthe product was outside thecompany’s control?

Are the details recorded in thedocumentation associated with the

returned product adequate andappropriate?Is returned product appropriatelydispositioned for reprocessing,reworking, or destruction?

14.51, 14.52

15. Complaints and Recalls

Area ofoperations /


Cf. Scope 4.2 15.


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16. Contract manufacturers (including Laboratories)

Area ofoperations /


Cf. Scope 4.2 16.

17. Agents, Brokers, Traders, Distributors, Repackers and Relabellers

Area ofoperations /


General Relevant sections ofPart II are applicable to

Agents, Brokers,Traders and Distributors(e.g. chapters 2, 3, 4, 6,7.4, 9, 10, 11.4, 14.52,

15).

17.10, 17.11

Repackers andrelabellers areconsidered asmanufacturers (fullcompliance with Part IIrequired)

17.11, 17.40

Traceability of APIs andintermediates

Effectiveness of thesystem

For some APIs, consider theavailability and completeness ofrequired documentation back to theoriginal manufacturer

Are these records readily available?

17.20

Transfer ofinformation

Is the customer informed of anyadditional manufacturing operationcarried out on behalf of Agents,Brokers, Traders, Distributors,Repackers and Relabellers (e.g.micronisation, Gamma irradiation,freeze-drying)?

17.60

Are the original API manufacturer’sname, address and the batchnumber(s) supplied provided to thecustomer?

9.43, 17.61

Is the original API manufacturer’sname and address included on theCoA and displayed on labels?

11.44

Is quality or regulatory relatedinformation exchanged betweenpartners in a timely manner?

17.60

In case of quality related problems,are Agents, Brokers, Traders,Distributors, Repackers andRelabellers involved?

Are they informed of any investigation

and actions undertaken?

17.71, 17.72


23/24

PI 030-1 23 of 24 13 January 2009

17. Agents, Brokers, Traders, Distributors, Repackers and Relabellers

Area ofoperations /


Repackaging

relabelling

Do procedures, records, and

environmental monitoring indicate thatcontrols are in place to avoid mix-up,contamination and cross-contamination?

17.4

Are samples retained? 11.7

Stability Is retest or expiry date available?When an API is repacked in adifferent type of container are themandatory stability studiesconducted?

17.2017.50

If micronisation, Gamma irradiation,

freeze-drying is performed on behalfof the Agents, Brokers, Traders,Distributors, Repackers andRelabellers are the mandatorystability studies conducted accordingto section 11.5?

17.50

11.5

18. APIs manufactured by Cell Culture / Fermentation

Area ofoperations /


See PIC/S AideMemoire PI-024

PIC/S Aide-Memoireon QC Laboratories

19. APIs for use in Clinical Trials

Area ofoperations /


This section is to bedeveloped at the nextrevision of the Aide-Memoire

19.

6. REVISION HISTORY

Date Versionnumber Reasons for revision


24/24

Acronyms:

ABTDRR: Agents, Brokers, Traders, Distributors, Repackers and Relabellers

APIs: Active Pharmaceutical Ingredients

ASMF: Active Substance Master FileBMR: Batch Manufacturing Record

CEP: Certificate of the European Pharmacopoeia

CoA: Certificate of Analysis

CTD: Common Technical Document

DMF: Drug Master File

OOS: Out of Specification

PQR: Product Quality Review

SMF: Site Master File

SOP: Standard Operating Procedures

Bibliography:

1) EMEA Note for Guidance on quality of water for pharmaceutical use(http://www.emea.europa.eu/pdfs/human/qwp/015801en.pdf )

2) WHO Guidelines for drinking-water quality(http://www.who.int/water_sanitation_health/dwq/guidelines/en/index.html )

3) Related PIC/S Aide Memoires and guidance documents:- Quality Controls Laboratories (PI 023)

- Biotech (PI 024)

- Utilities (PI 009)

- Explanatory notes for industry on the preparation of a Site Master File (PE 008)

These documents are available on the PIC/S website: ( http://www.picscheme.org )

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