inspection of active pharmaceutical ingredients
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PI 030-1 1 of 24 13 January 2009
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: info@picscheme.org 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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2. Quality Management System
Area ofoperations /
itemsNotes Crucial questions/Show me Supportingdocuments
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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2. Quality Management System
Area ofoperations /
itemsNotes Crucial questions/Show me Supportingdocuments
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 /
itemsNotes Crucial questions/Show me Supportingdocuments
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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4. Building and facilities
Area ofoperations /
itemsNotes Crucial questions/Show me Supportingdocuments
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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4. Building and facilities
Area ofoperations /
itemsNotes Crucial questions/Show me Supportingdocuments
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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4. Building and facilities
Area ofoperations /
itemsNotes Crucial questions/Show me Supportingdocuments
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 /
itemsNotes Crucial questions/Show me Supportingdocuments
Cf. Scope 4.2 6.
7. Materials management
Area ofoperations /
itemsNotes Crucial questions/Show me Supportingdocuments
Suppliersqualification
Critical materials andtheir suppliers
Have supplier control proceduresbeen defined and implemented?
7.11
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7. Materials management
Area ofoperations /
itemsNotes Crucial questions/Show me Supportingdocuments
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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7. Materials management
Area ofoperations /
itemsNotes Crucial questions/Show me Supportingdocuments
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 /
itemsNotes Crucial questions/Show me Supportingdocuments
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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8. Production and in process controls
Area ofoperations /
itemsNotes Crucial questions/Show me Supportingdocuments
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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8. Production and in process controls
Area ofoperations /
itemsNotes Crucial questions/Show me Supportingdocuments
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 /
itemsNotes Crucial questions/Show me Supportingdocuments
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 /
itemsNotes Crucial questions/Show me Supportingdocuments
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 /
itemsNotes Crucial questions/Show me Supportingdocuments
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 /
itemsNotes Crucial questions/Show me Supportingdocuments
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
Notes Crucial questions/Show me Supportingdocuments
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
Notes Crucial questions/Show me Supportingdocuments
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 /
itemsNotes Crucial questions/Show me Supportingdocuments
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 /
itemsNotes Crucial questions/Show me Supportingdocuments
Cf. Scope 4.2 15.
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16. Contract manufacturers (including Laboratories)
Area ofoperations /
itemsNotes Crucial questions/Show me Supportingdocuments
Cf. Scope 4.2 16.
17. Agents, Brokers, Traders, Distributors, Repackers and Relabellers
Area ofoperations /
itemsNotes Crucial questions/Show me Supportingdocuments
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
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17. Agents, Brokers, Traders, Distributors, Repackers and Relabellers
Area ofoperations /
itemsNotes Crucial questions/Show me Supportingdocuments
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 /
itemsNotes Crucial questions/Show me Supportingdocuments
See PIC/S AideMemoire PI-024
PIC/S Aide-Memoireon QC Laboratories
19. APIs for use in Clinical Trials
Area ofoperations /
itemsNotes Crucial questions/Show me Supportingdocuments
This section is to bedeveloped at the nextrevision of the Aide-Memoire
19.
6. REVISION HISTORY
Date Versionnumber Reasons for revision
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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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