ICH Q12 and reduction in post approval complexity Dr Frank Montgomery, Global Head, Reg CMC, AstraZeneca UK EFPIA Expert to ICH Q12 EWG

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1 ICH Q12 and reductin in pst apprval cmplexity Dr Frank Mntgmery, Glbal Head, Reg CMC, AstraZeneca UK EFPIA Expert t ICH Q12 EWG Tpra 2017 Oct 2017

2 Disclaimer The views presented d nt necessarily reflect the views f the ICH r AstraZeneca

3 What is the prblem and why Q12?* lack f a harmnized apprach n technical and regulatry cnsideratins fr lifecycle management...several gaps exist which limit full realizatin f intended benefits f ICH Q8, Q9, Q10 and Q11 pst-apprval peratinal flexibility has nt been achieved main emphasis at ICH t date has fcused n early stages f the prduct lifecycle *Paraphrased frm the Final Q12 Cncept Paper - Endrsed by the ICH Steering Cmmittee n 9 September 2014

4 What shuld Q12 d?* Harmnize change management in a mre transparent and efficient manner Facilitate risk-based regulatry versight harmnized expectatins acrss the ICH regins Emphasize cntrl strategy as a key cmpnent f the dssier Enhance use f regulatry tls fr prspective change management enabling strategic management f pst-apprval changes culd mitigate drug shrtages related t manufacturing and quality issues Supprt cntinual imprvement which can result in decreased prduct variability and increased manufacturing efficiency Facilitate the intrductin f innvatins

5 Prgress in Mntreal (May/June, 2017) Q12 Expert Wrking Grup (EWG) includes diversity f technical expertise (small and large mlecule, generic and innvatr, develpment, manufacturing, quality and regulatry, assessrs and inspectrs) EU, US, JP, Can, Sz, Brazil, Krea, C Tapei, Singapre, WHO EWG discussed remaining issues and reached alignment - Line by line review f guideline EWG reached Step 1 n Cre Guideline and Annexes ICH Management Cmmittee endrsed Step 2a Awaiting reginal publicatin fr cmment

6 Overview f Q12 6

7 Categrizatin f Changes Cnvergence tward risk-based categrizatin f pstapprval changes is encuraged as an imprtant step tward achieving the bjectives f Q12 Prir-apprval: Changes with sufficient risk t require regulatry authrity review and apprval prir t implementatin Ntificatin: Mderate- t lw-risk changes that d nt require prir apprval and generally require less infrmatin t supprt the change These changes are cmmunicated t the regulatry authrity as a frmal ntificatin that takes place within a defined perid f time befre r after implementatin, accrding t reginal requirements. In additin, the lwest risk changes are nly managed and dcumented within the Pharmaceutical Quality System (PQS) and nt reprted t regulatrs, but may be verified n rutine inspectin

8 Established Cnditins (EC) ECs are legally binding infrmatin (r apprved matters) cnsidered necessary t assure prduct quality As a cnsequence, any change t ECs necessitates a submissin t the regulatry authrity All regulatry submissins cntain a cmbinatin f ECs and supprtive infrmatin - Supprtive infrmatin is nt cnsidered t be ECs, but is prvided t share with regulatrs the develpment and manufacturing infrmatin at an apprpriate level f detail, and t justify the initial selectin f ECs and their reprting categry ECs in a submissin are either implicit r explicit: Implicit ECs are elements that are nt specifically prpsed by the applicant but are derived frm and revised accrding t reginal regulatin r guidance related t pst-apprval changes. Explicit ECs are specifically identified and prpsed by the applicant tgether with their prpsed reprting categry as part f a regulatry submissin

9 CTD Sectins That Cntain ECs CTD SECTION SECTION TITLE 3.2.P.3.1 Manufacturer(s) 3.2.P.3.2 Batch Frmula 3.2.P.3.3 Descriptin f manufacturing prcess and prcess cntrls 3.2.P.3.4 Cntrls f Critical Steps and Intermediates 3.2.P.3.5 Prcess validatin and/r evaluatin 3.2.P.4 Cntrl f Excipients 3.2.P.4.1 Specificatins 3.2.P.4.2 Analytical Prcedures 3.3.P.4.3 Validatin f analytical prcedures ESTABLISHED CONDITIONS General List with ntes Drug Prduct Manufacturing (including: testing, primary packaging, device assembly fr drug prduct-device cmbinatin prducts) sites Drug Prduct Batch Frmula (Qualitative and Quantitative) Individual unit peratins and their sequence in the manufacturing prcess Fr levels/details f ECs fr inputs (prcess parameters and material attributes) and utputs f individual unit peratins, reference is made t Chapter Identificatin f ECs fr the Manufacturing Prcesses Specificatins (e.g., test, elements f analytical prcedure and acceptance criteria) fr critical steps and intermediates including strage cnditins f critical intermediates Supprtive infrmatin Excipient Specificatin Fr each Quality Attribute n the specificatin Test Methd Acceptance Criteria Or, if applicable reference t pharmacpeial mngraph Reference t pharmacpeial mngraph and if nne exists, refer t Chapter Identificatin f ECs fr Analytical Prcedures Supprtive infrmatin 9

10 Identificatin f ECs EC and reprting categry may vary based n a spnsr s prduct and/r prcess understanding, ease f characterizatin and/r risks tied t prduct quality and perfrmance Apprpriate justificatin shuld be prvided t supprt the identificatin f ECs and prpsed reprting categries. Opprtunity t simplify many aspects f dssier t fcus ECs n thse elements f prcess imprtant t assure prduct quality Raw materials, Intermediates, IPCs, reference materials etc. Reduce and clarify the cmpliance cmmitment 10

11 AZ Example fr Analytical Prcedures Established Cnditins 1. CQA Acceptance criteria 2. Methd Descriptin The quantificatin f degradatin prducts f Prduct name tablets Y mgs is achieved by preparing a sample slutin that is analysed by liquid chrmatgraphy with UV detectin at using a suitable clumn and chrmatgraphic cnditins. Levels f individual degradatin prducts are determined by relative peak areas. 3. Methd perfrmance verificatin Methd specific perfrmance verificatin tests and criteria Methd Attribute Acceptance criteria Specificity N interference with the main peak r knwn degradatin prducts Linearity r Accuracy Mean recvery at each level 90% t 110% Repeatability RSD f 20% fr each specified degradatin prduct (perfrmed in accrdance with ICH Q2) Sensitivity Quantificatin limit (QL) 0.05% Methd equivalence Statistical equivalence demnstrated 11

12 Identificatin f Established Cnditins fr Manufacturing Prcesses The extent f ECs will vary based n a number f factrs, including prduct and prcess understanding, characterizatin, and the firm s develpment apprach A parameter based apprach, in which prduct develpment prir t regulatry submissin prvides a limited understanding f the relatinship between inputs and resulting quality attributes, will include a large number f inputs (e.g., prcess parameters and material attributes) alng with utputs (including in-prcess cntrls). An enhanced apprach with increased understanding f interactin between inputs and prduct quality attributes tgether with a crrespnding cntrl strategy can lead t identificatin f ECs that are fcused n the mst imprtant input parameters alng with utputs, as apprpriate. In certain cases, applying knwledge frm a data-rich envirnment enables a perfrmance based apprach in which ECs culd be primarily fcused n cntrl f unit peratin utputs rather than prcess inputs (e.g., prcess parameters and material attributes).

13 ECs fr Manufacturing Prcesses 13

14 ECs fr Manufacturing Prcesses (Chem) Input Materials Equipment and Parameters Output Perfrmance Measure Parameter Parameter Based Apprach API PSD 20-50um (PA) API Misture <1.0% (NM) Excipients #1-3 Specificatin Equipment type Diffusin blender (V-blender) (PA) Scale >10x Blend Speed Blend Time Hmgeneity methd Acceptable ranges and reprting categries (White bxes are ECs and grey nes are nt-ecs.) Enhanced Apprach 5-200um (NM) <1.0% (NL) Perfrmance Based Apprach 5-200um (NM) <1.0% (NL) Pharmacpeial Pharmacpeial Pharmacpeial 200kg (NM) 20rpm CPP (NM) 20 minutes CPP (NM) Diffusin blender (V-blender) (NM) 200kg (NL) 10-20rpm KPP (NL) minutes KPP (NL) Diffusin blender (V-blender) (NM) kg (NL) 15 rpm (NR) 20 minutes (NR) Nt Tested Nt Tested NIR nline analyser (PA) Hmgeneity Nt Tested Nt Tested <5% RSD IPC (NM) Cmments/Justificatin Refer t sectin 3.2.P.2. fr detailed justificatin and experimental data API misture and Pharmacpeial specificatins fr excipients 1-3 are ECs in all cases. Excipient specificatins managed in line with the Pharmacpeia. Equipment type is an EC in all cases. Enhanced Apprach API Misture has limited impact n quality demnstrated within the ranges explred. Particle size distributin (PSD) f API demnstrated n impact n disslutin r absrptin. DE studies shwed n significant impact n blend unifrmity fr 5-200um PSD f API. This allws reductin in reprting type fr API misture r PSD. Understanding f variability f blending n prduct perfrmance allws reductin in reprting type. Knwledge f the impact f scale n blending may allw dwngrading f the reprting categry (See 3.2.P.2). Hmgeneity (blend unifrmity <5%RSD) is required fr assurance f quality in the next manufacturing step. Experimental studies identified the range f blend speeds and times utilised withut significant impact n blend unifrmity as cnfirmed by successful prcess demnstratin. Blending parameters being defined as ECs means hmgeneity is nt rutinely measured but cnfirmed by end-prduct testing Perfrmance Based Apprach Using a perfrmance-based apprach (nline NIR analyser) in the cntrl strategy allws hmgeneity cnfirmatin in real-time. Use f the NIR analyser with feedback t blending perating parameters minimizes the need t rely n blend speed and time t ensure prcess cntrl. Therefre, these parameters are nt ECs. The NIR methd and blend hmgeneity specificatin are ECs. Enhanced understanding f blending and utput measurement allws fr a wider range f manufacturing scale. Typical perating cnditins fr blend speed and time described in Mdule 3.2 is supprtive infrmatin and mnitred t assure perfrmance. 14

15 Pst Apprval Change Management Prtcls (PACMPs) A PACMP prvides predictability and transparency in terms f the requirements and studies needed t implement a change An apprved PACMP needs t be maintained and assessed rutinely ensure that the utcmes f the initial risk assessment are still valid cnfirm that the cntrl strategy cntinues t ensure that the prduct will be prduced cnsistently fllwing implementatin f the change(s) The use f a PACMP is enabled thrugh an effective PQS that incrprates quality risk management principles and an effective change management system Whenever a CMC change is t be intrduced under a PACMP regulatry requirements with respect t GMP cmpliance, and inspectin r licensing status shuld be cnsidered

16 Prduct Lifecycle Management Strategy (PLCM) The PLCM dcument utlines the specific plan fr prduct lifecycle management, includes key elements Summary f Prduct Cntrl Strategy Prpsed ECs fr the prduct Reprting categry fr making changes t apprved ECs PACMPs t prspectively manage and implement ne r mre pstapprval changes Pst-apprval CMC cmmitments Use f a PLCM encurages prspective lifecycle management planning and facilitate regulatry assessment and inspectin The PLCM dcument shuld be updated thrughut the prduct lifecycle, as needed

17 Pharmaceutical Quality System (PQS) An effective PQS as established in ICH Q10 and in cmpliance with reginal GMPs is the respnsibility f a firm Q12 des nt require a specific inspectin assessing the state f the PQS befre the principles can be used. In the event that the PQS is fund nt t be cmpliant, it may result in restrictins n the ability t utilise flexibility in this guideline. Cnsistent with the basic requirements f ICH Q10, an effective change management system is necessary fr implementatin f this guideline Relatinship between Regulatry Assessment and Inspectin Regulatry assessment and inspectin are cmplementary activities Cmmunicatin between assessrs and inspectrs can facilitate regulatry review f a specific prduct submissin

18 Marketed Prducts Q12 includes tls fr changes t marketed prducts Structured Apprach t Analytical Prcedure Changes Incentivizes structured implementatin f equivalent analytical prcedures that are fit fr purpse (sme cmplex prducts and methds wuld be ut f scpe) specific criteria are defined fr changes t analytical prcedures used t test marketed prducts is described If fllwed, the analytical prcedure change can be made with immediate r ther pst-implementatin ntificatin, as apprpriate Data Requirements t Supprt CMC Changes - Stability Data Appraches t Supprt the Evaluatin f CMC Change

19 What shuld Q12 d?* Harmnize change management in a mre transparent and efficient manner Change Categrizatin Facilitate risk-based regulatry versight harmnized expectatins acrss the ICH regins Emphasize cntrl strategy as a key cmpnent f the dssier Enhance use f regulatry tls fr prspective change management PACMPs enabling strategic management f pst-apprval changes PQS Cnsideratins Established Cnditins PLCM culd mitigate drug shrtages related t manufacturing and quality issues Supprt cntinual imprvement which can result in decreased prduct variability and increased manufacturing efficiency Facilitate the intrductin f innvatins Tls fr Marketed Prducts

20 Thank Yu fr yur attentin! Acknwledgments: Q12 Expert Wrking Grup EFPIA Q12 Team Graham Ck, Markus Gese, Gerges France