Determine, as soon as possible, launch sites for DS andDP, clinical versus commercialClinical manufacturing facilities, used for launch, wouldneed to meet the same quality/GMP expectations ascommercial manufacturing facilitiesGaining concurrence on comparability strategy/protocolfor post-approval site changes in advance may lendconfidence to the manufacturer’s ability to ensuresustained supply post-launch, particularly whenexpediting launch upon initial approvalIf using a contract manufacturing organization (CMO)for DS/DP, ensuring there is the capacity to allow rapidscale-up and to support commercial volumes will becriticalConsider decoupling drug substance and drug productqualification lots (e.g., using clinical DS for DPqualification), when feasible to save time on the criticalpath to licensurePivotal clinical studies could be performed with materialfrom different scale and/or site than is intended for longterm commercial production (e.g., studies originallyexpected to be phase II studies could be used as pivotalstudies)Scaling-up phase III clinical lots to commercial scale forlaunch with bridging comparability study

Clinical manufacturing facilities, used for launch, wouldneed to meet the same quality/GMP expectations ascommercial manufacturing facilities. This will necessitateprioritization on gaining concurrence on comparabilitystrategy/protocol for post-approval site changes in advanceand may lend confidence to the manufacturer’s ability toensure sustained supply post-launch, particularly whenexpediting launch upon initial approval.

Some activities that might be considered to speeddevelopment activities include the following:

Use of Modelling to Facilitate Scale-up andVerification (small molecules and large molecules)Scale-up Verification using process modeling techniques (forexample multivariate analysis (MVA) or chemical reactionkinetics) can positively impact CMC development, in terms ofdelivering enhanced process understanding and accelerated

MANUFACTURING SCALE ANDLAUNCH SITE CONSIDERATIONS

scale-up and development. For drug substance andproduct processes designed at a small scale,verification that they scale-up as predicted tointermediate and commercial scale can be achievedmore rapidly and with greater confidence throughthe application of scientific principles, e.g. processkinetics and process modeling techniques such asMVA. This obviates the need for additionalexperiments at intermediate and commercial scales.The approach is aligned and supports plans tocommercialize from pilot-scale facilities. It providesenhanced process understanding more rapidly thantraditional qualification/verification approaches,giving confidence in predictions of how processes willrun at a larger scale.

Continuous Manufacturing (small molecules andlarge molecules)Under an accelerated access scheme, it may not befeasible to perform pivotal clinical studies with the“to be marketed commercial process” thusnecessitating further changes to the process that willbe reflected by updating/ supplementing the initialMarketing application. The assessment of the changesand the supportive data to ensure the safety andefficacy of the changing process will be completed ina step-wise manner as would be done with other“non-accelerated” products (i.e. estimate product risklevel, categorize the type of CMC change, evaluatethe outcome of in-vitro/ex-vivo characterization andassess – if applicable - need/ type of in-vivo testing). Inexpedited schemes, where appropriate and justified,the use of prior knowledge/ platform knowledge willbe leveraged for the comparability assessment. Threepotential manufacturing changes are proposed belowwith proposed supportive data packages. This is notan exhaustive list.

Cell lineA change of cell line is common during thedevelopment of a biotech product to ensure asufficient and robust commercial supply. However, itis considered a major change and is normally

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M A N U F A C T U R I N G C O N S I D E R A T I O N S F O R B R E A K T H R O U G H D R U G D E V E L O P M E N T

implemented as early as possible during development(prior to pivotal studies). It is therefore proposed thatsuch cell line change may be performed during or postpivotal studies to enable early licensure under theaccelerated access scheme for cases where there isconvincing comparability evidence. In such a scenario, acomprehensive analytical comparability package wouldbe required, ensuring that each potentially impactedCQA has been assessed. It may also be pertinent toinclude the use of established animal models in PK/ PDstudies to support the analytical comparability whereappropriate.

Process scale-up / Change of Site of ManufactureA change of the process scale and/ or site ofmanufacture is usually considered a major CMC change.Within an accelerated clinical program, it may not bepossible to perform the technical transfer into thecommercial facilities and/ or manufacture at full scalefor pivotal clinical studies. We consider it acceptablethat manufacture for pivotal studies and initial launchcould be performed at a smaller scale or a clinicalmanufacturing site (provided both adhere to cGMP),with analytical comparability data being presented attheir earliest availability to support the switch to thecommercial manufacturing site post-launch. Processvalidation would then be provided post-approval basedon data created at the commercial site.

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DSI Solutions

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