PRODUCT DEVELOPMENT GUIDE P RE-FORMULATION - …

1 International Journal of Generic Drugs International Journal 312of Generic Drugs e-* 0793 694X US/Canada ISSN 0793 7784 EuroISSN 0793 7822 Pacific RimPRODUCT DEVELOPMENT GUIDEPRE- formulation - SOFT GELATIN CAPSULESI ntroductionGuidelines for the DEVELOPMENT of a ANDA PRODUCT for the US market, Note: sometests or procedures may be unnecessary. The order of performing the variousstages may change depending on the PRODUCT under DEVELOPMENT . Theseguidelines may be modified for other geographic StageScope of PRODUCT DEVELOPMENT Stage 1 Literature SearchLiterature ResearchUSP BP Pharm.

2 Eur, PDR, Martindale, Merck, Florey, Vidal,Text and journalsFDA - FOIS ummary Basis of Approval - On request form FDAOn-linecomputerizedsearchFDA CDERE lectronic Data Base (articles and publication on testmethods, Dissolution synthesis procedures, drug impurities,pharmacokinetics and dynamics)Evaluation of Biostudy parameters, Dissolution evaluationOrange GUIDE + FDA CDER WWW Patent Consultant Stage 2 Active SourcingSourcing for ActiveRaw MaterialInternational Suppliers US, European, Asian, (ACIC-Canada) (AllChem-UK) (Lek-Czech), (Esteves; Moehs;Uquifa-Spain); (Biopharma, , Midy-Italy) (Chemcaps,Reddy; Tricon-India).

3 (Federa-Brussels) - Review supplierscatalogs & data SuppliersListRequest samples and C of A and SpecificationsEvaluate at least two suppliers 3 Active Evaluation Evaluate PotentialActivesEvaluate at least two or maximum three potential activesuppliers DMF availability Compliance with USP monograph Impurity profile and stability Potential Polymorphic forms Commitment for physical specifications (Bulk Density) Statement of non-patent infringementStage 4 Active PurchasingPurchase(Potential) ActiveMaterialEvaluate at least two potential active material suppliers forapproved supplier statusStage 5 Active Testing Testing of ActiveMaterial sampleChemical testing by the R&D analytical lab as pera.

4 Pharmacopoeia monograph (if present)b. Pharmacopoeia Forum (if available)c. In-house method (based on manufacturer)d. Supplier's test methods and specificationInternational Journal of Generic Drugs International Journal 313of Generic Drugs e-* 0793 694X US/Canada ISSN 0793 7784 EuroISSN 0793 7822 Pacific RimPRE- formulation - SOFT GELATIN CAPSULESD evelopmentStageScope of PRODUCT DevelopmentStage 6 Innovator's PRODUCT Purchasing DRUG PRODUCTI nnovator SamplesPurchase at least 3 different lots in smallest and largestpack size for each PRODUCT strengthStage 7 Innovator's PRODUCT Testing Innovator TestingEvaluate physical parameters.

5 -Capsule size, capsule color / US approved dyes, coding forprinting, pack sizes containers materials, closure types;cotton and desiccants, blister PhysicalTestingPhysical testingFill Weight & Uniformity; Shell disintegration & DissolutionEvaluation of capsule size and volume fill volumeEvaluation ofInnovator formulaingredientsSummary Formula in PDR; International PDRs (Italian,French, Swiss) and Innovators PRODUCT 's insert (obtain latestFOI -FDA)Perform actual analytical testing on innovator's information on:Particle size, crystal shape, habit, rugosityViscosity agents used (PVP 30 / 90)Presence of vegetable oil (type)Presence of PEG 400 Presence of polyethylene glycol solventEvaluation ofBiostudyReview FDA CDER Home page for listing and BiostudyparametersDissolution profileUSP monograph and FDA method - (where present)Dissolution.

6 12 unit Dissolution 8 Bulk Active TestingFIRST BATCHFROM APPROVEDSUPPLIERFull PhysicalcharacterizationPhysical characterization of bulk batch Polymorphism Particle size distribution (& method DEVELOPMENT ) Bulk and Tapped density (Need for size reduction ofmaterial) Microscopic observationFULL CHEMICALCHARACTERIZATIONC hemical characterization Assay Stressed Analysis Degradants (Expected) Impurity profile Optical rotation Enantiomeric purity TestingInternational Journal of Generic Drugs International Journal 314of Generic Drugs e-* 0793 694X US/Canada ISSN 0793 7784 EuroISSN 0793 7822 Pacific RimDEVELOPMENT BATCHES - SOFT GELATIN CAPSULESD evelopment StageScope of PRODUCT DevelopmentStage 9 ExcipientsEvaluateformulation withsuitable excipients Vegetable oil solubility / PEG 400 / PEG 600 / PG / PVP30 Antioxidants (dl-alpha Tocopherol (Vit.))

7 E USP) / Propylgallate)Stage 10 Container Closure SystemEvaluation ofsuitableContainer-ClosureSystemChoice of container-closure-liner system including: material composition, type of thermoplastic resin and resin pigments, manufacturers and suppliers, liners and seals used by closure manufacturer, cotton and desiccants. manufacturer's DMF numbers for all component parts Letters of Access for regulatory authorities to view DMFdossiersStage 11 Manufacturing ProcessEVALUATIONSUITABLEMANUFACTURINGPR OCESSESG elatin MassFill PreparationEncapsulationDrying stages Gel mass blending (rpm & time) Gel mass melting (temperature and vacuum) Gel mass color addition (temperature and rpm & time) Gel mass VISCOSITY and MOISTURE determination Gel mass deaeration (holding time) Fill mass (mixing rpm, time & propeller position)

8 Determination of Fill mass viscosity / SG / moisture Determination of Bulk Uniformity Analysis Wet shell weight / Fill weight Seal thickness Determination of Drying Parameters Determination of rotary tumbler drying parameters & time Determination of primary and secondary tray drying times Determine Bareiss hardnessFill materialPhysical Propertiesof oil or paste fill Viscosity - (Critical) Fill moisture SG (helps to control deaeration)FillingPhysical Propertiesof Filled Softgels Weight Uniformity Individual Fill Weight Limits ( ) Content Uniformity Average Fill Weight Limits ( ) Disintegration Dissolution profileFinal FormulaEstablishedAssessment of Final Master Formula and accelerated 1-3month stability 12 Bulk Active PurchasedActive materialBulk purchaseOrdering of Active material for Process Qualification (PQ)and Pivotal Batch(es).

9 On approval of final formula, ordersufficient material for the PQ (2) and Pivotal Lots (sufficientfor all strengths and batch sizes).NB: Never mix batch numbers in PQ and Pivotal Journal of Generic Drugs International Journal 315of Generic Drugs e-* 0793 694X US/Canada ISSN 0793 7784 EuroISSN 0793 7822 Pacific RimFULL LABORATORY EVALUATION - SOFTGELSD evelopmentScope of PRODUCT DevelopmentStage 13 Analytical EvaluationAnalytical testing ofSoftgels Dissolution - in USP medium (Multipoint profiles) and otherrelevant media versus Innovator's PRODUCT . Dissolutiontesting may not be possible where active strength is inmicrograms ( or mcg) U of C-for low active concentrations.

10 Refer to USPrequirements for uniformity of content vs. uniformity ofdosage units. Validation of analytical package Assay; Dissolution ;Content Uniformity completed prior to Process QualificationPROCESS OPTIMIZATIOND evelopmentScope of PRODUCT DevelopmentStage 14 Process OptimizationGEL & FILLMATERIALOPTIMIZATION[In suspension andpaste fills sizereduction of activematerial may benecessary todecrease activebulk densities - g/cc] Optimization of gel mass moisture (once per shellformula) Optimization of gel mass viscosity (once per shellformula) Deaeration of gel mass - (critical) Optimization of antioxidant percentage.