CHAPTER 2

DEVELOPMENTORAL TABLETSPRODUCT DEVELOPMENT GUIDE
PRE-FORMULATION - TABLETS
Introduction
Guidelines for the development of a ANDA product for the US market, Note: some tests orprocedures may be unnecessary. The order of performing the various stages may change
depending on the product under development. These guidelines may be modified for othergeographic zones.
Development Stage

Stage 1

Scope of Product Development

Literature Search

Literature Research

USP BP Pharm. Eur, PDR, Martindale, Merck, Florey, Vidal

FDA - FOI

Summary Basis of Approval

On-linesearch

computerized Electronic Data Base (articles and publication on test methods,Dissolution
synthesis
procedures,drugimpurities,pharmacokinetics and dynamics)
Evaluation of Biostudy parameters, Dissolution methods.
FDA CDER
Patent evaluation

Stage 2

Orange Guide + FDA CDER WWW Patent Consultant

ActiveSourcing

Sourcing for Active
Raw MaterialInternational Suppliers US, European, Asian, e.g. (ACIC-Canada)(AllChem-UK) (Lek-Czech), (Esteves; Moehs; Uquifa-Spain);(Biopharma, S.I.M, Midy-Italy) (Chemcaps, Reddy; Tricon-India);(Federa-Brussels) - Review suppliers catalogues & data critically.

Potential Suppliers List

Request samples and C of A and Specifications
Evaluate at least two suppliers fully.

Stage

3

EvaluateActives

Stage

ActiveEvaluation

Potential Evaluate at least two to three potential active suppliers• DMF availability• Compliance with USP monograph• Impurity profile and stability• Potential Polymorphic forms• Commitment for physical specifications• Statement of non-patent infringement

4

ActivePurchasing

Purchase(Potential) Evaluate at least two potential active material suppliers for
Active Material
approved supplier status

Stage

5

ActiveTestingTestingofActive Chemical testing by the R&D analytical lab as per
Material sample
a. Pharmacopoeia monograph (if present)b. Pharmacopoeia Forum (if available)c. In-house method (based on manufacturer)d. Supplier's test methods and specifications

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Sect:2
2 . 15Generic Development

CHAPTER 2

DEVELOPMENTORAL TABLETS

PRE-FORMULATIONDevelopment
Stage

Stage

6

DRUG PRODUCTInnovator Samples

Stage

7

Scope of Product Development
Innovator's

Product Purchasing

Purchase at least 3 different lots in smallest and largest pack sizefor each product strength

Innovator's

Product Testing

Innovator Testing

Evaluate physical parameters:tablet shape, tablet color, code for punch embossing, pack sizes
containers materials, closure types; cotton and desiccants.

Innovator PhysicalTesting

Physical testing
Weight; Thickness; Hardness; LOD; Friability; Disintegration:
Evaluation of tablet punch; size; score; embossing and shape

Evaluation of Innovator Summary Formula in PDR; International PDRs (Italian, French,
formula ingredients
Swiss) and Innovators product's insert (obtain latest FOI -FDA)
Perform actual analytical testing on innovator's product.
Microscopicobservation

Particle/crystal information onParticle size
Crystal shape, habit,Differentiation on the presence of specific excipients can beverified from microscopic observation. E.g., Cross-linked
cellulose's Starch and Avicel have a specific shapes andmorphology and maybe easily detected.

Evaluation of Biostudy
parameters

Review FDA CDER Home page for listing and Biostudy
parameters

Dissolution profile

USP monograph and FDA method - (where present)
Dissolution; 12 unit Dissolution Profile.

Stage

8Bulk

Active Testing

FIRST BATCH FROMAPPROVED SUPPLIER
Full Physicalcharacterization

Physical characterization of bulk batch• Polymorphism• B.E.T.
• Particle size distribution (& method development)• Bulk density;• Microscopic observation

FULL CHEMICALCHARACTERIZATION

Chemical characterization• Assay• Stressed Analysis• Degradants (Expected)• Impurity profile• Optical rotation• Enantiomeric purity• O.V.I. Testing

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CHAPTER 2

DEVELOPMENTORAL TABLETSDEVELOPMENT BATCHES
Development Stage

Stage

Scope of Product Development

9

Excipients

Evaluation of formuExcipient compatibility
lation with suitableassessment
excipients

Stage

10

Evaluation of suitable
Container-Closure
SystemStage

11usingDSC

methods

andstability

Container Closure System
Choice 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 DMF dossiers

Manufacturing Process• Wet granulation (aqueous or non aqueous)
high shear mixing / low shear mixing• FBD spray procedure), or• Dry mixing, dry granulation and/'or Slugging• Determination of order of mixing• Determination of pre-mixing (in Granulator)
Wet Granulation• Determination of fluid addition (if relevant)
Dry Granulation• Determination of granulation time (chopper I & II)• Determination of torque end-point value
SluggingandDry • Determination of Drying parameters
Granulation• Determination of LOD limits• Determination of testing temperature for checking LOD limits(State machine used e.g. Mettler™, Computrac™).
• Flow properties,GRANULATION• Density,
Physical Properties of• Particle-size distribution
Granulate• Compressibility
Compression• Weight,• Hardness,
Physical Properties of • Thickness,• Friability
Compressed Tablets• Disintegration• Dissolution
Final Formula
Assessment of Final Master Formula and accelerated 1-3 month
Establishedstability profile.
EVALUATIONSUITABLE
MANUFACTURING
PROCESSES

Stage

12

Active material
Bulk purchase

Bulk Active Purchased
Ordering of Active material for Process Qualification (PQ) andPivotal Batch(es).
On approval of final formula, order sufficient material for the PQ(2) and Pivotal Lots (sufficient for all strengths and batch sizes).
NB: Never mix batch numbers in PQ and Pivotal Lots.

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Sect:22 . 17

Generic Development

DEVELOPMENTORAL TABLETS

CHAPTER 2FULL LABORATORY EVALUATIONDevelopment

Stage13

Analytical testingtablets/Caplets

Scope of Product Development
Analytical Evaluationof • Dissolution - in USP medium (Multipoint profiles) and otherrelevant media versus Innovator's product• U of C-for low active concentrations. Refer to USP requirements
for uniformity of content vs. uniformity of dosage units.
• Validation of analytical package i.e. Assay; Dissolution ; ContentUniformity completed prior to Process Qualification

PROCESS OPTIMIZATIONDevelopment

Stage14GRANULATIONOPTIMIZATIONDRYING

Scope of Product Development
Process Optimization• Effect of granulation parameters• Granulation time
• Speed of choppers (I & II) or mixer blades• Solvent addition rate and overall amount• Ratio of intra-granulate Disintegrant and binders agents• Screen size for milling (e.g. 0.6 or 0.8mm)• Adjusting mill screen size up or down to fine tune hardness• Evaluation of optimized granulate and tablet attributes• FB Drying temperature versus target LOD and range limits andthe effect on granulate and tablet properties (flow, capping,sticking).

BLENDING◊ Blending times◊ Lubricant Split into two parts (pre-blending and final blending)◊ The effect on Content Uniformity, Granule lubrication andDissolution profile.

◊ Evaluation of unit dose sampling vs. Content Uniformity
COMPRESSION∗ Effect of hardness on tablet properties (aging, dissolution,friability).

PROCESSOPTIMIZATIONREPORT∗ Evaluation of Hardness Range Limits∗ Evaluation of stability results of optimized mfg. process∗ Prepare PO Report. This Process Optimization Report formspart of the product Development Report

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CHAPTER 2

DEVELOPMENTORAL TABLETSESTABLISHING AND INVITRO INVIVO CORRELATION
Development

Stage

15

IVIV Correlation

Scope of Product Development
Analytical Evaluation• Dissolution - in USP medium (Multipoint profiles) and otherrelevant media versus Innovator's product.
• Perform IVIV Bioavailability Study (where relevant)
Establish a Level A or C correlation without adjusting dissolution
parameters and time scale• Adjust the dissolution parameters or time scale to achieve aLevel A or C correlation (adjust only if necessary)

SCALE UPDevelopment

Stage16

Scale-up

Scope of Product Development

SCALE UP
Scale-up lot prepared if larger batch size scale up problems
anticipated.
Process Qualification batch andevaluated as a single batch.

Scale-up Report

Scale-up batch may be

The preparation of a Scale-up Report. The Scale-up report forms
part of the overall Development Report

PROCESS QUALIFICATIONDevelopment
StageStage

17

Scope of Product Development
Process Qualification

The process qualification batch is manufactured in order to detect any problems that may arise during
the manufacture of production size batches, allowing a solution prior the manufacture of the pivotal
demonstration batch. Scale-up to the pivotal batch size or 70% of the pivotal batch may be combinedwith qualifying the manufacturing process At this stage full manufacturing documentation is preparedalone standard procedures.

PRODUCTION
FACILITIES

Process Qualification batch should be compressed in a production(or production type with same principle and operation) tabletting
machineSize of pivotal and marketing batch confirmed (NLT 100 000 net/packed at target parameters or 10% of proposed market batch).

BATCH
DOCUMENTATION

Preparation of Master Formula and Processing Instructions
Discussion of formula, manufacturing process and control
parameters with production personnel and QA Staff

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CHAPTER 2

DEVELOPMENTORAL TABLETSPROCESS QUALIFICATION
Development StageStage

17 (Cont)

Scope of Product Development
Process Qualification

FINAL REVIEW and Review of proposed formula, manufacturing process and control
AUTHORIZATION
parameters with production personnel and QA Staff withauthorization signatures (RD; QA-QC; RA; and Production)
PROTOCOL

PQ. protocol prepared

KEY STEPS

Critical manufacturing steps designated and sampling and testing
parameters specified.

OPERATING
CONDITIONS

Presence of production and control personnel during PQ
manufacture

P.Q. REPORT

Upon completion prepare Process Qualification Report. This P-Q
report forms part of the overall Development Report

PIVOTAL BATCHDevelopment

Stage18

Scope of Product Development
Pivotal Production

PRODUCTION
FACILITIES

Pivotal batch MUST be compressed in a production tablettingmachine (or production type with same principle and operation)

BATCH
DOCUMENTATION

Preparation of FINAL Master Formula and Processing Instructions

REVIEW andAUTHORIZATION

Review of FINAL formula, manufacturing process and control
parameters with production personnel and QA Staff. Pivotalauthorization signatures (RD; QA-QC; RA; and Production)
attached.

OPERATING
CONDITIONS

Operation of production and control personnel during Pivotal
manufacture, aided by development team.

REPORT

The preparation of a Pivotal Report. This pivotal report forms partof the overall Development Report.

BIOEQUIVALENT STUDYStage

Scope of Product Development

Stage 19

BIOSTUDY Evaluation

BIOSTUDY Fasted

Perform Fasted / Food Effect Biostudy on Pivotal Lot Samples

BIOSTUDY[Food Effect]

Perform Food Effect Biostudy on Pivotal Lot Samples (See foodeffect guidelines, where appropriate)

HIGHEST DOSAGEBiostudy generally performed on highest strength of productOne or two studies

Fasted AND Food Effect Study may be required

WAIVER
CONDITIONS

For multiple strength products Invitro dissolution testing conductedin three different pH media on lower dosage forms

SIMILARITY TESTING

Perform Similarity Test [F2 Test] on dissolution results.

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Generic Development

CHAPTER 2

DEVELOPMENTORAL TABLETS

PRE-SUBMISSION AUDITING
Development Stage

Stage 20

Scope of Product Development
ANDA Pre-Submission Auditing

Development Report

Audit all raw data supporting Development Report

ANDA Regulatory File

Audit Plant and Laboratory Documentation as per ANDA

SOPs

Review SOP System and Update level

cGMP

Review cGMP of Manufacturing Processes

Biostudy Report

Evaluate and develop a IVIV correlation (Level A where possible.)

Validation Protocol

Product Process Validation Protocol complete and signed

ANDA SUBMISSION
Development Stage

Stage

21

ANDA Submission

Scope of Product Development
ANDA Submission
Submit ANDA structured as Part Two of this Handbook(9 Copies -as per Color system)(1 Field Copy)

VALIDATION BATCHES
DevelopmentStage

Stage

22

Scope of Product Development
Process Validation

Protocol

Process Validation Protocol for 3 consecutive marketing lots

Execute validation

Process Validation of 3 consecutive marketing lots

ReportProcess Validation Report

Similarity

Show intra-batch similarity

Bio-Validation
Similarity

Show inter-batch similarity between Biobatch (Pivotal) and theCommercial Validation Lots

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CHAPTER 2

DEVELOPMENTORAL TABLETSCOMMERCIAL RE-VALIDATIONDUE TO MAJOR CHANGE

Development
StageStage

23

Scope of Product Development
Process Re-validation

Formula Change

Revalidate procedure with new formula process or equipment withProcess Changea different operating principle

Equipment Change
Minor change

Follow SUPAC Rules Level I II or III

IMPORTANT NOTE ON DEVELOPMENT
Developers are encouraged to develop IVIVC for IR dosage forms, where applicableto the BCS, (Biopharmaceutical Classification System) in the expectation that theinformation will be useful in establishing appropriate dissolution specifications andthus permit certain post approval formulation and manufacturing changes to beeffected, - without additional bioequivalence studies.

The objective of developing an IVIVC is to establish a predictive mathematicalmodel describing the relationship between invitro dissolution settings and the actualinvivo drug-plasma parameters found, (such as AUC, Cmax, Tmax).

The invitro dissolution settings are adjusted (via media, pH agitation) until a I : Icorrelation is achieved (Level A) or a single dissolution point and a plasma
parameter is shown to correlate (Level C).
When more than one point correlates a multiple Level C is obtained - which may
possibly be upgraded to a Level A with additional development work.

This matching of dissolution settings with plasma levels, that are derived from aspecific IR formula and its corresponding manufacturing process, is in fact simply anarbitrary set of values that establish the so called 'predictive mathematical model'.

An IVIVC should be evaluated to demonstrate that predictability of the invivo
performance of the drug product (i.e. derived from the plasma parameters) from its invitro dissolution characteristics (e.g. equipment settings / and manufacturingchanges) is maintained over the product's dissolution profile

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Generic Development