ORAL TABLETS

DEVELOPMENT

CHAPTER 2

PRODUCT DEVELOPMENT GUIDE

PRE-FORMULATION - TABLETS
Introduction Guidelines for the development of a ANDA product for the US market, Note: some tests or procedures may be unnecessary. The order of performing the various stages may change depending on the product under development. These guidelines may be modified for other geographic zones. Development Stage Scope of Product Development

Stage 1
Literature Research FDA - FOI On-line search

Literature Search
USP BP Pharm. Eur, PDR, Martindale, Merck, Florey, Vidal Summary Basis of Approval

computerized Electronic Data Base (articles and publication on test methods, Dissolution synthesis procedures, drug impurities, pharmacokinetics and dynamics) Evaluation of Biostudy parameters, Dissolution methods. FDA CDER Patent evaluation Orange Guide + FDA CDER WWW Patent Consultant

Stage 2
Sourcing for Active Raw Material

Active

Sourcing

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

Potential Suppliers List

Stage
Evaluate Actives

Active

Evaluation

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

Stage

Active

Purchasing

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

Stage

Active

Testing

Testing of Active 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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ORAL TABLETS

DEVELOPMENT

CHAPTER 2

PRE-FORMULATION
Development Stage Scope of Product Development Innovator's Product Purchasing

Stage

DRUG PRODUCT Innovator Samples

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

Stage

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

Innovator Physical Testing

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. Microscopic observation Particle/crystal information on Particle size Crystal shape, habit, Differentiation on the presence of specific excipients can be verified from microscopic observation. E.g., Cross-linked cellulose's Starch and Avicel have a specific shapes and morphology and maybe easily detected. Review FDA CDER Home page for listing and Biostudy parameters USP monograph and FDA method - (where present) Dissolution; 12 unit Dissolution Profile.

Evaluation of Biostudy parameters Dissolution profile

Stage

Bulk

Active Testing

FIRST BATCH FROM APPROVED SUPPLIER Full Physical characterization

Physical characterization of bulk batch Polymorphism B.E.T. Particle size distribution (& method development) Bulk density; Microscopic observation Chemical characterization Assay Stressed Analysis Degradants (Expected) Impurity profile Optical rotation Enantiomeric purity O.V.I. Testing

FULL CHEMICAL CHARACTERIZATION

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DEVELOPMENT

CHAPTER 2

DEVELOPMENT BATCHES
Development Stage

Scope of Product Development Excipients

using DSC methods and stability

Stage

Evaluation of formuExcipient compatibility lation with suitable assessment excipients

Stage

10

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

Evaluation of suitable Container-Closure System

Stage

11

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 Slugging and Dry 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 Established stability profile. EVALUATION SUITABLE MANUFACTURING PROCESSES

Stage

12

Bulk Active Purchased

Ordering of Active material for Process Qualification (PQ) and Pivotal 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.

Active material Bulk purchase

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ORAL TABLETS

DEVELOPMENT

CHAPTER 2

FULL LABORATORY EVALUATION

Development Scope of Product Development Analytical Evaluation
of Dissolution - in USP medium (Multipoint profiles) and other relevant 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 ; Content Uniformity completed prior to Process Qualification

Stage

13

Analytical testing tablets/Caplets

PROCESS OPTIMIZATION
Development Scope of Product Development Process Optimization

Stage

14

GRANULATION 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 and the effect on granulate and tablet properties (flow, capping, sticking).

DRYING

BLENDING

Blending times Lubricant Split into two parts (pre-blending and final blending) The effect on Content Uniformity, Granule lubrication and Dissolution profile. Evaluation of unit dose sampling vs. Content Uniformity

COMPRESSION

Effect of hardness on tablet properties (aging, dissolution, friability). Evaluation of Hardness Range Limits Evaluation of stability results of optimized mfg. process Prepare PO Report. This Process Optimization Report forms part of the product Development Report

PROCESS OPTIMIZATION

REPORT

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ORAL TABLETS

DEVELOPMENT

CHAPTER 2

ESTABLISHING AND INVITRO INVIVO CORRELATION

Development Scope of Product Development Analytical Evaluation
Dissolution - in USP medium (Multipoint profiles) and other relevant 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 a Level A or C correlation (adjust only if necessary)

Stage

15

IVIV Correlation

SCALE

UP
Scope of Product Development

Development

Stage
Scale-up

16

SCALE

UP
Scale-up batch may be

Scale-up lot prepared if larger batch size scale up problems anticipated. Process Qualification batch and evaluated as a single batch.

Scale-up Report

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

PROCESS QUALIFICATION
Development Stage Scope of Product Development Process Qualification

Stage

17

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 combined with qualifying the manufacturing process At this stage full manufacturing documentation is prepared alone standard procedures.

PRODUCTION FACILITIES

Process Qualification batch should be compressed in a production (or production type with same principle and operation) tabletting machine Size 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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ORAL TABLETS

DEVELOPMENT

CHAPTER 2

PROCESS QUALIFICATION
Development Stage Scope of Product Development Process Qualification

Stage

17 (Cont)

FINAL REVIEW and Review of proposed formula, manufacturing process and control AUTHORIZATION parameters with production personnel and QA Staff with authorization signatures (RD; QA-QC; RA; and Production) PROTOCOL KEY STEPS OPERATING CONDITIONS P.Q. REPORT PQ. protocol prepared Critical manufacturing steps designated and sampling and testing parameters specified. Presence of production and control personnel during PQ manufacture Upon completion prepare Process Qualification Report. This P-Q report forms part of the overall Development Report

PIVOTAL BATCH
Development Scope of Product Development Pivotal Production
Pivotal batch MUST be compressed in a production tabletting machine (or production type with same principle and operation) Preparation of FINAL Master Formula and Processing Instructions Review of FINAL formula, manufacturing process and control parameters with production personnel and QA Staff. Pivotal authorization signatures (RD; QA-QC; RA; and Production) attached. Operation of production and control personnel during Pivotal manufacture, aided by development team. The preparation of a Pivotal Report. This pivotal report forms part of the overall Development Report.

Stage

18

PRODUCTION FACILITIES BATCH DOCUMENTATION REVIEW and AUTHORIZATION

OPERATING CONDITIONS REPORT

BIOEQUIVALENT STUDY
Stage Scope of Product Development

Stage 19
BIOSTUDY Fasted BIOSTUDY [Food Effect] HIGHEST DOSAGE One or two studies WAIVER CONDITIONS SIMILARITY TESTING

BIOSTUDY Evaluation
Perform Fasted / Food Effect Biostudy on Pivotal Lot Samples Perform Food Effect Biostudy on Pivotal Lot Samples (See food effect guidelines, where appropriate) Biostudy generally performed on highest strength of product Fasted AND Food Effect Study may be required For multiple strength products Invitro dissolution testing conducted in three different pH media on lower dosage forms Perform Similarity Test [F2 Test] on dissolution results.

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ORAL TABLETS

DEVELOPMENT

CHAPTER 2

PRE-SUBMISSION AUDITING
Development Stage Scope of Product Development ANDA Pre-Submission Auditing
Audit all raw data supporting Development Report Audit Plant and Laboratory Documentation as per ANDA Review SOP System and Update level Review cGMP of Manufacturing Processes Evaluate and develop a IVIV correlation (Level A where possible.) Product Process Validation Protocol complete and signed

Stage 20
Development Report ANDA Regulatory File SOPs cGMP Biostudy Report Validation Protocol

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

Stage

21

ANDA Submission

VALIDATION BATCHES
Development Stage Scope of Product Development Process Validation
Process Validation Protocol for 3 consecutive marketing lots Process Validation of 3 consecutive marketing lots Process Validation Report Show intra-batch similarity Show inter-batch similarity between Biobatch (Pivotal) and the Commercial Validation Lots

Stage
Protocol

22

Execute validation Report Similarity Bio-Validation Similarity

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DEVELOPMENT

CHAPTER 2

COMMERCIAL RE-VALIDATION
DUE TO MAJOR CHANGE
Development Stage Scope of Product Development Process Re-validation
Revalidate procedure with new formula process or equipment with a different operating principle

Stage

23

Formula Change Process Change 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 applicable
to the BCS, (Biopharmaceutical Classification System) in the expectation that the information will be useful in establishing appropriate dissolution specifications and thus permit certain post approval formulation and manufacturing changes to be effected, - without additional bioequivalence studies.

The

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

The

invitro dissolution settings are adjusted (via media, pH agitation) until a I : I correlation 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 a specific IR formula and its corresponding manufacturing process, is in fact simply an arbitrary 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 in vitro dissolution characteristics (e.g. equipment settings / and manufacturing changes) is maintained over the product's dissolution profile

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