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 1L i t e r a t u r e S e a r c h
Literature Research USP BP Pharm. Eur, PDR, Martindale, Merck, Florey, Vidal
FDA - FOI Summary Basis of Approval
On-line computerized search
FDA CDER Electronic Data Base (articles and publication on test methods, Dissolution synthesis procedures, drug impurities, pharmacokinetics and dynamics)
Evaluation of Biostudy parameters, Dissolution methods.
Patent evaluation Orange Guide  + FDA CDER WWW  Patent Consultant Stage 2A c t i v e S o u r c i n g
Sourcing for Active Raw Material 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.
Potential Suppliers List Request samples and C of A and Specifications
Evaluate at least two suppliers fully.
Stage 3A c t i v e E v a l u a t i o n
Evaluate Potential Actives 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 4A c t i v e P u r c h a s i n g
Purchase (Potential) Active Material Evaluate at least two potential active material suppliers for approved supplier status
Stage 5A c t i v e T e s t i n g
Testing of Active Material sample Chemical testing by the R&D analytical lab as per
a. Pharmacopoeia monograph (if present)
b. Pharmacopoeia Forum (if available)
c. In-house method (based on manufacturer)
d. Supplier's test methods and specifications
PRE-FORMULATION
Development
Stage
Scope of Product  Development Stage 6I n n o v a t o r's P r o d u c t P u r c h a s i n g
DRUG PRODUCT Innovator Samples Purchase at least 3 different lots in smallest and largest pack size for each product strength
Stage 7I n n o v a t o r's P r o d u c t T e s t i n g
Innovator Testing Evaluate physical parameters:-
tablet shape, tablet color, code for punch embossing, pack sizes
containers materials, closure types; cotton and desiccants.
Innovator Physical Testing Physical testing
Weight; Thickness; Hardness; LOD; Friability; Disintegration: Evaluation of tablet punch; size; score; embossing and shape
Evaluation of Innovator formula ingredients Summary Formula in PDR; International PDRs (Italian, French, 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.
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 8B u l k A c t i v e T e s t i n g
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
FULL CHEMICAL CHARACTERIZATION Chemical characterization • Assay
• Stressed Analysis
• Degradants (Expected)• Impurity profile
• Optical rotation
• Enantiomeric purity
• O.V.I.  Testing
DEVELOPMENT BATCHES
Development  Stage Scope of Product  Development Stage 9E x c i p i e n t s
Evaluation of formu-lation with suitable excipients Excipient compatibility using DSC methods and stability assessment
Stage 10C o n t a i n e r C l o s u r e S y s t e m
Evaluation of suitable 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
Stage 11M a n u f a c t u r i n g P r o c e s s
EVALUATION SUITABLE MANUFACTURING PROCESSES
Wet Granulation
Dry Granulation Slugging and Dry Granulation • 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)
• Determination of fluid addition (if relevant)
• Determination of granulation time (chopper I & II)
• Determination of torque end-point value
• Determination of Drying parameters
• Determination of LOD limits
• Determination of testing temperature for checking LOD limits  (State machine Mettler™, Computrac™).
GRANULATION Physical Properties of Granulate • Flow properties,
• Density,
• Particle-size distribution • Compressibility
Compression Physical Properties of Compressed Tablets • Weight,• Hardness,• Thickness, • Friability • Disintegration• Dissolution
Final Formula Established Assessment of Final Master Formula and accelerated 1-3 month stability profile.
Stage 12B u l k A c t i v e P u r c h a s e d
Active material Bulk purchase 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.
FULL LABORATORY EVALUATION Development Scope of Product  Development Stage 13A n a l y t i c a l E v a l u a t i o n
Analytical testing of tablets/Caplets • 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 Assay; Dissolution ; Content Uniformity completed prior to Process Qualification
PROCESS OPTIMIZATION
Development Scope of Product  Development
Stage  14P r o c e s s O p t i m i z a t i o n
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)
tablet hardness• Adjusting mill screen size up or down to fine tune hardness
• Evaluation of optimized granulate and tablet attributes DRYING• FB Drying temperature versus target LOD and range limits and
the 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 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
PROCESS OPTIMIZATION REPORT ∗ Prepare PO Report. This Process Optimization Report forms part of the product Development Report
ESTABLISHING AND INVITRO INVIVO CORRELATION
Development Scope of Product  Development
Stage 15A n a l y t i c a l E v a l u a t i o n
IVIV Correlation• 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)
S CA L E UP
Development Scope of Product  Development
Stage 16S CA L E UP
Scale-up Scale-up lot prepared if larger batch size scale up problems
anticipated.
Process Qualification batch and  Scale-up batch may be
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
Stage 17P r o c e s s Q u a l i f i c a t i o n
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
PROCESS QUALIFICATION
Development Stage Scope of Product  Development Stage 17 (Cont)P r o c e s s Q u a l i f i c a t i o n
FINAL REVIEW and AUTHORIZATION Review of proposed formula, manufacturing process and control parameters with production personnel and QA Staff with authorization 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 BATCH
Development Scope of Product  Development
Stage 18P i v o t a l P r o d u c t i o n
PRODUCTION FACILITIES Pivotal batch MUST be compressed in a production  tabletting machine (or production type with same principle and operation)
BATCH
DOCUMENTATION
Preparation of  FINAL Master Formula and Processing Instructions
REVIEW  and AUTHORIZATION 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.
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 part
of the overall Development Report. BIOEQUIVALENT STUDY
Stage Scope of Product  Development
Stage 19B I O S T U D Y E v a l u a t i o n
BIOSTUDY Fasted Perform Fasted / Food Effect Biostudy on Pivotal Lot Samples
BIOSTUDY [Food Effect]Perform Food Effect Biostudy on Pivotal Lot Samples (See food effect guidelines, where appropriate)
HIGHEST DOSAGE Biostudy generally performed on highest strength of product One or two studies Fasted AND Food Effect Study may be required
WAIVER CONDITIONS For multiple strength products Invitro dissolution testing conducted in three different pH media on lower dosage forms
SIMILARITY TESTING Perform Similarity Test [F2 Test] on dissolution results.

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