PRODUCT DEVELOPMENT GUIDE
P RE-FORMULATION - SOFT GELATIN CAPSULES 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. The 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 Rearch USP BP Pharm. Eur, PDR, Martindale, Merck, Florey, Vidal,
Text and journals
FDA - FOI Summary Basis of Approval - On request form FDA
On-line computerized arch
FDA CDER Electronic Data Ba (articles and publication on test methods, Dissolution synthesis proce
dures, 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-Brusls) - Review suppliers catalogs & 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 or maximum three potential active suppliers
• DMF availability
• Compliance with USP monograph
• Impurity profile and stability
• Potential Polymorphic forms
• Commitment for physical specifications (Bulk Density)
• Statement of non-patent infringement
Stage 4A c t i v e P u r c h a s i n g
Purcha (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 prent)
b. Pharmacopoeia Forum (if available)
c. In-hou method (bad on manufacturer)
d. Supplier's test methods and specification
PRE-FORMULATION - SOFT GELATIN CAPSULES 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 Purcha 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:-
Capsule size, capsule color / US approved dyes, coding for
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printing, pack sizes containers materials, closure types;
cotton and desiccants, blister packaging.
Innovator Physical Testing Physical testing
Fill Weight & Uniformity; Shell disintegration & Dissolution Evaluation of capsule size and fill volume
Evaluation of Innovator formula ingredients Summary Formula in PDR; International PDRs (Italian, French, Swiss) and Innovators product's inrt (obtain latest FOI -FDA)
Perform actual analytical testing on innovator's product.
Microscopic obrvation Particle/crystal information on:
Particle size, crystal shape, habit, rugosity Viscosity agents ud (PVP 30 / 90) Prence of vegetable oil (type) Prence of PEG 400
Prence of polyethylene glycol solvent
Evaluation of Biostudy Review FDA CDER Home page for listing and Biostudy parameters
Dissolution profile USP monograph and FDA method - (where prent)
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 and Tapped density (Need for size reduction of material)
新年大扫除的意义• Microscopic obrvation
FULL CHEMICAL CHARACTERIZATI ON Chemical characterization • Assay
• Stresd Analysis
• Degradants (Expected)• Impurity profile
• Optical rotation
• Enantiomeric purity
• O.V.I. Testing
DEVELOPMENT BATCHES - SOFT GELATIN CAPSULES Development Stage Scope of Product Development
Stage 9E x c i p i e n t s
Evaluate formulation with suitable excipients • Vegetable oil solubility / PEG 400 / PEG 600 / PG / PVP 30
• Antioxidants (dl-alpha Tocopherol (Vit. E USP) / Propyl gallate)
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 als ud 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
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EVALUATION SUITABLE MANUFACTURING PROCESSES Gelatin Mass
Fill Preparation Encapsulation Drying 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)
• 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 condary tray drying times • Determine Bareiss hardness
Fill material Physical Properties of oil or paste fill • Viscosity - (Critical)
• Fill moisture
• SG (helps to control deaeration)
Filling
Physical Properties of Filled Softgels • Weight Uniformity• Individual Fill Weight Limits (7.5%)
• Content Uniformity • Average Fill Weight Limits (5.0%)
• Disintegration• Dissolution profile
Final Formula Established Asssment 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
我的母亲老舍原文Active material Bulk purcha 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 - SOFTGELS 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 Softgels • Dissolution - in USP medium (Multipoint profiles) and other relevant media versus Innovator's product. Dissolution testing may not be possible where active strength is in micrograms (i.e. 0.25 or 0.5 mcg)
校车公司• 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
GEL & FILL MATERIAL OPTIMIZATION [In suspension and paste fills size reduction of active material may be to decrea active bulk densities from 0.6 -0.75g/cc to 0.35 - 0.45 g/cc]◊ Optimization of gel mass moisture (once per shell formula)
◊ Optimization of gel mass viscosity (once per shell formula)
◊ Deaeration of gel mass - (critical)
◊ Optimization of antioxidant percentage.
◊ Mixing process - rpm ; mixing time ; propeller position
◊ Fill material uniformity
◊ Ribbon Thickness adjustments for correct shell weights (once per shell formula)
◊ Seal Thickness (once per shell formula NLT 0.006")1
◊ Wet Shell Weight variation (± 8%)1
游泳姿势◊ Fill Weight variation (± 2%)1
◊ 1 Process capability performed.
DRYING♦ Drying time temperature versus shell moisture (in rotary
dryer)
♦ Primary drying time versus shell moisture (in tray dryer)
♦ Secondary drying time versus shell moisture (in tray
dryer)
♦ Bareiss hardness versus drying times.
♦ Softgel properties (Fill weights and Content Uniformity).
♦ Evaluation of Fill weight Range Limits (Qualification)
♦ Evaluation of stability results of optimized mfg. Process.
♦ Printing Inspection Limits
PROCESS OPTIMIZATION REPORT (PO)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 15
A n a l y t i c a l E v a l u a t i o n IVIV Correlation
(arch literature)• Dissolution - in USP medium (Multipoint profiles) and other relevant media versus Innovator's product. Dissolution
testing may not be possible where active strength is in
micrograms (i.e. 0.25 or 0.5 mcg)
• Perform IVIV Bioavailability Study (where relevant)我想牵着你的手
BSC System IVIVC 1 : 1 Correlation Dissolution ttings Plasma parameters D evelopers 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 uful in establishing appropriate dissolution
specifications and thus permit certain post approval
formulation and manufacturing changes to be effected, -
without additional bioequivalence studies.
T he objective of developing an IVIVC is to establish a
predictive mathematical model describing the relationship
between invitro dissolution ttings and the actual invivo
drug-plasma parameters found, (such as AUC, Cmax,
Tmax).
T he invitro dissolution ttings 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.
T his matching of dissolution ttings with plasma levels, that
are derived from a specific IR formula and its corresponding
manufacturing process, is in fact simply an arbitrary t of
values that establish the so called 'predictive mathematical
model'.
A n 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 ttings / and
manufacturing changes) is maintained over the product's
dissolution profile.
Not applicable to highly soluble materials Establish a Level A or C correlation without adjusting
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dissolution parameters and time scale.
Not applicable to highly soluble
materials
• Adjust the dissolution parameters or time scale to achieve
a Level A or C correlation (adjust only if necessary)
