Product Characterization and Development Production and Pharmacopoeial Ctrls Concept of AMD M Ph (PA) Unit 1

Trainer: Chandramouli R

PRODUCT DEVELOPMENT
Process of Formulation Development from initiation to commercialization is categorized in to four basic stages.
Stage-I Market Search: Future aspect of product. Patent Search: Product related information shall be taken by help of IPR Department. Literature Search : Search on API, Drug products, stability data,Packaging , Pharmacokinetics and Impurity related information.

Initiated by FRD and started through an indent to purchase Department. Physicochemical Characterization: Initiated by FRD to study the physicochemical compatibility study of drug substances with various excipients.

PRODUCT DEVELOPMENT
Analytical Development: Initiated by ARD and FARD developing a suitable method for routine analysis of drug substances and drug product.

PRODUCT DEVELOPMENT
Innovator Product Sourcing and Characterization Of Innovator Drug Product

Activity initiated by FRD by raising a request to concerned country manager for procurement of innovator samples.
1) 2) 3) 4) 5) 6) 7) Description Average Weight Uniformity of Weight Disintegration Time Assay Dissolution Rate Related Substance

Characterization of Drug Substances:

Particle size distribution and justification of particle sizeselected. Bulk Density, Tapped Density and Compressibility. Solubility and biopharmaceutical classification. Compatibility with excipients (mainly physical) Polymorphs Hygroscopicity Melting Point Partition Coefficient Biological Properties Shall Cover Pharmacodynamics Pharmacokinetics ADME, Bio-availability, Protein Buildup, Pharmacokinetics Parameters like Cmax, Tmax etc

PRODUCT DEVELOPMENT
Excipients Characterisation: Shall cover list of excipients selected, their grade, usage, reported concentration and level of usage in final formula. Note: Proper justification of inclusion/exclusion of any excipient as compared to innovator composition shall be explained. Justification for the use of quantity of any excipient more than reported range shall be explained. Chemical stability of the excipients if established separately shall be given, otherwise reference to 3 months/6 months accelerated stability data shall be mentioned. Characterisation with respective following test :
Description,Identification by IR & Chemical Test , Moisture Content , LOD , SOR ,

PRODUCT DEVELOPMENT
Stage-II Involves development of formulation \ process and followed by development batches , stability studies data generation in proposed pack configuration. Prototype Formulation Development & Analytical Method Development: This activity is lab scale development work to arrive at a suitable prototype formulation ,Process , Suitable Pack,Control

PRODUCT DEVELOPMENT
Step

INPUT

OUTPUT Feasibility report Arrival of Skeleton Formula / Process/ Package Configuration

RESPONSIBILITY

1 Product Initiation form issuance S T A G E I 2 Active Sourcing procurement/

Evaluation evaluation

MRK, FRD FRD/ PURCH FRD / COUNTRY MANAGER FRD/ IPR FRD,FARD FRD,FARD RAD

3 Reference product procurement 4 5 6 7

Literature / Patent Search Analytical method Development

Compatibility with Excipients

USFDA Office of Generic correspondence / Import License initiation

PRODUCT DEVELOPMENT
Step

INPUT

OUTPUT

RESPONS IB-ILITY

8 Formula optimization
( Qualitative and quantitative)

S 9 Process development ( Lab Scale) Release of Tentative T 10 Development batches for TTD A (i) Analytical Method Validation G (ii) Pilot BE ( If Required) E (iii) Stability Studies II Process 11 Process Optimization at
Manufacturing Location

Generation & Issuance of MFC/ MPC Specifications ( Draft)

FRD FRD FRD ARD CPD ARD

Recommendation of ( Location Specific) Location Specific Issuance of TTD to RAD / Manufacturing ARD Location

FRD

12 Generation / Finalization of

Technology Transfer Dossier

PRODUCT DEVELOPMENT
STEP

INPUT

OUTPUT

RESPONSIBILITY

13

Pre Exhibit Batch Manufacturing Approval of Mfg. Location Documents Exhibit Manufacturing ( Pivotal Test Batches) Initiation of Stability Studies

S T A G E III

14 15 16 17 18 19

Issuance of Batch , Processing records Pivotal Test Batch Sample

Location FRD/ Mfg. Location FRD,ARD,Mfg . FRD,Mfg.

Stability Report FRD,Mfg.

(CRO) RAD FRD Location specific /Mfg. QA/RAD

Submission of Test Sample for BE / Report Pivotal Bioequivalence Studies batch. Compilation record for ANDA Finalization & Filling Design and Release of Validation Protocol ANDA Filling

PRODUCT DEVELOPMENT
STEP

INPUT

OUTPUT

RESPONSIBILITY

20

S T A G E IV

Mfg. of three production batches ( Prospective Validation) Concurrent & Retrospective Validation

21

Validation Report Regulatory Agency

Mfg. / RAD RAD

METHOD DEVELOPMENT
AMD :Simultaneously performed Analytical Method Development by using trial development batches or innovator samples.
Availability of Requirement : Like WS, HPLC column, etc

Sequence of Method Development 1. Literature Survey: In USP/EP/any Pharmacopoeial forum

1.1 Chemical Abstract 1.2 National Library of Medicine ( http:www. ncbi.nih.gov) 1.3 Analytical Profile :Florey 1.4 Analytical Abstracts ( http:www.rsc.org) 1.5 Summary Basis of Approval (SBOA) of innovator product

2. Profile of Drug Product: (1) Solubility Profile (2) Analytical Profile (3) Stability Profile, Primary requirement is to the solubility of the drug product with following solution: (i) Water (ii) 0.1N HCl & 0.01N HCl (iii) pH 4.5 Acetate Buffer (iv) pH 6.8 Phosphate Buffer (v) pH 7.2 Phosphate Buffer

METHOD DEVELOPMENT 3. Initiation of Method Development: 3.1 Method of analysis for Dissolution 3.2 Method of analysis for Assay 3.3 Method of analysis for Related Substance 3.4 Method of analysis for Content Uniformity 3.5 Method of analysis for Preservative Content 4.0 Optimisation of Method : 4.1 Optimisation of Mobile Phase : Buffer & Strength, pH and composition of mobile Phase

METHOD DEVELOPMENT
Selection Of Buffer: LIMIT: 10mM TO 50mM Phosphate Buffer : P Ka 3 & 7 - pH 2-4 & 6-8 Acetate Buffer : P Ka 4.75 pH 3.8 To 5.8 Trifluoro Acetic Acid : pH-1.5 To 2.5 Citrate Buffer : pH- 2.0 To 7.0 ( ABOVE 230nm)

Different Types of Buffer Carbonate Buffers Carboxylic Acids Tris Buffer Borate Buffer Triethyl Amine Buffers Should Transmit The Light ADJUST THE pH OF THE BUFFER BEFORE ADDING THE ORGANIC SOLVENT.

METHOD DEVELOPMENT
Effect of pH Acidic Compounds: Acidic pH-Unionised form (Non Polar) Basic pH-Ionised form (Polar) Basic Compounds : Acidic pH-Ionised form (Polar) Basic pH-Unionised form (Non Polar) Water - Aqueous Phase - Neutral Compounds Pharma Analysis -Ionic Compounds Buffer-pH Control. Polarity Of Solvents: Water<methanol<Acetonitrile<Dioxane<Ethylacetatte<Acetone<Diethylet her<THF<Methylene chloride<CHCl3<CCl4<Iso-Octane< Hexane

METHOD DEVELOPMENT
4.2 Selection of Column: Length, Diameter,packing Material,shape of Particles,% of Carbon Load,pore Volume,surface Area,end Capping, IF The Mobile Phase pH is more than 7.0 Silica Will Start To Solubilised. If The Mobile Phase pH Is Less Than 2.0 Hydrolysis Of Bonded Phases Will Occurred.

CN <NH2 <C4<C6<PHENYL<C8<C18
Endcapped Columns Should Not Be Used With pH Less than 2.0 Endcapped and high coverage of C18 should not be used for m.p. with few % of organic.

METHOD DEVELOPMENT
4.3 Selection of solvent delivery system: 4.3.1 By Low pressure Gradient 4.3.2 By High Pressure Gradient 4.4 Selection of Flow Rate: 4.4.1 Retention Time 4.4.2 Column Back Pressure 4.4.3 Separation of Impurities 4.4.4 Peak Symmetries 4.5 Selection of Column Temperature 4.6 Selection of Detector Wavelength 4.7 Selection of Diluent for Test Preparation 4.8 Selection of Test Concentration, Injection Volumn 4.9 Establishment of Stability of Test Preparation 4.10 Establishment of System Suitability 4.11 Establishment of Specificity of Test Method 4.12 Establishment of Response Factor for known impurities

Method Development for Dissolution : 1.Specificity: 1 Placebo Preparation with different medium

METHOD DEVELOPMENT

Note: A Minimum of 5-time points and 15 minutes time point is must.

Placebo Interference NMT 2.0 % No any peak should be present at the retention time of main peak

Run the placebo sample at 150 RPM ( Paddle Basket) for 30 min and dilute according to STP and analyse the sample to check the interference

2. Method Precision Experiment 2 For IR Tab.,Cap, Other Dosage forms Acceptance Criteria RSD of dissolution results does not exceed 5.0% at Q point RSD of dissolution results does not exceed 10.0 %

For ER Tab.

Method Development for Dissolution : 3. Linearity and Range : Experiment 4. 1. For HPLC Method 1.1 For IR Tab., Cap, & Other dosage Unit. 1.2 For Extended Release Tab. 2. For UV Method 2.1 For IR Tab., Cap, & Other dosage Unit. 2.2 For Extended Release Tab. 4. Recovery Study Experiment 5 HPLC/ UV Method For IR Tab.,Cap, Other Dosage forms ( 50,100,150%) For ER Tab. (10,25,100,150 %)

METHOD DEVELOPMENT

Acceptance Criteria Square of the Correlation Coefficient r 2 should not be less than 0.99

Acceptance Criteria Mean recovery should be in the range of 95-105% of added amount

Method Development for Dissolution : Experiment 6.

METHOD DEVELOPMENT
Acceptance Criteria Difference between the response area obtained at initial and at different time intervals should not be more than 2 %

Solution Stability : ( HPLC , UV Method) Perform Sample solution stability at room temperature (1,2,3, & 5 hr) Perform Sample solution stability at refrigerator condition up to 15 hr temperature (1,2,3,5,7,9,11,13,15 hr) Filter Paper Variability: Order for preference of filters : Nylon > PVDF > PTFE

7.

% Difference between the area obtained by unfiltered standard /centrifuged sample solution and filtered std /sample solution should not be more than 2.0

Method Development for Assay : Experiment 1. Specificity: Inject the diluent into HPLC to check the interference

METHOD DEVELOPMENT
Acceptance Criteria

No interference peak should be present at the retention time of the main peak Prepare the placebo solution in actual No interference peak concentration & 5 times the concentration of should be present at the retention time of the main sample & inject into HPLC to check the peak interference Prepare the impurities solution at specification level & inject into HPLC to check the interference. However if the imp. level are low for eg. 0.1 or 0.2 % , prepare impurities at 1% level against sample concentration & check for interference. No interference peak should be present at the retention time of the main peak and peak homogenous or pure.

Method Development for Assay : Experiment 1.

METHOD DEVELOPMENT
Acceptance Criteria No interference peak should be present at the retention time of the main peak and peak homogenous or pure. No absorbance should be observed at specified wavelength No absorbance should be observed at specified wavelength No absorbance should be observed at specified wavelength

Treat the sample with acid , Base, Hydrogen Peroxide and Expose the sample in Heat,Phototytic Degradation & inject into HPLC to check the specificity of the method. For UV Method Check the absorbance of diluent at specified wavelength Prepare the placebo solution & check the absorbance at specified wavelength
Prepare individual impurities at specification level.if impurity level are less for eg. 0.1 or 0.2, Prepare the impurities 1% against sample concentration and check for interference

Method Development for Assay : Experiment 2. 3. 4. Method Precision: ( HPLC/ UV Method) Recovery Study:
( For HPLC/UV Method)

METHOD DEVELOPMENT
Acceptance Criteria

Assay values should be in the range of 98.0102.0 with RSD NMT 2.0% Recovery should be in the range of 98.0 102.0 % with NMT 2.0% Difference between the response area obtained at initial and at different time intervals should not be more than 2 % % Difference between the area obtained by unfiltered standard /centrifuged sample solution and filtered std /sample solution should not be more than 2.0

Solution Stability
( For HPLC/UV Method)

5.

Filter Paper Variability: Order for preference of filters : Nylon > PVDF > PTFE

Method Development for Related Substance : Experiment 1. Specificity: Inject the diluent into HPLC to check the interference Prepared the placebo solution and inject into HPLC to check the interference Prepared the impurities solution at specificity level & Inject into HPLC to check the interference Take individual impurity spectra of each impurity to see the max of individual imp.

METHOD DEVELOPMENT
Acceptance Criteria No interference peak should be present at the retention time of the main peak No interference peak should be present at the retention time of the main peak No interference peak should be present at the retention time of the main peak and peak homogenous or pure.

Method Development for Related Substance : Experiment Treat Placebo,API and Drug Product with Acid,Base,Hydrogen Peroxide and Expose sample in Heat,Photolytic Degradation & Inject into HPLC to check specificity . Compare the chromatogram with sample ( Normal Condition ) for comparison of the impurities. 2. Recovery Study: 1. Prepared the API and observed the area of the main peak and prepare the sample and observe the area of main peak.

METHOD DEVELOPMENT
Acceptance Criteria No interference peak should be present at the retention time of the main peak and peak must be homogenous or pure.

95 % of the area should be recovered when compared to the area of API.

Method Development for Related Substance : Experiment

METHOD DEVELOPMENT
Acceptance Criteria

2. Prepare the sample by adding the known Recovery should not be less quantity of the impurities into the test than 90.0 and should not be preparation in the range of 50 ,100 and 150 more than 110 % % of the specification level conc. and inject single injection 3. Response Factor: Prepare separately the solution of impurities standard and main drug in 1% of the sample concentration & inject in duplicate to HPLC & calculate the relationship between concentration and response of analyte. Calculate either response factor or Relative Response Factor as per the requirement

METHOD DEVELOPMENT
Method Development for Related Substance : Experiment 4. Solution Stability : Sample solution at room temperature: 1,2,3,& 5 hrs Sample solution at refrigerator condition : 1,2,3,5,7,9,11,13 & 15 hrs If sample run time is more than one hour inject periodically upto 24 hrs. 1,3,6,9,12,15,18,21 & 24 hrs. 5. Filter Paper Variability : For HPLC Method: Prep. Std solution , compare the results for filtered solution( after discarding the appx. Vol. ) to those for the unfiltered solution. Prep. Sample solution spiked with all imp.mix at specification level compare the result for filtered solutions to those centrifuged , unfiltered solution. Acceptance Criteria % Difference between the respective area obtained at initial and at different time intervals should not be more than 10%

% Difference between the area obtained by unfiltered Std/ Centrifuged all impurities mix sample solution & filtered Std/ all imp.mix sample solution should not be more than 10

METHOD DEVELOPMENT
Development Batches for Stability Studies: This activity perform by ARD based on stability protocol of FRD. Generated data will be utilized for Assigning tentative shelf life of product. 1.Observations and Conclusions after each experiment shall be given. 2.Optimization experiments for quantity finalized for each excipient shall be given. 3. Proposed formula for Process Optimization shall cover multimedia dissolution for all strengths.

ANALYTICAL METHOD VALIDATION

A: FORMULATION Analytical method validation for following test Validation for content uniformity Validation for assay Validation for dissolution Validation for related substance Validation for residual solvent

ANALYTICAL METHOD VALIDATION

B: Active pharmaceutical ingredient (API) Analytical method validation for following test Validation for assay Validation for related substance Validation of residual solvent

VALIDATION

Facility Val. A. Utility Val. HVAC Val. A. Water System Val. PQ Equipment Val. & Qualification URS,FD,DD,DQ, FAT,IQ,OQ,PQ Process Validation 1. Prospective Val. 2. Concurrent Val. 3. Retrospective Val.

Analytical Method Validation Sterilization Validation

Re-Validation

Equipment Cleaning Validation

Doubts?...