p1 PDF
p1 PDF
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Head of QA/RA ChemiDarou Co. m.sadatrezaei@chemidarou.com
Fundamentals
CMC (Chemistry, Manufacturing and Controls) QOS(quality overall summary) QBR (Question-based CMC Review) Drug substance Drug product Recommendations Acknowledgement
IND
NDA
Pre-clinical
Clinical
Commercialisation
Purpose
Any use in the US of a drug product not previously authorized for marketing in the US first requires submission of an IND to FDA.
FDA Objectives
To assure the safety and rights of the subjects (Phase 1) To ensure the quality of the scientific evaluation of drugs to allow the determination of safety and effectiveness (Phases 2 and 3)
Manufacturing
Technology Technology Transfer Transfer Post Approval changes
Composition Composition
& Process & Process
Selection Selection
Scale up
Equipment: Qualify
Unit operations Validation Process: Process flow Process monitoring Engineering run Validation Process monitoring
Process selection:
Granulation Direct compression Lyo.
6. Bioequivalence
Selection
FDA
CDER OGD
Composition
& Process
Process Development
Scale up
Technology Transfer
NDA
ANDA
book
Composition
& Process
Process Development
Scale up
Technology Transfer
Compund patent or NCE patent: Claim the active ingredient(s) Drug product patent: Claim formulation or composition Use patent: Claim indication or method of use Others such as: Polymorph, particle size, solvate, food effect, etc
Orange Book
All
FDA approved drug products listed(NDAs, Technology Candidate OTCs & ANDAs) Composition Process Scale up Development Transfer
Selection
Therapeutic equivalence Expiration dates: patent and exclusivity Reference Listed Drugs/brand drugs identified by FDA for generic companies to compare with their proposed products
& Process
Candidate
Composition
& Process
Selection
Scale up
Technology Transfer
http://www.accessdata.fda.gov/scripts/cder/ob/default.cfm
Paragraph
Composition
& Process
Process Development
Scale up
Technology Transfer
Exclusivity
Candidate
Scale up
Technology Transfer
Same route of administration Same dosage form Same strength Same conditions of use
APPLICANT
ANDA
Application Review
Labeling Review
Bioequivalence Review
Candidate
Composition
& Process
Selection
Process Development
Scale up
Technology Transfer
853
ANDAs submitted (as of 9/26/2011) 211 PIV submissions 148 ANDAs RTRd (as of 9/26/2011)
CMC:
Chemistry, Manufacturing and Controls
Assures the identity, purity, quality, and strength or potency as related to the safety and efficacy of new drugs throughout their life cycle:
IND (Investigative New Drugs) NDA (New Drugs) ANDA (Generic Drugs) Post Approval Changes
DRUG SUBSTANCE
- General Information
- Manufacture - Characterization - Control of Drug Substance - Reference Standards - Container Closure System - Stability
DRUG PRODUCT
Description and Composition Pharmaceutical Development Manufacture & Batch Records Control of Excipients Control of Drug Product Reference Standards and Materials - Container Closure System - Stability
The part of the CTD format (Module 2) that provides a summary of the CMC documentation of the application
o
Industry Challenges Technical Writing Skills Joint value-added training sessions with case studies.
- The aim of pharmaceutical development studies is to design a manufacturing process that will consistently perform and consistently deliver a product of the intended quality.
- Quality cannot be tested into products; quality should be built in by design.
Candidate
Composition
& Process
Selection
Process Development
Scale up
Technology Transfer
Common
General
framework for a science and risk-based assessment of product quality the important scientific and regulatory review questions to:
Contains
Comprehensively assess critical formulation and manufacturing process variables Set regulatory specifications relevant to quality Determine the level of risk associated with the manufacture and design of the product
Questions
Prepare a consistent and comprehensive evaluation of the ANDA Assess critical formulation & manufacturing variables
Questions
Recognize issues OGD generally considers critical Direct industry toward QbD (ICH Q8 and Q10)
Candidate
Composition Process GENERAL INFORMATION Development Scale up & Process MANUFACTURE CHARACTERIZATION CONTROL OF DRUG SUBSTANCE REFERENCE STANDARD CONTAINER CLOSURE SYSTEM STABILITY
Technology Transfer
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pH), partition coefficient, polymorphism, and Technology Candidate Composition Process hygroscopicity, Scale up melting Development Transfer Selection points? & Process
Formulation development Manufacturing process development Analytical methodology Product stability
Critical Material Attributes (CMA) Properties may or may not be CMA based on
Intended use or performance formulation Manufacturing process Analytical method Product stability
Candidate
Composition
& Process
Selection
Process Development
Scale up
Technology Transfer
Candidate
Composition
& Process
Selection
Process Development
Scale up
Technology Transfer
Question 3: Who manufacture drug substance? Question 4: How do the manufacturing process and controls
Selection
Process Development
Scale up
Technology Transfer
The name, address and responsibility of each manufacturer, including contractor and each proposed production site or facility involved in manufacturing and testing should be provided.
DMF . . . .
and characterized?
Candidate
Composition
& Process
Selection
Process Development
Scale up
Technology Transfer
Candidate
Composition
& Process
Selection
Process Development
Scale up
Technology Transfer
characterized?
Candidate
Composition
& Process
Selection
Process Development
Scale up
Technology Transfer
Question 7: what is the drug substance specifications? Question all Selection 8: Does it include & Process
Candidate Composition
Question 9: What is the justification for acceptance criterion? Particle size by dissolution study Impurity limit: meet ICH Q3A guideline
Scale up
Technology Transfer
Selection
Process Development
Scale up
Technology Transfer
Selection
Process Development
Scale up
Technology Transfer
Technology Process Scale up Development Transfer drug&substance stability studies support the Process
Candidate
Composition
& Process
Selection
Process Development
Scale up
Technology Transfer
Candidate
Composition
& Process
Selection
Process Development
Scale up
Technology Transfer
2.3.P.1 Description and Composition 2.3.P.2 Pharmaceutical development 2.3.P.2.1 components of the product Candidate Composition Process Development Scale up Selection & Process 2.3.P.2.1.1 Drug substance 2.3.P.2.1.2 Excipietns 2.3.P.2.2 Drug product 2.3.P.2.3 Manufacturing process development 2.3.P.2.4 Container closure system 2.3.P.3 Manufacture 2.3.P.4 Control of excipients 2.3.P.5 Control of drug product 2.3.P.6 Reference standards 2.3.P.7 Container closure system 2.3.P.8 Drug product stability
Technology Transfer
43
What are the components and composition of theTechnology final Composition Process Scale up product? What is the function of each excipient? Development Transfer Selection & Process
44
Do any excipients exceed IIG limits in the context of maximum daily dose and route of administration?
Composition Process Development
Candidate
Selection
Scale up
Technology Transfer
dex.cfm
Selection Refuse
Candidate
to Receive Reasons
Scale up
& Process
Composition
Process Development
Technology Transfer
(63) Submission Format Inadequacies (40) Bioequivalence Deficiencies (27) Inactive Ingredient Issues (23) Inadequate Stability Data (15) Packaging Configuration Issues
If product is an NTI drug or a non-simple dosage form Are there significant differences between this Technology Candidate formulationComposition Process and the RLD that present potential Scale up Development Transfer Selection concerns with & Process respect to product performance?
Example: CR product Indicate if the proposed product uses a different design/release mechanism than RLD If it is different, provide justification
Example CR product: RLD with IR+ER pellets Generic with ER pellets only
Candidate Composition
& Process
Selection
Process Development
Scale up
Technology Transfer
Example CR product: RLD with IR+ER pellets Generic with ER pellets only
Candidate Composition
& Process
Selection
Process Development
Scale up
Technology Transfer
The ICH guidanceComposition Q8 describes the purpose of pharmaceutical Technology Process Scale up development: Development Transfer Selection & Process Provide scientific understanding of product and manufacturing process Support the establishing of specification and manufacturing control
Which properties Composition or physical Process chemical characteristics of the Technology Scale up drug substance affect drug product development, manufacture Development Transfer Selection & Process or performance?
Candidate
Selection
Process Development
Scale up
Technology Transfer
2.3.P.2.1.2 PD-Excipietns
Candidate
What evidence supports compatibility between excipeitns and Technology Composition Process drug substance? & Process Development Scale up Transfer Selection
2.3.P.2.1.2 PD-Excipietns
Candidate
Statements below do not answer the question: Composition Process Scale up Excipients same as RLD Development Selection & Process Commonly used excipients Satisfactory accelerated stability data
Technology Transfer
Acceptable drug product stability is the goal. Quality by design(Qbd) requires that the mechanistic factors that affect stability be identified. Relying only on endproduct testing is not Qbd and is considered higher risk.
2.3.P.2.1.2 PD-Excipietns
Candidate Composition
& Process
Selection
Process Development
Scale up
Technology Transfer
Scale up
Transfer
bioequivalent
2.3.P.2.2 PD-Drug product(attributes of drug product) Technology Candidate Composition Process Scale up Development Transfer Selection & Process Characterization of RLD
Development
Scale up
Transfer
Development
Scale up
Transfer
Development
Scale up
Transfer
Development
Scale up
Transfer
Selection
Process Development
Scale up
Technology Transfer
Hand test
Emerging methods Acoustic Emission (Int. J. Pharm 205, 2000 79 71) Image processing (Powder Tech. 115, 2001 124 130) Off line methods
Granule Rheology
Granulation particle size In line instrumentation Main impeller motor amperage Main impeller motor power Main impeller shaft torque
Candidate
Composition
& Process
Selection
Process Development
Scale up
Technology Transfer
Technology Candidate geometric similarity Composition Process Assuming and Constant impeller Scale up tip speed:
Selection
& Process
Development
Transfer
2.3.P.3 Manufacture
Who manufactures the drug product? What are the unit operations in the drug product Technology Candidate Composition Process Scale up manufacturing process? Development Transfer Selection & Process What is the reconciliation of the exhibit batch?
& Process
119.66 kg (99.7%) 120.00 kg (100%)
Blend Yield* Tablet Compression Yield* 119.00 kg (99.6%) 971,261 units 119.48 kg (100%) 995,667 units 119.16 kg (99.9%) 967,333 units 119.26 kg (100%) 993,833 units 98.5% 119.46 kg (99.5%) 120.00 kg (100%)
Coating Yield* 117.28 kg 967,715 units (99.6%) 115.58 kg 971,261 units (100%) 117.96 kg 967,763 units (100.2%) 116.08 kg 967,333 units (100%) 98.5%
Packaging 100-count bottles 500-count bottles Yield* 4948 941 967,840 units (100%) 4966 942 967,715 units (100%) 4914 947 968,014 units (100%) 4934 948 967,763 units (100%) -98.5%
Candidate
What are the specifications for the inactive ingredients and are they appropriate per their intended function?
Composition
& Process
Selection
Process Development
Scale up
Technology Transfer
What is the drug product specification? Does it include all the critical drug product attributes? For each test in the specification, is the analytical method(s) suitable for its intended use and, if necessary, validated? What is the justification for the acceptance criterion?
Test / Method
Description
Specification
Visual
6.25 mg: Pink, round, bi-convex, unscored, film coated tablets, with WPI on one side and 3530 on the other side. 12.5 mg: White to off-white, round, bi-convex, unscored, film coated tablets, with WPI on one side and 3531 on the other side. The retention time of the major peak obtained in the chromatogram of the assay preparation corresponds to that in the chromatogram of the standard preparation as obtained in assay
The UV absorbance spectrum of a sample solution exhibit maxima at the same wavelengths as that of the standard preparation.
The retention time of the major peak obtained in the chromatogram of the assay preparation corresponds to that in the chromatogram of the standard preparation as obtained in assay Conforms The UV absorbance spectrum of a sample solution exhibit maxima at the same wavelengths as that of the standard preparation. Conforms 3.95% Conforms
The retention time of the major peak obtained in the chromatogram of the assay preparation corresponds to that in the chromatogram of the standard preparation as obtained in assay Conforms The UV absorbance spectrum of a sample solution exhibit maxima at the same wavelengths as that of the standard preparation. Conforms 3.85% Conforms
Water Content
NMT 6.0%
Assay (HPLC)
90.0% - 110.0%
98.5% Conforms
98.0% Conforms
Impurity A: Not detected. Largest Individual Unknown Impurity: (@ 33 min.) 0.05% (0.049) Total Impurities: 0.05% (0.049) Avg. 24% Range: 20% - 26% Avg. 30% Range: 26% - 33% Avg. 41% Range: 38% - 45% Avg. 54% Range: 51% - 59% Avg. 66% Range: 63% - 77% Avg. 86% Range: 81% - 99% Avg. 95% Range: 91% - 102% Avg. 101% Range: 98% - 103%
Impurity A: Not detected. Largest Individual Unknown Impurity: Less than LOQ of 0.05% Total Impurities: Less than LOQ of 0.05% Avg. 23% Range: 20% - 28% Avg. 30% Range: 27% - 36% Avg. 41% Range: 37% - 48% Avg. 53% Range: 50% - 61% Avg. 63% Range: 60% - 71% Avg. 82% Range: 75% - 97% Avg. 95% Range: 89% - 101% Avg. 101% Range: 100% - 103%
Medium: 900 mL of 0.01N HCl. Apparatus: Basket @ 75 In-House HPLC Test RCBT-00032-02
Candidate
Selection
Process Development
Scale up
Technology Transfer
What container/closure system(s) is proposed for packaging and storage of the drug product? Has the container/closure system been qualified as safe for use with this dosage form?
Recommendations
Implementation of QBR-QOS as a mean to facilitate the review and encourage industry to develop the new products based on Quality by design principles. Periodic Feedback Sessions between Industry & FDO. Reward & Recognition System
o
o o
Give priority review to top 3 companies which file the best filings
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Dr.Ali
Jabbari, Managing Director, ChemiDarou Co. Dr.Karimi, Iran FDO Mr.Alireza Hemmati, Head of training and public affairs ChemiDarou Co.