Mohsen Sadatrezaei Pharm.

D
Head of QA/RA ChemiDarou Co. m.sadatrezaei@chemidarou.com

Genesis of a new drug

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)

Product development process and milestones

Discovery
Candidate Candidate Form Selection Development

Manufacturing
Technology Technology Transfer Transfer Post Approval changes

Composition Composition
& Process & Process

Selection Selection

Process Process Development Development

Scale up

Properties: Potency Selectivity In vivo efficacy Toxicity

Salt form Polymorph Hydrate.

Excipients: Physical effects Chemical effects

Characterize: Raw materials

Establish criteria: Tech transfer

Equipment: Qualify

Unit operations Validation Process: Process flow Process monitoring Engineering run Validation Process monitoring

Process selection:
Granulation Direct compression Lyo.

NDA vs. ANDA Review Process

Brand Name Drug Generic Drug Technology Candidate Composition Process NDA Requirements ANDA Requirements Scale up Development Transfer Selection & Process 1. Chemistry 1. Chemistry
2. 3. 4. 5. Manufacturing Controls Labeling Inspection 2. 3. 4. 5. Manufacturing Controls Labeling Inspection

6. Animal Studies 7. Clinical Studies 8. Bioavailability

6. Bioequivalence

Department of health and human services

Candidate

Selection

FDA
CDER OGD

Composition
& Process

Process Development

Scale up

Technology Transfer

NDA

Full report on Safety and efficacy CMC Labeling

ANDA

Bioequivalency report CMC Labeling

 Orange Selection Patents

Candidate

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

I Candidate Selection Paragraph II Paragraph III Paragraph IV

Composition
& Process

Process Development

Scale up

Technology Transfer

Exclusivity

Five years NCE 180 days first to file

Candidate

Composition Process Same active ingredient(s) Development Selection & Process

Scale up

Technology Transfer

Same route of administration Same dosage form Same strength Same conditions of use

Compared to reference listed drug (RLD) - (brand name product)

12

APPLICANT

Generic Drug Review Process

ANDA

Application Review

Refuse to Receive Letter

Acceptable & Complete

Y

Request for Plant Inspection

Chemistry & Micro 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)

CTD (Common Technical Document):

The common format for the preparation of wellstructured harmonized application for submission to the FDA

CMC:
Chemistry, Manufacturing and Controls

(Quality Document, Module 3)

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

QOS Summary of Critical CMC Elements

Body of Data CMC Submission Package

The part of the CTD format (Module 2) that provides a summary of the CMC documentation of the application
o

QOS => Product Story => Better Informed Reviewer

o o

Industry Challenges Technical Writing Skills Joint value-added training sessions with case studies.

QbD (Quality by Design):

Designing and developing drug product formulations and manufacturing processes to ensure a pre-defined quality

ICH Q8 Pharmaceutical Development states:

- 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

QbR (Question-based Review):

QbR questions represent the current OGD thinking about what information is essential to evaluate an ANDA.

 Common

Technical Document Format Quality Overall Summary that will

address

the reviewers questions and guide reviewers through the application

eliminate unnecessary fact finding of information such as composition, specification, and manufacturing process, etc.

 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

guide reviewers to:

Prepare a consistent and comprehensive evaluation of the ANDA Assess critical formulation & manufacturing variables

Questions

guide industry to:

Recognize issues OGD generally considers critical Direct industry toward QbD (ICH Q8 and Q10)

Candidate

2.3.S.1 Selection 2.3.S.2 2.3.S.3 2.3.S.4 2.3.S.5 2.3.S.6 2.3.S.7

Composition Process GENERAL INFORMATION Development Scale up & Process MANUFACTURE CHARACTERIZATION CONTROL OF DRUG SUBSTANCE REFERENCE STANDARD CONTAINER CLOSURE SYSTEM STABILITY

Technology Transfer

28

 Question 1: What are the nomenclature, molecular structure,

molecular formula, and molecular weight?

Question 2: What are the pKa, aqueous solubility (as function of

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

An understanding of drug substance Properties is essential in:

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

ensure consistent production of drug substance?

Candidate Composition
& Process

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 . . . .

 Question 5: How was the drug substance structure elucidated

and characterized?
Candidate

Composition
& Process

Selection

Process Development

Scale up

Technology Transfer

Candidate

Composition
& Process

Selection

Process Development

Scale up

Technology Transfer

 Question 6: How were potential impurities identified and

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

attributes that affect manufacturing and quality of the drug product?

Technology Process Scale up the Development critical drug substance Transfer

Question 9: What is the justification for acceptance criterion? Particle size by dissolution study Impurity limit: meet ICH Q3A guideline

 Question 10: for each tests in specifications is the analytical

Candidate Composition
& Process

methods suitable for its intended use and if necessary validated?

Selection
Process Development

Scale up

Technology Transfer

 Question 11: How were the primary reference standard certified?

Candidate Composition
& Process

Selection

Process Development

Scale up

Technology Transfer

 Question 11: How were the primary reference standard certified?

Candidate Composition
& Process

Selection

Process Development

Scale up

Technology Transfer

 Question12 : what container closure system is used for

packaging and storage of drug substance stability?

Candidate Composition

Question13: What Selection

retest or expiration date and storage conditions for drug substance?

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

2.3.P.1 Description and Composition

Candidate

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

& Process http://www.accessdata.fda.gov/scripts/cder/iig/in

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

2.3.P.2 Pharmaceutical development

Candidate

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

2.3.P.2.1.1 PD-Drug Substance

Candidate

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?

2.3.P.2.1.1 PD-Drug Substance

Composition
& Process

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

2.3.P.2.2 PD-Drug product(attributes of drug product) Technology Candidate Composition Process

Selection What
Development & Process attributes should the drug product possess?

Scale up

Transfer

TARGET PRODUCT PROFILE

Once TPP is established formulation effort will be effective and focused
Dont tell the target is to have a stable and bioequivalent product Tell what attributes your product needs to have to be stable and

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

2.3.P.2.2 PD-Drug product(attributes of drug product) Technology Candidate Composition Process

Selection
& Process

Development

Scale up

Transfer

2.3.P.2.2 PD-Drug product(attributes of drug product) Technology Candidate Composition Process

Selection
& Process

Development

Scale up

Transfer

2.3.P.2.2 PD-Drug product(attributes of drug product) Technology Candidate Composition Process

Selection
& Process

Development

Scale up

Transfer

2.3.P.2.2 PD-Drug product(attributes of drug product) Technology Candidate Composition Process

Selection
& Process

Development

Scale up

Transfer

2.3.P.2.2 PD-Drug product(attributes of drug product)

Candidate How Technology Composition Process was the drug product designed toScale have these attributes? up Development Transfer Selection & Process Were alternative formulations and mechanisms investigated? How were excipients and their grades were selected? How was the final formulation optimized?

2.3.P.2.2 PD-Drug product(attributes of drug product)

Candidate Composition
& Process

Selection

Process Development

Scale up

Technology Transfer

2.3.P.2.3 Manufacturing process development

Candidate Why Selection Technology Composition Process was the manufacturing process described in 3.2.P.3 Scale up Development Transfer & Process selected for this drug product? How are the manufacturing steps (unit operations) related to the drug product quality? How were the critical process parameters identified, monitored, and/or controlled?

What is scale up experience with the unit operations in this process?

2.3.P.2.3 Manufacturing process development

For example: Candidate High shear Granulation: Composition Process Development Selection & Process Process variables:
Impeller rotation speed Chopper rotation speed Load of the mixer Liquid addition method
Scale up
Technology Transfer

Liquid flow rate

Wet massing time

2.3.P.2.3 Manufacturing process development

For example: Candidate High shear Granulation: Composition Process Development Scale up Selection & Process Granulation end point determination
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

2.3.P.2.3 Manufacturing process development

High shear Granulation scale up!

Technology Candidate geometric similarity Composition Process Assuming and Constant impeller Scale up tip speed:

Granulating liquid volume proportional to batch size

Selection

& Process

Development

Transfer

Wet massing time inversely proportional to RPM

2.3.P.2.4 PD Container closure system

What specific container closure attributes are necessary to ensure product performance? Technology Candidate Composition Process Scale up Light resistance Development Transfer Selection & Process Moisture protection

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?

2.3.P.3 Manufacture Exhibit batch reconciliation

Selection
6.25 mg Batch#XC6D007 Target Composition

Manufacturing Step Candidate

& Process
119.66 kg (99.7%) 120.00 kg (100%)

12.5 mg Target Process Batch#XC6D008 Scale up Development

Technology Limit Transfer

98.5%

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%

2.3.P.4 Control of excipients

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

2.3.P.5 Control of Drug Product

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?

Results for ANDA Batch

Test / Method
Description

Specification

6.25 mg, #XC6D007 Mfg. Date: 6/12/2007 120 kg / 1,000,000 tablets

Pink, round, bi-convex, unscored, film coated tablets, with WPI on one side and 3530 on the other side Conforms

12.5 mg, #XC6D008 Mfg. Date : 8/12/2007 120 kg / 1,000,000 tablets

White to off-white, round, bi-convex, unscored, film coated tablets, with WPI on one side and 3531 on the other side. Conforms

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

Identification A (HPLC): <621>

In-House HPLC Test RCBT-00032-00

B (UV): <197>

In-House HPLC Test RCBT-00032-00

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%

Karl Fischer apparatus USP <921> Method 1A

Assay (HPLC)

90.0% - 110.0%

In-House HPLC Test RCBT-00032-00

Content Uniformity (HPLC) <905> 10 Tablets: 85% - 115.0% % RSD NMT 6.0% or 30 Tablets: NMT 1 tablet outside the range of 85.0% to 115.0%, and no tablet outside the range of 75.0% to 125.0% % RSD NMT 7.8% Impurity A: NMT 0.1% Largest Individual Unknown Impurity: NMT 0.2% Total Impurities: NMT 0.5% USP <711> 15 minutes 20 minutes 30 minutes - 30 55% 45 minutes 60 minutes 55 80% 90 minutes 120 minutes NLT 80% 180 minutes

98.5% Conforms

98.0% Conforms

In-House HPLC Test RCBT-00032-00

(10 tablets) Range 98.3% - 100.0% % RSD = 1.4% Conforms

(10 tablets) Range 98.1% - 99.2% % RSD = 0.4% Conforms

Chromatographic Purity (HPLC) <621>

In-House HPLC Test RCBT-00032-02

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%

Dissolution (HPLC) <724>

Medium: 900 mL of 0.01N HCl. Apparatus: Basket @ 75 In-House HPLC Test RCBT-00032-02

2.3.P.6 Reference standard

How were the primary reference standard certified?

Composition
& Process

Candidate

Selection

2.3.P.7 Container closure system

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?

2.3.P.8 Drug product stability

What are the specifications for stability studies, including justification of acceptance criteria Technology that Candidate Composition Process Scale up Developmentrelease Transfer Selection differ from the drug product & Process specification? What drug product stability studies support the proposed shelf life and storage conditions? What is the post-approval stability protocol?

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

77

 Dr.Ali

Jabbari, Managing Director, ChemiDarou Co. Dr.Karimi, Iran FDO Mr.Alireza Hemmati, Head of training and public affairs ChemiDarou Co.