The Basics of CMC Ramnarayan Randad, Ph. D. Chemistry Reviewer DCI Office of Generic Drugs FDA Drug education workshop, Kansas City May 10, 2005 Basics of the CMC -Regulations  CMC = 21CFR314.50(d)(1) 	Additional requirements (ANDA) = 21CFR314.94(a)(9) 	Detailed information on: 			Drug substance (API) 			Inactive ingredients 			Drug product 			Master production records and 			Environmental impact Guidance's www.book118.com/cder/guidiance/index.htm Are developed in accordance with FDA’s Good Guidance Practices (Federal Register Sept. 2000, 56468-56480). Generally serve to meet regulatory expectations on particular topic. Are non binding on both pharmaceutical industry and FDA. Both may deviate with suitable justification. Chemistry, Manufacturing, Controls 	 CMC objective is to sufficiently characterize DS and DP so that important quality, safety, and efficacy attributes are established and controlled. Components and composition API, Excipients controls Manufacturing and controls Batch formulation and records Description of facilities Specs and tests Packaging Stability Basics of CMC –Component and composition Component and composition Describe function, and qualitative and quantitative formulation of DP.  List all components regardless of whether or not they appear in the FP (gases, solvents, water, ink etc). Reference to quality standards (USP/NF). Amount; per unit, ANDA, and production batch. Explanatory notes (overage, dosage form, coating, release mechanism etc). Example of composition statement Basics of CMC –Drug Substance DS: How to Submit Information CMC information the about drug substances can be incorporated in the application (NDA, ANDA) or by reference to pertinent information in another application, MF. A written statement that authorizes the reference, signed by the holder of the referenced application i.e. letters of authorization (LOA) should be submitted.  DMF’s are not approved. They are reviewed for adequacy. Drug Substance Please provide: DS Manufacturer’s COA OVI statement Applicants specifications and test results (COA). Information on reference standard/s.	 Primary RS, Secondary RS Source Qualification Retest schedule. Specifications A Specification is defined as a list of test, references to analytical procedures, and appropriate acceptance criteria that are numerical limits, ranges, or other criteria for the test described (ICH Q6A). Specifications are part of strategy to ensure product quality and consistency. Universal tests (description, ID, Assay, impurities) Specific tests (pH, particle size, polymorphic forms, chirality etc).  Basics of CMC –Excipients Excipients Provide specification and test results for all excipients Compendial: Test per monograph Non compendial: CMC, DMF, supporting data Novel (first time use in human) Same amount of information as DS.  Human or animal origin: source, origin, BSE DS and excipients compatibility. Own pharmacological activity (docusate sodium, caffeine, methionine) Basics of CMC –Manufacturing and controls Manufacturing and controls Name & address of manufacturing, testing facility/ies (to facilitate pre-approval inspections) Detailed description of manufacturing process. Flow diagram (from weighting to FP release; identify critical steps) . Blank batch and packaging record for production batch. Manufacturing and controls (cont.) Executed batch records Process controls (operational parameters, tests etc carried out for assurance for FP. The acceptance criteria may be numerical ranges, limits, or other) Reprocessing (approved process) and Reworking (process not described in the application, PAS) Basics of CMC –Finish product controls Drug Product Control Specifications (ICH Q6A). CGMP. CoA (Batch #, strength, size, date of manufacture, site of manufacture, c/c system, etc). Justify proposed specifications. Specification for Trademark Tablets (100 mg)	 	 	Tests		Acceptance Criteria	 Method	 Tablet Weight		440 mg ±5%			AP # 	 Dissolution		NLT 80% (Q) in 30 minutes		AP # U of Dosage Units	As per USP				HPLC; AP # Assay		95.0% to 105.0% LC (release)		HPLC, AP # 			90.0% to 110.0% LC (shelf-life)		 Water Content	NMT 1.0%				USP <921>; 								Method Ic	 Degradation Products						HPLC; AP # Specified Degradation Products			 · 		Degradant A			NMT 0.5%		 · 		Degradant B			NMT 0.6%		 · 		Degradant at RRT 6 XX		NMT 0.3%	 Unspecified Degradation Product			 · 		Individual Unspecified		NMT 0.10%		 Total Degradation Products			NMT 1.2%		 Basics of CMC – Analytical procedures and Method Validation Analytical procedures Analytical Procedures should be described in the submission. Analytical Procedures should be validated. Validation of Analytical Procedures is described in USP, Q2A and CDER Guidance and should demonstrate that the method is suitable for the intended use. CMC - DRUG PRODUCT Basics of CMC –Container-Closure Container Closure Description Primary packaging	 Material of construction of each packaging component Specifications, COAs  functional secondary packaging Same information as above Non functional secondary packaging 	 Brief description Container closure (contd.) Basics of CMC –Drug Product Stability Drug Product Stability Protocol, Specifications, and Commitment Stability data: Accelerated –1, 2, 3 months at 40°C, 75% RH Long-Term –3, 6, 9, 12, 18, 24 months at 25°C,  60% RH Stress studies or stability indicating method. 24 Months expiration if no significant degradation under accelerated. Drug Product Stability (Cont.) Commitments: Place at least one batch annually on stability at shelf-life storage conditions (25oC/60% RH). Report data to FDA annually. May have to withdraw batches that fail stability studies. Expiration Date may be extended with additional CRT stability data for 3 commercial batches & is annual reportable. Concluding thoughts Justify, Justify, Justify (Science? Evaluate?) Check, recheck for Consistency Product Description in manufacturing, controls, and labeling sections. Proposed specifications and data Packaging description in the manufacturing, stability, and labeling sections. Storage condition, stability testing conditions, and labeling sections. Chemistry, Manufacturing, Controls 	 CMC objective is to sufficiently characterize DS and DP so that important quality, safety, and efficacy attributes are established and controlled. Components and composition API, Excipients controls Manufacturing and controls Batch formulation and records Description of facilities Specs and tests Packaging Stability Thank You Coming up next…15- minute break Top Regulatory Issues in the Drug Industry AKA, 483’s and Warning Letters John Thorsky, ORA Kansas City District Director * * Brand Name Drug			Generic Drug NDA Requirements			ANDA Requirements 1. Chemistry				1. Chemistry 2. Manufacturing			2. Manufacturing 3. Controls				3. Controls 4. Labeling				4. Labeling 5. Testing				5. Testing 6. Animal Studies 7. Clinical Studies			6. Bioequivalence 8. Bioavailability NDA vs. ANDA Review Process Generic Drug Review Process Bioequivalence Review Labeling Review Chemistry & Micro Review Request for Plant Inspection APPLICANT ANDA Acceptable & Complete Application Review N Chem/Micro OK? Labeling OK? Bioequivalence OK? PreApproval Inspection Results OK? Not Approvable Letter Approval Withheld until Results Satisfactory Bio Deficiency Letter APPROVED ANDA N N N N Y Y Y Y Y Refuse to Receive Letter Specification for Trademark Tablets (100 mg)		 Tests			Acceptance Criteria	 Method				 Description		White, biconvex, 11 mm		Visual	 			diameter, 4 mm thick, film		 			coated tablet, with “identifier		 			code XYZ”on one side.		 Identification 		Retention time of the major peak	 HPLC, Test #1 		in the chromatogram of the assay	 AP1 # 			preparation corresponds to that	 EFG 			in the chromatogram of the		 			standard preparation obtained as		 			specified in the assay. 		 Identification 		Responds to the tests for sulfate	 USP 								 <191> Oral Tablets and Capsules Topical and Oral Powders Topical Solutions and Suspensions and Aerosols; Oral Solutions Low Ophthalmics; TDS; Nasal Aerosols and Sprays High Sterile Powders; Powders for Inj. Inhalation Powders Inhalation Aerosols and Solutions; Injections; Inj. Suspensions Highest Low Medium High Likelihood of Interaction Degree of Concern