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APIs Introduction
2006 FDA GMP China Training Program Peking University Ying Jie Convention Center April 24 26, 2006
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Agenda
ICH Q7A GMP GUIDANCE FOR APIs
ICH Q7AWhat is it?? What is an intermediate? What is an active pharmaceutical ingredient? API, drug substance, or BPC? Regulatory status of APIs abroad and in the US Guidance initiatives incorporated into Q7A Availability of Q7A on the Internet Importance of Q7A Process characteristics API Vs. Drug Products
Agenda
ICH Q7A GMP GUIDANCE FOR APIs
Implementation of Q7A worldwide Status of Q7A and other GMP documents Reaction to Q7 Use of Q7A during API inspections Scope Definition of manufacturing and should Interpreting and applying Q7A API Starting Materials Spectrum of CGMP controls in API processes
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What is ICH?
ICH Q7A GMP GUIDANCE FOR APIs
Implementation Of Q7A
ICH Q7A GMP GUIDANCE FOR APIs
Posted on EMEA website in November 2000 Published as Annex 18 to the EU Guide to Good Manufacturing Practices in July 2001
Implementation Of Q7A
ICH Q7A GMP GUIDANCE FOR APIs
Notice of Availability (NOA) published in Federal Register (Volume 66, No. 186) on September 25, 2001 Adopted by Japans Ministry of Health, Labour and Welfare (MHLW) on November 2, 2001
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Implementation Of Q7A
ICH Q7A GMP GUIDANCE FOR APIs
Adopted by Australias Therapeutic Goods Administration (TGA) in April 2001 Adopted by Pharmaceutical Inspection Convention/Pharmaceutical Inspection Cooperation Scheme (PIC/S) in May 2001
Implementation Of Q7A
ICH Q7A GMP GUIDANCE FOR APIs
World Health Organization (WHO) currently reviewing guidance to determine if they should adopt Q7A and promote it as an international standard that fulfills the function of global harmonization
Represents FDAs current thinking on a topic Does not confer any rights for or on any person Does not bind FDA or the public Alternate approach may be used if this satisfies the requirements of the applicable statutes and regulations
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CDERs Office of Compliance has revised CP 7356.002F with incorporation of systems-based inspection approach and reference to Q7A FDA will continue conducting inspections of API facilities
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Use of one guidance by both regulators and industry should facilitate inspections and enhance GMP compliance
Q7A
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PhRMA Guidelines for 21 CFR 211 does not apply FDAs Draft Guidance for Production, Packing, FDAs Guide APIs to manufacture of to Industry: Manufacturing, Repacking or Holding of Inspection of BPCs Processing or Holding Drugis obsolete is Substances APIs will not be finalized insufficient
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http://www.ifpma.org/ich1.html
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What Is an Intermediate?
ICH Q7A GMP GUIDANCE FOR APIs
A material produced during API processing that undergoes further molecular change or purification before it becomes the API May or may not be isolated
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Ladies and gentlemen. For purposes of this guidance, the terms active pharmaceutical ingredient and drug substance are equivalent!
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A - Actives E - Excipients
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Since implementation of EU/US MRA and issuance of Q7A, many countries are seeking legal authority to inspect and regulate API manufacturers Regulatory bodies worldwide are developing enforcement policies and qualifying personnel to inspect API manufacturers
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Definition of drug in the Federal Food, Drug, and Cosmetic Act encompasses APIs Section 501(a)(2)(B) of the Act requires that all drugs be manufactured, processed, packed, and held in accordance with current good manufacturing practice CGMP regulations (21 CFR 210 and 211) apply only to preparation of drug products 21
These CGMP regulations apply to finished dosage form drugs (under 210.3(b)(4) and 211.1) and are not binding requirements for chemical manufacturing.
Reference: Response to Comment 270 in the Preamble to the September 29, 1978 revisions to CGMP regulations (Page 45050)
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The Commissioner maintains that these regulations can serve as useful guidelines in the manufacture of chemicals. The agency plans to develop specific CGMP regulations on production of bulk drugs.
Reference: Response to Comment 270 in the Preamble to the Sept. 29, 1978 revisions to CGMP regulations (Page 45050)
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Importance of Q7A
ICH Q7A GMP GUIDANCE FOR APIs
First internationally harmonized tripartite GMP guidance developed jointly by industry and regulators under ICH umbrella Establishes one global GMP standard for APIs Intended to provide mutual recognition of GMPs in API production
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Importance Of Q7A
ICH Q7A GMP GUIDANCE FOR APIs
Intended to facilitate API inspections Impacts any manufacturer that markets APIs in ICH regions Addresses uniqueness of API processes
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API API
API API
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API API
Chemical & Biological Processing (synthesis, fermentation, extraction, purification)
APIs produced by chemical or enzymatic reactions, recombinant DNA, fermentation, recovery from natural materials, or a combination of these processes Usually involves synthesis, extraction, or crystallization resulting in significant changes to starting materials/intermediates Typically include purification steps
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Drug products formulated using bulk raw materials that are usually subjected to quality control by end users Generally involves physical processing and manipulations Typically do not include purification steps
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Process water quality Equipment cleaning and cleaning validation In process controls Application of GMPs Process validation Shelf life (expiry/retest date)
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Does not influence GMP expectations for laboratory controls and documentation No significant differences between a laboratory testing dosage forms and one testing APIs
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Inspectors will refer to the Q7A guidance during inspections to evaluate firms compliance with GMP expectations If alternative methods or procedures are in place, inspectors will review firms justification and determine if such alternatives are scientifically sound and accomplish the intended purposes
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Inspectors will paraphrase the language in the guidance when preparing inspectional observations Inspectors will NOT reference sections of Q7A in FDA 483 observations or EIR
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Applies to: APIs manufactured for use in human drug (medicinal) products Sterile APIs, but only up to the point immediately before the API is rendered sterile
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Applies to: APIs manufactured by chemical synthesis, extraction, cell culture/fermentation, recovery from natural sources, or any combination of these processes APIs used in production of drug products for clinical trials
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Applies to: APIs produced using blood or plasma as raw materials APIs or intermediates manufactured by cell culture or fermentation using natural or recombinant organisms (Chapter 18)
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Excludes: All vaccines, whole cells, whole blood and plasma, blood and plasma derivatives (plasma fractionation) and gene therapy APIs Bulk packaged drug (medicinal) products Radiopharmaceuticals and medical gases
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APIs intended for use in veterinary drug products Registration and filing requirements for APIs within the context of marketing/manufacturing authorizations or drug applications Pharmacopoeial requirements
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ICH Version In this guide the term should indicates recommendations that are expected to apply unless shown to be inapplicable or replaced by an alternative demonstrated to provide at least an equivalent level of quality assurance.
FDA Version In this guide the term should identifies recommendations that, when followed, will ensure compliance with CGMPs. An alternative approach may be used if such approach satisfies the requirements of the applicable statutes.
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If it doesnt say you have to do something, you probably dont have to do it If Q7A prohibits something, you probably shouldnt do it
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Earth
Wind
Fire
Water
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The same GMP concepts are valid in dosage form and API manufacturing Application of these concepts may differ
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Definition of Manufacturing
ICH Q7A GMP GUIDANCE FOR APIs
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Applying Q7A
ICH Q7A GMP GUIDANCE FOR APIs
Chemical Manufacturing
Outside scope Covered by Q7A
Production of Intermediates
Applying Q7A
ICH Q7A GMP GUIDANCE FOR APIs
Applying Q7A
ICH Q7A GMP GUIDANCE FOR APIs
Classical Fermentation/
Outside scope Covered by Q7A
The company should designate and document the rationale for the point at which production of the API begins. For synthetic processes, this is known as the point at which API Starting Materials are entered into the process.
A B C C D D E E FI FI API API
From this point on appropriate GMP, as defined in the guidance, should be applied to these intermediate and/or API manufacturing steps.
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A material used in the production of an API which is incorporated as a significant structural fragment into the structure of the API May be an article of commerce, a material purchased from one or more suppliers under contract or commercial agreement, or may be produced in-house Are normally of defined chemical properties and structure
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Important Clarification!
ICH Q7A GMP GUIDANCE FOR APIs
Q7A does not apply to steps prior to the introduction of the defined API starting material
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IN D U ST R IA L U SE S A P I U SE S
K ey Interm ediate
API
A P I Starting M aterial
API process begins with the use of Starting Material C to produce Intermediate D Level of control increases throughout synthesis of Intermediates E-F and API Control needed is highly dependent on the manufacturing process
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As a general rule, however, it is reasonable to expect GMP concepts to start to become applicable at that point where a starting material enters a biological or chemical synthesis or series of processing steps, where it is known that the end product will be a BPC. Reference: Sept. 1991 Guide to Inspection of Bulk Pharmaceutical Chemicals, Page 3
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Apply GMP controls beginning with the use of API starting materials
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Q7A Summary
ICH Q7A GMP GUIDANCE FOR APIs
Pragmatic balance of What vs. How Clarifies GMP expectations Not intended to ratchet up GMPs Should provide enough guidance to address CGMP problems in API production
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Division of Manufacturing and Product Quality Center for Drug Evaluation and Research 11919 Rockville Pike Room 439 Rockville, MD 20852 Voice Tele: FAX: E-mail: (301) 827-8940 (310) 827-8909 Nicholas.Buhay@fda.hhs.gov
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CGMP for
Manufacture of APIs
2006 FDA GMP China Training Program Peking University Ying Jie Convention Center April 24 26, 2006
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Others 3%
Program Objectives
Understand the scope of the Q7A guidance Recall how to use the guidance during inspections Understand several controversial issues in API production and how Q7A addresses these issues
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Important Clarification!
Q7A does not apply to steps prior to the introduction of the defined API starting material!
Apply GMP controls beginning with the use of API starting materials
APIs
Potable water acceptable for preparation of USP drug substances Purified water often used in later isolation and purification steps
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Blend Uniformity
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Early steps
Increasing GMPs
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OOS
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APIs
Validate critical processing steps determined to impact the quality and purity of the API
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Definition Of Critical
A process step, process condition, test requirement, or any other relevant parameter or item that must be controlled within predetermined criteria to ensure that the API meets its specification.
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APIs
Clear distinction between activities
Reprocessing is atypical Reprocessing is typical Reprocessing rarely improves drug quality Reprocessing generally improves API quality
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Definition of Reprocessing
Introducing an intermediate or API, including one that does not conform to standards or specifications, back into the process and repeating a crystallization step or other appropriate chemical or physical manipulation steps that are part of the established manufacturing process
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Definition of Reworking
Subjecting an intermediate or API that does not conform to standards or specifications to one or more processing steps that are different from the established manufacturing process to obtain acceptable quality material
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Reworking
Intermediates and APIs Only non-conforming batches Subject batch to one or more steps different from established 50 process
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Q7A Summary
Pragmatic balance of What vs. How Clarifies GMP expectations Not intended to ratchet up GMPs Should provide enough guidance to address CGMP problems in API production
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