API

The ICH Q7A Guidance CGMP for Manufacture of
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
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?
International Conference on Harmonization

Of Technical Requirements for the Registration of Pharmaceuticals for Human Use
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Implementation Of Q7A
Posted on EMEA website in November 2000 Published as Annex 18 to the EU Guide to Good Manufacturing Practices in July 2001
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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Adopted by Australias Therapeutic Goods Administration (TGA) in April 2001 Adopted by Pharmaceutical Inspection Convention/Pharmaceutical Inspection Cooperation Scheme (PIC/S) in May 2001
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
FDAs Industry Guidance Disclaimer

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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Implementation of Q7A Worldwide

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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Implementation of Q7A Worldwide

Use of one guidance by both regulators and industry should facilitate inspections and enhance GMP compliance
Q7A
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Status Of Q7A With Respect To Other API Guidance

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
Q7A is the definitive CGMP guidance for APIs.
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FDAs Industry Guidance Disclaimer

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For Additional Information on ICH

http://www.ifpma.org/ich1.html
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What Is an Intermediate?
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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What Is an Active Pharmaceutical Ingredient?

The intended use clause:

Any substance or mixture of substances intended to be used in the manufacture of a drug (medicinal) product and that, when used in the production of a drug, becomes an active ingredient of the drug product.
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What Is an Active Pharmaceutical Ingredient?

The pharmacological activity clause:

Such substances are intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease or to affect the structure and function of the body.
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API or Drug Substance?

Ladies and gentlemen. For purposes of this guidance, the terms active pharmaceutical ingredient and drug substance are equivalent!
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How Does An API Differ from a Bulk Pharmaceutical Chemical?

A - Actives E - Excipients
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Regulatory Status of APIs Abroad

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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Regulatory Status of APIs in the United States

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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API GMP Guidance Initiatives Incorporated Into Q7A

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Availability of Q7A Guidance on the Internet

http://www.fda.gov/cder/guidance/4286fnl.pdf http://www.fda.gov/cber/gdlns/ichactive.pdf http://www.emea.eu.int/pdfs/human/ich/410600en.pdf http://www.ifpma.org/ich5q.html#gmp http://www.picscheme.org/docs/pdf/gmpapi.pdf http://www.nihs.go.jp/dig/ich/quality/q7a/Q7Astep4.pdf

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Importance of Q7A
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
Intended to facilitate API inspections Impacts any manufacturer that markets APIs in ICH regions Addresses uniqueness of API processes
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Process Characteristics API Vs. Drug Product

API API
Drug Drug Product Product
Basic Basic Chemicals Chemicals
API API
Different Raw Materials
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Process Characteristics API Vs. Drug Product

API API
Chemical & Biological Processing (synthesis, fermentation, extraction, purification)
Drug Drug Product Product

Physical Processing (granulating, dissolving, mixing, compressing)
Different Facilities, Equipment and Processes 29
Characteristics of API Processes

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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Characteristics of Drug Product Processes

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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Typical API Production Facility

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Typical API Production Equipment

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Typical API Production Equipment

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Contained and Non-Contained Charging of a Reactor

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Flow Diagram API Production Building

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Typical API Synthesis Process

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Typical Fermentation API Process

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Uniqueness of API Processes Also Account for Differences In

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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Uniqueness Of API Processes

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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When Inspecting or Auditing API Manufacturers

FDA inspectors will wear an API hat!
DOSAGE DEVICES APIs 41
Reaction to ICH Q7A

Q7A contains no surprises!
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Use of Q7A During API Inspections

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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Use of Q7A During API Inspections

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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Section 1.3 Scope

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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Section 1.3 Scope

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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Section 1.3 Scope

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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Section 1.3 Scope

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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Q7A Does Not Address

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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Section 1.1 Meaning Of Should

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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Q7A Is Well Thought Out

If Q7A says you should do something, you probably should do it
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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If it doesnt prohibit something, its probably OK to do it
Where Does API Process Begin?

Earth
Wind
Fire
Water
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How Are GMPs Applied In API Processes?

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
Encompasses all API operations

Receipt of materials Production Packaging and repacking Labeling and relabeling Quality control and release Storage and distribution
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Table 1 Application of Q7A

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Increasing GMP Expectations
Applying Q7A
Chemical Manufacturing
Outside scope Covered by Q7A
Production of API Starting Material
Introduction of API Starting Material
Production of Intermediates
Isolation & Purification
Physical Processing & Packaging

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Applying Q7A
Biotech: Fermentation/ Cell Culture

Establishment of Master and Working Cell Banks
Maintain Working Cell Bank
Cell Culture and/or Fermentation

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Applying Q7A
Classical Fermentation/
Establishment /Maintenance of Working Cell Banks
Introduction of Cells into Fermentation

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Designating Where API Production Begins

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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Definition API Starting Materials

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!
Q7A does not apply to steps prior to the introduction of the defined API starting material
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Designating API Starting Material in a Multi-step API Process

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
F inal Interm ediate
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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Why Initiate GMP Controls With Use of API Starting Materials?

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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Spectrum of CGMP Controls in API Manufacturing

Controls increase as process proceeds to final isolation and purification steps
Apply GMP controls beginning with the use of API starting materials
Degree of control depends on process and manufacturing stage
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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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For Additional Information

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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Processes Inspected by FDA During API Inspections Abroad

Chemical Synthesis Nonsterile 81% Crude Bulk NEC 7%
Fermentation Nonsterile 6% Chemical Synthesis Sterile 2% Biotech/Crude Drug 1%
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!
Why Initiate GMP Controls With Use of API Starting Materials?

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
Spectrum of CGMP Controls in API Manufacturing

Controls increase as process proceeds to final isolation and purification steps
Apply GMP controls beginning with the use of API starting materials
Degree of control depends on process and manufacturing stage

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USP Expectations Process Water Quality

Drug Products
Potable water not acceptable for preparation of USP dosage forms Purified Water generally used for non-sterile dosage production
APIs
Potable water acceptable for preparation of USP drug substances Purified water often used in later isolation and purification steps
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Section 4.3 Process Water Quality

Water used in the manufacture of APIs should be demonstrated to be suitable for its intended use Unless otherwise justified, water should at a minimum, meet WHO guidelines for drinking (potable) water

If tighter chemical and/or microbiological specifications are necessary, these should be established

Water used in final isolation and purification steps of a non-sterile API intended for producing a sterile drug product should be monitored and controlled for: Total microbial counts Objectionable organisms Endotoxins
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Section 8.4 Blending of Intermediates/APIs

APIs Drug products
Quality of material introduced into blend
Blend Uniformity
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Defined as the process of combining materials within the same specification to produce a homogeneous intermediate or API
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Does not include: In process mixing of fractions from single batches Combining fractions from several batches for further processing
13

OOS batches should not be blended with other batches Acceptable blending operations include: Blending batches to increase batch size Blending tailings from batches of the same intermediate/API to form a single batch 14
Sections 8.4 Blending of Intermediates/APIs

Each batch introduced into a blend should have been:
Manufactured using an established process Individually tested and found to meet appropriate specifications prior to blending
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Sections 8.4 Blending of Intermediates/APIs

Blended batch should be tested for conformance to established specifications, where appropriate
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Where physical attributes of the API are critical, blending operations should be validated to show homogeneity of the combined batch
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Should include testing of critical attributes that may be affected by the blending process, such as: Particle size distribution Bulk density Tap density
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If blending could adversely affect stability, stability testing of final blended batches should be performed Expiry or retest date of blended batch should be based on the manufacturing date of the oldest tailings or batch in the blend
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Section 8.1 Critical Operations

Critical weighing, measuring, or subdividing operations should be witnessed or subjected to an equivalent control Other critical activities should be witnessed or subjected to an equivalent control
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Section 8.1 Process Deviations

Any deviation should be documented and explained Critical deviations should be investigated
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Section 8.2 Time Limits

Should be met if specified in the master production instruction Deviations from time limits should be documented and evaluated
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Section 8.2 Time Limits

May be inappropriate when processing to a target value where completion of process steps are determined by inprocess sampling and testing Intermediates held for further processing should be stored under appropriate conditions to ensure suitability for use
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Section 8.3 In-Process Sampling & Controls

In-process controls and acceptance criteria should be defined based on information gained during developmental stage or from historical data
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Type/extent of testing and acceptance criteria depends on:
Nature of intermediate or API Reaction or process step Degree of variability introduced by process
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Less stringent in-process controls may be appropriate in early processing steps Tighter controls may be appropriate for later processing steps
A B C D E F API
Early steps
Increasing GMPs
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Critical in-process controls should be in writing and approved by the quality unit Qualified production personnel can perform in-process controls and adjust process without prior Q.C. approval if adjustments are made within preestablished limits approved by Q.C. unit
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Out of specification (OOS) investigations are not normally needed for in-process tests performed for the purpose of monitoring and/or adjusting the process
OOS
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Process Validation Dosage Forms Vs. APIs

Drug Products
Validate all manufacturing steps, such as cleaning, weighing, measuring, mixing, blending, filling, packaging and labeling
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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Section 12.1 Process Validation

Should extend to those operations determined to be critical to the quality and purity of the API Critical parameters/attributes are normally identified during the development stage or from historical data, along with ranges necessary for reproducible operations
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Examples of Process Parameters

Temperature Pressure Vacuum Time (Duration) Flow Rate Cooling Rate Agitation Speed
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Section 12.4 Prospective Validation

Normally performed for all API processes Validation of API process should be completed before commercial distribution of the final drug product manufactured from that API
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Section 12.4 Concurrent Validation

Conducted when data from replicate production runs are unavailable: Limited number of API batches produced API batches produced infrequently API batches produced by a validated process that has been modified 34
Section 12.4 Concurrent Validation

Batches can be released and used in production of drug products for commercial distribution based on thorough monitoring and testing of the API batches
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Section 12.4 Retrospective Validation

Exception for well established processes used without significant changes to API quality due to changes in:
Raw materials Equipment Systems Facilities Production process
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May be used where:
Critical quality attributes and critical process parameters have been identified Appropriate in-process acceptance criteria and controls have been established
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May be used where (Continued):
Process/product failures attributed mostly to operator error or sporadic equipment failures unrelated to equipment suitability Impurity profiles have been established for existing API
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Batches should be
Representative of all batches produced during the review period, including those that failed specifications Sufficient in number to demonstrate process consistency
Retained samples can be tested
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Section 12.6 Periodic Review-Validated Systems

Systems/processes should be periodically evaluated to verify that they are still operating in a valid manner No need for revalidation if significant changes have not been made and a quality review confirms system or process consistently produces acceptable material
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Section 19.6- Validation of APIs Used In Clinical Trials

Process validation normally inappropriate because of
Process changes during API development Production of a single or limited number of API batches
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Section 19.6 Validation of APIs Used In Clinical Trials

Process validation should be conducted in accordance with Section 12 when batches are produced for commercial use, even when such batches are produced on a pilot or small scale
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Section 11.2 Impurity Profiles

Describes the identified and unindentified impurities present in an API a typical batch produced by a specific controlled production process
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Should include: Identity or some qualitative analytical designation Range of each impurity observed Classification of each identified impurity (e.g., inorganic, organic, solvent) 44

Impurity profile should normally be established for each API except those derived from: Herbal origin Animal tissue origin Biotechnology
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The impurity profile should be compared at appropriate intervals against the impurity profile in the regulatory submission or compared against historical data in order to detect changes to the API resulting from modifications in raw materials, equipment operating parameters, or the production process
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Reprocessing And Reworking

Dosage Forms
Vague distinction between activities
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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Reprocessing Vs. Reworking

Reprocessing
Intermediates and APIs Conforming or nonconforming batches Subject batch to one or more steps that are part of established process
Reworking
Intermediates and APIs Only non-conforming batches Subject batch to one or more steps different from established 50 process
Section 14.2 Reprocessing

Reprocessing of intermediates and APIs is generally acceptable If reprocessing is used for a majority of batches, it should be included as part of the standard manufacturing process
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Section 14.2 Reprocessing

Continuation of a process step after an in-process control test shows it is incomplete is considered part of the normal process, not reprocessing
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Sections 14.3 Reworking

Reason for non-conformance should be investigated before reworking batches Reworked batches should be subjected to appropriate evaluation, testing, stability testing, if warranted, and documentation to show that the reworked batches are of equivalent quality to that produced by the original process
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Impurity profile of each reworked batch should be compared against batches manufactured by the established process Additional analytical methods may be needed if routine methods are inadequate to characterize reworked batches
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Concurrent validation is appropriate Protocol should define
Rework procedure How performed and expected results
Interim results if only one batch
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Section 14.4 Recovery Of Materials/Solvents

Recovery of solvents, reactants, intermediates or the API from mother liquor or filtrate is acceptable provided
Approved procedures exist for recovery Recovered materials meet specifications and are suitable for their intended use
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Definition Of Mother Liquor

The residual liquid that remains after crystallization or isolation processes that may contain:
Unreacted materials Intermediates Levels of the API and/or impurities
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Solvents can be recovered and reused in the same processes or different processes provided recovery procedures are controlled and monitored Ensure solvents meet appropriate standards before reuse or co-mingling
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Fresh and recovered solvents can be combined if adequate testing shows suitability for use in manufacturing Use should be adequately documented
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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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For Additional Information

Nicholas Buhay Acting Director Division of Manufacturing and Product Quality Office of Compliance Center for Drug Evaluation and Research 11919 Rockville Pike Room 439 Rockville, MD 20852 Voice Tele: E-mail: (301) 827-8940 Nicholas.Buhay@fda.hhs.gov
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The ICH Q7A Guidance CGMP for Manufacture of

International Conference on Harmonization

FDAs Industry Guidance Disclaimer

Implementation of Q7A Worldwide

Implementation of Q7A Worldwide

Status Of Q7A With Respect To Other API Guidance

Q7A is the definitive CGMP guidance for APIs.

FDAs Industry Guidance Disclaimer

For Additional Information on ICH

What Is an Active Pharmaceutical Ingredient?

The intended use clause:

What Is an Active Pharmaceutical Ingredient?

The pharmacological activity clause:

API or Drug Substance?

How Does An API Differ from a Bulk Pharmaceutical Chemical?

Regulatory Status of APIs Abroad

Regulatory Status of APIs in the United States

Regulatory Status of APIs in the United States

Regulatory Status of APIs in the United States

API GMP Guidance Initiatives Incorporated Into Q7A

Availability of Q7A Guidance on the Internet

http://www.fda.gov/cder/guidance/4286fnl.pdf http://www.fda.gov/cber/gdlns/ichactive.pdf http://www.emea.eu.int/pdfs/human/ich/410600en.pdf http://www.ifpma.org/ich5q.html#gmp http://www.picscheme.org/docs/pdf/gmpapi.pdf http://www.nihs.go.jp/dig/ich/quality/q7a/Q7Astep4.pdf

Process Characteristics API Vs. Drug Product

Drug Drug Product Product

Basic Basic Chemicals Chemicals

Different Raw Materials

Process Characteristics API Vs. Drug Product

Drug Drug Product Product

Different Facilities, Equipment and Processes 29

Characteristics of API Processes

Characteristics of Drug Product Processes

Typical API Production Facility

Typical API Production Equipment

Typical API Production Equipment

Contained and Non-Contained Charging of a Reactor

Flow Diagram API Production Building

Typical API Synthesis Process

Typical Fermentation API Process

Uniqueness of API Processes Also Account for Differences In

Uniqueness Of API Processes

When Inspecting or Auditing API Manufacturers

FDA inspectors will wear an API hat!

DOSAGE DEVICES APIs 41

Reaction to ICH Q7A

Q7A contains no surprises!

Use of Q7A During API Inspections

Use of Q7A During API Inspections

Section 1.3 Scope

Section 1.3 Scope

Section 1.3 Scope

Section 1.3 Scope

Q7A Does Not Address

Section 1.1 Meaning Of Should

Q7A Is Well Thought Out

If Q7A says you should do something, you probably should do it

If it doesnt prohibit something, its probably OK to do it

Where Does API Process Begin?

How Are GMPs Applied In API Processes?

Encompasses all API operations

Table 1 Application of Q7A

Increasing GMP Expectations

Production of API Starting Material

Introduction of API Starting Material

Isolation & Purification