ICH Q7A and Its Use During Inspections Without Notes

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Office of Regional Operations

Center For Drug Evaluation and Research

U.S. Food and Drug Administration

Rockville, MD

ICH Q7A GMP Guidance for APIs

and its Use During Inspections

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Processes Covered During API Inspections Abroad - FY 2001

Chemical Synthesis Sterile

2%

Fermentation Nonsterile

6%

Crude Bulk NEC7%

Others3%

Biotech/Crude Drug1%

Chemical Synthesis Nonsterile

81%

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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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Agenda

• What is ICH?• Availability of Q7A on the Internet • What is an intermediate and API?• Regulatory status of APIs abroad and in US • Guidance initiatives incorporated into Q7A• Importance of Q7A• Process characteristics – APIs Vs. Drug

Products

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Agenda

• Implementation of Q7A • Status of Q7A and other GMP documents• Use of Q7A during inspections• Scope and meaning of “should”• Applying Q7A • API Starting Materials• CGMP controls in API processes

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Agenda

• Process water quality

• Blending of intermediates/APIs

• In-process controls/process validation

• Impurity profiles

• Reprocessing and reworking

• Recovery of materials/solvents

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Questions on ICH Q7A?

Please call or FAX Questions to:

Phone: 1-800-218-4880

FAX: 1-866-806-6087

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What Is ICH?

International

Conference on

HarmonizationOf Technical Requirements for the Of Technical Requirements for the Registration of Pharmaceuticals Registration of Pharmaceuticals

for Human Usefor Human Use

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What Is ICH?

• Established in 1990 between the European Union, Japan, and United States

• Committed to reducing duplication during research and development of new drugs while safeguarding quality, safety and efficacy

• Developed over 40 guidance documents mostly addressing technical/regulatory requirements for registering new human drug products

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ICH Members

• Regulatory agenciesEMEA - European UnionMHLW - JapanFDA - US

• Trade associationsEFPIA - EuropeJPMA - JapanPhRMA - US

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ICH Technical Topics

Quality (chemical and pharmaceutical QA)Q1, Stability Testing

Safety (in vitro and in-vivo pre-clinical studies)S1, Carcinogenicity Testing

Efficacy (clinical studies in human subject)E6, Good Clinical Practices

Multidisciplinary (cross-cutting topics)M1, Medical Terminology

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Q1: Stability

Q1A(R): Stability Testing of New Drugs and Products (Revised)

Q1B: Photostability Testing Q1C: Stability Testing for New Dosage Forms

Q1D: Bracketing and Matrixing Designs for Stability Testing of Drug Substances and Drug Products

Q2: Analytical Validation

Q2A: Text on Validation of Analytical Procedures

Q2B: Methodology

Q3: Impurities Q3A(R): Impurities in New Drug Substances (Revised)

Q3B(R): Impurities in New Drug Products (Revised)

Q3C: Impurities: Residual Solvents

Q4: Pharmacopoeias Q4: Pharmacopoeial Harmonisation

Q5: Biotechnological Quality

Q5A: Viral Safety EvaluationQ5B: Genetic Stability Q5C: Stability of Products

Q5D: Cell Substrates

Q6: SpecificationsQ6A: Chemical Substances with its Decision Trees

Q6B: Biotechnological Substances

Q7: GMP

Q7A: GMP for Active Pharmaceutical Ingredients

ICH Quality Topics Checklist

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The ICH Process For Harmonization Of Guidance

Step 1: Building of scientific consensus in joint regulatory/industry expert working groups. Draft then forwarded to ICH Steering Committee.

Step 2: Agreement by the Steering Committee to release the draft consensus text for wider consultation.

Step 3: Regulatory consultation in the three ICH regions. Consolidation of public comments.

Step 4: Final draft discussed by Steering Committee & “signed off” by three regulatory parties. Adoption recommended.

Step 5: Guidance incorporated into regulations or other appropriate mechanisms and implemented in ICH regions.

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For Additional Information On ICH

http://www.ifpma.org/ich1.html

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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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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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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

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“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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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

26Different Raw MaterialsDifferent Raw Materials

APIAPIAPIAPI DrugDrugProductProductDrugDrug

ProductProduct

BasicBasicChemicalsChemicals

BasicBasicChemicalsChemicals APIAPIAPIAPI

Process Characteristics API Vs. Drug Product

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APIAPIAPIAPIDrugDrug

ProductProductDrugDrug

ProductProduct

Chemical & Biological Chemical & Biological ProcessingProcessing

(synthesis, fermentation, (synthesis, fermentation, extraction, purification)extraction, purification)

Physical ProcessingPhysical Processing(granulating, dissolving, (granulating, dissolving,

mixing, compressing)mixing, compressing)

Different Facilities, Equipment and Processes Different Facilities, Equipment and Processes

Process Characteristics API Vs. Drug Product

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Characteristics ofAPI 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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Process water quality Blending of intermediates and APIs In process controls Process validation Reprocessing/Reworks Recovery of materials and solvents

Uniqueness of API Processes Also Account for Differences In

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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 AuditingAPI Manufacturers

Please wear your

API hat!

APIs

DOSAGE

DEVICES

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Implementation Of Q7A

• Posted on European Agency for the Evaluation of Medicinal Product’s (EMEA’s) website in November 2000

• Published as Annex 18 to the European Union’s (EU’s) Guide to Good Manufacturing Practices in July 2001

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• Notice of Availability (NOA) published in Federal Register (Volume 66, No. 186) on September 25, 2001

• Adopted by Japan’s Ministry of Health, Labour and Welfare (MHLW) on November 2, 2001

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• Adopted by Australia’s Therapeutic Goods Administration (TGA) in April 2001

• Adopted by Pharmaceutical Inspection Convention/Pharmaceutical Inspection Cooperation Scheme (PIC/S) in May 2001

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• 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

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Q7A Industry Guidance Disclaimer

“This guidance represents the Food and Drug Administration’s (FDA’s) current thinking on this topic. It does not create or confer any rights for or on any person and does not operate to bind FDA or the public. An alternative approach may be used if such approach satisfies the requirements of the applicable statutes and regulations.”

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FDA’s Implementation of Q7A

• CDER is revising CP 7356.002F, but no significant changes are planned in inspectional or regulatory approach

• Use of one guidance by both regulators and industry should facilitate inspections and enhance GMP compliance

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FDA’s Implementation of Q7A

• FDA’s March 1998 Draft Guidance for Industry - Manufacturing, Processing, or Holding Active Pharmaceutical Ingredients will not be finalized

• Q7A supercedes FDA’s draft API guidance

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Status Of Q7A With Respect To Other Documents

21 CFR 211 does not apply to manufacture of APIs

PhRMA Guidelines for Production, Packing,

Repacking or Holding of Drug Substances is

insufficient

FDA’s Guide to Inspection of BPCs

is obsolete

FDA’s Draft Guidance for Industry: Manufacturing, Processing or Holding APIs will not be finalized

Q7A is Q7A is thethe definitive definitive

GMP GMP guidance guidance for APIs!for APIs!

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Use of Q7A During API Inspections

• Refer to the Q7A guidance during inspections to evaluate firm’s compliance with GMP expectations

• If alternative methods or procedures are in place, review firm’s justification and determine if such alternatives are scientifically sound and accomplish the intended purposes

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Use of Q7A During API Inspections

• Paraphrase the language in the guidance when preparing inspectional observations

• Don’t reference sections of Q7A in FDA 483 observations or EIR

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Section 1.3Scope

• 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 1.3Scope

• 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 1.3Scope

• 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 1.3Scope

• 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

• Registration and filing requirements for APIs

• Pharmacopoeial requirements

• APIs for use in veterinary drug products

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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.

Section 1.1Meaning Of “Should”

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Section 1.1Meaning Of “Should”

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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Table 1 Applying Q7A

Increasing GMP Expectations

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Applying Q7A

Chemical Manufacturing

Production of

API Starting

Material

Introduction of

API Starting

Material

Production

of

Intermediates

Isolation

&

Purification

Physical

Processing &

Packaging

Outside scope

Covered by Q7A

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Applying Q7A

Classical Fermentation/

Establishment /Maintenance of Working Cell Banks

Introduction of

Cells into

Fermentation

Isolation

&

Purification

Physical

Processing &

Packaging

Outside scope

Covered by Q7A

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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.”

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Designating Where API Production Begins

“From this point on, appropriate GMP, as defined in the guidance, should be applied to these intermediate and/or API manufacturing steps.”

C D E FI APIA B C D E FI API

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DefinitionAPI Starting Materials

• Material used in production of an API that 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

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DefinitionAPI Starting Materials

• 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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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

Apply GMP controls beginning with the use of API starting materials

Controls increase as process proceeds to final isolation

and purification steps

Degree of control depends on process and manufacturing

stage

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USP ExpectationsProcess 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 4.3Process 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

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

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• 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 8.4Blending of Intermediates/APIs

Blend UniformityQuality of material introduced into blend

APIs Drug products

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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

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• 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

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Sections 8.4Blending 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 8.4Blending 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 8.1Critical 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 8.1Process Deviations

• Any deviation should be documented and explained

• Critical deviations should be investigated

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Section 8.2Time 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 8.2Time Limits

• May be inappropriate when processing to a target value where completion of process steps are determined by in-process sampling and testing

• Intermediates held for further processing should be stored under appropriate conditions to ensure suitability for use

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Section 8.3In-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

Early steps

A B C D E F APID E F API

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 pre-established limits approved by Q.C. unit

81


OOS

Out of specification (OOS) investigations are not normally needed for in-process tests performed for the purpose of monitoring and/or adjusting the process

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Process ValidationDosage Forms Vs. APIs

Validate all manufacturing steps, such as cleaning, weighing, measuring, mixing, blending, filling, packaging and labeling

Validate critical processing steps determined to impact the quality and purity of the API

Drug Products APIs

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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 12.1Validation

• 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 ofProcess Parameters

• Temperature

• Pressure

• Vacuum

• Time (Duration)

• Flow Rate

• Cooling Rate

• Agitation Speed

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Section 12.4Prospective 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 12.4Concurrent 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

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Section 12.4Concurrent 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 12.4Retrospective 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

91


• 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 12.6Periodic 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

96

Section 11.2Impurity Profiles

• Describes the identified and unindentified impurities present in an API a typical batch produced by a specific controlled production process

97


• Should include:

– Identity or some qualitative analytical designation

– Range of each impurity observed

– Classification of each identified impurity (e.g., inorganic, organic, solvent)

98


• 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

100

Reprocessing And Reworking

Dosage Forms

Vague distinction between activities

Reprocessing is atypical

Reprocessing rarely improves drug quality

APIs

Clear distinction between activities

Reprocessing is typical

Reprocessing generally improves API quality

101

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

102

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

103

Reprocessing Vs. Reworking

Reprocessing

Intermediates and APIs

Conforming or non-conforming 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 process

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Section 14.2Reprocessing

• 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

105

Section 14.2Reprocessing

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

106

Sections 14.3Reworking

• 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

107


• 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

108


• Concurrent validation is appropriate

• Protocol should define

– Rework procedure

– How performed and expected results

• Interim results if only one batch

109

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

110

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

111


• 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

112


• Fresh and recovered solvents can be combined if adequate testing shows suitability for use in manufacturing

• Use should be adequately documented

113

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

ICH Q7A and Its Use During Inspections Without Notes

Documents

q7a api

ich q7a gmp guidance

ich http

ich process

drug evaluation

availability of q7a

biotechcrude drug

issuance of q7a