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Understanding GMP Regulations and Compliance for API and Excipients with Examples of Deviations


A detailed understanding of the Good Manufacturing Practices for Active Pharmaceutical Ingredients and excipients is important to drug manufactures. As most APIs and Excipients are intended for use by patients, manufacturers, distributors, and the entire supply chain are required to maintain certain high standards set forth by the regulatory authorities.

This article provides some of the related deficiencies found during inspections of manufacturing facilities. These examples will help you avoid common pitfalls with respect to APIs and Excipients. At the end of this article, you will find links to relevant regulatory documents categorized by APIs and Excipients.

    Definitions

    APIs

    An active pharmaceutical ingredient is defined in ICH Q7 as "any substance or mixture of substances intended to be used in the manufacture of a drug product and that, when used in the production of a drug, becomes an active ingredient in the drug product. 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."

    Excipients

    The U.S FDA has not provided a formal regulatory definition of the term "Excipient". Nevertheless, the nonclinical safety studies for excipients provides some background:

    'In this guidance, the phrase new excipients means any inactive ingredients that are intentionally added to therapeutic and diagnostic products, but that: (1) we believe are not intended to exert therapeutic effects at the intended dosage, although they may act to improve product delivery (e.g., enhance absorption or control release of the drug substance); and (2) are not fully qualified by existing safety data with respect to the currently proposed level of exposure, duration of exposure, or route of administration. Examples of excipients include fillers, extenders, diluents, wetting agents, solvents, emulsifiers, preservatives, flavors, absorption enhancers, sustained release matrices, and coloring agents.

    Examples of deviations from FDA warning letters

    • Failure to thoroughly investigate any unexplained discrepancy or failure of a batch or any of its components to meet any of its specifications, whether or not the batch has already been distributed (21 CFR 211.192).
    • Failure to establish adequate written procedures for production and process control designed to assure that the drug products you manufacture have the identity, strength, quality, and purity they purport or are represented to possess (21 CFR 211.100(a)).
    • Failure to clean, maintain, and, as appropriate for the nature of the drug, sanitize and/or sterilize equipment and utensils at appropriate intervals to prevent malfunctions or contamination that would alter the safety, identity, strength, quality, or purity of the drug product beyond the official or other established requirements (21 CFR 211.67(a)).
    • Failure to ensure that water used in the (b)(4) manufacturing steps of a non-sterile API intended for a sterile drug product is monitored and controlled for total microbial counts, objectionable organisms, and endotoxins.
    • Failure to ensure that equipment surfaces in contact with API do not alter the quality of the API beyond the official or other established specifications
    • Failure to transfer all quality or regulatory information received from the API manufacturer to customers.
    • Failure to have the procedures and processes necessary to ensure the API manufactured at the facility meet established specifications for quality and purity.
    • Failure to establish and follow adequate written procedures for cleaning equipment and its release for use in the manufacture of API.
    • Failure to demonstrate that the water used in the manufacture of your API is suitable for its intended use.
    • Failure to ensure the identity of components, including active ingredients and excipients from various suppliers (21 CFR 211.84(d)(1) and (2)).
    • Failure to use equipment in the manufacture, processing, packing, or holding of drug products that is of appropriate design, adequate size, and suitably located to facilitate operations for its intended use and for its cleaning and maintenance (21 CFR 211.63).
    • Failure to provide equipment for adequate control over air pressure, micro-organisms, dust, humidity, and temperature when appropriate for the manufacture, processing, packing, or holding of a drug product (21 CFR 211.46(b)).

    GMP Regulations for APIs with names of related documents

    EU GMP Basic requirements for active substances used as starting materials - EU GMP for APIs provides GMP guidance for the manufacture of active substances under an appropriate system for managing quality.

    'The ICH guidance Q7 Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients is intended to provide guidance regarding good manufacturing practice (GMP) for the manufacturing of active pharmaceutical ingredients (APIs) under an appropriate system for managing quality.' - FDA Guidance for Industry: Q7 Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients - Questions and Answers.

    • According to the Compliance Program Guidance Manual for Active Pharmaceutical Ingredients 7356.002F the FDA considers the requirements in 21 CFR 210 and 211 as applicable to API manufacturing.
    • The same document states that ICH Q7 represents the Food and Drug Administration's (FDA's) current thinking on CGMPs for API's.

    FDA expects API manufacturers to apply current Good manufacturing Practice (CGMPs) to the API process. This Guidance Manual contains specific FDA requirements.

    PIC/S Procedure for Handling Rapid Alerts and Recalls Arising from Quality Defects (PI 010-5) July 2017

    FDA Program 7356.002F Active Pharmaceutical Ingredients (APIs)

    APIC - Good manufacturing practices for Active ingredient manufacturers, with EFPIA, 1996

    APIC - Quality Management System for Active pharmaceutical Ingredient manufacturers - Integrating GMP into ISO 9001, December 1997

    APIC - Manufacture of sterile active pharmaceutical ingredients - guidance 1999

    APIC - Guidance on Aspects of Cleaning Validation in Active pharmaceutical Ingredient manufacturing plants - Policy, 1999

    APIC - Good Manufacturing Practices in Active Pharmaceutical Ingredients Development, 1999

    APIC - Guidance on aspects of cleaning validation in active pharmaceutical ingredient plants, guidance 2000

    APIC - Computer validation Guide, December 2002

    ICH E2A CLINICAL SAFETY DATA MANAGEMENT: DEFINITIONS AND STANDARDS FOR EXPEDITED REPORTING

    APIC - GUIDANCE ON ASPECTS OF CLEANING VALIDATION IN ACTIVE PHARMACEUTICAL INGREDIENT PLANTS

    Auditing Guide - Annex 1 - Pre-Audit Questionnaire

    Auditing Guide - Annex 3 - Audit Report Template

    ICH Q11 Guideline: Development and Manufacture of Drug Substances (Chemical Entities and Biotechnological/Biological Entities) Questions and Answers

    APIC - Statement on Good distribution practices

    APIC - Quality Agreement for Laboratories; Guideline and Templates

    API-Mix (or mixtures) and CEPs

    APIC - Guideline for the Establishment of a Control Procedure for Technical Equipment, including related Utilities, Computerised Systems and Facilities used in the Manufacture of APIs and Intermediates (revised Nov.2018)

    APIC - GMPs for APIs: "How to do" Document - Interpretation of the ICH Q7 Guide Version 11

    WHO Supplementary guidelines on Good Manufacturing Practices: Validation

    WHO Good Distribution Practice for pharmaceutical products

    WHO Propasal to waive in vivo bioequivalence requirements for WHO Model List of Essential Medicines immediate release, solid oral dosage forms

    PIC/S Guide to Good Manufacturing Practice for Medicinal Products (PE 009-14) Part II

    APIC Qualification of existing equipment

    APIC - Guide for auditing Registered Starting Material manufacturers

    Eudralex Volume 2C Guidance on elements required to support the significant benefit in comparison with existing therapies of a new therapeutic indication in order to benefit from an extended (11 years) marketing protection period (November 2007)

    Eudralex Volume 3 NOTE FOR GUIDANCE ON Quality of Biotechnological Products: Viral Safety Evaluation of Biotechnology Products Derived from Cell Lines of Human or Animal Origin

    Eudralex Volume 3 Reflection paper on the pharmaceutical development of intravenous medicinal products containing active substances solubilised in micellar systems (non-polymeric surfactants)

    Annex 1 - Contract between Auditor and the API Compliance Institute

    Annex 2 - Agreement on Audit Execution

    Annex 3 - Secrecy Agreement

    Standardised Letters related to Shared 3rd Party Audits: Letter 2 - Letter to the API Manufacturer

    Standardised Letters related to Shared 3rd Party Audits: Letter 3 - Letter from the API Manufacturer to the customer

    APIC - Quality Management System (QMS) for Active Pharmaceutical Ingredients (API) Manufacturers - Integrating GMP (ICH Q7a) into ISO (9001:2000), September 2005

    FDA Guidance for Industry: Process Validation: General Principles and Practices

    Eudralex Volume 3 Note for Guidance on Quality of Water for Pharmaceutical Use

    APIC - Quick Guide for API Sourcing, 2008

    PIC/S Aide Memoire on INSPECTION OF ACTIVE PHARMACEUTICAL INGREDIENTS (PI 030-1)

    FDA Guidance for Industry: Q4B Evaluation and Recommendation of Pharmacopoeial Texts for Use in the ICH Regions Annex 11: Capillary Electrophoresis General Chapter

    Eudralex Volume 3 ICH Q4B Annex 11: Evaluation and Recommendation of Pharmacopoeial Texts for Use in the ICH Regions on Capillary Electrophoresis General Chapter

    ICH Q4B Annex 11: Evaluation and Recommendation of Pharmacopoeial Texts for Use in the ICH Regions on Capillary Electrophoresis General Chapter

    APIC - Quality Agreement Guideline & Template

    Quality Agreement Template for Generic APIs

    Eudralex Volume 10 Annex 1 revised: Clinical Trial Application Form

    EU GMP Basic requirements for active substances used as starting materials - EU GMP for APIs

    WHO Pharmaceutical products containing hazardous substances

    Auditing Guide - Annex 1 - Pre-Audit Questionnaire

    Auditing Guide - Annex 3 - Audit Report Template

    APIC - Supplier Qualification and Management Guideline

    WHO Technical supplements to Model guidance for the storage and transport of time and temperature sensitive pharmaceutical products

    PIC/S Questions & Answers DISTRIBUTION ACTIVITIES FOR APIs (PS INF 20 2011)

    WHO Guidelines on transfer of technology in pharmaceutical manufacturing

    FDA Guidance for Industry: Non-Penicillin Beta-Lactam Drugs: A CGMP Framework for Preventing Cross-Contamination

    Template for the 'written confirmation' for active substances exported to the European Union for medicinal products for human use

    FDA Guidance for Industry: Heparin for Drug and Medical Device Use: Monitoring Crude Heparin for Quality

    EU/51/2013 Decision on the assessment of a third country's regulatory framework applicable to active substances of medicinal products for human use and of the respective control and enforcement activities

    FDA Guidance for Industry: Completeness Assessment for Type II API DMFs unter GDUFA

    APIC - Guideline for Qualification & Management of Contract Quality Control Laboratories

    Guidelines On The Principles Of Good Distribution Practices of Active Substances For Medicinal Products For Human Use

    APIC - Guidance on Handling of Insoluble Matter and Foreign Particles in APIs

    2012/715/EU Commission implementing decision of 22 November 2012 establishing a list of third countries with a regulatory framework applicable to active substances for medicinal products for human use and the respective control and enforcement activities

    2013/196/EU Commission Implementing Decision of 24 April 2013 amending Implementing Decision 2012/715/EU establishing a list of third countries with a regulatory framework applicable to active substances for medicinal products for human use and the respec

    2013/262/EU Commission Implementing Decision of 24 April 2013 amending Implementing Decision 2012/715/EU establishing a list of third countries with a regulatory framework applicable to active substances for medicinal products for human use and the respec

    2013/301/EU Commission Implementing Decision of 24 April 2013 amending Implementing Decision 2012/715/EU establishing a list of third countries with a regulatory framework applicable to active substances for medicinal products for human use and the respec

    2015/1057/EU Commission Implementing Decision of 24 April 2013 amending Implementing Decision 2012/715/EU establishing a list of third countries with a regulatory framework applicable to active substances for medicinal products for human use and the respe

    APIC - eCTD How to do Document

    APIC - GDP for APIs: "How to do" Document

    FDA Guidance for Industry: Completeness Assessments for Type II API DMFs under GDUFA

    Eudralex Volume 3 Quality Working Party questions and answers on API mix

    ICH E2A CLINICAL SAFETY DATA MANAGEMENT: DEFINITIONS AND STANDARDS FOR EXPEDITED REPORTING

    APIC - GUIDANCE ON ASPECTS OF CLEANING VALIDATION IN ACTIVE PHARMACEUTICAL INGREDIENT PLANTS

    Auditing Guide - Annex 1 - Pre-Audit Questionnaire

    Auditing Guide - Annex 3 - Audit Report Template

    ICH Q11 Guideline: Development and Manufacture of Drug Substances (Chemical Entities and Biotechnological/Biological Entities) Questions and Answers

    APIC - Statement on Good distribution practices

    APIC - Quality Agreement for Laboratories; Guideline and Templates

    API-Mix (or mixtures) and CEPs

    APIC - Guideline for the Establishment of a Control Procedure for Technical Equipment, including related Utilities, Computerised Systems and Facilities used in the Manufacture of APIs and Intermediates (revised Nov.2018)

    APIC - GMPs for APIs: "How to do" Document - Interpretation of the ICH Q7 Guide Version 11

    GMP Regulations for Excipients with names of related documents

    The IPEC Excipient Information Package (EIP): Template & User guide 2012

    The IPEC Risk Assessment Guide for Pharmaceutical Excipients Part 1 - Risk Assessment for Excipient Manufacturers 2017

    The IPEC Good Distribution Practices Guideline

    The Joint IPEC-PQG Good Manufacturing Practices Guideline

    The IPEC Europe Co-processed Excipient Guide for Pharmaceutical Excipients 2017

    PIC/S GUIDELINES ON THE FORMALISED RISK ASSESSMENT FOR ASCERTAINING THE APPROPRIATE GOOD MANUFACTURING PRACTICE FOR EXCIPIENTS OF MEDICINAL PRODUCTS FOR HUMAN USE

    The IPEC Technically Unavoidable Particle Profile (TUPP) Guide 2015

    The IPEC Europe 'How-To' Document on EU Guidelines on Risk Assessment for Excipients 2015

    Eudralex Volumen 2C Guideline on Excipients in the labelling and package leaflet of medicinal products for human use (March 2018)

    Annex to the European Commission guideline on 'Excipients in the labelling and package leaflet of medicinal products for human use' (SANTE-2017-11668)