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.
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."
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.
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.
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)
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
Managing Microbiological Out of Specification (OOS) and Out of Trend (OOT) Results in Sterile and Non-Sterile Production FDA & ICH Expectations and Guidance
The objective of this interactive, live training webinar is to explore the management of OOS practices and suggested avenues to take to minimize deviations, OOT, OOS and CAPA and how to attack these situations should they occur. It is also designed to determine how FDA and ICH regulations and guidances may impact them. It will also reference the new PDA TR 88, “Microbial Data Deviation Investigations in the Pharmaceutical Industry”.
Sterile Filtration of Pharmaceutical Products - Validation and Regulatory Requirements
It is important that the sterile filtration process is fully understood and properly validated for your particular application. The process requirements and validation needs differ based on the filtration requirement. This webinar will offer attendees a comprehensive understanding of the same while emphasizing the different types of sterilizing filtration available and their application to your particular system. For instance, the application of sterile filtration to use-point compressed air will be discussed in detail.
HVAC and GMP Environmental Control - for Pharmaceutical Cleanrooms
Environmental control of pharmaceutical cleanrooms is essential to the manufacture of a quality product. Control of such conditions as airborne particulate, microorganisms, temperature, humidity, differential pressure, airflow, air velocity and personnel is crucial to protect the product from contamination. Therefore, the design, validation and ongoing monitoring of a cleanroom HVAC system are necessary to assure the quality and safety of the pharmaceutical product. This training program will offer attendees a proper understanding of the cleanroom environment and its testing requirements according to international regulatory standards from a compliance perspective.
ICH Q7A GMPs for Active Pharmaceutical Ingredients Training Course
This live, interactive training webinar will examine a variety of the issues surrounding raw materials to include what materials should be tested and to what extent during Phase 1, 2 and 3. It will cover testing requirements as part of “Laboratory Controls” during each Phase and what laboratory testing may be optional until the ingredient moves to its next Phase.
The Unthinkable: Violence in Healthcare from Bullying to an Active Shooter
The healthcare environment creates a major challenge in the prevention and intervention of violence. The rate of injuries and illness from violence in the healthcare industry is more than three times greater than violence in all private industry. This training program will explore what makes violence in healthcare unique and its negative ramifications on quality patient care.
Auditing API Facilities: A MUST to properly prepare for an FDA Regulatory API GMP Inspection
In this FDA inspection webinar attendees will learn the basic understanding of Active Pharmaceutical Ingredient Good Manufacturing Practices (ICH Q7) and the most important elements of API GMP to avoid serious deviations and failures during either a Pre-Approval or GMP Inspection.
Data Integrity in the Pharmaceutical Laboratory: Practical Steps to Identify and Avoid Data Integrity Issues
This webinar will discuss in detail the fundamentals of data integrity including the FDA guidance document. It will teach attendees practical steps to identify and avoid data integrity issues in pharmaceutical laboratory.
Establishing a Reduced Testing Program for Pharmaceutical & Medical Device Components
This training will help you understand FDA expectations for reduced testing of Pharmaceutical & Medical Device components and will develop your confidence in maintaining control of supplier quality.
Pharmaceutical Compressed Air - Quality GMP Standards and Requirements
This webinar will take you through the primary sources of compressed air contamination. It will also detail GMP standards and requirements pertaining to compressed air quality.
Good Manufacturing Practices for Active Pharmaceutical Ingredients (APIs)
This webinar will cover ICH Q7, Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients (API). Attendees will gain a deeper understanding of the importance of GMPs for APIs, apply these principles in their current roles in order to better manage quality, make improvements, solve problems and make decisions.
Sterilization of Pharmaceutical Products and Medical Devices
This webinar will discuss in detail the methods of sterilization to be used on medical devices and pharmaceutical products including advantages and disadvantages of each method. Also attendees will understand the regulations pertaining to sterilization of products that will help to decide with method to use for their product. Validation of each sterilization method will be discussed and how best to prove to a regulatory body the products being treated are considered sterile.
Perceptions of The Health Risks of Cosmetics, and What it means to Their Regulation
This webinar will discuss some of the major issues in the regulation of cosmetics. Upon completion of the session attendees will learn how regulators regulate cosmetics compared to other categories, fine line between cosmetics and drugs, and future directions for cosmetic regulations.
Being Prepared for an Active Shooter Incident at Workplace
This training program will take attendees through the actions to take when confronted with an active shooter and in assisting responding law enforcement officials. It will help recognize potential workplace violence indicators and describe actions to take to prevent and explore the General Duty Clause of the OSH Act.
ICH Q10 - Moving From GMPs To A Pharmaceutical Quality System
This ICH Q10 training /webinar will discuss the evolution and interpretation of the pharmaceutical GMPs as a quality control regulation to the Quality Assurance emphasis of the Pharmaceutical Quality System as defined in ICH Q10.
Understanding the Current FDA Requirements for Raw Materials and Components
This webinar will cover the current FDA requirement for raw materials used in producing APIs and drug products. Attendees will learn how to ensure that raw materials are of acceptable identity, quality and purity before use. This webinar will also provide best practices for avoiding FDA warning letters and 483 observations.
Technology Transfer of a Pharmaceutical Manufacturing Process
This expert instruction on technology transfer of a pharmaceutical manufacturing process will highlight with real world examples hidden traps in technology transfer not covered under its requirements. This webinar will help attendees ensure the success of tech transfer under any circumstance regardless of fields, countries, cultures, and applications.
Pharmaceutical Government Price Reporting: Impact of Obamacare
This webinar on drug price reporting will discuss the changes to the Medicaid Drug Program and its impact on pharmaceutical and biotech companies.
Delivering Biopharmaceutical Facilities in a Risk Based World: The Role of GEP, QbD, and E2500
This Biopharmaceutical training will introduce and link the concepts of GEP and QbD and also identify synergies with the new ASTM E2500 standard Biopharmaceutical Active Pharmaceutical Ingredients (APIs) must be produced according to Good Manufacturing Practices outlined in FDA and ICH guidelines in order to be marketed to the public. This webinar will review the areas that an inspector may examine when conducting an audit of a biopharmaceutical API supplier to ensure it complies with regulatory requirements.
Auditing an Active Pharmaceutical Ingredient (API) Contract Manufacturing Organization (CMO)
This webinar will discuss in detail key auditing elements of an Active Pharmaceutical Ingredient (API) facility/operation. It will cover selection, designation and documentation of starting materials; qualification of analytical methods; control requirements for multi-product/multi-processing API production facility; QA review and release of API and much more.
