Quality of Medicines: Questions and Answers – Part 1

EMA Technical Guidance Document

Introduction

Quality of Medicines: Questions and Answers – Part 1 is an EMA technical guidance document that clarifies common regulatory questions concerning the quality of human and veterinary medicinal products in the European Economic Area (EEA).

For regulatory affairs professionals and pharmaceutical manufacturers, this guidance provides practical clarification on the classification of active substances and finished products, the acceptability of active pharmaceutical ingredient (API) mixes, and the appropriate regulatory submission pathways, including the Active Substance Master File (ASMF) procedure and the Certificate of Suitability (CEP). It also explains how Good Manufacturing Practice (GMP) requirements apply to different manufacturing scenarios.

In this article, we summarise the key questions and answers to help readers better understand the regulatory principles and their practical implications for pharmaceutical quality management.

What the Document Is

The document is maintained by EMA's Quality Working Party (QWP), a joint working party of the Committee for Medicinal Products for Human Use (CHMP) and the Committee for Medicinal Products for Veterinary Use (CVMP).

It provides the European Economic Area's (EEA) harmonised position on quality issues that are subject to different interpretations or require clarification, typically arising during assessment procedures.

Important Notes

Read this document alongside the European Pharmacopoeia, EMA quality guidelines and other relevant guidance.
H indicates applicability to human medicinal products; V indicates applicability to veterinary medicinal products.
Part 1 covers the topics presented below. Part 2 addresses finished-product topics, while later parts cover impurities, process control and other quality issues.

1. Active Substance – ASMF Procedure

Q1. Can a mixture of an active substance with an excipient be submitted through an ASMF?

No. The blending of an active pharmaceutical ingredient (API) with an excipient is considered the first step in the manufacture of the finished product, rather than part of the active substance. Exceptions exist only when:

The active substance is unstable on its own without a stabilising agent; or
It is a herbal dry extract that cannot be produced as a solid without excipients.

Regulatory Consideration

Product-specific attributes, such as particle size, microbial quality and bacterial endotoxins, should instead be included in Module 3.2.S of the marketing authorisation dossier, rather than in the ASMF, to preserve the "one version" philosophy.

2. API Mix – Definition and Acceptability

Q2. What is an API mix?

An API mix is a mixture of an API with one or more excipients, for example, adding an antioxidant or introducing an API into a matrix.

Manufacturing an API mix is considered the first step of finished-product manufacture.

Key Clarifications

The regulatory approach to an API mix depends on the reason for preparing the mixture and the applicable manufacturing requirements.

Scenario	How to Handle
API mix needed for stability or safety reasons	Can be submitted under Module 3.2.S, as an ASMF, or via a CEP. GMP Part II must be followed, and a re-test period may be accepted.
API mix for workability or other non-safety/stability reasons	The steps must be described in CTD Section 3.2.P and conducted under GMP Part I.
Sterile API mix	GMP Part I is mandatory for sterilisation and all downstream steps.
Pharmacopoeial monograph states "A suitable antioxidant may be added"	This statement alone justifies the API mix, but the choice and level of antioxidant require additional justification and a control test.
APIs in solution (e.g. benzalkonium chloride solution)	These are considered API mixes. ASMFs for solutions are acceptable under the conditions described in Q1.b.
A Ph. Eur. monograph exists for the API mix	An ASMF can be accepted or a CEP granted.

Key Takeaway

The classification of an API mix and its regulatory submission route depend on the purpose of mixing, the nature of the material and the applicable manufacturing requirements. Product-specific quality attributes should be addressed in the relevant marketing authorisation dossier module.

Abbreviations

API – Active Pharmaceutical Ingredient

ASMF – Active Substance Master File

CEP – Certificate of Suitability to the Monographs of the European Pharmacopoeia

CHMP – Committee for Medicinal Products for Human Use

CTD – Common Technical Document

CVMP – Committee for Medicinal Products for Veterinary Use

EEA – European Economic Area

EMA – European Medicines Agency

GMP – Good Manufacturing Practice

MA – Marketing Authorisation

Ph. Eur. – European Pharmacopoeia

QWP – Quality Working Party

Caution: Where different sources of APIare used in the same medicinal product,particular care is needed with API mixes toavoid a product with inconsistent compo-sition.

This article summarises selected content from the referenced material for informational purposes. Please consult the applicable EMA guidance and official regulatory documents for authoritative regulatory interpretations.

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