APIC 发布 API 的 GDP 如何实施文件第 3 版
GDP for APIs: “How to do” Document
APIC 发布《API 的 GDP 如何做》文件第 3 版（2026 年 6 月），逐条解释 EU GDP 指南在原料药分销中的实施方式。文件以表格对照 2015 年 EU GDP 指南、WHO TRS 996 附件 6 与 ICH Q7，并纳入 Regulation (EU) 2021/1280 对兽用原料药的约束性要求。文件说明重包装、重新贴标或分装属生产活动，应按 GMP 管理。
文件以表格逐条对照 EU GDP 指南、WHO TRS 996 与 ICH Q7，给出 API 分销环节的实践解释与示例。
APIC 技術出版物：GDP for APIs: “How to do” Document
官方目錄發布日：2026-07-10（原文 10/07/2026，DD/MM/YYYY）；文件版本或修訂日期另見正文。
本文為 APIC 技術資料，不是監管機關發布的法規。
PDF 文字版；图形和原始排版请参阅官方 PDF。
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ACTIVE PHARMACEUTICAL INGREDIENTS COMMITTEE
GDP for APIs:
“How to do” Document
Interpretation of the EU Guidelines on the Principles of Good Distribution Practice for active substances for
medicinal products for human and veterinary use, in parallel with the WHO Guideline Good Trade and Dis-
tribution Practices for Pharmaceutical Starting Materials and the relevant chapter of ICH Q7
Version 3 – June 2026
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Preamble
The original version of this guidance document has been compiled by a subdivision of the APIC Good Distri-
bution Practice Task Force on behalf of the Active Pharmaceutical Ingredient Committee (APIC) of CEFIC.
Task Force Members:
Dr. Lars Albermann, Merck KGaA
Tom Buggy, DSM
Dario Lopez, Centrient Pharmaceuticals
Dr . Georg Strasser, Janssen Pharmaceutica NV
Dr. Ulrich Kestel, Fareva
Kristina Kos, Teva
Dr. Jelle Van Gauwbergen, Janssen Pharmaceutica NV
Jeffrey Speakman – Evonik
Pierre Krebbers – Aspen pharma
Enno Schweinberger – Siegfried
Martina Rubes – Dipharma
Philippe Lienart – Roquette
Marcel Kamsteeg – Corbion
Philippe Pessina – Sequens
Steven De Strycker – Johnson & Johnson
Anne Lage – Siegfried
Dirkjan Vanzoelen – Ardena
Jeroen Geeven – Ardena
Kai Doderer – Evonik
Vera Branco – Hovione
Erika Vergara – Dow
Ivana Martinovic – TEVA Pharmaceutical Industries Ltd.
With Support and Review from:
Pieter Van der Hoeven, APIC, Belgium
Francois Vandeweyer, Janssen Pharmaceutica NV
Annick Bonneure, APIC Belgium
The APIC Quality Working Group
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Table of Contents
Chapter 1 Introduction................................................................................................................................ 4
1.1 Objective ................................................................................................................................................ 4
Requirements for veterinary APIs ................................................................................................................. 5
1.2 Regulatory applicability ......................................................................................................................... 6
Chapter 2 Scope .......................................................................................................................................... 7
Chapter 3 General Considerations ............................................................................................................. 8
Chapter 4 Good Distribution Practices for API ......................................................................................... 8
4.1 How to use the “How to do” - Document .............................................................................................. 8
4.2 “How to do” - Document ......................................................................................................................... 9
Chapter 5 – Glossary of terms ......................................................................................................................... 33
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Chapter 1 Introduction
1.1 Objective
APIC Good Distribution Practices for Active Pharmaceutical Ingredients
“How to do” Document
Historical Background
In the past there have been no separate regulations on GDP for distributors of APIs.
GMP Part II / ICH Q7 for manufacturers of APIs had been the only guidelines partially covering GDP
for APIs. They affect primarily the handling of APIs at the manufacturing site, but not distribution
outside the site.
The WHO Guide on GTDP for Pharmaceutical Starting Materials has been a reference document
with broad acceptance in industry on a voluntary basis.
With the EU Falsified Medicines Directive (Directive 2011/62/EU), the application of GDP for APIs
became mandatory. The EU Commission Guideline on principles of Good Distribution Practice of
active substances for medicinal products for human use, issued on 19 March 2015, was the first
legally binding document specifically addressing distribution activities for APIs. On 2 August 2021,
Commission Implementing Regulation (EU) 2021/1280 was issued regarding the distribution of APIs
for veterinary medicinal products under Regulation (EU) 2019/6.
In addition, PIC/S issued, in July 2018, a guideline (PI 047-1, 2018) on the principles of Good Distri-
bution Practice of active substances for medicinal products for human use; the requirements in this
document are largely identical to those in the EU guideline.
ACKNOWLEDGEMENTS
This document was developed by representatives of member companies of the Active Pharmaceu-
tical Ingredients Committee (APIC).
Purpose of the Document
This document was written by experts from the European industry (CEFIC APIC).
It is essentially an interpretation of "how to" implement the EU Commission Guideline on the prin-
ciples of Good Distribution Practice (GDP) for active substances for medicinal products for human
use, published by the European Commission DG SANCO on 19 March 2015, based on practical ex-
perience.
In addition, the following guidelines were taken into account in the preparation of this document:
WHO “Good trade and distribution practices for pharmaceutical starting materials – TRS 996, Annex
6”; ICH Q7 / APIC “How to do” Document on ICH Q7; “PIC/S Guide to Good Distribution Practice for
Medicinal Products”; and Regulation (EU) 2021/1280 on good distribution practice for active sub-
stances used as starting materials in veterinary medicinal products.
This guide provides additional explanatory notes on the EU Commission Guideline on the principles
of Good Distribution Practice of active substances for medicinal products for human and veterinary
use.
The explanatory notes in this guide reflect the views of the Active Pharmaceutical Ingredients Com-
mittee (APIC) and not necessarily those of the European Commission or WHO.
This document does not intend to provide an exhaustive list of “how to” comply with the require-
ments and recommendations mentioned above.
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It provides examples of potential solutions and further detail on how requirements and recommen-
dations can be met and/or interpreted.
The word “should” is used several times in the EU Guideline on the Principles of GDP for APIs. It
indicates requirements and recommendations that are expected to apply unless they can be shown
to be inapplicable or replaced by an alternative that provides at least an equivalent level of quality
assurance. Therefore, “should” does not mean that the requirement does not have to be met simply
because it is not phrased as “must”.
This document is intended to be a living document describing current practice and supporting the
implementation of the EU Commission Guideline on the principles of GDP for active substances for
medicinal products for human and veterinary use. Suggestions and questions from industry or reg-
ulators to CEFIC APIC are welcome.
This document has been prepared to provide guidance for companies involved in the distribution
of active pharmaceutical ingredients.
Examples based on practical experience are provided to support the application of GDP. However,
alternative approaches may also be acceptable.
Regulatory Requirements
Within the EU, according to Article 46 of Directive 2011/62/EU of the European Parliament and of
the Council of 8 June 2011 amending Directive 2001/83/EC on the Community code relating to me-
dicinal products for human use, companies should apply the following measures to prevent the
entry of falsified medicinal products into the legal supply chain.
The holder of a manufacturing authorization shall at least be obliged to use only active substances,
which have been manufactured in accordance with good manufacturing practice for active sub-
stances and distributed in accordance with good distribution practices for active substances. Dis-
tributors of active substances may, according to Article 111 of the same directive, become subject
to inspections by the competent authority.
Furthermore, the holder of the manufacturing authorization shall verify compliance with good man-
ufacturing practices and good distribution practices by conducting audits at the sites of active sub-
stance manufacturers and distributors.
Requirements for veterinary APIs
In general the guideline for veterinary APIs (Implementing Regulation (EU) 2021/1280) does not
change the underlying GDP principles established in guideline for human APIs (EU Guidelines on
GDP 19 March 2015); rather, it transforms them into binding, harmonised and enforceable legal
requirements for the veterinary sector. Many passages of guidelines are identical or at least similar.
Both guidelines are applicable for APIs and the scope exclude Intermediates. Most significant dif-
ference is the legal status: The 2015 Guideline provides interpretative guidance under Directive
2001/83/EC and allows for flexibility in implementation. By contrast, Regulation (EU) 2021/1280 is
adopted under Regulation (EU) 2019/6 and is directly applicable and legally binding in all EEA Mem-
ber States (including Switzerland). From a content perspective, the requirements for self-inspec-
tions under Article 23 of Regulation (EU) 2021/1280 represent the most significant difference.
This document reflects the APIC experts’ interpretation of the following guidelines:
- Guideline (EU) 2015/C 95/01 of 19 March 2015 on principles of Good Distribution Practice
of active substances for medicinal products for human use
- Implementing Regulation (EU) 2021/1280 of 2 August 2021 as regards measures on good
distribution practice for active substances used as starting materials in veterinary medicinal
products in accordance with Regulation (EU) 2019/6
In addition, aspects of the following guidelines and documents were also taken into account:
- Falsified Medicines Directive (Directive 2011/62/EU)
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- ICH Q 7 (EU GMP Part II): Good manufacturing practice for active pharmaceutical ingredi-
ents
- APIC ICH Q7 "How to do"
- ICH quality documents (EU GMP Part II) “Quality Risk Management Q9”
- WHO Technical Report Series (TRS) No. 957, Annex 5 – WHO Good Distribution Practices
for Pharmaceutical Products
- WHO Technical Report Series (TRS) No. 996, Annex 6 –WHO good trade and distribution
practices for pharmaceutical starting materials
-
- 2013/C 343/01 Guidelines of 5 November 2013 on Good Distribution Practice of medicinal
products for human use
- PIC/S Guide to Good Distribution Practice for Medicinal Products
1.2 Regulatory applicability
This document is applicable to the distribution* of active substances for human and veterinary
medicinal use in Europe.
*See paragraph 1.2 of the EU Commission Guideline on principles of Good Distribution Practice of active sub-
stances for medicinal products for human use and Article 2 (i) Regulation (EU) 2021/1280 for veterinary me-
dicinal products.
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Chapter 2 Scope
According to the European Falsified Medicines Directive, Manufacturing Authorization Holders are
responsible to use only active substances which have been distributed in accordance with Good
Distribution Practices for active substances. This is one significant new requirement in the EU Falsi-
fied Medicines Directive.
In the EU framework for human and veterinary medicinal products, the scope relevant to this doc-
ument can be summarized as follows:
1. For human medicinal products, the EU GDP Guideline applies to the distribution of active sub-
stances as defined in Article 1(3a) of Directive 2001/83/EC. For veterinary medicinal products, cor-
responding GDP requirements apply under Regulation (EU) 2021/1280 (respectively Regulation (EU)
2019/6, Article 4). In both cases, an active substance is a substance or mixture of substances in-
tended to be used in the manufacture of a medicinal product and that, when used in its production,
becomes an active ingredient of that product.
2. In view of these guidelines, the distribution of active substances for medicinal products for human
& veterinary use (hereafter 'active substances') is defined as procuring, importing, holding, supply-
ing or exporting active substances.
3. Activities consisting of re-packaging, re-labelling or dividing up of active substances are manufac-
turing activities and as such are subject to the guidelines on Good Manufacturing Practice of active
substances.
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Chapter 3 General Considerations
This document is based on the EU Commission Guideline on the principles of Good Distribution Practice of active
substances for medicinal products for human and veterinary use and therefore follows the same structure.
This APIC document provides guidance on practical approaches, with examples, for applying the principles of
the EU GDP guideline for APIs.
The APIC document applies to steps in the distribution/supply chain starting from the point at which an API is
transferred outside the control of the original manufacturer's material management system.
Some sections and/or sub-sections of this document may not apply to all parties involved. This document is
intended to provide guidance on the application of GDP; however, alternative approaches may be acceptable.
Specific guidance on storage conditions is described in regulatory documents such as USP chapter <659> Pack-
aging and Storage Requirements and the EMEA Guideline on Declaration of Storage Conditions
CPMP/QWP/609/96/Rev 2 (EMEA 2007).
Chapter 4 Good Distribution Practices for API
4.1 How to use the “How to do” - Document
The requirements have been interpreted for APIs by APIC, taking into consideration the requirements given in
the ICH Q7 / APIC “How to do” Document on ICH Q7. Reference has also been made to WHO Technical Report
Series 996 Annex 6 on Good Trade and Distribution Practices for Pharmaceutical Starting Materials.
The interpretation of APIC must be read and considered in conjunction with the requirements of the EU GDP
guideline. The references in the other columns should help the user of this document to find the respective
paragraphs in the APIC “How to do” document on ICH Q7 and WHO TRS report
The application of the interpretations in this table should always take into consideration the potential inherent
risks related to the API and the conditions under which the API is handled and distributed. Risk assessments
should be based on sound scientific evaluation and appropriate risk management tools, as referenced, for ex-
ample, in ICH Q9.
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4.2 “How to do” - Document
EU Guidelines on GDP 19 March 2015
APIC Comments
on principles of Good Distribution Practice of active WHO TRS N°996, 2016
taking into account ICHQ7 / additional requirements
substances for medicinal products for human use annex 06
Introduction
These guidelines are based on the fourth paragraph of
Article 47 of Directive 2001/83/EC (1).
(1) Directive 2001/83/EC of the European Parliament and of
the Council of 6 November 2001 on the Community code re-
lating to medicinal products for human use (OJ L 311,
28.11.2001, p. 67)
They follow the same principles that underlies the The Guidelines of 5 November 2013 on Good Distribution Practice
guidelines of Eudralex Volume 4, Part II, Chapter 17, of medicinal products for human use are referenced to provide an
with regard to the distribution of active substances overall definition of good distribution practice; however, the simi-
and the Guidelines of 5 November 2013 on Good Dis- larity is not fully applicable to APIs.
tribution Practice of medicinal products for human use
(2)
(2)
OJ C 343, 23.11.2013, p. 1
These guidelines provide stand-alone guidance on
Good Distribution Practice (GDP) for importers and
distributors of active substances for medicinal prod-
ucts for human use. They complement the rules on
distribution set out in the guidelines of EudraLex Vol-
ume 4, Part II, and apply also to distributors of active
substances manufactured by themselves.
Any manufacturing activities in relation to active sub- Repackaging, relabeling, or dividing-up activities performed during
stances, including re-packaging, re-labelling or dividing distribution are considered GMP-relevant.
up, are subject to Commission Delegated Regulation Therefore, they should comply with the requirements of Commis-
(EU) No 1252/2014 (3) and EudraLex Volume 4, Part II. sion Delegated Regulation (EU) No 1252/2014 and EudraLex Vol-
(3) ume 4, Part II.
Commission Delegated Regulation (EU) No 1252/2014 of
28 May 2014 supplementing Directive 2001/83/EC of the Eu-
ropean Parliament and of the Council with regard to princi-
ples and guidelines of good manufacturing practice for active
substances for medicinal products for human use (OJ L 337,
25.11.2014, p1
Additional requirements apply to the importation of It is recommended that specific requirements for importing APIs
active substances, as laid down in Article 46b of Di- (e.g. national requirements) be defined.
rective 2001/83/EC.
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EU Guidelines on GDP 19 March 2015
APIC Comments
on principles of Good Distribution Practice of active WHO TRS N°996, 2016
taking into account ICHQ7 / additional requirements
substances for medicinal products for human use annex 06
Distributors of active substances for medicinal prod-
ucts for human use should follow these guidelines as
of 21 September 2015.
Chapter 1 - Scope
1.1 These guidelines apply to distribution of active Introduction Transportation companies do not need to be certified by authorities.
substances, as defined in Article 1(3a) of Directive However, they should follow parts of the GDP guideline relevant to
2001/83/EC, for medicinal products for human use. The scope of this WHO guidance on Good trade and distri- their activities.
According to that provision, an active substance is any bution practices for pharmaceutical starting materials is
substance or mixture of substances intended to be applicable to any ingredient that is used in the manufacture It is the responsibility of distributors (GDP-certified parties contract-
used in the manufacture of a medicinal product and of a medicinal product, including APIs, excipients and any ing transporters) to verify that the selected transport companies are
that, when used in its production, becomes an active others. able to apply these requirements, including a quality system, appro-
ingredient of that product intended to exert a pharma- priate personnel, and good documentation practices, in relation to
cological, immunological or metabolic action with a the criticality of their activities.
view to restoring, correcting or modifying physiologi-
cal functions or to make a medical diagnosis.
1.2 For the purpose of these guidelines, distribution of This guideline applies only to distribution activities, including trans-
active substances shall comprise all activities consist- portation (i.e. no product container is opened during such activi-
ing of procuring, importing, holding, supplying or ex- ties).
porting active substances, apart from brokering.
The definition of brokering activities provided in the EU guideline is
as follows:
All activities related to the sale or purchase of active substances
that do not include physical handling and that consist of negotiating
independently and on behalf of another legal or natural person.
1.3 These guidelines do not apply to intermediates of Although the API intermediates are not directly in scope The EU guideline does not apply to intermediates or starting materi-
active substances. of this guideline, the sense of this guideline fits best to API als; it applies only to active substances.
intermediates and might be applied in the general sense According to EU Guideline on GMP for medicinal products for hu-
to API intermediates (e.g. regarding Supplier qualification, man and veterinary use; volume 4 part 1 chapter 5
Traceability, Transport conditions, Handling of noncon- (5.29) supply chain traceability should be established and the asso-
formities) ciated risks, from active substance starting materials to the finished
medicinal product, should be formally assessed and periodically ver-
ified. Appropriate measures should be put in place to reduce risks to
the quality of the active substance
Chapter 2 – Quality System
Damage management – responsibility for material to
be distributed
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EU Guidelines on GDP 19 March 2015
APIC Comments
on principles of Good Distribution Practice of active WHO TRS N°996, 2016
taking into account ICHQ7 / additional requirements
substances for medicinal products for human use annex 06
2.1 Distributors of active substances should develop 1.2 Quality management should include: These requirements are also covered by GMP (EudraLex Volume 4,
and maintain a quality system setting out responsibili- Part II – see in particular Chapters 2 and 17).
ties, processes and risk management principles. - an appropriate infrastructure or “quality system”, en- Parties involved in the distribution of APIs should establish a Quality
Examples of the processes and applications of quality compassing the organizational structure, procedures, pro- Management System to manage the quality of their products and
risk management can be found in EudraLex Volume 4, cesses and resources. The size, structure and complexity services and to maintain the original quality of the APIs. As an es-
Part III: GMP related documents, ICH guideline Q9 on of the distributor and its activities should be taken into sential prerequisite for any Quality Management System, top man-
Quality Risk Management (ICH Q9). consideration when developing or modifying the quality agement should establish a corporate quality policy. The parties in-
system; volved should share responsibility for ensuring that the API pro-
vided by the distributor conforms to the mutually agreed specifica-
1.3 The system should cover for example, but not be lim- tion requirements of the pharmaceutical manufacturer and/or is
ited to, the quality assurance principles in these guide- suitable for its intended use.
lines. Quality Risk Management principles should be integrated into the
quality management system.
2.2 Individual responsibilities should be clearly defined,
understood by the individuals concerned and recorded in
writing (as job descriptions or in a contract). Certain activi-
ties, such as supervision of performance
of activities in accordance with local legislation, may re-
quire special attention. Personnel should be suitably quali-
fied, trained and authorized to undertake their duties and
responsibilities.
2.2 The quality system should be adequately re- 1.4 All parties involved in the manufacture and supply chain These requirements are also covered by GMP (EudraLex Volume 4,
sourced with competent personnel, and suitable and must exercise responsibility to ensure the quality and Part II – see in particular Chapters 2 and 17).
sufficient premises, equipment and facilities. It should safety of the materials and products, and that they are fit
ensure that: for their intended use in accordance with their specifica- A system should be in place to control documents and data related
tions. to the applicable Quality System requirements. As a minimum, the
Quality Manual should include the following elements:
(i) active substances are procured, imported, held, 2.1 There should be an adequate organizational structure - scope of the Quality Management System,
supplied or exported in a way that is compliant with and a sufficient number of personnel should be employed - organizational structure, including a description of top manage-
the requirements of GDP for active substances; to carry out all the tasks for which the supplier is responsi- ment responsibilities,
ble. - written procedures, processes, and resources, or references to
them, and
4.1 Materials should be purchased from approved suppli- - a description of the sequence and interaction between procedures
ers in accordance with mutually agreed formal specifica- and departmental functions.
tions. The Quality Management System should also include a procedure
to verify that any API supplier or relevant service provider has the
capability to consistently meet previously agreed requirements.
This may include periodic audits of service providers.
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EU Guidelines on GDP 19 March 2015
APIC Comments
on principles of Good Distribution Practice of active WHO TRS N°996, 2016
taking into account ICHQ7 / additional requirements
substances for medicinal products for human use annex 06
Any computerized system used to ensure the required traceability
and data integrity should be properly installed, qualified, and con-
trolled.
(ii) management responsibilities are clearly specified; 2.2 Individual responsibilities should be clearly defined, Requirements are also covered by GMP (EudraLex Volume 4, Part II
understood by the individuals concerned and recorded in – see in particular chapter 2)
writing (as job descriptions or in a contract). Certain activi-
ties, such as supervision of performance of activities in ac- Refer to Chapter 3 below for personnel requirements.
cordance with local legislation, may require special atten-
tion. Personnel should be suitably qualified, trained and
authorized to undertake their duties and responsibilities.
(iii) active substances are delivered to the right recipi- 13.4 There should be a written and approved contract or Requirements are also covered by GMP (EudraLex Volume 4, Part II
ents within a satisfactory time period; formal agreement between the contract giver and contract – see in particular chapter 10.24 and 17)
acceptor that addresses and defines in detail the responsi- There should be an organization and corresponding processes in
bilities with respect to GTDP and which party is responsible place to ensure the product is shipped to the right customer (see also
for which quality measures "delivery to customers" item 6.13, 6.14 and 6.15) .
Note: The satisfactory timeframe should be defined in the supply
agreement or service level agreement, taking into account the need
to avoid customer stock shortages (refer to Chapter 6, Operations).
Active substances should always be transported in a manner that
avoids unjustified periods of storage. (See also Chapter 5, “Glossary
of terms”.)
(iv) records are made contemporaneously; Partially covered by chapter 6.1 These requirements are part of good documentation practices, in-
cluding ALCOA principles. Refer to Chapter 4 on documentation for
6.1 Documents, in particular instructions and procedures more details.
relating to any activity that might have an impact on the
quality of materials, should be designed, completed, re-
viewed and distributed with care. Documents should be
completed, approved, signed and dated by appropriate
authorized persons and should not be changed without
authorization. Specifications for materials, including pack-
aging materials, should be available, reviewed and revised
on a regular basis.
(v) deviations from established procedures are docu- 11.1 non-conforming materials should be handled in ac- The conclusions of deviations with impact on the product should be
mented and investigated; cordance with a procedure that will prevent their introduc- risk based.
tion or reintroduction into the market. Records covering all If there are deviations with potential impact on the product quality
activities, including destruction, disposal, return and reclas- (e.g. the storage conditions, damages ….,) the API manufacturer
sification, should be maintained. should provide support as needed.
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EU Guidelines on GDP 19 March 2015
APIC Comments
on principles of Good Distribution Practice of active WHO TRS N°996, 2016
taking into account ICHQ7 / additional requirements
substances for medicinal products for human use annex 06
11.2 An investigation should be performed to establish There should be a communication process in place between the cus-
whether any other batches are also affected. Corrective tomer/distributor and the API manufacturer regarding deviations oc-
and preventive measures should be taken where neces- curring at distributor level, to ensure that the reporting of the devia-
sary. tion is performed in a timely manner.
The responsibility for investigating such deviations should be defined
in the relevant contracts (e.g. quality agreements or supply agree-
ments) and aligned with the applicable INCOTERM conditions.
The management of deviations and damage during storage and
transport should involve all relevant parties in the supply chain.
(vi) appropriate corrective and preventive actions, Partially covered by chapter 1.9 and 11.2 Self-explanatory
commonly known as ‘CAPA’, are taken to correct devi-
ations and prevent them in line with the principles of 1.9 A system should be in place for the performance of
quality risk management; regular internal audits with the aim of continuous im-
provement. The findings of the audit and any corrective
and preventive actions taken, including verification of
their effectiveness, should be documented and brought to
the attention of the
responsible management.
11.2 An investigation should be performed to establish
whether any other batches are also affected. Corrective
and preventive measures should be taken where neces-
sary.
(vii) changes that may affect the storage and distribu- Partially covered by chapter 1.2 and 6.1 There should be a communication process in place to ensure that any
tion of active substances are evaluated. change at distributor level (changes to what has been committed and
1.2 Quality management should include agreed in the quality agreement) will be assessed by the manufac-
turer of the API prior to implementing the change and communicated
- a robust deviation management and change control pro- to the customer in a timely fashion.
gramme designed to ensure that quality is continually as-
sessed and maintained: these should include a customer
notification where appropriate;
6.1 Documents, in particular instructions and procedures
relating to any activity that might have an impact on the
quality of materials, should be designed, completed, re-
viewed and distributed with care. Documents should be
completed, approved, signed and dated by appropriate
authorized persons and should not be changed without
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EU Guidelines on GDP 19 March 2015
APIC Comments
on principles of Good Distribution Practice of active WHO TRS N°996, 2016
taking into account ICHQ7 / additional requirements
substances for medicinal products for human use annex 06
authorization. Specifications for materials, including pack-
aging materials, should be available, reviewed and revised
on a regular basis.
2.3 The size, structure and complexity of the distribu- 1.2 Quality management should include An appropriate organization should be in place with an adequate
tor’s activities should be taken into consideration number of resources.
when developing or modifying the quality system. - an appropriate infrastructure or “quality system”, en-
compassing the organizational structure, procedures, pro-
cesses and resources. The size, structure and complexity
of the distributor and its activities should be taken into
consideration when developing or modifying the quality
system
Chapter 3 – Personnel
3.1 The distributor should designate a person at each 1.2 Quality management should include There should be an organization in place to implement and maintain
location where distribution activities are performed the quality system, with a designated representative at each loca-
who should have defined authority and responsibility - an independent quality unit (or designee), which is re- tion.
for ensuring that a quality system is implemented and sponsible for all quality-related matters Key quality responsibilities should not be delegated. These responsi-
maintained. The designated person should fulfil his re- bilities should be described in writing, for example in the form of a
sponsibilities personally. The designated person can contract or agreement between the relevant parties.
delegate duties but not responsibilities.
3.2 The responsibilities of all personnel involved in the 2.1: There should be an adequate organizational structure The organization should be documented in an organizational chart
distribution of active substances should be specified in with clear indication of personnel responsible for distribution activi-
writing. The personnel should be trained on the re- 2.2: Individual responsibilities should be clearly defined, ties. Levels of authorization should be clearly defined in job descrip-
quirements of GDP for active substances. They should understood by the individuals concerned and recorded in tions.
have the appropriate competence and experience to writing (as job descriptions or in a contract). Certain activi- There should be an adequate number of personnel qualified
ensure that active substances are properly handled, ties, such as supervision of performance of activities in ac- through appropriate education, training, and/or experience to per-
stored and distributed. cordance with local legislation, may require special atten- form and supervise activities relating to API distribution. A system
tion. Personnel should be suitably qualified, trained and for planning, documenting, and following up on training should be
authorized to undertake their duties and responsibilities. in place.
For personnel directly involved in GDP processes, it is recom-
2.3 All personnel should be aware of the principles of the mended that GDP-focused training be provided.
appropriate guidelines, including but not limited to GTDP
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EU Guidelines on GDP 19 March 2015
APIC Comments
on principles of Good Distribution Practice of active WHO TRS N°996, 2016
taking into account ICHQ7 / additional requirements
substances for medicinal products for human use annex 06
3.3 Personnel should receive initial and continuing Chapter 2.2: Personnel should be suitably qualified, Personnel involved should be trained in the handling of the mate-
training relevant to their role, based on written proce- trained rial, taking into account the requirements of the material safety
dures and in accordance with a written training pro- data sheet.
gram. 2.4 Personnel should receive initial and continuing train- Personnel should be trained on GDP principles and on the chapters
ing relevant to their tasks. Training should be provided by relevant to their area of responsibility. For transport companies, the
qualified trainers in accordance with a training pro- training program should be aligned with the activities for which
gramme. The effectiveness of training should be verified they are responsible.
where appropriate. Training records should be main- All relevant personnel should receive initial and periodic refresher
tained. All personnel should be motivated to support the training commensurate with the potential impact of their activities
establishment and maintenance of quality standards. on the API.
Applicable quality standards should form part of a regular training
program delivered by qualified personnel, and the training should
be documented.
3.4 A record of all training should be kept, and the ef- 2.4 Personnel should receive initial and continuing train- Records should be maintained listing the name, address, and quali-
fectiveness of training should be periodically assessed ing relevant to their tasks. Training should be provided by fications of any contracted service provider and the type of service
and documented. qualified trainers in accordance with a training pro- they provide.
gramme. The effectiveness of training should be verified
where appropriate. Training records should be main-
tained. All personnel should be motivated to support the
establishment and maintenance of quality standards.
Chapter 4 - Documentation
4.1 Documentation comprises all written procedures, 6.10 Records should be kept and must be readily available Self-explanatory
instructions, contracts, records and data, in paper or upon request in accordance with GMP and GSP (Good If computerized systems are used at distributor level, then the com-
in electronic form. Documentation should be readily Storage Practices) * puter systems should be validated.
available or retrievable. All documentation related to
compliance of the distributor with these guidelines *Guide to good storage practices for pharmaceuticals. In: WHO
should be made available on request of competent au- Expert Committee on Specifications for Pharmaceutical Prepara-
thorities. tions: thirty-seventh report. Geneva: World Health Organization;
2003: Annex 9 (WHO Technical Report Series, No. 908)
4.2 Documentation should be sufficiently comprehen- 6.2 Documents should have unambiguous contents: their Self-explanatory
sive with respect to the scope of the distributor’s ac- title, nature and purpose should be clearly stated. They
tivities and in a language understood by personnel. It should be laid out in an orderly manner and be easy to
should be written in clear, unambiguous language and check.
be free from errors.
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on principles of Good Distribution Practice of active WHO TRS N°996, 2016
taking into account ICHQ7 / additional requirements
substances for medicinal products for human use annex 06
4.3 Any alteration made in the documentation should No direct requirement, but should be covered by § 6.10 Self-explanatory
be signed and dated; the alteration should permit the Refer to good documentation practices for data in paper and in
reading of the original information. Where appropri- 6.10 Records should be kept and must be readily available electronic form.
ate, the reason for the alteration should be recorded. upon request in accordance with GMP and GSP
4.4 Each employee should have ready access to all No direct requirement, but should be covered by § 2.2 Self-explanatory
necessary documentation for the tasks executed.
2.2 […] Personnel should be suitably qualified, trained
and authorized to undertake their duties and responsibili-
ties.
Procedures
4.5 Written procedures should describe the distribu- 6.1 Documents, in particular instructions and procedures Comment:
tion activities which affect the quality of the active relating to any activity that might have an impact on the Written procedures should be in place, and the corresponding pro-
substances. This could include receipt and checking of quality of materials, should be designed, completed, re- cesses should be implemented.
deliveries, storage, cleaning and maintenance of the viewed and distributed with care. Documents should be
premises (including pest control), recording of the completed, approved, signed and dated by appropriate
storage conditions, security of stocks on site and of authorized persons and should not be changed without
consignments in transit, withdrawal from saleable authorization. Specifications for materials, including pack-
stock, handling of returned products, recall plans, etc. aging materials, should be available, reviewed and revised
on a regular basis.
4.6 Procedures should be approved, signed and dated 6.1 […] Documents should be completed, approved, Self-explanatory
by the person responsible for the quality system. signed and dated by appropriate authorized persons and
should not be changed without authorization. […]
4.7 Attention should be paid to the use of valid and Not detail as such (APIC 2014):
approved procedures. Documents should be reviewed Procedures on document control should be established.
regularly and kept up to date. A revision history of documents should be readily available.
Version control should be applied to procedures. After Changes to procedures should be considered in the training pro-
revision of a document a system should exist to pre- gram
vent inadvertent use of the superseded version. If an electronic system is used to control the revision and approval
Superseded or obsolete procedures should be re- of SOPs, the system should be validated and should comply with
moved from workstations and archived. data integrity principles, including audit trail requirements.
If a paper-based system is used, it should be managed in a con-
trolled manner under Quality Unit oversight.
Records
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APIC Comments
on principles of Good Distribution Practice of active WHO TRS N°996, 2016
taking into account ICHQ7 / additional requirements
substances for medicinal products for human use annex 06
4.8 Records should be clear, be made at the time each Partially covered by §6.10 Comment:
operation is performed and in such a way that all sig- Retention periods of documents should be established. The security
nificant activities or events are traceable. 6.10 Records should be kept and must be readily available and methods of archiving and retrieval of such records should be
Records should be retained for at least 1 year after the upon request in accordance with GMP and GSP ensured. Record retention schedule and practices for distribution
expiry date of the active substance batch to which records should be specified in the quality agreement.
they relate.
For active substances with retest dates, records should
be retained for at least 3 years after the batch is com-
pletely distributed.
4.9 Records should be kept of each purchase and sale, Partially covered by §6.8, 6.3 and 6.4 Requirements are also covered by GMP (EudraLex Volume 4, Part II
showing the date of purchase or supply, name of the – see in particular chapter 6.30 and 10.24 )
active substance, batch number and quantity received 6.8 Each container should be identified by labelling bear- Comment:
or supplied, and name and address of the supplier and ing at least the following information: Recommendation: In addition to the records requested by the EU
of the original manufacturer, if not the same, or of the – the name of the pharmaceutical starting material (in- GDP guideline, the quantity of each shipment of each batch should
shipping agent and/or the consignee. Records should cluding grade and reference to pharmacopoeias where also be retained and be readily available.
ensure the traceability of the origin and destination of relevant);
products, so that all the suppliers of, or those supplied – if applicable, the International Nonproprietary Name
with, an active substance can be identified. Records (INN);
that should be retained and be available include: – the amount (weight or volume);
– the batch number assigned by the original manufacturer
I. identity of supplier, original manufacturer, ship- or the batch number assigned by the repacker, if the ma-
ping agent and/or consignee; terial has been repacked and relabelled;
II. address of supplier, original manufacturer, ship- – the retest date or expiry date (where applicable);
– the storage conditions;
ping agent and/or consignee;
– handling precautions, where necessary;
III. purchase orders;
– identification of the original manufacturing site;
IV. bills of lading, transportation and distribution – name and contact details of the supplier.
records;
V. receipt documents; 6.3 Certificates of analysis (COAs) issued by the original
VI. name or designation of active substance; manufacturer should be provided. If additional testing is
VII. manufacturer’s batch number; done, all COAs should be provided.
COAs should document product traceability back to the
VIII. certificates of analysis, including those of the
manufacturer by naming the original manufacturer and
original manufacturer; the manufacturing site. COAs should indicate which re-
IX. retest or expiry date. sults were obtained by testing the original material and
which results came from skip-lot testing or other testing
and should specify the organization responsible for issuing
the COA.
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taking into account ICHQ7 / additional requirements
substances for medicinal products for human use annex 06
6.4 Before any material is sold or distributed, the supplier
should ensure that the COAs and results are available and
that the results meet the required specifications
6.3 Certificates of analysis (COAs) issued by the original A distributor should not change the original title and data of the
manufacturer should be provided. If additional testing is CoA or other quality documents. Whenever possible, the original
done, all COAs should be provided. COAs should docu- manufacturer’s documentation should be used, or transcription of
ment product traceability back to the manufacturer by data should be verified.
naming the original manufacturer and the manufacturing The original manufacturing site should be identified by name or
site. COAs should indicate which results were obtained by unique identifier on the CoA or any other document agreed upon
testing the original material and which results came from with the customer
skip-lot testing or other testing and should specify the or- Comment:
ganization responsible for issuing the COA. Records should be readily available and should ensure traceability of
the supply chain for products/APIs from origin (manufacturer),
6.5 The original manufacturer and the intermediaries han- through suppliers/distributors, to destination (purchaser).
dling the material should always be traceable and trans-
parent; and this information should be made available to
authorities and end-users, downstream and upstream,
when requested.
6.4 Before any material is sold or distributed, the supplier API should normally be released according to their specification for
should ensure that the COAs and results are available and shipment. In case of API pending final release testing, API could be
that the results meet the required specifications. shipped under quarantine when authorized by the quality unit, in
agreement with customer and according to local legislation. Appro-
priate controls and documentation should be in place.
The process for transfer under quarantine should be defined in a pro-
cedure. The Quality Unit of both sites needs to approve shipment un-
der quarantine, and the receiving site must not use the material be-
fore a certificate of analysis for the batch in scope has been issued.
Before shipment under quarantine, the manufacturing batch record
should be reviewed and approved by the Quality Unit.
Additionally: 6.9 Relevant storage and handling information and safety --
data sheets should be available
Chapter 5 – Premises and Equipment
5.1 Premises and equipment should be suitable and 3.1 Premises, including laboratory facilities, must be lo- Requirements are also covered by GMP (EudraLex Volume 4, Part II
adequate to ensure proper storage, protection from cated, designed, constructed, adapted and maintained to – see in particular chapter 4)
contamination, e.g. narcotics, highly sensitising mate- suit the operations to be carried out. Their layout and de-
rials, materials of high pharmacological activity or tox- sign must aim to minimize the risk of errors and permit ef- Buildings and facilities used in the distribution of APIs should be lo-
icity, and distribution of active substances. They cated, designed, and constructed to facilitate cleaning, maintenance,
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taking into account ICHQ7 / additional requirements
substances for medicinal products for human use annex 06
should be suitably secured to prevent unauthorised fective cleaning and maintenance in order to avoid contam- and operations as appropriate to the type and stage of handling.
access. Monitoring devices that are necessary to guar- ination, cross-contamination, mix ups, build-up of dust, dirt Where the equipment itself (e.g., closed or contained systems) pro-
antee the quality attributes of the active substance or waste and, in general, any adverse effect on the quality vides adequate protection of the product, such equipment can be lo-
should be calibrated according to an approved sched- of materials. cated outdoors. Equipment should be qualified before use to ensure
ule against certified traceable standards. that it is functioning as intended.
3.4 Suitable supporting facilities and utilities (such as air
control, ventilation and lighting) should be in place and ap- Defined physical areas or other control systems (e.g. computerized
propriate to the activities performed, in order to avoid con- systems) should be in place for activities such as receipt, identifica-
tamination, cross-contamination and degradation of the tion, and quarantine of incoming products. Sufficient warehouse
material. Utilities that could affect product quality should space should be available to allow efficient movement without dam-
be identified and monitored. aging packaged products and to facilitate cleaning.
3.2 Measures should be in place to prevent unauthorized Appropriate access control for the premises should be ensured.
persons from entering the premises
Adequate lighting should be provided in all areas to facilitate clean-
ing, maintenance and proper operations.
Comment: also applicable to Sections 6.7 and 6.8.
4.10 Where special storage conditions are required (e.g. Requirements are also covered by GMP (EudraLex Volume 4, Part II
particular temperature, humidity or protection from light) – see in particular chapter 7.4)
these should be provided, monitored and recorded as ap- Facilities should also be designed to minimize potential contamina-
propriate. tion. The risk of contamination and mix up should also be considered
in respect to the flow of products and personnel through the build-
4.11 Highly active materials, narcotics, other dangerous ings or facilities.
drugs and substances presenting special risks of abuse,
fire or explosion should be stored in safe, dedicated and
secure areas. In addition and where applicable, interna-
tional conventions and national legislation are to be ad-
hered to
4.12 Special attention should be given to the design, use,
cleaning and maintenance of all equipment for bulk han-
dling and storage, such as tanks and silos.
5.1 Equipment must be located, designed, constructed, Requirements are also covered by GMP (EudraLex Volume 4, Part II
adapted, qualified, used, cleaned and maintained to suit – see in particular chapter 5)
the operations to be carried out. Its layout, design and use A set of current drawings should be maintained for facilities and crit-
should aim to minimize the risk of errors and permit effec- ical installations (e.g. instrumentation and utility systems). Schedules
tive cleaning and maintenance so as to avoid cross-con- and procedures (including responsibilities) should be established for
tamination, build-up of dust or dirt and any adverse effect the preventive maintenance and calibration program of the facility.
on the quality of materials.
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taking into account ICHQ7 / additional requirements
substances for medicinal products for human use annex 06
5.2 Defective equipment should not be used and should
either be removed or labelled as defective. Equipment
should be disposed of in such a way as to prevent any mis-
use. 5.3 The status of the equipment should be readily
identifiable.
5.9 Procedures should be in place for the operation and
maintenance of equipment. Lubricants and other materi-
als used on surfaces that come into direct contact with
the materials should be of the appropriate grade, e.g.
food-grade oil, and should not alter the quality of the ma-
terials.
5.10 Washing and cleaning equipment should be chosen
and used such that it cannot be a source of contamination
5.6 Balances and other measuring equipment of an appro-
priate range and precision should be available and should
be calibrated in accordance with a suitable schedule.
Chapter 6 – Operations
Orders
6.1 Where active substances are procured from a Not detailed as such
manufacturer, importer or distributor established in
the EU, that manufacturer, importer or distributor
should be registered according to Article 52a of Di-
rective 2001/83/EC.(1)
(1) Extract from Directive 2001/83/EC- Article 52a
1. Importers, manufacturers and distributors of active
substances who are established in the Union shall reg-
ister their activity with the competent authority of the
Member State in which they are established.
2. The registration form shall include, at least, the fol-
lowing information:
(i) name or corporate name and permanent address;
(ii) the active substances which are to be imported,
manufactured or distributed;
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substances for medicinal products for human use annex 06
(iii) particulars regarding the premises and the tech-
nical equipment for their activity.
Receipt
6.2 Areas for receiving active substances should pro- 4.3 There should be authorized procedures describing the Self-explanatory
tect deliveries from prevailing weather conditions dur- activities relating to the receipt, storage and distribution The use of a checklist is recommended to capture the relevant
ing unloading. The reception area should be separate of materials. Steps should be taken to ensure and docu- points.
from the storage area. ment that the arriving consignment is correct and that the
Deliveries should be examined at receipt in order to products originate from approved suppliers. Deliveries
check that: should be examined to check that containers have not
(i) containers are not damaged; been damaged, altered or tampered with, and that clo-
(ii) all security seals are present with no sign of tam- sures and security seals are intact.
pering;
(iii) correct labelling, including correlation between
the name used by the supplier and the in-house name,
if these are different;
(iv) necessary information, such as a certificate of
analysis, is available; and
(v) the active substance and the consignment corre-
spond to the order.
6.3 Active substances with broken seals, damaged Partially covered by § 4.2 and 4.3 Self-explanatory.
packaging, or suspected of possible contamination
should be quarantined either physically or using an 4.2 Actions should be taken to minimize the risk of falsi-
equivalent electronic system and the cause of the is- fied or non-conforming materials entering the supply
sue investigated. chain.
4.3 There should be authorized procedures describing the
activities relating to the receipt, storage and distribution
of materials. Steps should be taken to ensure and docu-
ment that the arriving consignment is correct and that the
products originate from approved suppliers. Deliveries
should be examined to check that containers have not
been damaged, altered or tampered with, and that clo-
sures and security seals are intact.
6.4 Active substances subject to specific storage Partially covered by 4.11 and 4.9 Self-explanatory
measures, e.g. narcotics and products requiring a spe- The specific storage measures should be written and communicated
cific storage temperature or humidity, should be im- 4.11 Highly active materials, narcotics, other dangerous to relevant personnel.
mediately identified and stored in accordance with drugs and substances presenting special risks of abuse,
written instructions and with relevant legislative provi- fire or explosion should be stored in safe, dedicated and
sions. secure areas. In addition, and where applicable, interna-
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taking into account ICHQ7 / additional requirements
substances for medicinal products for human use annex 06
tional conventions and national legislation are to be ad-
hered to.
4.9 The required storage conditions, as specified for the
material, should be maintained within acceptable limits at
all times during storage. Appropriate checks to confirm
that required shipping conditions have been met should
be conducted as soon as possible after receipt. The prod-
uct should be transferred to appropriate storage facilities
immediately after checks to be made in the goods receiv-
ing area have been conducted.
6.5 Where the distributor suspects that an active sub- Partially covered by § 4.2 and 4.3, see just before Self explanatory.
stance procured or imported by him is falsified, he It is recommended that the process for notifying the authority be
should segregate it either physically or using an equiv- described in a protocol or procedure.
alent electronic system and inform the national com-
petent authority of the country in which he is regis-
tered.
6.6 Rejected materials should be identified and con- Partially covered by § 4.2 and 11.1 Self explanatory
trolled and quarantined to prevent their unauthorised
use in manufacturing and their further distribution. 4.6 Segregated areas should be provided for the storage
Records of destruction activities should be readily of received, quarantined, rejected, recalled and returned
available. material, including materials with damaged packaging.
Any system replacing physical segregation, such as elec-
tronic segregation based on a computerized system,
should provide equivalent security and should be appro-
priately qualified and validated.
11.1 Non-conforming materials should be handled in ac-
cordance with a procedure that will prevent their intro-
duction or reintroduction into the market. Records cover-
ing all activities, including destruction, disposal, return
and reclassification, should be maintained.
Storage
6.7 Active substances should be stored under the con- Covered by § 4.9 and 4.10
ditions specified by the manufacturer, e.g. controlled Self explanatory
temperature and humidity when necessary, and in 4.9 The required storage conditions, as specified for the
such a manner to prevent contamination and/or mix material, should be maintained within acceptable limits at Non controlled storage is considered acceptable supported by a risk
up. all times during storage. Appropriate checks to confirm assessment and temperature monitoring data of the facility.
The storage conditions should be monitored and rec- that required shipping conditions have been met should
ords maintained.
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taking into account ICHQ7 / additional requirements
substances for medicinal products for human use annex 06
The records should be reviewed regularly by the per- be conducted as soon as possible after receipt. The prod- Materials should be stored under conditions and for a period that
son responsible for the quality system. uct should be transferred to appropriate storage facilities have no adverse effect on their quality and should normally be con-
immediately after checks to be made in the goods receiv- trolled to ensure the oldest stock is used first.
ing area have been conducted.
4.10 Where special storage conditions are required (e.g. 2013/C 343/01 EUROPEAN COMMISSION Guidelines on Good Distri-
particular temperature, humidity or protection from light) bution Practice of medicinal products for human use state in Chapter
these should be provided, monitored and recorded as ap- 9.2 last paragraph “Provision should be made to minimize the dura-
propriate. tion of temporary storage while awaiting the next stage of the trans-
portation route.”
The GDP Group of the ECA Foundation states in its FAQ that “This
duration should be specified in company SOPs based on risk assess-
ment. The current industry practice is up to 72 hours storage at tem-
porary facilities. Longer storage periods are classed as long-term
storage of product and the facility must have a license to operate.”
An SOP should be in place to address events that lead to deviations
from temporary storage time limits or conditions. The disposition of
the product should be determined on the basis of a risk assessment.
6.8 When specific storage conditions are required, the Partially covered by § 4.10 Self explanatory.
storage area should be qualified and operated within
the specified limits. 4.10 Where special storage conditions are required (e.g.
particular temperature, humidity or protection from light)
these should be provided, monitored and recorded as ap-
propriate
6.9 The storage facilities should be clean and free from Partially covered by § 4.7 and 4.20
litter, dust and pests. Adequate precautions should be Materials stored in fiber drums, bags or boxes should be stored off
taken against spillage or breakage, attack by micro-or- 4.7 The storage areas should be kept clean and dry the floor and, when appropriate, suitably spaced to permit cleaning
ganisms and cross-contamination. and inspection.
4.20 Storage areas should be clean and free from accumu-
lated waste and from vermin. A written sanitation pro-
gramme should be available, indicating the frequency of
cleaning and the methods to be used to clean the prem-
ises and storage areas
6.10 There should be a system to ensure stock rota- 4.16 A default system should be in place to ensure that
tion, e.g. ‘first expiry (retest date), first out’, with regu- those materials due to expire first are sold or distributed Materials should be stored under conditions and for a period that
lar and frequent checks that the system is operating first (earliest expiry/first out). Where no expiry dates are have no adverse effect on their quality and should normally be con-
correctly. Electronic warehouse management systems specified for the materials, the first in/first out principle trolled to ensure the oldest stock is used first.
should be validated. should be applied
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substances for medicinal products for human use annex 06
6.11 Active substances beyond their expiry date 4.17 A process should be in place to ensure that materials Self explanatory
should be separated, either physically or using an that have reached their expiry or retest date should be
equivalent electronic system, from approved stock withdrawn immediately from saleable stock. Materials
and not be supplied. with a retest date should be retested according to the ap-
propriate specifications. Materials with an expiry date
should not be retested or used after that date.
6.12 Where storage or transportation of active sub- Covered with more details upon § 13 Contract activities Self explanatory
stances is contracted out, the distributor should en- See APIC quality agreement templates (reference).
sure that the contract acceptor knows and follows the 13.1 Any activity performed, as referenced in the GMP
appropriate storage and transport conditions. There and GTDP guidelines, delegated to another party, should
must be a written contract between the contract giver be agreed upon in a written contract.
and contract acceptor, which clearly establishes the
duties of each party. The contract acceptor should not 13.2 The contract giver should evaluate the proposed con-
subcontract any of the work entrusted to him under tract acceptor’s compliance with GTDP before entering
the contract without the contract giver’s written au- into an agreement.
thorization.
13.3 All contract acceptors should comply with the re-
quirements in these guidelines. Special consideration
should be given to the prevention of cross-contamination
and to maintaining traceability.
13.4 There should be a written and approved contract or
formal agreement between the contract giver and con-
tract acceptor that addresses and defines in detail the re-
sponsibilities with respect to GTDP and which party is re-
sponsible for which quality measures.
13.5 Subcontracting may be permissible under certain
conditions, subject to approval by the contract giver, es-
pecially for activities such as sampling, analysis, repacking
and relabelling
Deliveries to customer
6.13 Supplies within the EU should be made only by Not detailed as such Recommendation: Official Databases like EudraGMDP database
distributors of active substances registered according provide a source to check Manufacturing and Import authorizations
to Article 52a of Directive 2001/83/EC to other distrib- (MIA’s), GMP/GDP certificates and API registrations of registered
utors, manufacturers or to dispensing pharmacies. manufacturers and distributors.
These should be checked prior to delivery of APIs to the customer.
Article 52a If none of these documents are available in an official database (e.g.
1. Importers, manufacturers and distributors of active EudraGMDP), for example in the case of brokers or pharmacies, it is
recommended that the customer provide them before API dispatch.
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substances for medicinal products for human use annex 06
substances who are established in the Union shall reg- If the manufacturer holds a GMP certification, no separate GDP cer-
ister their activity with the competent authority of the tification is required.
Member State in which they are established. Particular caution is advised if the company being supplied only has
2. The registration form shall include, at least, the fol- a license to broker. In such a case the "delivery address" should be
lowing information: checked, since a broker is typically not allowed to physically receive
(i) name or corporate name and permanent address; pharmaceutical products.
(ii) the active substances which are to be imported, .
manufactured or distributed;
(iii) particulars regarding the premises and the tech-
nical equipment for their activity.
6.14 Active substances should be transported in ac- Requirements covered by the § 12 with more details Self explanatory
cordance with the conditions specified by the manu- Refer to the APIC statement on Good distribution practices for defi-
facturer and in a manner that does not adversely af- 12.1 Materials should be loaded, unloaded and trans- nition of Product temperature range when distributing the product
fect their quality. ported in a manner that will ensure the maintenance of under non-controlled temperature.
Product, batch and container identity should be main- controlled conditions where applicable (e.g. temperature,
tained at all times. All original container labels should protection from the environment). The transport process
remain readable. should not adversely affect the materials. Any carrier used
for transport should be approved according to a written
procedure unless the carrier has been selected by the cus-
tomer.
12.2 Requirements for special transport and/or storage
conditions should be stated on the label and/or in the
transport documentation. If the pharmaceutical starting
material is intended to be transferred outside the control
of the manufacturer’s materials management system, the
name and address of the manufacturer, quality of con-
tents, special transport conditions and any special legal re-
quirements should also be included on the label and/or in
the transport documentation.
12.3 The supplier of the materials should ensure that the
contract acceptor for transportation of the materials is
aware of and provides the appropriate storage and
transport conditions, e.g. through audits.
12.4 Procedures should be in place to ensure proper
cleaning and prevention of cross-contamination when liq-
uids (tanks) and bulk or packed materials are transported
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taking into account ICHQ7 / additional requirements
substances for medicinal products for human use annex 06
6.15 A system should be in place by which the distri- Requirements covered by the § 9.1 & 9.5 Prior to a recall a notification of the competent authority is re-
bution of each batch of active substance can be read- quired. The recall decision should be in agreement with the compe-
ily identified to permit its recall. 9.1 There should be a system for recalling promptly and tent authority.
effectively from the market, materials known or sus-
pected to be defective
9.5 In the event of serious or potentially life-threatening
situations, all customers and competent authorities in all
countries to which a given material may have been distrib-
uted should be promptly informed of any intention to re-
call the material
Transfer of Information
6.16 Any information or event that the distributor be- Partially covered under recall procedure, see §9.5 Recommendation: To ensure a continuous supply of the general
comes aware of, which have the potential to cause an 9.5 In the event of serious or potentially life-threatening public with medicinal products, manufacturers need to know as
interruption to supply, should be notified to relevant situations, all customers and competent authorities in all early as possible about anything that has the potential to disrupt
customers. countries to which a given material may have been distrib- the supply chain. Therefore suppliers/distributors must inform their
uted should be promptly informed of any intention to re- relevant customers if they become aware of any information or
call the material event that has the potential to lead to supply disruptions as agreed
in the quality agreement.
6.17 Distributors should transfer all product quality or Partially covered under recall procedure, see §9.2 and 9.5 Self explanatory
regulatory information received from an active sub-
stance manufacturer to the customer and from the 9.2 The original manufacturer should be informed in the
customer to the active substance manufacturer. event of a recall.
9.5 In the event of serious or potentially life-threatening
situations, all customers and competent authorities in all
countries to which a given material may have been distrib-
uted should be promptly informed of any intention to re-
call the material
6.18 The distributor who supplies the active substance Covered by § 6.3 and 6.5 Self explanatory
to the customer should provide the name and address
of the original active substance manufacturer and the 6.3 Certificates of analysis (COAs) issued by the original
batch number(s) supplied. A copy of the original certif- manufacturer should be provided. If additional testing is
icate of analysis from the manufacturer should be pro- done, all COAs should be provided. COAs should docu-
vided to the customer. ment product traceability back to the manufacturer by
naming the original manufacturer and the manufacturing
site. COAs should indicate which results were obtained by
testing the original material and which results came from
skip-lot testing or other testing and should specify the or-
ganization responsible for issuing the COA.
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on principles of Good Distribution Practice of active WHO TRS N°996, 2016
taking into account ICHQ7 / additional requirements
substances for medicinal products for human use annex 06
6.5 The original manufacturer and the intermediaries han-
dling the material should always be traceable and trans-
parent; and this information should be made available to
authorities and end-users, downstream and upstream,
when requested
6.19 The distributor should also provide the identity of Also covered by § 6.5 Self-explanatory
the original active substance manufacturer to compe-
tent authorities upon request. 6.5 The original manufacturer and the intermediaries han-
The original manufacturer can respond to the compe- dling the material should always be traceable and trans-
tent authority directly or through its authorised parent; and this information should be made available to
agents. (In this context ‘authorised’ refers to author- authorities and end-users, downstream and upstream,
ised by the manufacturer.) when requested
6.20 The specific guidance for certificates of analysis is Not detailed as such, limited information detailed in § 6.3 Self-explanatory
detailed in Section 11.4 of Part II of EudraLex Volume
4. 6.3 Certificates of analysis (COAs) issued by the original
manufacturer should be provided. If additional testing is
done, all COAs should be provided. COAs should docu-
ment product traceability back to the manufacturer by
naming the original manufacturer and the manufacturing
site. COAs should indicate which results were obtained by
testing the original material and which results came from
skip-lot testing or other testing and should specify the or-
ganization responsible for issuing the COA.
Chapter 7 – Returns, complaints and recalls
Returns
7.1 Returned active substances should be identified as Requirements covered by the § 10.1 Returned APIs should be identified as such and held pending resolu-
such and quarantined pending investigation. tion.
10.1 Goods returned to the supplier should be appropri- Procedures for holding, labeling, testing, and any processing of the
ately identified and quarantined. The conditions under returned API should be defined.
which returned goods have been stored and shipped
should be evaluated to determine the quality of the re-
turned goods
7.2 Active substances which have left the care of the Partially covered under § 10.1 and 10.2, with less require- If one of the conditions is not met, the distributor may return the
distributor, should only be returned to approved stock ments material to the manufacturer who has to perform investigation and
if all of the following conditions are met: verify the status of the material and decide if the material may be
(i) the active substance is in the original unopened 10.1 Goods returned to the supplier should be appropri- returned in the approved stock.
container(s) with all original security seals present and ately identified and quarantined. The conditions under In addition to examination, testing of returned product could be
is in good condition; which returned goods have been stored and shipped considered based on a risk assessment.
(ii) it is demonstrated that the active substance has should be evaluated to determine the quality of the re-
been stored and handled under proper conditions. turned goods
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taking into account ICHQ7 / additional requirements
substances for medicinal products for human use annex 06
Written information provided by the customer should
be available for this purpose; 10.2 The quality unit or designee should decide on the dis-
(iii) the remaining shelf life period is acceptable; position of the returned goods following a formal and doc-
(iv) the active substance has been examined and as- umented investigation process. Corrective and preventive
sessed by a person trained and authorised to do so; actions should be taken where appropriate.
(v) no loss of information/traceability has occurred.
This assessment should take into account the nature
of the active substance, any special storage conditions
it requires, and the time elapsed since it was supplied.
As necessary and if there is any doubt about the qual-
ity of the returned active substance, advice should be
sought from the manufacturer.
7.3 Records of returned active substances should be Partially covered under § 10.1 and 10.2, with less require- Self explanatory
maintained. For each return, documentation should ments Records of returned products should be maintained and should in-
include: clude the name of the APIs and the lot number (or batch number),
(i) name and address of the consignee returning the reason for the return, quantity returned, date of disposition, and ul-
active substances; timate fate of the returned API.
(ii) name or designation of active substance, active
substance batch number and quantity returned;
(iii) reason for return;
(iv) use or disposal of the returned active substance
and records of the assessment performed.
7.4 Only appropriately trained and authorised person- Partially covered under § 10.2, with less requirements Self explanatory
nel should release active substances for return to
stock. Active substances returned to saleable stock
should be placed such that the stock rotation system
operates effectively.
Complaints and recalls
7.5 All complaints, whether received orally or in writ- Requirements covered by the § 8 Procedures for holding, labeling, testing, and any processing of the
ing, should be recorded and investigated according to returned APIs or API intermediates should be defined.
a written procedure. In the event of a complaint about 8.1 All complaints and other information concerning po-
the quality of an active substance the distributor tentially defective materials must be carefully reviewed Complaints and information about possible defects during distribu-
should review the complaint with the original active according to written procedures that describe the action tion activities should be systematically documented and investi-
substance manufacturer in order to determine to be taken and specify the criteria on which a decision to gated, based on a written procedure with assigned responsibilities.
whether any further action, either with other custom- recall a product should be based. Records of complaints
ers who may have received this active substance or should be retained and evaluated for trends at defined in- Investigations should be formally conducted and written up in a
with the competent authority, or both, should be initi- tervals. timely manner to establish if the complaint is justified, to identify
ated. The investigation into the cause for the com- root cause(s), to define any initial and/or follow up action(s), and
plaint should be conducted and documented by the 8.2 Any complaint concerning a material defect should be the method of communication, e.g. to the customer, original manu-
appropriate party. recorded and thoroughly investigated to identify the facturer, authorities etc.
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APIC Comments
on principles of Good Distribution Practice of active WHO TRS N°996, 2016
taking into account ICHQ7 / additional requirements
substances for medicinal products for human use annex 06
origin or reason for the complaint (e.g. the repackaging Complaint records should be retained and regularly evaluated for
procedure or the original manufacturing process). Correc- trends, frequency and criticality in order to identify possible addi-
tive and preventive actions should be taken where appro- tional needs for corrective or preventive actions.
priate and recorded.
8.3 If a defect in a pharmaceutical starting material is dis- Investigations should identify whether the reported defect is lim-
covered or suspected, consideration should be given to ited to a single batch of material, or if other batches need to be
whether other batches should be checked. considered as part of the investigation. Any additional batches im-
plicated should be identified accordingly.
8.4 Where necessary, appropriate follow-up action, possi- The original manufacturer of the API has to be informed about de-
bly including a recall, should be taken after investigation fects with a potential impact on the product quality.
and evaluation of the complaint.
8.5 The manufacturer and customers should be informed For product recalls see section 9.
if action is needed following possible faulty manufactur-
ing, packaging, deterioration or any other serious quality
problems with a pharmaceutical starting material
7.6 Complaint records should include: Not detailed as such, limited information detailed in § 9.6 Self-explanatory
(i) name and address of complainant; regarding recall information
(ii) name, title, where appropriate, and phone number
of person submitting the complaint; 9.6 All records should be readily available to the desig- Responsibilities on final decision should be specified in the quality
(iii) complaint nature, including name and batch num- nated person(s) responsible for recalls. These records agreement.
ber of the active substance; should contain sufficient information on materials sup-
(iv) date the complaint is received; plied to customers (including exported materials).
(v) action initially taken, including dates and identity
of person taking the action;
(vi) any follow-up action taken;
(vii) response provided to the originator of complaint,
including date response sent;
(viii) final decision on active substance batch.
7.7 Records of complaints should be retained in order Self-explanatory
to evaluate trends, product related frequencies, and
severity with a view to taking additional, and if appro-
priate, immediate corrective action. These should be
made available during inspections by competent au-
thorities.
7.8 Where a complaint is referred to the original active Partially covered under §8.5 Self-explanatory
substance manufacturer, the record maintained by the
distributor should include any response received from 8.5 The manufacturer and customers should be informed
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APIC Comments
on principles of Good Distribution Practice of active WHO TRS N°996, 2016
taking into account ICHQ7 / additional requirements
substances for medicinal products for human use annex 06
the original active substance manufacturer, including if action is needed following possible faulty manufactur-
date and information provided. ing, packaging, deterioration or any other serious quality
problems with a pharmaceutical starting material.
7.9 In the event of a serious or potentially life-threat- Requirements covered by the § 9 but also § 8.5 with addi- Additionally the original manufacturer of the API should be in-
ening situation, local, national, and/or international tional requirements formed about the situation
authorities should be informed and their advice
sought. 9.1 There should be a system for recalling promptly and
effectively from the market, materials known or sus-
pected to be defective.
9.5 In the event of serious or potentially life-threatening
situations all customers and competent authorities in all
countries to which a given material may have been distrib- Confirmed complaints related to distribution with product quality
uted should be promptly informed of any intention to re- impact should be communicated upstream to the manufacturer and
call the material. also downstream to the customer(s) in case they may have received
product with the same batch number.
8.5 The manufacturer and customers should be informed
if action is needed following possible faulty manufactur-
ing, packaging, deterioration, or any other serious quality
problems with a pharmaceutical starting material.
7.10 There should be a written procedure that defines Requirements covered by the § 9.3 and additional require- There should be established written procedures for the organiza-
the circumstances under which a recall of an active ments with the §9.7 tion of any recall activity; implemented system should be frequently
substance should be considered. tested on functionality (mock recall)
9.3 There should be established written procedures for The effectiveness of recall arrangements should be evaluated on a
the organization of any recall activity; these should be reg- regular basis through mock recalls. A mock recall is intended to
ularly checked and updated. evaluate the traceability system for material distribution and to
confirm that the product can be retrieved in the event of an ad-
9.7 The effectiveness of the arrangements for recalls verse issue.
should be evaluated at regular intervals Functions involved in the supply chain should implement written pro-
cedures to manage API recall (retrieval) promptly and effectively. The
procedure should:
- describe how the process of recall (retrieval) should be managed,
based on the risk involved,
- describe a decision making process with defined responsibilities,
- define the functions involved in the process (e.g. Quality Assurance,
sales, logistics, competent authorities etc.)
- define the steps needed to retrieve the product
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on principles of Good Distribution Practice of active WHO TRS N°996, 2016
taking into account ICHQ7 / additional requirements
substances for medicinal products for human use annex 06
Recalled, quarantined, rejected, or returned products should be
identified and controlled under a quarantine system designed to
prevent their unauthorized distribution and use in manufacturing or
for sale
7.11 The recall procedure should designate who Not detailed as such Self-explanatory
should be involved in evaluating the information, how In case of a recall in addition agents, brokers, distributors should
a recall should be initiated, who should be informed transfer all quality or regulatory information received from an API
about the recall, and how the recalled material should or intermediate manufacturer to the customer and from the cus-
be treated. The designated person (cf. Section 3.1) tomer to the API or intermediate manufacturer.
should be involved in recalls.
Chapter 8 – Self inspections
8.1 The distributor should conduct and record self-in- Requirements covered by the § 9.5 Internal audits should be carried out on a regular basis to determine
spections in order to monitor the implementation of whether the Quality Management System complies with the GDP
and compliance with these guidelines. Regular self-in- 1.9 A system should be in place for the performance of guidelines and to support continuous improvement. Audits and fol-
spections should be performed in accordance with an regular internal audits with the aim of continuous im- low-up actions should be conducted in accordance with docu-
approved schedule. provement. The findings of the audit and any corrective mented procedures. Different areas and functions should be au-
and preventive actions taken, including verification of dited. Audit results should be documented and discussed with the
their effectiveness, should be documented and brought to management personnel responsible for the audited area and,
the attention of the responsible management. where relevant, with company management. Corrective and pre-
ventive actions should be taken in response to non-conformities
identified.
Ongoing oversight of plans and actions should be performed by the
company’s Quality department and senior management.
The auditor should be independent of the area being audited,
knowledgeable in the subject under inspection, and experienced in
audit techniques.
Additional WHO transport guidance 12. Dispatch and transport
12.1 Materials should be loaded, unloaded and trans- See 6.14 of EU GDP
ported in a manner that will ensure the maintenance of
controlled conditions where applicable (e.g. tempera-
ture, protection from the environment). The transport
process should not adversely affect the materials. Any
carrier used for transport should be approved according
to a written procedure unless the carrier has been se-
lected by the customer.
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APIC Comments
on principles of Good Distribution Practice of active WHO TRS N°996, 2016
taking into account ICHQ7 / additional requirements
substances for medicinal products for human use annex 06
. 12.2 Requirements for special transport and/or storage Covered by § 6.14 of EU GDP
conditions should be stated on the label and/or in the
transport documentation. If the pharmaceutical starting
material is intended to be transferred outside the con-
trol of the manufacturer’s materials management sys-
tem, the name and address of the manufacturer, quality
of contents, special transport conditions and any special
legal requirements should also be included on the label
and/or in the transport documentation
12.3 The supplier of the materials should ensure that the Covered by § 6.14 of EU GDP
contract acceptor for transportation of the materials is
aware of and provides the appropriate storage and
transport conditions, e.g. through audits.
12.4 Procedures should be in place to ensure proper Covered by § 6.14 of EU GDP
cleaning and prevention of cross-contamination when
liquids (tanks) and bulk or packed materials are trans-
ported.
12.5 The bulk transport of pharmaceutical starting mate-
rials requires numerous precautions to avoid contamina-
tion and cross-contamination. The best practice is to use
dedicated equipment, tanks or containers.
12.6 Packaging materials and transportation containers
should be suitable to prevent damage to the pharmaceu-
tical starting materials during transport
12.7 For bulk transport, validated cleaning procedures
should be used between loadings, and a list of restricted
previous cargoes must be supplied to the transport com-
panies
12.8 Steps should be taken to prevent unauthorized ac-
cess to the materials being transported
12.9 General international requirements regarding
safety aspects (e.g. prevention of explosion and of con-
tamination of the environment) should be observed.
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Chapter 5 – Glossary of terms
Terms Definition
A specific quantity of material produced in a process or series of processes so that it is expected to
be homogeneous within specified limits. In the case of continuous production, a batch may corre-
Batch
spond to a defined fraction of the production. The batch size can be defined either by a fixed quan-
tity or by the amount produced in a fixed time interval.
A unique combination of numbers, letters and/or symbols that identifies a batch (or lot) and
Batch number
from which the production and distribution history can be determined.
All activities in relation to the sale or purchase of active substances that do not include physical
Brokering of active subs-
handling and that consist of negotiating independently and on behalf of another legal or natural
tances
person.
The demonstration that a particular instrument or device produces results within specified limits by
Calibration comparison with those produced by a reference or traceable standard over an appropriate range of
measurements.
Consignee The person to whom the shipment is to be delivered whether by land, sea or air.
The undesired introduction of impurities of a chemical or microbiological nature, or of foreign mat-
Contamination ter, into or onto a raw material, intermediate, or active substance during production, sampling,
packaging or repackaging, storage or transport.
Distribution of active subs- All activities consisting of procuring, importing, holding, supplying or exporting of active substances,
tances apart from brokering.
Devia Departure from an approved instruction or established standard.
The date placed on the container/labels of an active substance designating the time during
Expiry date which the active substance is expected to remain within established shelf life specifications if
stored under defined conditions, and after which it should not be used.
Any active substance with a false representation of:
a/ its identity, including its packaging and labelling, its name or its components as regards any of
Falsified active substance the ingredients and the strength of those ingredients;
b/ its source, including its manufacturer, its country of manufacture, its country of origin; or
c/ its history, including the records and documents relating to the distribution channels used.
Holding Storing active substances.
A documented description of the operations to be performed, the precautions to be taken and
Procedure
measures to be applied directly or indirectly related to the distribution of an active substance.
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Obtaining, acquiring, purchasing or buying active substances from manufacturers, importers or
Procuring
other distributors.
A systematic process for the assessment, control, communication and review of risks to the qual-
Quality risk management
ity of an active substance across the product lifecycle.
The sum of all aspects of a system that implements quality policy and ensures that quality objec-
Quality system
tives are met (ICH Q9).
The status of materials isolated physically or by other effective means pending a decision on the
Quarantine
subsequent approval or rejection.
Retest date The date when a material should be re-examined to ensure that it is still suitable for use.
All activities of providing, selling, donating active substances to distributors, pharmacists, or manu-
Supplying
facturers of medicinal products.
The record of the individual who performed a particular action or review. This record can be initials,
Signed (signature)
full handwritten signature, personal seal, or authenticated and secure electronic signature.
Transport (transportation) Moving active substances between two locations without storing them for unjustified periods of time.
A documented program that provides a high degree of assurance that a specific process, method, or
system will consistently produce a result meeting pre-determined acceptance criteria.
One of the common validations in the context of GDP is the validation of the transport. If a
transport validation is applicable the following aspects might be considered:
- Outcome of the transport risk assessment
- Parameters to be assessed (Temperature, humidity, light exposure)
Validation - Packaging configuration during transportation
- Modes of transport (e.g. road, air, sea)
- (Transport routes (typically not defined in detail))
- Planned transport duration
- Seasonal considerations (winter, summer)
- Monitoring the transport with corresponding dataloggers
来源：APIC 原料药质量技术文件 · apic.cefic.org