Cefic/APIC "How to do"- Document

ACTIVE PHARMACEUTICAL INGREDIENTS COMMITTEE

GDP for APIs:

“How to do” Document

Interpretation of the WHO Guideline GOOD TRADE AND DISTRIBUTION PRACTICES FOR
PHARMACEUTICAL STARTING MATERIALS and the EU GUIDELINES ON THE PRINCIPLES OF GOOD
DISTRIBUTION PRACTICES FOR ACTIVE SUBSTANCES FOR MEDICINAL PRODUCTS FOR HUMAN
USE

Version 2 – March 2019

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Preamble

The original version of this guidance document has been compiled by a subdivision of the APIC
Good Distribution Practice Task Force on behalf of the Active Pharmaceutical Ingredient Com-
mittee (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
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
1.2 Regulatory applicability ......................................................................................................5
Chapter 2 Scope ..........................................................................................................................6
Chapter 3 General Considerations .............................................................................................7
Chapter 4 Good Distribution Practices for API .........................................................................7
4.1 How to use the “How to do” - Document ............................................................................7
4.2 “How to do” - Document .......................................................................................................8
Chapter 5 – Glossary of terms .......................................................................................................37
Chapter 6 References ................................................................................................................39

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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.
The GMP Part II /ICH Q7 for the manufacturers of API have been the only Guidelines partially cov-
ering GDP for API. These affect more the handling of APIs at the manufacturing site, but not the
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 is
becoming mandatory. The EU Commissions Guideline on principles of Good Distribution practices
of active substances for medicinal products for human use issued on 19 March 2015 is the first
regulatory binding document specifically for distribution activities of APIs.

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 Commissions Guideline on principles
of Good Distribution Practices (GDP) of active substances for medicinal products for human use,
published by the European Commission DG SANCO on 19 March 2015, based on practical experi-
ence.
This guide provides in particular additional explanatory notes to the EU Commissions Guideline on
principles of Good Distribution practices of active substances for medicinal products for human use.
The explanatory notes in this guide are the views of The Active Pharmaceutical Ingredients Commit-
tee (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.
It does provide examples of potential solutions and more detail on how requirements and recom-
mendations 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 shown to be inap-
plicable or replaced by an alternative that can be shown to provide at least an equivalent level of
quality assurance. Hence, « should » does not mean that because it is only a «should», and not a
«must», then this requirement does not have to be met.

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This document is meant to be a “living document” to describe current practice and to help with the
implementation of the EU Commissions Guideline on principles of GDP of active substances for me-
dicinal products for human use. Suggestions and/or questions from industry or regulators to CEFIC
APIC (http://apic.cefic.org) are welcomed. These will be discussed regularly by the industry experts
and clarifications and improvements incorporated into the document.
This document has been written to provide guidance for those companies involved in the distribu-
tion of active pharmaceutical ingredients.
Examples based on practical experience are provided to facilitate the application of GDP. However,
alternative approaches may be acceptable.

Regulatory Requirements
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 medicinal products
for human use, companies should be aware to apply the following to prevent the entry into the
legal supply chain of falsified medicinal products.
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 manufacturer and
distributors sites of active substances.

1.2 Regulatory applicability

EU guideline is applicable to distribution* of active substances for human use within EA countries
since 21 September 2015.

*See paragraph 1.2 of the EU Commissions Guideline on principles of Good Distribution practices
of active substances for medicinal products for human use

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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 significantly new requirement in the EU Fal-
sified Medicines Directive.

In the EU Commissions Guideline on principles of Good Distribution Practices of active substances

for medicinal products for human use, the scope is defined as follows:
1. These guidelines apply to distribution of active substances, as defined in Article 1(3a) of Directive
2001/83/EC, for medicinal products for human use. According to that provision, an active substance
is any substance or mixture of substances intended to be used in the manufacture of a medicinal
product and that, when used in its production, becomes an active ingredient of that product in-
tended to exert a pharmacological, immunological or metabolic action with a view to restoring,
correcting or modifying physiological functions or to make a medical diagnosis.
2. In view of these guidelines, the distribution of active substances for medicinal products for human
use (hereafter 'active substances') is defined as the procuring, importing, holding, supplying or ex-
porting 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 Commissions Guideline on principles of Good Distribution Prac-
tices of active substances for medicinal products for human use, and therefore it follows the same
structure.

This APIC document provides guidance on practical approaches with examples on the application of
EU Commissions GDP guideline for API principles.

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 sys-
tem.
Some sections and/or sub-sections in this document may not apply to all involved parties. This doc-
ument is meant to provide guidance in the application of the GDP; however, alternative approaches
may be acceptable.
Specific guidance on storage conditions are described in regulatory documents as USP chapter <659>
Packaging and Storage Requirements and 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 ICH Q7 / APIC “How to do” Document on ICH Q7. Reference has also been made to the WHO
technical report annex 6 on Good trade and distribution practices for 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 in consideration the potential
inherent risks related to the API or the conditions under which the API is handled and distributed.
The risk assessments should be based on sound scientific evaluation and appropriate risk manage-
ment tools, as referenced for example in ICH Q9.

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4.2 “How to do” - Document

EU Guidelines on GDP 19 March 2015
ICH Q7 / APIC „How to do” Document on ICH
on principles of Good Distribution Practice of active APIC WHO TRS 886 annex 06
Q7
substances for medicinal products for human use
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 Commu-
nity code relating to medicinal products for human use
(OJ L 311, 28.11.2001, p. 67)
They follow the same principles that underlies the guide- Guidelines of 5 November 2013 on Good Distri-
lines of Eudralex Volume 4, Part II, Chapter 17, with re- bution Practice of medicinal products for human
gard to the distribution of active substances and the use reference is to provide overall definition of
Guidelines of 5 November 2013 on Good Distribution the good distribution practices, similarity not ap-
Practice of medicinal products for human use (2). plicable to API
(2) OJ C 343, 23.11.2013, p. 1
These guidelines provide stand-alone guidance on Good
Distribution Practice (GDP) for importers and distribu-
tors of active substances for medicinal products for hu-
man use. They complement the rules on distribution set
out in the guidelines of EudraLex Volume 4, Part II, and
apply also to distributors of active substances manufac-
tured by themselves.
Any manufacturing activities in relation to active sub- Repackaging/relabeling or dividing-up activities
stances, including re-packaging, re-labelling or dividing made during distribution should comply with re-
up, are subject to Commission Delegated Regulation quirements from Commission Delegated Regula-
(EU) No 1252/2014 (3) and EudraLex Volume 4, Part II. tion (EU) No 1252/2014 and EudraLex Volume 4,
(3) Commission Delegated Regulation (EU) No 1252/2014 of 28 Part II.
May 2014 supplementing Directive 2001/83/EC of the European
Parliament and of the Council with regard to principles 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 ac- It is recommended to describe specific require-
tive substances, as laid down in Article 46b of Directive ments (e.g. national requirements) to import API
2001/83/EC.
Distributors of active substances for medicinal products
for human use should follow these guidelines as of 21
September 2015.

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EU Guidelines on GDP 19 March 2015
ICH Q7 / APIC „How to do” Document on ICH
on principles of Good Distribution Practice of active APIC WHO TRS 886 annex 06
Q7
substances for medicinal products for human use
Chapter 1 - Scope
1.1 These guidelines apply to distribution of active sub- Transportation companies do not need to be cer-
stances, as defined in Article 1(3a) of Directive tified by authorities. However, they should follow
2001/83/EC, for medicinal products for human use. Ac- parts of the GDP guideline relevant to their activ-
cording to that provision, an active substance is any sub- ities.
stance or mixture of substances intended to be used in
the manufacture of a medicinal product and that, when It is the responsibility of distributors (GDP certi-
used in its production, becomes an active ingredient of fied parties contracting transporters) to verify
that product intended to exert a pharmacological, immu- that selected transporting companies are able to
nological or metabolic action with a view to restoring, apply these requirements like quality system, ap-
correcting or modifying physiological functions or to propriate personnel, good documentation prac-
make a medical diagnosis. tices…. In relation to the criticality of their activi-
ties.
1.2 For the purpose of these guidelines, distribution of This guideline only applies to distribution activi-
active substances shall comprise all activities consisting ties including transportation (meaning that no
of procuring, importing, holding, supplying or exporting container of product is opened during such activ-
active substances, apart from brokering. ities).

Brokering activities definitions provided in the EU

guideline: All activities in relation 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 ac- The guideline does not apply to intermediates or
tive substances. starting materials. It only applies to active sub-
stances.
According to EU Guideline on GMP for medicinal
products for human and veterinary use; volume
4 part 1 chapter 5 (5.29) supply chain traceability
should be established and the associated risks,
from active substance starting materials to the
finished medicinal product, should be formally
assessed and periodically verified. Appropriate
measures should be put in place to reduce risks
to the quality of the active substance
However, this requirement should be referred to
as Manufacturing Supply Chain traceability up to

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EU Guidelines on GDP 19 March 2015
ICH Q7 / APIC „How to do” Document on ICH
on principles of Good Distribution Practice of active APIC WHO TRS 886 annex 06
Q7
substances for medicinal products for human use
starting material and should not be considered
Distribution Supply Chain Traceability starting
from final API.
Chapter 2 – Quality System
Damage management – responsibility for material to be
distributed
2.1 Distributors of active substances should develop and Parties involved in the distribution of APIs should 2. QUALITY MANAGEMENT Chapter1 with 1.1, 1.2, 1.3, 1.4, 1.5,
maintain a quality system setting out responsibilities, establish a Quality Management System to man- 2.1 Principle 1.6, 1.7, 1.8, 1.9
processes and risk management principles. age the quality of their products and services, to Chapter 2.11 Chapter 2.2
Examples of the processes and applications of quality maintain the original quality of the APIs. As an es- Chapter 17.30
risk management can be found in EudraLex Volume 4, sential prerequisite for any Quality Management Chapter 17.11
Part III: GMP related documents, ICH guideline Q9 on System, the top management should elaborate a
Quality Risk Management (ICH Q9). corporate quality policy. Parties involved should
share responsibility for assuring that the API pro-
vided by the distributor conforms to the mutually
agreed specification requirements of the pharma-
ceutical manufacturer and/or is suitable for the
intended use of the API.
Quality Risk Management principles should be in-
tegrated into the quality management system.
2.2 The quality system should be adequately resourced A system should be in place to control documents Chapter 17.3 Chapter 1.4
with competent personnel, and suitable and sufficient and data that relate to the requirements of the Chapter 2.1 Chapter 13.4 (contract activities)
premises, equipment and facilities. It should ensure that: applicable Quality System. The Quality Manual Chapter 3.1 Chapter 4.1
(i) active substances are procured, imported, held, sup- should include as a minimum the following ele- Chapter 6 with 6.1, 6.2
plied or exported in a way that is compliant with the re- ments: Chapter 1.6, 1.7
quirements of GDP for active substances; - scope of the Quality Management System,
- organizational structure including description of
responsibility of top management,
- written procedures, processes and resources or
reference to them, and
- a description of the sequence and interaction
between the procedures and departmental func-
tions.
The Quality Management System should also in-
clude a procedure to verify that any supplier of
APIs, or relevant service providers has the capa-

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EU Guidelines on GDP 19 March 2015
ICH Q7 / APIC „How to do” Document on ICH
on principles of Good Distribution Practice of active APIC WHO TRS 886 annex 06
Q7
substances for medicinal products for human use
bility to consistently meet previously agreed re-
quirements. This may include periodic audits of
the service providers.
The related computerized system ensuring the
required traceability and data integrity should be
properly installed, qualified and controlled.
(ii) management responsibilities are clearly specified; Refer to chapter 3 for personnel Chapter 2.10 Chapter 13.4 (contract activities)
Chapter 2.13 Chapter 1.4, 1.5
Chapters 2.2 and 2.3 Chapter 1.2
Chapter 2.2
(iii) active substances are delivered to the right recipi- There should be an organization in place to en- Chapter 17 Chapter 13.4 (contract activities)
ents within a satisfactory time period; sure the product is shipped to the right customer. Chapter 10.24
Note: Satisfactory time outlined in the supply
agreement or following service level agreement
should be determined considering the customer
will not be into shortage (refer to chapter 6 oper-
ations).
(iv) records are made contemporaneously; Compliance with good documentation practices, Chapter 2.15 Chapter 6 with 6.1, 6.2
refer to chapter 4 Documentation. Chapter 6.10 (APIC):
ALL data generated should follow ALCOA (At-
tributable, Legible, Current, Original, Accurate)
principles
(v) deviations from established procedures are docu- Chapter 2.16, chapter 2.13 Chapter 11.1, chapter 11.2
mented and investigated; The conclusions of deviations with impact on the Chapter 10.21 (APIC):
product should be risk based. Appropriate protective outer packaging and a
If there are deviations with potential impact on reliable shipper should be chosen to avoid
the product quality (e.g. the storage conditions, damage during transport. For sensitive prod-
damages ….,) the API manufacturer should pro- ucts special shipping conditions should also be
vide support as needed. specified. Records of those conditions should
There should be a communication process in be available to the manufacturer on demand
place between the distributor and the API manu- and at any time.
facturer regarding deviations occurring at distrib- The shipping conditions records should be re-
utor level, to ensure that the reporting of the de- viewed for compliance to the acceptance crite-
viation is performed in a timely manner. Quality ria on arrival. If deviations occurred an investi-
agreements should be in place to cover such re- gation should be initiated and actions justified
quirements and responsibilities. and documented.
Investigations should typically be performed by
the distributor.

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EU Guidelines on GDP 19 March 2015
ICH Q7 / APIC „How to do” Document on ICH
on principles of Good Distribution Practice of active APIC WHO TRS 886 annex 06
Q7
substances for medicinal products for human use
Drug product customer involvement at this step
may be needed depending on the INCOTERM con-
ditions regarding deviations during the distribu-
tion of APIs.
Management of deviations and damages during
storage and transport should be handled with all
of the relevant parties in the supply chain lane.

(vi) appropriate corrective and preventive actions, com- Self-explanatory Chapter 2.16 Chapter 1.9
monly known as ‘CAPA’, are taken to correct deviations Chapter 2.17 Chapter 11.2
and prevent them in line with the principles of quality
risk management;
(vii) changes that may affect the storage and distribution There should be a communication process in Chapter 17.60 Chapter 6.1
of active substances are evaluated. place to ensure that any change at distributor Chapter 13 Chapter 7.8
level (changes to what has been committed and
agreed in the quality agreement) will be assessed
by the manufacturer of the API prior to imple-
menting the change and communicated to the
customer in a timely fashion.

2.3 The size, structure and complexity of the distribu- Appropriate organisation in place with adequate -- Chapter 12.3
tor’s activities should be taken into consideration when number of resources Chapter 13 with 13.1, 13.2, 13.3, 13.4,
developing or modifying the quality system. 13.5
Chapter 3 – Personnel
3.1 The distributor should designate a person at each lo- There should be an organization in place to imple- Chapter 2.10 : Company management should Chapter 1.2: an independent quality
cation where distribution activities are performed who ment and maintain the quality system with a des- empower Quality responsibility unit (or designee), which is responsible
should have defined authority and responsibility for en- ignated representative at each location. Chapter 2.2: Responsibilities of the Quality for
suring that a quality system is implemented and main- The main quality responsibilities should not be Unit(s) all quality-related matters
tained. The designated person should fulfil his responsi- delegated. These responsibilities should be de-
bilities personally. The designated person can delegate scribed in writing e.g. in form of a contract/agree-
duties but not responsibilities. ment between the concerned parties.

3.2 The responsibilities of all personnel involved in the The organization should be documented in an or- Chapter 3.1: Personnel qualifications Chapter 2.1: There should be an ade-
distribution of active substances should be specified in ganizational chart with clear indication of person- Chapter 3.11: the responsibilities of all person- quate organizational structure
writing. The personnel should be trained on the require- nel responsible for distribution activities. Levels of nel engaged in the manufacture of intermedi- Chapter 2.2: Individual responsibilities
ments of GDP for active substances. They should have authorization should be clearly defined in job de- ates and APIs should be specified in writing should be clearly defined
the appropriate competence and experience to ensure scriptions.

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EU Guidelines on GDP 19 March 2015
ICH Q7 / APIC „How to do” Document on ICH
on principles of Good Distribution Practice of active APIC WHO TRS 886 annex 06
Q7
substances for medicinal products for human use
that active substances are properly handled, stored and There should be an adequate number of person- Chapter 3.12: Training should range from Chapter 2.3: All personnel should be
distributed. nel qualified by appropriate education, training “basic introduction” training through to job aware of the principles of the appropri-
and/or experience to perform and supervise ac- specific training ate
tivities concerning API distribution. A system for guidelines, including but not limited to
planning, documentation and follow up of the GTDP
training should be in place.

3.3 Personnel should receive initial and continuing train- Involved personnel should be trained in the han- Chapter 3.12: Chapter 2.2: Personnel should be suit-
ing relevant to their role, based on written procedures dling of the material taking the requirement of The need for GMP training should be periodi- ably qualified, trained
and in accordance with a written training program. the material safety data sheet into account. cally evaluated, conducted if needed and docu- Chapter 2.4: Personnel should receive
Personnel should be trained on the GDP princi- mented as part of the individual training pro- initial and continuing training relevant
ples and the chapters relevant for their field of gram of the employee to their tasks.
responsibility. For transport companies, the Chapter 2.5: Personnel dealing with
training program should fit the intended activi- hazardous materials (…) should be
ties within their responsibility given specific training
All involved personnel should receive initial and
regular follow-up training according to the po-
tential impact of the activities on the API.
Quality standards applied should be part of a
regular training program provided by qualified
individuals and the training should be docu-
mented.
3.4 A record of all training should be kept, and the effec- Records should be maintained listing the name, Chapter 3.12: Chapter 2.4: Training records should
tiveness of training should be periodically assessed and address, and qualifications of any contracted ser- GMP training should be scheduled regularly be maintained
documented. vice provider and the type of service they pro- and conducted according to a plan.
vide. Training records should indicate names of the
people trained, subject of the training in key-
words, date of the training and name of the
trainer.
Chapter 4 - Documentation
4.1 Documentation comprises all written procedures, in- Self-explanatory Chapter 6.15 (ICH Q7) During the retention pe- Chapter 6.10 Records must be kept and
structions, contracts, records and data, in paper or in If computerized systems are used at distributor riod, originals or copies of records should be must be readily available upon request
electronic form. Documentation should be readily availa- level, then the computer systems should be vali- readily available at the establishment where in accordance with GSP (2).
ble or retrievable. All documentation related to compli- dated. the activities described in such records oc-
ance of the distributor with these guidelines should be curred. Records that can be promptly retrieved
made available on request of competent authorities. from another location by electronic or other
means are acceptable.

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EU Guidelines on GDP 19 March 2015
ICH Q7 / APIC „How to do” Document on ICH
on principles of Good Distribution Practice of active APIC WHO TRS 886 annex 06
Q7
substances for medicinal products for human use
Chapter 6.16 (ICH Q7) Specifications, instruc-
tions, procedures, and records can be retained
either as originals or as true copies such as
photocopies, microfilm, microfiche, or other
accurate reproductions of the original rec-
ords…

Chapter 6.11 and 6.12 (APIC)

4.2 Documentation should be sufficiently comprehen- Self-explanatory -- Chapter 6.2 Documents should have
sive with respect to the scope of the distributor’s activi- unambiguous contents: their title, na-
ties and in a language understood by personnel. It ture and purpose should be clearly
should be written in clear, unambiguous language and stated. They should be laid out in an or-
be free from errors. derly manner and be easy to check.
4.3 Any alteration made in the documentation should be Self-explanatory Chapter 6.14 (APIC) No pencil, no white out --
signed and dated; the alteration should permit the read- Refer to good documentation practices for data and no crossing out and no obliteration of an
ing of the original information. Where appropriate, the in paper and in electronic form. original entry that is subsequently corrected.
reason for the alteration should be recorded.
Chapter 6.18 (ICH Q7) If electronic signatures
are used on documents, they should be au-
thenticated and secure.
4.4 Each employee should have ready access to all nec- Self-explanatory -- --
essary documentation for the tasks executed.
Procedures
4.5 Written procedures should describe the distribution Comment: Chapter 10.2 (APIC) 4.5 Written procedures should describe
activities which affect the quality of the active sub- Written procedures need to be in place and re- the distribution activities which affect
stances. This could include receipt and checking of deliv- spective processes implemented. the quality of the active substances.
eries, storage, cleaning and maintenance of the prem- This could include receipt and checking
ises (including pest control), recording of the storage of deliveries, storage, cleaning and
conditions, security of stocks on site and of consign- maintenance of the premises (including
ments in transit, withdrawal from saleable stock, han- pest control), recording of the storage
dling of returned products, recall plans, etc. conditions, security of stocks on site
and of consignments in transit, with-
drawal from saleable stock, handling of
returned products, recall plans, etc.
4.6 Procedures should be approved, signed and dated by Self-explanatory Chapter 2.21 4.6 Procedures should be approved,
the person responsible for the quality system. signed and dated by the person re-
sponsible for the quality system.

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EU Guidelines on GDP 19 March 2015
ICH Q7 / APIC „How to do” Document on ICH
on principles of Good Distribution Practice of active APIC WHO TRS 886 annex 06
Q7
substances for medicinal products for human use
4.7 Attention should be paid to the use of valid and ap- (APIC 2014): 6.11 (ICH Q7) The issuance, revision, supersed- --
proved procedures. Documents should be reviewed reg- Procedures on document control should be es- ing and withdrawal of all documents should be
ularly and kept up to date. tablished. controlled with maintenance of revision histo-
Version control should be applied to procedures. After A revision history of documents should be readily ries.
revision of a document a system should exist to prevent available.
inadvertent use of the superseded version. Changes to procedures should be considered in Chapter 6.11 (APIC):
Superseded or obsolete procedures should be removed the training program Regarding revision of documents, the company
from workstations and archived. should define e.g. in a SOP when and how doc-
uments are revised.. If an electronic system is
used to control the revision and approval of
SOP’s the system should be validated and
found in compliance with data integrity princi-
ples including audit trail.
If a paper based system is used this must be
managed in a controlled manner with Quality
Unit oversight. During the document life cycle
the periodical review of its content should be
performed and documented. If needed the
document should be revised. The revision his-
tory of the document shall be traceable over
the retention period. Where electronic docu-
ment management systems are used the de-
tails of the document history can be retained
in the metadata and so does not have to ap-
pear on the document itself
Records
4.8 Records should be clear, be made at the time each Comment: 6.12 (APIC) --
operation is performed and in such a way that all signifi- Retention periods of documents should be es- It is good industry practice to consider retaining
cant activities or events are traceable. tablished. The security and methods of archiving records for the period of time the drug prod-
Records should be retained for at least 1 year after the and retrieval of such records should be ensured. uct(s) in which the API was used may be availa-
expiry date of the active substance batch to which they Record retention schedule and practices for dis- ble on the market.
relate. tribution records should be specified in the qual- )
For active substances with retest dates, records should ity agreement.
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, Comment: 6.30 (ICH Q7) Records should be maintained --
showing the date of purchase or supply, name of the ac- Recommendation: In addition to records re- including:
tive substance, batch number and quantity received or quested by EU Guidelines on GDP: Quantity of

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substances for medicinal products for human use
supplied, and name and address of the supplier and of each shipment of each batch should also be re- ― The name of the manufacturer, identity
the original manufacturer, if not the same, or of the tained and be available. and quantity of each shipment of each
shipping agent and/or the consignee. Records should en- batch of raw materials, intermediates or la-
sure the traceability of the origin and destination of
belling and packaging materials for API's; …
products, so that all the suppliers of, or those supplied
with, an active substance can be identified. Records that
Chapter 10.24 (APIC)°:
should be retained and be available include:
Full traceability for all shipments from the
I. identity of supplier, original manufacturer, ship-
manufacturer to its external customer(s) has to
ping agent and/or consignee; be in place. If APIs or intermediates are deliv-
II. address of supplier, original manufacturer, ship- ered to a broker, full traceability has to be en-
ping agent and/or consignee; sured by the broker as well according to chap-
III. purchase orders; ter 17. (Remarks: In this case the final user of
IV. bills of lading, transportation and distribution rec- the API is unknown to the API producer, there-
ords; fore full traceability to the end customer
should be the duty of the broker).
V. receipt documents;
VI. name or designation of active substance; Chapter 17.2
VII. manufacturer’s batch number;
VIII. certificates of analysis, including those of the origi- Chapter 11.4
nal manufacturer;
IX. retest or expiry date.

--- (NEW LINE ADDED FOR WHO REQUIREMENTS) --- A distributor should not change the original title 6.30 (APIC) The objective of this record keep- 6.3 Original Certificates of Analysis
and data of the CoA or other quality documents. ing is to trace the above Materials back to the (COAs) should ac-company materials
Whenever possible, the original manufacturer’s suppliers production records and trace forward supplied by manufacturers to suppliers.
documentation should be used, or transcription until the API-batch delivered to individual cus- COAs issued by the manufacturer
of data should be verified. tomers in case of any failure occurring in the should indicate which results were ob-
The original manufacturing site should be identi- supply chain. tained by testing the original material
fied by name or unique identifier on the CoA or and which results came from skip lot
any other document agreed upon with the cus- testing. The use of the Model COA as
tomer adopted by the WHO Expert Commit-
Comment: tee on Specifications for Pharmaceuti-
Records should be readily available and ensure cal Preparations is recommended (1).
traceability of supply chain of products/APIs from 6.5 The original manufacturer and in-
the origin (manufacturer), via suppliers/distribu- termediaries handling the material
tors, to the destination (purchaser)

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substances for medicinal products for human use
should always be traceable and the in-
formation available to authorities and
end-users, downstream and upstream.

--- (NEW LINE ADDED FOR WHO REQUIREMENTS) --- API should normally be released according to Chapter 10.20 (APIC): 6.4 Before any material is sold or dis-
their specification for shipment. In case of API The process of transfer under quarantine tributed, the supplier should ensure
pending final release testing, API could be shipped should be established. Quality unit of both sites that the COAs and results are available
under quarantine when authorized by the quality need to approve the shipment under quaran- and that the results are within the re-
unit, in agreement with customer and according tine and the receiving site cannot use the mate- quired specifications. Alternatively the
to local legislation. Appropriate controls and doc- rial before a CoA of the batch in scope is issued. customer should be informed without
umentation should be in place. Before shipment under quarantine the manu- delay of the results as soon as these
API should remain in quarantine until full release facturing batch record should be reviewed and become available. For each shipment
CoA is obtained by manufacturer. approved by the quality unit the COA should be forwarded to the
pharmaceutical product manufacturer.
Additionally: -- -- 6.9 Relevant storage, handling and
safety data sheets should be available.
Chapter 5 – Premises and Equipment
5.1 Premises and equipment should be suitable and ade- Buildings and facilities used in the distribution of Chapter 4.11 Buildings and facilities should Premises, including laboratory facili-
quate to ensure proper storage, protection from con- APIs should be located, designed, and con- have adequate space for the orderly place- ties, must be located, designed, con-
tamination, e.g. narcotics, highly sensitising materials, structed to facilitate cleaning, maintenance, and ment of equipment and materials to prevent structed, adapted and maintained to
materials of high pharmacological activity or toxicity, operations as appropriate to the type and stage mix-ups and contamination. suit the operations to be carried out.
and distribution of active substances. They should be of handling. Where the equipment itself (e.g., Chapter 4.12 Where the equipment itself (e.g. Their layout and design must aim to
suitably secured to prevent unauthorised access. Moni- closed or contained systems) provides adequate closed or contained systems) provides ade- minimize the risk of errors and permit
toring devices that are necessary to guarantee the qual- protection of the product, such equipment can be quate protection of the material, such equip- effective cleaning and maintenance in
ity attributes of the active substance should be cali- located outdoors. Equipment should be qualified ment can be located outdoors. order to avoid contamination, cross-
brated according to an approved schedule against certi- before use to ensure that it is functioning as in- Chapter 4.13 the flow of materials and person- contamination, mix ups, build-up of
fied traceable standards. tended. nel through the building or facilities should be dust, dirt or waste and, in general, any
designed to prevent mix ups or contamination. adverse effect on the quality of materi-
There should be defined areas or other control Chapter 4.14 there should be defined areas or als.
systems for the following activities: receipt, iden- other control systems for the following activi-
tification and quarantine of incoming products. ties : Measures should be in place to prevent
Sufficient spaces should be available in the ware- -receipt, identification of materials unauthorized persons from
houses to allow efficient movements without Quarantine before release or rejection of inter- entering the premises.
damaging the packaged products as well as to al- mediates and APIs;
low for cleaning. Holding rejected materials before further dis- Suitable supporting facilities and utili-
position (e.g., return, reprocessing or destruc- ties (such as air control, ventilation and
Proper aAccess control of the premises should be tion); lighting) should be in place and appro-
ensured. Storage of released materials; priate to the activities performed, in

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substances for medicinal products for human use
. order to avoid contamination, cross-
Adequate lighting should be provided in all areas 4.20 All utilities that could impact product contamination and degradation of the
to facilitate cleaning, maintenance and proper op- quality (e.g. heating, ventilation and air condi- material. Utilities that could affect
erations. tioning) should be qualified and appropriately product quality should be identified
monitored and action should be taken when and monitored.
Comment : also applicable for 6.7 and 6.8 limits are exceeded.
Drawings for these utilities should be available.

Chapter 4.50 adequate lighting should be pro-

vided in all areas to facilitate cleaning, mainte-
nance, and proper operations.

Chapter 4.21 Adequate ventilation, air filtra-

tion and exhaust systems should be provided,
where appropriate. These systems should be
designed and constructed to minimize risks of
contamination and cross-contamination and
should include equipment for control of air
pressure, microorganisms, dust, humidity and
temperature, as appropriate

Chapter 10.11 (APIC):

Acceptable separate storage areas for such ac-
tivities may solely be marked shelving or floor
spaces with the exception of areas for rejected
or recalled products in which physical barriers
should be utilised to prevent unauthorised use,
e.g. locked cages, are-as or rooms.
Alternative systems may be computerised
stock control with restricted access. These do
not require separated areas.
Physical separation of non-conforming (e.g. re-
turned material) product is necessary. Sepa-
rate identified areas should be used.

Chapter 10.10 (APIC)

--- (NEW LINE ADDED FOR WHO REQUIREMENTS) --- Facilities should also be designed to minimize po- Chapter 7.4 storage Chapter 4.10 Where special storage
tential contamination. The risk of contamination conditions are required (e.g. particular

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substances for medicinal products for human use
and mix up should also be considered in respect Materials should be stored in a way that the temperature, humidity or protection
to the flow of products and personnel through the quality of the raw material cannot be nega- from light) these should be provided,
buildings or facilities. tively influenced taking into account light, monitored and recorded as appropri-
time, temperature and humidity. Sufficient ate.
space should be available in the warehouses to
allow efficient movements without damaging Chapter 4.11 Highly active materials,
the packaged materials as well as to allow for narcotics, other dangerous drugs and
cleaning. It is good practice to store the mate- substances presenting special risks of
rial at sufficient distances from walls. abuse, fire or explosion should be
The floor of the warehouses should be easy to stored in safe, dedicated and secure ar-
clean. eas. In addition and where applicable,
international conventions and national
legislation are to be adhered to.

Chapter 4.12 Special attention should

be given to the design, use, cleaning
and maintenance of all equipment for
bulk handling and storage, such as
tanks and silos.
--- (NEW LINE ADDED FOR WHO REQUIREMENTS) --- A set of current drawings should be maintained Chapter 5.16 A set of current drawings should Chapter 5.1 Equipment must be lo-
for facilities and critical installations (e.g. instru- be maintained for equipment and critical in- cated, designed, constructed, adapted,
mentation and utility systems). Schedules and stallations (e.g. instrumentation and utility sys- qualified, used, cleaned and main-
procedures (including responsibilities) should be tems). tained to suit the operations to be car-
established for the preventive maintenance and ried out.
calibration program of the facility. Chapter 5.2 Equipment Maintenance and Its layout, design and use should aim to
Cleaning minimize the risk of errors
Chapter 5.20 Schedules and procedures (in- and permit effective cleaning and
cluding assignment of responsibility) should be maintenance so as to avoid cross con-
established for the preventative maintenance tamination, build-up of dust or dirt and
of equipment. any adverse effect on the
quality of materials.
Chapter 5.3 Calibration
Chapter 5.30 Control, weighing, measuring, 5.2 Defective equipment should not be
monitoring and test equipment that is critical used and should either be removed or
for assuring the quality of APIs should be cali- labelled as defective. Equipment
brated according to written procedures and an should be disposed of in such a way as
established schedule. to prevent any misuse.

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substances for medicinal products for human use
Chapter 5.31 Equipment calibrations should be 5.3 The status of the equipment should
performed using standards traceable to certi- be readily identifiable.
fied standards, if existing.
Chapter 5.32 Records of these calibrations 5.9 Procedures should be in place for
should be maintained. the operation and maintenance of
Chapter 5.33 The current calibration status of equipment. Lubricants and other mate-
critical equipment should be known and verifi- rials used on surfaces that come into
able. direct contact with the materials
Chapter 5.34 Instruments that do not meet should be of the appropriate grade,
calibration criteria should not be used. e.g. food-grade oil, and should not alter
Chapter 5.35 Deviations from approved stand- the quality of the materials.
ards of calibration on critical instruments
should be investigated to determine if these 5.10 Washing and cleaning equipment
could have had an impact on the quality of the should be chosen and used such that it
…. API(s) manufactured using this equipment cannot be a source of contamination.
since the last successful calibration. Chapter 5.6 Balances and other meas-
uring equipment of an appropriate
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 manu- The EudraGMDP database provides a source to -- --
facturer, importer or distributor established in the EU, check GMP/ GDP certificates and API registrations
that manufacturer, importer or distributor should be of registered API manufacturers, importers and
registered according to Article 52a of Directive distributors.
2001/83/EC. If the supplier cannot be found in the EudraGMDP
database, he should be asked to provide this doc-
umentation.

Receipt
6.2 Areas for receiving active substances should protect Self-explanatory 7.2 Receipt and Quarantine (ICH Q7) 4. Procurement, warehousing and stor-
deliveries from prevailing weather conditions during un- Checklist would be recommended to capture dif- 7.20 Upon receipt and before acceptance, each age
loading. The reception area should be separate from the ferent points. container or grouping of containers of materi- 4.3 Receipt and dispatch bays should
storage area. als should be examined visually for correct la- be equipped with the means to protect
Deliveries should be examined at receipt in order to belling (including correlation between the materials from adverse environmental
check that: name used by the supplier and the in-house conditions. Reception areas should be

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substances for medicinal products for human use
(i) containers are not damaged; name, if these are different), container dam- designed and equipped to allow con-
(ii) all security seals are present with no sign of tamper- age, broken seals and evidence of tampering or tainers of incoming materials to
ing; contamination. Materials should be held under be cleaned before storage if appropri-
(iii) correct labelling, including correlation between the quarantine until they have been sampled, ex- ate. Upon receipt, material should be
name used by the supplier and the in-house name, if amined or tested as appropriate, and released segregated until released by the quality
these are different; for use. unit.
(iv) necessary information, such as a certificate of analy- 7.2 Receipt and Quarantine (APIC)
sis, is available; and Before acceptance of incoming materials the
(v) the active substance and the consignment corre- packaging should be checked visually. The ma-
spond to the order. terials should be sampled, tested and released.
As long as the material is not released it must
be held under quarantine; this can be realised
in different ways e.g. separate areas or
through a validated computer system. These
systems or others may also be used to identify
the status of the material.
Incoming stock materials should be released
before mixing them with the existing stock.
This new stock should get a new lot number.
6.3 Active substances with broken seals, damaged pack- Self-explanatory. See 7.2 above --
aging, or suspected of possible contamination should be
quarantined either physically or using an equivalent
electronic system and the cause of the issue investi-
gated.
6.4 Active substances subject to specific storage Self-explanatory 10. STORAGE AND DISTRIBUTION (ICH Q7) --
measures, e.g. narcotics and products requiring a spe- The specific storage measures should be written 10.1 Warehousing Procedures
cific storage temperature or humidity, should be imme- and communicated to relevant personnel.
diately identified and stored in accordance with written Chapter 10 (APIC):
instructions and with relevant legislative provisions. In general all storage conditions should be es-
tablished based on stability data or suitability
for use information. This data can be derived
from formal stability studies for APIs.

6.5 Where the distributor suspects that an active sub- Self-explanatory. -- --

stance procured or imported by him is falsified, he It is recommended to describe the process of in-
forming the authority in a protocol or procedure.

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substances for medicinal products for human use
should segregate it either physically or using an equiva-
lent electronic system and inform the national compe-
tent authority of the country in which he is registered.
6.6 Rejected materials should be identified and con- Self-explanatory 7.4 Storage (ICH Q7) --
trolled and quarantined to prevent their unauthorised 7.44 Rejected materials should be identified
use in manufacturing and their further distribution. Rec- and controlled under a quarantine system de-
ords of destruction activities should be readily available. signed to prevent their unauthorised use in
manufacturing.
Storage
6.7 Active substances should be stored under the condi- 10. STORAGE AND DISTRIBUTION (ICH Q7) --
tions specified by the manufacturer, e.g. controlled tem- Self-explanatory 10.1 Warehousing Procedures
perature and humidity when necessary, and in such a 10.10 Facilities should be available for the stor-
manner to prevent contamination and/or mix up. Non controlled storage is considered acceptable age of all materials under appropriate condi-
The storage conditions should be monitored and records supported by a risk assessment and temperature tions (e.g. controlled temperature and humidity
maintained. monitoring data of the facility. when necessary). Records should be maintained
The records should be reviewed regularly by the person of these conditions if they are critical for the
responsible for the quality system. Materials should be stored under conditions and maintenance of material characteristics.
for a period that have no adverse effect on their 7.4 Storage (ICH Q7)
quality and should normally be controlled to en- 7.40 Materials should be handled and stored in
sure the oldest stock is used first. a manner to prevent degradation, contamina-
tion, and cross-contamination.
2013/C 343/01 EUROPEAN COMMISSION Guide- 7.41 Materials stored in fiber drums, bags, or
lines on Good Distribution Practice of medicinal boxes should be stored off the floor and, when
products for human use state in Chapter 9.2 last appropriate, suitably spaced to permit cleaning
paragraph “Provision should be made to minimize and inspection.
the duration of temporary storage while awaiting 7.42 Materials should be stored under condi-
the next stage of the transportation route.” tions and for a period that have no adverse ef-
The GDP Group of the ECA Foundation states in its fect on their quality and should normally be
FAQ that “This duration should be specified in controlled so that the oldest stock is used first.
company SOPs based on risk assessment. The cur-
rent industry practice is up to 72 hours storage at
temporary 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 deal with events that
lead to deviations to the temporary storage time
and conditions. The fate of the product should be
decided based on a risk assessment.

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substances for medicinal products for human use
6.8 When specific storage conditions are required, the Self-explanatory. --
storage area should be qualified and operated within the
specified limits.
6.9 The storage facilities should be clean and free from -- --
litter, dust and pests. Adequate precautions should be Materials stored in fibre drums, bags or boxes
taken against spillage or breakage, attack by micro-or- should be stored off the floor and, when appro-
ganisms and cross-contamination. priate, suitably spaced to permit cleaning and in-
spection.

6.10 There should be a system to ensure stock rotation, 7.4 Storage --

e.g. ‘first expiry (retest date), first out’, with regular and Materials should be stored under conditions and 7.42 Materials should be stored under condi-
frequent checks that the system is operating correctly. for a period that have no adverse effect on their tions and for a period that have no adverse af-
Electronic warehouse management systems should be quality and should normally be controlled to en- fect on their quality, and should normally be
validated. sure the oldest stock is used first. controlled so that the oldest stock is used first

6.11 Active substances beyond their expiry date should Self-explanatory 7.2 Receipt and Quarantine (ICH Q7) --
be separated, either physically or using an equivalent 7.20 Upon receipt and before acceptance, each
electronic system, from approved stock and not be sup- container or grouping of containers of materi-
plied. als should be examined visually for correct la-
belling (including correlation between the
name used by the supplier and the in-house
name, if these are different), container dam-
age, broken seals and evidence of tampering or
contamination. Materials should be held under
quarantine until they have been sampled, ex-
amined or tested as appropriate, and released
for use.
6.12 Where storage or transportation of active sub- Self-explanatory 10.2 Distribution Procedures (ICH Q7) --
stances is contracted out, the distributor should ensure See templates of Quality agreements (APIC refer- 10.21 APIs and intermediates should be trans-
that the contract acceptor knows and follows the appro- ence) ported in a manner that does not adversely af-
priate storage and transport conditions. There must be a fect their quality.
written contract between the contract giver and con- 10.23 The manufacturer should ensure that
tract acceptor, which clearly establishes the duties of the contract acceptor (contractor) for trans-
each party. The contract acceptor should not subcon- portation of the API or intermediate knows
tract any of the work entrusted to him under the con- and follows the appropriate transport and stor-
tract without the contract giver’s written authorization. age conditions.

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substances for medicinal products for human use

Chapter 10.21 (APIC):

Logistics companies who are contracted to
move API should be qualified. A quality agree-
ment should also be in place (or equivalent)
which details the key requirements for the safe
and effective transportation of the API.

Deliveries to customer
6.13 Supplies within the EU should be made only by dis- Recommendation: The EudraGMDP database -- --
tributors of active substances registered according to Ar- provides a source to check Manufacturing and
ticle 52a of Directive 2001/83/EC to other distributors, Import authorizations (MIA’s), GMP/GDP certifi-
manufacturers or to dispensing pharmacies. cates and API registrations of registered manu-
facturers and distributors.
These should be checked prior to delivery of APIs
to the customer. If none of these documents are
available on the EudraGMDP database it is rec-
ommended to ask the customer to provide these
prior to API dispatch.
If Manufacturer holds a GMP certification, no sep-
arate GDP certification is required.
.
6.14 Active substances should be transported in accord- Self-explanatory 10.2 Distribution procedures (ICH Q7) --
ance with the conditions specified by the manufacturer Refer to the APIC statement on Good distribution 10.23 Appropriate transport and storage re-
and in a manner that does not adversely affect their practices for definition of Product temperature quirements are typically conveyed to the ship-
quality. range when distributing the product under non- per on the bill of lading. If very special storage
Product, batch and container identity should be main- controlled temperature. conditions are required to avoid alteration, it
tained at all times. All original container labels should re- might be necessary to monitor the shipping
main readable. conditions and to retain records of these con-
ditions.

17. AGENTS, BROKERS, TRADERS,

DISTRIBUTORS, REPACKERS, AND RELABELLERS
(ICH Q7)
17.2 Traceability of Distributed APIs and Inter-
mediates

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substances for medicinal products for human use
17.20 Agents, brokers, traders, distributors, re-
packers, or relabellers should maintain com-
plete traceability of APIs and intermediates
that they distribute. Documents that should be
retained and available include:
− Identity of original manufacturer
− Address of original manufacturer
− Purchase orders
− Bills of lading (transportation documenta-
tion)
− Receipt documents
− Name or designation of API or intermediate
− Manufacturer’s batch number
− Transportation and distribution records
− All authentic Certificates of Analysis, includ-
ing those of the original manufacturer
− Retest or expiry date

Chapter 17.20 (APIC): It is essential that the

identity (i.e. name) and the address of the orig-
inal manufacturer be given to the customer
(see also § 17.61. If the Agent, Broker, Trader,
Repacker, etc. does not know or cannot pro-
vide the name and address of the original man-
ufacturer of the commercially available inter-
mediate or API this would then be a serious vi-
olation of this GMP Guide.
It is already known by many Brokers, Traders,
Re-packers, etc. that one should not accept at
face value certain names and addresses of
companies provided by state con-trolled ex-
port agencies, as their practice of changing the
source of the API depending on which state
company has stocks available are well known.
It should be pointed out that in the EU, if a
"Qualified Person" releases a Medicinal Prod-

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substances for medicinal products for human use
uct made from an API from an unknown manu-
facturer this would be a serious violation of
his/her ethical duties as a "Qualified Person".
The inclusion of the wording "authentic" Certif-
icates of Analysis is to indicate that it is not ac-
ceptable to photocopy the Certificate of Analy-
sis of the original manufacturer onto the letter
heading of the Agent, Broker, Trader, etc.
It is a current expectation that besides the doc-
uments listed in the ICHQ7 there should be a
written statement on regulatory and quality re-
quirements such as: TSE/BSE – heavy met-
als/catalysts – residual solvent ... from the
manufacturer if applicable
In general the customer should receive all nec-
essary information to fulfill his Regula-tory and
Legal obligations.

6.15 A system should be in place by which the distribu- Self-explanatory 10.2 Distribution procedures (ICH Q7) --
tion of each batch of active substance can be readily 10.24 A system should be in place by which the
identified to permit its recall. distribution of each batch of intermediate
and/or API can be readily determined to per-
mit its recall.

Chapter 10.24 (APIC): Full traceability for all

shipments from the manufacturer to its exter-
nal customer(s) has to be in place. If APIs or in-
termediates are delivered to a broker, full
traceability has to be ensured by the broker as
well according to chapter 17. (Remarks: In this
case the final user of the API is unknown to the
API producer, therefore full traceability to the
end customer should be the duty of the bro-
ker).

Transfer of Information

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substances for medicinal products for human use
6.16 Any information or event that the distributor be- Recommendation: To ensure a continuous sup- -- --
comes aware of, which have the potential to cause an in- ply of the general public with medicinal prod-
terruption to supply, should be notified to relevant cus- ucts, manufacturers need to know as early as
tomers. possible about anything that has the potential to
disrupt the supply chain. Therefore suppliers/dis-
tributors must inform their relevant customers if
they become aware of any information or event
that has the potential to lead to supply disrup-
tions as agreed in the quality agreement.
6.17 Distributors should transfer all product quality or Self-explanatory 17 AGENTS, BROKERS, TRADERS, --
regulatory information received from an active sub- DISTRIBUTORS, REPACKERS, AND RELABELLERS
stance manufacturer to the customer and from the cus- 17.6 Transfer of Information
tomer to the active substance manufacturer. 17.60 Agents, brokers, distributors, repackers,
or relabellers should transfer all quality or reg-
ulatory information received from an API or in-
termediate manufacturer

Chapter 17.60 (APIC):

This section is included to ensure that infor-
mation which would normally be trans-ferred
by the API manufacturer to the dosage form
manufacturer (In General the cus-tomer should
receive all necessary information to fulfill his
Regulatory and Legal obligations) as required
under § 13.17 is transferred instead to the
Agent, Broker, Trader, Re-packer, etc.
The meaning of "all quality and regulatory in-
formation received from the API manu-fac-
turer" means much more than the information
listed in § 17.20 and would of course cover any
changes made by the manufacturer to the pro-
cess, the specifications (specifically the dele-
tion of a test parameter) the test methods or
the retest date.
6.18 The distributor who supplies the active substance Self-explanatory 17. AGENTS, BROKERS, TRADERS, --
to the customer should provide the name and address of DISTRIBUTORS, REPACKERS, AND RELABELLERS
the original active substance manufacturer and the 17.6 Transfer of Information

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substances for medicinal products for human use
batch number(s) supplied. A copy of the original certifi- 17.61 The agent, broker, trader, distributor, re-
cate of analysis from the manufacturer should be pro- packer, or relabeller who supplies the API or
vided to the customer. intermediate to the customer should provide
the name of the original API or intermediate
manufacturer and the batch number(s) sup-
plied.

Chapter 17.61 (APIC):

This is an unequivocal statement, specifically
inserted in the ICH Q7 guide at the request of
the dosage form manufacturers and supported
by the authorities. It makes it clear that the
process of covering up the source of APIs,
("neutralizing"), is no longer acceptable.
It is a current expectation that traceability
must be assured over the full supply chain and
a system should be in place to control supply
chain integrity.
6.19 The distributor should also provide the identity of Self-explanatory 17. AGENTS, BROKERS, TRADERS, --
the original active substance manufacturer to competent DISTRIBUTORS, REPACKERS, AND RELABELLERS
authorities upon request. 17.6 Transfer of Information
The original manufacturer can respond to the competent 17.62 The agent should also provide the iden-
authority directly or through its authorised agents. (In tity of the original API or intermediate manu-
this context ‘authorised’ refers to authorised by the facturer to regulatory authorities upon re-
manufacturer.) quest. The original manufacturer can respond
to the regulatory authority directly or through
its authorized agents, depending on the legal
relationship between the authorized agents
and the original API or intermediate manufac-
turer.

Chapter 17.62 (APIC):

The authorities expect that Agents, Brokers,
Traders, Re-packers, etc. will not only comply
with this guide but also actively cooperate with
the authorities to clarify matters which only
the Agents, Brokers, Traders, Re-packers, etc.
may be aware of. Hence when the authorities

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substances for medicinal products for human use
have reasons to involve Agents, Brokers, Trad-
ers, Re-packers, etc. in their investigations, the
latter are obliged to respond to "a request" in
a timely manner. Agents, Brokers, Traders, Re-
packers, etc. should therefore, in order to min-
imize any risks to patients, reply promptly and
fully to such requests for information from the
authorities.

6.20 The specific guidance for certificates of analysis is Self-explanatory 11.4 Certificates of Analysis --
detailed in Section 11.4 of Part II of Eudralex Volume 4. 11.40 Authentic: true, accurate record of re-
sults obtained, signed (also electronically) by
authorised person (from Q-Unit) and dated for
every batch (API and/or Intermediate) that is
released from the manufacturing site.
11.41 The Certificate of Analysis requires the
date of manufacture (there must be a proce-
dure that describes how the manufacturing
date is defined. Preferably be set by the final
purification step of the API).
Retest and expiry dates are calculated from the
manufacturing date.
11.42 Actual values should be reported if nu-
merical results are obtained.
If the result is lower than the limit of detection
(LOD) the result is reported as “not detected”
(ND).
If the result is between the LOD and limit of
Quantification (LOQ) the result is re-ported as
< LOQ.
Results above the LOQ must be reported with
the actual numerical result.
Non-numeric results can be reported as “Con-
forms or complies”.
Certificates should make reference to the ana-
lytical test methods used. This can be done by
referring each individual test ID on the CoA or

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substances for medicinal products for human use
by making a reference to the overall specifica-
tion used.
Certificates of Analysis for blended batches
should be based on the results of sampling and
testing the blend and not just taken from one
of the components.
11.43 The signature can be a manual signature
or produced by a validated computer system
which provides a degree of control equivalent
to a manual signature.
The certificate of analysis should allow tracea-
bility to the original manufacturing site(source)
and the way to contact the organisation that
issues it.
Chapter 7 – Returns, complaints and recalls
Returns
7.1 Returned active substances should be identified as Returned APIs should be identified as such and 14.5 Returns 10.1 Goods returned to the supplier
such and quarantined pending investigation. held pending resolution. should be appropriately identified and
Procedures for holding, labeling, testing, and any 10. STORAGE AND DISTRIBUTION handled in accordance with a proce-
processing of the returned API should be de- 10.1 Warehousing Procedures 10.11 dure addressing at least the keeping of
fined. the material in quarantine in a dedi-
cated area, and its assessment and dis-
17. AGENTS, BROKERS, TRADERS, position by a designated person.
DISTRIBUTORS, REPACKERS, AND RELABELLERS Where any doubt arises over the qual-
17.8 Handling of Returns 17.80 (APIC) ity of the materials, they should not be
It is a current expectation that system should considered suitable for reissue or re-
be in place to evaluate the disposition decision use.
of returned materials. Control of the presence
of the proper unique sealing for container in-
tegrity and information about storage condi-
tions outside control of the agents, broker...
should be available for the decision-making
process. If the proper unique seal or storage
conditions are not available or known rejecting
and destroying the product is advised.

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substances for medicinal products for human use
7.2 Active substances which have left the care of the dis- If one of the conditions is not met, the distribu- -- --
tributor, should only be returned to approved stock if all tor may return the material to the manufacturer
of the following conditions are met: who has to perform investigation and verify the
(i) the active substance is in the original unopened con- status of the material and decide if the material
tainer(s) with all original security seals present and is in may be returned in the approved stock.
good condition; In addition to examination, testing of returned
(ii) it is demonstrated that the active substance has been product could be considered based on a risk as-
stored and handled under proper conditions. Written in- sessment.
formation provided by the customer should be available
for this purpose;
(iii) the remaining shelf life period is acceptable;
(iv) the active substance has been examined and as-
sessed by a person trained and authorised to do so;
(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 re-
quires, and the time elapsed since it was supplied. As
necessary and if there is any doubt about the quality of
the returned active substance, advice should be sought
from the manufacturer.
7.3 Records of returned active substances should be Self-explanatory -- --
maintained. For each return, documentation should in- Records of returned products should be main-
clude: tained and should include the name of the APIs
(i) name and address of the consignee returning the ac- and the lot number (or batch number), reason
tive substances; for the return, quantity returned, date of disposi-
(ii) name or designation of active substance, active sub- tion, and ultimate fate of the returned API.
stance 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 personnel Self-explanatory -- --
should release active substances for return to stock. Ac-
tive substances returned to saleable stock should be
placed such that the stock rotation system operates ef-
fectively.
Complaints and recalls

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substances for medicinal products for human use
7.5 All complaints, whether received orally or in writing, Procedures for holding, labeling, testing, and any 10. STORAGE AND DISTRIBUTION 9.1 There should be a system for re-
should be recorded and investigated according to a writ- processing of the returned APIs or API intermedi- 10.2 Distribution Procedures calling promptly and effectively from
ten procedure. In the event of a complaint about the ates should be defined. 10.24 the market, materials known or sus-
quality of an active substance the distributor should re- pected to be defective.
view the complaint with the original active substance Complaints and information about possible de-
manufacturer in order to determine whether any further fects during distribution activities should be sys-
action, either with other customers who may have re- tematically documented and investigated, based
ceived this active substance or with the competent au- on a written procedure with assigned responsi-
thority, or both, should be initiated. The investigation bilities.
into the cause for the complaint should be conducted
and documented by the appropriate party.

Investigations should be formally conducted and

written up in a timely manner to establish if the
complaint is justified, to identify root cause(s), to 10. STORAGE AND DISTRIBUTION 9.4 All recalled materials should be
define any initial and/or follow up action(s), and 10.1 Warehousing Procedures stored in a secure, segregated area
the method of communication, e.g. to the cus- 10.11 while their fate is decided.
tomer, original manufacturer, authorities etc. 7. MATERIALS MANAGEMENT
Complaint records should be retained and regu- 7.4 Storage
larly evaluated for trends, frequency and critical- 7.44
ity in order to identify possible additional needs
for corrective or preventive actions.

15. COMPLAINTS AND RECALLS 8.1 All complaints and other infor-
Investigations should identify whether the re- 15.10 mation concerning potentially defec-
ported defect is limited to a single batch of mate- 15.13 tive materials must be carefully re-
rial, or if other batches need to be considered as 17. AGENTS, BROKERS, TRADERS, viewed according to written proce-
part of the investigation. Any additional batches DISTRIBUTORS, REPACKERS, AND RELABELLERS dures that describe the action to be
implicated should be identified accordingly. 17.7 Handling of Complaints and Recalls taken, and including the criteria on
The original manufacturer of the API has to be in- 17.70 APIC: which a decision to recall a product
formed about defects with a potential impact on It is a current expectation that any relevant should be based.
the product quality. critical complaint or request for recall related
to the customer should immediately be in-
formed to the related customers and suppliers. 8.2 Any complaint concerning a mate-
For product recalls see section 9. rial defect should be recorded and

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substances for medicinal products for human use
17.71 APIC: thoroughly investigated to identify the
It is a current expectation that the outcome of origin or reason for the complaint (e.g.
any relevant critical investigation and correc- the repackaging procedure, the original
tive/preventive actions defined related to the manufacturing
customer should be informed promptly to the process, etc.).
customer(s). And it is also current expectation
that a system should be in place to assure a re-
call of all products involved can be accom-
plished in a timely manner. A regular Mock re-
call audit/exercise, on the most complex distri-
bution system, is advised to be performed and
documented. Legal time frames for reporting
potential recalls to Health Authorities and cus- 8.3 If a defect in a pharmaceutical
tomers should be followed. starting material is discovered or sus-
pected, consideration should be given
6. DOCUMENTATION AND RECORDS as to whether other batches should be
6.5 Batch Production Records (Batch Produc- checked.
tion and Control Records)
6.53 (APIC): An investigation has to be set up 8.4 Where necessary, appropriate fol-
at every critical deviation when the origin of low-up action, possibly including a re-
the deviation or when the impact on the prod- call, should be taken after investigation
uct quality isn’t known. A SOP on investiga- and evaluation of the complaint.
tions of critical process deviations should de-
fine what is to be understood by critical. Com-
pare other (related) batches with the same de-
viation. Use of the principles in ICH Q9 (Quality
risk assessment) is a very useful way to classify
critical deviations

15. COMPLAINTS AND RECALLS

15.12

6. DOCUMENTATION AND RECORDS

6.5 Batch Production Records (Batch Produc-
tion and Control Records)
6.53
15. COMPLAINTS AND RECALLS
15.13

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substances for medicinal products for human use
15.14
17. AGENTS, BROKERS, TRADERS,
DISTRIBUTORS, REPACKERS, AND RELABELLERS
17.7 Handling of Complaints and Recalls
17.71
7.6 Complaint records should include: Self-explanatory 17. AGENTS, BROKERS, TRADERS, 9.6 All records should be readily availa-
(i) name and address of complainant; DISTRIBUTORS, REPACKERS, AND RELABELLERS ble to the designated person(s) respon-
(ii) name, title, where appropriate, and phone number of 17.2 Traceability of Distributed APIs and Inter- sible for recalls. These records should
person submitting the complaint; Responsibilities on final decision should be speci- mediates contain sufficient information on mate-
(iii) complaint nature, including name and batch number fied in the quality agreement. 17.20 rials supplied to customers (including
of the active substance; exported materials).
(iv) date the complaint is received;
(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, in-
cluding date response sent;
(viii) final decision on active substance batch.
7.7 Records of complaints should be retained in order to Self-explanatory Chapter 17.71
evaluate trends, product related frequencies, and sever-
ity with a view to taking additional, and if appropriate,
immediate corrective action. These should be made
available during inspections by competent authorities.
7.8 Where a complaint is referred to the original active Self -explanatory refer to 17.60 ICH Q7 (WHO 8.5)
substance manufacturer, the record maintained by the
distributor should include any response received from
the original active substance manufacturer, including
date and information provided.
7.9 In the event of a serious or potentially life-threaten- Additionally the original manufacturer of the API 15. COMPLAINTS AND RECALLS 9.5 In the event of serious or poten-
ing situation, local, national, and/or international au- should be informed about the situation 15.15 tially life-threatening situations all cus-
thorities should be informed and their advice sought. tomers and competent authorities in
all countries to which a given material
may have been distributed should be
promptly informed of any intention to
recall the material.

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on principles of Good Distribution Practice of active APIC WHO TRS 886 annex 06
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substances for medicinal products for human use
Confirmed complaints related to distribution 17. AGENTS, BROKERS, TRADERS, 8.5 The manufacturer and customers
with product quality impact should be communi- DISTRIBUTORS, REPACKERS, AND RELABELLERS should be informed if action is needed
cated upstream to the manufacturer and also 17.6 Transfer of Information following possible faulty manufactur-
downstream to the customer(s) in case they may 17.60 ing, packaging, deterioration, or any
have received product with the same batch num- other serious quality problems with a
ber. pharmaceutical
starting material.
7.10 There should be a written procedure that defines There should be established written procedures 15. COMPLAINTS AND RECALLS 9.3 There should be established written
the circumstances under which a recall of an active sub- for the organization of any recall activity; imple- 15.13 procedures for the organization of any
stance should be considered. mented system should be frequently tested on 15.14 recall activity; these should be regularly
functionality (mock recall) checked and updated.
The effectiveness of the arrangements for recalls 9.7 The effectiveness of the arrange-
should be evaluated on regular basis via so called ments for recalls should be evaluated
Mock recall. at regular intervals
Mock recall is to evaluate the traceability system
in material distribution and to ensure that the
product can be returned in case of any adverse
problem.
Functions involved in the supply chain should im-
plement written procedures to manage API recall
(retrieval) promptly and effectively. The proce-
dure 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 au-
thorities etc.)
- define the communication process and docu-
mentation, and
- define the steps needed to retrieve the product

Recalled, quarantined, rejected, or returned

products should be identified and controlled un-
der a quarantine system designed to prevent

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substances for medicinal products for human use
their unauthorized distribution and use in manu-
facturing or for sale

7.11 The recall procedure should designate who should Self-explanatory -- .

be involved in evaluating the information, how a recall In case of a recall in addition agents, brokers, dis-
should be initiated, who should be informed about the tributors should transfer all quality or regulatory
recall, and how the recalled material should be treated. information received from an API or intermedi-
The designated person (cf. Section 3.1) should be in- ate manufacturer to the customer and from the
volved in recalls. customer to the API or intermediate manufac-
turer.
Chapter 8 – Self inspections
8.1 The distributor should conduct and record self-in- Internal audits should be carried out on a regular 2.2 Responsibilities of the Quality Unit(s) 1. Quality management
spections in order to monitor the implementation of and basis to determine whether the quality manage- 7. Making sure that internal audits (self-inspec- 1.9 A system should be in place for the
compliance with these guidelines. Regular self-inspec- ment system complies with the GDP guidelines tions) are performed; performance of regular internal audits
tions should be performed in accordance with an ap- and with the aim to have continuous improve- 2.4 Internal Audits (Self Inspection) with the aim of continuous improve-
proved schedule. ment. The audit and follow up actions should be 2.40 In order to verify compliance with the ment. The findings of the audit and any
carried out in accordance with documented pro- principles of GMP for APIs, regular internal au- corrective and preventive actions
cedures. Different areas and functions need to dits should be performed in accordance with taken, including verification of their ef-
be audited. Audit results should be documented an approved schedule. fectiveness, should be documented
and discussed with management personnel hav- 2.41 Audit findings and corrective actions and brought to the attention of the re-
ing responsibility in the area audited and, if rele- should be documented and brought to the at- sponsible management.
vant, to the firm management. Furthermore, cor- tention of responsible management of the
rective action and preventive action should be firm. Agreed corrective actions should be com-
undertaken on the non-conformities found. pleted in a timely and effective manner.
Ongoing oversight of the plans and actions
should be performed by the firm's Quality de-
partment and by the senior management.
The Auditor should be independent of the areas
subjected to audit and knowledgeable with in-
spected subjects and experienced in auditing
skills.

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Chapter 5 – Glossary of terms

Terms Definition
A specific quantity of material produced in a process or series of pro-
cesses so that it is expected to be homogeneous within specified lim-
its. In the case of continuous production, a batch may correspond to
Batch
a defined fraction of the production. The batch size can be defined
either by a fixed quantity or by the amount produced in a fixed time
interval.
A unique combination of numbers, letters and/or symbols that iden-
Batch number tifies a batch (or lot) and from which the production and distribution
history can be determined.
All activities in relation to the sale or purchase of active substances
Brokering of active subs-
that do not include physical handling and that consist of negotiating
tances
independently and on behalf of another legal or natural person.
The demonstration that a particular instrument or device produces
results within specified limits by comparison with those produced by
Calibration
a reference or traceable standard over an appropriate range of meas-
urements.
The person to whom the shipment is to be delivered whether by
Consignee
land, sea or air.
The undesired introduction of impurities of a chemical or microbio-
logical nature, or of foreign matter, into or onto a raw material, inter-
Contamination
mediate, or active substance during production, sampling, packaging
or repackaging, storage or transport.
Distribution of active All activities consisting of procuring, importing, holding, supplying or
substances exporting of active substances, apart from brokering.
Deviation Departure from an approved instruction or established standard.
The date placed on the container/labels of an active substance desig-
nating the time during which the active substance is expected to re-
Expiry date
main within established shelf life specifications if stored under de-
fined 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 the ingredients and the strength of
Falsified active subs- those ingredients;
tance 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 dis-
tribution channels used.
Holding Storing active substances.
A documented description of the operations to be performed, the
Procedure precautions to be taken and measures to be applied directly or indi-
rectly related to the distribution of an active substance.
Obtaining, acquiring, purchasing or buying active substances from
Procuring
manufacturers, importers or other distributors.
A systematic process for the assessment, control, communication
Quality risk management and review of risks to the quality of an active substance across the
product lifecycle.
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The sum of all aspects of a system that implements quality policy and
Quality system
ensures that quality objectives are met (ICH Q9).
The status of materials isolated physically or by other effective
Quarantine
means pending a decision on the subsequent approval or rejection.
The date when a material should be re-examined to ensure that it is
Retest date
still suitable for use.
All activities of providing, selling, donating active substances to dis-
Supplying
tributors, pharmacists, or manufacturers of medicinal products.
The record of the individual who performed a particular action or re-
Signed (signature) view. This record can be initials, full handwritten signature, personal
seal, or authenticated and secure electronic signature.
Transport (transporta- Moving active substances between two locations without storing
tion) them for unjustified periods of time.
A documented program that provides a high degree of assurance
Validation that a specific process, method, or system will consistently produce a
result meeting pre-determined acceptance criteria.

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Chapter 6 References

“GOOD TRADE AND DISTRIBUTION PRACTICES FOR PHARMACEUTICAL STARTING MATERIALS”

World Health Organization, WHO Technical Report Series, No. 996 annexe 06

“GUIDELINES ON THE PRINCIPLES OF GOOD DISTRIBUTION PRACTICES FOR ACTIVE SUBSTANCES FOR
MEDICINAL PRODUCTS FOR HUMAN USE”
European Commission, March 2015

ICH quality documents (EU GMP Part II) “GOOD MANUFACTURING PRACTICE GUIDE FOR ACTIVE
PHARMACEUTICAL INGREDIENTS Q7”
Current Step 4 version, dated 10 November 2000
http://www.ich.org/products/guidelines/quality/article/quality-guidelines.html

ICH quality documents (EU GMP Part II) “QUALITY RISK MANAGEMENT Q9”
Current Step 4 version, dated 9 November 2005
http://www.ich.org/products/guidelines/quality/article/quality-guidelines.html

GMPs for APIs: “How to do” document, Interpretation of the ICH Q7 Guide,
ACTIVE PHARMACEUTICAL INGREDIENTS COMMITTEE, Version 9, update August 2016

European Commission
GOOD DISTRIBUTION PRACTICE FOR MEDICINAL PRODUCTS FOR HUMAN USE
QUESTIONS AND ANSWERS - VERSION 1.0 - 13 November 2013

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