No

Issue 29 | Nov/Dec 2020

29

ECA´S GOOD PRACTICE GUIDE

INTEGRATED QUALIFICATION
AND VALIDATION
Blind trust in Pharma Con- Particularities Medicinal pro-
supplier certi- gress Production of Russian GMP ducts or dietary
ficates and in- & Technology inspections supplements?
adequate final 2020 live online
testing
 Editoral
Publisher:
CONCEPT HEIDELBERG GmbH
Qualification and validation: lean and cost-efficient – Rischerstraße 8
is that possible? 69123 Heidelberg
HRB Mannheim Nr. 705125

Hardly any other topic is so closely connected with the production of large quan- General Manager:
Oliver Schmidt
tities of paper as that of validation and qualification. DQ, IQ, OQ and PQ docu-
ments are created by the folder. But is that really necessary? Is it possible to Chief Editors:
Oliver Schmidt
streamline documentation and processes and still act in accordance with EU and Wolfgang Heimes
FDA GMP regulations?
Editors:
Dr Gerhard Becker
Together with representatives from the pharmaceutical industry, system manu- Dr Robert Eicher
facturers and engineering companies, an ECA Foundation task force has created Dr Markus Funk
Anne-Theresa Guenster
a Good Practice Guide. Two drafts were presented and discussed at international Dr Andrea Kuehn-Hebecker
conferences. Now the final version is available. On 40 pages, it describes how a Dr Andreas Mangel
Sven Pommeranz
"lean qualification" with the involvement of suppliers can be successfully imple- Oliver Schmidt
mented nowadays. It shows how repeated execution of one and the same test in Wolfgang Schmitt
Axel H. Schroeder
different qualification phases (FAT, SAT, IQ or OQ) can be avoided.
Editors of this Issue:
Sven Pommeranz
Please read the article of my colleague Mr. Sven Pommeranz, who was actively Dr Gerhard Becker
involved in the creation of the guide. Further interesting GMP topics can be found Dr Robert Eicher
Alexander Podarewski
in this issue. Dr Markus Funk

Graphic Concept:
Enjoy reading! Rebecca Illi
Oliver Schmidt
Production:
abcdruck GmbH
Waldhofer Straße 19
69123 Heidelberg

Contact:
[email protected]

Content Any reprints of text and

images require specific
pre-approval by the
editorial office.
Photo Credits:
4 Cover story Final Version: ECA´s Good Practice Guide Integrated Cover/Page 4: iStock, ID: 873419014

4
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Qualification and Validation Page 9: AdobeStock, ID: 31903818
A guide to effective qualification based on Customer – Supplier Partnership Page 12: iStock, ID: 1153276321
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6 Blind trust in supplier certificates and inadequate final testing Help us improve the

6
Facts, trends and important documents - An analysis of current warning letters quality of the GMP
Journal. Follow this
QR-Code and rate the
articles inside this
issue:
9 Pharma Congress 2020: Exchanging ideas and experiences online

9
The Pharma Congress Production & Technology took place online for the first time this year.
Here are some of its highlights.

12 Particularities of Russian GMP inspections from a specialist interpreter's

12
point of view
Many European pharmaceutical companies seek to enter the Russian market, but have little
2 to no experience with the Russian authorities and their inspectors.

14 GDP for APIs

14
The new "Guidance on interpretation and implementation" of the ECA Foundation and
Pharmaceutical Quality Group of the Chartered Quality Institute.
NEWS FROM OUR ASSOCIATION
www.eca-foundation.org

The final version is thus a comprehensive revision, also com-

In the following you can find again what prising new chapters about process validation and equipment
the ECA’s Interest and Working Groups qualification as well as a new chapter on electronic qualifica-
have been working on so far in 2020. tion. The final version will be published at a Launch Confer-
ence 27/28 October 2020 (see also p. 4-5 of this issue).
Dr Afshin Hosseiny ƒ A face-to-face meeting of the above mentioned task force was
(Chairman ECA Foundation) planned before the Launch Conference on 26 October 2020.
Due to Covid-19 this meeting will be organized online. Due to
this pandemic courses/conferences are also already and – for
the time being – will continue to be conducted online.
European QP Association ƒ A survey about electronic documentation in qualification pro-
ƒ To revise the European QP Association’s Good Practice Guide jects was published in the GMP-News.
Ulrich Kissel sent out an updated and revised draft for com- www.validation-group.org
ments. The final version is planned to be available for publica-
tion until November.
ƒ The results of the survey on Remote QP Certification were European GDP Association
published on the EQPA Website (Members’ Area) and in the ƒ Emil Schwan was invited to join the Advisory Board and accept-
EQPA Membership Letter. ed his nomination. From 2017 until May 2020 Emil Schwan was
ƒ The QP Association’s IMP-Working Group has set up a survey a Member of the GDP Association Authority Advisory Board.
on “Compassionate Use / Managed Access Release Require- After eight years working for the Swedish Medical Products
ments” to help getting an overview of the various regulatory Agency (MPA), he decided to leave the agency. He is now work-
requirements and concepts. ing as a Senior Consultant for RegSmart Life Science AB.
ƒ Background: Non-approved medicines can be made available ƒ The next board meeting will take place in June 2021.
to patients suffering from life-threatening or serious medical ƒ The final document “GDP for active substances guidance on
conditions where no satisfactory treatment option exists. interpretation and implementation” has been published in
ƒ Numerous concepts exist that can apply to individual patients June 2020. Since August 2020, the interactive PDF version is
or groups of patients. These concepts relate to products that accessible free of charge in the member's area of the European
are typically in Clinical Development and/or a Market Authori- GDP Association website. The GDPA website was updated
zation Application is ongoing. Such concepts are named e.g. accordingly.
compassionate use, named patient use, expanded access, ƒ A GMP and GDP Conference is scheduled to take place in June
managed access, pre-approval access, post-trial access, and 2021. The second day will be a “joint day” – the GMDP Forum.
others. A draft version of the agenda was created. First speakers were
ƒ EQPA has sent the team´s consolidated final version of com- already invited.
ments to the Annex 21 draft to the EU Commission. The team ƒ Markus Funk wrote an article about “GDP für Wirkstoffe“ (GDP
was working hard and collected numerous significant com- for APIs) for the GMP Journal. This article refers to the "GDP for
ments. EQPA highly recommends a 2nd draft, the current one active substances guidance on interpretation and implemen-
has significant shortcomings, which to EQPA’s assessment can tation”.
not be closed in one next step. ƒ Prabjeet Dulai represented the ECA and the European GDP
ƒ IWG/Interested parties meeting with EMA: EFPIA is taking the Association at the 5th Annual International GDP Conference in
lead to co-ordinate the IWG/Interested parties meeting with Serbia 2020. Originally the conference was planned for April
EMA. ECA/EQPA are invited to prepare a letter to trigger dis- 2020 but due to Covid-19 it was postponed and took place in
cussion with EMA-IWG. It is expected that EMA-IWG will September. The title of her presentation was “The Power of
make themselves available in a teleconference as in the last Building Relationships - the role of the European GDP Associa-
years. This would be the third year in a row, where no face to tion".
face meeting at EMA will be organised. Due to limited resourc- www.good-distribution-practice-group.org
es at EMA telecons were organised during the first months of
the new year and not in November as before.
ƒ The EQPA Newsletter is now available in the download section Visual Inspection Group
of the members’ area. ƒ The Visual Inspection Group’s Position Paper on CCIT was pub-
www.qp-association.eu lished as version 2.0 already in March 2020. Further, the new
version 3.2 of the ECA Guidance on Visual Inspection 3.2 was
published on the group’s webpage in May 2020. 3
Validation Group ƒ Due to the corona crisis, but considering the importance of
ƒ The Validation Group’s Task Force developed ECA´s Integrated face-to-face meetings, it has been decided to postpone the
Qualification and Validation Draft Guide to a final version. It Group’s meeting to 2021. It will now take place in November in
implemented feedback from the 2019’s Launch Conference. Berlin, Germany.
continued on back page
 Final Version: ECA´s Good Practice Guide
Integrated Qualification and Validation
A guide to effective qualification based on Customer – Supplier
Partnership

With the "mother of all validation guidelines", the FDA Process With the publication of a draft of the FDA Guidance for Industry,
Validation Guideline from 1987, the subject of equipment qualifica- Process Validation: General Principles and Practices in 2008, it be-
tion took on a new significance. Suddenly, IQ, OQ and PQ were came clear that in addition to process validation, the topic of qual-
terms that needed further clarification. With the EU GMP guide- ification would also change. In the now final version from 2011,
lines becoming valid in 1992, the topic of qualification also gained there is no longer any talk of DQ, IQ, and OQ, but the term qualifica-
increased importance in the EU (then still EC). However, the cor- tion still exists. However, in the US Process Validation Guideline,
responding requirements in chapter 3 of the guide were not very qualification is integrated into the Validation Life Cycle Concept
concrete. It was a PIC document, then called PH 1/96, that deep- with its three-stage approach (process design, process qualifica-
ened the qualification topic. Other than the US-Guideline, it was tion and continued process verification). Qualification is now a
also supplemented by design qualification. Starting from the mid sub-stage of process qualification and thus a part of the entire
to end 90's the qualification requirements for equipment fairly "ex- validation lifecycle.
ploded". The first critical voices warned against "overdoing" ("Vali-
dation is not a religious experience or FDA wants McDonalds and The revision of Annex 15 of the EU GMP guidelines (valid since Oc-
we give them Cordon Bleu", Crosson, Campell, Warren, Journal of tober 1, 2015) also brought some changes in the area of qualifica-
Validation Technology 08/03). With the coming into effect of An- tion. The four "classic" qualification levels DQ, IQ, OQ, PQ were in
nex 15 to the EU-GMP guideline in 2001, the qualification require- parts defined slightly differently and requirements for User Re-
ments also became more concrete at EU/EC level. An ISPE "White quirement Specifications (URS) and/or a functional specification
Paper" from the year 2005 first attempted to counteract this trend were added. Optional Factory Acceptance Tests (FAT) and Site Ac-
and showed where "the journey" to a modern qualification could ceptance Tests (SAT) were also included. Both activities can, if ap-
lead. The ASTM document E 2500 implemented this white paper. propriate and justified, be included in the qualification without

4
About the Author
Sven Pommeranz is Operations Director and organises and conducts courses and conferences on behalf of the ECA Academy in the area validation.
having to repeat these tests (an exception is if the transport would ysis can cover both the technical qualification aspects and the pro-
have an impact on the original FAT test). The specifications for the cess validation aspects as a result of the control strategy for the
qualification levels in 'Annex 15 are only mentioned as a possible PAT equipment. An example of a modern process validation includ-
variant. A reference to alternative approaches? The justified inte- ing process capability indices is given to illustrate the contents of
gration of external data sources, e.g. suppliers, is explicitly men- the chapter. The fact that PQ-tests are possible before ordering a
tioned. standard equipment from a potential equipment supplier is de-
scribed as a further possibility of an extended integration of pro-
cess requirements into the qualification.
A completely new chapter gives an outlook on the requirements for
electronic qualification documentation. Even if all documents are
delivered electronically by the supplier, many companies still print
these documents, work with the printed documents and then ar-
chive them as paper documentation. Is that still up-to-date? Sug-
gestions on how to deal with scanned qualification documents and
which GMP requirements must be met by complete electronic
documentation are explained in this chapter. It is a look into the
(near?) future of qualification.

The Annexes are very important for the applicability of the Good
Practice Guide. They contain sample documents and templates
that are successfully used in the pharmaceutical industry and in
plant engineering and construction. Be it - in terms of an integra-
tive approach - user requirements coming from the product or the
process. Just like a classic user requirement for a piece of equip-
ment. In order to be able to sensibly involve suppliers in the quali-
fication process, they must be suitable - and this must be justified.
A separate appendix describes the conditions for this. Further-
Fig. 1: Extended Project Life Cycle Model with quality risk management activities more, tables for risk analyses are included as annexes, as well as
pragmatic "templates" for project-related changes (Change Man-
agement) and deviations. A central document in a joint qualifica-
It is precisely this possibility that the final version of the ECA Good tion project between suppliers and pharmaceutical customers is a
Practice Guide "Integrated Qualification and Validation - A guide to "Project Quality Plan (PQP)". It controls the documentation require-
effective qualification based on Customer - Supplier Partnership" ments and qualification activities on both sides. This PQP is then
takes up. A "Task Force" with members from the pharmaceutical broken down into test plans. There are sample templates for both
industry, plant manufacturers and engineering companies has cre- documents mentioned above. An example of a questionnaire for
ated the guide. The guide was designed based on the requirements the categorization of equipment supplements the separate guide
of Annes 15 of the EU GMP guidelines and supplemented by as- chapter on the same topic.
pects of ASTM Guide 2500. Based on two drafts that were present-
ed at two international qualification conferences and their feed- Conclusion: Based on the requirements of Annes 15 of the EU GMP
back, the final version will be available in autumn. The final version Guide and supplemented by aspects of the ASTM Guide 2500, the
also includes references to the new "Commissioning and Qualifica- final version of the ECA Good Practice Guide "Integrated Qualifica-
tion Guide" of the International Society of Engineering (ISPE) A tion and Validation - A guide to effective qualification based on
technical and regulatory review ensures market acceptance. On Customer - Supplier Partnership" describes in just under 40 pages
almost 40 pages, a very compact description is given of how a "lean what "lean qualification" can look like today. Annexes to the guide
qualification" can be successfully completed today with the in- with sample documents, which are successfully used in the phar-
volvement of suppliers. The often nonsensical repeated execution maceutical industry and in plant construction, ensure direct practi-
of one and the same test in different qualification phases (FAT, SAT, cal relevance.
IQ or OQ) is explicitly addressed. The guide is structured in such a
way that it shows the qualification topic from the perspective of a
pharmaceutical company (customer) and from the perspective of a
supplier. A separate chapter then describes the interaction of the
two parties involved. Supplementary chapters on equipment cat-
egorization and an overview, which explains in particular the ap-
plication of quality risk management throughout the entire qualifi-
cation/verification process, contribute directly to the applicability.

In a subchapter the integration of process validation into the quali- 5

fication is explicitly discussed. In principle, this is what was also
introduced as an innovation in the FDA Guidance on Process Vali-
dation: Qualification and validation are more closely connected.
Especially in modern PAT controlled processes, the initial risk anal-
 Blind trust in supplier certificates
and inadequate final testing
Facts, trends and important documents - An analysis of
current warning letters

A look at the warning letters to pharmaceutical companies of the

last 9 months of the current fiscal year (Oct. 2019 - June 2020)
shows that the most frequent GMP violations found by FDA inspec-
tors during their visits to production sites are essentially the same
as those of the previous fiscal year 2019 (see Fig. 1). They refer to
deviations from regulations formulated in the following para-
graphs of 21 CFR 211:

§211.84 Testing and approval or rejection of components,

drug product containers, and closures. (Subpart D–
Equipment)
cited in 24 Warning Letters
§211.100 Written procedures; deviations. (Subpart F–Produc-
tion and Process Controls)
cited in 24 Warning Letters
§211.22 Responsibilities of quality control unit. (Subpart B– Fig. 1: Comparison of the frequencies of the cited paragraphs of 21 CRF 211
Organization and Personnel)
cited in 23 Warning Letters
§211.165 Testing and release for distribution (Subpart I–Labo- §211.192 Production record review. (Subpart J–Records and
ratory Controls) Reports)
cited in 23 Warning Letters cited in 19 Warning Letters

6
About the Author
Dr. Gerhard Becker is Operations Director and organises and conducts courses and conferences on behalf of the ECA Academy in analytical and
compliance topics.
§211.67 Equipment cleaning and maintenance. (Subpart D– §211.84 Testing and approval or rejection of components, drug
Equipment) product containers, and closures. (Subpart D–Equipment)
cited in 11 Warning Letters
§211.166 Stability testing. (Subpart I–Laboratory Controls) General description of GMP deficiencies:
cited in 10 Warning Letters "Your firm failed to test samples of each component for identity and
conformity with all appropriate written specifications for purity,
In the following, these GMP violations of the first 9 months of the strength, and quality."
fiscal year 2020 will be viewed from a broader perspective that "Your firm failed to conduct at least one test to verify the identity of
places more emphasis on the "lessons learnt" aspect. First, howe- each component of a drug product."
ver, a look at the systematics of the GMP Warning Letters. "Your firm also failed to validate and establish the reliability of your
component supplier's test analyses at appropriate intervals."
The structure of FDA-Warning Letters
FDA request for documents ("In response to this letter, provide ..."):
Most GMP-Warning Letters are based on the following scheme: • A compilation of chemical and microbiological specifica-
tions for incoming inspection and release by Quality Control
1. Introduction: of all components required for the manufacture of the drug
• Indication of the production site inspected and the time of the product.
inspection • A description of how the components are tested for compli-
• Indication of general violations of GMP requirements accor- ance with the specifications.
ding to 21 CFR Parts 210 and 211. • Information to establish a robust reliability check of the in-
• Confirmation with reference to the Food, Drug, and Cosmetic formation on the supplier's Certificates of Analysis. The FDA
Act that the products manufactured at this site are not in com- also requires information on the initial validation and periodic
pliance with GMP ("adulterated"). re-validation of this information.
• Confirmation with brief justification that the company's res- • A declaration of commitment to perform at least one identi-
ponse to the deficiency report (Form 483) sent out shortly af- ty check for each component batch as an incoming inspec-
ter the inspection was reviewed and found to be inadequate. tion.
• A summary of the results of the incoming inspections of all
2. Description of the observed GMP violations: components performed as part of the reliability check of the
• General description of the deficiency, including the paragraph supplier certificates.
from 21 CFR 211 (usually highlighted in bold). "Your firm failed • An SOP on the Supplier Certificate Validation Program.
to..." • A summary of the procedures for qualification and supervi-
• Detailed description with details of the area, product batches, sion of external laboratories that perform tests on finished
personnel present, documents and, in some cases, the course medicinal products.
of a non-GMP-compliant procedure, etc. • A report on the comprehensive review of the entire materi-
al system. This report should include information on the qua-
3. Brief description of the company's response to Form 483 re- lification of all component, packaging and closure system
garding the GMP violation in question – "Your response stated suppliers and on expiration dates or re-testing periods. The
that...". FDA also wants to see a credible justification that quality con-
trol is able to prevent the use of unsuitable materials.
4. Justification by the FDA as to why the response is considered
"inadequate" – "Your response is inadequate...". §211.100 Written procedures; deviations. (Subpart F–Production
and Process Controls)
5. Request for additional documents – "In response to this letter,
provide ...". General description of GMP deficiencies:
"Your firm failed to establish adequate written procedures for produc-
The following extended analysis of the main "GMP sins" refers to tion and process control designed to assure that the drug products you
the 3 most frequent violations related to the 21 CFR sections manufacture have the identity, strength, quality, and purity they pur-
211.84, 211.100, 211.22, 211.165 and 211.192. The following passa- port or are represented to possess."
ges from the Warning Letters are considered:
FDA request for documents ("In response to this letter, provide ..."):
• The general description of the GMP deficiencies (2.) • A summary of the Process Validation Program. The program
• The additional demand for documents (5.) should include information on process performance qualifica-
tion and continuous monitoring of intra-batch and inter-batch
The text passages describing the FDA's document requirements variations that demonstrate that the manufacturing process is
represent an extract from all Warning Letters of the period under under control throughout the life cycle of the product.
consideration (Oct. 2019 - June 2020). They represent the essence • Deadlines for process performance qualification for each
of what formulations are used in the individual Warning Letters, drug on the market. 7
each with a different weighting. • Process Performance Qualification Protocols
• SOPs for the qualification of production buildings, rooms
and equipment.
 §211.22 Responsibilities of quality control unit. (Subpart B- Orga- submitted.
nization and Personnel) • A list of all analytical methods, specifications and standard
operating procedures used for final product testing before
General description of GMP deficiencies: market release.
"Failure to establish an adequate quality unit with adequate facilities • A summary of test results from retrospective testing of re-
and procedures to ensure that drugs are manufactured in compliance tained samples of all product batches shipped to the United
with CGMP regulations and meet established specifications for identity, States. Test results should include information on identity,
strength, quality, and purity." active ingredient content, and other appropriate chemical and
microbiological quality characteristics.
FDA request for documents ("In response to this letter, provide ..."): • Information on corrective actions taken on OOS results (noti-
• A comprehensive assessment and remediation plan to ensu- fication to customers, recalls)
re that the quality unit has the authority and resources neces- • If the final product testing is outsourced to third parties: Sum-
sary to effectively perform its duties. This plan should outline mary of the procedure for qualification and evaluation of the
‑ Whether all procedures are robust and appropriate, performance of external testing laboratories. It must be de-
‑ according to which requirements the quality unit monitors monstrated that the methods used in the testing laboratory
all procedures in connection with the production proces- have been validated beforehand.
ses,
‑ that the quality unit carries out a final review for each §211.192 Production record review. (Subpart J–Records and Re-
batch with the associated data before its release decision, ports)
‑ that the supervision by the quality unit, the examination
and approval of cause investigations in case of deviations General description of GMP deficiencies:
and the transfer of duties of the quality unit to third par- "Your firm failed to thoroughly investigate any unexplained discrepancy
ties serve to ensure the product quality. or failure of a batch or any of its components to meet any of its specifi-
If there are GMP deficiencies for certain areas or facilities, such as cations, whether or not the batch has already been distributed."
the documentation system or water supply, the FDA requires the
relevant documents (SOPs, protocols, etc.). FDA request for documents ("In response to this letter, provide ..."):
§211.165 Testing and release for distribution. (Subpart I–Labora- • A comprehensive evaluation of the procedure to be followed
tory Controls) in case of deviations. This includes OOS results in quality con-
trol, deviations from quality parameters in production, supply
systems (e.g. water) and complaints about quality defects in
the finished drug.
GMP Update 2019/2020 • CAPA plans to improve deviation management in the areas
Webinar concerned; to this end, the relevant documents, e.g. validati-
Thursday, 17 December 2020 15.00 - 16.30 h on plans and protocols of the water system, of production pro-
cesses or SOPs for handling OOS results must be attached
This webinar provides an overview of all • A standard operating procedure to verify the effectiveness
recent changes in the GMP requirements. of CAPA measures.

Learn more about this course: The useful "lessons learnt" from the analysis of the Warning Letters
www.gmp-compliance.org consist on the one hand in the observation of the most frequently
cited GMP violations; on the other hand, the analysis of what the
FDA requires of the inspected companies in terms of evidence and
documents relating to GMP deficiencies provides valuable infor-
mation for the review of quality systems and operational procedu-
res in GMP-relevant areas. Knowing which documentation the FDA
General description of GMP deficiencies: is particularly interested in can be very useful in preparing for an
"Your firm failed to have, for each batch of drug product, appropriate inspection.
laboratory determination of satisfactory conformance to final specifi-
cations for the drug product, including the identity and strength of each Note: In the ECA Members Area, you will soon find the complete
active ingredient, prior to release". analysis of the "Top Ten Failures" of the Warning Letters of the fis-
"Your firm failed to conduct, for each batch of drug product, appropria- cal year 2020 according to the systematics presented in this artic-
te laboratory testing, as necessary, required to be free of objectionable le. This will provide you with a comprehensive compilation of the
microorganisms and your firm failed to establish the accuracy, sensiti- documents that should not be missing from any FDA inspection.
vity, specificity, and reproducibility of its test methods."

FDA request for documents ("In response to this letter, provide ..."):
8 • A review of all routine work in the laboratory including all
analytical procedures, technical equipment and the compe-
tence of the laboratory staff. As part of this review, a CAPA
plan for the rehabilitation of the laboratory system and a pro-
cedure to ensure the effectiveness of the CAPA plan must be
Pharma Congress 2020: Exchanging
ideas and experiences online
The Pharma Congress, the largest event of its kind in the pharma- and production to congress participants and visitors in over 20
ceutical industry, has a longstanding tradition: this year, it was to presentations, was also well received.
take place for the 22nd time - and with its parallel conference
tracks, the social event and the PharmaTechnica with almost 90 In the first online edition of the congress, the conferences once
exhibitors, it would have brought together national and interna- again focused on reports from operators who shared and discussed
tional participants, speakers, exhibitors and visitors for profes- their experiences from current new construction and conversion
sional exchange once more. However, the Corona Pandemic with projects and the use of new technologies.
rapidly increasing infection rates worldwide made it clear that
holding a congress of this magnitude on site would not be feasible. Merck: New building for packaging
In order to enable participants to exchange ideas and information Mr. Oliver Kärst, Head of Pharma Engineering at Merck, reported on
and to provide exhibitors with a platform for presenting their latest the new building of the Pharma Packaging Center for solid dosage
products and services, the congress with conferences and Phar- forms in Darmstadt during the 22nd Pharma Technology Confer-
maTechnica were moved to September and conducted online - ence. The new packaging plant was necessary for various reasons.
with great success. A total of 850 participants logged on to the live On the one hand, space requirements have increased enormously.
online conferences and to visit the virtual exhibition PharmaTech- At times, tablets produced in Darmstadt had to be sent to Mexico
nica from September 15-17. The PharmaTechnica Forum on the for packaging and then back to Germany. From a GMP viewpoint,
third day, which was created to give exhibitors the opportunity to the packaging plant was also no longer up to date. For example, the
introduce the latest developments in pharmaceutical technology areas for primary and secondary packaging were not separated. A

About the Author 9

Dr Robert Eicher is Operations Director and organises and conducts courses and conferences on behalf of the ECA Academy around pharma
technology.
 conversion of the existing building from 1930 would have been just Compressed gases used in aseptic processes should be filtered
as expensive as a new building. However, a new building also had sterilely. The pore size of the sterile filter corresponds to the phar-
the advantage of being able to build the packaging plant closer to macopoeia specification (0.22 µm). Sterile filtration should be per-
the production area, eliminating internal transport routes. formed at the point of use. A central note of great importance is the
integrity check during batch release. Instructions for checking the
Planning a new building is always a long-term matter, explains Mr. filter integrity can also be found in other guidelines such as the
Kärst. A new building for packaging was already an issue in the ISPE Practice Guide Process Gases. Here the following points are
1990s. The project was finally approved in 2015 and construction mentioned: before use, after use, at a predetermined interval as
was scheduled to start in 2016. well as after events that are exposing the filter to elevated stress
levels (e.g. sterilization). Although an integrity check before each
By assuming responsibility for the project, Mr. Kärst initially tried batch release cannot be directly recognized here, the note before
to streamline the project team. But in fact, there was still a lack of and after use also indicates this.
department and thus project members, and the final team consist-
ed of 58 members. Of course, not everyone always had to attend a
project meeting, added Mr. Kärst, but it was not always easy to find
meeting rooms with enough chairs. Fundamentals of Visual Inspection
Live Online Training
One challenge in the project was the clearing of the building site. 3 December 2020
Whoever builds a new building in Darmstadt must first demolish
three old buildings, Mr. Kärst quoted an old Darmstadt "rule". The Best Practice for Manual and Automated
preparation of the ground also took up more time than originally Visual Inspection of Parenterals
planned. The reason for this was Darmstadt's location in an earth-
quake zone and the associated construction measures such as the Learn more about this course:
erection of CMC columns. A planning error in the media supply for www.gmp-compliance.org
a mezzanine floor also led to a delay. All in all, a high-bay ware-
house is quickly set up, reported Oliver Kärst, but there is a lot to
do inside of it. For example, a lot of time was spent on adjusting the
pressure levels.

The first packaging lines were installed in mid-2018. Handover to In the Annex 1 Draft you will also find central information on leak-
production took place in March 2019. A total of eight blister lines age testing of containers. Mr. Feuerhelm explicitly pointed out that
are in operation, primary and secondary packaging are consistently there are two ways to guarantee tightness: the 100% control for
separated, as are the areas for hormone and non-hormone areas. containers that have been closed by melting and for the other con-
In the connected automated high-bay warehouse, 3600 pallet tainers a sufficient CCI concept [Container-/Closure-Integrity]. The
spaces are available. Future-oriented technologies have also been CCI concept always consists of several measures at GMP level,
implemented, such as paperless production, the use of Augmented which ensure that the integrity of the packaging closure system is
Reality (AR) in the execution of set-up procedures and error pre- maintained.
vention by Robotic Process Automation (RPA) for batch release pro-
cess steps. Compared to the currently valid version of the EU-GMP Annex 1,
the visual inspection requirements in the Annex 1 Draft have been
The project costs also totaled 63 million euros, Mr. Kärst concluded. changed. New in particular is the demand for the classification of
defects and the evaluation of the risk of defects for humans. The
Technical view on Annex 1 evaluation of the patient risk is difficult. There are currently hardly
any concrete scientific statements on patient risk, added Klaus
In his presentation, Klaus Feuerhelm, GMP inspector at the Baden- Feuerhelm.
Württemberg Pharmacovigilance Control Center, addressed
changes in the EU GMP Annex 1 Draft from a technical perspective. A collection of the defects arising in the process should be pre-
In particular, he dealt with media (compressed air), leak testing and sented in a defect library. This defect library will then also be used
the visual inspection of parenteralia. for staff training. The staff performing the inspection should un-
dergo a qualification for visual inspection at least once a year. The
First he referred to essential guidelines in connection with com- qualification of the employees is described. The qualification
pressed air and sterile filtration. In addition to the legal basis he should be performed using appropriate samples from the manu-
mentioned the ISPE Good Practice Guide Process Gases, the ISPE facturer's defect library records and taking into account worst case
Baseline Sterile Product Manufacturing Facilities, the ISO Standard scenarios (e.g., inspection time, line speed when the product is
8573-1 Compressed Air as well as VDMA Document 15390-2 Com- transferred to the operator by a conveyor system, container size or
pressed Air Purity - Part 2. fatigue at the end of the shift) and should include visual inspection.
10
As another important document he mentioned chapter 6.19 in the At the end of his presentation, Mr. Feuerhelm gave some more in-
EU-GMP Annex 1 Draft, where I find the following points among formation about AQL in manual control. From a regulatory point of
others: view, AQL testing is not yet mandatory in Europe, but is state of the
art. Most companies that perform visual inspections are now prac-
ticing this in most cases. In the USP Informational Chapter <1790> In the second part of his lecture Mr. Feuerhelm discussed the
you can find detailed information about the AQL. The number of meanwhile permitted cold production of WFI according to EU-GMP
critical defects should be zero in the AQL-test. This is also required Annex 1 Draft. The method has not yet become established in
in the USP <1790>. If an AQL limit value is exceeded, the entire Baden-Württemberg. Only one drug manufacturer is said to use it.
batch should be 100% re-tested, explained Klaus Feuerhelm. For Klaus Feuerhelm addressed the question of whether reverse osmo-
the release decision two criteria must be evaluated: the trend anal- sis is absolutely necessary and, if it is used, whether double reverse
ysis of the 100% batch inspection and the result of the manual AQL osmosis is appropriate.
inspection.
At first glance, reverse osmosis does not appear to be absolutely
WFI und WFI-Kalterzeugung necessary and a different system design would be conceivable. The
pharmacopoeia monograph with the statement speaks for this in
In a second presentation Klaus Feuerhelm talked about current particular:
GMP requirements for pharmaceutical water including WFI and "produced by a purification process that is equivalent to distillation"
WFI cold production. In particular, he addressed changes due to
the EU GMP Annex 1 Draft, filters in water systems and the WHO This sentence is not isolated in the pharmacopoeia, added Klaus
Guide on the production of WFI by non-distillative methods, which Feuerhelm. Because in the following, further possibilities are enu-
is also still in draft status. merated and this allows the assumption that the reverse osmosis
is also necessary. This is formulated even more clearly in Annex 1
Regarding the innovations in the Annex 1 Draft, Mr. Feuerhelm Draft:
mentioned the references to dead legs and references to pipes
with gradients. The formulation "Where filters are included in the Where the WFI is produced by methods other than distillation, further
system..." is unfortunate according to Mr. Feuerhelm. Here, one techniques such as nanofiltration and ultra-filtration as well as electro-
could assume that filters could also be installed in the warehouse deionization (EDI) should be considered in conjunction with reverse
and distribution system, which is unacceptable from a GMP point osmosis (RO) membranes.
of view. Filters could only be installed in the processing area itself
and, possibly, at the point of use. From his point of view, however, According to Mr. Feuerhelm a reverse osmosis would be necessary
filters at the point of use are controversial and there should be suf- in any case.
ficient justification if this is to be implemented.
However, a one-step reverse osmosis seems to be sufficient. The
Also included in the draft was the requirement for a turbulent flow. formulation "by reverse osmosis, which may be single-pass or double-
This requirement can be found in practically all current guidelines pass" is clear. But there seem to be situations, where a double re-
for pharmaceutical water, added Klaus Feuerhelm. Areas without verse osmosis can make sense. Mr. Feuerhelm quotes the ISPE
turbulent flow are considered susceptible to biofim formation. handbook "Production of water for injection without distillation". Here
Summing up, he pointed out that essential aspects for WFI sys- it says: "Depending on the nature of the raw water, it has to be
tems such as dead legs, biofilm formation, importance of sanitiza- checked whether a reverse osmosis process has to be carried out in
tion, filters in water systems or turbulent flow are finally addressed. one or two steps. A two-stage reverse osmosis increases the pro-
But he also critically noted that certain points, such as rouging, are cess safety".
still being ignored. The newly published ISPE Baseline Water and
Steam Systems devoted over 15 pages to the topic of rouging. In the Finally, Mr. Feuerhelm briefly dealt with the draft of the WHO doc-
opinion of Mr. Feuerhelm, the topic is still far from being sufficient- ument "PRODUCTION OF WATER FOR INJECTION BY MEANS
ly discussed. OTHER THAN DISTILLATION". In his opinion there are no essential
references or innovations to be found here.

ECA QP
An ECA Foundation Interest Group

11

qp-forum.org
 Particularities of Russian GMP inspections
from a specialist interpreter's point of view

Introduction Success rate in passing the inspection

Many European pharmaceutical companies seek to enter the Rus- About 30 % of Russian inspections are not passed. The rate for
sian market, but have little to no experience with the Russian au- large international pharmaceutical companies is only about half as
thorities and their inspectors. high as for small and medium-sized companies. Even at large phar-
maceutical companies that have the European and American GMP
In the first two years after the establishment of the Russian inspec- certificates, Russian inspectors often find considerable irregulari-
tion authority GILS i NP on 12 April 2016, Indian pharmaceutical ties, as a result of which Minpromtorg refuses to issue the Russian
manufacturers were inspected most frequently, but since 2018 certificate. These irregularities are usually found in the production
German companies have been at the forefront. This will not change of sterile drugs. Typical findings are missing or insufficient root
for some time to come. What should German pharmaceutical com- cause analyses or deviations in aseptic handling.
panies know about the challenges of Russian GMP inspections?
European and Russian GMP guidelines
"The State Institute of Drugs and Good Practices", which is subordi-
nate to the Ministry of Industry and Trade (Minpromtorg) of the The GMP guidelines currently in force in Russia are a direct transla-
Russian Federation, is the competent authority for GMP inspec- tion of version 4.0 of the 2013 European GMP guidelines. The Rus-
tions. The GILS i NP institute is responsible for conducting the in- sian GMP guidelines have not been changed since the authority
spections. The application for issuance of the Russian GMP certifi- was established in 2016. However, it is planned that Russia will
cate is submitted to Minpromtorg. carry out inspections according to the new GMP guidelines of the

12
About the Author
Alexander Podarewski is the Managing Director of the specialist translation agency AP Fachübersetzungen in Nuremberg.
Eurasian Economic Union (EAEU) from June 2020. These new GMP documents have been submitted subsequently. As soon as the re-
guidelines of the EAEU are a translation of the European GMP port is completed, the regulatory authority of the manufacturer's
guidelines as amended in 2015. They are already finished and ap- respective country is informed. Deviations are frequently found in
proved by the EAEU, but Russian inspections are currently still connection with the approval dossier, aseptic production and sam-
based on Russian GMP guidelines. The implementation will proba- pling of incoming raw materials.
bly be delayed by another 6-12 months due to the coronavirus epi-
demic. Russian inspections are therefore not fundamentally different from
those by other countries. Russian inspectors ensure that the pro-
duction at the inspected site complies with Russia's current GMP
guidelines.
Inspection Management
Live Online Training If the product intended for Russia is manufactured, filled, packaged
17/18 November 2020 etc. on different lines or plants, the Russian inspectors want to see
all these lines and plants.
Learn more about the purpose and organi-
sation of regulatory inspections. Naturally, all foreign inspections have certain national particulari-
ties, e.g. interpretations and approach of the experts. Not all in-
Learn more about this course: spectors classify violations as critical/major/minor in the same
www.gmp-compliance.org way. Everything depends on the interpretation of the individual
inspector and their qualification and experience.

Misunderstandings with major implications

The production processes are inspected according to the manufac-

Course of a Russian inspection turer's application for each individual preparation. You have to be
very careful here and should only specify the products that are rel-
An inspection starts with the manufacturer submitting an applica- evant for the target country and therefore should be part of the
tion for inspection and a list of documents to the Minpromtorg. inspection when you submit your application. In one specific case,
Within 10 days, the Ministry reviews the submitted documents. If a misunderstanding led to all products produced at the site being
there are no questions regarding the documents, an order is pre- registered for the Russian inspection. This only came to light during
pared to carry out the inspection and forwarded to the GILS i NP the inspection. Originally only two preparations were to be listed
institute. The institute prepares a schedule, coordinates it with the for Russia. The mistake lay with the Russian consulting firm that
Minpromtorg of the Russian Federation, notifies the manufacturer submitted the application to Minpromtorg. The reason for the mis-
and draws up an inspection plan, taking into account the elements understanding was a translation error in the communication: All
of the production process to be inspected. The inspection plan is the products at the site were listed by mistake instead of just two
then sent to the manufacturer. This enables the company to pre- which were relevant for Russia. The inspectors expressed under-
pare for the inspection, have the necessary documents ready and standing for the error. Nevertheless, the inspectors had to inspect
make them available to the inspectors. An inspection team of at all products according to the application.
least two inspectors – depending on the production volume to be
inspected – visits the site. The average duration of an inspection is The task of the inspectors is to check that the medicines delivered
3 to 5 days. If there are several pharmaceutical companies in the to Russia are safe for the citizens of their country. They often say at
same region, GILS i NP tries to organize everything so that the in- the beginning of the inspection, right after the start: "We will not
spections can be carried out as quickly as possible. only check compliance with GMP standards, but also that you are
actually manufacturing what you have stated in your application."
An opening meeting is held at the beginning of an inspection; a They have a reputation for being very diligent about compliance
summary of the results and observations of the day is given at the with regulations, for being very strict, but also competent and fair.
end of each working day and a final meeting is held at the end of All inspectors of the Russian authority have a background in the
the inspection. industry. Besides some experienced inspectors, many of them are
quite young, but some of them surprise even "veterans" of the
If violations are found, these will be communicated to the site rep- pharmaceutical industry with their professionalism and experience
resentatives at the final meeting during the inspection. The viola- in the whole production. As a rule, the inspection is carried out
tions are not classified. The inspection report will be prepared competently, objectively and exactly according to the formal spec-
within 30 calendar days after the inspection at the site has been ifications. It is very important that the inspectors always feel that
completed. Upon its completion, one copy remains with GILS i NP, the answers are open and honest and that nothing is concealed.
a second copy is sent to the manufacturer's Russian representa-
tive, and a third is sent to Minpromtorg for decision-making. The As with other international GMP inspections, each pharmaceutical
inspection report can only list non-conformities that were men- company inspected should task experienced staff with answering 13
tioned in the final meeting. However, there may be fewer non-con- the inspectors' questions wherever possible. And of course it is es-
formities if the relevant issues have been clarified and the relevant sential to commission reliable interpreters who are up to the task.
 GDP for APIs

The new "Guidance on interpretation and imple- starts earlier, namely with the transport of the active pharmaceuti-
mentation" of the ECA Foundation and the Phar- cal ingredients (APIs) used for production. Since September 2015,
maceutical Quality Group of the Chartered Qual- the "Guidelines of 19 March 2015 on the principles of Good Distri-
ity Institute bution Practice for active pharmaceutical ingredients of medicinal
products for human use (2015/C 95/01)" have been in force. These
Introduction guidelines define requirements for the storage and transport of ac-
tive pharmaceutical ingredients, which have to be implemented by
Medicinal products are subject to special regulations for storage manufacturers, distributors and pharmaceutical companies. A cen-
and transport. Good Distribution Practice (GDP) is the part of qual- tral concern that prompted the EU Commission to publish this
ity assurance that ensures that the quality of medicinal products is document was the fight against counterfeit medicines and active
maintained at all stages of the supply chain. The topic of GDP ingredients. These guidelines are intended to ensure comprehen-
therefore affects all partners in the distribution chain. sive and seamless control of the supply chain.

The introduction to the "Guidelines of 5 November 2013 on Good In June 2020 the "Good Distribution for Active Substances Guid-
Distribution Practice for medicinal products for human use (2013/C ance on interpretation and implementation" was published as a
343/01)" states that compliance with these guidelines "will ensure joint publication of the ECA Foundation and the Pharmaceutical
control of the distribution chain and consequently maintain the Quality Group (PQG) of the Chartered Quality Institute. The mono-
quality and the integrity of medicinal products". graph is based on the text of the EU GDP Guidelines for active sub-
stances for medicinal products for human use, but its principles are
However, GDP is not limited to pharmaceuticals. Rather, GDP applicable to all areas of the global distribution network.

14
About the Author
Dr. Markus Funk is Operations Director and organises and conducts courses and conferences on behalf of the ECA Academy in the areas GDP and
analytics.
Guidelines and supplementary documents • Chapter 1 - Scope: It is first clarified that the guidelines apply
to the distribution of active substances within the scope of
Even before the EU GDP guidelines, guides and supplementary Article 1(3a) of Directive 2001/83/EC intended for medicinal
documents containing recommendations for the distribution of ac- products for human use. An active substance within the scope
tive substances were published. of the guideline is "any substance or mixture of substances in-
tended to be used in the manufacture of a medicinal product and
The WHO Guideline on "Good trade and distribution practices for that, when used in its production, becomes an active ingredient of
pharmaceutical starting materials" was released in 2003, with a new that product intended to exert a pharmacological, immunological
version last published in 2016. This WHO guideline contains general or metabolic action with a view to restoring, correcting or modify-
principles to ensure good practice in the supply chain for pharma- ing physiological functions or to make a medical diagnosis." It is
ceutical starting materials and is applicable to both active ingredi- further specified that the "distribution of active substances shall
ents and excipients. It describes the requirements for the quality comprise all activities consisting of procuring, importing, holding,
system, organization and personnel. Further chapters deal with supplying or exporting active substances, apart from brokering."
documentation, storage and transport, returned goods and recalls. • Chapter 2 - Quality system: The requirements in this respect
are quite extensive. For example, distributors must, as part of
their quality system, operate a complete deviation manage-
ment system with a CAPA system based on risk analysis, as
Temperature Qualification well as a change management system.
in Storage • Chapter 3 - Personnel: Among other things, it is required that
Webinar personnel be trained in accordance with a written training
Monday, 30 November 2020 program and then undergo continuing training.
14.00 – 15.30 h CET • Chapter 4 - Documentation: This chapter is divided into gen-
eral documentation requirements and detailed regulations on
"procedures" and "records". All distribution activities that in-
Learn more about this course: fluence the quality of the active ingredients must be recorded
www.gmp-compliance.org in writing. For a complete traceability of the supply chain, re-
cords must be kept of every purchase and sale.
• Chapter 5 - Premises and Equipment: This specifies that prem-
ises and equipment must be suitable for the proper storage,
protection against contamination and distribution of active
substances.
In recent years, guidelines and supplementary documents have • Chapter 6 - Operations: This chapter is divided into "Orders",
also been published by other organizations that deal with the topic "Receipt", "Storage", "Delivery to customers" and "Transfer of
of GDP for active substances, amongst which are: information". It is of particular importance that active sub-
• APIC: GDP for APIs "How to do" Document, stances should always be stored or transported under the
• IPEC Guideline: Good Distribution Practices Guide for Pharma- conditions specified by the manufacturer so that their quality
ceutical Excipients, is not impaired. Where necessary, these operations must be
• PIC/S Expert Circle on APIs: Questions & Answers document carried out under controlled temperature or humidity.
regarding Distribution Activities for Active Pharmaceutical In- • Chapter 7 - Returns, complaints and recalls: This chapter de-
gredients (APIs) (PS INF 20 2011), tails the procedures for returns, complaints and recalls. In par-
• PIC/S: Guideline on the Principles of Good Distribution Prac- ticular, this includes specific documentation requirements and
tice of Active Substances for Medicinal Products for Human the requirement that these procedures be performed only by
Use (PI 047-1). appropriately trained and authorised personnel.
• Chapter 8 - Self-inspections: Distributors should conduct self-
EU GDP Guidelines inspections according to an approved schedule and keep re-
cords of them.
The "Guidelines of 19 March 2015 on principles of Good Distribu- • Annex: The Appendix contains a detailed glossary of terms
tion Practice of active substances for medicinal products for hu- used in the guidelines.
man use (2015/C 95/01)" are divided into an introduction, eight
chapters and an annex: The "Good Distribution for Active Substances
Guidance on interpretation and implementation"
• Introduction: The introduction points out that the text is
based on the same principles as the guidelines of 5 November The EU GDP guidelines and the resulting requirements are quite
2013 on Good Distribution Practice for medicinal products for comprehensive and detailed and the involved partners have to face
human use. The regulations are intended to serve as inde- some challenges. Although the guidelines are primarily aimed at
pendent guidance for Good Distribution Practice and are wholesalers and manufacturers, they are of fundamental impor-
aimed at importers and distributors of active substances for tance for all service providers involved in the supply chain (e.g. 15
medicinal products for human use. They complement the rules warehouses, transport and distribution companies). It is not sur-
the provisions on distribution in the EudraLex guidelines (Vol- prising that there are always uncertainties in view of the relatively
ume 4, Part II) and also apply to distributors of active sub- complex regulations. The question often arises as to how exactly the
stances manufactured by themselves. individual requirements are to be implemented in business practice.
 Against this background, the ECA Foundation together with the lines of 19 March 2015 on principles of Good Distribution Practice
Pharmaceutical Quality Group (PQG) of the Chartered Quality Insti- of active substances for medicinal products for human use (2015/C
tute published a guide on interpretation and implementation 95/01)". The individual chapters and subchapters are commented
("Good Distribution Practice Guidance on Interpretation and Imple- on in detail, with explanations given for the respective purpose or
mentation") in 2018. The chapters are built around the structure the rationale behind the individual regulations. In addition, the ad-
and text of the EU GDP Guidelines of 2013. The document is the vantages and risks associated with the respective regulation are
result of a joint project of the PQG and the ECA Foundation with its pointed out. Furthermore, a detailed description is given of how
European GDP Association, in which individual chapters on the in- the requirements can be implemented in practice. For better un-
terpretation of the EU GDP Guidelines were initially created. derstanding, the original text of the guideline is printed in a differ-
ent color. The explanations are supplemented by some diagrams
In June 2020, the "Good Distribution for Active Substances Guid- and flow charts as well as references to other directives and guide-
ance on interpretation and implementation" was published as a lines.
further document that deals specifically with GDP for active sub-
stances and is intended to provide companies with assistance and The work can be purchased as a book in DIN A 5 format via the
concrete recommendations for action in implementing the require- website www.pqg.org. For members of the European GDP Associa-
ments. tion it is available as an interactive PDF document in the members'
area at www.good-distribution-practice-group.org.
The structure of the document is based on the text of the "Guide-

Sources:
Guidelines of 5 November 2013 on Good Distribution Practice of medicinal products for human use (2013/C 343/01).
Guidelines of 19 March 2015 on principles of Good Distribution Practice of active substances for medicinal products for human use (2015/C 95/01).
WHO Technical Report Series, No. 917, 2003: Good trade and distribution practices for pharmaceutical starting materials.
WHO Technical Report Series No. 996, 2016: Good trade and distribution practices for pharmaceutical starting materials.
APIC: Good Distribution Practices for Active Pharmaceutical Ingredients “How to do” Document.
PIC/S Expert Circle on APIs: Questions & Answers document regarding Distribution Activities for Active Pharmaceutical Ingredients (APIs) (PS INF 20 2011).
ECA Foundation/The Pharmaceutical Quality Group of the Chartered Quality Institute: Pharmaceutical Quality Group Monograph No. 13 – Good Distribution for
Active Substances Guidance on interpretation and implementation.

GDP for Beginners

Live Online Training
23/24 February 2021

Learn more about relevant aspects regarding the current GMP and GDP require-
ments and current developments in storage, transportation and Cold Chain
Management of medicinal products.

Learn more about this course:

www.gmp-compliance.org

16
 ƒ To fulfil the demand of training, however, a short-term course
covering the fundamentals of visual inspection will take place
online in December 2020.
ƒ The ECA Visual Inspection Group provided their feedback to
the new Annex 1 Draft to the ECA Annex 1 Task Force.
www.visual-inspection.org

GMP Handbooks • GMP Regulations

FDA cGMP Guide
y 21 CFR 210/211 cGMP Guide in English
y Paperback in the handy format 11.5 x 15 cm,
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ECA Good Practice Guide - GMP Matrix

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"FDA cGMP, EU GMP and ISO 9001 Matrix for a pharmaceutical Quality System - A GMP Roadmap"
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FDA's cGMP Guide, the EU GMP Guide and ISO 9001.
In addition, the Good Practice Guide contains a ISO 9001/ICH10 Matrix.
In total, the Guide has 683 pages.
EU Guidelines to Good Manufacturing Practice
Part 1, Part 2 and Part 3
incl. Annexes 1-19
y Paperback in the handy format 11.5 x 15 cm
y GMP Guide in English
ICH Q7 GMP for Active Pharmaceutical Ingredients
with a Side-by-Side comparison and APIC‘s How-to-do Document (Version 11, November 2018)
y Paperback in the handy format 15 x 11,5 cm
y Complete text of ICH Q7 GMP for APIs and comparison of the interpretation
by the Active Pharmaceutical Ingredients Committee (APIC)

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