No

Issue 41 | Oct/Nov 2024

41

DEVELOPMENT OF MODERN PHAR-

MACEUTICALS, VACCINES AND MORE
CTR Implementa- RWD and RWE to Product, Process, Handling external
tion – A QP's Per- Support Medicinal People Personnel in the
spective Product Develop- Adressing the criti- GMP Environment
ment cal Pillars of Annex
1 Compliance
 Editoral
Publisher:
CONCEPT HEIDELBERG GmbH
GMP Trends Rischerstraße 8
69123 Heidelberg
HRB Mannheim Nr. 705125
In this issue of the GMP Journal, we delve into some of the most pressing topics
in the pharmaceutical and healthcare sectors. From the Qualified Person’s per- General Manager:
Oliver Schmidt
spective on the EU Clinical Trial Regulation (CTR) to the growing importance of
Real-World Data (RWD) and Real-World Evidence (RWE) in medicinal product Chief Editors:
Oliver Schmidt
development, we explore the ways in which these advancements are shaping the Wolfgang Heimes
future of regulatory practices.
Editors:
Dr Gerhard Becker
We also focus on the critical pillars of Annex 1 compliance – product, process, Dr Robert Eicher
and people – and how they collectively ensure the safety and efficacy of sterile Dr Markus Funk
Anne Theresa Guenster
manufacturing. Additionally, we take a closer look at the complexities of manag- Dr Andrea Kuehn-Hebecker
ing external personnel within GMP-regulated environments, particularly in rela- Dr Andreas Mangel
Clemens Mundo
tion to outsourced cleaning services. Sven Pommeranz
Oliver Schmidt
Wolfgang Schmitt
We hope this edition provides valuable insights and fosters discussions on how Axel H. Schroeder
to navigate the evolving landscape of global healthcare regulations.
Editors of this Issue:
Dr Gerhard Becker
Enjoy reading! Dr Markus Dathe
Dr Markus Funk
Dr Jaime Guardiola
Oliver Schmidt Dr Andrea Kühn-Hebecker
Dr Ana Kuschel
Anne Theresa Günster
Clemens Mundo
Axel H. Schroeder

Content
Robert G. Schwarz
Dr Andreas Schwinn

Graphic Concept:
4 Cover story Development of modern Pharmaceuticals, Vaccines and more Rebecca Illi

4
Part 2: Opportunities and Risks
Production:
abcdruck GmbH
Waldhofer Straße 19
69123 Heidelberg
7 CTR Implementation – A QP's Perspective

7
Contact:
[email protected]

Any reprints of text and

13 Real-World Data (RWD) and Real-World Evidence (RWE) to Support Medicinal images require specific
pre-approval by the

13
Product Development editorial office.
Photo Credits:
Cover/Page 4: iStock, ID: 1209892070
Page 7: iStock, ID: 24565009
15 Product, Process, People Page 13: iStock, ID: 47321766
Page 15: West

15
Addresssing the critical Pillars of Annex 1 Compliance Page 26: Fotolia, ID: 166977199
Page 29: iStock, ID: 1775106

19 Handling external Personnel in the GMP Environment

19
Example: Outsourced Cleaning

25 Valsartan

25
Six years after the six-years Valsartan scandal. Has the knowledge gained been comprehensively
and critically appraised?

28 GMP Hot Spots as seen in the Warning Letters

28
Release Testing of the Finished Product

2
31 ICH Q7 Training Week

31
Data Integrity in the Light of ICH Q7

34 Analytical Instrument Qualification and System Validation

34
The ECA Analytical Quality Control Group's News Guide
NEWS FROM OUR ASSOCIATION
www.eca-foundation.org

Publications
European QPIn the following you can find again what A new issue of the EQPA Newsletter was pub-
Association the ECA’s Interest and Working Groups lished including articles on the results of the sur-
have been working on from May veys on the position of the QP in the MIAH organ-
Board Developments through August 2024. ization, Remote Certification and QPShare. The
Updated Job Descrip- new edition is also available in the members’
tion Template Dr Afshin Hosseiny area.
In EQPA’s efforts(Chairman ECA Foundation) t o
hold contents and European QP Association Website
materials provided to members up to date, EQPA’s job description
template was modernized. The members of the recently created
Engagement Board worked out version 2 of the EQPA job descrip- Validation Group
tion template providing concise and easy to use guidance to the
subject. It is now available to all EQPA members on the webpage. Board Developments
The next meeting is scheduled for 4 November 2024 on site before the
Surveys Equipment Qualification Forum.
Survey on Chinese Counterespionage Law
China has revised its counterespionage law. Com- Guideline Developments
pared to the previous version, the new version The Good Practice Guide (GPG) on Integrated
expands the government's powers to combat Qualification and Validation is in the final phase
espionage and emphasises the role of the public of development.
in this task. In theory, activities carried out as part
of an audit or inspection can now also be punish- For 2024 the launch of version 3.0 with a slightly
able by law. Espionage suspects may be prevent- changed name Good Practice Guide Qualification
ed from leaving China by order of the national security authorities and Validation (subtitle will be unchanged) is
at provincial level or higher. This provision also applies to foreign- planned at the Equipment Qualification Forum 05/06 November
ers. 2024 on-site in Heidelberg.

For that reason the EQPA as well as the GMP Auditor Association Surveys
asked for feedback with regard to their members’ awareness, Surveys on AI in qualification projects and regarding DoE are
understanding and implication of the Chinese revised counteres- planned.
pionage law.
Validation Group Website
Survey results on the QP’s position within the MIAH organization
The survey results summary report on the QP’s position within the
MIAH organization have been published. European GDP Association
Survey of the IMP Working Group on the CTR Board Developments
The EU Clinical Trial Regulation (536/2014) (CTR) is mandatory for The next board meeting is scheduled for fall 2024 (online Meeting
all new Clinical Trial Applications (CTA) in the European Economic via Webex).
Area (EEA) to be submitted under the CTR. Initial submissions
under the Clinical Trial Directive (2001/20/EC) (CTD) are no longer It is planned to hold a face-to-face board meeting during the GMP
possible. The European QP Association (EQPA) would like to know, & GDP Forum in June 2025 in Barcelona.
via a short survey, how the new regulation, and related guidelines,
have affected IMP QPs in the relevant aspects of clinical trials. The Guideline Developments
results of this survey will be shared and discussed at the IMP Pre- A review and update of the existing
conference of the Qualified Person Forum on 27 Nov 2024 in ECA/PQG GDP monograph is planned.
Amsterdam and will also be published on the EQPA website. Comments from the GDPA perspectice
were provided to PQG.
You will find detailed reports on the survey results in the survey
section of the EQPA Website members' area. Surveys
A survey is planned for fall/winter 2024. 3
European GDP Association Website

continued on page 36
 Development of modern Pharmaceuticals,
Vaccines and more
Part 2: Opportunities and Risks

Life in a globalized world offers opportunities as well as risks in reduce the effectiveness of medication. It is therefore important to
many areas. One example would be information technology with manage the use of antibiotics and other medicines responsibly in
the ‘hot topic’ of artificial intelligence and its opportunities and order to minimize the development of resistance. In addition, ethi-
risks. Others would be supply chain challenges vs. production cost cal issues may also arise in relation to the development and use of
optimization or health risks such as pandemics or rare diseases vs. pharmaceuticals, vaccines and ATMPs. It is important that research
global scientific resources in drug and vaccine development, espe- and development is carried out in accordance with ethical princip-
cially modern biological therapy options. Of course, the develop- les and that the interests of patients and society are taken into ac-
ment of modern pharmaceuticals, vaccines and advanced therapy count.
medicinal products (ATMPs) offers many opportunities. They make
it possible to treat and cure previously incurable diseases, improve Overall, the development of modern pharmaceuticals, vaccines as
people's quality of life and contribute to continuous progress in well as other novel developments offer great opportunities for me-
medicine. The pandemic has shown that new medicines and vacci- dicine, health and people's everyday lives. However, it is important
nes can save lives and improve public health. that these opportunities are accompanied by a conscious approach
to the risks in order to ensure the safety and efficacy of these pro-
On the other hand, there are risks that must be considered when ducts.
developing such products. Undesirable side effects can occur that
compromise patient safety. Another risk is the possible develop- Part 2: Vaccines in today's world
ment of resistance to drugs, as is the case with antibiotics, for ex-
ample. This can make certain diseases more difficult to treat and One of the major challenges in today's era of globalization, rapid

About the Authors

4 Clemens Mundo has been with CONCEPT HEIDELBERG since Dipl. Biol. Axel H. Schroeder has been working at CONCEPT
2023 as operational director and is in charge of the area of bio- HEIDELBERG since 2008 and is head of the microbiology depart-
technology. ment.
travel and global mobility is to be adequately prepared for pande- • Stockpiling: Many countries are stockpiling medicines, pro-
mics. This requires, among other things, the development of mo- tective equipment and other essential resources to be better
dern vaccines that fulfil a number of requirements: prepared in the event of a pandemic. This also includes the
creation of emergency reserves for vaccines.
• Safety: adverse vaccine reactions are minimized through ex- • Strengthening healthcare systems: Improving the capacity
tensive clinical trials and post-market surveillance and flexibility of healthcare systems to cope with an increase
• Efficacy: Vaccines should have a high protective effect against in patients during a pandemic.
the respective disease and be tested as comprehensively as • Communication and education: Clear, repeated and transpa-
possible in clinical trials rent communication to the population about health risks, pre-
• Long-term protection: Protection should be as long-lasting as ventive measures and behavior during a pandemic.
possible
• Stability and storage: Ensuring the highest possible stability
under different storage and transport conditions while com-
plying with quality and safety standards for worldwide use GMP for Vaccine Manufacturers
• Adaptability: Flexible adaptation of the vaccine to new vari- 19/20 November 2024
ants of the pathogen should be as simple as possible Hamburg, Germany
• Production and availability: options for rapid production, pre-
pared distribution channels Classic and modern Technologies – Regula-
• Acceptance by the population: Clear communication and edu- tory Requirements and Practical Implemen-
cation about the benefits, risks and advantages of vaccination tation
• Ethics and accountability: Ethical standards must be adhered
to in the development and distribution of vaccines. Distributi- Learn more about this course:
on should be equitable and transparent to ensure that all po- www.gmp-compliance.org
pulation groups have access

When we talk about possible pandemics and how to prepare for

them, other measures are also relevant, e.g:
One step in this direction is CEPI, the Coalition for Epidemic Prepa-
• Early warning systems, surveillance and response: improved redness Innovations, an international organization focused on ac-
surveillance systems for early detection of potential pande- celerating the development of vaccines against new and emerging
mics (artificial intelligence, big data analysis and telemedicine) infectious diseases. CEPI was founded in 2017 in response to the
with cooperation between international organizations and na- lack of preparedness for epidemics, particularly the outbreak of
tional health authorities, including in subsequent pandemic Ebola in West Africa.
responses and including the development of pandemic plans.
• Research and development: Investment in potential new vac- CEPI's main objectives in relation to pandemics are:
cines, antiviral drugs and other therapies will be increased -
including with regard to platform technologies. • Accelerated vaccine development: Especially for emerging

12th Congress
Düsseldorf, 25-27 November 2024

25 November 2024: Pre-Conference Event

5th International Mycoplasma qPCR Testing User Day

26/27 November 2024: Congress & Exhibition

Alternative and Rapid Microbiological Methods
Cell and Gene Therapies/ATMPs - Quality and Safety
5
Endotoxin and Pyrogen Testing
Bioassays/Potency Assay
and more
 diseases where conventional development approaches may mance testing strategies (readouts) under a common approach can
be too slow. accelerate the development and regulatory approval of vaccines to
• Promoting research and development: Funding/supporting enable a faster response to future emerging threats and support
research projects for the development of vaccines (and plat- the 100-day mission.
form technologies) against various pathogens, including viru-
ses that are considered potential pandemic triggers. The network focuses on evaluating vaccine samples against the
• Collaboration with partners such as governments, internatio- CEPI priority list of pathogens of public health concern or listed in
nal organizations, academic institutions, testing laboratories the WHO R&D plan, including Lassa, Nipah, MERS, Ebola, Chikun-
gunya, Rift Valley fever, COVID-19 and other betacoronaviruses.
The members of the network also support the detection, contain-
ment and control of other viral threats with epidemic or pandemic
Modern Microbiology Laboratory potential, such as Mpox and Marburg.
Live Online Training
10-12 December 2024 They are also ready to accelerate the evaluation of vaccine samples
against a disease X – a novel or as of yet unidentified pathogen - by
Best Lab Practice developing standardized procedures, supporting the technology
transfer of these procedures to other laboratories in the network
and testing samples from clinical trials of potential vaccine candi-
Learn more about this course: dates against such pathogens.
www.gmp-compliance.org
Providing additional laboratories and testing facilities for vaccines
in each region will help reduce the time for clinical evaluation, sup-
porting the CEPI-led and G7 and G20 endorsed goal of developing
vaccines within 100 days of identifying a viral threat. More local
testing will also reduce the financial and environmental costs nor-
and pharmaceutical companies to effectively leverage resour- mally associated with shipping vaccine samples long distances,
ces and expertise for vaccine development. while improving the sustainable infrastructure for outbreak prepa-
• Prioritization of pathogens: CEPI identifies and prioritizes pa- redness in the region.
thogens that are considered a threat to global health.
• Providing funding for vaccine projects and clinical trials to Months have passed since COVID-19 was mentioned in the media.
support vaccine development. However, we must not forget to take precautions to ensure a stable
healthcare system. Many have contributed to combating and con-
CEPI's Centralized Laboratory Network plays a critical role in taining the COVID-19 pandemic. Many have fallen ill, died and/or
strengthening global pandemic preparedness, particularly by foste- suffered after-effects. However, despite problems with develop-
ring innovation and accelerating vaccine development. CEPI is the ment, production and distribution, a vaccine was developed and
largest global group working to standardize the evaluation of vacci- distributed. This proved that rapid vaccine development is possible
nes being developed against some of the world's most dangerous, and that it is the most important medical treatment.
and in most cases deadly, diseases. Harmonizing vaccine perfor-

Literature:
• Coalition for Epidemic Preparedness Innovations (CEPI), 2016, https://cepi.net/

Photo: Courtesy Sartorius Stedim Biotech S.A

Virus Safety – Best Practices and

Emegering Trends
6 18/19 February 2025,Vienna, Austria
gmp-compliance.org
CTR Implementation – A QP's Perspective
Introduction The professional guild of Qualified Persons watches these develop-
ments closely4, and with a specific perspective: “ The qualified per-
On 31 January 2025, the transition from the Clinical Trial Directive son … shall be responsible for … verifying that each production
2001/20/EC (CTD)1 to the Clinical Trial Regulation (EU) No batch has been manufactured and checked in compliance with …
536/20142 (CTR) will end3. We have been observing this difficult the information provided pursuant to Article 25 of Regulation (EU)
birth for more than a decade. We have learned that a regulation No 536/2014”5 meaning the “Data submitted in the application
could be in two seemingly contradicting lifecycle states simultane- dossier”6 (similar references are found in Annex 167 and Annex 138
ously: “in force” and “not applicable”. Applicability was finally to the EU GMP Guide).
reached on 31 January 2022; since then, we have been in the tran-
sitioning phase.

1
CTD: DIRECTIVE 2001/20/EC OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 4 April 2001 on the approximation of the laws, regulations and administrative provisions of the Member States re-
lating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use.
2
CTR: REGULATION (EU) No 536/2014 OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 16 April 2014 on clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC.
3
There are discussions of an extension of the transition timeline.
4
EU Clinical Trial Regulation - experience so far, Claudius Pop Oral presentation, QP Forum / IMP Pre-Conference Session, Vienna, October 11th, 2023.
5
DELEGATED REGULATION (EU) 2017/1569, Article 12. DELEGATED REGULATION (EU) 2017/1569 of 23 May 2017, supplementing Regulation (EU) No 536/2014 of the European Parliament and of the Council
by specifying principles of and guidelines for good manufacturing practice for investigational medicinal products for human use and arrangements for inspections, Official Journal of the European Union,
16.09.2017.
6
CTR, Article 25.
7
Annex 16: General Principles. EudraLex Volume 4, EU Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use, Annex 16: Certification by a Qualified Person and Batch
Release, Brussels, 12 October 2015.
8
New Annex 13: Detailed Commission guidelines on good manufacturing practice for investigational medicinal products for human use, pursuant to the second subparagraph of Article 63(1) of Regulation (EU)
No 536/2014, C(2017) 8179 final, Brussels, 08.12.2017, lines: 510-513.

7
About the Author
Dr Andreas Schwinn is Senior QP at Roche Pharma AG in Grenzach-Wyhlen, Germany, and is part of the German QP Association (GQPA) leadership
team.
 Expectations Authorities undergo the same development: different Member
States and assessors may produce different outcomes.
The QP community was looking forward to the CTR becoming ap-
plicable. Thus, we see things improving rapidly.

The main promises were9,10: The learning curve is also reflected in the change history of the in-
• A consistent ruleset on Clinical Trials across the EU. volved guidance documents, e.g., the CTR Q&A, which reached
• An environment that is favorable for conducting Clinical Tri- version 6.8 within 26 months.
als11.
• Streamlined applications via a Who has access to CTIS?
• Single entry point or EU portal, a Only a limited number of people have access to the database. Ini-
• Centralized Database, with tially, this led to situations where people needing certain CTIS
• One single set of documents, assessed in documents (e.g., a QP requesting the part 1 assessment report of
• One harmonized review and authorization procedure. an IIT) faced significant difficulties getting them.
• Better transparency of clinical trials and trial outcomes
through public access to the database. Approval timelines not met
There are defined approval timelines under CTR12, e.g., 60-10613
As a QP, my hopes were particularly on the single set of documents days for a new application and 2214 days for a transitioning applica-
and the harmonized authorization procedure. I am aware that tion under the expedited administrative procedure. Approval time-
hereby, I am inadvertently admitting occasional challenges in veri- lines were not met in the beginning and, in some cases, are not met
fying what information, including amendments, was approved at a today.
certain point in time in each participating member state for a cer-
tain Clinical Trial submitted per CTD – despite sophisticated sys- Database errors
tems and considerable efforts. Another learning curve example is a mistake in the database that
often provided an incorrect MIA number of the site of certification
Experiences and import in the application form15.

Will reality live up to our expectations and the implied promises? Transparency requirements
I would probably best describe our experiences as mixed. As QPs, the ambassadors of GMP in our organizations, we were
struggling with the request to provide redacted QP declarations,
Initial difficulties without name and signature, together with the usual signed QP
declaration. Sharing an unauthorized document is a GMP violation.
Learning Curve The rationale for the request was that the QP declarations were
Every change process is challenging, and the magnitude of this ef- published in the EU database and publishing personal data like the
fort is obvious. QP’s name or electronic signature is against data protection rules.
Fortunately, with the revised CTIS transparency rules of 05-Oct-
We are still on a steep learning trajectory, and our experience is 202316, the QP declaration will no longer be published.
still limited. We are all learning and improving, including the au-
thorities and the CTIS database. Note: Redaction was also used for Company Confidential Informa-
tion (CCI); thus, this aspect did not affect me as a QP.
It took a while for us QPs to safely identify the new documents,
name them correctly, and find the required information in them. Transition
Documents that I consider relevant for the QP release are: Trials under CTD need to be transitioned to CTR. This transitioning
• Approval screenshot with conclusions from the CTIS data- of all running clinical studies is a significant effort. For Roche alone,
base, this means 150 Roche-sponsored studies and about the same num-
• Assessment Report Part I, ber of IITs and Collaborations that are to be transitioned. Due to
• Application form, good planning, execution, and monitoring, we are making good
• RFI documentation, progress. Thus, the threat is imminent since after 31 January 2025,
• Conditions and Commitments, the continuation of a clinical trial without transitioning would be
• Labels, “considered non-compliant and in breach of the CTR”17, or simply
• Relevant Q-IMPD sections. put, illegal.

9
CTR practice guide: Clinical Trials Regulation (EU) No 536/2014 in practice, The rules governing medicinal products in the European Union, VOLUME 10 - Guidance documents applying to clinical trials, March
2024, version 05.
CTR Q&As: CLINICAL TRIALS REGULATION (EU) NO 536/2014, QUESTIONS & ANSWERS, VERSION 6.8, he rules governing medicinal products in the European Union VOLUME 10 - Guidance documents

8
10

applying to clinical trials, March 2024, section 1.1.

11
This article was based on the CTR Q&As 6.8.
12
CTIS Evaluation Timelines, CTIS Training Programme, EMA, Version 2.0 – February 2024.
13
106 days includes 15 days for validation questions and 31 days for part I and II RFIs.
14
Note: if there are RFIs, the regular timelines apply.
15
See CTIS Application Form under: Compliance with GMP for the medicinal product / Authorisation number of manufacturing and import. The MIA number is taken from one of the uploaded MIAs, thus, not
necessarily the site of certification and import.
16
Transparency Rules: Revised CTIS Transparency Rules, Revised CTIS Transparency Rules, EMA/263067/2023
17
CTR transition guidance: Guidance for the Transition of clinical trials from the Clinical Trials Directive to the Clinical Trials Regulation, May 2024, Version 4, page 3, section 1.
Progress since EMA introduced the Expedited Transition Proce- • The same applies to a potential “approval subject to condi-
dure. The Expedited Transition Procedure is based on previously tions.” These are fully transparent and traceable to prior Q&As.
submitted documentation – no modifications are submitted with • We have a consistent and predictable approval timeline for all
the transitioning application. EU studies (106 days, including validation questions and RFI).
And ethics approval is already included. On the downside, for
Thus, for a multi-national trial, the protocol, IMPD, and IB must be most countries, this is longer than before.
either the same in all countries or have to be harmonized via a sub-
stantial amendment before the transition or can be consolidated In general, we very much appreciate that the authorities were open
with the transition “reflecting the common core provisions and to input from industry (e.g., implementing the IMPD-Q-only sub-
capturing the differences regarding the nationally authorised tri- mission or, finally, allowing the transition of Investigator Initiated
als.”18. Trials (IITs) with a Cross-reference to a CTD study, see below).

Pre-transition harmonization proves to be time-consuming and af- We see another promising discussion with single health authori-
fects the transition date. ties.22 Some Member States had been applying much quicker ap-
proval timelines under CTD than those defined under CTR. There
A timeline of 22 days is foreseen for approval under the expedited are experiments with “fast-track submissions” under CTR. This
administrative procedure. The record that we observed in Roche would be very promising, particularly for Phase 1 trials.
was 54 days19.
Challenging Surprises
In general, it is not foreseen to cross-refer to CTD studies20 (see
also under Challenging Surprises). Luckily, this was recently Cross-referencing to CTD trials is not allowed
changed and is now acceptable for the transitioning application of A seemingly minor detail created a massive roadblock in the begin-
IITs21. ning. Cross-references to CTD trials were not allowed for CTR tri-
als. Under CTD, cross-references were the main mechanism that
The transition does not require updating the labels to reflect CTR made IITs and Collaborations possible without disclosing compa-
requirements with the transitioning application. This should occur ny-confidential information (CCI) to the Sponsor. CTIS does not al-
with the first substantial modification after the transition. This ob- low submitting an IMPD to another Sponsor’s trial without disclos-
viously simplifies the transition and removes labeling logistics ing the IMPD to the sponsor.
from the critical path.
As a consequence, no new IITs with development products were
Positive Surprises initiated for a significant time. Then, the concept of the IMPD-Q-
only submission was proposed. The product owner can submit the
Apart from the observed difficulties, several aspects are very posi- IMPD-Q using a different EU CT number than the Sponsor’s trial.
tive:
• We indeed have a single set of documents – in contrast to hav- While this was received with great relief, this concept came with
ing one set per EU member state (on average 7 EU countries new challenges:
per study). However, later in this publication, I will highlight • Both submissions from the Sponsor and product owner must
where authorities fail to deliver the initial promises (e.g., mul- occur within 24 hours,
tiple sets of cmc data are allowed, and country-specific chang- • Transparent referencing is required for both submissions,
es to QP declarations). • It is quite difficult to make sure the information in both sub-
• A change that we had been looking forward to was that the missions is aligned (and we saw some learning curve here),
label is a required element of the part I documentation. For • Interestingly, the IMPD-Q-only submission does not foresee
the first time, I, as a QP, have undoubted evidence that a cer- substantial modifications. Changes are implemented via with-
tain label was submitted and approved in all EU countries. drawals and resubmissions. Again, matching information must
• An unexpected benefit was the clear visibility of any Requests be provided in both submissions,
for Information (RFI) from the authorities and the respective • These new aspects need to be covered contractually between
company responses (Q&A). It is immediately visible in the ap- sponsor and PO (product owner).
proval screenshot and the assessment report.
Before CTR, the visibility of Q&A for the QP was dependent on QP declarations – new requirements
my ability to read the local language approval letters and Q&A In the section above, we cherished the “Single Set of Documents.”
documentation or dependent on the working style of the in- Thus, we see multiple country-specific requests for documents
volved regulatory coworkers (the information was always that should not be required per the CTR Q&A.
available but not necessarily in plain sight for the QP).

18

19
CTR transition guidance, page 7, section 8.
Transitioning ongoing Studies from CTD to CTR, Roche’s strategy and experience transitioning a large portfolio of CTD studies to the CTR in time by the end of the transition period, Author: Sandrine Ver-
9
straete, Co-Authors: Samia Dridi, Natalia Lugli, Valentina Geisseler-Homann, Duncan Terrett, Rina Gamboni, Joanna Gaspar-Neves, F. Hoffmann-La Roche Ltd, Basel (Switzerland), Poster Presentation, DIA
Europe, Brussels, 12-14 March 2024.
20
CTR Q&As, section 3.8, answer 174.
21
CTR Q&As, section 2.15, answer 128.
22
Regulatory aspects of the implementation of CTR and work in CTIS: updates and clarifications specific for early phase, tips for a smooth validation, Anne LENAERS, FAMHP, Brussels, 15.09.2023
 In theory, no more QP Declarations are required for Active Pharma- the respective product for this country.
ceutical Ingredient sites, and no more QP declarations are required
for MRA Sites23. Taking the CTR Q&A literally, we cannot exclude that we could also
have different IMPD versions in the same trial. We are observing
Thus, single member states concerned requested those QP decla- this closely, and we do not want to return to country-specific regu-
rations that are explicitly not required, in particular for 3rd country latory compliance assessments.
Biologics Drug Substance manufacturers and even for Cell Bank
manufacturers. Pushback, referencing EMA's own guidance, result- Study Start
ed in even more RFIs, so the best tactics appeared to give in. Another source of discussion was that, in theory, a study could
start after a member state issues a positive decision on parts I and
From a strategic point of view, we urge the authorities to align and II25. Our process foresees the release of medication once the RMS
adhere to their own guidance. and all MSCs have documented their part I and II approval.

Requests for Information (RFIs) Labeling

RFIs are a topic of discussion:
• Above, I appreciated the new transparency; Labeling requirements are defined in the CTR, chapter 10, articles
• On the other hand, the same information appeared multiple 66 to 69, and CTR Annex VI. Upon the CTR's initial publication, the
times redundantly; new requirement to print the period of use on the immediate pack-
• We saw identical RFIs coming from multiple member states aging was discussed intensely. Luckily, once the CTR came into
without any consolidation. force, corrections began, and Annex VI26 was revised. In short, the
• Since replying to those RFIs is subject to strict timelines, this period of use is handled like with the old Annex 1327.
contrasts with answering the same questions multiple times.
After 31.01.2025, labels are required to comply with Annex VI. For
Multiple sets of cmc data are still possible transitioned trials, CTR-compliant Labels shall be submitted using
An unexpected blow was that in contrast to the “Single Set of Doc- the first substantial modification after the transition. After new la-
uments” paradigm, differences in part I documents in single mem- bels are approved, any superseded label should no longer be used.
ber states are still possible.
A related practical aspect: For IITs, we often have the EudraCT
CTR Q&A states, ”… each Member State Concerned takes an indi- number on labels, which will be outdated after the transition. Ac-
vidual decision and can disagree with a positive conclusion by the cordingly, we are switching to the EU CT number. Submission will
RMS. … several versions of the part I documents may exist”24. be with the first SM after transition.

So far, we only observed different study protocol versions in the The CTR allows the member states to determine the language of
same trial, e.g., one study arm was not approved in a certain mem- the labelling28. Annex II to the CTR Q&A provides further clarifica-
ber state. Thus, this is release-relevant since we should not release tion: “EN labelling is acceptable for an IMP that is only adminis-

23
CTR Q&As, Section 8.4, Answer 417.
24
CTR Q&As, section 3.15, answers 204 and 205.
25
CTR Q&As, section 2.5, answer 92.
26
Commission Delegated Regulation (EU) 2022/2239, of 6 September 2022, amending Regulation (EU) No 536/2014 of the European Parliament and of the Council as regards labelling requirements for unautho-
rised investigational and unauthorised auxiliary medicinal products for human use, Official Journal of the European Union, 15.11.2022
27
Old Annex 13: EudraLex, The Rules Governing Medicinal Products in the European Union, Volume 4, EU Guidelines to Good Manufacturing Practice, Medicinal Products for Human and Veterinary Use, Annex
13, Investigational Medicinal Products, Brussels, 03 February 2010, ENTR/F/2/AM/an D(2010) 3374.
28
CTR, Article 69.

10
tered by the physician (or qualified health professional) and not Authorization Numbers) without any submission.
handed to the patient.”
Since we frequently see supply shortages of generic products, a
While this was practiced before, it is now legally defined - contrast- seamless replacement of an unavailable Comparator or AxMP
ing the old Annex 1329. could be very beneficial.

Another new aspect is that commercial products may be used Interestingly, this possibility did already exist under CTD; however,
without labelling if the study concepts allow this30. it was not widely used: The application form standard under CTD35,
in section D.2.2., used a disclaimer “(where) the protocol allows
Finally, per the CTR, hospitals are entitled to perform re-labeling or that any brand of the IMP with a Marketing Authorisation in that
re-packaging activities for use in other hospitals in the same Clini- Member State be administered to the trial subjects.” This disclaim-
cal Trial and Member State31 without having an MIA. For example, er excluded nationally authorised products from usage in other
they could label commercial products with the required additional countries and removed many standard-of-care products from the
particulars “(a) name of the main contact; (b) clinical trial reference scope.
code allowing identification of the clinical trial site, investigator,
sponsor, and subject; (c) 'For clinical trial use only' or similar word- Noteworthy Facts
ing.”32
In the section below, I listed several facts that may sound as if they
As a QP, I cannot say that I like the proposed freedom: I primarily were outside the horizon of a Qualified Person. I think they are
see noteworthy – please check for yourself:
• A lack of supply chain control,
• Higher costs for local sourcing, AxMPs
• Potential for misuse of medication outside the intended Clini- In line with the CTR implementation, the guidance on AxMPs was
cal Trial, recently revised36, providing changes to the definition (IMP vs.
• Difficulties in performing drug accountability, AxMP), requirements for authorized and non-authorized AxMPs,
• And the potential to negatively affect the reliability of study labelling, and submission documentation. The impact of this docu-
data. ment is still being discussed, e.g.37

On the other hand, considering the typical desperation of Clinical Conditions

Colleagues when confronted with IMP lead times of three to seven A Clinical Trial Application can be authorized, authorized subject to
months, I understand the intention. There are scenarios where, conditions, or rejected38.
subject to appropriate controls, this approach can make sense.
Per default, a condition will not prevent the start of the trial. Thus,
Supply Strategy in exceptional cases, the study start can be delayed until the condi-
tion is met. So far, we found conditions written clearly, leaving no
In the turmoil of implementing CTR submissions and switching all doubt if a condition implies approval or delay. For a QP, this can be
running studies, it went almost unnoticed that the CTR includes a crucial distinction: It means that I can either certify the study
several aspects with a potentially significant impact on our IMP medication or not.
supply strategy.
Mother and Daughter Trials
Relabelling at hospitals The concept of cross-referencing now uses a new terminology:
The possibility of relabelling at hospitals33 would allow us to source “mother” and “daughter” trials39. An approved IMPD-Q in a mother
comparators at the said hospitals, perform relabelling, and distrib- trial automatically leads to approval in all daughter trials. This re-
ute the product within the same country for the same trial. Such a quires that all Member States Concerned in the daughter trial par-
concept would undoubtedly be a paradigm change for our supply ticipate in the mother trial. A new mother trial must be selected
strategy. I did express my hesitation above. when the first trial ends. While cross-referencing is a rather manu-
al process in CTIS, the benefits of having only one IMPD-Q for all
Submission per Active Substance or ATC code trials could outweigh the extra administrative effort.
Commercial products can be submitted “per active substance or
ATC code”34. This would allow, for example, changing between dif- Substantial modifications
ferent Generic Comparators or AxMPs (with different Marketing The term “substantial modification” (SM) now replaces the “sub-

29
Old Annex 13, article 28.
30
CTR, Article 67, 1. (b).
31
CTR, Article 61, paragraph 5. (a).
32
CTR, Article 67, paragraph 2. and CTR, Annex VI, Section C.
CTR, Article 61, paragraph 5. (a).
11
33

34
CTR Q&As, section 3.16, answer 206 and CTR Q&A, Annex V.
35
CTD Application Form: Annex 1 Clinical Trial Application Form, REQUEST FOR AUTHORISATION OF A CLINICAL TRIAL ON A MEDICINAL PRODUCT FOR HUMAN USE TO THE COMPETENT AUTHORITIES AND
FOR OPINION OF THE ETHICS COMMITTEES IN THE COMMUNITY.
36
Auxiliary Medicinal Products in Clinical Trials, Recommendations on the use of Auxiliary Medicinal Products in Clinical Trials written and endorsed by the Clinical Trials Coordination and Advisory Group (CTAG),
01 March 2024
37
CTIS Bitesize Talk: Alternate IMPD-Q and New guidance AxMP, YouTube video, 19.32 – 1:14:32, European Medicines Agency, 30.04.2024
38
CTR Q&As, section 2.8, answers 100 - 104.
39
CTR Q&As, section 3.8, answers 173 - 178.
 stantial amendment.” The definition is very broad: “They are likely SM (or verify that it is not required). Note: No other restart activi-
to have a significant impact on: the safety or rights of the subjects ties may occur before the approval of the SM, in particular, the
and/or the reliability and robustness of the data generated in the start of recruitment48.
clinical trial”40. In addition, the CTR Q&A provides an insightful list
of examples41 in addition to the known guidances42,43. A new limita- Urgent Safety Measure (USM)
tion exists: only one SM is possible at a time. To submit an addi- The USM49 is a means to notify the member states concerned
tional SM, you must wait for the first one to be approved (or with- through the EU portal where an unexpected event is likely to seri-
draw it) - this is obviously a significant drawback for our regulatory ously affect the benefit-risk balance. The USM describes the event
colleagues. and the measures taken. A USM may involve a temporary halt and
an SM before restart. The impact on QP certification is described
Changes relevant to the supervision of the trial (Art 81.9 change) above.
The Article 81.9 change represents a new concept for changes rel-
evant to the trial's supervision. This change will require updating Financing and Sponsorship
certain information or documents in the CTIS database, but no ap- While it is a Sponsor’s responsibility to set up the financing of a
proval is required. Clinical Trial, the sole financing of a trial does not imply sponsor-
ship50 or Sponsor liabilities, accordingly. This is primarily interest-
Non-substantial modifications (NSM) ing for a company that supports IITs. Thus, also for a QP of the
The concept of a non-substantial amendment remains, but it is manufacturer’s organization, it is important to delineate their own
now called a non-substantial modification (NSM). It means a responsibilities from those of the Sponsor51.
change that involves, e.g., an editorial update to study documents.
Such an NSM will be implemented with the next substantial modi- Conclusion
fication44 of the respective document45.
The CTR is probably the most significant regulatory development
Addition of a new member state concerned (MSC) for Clinical Trials and IMPs in the last two decades – or my profes-
There is a new submission type to add member states concerned sional experience as a QP. It profoundly impacts my work as a QP
(MSC). It requires approval from Parts I and II by the new MSC. (all pharmaceutical industry in the EU). Some of these develop-
Expected timeline: 52-83 days46. ments were not visible at first glance and are still unfolding. Diving
into the details of these many impacts, increasing my understand-
Temporary halt and restart of a trial ing, discussing them with other QPs, and finally summarizing it for
A temporary halt47 means an interruption of a trial that is not de- my peer group was a rewarding exercise in itself - I hope you find
scribed in the protocol. It is executed by the Sponsor and implies this useful as well.
the intent to resume the trial. A temporary halt is notified to the
authorities, e.g., with an Urgent Safety Measure. The restart is typ- Note: This publication represents the author's personal opinions. It
ically a Substantial Modification (SM). CTR says restart is an SM “if uses information gathered from QP colleagues in the German QP
the reasons for the temporary halt have the potential to affect the Association, and experience gathered as a QP of Roche Pharma AG.
benefit/risk balance (i.e., concern related to safety, lack of efficacy It does not reflect official statements of the GQPA, Roche Pharma
or IMP quality defect).” AG, or F. Hoffmann-La Roche, Inc.

If this is not the case (e.g., an IMP shortage), the restart can be noti- Thanks a lot to the reviewers of this document:
fied (under CTD, the restart was always a substantial amendment). Dr. Rina Gamboni, F. Hoffmann-La Roche, Inc.
Henriette Granse, Roche Pharma AG
Why is this important for a QP? A temporary halt can imply a stop Tillmann Lindenblatt, Fisher Clinical Services GmbH
of certification. Dr. Natalia Lugli, F. Hoffmann-La Roche, Inc.
Dr. Gabriele Oleschko, Merck KgaA
It may be necessary to revoke certifications, reject products, or
even initiate a recall.

After the decision to restart a trial and before resuming certifica-

tion, a QP typically needs to wait for the approval of the respective

40
CTR Q&As, section 3.1, answer 131.
41
CTR Q&As, Annex IV.
42
Guideline on the requirements for quality documentation concerning biological investigational medicinal products in clinical trials, 27 January 2022, EMA/CHMP/BWP/534898/2008 Rev. 2, Committee for
Medicinal Products for Human Use (CHMP)
43
Guideline on the requirements to the chemical and pharmaceutical quality documentation concerning investigational medicinal products in clinical trials, 27 January 2022, EMA/CHMP/QWP/545525/2017
Rev. 2, Committee for Medicinal Products for Human Use (CHMP)
44
CTR Q&As, section 3.4, answer 144+145.

12 CTR Benefits and Challenges from the sponsors perspective, Author: Natalia Lugli, Co-Authors: Samia Dridi, Rina Gamboni, Joana Gaspar Neves, Valentina Homann, Duncan Terrett, Sandrine Verstraete, F.
45

Hoffmann-La Roche Ltd | Pharma Drug Regulatory Affairs, Poster Presentation, DIA Europe, Brussels, 12-14 March 2024.
46
CTR Q&As, section 2.10, answers 113-115.
47
CTR Q&As, section 10.4, answers 440 - 444.
48
CTR Q&As, section, 10.1, answer 433.
49
CTR, article 54.
50
CTR Q&As, section 5.3, answer 226-228.
51
Guideline on the responsibilities of the sponsor with regard to handling and shipping of investigational medicinal products for human use in accordance with Good Clinical Practice and Good Manufacturing
Practice, 14 September 2022, EMA/INS/GMP/258937/2022.
Real-World Data (RWD) and Real-World
Evidence (RWE) to Support Medicinal
Product Development
The use of Real-World Data (RWD) and Real-World Evidence (RWE) streamlining processes for marketing authorization holders
is playing an increasingly important role in the development, au- (MAHs). The speed and efficiency of evidence generation are en-
thorization, and monitoring of medicinal products. To move for- hanced, which in turn may shorten the approval steps for specific
ward, the European Medicines Agency (EMA) has published a com- studies.
prehensive document explaining how RWE, derived from RWD,
can support regulatory decision-making. The document focuses on EMA’s document (Real-world evidence provided by EMA - Support for
the practical applications of RWE, such as filling evidence gaps, im- regulatory decision-making) published on the agency’s Big Data
proving efficiency in regulatory processes, and generating evidence website highlights that scientific questions can currently be ad-
in a timely manner to aid in the decision-making processes of regu- dressed using three main RWE approaches:
lators. Furthermore, the EMA can assist in identifying the best re-
sources to answer specific research questions, conducting target- 1. DARWIN EU® (Data Analysis and Real-World Interrogation
ed analyses, and ensuring independent and transparent evidence Network)
generation. 2. Internal Electronic Health Databases from various EU coun-
tries
Applications and Benefits of RWD/RWE 3. Studies conducted under EMA framework contracts

One of the major advantages of utilizing RWE is that it can comple- These approaches allow rapporteurs, assessors, or national regula-
ment evidence gathered from traditional clinical trials, particularly tory representatives to submit questions to the EMA, aiding in the
in areas where data gaps exist throughout the product lifecycle. evaluation of medicinal products by providing additional data to
The use of RWE allows for multiple products to be monitored si- support their assessments with regard to efficacy and safety.
multaneously, avoiding unnecessary duplication of studies and

13
About the Author
Dr Andrea Kühn-Hebecker is Operations Director and organises and conducts courses and conferences on behalf of the ECA Academy in the area
packaging, herbal medicinal products, development and Lifecycle Management.
 EMA's Technological Advancements: Scientific Ex- Additionally, an annex in the reflection paper summarizes existing
plorer regulatory guidance and resources related to RWD and RWE.

In March 2024, the EMA introduced the Scientific Explorer, an AI- RWD in Non-Interventional Studies (NIS)
enabled tool designed to assist EU regulators in navigating regula-
tory scientific information. The tool offers focused and precise Non-interventional studies (NIS) or so-called “observational stud-
searches of the EMA network’s sources, simplifying and accelerat- ies”, which do not involve randomization or blinding, are increas-
ing decision-making processes. This AI-driven tool is part of EMA’s ingly recognized as valuable sources of RWD for regulatory pur-
broader efforts to modernize its regulatory practices and improve poses. While clinical trials remain the primary source for assessing
access to relevant RWD and RWE. the benefits and risks of investigational medicinal products (IMPs),
NIS have gained traction in post-authorization safety assessments.
Insights from EMA’s Pilot Study on RWE The EMA has published a draft Reflection Paper on the use of RWD
in NIS to generate RWE, which was open for public comment until
Between September 2021 and February 2023, the EMA conducted August 2024. The draft addresses the methodological challenges of
a pilot project to generate RWE to support regulatory evaluations. NIS and explores ways to improve their acceptance for efficacy as-
This initiative, detailed in an article published in Clinical Pharmacol- sessments. The EMA’s ongoing projects aim to generate more
ogy & Therapeutics (“Real-World Evidence to Support EU Regulato- structured RWD and incorporate this data into regulatory decision-
ry Decision Making—Results from a Pilot of Regulatory Use Cas- making processes, thereby expanding the role of NIS in evaluating
es”), provided key insights into how RWE can be integrated into medicinal products.
regulatory decision-making.
Furthermore, following the previously published ICH reflection pa-
The pilot study revealed several important lessons: per on Real-World Evidence (RWE) and Real-World Data (RWD) to sup-
port regulatory decision-making, the ICH M14 Guideline on General
• Complementarity with Clinical Trials: RWD and RWE can en- Principles on Plan, Design and Analysis of Pharmacoepidemiological
hance the evidence provided by traditional clinical trials, help- Studies that utilize Real-World Data for Safety Assessment of Medicines
ing to fill evidence gaps at various stages of a product’s lifecycle. has been published in May 2024 for public consultation. This guide-
• Timely Evidence Generation: There is a need for faster access line focuses on non-interventional studies using RWD, offering rec-
to representative data to meet regulatory timelines. ommendations for the safety assessment of medicines, including
• Collaboration and Communication: Early and close interaction drugs, vaccines, and other biological products.
with stakeholders, including the agency's scientific Commit-
tees, is crucial for understanding research questions and en- The ICH M14 Guideline aims to align international best practices on
suring the relevance of studies conducted. planning and conducting safety studies with RWD, while expand-
ing the potential for using RWE to assess medicine effectiveness
The agency aims to leverage these insights to maximize the poten- and utilization in routine clinical practice. The guideline also con-
tial of RWE in future regulatory frameworks. nects with other ICH efforts, such as the ICH E6(R3) (Good Clinical
Practice (GCP)) and the ICH M11 (CeSHarP) guideline, which focus-
Harmonization Efforts es on clinical trials and the corresponding protocols.

The EMA has taken steps to harmonize the use of RWE in regula- Conclusion
tory environments. One key initiative is the ICH Reflection Paper on
Real-World Evidence (RWE) and Real-World Data (RWD) to support The European Medicines Agency’s initiatives around RWD and
regulatory decision-making, which aims to standardize terminology RWE reflect a significant shift towards integrating real-world data
and converge principles for planning and reporting RWD-based into the regulatory framework for medicinal product development.
studies. The paper, which was revised following a public consulta- By harmonizing standards, utilizing advanced technologies like ar-
tion from June to September 2023, outlines the following areas for tificial intelligence (AI), and expanding the scope of non-interven-
harmonization: tional studies, the EMA is streamlining processes and enhancing
the robustness of evidence used in regulatory decisions. These ef-
• Standardization of Terminology: Aligning definitions for RWD forts not only promise faster and more comprehensive evaluations
and RWE to ensure consistency across regulatory frameworks. but also enable a more responsive regulatory environment that can
• Protocol and Report Format: Establishing a common format adapt to the evolving regulatory landscape of (investigational) me-
for study protocols and reports submitted throughout the life- dicinal products.
cycle of a medicinal product.
• Study Registration: Encouraging the registration of protocols
and reports to promote transparency and accountability.

14
Product, Process, People
Addressing the critical Pillars of EU GMP Annex 1 Compliance

When official rules or regulations are updated, changes can often The expected benefit is fewer deviations in manufacturing, as il-
be summarised in headlines or distilled into key takeaways. lustrated in Figure 1, and improved supply chain integrity. At an

Such a task was arguably not possible when the revised EU GMP
Annex 1 came into force on 25th August 2023. Rather than subtly
tweaking the rules governing the manufacture of sterile medicinal
products in the European Union, EU GMP Annex 1 effectively reset
standards in this area for pharmaceutical companies across the
globe.

The holistic nature of the updated regulations places emphasis on

a range of areas that in themselves are already comprehensive in
scope. This includes the role of primary packaging components,
where attention has been given to an in-depth understanding of
container closure integrity (CCI), and the wider requirement for a
comprehensive, evidence-based contamination control strategy
(CCS). Both of these are focused on reducing contamination, such
as particulates, microbes, and pyrogens throughout the whole
sterile manufacturing process. Figure 1: Particulate contamination and lack of sterility cause most U.S. product
recalls attributable to primary packaging1

About the Authors 15

Dr Ana Kuschel ... is a Principal Scientific Affairs at West Phar- Niamh Bissett is a Director of Business Transformation at West
maceutical Services and an active member of the ISO TC 76 and Pharmaceutical Services and has over 20 years of experience in
PDA Packaging Science groups. quality compliance and program management
 operational level, this means there must be a collective and con-
certed commitment to limiting contamination at every step of a This ‘top-down, bottom-up’ approach ensures contamination is
sterile drug product’s lifecycle to meet the overarching goal of en- controlled consistently at all levels across the organisation, both
hancing patient safety. operationally and culturally. To satisfy both the suppliers’ own am-
bitions and regulatory expectations for continual improvement, a
Suppliers of primary packaging materials are expected to develop lifecycle management approach should be established, ensuring
their own CCS in anticipation of the demands set out by EU GMP sustained compliance as regulations evolve. This relies on continu-
Annex 1. A combined global approach with site-level implementa- al internal and external benchmarking as part of an ongoing ‘Plan
tion ensures strategic ambitions are delivered locally on the Do Check Adjust’ (PDCA) methodology. Such measures are not,
ground. This is manifested through an enterprise-wide master CCS however, designed exclusively to satisfy internal requirements.
that defines the overarching objectives and requirements for EU Rather, the ambition to complement a customer’s own CCS, plug-
GMP Annex 1 compliance in a single-source document as illustrat- ging the best-practice approach into wider contamination control
ed in Figure 2. efforts as a trusted supply chain partner. An example of a CCS de-
velopment process flow is shown below (Figure 3).

A critical aspect to be considered in the journey to align a manu-

facturing site with EU GMP Annex 1 is the development of a Change
Management Communication Strategy. This should underline the
importance of ongoing efforts to control contamination in a very
human way, helping inform and educate team members as per the
demand for personnel to have a “specific focus on the principles
involved in the protection of sterile product during the manufac-
turing, packaging and distribution processes” as set out in EU GMP
Annex 1. With the ultimate goal of reinforcing a mindset shift to-
wards the notion of continual improvement with regard to con-
tamination risk, using the fact that every product produced has a
patient’s name on it as a motivating factor.

At the point of initial engagement with a customer to assess pri-

mary packaging components, in light of EU GMP Annex 1 require-
ments, the focus should be placed on the four areas of product,
process, protection and proof, see Figure 4.

Product considers the quality levels of current components and

whether they are sufficient to meet a sterile injectable manufac-
Figure 2: Example of manufacturing controls for primary packaging elastomer, turer’s contamination control objectives.
including individual and collective effectiveness of the controls measured
through the product process flow. Process considers any potential changes to processing that might
be required, taking into account whether components are steri-
lized in-house or supplied in ready-to-use form, whether they will
The enterprise master CCS is complemented by an individual Con- be introduced into restricted access barrier systems (RABS) or iso-
tamination Control Plan (CCP) at each supplier production site, the lator fill-finish lines, and the context within which vial crimping
latter of which provides location-specific details on compliance takes place.
with global requirements while enabling cross-site sharing of best-
practices. Protection considers the various factors that can have an impact

16

Figure 3: CCS journey development process flow: from global development to site implementation.
Figure 4: Key considerations when assessing primary packaging components for EU GMP Annex 1 readiness.

on CCI and how it is managed throughout a product’s lifetime. Fi- To ensure primary packaging elastomer components meet this de-
nally, proof considers the importance of suppliers evidencing their manding level of component quality, controls need to be imple-
own CCS so that it can be incorporated into a customer’s wider mented at each manufacturing step to eliminate possible sources
holistic plan. of risk. In the early stages, this includes segregation of materials,
isolation of utensils and line clearance procedures, supported by
It is these individual components that can be regarded as being at exhaust systems and filters, as well as low particulate environ-
the core of maintaining sterility for parenterally administered drug ments molded/formed components are then washed, vision in-
products. From a physical and chemical perspective, packaging spected, packed, and sterilised with validated processes before
components must adhere to the highest quality standards if they being shipped.
are to deliver on the requirements set out by the revised EU GMP
Annex 1. Elastomer raw materials, dimensional tolerance, coating Together, these controls all conspire to optimize conditions so that
performance, extractables and leachables profile, and integration particle generation is restricted to the subvisible range.
with production environments are all factors that must be con-
trolled to avoid introducing risks.

17

Figure 5: Illustration of manufacturing steps and respective controls for elastomeric closures.
 An example in the market are elastomeric components that specify fined in relation to a drug product’s maximum allowable leakage
both subvisible and visible particles ranges. limit (MALL). The selection of the test method will depend on mul-
tiple factors including, but not limited to, the drug product itself
Pharmaceutical companies rely on automated vision inspection and corresponding storage conditions. It is noted that one single
systems to help ensure product safety. Ideally, primary packaging test method may not be sufficient, and that the leak test(s) chosen
elastomer components should also have vision inspection systems should be capable of demonstrating the ability of the specific con-
implemented in their manufacturing line, with the goal of reducing tainer closure integrity to meet the MALL for the product of inter-
the end-of-line reject rate via the detection of visible particulate est. The CCI should also be built into the overall process via a ho-
matter and other defects. The vision inspection system and tight listic approach considering all CCI aspects and elements of a
manufacturing controls enable a higher acceptable quality level control strategy, starting with the right elastomer component se-
(AQL). lection at the product design, to address all risks and how to pre-
vent and control them.3
Another area of focus introduced in the revised EU GMP Annex 1 is
in the form of extractables and leachables. The guidance calls for Primary packaging components can therefore be seen to answer
“an assessment of leachable profile studies, including safety concerns” the most demanding questions in relation to contamination con-
that reflects processing conditions and is rooted in a scientific ra- trol, demonstrating alignment with the requirements set out in EU
tionale to evaluate the risk of impurities in the drug product. En- GMP Annex 1. However, suppliers should be cognisant of the fact
suring that a drug product is safe and effective means selecting an that components are rarely considered in isolation and must also
elastomer closure system that will not significantly interact with appreciate how they integrate within cleanroom environments if
the drug nor adversely affect the patient. That can be achieved via they are to truly support a seamless, end-to-end approach to mini-
carefully selecting and characterising the elastomer closure raw mising the risk of microbial contamination in Grade A and Grade B
material ingredients and processing steps to reduce the risk asso- areas. For example, the provision of flexible secondary packaging
ciated with leachables and using a barrier film applied in the elas- options ensures facilities with isolators and RABS (as advocated in
tomer closure surface facing the drug product. (Figure 6). EU GMP Annex 1) can support the use of rapid transfer ports to al-

Figure 6: Depiction of closures with a laminated barrier film applied to the closures surface. The blue color indicates the area of the barrier film coverage and is for il-
lustration purposes only.

Clinical examples demonstrating the effectiveness of a protective low components to be introduced without the use of glove ports
barrier properties include: Eprex® packaged using laminated stop- and in a way that reduces turbulent airflow.
pers reduced the incidence of pure red cell aplasia (PRCA) by creat-
ing a barrier to a rubber accelerator leaching from the elastomer But even with the most streamlined processes and the highest
closure; and metal ion induced degradation of epinephrine in lido- specification components, sterile manufacture must also continue
caine-epinephrine injection resulting in lidocaine ineffectiveness to address the human factor if contamination control is to be man-
was mitigated with laminated closures.2 aged in a truly holistic way. As discussed above, people should rep-
resent a vital pillar in supplier journey not just to comply with EU
As well as protecting the integrity of the drug product within the GMP Annex 1 but to implement continuous improvement when it
primary container, EU GMP Annex 1 also places clear emphasis on comes to contamination control. The belief is that these elements
CCI as a means of maintaining drug product sterility and quality. must all come together in a multi-faceted approach, with compo-
Drug manufacturers are referred to USP <1207> to demonstrate a nent quality, production principles and personnel all aligned on the
container closure system can maintain CCI, where integrity is de- critical responsibility of bringing ever safer products to market.

18 1
https://www.fda.gov/drugs/drug-safety-and-availability/drug-recalls and https://www.fda.gov/vaccines-blood-biologics/safety-availability-biologics/recalls-biologics (Accessed February 2, 2024)
2
Boven, K, et.al., The increased incidence of pure red cell aplasia with an Eprex formulation in uncoated rubber stopper syringes, Kidney Int. 67(2005) 2346-2353.
Milano E.A. et.al., Aluminum Catalysis of Epinephrine Degradation in Lidocaine Hydrochloride with Epinephrine Solutions. J Parenter Sci Technol. 36 (1982) 232-236.
3
Wuchner, K. et. al., Industry perspective on a holistic container closure integrity approach to parenteral combination products, European Journal of Pharmaceutics and Biopharmaceutics 194 (2024) 20–35.

NovaPure and FluroTec are registered trademark of West Pharmaceutical Services, Inc., in the United States and other jurisdictions.
Handling external Personnel in the
GMP Environment
Example: Outsourced Cleaning

This article is intended to consider cleaning processes in pharma- Definitions/terminology

ceutical production, i.e. GMP-regulated areas. With the release of
the Annex 1 to the EU GMP Guideline in August 2022, the almost The term "contamination" is often used without considering its
all-encompassing topic of "contamination control" has come to clear distinction from "impurity" by definition. Accordingly, con-
play an important role in the context of the manufacturing of ster- tamination is merely the presence or introduction of a hazard (def-
ile products. It explicitly addresses and recommends the transfer inition from the Austrian Food Safety and Consumer Protection
of aseptic manufacturing strategies, including the contamination Act). Thus, in contrast to an impurity, a contamination is always of
control strategy, to the manufacture of non-sterile pharmaceutical exogenous origin, whereas an impurity arises during the produc-
dosage forms. Cleaning processes in general are of significance tion process and must be actively removed. As an example, an en-
there for a variety of measures. Particularly in the context of a con- dotoxin build-up in biotechnological processes with certain pro-
tamination control strategy, the cleaning of surfaces that come duction organisms (e.g.: E. coli) can be mentioned here. Exactly the
into contact with the product, especially the control of so-called same substance can occur as a contaminant in the case of micro-
cross-contamination, should be considered. This is described in biological contamination, for which no specific depletion or remov-
regulatory terms with regard to its validation in Annex 15 to the EU al procedures are provided in the routine process.
GMP Guideline in the valid version of 2015. However, within the
scope of this article, only the cleaning of surfaces that do not come Furthermore, contamination is always a question of quantity and
into contact with the product, such as surfaces of the cleanrooms depending on context. A distinction is made here between:
themselves, will be discussed. Thus, all surfaces "subject to clean- • Non-critical contamination:
ing validation" are not part of the following observations and con- The concentration is below a threshold value (acceptance lim-
siderations. it).

19
About the Author
Robert G. Schwarz is lecturer at the FH Camus in Vienna, Austria. He has 20 years of experience in aseptic processing, contamination control and
clean room technology.
 • Critical contamination: In addition, the client must ensure that an adequate change control
Quantity of contamination exceeds a risk-based threshold (ac- system is established at the contractor as service provider. This is
ceptance limit); described in Chapter 7 under item 7.12:

We typically mean critical contamination when we refer to "con- "The Contract Acceptor should not make unauthorized changes, out-
tamination." side the terms of the Contract, which may adversely affect the quality
of the outsourced activities for the Contract Giver."
To avoid or adequately remove this contamination, cleaning pro-
cesses, and other measures, are essential. These points should be clarified in advance and also recorded in
writing in documents such as quality agreements.
Regulatory requirements and guidelines
Guidelines on personnel and cleaning (according
In order to fully understand the requirements associated with out- to Annex 1)
sourcing cleaning processes to external service providers, two cat-
egories of requirements need to be identified: The specifications on these topics apply equally to internal and ex-
1. Identifying the general requirements imposed on pharmaceuti- ternal personnel. In addition, the requirements of the new Annex 1
cal manufacturing companies that outsource activities. can also be applied to the manufacture of non-sterile medicinal
2. Then, specific requirements for personnel in the cleanroom and products. This is explicitly mentioned in chapter 1 ("Scope"):
the cleaning process must be determined.
“The intent of the Annex is to provide guidance for the manufacture of
sterile products. However, some of the principles and guidance, such as
contamination control strategy, design of premises, cleanroom classifi-
cation, qualification, validation, monitoring and personnel gowning,
Contamination Control Strategies may be used to support the manufacture of other products that are not
5-7 November 2024 intended to be sterile such as certain liquids, creams, ointments and
Berlin, Germany low bioburden biological intermediates but where the control and re-
duction of microbial, particulate and endotoxin/4.2 pyrogen contami-
Requirements, Measures, Strategies nation is considered important. Where a manufacturer elects to apply
guidance herein to non-sterile products, the manufacturer should
clearly document which principles have been applied and acknowledge
Learn more about this course: that compliance with those principles should be demonstrated.“
www.gmp-compliance.org
Regarding the result of cleaning, there are the following specifica-
tions in Annex 1 under point 3:

"[...] Appropriate cleanliness levels in the “at rest” and “operational”

Basic requirements for outsourcing activities states should be maintained."

It should be emphasized that the ultimate responsibility lies with In connection with outsourced activities in the cleanroom in gen-
the "marketing authorization holder", i.e. the pharmaceutical man- eral, but specifically for cleaning processes, it is crucial that all em-
ufacturer. All parties involved, both the contract giver and the con- ployees involved are aware of what "appropriate" means in this
tract acceptor, must be aware of this. context and in which prerequisites, measures and processes and
reflected in this degree of cleanliness.
This is the aim of the EU GMP Guideline in Chapter 7 ("Outsourced
Activities") under point 7.7: In this context, it is also pointed out that cleaning itself involves
contamination risks. This can be caused by inadequate dressing
"The Contract Giver should monitor and review the performance of the procedures of the external personnel, cleanroom behavior, clean-
Contract Acceptor and the identification and implementation of any ing techniques and the like. In particular, microbiological contami-
needed improvement." nation of the cleanroom can pose a risk to the product due to the
proliferation of microorganisms or the formation of (endo)toxins.
This is usually specified as part of a quality contract. One aspect of This issue is addressed in point 9,23 of Annex 1:
this requirement is the communication structure, which is an es-
sential part of the collaboration. This defines who holds the com- "[...] Viable particle monitoring should also be performed within the
munication roles at the client and contractor, and thus which em- cleanrooms when normal manufacturing operations are not occurring
ployee is authorized to give instructions to whom. It makes sense (e.g. post disinfection, prior to start of manufacturing, on completion of
to define a "pair" of persons with the corresponding functions for the batch and after a shutdown period), and in associated rooms that
20 each shift. This guarantees that an employee of the contractor does have not been used, in order to detect potential incidents of contami-
not take instructions from an "unauthorized" employee of the cli- nation which may affect the controls within the cleanrooms. In case of
ent and, in the worst case, activities are carried out incorrectly, late an incident, additional sample locations may be used as a verification of
or not at all. the effectiveness of a corrective action (e.g. cleaning and disinfection)."
Last but not least, the topic of training is addressed, which is ex- Here, as well as in general, the following parameters are to be con-
tremely relevant in all aspects of outsourcing cleaning activities, as sidered in the context of the evaluation of these cleaning process-
the activity is performed in the manufacturing area of medicinal es:
products. The working environment in cleanrooms, by its nature, • Experience of the persons carrying out the process
demands a specific behaviour and procedures, and the robustness • Training of the persons carrying out the process
& reproducibility of manual cleaning processes are to be consid-
ered critical. This is described in point 7.3 of Annex 1: And thereby

"All personnel including those performing cleaning, maintenance, • Qualification of the persons carrying out the process
monitoring and those that access cleanrooms should receive regular • Behaviour of the persons carrying out the process
training, gowning qualification and assessment in disciplines relevant
to the correct manufacture of sterile products. This training should in- But in principle, apart from the random checks, the above points
clude the basic elements of microbiology and hygiene, with a specific must be fulfilled, because it is not the control, but the system that
focus on cleanroom practices, contamination control, aseptic tech- is the guarantee of a robust cleaning with consistent results, and
niques and the protection of sterile products (for those operators en- the basis for this is the correct application of the trained tech-
tering the grade B cleanrooms and/or intervening into grade A) and the niques.
potential safety implications to the patient if the product is not sterile.
The level of training should be based on the criticality of the function The cleaning is done:
and area in which the personnel are working." • "from top to bottom"
• "from the inside to the outside"
It is also pointed out in Annex 1 Section 2.0 relevant for the Con- • "in airlocks according to the specifications (clothing, tech-
tamination Control Strategy that Cleaning as well as Disinfection is nique, products) of the subsequent higher RRK"
amongst the important elements. This reflects Cleaning’s listing • "covering the whole area by correct technique (overlapping)".
under point XIII.
Part of the training in the correct application of these cleaning
Importance of (cleanroom) cleaning techniques can be, in addition to video-supported training, a video
recording of the trainee himself to enable optimization of his own
Macroscopically and subjectively from the point of view of the procedure. Particularly in the case of higher cleanroom classes, a
cleaning personnel, pharmaceutical production areas, in particular look beyond the end of one's nose should also be offered as part of
cleanrooms of cleanroom class A and B, are (almost) always clean the theoretical training and, in addition to "What is to be done?",
or sterile anyway. Why, then, is a cleaning process, which is usually also "Why is it done in this way?
very time-consuming, necessary? The answer can be found in the
sub-visual area. Among the various physical, chemical or particu- Furthermore, especially due to the criticality in high cleanroom
late types of contamination, microbial contamination is of particu- classes (keyword: "I am cleaning an optically clean surface"), a visu-
lar importance, in addition to cross-contamination (product or ac- alization of the cleaning success by applying fluorescent substanc-
tive ingredient carryover). Firstly, this has a time-dependent es to test surfaces within the scope of the practical parts of a train-
component due to the proliferative capacity of microorganisms; ing course has proven successful. Here, a more in-depth
secondly, possible toxin production by microorganisms can pose understanding is achieved through the "learning by doing" effect.
an additional risk to product quality and consequently to patient Cleaning in test rooms outside the cleanrooms in production-spe-
safety. cific clothing with the cleaning utensils to be used can also be part
of the practical training in order to highlight potential weak points,
This issue must be addressed again and again during the training of e.g. in cleaning techniques.
employees who are entrusted with the cleaning of cleanrooms.
This is especially the case in class A/D cleanrooms, where sterile Due to the criticality of microorganisms in the production environ-
drugs are produced aseptically and the hazard is, so to speak, an ment, cleaning and disinfection processes in production areas
invisible one. This eliminates the thought process "But everything must be developed and implemented with the following consider-
is clean here! Why should I clean there?" and an awareness of the ations in mind:
immense importance of room cleaning activities within the overall • Cleaning removes contaminants, product residues and, where
contamination control strategy is achieved and consolidated. This applicable, microorganisms from surfaces
ensures that the non-product-contacting surfaces in these pro- • Cleaning and disinfection interrupt the contamination chain of
cess- and product-critical areas are not only clean (free of visible microorganisms
impurities), but also free of visible and subvisible, microbial and • Cleaning removes the nutrient substrate required by the mi-
particulate, impurities. croorganisms for reproduction
• Disinfection inactivates or reduces the microorganisms
These cleaning processes of the surfaces in the production rooms • Both serve to prevent the transfer of dirt, product residues
of pharmaceuticals can only be subjected to a random process and microorganisms into the products
check as a success control. On the one hand, the environmental 21
monitoring serves for the control, which represents a random, lo- A point that is discussed again and again, mainly from an economic
cal microbial control of the surfaces, on the other hand, a visual point of view, is whether the ever-increasing regulatory pressure
inspection of the processes within the scope of the "Quality Assur- and workload in surface cleaning is still in proportion to the bene-
ance Oversight", which then represents a random sample. fit. At this point, one should ask how many resources are invested
 in the processes of maintaining the degree of cleanliness in phar- es or products require it, such as containment requirements or ra-
maceutical production areas: on the one hand, in maintaining the diopharmaceuticals.
cleanliness of the air by HVAC systems and, on the other hand, in
maintaining the cleanliness of the surfaces by qualified cleaning Table 1: Challenge process understanding
personnel and equipment. Third-party cleaning In-house cleaning
Often no understanding of the Often too little understanding
In general, it should be said that even when outsourcing the clean-
production process, thus po- of the cleaning process itself
ing processes, they must be carried out by qualified personnel. One
tential hazard
should sensitize oneself and possibly also the purchasing depart-
ment and ask the following questions: Outside cleaning personnel
• Are you having your cleanroom ventilation system built by should definitely consider the
someone who specializes in air conditioning for offices? production process → also a
• Are you having your cleanroom cleaned by someone who spe- confidentiality issue
cializes in general building maintenance?
•
Improving the quality and efficiency of cleanroom cleaning can of- Table 2: Challenge of time resources
ten be achieved by simple measures or changes in perspective. The Third-party cleaning In-house cleaning
measures here are to create cleaning SOPs, with illustrated in-
Personnel may focus exclu-
structions as far as possible, and to establish general basic cleaning Cleaning personnel often have
sively on cleaning
techniques that are independent of the room or zone. other duties as well

It is almost more important to establish an understanding that If production personnel is also

cleaning processes are an integral part of the production process responsible for cleaning, it is
and not low-priority and detached "support processes". questionable whether enough
time is reserved for proper
Outsourcing using the example of cleaning cleaning

Comparison of third-party cleaning – internal cleaning

The following comparison regarding cleanroom cleaning can be Table 3: Motivation
seen as an example for other fields of activity (e.g..: Maintenance Third-party cleaning In-house cleaning
and repair technicians for production equipment, ventilation sys-
Cleaning in cleanrooms is seen Cleaning by production per-
tems or media systems, IT services for GMP-relevant computerized
as an important, "special" task sonnel: sometimes not seen as
systems, ...).
equivalent work to production
activities (which it is, especially
Before outsourcing cleaning activities, the advantages and disad-
in the cleanroom environ-
vantages of using external or in-house personnel should be record-
ment!)
ed and weighed up in detail, especially in relation to the processes
concerned. The outsourcing itself, but also the weighing up of pros Cleaning of visually "clean" sur- Cleaning of visually "clean" sur-
and cons, should be seen as part of the contamination control faces faces
strategy, particularly with regard to the new version of Annex 1.
This should be carried out and documented as part of a risk assess-
ment. Even now, in order to meet the requirements of a QRM, it is Table 4: Staff turnover
necessary to perform and document a decision based on a risk as- Third-party cleaning In-house cleaning
sessment. Ultimately, the impact on product quality and patient
In some companies: frequently Always the same personnel
safety must always be evaluated.
changing personnel, thus re- (used to tasks, therefore less
peated training necessary (incl. mistakes, can serve each other
The author has chosen the following seven topics and tries to com-
cleanroom qualification), lack as back-up )
pare the advantages and disadvantages of in-house cleaning and
of routine
third-party cleaning:
• Process understanding Trained back-up personnel
• Time resources should be available
• Motivation
• Staff turnover
• Cleaning systems Table 5: Cleaning systems
• Suggestions for improvement Third-party cleaning In-house cleaning
• Economic aspects
22 Experience with cleaning sys- Research necessary to create
tems, individual components and optimize a cleaning system
This is not a complete list, but it can serve as a starting point for an
are harmonized
assessment, as the topics mentioned are generally relevant in all
pharmaceutical manufacturing companies. This list of topics can be
expanded as desired to include company-specific topics if process-
Table 6: Suggestions for improvement nal personnel during "peaks" in the workload. Routine operations
Third-party cleaning In-house cleaning are usually carried out by the company's own staff, who are then
supported by external staff when the workload increases.
Has experience with cleaning Knows the production process
systems better
During production shutdowns, cleaning activities are often carried
Knows the trends on the mar- Brings suggestions for im- out "hand in hand" with preventive maintenance activities, includ-
ket and can therefore more provement from the point of ing the cleaning of ventilation systems during the maintenance
easily bring suggestions for op- view of the production process shutdown. The final preliminary cleaning before the cleanrooms
timization are put back into operation is also a process that involves a lot of
extra work for routine personnel and for which external cleaning
personnel are often called in.
Table 7: Economic aspects
Third-party cleaning In-house cleaning On the other hand, there are also areas where the use of third-
party cleaning personnel is not recommended. In the aseptic pro-
A result is bought in, i.e. there
More flexible duction of sterile pharmaceuticals, these include the cleanroom
is a fixed calculation basis
areas of classes A and B, in particular the equipment surfaces in
these areas. Depending on the production process, certain equip-
No resource bottlenecks in the Qualification of employees ment surfaces should also be cleaned by in-house personnel, irre-
event of staff absences (sick- (cleanroom approval required spective of the cleanroom classification. In addition to areas with
ness, vacation, etc.), insofar as anyway, overlapping training sensitive process steps, this particularly applies to systems with a
back-up is planned contents) large number of sensitive measuring sensors or to work surfaces
with critical instruments, such as scales. Lifting the scales for the
Based on these comparisons and a weighting of the parameters, a purpose of cleaning the work surface underneath can have a mas-
decision can be made below as to where third-party cleaning sive impact on the subsequent weighing accuracy and result in a
should be used and implemented. re-adjustment or even re-calibration. If this goes undetected, there
can be a negative impact on product quality and patient safety. In
Where does third-party cleaning make sense? addition, containment requirements may also contribute to the de-
cision not to outsource certain cleaning processes.
The following considerations are merely recommendations by the
author and do not represent binding or official requirements. What should be considered when outsourcing
Consideration should be given to outsourcing the cleaning of large (clean)room cleaning?
areas, such as "low" cleanroom classes (RRKc or D) or so-called
CNC areas (CNC, "controlled not classified"), which are monitored In general, it is always a good practice to request references from
in one or more microbiological and/or physical environmental pa- potential suppliers and service providers in order to assess wheth-
rameters. er prior knowledge and expertise in the pharmaceutical environ-
ment in general and possibly for areas with specific requirements
The outsourcing of regularly recurring cleaning activities with con- (aseptic production, multi-product plants, shift production or pos-
sistent requirements, but which do not fall under "routine activi- sibly up to continuous production) is already existing.
ties" is also worth considering.
A standardized questionnaire (at least for the basic requirements)
In such cases, "peaks" in the cleaning effort, e.g. basic cleaning dur- can be a great help, especially if outsourcing is to take place for
ing shutdown (production downtime, e.g. for maintenance purpos- several buildings or even subsidiaries. This facilitates a harmonized
es) or during changeover (product change during campaign pro- approach and also dealing with inspectors from authorities and ex-
duction) are absorbed by increasing capacity with external ternal auditors. The following questions are examples to be ex-
personnel. This procedure generally reflects the usual use of exter- panded according to specific requirements:
• "How do you proceed with cleaning?"
• "What cleaning and disinfecting agents do you use and why?"
(possibly you specify them, or even provide them)
• "Are your cleaning and disinfecting agents "ready-to-use" or
Cleaning Validation individually self-mixed or diluted?"
Live Online Training • "What are the qualifications of your staff?"
12-14 November 2024 • "How do you determine cleaning intervals for non-cleanroom
areas?"
incl. Pre-Course: Impact of Annex 1 Revision • "How do you guarantee employee training status?"
on Cleaning Validation
It makes sense to define and document exactly what is expected
Learn more about this course: from the external cleaning company. In addition, define non-goals 23
www.gmp-compliance.org of the cooperation in addition to the goals, similar to a project man-
agement matrix. The non-goals here relate in particular to activi-
ties that are not to be carried out by the external company employ-
ees under any circumstances. Unfortunately, experience has
 shown that "well meant is not well done". Points that should in any clothing, since the storage areas for this are cleaned by third-party
case be part of the quality agreement include: personnel anyway. Furthermore, it can make also sense to transfer
• Who bears the costs for the qualification? (e.g., approval for the administration of the documents, such as cleaning logs for
cleanroom classes) cleanrooms and equipment, which are to be filled out, to the exter-
• When is cleaning to take place? nal personnel.
• Who assumes responsibility for which areas?
What remains...
As already mentioned, the topic of communication interfaces or
contact persons plays a central role. It is essential to define where The execution of cleanroom cleaning in pharmaceutical manufac-
the cleaning of the company's internal personnel ends and where turing areas is a matter of trust when outsourcing this process. This
the cleaning of third-party cleaning personnel begins and, even critical and integral process step in the production flow can rarely
more importantly, who may or should give instructions to whom. be fully controlled in its execution. In addition, people from outside
This must also be known to employees of the client in order to be the company gain deep insights into the company's own produc-
able to guarantee the smooth running of the service – in this case tion processes, which is naturally an important factor in the careful
cleanroom cleaning. selection of a cooperation partner. Thus, in this area of tension in a
GMP-regulated environment, it is necessary to find the balance be-
The aim of this outsourcing is a longer-lasting cooperation with the tween trust and "documented evidence", whereby a risk evaluation
possibility of sensibly extending areas of responsibility. This can in accordance with quality risk management and, in the future,
mean that, for example, certain control tasks can also be carried contamination control strategy should also be applied here in any
out, such as changing the entry lists to cleanroom areas on each case.
working day or, for example, the administration of cleanroom

Become a Member
of the New GMP
Auditor Association
Join the Association at no costs. As a registered member you will be able to
access the members area. Here you will find:

• The latest version of the GMP Handbook – A Guide for GMP Auditors
• An exclusive Discussion Forum for GMP Auditors

Please find more information about the Association at

24 gmp-auditor.gmp-compliance.org
 Valsartan
Six years after the six-year Valsartan scandal. Has the knowledge
gained been comprehensively and critically appraised?

Between 2012 and 2018, several antihypertensive drugs from the This was the reason that such impurities appeared in a generic
group of sartans containing an impurity classified as potentially drug, but not the reason that they were not detected for years.
carcinogenic, nitrosamines, were consumed worldwide1. Both types of active ingredient, before and after the change in syn-
thesis, complied with the regulations. Both met the requirements
To briefly summarize the facts: of the Ph.Eur. monograph in force at the time, a new CEP was is-
In 2012, a Chinese company made a change in the synthesis of the sued after the change, thousands of API CoAs and Annex 16 batch
active pharmaceutical ingredient (API) valsartan. This change led certificates were issued between 2012 and 2018 confirming the
to the formation of nitrosamines, which remained as an impurity in GMP compliance of the products. The Chinese manufacturer could
the final API and consequently in the medicinal product. have started from the beginning with the synthesis route applied in
2012. The situation would have been the same.
This impurity was discovered more or less by chance in 2018. The
German Federal Health Agency (BfArM) was informed by a govern- The requirements for impurities according to Ph.Eur. General mon-
mental surveillance authority of another country that the impurity ograph "Substances for pharmaceutical use", No 2034 are:
N-nitrosodimethylamine was discovered in the active substance
valsartan produced by the Chinese active substance manufacturer Related substances
"ZHP Co LTD". The notification is based on the test results of the Unless otherwise specified or justified and approved, organic impurities
active substance manufacturer, which were carried out in the in active substances shall be disclosed, identified where possible, and
course of production for a finished medicinal product manufacturer labeled as indicated ...
from Spain. (BfArM on “Valsartan; Questions and answers on the
background”). ... Identification threshold (human use) > 0.1%.

25
About the Author
Dr Jaime Guardiola is owner of DocJaGuar Consulting and has over 40 years of industrial experience in production, development, regulatory affairs,
quality control and quality management.
 That is, if the impurity content is less than 1%, it does not need to Nowadays, supply chains can be quite complicated and involve
be identified. How this works was clearly explained, for example, in more than one responsible party or person (QP).
2019 by
For example, an EU marketing authorisation holder (MAH) and dis-
Impurity Control in the European Pharmacopoeia 2019 Training tributor of valsartan tablets imports the active substance from a
Session “The European Pharmacopoeia” 10-11 September 2019, Chinese company. The marketing authorisation holder supplies the
Iselin, New Jersey, USA active substance to a manufacturing authorisation holder (CMO) in
the EU who manufactures the final medicinal product and issues
European Directorate for the Quality of Medicines and Healthcare the QP certification for each batch of product according to Annex
(edqm) paper, page 25. 16.

China
API Manufacturer

API

Batch Certification Annex 16

for final products other than
EU Country QP API Declaration for
Valsartan tablets MAH/MIAH* API Valsartan

API
CoA (QP singned)
Release for production

EU Country
CMO

Final Drug Product

But do not forget that according to Option 2 the substances to be CoA & CoC
detected and evaluated (% content) must present similar behavior Batch certificate acc. to Annex 16
toward the detection system, response factors should be identical.
Only under this condition it can be assumed that a certain value of
a peak area corresponds to a w/w concentration. Thus, if the % MAH
value is below 0.1%, the requirements are fulfilled, but there re-
mains an uncertainty about the criticality of the (unidentified) im-
purity and the real content.
Distribution

This could explain why the nitrosamine contamination remained

Flow Chart Supply Chain Example
undetected when the synthesis of the active ingredient was *) MAH possesses a MIAH limited to batch certification/release
changed.

Who can assure that a case similar to the so-called Valsartan scan- In the valsartan case, the main issue is the supply and quality of the
dal will not happen again? active substance, so the following questions need to be clearly an-
swered:
On the other hand, a change in the manufacturing process of ingre-
dients, bulk material or final product is nothing unusual. The • Has the Chinese company been properly qualified by or on be-
change control (CC) policy is one of the most important chapters in half of the MAH/MIAH?
a marketing authorisation holder's pharmaceutical quality man- --> Check audit report and whether the QA system and change
agement system (MAH is also the holder of a Manufacturing Au- control SOP items are in place and properly implemented.
thorisation as indicated in the hypothetical example below). • Was the Chinese company routinely audited by or on behalf of
the MAH/MIAH?2
In this case, was the change in active ingredient synthesis carried --> Review of the QP declarations ("Declaration of Compliance
out thoroughly and correctly in accordance with the CC policy and with Good Manufacturing Practice in the Production of Active
all other rules and guidelines designed to ensure the safety, effica- Substances"), Check the audit reports; frequency, findings,
cy, and quality of the marketed pharmaceutical products? In other CAPA plans and last but not least the main changes since the
words, were there no indications or clues between 2012 and 2018 last audit.
26 that would have suggested further investigation? • How did MAH deal with the new CEP after the change in 2012?
Was the document evaluated or simply filed?
To answer this question, one has to analyse all the steps of the sup- --> Check the information flow in the company - Regulatory
ply chain in detail. Affairs, QA, QP - and the completion of the process.
• Are all relevant QP statements properly documented and
 signed by the MAH/MIAH's QP? However, in January 2022 the edqm published a public document
--> Review audit records and ensure that they have been car- (PA/PH/CEP (21) 57) entitled "CEP ... Responsibility of CEP holders
ried out in a timely manner and that the change control policy towards their customers" and on 08. March 2023 the supplement
has been taken into account, especially in the first audit after 11.2 to the European Pharmacopoeia. This supplement edition lists
2012. several (24) updated monographs which were supposed to enter
• Are the Product Quality Reports (PQR) for the periods 2011, into force on 01. July 2023.
2012 and 2013 properly signed and available?
--> Review according to "EudraLex Volume 4 EU Guidelines on But why not intensify experimental control in parallel? It was not
GMP Chapter 1"; such reviews should normally be carried out that difficult to identify a few ppm nitrosamines (limit test Ph.Eur.
and documented annually, taking into account previous as- 11.0 01/2022:20542; 30ppb). It is relatively easy to stop analysing
sessments, and should include at least: impurities at 0.1% peak area and disregard LT 0.05% (500 ppm) and
Paragraph(i) not worry about it any further. The analytical procedure can be im-
A review of source materials, including packaging materials proved if the impurity level is low. For example, the sensitivity of
used in the product, in particular those from new sources. A the HPLC method can be improved, also combined with other
review of the traceability of the supply chain of active sub- methods such as MS and MS/MS, improve preparative HPLC, etc..
stances and any changes made to the procedures or methods But also optimising sample preparation, which should focus on the
of analysis is also relevant. impurities and not only on the main substance, possibly by sam-
pling in earlier synthesis steps. If necessary, experiments should be
Other aspects such as the ongoing stability data could also have carried out with modified reaction conditions to increase the yield
given an indication of differences between the two drug quality of impurities. Such experimental work should be submitted when
properties, namely the impurity profile in the HPLC chromato- applying for a CEP, which was probably not the case with the vals-
grams, something that should be followed in any stability testing. artan scandal. ICH Q3A (R2) (last update 2006) refers to "impurities
in new drug substances". If an API chemical synthesis of an already
A single analytical study was more effective than six years of sup- approved product is changed, it is only logical to follow this guide-
plier evaluation. line again.

The outcome of such a study on a real case should show whether Finally, a reminder recently published in an ECA newsletter (30.
the GMP framework is so comprehensive that no new guideline May 3023; "What does FDA actually mean by CGMP?):
needs to be developed. If so, attention must be paid to how, where
and under which QP responsibility the rule in question was not cor- The FDA emphasises that CGMP are minimum requirements. Mod-
rectly applied. ern, comprehensive quality systems and risk management con-
cepts can also go beyond these requirements.

1
Note: Care has been taken to indicate the criticality of the impurities. The nitrosamines are mostly classified as "potentially" carcinogenic. Carcinogenicity has been demonstrated for some animals, but the
available data do not appear to be sufficient to classify them as "carcinogenic" to humans.
2
Note: It is common practice to outsource activities such as conducting audits. Of course, this must be done in compliance with the rules of good contract manufacturing. In such cases, it is common to enga-
ge a third party inspection body. This is a supplier that has to be qualified and audited like the others, e.g. laboratory, pest control service, primary packaging material manufacturer, etc.

Validation in Pharmaceutical Analysis

Specificity/Selectivity, Response (Calibration Model), Impurities
and Quantitation Limit
Online Training Recording
gmp-compliance.org

27
 GMP Hot Spots as seen in the
Warning Letters – Release Testing
of the Finished Product
At the end of each GMP compliant production process and prior to procedures that shall include the method of sampling and the
the release for distribution the batch has to be tested for compli- number of units per batch to be tested. Such written procedure
ance with the specifications laid down. For the US-American eco- shall be followed.
nomic area the requirements for release testing of batches of the
finished product as described in the Code of Federal Regulations, (d) Acceptance criteria for the sampling and testing conducted by
21 CFR 211.165 Testing and release for distribution, are mandatory. the quality control unit shall be adequate to assure that batches of
The six sections of this paragraph contain the following provisions: drug products meet each appropriate specification and appropri-
ate statistical quality control criteria. This is the condition for their
(a) Prior to release each batch of the finished product shall be test- release. The statistical quality control criteria shall include appro-
ed for compliance with the specifications. This includes testing of priate acceptance levels and/or appropriate rejection levels.
identity and strength of the active ingredient.
Where sterility and/or pyrogen testing are conducted on shortlived (e) The accuracy, sensitivity, specificity, and reproducibility of test
radiopharmaceuticals, such radiopharmaceuticals may be released methods employed shall be established and documented. Such
prior to the test results being available provided such testing is validation and documentation may be accomplished in accordance
carried out as soon as possible. with § 211.194(a)(2).

(b) There shall be appropriate laboratory testing of each batch of (f) Drug products failing to meet established standards or specifi-
drug product required to be free of objectionable microorganisms. cations and any other relevant quality control criteria shall be re-
jected. Reprocessing may be performed. Prior to acceptance and
(c) Any sampling and testing plans shall be described in written use, reprocessed material must meet appropriate quality stand-

28
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.
ards, specifications, and any other relevant criteria. The percentage of Warning Letters citing 211.165 has settled at a
little over 40% in the last two fiscal years. In absolute numbers this
This is the basis on which the FDA evaluates whether the quality means 30 Warning Letters in the FY 2023 and 18 in the FY 2022.
control in companies producing drug products is compliant with
GMP. Categorisation of GMP Deficiencies Associated
with the Release Testing of the Finished Product
The Guides to Inspections contain guidelines for the FDA inspec-
tors for their work on site: The deficiencies described in the Warning Letters can be divided
into the following categories:
FDA Guide to Inspections of Pharmaceutical Quality Control Labo-
ratories (July 1993) No Microbiological Testing
FDA Guide to Inspections of Microbiological Pharmaceutical Qual- One of the GMP deficiencies cited most often in the Waning Letters
ity Control Laboratories (July 1993) is the lack of testing of the finished product for objectionable mi-
croorganisms according to 211.165(b). FDA inspectors have ob-
In spite of the fact that it is a basic GMP requirement to release a served this especially at producers of hand sanitizers.
batch only after final testing has been carried out, and although
this is described clearly and explicitly in the pharmaceutical guide- Incomplete Release Testing
lines, FDA inspectors repeatedly encounter in some cases serious This deficiency is described nearly as often. Contrary to the re-
GMP violations in the area of quality control of finished products quirements of 211.165(a) according to which release testing shall
when they carry out inspections on site. include testing for compliance with the specifications of the fin-
ished product including identity and strength of the active ingredi-
The following chart shows the percentage of Warning Letters ad- ent, manufacturers have released their drug products on the basis
dressed to manufacturers of drug products because of deficiencies of incomplete testing (such as odour, appearance or other physical
concerning the requirements of 211.165 over a period of five years. parameters). In single cases the product was even released prior to
the receipt of the test results.

The lack of testing of the batches of the

finished product for impurities is also
described several times in the Warning
Letters.

No Acceptance of Responsibility for

the Release Testing
Several contract companies finishing
the product for instance by only filling it
up have transferred the responsibility
for release testing to the customer. But
according to the FDA the production
site carrying out the last manufacturing
step immediately prior to the release of
the drug product is obliged to carry out
the batch release. FDA considers the
transferral of responsibility to be a GMP
violation.
Figure 1: Percentage of Warning Letters with notifications of deficiencies associated with the testing of the fin-
ished product according to 21 CFR 211.165 for the fiscal years 2019 - 2023 No Rejection of the Batch in Case of a

All GMP Information at Hand – anytime, anywhere!

With the GMP WebApp from the ECA Foundation you get
ƒ GMP News
ƒ Major GMP Guidelines
ƒ GMP Trainings
ƒ a comprehensive Search function
ƒ GMP Guideline Manager (for ECA members only) 29
on your smartphone or tablet PC

go to
app.gmp-compliance.org
 Failed Release Testing • An action plan and timelines for conducting full chemical and
In several cases the quality control unit did not reject a batch or microbiological testing of retain samples of all batches dis-
place a hold on it after the final testing failed. tributed to the United States that are within expiry as of the
date of the Warning Letter.
Use of Non-validated Methods for the Release Testing • A summary of the results obtained from testing retain sam-
According to 211.165(e) only validated methods may be used for ples.
release testing. In some cases, FDA inspectors discovered that the • A comprehensive independent assessment of the methods,
quality control units released batches of the finished product after procedures, equipment, documentation of the quality control
testing with non-validated methods. unit, and analyst competencies. Based on this review, provi-
sion of a detailed plan to remediate the deficiencies and eval-
uation of the effectiveness of the laboratory system.
Follow-up Requests from the FDA
If these proofs can be provided in the course of an FDA inspection
Usually Warning Letters contain a follow-up request for docu- the topic „release testing“ shouldn‘t pose a problem.
ments/evidence in respect to each GMP deficiency associated with
one of the paragraphs of CFR 211. In the case of 211.165 the FDA Note: You can find the complete analyses of the Warning Let-
demands the following: ters of the fiscal years 2022 and 2023 as well as further docu-
ments relevant in this context in the members’ area of the ECA
• A list of chemical and microbial specifications of the finished website.
product, including the relevant test methods.

ECA GMP/GDP Certification Programme

Highly qualified personnel is a crucial factor in the GMP-compliant manufacturing of APIs, drugs and medical devices.
While your college and university education provides the scientific basis, the ECA GMP/GDP Certification Programme
complements your professional training with a well-established certification.

Certification Opportunities
ECA Certified Validation Manager ECA Certified Sterile Production Manager
ECA Certified Quality Assurance Manager ECA Certified Pharmaceutical Development Manager
ECA Certified API Production Manager ECA Certified Biotech Manager
ECA Certified Quality Control Manager ECA Certified GMP Auditor
ECA Certified Technical Operations Manager ECA Certified GDP Compliance Manager
ECA Certified Computer Validation Manager ECA Certified Packaging Manager
ECA Certified Regulatory Affairs Manager ECA Certified Data Integrity Manager
ECA Certified Microbiological Laboratory Manager

For more information please see

www.gmp-certification.org

30
ICH Q7 Training Week 2023:
Data Integrity in the Light of ICH Q7

From 19-23 June 2023, the ICH Q7 training week took place in Mu- This time, as part of the compliance courses, Dr Markus Dathe held
nich, Germany. Many interested participants from a large variety of the presentation “Data Integrity in the light of ICH Q7” and pointed
countries got together with the speakers to discuss and debate out the following:
well-established and current topics in the field of chemical and bi-
otech APIs and their legal GMP requirements. The event was sup- “The ICH Q7 guideline1 has been existing since 2000 and was
ported by the representative of the APIC Task Force "Third Party amended in 2015 with a Questions and Answers document2 sup-
Manufacturing" Mauro Menichelli. porting a clear interpretation and modernizing the guideline. ICH
Q7 was unique at its time because it included in a holistic
and comprehensive way the modern elements of quality
assurance and quality management: for example risk con-
trol, computer system validation and integrated quality ap-
proaches. The Q&A document officially adapted the ICH
Q93 and Q104 risk-based approaches and clearly integrated
Q7 in the ICH Pharma Quality System (PQS). ICH Q7 antici-
pates major elements of Data Integrity (DI), even though it
was created just before Data Integrity became a major top-
ic in the pharmaceutical industry.

Fig.1: ICH Q7 Training Week in Munich, June 2023. The question we want to explore is whether Data Integrity
is a completely new approach or just a different perspec-

31
Anne Günster joined CONCEPT HEIDELBERG in 2019 and or- Dr Markus Dathe has been GMP Sytems Coordinator in the Syn-
ganises and conducts courses and conferences on behalf of the thetic Small Molecules Development at Roche since 2011.
ECA Academy in the areas API Manufacturing, Regulatory Af-
fairs, Documentation and Laboratory Data Integrity.
 tive on already existing GMP requirements as
those arising from ICH Q7.

Data Integrity can be described as “the opposite

of data corruption, which is a form of data loss.
… In short, data integrity aims to prevent unin-
tentional changes to information.” And “Data in-
tegrity refers to maintaining and assuring the
accuracy and consistency of data over its entire
life-cycle, and is a critical aspect to the design,
implementation and usage of any system which
stores, processes, or retrieves data.”5

In general, Data Integrity elements are categorized by it is quite interesting, how much alignment between Data Integrity
• Physical Integrity (e.g. safety, security, durability) and the Q7 elements are to be found. Furthermore, ICH Q7 is one of
• Logical Integrity (e.g. context, plausibility) the first examples for a systematic quality risk management. In
• Scientific Integrity (e.g. correctness, accuracy) particular, it can be seen as an application of pragmatic risk catego-
rization determined by the distance to the patient and the influ-
It is important to understand that Data Integrity is not Data Quali- ence on the quality of the (medicinal) product. A principle, which is
ty, even though it is one of the elements and a prerequisite to it. nowadays the standard for many DI guidelines (compared to e.g.
Using data, we collect information which is aggregated to knowl- FDA’s and MHRA’s guidelines) which are using the concepts of di-
edge; if we use wrong data, we may use wrong information to con- rect and indirect data (direct influence on patient safety and prod-
clude wrong things. This can be a threat to patients at the end. uct quality or not), adding complexity as a risk criterium via the
static and dynamic (interactive) data.
Data Integrity requirements and measures can be divided into the
following facts: In their 2004 document “PHARMACEUTICAL CGMPS FOR THE
• organizational 21ST CENTURY — A RISK-BASED APPROACH”6, the FDA explains
• technical their “Strategic Action Plan for Protecting and Advancing America’s
• records/documents/data Health”. The Agency’s Strategic Plan identified efficient risk man-
agement as a key element: “Efficient risk management requires us-
If you compare these Data Integrity elements with Q7, represented ing the best scientific data, developing quality standards, and using
by the chapters where organizational elements are marked yellow, efficient systems and practices that provide clear and consistent
system and process relevant green, and the records/documents/ decisions …”. Taking this plan into consideration, risk management,
data are labelled blue best scientific data and consistent decision making is calling out
already for what we later call Data Integrity.

32
Supported by

a sector group of
It is important to understand that (quality) risk management is es- and Data Integrity ensure systematic, efficient and effective re-
sential to the implementation and maintenance of Data Integrity sults. This includes the acceptance of risks!
concepts. In order to control the risks they need to be categorized.
As per practical experience, hybrid records (i.e. systems maintain-
ing both paper and electronic records, typically with “paper lead”)
bear the highest risks to data and records, and are for that reason
Handling of Foreign Particles in APIs in the main focus of inspections and audits. Due to high efforts for
and Excipients the second person review of both paper and electronic records, and
Live Online Training due to the need to assure that both are correct, consistent and syn-
5/6 February 2025 chronized, they expose the organizations to high financial and
regulatory risks.
Risk Analysis, Preventive Measures and
Incident Management Since classical GMP regulations like ICH Q7 and the current Data
Integrity standards are founded on the same basic principles, it
Learn more about this course: rather seems to be a natural extension of the GMPs to the 21st cen-
www.gmp-compliance.org tury than a completely new metamorphosis – set by the authorities
to assure the safety of the public and the best product quality.

This presentation was one of the lectures of the joint sessions of

Such a categorization must be simple and easy to be applied fast, the Compliance Courses for APIs produced by chemical synthesis
consistently and reliably. A systematic approach is necessary to im- and cell culture/fermentation. As usually, these courses were fol-
plement a holistic Data Integrity strategy. Such holistic and sys- lowed by the Auditor Training which was characterized by many
tematic approaches are based on a Data Integrity risk analysis, role plays and discussion sessions. Once again, the ICH Q7 Training
which is again the base for deriving governance concepts including Week was full of interesting topics and beneficial for both speakers
master data. For the data (quality) strategy risks are collected in a and attendees.
register/inventory which also comprises measures and uses clas-
sifications to maintain an overview of the organization’s data, sys- Note: The upcoming ICH Q7 Training Week will take place live
tems, and processes throughout the lifecycle and to consistently online in November 2024. For more information, please visit
control them. Libraries of such risks, measures, methods to GMP the ICH Q7 Week website.

1
ICH Q7 Good manufacturing practice for active pharmaceutical ingredients - Scientific guideline, 200
2
ICH guideline Q7 on good manufacturing practice for active pharmaceutical ingredients – questions and answers, 2015
3
ICH guideline Q9 on quality risk management, 2005
4
ICH guideline Q10 on pharmaceutical quality system, 2008
5
Wikipedia: Data Integrity, https://en.wikipedia.org/wiki/Data_integrity, called on 10-Oct-2023
6
FDA, PHARMACEUTICAL CGMPS FOR THE 21ST CENTURY — A RISK-BASED APPROACH, FINAL REPORT, 2004

How to register APIs in Brazil

Focus on CADIFA and obtaining a Brazilian GMP Certificate
Live Online Training on 13 February 2025
gmp-compliance.org

33
 Analytical Instrument Qualification and
System Validation
The ECA Analytical Quality Control Group’s New Guide

In the laboratories of the pharmaceutical quality control there is a The 4Qs Model
large number of analytical instruments that have to be qualified
according to the GMP Guidelines and maintained in this qualified Qualification is often subdivided into four stages:
state. To achieve this, it is necessary to define, manage, and docu- 1. Design Qualification (DQ): Documented collection of activities
ment the type, extent, and processes for qualification, calibration, that define the functional and operational specifications and
and control of inspection, measuring, and testing equipment in a intended use of the instrument.
traceable manner. This is required both for internal purposes and 2. Installation Qualification (IQ): Assurance that the instrument
for external bodies such as clients and regulatory authorities. is delivered as designed and specified, is properly installed in
the selected environment, and that this environment is suita-
Analytical Instrument Qualification (AIQ) includes the process ble for the instrument.
which guarantees that an analytical instrument performs suitably 3. Operational Qualification (OQ): Verification that the instru-
for its intended purpose. Use of a qualified instrument in analyses ment will function according to its operational specification
contributes to confidence in the validity of generated data.1 testing in the selected environment.
4. Performance Qualification (PQ): Confirmation that the instru-
System Validation (SV) is the documented process carried out in ment performs according to the specifications and require-
order to guarantee that a computerized system works properly, ments defined by the user in its actual operating environment.
and that it complies with the defined requirements and provisions.
Transferring these requirements to the qualification of analytical
instruments may result in various challenges. One essential point
is that laboratories usually choose from instruments available on

34
About the Author
Dr Markus Funk is Operations Director and organises and conducts courses and conferences on behalf of the ECA Academy in analytical and
GDP topics.
the market and don’t develop the design themselves. Furthermore,
the 4Qs model sometimes proves to be too rigid, especially in its Subsequently, the three lifecycle stages are discussed: Stage 1
application to computerized systems. In practice it is often difficult (Specification and Selection), Stage 2 (Qualification/Validation of In-
to clearly define the difference between the activities in the OQ struments and Systems), and Stage 3 (Continued Performance Veri-
stage and the PQ stage. fication). The Guide emphasizes the importance of the User Require-
ments Specification (URS), and highlights the fact that the URS may
Against this background the ECA Analytical Quality Control Group change in the course of the lifecycle and should, therefore, be re-
(AQCG) has published a new guide with the title "Guide for an Inte- garded as a „living“ document. Depending on the classification into
grated Lifecycle Approach to Analytical Instrument Qualification the groups A, B or C the requirements in this stage may range from a
and System Validation". This Guide offers scientifically substanti- simple monitoring to a comprehensive qualification of the instru-
ated qualification strategies which also take into consideration the ment and validation of the control software. In stage 3 special atten-
intended use of the instrument or system. The lifecycle approach tion needs to be paid to the routine monitoring by means of trend
presented in the new Guide deliberately deviates from the 4Qs analysis, to the change management in the case of software updates
model with its four stages. as well as to the backup and archiving of the data generated.

Structure and Content of the new Guide

Dr Christopher Burgess (Chairman of the ECA AQCG-Board) and Dr

Bob McDowall (Board Member of the AQCG and Board Member of Analytical Instrument Qualification
the ECA Data Integrity & IT Compliance Interest Group)2 had leading and System Validation
roles in preparing the document. The Guide comprises 153 pages 26/27 November 2024
altogether and is divided into twelve main chapters and six illustra- Düsseldorf/Neuss, Germany
tive „How To“ appendices. Furthermore, the guide contains a tech-
nical glossary with 19 pages, 111 references, 38 figures and 24 over- Part of PharmaLab 2024
view tables that further illustrate and elaborate the contents.

The Guide offers a more flexible approach which aims to provide a Learn more about this course:
uniform lifecycle model suited for analytical instruments as well as www.pharmalab-congress.com
for computerized laboratory systems while putting the main focus
on instruments operated according to the GMP regulations. The
approach takes into account the proposals which are currently dis-
cussed within the framework of the revision of USP General Chap- Appendices of the Guide
ter <1058>.
The so-called „How to“ appendices are an important component of
The Guide also refers to other regulations and standards such as the Guide. These appendices aim to apply the aspects described in
the US GMP 21 CFR 211, the EU GMP Guidelines Parts 1 and 2, the the main chapters to concrete examples of apparatuses, instru-
USP General Chapter <1058> (Analytical Instrument Qualification), ments and systems. For this, examples were chosen from all three
the GAMP Guide and relevant ISO standards. USP groups and their sub-groups starting with apparatuses from
group A1 (vortex mixer) up to group C3 (NIR spectrometer for iden-
After presenting in detail the specific roles and responsibilities of tification of raw materials). These appendices offer practical in-
the different stakeholders, including laboratory, quality assurance, structions for the application of the Guide’s theoretical principles to
procurement, suppliers and contracting parties it is outlined why the specific requirements and challenges concerning the qualifica-
the Analytical Instrument Qualification and System Validation tion and validation of different laboratory apparatuses and systems.
(AIQSV) as integral part of the Analytical Procedure Lifecycle (APL)
is indispensable for ensuring data integrity. Moreover, the differ- Download Free of Charge
ence between „fitness for intended use“ and „fitness for intended
purpose“ is explained, and the importance of a structured lifecycle The guide can be downloaded as PDF file in the members' area on
process is highlighted. the AQCG website (www.analytical-quality-control-group.org).
The AQCG has already developed several other documents which
The chapter „Risk-Based Classification of Analytical Instruments can also be downloaded there free of charge.
and Systems“ explains the risk-based classification according to
the USP General Chapter <1058>. Analytical instruments and sys- • SOP on Out-of-Specification (OOS) Results
tems are divided into three main groups which may be further dif- • Guidance: Out of Expectation (OOE) and Out of Trend (OOT)
ferentiated according to their use. Based on this follows the pres- Results
entation of a risk-based system for the classification of the • Guidance: GMP Data Governance and Data Integrity
instruments into these groups. The Guide is not based on the 4Qs
model (DQ, IQ, OQ and PQ) but proposes instead a flexible AIQSV You can find further information on the AQCG website, and may 35
lifecycle stage model which is based on an article on the revision of also apply for free membership there.
the USP General Chapter <1058> from the year 2022.3
1
USP General Chapter <1058> Analytical Instrument Qualification.
2
Website of the ECA Foundation: https://www.eca-foundation.org/.
3
Christopher Burgess, M L Jane Weitzel, Jean-Marc Roussel, Oscar Quattrocchi, Joachim Ermer, Rosty Slabicky, Gregory P Martin, and Gabriel Vivó-Truyols, Analytical Instrument and System (AIS) Qualification
to Support Analytical Procedure Validation over the Life Cycle, Pharmacopoeial Forum, 2022. 48(1).
 ATMP Group Analytical Quality Control Group

Board Developments Board Developments

Gert Viville (Janssen Pharmaceutica NV) will step down from this A face-to-face Board Meeting is planned for 24 November 2024 at
team. The next board meeting should take place in Nov 2024 (on- PharmaLab in Düsseldorf/Neuss, Germany. Further meetings will
line Meeting via Webex). take place as needed.

Guideline Developments Guideline Developments

It is planned to write a position paper on ICH Q6. A draft version Selected questions raised during the Live Online
has already been written and shared with the members for com- Training “Introduction to the AQCG’s new ECA
ments. The comments will be discussed in Nov during the meeting. Guide for an Integrated Lifecycle Approach to
Analytical Instrument Qualification and System
Events Validation” on 29 April 2024 with the teaching
Five new training courses were discussed, designed and planned in team's answers were published in the AQCG
collaboration with the ATMP Board. Many of these training courses newsletters.
have speakers from the Board
Miscellaneous
ATMP Group Website The PharmaLab Congress will take place from 25-27 November
2024 in Düsseldorf/Neuss. This year, the program includes a new
track on Analytical Instrument Qualification and System Valida-
Pharmaceutical Microbiology Group tion, where several Board members of the ECA Analytical Quality
Control Group (AQCG) will be part of the speaker team.
Board Developments
Due to her involvement in the EMC and her comments on the Analytical Quality Control Group Website
PharmEur NGS chapter, Anna Liznar from Pathoquest will be invit-
ed to the next Board meeting – which is planned on 25 November
on-site in Neuss, Germany. The chairs of the ATMP Groupe are ex- GMP Auditor Association
pected to be present at times to coordinate joint activities.
Board Developments
Guideline Developments The first face-to-face meeting of the Board was held on 24 June
The NGS Task Force, which was founded last year, collected com- 2024 in Barcelona. One of the main tasks was the further develop-
ments on the new NGS chapter in PharmEur in June and submitted ment of the GMP-Auditor’s Handbook and the action plan for
them on time. 2024/2025.

Pharmaceutical Microbiology Group Website Guideline Developments

GMP-Auditor Handbook
In the course of the first GMP-Auditor Forum, the “ECA Good Prac-
Visual Inspection Group tice Guide – GMP Auditors Reference Handbook” (Version 2.0 June
2024) was published in the download area of the Association’s
Board Developments website and in the Download for the delegates of the conference.
There are no changes planned within the board. The board meeting Previous version and chapters published before were replaced.
is scheduled for November in Berlin.
A project plan was developed by the chair for further improve-
Guideline Developments ments and amendments.
The group is discussing an update of the CCIT position paper.
Surveys
Events Survey on Chinese Counterespionage Law
A new online conference specifically on the use of AI in automated China has revised its counterespionage law. Com-
visual inspection was developed and will take place end of Octo- pared to the previous version, the new version
ber. expands the government's powers to combat es-
pionage and emphasises the role of the public in
Visual Inspection Group Website this task. In theory, activities carried out as part
of an audit or inspection can now also be punish-
36 able by law. Espionage suspects may be prevent-
ed from leaving China by order of the national
security authorities at provincial level or higher. This provision also
applies to foreigners.
For that reason the EQPA as well as the GMP Auditor Association June 2024 in Barcelona. More than 60 experienced GMP-Auditors
asked for feedback with regard to their members’ awareness, un- discussed current topics and exchanged opinions and experienc-
derstanding and implication of the Chinese revised counterespio- es with other auditors in moderated sessions, during presenta-
nage law. Results can be found in the survey section of the mem- tions and networking breaks.
bers’ area.
GMP Auditor Association Website
Events
GMP-Auditor Forum
The first GMP Auditor Forum of the Association was held on 25/26

GMP Handbooks • GMP Regulations

FDA cGMP Guide

ECA Good Practice Guide - GMP Matrix

(Version 21 of May 2018)
"FDA cGMP, EU GMP and ISO 9001 Matrix for a pharmaceutical Quality System - A GMP Roadmap"

EU Guidelines to Good Manufacturing Practice

Part 1, Part 2 and Part 3
incl. Annexes 1-19

ICH Q7 GMP for Active Pharmaceutical Ingredients

with a Side-by-Side comparison and APIC‘s How-to-do Document (Version 16, July 2022)

To order, please visit www.gmp-compliance.org/publications/gmp-publications.

Important: ECA Members receive a discount of 35% for GMP publications.
Check the ECA Members Area to find the ECA Promotion Code.

ISSN 1867-7975