No

Issue 35 | Oct/Nov 2022

35

ANNEX 1 REVISION
CONSIDERATION OF SOME RELEVANT POINTS
OF THE FINAL VERSION
Questions and Cross-contami- Data flows, Data GMP for APIs
Answers on (Re- nation and Lifecycle, and
duced) Sampling Sustainability ALCOA+
 Editoral
Publisher:
CONCEPT HEIDELBERG GmbH
EU GMP Annex 1 - the revision of one of the most important Rischerstraße 8
guidelines in the GMP environment 69123 Heidelberg
HRB Mannheim Nr. 705125

On August 25, 2022, the EU Commission published the long-awaited revision of General Manager:
Oliver Schmidt
Annex 1 "Manufacture of Sterile Medicinal Products".
Chief Editors:
Oliver Schmidt
Hardly any other guideline has been commented on so extensively in advance. Wolfgang Heimes
When the draft of the now finalized guideline was published in 2017, there were
over 6000 comments. Therefore, for the second draft, published in 2020, only rec- Editors:
Dr Gerhard Becker
ognized industry associations and organizations such as the ECA and European QP Dr Robert Eicher
Association were invited to comment. And still there were over 2000 comments Dr Markus Funk
Anne-Theresa Guenster
and intense debates. Dr Andrea Kuehn-Hebecker
Dr Andreas Mangel
Sven Pommeranz
In this GMP Journal, you will find as an editorial an assessment of the most important Oliver Schmidt
changes in Annex 1, which has grown in size from the original 16 to now 58 pages. Wolfgang Schmitt
Axel H. Schroeder

You will also find many other GMP topics in interesting articles in this issue. Editors of this Issue:
Dipl. Biol. Axel H. Schroeder
Dr Markus Funk
Enjoy reading! Dr Felix Kern
Fritz Röder
Orlando López
Oliver Schmidt Anne-Theresa Guenster
Dr Ulrich Kissel
Dr Robert Eicher
Robert G. Schwarz
Dr Andreas Mangel

Content Graphic Concept:

Rebecca Illi
4 Cover story Annex 1 Revision

4
Consideration of some relevant points of the final version Production:
abcdruck GmbH
Waldhofer Straße 19
69123 Heidelberg

7 Questions and Answers on (Reduced) Sampling Contact:

7
Regulatory requirements, sample drawing and prerequisites for reduced sampling. info@gmp-compliance.org

Any reprints of text and

images require specific
10 Cross-contamination and Sustainability: The Trouble with Contamination pre-approval by the
editorial office.

10
How can the two hot topics of cross-contamination and sustainability in pharmaceutical opera- Photo Credits:
tions be balanced out? Cover/Page 4: iStock, ID: 1311600192
S.7: AdobeStock, ID: 94463900
Page 10: iStock, ID: 538408451
13 Data flows, Data Lifecycle, and ALCOA+ Page 13: iStock, ID: 1339775923

13
Page 19: iStock, ID: 1223994482
This article provides insight into the collection, assessment and application of data. Page 22: iStock, ID: 1312767508
Page 24: iStock, ID: 136642575
Page 27: Sartorius
Page 29: iStock, ID: 527883021
19 GMP for APIs - Live Online ICH Q7 Training Week - Interviews Page 33: iStock, ID: 1367696835

19
A look back at the ICH Q7 Week in November 2021.

22 Developments on GMP Classification of Fiscal Imports

22
How does the new Annex 21 to Eudralex Vol. 4 influence fiscal importation?

24 GMP-compliant equipment design: The GMP Equipment Design Guide

24
There are no specific regulatory requirements for what constitutes as good equipment design.
The new ECA GMP Equipment Design Guide provides guidance.
2
29 Questions and Answers about Cleaning Validation - Part 1

29
Speaker Robert G. Schwarz answers frequently asked questions about cleaning validation

33 Questions and Answers to Cloud Computing in a GxP Environment

33
Nine experts from the pharmaceutical industry and regulatory authorities answer frequently
asked questions on cloud computing.
NEWS FROM OUR ASSOCIATION
www.eca-foundation.org
In the following you can find again what
the ECA’s Interest and Working Groups
have been working on in the second
third of 2022.
Dr Afshin Hosseiny
(Chairman ECA Foundation)
European QP Association
The Board will meet face-to-face in early December in Berlin (after
the QP Forum).
White Paper on Annex 21 and fiscal importation
The EQPA has published a paper in the download section of the
members’ area discussing “Developments on GMP classification of
fiscal imports”. Background: The potential need for an Annex 21,
finally published in February 2022, was identified during the devel-
opment of Annex 16 – when the authors concluded that not all top-
ics around importation could be clarified. One dominant and main
driver for the new Annex 21 is thus the existence of fiscal importa-
tion and whether such concepts of international money transac-
tions crossing outside boarders of the EU should be handled
according to GMP regulations or not. The issue was legally com-
plex. Annex 16 was cleared to be published in 2016, the solution on
fiscal importation was expected to come with Annex 21. It did not.
For more details please see the background article in the members'
area of the EQPA website.
Survey on Contract QP Activities
According to Article 48 of Directive 2001/83/EC each manufactur-
er has to have at his disposal at least one Qualified Person. There
are no details on the contractual arrangement for this “disposal of
services”, though.
As QPs in many member states offer their service as independent
entrepreneurs and “contract QPs”, these states have developed
rules and expectations posed on independent QPs usually without
own MIA. Therefore, EQPA has sent out a survey in April to find out
more about this area of QP activities, which is not harmonized
within the EU. With more than 350 QPs participating, this is a high
response rate for such a specific survey topic. One third of the
responses provided came from contracted QPs. The results were
published in the members’ area on EQPA’s website. as well as in the
EQPA Newsletter issue from June 2022.
Draft Act to amend Annex VI to Clinical Trial Regulation (EU)
On 01 June 2022 the Commission launched a Draft Act to amend
Annex VI to Clinical Trial Regulation (EU) No 536/2014. As outlined
on the Commission’s website, “this initiative eliminates the obliga-
tion to include an expiry date on the immediate packaging of unau-
thorised medicinal products used in clinical trials in specific cir-
cumstances (e.g., on syringes). The aim is to prevent additional
safety and quality risks associated with the relabelling procedure
and the need for more frequent re-supply, which may lead to delays
in clinical trials.”
The EQPA’s IMP Working Group has asked members for feedback to
enable the group to provide consolidated feedback from the IMP
Working Group/ European QP Association.
Overall, the IMP Working Group appreciates the ongoing revision
of Annex VI to Clinical Trial Regulation (EU) No 536/2014 and
agrees that re-labelling procedures of immediate packaging would
add significant safety and quality risks to clinical trial medication.
Comments were sent to the EU Commission.
National requirements for QPs beyond EU requirements
EU law is built on parent acts including directive 2001/83/EC and
since end of January 2022 the Regulations 536/2014 on Clinical Tri-
als (CTR) and Regulation 2019/6 on Veterinary Medicines (VMR).
EudraLex Volume 4 includes a common interpretation of how to
comply with EU legislative expectations. The specific responsibili-
ties of the QP are not really numerous as defined in directive
2001/83/EC. However, the EQPA knows from discussions and pre-
vious surveys that countries may add specific additional require-
ments and personal responsibilities for QPs beyond this directive
and the GMP Guides.
With this survey sent out end of July with a reminder end of August,
the EQPA was looking for more insight in this. Results should also
support argumentation for a better harmonisation across the
Member States.
QP Education Course in Copenhagen
For the first time after more than two years of live online trainings,
the QP Education Course (Module B) was held live on-site again
(02/03 June 2022, Copenhagen, with a pre-course session on 01
June). Altogether 30 delegates have attended (15 for the Education
Course and 15 both the Education Course plus the pre-course ses-
sion). According to the feedback, delegates enjoyed asking ques-
tions live and the discussions. The overall average rating of the pre-
course session on Soft Skills was 1.2 (1 = very good, 6 = bad). The
overall average rating of the QP Education Course was 1.45.
EMA has opened a short 1-month public consultation on a draft set
of Questions and Answers on remote batch certification by the
Qualified Persons. Ulrich Kissel has created a consolidated EQPA
feedback document which has also taken into account feedback
received by EQPA members. Details were discussed during a face-
to-face meeting in the course of the QP Education Course in Copen-
hagen. Consolidated comments were sent to EMA.
The EQPA is working with other stakeholders on an industry fol-
low-up on COVID-19 & supply chain activities: As a follow-up of the
EMA-IWG-Industry meeting, industry would like to provide to the
IWG the feedback on the EMA-IWG action item: ‘The Interested 3
Parties are invited to provide suggestions for consideration by IWG
on potential alternative measured to manage expiring GMP-certif-
icates at the end of 2022’.
continued on page 37
 Annex 1 Revision
Consideration of some relevant points of the final version
A look back
The aseptic filling of a sterile medicinal product must be carried out
in a controlled environment. (Grade A). The relevant part of the EU
GMP Guidelines for this type of manufacturing is the document’s
Annex 1 . After a long revision period of the previously valid version
of 2008 and two rounds of comments, the long-awaited revised
Annex 1 on the manufacture of sterile medicinal products was fi-
nally published by the European Commission on 25 August 2022
(1). The main reason for the update was to reflect changes in the
regulatory environment and in manufacturing, which includes a
significant shift towards the application of quality risk management
principles. The new Annex 1 will enter into force on 25 August 2023.
The European Commission published a first draft in 2017 for public
comment. This resulted in over 6000 submitted comments from
industry, stakeholder organisations and others. A second com-
ment period on the revised draft in 2020, which included a target-
ed consultation period by recognised stakeholders from industry
4 About the Author
Dipl. Biol. Axel H. Schroeder has been working at CONCEPT HEIDELBERG since 2008 and is head of the microbiology department.
and organisations such as ECA and EQPA, received over 2000 com-
ments. The intense debates, e.g. on the prominent PUPSIT (Pre-
Use Post Sterilisation Integrity Test), were no surprise as there
were significant revisions, additions and much more detail, result-
ing in an expansion of the document from 16 to now 58 pages.
We should acknowledge here the efforts of both industry and regu-
latory bodies, including the WHO (World Health Organisation) and
the PIC/S (Pharmaceutical Inspection Co-Operation Scheme), in
issuing a much more modern guide to the manufacture of sterile
products. They have thus also succeeded in creating an agreed
document between the three institutions EMA, WHO and PIC/S.
The FDA also contributed to the revision. Accordingly, the revised
PIC/S Annex 1, which is now identical to the EU Annex 1, was pub-
lished at the end of September. Although the final version will only
come into force after a transitional period of one year, it is expected
that the current version will form the basis for the inspection of
sterile products and components intended for the manufacture of
sterile medicinal products.
Relevance for the production of many modern ac-
tive substances and therapies
Although the title in both drafts no longer referred exclusively to
sterile medicinal products, it was not changed in the end and re-
mains "Manufacture of sterile medicinal products". Presumably
also in order to minimise global effects on the basis of a European
guideline and not to force discussions about the validity and con-
trollability outside the EU too much, especially since a correspond-
ing control by the inspecting European authorities would hardly be
possible. Nevertheless, one aim of Annex 1 is to also provide a
guideline for the manufacture of sterile products in general. Active
ingredients, excipients, primary packaging materials and finished
dosage forms are explicitly listed as sterile product types. In addi-
tion, some of the principles and guidance in Annex 1 can also be
applied to other products that are not intended to be sterile, such
as biological intermediates with low biological load. Overall, the
aim is to prevent any microbial, particulate or endotoxin contami-
nation of the final product. To emphasise one of the key principles
of the previous and new Annex 1: "Sterility or other quality aspects
should not be determined solely by a test of the final process or
product."
As a result, the new Annex 1 is now of greater importance to many
suppliers of packaging materials, starting materials, active ingredi-
ents and CDMOs. Although there is a separate complete GMP
guideline for advanced therapy medicinal products (ATMP) with
Eudralex Vol. 4, Annex 1 certainly also concerns modern active in-
gredients or therapeutic approaches such as mRNA and viral vec-
tors if these are not used for ATMP but e.g. for vaccines. Often,
these products are not released with the indication "sterile", but are
sterile-filtered and then aseptically filled into previously sterilised
containers or bags. Given the potential variability in filtration per-
formance of these products, the overall contamination control
strategy becomes increasingly important.
Annex 1
Final Version and
its Impact
Current requirements on
aseptic manufacturing
Live Online Conference on
14/15 December 2022
gmp-compliance.org
No way around it: Contamination Control Strategy
The "Contamination Control Strategy" (CCS) is a frequently dis-
cussed topic in all debates on Annex 1. Already in the draft versions
it was stated:
"Contamination Control Strategy (CCS) - A planned set of controls for
microorganisms, pyrogens and particulates derived from current prod-
uct and process understanding that ensures process performance and
product quality. Controls may include parameters and attributes re-
lated to active ingredient, excipient and drug materials and compo-
nents, facility and equipment operating conditions, in-process controls,
final product specifications and associated methods and frequency of
monitoring and control."
Various support documents and templates have already been pub-
lished for this purpose (2, 3) to assist pharmaceutical manufactur-
ers in creating their own CCS, which will be a must in the future,
more precisely by 25 August 2023! The aim of a holistic CCS is to
move away from sterility based only on an audit of the final process
or product, towards detailed process knowledge and all potential
sources of contamination. There is a long list of elements that need
to be considered, from equipment and process design to corrective
and preventive actions. Different areas of responsibility play a role,
as contamination control measures may reside in different depart-
ments, from production to engineering to quality assurance or
quality control. While it is acknowledged that the manufacturer
may already have control systems in place that do not need to be
replaced, these need to be referred to in the CCS, or to make the
CCS a coordinated whole and take into account any interactions. It
should also provide a better opportunity to identify any gaps in the
existing system.
The guideline of the ECA Contamination Control Strategy Task
Force listed at the references will be updated shortly after the pub-
Changes,
Developments
and
Experiences
5
 lication of the final Annex 1. It has the following structure: supplier qualification, extractables assessment, integrity verifica-
tion throughout the process, incoming inspection, operator train-
The ECA Guide contains a 3-stage-approach to achieve "CCS-readi- ing and more are listed. Another new and interesting chapter deals
ness." with "closed systems", which includes considerations on how to
• Stage 1: Development (or review and refinement/improve- design and use a closed system and what measures should be tak-
ment) of the CCS en to ensure the integrity of the system, especially when a closed
• State 2: Compilation of the CCS documents system is used in an area with a classification lower than Grade A.
• Stage 3: Evaluation of the CCS Closed reprocessing considerations also include the use of a sterile
connection device, which is now referred to throughout the
Annex 1 document as an 'intrinsic sterile connection device'.

Laboratory Optimization, Automation This is intended to address only some of the relevant issues at this
and Digitalization point. A separate article could be dedicated to the topic of quality
Part of PharmaLab Congress 2022 risk management alone, and more "trivial" topics such as "clean-
room socks", which can become a challenge for the manufacturer
Düsseldorf/Neuss, Germany but also for the reprocessing cleanroom laundry (or disposable
22 November 2022 socks? Is that sustainable?) remain undiscussed here. The subchap-
ter "Barrier Technologies" in the chapter "Premises" has also been
extensively expanded, almost doubling in size. The topics of back-
Learn more about this course: ground environment, gloves and decontamination methods have
www.pharmalab-congress.com been dealt with separately for both isolators and RABS. The
subchapters "Form-Fill-Seal (FFS)" and "Blow-Fill-Seal" in the
chapter "Production and Specific Technologies" have almost tripled
in size and go into much more detail.

This document is intended to provide guidance for two possible
cases:
1. For a new plant, new equipment, e.g., for:
• Mapping of the manufacturing processes to identify possible
sources of contamination.
• Carrying out a risk assessment to evaluate the risk of contam-
ination.
• Establishing preventive measures and their controls in a holis-
tic system (including the definition of responsibilities).
• Assessing and managing the residual risk of contamination.
2. For an existing facility that has already carried out a risk assess-
ment, e.g., for:
• Evaluation of existing contamination control measures
• Analysis and overview of possible gaps
• Risk assessment and, if necessary, the addition of further
measures and integration into the overall system (including
determination of responsibilities)
• Managing the residual risk of contamination
The Single Use Issue:
As mentioned, the implementation period for Annex 1 ends on
25 August 2023, i.e. exactly one year after publication in Eudralex
Volume 4, only for one section, Chapter 8.123 "Product transfer/
loading/unloading areas for freeze dryers" the deadline is two
years, i.e. until 25 August 2024. At this point, the objections of the
industry for longer deadlines for some sections have probably been
listened to.
More detailed information and examples of the Authority's expec-
tations and industry implementations can be expected at the ECA
Live Online Annex 1 Conference on 14 and 15 December 2022.
Modern Microbiology Laboratory
Mastering the challenges of classic and
modern microbiological methods
Live Online Training
6-8 December 2022

The new Annex 1 recognises the use of single-use systems (SUS) in Learn more about this course:
the manufacture of sterile products and includes a separate para- www.gmp-compliance.org
graph listing "some specific risks associated with SUS that should
be assessed in the context of the CCS": Drug Interaction (e.g.
Leachables and Extractables play a role in SUS), Integrity ("risk of
holes and leaks") and Particle Contamination. Expectations such as

6 References:
1
European Commission (2022), EU GMP Annex 1 https://health.ec.europa.eu/latest-updates/revision-manufacture-sterile-medicinal-products-2022-08-25_en (assessed 29 Aug 2022).
2
ECA Foundation (2022), Contamination Control Strategy – A New Guideline from ECA, https://www.eca-foundation.org/news/eca-foundation-ccs-task-force-guidance.html
(assessed 29 Aug 2022).
3
El Azab W (2021), Contamination Control Strategy: Implementation Road Map. PDA J Pharm Sci Technol., 75(5):445-453.
Questions and Answers on
(Reduced) Sampling
Testing of active pharmaceutical ingredients (APIs), excipients,
packaging materials, intermediates and finished products is one of
the main tasks of the quality control unit in the pharmaceutical in-
dustry. During sampling, a small part of a batch or delivery is taken
and analyzed. The results are then used to draw conclusions about
the quality of the entire batch or delivery. Correct sampling plays a
key role in this process. Any analytical method cannot compensate
for errors that have occurred during sampling, no matter how good
it may be.
Regulatory Requirements for Sampling
First of all, country-specific requirements may need to be consid-
ered. In Germany, for example, the Ordinance on the Manufacture
of Medicinal Products and Active Pharmaceutical Ingredients (Arz-
neimittel- und Wirkstoffherstellungsverordnung (AMWHV)1 must
be followed with regard to sampling. § 14 (1) AMWHV contains the
general requirement to test starting materials and finished prod-
ucts, if applicable intermediate products and containers, outer
About the Author
Dr Markus Funk joined CONCEPT HEIDELBERG in October 2019 as operational director and is in charge of the topics GDP and analytics.
packaging, packaging and labeling materials, and package inserts in
accordance with test instructions. In this context, according to
§ 12 (1) AMWHV, the head of quality control has the task of approv-
ing the specifications, sampling plans and test instructions. He or
she finally has to decide on the approval or rejection of starting ma-
terials, packaging materials and intermediate products.
The various GMP regulations, in particular the EU GMP Guidelines,
provide a number of more or less specific requirements for sam-
pling. Sampling is described in more detail in Chapters 6.11 to 6.14
of the EU GMP Guidelines Part I.2 The sample taking should be done
and recorded in accordance with approved written procedures.
Chapter 6.11 lists aspects that must be determined in advance for
this purpose, such as the method of sampling, the amount of the
sample to be taken, and instructions for the cleaning and storage of
sampling equipment. According to Chapter 6.12, samples should be
representative of the batch of materials or products from which
they are taken. Furthermore, the sampling plan used should be ap-
propriately justified and based on a risk management approach.
7
 Chapter 6.13 provides instructions for labeling and handling of the
sample containers and Chapter 6.14 contains a reference to Annex
19 of the EU GMP Guidelines.3
In addition, the EU GMP Guidelines Part I also contain other require-
ments for sampling. For example, according to Chapter 3.22, sam-
pling of starting materials should normally be done in a separate
area. If it is performed in the storage area, measures must be taken
to prevent contamination or cross-contamination. Specifications
must be available for both starting materials and primary or printed
packaging materials (Chapter 4.14) and finished products (Chapter
4.16), including directions for sampling. According to Chapter 4.25,
written procedures should be available that include methods of
sampling and equipment to be used, the amounts of samples to be
taken, and any precautions to be observed to avoid contamination
of the material or any deterioration in its quality. These procedures
must also be readily available to the quality control department, as
can be seen in Chapter 6.7.
Quality Control of Starting Materials
(APIs and Excipients)
Live Online Training
7/8 February 2023
Practical oriented advice regarding the
testing of APIs and excipients
Learn more about this course:
www.gmp-compliance.org
In addition, Annex 8 of the EU GMP Guidelines4 must be considered,
which contains additional information on the sampling of starting
and packaging materials as well as on the personnel who take sam-
ples.
The principle sampling requirements for API manufacturers are
largely similar to those for pharmaceuticals. Provisions in this re-
gard can be found in particular in Chapter 7.3 (Sampling and Testing
of Incoming Production Materials), Chapter 8.3 (In-process Sam-
pling and Control) and 11.7 (Reserve/Retention Samples) of the EU
GMP Guidelines Part II.5
For the United States, the Code of Federal Regulations must be
followed. Requirements for sampling can be found in 21 CFR 211
(Current Good Manufacturing Practice for Finished Pharmaceuti-
cals), mainly in Subpart I (Laboratory Controls) and Subpart E (Con-
trol of Components and Drug Product Containers and Closures).
Does the Sample Drawing have to be carried out
by the Quality Unit?
8 CONCEPT HEIDELBERG and the ECA Academy regularly hold semi-
nars dealing with different aspects of sampling. In one of these
events, the question came up whether sampling must be carried
out by quality control employees or if other persons, e.g. warehouse
or production staff, may also draw the samples.
As shown above, the sampling requirements are described in the
EU GMP Guidelines. Although the EU GMP Guideline Part I states
that quality control is concerned with sampling (Chapter 6, Princi-
ple) and that quality control personnel should have access to the
production areas for sampling (Chapter 6.4), there is no explicit re-
quirement that the persons taking the samples have to belong to
the quality control department. This requirement cannot be derived
from the other passages of the EU GMP Guidelines either.
It is clear that the personnel must be trained and approved for sam-
pling. This already follows from the general principles described in
Chapter 2 of the EU GMP Guidelines Part I or Chapter 3 of the EU
GMP Guidelines Part II, according to which personnel with the nec-
essary qualifications and practical experience must be available for
all GMP-relevant activities and should also receive continuing train-
ing. Chapter 1.9 of the EU GMP Guideline Part I further states: „Sam-
ples of starting materials, packaging materials, intermediate products,
bulk products and finished products are taken by approved personnel and
methods“. Annex 8 of the EU GMP Guidelines additionally stipulates
the following: “Personnel who take samples should receive initial and
on-going regular training in the disciplines relevant to correct sampling.”
As with Part I, Part II of the EU GMP Guidelines does not contain any
specific statements on who exactly has to conduct the sampling.
However, an interesting note can be found in the ICH Q7 guideline6
question and answer document.7 Number 2.4 deals with the ques-
tion of whether ICH Q7 requires that sampling be performed by the
quality unit. The answer to this question is a clear "no." In explaining
the reasoning, it is stated that ICH Q7 does prescribe specifically
who should perform the sampling. However, the quality unit is re-
sponsible for reviewing and approving sampling plans and proce-
dures. Sampling should also be performed by appropriately trained
personnel and appropriately documented.
The fact that the quality unit is responsible for reviewing and ap-
proving sampling plans and procedures is also a legal requirement
for the United States. A provision stating this can be found in 21
CFR 211.160.
It can thus be summed up that it cannot be concluded from the
GMP regulations that sampling must be performed by quality con-
trol staff. However, it is clearly specified that the employees con-
cerned must be trained, that the sampling procedures must be ap-
proved by the quality control department, and that the overall
responsibility also lies with the quality control department.
Under what Prerequisites is Reduced Sampling
Acceptable?
Another topic repeatedly discussed in the CONCEPT HEIDELBERG
and ECA Academy seminars is reduced sampling of starting materials.
Reduced sampling means that not all containers of a delivery or a
batch are sampled, but only a previously specified number. This is
to be distinguished from reduced testing, in which only individual
pre-specified parameters of a specification are tested. In principle,
both concepts can also be combined.
On the one hand, this article is intended to highlight the conditions
under which reduced sampling is possible in principle. On the other
hand, it will be discussed whether each individual container of a
starting material must be sampled for identification purposes, or According to Chapter 7.30 of the EU-GMP Guidelines Part II “at least
whether a random sample can also be sufficient in this respect. one test to verify the identity of each batch of material should be con-
ducted. […] Supplier's Certificate of Analysis can be used in place of per-
forming other tests, provided that the manufacturer has a system in
place to evaluate suppliers”. Chapter 7.31 says that “full analyses
Validation in Pharmaceutical Analysis should be conducted on at least three batches before reducing in-house
Part 1 "ICH Q2 Revision, Lifecycle Concept, testing. However, as a minimum, a full analysis should be performed at
Precision, and Accuracy" AND Part 2 "Speci- appropriate intervals and compared with the Certificates of Analysis.
ficity/Selectivity, Response (Calibration Reliability of Certificates of Analysis should be checked at regular inter-
Model), Impurities and Quantitation Limit" vals.” Chapter 7.32 contains an exception for processing aids, haz-
ardous or highly toxic raw materials. These do not need to be test-
Live Online Training ed, provided that the manufacturer's certificate of analysis is
14/15 March 2023 available and shows that they conform to the specification.

Learn more about this course:
www.gmp-compliance.org
For these questions, as with sampling in general, there may be
country-specific laws. For Germany, the basic rules laid down in the
AMWHV must first be noted. According to § 13 (3) AMWHV, only
active ingredients and excipients that have been manufactured in
accordance with GMP and whose quality has been determined and
appropriately identified may be used as starting materials for the
manufacture of medicinal products. Suppliers of starting materials
and primary and secondary packaging materials used in the manu-
facture of medicinal products must, in accordance with § 11 (2)
AMWHV, be qualified within the framework of the QM system of
the processing plant in accordance with a procedure laid down in
writing or electronically. For active ingredient suppliers, an on-site
audit is even mandatory in line with § 11 (3) No. 1 AMWHV.
At the EU level, the following can be noted: In principle, according
to Chapter 5.35 of the EU GMP Guidelines Part I, manufacturers of
finished products are responsible for any testing of the starting ma-
terial as described in the marketing authorisation dossier. They can
utilise partial or full test results from the approved starting mate-
rial manufacturer. In this case, however, at least identification test-
ing of each batch according to Annex 8 is required. In addition, the
requirements described in chapter 5.36 (audit performed, quality
history, evaluation of the test results by comparison with the re-
sults of own full analyses, etc.) must be fulfilled. As a rule, at least
three full analyses are expected before test results are used from
the approved starting material manufacturer.
How the identity of a batch of a starting material must be ensured
is also described in Chapter 5 of the EU GMP Guidelines Part I. If one
material delivery is made up of different batches, each batch must
be considered individually, i.e. sampled, tested and released sepa-
rately, in accordance with Chapter 5.31. According to Chapter 5.33,
the identity of the contents of each container of starting material
must be ensured.
Annex 8 of the EU GMP Guidelines formulates the general expecta-
tion to take samples from all containers and to perform an identity
test on each sample. However, it is expressly permissible “to sample
only a proportion of the containers where a validated procedure has
been established to ensure that no single container of starting material
has been incorrectly labelled.“
Annex 8 also lists the aspects to be taken into account in such a
validation. For example, the manufacturer of the starting material
in question must have a functioning quality system and the manu-
facturing conditions under which the starting material is produced
and controlled must be evaluated. Under these prerequisites, iden-
tity testing is possible on only part of the containers, provided that
the starting materials comes from a single product manufacturer or
plant, and also for starting materials coming directly from a manu-
facturer or in the manufacturer’s sealed container. For the latter, a
history of reliability and regular audits of the manufacturer’s quality
assurance system must be conducted by the purchaser (the manu-
facturer of the medicinal product) or by an officially accredited
body. Conversely, in cases where starting materials are supplied by
intermediaries and the source of manufacture is unknown or not
audited, and in the case of starting materials for use in parenterals,
it is considered unlikely that validation can succeed. In these cases,
an identity check will therefore generally have to be carried out on
a container-by-container basis.
With regard to the requirements applicable to the US, the following
can be stated: 21 CFR Part 211.84 requires that sampling be based
on statistical criteria and that each lot shall be withheld from use
until it has been sampled, tested, or examined, as appropriate, and
released for use by the quality control unit. Part 211.84(b) requires
that representative samples be taken from each shipment of a
batch for testing or examination. The number of containers to be
sampled and the amount of material to be taken from each con-
tainer must be based on appropriate statistical criteria and should
also take into account the supplier's quality history. Further infor-
mation on the interpretation of the regulations can be found in a
question and answer catalog published on the FDA website.8

9
1 Verordnung über die Anwendung der Guten Herstellungspraxis bei der Herstellung von Arzneimitteln und Wirkstoffen und über die Anwendung der Guten fachlichen Praxis bei der Herstellung von Produkten menschli-
cher Herkunft (Arzneimittel- und Wirkstoffherstellungsverordnung - AMWHV).
2
EU Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use, Part I - Basic Requirements for Medicinal Products.
3
EU Guidelines to Good Manufacturing Practice Medicinal Products for Human and Veterinary Use, Annex 19: Reference and Retention Samples.
4
EU Guidelines to Good Manufacturing Practice Medicinal Products for Human and Veterinary Use, Annex 8: Sampling of Starting and Packaging Materials.
5 EU Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use – Part II: Basic Requirements for Active Substances used as Starting Materials.
6
ICH Q7 – Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients.
7
Q7 Q&As – Questions and Answers: Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients (https://www.ich.org/page/quality-guidelines).
8
Questions and Answers on Current Good Manufacturing Practices—Control of Components and Drug Product Containers and Closures (https://www.fda.gov/drugs/guidances-drugs/questions-and-answers-current-
good-manufacturing-practices-control-components-and-drug-product).
 Cross-contamination and Sustainability:
The Trouble with Contamination
The topic of cross-contamination and its prevention is becoming
increasingly important in government audits. Not only the meas-
ures taken to prevent cross-contamination are explicitly inquired
about, but also how the success of these measures is tested in sur-
face sampling. At the same time, production plants face the major
challenge of sustainability, which contrasts with the increased en-
ergy and material requirements for prevention measures.
Cross-contamination, according to the glossary of the EU GMP
Guidelines1, is contamination of a starting material or product with
another material or product. This can occur through the uncon-
trolled release of particles, gases, aerosols or organisms, as well as
through residues on work clothing or equipment, for example due
to inadequate cleaning.
Various technical and organizational measures are suggested to
prevent the occurrence of cross-contamination. These include
physical separation, for example by producing solids in one build-
About the Authors
10
Dr Felix Kern is a pharmacist and Head of Compliance Launch
and Technology Center at Merck KGaA in Darmstadt.
ing and sterile liquids in another. There is also the option of separa-
tion within a building, for example by producing products of differ-
ent risk categories in assigned areas and/or with assigned
equipment. Other options are the campaign mode, in which several
batches of the same product are produced one after the other with
only dry cleaning in between, and the establishment of airlock sys-
tems for personnel, equipment or materials. Roughly summarized,
the following six areas can be identified to build a "CroCo" risk
analysis. It is not possible to subdivide this into "technical" and "or-
ganizational" measures the same way the GMP Guidelines, Section
5.21, do, since both types of measures play a role in all of the six
areas.
However, with the emerging topic of "sustainability," new ques-
tions and problems arise regarding the avoidance of cross-contam-
ination. Specifically, sustainability is about avoiding energy, carbon
dioxide, waste, and the use of cleaning agents. The latter should be
used as sparingly as possible and also have good biodegradability.
Fritz Röder is Site Account Engineer at Merck KGaA,
Darmstadt.
Fig. 1: Possible structure of a risk analysis for cross-contamination.
If the six areas mentioned above are evaluated further in detail,
many material- and energy-intensive measures emerge. These in-
clude the establishment of exhaust systems directly at the produc-
tion sites to collect any particles that emerge. Material-intensive
protective clothing concepts are designed to prevent residues on
the work clothing from being transferred to the product. This in-
cludes the continuous replacement of GMP clothing in the chang-
ing rooms, but also the use of special protective clothing that must
be pulled over the GMP protective clothing when entering special
production areas. In addition, there is the use of gloves, hard hats
and special beard covers. Another important focus is on cleaning:
the most critical issue is cross-contamination between different
products. Before changing from a batch of one product to a batch
of another product in a production area, wet cleaning must be per-
formed according to specified cleaning procedures to remove resi-
dues in the area and on the equipment. For this purpose, consider-
able quantities of cleaning agents and disinfectants are sometimes
used and discharged into the wastewater. Another major energy
drain relates to ventilation systems. Did you know that up to 90%
of the energy demand in a pharmaceutical building is caused by
ventilation systems? But this also depends on the mode of opera-
tion. By extracting more air in a production room in a solida opera-
tion than air is introduced into the adjacent corridor, an air gradient
is created in the production room, a differential pressure. This air
gradient keeps any particles that may occur in the production room
and prevents any contamination of the adjacent corridor or even
other production rooms ("clean corridor concept"). In addition, an
effective monitoring system must be set up to constantly monitor
the differential pressures and generate appropriate alarms in the
event of a drop below predefined limits.
Many of the measures listed above partly require a high input of
energy, but also of materials. The challenge for the pharmaceutical
entrepreneur in the future will be to find a good balance between
"cross contamination risk", "use of materials and cleaning agents"
and "energy requirements of the plant". We would like to share
some ideas with you below.
1. Materials
With regard to "avoidance of materials", the focus is less on the raw
and auxiliary materials used in manufacturing, but rather on all ma-
terials that are otherwise required for production in general. Dis-
posable or reusable clothing, the above-mentioned "special pro-
tective clothing", sampling materials, packaging, single-use
equipment, but also paper for documentation purposes are of in-
terest here. In many cases, the question "single-use vs. reusable"
now arises. This cannot be answered in a general way, because 11
cleaning also costs resources. You can use the carbon footprint to
evaluate all your processes and materials (e.g., in accordance with
ISO 140672). It is important that you correctly define the "scope" for
your assessment. As a rule of thumb, the more often you can reuse
 a reusable item, the better the result for the reusable item.
2. Buildings
Quite essential in terms of cross-contamination and sustainability
is the ventilation concept. High air exchange rates in a room do
ensure a short recovery time and thus faster removal of particles
and other contaminants. However, this is countered by significant-
ly higher energy requirements. How far can you safely reduce your
air exchange rates? Another possible solution, depending on the
building design, could be to drastically reduce the outside air por-
tion of the ventilation. This way, you can maintain strong circula-
tion within the building, but not lose the enthalpy expended. Of
course, this requires an appropriate design of the ventilation sys-
tem. Degree of automation of the ventilation, HEPA filters in the
supply and/or exhaust air, exhaust air connections at the bottom of
the room, frequency-directed fans, and heat recovery are the is-
sues that must be considered. However, the possibilities and dis-
cussion points for a ventilation system do not end there. Adiabatic
humidification of supply or exhaust air (in this case for heat recov-
ery purposes), solar-powered reheaters or geothermal energy are
further topics to get even closer to "enlightenment" in terms of
sustainability. Last but not least, you can think about the real re-
quirements of your humidity in operation. Above all, however, the
latter points must always be considered from the point of view of
hygiene and microbiological load. For sterile operations, this issue
is thus even more critical. Here, the risk analysis for cross-contam-
ination does not focus on particles in the first place, but on micro-
biology.
substances should be used for cleaning/disinfection. Chlorine and
fluorine compounds, for example, have poor biodegradability.
However, the degradability is offset by the efficacy and concentra-
tion of the detergents and disinfectants mentioned, which affects
the evaluation in the risk analysis for cross-contamination. Inci-
dentally, the same applies to sterilization processes, where the as-
sessment is even more difficult.
Summary
Sustainability and the changes that come with it are finding their
way into pharmaceutical operations more and more. However, it
can be observed that QA representatives as well as the regulatory
side rightly demand a minimum level of control, hygiene and pre-
vention of contamination in GMP operations. This can lead to con-
flicts. Who will be proven right? How can pharmaceutical process-
es be made more sustainable without having to forego the previous
safeguarding of processes and the corresponding control? Here,
representatives of quality and the environment will have to agree
on compromises. The key lies in good control strategies and holis-
tic assessment of all risks. Perhaps we in GMP will also eventually
find our way to "integrated management systems" that consider
quality, environment, safety and health together under one roof?

3. Cleaning and disinfection agents:

Cleaning and disinfection is a central element of the aforemen-

tioned risk analysis. The new sustainability requirements will aim
to run cleaning processes at lower temperatures (e.g. CIP/WIP). In
addition, the quantities of cleaning agents and disinfectants should
be reduced as much as possible, and ideally, readily degradable

1 https://www.bundesgesundheitsministerium.de/gmp.html, retrieved 04.02.22

2
https://www.beuth.de/de/norm/din-en-iso-14067/289443505, retrieved on 04.02.2022

Quality Oversight for Virtual Companies
Live Online Training on 17 November 2022
12
gmp-compliance.org
Data flows, Data Lifecycle, and ALCOA+
Summary
The points discussed in this article and summarized in Table 1, pro-
vide the data1 integrity compliance by design2. Data Governance is
the strategic document implementing and enforcing the tactical
elements discussed in this article. Data Governance is discussed in
Reference 3.
Table 1, the Data flows, Data Lifecycle, ALCOA, and Key Expecta-
tions, provides, per typical data/records flow, the data/records
attribute(s) associated with the data flow and the associated typi-
cal data/records integrity controls. The "Key Expectations" in Table
1 came from “A Computer Data Integrity Compliance Model”2.
Data lineage is the process of understanding, recording, and visual-
izing data as it flows from data sources to consumption and in-
cludes all transformations the data underwent, how data transfor-
mation, what changed, and why. A data flow map is a valuable tool
to visualize data flow and the risks and vulnerabilities of electronic
About the Author
Orlando López is a seasoned expert with worldwide experience in pharmaceutical device and medical device e-compliance.
systems, particularly interfaced systems. It shows the complete
data flow from start to finish.
A record is considered to have integrity if it is complete and
protected from unauthorized addition, deletion, alteration, use,
and concealment.
36 CFR Part 1236.10
Specifically, understanding the data flows among the components
of an electronic system aids in correctly implementing the appro-
priate integrity controls needed. The definition of data integrity in
NIST SP 800-57P14 provides four specific data flows associated
with the appropriate data/records integrity controls: data created,
while in transit, during processing or stored.
These four typical data flows can be correlated with the data lifecy-
cle5. Table 1 provides this correlation.
The essential management measures and technical means should
13

Fig. 1: Typical Manufacturing Data flows
be adopted for the data/records collected, processed with, while in
transit to, and stored by an electronic system6.
A typical manufacturing system (Figure 1) is used as an example to
explain the relationships between Data flows, Data Lifecycle, AL-
COA, and the data integrity controls per typical data flow as de-
scribed in Table 1.
Introduction
Many published articles, regulatory authority guidelines, and glob-
al industry group guidelines provide information about data integ-
rity, primarily illustrating ALCOA7 and ALCOA+8. The emphasis of all
regulators is on the ALCOA principles to outline regulatory expec-
tations. ALCOA These are is considered principles that ensure the
integrity of data in its lifecycle.
In the data/records framework applicable to data flows9, ALCOA
and all its variants indicate reliability10, but it cannot be used to
determine the appropriate data/records integrity controls. Not all
ALCOA principles are applicable in all data flows.
There may be some inconsistencies by the software developers
and/or by the data/e-records11 risk evaluators about which situa-
tion an ALCOA principle is applicable.
The other rarely discussed item 0in many articles about data integ-
rity is the controls needed to preserve the data element in a typical
data flow through the electronic system12. In a high-level frame-
work, the data flows involved are data “created, while in transit,
during processing or stored.”4 A record that has integrity in all of
14 these data flows is complete and unaltered. Only personnel or
electronic systems with appropriate access levels can modify the
records in case of any alteration. In the case of altered data/re-
cords, there is traceability with the original data/records.
Understanding the data flows between the
components of an electronic system enables
the implementation of the correct applicable
integrity controls needed per specific pro-
cess.
The validation process applicable to work-
flows ensure that the intended steps, re-
quirements, design, and qualification/verifi-
cation results are accurate, performed
adequately, and documented. The mainte-
nance and operation phases provide that any
modification maintains the validated state of
each workflow.
This paper provides the relationships be-
tween data flows, data lifecycle, ALCOA, and
key data integrity controls per typical data/
records flow.
Even though many of the references in this
article are related to manufacturing, this ar-
ticle applies to all GxP regulations13.
Understanding Data Integrity
As per NIST SP 800-57P1, data integrity refers to the “property that
data has not been altered14 in an unauthorized manner since it was
created, while in transit, during processing or stored." This defini-
tion is consistent with ISO 15489, INFOSEC, 44 USC, Sec. 3542, 36
CFR Part 1236.10, and ANSI/IEEE and embraces the state or condi-
tion that e-records integrity is a measure of the validity and fidelity
of a data object15.
During the data/records lifecycle16, 17, data/records are placed in
one of the data flows mentioned above. Each data flow can be cor-
related with the key expectations regarding the controls to main-
tain the data/record with integrity. Refer to Table 1. It is vital to
recognize the data/records lifecycle elements (Figure 2) to ensure
the proper controls.
E-records, as informational objects, have a life cycle that begins
with data capture, maintenance and use, and disposal18.
As depicted in Figure 2, as part of the data utilization, the data can
be analyzed, archived, extracted, loaded, migrated, processed, re-
ported, retained, retrieved, transformed, transmitted, and so on.
Work in progress corresponds to the data generation and is consid-
ered sensor data. The e-records handling function starts after sen-
sor data is captured. A sensor or transient data becomes an e-re-
cord after being captured and saved to a repository for e-records19.
During maintain and use e-records are kept and used for their in-
tended purpose. The e-records must be authentic, trustworthy,
and reliable to allow those individuals who depend on the e-re-
cords to fulfil their job functions correctly.
In some situations, the processes' abilities are retained throughout
the active phase as the tools required to use the records are the
same tools used for their creation.
E-records that are no longer active are usu-
ally moved to separate e-records storage for
long-term retention or retention. These inac-
tive records need to be kept meeting reten-
tion schedule requirements, but often they
are maintained with the read/view attribute.

The disposal of the e-records is the end of re-

tention and destruction of e-records, includ-
ing content, attributes, and audit trails.

Note that the business requirements that

cause the e-records handling requirements
drive the selection of appropriate supporting
technologies. The technologies pose ques-
tions associated with ongoing internal and
external secondary access to records, support
the selection of appropriate technologies, and
identify important system migration issues20.

Table 1 provides, per typical data/records

flow, the data/records attribute(s) associated
with the data flow and the associated typical Fig. 2: Typical Manufacturing Data flows
data/records integrity controls. The “Key Ex-
pectations” in Table 1 came from “A Computer
Data Integrity Compliance Model”2.
The integrity of GMP data/records should be safeguarded through-
out the retention period during entry or collection, storage, trans-
mission, and processing.
Applicability of the Concept from Figure 1
Figure 1 represents a typical PLC manufacturing data flow. In this
figure, the PLC is connected to an instrument/equipment on the
left-hand side of the figure and a Historian or supervisory control
and data acquisition (SCADA) to the other end. In addition to these
two connections, the PLC is connected to a supervisory system.
memory in a format that is not vulnerable to manipulation,
loss or change.
• Built-in checks (EU Annex 11 p5) verify the data after the
transformation.
The ALCOA elements associated with sensor data are accurate,
complete, and consistent.
The equipment connected to the I/O card, maybe an electronic sub-
system with some limited manual adjustable input data and the gen-
erated GxP data22 is not stored but sent via an interface to the PLC23.
The Supervisory system has the same characteristics as the sub-
system above.

The information received from the instrument/equipment and im- The PLC is connected to the SCADA / Historian subsystem, where
mediately 0before the SCADA repository is considered transient or GxP data are permanently stored, and the GxP data can be main-
sensor21 data since it is not saved to a repository for e-records. tained and used by the user to generate results.

The sensor data may use virtual memory as transient data storage.
The data are written to disk as virtual memory is not a true e-re-
cord since it serves as temporary data storage for the instrument
or equipment application.
The sensor data in temporary data storage cannot be used nor
maintained.
The associated sensor data integrity controls contained in Table 1
are:
• The interface between equipment and computer should be
qualified and checked periodically to ensure data/record ac-
curacy and reliability.
• The accuracy and reliability of the raw data depend not only on
properly calibrated instruments and equipment but also on
the integrity of the raw data produced by the recording action.
• Sensor data captured by the system should be saved into
An e-record is generated after the sensor data (a.k.a. transient
data) is recorded in a repository for e-records (e.g., SCADA, Histo-
rian, data server, and so on). After the sensor data24 is recorded, the
e-records lifecycle begins. The e-records recorded in the SCADA /
Historian are called original records25.
The overall e-records integrity controls applicable to all e-records
in storage are:
• Qualify the repositories of e-records for their intended use.
• Retain records in their original format.
• User access controls to the records repository shall be config-
ured and enforced to exclude unauthorized access and chang-
es to and deleting data/records. 15
• A backup must be performed for disaster recovery to data/re-
cords, metadata and system configuration settings on storage.
The backup copy must be a true copy of the backed-up records.
• Original data/records or a true copy are subject to periodic re-
 view by qualified personnel. Data / e-records should be peri-
odically checked for accessibility, readability and integrity.
• Data/records should be traceable to the original data/records
by documenting changes to the original data/records. An audit
trail must be created for any modification to and deletion of
data/records.
• Verification of data/records retrievability is required before mod-
ifying the electronic system application and/or infrastructure.
The ALCOA elements associated with e-records in storage are At-
tributable, Legible, Contemporaneously, Original, Accurate, Com-
plete, Consistent, Enduring, and Available.
In addition to the brief description of the data lifecycle, ALCOA at-
tributes, and critical expectation integrity controls to the sensor
data and e-records in storage data flows, Table 1 contains the data
lifecycle, ALCOA attribute, and overall e-records integrity controls
for e-records while in transit, during processing, and capture.
Data flows
As specified before, understanding the data flow between the
components of an electronic system permits a straightforward im-
plementation of the appropriate integrity controls needed per spe-
cific process.
From start to finish, the complete data flow is the process of under-
standing, recording, and visualizing data as it flows from data
source systems to data consumption (e.g., business intelligence).
Dataflows must include all the data underwent along the way and
how the data was transformed, what changed, and why26.
The data lineage tool or data flow map27 is a helpful tool in under-
standing the risks and vulnerabilities of electronic systems, par-
ticularly interfaced systems.
As per NIST SP 800-57P1, there are four basic flows of information:
data entry/collection, routes between each destination, during
processing, and storage points.
In each of the above primary data flows, the data integrity control's
objective is to prevent and detect any data integrity issues.
The prevention is performed during the design of the data handling
applications to ensure that data is stored, archived or disposed of
safely and securely during and after the retirement of the electron-
ic system.
The design of the data handling applications function(s) includes
the records identification and associated flow and the source of the
original records.
Any data integrity issue is detected through periodic reviews, ex-
ternal and internal audits, regulatory inspections, and the investi-
gation of incidents not intended by the electronic system.

NIST SP 800-57P1 Data Lifecycle ALCOA Key Expectation

(Basic data flows)
Sensor Data
Note: not considered data/re-
cord. It is considered transient
data or sensor data.
Data / records entry / collec-
tion29
16
Data generation and capture
(pre-recording)28
Data Capture (Data save (data
recording, preservation))
Accurate • The interface infrastructure
Complete between equipment and com-
Consistent puter should be qualified and
checked periodically to ensure
data/record accuracy and relia-
bility. (211.68(b))
• The accuracy and reliability of
the raw data depend not only on
properly calibrated instruments
and equipment but also on the
integrity of the raw data produ-
ced by the recording action.
• Sensor data captured by the
system should be stored in
memory in a format that is not
vulnerable to manipulation, loss
or change.
• Built-in checks (EU Annex 11
p5) verifying the data after the
transformation.
Attributable • Systems should be designed
Contemporaneously for the capture of data/records
Original accurately30 whether
Accurate acquired through the manual
Complete (EU Annex 11 p6) or automated
Consistent means (EU Annex 11 p5).
Enduring • Data/records should be reli-
Available ably recorded, documented,
or saved when generated.
Evidence after generated was
done.
• Critical data/records31
entered manually by an author-
ized person into the computer
system required input verifica-
tion to prevent incorrect data
entry (EU Annex 11 p 6).
Storage32 Maintain and use (Access, use, Attributable Access limitation of user’s
and reuse) Legible interactions with data and the
Contemporaneously handling system is established
Original by following a logical and
Accurate physical procedural control,
Complete including segregation of duties.
Consistent (EU Annex 11 p 12; Part 11.10(d)
Enduring and (g)).
Available
• Qualify repositories of records
for their intended use.
• Retain records in their original
format.
• User access controls shall
be configured and enforced to
exclude unauthorized access
and changes to and deletion of
data/records.

• Backup must be performed for

disaster recovery to data /
records, metadata and system
configuration settings on stor-
age. The backup copy must be
a true copy of the backed-up
records.
• Original data/records or a true
copy33 are subject to periodic
review by qualified personnel.
• Data/records should be trace-
able to the original data/records
by documenting changes to the
original data/records.
• Data / e-records should be
periodically checked for accessi-
bility, readability and integrity.
• Verification of data/records
retrievability is required to
modify the electronic system
application and/or infrastruc-
ture.
While in transit34 Maintain and use - Transmission Attributable • Qualify the infrastructure in
Contemporaneously which data/records are trans-
Original mitted.
Complete • Enable controls to ensure the
Consistent transmitted data/records have
remained unaltered during
transmission. (EU Annex 11 p5)
• Ensure that the source
system's data/records are GMP
controlled, including its reli-
ability.
• Data/records should be trace-
able to the original data/records
by documenting changes to the
original data/records.
Maintain and use - Migration • Validation of the migration
process includes verifications
that data/records are not
altered in value and/or meaning
during this migration process.
• Key expectations include
those listed on “While in
transit.”
Maintain and use - Archiving / • The data/records must be
Obsolescence retrievable in a timely way.
• Validation of the retrieving
/ loading Archiving process
includes verifications that data/
records are not altered in value
and/or meaning during this
migration process.
• Key expectations include
those listed on “While in
transit.”
Maintain and use - Retrieving/ • Qualify the infrastructure in
loading which data/records are trans-
mitted.
• Enable and qualify controls to
ensure the retrieved or loaded
have remained unaltered during 17
transmission. (EU Annex 11
p4.8)
• Ensure that the source
system's data/records are GMP
controlled, including its reli-
ability.
 Processing35 (Part 11.10(f)) Maintain and use - Use and • Validate systems perform-
reuse ing GMP functions for their
intended use, particularly data/
records operation, integration,
transformations [36], and man-
agement. Electronic systems
perform functions like archiv-
ing, audit trails, e-signatures,
operational checks, printouts/
reports, security, sequencing,
extraction, transformation,
loading, and so on.
Maintain and use - Migration See migration as part of data/
records on "While in transit."
Maintain and use - Archiving / See archiving as part of data/
Obsolescence records on “While in transit.”
Disposal (Data / records retire- • Tagged to discard and remove
ment37) from repository according to an
approved procedure.
• Must be performed an impact
analysis of the tagged data/
records documentation to
consider documentation retire-
ment.
• Where a data/record is
deleted before meeting its
approved retention schedule,
an audit trail of the deletion is
good practice until the end of
the approved retention period.
• A register shall be available to
record data/records retired.
Maintain and use (Data Presen- • The ability to generate ac-
tation (e.g., business intelli- curate and complete copies of
gence38)) records in human-readable and
electronic forms suitable for
inspection, review, and copying
by the agency. (Part 11.10(b));
EU Annex 11 p8)
Table 1 – Data flows, Data Lifecycle, ALCOA, and Key Expectations.

1 Data is defined as the contents of a record. It is the basic unit of information with a unique meaning and can be transmitted. (ISO/IEC 17025).
2
López, O., “A Computer Data Integrity Compliance Model”, Pharmaceutical Engineering, Vol. 35 No. 2, March/April 2015.
3
López, O., "Electronic Records Governance,” in Data Integrity in Pharmaceutical and Medical Devices Regulation Operations,” O. López, Eds. (Taylor & Francis Group, Boca Raton, FL, 1st ed., 2017), pp. 133-141.
4
NIST, “SP 800-57 Part 1 Rev. 5 - Recommendation for Key Management: Part 1 – General,” May 2020.
5 NARA, “Universal Electronic Records Management Requirements,” Version 2.03, June 2020.
6
CFDA, “Data Record and Management,” December 2020.
7
ALCOA - Attributable, Legible, Contemporaneous, Original. Accurate.
8
ALCOA+ – ALCOA and Complete, Consistent, Enduring, Available.
9 Data flow - A graphical representation of the "flow" of data through an information system. (PIC/S).
10
López, O., “A Computer Data Integrity Compliance Model”, Pharmaceutical Engineering, Vol. 35 No. 2, March/April 2015.
11
Record is defined as the collection of related data treated as a unit (ISPE/PDA, “Technical Report: Good Electronic Records Management (GERM),” July 2002)
12
Electronic system - Electronic system means systems, including hardware and software, that produce e-records.
13 GxP - The underlying international life science requirements such as those outlined in the US FD&C Act, US PHS Act, FDA regulations, EU Directives, Japanese MHL.W regulations, Australia TGA, or other applicable
national legislation or regulations under which a company operates. (GAMP Good Practice Guide, IT Infrastructure Control and Compliance, ISPE 2005)
14
Alteration of e-records includes the insertion, deletion, and substitution of data within the record.
15
López, O., “Maxims of Electronic Records Integrity,” Pharmaceutical Technology, May 2019.
16
CEFIC, “Practical risk-based guide for managing data integrity,” March 2019 (Version 1)
17 ECA, “GMP Data Governance and Data Integrity,” Section 9.3.15, Rev 2, January 2018.
18
MHRA, “MHRA GMP Data Integrity Definitions and Guidance for Industry”, March 2018.
19
Repository for e-records - A direct access device on which the electronic records and metadata are stored.
20
Center for Technology in Government University at Albany, SUNY, “Practical Tools for Electronic Records Management and Preservation,” July 1999.
21 Sensor (a.k.a. transient) data is the output of a device that detects and responds to some input from the physical environment.
22
GxP data - Data generated to satisfy a GxP regulation requirement.
23
CEFIC, “Practical risk-based guide for managing data integrity,” March 2019 (Version 1).
24
Data - The contents of the record are the basic unit of information that has a unique meaning and can be transmitted. (ISO/IEC 17025)
25 Original record - Data as the file or format in which it was initially generated, preserving the integrity (accuracy, completeness, content and meaning) of the record.
26
https://www.imperva.com/learn/data-security/data-lineage/
27
A data flow map is a way of representing a flow of data through a process or a system (usually an information system). The data flow map also provides information about the outputs and inputs of each entity and the
process itself.
28
Pre-recording – During the generation and transformation stage, the actions that involve sensor data collections are performed. The transformation includes those actions that scale and convert data to digital.
29
Data entry or collection. - The process of placing an object under records management control for disposition and access purposes (López, O., “A Computer Data Integrity Compliance Model,” Pharmaceutical Engineering
35, No 2 (March/April 2015); 79-87).
30
Data accuracy refers to whether the data values stored for an object are the correct values.
31 Critical Data - data with high risk to product quality or patient safety. (ISPE GAMP COP Annex 11 – Interpretation, July/August 2011).
32
Storage - Data storage is the recording (storing) information (Data) in a storage medium.
33
True copy - An exact copy of an original record, which may be retained in the same or different format in which it was initially generated, e.g., a paper copy of a paper record, an electronic scan of a paper record, or a
paper record of electronically generated data. (MHRA)
34
Data Transmission - Data transfer is transferring data between different data storage types, formats, or computer systems (MHRA, "GxP Data Integrity Guidance and Definitions," March 2018). This data flow requires
retrieving data from the source repository and loading the data to the recipient repository.

18
35 Data Processing – (1) A sequence of operations performed on data to extract, present, or obtain information in a defined format (López, O., “A Computer Data Integrity Compliance Model,” Pharmaceutical Engineering
35, No 2 (March/April 2015); 79-87). (2) All system transactions ad defined by MHRA (GxP Data Integrity Guidance and Definitions, Mar 2018), Section 6.12.
36
Data transformation - Processing data that can result in the creation of additional data. Data transformations are widespread in Big Data environments.
37
Data/records retirement - Company records/data meeting the approved retention time are tagged for physical deletion of the associated repository per approved procedure.
38
Business intelligence (BI) refers to the procedural and technical infrastructure that collects, stores, and analyzes the data produced by a company's activities. BI is a broad term that encompasses data mining, process
analysis, performance benchmarking, and descriptive analytics.
GMP for APIs
Live Online ICH Q7 Training Week - Interviews
At the end of 2021, the ICH Q7 Training Week was held as a live
online event and was once again supported by the representative
of the APIC Task Force "Third Party Manufacturing" Dr Jens Brillault.
For the first time, together with Francois Vandeweyer, who is one
of the well-known speakers of the ICH Q7 Training week, he has
committed to answer in an interview the most important questions
and topics in relation to the Compliance and Auditor courses of the
Training Week.
Both Compliance Courses “ICH Q7 Compliance for APIs Manufac-
tured by Chemical Synthesis" and "ICH Q7 Compliance for APIs
Manufactured by Cell Culture/Fermentation” had lectures to com-
pliance topics from the areas of chemical and biotechnological
manufacturing of active pharmaceutical ingredients (APIs) and in-
formed about the topics GMP and legal requirements of active phar-
maceutical ingredients. That is why the first questions, which was
raised in the interview, was named “What, in your opinion, are the
most crucial points when it comes to the implementation of ICH Q7?”. Dr
Jens Brillault and Francois Vandeweyer gave the following answers:
About the Author
Anne Günster joined CONCEPT HEIDELBERG in 2019 and organises and conducts courses and conferences on behalf of the ECA Academy in the areas
API Manufacturing, Regulatory Affairs, Documentation and Laboratory Data Integrity.
Brillault:
a) Initial establishing of a Quality management system (QMS)
according to ICH Q7: Guidelines only tell you what to do, not
how to do. How to do documents or Q&A documents issued by
authorities could help a lot. I assume that one can’t establish
such a system without support of experienced employees (e.g.
consultants).
b) Lifecycle of QMS: Every system has to be dynamic. Otherwise
it will be outdated soon. So it is important to improve and adopt
the QMS frequently to updated regulations or industry best
practice. Checking latest APIC documents or exchange with
other companies could help (e.g. in APIC Task forces). Also train-
ing/seminars are suitable to stay informed about changes and
updates.
Vandeweyer:
The right quality culture, supported by management, must be in
place. ICH Q7 requirements implementation will only be suc-
19
 cessful, if all departments and all employees support the quality
mind set.
Francois Vandeweyer
... worked for Johnson & Johnson in various positions
for many years and now operates as a freelance GMP
consultant.
In relation to the first question and the implementation of ICH Q7
we asked “What are the most common problems and mistakes when
implementing ICH Q7?”. The speakers answered as follows:
Vandeweyer:
ICH Q7 should be read as a whole. Meaning, if you read chapter
by chapter on its own and start implementation problems and
mistakes will occur. Important is to see and understand the re-
lationship between the chapters. Example: When implementing
the requirements of the chapter on “documentation”. This must
be reflected in all other chapters like Roles & Responsibilities,
validation, Facitlities, lab,…..
Brillault:
The implementation of a GMP QMS cannot only be manged by
the Quality Unit. Understanding and acceptance of GMP as-
pects/rules must be broadly distributed over the whole API site.
The principle of “Quality Culture” must be applied. This means
every department needs to understand its role in the overall
manufacturing process and everybody must understand and ac-
cept his contributing role to build a mature and well operating
QMS and finally to ensure patients safety.
API Regulatory Starting Materials
Live Online Training
9/10 February 2023
All relevant aspects regarding API regulatory
starting materials will be discussed
Learn more about this course:
www.gmp-compliance.org
As Francois Vandeweyer, who was formerly the representative of
the APIC Task Force "Third Party Manufacturing", is a speaker of the
ICH Q7 Training week for a long time, we additionally asked him to
answer the question “You have been part of the ICH Q7 Week for sev-
eral years now. How does the course, and its set-up, benefit the par-
ticipants?”.
20 Vandeweyer:
The combination of information on hot ICH topics by experi-
enced speakers and soft skills auditor training is a unique con-
cept. Related to the ICH topics the information presented dur-
ing the courses is focussed on “How to do it”, “How to implement
the ICH Q7” and “What to do”- rules. Related to the auditor
training the focus is here in soft auditing skills. How to deal with
difficult audit situations (talkative auditee – silent auditee – an-
gry auditee,…) trained in active role plays. It will become clear
that a good auditor must be a good listener and a good observ-
er.
Also this ICH Q7 Training Week, which was held on 22-26 Novem-
ber 2021, was yet again characterized by the questions and com-
ments of the participants, to which the speakers were always hap-
py to respond and suggest solutions. Additionally, to support the
implementation of the ICH Q7 requirements, all participants also
received the new edition of the "ICH Q7 Side-by-Side Comparison"
booklet, which compares the „ICH Q7 Guideline - GMP for Active
Pharmaceutical Ingredients" requirements with the "How to do"-
Document - Interpretation of ICH Q7 Guide and "Review form" of
APIC, by mail - even though we were not able to meet in person in
2021, we do not want to give up this long-held tradition and will
continue it.
Dr. Jens Brillault
... is Quality Director at CU Chemie Uetikon in Germa-
ny and actively involved in the work of the APIC task
forces.
As usual, the Compliance Courses were followed by the ICH Q7 Au-
ditor Training Course of the APIC Audit Program. Last year, the
course was characterized by the great participation and interactiv-
ity of the participants and speakers. During the two days of the
auditor course, not only surveys, presentations and Q&A sessions,
but also the execution, presentation and subsequent analysis of
role plays took a central position and shed light on the new daily
audit routine created by the corona pandemic - remotely and
onsite.
Dr Jens Brillault opened the course as APIC representative and
gave a detailed overview of the APIC Audit Program and the activi-
ties of the APIC working groups. The requirements and prerequi-
sites that APIC places on auditors were clearly listed and explained.
Francois Vandeweyer then presented specific audit situations and
showed how to prepare for them. Using surveys, he guided partici-
pants through each scenario and helped them develop solutions to
specific issues.
Due to the special situation created by the corona pandemic in
2020/2021 and the resulting changes in the pharmaceutical indus-
try, the topic of remote audits was of great importance throughout
the entire auditor training course and was examined again in detail
in the presentations. That’s why we’ve asked the speakers to re-
spond on the following question “What are the most important
things to keep in mind when conducting remote audits?”.
Brillault:
Schedule a preparation meeting and check IT systems and com-
municate documents, which should be available during the au-
dit. A splitting of the audit time on more than one day could be
useful (e.g. 2 days (each day 5 hours), instead of one day with 8
hours). This will allow the auditee to prepare requested docu-
ments (very relevant if there is paper based system in place).
 Vandeweyer:
Prepare, Prepare, Prepare!!! Preferably: 1-2 months before the
audit - Auditor and the site Quality Head should discuss the au-
dit and related documents (questionnaire, pre-audit documen-
tation, virtual tour of GMP areas, time-zone differences, use of
translators if applicable). 2-4 weeks before audit: Additional
documents/records if required and test communication tools
for virtual inspection rooms including back-up.
This feedback directly brought us to the next question named “In
your experience, what are the most common problems and mistakes
with remote audits?”, which was answered as follows:
Vandeweyer:
• Time is the biggest enemy of an auditor, even more for re-
mote audits than for on site audits.
• Take into account culture differences when having face
time meetings and potential time differences.
• Make sure you consider:
‑ the Lack of face-to-face interaction and inability to ob-
serve body language.
‑ Auditors are unable to observe facility and equipment
cleanliness and maintenance plus operating processes
without virtual tours.
‑ Small sites can only support one audit stream
‑ Technology and connectivity dependent, test upfront
Brillault:
• IT issues are not checked/ solved upfront.
• Unstable Internet connections.
• Details regarding site tour not clarified upfront (pictures,
video or live streaming?).
Brillault:
Start with a risk assessment for selection of sites/companies
where a remote audit makes sense at all. Start with a low prior-
ity supplier, so that you can gain experience and improve your
process/audit style before you carry one with critical audits.
Vandeweyer:
Avoid working with pre-recorded movies or pictures from the
facility. Better is to be prepared to be able to support virtual
tours. Test supportive systems and make sure a strong confi-
dentiality agreement is in place before sharing documents. Take
into consideration that screen shots can be made. The best is, if
possible, to share documents on a secure “server” – “cloud” de-
signed for this audit with strong access control.
The final Q&A session was followed by the final written exam for
some of the participants seeking for the APIC Audit Program certi-
fication, which traditionally marks the end of the ICH Q7 Training
Week.
Note: The ICH Q7 Training Week will again take place from Novem-
ber 21 - 25, 2022 in Heidelberg, Germany. This year's ICH Q7 Week
auditor course will again feature new aspects of remote and on-
site auditing - on the one hand through the speakers' presentations
and case studies, and on the other hand through the audit situa-
tions presented by the participants. Further information can be
found on the "ICH Q7 Week" website!

The final question was also related to remote audits. As this topic is
of high interest and still needs to be set up by many companies we
were interested to know “What advice would you give a company that
is only just starting to conduct their audits remotely?”. Dr Jens Brillault
and Francois Vandeweyer provided the following feedback:

ICH Q7 Training Courses 2022

ICH Q7 in modern API Manufacturing – what to do and how to do
21-25 November 2022, Heidelberg, Germany
www.ichq7-week.org

21

a sector group of
 Developments on GMP Classification
of Fiscal Imports
In February 2022, the long-awaited Annex 21 to Eudralex Vol. 4
was published. From its concept paper back in 2015 it took seven
years to finalize this relatively short annex. In fact, the potential
need for an Annex 21 was identified only during the development
of Annex 16 (issued in 2016) when the authors of said annex con-
cluded that not all topics around importation could be clarified. A
further delay of Annex 16 was avoided. Therefore, one dominant
and main driver for the existence of Annex 21 is the existence of
fiscal importation and whether such concepts of international
money transactions crossing outside boarders of the EU should be
handled according to GMP regulations or not. The issue was legally
complex. Annex 16 was cleared to be published in 2016, the solu-
tion on fiscal importation was expected to come with Annex 21. It
did not.
Hold on, we first need to understand the term fiscal importation. A
fiscal importation would happen, if a company performs invoicing
from outside EU territory to inside EU territory without a parallel
physical flow of goods. Recipient of the invoice would usually be an
EU affiliate of the same international company conglomerate than
the company issuing the invoice. Characteristics of such fiscal im-
22
About the Author
Dr Ulrich Kissel is Chairman of the European QP Association.
port is the decoupling of financial and physical flows of goods. A
physical import may or may not happen at a different time involv-
ing the same or different parties.
Why would companies do fiscal importations? Although other driv-
ers cannot be excluded, the main driver for such company behavior
is translocation of earnings from one country to another country.
The original value may be generated within EU or outside EU which
is not important for our discussion. The target is to benefit from
lower tax rates under such financial constructions. The set-up can
be executed in compliance to financial legal rules.
Back to Annex 21. In chapter 2.1 of Annex 21, we find the clear
statement that “fiscal transactions are not part of this annex”. ECA/
EQPA together with many industry associations have always ar-
gued during the development process of Annex 21 that fiscal trans-
actions should not become part of GMP rules. The parties even ar-
gued that this would be an overload and unfavourable mix-up of
technical regulations with fiscal regulations. Another place than
GMP rules in the legal system for such regulations should be found.
– An early conclusion of ECA/EQPA and other parties about the
sentence cited above therefore was that the comments have been
heard. Instead, this is not fully the correct conclusion.
The truth is more like not part of, not regulated. We today have to
conclude, that the statement within Annex 21 does only summa-
rize that no European harmonization has been achieved and na-
tional interpretation of the relationship of GMP and fiscal transac-
tions continue to apply. Annex 21 has not met one of its most
important goals to close this discussion on fiscal importation and
to provide an applicable rule for all member states. In consequence,
for many QPs in several member states this may result in the na-
tional expectation, that such fiscal transactions require a QP certi-
fication. EQPA currently has no overview in which member states
this applies. We hear more or less strict statements and enforce-
ments from several member states.
In the environment of GMP it is rare that cases are escalated to
courts and even higher courts have to provide us with court deci-
sions. For fiscal transactions money is in the play and the likelihood
for court decisions increases. In Germany the appropriate federal
court came now to a remarkable decision on a specific case of fiscal
importation. The established and followed set-up was found illegal
not on the basis of fiscal rules but on the basis of the national drug
law which brings us into the hemisphere of GMP.
It is worth to look at this court decision1. The court decision first
acknowledges how the supply chain was set up. A manufacturer
(MIAH holder) established in France under French law delivers
physically finished product to a Wholesale Authorization Holder
established in Germany under German law. The invoice for the
goods physically received from France is issued by another Whole-
sale Authorization Holder established in Switzerland under Swiss
law. The goods are paid for to Switzerland. All three entities belong
to the same larger organization and are affiliates to each other. The
company confirms that this financial set-up is maintained for tax
reasons.
The set-up constitutes a typical fiscal importation from Switzer-
land to Germany. The court takes reference to the following legal
documents:
I. directive 2001/83/EC art. 40 par. 3, art. 77 par. 1, art. 80 par. 1,
art. 85a, 85b par. 1 sub-par. 2
II. German drug law § 4 par. 22 and 32, §§ 52a, 52c, 69 par. 1
sentence 1, § 72 par. 1 sentence 1
III. German GDP ordinance § 1 sentence 1, § 4a par. 1
and comes to the verdict, that medicinal product Wholesale Au-
thorization Holders are only allowed to order (and pay for) prod-
ucts from establishments who hold the appropriate authorization
from another EU member state. A Swiss Wholesale Authorization
is not equivalent to such required EU Wholesale or Manufacturing
Authorization.
The applied logic is the following: Wholesalers fill their stock by
taking ownership. Ownership is independent from physical flows
and already taken over by paying for the invoice on such stock. The
1 ECLI:DE:BVerwG:2021:250221U3C1.20.0
financial transaction determines where the goods are coming from
in addition to the physical movement of the goods. In this meaning
the financial invoicing from outside EU – in this case Switzerland
– becomes import in such a way that a manufacturing and importa-
tion authorization is required.
The QP assumes the responsibility to certify any imported batch of
a drug product. This is defined in art. 51 par. 1b of directive 2001/83/
EG for imported batches and found fully applicable on fiscal im-
ports according to the court decision. We know from the develop-
ment of Annex 16 followed by the development of Annex 21 that
both documents do not necessarily define a concept how such QP
certification of a financial import would need to look like. Meaning-
fully, the court decision cites directive 2001/83/EC art. 51 par. 1b
that each imported batch needs to undergo the appropriate con-
trols including importation testing. The only escape here to argue
that such fiscal import would not automatically cause any new im-
portation testing is the wording of art. 51 par. 1b which does not
explicitly require a strict sequence of events such as the full testing
upon importation always should happen after importation.
The High Court of Germany decided not to involve the European
Court. The company has changed their procedures and stopped fis-
cal importation subject to the court case (verbal communication).
Conclusions
Up to today no GMP regulation covers fiscal importation. Annex 21
explicitly takes fiscal importation out of scope. EQPA argues since
many years, that politically or otherwise not favoured fiscal behav-
iours should not be healed by means of GMP rules. The QP should
not be held responsible for financial transactions and set-ups like
fiscal import. The cited court decision extracts from German law
but also directly from directive 2001/83/EC that already today fis-
cal import is one kind of import according to drug laws and requires
a MIAH. The QP of the MIAH has to ensure full applicability of art.
51 par. 1b of the directive and needs to take action on certification.
This court decision will surely be assessed by the European Com-
mission and other member states. It is applicable in Germany. We
are still waiting for an official and harmonized European approach
to fiscal import. One favoured solution would be, that cited articles
in directive 2001/83/EC will become modified in such a way that
the QP is not involved any more.
BERLIN, GERMANY & LIVE ONLINE
01- 02 December 2022
23
 GMP-compliant Equipment Design:
The GMP Equipment Design Guide
What does "GMP-compliant equipment design" mean? This ques-
tion comes up very often. Mostly, it is companies that have not yet
supplied equipment or facility parts to the pharmaceutical industry
that ask this question. But the question is also heard again and
again at seminars, in this case from representatives of the pharma-
ceutical companies themselves. And the issue is not limited to the
pharmaceutical industry alone. Transformed industries, such as
medical device, cosmetics or diagnostics manufacturing, also want
GMP-compliant equipment from their suppliers. Inquiries to this
effect often cause equipment manufacturers to shrug their shoul-
ders, because the requirements are overloaded, imprecise or sim-
ply not correct. But why is that? After all, authorities play an impor-
tant role in the pharmaceutical industry, from clinical studies to
the approval of a drug to GMP inspections. Why is there no regula-
tory authorization of GMP equipment? Why not a badge compara-
ble to the TÜV?
This is relatively easy to answer. There is no one equipment design
that can be compliant for pharmaceutical manufacturing facilities.
There are numerous pharmaceutical manufacturing processes,
from dry granulation and tableting to fermentation or sterile filling.
If you add manufacturing processes from chemical active ingredi-
24
About the Author
Dr Robert Eicher is Operations Director and organises and conducts courses and conferences on behalf of the ECA Academy around pharma tech-
nology.
ent production and the production of medical devices (from walk-
ing sticks to artificial heart valves), there are many more. And the
product itself can also place a wide variety of demands on the pro-
duction equipment. For example, it makes a big difference to the
design of a facility whether the product to be manufactured must
be sterile or non-sterile, or whether it is a high-potency product.
However, a product or an intermediate product may also be sensi-
tive to oxygen or moisture. This, of course, also affects the design
of the equipment. On rare occasions, however, requirements of au-
thorities in different countries may differ. For example, until re-
cently, the method of manufacturing WFI (water for injection) was
more heavily regulated in Europe than in the U.S. or Japan. In Eu-
rope, production was limited to distillation. A plant producing WFI
by reverse osmosis, for example, would thus not have been GMP-
compliant in Europe. In other countries, it is still not allowed today.
The design of a plant therefore depends, among other things, on
the intended use and the product to be manufactured. This knowl-
edge lies with the manufacturer of the product, not with an author-
ity. A "GMP authority" can therefore not take responsibility for the
design of the equipment or confirm it as GMP-compliant by means
of a "label" or certificate.
Let us return to the question: What is GMP-compliant equipment
design?
In principle, this vague requirement can be broken down to four
very obvious requirements for pharmaceutical manufacturing
equipment:
1. the equipment must not have a negative impact on product
quality
2. the equipment must be easy to clean
3. the equipment must comply with the applicable technical
regulations
4. the equipment must be suitable for its purpose.
These 4 points can also be found in different wording in numerous
guidelines of GMP-relevant authorities, but are still so unspecific
that they require further explanation.
What does "The system must not negatively influence the prod-
uct quality" mean?
This means that there must be no interaction between the surfaces
in contact with the product and the product itself that could nega-
tively affect its quality. Substances may not be released by the sys-
tem, nor may components of the product be adsorbed. Likewise,
no chemical reactions may take place on the surface. The equip-
ment must also not release any substances that could damage the
quality of the product; the key words here are lubricants, rust or
abrasion. The latter can probably never be 100% avoided, just as
material exchange between an internal surface and the product
will never be zero. The question here is rather what is tolerable
without negatively affecting the product quality. This depends both
on the type of material and thus the type of substances that can
leak out, and on the type of product.
What does "the equipment must be easy to clean" mean?
There are two objectives here. Firstly, surfaces (in most cases the
internal surfaces in contact with the product) should be smooth.
Cleaning the equipment by wiping or rinsing is much easier and
more effective with smooth surfaces than if the surface has grooves
or cracks. For one, bacteria can survive well in these grooves and
resist cleaning and even disinfection or sterilization, and product
residues can also remain in grooves and gradually pass into subse-
quent products. This is referred to as cross contamination. The pos-
sible survival or remaining of microorganisms in cracks or grooves
plays a role above all in the production of sterile pharmaceuticals.
The problem here is that microorganisms, unlike chemical contam-
inants, can multiply. A handful of bacteria has become many mil-
lions after half a day, which can mean microbial contamination of
the product manufactured in the facility. And even if no viable
germs end up in the product at the end of the day, it is their meta-
bolic products or cellular components that can cause major prob-
lems. A generally accepted value for surface roughness (the
smoothness) is 0.8 µm. Seal sites can also be problematic, i.e.,
small gaps between the seal and the sealing site.
Even more serious than surfaces that are too rough are places in
the system that are difficult to reach. Most systems are cleaned by
rinsing or automatically by means of CIP (Cleaning in Place) sys-
tems. So-called dead spaces are feared here, i.e. places in the sys-
tem that are not wetted by the cleaning medium (spray shadows)
or to which the cleaning medium cannot reach. In plant engineer-
ing, this is referred to as "dead legs". The flow through dead legs is
poorer, they are therefore more difficult to clean, and during ther-
mal sanitization it takes longer for these "branches" to also reach
the set temperature. Of course, larger quantities of a previous
product are more likely to remain in parts of the system that are
difficult to clean - keyword cross contamination, see above. This
risk is much higher in multipurpose systems than in so-called ded-
icated equipment, i.e. systems in which only one product is manu-
factured.
GMP-compliant Equipment Design
Live Online Training
16/17 November 2022
From Process & Product Requirements to
an appropriate Equipment Design
Learn more about this course:
www.gmp-compliance.org
What does "The equipment must comply with the applicable
technical regulations" mean?
Genuine, legally binding GMP regulations are very unspecific, espe-
cially when it comes to technical matters. For one thing, the au-
thors are usually not engineers, and for another, as already de-
scribed, the products manufactured and the equipment used are so
varied that generally applicable and at the same time concrete
specifications are almost impossible. Furthermore, the GMP speci-
fications would always have to be changed if technological innova-
tions were to occur. The following therefore applies: the equipment
must comply with the state of the art, the requirement of, for exam-
ple, good cleanability still applies, even if new cleaning agents,
cleaning processes or similar should become available. So the ques-
tion is, which technical rules have to be observed or where can one
read up on the current state of the art? Of course, this depends on
the type of equipment. In a few cases, the pharmacopoeias or
guidelines from GMP-relevant authorities with an advisory, i.e.
non-mandatory, character are helpful here. It is also always a good
idea to know the relevant ISO standards or (in Germany) VDI guide-
lines. Often, interest groups publish documents that contain fur-
ther information, e.g. the ECA, the ISPE, the PDA or the EHEDG. The
pharmaceutical industry also uses standards from the food indus-
try, especially when it comes to cleanability. It is important to know
that these rules are rarely binding. They are nevertheless very often
used, as this saves the need to prove that one's own chosen proce-
dure complies with the rules and leads to an equal or better result.
What does "The equipment must be suitable for its purpose" 25
mean?
This is one of the most important and yet least universally under-
stood specifications. It means that the product produced in the
 equipment meets all pre-determined quality requirements and
thus has the effect that the patient needs (and that has been previ-
ously proven in a clinical trial). The suitability of the equipment is
proven by the qualification of the equipment, which plays an im-
portant role in process validation. Again, qualification is product
specific. Equipment that is suitable (qualified) for product A does
not necessarily have to be equally suitable for product B. Through
re-qualification, this suitability must be shown again and again
regularly. The pharmaceutical company must prove through quali-
fication that the equipment is suitable for the intended purpose or
use. The pharmaceutical manufacturer does not have to carry out
the qualification themselves. Often the qualification is sold with
the equipment as a package. However, the pharmaceutical com-
pany remains responsible for this under pharmaceutical law. An
important part of the qualification as well as the recurring meas-
ures, which are to maintain the qualified condition of the system, is
the calibration. Here, too, the requirements are dictated by the de-
mands of the product. For a very temperature-sensitive product,
the temperature measurement must be much more accurate than
for a less sensitive product.
These four explanations now shed a little more light on the ques-
tion of what "GMP-compliant equipment design" is all about. But it
should be a little more concrete. This is where a new guidance
document has recently come to the rescue, with numerous tips and
interpretations of official requirements. The guidance was devel-
oped by a task force that included experts in pharmaceutical tech-
nology and engineering. The Task Force initially developed a docu-
ment in German and it was first published by CONCEPT
HEIDELBERG. Although the book "GMP Equipment Design Guide"
cannot show the requirements for all conceivable manufacturing
equipment or replace a technical study, it can be a guide through
the thicket of GMP equipment design, create understanding and
provide more detailed procedures for the respective individual
case or refer to further literature or sources.
The new document is divided into 13 chapters. In chapters 1-4, in
addition to an understanding of GMP-compliant system design, the
pharmaceutical principles of risk analysis and documented evi-
dence of a GMP-relevant issue are elaborated. Chapters 5 to 13
provide guidance on specific sub-aspects of equipment as they
may be used in the manufacture of pharmaceuticals.
Fundamentals of Visual Inspection
Best Practice for Manual and Automated Visual Inspection of Parenterals
26 Live Online Training on 15 February 2023
gmp-compliance.org
1. Introduction: what does GMP-compliant equipment design
mean?
2. Overview: general GMP rule works, standards, interest groups
and state of the art
3. Risk analysis: the key to pharma success?
4. Evidence: URS, FDS -> GMP design -> qualification
5. Material selection for hygiene critical areas
6. Surface requirements: surface quality grades and surface
treatments
7. Hygienic design - basic aspects
8. Piping and fittings; joints, welding & seam control
9. Process environment requirements: the clean room
10. Electrical, instrumentation and control (EI&C) in the GMP-
regulated environment
11. Requirements for automation and control systems
12. Documentation in the life cycle of GMP equipment
13. Quality assurance systems required by the equipment supplier
A brief explanation of some of the more detailed chapters follows
below.
"Hygiene-critical" in the heading of Chapter 7 refers to areas or
products for which there are microbiological requirements. This
applies to all pharmaceutical products; for sterile drugs, of course,
the hygiene risk is much greater than for solid drugs intended for
oral administration.
Two types of materials are widely used in pharmaceutical equip-
ment manufacturing: Polymers and stainless steels. As metallic
materials, stainless steels usually exhibit these basic properties.
For pharmaceutical applications, stainless steels with the material
designation 1.4301/AISI 304, 1.4401/AISI 316, 1.4404/AISI 316L or
1.4435/AISI 316L have become widely established. In principle,
metal surfaces in contact with the product may be modified by a
surface treatment or coating. However, the surface modification
used must also completely fulfill all the basic material properties
mentioned above. In other words, no substances may be absorbed
or released, no reactions may occur on the surfaces, etc.
Some guidelines contain more detailed information on material se-
lection. These help the user to specify the generally applicable ma-
terial requirements. One example is the EHEDG (European Hygien-
ic Engineering and Design Group), which has published various
guidelines on hygienic equipment design. The most important
overarching guide is Document 8. For example, for material selec-
tion for stainless steels, this document lists some background in-
formation such as the influence of pH, temperature and chloride
ion content on possible corrosion. For polymers, the document
lists possible polymers such as POM, perfluorinated polymers such
as PFA, FEP and ETFE, PVDF, PC, PEEK, PE-HD, PP, PVC, PSU, PPSU
and PESU. Common PTFE is critical due to its porosity, as this prop-
erty can result in insufficient cleanability depending on the applica-
tion. A selection of elastomers is also mentioned: EPDM, FKM,
FFKM, HNBR, NR, NBR and silicone rubber can be used in the food
industry.
However, the choice of materials for hygienic production areas is
not limited to the equipment. The surrounding area must also be
considered. Walls, ceilings and floors can become sources of con-
tamination if the wrong materials are selected. The EHEDH has
also published a document on this subject, and Chapter 9 is also
devoted to the cleanroom.
Since both the adsorption and desorption of substances and reac-
tions on the surface of the manufacturing equipment may occur,
the surfaces in contact with the processed product have a particu-
lar influence on its quality. For this reason, surface treatment pro-
cesses and surface qualities of metallic materials, as they are most-
ly used in pharmaceutical system engineering, have to be
considered in detail.
From a technical-scientific point of view, surfaces can be described
by three characteristics: topography, morphology and energy level.
In pharmaceutical and biotechnological plant engineering, the con-
sideration of selected togographic and morphological features has
become established. In this context, the ASME BPE and the DIN
standards for stainless steel components for aseptic applications
in the chemical and pharmaceutical industries are particularly wor-
thy of mention. Here, visual inspection with regard to geometric
irregularities (defects) and impurities, such as oil and grease resi-
dues, corrosion products and water spots, are mentioned, among
other things, as are key figures for surface roughness. The surface
profilometry method is the most widely used measurement meth-
od for determining surface roughness. In pharmaceutical equip-
ment manufacturing, an Ra value of ≤ 0.8 µm has become estab-
lished as a specification. However, there is little scientifically
proven data on the significance of the Ra value for the operating
behavior of a surface in contact with the product. However, experi-
ence from pharmaceutical and biotechnological equipment manu-
facturing since the early 1990s shows that surfaces with Ra values
in the range of 0.1-0.8 µm do not exhibit any measurable differ-
ences with regard to the risk of corrosion, the accumulation of mi-
croorganisms and cleanability, provided that the materials and
machining processes are the same. Various methods are available
for treating the surface: mechanical, chemical and electrochemical
processes, with which different surface finishes can be achieved.
According to the current state of the art, the minimum require-
ments are met by surface finishes H3 and H4 to DIN 11866 ff. and
SF1, SF2 and SF3 to ASME BPE. These surface grades are suitable
for surfaces in contact with processes and products. For higher re-
quirements on corrosion resistance, surface cleanliness and clean-
ability, the electropolished surface grades HE3 and HE4 to DIN
11866 ff. or SF4, SF5 and SF6 to ASME BPE should be used.
Another important aspect of equipment design is the connection of
system parts or systems to each other, i.e. the connection technol-
ogy, such as the welding of pipes. In addition to the actual connec-
tion, the geometry also plays a role here. For example, pipes must
be installed with a minimum gradient so that no stagnant liquids
can form in the pipe - the keyword here is residual drainability of
systems or system components.
Single-Use Disposables - What you
need to know
Live Online Training
14 February 2023
Overview on available Single-Use Technol-
ogy and how it can be implemented
Learn more about this course:
www.gmp-compliance.org
An old standard DIN EN729-1 (1994) contains the important state-
ment: "Quality cannot be tested into a product... Even the most
comprehensive and sophisticated non-destructive testing does
not improve the quality of a weld". Great attention is therefore paid
in pharmaceutical plant engineering to welding, or the quality of
welds. The most important method is tungsten inert gas (TIG)
welding. There is no European guideline or standard that would
fully meet the requirements of pharmaceutical & biotech plant en-
gineering. Therefore, the ASME-BPE is usually used. As early as
1997, this standard defined very useful and clear quality criteria for
welding work in such a way that they can be used on the construc-
tion site.
The quality of a weld seam is judged by the discoloration or tarnish
of the weld seam. Since the introduction of automatic welding ma-
chines with automatic residual oxygen measurement, defects no
longer occur. Further criteria are the through-welding, the uni-
formity of the seam width and height, the absence of cracks, pores,
inclusions or alignment errors.
Automatic orbital welding of stainless steel tubing is state of the
art in GMP equipment construction. Special cases are difficult,
such as when there is no space for the welding gun and the seam
has to be welded by hand. Here, particularly qualified and certified
personnel are required - although, unfortunately, there is no "offi-
cial training certificate" for this to date.
However, even if the quality is to be provided by the welding, the
inspection of the weld seams plays a major role. This is done by
means of endoscopy, which has become much easier and better in
the last 30 years due to the availability of endoscope equipment.
The scope of this inspection must be specified, such as 100% of the
manual welds and 10-30% of the orbital welds. 27
In addition to the permanent connection, the welding, there are
also detachable connections in GMP systems. These are essential-
ly: the dairy coupling, the clamp (or "tri-clamp"), the sterile connec-
 tion and other manufacturer-specific solutions. The so-called dairy
coupling is often found in the food industry. Due to the high viscos-
ity of many products, pipes there often have to be opened for
cleaning, which is very easy to do with a hook wrench.
The main disadvantage of the dairy coupling is the gap in the seal-
ing geometry. As a result, this connection is generally no longer
used in new pharmaceutical equipment. Only GMP systems which
are regularly disassembled for cleaning still use such components
in isolated cases. The most commonly used detachable connection
in the GMP area is the clamp according to DIN 32676 / ISO 2852. It
is also colloquially referred to as Tri-Clamp, but this is a protected
brand name of the company Tri-Clover, which sells these compo-
nents. In sterile technology, connections according to DIN 11864
are used ideally. These are free of dead spaces, but have the disad-
vantage that the highest processing accuracy is required in pipeline
construction.
Let's come back to the less specific requirements in official guide-
lines when it comes to equipment design. Even if the requirements
are brief, unspectacular and, as already mentioned, not very spe-
cific, in the GMP environment it is always necessary to prove com-
pliance with requirements or specifications, in other words, to
document them. The documentation serves as proof that some-
thing has really been done and for the traceability of actions that
have been carried out. After all, if errors or deviations have oc-
curred in production, the documentation is used for root cause
analysis, to evaluate the effects and to prevent errors in the future.
This also applies to the technical documentation of the rooms,
plants and equipment, starting with the planning documents and
ending with those documents that are required after completion
for the smooth operation of a facility.
The qualification documentation is extremely important, as it pro-
vides evidence that the facility is suitable for your (GMP) purpose.
This starts with the user requirements (URS / User Requirement
Specification) and continues via the supplier's design specification
(FDS) into the other documents of the various qualification phases
IQ, OQ and PQ.
28
www.pharma-congress.com
Important documents that arise in the context of a qualification
and are therefore subject to GMP are P&I diagrams, isometrics
with weld documentation and testing, lists of devices and ma-
chines with process engineering data, lists of measuring points,
cable diagrams, wiring diagrams and active circuit diagrams, func-
tional diagrams and floor plans.
The material certificates should also be mentioned here. These en-
sure that the equipment was built from the materials required by
the pharmaceutical manufacturer (as is well known, the material of
the facility must not have any negative product influence). If the
pharmaceutical manufacturer cannot carry out the material testing
or identification himself, this is where the material certificates
come into play. For metallic materials, these are the certificates
according to DIN EN 102004: Certificate 2.2 (non-specific test) and
3.1 (conformity of the material with the order, stating results of
specific test). As far as possible, a 3.1 certificate should be required,
as this is the only way to ensure traceability of the certificate to
each component. In the case of polymer components, this is often
not possible, so that certificates in which the manufacturer himself
confirms compliance with the requirements are generally accepted
here.
Material certificates for polymers that come into contact with
products and media (such as seals) are certificates of conformity
issued by manufacturers confirming that they have complied with
certain standard or regulatory requirements. In the case of poly-
mers and elastomers, these are in particular requirements originat-
ing from the food sector, i.e. guaranteeing suitability for foodstuffs.
As a rule, conformity means that the material is not toxic if swal-
lowed. Of course, such a certificate of conformity cannot guarantee
general compatibility with the product, process media, etc. Decla-
rations of conformity according to CFR 21 177.2600 Food (US FDA)
are well known here. For substances that could unintentionally get
into the product (e.g. lubricants), stricter requirements apply. The
classification according to USP (US Pharmacopoeia) should be
mentioned here, as well as DIN EN ISO 10993. Here, too, conform-
ity is confirmed by the manufacturer (supplier).
Questions and Answers about
Cleaning Validation - Part 1
In March 2022, ECA Academy conducted an online training on
cleaning validation - during which participants had many ques-
tions. Due to the large number of questions answered, we have
split this post. Below you can find the first part of the questions
answered by the speaker Robert G. Schwarz from FH Campus in
Vienna.
All answers reflect the opinion of the speaker and are based on his
experience.
1. Best practice documents: ISPE 'Guide to Cleaning Validation' is
not mentioned - why not? It seems to contain a lot of practical
and detailed advice.
It is also a recommendable best practice document.
2. Therapeutic macromolecules – “PDE limits may not be re-
quired”: You still must be sure that (almost) all these APIs are
degraded/de-natured and that they haven't found their way into
About the Author
Robert G. Schwarz is a lecturer at the FH Campus in Vienna. He has 20 years of practical experience in aseptic processing, contamination control
and cleanroom technology.
nooks and crannies?
Yes, I agree. Full contact time and submersion is a must to apply a
“degradation-strategy" for CV.
3. Do you suggest of using NOEL over NOAEL when determining
PDE value?
I suggest using NOEL, because a desired effect of product 1 with
patient A could be an adverse effect for patient B using product 2.
4. Regarding worst case parameters: 'Stickiness' or adhesive
force could also influence difficulty of cleaning?
In a multi-purpose scenario, we use the most toxic substance for
limit calculation but need to take into consideration cleanability of
the different products. I recommend performing lab scale studies
to determine the hardest to clean product.
29
 5. Would 'visual clean' be a prerequisite for e.g., sampling or is it
not considered at all anymore?
Yes, it is a prerequisite, although the limits of sampling methods
used for analytical acceptance criteria could be higher. “Visual
clean” is a general GMP-requirement.
6. Is a requirement of all piping being completely filled during CIP
compatible with the requirement of turbulent flow?
Yes, the flow condition and the media volume stream must assure
this. It should be part of the URS of the equipment and I recom-
mend measuring flow velocity in piping as an IPC because it is a
critical process parameter for cleaning.
7. When brushes are used Inspectors also challenge cleanliness
of the brushes. What is the recommendation?
I would recommend using single use brushes or single use wipes
instead of brushes. If possible, switch to an automated cleaning
process.
8. Is it necessary to perform tests for detergent residue after a
product batch, or is after e.g., a water-batch enough? Is it re-
quired to demonstrate a possible detergent-product interaction?
Yes, it is a requirement from Annex 15 of EU-GMP Guideline. I’d rec-
ommend having pre-rinse steps with tap water or PW and then us-
ing cleaning agents to avoid interaction with a major amount of
product residues.
9. After the first 3 cleaning validation runs, how often must we
revise the cleaning processes? Re-validation?
Risk based approach in VMP. This is also defined in cleaning valida-
tion report specific for the cleaning process, the equipment and the
products. Usually, shorter frequencies at the beginning of routine
cleaning (routine production) are advisable and elongen the fre-
quency data based.
10. Where can we find in the regulations that visual clean is not
enough anymore?
Annex 15 of EU-GMP Guideline states that it is as not enough as a
SOLE criterion. Visually clean should be done whenever possible
(at every cleaning run).
 
11. Would it make sense to perform risk assessment on cleaning
already during product development?
Yes, this makes perfect sense. Additionally, if I can perform lab
scale studies with product at that stage it would be highly. Further-
more, a first estimation in a log-step scale of the toxicity could be
performed when already having data available of comparable sub-
stances as part of legacy products.
30 12. Is it possible to cover manual cleaning only by risk assess-
ment, if it is only manually cleaned not product/ indirect product
contact equipment/ process aids?
Yes, from a regulatory point of view it is possible, because only di-
rect product contact surfaces are needed to undergo cleaning vali-
dation according to Annex 15 of EU- GMP Guideline. BUT I’d recom-
mend performing at least a risk evaluation for indirect product
contact parts for non-steriles and include indirect product contact
parts for aseptic processing in the cleaning validation.
13. Is the efficacy criteria also applicable to excipients?
Based on the fact that each excipients has its specific function (sta-
bilizer for pH or osmolarity, preservative , ...) this needs to be taken
into consideration in the risk assessment as well when focusing on
interaction with residues. For the efficacy of the cleaning process,
we need to consider that excipients could be the hardest to clean
substances in the product matrix that may especially accumulate
in cleaning processes within campaigns (batch-to-batch cleaning)
or when using dedicated equipment.
14. Purity: How can you set purity requirements for excipients?
I.e., Assay in Spec is only >85 %?
You need to know from the production process of the excipients
what the remaining 15 % are consisting of. Usually this is hard to
evaluate and therefore high purity is requested for excipients. Ad-
ditionally, it is depending on the process step.
15. Is there a legal definition for dedicated equipment meaning?
No, at least I didn’t find one even the term dedicated equipment is
widely used in regulatory documents.
16. 3 CV runs should not be used anymore, it should be deter-
mined by risk assessment. What points should be considered in
this RA when determining number of CV runs?
Risk basement with 3 runs initially and during first production runs
intense sampling to get data and based on this the frequency of
OCV is determined. Critical factors are the type of cleaning process
(manual, COP, WIP, CIP in ascending criticality), is it a cleaning pro-
cess for multi-purpose or dedicated equipment, which production
step(s9 is the equipment used for and how critical are the sub-
stances regarding cleanability and toxicity.
17. Visual clean is not enough for dedicated equipment, correct?
Annex 15 of EU-GMP Guideline states that it is as not enough as a
SOLE criterion. Visually clean should be done whenever possible
(at every cleaning run)
18. How do you validate chromatography equipment?
Part of last talk – life cycle validation. No direct sampling possible
in routine usage, so the number of cycles needs to be validated that
includes cleaning validation. OCV only rinse sampling.
19. How do you set limits for bioburden for medical devices?
I’d recommend performing a risk-based approach taking the clas-
sification of the medical device into consideration as well as a (if
applicable) subsequent sterilization process. This should also in-
clude endotoxins!
For IVDS the impact of any bioburden or toxin contamination needs
to be taken into consideration regarding its influence on the result
of the IVD-System and subsequent medical treatment of a patient
20. Is there any guideline for excipients available?
IPEC-PQG ´Good Manufacturing Practice Guide, (www.ipec-eu-
rope.org)
21. How do limits differ for medical devices and pharma?
Standard Guide for Validation Cleaning Process used during the
Manufacture of Medical Devices ASTM F3127-16, (www.astm.org)
22. Is riboflavin test acceptable for spray ball cleaning validation?
Any alternatives?
It is acceptable for the spray pattern test to show full surface cov-
erage in equipment OQ. To include the mechanical abrasion other
substances that enhance the “stickiness (PEG, gelatin, ...) could be
added for cleaning process development purposes. Any fluorescent
substance will serve the purpose of riboflavin but riboflavin is the
least human-toxic substance of the different substances (Na-fluo-
resceinate, Luciferine, …) that are, or better were, commonly used.
The Validation Manager in the
Pharmaceutical Industry
Heidelberg, Germany
29-31 March 2023
Overview of the cGMP requirements on the
whole range of validation/qualification
Learn more about this course:
www.gmp-compliance.org
23. For medical devices: How extensive do extractables and
leachables projects need to be? Required as a precursor to clean-
ing validation?
Mainly important for those medical device classes that get into the
patient and even more severe stay there longer. Besides that, ma-
jor topic is leachables from primary packaging material and after
that extractables during cleaning process. So it is an interaction.
For extractables I need a defined cleaning process and for the ma-
terials that potentially release extractables I need to consider this
for cleanability.
24. Considerations for COP in washrooms and washers?
COP in washrooms are manual cleaning processes that are hard to
validate. Low robustness and high variability demand extensive
safety margins for validation cycles, usually for the CPP “time” or
skipping the CPP “mechanics”. For washers it is important to have
distinct loading patterns and to verify that no segregation require-
ments are violated when using a COP process including equipment
from different processes with different product residues. Some-
times even a change-over cleaning with an empty chamber clean-
ing run is necessary to fulfill these requirements.
25. In case pipes are only blown out with nitrogen. How can you
take a rinse sample? Do you have experience on that?
Usually, it is taken at the final rinse step prior the drying with nitro-
gen. If it is only blown out with nitrogen and no “liquid” cleaning is
performed it is possible to perform a solvent rinse with an ade-
quate solution where the residues are highly soluble.
26. Swab solvent includes phosphoric acid due to recovery rate,
is a special cleaning step necessary?
I’d recommend a rinse step with PW or WFI and measuring the
conductivity as an IPC.
27. Some references are against the use of templates as there
may be accumulation of contaminant under the template or the
template itself may contaminate. What is your opinion?
I totally agree and would avoid it wherever possible. It is better to
train the sampling operators to perform a worst-case sampling and
sample AT LEAST XXXcm².
28. In addition to determining the recovery rate on the sampled
surfaces (coupons), should there also be an individual determi-
nation of the recovery rate for those performing the swab sam-
pling (how "well" is the swab sampling performed)?
I’d recommend to set-up a minimum required recovery rate (e.g.,
75%) to be achieved by every sampling operator to be qualified but
no individual recovery rates (could lead to calculation errors and
deviations). This also reflects a worst-case concept
29. Could You pls tell best practice to sample CHT (MiBi sam-
pling) of a conventional GL API reactor?
Based on my experience I’d recommend performing final rinse and
contact plate sampling over MiBi-swab sampling due to usually
higher recovery rates for those sampling methods.
30. How do you determine recovery rate for swabbing?
A recovery study determines the amount in percentage of a residue
that was initially on the equipment that can be detected with an
adequate sampling and analytical method. For detailed description
see also:
https://www.pharmtech.com/view/best-practices-cleaning-vali-
dation-swab-recovery-studies
https://www.researchgate.net/publication/318106664_On_
Cleaning_Validation_Recovery_Studies_Common_Misconceptions
31. Would you perform a recovery study using drug product or
just the API, if you are working with e.g. capsule filling equip-
ment? 31
I would use drug product because it represents the residues on the
surface after cleaning better. Excipients could influence the recov-
ery rate due to effects making the abrasion of the residues harder
 during swabbing which leads to a lower recovery. I’d always recom-
mend sticking as close as possible to the “real process” when per-
forming lab studies. This of course needs to be addressed in a risk
assessment.
32. Why is it necessary to have the recovery rate before the anal-
ysis? Isn't it possible to adapt the result later?
If the recovery isn’t determined as part of the “sampling procedure
validation” which is part of the analytical method validation it
could lead to are-validation of the analytical method based on the
adoption of the sampling or even the analytic method itself. It is
part of the system suitability test. of analytical method develop-
ment.
33. If swab sampling and rinse sampling should be performed,
which should be done first?
Usually when performing a final rinse sampling it is done first be-
cause the swab sampling interferes with the surface.
If solvent rinse would interfere with the analysis of the swab, which
is really rarely the case it can be switched supported by a risk as-
sessment evaluating the impact of the swab sampling onto the sol-
vent rinse.
34. What are best practices to sample hoses and production
equipment brushes, especially for microbiology?
I’d use those, whenever possible, as single use. Alternatively, a
rinse sampling can be performed for the hoses and for the brushes
submerging them in a container and taking the media sample out
of the container could be an option.
35. How do you set acceptance limits for detergents for TOC?
According to EMA “Shared facilities” Guideline long term toxicity
data are only needed for product components. So for detergents
we can use the LD50-value of the MSDS.
36. For detergent residue validation, is it necessary to perform an
extra swab or rinse sampling, or is it sufficient to rely on the con-
ductivity meter?
Analytical Methods for Cleaning Validation
32 Live Online Training on 31 May - 2 June 2023
gmp-compliance.org
If the correspondence of concentration and conductivity is very
high and could be shown with data this could work. I’d recommend
drawing final rinse samples for conductivity because usually, based
on my experience, you don’t get exact results based on equipment
design during an online-measurement compared to an offline-
analysis. Alternatively, pH-measurement is a more robust process
and could be used, if good correlation from pH to concentration of
the detergent could be shown, cold be used as an IPC online solely.
37. If MACO calculation supported by efficacy data allows very
high substance carry-over, would it be sufficient to support visu-
al check with residue on evaporation data in order to verify
cleanliness?
Only for OCV not for CV itself. But this is basically to fulfill regula-
tory requirements. I ‘d also recommend using analytic methods om
a significant lower frequency than checking visual cleanliness in
combination with a solid qualification strategy for operators per-
forming visual clean checks. Some companies also implement a
4-eyes-check with two operators to mitigate the risk of a subcon-
scious bias leading to false compliant results.
38. Is toxicological evaluation required when changeover from
one product to another in API production is practically biologi-
cally the same API family?
The fact that it is “practically biologically the same” needs to be
evaluated in the toxicological assessment or at least in an risk as-
sessment during clinical trial phase where this fact is even more (or
at least earlier) important than for CV. Better alternative is a deg-
radation-strategy avoiding HBELs.
39. What is you suggested changeover procedure during the
product change-over –additional cleaning, testing?
Not necessarily if you have validated the campaign length properly
but usually cleaning between batches and cleaning between prod-
ucts are two different cleaning processes with different scopes.
You will find the second part of this article in the next issue of the GMP
Journal.
Questions and Answers to Cloud
Computing in a GxP Environment
The trend in the pharmaceutical industry is also moving towards
cloud computing. Financial but also organizational advantages
speak for the cloud. At the same time, however, potential dangers
and regulatory restrictions should also be taken into account. Nine
experts from the pharmaceutical industry and regulatory authori-
ties answer a comprehensive catalog of questions from the follow-
ing GxP-relevant topics:
• Basics of Cloud Computing Technology
• Regulations and Expectations of Inspectors
• Customer-Supplier-Relationship
• Requirements for Cloud Service Providers (CSP)
• Requirements for Supplier Evaluation and Supplier Audits
• Requirements for Qualifcation / Validation
The experts:
Frank Behnisch, CSL Behring GmbH, Marburg
Klaus Feuerhelm, formerly Local GMP Inspectorate /Regierungsprä-
sidium Tübingen
About the Author
Dr Andreas Mangel organises and conducts courses and conferences for the ECA Academy in the areas sterile production and computer validation.
Oliver Herrmann, Q-FINITY Quality Management, Dillingen
Eberhard Kwiatkowski, PharmAdvantageIT GmbH, Neuschoo
Stefan Münch, Körber Pharma Consulting, Karlsruhe
Yves Samson, Kereon AG, Basel
Dr. Wolfgang Schumacher, formerly F. Hoffmann-La Roche AG, Basel
Dr. Arno Terhechte, Local GMP Inspectorate / Bezirksregierung
Münster
Sieghard Wagner, Chemgineering Germany GmbH, Stuttgart
1. Basics of Cloud Computing Technology
What’s the meaning of IaaS / PaaS / SaaS / XaaS?
IaaS, PaaS, and SaaS are abbreviations and different grades (or ser-
vice models) of various cloud service provider (CSP) offerings.
“aaS” always stands for “as a Service”. In XaaS, the X is a place-
holder for either I, P, or S, meaning Infrastructure, Platform, or
Software. Sometimes, XaaS is also called “Anything as a Service” or
“Everything as a Service” and can take very specific characteristics
like “High Performance Computing as a Service (HPCaaS)” or “Arti-
33
 Table 1: Cloud Services – Service Models and Responsibilities
ficial Intelligence as a Service (AIaaS)”.
CSPs offer various services and benefits depending on the basic
service model, and the tasks to be executed may shift accordingly
(see Table 1):
• For computerized systems or applications that are being oper-
ated traditionally on premise, the regulated company (or its IT
department or IT service provider, if outsourced), is responsi-
ble for all tasks related to computerized system validation
(CSV).
• IaaS: If the infrastructure is provided and managed by the CSP,
the model is called IaaS. Here, the tasks and responsibilities of
the regulated company start with the installation of the oper-
ating system.
• PaaS: At the next level, the CSP takes over installation and op-
eration of both, infrastructure and operating system. The reg-
ulated company steps in with the configuration of the runtime
environment.
• SaaS: For this model, the CSP provides and operates the con-
figuration of the runtime environment and the application on
top of infrastructure and operating system.
In other words, the activities shift from user (regulated company as
client) to cloud service provider (supplier). However, the responsi-
bility for validation and operation of the application and all related
topics like data integrity, data privacy, data security etc. remains
with the regulated company.
2. Basics of Cloud Computing Technology
What cloud models are there and where do they apply in the GxP envi-
ronment?
34
Basically, the classification of cloud models is not uniformly regu-
lated. A so-called "Deployment Model" has been formulated by
NIST (National Institute of Standards and Technology), which de-
scribes a widely used classification1:
• Private Cloud
In a private cloud, the cloud infrastructure is operated for one
organization only. It can be organized and managed by the
organization itself or by a third party and can be located in
the data center of the organization itself or in the premises of
third parties.
• Public Cloud
We speak of a public cloud if the services can be used by the
general public or a large group, such as an entire industry sec-
tor; these services are provided by the respective cloud ser-
vice provider in its facilities/data centers.
• Community Cloud
In a community cloud, the cloud infrastructure is shared by
several institutions that have similar interests (e.g., regarding
security, compliance). Such a cloud can be operated by one of
these institutions or a third party.
• Hybrid Cloud
If several cloud infrastructures, which are independent of each
other, are shared via standardized interfaces, this is called a
hybrid cloud.
While in a private cloud, where provider and user are usually identi-
cal, the user has complete control over the services used, in a pub-
lic cloud the user transfers control to the cloud service provider.
However, the definitions above do not cover all variants of cloud
services, leading to further definitions such as "virtual private
cloud", etc. Another common distinction of cloud models is the clas-
sification by "Service Models" (SaaS, PaaS, IaaS) - see question 1.
Basically, all "Deployment Models" or "Service Models" are also
used in the GxP-regulated industry. Here, the selection of the cloud
model is primarily based on the criticality of the GxP process sup-
ported by the cloud service and the data processed in the process.
For example, tools to support the training process, so-called Learn-
ing Management Systems (LMS), are often licensed as public cloud.
In contrast, very critical applications, such as the management of
trial master files, are at most operated as a community cloud ser-
vice.
Regardless of the criticality of processes and data, the particular
characteristics of the supported process support the use of com-
munity or private cloud offerings: The more specialized a process is
- e.g., maintaining a trail master file - the smaller and more special-
ized the group of potential subscribers becomes.
3. Basics of Cloud Computing Technology
What are the reasons for choosing a particular cloud model (private
cloud, community cloud, public cloud)?
In addition to commercial reasons, which will not be discussed fur-
ther here in the context of GxP-regulated applications, practical
reasons often play a role in the choice of a cloud model. In particu-
lar, smaller companies with correspondingly limited IT resources
tend to use a cloud service which they would not be able to provide
with their own resources. This may be because they do not have
the personnel resources to offer all the topics required, or because
they simply do not have the necessary expertise (process-related,
technical, data security).
In the GCP area, the special conditions prevailing there also pro-
mote the use of cloud services for very practical reasons: Clinical
trials are shared with many parties (hospitals, physicians, CMOs,
sponsors), usually worldwide. In addition, the composition of the
parties involved is not a fixed group, but is subject to change. Cloud
services, with their universal accessibility via the Internet, support
this way of working and are designed for 24x7 operation due to
their international orientation.
Another factor to be considered, especially when choosing cloud
services, is the security requirements of the GxP process supported
by the system. In Annex 11, the pharmaceutical company is explic-
itly requested to align the required security measures with the
risk2. This may mean that particularly sensitive data should often
not be processed in a public cloud for reasons of GxP data integrity.
A decision of this kind requires the cooperation of all specialist dis-
ciplines (IT, Process Owner, QA) in order to achieve a well-consid-
ered, technically justified risk assessment. This requires in-depth IT
expertise in particular, since the topic of "data security" can be very
Cloud Computing in a GxP Environment
Challenges and Solutions
Live Online Training on 22-24 February 2023
gmp-compliance.org
complex (nesting of cloud services, redundancies across multiple
data centers, authentication providers used, ...) and is subject to
permanent change.
If the business process to be supported by a computer-based sys-
tem places high demands on the availability of data and functions,
this can have a direct influence on the suitability of cloud-based
services:
- Be it that the additional dependency on an internet connection
alone argues for an 'on premise' implementation that is accessible
via LAN;
- While the highly-redundant design across multiple regions as
well as the ease of horizontal scalability can be crucial for the use
of a cloud service, as opposed to an installation on the local net-
work.
Especially in the GCP area, data protection requirements (e.g., for
personal data in clinical trials) play an essential role. Data protec-
tion thus determines whether the desired cloud service is even
considered and, if so, in which country the data centers used must
be located.
Even if this is not based on GxP requirements, high demands on the
confidentiality of sensitive data (e.g., data from clinical research or
product development) can also determine whether a cloud service
is even considered or with what restrictions.
4. Basics of Cloud Computing Technology
Are SaaS closed systems per 21 CFR Part 11?
Well, it depends …
The terms SaaS and “Closed System” are not related, i.e. one does
neither imply nor exclude the other. First and foremost, SaaS is a
service model for providing a software application in the cloud (i.e.
via internet) by a cloud service provider (CSP). This requires data to
be transferred at least temporarily to the cloud and to store and
process data in the cloud, typically permanently.
On the other hand, the definitions of “open” and “closed” systems
do not refer to the way data or applications are provided, but de-
fine the expected level of control. This control of data and applica-
tions is primarily realized by operational and technical measures
related to access protection, user identity and rights management,
35
 and encryption. Thus, the level of control is not independent of
SaaS, but represents a different dimension.
In §11.3(b)(4), 21 CFR part 11 defines a closed system as “an environ-
ment in which system access is controlled by persons who are re-
sponsible for the content of electronic records that are on the sys-
tem”. Contrastingly, §11.3(b)(9) defines an open system as a system
that lacks this control. Consequently, resulting measures for vali-
dation, data privacy etc. differ significantly for closed and open sys-
tems and are being defined in detail in paragraphs §11.10 and
§11.30, respectively.
Hence, an application provided per SaaS may be an open system,
but will usually be operated as a closed system, particularly if criti-
cal, sensitive, or trustworthy data (generally: data worth to be pro-
tected) are being processed.
5. Regulatory Basis and Expectations of Inspec-
tors
The AMWHV (Arzneimittel- und Wirkstoff-Herstellungs-Verordnung)
requires that all data according to the manufacturer's authorization
reside on the premises. Is then a cloud solution possible at all?
The EFG (Expert Working Group) 11 has interpreted the legal basis
for this question as part of a vote on the "Requirements for the
storage of electronic data".
Section 20 of the AMWHV stipulates that documents must be
stored "in a suitable area of the premises covered by the permit
pursuant to Section 13, Section 72 or Section 72c (4) of the German
Medicines Act."
The trend toward digitization and the replacement of paper-based
documentation with electronic records (e-records) is steadily in-
creasing in the pharmaceutical environment. At the same time,
computerized systems are being introduced globally by multina-
tional corporations as client/server solutions. This concerns Enter-
prise Resource Planning (ERP) systems, Manufacturing Execution
Systems (MES), Laboratory Information and Management Systems
(LIMS), but also systems for change, CAPA and training manage-
ment. In recent years, there has been a massive trend to outsource
some or all of the IT and computer-based systems to third parties
in favor of various cloud service models: Infrastructure as a Service
(IAAS), Platform as a Service (PAAS), and Software as a Service
(SAAS), with the latter becoming more prevalent as a service mod-
el.
In the case of electronic documentation, the requirement to store
e-records/documents in rooms covered by the permit pursuant to
Section 13, Section 72 or Section 72c (4) of the German Medicines
Act is met if at least one terminal (e.g. terminal or PC plus printer)
is available in the rooms covered by the permit, so that access to
the entirety of the data and metadata is possible, readable print-
outs and copies on data carriers can be generated. Likewise, the
36 1 The NIST Definition of Cloud Computing, Special Publication 800-145, Sept. 2011
2 EU GMP Annex 11 [12.2]: The extent of security controls depends on the criticality of the computerised system.
requirements for qualification of the IT infrastructure (IAAS, PAAS),
validation of the application (SAAS) and ensuring availability, read-
ability and integrity must be fulfilled by an (internal or external)
service provider.
Computerised System Validation:
Introduction to Risk Management
AND the GAMP 5 Approach
Live Online Training
22-25 November 2022
Learn more about this course:
www.gmp-compliance.org
6. Requirements for the Cloud Service Provider
(CSP).
Are common certifications (e.g., 27000ff) reliable evidence that a cloud
service provider is suitable, or what requirements must a certification
fulfill in order for it to play a role in the suitability of a CSP?
The fact that suppliers and service providers must have a quality
assurance system is derived from EU-GMP Annex 11:
3.4 Quality system and audit information concerning suppliers or de-
velopers of software and systems used should be made available to in-
spectors upon request.
What kind of quality system it should be cannot be determined
from Annex 11. However, EFG 11 comments on this issue in their
Votum V1100202 "Requirements for the retention of electronic
data". It states:
In the following, requirements for the quality of the CSP and data integ-
rity (for data in motion and at rest) are formulated, which are not ex-
plicitly found in the EU GMP Guideline in this way, but are considered
reasonable from the point of view of EFG 11:
- CSPs that process confidential data or data with high availability re-
quirements under their responsibility must have a certified ISMS (e.g.,
according to DIN 27001).
Whether this can be enforced from a legal perspective, however,
remains to be seen.
NEWS FROM OUR ASSOCIATION
www.eca-foundation.org

A paper for the EMA GMP/GDP IWG on Qualified Persons (art. 48 of
Directive 2001/83/EC) Practical Experience Requirements was
prepared by the EQPA/ECA (lead) and EFPIA. During the meeting of
the GMP/GDP IWG meeting with Interested Parties, on 10 March
2022, the lack of harmonisation in the interpretation and transpo-
sition of the practical experience requirements for Qualified Per-
sons (QPs) laid down in EU legislation was presented. A proposal
was therefore made to harmonise approaches, for example through
guidelines. The Commission’s representative at the meeting invited
the Interested Parties to submit a proposal directly to the Commis-
sion in the context of the ongoing revision of the EU general phar-
maceuticals legislation. EQPA, together with ECA Foundation (ECA)
and EFPIA wrote a problem statement with a detailed proposal and
rationale.
www.qp-association.eu
Validation Group
ƒ The Board set up a meeting on-site for mid of November 2022.
ƒ The sub-groups have started to update their chapters of the
Group's Good Practice Guide Integrated Qualification and Val-
idation Guide. The sub-group covering electronic documenta-
tion received a big interest. This group had exchanged their
results with ECA´s Data Integrity and IT Compliance Group. Its
head, Dr. Wolfgang Schumacher, has reviewed the electronic
documentation chapter. The development of a version 2.2 of
the Integrated Qualification and Validation Guide is in pro-
gress and will be published at the Qualification and Validation
Forum mid of November 2022 in Heidelberg, Germany.
ƒ In addition to courses on Process Validation, Cleaning Valida-
tion, Process Understanding and on Ongoing/Continued Pro-
cess Verification online and on-site, the Qualification and Val-
idation Forum end of Nov replaces the Launch Conferences.
• A report with actions was finalised and circulated among the
members. Moreover, the GDPA business plan was updated,
the objective was reformulated.
• Markus Funk has prepared an article on “Common and Typical
GDP Violations – an Evaluation of GDP Non-Compliance Re-
ports since 2014” for the GMP Journal.
• The second GMP & GDP Forum is planned to take place in
2023. The group started to plan the content and discussed
ideas. Possible external speakers were contacted/invited.
www.good-distribution-practice-group.org
Pharmaceutical Microbiology Group
• A board meeting has been scheduled to take place at the end
of November at PharmaLab 2022.
• The draft of the chapter on Identification of the Deviation
Guide has been reviewed – and the authors are working on the
analysis of the comments.
www.pharmaceutical-microbiology.org
ATMP Group
• The board of the Group invited Dr Ulrike Herbrand to join as
Bioassay Expert.
• A board meeting has been scheduled for mid of October.
• At PharmaLab 2022 a two-days track with ATMP Topics has
been scheduled. Further, for first time an ATMP Track is
planned to take place at the 25th PharmaCongress in March
2023.
www.atmp-group.org

www.validation-group.org Data Integrity & IT Compliance Group

• Version 3 of the DI guide is ready and will be published after a
revision of the references.
European GDP Association
• Afshin Hosseiny, who has been the European GDP Associa- www.it-compliance-group.org
tion's Advisory Board Chairman since its foundation, has de-
cided to step down from this position. For this reason, Alfred
Hunt joined as the Deputy Chair in 2021. After a year of the
two working together, Alfred Hunt has taken over the role as
the Chairman in June 2022. Afshin Hosseiny left the Board, but
as he is also Chairman of the ECA Executive Board, he will con-
tinue to support the activities of the European GDP Associa-
tion.
• Further, Prabjeet Dulai has resigned from her position of Di-
rector of Regulatory Affairs and Communication and left the
GDPA Board. She has also withdrawn from the ECA speakers'
panel. 37
• The annual board meeting took place mid of June 2022. Like in
the year before, the meeting was held online. The next board
meeting is scheduled to take place in June 2023.
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 11, November 2018)

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