Without measurement there is no control

Validation and Qualification Approach Outlined in

New Annex 1 Revision

Introduction
In August 2022, a new EU GMP Volume 4 Annex 1 revision was issued, proposing new regulations for sterile
drug products and production. This 2022 release replaces the most recent draft from 2020 and the existing
2008 revision. The updated revision further emphasizes validation and qualification topics. In the new, longer
Annex 1, (composed of 59 pages instead of the 16 of the previous version) better detail about specific needs
and requirements for premises, equipment, utilities, and personnel are described to provide guidance for the
manufacturing of sterile products. Some of the principles and guidance, such as contamination control strategy,
design of premises, cleanroom classification, qualification, validation, monitoring, and personnel gowning,
may be used to support the manufacturing of other products that are not intended to be sterile; the control and
reduction of microbial, particulate, and endotoxin/pyrogen contamination is considered important in these non-
sterile applications[1].
Outside of the Annex 1 document, Part 1 Chapter 3 of the Eudralex Volume 4 provides the basic requirements
and characteristics of equipment and premises to avoid cross-contamination, build-up of dust or dirt,
and, in general, any adverse effect on the quality of products; however, in the initial part of the new Annex 1,
facilities, equipment, and processes are included as part of the process life-cycle. Product and process should
be appropriately designed, qualified, validated, and, where applicable, subjected to ongoing verification
according to the relevant sections of the Good Manufacturing Practices (GMP) guidelines. This is the first special
requirement in the Annex 1 regulations to be considered in minimizing risks of microbial, particulate, and
endotoxin/pyrogen contamination. Each pharmaceutical process, system, utility, or equipment is designed
and built for a purpose, and the respective validation or qualification demonstrates the implementation and
adherence to that intended purpose and use via a series of evidence.
Validation and qualification have a central role in the identification of potential critical quality attributes
(CQAs) of the drug product. Product characteristics that have an impact on product quality can be studied and
controlled and included in the definition of a control strategy [2].
Processes, equipment, facilities, and manufacturing activities should be See the Risk Assessment as a
managed in accordance with quality risk management (QRM) principles Process Quality Assurance Tool by
for all steps after and including the design stage, and manufacturers must PMS for more details about risk
management!
understand their processes and control their variability.
.

But what are validation and qualification?

Talking about validation and qualification, it’s easy to get confused. They are usually used interchangeably, but
it is more correct to think about the word “validation” as one that can be broadened to include the concept of
qualification.

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 Validation and Qualification Approach Outlined in New Annex 1 Revision

In accordance with the principles of the GMP (Good Manufacturing Practices), both validation and qualification are
actions to demonstrate that the expected results are achieved, but there is some difference between the two.
Without intending to provide a definition, we can say that validation ensures that any procedure, process,
equipment, material, activity, or system leads to the expected results, and qualification is the action of providing
the demonstration that equipment works correctly.
Validation is a critical concept in the pharmaceutical manufacturing industry, and there are varying definitions
within the field. One of them is provided by Agalloco: Validation is a defined program, which in combination with
routine production methods and quality control techniques, provides documented assurance that a system is
performing as intended and/or that a product conforms to its predetermined specifications. When practiced in a
life-cycle model, it incorporates design, development, evaluation, operation and maintenance considerations to
provide both operating benefits and regulatory compliance [3].
Based on this definition, there are some key quality attributes to consider when talking about validation, including
documented evidence (data integrity) and consistency in terms of reproducibility and design (pre-determined,
planned, and performed by trained personnel).
Validation is a concept that can be associated with processes. Validation covers the initial validation of new
processes (regulatory submission), but as required by GMP, validation can also be associated with the rest of the
life-cycle of a process. This could include considering subsequent validation of modified processes, site transfers,
and/or ongoing process verification. This approach should be applied to link product and process developments;
it will ensure validation of the commercial manufacturing process and maintenance of the process in a controlled
state during routine commercial production.
To run validation, the critical process parameters (CPP), critical quality attributes (CQA), and their associated
acceptance criteria should be established. These critical process characteristics should be based on development
data or documented process knowledge.
Process validation may be developed using several approaches:

• concurrent approach
• traditional approach
• continuous verification approach

• hybrid approach

Irrespective of the approach used, processes must be shown to be robust and must ensure consistent product
quality before any product is released to the market. Process validation should establish whether all quality
attributes and process parameters that are considered important for ensuring the validated state and acceptable
product quality can be consistently met by the process. The basis by which process parameters and quality
attributes are identified as being critical or non-critical should be clearly documented and should consider the
results of any risk assessment activities.
As proposed by EU GMP Volume 4 Annex 15, validation should be well planned (protocol and report needed) and
key elements of the site qualification and validation program (e.g., validation approach: traditional, concurrent,
continuous verification) should be clearly defined and documented in a validation master plan (VMP) or
equivalent document [4].

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 Validation and Qualification Approach Outlined in New Annex 1 Revision

Qualification is a similarly phasic and documented

process. Qualification activities should consider all stages
of the process life-cycle from initial development and
the specification of requirements by the user through to
the end of the use of the equipment, facilities, utilities,
or systems. All data obtained should be adequately
summarized, reviewed, and archived. Qualification is
the overall process of assessing the level of compliance
of equipment with its intended use. Equipment must
be qualified according to the required characteristics of
the environment using methodology in accordance with
the requirements of Annex 15. Qualification (including
classification) should be clearly differentiated from
operational monitoring [1].
Qualification is a concept associated with equipment,
facilities, utilities, or systems. Examples of utilities are
steam, water, air, or other gases, and examples of systems
are cleanrooms and premises, personnel (gowning and
training), instruments (production and QC), methods, and
suppliers. Equipment and systems should be designed,
installed, qualified, operated, maintained, and monitored
in a manner to ensure that everything functions as
expected and supports process validation. For equipment,
facilities, and utilities, each qualification must be
completed and signed off before the subsequent one is allowed to begin. Additionally, all qualifications must be
completed and implemented before the final validation can be approved and the process released for routine use.
Where appropriate, qualification documents may be combined (e.g., installation qualification (IQ) and operational
qualification (OQ)) [4].
Each qualification consists of a protocol that has been predetermined and approved before work is allowed to
begin. This is reflected in a report where obtained results are recorded.
For large and complex projects, planning takes on added importance and separate validation plans may
enhance clarity [4].
The qualification phases are:

• User-required specification (URS)

• Design qualification (DQ)
• Factory acceptance testing (FAT)/Site acceptance testing (SAT)
• Installation qualification (IQ)
• Operational qualification (OQ)
• Performance qualification (PQ)
• Requalification

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 Validation and Qualification Approach Outlined in New Annex 1 Revision

Applying these concepts to process validation at each validation and qualification step, valuable information is
collected in lab notebooks and on analytical data sheets. All this data can be used to identify sources of variability
and critical process parameters (time, temperature, pH, flow rate). The challenge for validation is to glean all
the process variability knowledge from the development process and apply it to controlled, statistically valid
experiments that result in a robust, well monitored, well analyzed, and controlled processes producing consistent
product [5].
Ultimately, taking everything into account, qualification is a part of validation. Validation and qualification must
be the link between pharmaceutical development and routine processes, establishing the defined way to obtain a
final quality product.

Why validation and qualification are so important in a pharmaceutical process?

With the inclusion of validation and qualification in the flexible and scientifically sound pharmaceutical processes
proposed by the new Annex 1 revision, an overall review of
pharmaceutical development is essential.
The aim of pharmaceutical development is to design a quality
product and a manufacturing process to consistently deliver
the intended performance of the final product. The information
and knowledge gained from manufacturing experience and
pharmaceutical development studies provide scientific
understanding to support the establishment of the design
space - a multidimensional combination and interaction of
input variables (e.g., material attributes and process parameters
that have been demonstrated to provide assurance of quality).
Working within the design space is not considered to be a
change. Movement outside the design space is a change and
would normally initiate a regulatory post-approval change
process [2].
Process development studies should provide the basis for any
process control requirements. Similarly, process improvements
should be supported by several quality aspects including
equipment qualification and process validation (or continuous
process verification, an alternative approach in which
manufacturing process performance is continuously monitored
and evaluated, where applicable) [2].
QRM (Quality risk management) should be considered an
important tool in overall manufacturing process control.
When QRM principles are applied to validation, it supports the
robustness of the process in terms of reproducibility within
established specifications. The addition of QRM principles effectively incorporates scientific rationales and a
risk assessment as critical aspects for considering the raw data and for considering the quality of the product for
the final customer. Qualification, as a part of process validation, creates data on critical systems (e.g., equipment,

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 Validation and Qualification Approach Outlined in New Annex 1 Revision

personnel, materials...) that can be used to evaluate the process and document its quality over time (and during
routine usage). Installation, operational, and performance evidence for a piece of equipment or system guarantees
that the user requirement for assuring product quality for an intended purpose is achieved.
The application of a systematic quality by design approach to development and the application of a quality risk
management approach to the manufacturing process (linked to an appropriate pharmaceutical quality system)
both generate opportunities to enhance science- and risk-based regulatory methods. A better understanding of
the product and its manufacturing process (systematic evaluation) can create a basis for more flexible approaches.
Understanding of a product can include prior knowledge, experimentation, and risk assessment as well as the
material attributes and process parameters that can influence product CQAs; additionally, it is important to
determine the functional relationships that link material attributes and process parameters to product CQAs.
Enhanced product and process understanding in combination with quality risk management help establish
an appropriate control strategy which can, for example, include a proposal for a design space(s) and/or real-
time release testing. As a result, this more systematic approach could facilitate continual improvement and
innovation throughout the product life-cycle (See ICH Q10) [2].
Based on the above, design and intended purpose are important points to be assessed during process validation
and qualification phases where unexpected results can also be useful to better understand the design space
(deviations are important and therefore should not be hidden!). Validation and qualification phases are very
important for the entire process in terms of accountability and reproducibility from a quality point of view.
The main driver may be a better understanding of the process and higher predictability of the outcome.
Knowing a process well means that the materials brought in will likely produce a usable and/or sellable product.
The scattered variable data that is typical of the development phase (process/controls, process variability, and
critical process parameters) are brought into tighter alignment and control in commercial production to support
a robust validation process for facilities, utilities, equipment, process analytical methods, and computer control
systems.
This limits the risk of shortages and lowers costs due to fewer rejections. The level of development will depend on
the complexity of the process and product and on the opportunities chosen or desired by the applicant.
Developing and applying agreed-upon industry standards for validation help to:

• yield reliable, self-validating outputs at each stage of the development process

• eliminate redundancy in testing and documentation
• eliminate ambiguity in specifications
• eliminate gaps and overlaps in departmental roles and responsibilities
• allow regulators to audit the standards rather than individual tests
• save companies time and resources
• adapt readily to innovation

Considering the above-mentioned topics, the path forward for companies struggling with validation is threefold:

• Develop an integrated validation plan.

• Select the appropriate statistical tools to conduct and analyze the results of multivariate experiments.
• Enhance the engineering systems that initiate, support, and maintain the validated state of processes
and associated infrastructure.

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 Validation and Qualification Approach Outlined in New Annex 1 Revision

This proposed approach provides for a complete understanding of the process. For this purpose, a positive and
flexible organizational structure should include development, engineering, production, quality, and statistics for
the validation team, including roles and responsibilities [5].

So how can PMS help you with these crucial activities? Let Particle Measuring Systems
The PMS product line covers validation and qualification needs because industry experts support your risk
assessment and contamination
PMS supplies products as well as advisory services to provide complete control strategy needs. Learn more!
solutions: a combination of hardware, software, and/or services to offer a
wide-range of high-quality services to customers.
For pharmaceutical processes such as manufacturing, packaging, sterilization, filtration, cleaning, and
environmental monitoring, PMS can be on-site with the customer to show, as an example, the appropriateness of
the chosen method to the material being tested.
Example:
The ability of media to reveal the presence of microorganisms in a test sample is useful during a
continuous monitoring via the BioCapt Single-Use® (BCSU) device. The BCSU device is the automated
microbial capturing and identification system supplied by PMS to recover viable contamination in routine
environmental monitoring sampling activities.
The performance qualification package for the BCSU could include multiple factors, such as choice of
operational use conditions, feasibility studies, selection of isolates, and reproducibility of the system itself.
The PMS Advisory team is available to define the best PQ protocol for each customer based on their needs.
In addition, PMS as a product vendor, advisory, and services supplier helps its customer with all of the
equipment qualification phases. As the provider of PharmaIntegrity® and FacilityPRO® systems, PMS supplies
FAT documentation and helps its customers through SAT steps. The installation manager of the supplier reviews
and confirms all aspects of the installation and
functionality of the project equipment, and the
buyer approves SAT protocol, procedures, validation,
and other related documents shared by PMS. PMS
is always at the customer’s side for any requests or
needs, supervising and facilitating system testing on
a mutually agreeable date.
PMS GMP Services follows the new Annex 1
requirements on the design/operation of the
installation qualification of cleanrooms and clean
air equipment (as one example). Currently, this
qualification should at least include installed filter
system leakage and integrity testing; airflow tests
for volume and velocity; air pressure difference
tests; airflow direction tests and visualization; microbial, airborne, and surface contamination; temperature
measurement tests; relative humidity tests; recovery tests; and containment leak tests. Reference to the
qualification of cleanrooms and clean air equipment can also be found in the ISO 14644 series of standards.
Cleanroom classification is part of cleanroom qualification and is a method of assessing the level of air cleanliness

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 Validation and Qualification Approach Outlined in New Annex 1 Revision

for a cleanroom or clean air equipment by measuring the total particle concentration against a standard
specification [1].

PMS Instruments and Regulations

As per USP <1058>, instruments can generally be classified as belonging to Groups A, B, or C. It should be noted
that the same type of instrument can fit into one or more categories, depending on its intended use.
Group A includes the standard, least complex instruments that are used without measurement capability or user
requirement for calibration, such as a magnetic stirrer or vortex mixer. Proper function is ensured by observation,
and no further qualification activities are needed for this group [6]. PMS is not a supplier of Group A instruments,
but PMS is a leader in the industry for supplying instruments of Group B and C for environment monitoring. Group
B includes instruments that may provide measurements or experimental conditions that affect a measurement.
Examples include PMS Lasair® Pro or MiniCapt® Mobile equipment. Proper function of instruments in this group
may require only routine calibration, maintenance, or performance checks. The extent of activities may depend on
the criticality of the application. Generally, these instruments have firmware but not software that is updated by
the user.
Group C consists of analytical instruments with a significant degree of computerization and complexity, such
as the PMS PharmaIntegrity software system. In this case, all the elements of qualification, including software
validation, must be considered to ensure proper functioning of instruments in this group [6].

Requalification
Cleanroom and clean air equipment requalification should be carried out periodically by the PMS GMP Service
department, following defined procedures as per Annex 1 requirements. Requalification should, at a minimum,
include the following: cleanroom classification in terms of total particle concentration, integrity tests of final filters,
airflow volume measurements, verification of air pressure differences between rooms, and air velocity tests
Note about air velocity testing: For grade B, C, and D areas the air velocity test should be performed
according to a risk assessment documented as part of the CCS. Also, air velocity testing is required for filling
zones supplied with unidirectional airflow (e.g., when filling terminally sterilized products or background
to grade A areas and RABS). For grades with non-unidirectional airflow, a measurement of recovery testing
should replace velocity testing.
The maximum time interval for requalification of grade A & B areas is 6 months. The maximum time interval for
requalification of grade C & D areas is 12 months [1].
Additionally, the same support could be supplied by PMS in cases of personnel disqualification due to an APS
failure. In this case, the PMS Advisory team is available for training sections on aseptic technique, gowning
procedure, and personnel behaviors that can be useful evidence to support this process.

Conclusion
Quality cannot be tested in products alone; quality should be built in by design. From the initial pharmaceutical
development phase onward, design and intended purpose are two focal points for product quality. To attain full
comprehension of the pharmaceutical process, personnel must have appropriate levels of scientific knowledge.
Processes, equipment, facilities, and manufacturing activities should be managed in accordance with QRM

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 Validation and Qualification Approach Outlined in New Annex 1 Revision

principles to provide a proactive means of identifying, scientifically evaluating, and controlling potential risks to
quality. Firstly, QRM priorities should include appropriate design of the facility, equipment, and processes. This
should be followed by the implementation of well-designed procedures and, finally, the application of monitoring
systems as the element that demonstrates that the design and procedures have been correctly implemented and
continue to perform in line with expectations [1].
It is especially important that the underlying process knowledge for design space justification (if used) and for
development of any mathematical models to confirm a process control strategy (if used) should be available [4].
Considering this holistic approach and the new details indicated in the new Annex 1, validation and qualification
are two critical and complex phases to consider in defining product quality.
PMS is always there to support customers through every step of this complex path to achieve the best practices
required by GMPs.

References
[1] Eudralex Volume 4 EU Guidelines for Good Manufacturing Practice for Medicinal Products for Human and
Veterinary Use. Annex 1: Manufacture of Sterile Medicinal Products.
[2] ICH guideline Q8 (R2) on pharmaceutical development. 22 June 2017 EMA/CHMP/ICH/167068/2004 Committee
for Human Medicinal Products
[3] Agalloco J. Validation: a new perspective. In: Medina C, editor. Compliance handbook for pharmaceuticals,
medical devices, and biologics. Boca Raton, FL: CRC Press; 2004.p. 85–128
[4] Eudralex Volume 4 EU Guidelines for Good Manufacturing Practice for Medicinal Products for Human and
Veterinary Use. Annex 15: Qualification and Validation. Ref. Ares (2015)1380025 - 30/03/2015
[5] Quality by Design, Validation, and PAT: operational, statistical, and engineering perspectives, 2 August 2008.
[6] USP <1058> Analytical instrument qualification

Serena Steidl
Advisory Specialist, Particle Measuring Systems.

Serena has a strong scientific background in Microbiology and Biotechnology. She has
worked in several pharmaceutical companies to support quality control department. She
especially skilled in excellent knowledge of cGMP and quality assurance. She started her
career as quality technician and over the years she moved to management role working
in immuno-chemical, chemical, and microbiological departments in collaboration
with other divisions. She was involved in many projects such as: disinfectants strategy,
environmental sampling plan definition, scheduling and release of products, product
stability management, change control, method, and process validation.

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information should be addressed to Particle Measuring Systems, Inc. at +1 303-443-7100. App Note 326. 03092023

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