Overview of the Cleaning Validation project conducted as Consultant&Engineer for Altran spa within Takeda's Manufacturing Site at Rieti, a specialized company for the product of human plasma derivates.

1. Cleaning Validation Support
Takeda Manufacturing Spa (Rieti)
Nunziangelo Ventricelli – Consultant&Engineer for Altran Spa (EILIS)

2. Aim of the project was to supply a continuous technical support for
Cleaning Validation activities within the related department in
Takeda’s manufacturing site at Rieti (Italy).
The duration of the project (1 year foreseen) was extremely
connected to the satisfaction of client’s expectations (see also slide
n°4).

3. Client Background
Takeda’s manufacturing site at Rieti is a FDA approved
biopharmaceutical company specialized for the production of
human plasma derivates.
The manufacturing process includes to initially thaw crude
plasma in order to obtain, through different process phases, the
final Drug Substance that is finally stored as concentrated bulk.
The DS is send to other manufacturing sites for further
operations. Different equipment and methods such as tanks,
centrifuges, ultrafilters, chromatography, filter pressers are
adopted within manufacturing site.
Personal Background
My technical background completely fits the needs of Takeda’s
company. In fact, my previous experiences in Cleaning Validation
and in Biopharmaceutical Industry were a strong driver for the
final choosing of my job profile on this project.

4. Client Goals
The expectations/goals of the client were to receive a
continuous technical support for cleaning validation activities.
These were mainly related to the drafting of validation
documentation and managing of the on-the-floor activities.
Another important expectation of the client was to
continuously receive from the consultant, in a proactive way, a
different point of view for the approach to validation, and
GMP, generally, activities.
Personal Goals
My personal goals were mainly attributable to improve
technical features, specifically, related to cleaning validation
area. Takeda’s Rieti plant, in fact, represents a unique company
in the global pharmaceutical scenario for the type of products
manufactured.

5. PRINCIPLES: What does it mean Cleaning Validation?
All the activities that aim to demonstrate, with documented evidence, that the approved cleaning process (automatized, semi-
automatized, manual) are able to remove products and cleaning agents with efficacy, reproducibility and consistency.
All the analytical methods and the acceptance criteria adopted have to be selected on the basis of appropriate scientific rationales.
SCIENTIFIC RATIONALES: These two words are the key words to manage cleaning validation activities. The scientific rationales
are built up on the basis of the following approaches: RISK MANAGEMENT and COMPANY’s EXPERIENCE/KNWOLEDGE.
RISK MANAGEMENT: Within Takeda’s manufacturing site, the
risks associated to cleaning validation are addressed and
mitigated using a risk based approach. This approach is defined
considering the most important global guidelines (ICH , Annex
15, PICs) for the entire workflow. For example: the acceptance
criteria to be adopted for cleaning validation are set on the basis
of chronic toxicity principles such as the Permitted Daily
Exposure approach “PDE”, which considers the potential toxicity
effect of products and/or cleaning agents when injected in
human patients for his entire life.
COMPANY’s EXPERIENCE/KNOWLEDGE: Takeda’s
manufacturing site at Rieti is a company specialized in plasma
derivates production. related to Cleaning Validation. Plasma
derivates are considered endogenous product of human
organism. Arguments like this, in association with a good
knowledge of product itself and manufacturing process, are
kept into consideration for the definition of activities and
scientific rationales

6. CV Process Workflow & Documentation
STEP 1  Preliminary/Study Phase
During this phase, on the basis of the equipment to be cleaned (it use, design, role/position within the
manfacturing process) a potential cleaning procedure is individuated by engineering department.
The Cleaning Validation Study Protocol is the reference document for the management of activities aimed to
obtain the first explorative data on the efficacy, reproducibility and consistency of cleaning process
previously individuated. Within this document the analytical methods, the acceptance criteria and the
number of cleaning runs are also defined.
STEP 2  Preliminary/Study Phase
Explorative data are collected and analysed within a Study Report. On the basis of data obtained, the
potential cleaning process should become or not the main candidate to be validated. In case of the cleaning
process is not able to demonstrate efficacy, reproducibility and/or consistency, adjustements to this cleaning
process and/or alternative cleaning processes could be proposed and newly preliminary studies could
performed.
STEP 3  Risk Assessment Phase
During this phase, a Cleaning Validation Risk Assessment is written. This is considered a driver document, a
reference for the analysis and mitigation of the risks associated to cleaning process. Appropriate scientific
rationales are supplied in order to individuate CPPs and CQAs (acceptance criteria included) and how they are
addressed. Cleaning validation runs to be performed and Dirty and Clean Hold Times to be challenged are
also individuated.
STEP 4  Validation Phase
On the basis of RA guidelines, the following validation protocols, to manage CV activities (sampling plan,
analytical methods), are written:
• Validation Protocol for the management of cleaning procedure and Dirty Hold Time validation;
• Validation Protocol for the management of Clean Hold Time validation.
STEP 5  Final Phase
All the CV data (analytical data, Dirty and Clean Hold Time challenged, samplings, potenital deviations
occurred) are collected and analysed within Final Reports in order to demonstrate and confirm the efficacy,
reproducibility and consistency of cleaning proces.

7. OVERALL PERFORMANCE
CLIENT’S GOALS/EXPECTATIONS: All the
goals/expectations of the client were achieved. All the
cleaning activities were completed on time and assuring a
high quality level.
Furthermore, concurrently with the routine activities, in
collaboration with the client, a deep review of Risk
Assessment approach and documents wording were
executed.
PERSONAL GOALS/EXPECTATIONS: All my
goals/expectations were completely satisfied. I improved
my technical skills for Cleaning Validation by studying a
new risk-based approach since Takeda’s manufacturing
site at Rieti represents a unique site in global GMP
pharmaceutical industry.
The project was renewed several times for the Cleaning
Validation Support project (total duration: 1 year).
Furthermore, a new project, associated to Cleaning
Validation activities for Rieti’s manufacturing site
expansion, with a different business model, was assigned
to Altran spa.
My personal technical portfolio had been enriched thanks
to this project experience
EFFECT
EFFECT