BT6002 - Research Dissertation - Patrick O'Flynn - 110329811

Development of a
Quality Management System
for the GMP Bioprocessing
Production and Training Platform
By:
Patrick O’Flynn
A dissertation submitted in partial fulfilment for the degree of Masters in Applied
Science (Biotechnology) 2015
In the School of Biochemistry and Cell Biology
At University College Cork
Head of Department: David Sheehan
Course Coordinator: Dr. Justin McCarthy
Supervisor: Dr. Colman Casey
Submitted: 22nd
of September 2015

1
Table of Contents
Glossary/Abbreviations................................................................................................................. 2
Acknowledgements....................................................................................................................... 3
Abstract......................................................................................................................................... 4
Introduction................................................................................................................................... 5
Quality .......................................................................................................................................... 5
Quality Management Systems ...................................................................................................... 7
General Requirements............................................................................................................... 7
Documentation Requirements................................................................................................... 9
Quality Manual ................................................................................................................... 12
Quality plan......................................................................................................................... 14
Management Responsibilities ................................................................................................. 16
Resource Management............................................................................................................ 17
Product Realisation................................................................................................................. 20
Measurement, Analysis and Improvement.............................................................................. 22
Quality Risk Management .......................................................................................................... 24
Quality based technology and practice ....................................................................................... 27
Overview of the UCC facility and its purpose............................................................................ 30
Project Scope .............................................................................................................................. 32
Methodology............................................................................................................................... 34
Facility Folder......................................................................................................................... 36
Equipment Folder.................................................................................................................... 38
Production Folder.................................................................................................................... 39
Quality Control Folder............................................................................................................ 40
Quality Assurance Folder ....................................................................................................... 41
Results......................................................................................................................................... 43
Discussion................................................................................................................................... 69
Bibliography ............................................................................................................................... 74
Appendices.................................................................................................................................. 76

2
Glossary/Abbreviations
GMP Good Manufacturing Practice
GLP Good Laboratory Practice
ICH
International Conference on
Harmonisation
CTD Common Technical Document
QMS Quality Management System
QA Quality Assurance
QC Quality Control
SOP Standard Operating Procedures
DRF Data Recording Form
QP Qualified Person
QbD Quality by Design
HACCP Hazard Analysis Critical Control Point
PRP Prerequisite Program
EU European Union
ISO
International Organisation for
Standardisation
EEC European Economic Community
FDA Food and Drug Administration
WHO World Health Organisation
HEPA filter High Efficiency Particulate Air filter
EOP Equipment Operating Procedure
LUMAC Log of Use Maintenance and Cleaning
KPI Key Performance Indicators
CAPA Corrective Action Preventive Action
QO Quality Objective
IQ Installation Qualification
OQ Operational Qualification
PQ Performance Qualification
PV Process Validation
AV Analytical Assay Validation

3
Acknowledgements
I would like to thank Dr. Colman Casey for supervising this project and for all his
advice and support throughout the course of the writing this thesis. His background in
GMP manufacturing shone through in his comments.
I would like to thank Mr. Jimmy Meade for always being available to lend a helping
hand, to give advice or to discuss plans for the facility throughout the course of this
project. As the project manager of the facility, his input proved invaluable and he was
also very approachable and friendly in every encounter.
I would like to thank Dr. Magdalena Tyndyk for her support during the literature review
portion of this project and for organising the visit to NIBRT. It was most beneficial to
see a fully-fledged GMP bioprocessing training facility first hand.
I would like to thank John Milne from NIBRT in Dublin for his time he so graciously
donated to this project. The tour of the NIBRT facility and all his words of advice were
very helpful in understanding the key aspects of quality in a GMP facility. His industrial
templates from his previous company were extremely useful in developing the QMS for
this project.
I would like to thank Michelle Aherne for her input into the project via her
contamination control plan and cleaning procedures which can be found in the
“Facility” folder of the documentation system. Her cooperation as a fellow student
made completing the project all the smoother.

4
Abstract
Quality can be described as a “dynamic state associated with products, services, people,
processes and environments that meets or exceeds expectations”. Its true value lies in its
association with one of these items as opposed to existing as an entity in its own right.
A Quality Management System (QMS) is not focused on operation details but more so
on how well these operations are controlled and monitored. A QMS is designed to
generate confidence that a process is under control and producing a product or service
of good quality so long as the quality procedures in place are followed correctly.
The purpose of this project was to develop a Quality Management System for the GMP
Bioprocessing facility in UCC. It involved designing a documentation system for the
facility as well as the generation of key quality documents. This included procedures for
equipment operation, the preparation of SOPs, master formulae, validation protocols
and reports, as well as a validation master plan.
A framework for the QMS has been successfully completed and a sizeable amount of
documentation generated within this. Samples of these documents can be found in the
results section of this paper as well as an overview illustration of the documentation
system. An equipment tracking system has also been developed to allow for a smooth
categorisation and quantification of all current and newly procured equipment. This will
aid the determination of calibration and maintenance schedules for relevant equipment
in the facility as well as keep track of operations involving said equipment.
In continuation of this project, a quality consultant has been hired to finalise current
procedures and generate the remaining documents needed to operate the facility at a
GMP level. She will also advise on a number of other aspects of the facility’s quality
operations as part of its final preparations. Equipment is also still being procured for the
facility. Key personnel are to be trained on the production equipment in line with the
final validation tests. The facility is planned to be up and running by early 2016
following the completion of these objectives.

5
Introduction
Quality
Quality is a term which, on its own, has little or no meaning and it is only when applied
to a particular context that it is given some purpose. Despite the lack of a universal
agreement, there are enough similarities among the definitions for quality that common
components can be elucidated. Quality can be applied to products, services, people,
processes and environments. It involves meeting or exceeding the expectations of the
customer and it is in a constantly evolving state (Quality today might not be considered
quality tomorrow). From this, it can be said that quality is a “dynamic state associated
with products, services, people, processes and environments that meets or exceeds
expectations” (1).
In manufacturing, quality is closely related to conformance and reproducibility. The
ability of a process to produce a product consistently with minimal deviation is a direct
measure of its level of quality. A proactive tool used by pharmaceutical quality
assurance departments for attaining this level of quality is Good Manufacturing Practice
(GMP). GMP is that part of quality assurance which ensures that products are
consistently produced and controlled to the quality standards appropriate for their
intended use and as required by the marketing authorisation (EU definition). GMP
covers every aspect of the production process and involves detailed, written procedures
for every activity that can affect quality(2). With this proactive approach, manufacturers
can prevent future failures in their processes by setting quality standards in place ahead
of time. This generates confidence in the mind of the consumer and leads to an overall
more successful business with a greater degree of consumer loyalty.

6
For quality to be achieved, the correct documentation must be maintained. This is to
ensure that every aspect of the organisation is well-informed with regard to the
standards that need to be upheld. The major documents involved in the quality process
are the quality manual, which outlines the organisations overall attitude towards quality
and the quality plan which outlines quality with respect to a specific product. Each
serves its own purpose in the overall quality management system (QMS) of an
organisation. One of the most influential authorities in the quality systems field is the
International Organisation for Standardisation (ISO). Their technical committees have
produced a number of standards regarding many aspects of industrial manufacture of
goods and services. A prime example is the ISO9001 standard for quality systems
management. This will be discussed in more detail later on.
The International Conference on Harmonisation (ICH) has been putting great effort into
standardising the development and registration of safe, effective and high quality
medicines around the world. The use of their Common Technical Document (CTD)
ensures that all quality, safety and efficacy information is assembled in a common
format. This has led to a harmonised regulatory review process and has eliminated the
need for industry to reformat their information for each ICH authority. They have also
developed the ICH Q10 “Pharmaceutical Quality System” which is based on ISO
quality concepts, applicable GMP regulations and complements previous documents,
ICH Q8 “Pharmaceutical Development” and ICH Q9 “Quality Risk Management”.
Such powerful resources are available online and have proven invaluable for the
international regulation of pharmaceuticals (3–5).

7
Quality Management Systems
General Requirements
A quality Management System (QMS) is an assortment of processes in a business with
the aim of achieving the quality policy and objectives in order to meet customer needs.
To ensure that an organisation functions correctly, it needs to determine and manage
numerous linked activities. Those activities which use resources and are managed in
order to enable the transformation of inputs into outputs, can be considered processes.
The process approach to developing, implementing and improving the effectiveness of a
QMS is promoted by the ISO9001 standard and aims to improve customer satisfaction
by meeting customer requirements (6). The advantage of such an approach is the
constant control that it provides over the linkage between each process within the
system, as well as over their combination and interactions. A methodology known as
“Plan-Do-Check-Act” (PDCA) is often applied to these processes to ensure continued
improvement. Objectives and processes necessary to achieve customer requirements and
the organisations policies are established (plan). These processes are implemented (Do).
Processes and product are monitored and measured against policies, objectives and
product requirements and the results reported (Check). Action is taken to continually
improve process performance (Act). Figure 1 illustrates the continual improvement
cycle of an effective QMS based on ISO9001 standards (7).

8
Figure 1 – Continual Improvement cycle of an effective QMS based in ISO9001 standards (6)

9
Documentation Requirements
ISO9001 requires that a QMS maintain a documentation system to keep track of process
performance and for proving compliance to the quality standard. These documents
include statements of a quality policy and objectives, the quality manual, documented
procedures and records required by the ISO as well as those determined by the
organisation to be necessary to ensure effective planning, operation and control of its
processes. Documented procedures are defined in ISO9001 as a procedure that “is
established, documented, implemented and maintained”. The quality policy is a
document put together in a joint effort between the management and quality experts. It
describes the quality objectives of the organisation as well as acceptable levels of
quality and responsibilities of specific departments to ensure this quality (8). This is a
long term strategy which usually has a scope of about 10 years. All this information is
contained in the quality manual which is the overall document outlining the quality
system of a company.
Documented procedures must be put in place to outline the controls needed for the
documents of a QMS. They need to be approved for adequacy prior to issue, reviewed,
updated and re-approved as necessary, changes and current revision status of documents
identified and relevant versions available at point of use. Documents must remain
legible and readily identifiable. External documents needed for the planning and
operation of the QMS need to be identified and their distribution controlled. Obsolete
documents need to be suitably identified to prevent unintentional use if they are retained
for any reason.
Documentation control procedures are especially important in the case of records. These
are a special type of document which are required to provide evidence of conformity to
requirements and of the effective operation of the QMS. The organisation must establish
a documented procedure for the necessary level of control required for the
identification, storage, protection, retrieval, retention and disposition of records. All
records need to be legible, readily identifiable and retrievable. See Figure 2 for an
illustrated overview of the documents involved in a QMS (1).

10
To achieve GMP compliance, a manufacturer must maintain a Site Master File,
describing the GMP related activities. This is divided into 2 primary types of
documentation: instruction and record/report.
Instruction documents include specifications, procedures, protocols, technical
agreements and manufacturing formulae, processing, packaging and testing instructions.
These outline product requirements, give direction for operations and serve as a basis
for quality evaluation.
Records, reports and certificates of analysis provide evidence of all actions taken to
demonstrate compliance as well as summaries of product testing results together with
evaluation for compliance within a state specification. Raw data here, as defined in
Eudralex volume 4, part 1, chapter 4, will form the basis for all quality decisions
regarding batch release (9).

11
Figure 2 - Documents of a Quality Management system (1)

12
Quality Manual
The quality manual is a collection of documents that outline an organisation’s QMS.
ISO9001 requires that the quality manual include:
a) The scope of the quality management system, including details of and
justification for any exclusions. Such exclusions are limited to Clause 7 (Product
realisation) and they must not affect the organisation’s ability or responsibility to
provide product that meets customer and applicable statutory and regulatory
requirements.
b) The documented procedures established for the quality management system, or
reference to them.
c) A description of the interaction between the processes of the quality
management system.
This information can be found in the quality policy statement, quality policies, Standard
Operating Procedures (SOPs) and work instructions. These documents do not relate to a
specific product but give a more general description of how a business is run. Each
company will have its own style of manual from checklists and flowcharts to workflow
embedded into IT systems. They can also choose whether to opt for hardcopy or
softcopy. The extent of the QMS is dependent on the size of the organisation, type of
activities, complexity of processes and their interactions and the competence of the
personnel involved. However, so long as the quality manual includes a quality policy,
measureable quality objectives/policies and documents needed to control the processes,
such as procedures then it will achieve the requirements set out in ISO 9001(6). See
figure 3 below for an illustrated overview of the components of a quality manual.

13
Figure 3 - overview of the documents found in the Quality Manual (6)

14
Quality plan
A quality plan is a document or collection of documents which lay out the quality
standards, practices, resources and specifications with regard to a specific product. It is
a collection of efforts put into identifying the customer requirements, quality criteria
and standards as well as the daily Quality Assurance (QA) and Quality Control (QC)
activities that will be required.
At the highest level, quality goals are implemented in a strategic fashion across the
organisation with the aim of ensuring each function contributes towards the top-level
goal. At lower levels, quality plans play the part of an actionable plan which can take
many forms depending on the desired outcome. There are a number of aspects which
the plan should define. These are illustrated in figure 4 below (10).

15
Figure 4 – Illustration of Quality plan outline (10)

16
Management Responsibilities
Quality is an ethos that must be promoted within an organisation. It is not the
responsibility of one member or even a group but it is a shared duty amongst everyone
in the organisation. Every procedure in every process needs to be carried out with a
focus on customer satisfaction and continual improvement as part of the QMS. In
accordance with ISO9001, top management is required to prove its commitment to this
idea. It can do so by communicating to the organisation the importance of meeting
customer requirements as well as those of the regulator, establishing the quality policy
and objectives, conducting management reviews and ensuring resources are available
for all processes in the QMS.
The Eudralex guidelines for GMP demand that senior management take the ultimate
responsibility to ensure the quality system is in place, well-resourced and that the roles,
responsibilities and authorities within the organisation are clearly defined,
communicated and implemented (2). The exact structure of the organisation and the
way in which responsibility is delegated will depend heavily on the overall company
objective. For smaller companies, a structure that allows close control over company
growth, development and quality is more suited as it is less formal and gives the
founder a more intimate control over growth and development. For larger companies, a
hierarchical structure works better as it clearly defines roles and responsibilities for each
member. The hierarchical structure allows for transparency and clear separation of the
roles and responsibilities for each level of management.
Top management is also charged with reviewing the organisations QMS to ensure its
continued suitability, adequacy and effectiveness. The review should take place at
regularly planned time intervals and include the assessment of opportunities for
improvement as well as any need for changes to the QMS, quality policy or quality
objectives. The review input shall include information from sources such as audits,
customer feedback, process performance and follow-up actions from previous
management reviews. The review output will take the form of any decisions or actions
regarding improvement of the QMS and its processes as well as improvement of
product related to customer requirements and resource needs.

17
Resource Management
The QMS is a collection of processes which collectively achieve the quality objectives
when correctly implemented. These processes use resources and are managed to
transform inputs into outputs. The organisation is required to provide the resources
needed to implement the QMS and its continual improvement as well as enhance
customer satisfaction by meeting customer needs. Resources are categorised in ISO9001
as human resources, infrastructure and work environment. The requirements of each of
these resources will be determined, provided and maintained by the organisation itself
with respect to each specific process.
Human resources refer to the personnel carrying out the work which affects product
requirements. Their competency for the job is based on their education, training, skills
and experience. The organisation decides what level of competency is required for its
personnel. It must also provide training where applicable and maintain appropriate
records of education, training, skills and experience. In a GMP process, some key
personnel whose requirements are outlined in Eudralex, Volume 4 Chapter 2 are also
required. These are the head of production, the head of quality control and an adequate
number of Qualified Person(s) (QP). The roles of these positions are clearly defined in
legislation. The heads of production and quality must be independent from each other
and each batch released from the site must be passed and signed by a qualified person.
(11). See the figure below for an overview of how a quality department’s personnel in a
pharmaceutical company is organised. Note the presence of the key personnel and their
position in the management hierarchy.
Infrastructure refers to the buildings, workspace, associated utilities, process equipment
(hardware, software) and supportive services (transport, communication, information
systems) utilised by the processes in the QMS. The work environment refers to the
conditions under which the work is performed. This includes physical, environmental
and other factors such as noise, temperature, lighting etc. Eudralex volume 4 chapter 5
designates the guidelines for GMP requirements regarding the production process and
suitable resource management therein. All production operations, including handling of
materials and products, must be carried out by competent people in accordance with
written procedures and duly recorded as proof of their occurrence. A suitable
contamination control strategy must be set in place as part of the quality risk
management system to protect the product quality. Technical measures for this include

18
the use of barrier isolation technology, single use disposable technology and use of
equipment designed for ease of cleaning. Organisational measures include separating
production areas on a campaign basis (dedicated at different times) with intermediary
cleaning of a validated effectiveness. These measures along with the rest of the
guidelines are enacted to ensure that product quality is in compliance with the relevant
manufacturing and marketing authorisations (12).
In Europe, quality departments of a GMP manufacturer require the function of a QP to
sign off on every batch that leaves the site. This delegates the responsibility of that
batch to the QP and any issues or complaints that may arise with it. This is not a
universal agreement as can be seen in the case of the U.S. The role of the QP is not
defined nor required by American regulations. They prefer to have a quality unit, a team
of individuals, at the top of the hierarchy. They make a group decision on each batch
and take the place of the QP, in US legislation (13). Each approach stems from a
separate philosophical origin but the end result is the same, releasing medicinal products
that are safe, effective and of the highest quality. The quality departments in either case
are charged with ensuring the implementation of the quality system but this does not
absolve the manufacturing personnel from building quality into the product. Quality is a
culture in an organisation and is not to be delegated to any one person or department.
Quality by design (QbD) is a common ethos in the pharmaceutical industry. It involves
building quality into a product and associated processes such that product consistently
attains a predefined quality at the end of the manufacturing process. This complements
the quality system and provides a strong framework for developing a GMP-compliant
pharmaceutical process. See Figure 5 for an illustrated overview of a European quality
department in a GMP manufacturing facility.

19
Figure 5 - overview of a quality department in a pharmaceutical organisation based on Eudralex
GMP requirements (14)

20
Product Realisation
The organisation is required to plan and develop all processes required for product
realisation. Clause 7 of ISO 9001 outlines the specific processes which must be defined
in the QMS as seen below:
1. Planning of product realisation
The product realisation plan must outline all production and manufacturing process
requirements in consistence with the other processes of the QMS. This includes the
development of quality objectives and requirements of the product as well as
documentation to keep track of all activities regarding the processes. This is
necessary to allocate the correct resources for the production stage to ensure
employee activities, materials and production capacity is correctly applied to meet
customer needs (15).
2. Customer-related processes
All processes related to the customer must be built on pre-determined requirements
of the product for the consumer and these requirements reviewed prior to
committing to supply said product. Effective communication with the consumer
must be maintained with regard to product information, enquiries, customer
feedback and complaints.
3. Design and development
The design and development of product needs to be planned with appropriate
review, verification and validation processes implemented as required. Inputs and
outputs to the process must be determined. A change control system must also be in
place to properly implement and record any changes made to the product design and
development. These will also be reviewed, verified and validated before
implementation.
4. Purchasing
The organisation must also outline its purchasing process regarding supplier
selection and monitoring. This is to ensure that all materials bought in are traceable
and that suppliers can be tracked down if needs be. They must be regularly
measured, analysed and improved.

21
5. Production and Service provision
Production and provision of service needs to be carried out in a controlled
environment to ensure consistency. This includes the application of suitable
equipment and work instructions, where necessary, as well as implementing
monitoring and measurement systems. Validation of processes involved will also
help achieve this goal.
6. Control of monitoring and measuring equipment
Calibration must be carried out on all equipment following installation and at
regular time points to ensure that all measurements are accurate and within
specification. Adjustments shall be made as necessary and records of the calibration
results will be maintained.

22
Measurement, Analysis and Improvement
A quality system is a proactive tool used to ensure consistent and continual
improvement of quality in the product and the process. Within a pharmaceutical quality
department there are a number of components specialised in measuring, analysing and
improving product quality. The quality control unit is responsible for the testing and
sampling of product and ensuring it is of suitable quality, safety and efficacy prior to
batch release. Activities include laboratory quality assays, overseeing control of
reference samples as well as the establishment, validation and implementation of all
quality control procedures. The head of quality control will oversee all operations
undertaken by the QC unit. All QC personnel will have access to production areas for
sampling and investigative purposes but it is imperative that the QC unit is independent
of production. This is to ensure the validity of their results and prevent any conflict of
interest (16). All findings by the QC unit are reported to the QP and this raw data plays
a deciding role in whether the batch is released or not.
In the case of complaints and recalls, the organisation must also have appropriate
response channels in place to ensure every case is handled swiftly and fairly.
Appropriately trained personnel must be appointed for handling complaint and quality
defect investigations. This is usually an inter-disciplinary team including quality
management personnel and the QP responsible for the batch. Complaints indicating
potential quality defects warrant an appropriate root cause analysis and corrective and
preventative action (CAPA) procedure to be carried out. This involves determining the
cause of the defect, whether it is human error or an issue with the process/machinery,
and carrying out appropriate CAPAs to resolve the problem. Quality defect records need
to be maintained and reviewed for trend analysis purposes. This will highlight any
recurring problems. Complaints that do not indicate potential quality defects should be
documented and communicated to the appropriate group or person responsible for
handling complaints of that nature (17).

23
While the QC unit is focused on product quality, the validation unit is focused on the
process. For a process to be GMP compliant, it must be validated to the specifications
required for the marketing authorisation. This includes the prospective validation
carried out before production as well as concurrent validation carried out during
operation. Any changes to the process must be carried out according to an appropriate
change control procedure. This includes possible improvements to the process following
process optimisation experimentation. A technology transfer operation brings the small
scale changes up through pilot and into the large scale. This new process needs to be
revalidated to ensure that product quality has not been altered. Change control is a
major part of the quality system as it enables the company to improve its processes in
response to changes in customer needs, regulatory requirements or to accommodate
newer technologies.

24
Quality Risk Management
Quality systems can be a very effective tool in running a business. They aid in building
quality into the process and therefore placing product quality as the number one
objective of the organisation. The ISO 9001 standard for quality systems management
has been a resounding success used by over one million companies in over 170
countries. It has proven that quality is important, not just for the product and the
consumer but also for the producer. A quality system leads to efficiencies with returns
including increased profitability, consumer loyalty and trust in the brand name.
Quality risk management complements quality systems. While it is possible to
determine a suitable level of quality required of a product, it is difficult to exactly define
the required level of risk management in a process. This is because each stakeholder
may perceive potential harms, their probability and severity in a different way.
Nonetheless, quality risk management is based on two primary principles to aid in
controlling the level of risk involved in the production process. Firstly, evaluation of
risk to product quality is based on scientific knowledge and is linked to the protection of
the customer (or patient, in the case of medicines). Secondly, the level of effort,
formality and documentation involved in the quality risk management system should be
proportionate to the level of risk (4). In general, quality risk management is a systematic
approach used to assess, control, communicate and review the risks to product quality
involved in the process. A widely used and very apt example of such a system is the
Hazard Analysis and Critical Control Points (HACCP) system used in the food industry.
Due to the success of the ISO 9001, the ISO decided to set up a working group to
develop a similar standard for the food industry. The new approach would have a focus
on food safety with the incorporation of prerequisite programmes (PRPs) and Hazard
Analysis Critical Control Point (HACCP) principles, which form the basis of ISO
22000. This family of standards outline the requirements of any and all organisations in
the food chain regarding food safety management systems (18).

25
HACCP is a systematic approach to identifying hazards in the food chain and
establishing a set of procedures and control points to either prevent the entry of or
eliminate these hazards before they reach the consumer. It outlines the overall plan
regarding food safety in a process. The PRPs are more specific e.g. hygiene procedures
that focus on the production environment i.e. the people and the facility. They are
enacted as part of the HACCP plan and are a means by which a company can manage
critical control points in their processes.
For a food safety management system to be compliant with ISO 22000 it must be based
on the principles of HACCP. These principles are outlined by both the Food Safety
Authority of Ireland (FSAI) and the Food and Drug Administration (FDA) of the USA.
An illustration can be seen in figure 6 below (19).

26
Figure 6 – Outline of the principles of HACCP and their implementation in a food safety
management system (19)

27
Quality based technology and practice
Manufacturers are constantly looking for ways to improve their processes and build
more quality into their systems. Many technologies have been developed through these
endeavours. An example in GMP manufacturing is the cleanroom. This technology
allows for product to be handled in a controlled environment where quality is ensured
and risk management can be precisely executed.
The idea of a cleanroom originated in hospitals over 100 years ago when surgeons
realised that a filtered, cleaner air supply in the operating room resulted in fewer
infections during open surgery (20). Cleanroom technology is now being used in
numerous industries including electronics, pharmacy, biotechnology and medical
devices. Manufacturers realised that products that are used directly in patients or that
require protection from viable and/or non-viable particles require a more controlled
environment during their production. This is what the clean room provides as it is a
controlled environment where airborne particle concentrations are monitored and
maintained within specified limits so as to minimise contamination of the product.
The aim of the cleanroom is to protect the product from contamination sources such as
personnel, process equipment and surfaces. The cleanroom facility is a delicate
component of the process so the utmost care and consideration must be implemented in
its design, construction and start-up. The designer can implement strategies and
technologies such as HEPA filters, pressure differentials, airflow patterns, air locks,
barrier/isolation technology and personnel/material flow paths into their plans to
achieve this goal (21).

28
The European Economic Community (EEC) uses alpha grades A, B, C and D to define
cleanrooms used in the manufacture of sterile medicinal products. See Table 1 below for
further details regarding these classifications. Grade A cleanliness is designated to high
risk operations where the product is directly in contact with the air e.g. filling zone. A
laminar airflow in a closed isolator with glove boxes may provide this. The laminarity
of the airflow needs to be constantly monitored, maintained and validated. Grade B
cleanliness is required for aseptic preparation and filling. It is usually implemented in
the background environment of the grade A zone. Grade C and D can be applied to
areas where less critical stages of the sterile product manufacturing process take place.
Turbulent airflow can sufficiently dilute the air in these areas (22).
Table 1 EEC Clean room and clean air device classification (22)
Maximum permitted number of particles per m3
equal to or
greater than the tabulated size
At Rest In Operation
Grade 0.5µm 5.0µm 0.5µm 5.0µm
A 3520 20 3520 20
B 3520 29 352 000 2 900
C 352 000 2 900 3 520 000 29 000
D 3 520 000 29 000 Not Defined Not Defined
Personnel are common and unpredictably variable sources of contamination in a
cleanroom. Therefore a high level of training in aseptic procedures is required to
mitigate these risks. It is the responsibility of the manufacturer to ensure that all
personnel involved in the production process are trained adequately for their job. All
staff are required to receive basic training on the theory and practice of the quality
management system and on GMP. Newly recruited personnel must also be trained
appropriately for the duties allocated to them. Continuous training and periodical
assessment should be implemented and training records kept. With regard to
cleanrooms, personnel working in clean areas where infectious or sensitising materials
are handled, must receive specific training (11). This involves medical examination of
personnel as well as instruction on the required level of personal hygiene and gowning
practice.

29
The ISO have outlined requirements for cleanroom design in ISO 14644-4 (23). A
common strategy for protecting the integrity of the cleanroom while minimising cost
and technical complexity is the “Shell-like” system seen in Figure 7. The critical
product zone is surrounded by zones of lower cleanliness classification. This keeps the
zone with the highest cleanliness demands down to a minimum size. This “process
core” is also protected from the outdoor environment by multiple layers of successively
cleaner areas. Movement of personnel, materials and waste are also co-ordinated so as
to remove as much risk of contamination of the product as possible.
Figure 7 - Shell-like contamination control concept (23)

30
Overview of the UCC facility and its purpose
The Cork facility is made up of 2 sections, a production area and a training suite. It will
serve 3 major functions to support the local industry:
1. Production of small clinical scale probiotics for the Alimentary Pharmabiotic Centre
(APC).
2. Training area for cGMP for undergraduate and postgraduate use.
3. Training area for cGMP for Pharma/Biopharma industry use.
The production area was the main determinant in dictating the size and scope of the
facility. It will be used to produce clinical material and support early phase clinical trials
(phase I and II). Such products must be produced under controlled, monitored and
traceable conditions in accordance with the FDA rules for Current Good Manufacturing
(cGMP) in Manufacturing, Packaging, Labelling or Holding Operations for Dietary
Supplements 2010 (24). These requirements determined the overall area design with
respect to accessibility/security, contamination control, air handling, water purification,
environmental control, personnel training, equipment maintenance and operation. The
standard equipment often seen in secondary pharmaceutical manufacturing facilities is
well suited to the purposes of such a facility. It is constructed with suitable materials
and allows for Clean in Place (CIP) procedures.
The National Institute for Bioprocessing Research and Training (NIBRT) is an all-
encompassing centre of excellence for training and research in all aspects of
bioprocessing. The facility in Dublin, Ireland is built to the same specifications of a
modern bioprocessing plant along with a full array of state of the art equipment. Thus, it
replicates those same conditions to which personnel in an industrial setting will be
exposed. Currently, many companies all around Ireland use this facility to train their
personnel. With the growth and expansion of the biotechnology industry, Cork has
become home for quite a number of companies whose products are based on
bioprocessing techniques. Following this, it is anticipated that NIBRT will use the Cork
training facility as a local base for the training of select personnel in GMP practices.

31
The principles of GMP operation are already a major teaching point in many
undergraduate and postgraduate courses in the School of Pharmacy, School of Process
and Chemical Engineering and School of Biochemistry. With such a strong
pharmaceutical and biotechnological presence in the Cork and Munster area, it makes
sense that the local colleges are implementing more GMP-related course content into
their degree programmes. The major limitation for now is the lack of practical training
facilities to help supplement the lecture material. The UCC simulated cGMP Training
facility would serve this exact purpose and provide that much needed “realism” factor
for the students, thus giving them a much more fulfilling experience.
Due to the constant growth of the local pharmaceutical and biotechnology industries,
there is an increased demand for training graduates in cGMP operation. Local
manufacturing companies are regularly sending their employees to either Tallaght
Institute of Technology and/or NIBRT in UCD for their hands-on cGMP training
requirements. With such a large number of companies in Cork, it would be much more
cost effective to operate such a training facility locally. The UCC simulated cGMP
Training facility could also serve this purpose and provide training for industry acting in
collaboration with NIBRT. This removes the need for employees to travel, hastens the
training process and reduces cost for the local companies.
An overview of several regulatory documents as well as a number of industrial
templates was conducted and relevant pieces extracted to form the basis of a simulated
cGMP area for training and Probiotic production. The main documents followed
include:
 Eudralex Volume 4 Good Manufacturing Practice for Medicinal Productions for
Human and Veterinary use Chapter 4: Documentation (9).
 A WHO guide to good manufacturing practice (GMP) requirements. Part 1:
Standard operating procedures and master formulae (25).
 A WHO guide to good manufacturing practice (GMP) requirements. Part 2:
Validation (26).
 Industrial templates for a number of SOPs and a Validation Master Plan
provided by John Milne from NIBRT.

32
Project Scope
The purpose of this project is to design a quality system for the facility. It involved the
generation of a documentation system for the co-ordination of all operations in the
facility. This includes detailed written procedures for all operations taking place in the
facility as well as sufficient data record forms to record the occurrence of these
operations. While it would be impossible to develop every procedure needed for the
whole facility in the time allowed, the scope of this project is to set up a framework for
the quality system and to generate as many procedures as possible. The completed
procedures will act as a base upon which more quality documentation can be built.
Templates for operational documents were also generated. This will allow for a
smoother completion of the facility once it is fully equipped.
A hardcopy database of all relevant documents were set up and filed in an orderly
manner. They will be stored in a secure office so that personnel can easily access them
while ensuring their safekeeping. All documents prepared as part of this project as well
as any future documents will be stored here. An organised documentation system is
vital for any GMP facility to ensure smooth day-to-day running as well as providing
easy access to the regulatory information.
Equipment is currently being procured for the facility. An equipment tracking system
has been set up for keeping record of all activities surrounding this equipment. This will
include equipment tracker codes for unambiguous referencing. Equipment Logs will
keep track of those who used the equipment, when and for what purpose. EOPs will
provide operators with a guide for using the machines. All current equipment will be
quantified and a system set in place to track new equipment as it comes in.

33
The quality system will also outline the accessibility and security aspects of the facility.
Currently, the facility does have a swipe card access system in place so that only
registered personnel can gain entrance. Once the facility is operational, there will need
to be other more restrictive measures in place to protect its integrity. Proper signage
will be put in place to help identify when the facility is in GMP operation. During this
“GMP mode”, access to critical areas will have to be restricted to trained personnel who
are gowned correctly and have received the proper level of training. Entry and exit to
the facility should be documented by a sign in/out system. These personnel must follow
the SOPs for each task and all operations must be logged and documented. A suitable
level of contamination control must also be implemented to prevent product
contamination. A parallel project being undertaken by a colleague, Michelle Aherne,
dovetails with this project as it involves the development of a contamination control
plan for the facility.

34
Methodology
This project involves the development of a quality system based on regulatory
documentation and industrial template procedures. The relevant parts of these
documents were extracted and used to form a basis for the system described in the
following pages. An overall explanation of the documentation system has been
illustrated through figures 8-13 and by the accompanying text. Some of the more
important documents have been inserted into the results section which has a more
detailed description of their contents and serve to show the extent of the quality system
that has been developed.
Figure 8 - Overall view
The system is divided into 5 folders as can be seen in Figure 8. The documentation
contained within each of these is outlined in the following pages. The aim of the system
is to aid in the efficient organisation and administration of operations at the GMP
Bioprocessing Training and Production facility. It has been devised from WHO
guidelines on GMP documentation (25,26).
The basic principle is that every operation or action in the facility has a Standard
Operating Procedure (SOP) and a corresponding Data Record Form (DRF) where
appropriate. A simple example is an Equipment Operating Procedure (EOP) and the
corresponding LUMAC Logbook for that piece of equipment. A document numbering
system is used for each category of document to keep track of all approved documents.
Documentation for GMP facility
Facility Equipment Production
Quality
Control
Quality
Assurance

35
The system has been generated in an electronic format but it will be applied to the
process in a hard copy format. All documentation will have to be printed and approved
prior to their application. Master copies of SOPs will be printed on white paper and
filed in the main office. Draft Copies will also be printed on white paper but will be
rubber stamped with the word DRAFT to signify their draft status. Copies of SOPs must
be approved and signed for prior to distribution. These will be printed on green paper
and must be returned to the main office when no longer needed or if the master copy
undergoes a revision. These copies must then be destroyed when superseded by the final
approved copy. This is described in SOP # 50-001-01.
The major document of the facility is the Validation Master Plan (VMP). This outlines
all validation operations in the facility. During inspections, a facility’s VMP is often
seen as a representative document for the quality system in place. The VMP is kept in
the main office and filed in the Validation and Change Control subfolder of the
Quality Assurance folder.

36
Facility Folder
The Facility Folder is designed to hold all documentation pertaining to the facility itself
(building and utilities). This is visually illustrated in Figure 9. The contamination
control plan and all its procedures and data recording forms will be documented in the
Facility folder.
Figure 9 - Focus on Facility
The “Systems” folder holds all SOPs regarding the Operation, Maintenance and
Calibration of utilities in the facility. This includes procedures regarding the HVAC
system and purified water loop as well as aseptic sampling of process equipment such
as a the Bioreactor.
The “Cleaning of Facility”, “Disinfection, Fumigation”, “Environment Monitoring” and
“Pest Control” folders hold SOPs, DRFs and Logbooks regarding each of their relevant
topics.
The “Flow Plans” folder contains details for the flow of product, supplies, staff and
waste disposal. This includes flow plans and diagrams. The Validation Master Plan will
also reference flow details.
Facility
Systems
Operation,
Maintenance,
Calibration
Cleaning of
Facility
SOPs, DRFs
and Logs
Disinfectant,
Fumigation
SOPs, DRFs
and Logs
Environmental
Monitoring
SOPs, DRFs
and Logs
Pest Control
SOPs, DRFs
and Logs
Flow plans
Product,
Supply,
Staff,
Waste and
Dosposal
Cleaning and
Sterilisation
Garments,
Glassware
Access
Control,
Gowning
SOPs
Entry and Exit
to
Cleanrooms
SOPs,
Posters
Equipment Production
Quality
Control
Quality
Assurance

37
The “Cleaning and Sterilisation” folder contains SOPs for the cleaning and sterilisation
of materials that will come in direct contact with the product. These materials must be
more stringently cleaned and maintained as their direct contact with the product has a
direct impact on product quality.
The “Access Control and Hygiene” folder contains a number of SOPs outlining
activities such as Access Control, Hygiene, Gowning, Degowning, Material Transfer
and Personnel Conduct.
Note: Regarding the Facility folder
The scope of this project only extends as far as the development of a framework for the
facility folder and organising it into the rest of the system. All procedures, data
recording forms and other documents found form part of the contamination control plan
for the facility, as prepared separately.

38
Equipment Folder
The Equipment folder has been designed to hold all the documentation pertaining to the
equipment in the facility. This is visually outlined in Figure 10.
Figure 10 - Focus on Equipment
The Operation, Maintenance and Calibration category is probably the most important as
this contains the Equipment Operating Procedures (EOPs). These will be heavily
referenced throughout the system in other SOPs requiring the use of the equipment. The
LUMAC (Log of use, maintenance and cleaning) logbook system is designed to keep
track of all activities involving the operation, maintenance and cleaning of equipment.
All operation manuals, product specifications, data sheets, health and safety information
for the equipment and cleaning reagents used in their maintenance are also stored in this
folder.
A number of EOPs have been written and implemented as framework examples which
can be added to as the facility nears completion. The LUMAC logbook system has also
been implemented as part of this project with template documents and SOPs regarding
their use.
Facility Equipment
Operation,
Maintenance and
Calibration
Equipment
Operating
Procedures
(EOPs)
Equipment Data
Record Forms
LUMAC, logs and
other DRFs.
Preparation of
Cleaning
Solutions
SOPs for cleaning
solutions
Cleaning agents
data sheets,
product info for
cleaning agents
Equipment
monitoring and
alarms
procedures,
schedules,
parameters.
Calibration of
NIST equipment
Procedures and
Records
Operation
Manuals
Maunals, product
info etc.
Production Quality Control Quality Assurance

39
Production Folder
The production folder has been designed to hold all documentation directly pertaining
to production operations. This is visually outlined in Figure 11.
Figure 11 - Focus on Production
The Master Formulae (MF) folder contains SOPs for the writing, approval, distribution
and utilisation of the MF and Batch Processing Records as well as a template for an MF.
This has been implemented so that a fresh MF plan can be set up with each new client
while still using the same template each time. This gives some uniformity to an
otherwise flexible and dynamic process.
The other folders will contain documents pertaining to specific sections of the
production process which can be categorised according to each individual campaign and
client. The Biological Starting Materials folder will hold the records for all biological
materials (bacteria, fungi, cells, viruses etc.) used in production processes in the facility.
This record is critical to document all biological materials being used in the facility.
Documentation for GMP
facility
Master Formulae
SOP, Template and
guide to MF
In-Process Tests
SOPs, DRFs for
tests
Preparation of
Process Buffers and
Solutions
SOPs, DRFs for
sol. prep.
Environmental
Sampling
SOPs, DRFs, EU
guidelines
Biological Starting
Materials
SOP for regulation.
data sheets for all
bio materials.
Raw
Materials
Specifications,
Product Codes
Supplier
Approval
Receipt and
Storage
Quarantine,
Release and
Approval.
Quality Control Quality Assurance

40
Quality Control Folder
The Quality Control folder has been designed to hold all documentation pertaining to
quality control operations. This is visually illustrated in Figure 12.
Figure 12 - Focus on Quality Control
The different operations have been broken down into categories for ease of reference
and filing of results. Each sub-folder will contain SOPs and DRFs for the relevant
operations therein. The Analytical Assay folder will be heavily referenced throughout
the other folders in SOPs requiring the application of such assays for the relevant tests.
This folder will be more suitably utilised once the facility is complete and there are
processes occurring which can be tested and monitored. As part of this project, a
detailed framework for all documentation regarding quality control has been developed
to aid the future progression.
Facility Equipment Production Quality Control
Product
Testing and
Release
SOPs, DRFs,
QC Data
sheets
Raw Material
Testing
SOPs, DRFs,
QC Datasheets
Analytical
Assays
SOPs, DRFs
Samples - Test
and Retention
SOPs, Coded
sample log,
Summary
Protocol of QC
results
Collected QC
Datasheets
Stability
studies
SOPs, DRFs
Reference
Standard and
Control
Maintenance
and Testing
Recertification
of QC
equipment
Calibration
records
QC reagent
and material
preparation
SOPs, DRFs
Quality Assurance

41
Quality Assurance Folder
The Quality Assurance Folder has been designed to hold all documentation pertaining
to Quality Assurance and administrative operations. This is illustrated in Figure 13.
Figure 13 - Focus on Quality Assurance
The Batch record review folder contains all documents related to reviewing the
production process. This includes batch record sheets, batch approval log and SOPs for
the review of a batch process. These are essential in ensuring the product has been
produced to the pre-determined specifications. Adverse events are documented through
incident reports and suitable CAPAs (corrective action, preventive action) are initiated
in response to these. Procedures for all these activities have been developed and
implemented.
The SOPs outlining the procedures for the quarantine, release, rejection and storage of
product will be kept together in the same folder for ease of reference. In the case of
storage, temperature monitoring must be maintained to avoid deviations in storage
conditions. Product Distribution, Complaints and Recall procedures and records are all
documented together for ease of reference. These folders will be utilised once the
facility starts producing and handling product.
Quality
Control
Quality
Assurance
Batch Record
Review
Batch record
sheets,
approval log,
SOP etc.
Quarantine,
Release,
Rejection,
Storage
SOPs for each
step.
Temperature
monitor
records
Product
Distribution,
Complaints,
Recall
Procedures
and Records
Adverse
Events
Reports
Incident
reports (SOP
and DRFs)
Employee
records
professional
(CVs) and
health records.
Training and
Responsibility
Training
records,
responsiblity
descriptions
Validation and
Change
Control
Protocols,
Reports,
Validation
Master Plan.
Directories,
Document
control
SOP Master
list, LUMAC
list, tracker
codes, SOP
prep. etc.
Inspection
Internal,
Contractor and
Vendor Audits
Audit SOP and
records,

42
All employee records will be maintained together in a secure cabinet in the main office
to protect the privacy of each individual. This will include both professional (CVs) and
health records. Folders have been prepared for some personnel already and these can be
added to as more people are employed to work in the facility.
All training received by staff as part of their employment in the facility will be
documented in the training records. The responsibilities of all staff members will be
outlined in a clear and concise manner. A general SOP outlining the responsibilities of
quality operations personnel has been prepared as well as some training log template
documents. Further training documentation can be added to these as the quality system
is further developed.
The Validation and Change control folder contains the Validation Master Plan, SOPs
for the preparation of validation protocols and reports as well as template versions of
these documents. All validation in the facility is to be documented in this folder. As part
of this project, a template Validation Master Plan has been prepared as well as templates
for an array of validation protocols and reports (IQ, OQ, PQ, PV, AV) and SOPs for
their preparation.
The Directories and Document Control folder contains the SOP master list as well as
other similar directories for the purpose of documentation control (Equipment tracker
codes, LUMAC directory, Validation protocol/report lists etc.). These have been
prepared as Microsoft Excel worksheets and can be updated as necessary.
The procedure for the preparation, authorisation and distribution of SOPs is also found
here along with procedures explaining the equipment tracker code, storage unit tracker
code and LUMAC logbook systems.
The Inspection is designed to hold all documentation regarding quality assurance audits
of the production suite. This includes internal, contractor and vendor audits where
appropriate. SOPs outlining the suitable actions to be taken during audits as well as a
log template for these audits have been prepared as part of this project.

43
Results
To put in place the quality system for the facility, it was necessary to create critical
procedures that form the backbone of the operation of the facility. These form the basis
of the results section. The procedures of a QMS form the framework of the system and
provide vital instruction for personnel within the organisation. Their application is
essential to the achievement of quality operations within the facility and aid in
continuous improvement initiatives. This includes regular review of the procedures to
find newer, more effective ways to carry out the processes of the facility. An SOP
review and re-approval procedure must take place on a regular time basis to ensure all
aspects of the facility are kept up-to-date.
The specific procedures included in the results section are key documents that influence
the preparation and/or application of numerous other documents in the system. Their
instruction will be instrumental in getting the facility up and running as swiftly as
possible. They have been written, reviewed and approved by separate members of the
quality team to ensure they provide suitable instruction for the tasks outlined. An
organised and well-maintained documentation system is a key requirement to meeting
the guidelines of GMP and an essential component of any QMS.
The SOP for the preparation, authorisation and distribution of SOPs appears first in this
section. This procedure explains the format and style in which all SOPs must be
prepared. It describes the SOP number referencing system and how master copies, extra
copies and draft copies should be handled. Such a document is vital to the QMS as it
helps to maintain uniformity across all procedures therein. Personal preparing the SOPs
have a template to work from and those following the instructions will find the familiar
format easily recognisable. This aids the overall implementation of every procedure on-
site. The SOP Master List has also been included in this thesis (Appendix 1).
A number of documents pertaining to equipment are presented. The SOP regarding the
Equipment Tracker code system gives a detailed explanation of how equipment is
categorised and quantified in the facility. Each piece of equipment is assigned a unique
tracker code for unambiguous referencing in reports and relevant documentation. A
sample EOP has been inserted after this as an example of the kind of instruction that has
been prepared for operation personnel. Note that the EOP number is only specific to the
model of the equipment while the tracker code will differentiate between two devices of

44
the same make and model. A page from a Log of Use Maintenance and Cleaning
(LUMAC) logbook has also been included here. The headings include details such as
start time, end time, activity performed and who carried out the activity. These serve to
show the detail with which equipment operation is monitored. All LUMAC logbooks
are issued by quality personnel and their status is tracked through logbook numbers.
Full logbooks are returned to the main office and kept there as records of all operations
involving equipment. Together, these documents provide a detailed explanation of the
documentation requirements surrounding equipment in the facility. Part of the
Equipment Directory has been attached to this thesis to illustrate the depth of the system
(Appendix 2).
The SOPs for the preparation of validation protocols and reports are inserted after the
equipment procedures. These describe the format and style required for validation
documentation. Validation is a hugely important step in achieving the requirements of
GMP guidelines. It instils confidence in the quality of the process and by extension, the
product. A validated process is also an efficient one so in addition to creating high
quality product, the process is also operating extremely cost-effectively. This widens the
profit margin and broadens the scope for reinvestment in the organisation for further
expansion. Also included, are some pages from the Validation Master Plan showing the
flow patterns of Personnel, Materials and Product through the facility (Appendix 3).
The Master Formula is the major production document and usually describes the entire
process and contains the batch record sheets. A Master Formula template has been
prepared as a guideline for use with any process carried out in the facility. While many
different products will be produced here, each master formula will start with the same
template, providing some uniformity to an otherwise dynamic facility. The SOP for the
writing, approval, distribution and utilisation of the Master Formulae is the final
document to appear in the results section.

45
Standard Operating Procedure
Page 1 of 6
Title:
Standard procedure for the preparation, authorisation
and distribution of SOPs
SOP Number: 50-001-01
Location:
Whole facility
Replaces:
Date printed: Effective Date:
Written by:
Name: Patrick O’Flynn
Date: 28/05/15
Reviewed by:
Name: Jimmy Meade
Date: 01/06/2015
Approved by:
Name: Colman Casey
Date: 05/06/2015
1. Purpose
The purpose if this Standard Operating Procedure is to ensure that all relevant
personnel are familiar with the method in which Standard Operating Procedures
(SOPs) are to be prepared, authorised and distributed. This applies to all SOPs
prepared at the UCC GMP Bioprocessing production and training platform.
2. Scope
This applies to all SOPs prepared at the UCC GMP Bioprocessing production
and training platform.
3. Responsibility
3.1 It is the responsibility of the Area Manager to ensure that all relevant personnel
receive the appropriate training in order to understand and comply with this
SOP.
3.2 It is the responsibility of all relevant personnel to ensure that they understand
and comply with this SOP and to inform the Area Manager of any difficulty
encountered.

46
Page 2 of 6
Standard procedure for the preparation, authorisation
and distribution of SOPs
SOP no. 50-001-01
4. Procedure:
4.1 Page headings for SOPs
All SOPs should contain the heading detailed below on the first page (with the
relevant information entered). In the case of external approval by a Client, the
company name should also be entered in the “Approved by” section.
Page x of x
Title:
SOP Number:
Location:
Replaces:
Written by:
Name:
Date:
Reviewed by:
Name:
Date:
Approved by:
Name:
Date:
The following heading should be inserted at the top of all subsequent pages in
the SOP (and relevant information entered):
Page x of x
Short Title SOP No.

47
Page 3 of 6
Standard procedure for the preparation,
authorisation and distribution of SOPs
SOP no. 50-001-01
4.2 SOP numbering system
SOPs should be numbered in the format AA-BBB-CC, where AA corresponds
to the digits representing the SOP series, BBB corresponds to the digits
representing the SOP number within that series and CC corresponds to the digits
representing the revision number.
There series codes (AA) are as follows
10: Facility
20: Equipment
30: Production
40: Quality Control
50: Quality Assurance
For example, SOP number 10-005-01 would indicate revision number 1 of
SOP number 5 in the Facility series.
4.3 Page numbering
The automatic page numbering facility should be used to number the pages of
each SOP “Page * of *”. This should be placed in the heading of each page as
found in the sample above and in this procedure.
4.4 Approval/ authorisation
All SOPs must be approved by the Project Manager/relevant area manager, UCC
and authorised by the Q.A. manager, UCC. All SOPs which require external
approval must be approved by appropriate personnel. Original copies of each
SOP, containing the relevant signatures, will be held on file by the Q.A.
Department, UCC.
4.5 Contents of SOPs
The Contents of each SOP, in series 10, 20, 30 and 40 should be arranged in the
following sequence:
1. Purpose
2. Scope
3. Responsibility
4. Materials and Equipment
5. Procedure
6. Reporting
7. Reference Documents

48
Page 4 of 6
SOP no. 50-001-01
The Contents of each SOP in the 50 (QA) series should be arranged in the
following sequence:
1. Purpose
2. Scope
3. Responsibilities
4. Procedures
5. References
If a particular section does not apply, this should be specified (e.g. “7. Reference
Documents – not applicable”).
4.5.1 Use of subsections
Subsections should be used to divide a series of instructions into a number of
discrete units. For example, section 6 (procedures) may have subsections dealing
with descriptions/ definitions and safety:
5. Procedures
5.1 Descriptions / definitions
5.2 Safety
5.3 etc.
4.6 Distribution of SOPs
4.6.1 Approved copies of all relevant SOPs shall be distributed by the QA
Department. The pages of SOPs should be stapled together before
distribution.
4.6.2 Approved copies of SOPs will be issued on green paper, (which is
controlled by the QA Department).
4.6.3 In cases where revisions of existing SOPs are to be distributed, all copies
of the previous revision must first be returned to the QA Department.
Copies of old/obsolete SOPs will be destroyed. The original SOP will be
held on file by QA.
4.6.4 A master list of SOPs will be help by the QA Department who will
assign numbers to new SOPs, assign dates and update the SOP master
list as required.
4.6.5 The distribution log book for SOPs is updated and relevant personnel in
each area sign for SOP issuance, on receipt. The distribution list of SOPs
held on file is updated accordingly.
4.6.6 A training log is prepared for each SOP and is completed by the relevant
personnel as they are trained in the specific SOPs.

49
Page 5 of 83
SOP no. 50-001-01
4.7 Draft SOPs
4.7.1 Written procedures should be available for all relevant operations. If an
S.O.P. has not yet been approved (e.g. by Clients), a draft S.O.P. should be
available (stamped with a draft label). The draft SOP will be issued on
white paper.
4.7.2 Any draft SOPs in use must have a signed authorisation by Q.A.
4.7.3 Draft copies of SOPs must be destroyed immediately once the authorised
and approved version becomes available.
4.8 Revision of SOPs
Approved SOPs must not be amended in any way. If it becomes necessary to
alter the contents of any section of an SOP, a revised SOP shall be prepared. The
revision number shall be indicated in the numbering code (see section 3.1.1
above). All changes involved in the revision of the SOP must be listed (by
section and subsection number) on the attachment sheet where applicable (see
attachment 1).
4.9 Review of SOPs
All SOPs must be reviewed every two years. The QA manager shall maintain a
master list of all SOPs and inform the relevant personnel when individual SOPs
are due for review. New and revised SOPs shall be circulated for review to
relevant personnel using the SOP Review Form.. Any changes to a revised SOP
must be indicated on the attachment sheet. A list of SOPs that has been reviewed
is held on file by QA. If after two years an SOP is deemed to require no changes
then the SOP s to be reissued for the approval cycle, however the SOP will
retain the same revision number as the previous revision. The review date for the
SOP will be based on the new authorisation date.
5. References
Data Record Form # 50-008 SOP distribution sign off sheet
Directories: SOP Master List
SOP copies

50
Page 6 of 6
SOP no. 50-001-01
Attachment 1
Standard Operating
Procedure
SOP Review Form
SOP No. :
Title of the Procedure :
Changes Associated with this revision:
(There is an SOP Review Form attached to every SOP in the system but to avoid
redundancy in this thesis, it will only appear once here as an example.)
Reviewed by: ___________________________
Circulated to: Initial and Date
__________________________ _____________________________
__________________________ _____________________________
__________________________ _____________________________
__________________________ _____________________________
__________________________ _____________________________

51
Page 1 of 2
Title:
authorisation and application of
Equipment Tracker codes
Location:
Whole facility
Replaces:
Written by:
Date: 03/06/15
Reviewed by:
Name: Jimmy Meade
Date: 08/06/2015
Approved by:
Name: Colman Casey
Date: 12/06/15
1. Purpose
The purpose of this Standard Operating Procedure is to ensure that all relevant
personnel are familiar with the method in which equipment tracking codes are
assigned. This applies to all pieces of equipment in the UCC GMP
Bioprocessing production and training platform.
2. Responsibility
2.1 It is the responsibility of the Area Manager to ensure that all relevant personnel
SOP.
and comply with this SOP and to inform the Area Manager of any difficulty
encountered.
2.3 QA personnel are responsible for the authorisation of equipment tracker codes
and for maintaining the master list of on-site equipment.

52
Page 2 of 2
authorisation and application of Equipment Tracker
codes
SOP no. 50-008-01
3. Procedure:
3.1 Code explanation
Each piece of equipment in the facility is given a unique code to aid its
identification in documentation and for ease of reference. The code is made up
of two parts – XXXX-EYYY
3.1.1 The first part of the code (XXXX) indicates the room in which the
equipment is located. The code of the room itself will be inserted here
(e.g. 048, 051C, 051D etc.)
3.1.2 The second part of the code (YYY) identifies the equipment itself and
differentiates it from other equipment in the same room. It is a three digit
number starting at 001 for each room with E at the beginning to
disambiguate from storage units.
3.2 Code Application
3.2.1 Each piece of equipment is assigned a unique tracker code and labelled
appropriately.
3.2.2 This will follow the format as described in 3.1 of this SOP.
3.2.3 New equipment will take the next consecutive number in the series after
the most recent addition to the room (e.g. 001, 002, 003 etc. with 003
being the newest piece of equipment).
3.2.4 This code will be noted in the EOP of the equipment and will be used for
its identification in the LUMAC logbook system and other relevant
documentation.
3.2.5 QA personnel must authorise these codes so as to prevent confusion or
ambiguity in the master list.
4. Reference Documents – Not applicable

53
Page 1 of 3
Title:
Operation, Maintenance and Calibration of the
LEEC Drying Cabinet model B2, supplier
Biosciences
Location:
Media Preparation Laboratory – Room code 048
Replaces:
Written by:
Date: 08/06/15
Reviewed by:
Name: Jimmy Meade
Date: 15/06/2015
Approved by:
Name: Colman Casey
Date: 19/06/2015
1. Purpose
This procedure explains the operation, maintenance and calibration of:
LEEC Drying Cabinet,
Model B2,
Supplier Biosciences.
Equipment Tracker Code: 048-001
2. Scope
This EOP is for the drying cabinet in the Media Preparation lab, room code 048.
It will be used for drying out materials and chemicals involved in the media
preparation process. This drying cabinet must not be used for any other purposes
than those indicated.
3. Responsibility
3.1 The production microbiologist is responsible for the correct operation, routine
maintenance, cleaning and disinfecting of the drying cabinet and recording all
operations in the LUMAC logbook. The production manager is responsible for
ensuring these procedures are followed.
3.2 The Maintenance department is responsible for making adjustments and repairs
to the drying cabinet and for recording them in the LUMAC logbook.
3.3 QA must be notified of any repairs via an incident/deviation report and QA will
assess the need for revalidation after repairs.

54
Page 2 of 3
LEEC B2 Drying Cabinet
048-001
SOP No. 20-002-01
4.1 Drying Cabinet, Supplier Biosciences, model LEEC B2,
Tracker Code: 048-E001
Description: 0 Fan, 1 Shelf
Temp rang: 50o
C above ambient
Capacity: 255L
Voltage/Power rating: 240V, 50Hz
Dimensions: 864h x 635w x 610d mm
4.2 Cleaning reagents: Detergent
4.3 LUMAC logbook
5. Procedure: see referenced pages in the Operating Instructions for further detail if
required.
NOTE: Obey all safety instructions outlined in the manual for relevant procedures.
5.1 Operation (see section 3 for details)
5.1.1 Ensure the oven is connected to the electrical supply by checking that the
green neon lamp is illuminated.
5.1.2 Turn on the heaters. The amber neon lamp should illuminate once
they’re on.
5.1.3 Turn the control knob clockwise to increase the temperature and anti-
clockwise to decrease the temperature.
5.1.4 The Simmerstat energy regulator controls the heating relative to ambient
temperature. Any marked changes in ambient temperature should be duly
noted and adjustments made to the oven temperature to avoid deviations.
5.1.5 Adjust the shelf for the purposes of the current use. It is important not to
place objects on the perforated floor as this inhibits the distribution of
heat. Take care not to overload the shelves either as this could cause
damage to the oven and its contents if they were to fall.

55
Page 3 of 3
LEEC B2 Drying Cabinet
048-001
SOP No. 20-002-01
5.2 Cleaning: (see section 4 for details)
5.2.1 Prepare a solution of a mild detergent as per the manual.
5.2.2 Using a cloth dampened with the solution, wipe down the interior
surfaces of the drying oven.
5.2.3 Ensure the oven is sufficiently cleared of detergent solution and dried out
before using again.
5.3 Maintenance
5.3.1 The appliance is maintenance-free.
6. Reporting
6.1 Record each use, maintenance and cleaning operations as well as any repairs
performed in the LUMAC logbook.
6.2 All samples in the cabinet must be clearly marked and or labelled.
6.3 Report all problems in the operation of the drying cabinet immediately to the
supervisor.
SOP: 50-007-01 Preparation, distribution and application of LUMAC logbooks.
SOP: 20-001-01 Preparation of suitable cleaning reagents for specific surfaces.
LEEC B2 Drying Cabinet Operating Instructions.
LUMAC logbook.

56
Plant Log of Use,
Maintenance and Cleaning
Logbook No. ________________________________
Equipment Code ________________________________
Description ________________________________
Function ________________________________
Date Issued ________________________________

57
LUMAC
Log Page 1
SOP reference No. 50-007-01
Issued By:
Date:
Plant Log of Use, Maintenance and Cleaning
Name of Equipment ____________________ Serial No./Asset No._____________________
Date
Start
Time
Started
by/
Date
Product
Name/
Batch
Number
Activity/Operation Performed
Stop
Time
Stopped
by/
Date
Checked
by/ Date
Reviewed By _____________________ Date ____________________________

58
Page 1 of 4
Title:
Standard procedure for the preparation of
validation protocols.
Location:
Whole facility
Replaces:
Written by:
Date: 15/06/15
Reviewed by:
Name: Jimmy Meade
Date: 22/06/2015
Approved by:
Name: Colman Casey
Date: 26/06/2015
1. Purpose
The purpose of the SOP is to define how validation protocols should be written
for equipment and systems in the UCC GMP Bioprocessing Platform.
2. Responsibility
2.1 It is the responsibility of the QA manager to ensure that all relevant personnel
SOP.
and comply with this SOP and inform the QA manager of any difficulty
encountered.
3. Procedure:
3.1 The following is the format to be followed when writing a validation protocol.
Separate documents are prepared for Installation Qualification, Operational
Qualification and Performance Qualification / Process Validation.
3.2 The document should be prepared using the layout below as a guide.
3.2.1 Cover Page – This will contain the protocol number, title, revision
number, date, author, approvals (dept. title and dates) and the number of
total protocol pages not including attachments.

59
Page 2 of 4
Standard procedure for the preparation of validation
protocols.
SOP no. 50-003-01
3.2.2 Table of Contents
3.2.3 Purpose/Objective – The protocol objective is to define the system
qualification. Successful completion of these qualification requirements
will provide assurance that the system will perform as prescribed in the
processing environment.
3.2.4 Description – The equipment system is described and operational
criteria defined.
3.2.5 Methodology – description of the Installation Qualification (IQ),
Operational Qualification (OQ) or Performance Qualification (PQ) test
functions. The description should be detailed adequately to provide
meaningful direction to the validation team.
IQ is the stage in the process validation normally executed by the
engineering group. The installation of equipment, piping, services and
instrumentation is undertaken and checked to engineering drawings
(piping and instrumentation drawings, P & ID) and plant functional
specification developed during the project planning stage. IQ will
involve the identification of all system elements, service conduits and
gauges and a documented record that all installed equipment satisfies the
planned requirements.
Maintenance requirements must be identified and documented for each
installed item. Supplier operating and working instructions, maintenance
and cleaning requirements must also be collected and collated. This
should form the minimum documentation and record for a satisfactory
installation.
OQ is generally referred to as the commissioning. Critical variable
studies of the operation of the equipment and systems will define the
critical characteristics for the operation of the system or sub-system. All
testing equipment should be identified and calibrated before use. Test
methods should be authorised and implemented. SOPs for the operation,
cleaning activities, maintenance requirements and calibration schedules
of equipment and services should be drafted.

60
Page 3 of 4
protocols.
SOP no. 50-003-01
PQ is performed on utility systems where baseline testing is transferred
into a long term testing programme. This establishes the daily
operational performance factors for the systems.
Process Validation (PV) is performed after all the equipment and support
utilities have been successfully qualified as described above. The PV will
demonstrate that the process is capable of manufacturing predetermined
products reproducibly within the established quality characteristics.
3.2.6 Acceptance Criteria – for the IQ, OQ or PQ testing, the criteria for the
acceptance of the system as validated must be defined.
This may include testing results, documentation requirements and
conformance to key design criteria.
3.2.7 Deviation List – All deviations from the protocol or acceptance criteria
must be documented.
3.2.8 Summary Conclusions – A summary of validation activities completed.
3.2.9 Attachments – Analysis, tabulation, results and any other
documentation requirements specified in the protocol.
3.3 Protocols Prepared by Contractors/Vendors
3.3.1 In some cases, contractors may carry out validation or vendors for
equipment may carry out validation at the time of installation.
3.3.2 In all cases, protocols not prepared by UCC must be approved by UCC
prior to execution.
3.3.3 Protocols will be given the next sequential UCC number for ease of
reference.
3.3.4 If additional details are required then UCC will prepare a supplement or
ask the vendor to amend the protocol.
3.3.5 A summary report should be prepared for all executed protocols.
3.3.6 After execution, validation documentation will be reviewed and
approved by UCC and filed in the usual manner.

61
Page 4 of 4
protocols.
SOP no. 50-003-01
3.4 Document Numbering System
3.4.1 Each protocol will be assigned a unique document number. The same
code number will be utilised for the number of summary reports and will
be used on all validation forms. A master list of protocols is maintained.
3.4.2 Protocol numbers take the format VP-YEAR-YY-XX.
XX is the protocol number which is assigned sequentially.
YY indicates the protocol type.
For example, protocol number VP-2015-IQ-01 would be the first
validation protocol of the year 2015 and it is an Installation Qualification
protocol.
The corresponding report will have the number VR-2015-IQ-01.
If the need arises, a reference to the specific client can be placed in
brackets after the protocol type such as VP-2015-IQ-01 (client).
3.4.3 A revision number of “0” will be assigned to all first draft documents.
The revision number will remain until the document has been fully
approved. Any revision made to the draft documents will be resubmitted
for approval in the entirety, with a new approval date. Revisions made
after draft approval will have a sequential revision number assigned to
each new draft.
3.4.4 The protocols must be fully approved and signed off before the
validation can commence.
PIC guidelines of “Principe’s of qualification and validation in pharmaceutical
manufacture”
UCC GMP Bioprocessing Platform Validation Master Plan

62
Page 1 of 2
Title:
Standard procedure for the preparation of
validation reports
Location:
Whole facility
Replaces:
Written by:
Date: 17/06/15
Reviewed by:
Name: Jimmy Meade
Date: 22/06/2015
Approved by:
Name: Colman Casey
Date: 22/06/2015
1. Purpose
The purpose of the SOP is to define how validation reports should be written for
equipment and systems in the UCC GMP Bioprocessing Platform.
2. Responsibility
2.1 It is the responsibility of the QA manager to ensure that all relevant personnel
SOP.
and comply with this SOP and inform the QA manager of any difficulty
encountered.
3. Procedure:
Upon completion of the qualification and validation testing, a validation report
is prepared for each piece of equipment or system. The report will contain the
following sections as a minimum.
3.1 Cover page/ Approval page
This contains the report protocol number, revision number, date, title and the
sign off for certification of the system or process. The reviewers sign that the
validation package is complete and that the acceptance criteria established in the
protocol have been satisfied. The report number, revision number, date title,
written by, approvals (Dept. Title, signature and dates) will be included on this
page. The time frame between completion of the report and final sign-off should
be no longer than six weeks.

63
Page 2 of 2
reports.
SOP no. 50-004-01
3.2 Objective and Description
This section defines the purpose of the study, describes the system or process to
be validated and explain the experimental design of the protocol that was
utilised.
3.3 Procedure Section
The procedure followed to validate the system or process will be briefly
described. Results obtained will be summarised.
3.4 Deviations
Any deviations in terms of procedure or results from those originally defined in
the protocol will be documented and discussed as to their impact upon the
validation study.
3.5 Conclusions
Based on the validation data that was obtained, recommendations will be made
regarding the acceptability of the system for its intended purpose.
PIC guidelines of “Principe’s of qualification and validation in pharmaceutical
manufacture”
UCC GMP Bioprocessing Platform Validation Master Plan

64
Page 1 of 5
Title:
Standard procedure for the writing, approval,
distribution and utilisation of the Master Formulae
Location:
Production suite
Replaces:
Written by:
Date: 21/06/15
Reviewed by:
Name: Jimmy Meade
Date: 29/06/2015
Approved by:
Name: Colman Casey
Date: 03/07/2015
1. Purpose
The purpose of this SOP is to describe the writing, approval and distribution and
use of the Master Formulae as instructions for operators involved in the
production processes of the Bioprocessing facility.
2. Scope
This SOP applies to all Master Formulae and accompanying documentation
prepared and used for the instruction of production operations in the
Bioprocessing facility.
3. Responsibility
3.1 The QA and Production Managers are responsible for meeting with the client
and writing the Master Formulae to suit their needs.
3.2 It is the responsibility of the QA department authorise the distribution of the
Master Formulae and to review them as necessary.
3.3 All operators involved in the production process are responsible for following
the instructions of the Master Formulae to the best of their trained ability and for
reporting any issues to the supervisor.
4.1 Will vary according to the details of the individual Master Formulae.

65
Page 2 of 5
SOP No. 30-001-01
5. Procedure:
The instructions for the manufacturing method are also written procedures but
are not called SOPs. The full procedure is detailed in a Master Formula which
details preparations to be made, the equipment to be used, and the method to be
followed. GMP documents from the WHO and other countries all require that a
Master Formula be prepared and approved for each batch size of every product
manufactured.
The Master Formula can be prepared as a set of documents: one for each
segment of the full production process, or a single overall document that
contains parts which describe each of the process steps. This will vary with
different products and changing client needs. Regardless, the sections of the MF
should correspond to the chronological operations for the major process steps.
There must also be spaces provided for data recording, approval and verification
initials and space for review by a supervisor.
Master Formula
Document that explains the detailed steps included in a facility’s methods for
producing a batch of a product.
Batch
Batches are defined as a specific quantity of a drug or material that is produced
in a single manufacturing operation having a uniform character and quality and
which meets pre-determined specifications.
Batch Processing Records
Batch Processing Records are built up by filling in the blanks on approved MF
sheets. An approved copy of the MF is required by the production department
for each production run of a batch. The batch processing record document must
be verified by QA or QC as an exact replica of the current MF before being
released for a production run.
Batch Processing Record Review
A product record is assembled from the batch processing records, lyophilisation
record, environmental monitoring records, inspection records, quality control
records etc. The final release of the product can only occur when the entire
product record has been reviewed and approved by a Production Manager and
QC and QA departments according to SOP – Batch Processing Record Review.

66
Page 3 of 5
SOP No. 30-001-01
5.1 Writing
5.1.1 Headings and Footers
Each page of the document should include the heading below with the relevant
sections filled in according to the details of the individual maser formulae. The
footer of each page should have space for the Effective date and two dated
authorisation signatures to be written. See below for an example.
GMP Bioprocessing
Platform,
University College Cork
Page 66 of 83
Master Formula: Doc # 001 Revision No. 1
Client Company A
Process Steps Fermentation, Recovery, Product Formulation, Product
Storage (etc.)
Product Name Probiotic XXX Batch Size
Product Code #### Lot Number
5.1.2 Front Page
The front page of the Master Formulae document should include a table with
spaces for written by, edited by, production approval and authorisation
signatures. It should also include a table of contents for the master formula
outlining section numbers, descriptions and page numbers. Any other important
details regarding the client or the product should be placed on the front page for
ease of reference. (See attachment 2a for details).
5.1.3 Sections
The document should be split up according to sections of the process and the
number of days required per section. For example, Part 1 may be Fermentation
and this could take 3 days. Fermentation will make up 1 section within the
document and the 3 days will make up 3 separate sections again. Each day’s
activities should be categorised as follows:
a) Preparation
b) Manufacturing Instructions
c) Clean up
d) Reporting

67
Page 4 of 5
SOP No. 30-001-01
The instructions for each day should be started on a new page to help minimise
the number of pages brought into the production area at any one time. The next
stage on the process (e.g. Recovery) should be a whole new section again and
formatted in the same way. This all helps to segment the paperwork and keep the
operation organised. (See attachment 2b for details).
5.2 Approval and Distribution
5.2.1 The writing of the Master Formulae should be a joint effort between the
Bioprocessing facility personnel and the client. The QA and Production
managers should meet the client and discuss their needs. Once an
agreement has been reached, the final draft of the Master Formulae is
signed by representatives of both the Bioprocessing facility and the client
as proof of approval and authorisation of the document. Any revisions
must be approved in the same way.
5.2.2 The Master Formulae are kept in the QA department and production
personnel are provided with Batch Processing Records. These are
approved by QA or QC as an exact replica of the current MF before
being released for a production run.
5.3 Utilisation
5.3.1 Batch Processing Records are to be kept close to hand at all times during
operations and the step-by-step guide to be followed exactly.
5.3.2 Any blank spaces designated for data recording should be filled in as the
operation processes to show that the production events occurred as
directed. Any deviations are to be noted in the margins.
5.3.3 Ensure that copies of any referenced SOPs are available to production
personnel at all times during production and that these procedures are
followed correctly.
5.3.4 All Batch Processing Records must be reviewed and approved by a
Production Manager and QC and QA departments according to SOP –
Batch Processing Record Review.

68
Page 5 of 5
SOP No. 30-001-01
6. Reporting
6.1 All details regarding writing, approval, distribution and utilisation should be
effectively communicated between the facility personnel and the client.
6.2 Any and all changes/revisions to the document should be reported to the relevant
parties involved (client, production personnel etc.)
6.3 All Batch Processing Records must be reviewed by a supervisor and then by the
Production Manager and QC and QA departments before product approval.
6.4 Operators should report any issues with the Batch Processing Record
instructions to the supervisor immediately.
SOP: 50-006-01 Batch Processing Record Review
DRF: 50-001 Batch Processing Record Review and Approval Log
Master Formula for GMP Facility (template)

69
Discussion
A Quality Management System is not focused on operation details but more so on how
well these operations are controlled and monitored. The point of a QMS is to generate
confidence that the process is under control so long as the procedures in place are
followed correctly. Employees are trained sufficiently to make reasonable decisions
within the scope of their position and take responsibility for the outcome of these
decisions. This delegation of responsibility requires the upper ranks of management to
place trust in their employees and to avoid micro-managing where possible.
Management ranks can be broken up into 3 simple categories; Top, Middle and
Employee (1). Each level of the hierarchy has its own equally important role to play in
the smooth operation of processes within the organisation. Top Management focuses on
the “helicopter view” of the market and keeps an eye on the horizon while planning for
the future. From this perspective, new competition as well as new technologies coming
into the market can be anticipated and adequately planned for. Middle Management
focuses on the current management of the business and the day-to-day running of
operations. This allows top management to confidently focus on their duties knowing
that the QMS is being correctly implemented. Personnel in the Employee level of the
management hierarchy are charged with effectively carrying out the operations required
by the processes of the organisation. Greater competence here, through adequate
training, relieves pressure on all higher levels of the hierarchy. See figure 14 below for
an illustration of a management hierarchy within an organisation.
Figure 14 - Simple Management Hierarchy (1)

BT6002 - Research Dissertation - Patrick O'Flynn - 110329811

BT6002 - Research Dissertation - Patrick O'Flynn - 110329811

Recommended

Recommended

More Related Content

What's hot

What's hot (18)

Similar to BT6002 - Research Dissertation - Patrick O'Flynn - 110329811

Similar to BT6002 - Research Dissertation - Patrick O'Flynn - 110329811 (20)

BT6002 - Research Dissertation - Patrick O'Flynn - 110329811