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 m

3 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.

Documentation for GMP facility

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.

Documentation for GMP facility

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

Facility Equipment Production

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.

Documentation for GMP facility

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.

Documentation for GMP facility

Facility Equipment Production 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.

Standard Operating Procedure

Page x of x

Title:

SOP Number:

Location: Replaces:

Date printed: Effective Date:

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

Standard procedure for the preparation,

authorisation and distribution of SOPs 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

Standard procedure for the preparation,

authorisation and distribution of SOPs 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

Standard procedure for the preparation,

authorisation and distribution of SOPs 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

Standard Operating Procedure

Page 1 of 2

Title:

Standard procedure for the preparation,

authorisation and application of

Equipment Tracker codes

SOP Number: 50-008-01

Location:

Whole facility Replaces:

Date printed: Effective Date:

Written by:

Name: Patrick O’Flynn

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

receive the appropriate training in order to understand and comply with this

SOP.

2.2 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.

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

Standard procedure for the preparation,

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

Standard Operating Procedure

Page 1 of 3

Title:

Operation, Maintenance and Calibration of the

LEEC Drying Cabinet model B2, supplier

Biosciences

SOP Number: 20-002-01

Location:

Media Preparation Laboratory – Room code 048 Replaces:

Date printed: Effective Date:

Written by:

Name: Patrick O’Flynn

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. Materials and Equipment

4.1 Drying Cabinet, Supplier Biosciences, model LEEC B2,

Tracker Code: 048-E001

Description: 0 Fan, 1 Shelf

Temp rang: 50oC 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.

7. Reference Documents

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

Standard Operating Procedure

Page 1 of 4

Title:

Standard procedure for the preparation of

validation protocols.

SOP Number: 50-003-01

Location:

Whole facility Replaces:

Date printed: Effective Date:

Written by:

Name: Patrick O’Flynn

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

receive the appropriate training in order to understand and comply with this

SOP.

2.2 It is the responsibility of all relevant personnel to ensure that they understand

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

Standard procedure for the preparation of validation

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

Standard procedure for the preparation of validation

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.

4. Reference Documents

PIC guidelines of “Principe’s of qualification and validation in pharmaceutical

manufacture”

UCC GMP Bioprocessing Platform Validation Master Plan

62

Standard Operating Procedure

Page 1 of 2

Title:

Standard procedure for the preparation of

validation reports

SOP Number: 50-004-01

Location:

Whole facility Replaces:

Date printed: Effective Date:

Written by:

Name: Patrick O’Flynn

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

receive the appropriate training in order to understand and comply with this

SOP.

2.2 It is the responsibility of all relevant personnel to ensure that they understand

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

Standard procedure for the preparation of validation

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.

4. Reference Documents

PIC guidelines of “Principe’s of qualification and validation in pharmaceutical

manufacture”

UCC GMP Bioprocessing Platform Validation Master Plan

64

Standard Operating Procedure

Page 1 of 5

Title:

Standard procedure for the writing, approval,

distribution and utilisation of the Master Formulae

SOP Number: 30-001-01

Location:

Production suite Replaces:

Date printed: Effective Date:

Written by:

Name: Patrick O’Flynn

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. Materials and Equipment

4.1 Will vary according to the details of the individual Master Formulae.

65

Page 2 of 5

Standard procedure for the writing, approval,

distribution and utilisation of the Master Formulae 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

Standard procedure for the writing, approval,

distribution and utilisation of the Master Formulae 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

Standard procedure for the writing, approval,

distribution and utilisation of the Master Formulae 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

Standard procedure for the writing, approval,

distribution and utilisation of the Master Formulae 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.

7. Reference Documents

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)

70

The basic QMS strategy involves 3 key pillars surrounded by clear instructions, up-to-

date reporting and regular management review. These pillars are KPI, CAPA and QO.

Key Performance Indicators – the KPIs in a QMS are the points in the process that are

tangible and can be measured with metric units to give a direct indication of

performance. A simple example would be, in the case of a weighing scale calibration

firm, the average time spent calibrating a weighing scale. This KPI can be clearly

instructed by way of an ideal estimate (ie. Maximum time per scale is 30 minutes), the

time spent on each weighing scale can be reported by a start and end time for each job

and these figures can be regularly reviewed at each management meeting.

Corrective Action Preventive Action – The CAPAs are procedures put in place to

remedy any non-conformance KPI measurements. They detail what to do when things

go wrong, how to fix the problems and who makes the relevant decisions. To stick with

our simple example, a non-conformance measurement here would be if the average

calibration time exceeded 30 minutes. The actions involved here would include an

investigation into the root-cause of the non-conformance and implementation of suitable

corrective action where necessary.

Quality Objectives – The QOs of a QMS are those future plans for the organisation that

aim to improve overall quality within the process. These plans outline what is to be

achieved, how this will be resourced, the timeline for the project and how this will

improve overall quality. Staying with our weighing scale example, a quality objective

could be to set up a standardised printing system for all weighing scales in the

laboratory. This reduces the chance of errors from analysts manually recording results.

automated printouts from analytical devices are also recommended for GLP

compliance. See figure 15 below for an illustration of the QMS strategy and how it is

built on these 3 pillars of quality.

71

Figure 15 - Illustration of the QMS strategy based on the 3 pillars of quality (1)

72

The purpose of this project was to design a QMS for the GMP Bioprocessing

production and training facility. It involved the generation of a documentation system

for the co-ordination of all operations in the facility. This included detailed written

procedures for some of the 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 was to set up a framework for the quality system and to

generate as many procedures and formal business documents as possible. Further

documentation, completed outside the scope of this project, could be added to this

framework to continue building the quality system. An equipment tracking system was

also developed. This again will be built on by future users and will include equipment

tracker codes, equipment logbooks and EOPs for referencing, recording and instructing

equipment use respectively.

As can be seen in the results section of this paper, the project was successful in

developing a quality system framework and initiating the generation of key

documentation which will be required once the facility is up and running. The

instructions found in SOP 50-001-01 describing how all SOPs should be prepared,

authorised and distributed will be adhered to for all future SOPs written as part of this

quality system. This will maintain a certain level of uniformity within the

documentation system as the facility is progressed towards completion. The equipment

tracking system will 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.

SOPs 50-003-01 and 50-004-01 outline how validation protocols and reports should be

prepared, respectively. A number of protocol and report templates have also been

prepared for the Installation Qualification (IQ), Operation Qualification (OQ),

Performance Qualification (PQ), Process Validation (PV) and Analytical Assay

Validation (AV) aspects of validation as part of this project. An outline Validation

Master Plan (VMP) template has also been developed and can be found in the

Validation subfolder of the Quality Assurance folder. This outlines the whole approach

to quality and validation within the facility and acts as a guideline for many quality

73

operations onsite. Appendix 3 of this paper is taken directly from this VMP and outlines

flow plans for personnel, materials and product through the facility.

SOP 30-001-01 outlines the format that the Master Formulae should be prepared in and

a template example of this has also be developed as part of this project. Part of the plan

for the production suite is to rent it out to clients for the purpose of producing their lab

scale product in large enough quantities for clinical trials. The Master Formula SOP will

serve a similar purpose to that of SOP 50-001-01. It will provide some level of

uniformity to production operations in the facility even though each campaign may well

be a completely different product to the last. Writing, approval, distribution and

utilisation of these documents will be made easier by this uniformity.

Regarding future perspective, the facility is planned to be up and running by early 2016.

A quality consultant has been hired to help with finishing off the quality system

developed as part of this project. She will aid in the fine tuning of current procedures as

well as the generation of the remaining documentation for the facility. Her input will

ensure that quality operations at the facility are up to the standards recommended by

GMP guidelines set by both Eudralex and the WHO. Key personnel are also to be

trained in the operation of the production equipment within the next few months.

Equipment is currently being procured for both the training and production suites. As

each device enters the facility, it will be assigned an equipment tracker code (ETC) and

a suitable SOP prepared for its operation and maintenance. Calibration schedules will

also be decided upon for all relevant devices, e.g. lab balances, pH meter, conductivity

meters, incubators, heating ovens etc. Some devices and systems will also need to be

qualified and subsequently validated. Completion of these objectives will most certainly

help prepare the facility for its opening date in early 2016 and aid all operations

thereafter.

74

Bibliography

1. Goetsch DL, Davis SB. Quaity Management - Introduction to Total Quality

Management for Production Processing and Services. 4th edition.

2. Eudralex Volume 4 Good Manufacturing Practice for Medicinal Productions for

Human and Veterinary use Chapter 1: Pharmaceutical Quality System.

3. ICH Harmonised Tripartite Guideline Pharmaceutical Development Q8(R2) Current

Step 4 version dated August 2009.

4. International conference on harmonisation of technical requirements for registration

of pharmaceuticals for human use. ICH Harmonised Tripartite Guideline Quality

Risk Management Q9 Current Step 4 version dated 9 November 2005.

5. ICH Harmonised Tripartite Guideline Pharmaceutical Quality Sytem Q10 Current

Step 4 version dated 4 June 2008.

6. ISO 9001:2008(en) Quality Management Systems - Requirements.

7. Developing an Asset Maintenance Quality Management System to ISO 9001

Requirements [Internet]. Available from: http://www.lifetime-

reliability.com.au/free-articles/iso9001-quality-management-tips/maintenance-

management-iso9001-quality-system.html

8. ISO 9000 quality systems handbook by David Hoyle 2005 ISBN 0-7506-6785-0

page 234.

9. Eudralex Volume 4 Good Manufacturing Practice for Medicinal Productions for

Human and Veterinary use Chapter 4: Documentation.

10. The Certified Manager of Quality/Organizational Excellence Handbook, ASQ

Quality Press, Fourth Edition, 2014, Pages 266-268.

11. EudraLex The Rules Governing Medicinal Products in the European Union Volume

4 EU Guidelines for Good Manufacturing Practice for Medicinal Products for

Human and Veterinary Use Part 1 Chapter 2: Personnel.

12. Eudralex Volume 4 Good Manufacturing Practice for Medicinal Productions for

Human and Veterinary use Chapter 5: Production.

13. FDA. Guidance for Industry Quality Systems Approach to Pharmaceutical CGMP

Regulations.

14. Eudralex Volume 4 Good Manufacturing Practice for Medicinal Productions for

Human and Veterinary use Chapter 2: Personnel.

15. Fargher, Hugh E., and Richard A. Smith. “Method and system for production

planning.” U.S. Patent No. 5,586,021. 17 Dec. 1996.

16. Eudralex Volume 4 Good Manufacturing Practice for Medicinal Productions for

Human and Veterinary use Chapter 6: Quality Control.

75

17. Eudralex Volume 4 Good Manufacturing Practice for Medicinal Productions for

Human and Veterinary use Chapter 8: Complaints, Quality Defects and Product

Recalls.

18. ISO 22000 Food Safety Management Systems - Requirements for any organisation

in the food chain, 2005.

19. Food Safety Authority of Ireland.

https://www.fsai.ie/food_businesses/haccp/principles_of_haccp.html.

20. W. Whyte. Cleanroom Technology - Fundamentals of Design, Testing and

Operation. 1st ed. University of Glasgow, UK; 2001.

21. W. Whyte. Cleanroom Design. 2nd Edition. 1999.

22. Eudralex Volume 4 Annex 1 - Manufacture of Sterile Medicinal Products.

23. ISO 14644-4: Cleanrooms and associated controlled environments — Part 4:

Design, construction and start-up, 2001.

24. FDA Guidance for Industry: Current Good Manufacturing Practice in

Manufacturing, Packaging, Labeling, or Holding Operations for Dietary

Supplements; Small Entity Compliance Guide [Internet]. Available from:

http://www.fda.gov/Food/GuidanceRegulation/GuidanceDocumentsRegulatoryInfor

mation/ucm238182.htm

25. Gillian Chaloner-Larsson, Roger Anderson, Anik Egan. A WHO guide to good

manufacturing practice (GMP) requirements. Part 1: Standard operating procedures

and master formulae. World Health Organisation; 1997.

26. Gillian Chaloner-Larsson, Roger Anderson, Anik Egan. A WHO guide to good

manufacturing practice (GMP) requirements. Part 2: Validation. World Health

Organisation; 1997.

76

Appendices

Appendix 1: SOP Master List

Contents of the Facility folder are to be credited to Michelle Aherne as part of her

project.

The contents of the Equipment, Production, Quality Control and Quality Assurance

folder are to be credited to this project (Patrick O’Flynn).

SOP No. Facility

10-001-01 Bioprocessing Unit Cleaning of restricted areas Pilot Plant 10-002-01 Bioprocessing Unit Cleaning of restricted areas Training suite 10-003-01 Access Control Pilot plant 10-004-01 Access Control Training suite 10-005-01 Hygiene, Gowning, Degowning Pilot plant 10-006-01 Hygiene, Gowning, Degowning Training suite 10-007-01 Material transfer Pilot plant 10-008-01 Material Transfer Training suite 10-009-01 Personnel Conduct Code Pilot plant 10-010-01 Personnel Conduct Code Training Suite

10-011-01 Cleaning, sterilisation and depyrogenation of materials coming into contact with product, Pilot plant

10-012-01 Cleaning, sterilisation and depyrogenation of materials coming into contact with product, Training suite

10-013-01 Environmental monitoring programme Pilot plant 10-014-01 Environmental monitoring programme Training suite

10-015-01 Reporting of Production Incidents/Deviations and Resulting Actions Pilot plant

10-016-01 Reporting of Production Incidents/Deviations and Resulting Actions Training suite

10-017-01 Aseptic sampling of Bioreactor Pilot Plant 10-018-01 Aseptic sampling of Bioreactor Training suite

77

SOP No. Equipment

20-001-01 Preparation of Suitable Cleaning Reagents for Specific Surfaces 20-002-01 Operation, Maintenance and Calibration of LEEC B2 Drying Cabinet

20-003-01 Operation, Maintenance and Calibration of IKA C-MAG HS 10 Magnetic Hotplate Stirrer

20-004-01 Operation, Maintenance and Calibration of Jenway 4520 Conductivity meter 20-005-01 Operation, Maintenance and Calibration of Jenway 3520 pH meter 20-006-01 Operation, Maintenance and Calibration of Miele G7883 Dishwasher 20-007-01 Operation, Maintenance and Calibration of Sortorius AX224 Lab Balance 20-008-01 Operation, Maintenance and Calibration of Bioair Safemate 1.2 Biosafety Hood 20-009-01 Operation, Maintenance and Calibration of Biostat B Bench Top Fermenter 20-010-01 Operation, Maintenance and Calibration of D-DCU 100L Fermenter

20-011-01 Operation, Maintenance and Calibration of Sartoflow Advance, TF microfiltration unit

20-012-01 Operation, Maintenance and Calibration of Sartoflow beta plus, TF microfiltration unit

20-013-01 Operation, Maintenance and Calibration of Bioair Aura HZ 48 Biosafety Hood 20-014-01 Operation, Maintenance and Calibration of Bioair Safemate 1.5 Biosafety Hood 20-015-01 Operation, Maintenance and Calibration of Zirbus Sublimator 4x5x8 20-016-01 Operation, Maintenance and Calibration of Bioair Safemate 0.9 Biosafety Hood 20-017-01 Operation, Maintenance and Calibration of Memmert INP 500 Incubator 20-018-01 Operation, Maintenance and Calibration of Sartorius AZ612 Lab Balance 20-019-01 Operation, Maintenance and Calibration of Interscience Scan 300 Colony Counter

20-020-01 Operation, Maintenance and Calibration of Thermoscientific Heratherm OMH60SS Oven

20-021-01 Operation, Maintenance and Calibration of Scientific Inc. Vortex Genie 2 Vortex Mixer

SOP No. Production

30-001-01 Writing, approval, distribution and utilisation of the Master Formulae 30-002-01 Regulation of Biological Starting Materials 30-003-01 Raw Material Specification Sheet

SOP No. Quality Control

40-001-01 Method for Sampling Raw Materials and Production Components

SOP No. Quality Assurance

50-001-01 Preparation, authorisation and distribution of SOPs 50-002-01 Responsibilities of Quality Operations Personnel 50-003-01 Preparation of Validation Protocols 50-004-01 Preparation of Validation Reports 50-005-01 Reporting of Production incidents, Deviations and Resulting Actions 50-006-01 Batch Processing Record Review 50-007-01 Preparation and use of LUMAC logbooks 50-008-01 Equipment Tracker codes 50-009-01 SOP Storage Unit Tracker codes 50-010-01 Quality Audits, General 50-011-01 Quality Assurance Self-inspection

78

Appendix 2: Equipment Directory (partial)

Extracted from the Equipment Directory system which was prepared as

part of this project.

Production Suite Equipment Directory

Tracker Code Name/Description EOP No.

048-E001 LEEC B2 Drying Cabinet 20-002-01

048-E002 IKA C-MAG HS 10 magnetic hotplate stirrer 20-003-01

048-E003 IKA C-MAG HS 10 magnetic hotplate stirrer 20-003-01

048-E004 Jenway 4520 Conductivity meter 20-004-01

048-E005 Jenway 3520 pH meter 20-005-01

048-E006 Miele G7883 Dishwasher 20-006-01

048-E007 Sartorius AX224 Lab Balance 20-007-01

051C - E001 Bioair Safemate 1.2 biosafety cabinet 20-008-01

051C - E002 Bench top Fermenter 20-009-01

051C - E003 BIOSTAT 100L Fermenter 20-010-01

051C - E004 Bench top TF microfiltration unit 20-011-01

051C - E005 SartoFlow TF microfiltration unit 20-012-01

051D - E001 Bioair Aura HZ 48 biosafety cabinet 20-013-01

051D - E002 Bioair Safemate 1.5 biosafety cabinet 20-014-01

051D - E003 Zirbus 4x5x8 Sublimator 20-015-01

051E - E001 Bioair Safemate 0.9 biosafety cabinet 20-016-01

051E - E002 Memmert INP 500 Incubator 20-017-01

051E - E003 Memmert INP 500 Incubator 20-017-01

051E - E004 Sartorius AZ612 Lab Balance 20-018-01

051E - E005 Interscience Scan 300 Colony Counter 20-019-01

051E - E006 Thermoscientific Heratherm OMH60SS Oven 20-020-01

051E - E007 Vortex Genie 2 vortex mixer 20-021-01

051E - E008 Vortex Genie 2 vortex mixer 20-021-01

79

Appendix 3: Personnel, Product and Waste Flow

Extracted from the Validation Master Plan which was prepared as part of

this project.

Personnel Flow

Training Facility Personnel

Production Facility Personnel

80

Materials Flow

Training Suite Materials

Production Suite Materials

81

Product Flow

Training Suite Product

Production Suite Product

82

Room Allocations:

Training Suite: Changing Room 050

Media Preparation 050A

Culture Preparation 050B

Bioreactor Training 050C

Purification Training 050D

Autoclave Room 050F

Corridor 060

Airlock 061

Common Exit Lobby 062

Common Exit Airlock 063

Production Suite: Media Preparation 048

Freezer Storage 049

Sterilisation Room 051A

Gowning Lobby 051

Culture Preparation 051B

Fermentation and Recovery 051C

Product Formulation 051D

Product Testing 051E

Product Freezer Storage 051F

Corridor 065

Corridor 066

1st Airlock 064

Common Exit Lobby 062

Common Exit Airlock 063

Ancillary Areas: Shared External Corridor 069

Staircase 10

Independent GMP Clean Room 051G