Planning for Installation and Operational Qualification ......tools allows to plan the next stages...

Planning for Installation and Operational Qualification for a New

Granulation Line on a Risk-based Approach

Inês Aniceto de Mendonça Neves Correia

Thesis to obtain the Master of Science Degree in

Master in Pharmaceutical Engineering

Supervisor(s): Prof. Dr. José Monteiro Cardoso de Menezes

MSc. Mara Diana Saavedra Cardoso Doria

Examination Committee

Chairperson: Prof. Pedro Paulo De Lacerda e Oliveira Santos

Supervisor: MSc. Mara Diana Saavedra Cardoso Doria

Members of the Committee: Dr. Rui Miguel Dias Loureiro

December 2019

I

Preface

The work presented in this thesis was developed in the company Labatec Farmacêutica S.A. (Sintra, Portugal),

during the period March-September 2019, under the supervision of MSc. Mara Doria. The thesis was co-

supervised at Instituto Superior Técnico by Prof. Dr. José Cardoso de Menezes.

I declare that this document is an original work of my own authorship and that it fulfills all the requirements of

the Code of Conduct and Good Practices of the Universidade de Lisboa.

II

Acknowledgements

I would like to express my sincere gratitude:

To Professor José Cardoso de Menezes for the opportunity to approach the professional world and for the

opportunity to experiment to work with the iRisk tool;

To Mara, for her continuous support throughout the internship, her wise advice and guidance during the

writing of the thesis, but also for her patience and motivation. Her leadership was essential, especially in

helping me to define a clear scope for this work. Furthermore, for giving me the opportunity to understand

the functioning of the quality assurance department and teaching me the tasks to perform in it;

To all Labatec team, for the affection and welcome from day one, but also for their patience and support in

overcoming numerous obstacles I had to face through my research.

To Diogo, my all-hour companion, who shared this adventure with me. Thank you for the discussion of ideas,

for the readings and amendments, for the time I stole from you while I was writing. Our academic projects

crossed paths with our life project: I hope that the end of the first ones will mean a new phase in our lives.

Thank you for being who you are and for being by my side.

Last, but not the least, I would like to thank my family: a special word to my little brother Frederico, but also

to my parents, for supporting me spiritually, not only while writing this thesis, but also throughout my life, in

general. Without them, none of this would have been possible.

III

Abstract

With the aim of increasing the volume of oral solid drug products – tablets and capsules production, Labatec

started in 2018 the construction of a new factory in Portugal. With the acquisition of new equipment for

production, there is also a need to successfully complete the qualification activities. The first drug product that

will be manufactured in the new facility is an oral solid tablet. The manufacturing process of this product begins

with a granulation and, therefore this was the equipment chosen for the scope of this thesis. This work describes

the first stages of qualification of the new equipment in accordance with the principles described in the guideline

EudraLex, Volume 4, Annex 15. The granulation line consists of a high shear mixer, a fluid bed dryer, a pneumatic

transport mechanism and two sieving mills. The User Requirement Specifications for the new line were first

defined and a Design Qualification was performed, by crossing the previously defined specifications with the

information and documents of the equipment supplier. The last part of this project includes a functional risk

assessment, through which it was possible to plan the next stages of qualification (Installation Qualification and

Operational Qualification). It also includes an example of the results obtained by using the iRisk risk management

tool.

Keywords: Equipment Qualification, Risk Assessment, High Shear Mixer, Fluid Bed Dryer, Granulation

IV

Resumo

Com o objetivo de aumentar o volume de produção de medicamentos sólidos orais – comprimidos e cápsulas,

a Labatec iniciou, em 2018, a construção de uma nova fábrica em Portugal. Com a aquisição de novos

equipamentos para a produção, surge também a necessidade de concluir com sucesso as atividades de

qualificação. O primeiro medicamento que irá ser fabricado nas novas instalações é um comprimido sólido oral.

O processo de fabrico deste produto começa com uma granulação, razão pela qual este foi o equipamento

escolhido para o âmbito desta tese. Este trabalho descreve as primeiras etapas de qualificação do novo

equipamento de acordo com os princípios descritos na diretriz EudraLex, Volume 4, Anexo 15. A linha de

granulação é composta por um misturador de alta velocidade, um secador de leito fluidizado, um mecanismo de

transporte pneumático e dois tamisadores. Primeiro definiram-se os requerimentos/especificações para a nova

linha e foi realizada uma Qualificação de Design, cruzando as especificações previamente definidas com as

informações e documentos do fornecedor do equipamento. A última parte deste projeto inclui uma avaliação de

risco das funcionalidades, através da qual foi possível planear as próximas etapas de qualificação (Qualificação

de Instalação e Qualificação Operacional), incluindo também um exemplo dos resultados obtidos com a utilização

da ferramenta de gestão de risco iRisk.

Palavras Chave: Qualificação de Equipamentos, Análise de Risco, Misturador, Secador em Leito Fluidizado,

Granulação

V

Content

Preface ................................................................................................................................................................ I

Acknowledgements ........................................................................................................................................... II

Abstract ............................................................................................................................................................ III

Resumo ............................................................................................................................................................. IV

Abbreviatures .................................................................................................................................................. VII

Figures ............................................................................................................................................................ VIII

Tables ............................................................................................................................................................. VIII

1. Introduction ............................................................................................................................................... 1

1.1 Objective ........................................................................................................................................... 1

1.2 The Company: Labatec ...................................................................................................................... 1

1.3 Mydocalm ............................................................................................................................................... 2

1.4 Mydocalm Manufacturing Process ......................................................................................................... 3

1.3 Qualification and Validation .............................................................................................................. 3

1.3.1 Qualification .................................................................................................................................... 4

1.3.2 Validation ........................................................................................................................................ 5

1.4 Risk Management .............................................................................................................................. 6

1.4.1 Risk Management Tools .................................................................................................................. 8

1.4.2 iRISK ................................................................................................................................................ 9

2. Granulation .............................................................................................................................................. 11

2.1 Granulation Process .............................................................................................................................. 11

2.3 Diosna Granulation Line ....................................................................................................................... 12

3. Results: Qualification of Granulation Line ............................................................................................... 15

3.1 General Risk Assessment ...................................................................................................................... 15

3.2 User Requirements Specification .......................................................................................................... 17

3.4 Functional Risk Assessment .................................................................................................................. 25

3.4.1 FMEA Methodology ...................................................................................................................... 25

3.4.2 iRisk Tool ....................................................................................................................................... 43

3.5 Design Qualification .............................................................................................................................. 44

VI

4. Conclusion and Further Work .................................................................................................................. 53

5. References ............................................................................................................................................... 54

Annex 1 – General Risk Assessment Form filled for Granulation Line ............................................................ 55

Annex 2 – iRisk Report ..................................................................................................................................... 56

VII

Abbreviatures

DQ – Design Qualification

EMA – European Medicines Agency

FBD – Fluid Bed Dryer

FDA – Food and Drugs Administration

FMEA – Failure Mode Effects Analysis

FMECA – Failure Mode Effects and Criticality Analysis

FRA – Functional Risk Assessment

FTA – Fault Tree Analysis

GEP – Good Engineering Pratices

GMP – Good Manufacturing Practices

GRA – General Risk Assessment

HSM – High Shear Mixer

ICH – International Council for Harmonization of Technical Requirements for Pharmaceuticals for Humane Use

IQ – Installation Qualification

OOS – Out of Specification

OQ – Operational Qualification

PLC – Programmable Logic Controller

PQ – Performance Qualification

QMS – Quality Management System

QR – Qualification Report

QRM – Quality Risk Management

RPN – Risk Priority Number

RQ - Requalification

SOP – Standard Operational Procedure

URS – User Requirement Specification

VC – Vacuum Conveyor

VMP – Validation Master Plan

WIP – Wash in Place

VIII

Figures

Figure 1: Labatec Logo ....................................................................................................................................... 1

Figure 2: Labatec's worldwide presence ........................................................................................................... 2

Figure 3: Tolperisone HCl chemical formula ...................................................................................................... 2

Figure 4: Packages of Mydocalm 50mg and 150mg .......................................................................................... 2

Figure 5: Mydocalm process flow ...................................................................................................................... 3

Figure 6: Stages of qualification (adapted from) ............................................................................................... 4

Figure 7: Typical risk management process....................................................................................................... 7

Figure 8: iRISK platform logo ............................................................................................................................. 9

Figure 9: High Shear Mixer .............................................................................................................................. 12

Figure 11: Sieving mill ...................................................................................................................................... 13

Figure 10: Fluid Bed Dryer ............................................................................................................................... 13

Figure 12: Vacuum Conveyor .......................................................................................................................... 14

Figure 13: Qualification process in Labatec ..................................................................................................... 15

Figure 14: Summarization of the risks based on (a)RPN; (b) Severity, Detectability and Ocorrence .............. 43

Figure 15: Risk matrix ...................................................................................................................................... 44

Tables

Table 1: Definitions of different stages of qualification according to Eudralex, Volume 4, Annex 15 .............. 4

Table 2: Advantages and disadvantages of granulation .................................................................................. 11

Table 3: Classification of drying processes ...................................................................................................... 11

Table 4: General Risk Assessment Questions and Answer for Granulation Line ............................................. 16

Table 5: User Requirement Specifications for Granulation Line Equipment ................................................... 18

Table 6: Categorization of Risk Level ............................................................................................................... 26

Table 7: Risk Assessment Matrix for Granulation Line .................................................................................... 28

Table 8: Design Qualification for Diosna Granulation Line .............................................................................. 44

1

1. Introduction

As the demand for drug products increases1, there is a need for the pharmaceutical industry to expand its

business. This expansion may involve increasing the level of production in the same facility, buying new

equipment and scale up manufacturing processes, hiring another company to produce the products or opening

new facilities, when increasing production is not possible in existing facilities. In any case, the use of new

equipment implies qualification and validation processes, that are a legal requirement imposed by all health

authorities. The equipment must be qualified for the intended use, not only because the guidelines indicate it,

but also because ensuring a good qualification of the equipment gives the manufacturer confidence in the

performance of the equipment during the validation phase and allows an in depth knowledge of the

equipment, giving the perception of the ranges in which it can operate.

1.1 Objective

The main objective of this thesis is to implement the first steps to be taken in the qualification stage of a new

equipment. The first phase when acquiring a new equipment is to define the User Requirement Specifications

(URS) and to perform a Design Qualification (DQ). These two steps are an important baseline for further

qualification of the equipment as they ensure that the machine fulfils the functions for which is intended to and

that the design of the equipment meets the requirements of the user. Furthermore, the use of risk management

tools allows to plan the next stages of qualification (Installation Qualification (IQ) and Operational Qualification

(OQ)).

1.2 The Company: Labatec2

Labatec (figure 1) is a Swiss-based pharmaceutical company with more than 60 years of experience in the

production and distribution of pharmaceutical products.

The company has a production facility in Switzerland and has a portfolio of more than 65 products, including

medicines in the areas of musculoskeletal, oncology, antibiotics, antituberculotics, anaesthetics and hormonal

contraceptives. The main distribution sites are the Middle East North Africa Region and Switzerland (figure 2).

Last year, Labatec entered in an expansion period, aspiring to increase production capacity in order to meet

market needs. A new factory is being built in Portugal to meet this goal.

Figure 1: Labatec Logo2

2

At the new plant in Portugal, solid medicines for oral administration (tablets and capsules) will be produced.

1.3 Mydocalm

Mydocalm will be the first medicine that will be produced in Labatec’s new facility. Labatec has a valid

marketing authorization for Suisse market since 1968.

The active pharmaceutical ingredient present is Tolperisone HCl (2-methyl-1-(4-methylphenyl)-3-(1-

piperidinyl)-1-propanone hydrochloride) – figure 3.

Mydocalm is a muscle relaxant used for the treatment of spasticity and muscle spasm by acting in the central

nervous system3.

Tolperisone HCl is presented in two dosages of film coated tablets: 50 and 150 mg (figure 4).

Figure 2: Labatec's worldwide presence2

Figure 4: Packages of Mydocalm 50mg and 150mg4

Figure 3: Tolperisone HCl chemical formula3

3

1.4 Mydocalm Manufacturing Process

The manufacturing process of Mydocalm and the equipment used for each unit operation is outlined in figure

5. The process begins with a granulation, followed by sieving to check the particle size. After mixing the remaining

excipients, the mixture is compressed and then proceeded to coating. At the end the tablets go into the

packaging.

Before the beginning of production, all equipment have to be qualified and the manufacturing process has to

be validated in order to ensure reproductibility of production and product quality. As Mydocalm is already

manufactured in the Swiss facility, the knowledge acquired there can be used to improve the manufacturing

process in Portugal. As the first stage of the process is granulation, this was the equipment chosen for the scope

of this dissertation.

1.3 Qualification and Validation

It is important to begin by distinguishing qualification from validation. According to EudraLex, qualification is

the “action of proving that any equipment works correctly and actually leads to the expected results”5, whereas

validation is the “action of proving, in accordance with the principles of Good Manufacturing Practice (GMP),

that any procedure, process, equipment, material, activity or system actually leads to the expected results”5.

Most of the time these two concepts work together, as in the end they have the same objective: get the process

or equipment to do what they are intended to do and to be accepted by the regulatory agencies.

Another definition that should be kept in mind is the concept of validation master plan (VMP). This document

consists of the description of qualification and validation system for the company5. In accordance to EudraLex

Annex 15, a VMP must include “qualification and validation policy; organisational structure including

responsibilities for qualification and validation activities; summary of facilities, equipment, systems, processes

on site and the qualification and validation status; change control and deviation management for qualification

and validation; guidance on developing acceptance criteria; references to existing documents; qualification and

validation strategy”5.

Keeping these definitions in mind, the processes of qualification and validation will be explained in further

detail.

Blending

Servolift Blender

Granulation

Diosna High Shear Mixer

Film Coating

Bohle Coating Machine

Tabletting

Korsh Compressing Machine

Packaging

Figure 5: Mydocalm process flow

4

1.3.1 Qualification

Qualification is divided in different stages between the initial development of the user requirements and the

use of the equipment/facility/system. In table 1 are defined, according to Eudralex, the five stages of

qualification.

Figure 6 shows a diagram with a sequence of steps to be considered to implement a qualification system.

Table 1: Definitions of different stages of qualification according to Eudralex, Volume 4, Annex 15

Qualification Definition

URS “The set of owner, user and engineering requirements necessary and sufficient to

create a feasible design meeting the intended purpose of the system”5

DQ “The documented verification that the proposed design of the facilities, systems and

equipment is suitable for the intended purpose”5

IQ

“The documented verification that the facilities, systems and equipment, as installed

or modified, comply with the approved design and the manufacturer's

recommendations”5

OQ “The documented verification that the facilities, systems and equipment, as installed

or modified, perform as intended throughout the anticipated operating ranges”5

Performance

Qualification (PQ)

“The documented verification that systems and equipment can perform effectively

and reproducibly based on the approved process method and product specification”5

The first step of the qualification is explaining, in a written document (i.e., URS), what the company wants for

the equipment.

The URS should be clear, concise, verifiable, comprehensive and should express specifications and not design

solutions. In addition to process and product specifications they should also include all applicable and required

GMP specifications. Usually the URS are defined by the user’s department and/or subject matter experts.

Figure 6: Stages of qualification (adapted from6)

5

After writing the URS and selecting the equipment to acquire, it is necessary to ensure that the design

complies with the URS and with the GMP in a DQ5. It is necessary to match the vendor quotation with URS and

confirm that all URS are covered by the vendor specifications of the equipment and provide the results in a DQ

report.

Following DQ, the equipment should be installed, and IQ should be performed including: “verification of the

correct installation of components, instrumentation, equipment, pipe work and services against the engineering

drawings and maintenance requirements; calibration of instrumentation and verification of the materials

construction”5.

The next step in qualification is OQ, which include tests, both to guarantee that the system is operating as

designed and to verify the operation limits. Sometimes IQ and OQ could be performed simultaneously in an

Installation/Operation Qualification (i.e., IOQ)5.

To complete qualification it is necessary to perform the PQ. Depending on the case, this stage of qualification

can be performed with OQ or with the process validation. In PQ phase, there should be performed tests that

cover the operating range and ensure that all batches behave the same way under supposed operating

conditions5.

After all qualification steps, a process validation should be performed. Equipment that have been qualified

should be evaluated from time to time, by a process called re-qualification (RQ), to ensure that they continue in

a state of control5.

1.3.2 Validation

The main objective of validation is to prove that processes are robust and that the product quality is

consistent and in accordance with GMP. In validation protocols “the critical systems, attributes and parameters

and the associated acceptance criteria”5 should be defined.

There are four types of process validation: concurrent validation, traditional process validation, continuous

process verification and the hybrid approach.

Concurrent Validation

Concurrent Validation is an exceptional form of validation. It is only used if “there is a strong benefit-risk ratio

for the patient”5. In this type of validation, the routine production starts before the validation process has been

completed. However, to perform concurrent validation, there should be enough information and documents to

support that the product meets the acceptance criteria5.

Traditional Process Validation

This is the most used validation procedure, where reproducibility is confirmed by producing under routine

conditions a defined number of batches. Usually a minimum of three consecutive batches is considered

6

acceptable to validate a process. However, a different number of batches could be used, if justified, based on

quality risk management (QRM) principles5.

According to EudraLex, Annex 15 and European Medicines Agency (EMA) guideline on process validation, the

process validation protocols should include: description of the process; functions and responsibilities; critical

quality attributes and critical process parameters with associated limits; list of equipment/facilities to be used

with calibration status; list of analytical methods and method validation; In Process Controls and other tests with

acceptance criteria; sampling plan, methods for recording and evaluating results; and process for release and

certification of batches5,7.

Continuous Process Verification

Continuous process verification is used in cases where the product has been developed by a quality by design

approach (“a systematic approach that begins with predefined objectives and emphasises product and process

understanding and process control, based on sound science and quality risk management”5). In these cases,

control strategies have proved to guarantee high degree of assurance of product quality during development, so

that a continuous process verification could be a substitute of traditional validation5,7.

Hybrid approach

As the name suggests, this approach is a mixing between traditional validation and continuous process

verification. This is used when there is enough information about product and process acquired from

manufacturing experience and historical batch data5,7.

1.4 Risk Management

One of the great challenges of the pharmaceutical industry is to guarantee the quality oversight over the

product lifecycle. For this to happen, it is extremely important to have a quality management system (QMS) well

implemented within the company. It is normal that many of the processes that occur in the company's facilities

involve some risks. Thus, it is crucial to have the proper tools and process to manage those risks.

Risk management is not an optional concept for the pharmaceutical industries. On the contrary: it is

mandatory in order to comply with the regulatory requirements in force.

According to International Council for Harmonization (ICH) Q9 of “Quality Risk Management” the two

fundamental principles of QRM are “the evaluation of the risk to quality should be based on scientific knowledge

and ultimately link to the protection of the patient; and the level of effort, formality and documentation of the

QRM process should be commensurate with the level of risk” 8.

In pharmaceutical industry, risk quality management applications are numerous. In the context of this thesis

the emphasis will be put in their application to installations, equipment and systems. Through risk management

it is possible to take informed decisions about the construction materials that will be in contact with the

manufactured product, to determine which utilities are necessary for the operation of the factory and the

7

equipment, which maintenance and calibrations are appropriate for each system, which cleanings are necessary

to protect the product and to determine the extension of qualification activities to guarantee the proper balance

between risk and benefit.

Figure 7 represents the model for risk assessment, control, communication and revision through product

lifecycle proposed in ICH Q98.

When beginning a QRM process, it is important to start by defining the problem or risk question. Then the

first step, risk assessment, can be initiated.

In a risk assessment the hazards are identified, analysed and evaluated. The three essential questions to

answer in a risk assessment are8:

1. What might go wrong?

2. What is the likelihood (probability) it will go wrong?

3. What are the consequences (severity)?

Through the first question the risks are identified: What are the hazards that can occur in this process?

After the identification of the hazards, a risk analysis should be performed by answering questions two and

three. Also, in some risk management tools, the question “Can the hazard be easily detected?” is significant. In

Figure 7: Typical risk management process8

8

the risk analysis it is analysed the probability of occurrence and severity of harms and, in some cases, their

detectability 8.

Following the risk analysis, there is the risk evaluation. In this phase, the identified and analysed risks are

compared with the defined risks criteria8. These criteria can be given, among others, by company procedures,

regulatory guidelines and experience.

After the risk assessment, the next step is risk control. In this phase it is decided what measures should be

taken to reduce the risk until it reaches an acceptable level. The more significant the risk, the greater the level of

effort to reduce it. Risk control is addressed by getting the answers to the questions8:

• Is the risk above an acceptable level?

• What can be done to reduce or eliminate risks?

• What is the appropriate balance among benefits, risks and resources?

• Are new risks introduced as a result of the identified risks being controlled?

In order to reduce a risk, there are several risk mitigation measures, such as acting on the probability of its

occurrence, its severity and, in some cases, on the detectability of the risk: if the detectability is increased, then

the level of risk decreases. It is important to bear in mind, that when implementing risk reduction measures, new

risks may arise, which should also be considered8.

The last step of risk control is the acceptance of the risk, which means the decision to accept the risk. Since it

is not always possible to eliminate the entire risk, at this stage it is important to understand if the risk reduction

is enough to bring the risk within the specified acceptable levels and to accept it in accordance with those

parameters. Acceptance of a risk should be decided on a case-by-case basis through the risk analysis concerned

and the experience of those accepting the risk. If risk control does not reach acceptable levels, then a new risk

assessment should be performed, until a level of risk considered acceptable is reached8.

Risk communication should be present during all stages of the risk management process. Where relevant, the

risks and results of the process should be communicated to all stakeholders (e.g. regulators, patients, within the

company...)8.

The final step in a risk management process is to revise the previous exercise and analyse the impact of

further risks introduced and to monitor risks in order to be able to integrate new knowledge and experience, if

necessary. It is important that risk management processes are monitored as an integral part of the QMS8.

1.4.1 Risk Management Tools

There are several risk management tools applicable in the pharmaceutical industry that are recognized by

regulators. Regardless of the risk tool used, the important aspect is that decisions made based on risk

management are supported by documented, transparent and reproducible methods8.

Four of the most commonly used risk management tools are explained below.

9

Basic Risk Management Facilitation Methods8

This tool is based on simple data structuring techniques and decision-making facilitation such as: flowcharts,

process mapping, cause and effect diagrams (also known as Ishikawa diagram or fish bone diagram).

Failure Mode Effects Analysis (FMEA)8

FMEA allows an assessment of the potential failure modes for the process and their most likely effect. FMEA

is based on the severity, probability of occurrence and detactability of each failure mode. This tool also allows to

schematize actions to reduce/eliminate risks. This tool has the great advantage of dividing a complex analysis

into simpler steps.

According to ICH Q9, one of the areas of use of FMEA is the analysis of equipment, facilities and manufacturing

operations.

Failure Mode, Effects and Criticality Analysis (FMECA)8

FMECA is an extended FMEA that takes into consideration the degree of severity of the consequences and

not only the severity, probability and detectability of the failure mode. To use FMECA it is necessary that product

or process specifications are established. This tool is mainly used for risks related to manufacturing processes.

Fault Tree Analysis (FTA)8

FTA is a schematic way of evaluating failures one at a time, although in some cases multiple causes of failure

can be combined through casual chains. The results are demonstrated in a fault mode tree. This tool is widely

used to discover the root cause of a failure, for example to investigate a complaint or a deviation.

1.4.2 iRISK

The iRISK tool (figure 8), developed by 4Tune Engineering, enables the pharmaceutical company to have all

risk management tools integrated into a single platform. This risk management platform allows the identification,

quantification and supports the prioritization of risks and the formulation of risk mitigation strategies for new or

existing processes9.

This platform allows several people to work simultaneously, thus facilitating the work that was previously

done on paper, being aligned with Food Drug and Administration (FDA), EMA GMP-Annex 15 and ICH guidelines9.

Figure 8: iRISK platform logo9

10

By using this program, it is possible to reduce the risks, have a traceability of all risks and actions, facilitate

the continuous revaluation and control of risks, reduce time of performing risk assessments, standardize the

assessment criteria of risks within the same company, among other advantages9.

11

2. Granulation

2.1 Granulation Process

According to Larry L. Ausburger and Stephen W. Hoag, granulation is “any process whereby small particles

are gathered into larger, permanent masses in which the original particles can still be identified” 10. In this case,

the main objective of granulation is to create granules to be used in the manufacture of tablets. However, they

can also be applied in filling hard gelatine capsules or to be packed in sachets10.

Granulation helps to avoid segregation and improves flow and compression characteristics of the blend. In

other words, granulation is the operation that provides the blend with propitious conditions to compression,

when the blend cannot be directly compressed10,11. Also, if the granulation procedure is robust enough, it will

allow the product to be consistent, as granulation will harmonise the blend, protecting the process from

variations caused by the alterations in the specifications of raw materials.

In table 2 it is described the advantages and disadvantages of using granulation in the manufacturing process,

instead of using direct compression of the blend.

Table 2: Advantages and disadvantages of granulation10

Advantages Disadvantages

Better flow of the granules Higher production costs (increased time, labour,

equipment, energy…)

Granules are more compactible Additional steps to remove liquid

Handling of powders maintaining blend quality Material loss and material transfer

Most of the times direct compression is not possible, so granulation is the better solution

Difficulties in detecting the end-point

There are two main granulations processes: wet and dry granulation. In dry granulation the agglomeration of

the dry powders occurs by direct physical compaction, whereas in wet granulation granules are formed by

addition of a blending liquid10.

After a wet granulation it is essential to dry the granules in order to reduce the liquid content used in

granulation10. Drying is usually done by evaporative processes and it is possible to do it in a single-pot processor.

Some examples of drying processes are tray drying, counter-current drying and fluidized bed drying. In table 3 is

shown two possible classifications for drying processes.

Table 3: Classification of drying processes10

Classification of drying processes

Direct Material is exposed to a hot gas

More efficient

Indirect Heating transfer occurs by heating the walls of

dryer

Stagnant bed Particles are on top of one another

Particles do not move

Moving Bed Particles flow over others

Volume is expanded

12

By doing the processes in a single-pot, that is to say, granulation and drying done in a single equipment, the

advantages are10: Reduced investment in equipment; Reduced manufacturing time; Reduced need of operators;

Risks of contamination are minimized; Less losses in product transfer.

2.3 Diosna Granulation Line

The equipment chosen for granulation phase was a Granulation Line from Diosna supplier. This granulation

line allows the manufacturing of pharmaceutical granules in a closed system. It is composed of a mixer granulator

and a fluid bed dryer (FBD). The two main components are directly connected and can operate together or

separately.

Some of the advantages of this line are12: fast product transfer, less material loss, separation of production

and technical area.

The mixer granulator is a high shear mixer (HSM) (figure 9) with a usable volume of 550L. This

mixer/granulator is used for the manufacture of granules. It is loaded by suction of raw materials supported by

vacuum. During the mixing process a binder solution is added by spray nozzles. The bowl geometry, mixing tool

and chopper shape achieve the manufacture of a homogeneous granule quality.

The FBD (figure 10) directly linked to the HSM has a usable volume of 680L. The product is sucked out of the

HSM by the aid of negative pressure of the FBD. During the process, the product is dried by passing a current of

hot dry air between the granules.

Figure 9: High Shear Mixer

13

In addition to these two main components, the granulation line also includes a sieving mill for wet milling and

another for dry sieving (figure 11) and a vacuum conveyor (VC).

The sieving mil for wet milling is installed below the mixer outlet in order to homogenise the wet granules

that are produced in the HSM. The sieving mill for dry milling is used for calibration and homogenisation of dried

Figure 10: Sieving mill

Figure 11: Fluid Bed Dryer

14

granules during discharge of the fluid bed plant and it can be also used for raw materials sifting during charging

of the HSM.

The pneumatic vacuum conveyor (figure 12) is used for dust-free feeding and discharge of the

powders/granules. The HSM feeding is through this equipment as well as the discharging of HSM and FBD.

Figure 12: Vacuum Conveyor

15

3. Results: Qualification of Granulation Line

In order to qualify systems and equipment, the company follows the steps outlined in figure 13.

In addition to the concepts mentioned above, which are described in the EMA guidelines and in Eudralex,

Labatec uses two more documents: The GRA and the FRA.

GRA methodology is used to evaluate the potential impact of systems and equipment on product quality

according to the complexity of the machine, whereas FRA is used to define measures to minimize the risks

associated to the equipment on product quality.

In the following points the first four steps of Diosna Granulation Line Qualification will be described: GRA,

URS, FRA and DQ.

3.1 General Risk Assessment

According to the methodology described in the company's procedures, a GRA must be performed before the

purchase of every new equipment.

The GRA is done to assess the impact that the equipment will have on the product quality or manufacturing

process, assessing whether the impact is direct, indirect or whether the equipment has no impact on the

product/process.

The impact is assessed through the answers given to a questionnaire with 16 questions, which should be

answered with yes or no for the equipment under analysis. If any of the questions from 1 to 12 is answered yes,

Figure 13: Qualification process in Labatec

- - - According to GRA result

16

a complete qualification must be performed (URS, FRA, DQ, IQ, OQ, PQ and QR). If only questions from 13 to 16

are answered in the affirmative, the system is considered to have indirect impact. In such a case, the only steps

of qualification needed are URS, FRA, IQ, OQ and QR. If none of the questions are answered affirmatively, the

system is considered to have no impact and, consequently, no qualification activity is needed.

The completed GRA form for this equipment can be found in Annex 1. Table 4 describes the questions of the

GRA and the respective answers for the Granulation line.

Table 4: General Risk Assessment Questions and Answer for Granulation Line

Question Description Answer

1

Is the system in direct contact with the product or with the environment where the

product is processed?

In normal operation, does the system have a direct impact on product’s quality or its

surrounded environment?

Does the failure of the system have a direct impact on product quality?

(e.g. of environment: air quality)

Yes

2

Does the system provide an excipient, ingredient or solvent which is in contact with the

process / product?

Does the system produce or have direct contact with an excipient, ingredient or solvent

which is in contact with the process / product? (e.g. water for injection)

Yes

3 Is the system used in cleaning / steaming / sterilization of product contact surfaces?

(e.g. clean steam, CIP, SIP systems) Yes

4 Does the system preserve the product status, such as product safety, identity, strength,

purity, or quality? (e.g. nitrogen, clean rooms, warehouse) Yes

5 Does the system produce data used to accept / reject the product?

(e.g. processing, storing and transfer of data) Yes

6 Is it a process control system that may affect product’s quality, which don’t have an

independent verification system to control its performance in place? (e.g. PLC, DCS) No

7

Is the system used / involved in producing stability batches, pilot batches or production

batches for bioequivalence / bioavailability?

Is the system used for GLP or GVP studies?

Yes

8

Is the system used / involved in producing stability batches, pilot batches or production

batches for process validation?

Can the system affect the validity of validated analytical test methods?

Can the system affect the data generated from a validated test method?

Yes

9 Is the system involved in the manufacture, processing, packaging, holding or

distribution of the product? Yes

17

Question Description Answer

10

Is the system used to handle GxP samples?

Is the system used to produce or process data that will be used in regulatory

submissions?

Yes

11 Is the system used in the collection, processing, analysis or storage of data related to

drug / patient safety? Yes

12

Is the system used for distribution or collection of information in the event of a

commercial product recall?

Is the system used in pre-clinical studies or in-patient follow-up of and clinical trials?

No

13 Does the system supply a utility or function for a direct impact system? No

14 Can the system affect the performance of a direct impact system? No

15 Does the system provide information that is used for a regulatory submission or in a

technical report that support the submission? Yes

16 Does the system supply a utility / function for a laboratory test or support equipment? No

Taking into consideration the answers to the questions, the granulation line, as expected, is considered to

have direct impact on product and manufacturing process, which means that a complete qualification has to be

performed.

3.2 User Requirements Specification

The subsequent step after the GRA is writing the URS (table 5). The URS specify the requirements that the

equipment must comply with, including any GMP requirements, mandatory, optional and desirable

requirements.

The URS are divided into categories according to:

• Process User Requirements: requirements related to product/process quality or GMP compliance.

These requirements shall be incorporated into the design and verified during qualification activities.

• General User Requirements and Constraints: requirements not directly related to the product quality

or GMP. However, they can have the potential to be critical to personnel safety and/or other legal

requirements, including business relations between the supplier and the company.

The URS are also divided into types in order to organize the ideas: product requirements, process control

requirements, operational specifications, data and security requirements, safety requirements, environment

requirements, utilities, construction requirements and life cycle and business requirements. There are

requirements for the all granulation line and others specific for each part of the equipment: HSM, FBD, Mill and

VC.

18

Table 5: User Requirement Specifications for Granulation Line Equipment

Item Requirement Piece Type

Product

1 The whole line shall be able to process all types of powder for all types of

manufacturing processes in a completely closed system. All

Process User

Requirement

2

The line shall operate granulation &/or mixing processes using water &/or

different organic solvents, including but not limited to, Ethanol, Isopropyl

alcohol, acetone, dichloromethane, etc…

All Process User

Requirement

3 The full bowl capacity shall be 600 litres. HSM Process User

Requirement

4

The Fluid Bed Dryer with the intended unit to purchase shall function only

for wet powder drying, but prepared for accepting future intended

technologies, in a way commonly described as “plug and play”, including,

but not limited to:

• Top Spray granulation;

• Bottom Spray granulation and/or coating.

FBD Process User

Requirement

5 The drying bowl’s volume shall be of not less than 510 litres. FBD Process User

Requirement

6

The milling system described below is applicable for wet milling as well as

for dry milling. The type/brand should preferably be from Frewitt “ConiWitt

200” or “TurboWitt C-20”.

Mill Process User

Requirement

7 The vacuum conveyor is to be used for conveying pharmaceutical powder

for human use. VC

Process User

Requirement

8

The vacuum conveyor shall be of a capacity (rate of transfer) in-line with the

cone mill capacity (up to 500 – 1000 kg/h), in order not to create a rate

limiting step while using the vacuum conveyor.

VC Process User

Requirement

Process Control

9 Control systems for the HSM, FBD, and all other auxiliary equipment, should

have the possibility of operating together &/or separately. All

Process User

Requirement

10 The programmable logic controller (PLC) shall be from SIMENS and of a

model not later than S7. All

General User

Requirement

11 Multiple access control for the machine parameters. All Process User

Requirement

19


12 Able to set and control the granulation spray system parameters, air

pressure, fluid flow rate, granulation time. HSM

Process User

Requirement

13 Product temperature sensor is required. HSM Process User

Requirement

14 Full control over temperature and humidity for inlet air, while monitoring

the same for outlet air. FBD

Process User

Requirement

Operational Specifications

15

Product loading through vacuum created within the bowl, using an electrical

vacuum pump, with a GMP valve, the use of ball valves for products is

completely prohibited.

HSM Process User

Requirement

16

Wash in Place (WIP) Construction with all connections, spray balls at

different positions, hidden, covered, protruding only during the cleaning

process. Air flush after terminating the cleaning is mandatory to ensure no

more liquid could leak out over the following production.

HSM

FBD

Process User

Requirement

17 The inlet air dehumidification shall use proper dehumidification technology,

for example, but not limited to, condensation. FBD

Process User

Requirement

18

Intended product inlet for processing is transferred through a product

transfer tube into the fluid bed dryer, by the aid of a negative pressure

created by and within the fluid bed dryer, by suspending the particles into

the air, through extracting more air volume than the inlet air volume.

FBD Process User

Requirement

19 Mill can be utilized as a rotary sifter, for example, “Turbo-Witt C-20” for

sifting and loading to the HSM in one step. Mill

Process User

Requirement

20 The vacuum conveyor to be able to convey powders for a distance up to 10

meters and height up to 4 meters excluding the conveyor height. VC

Process User

Requirement

21 Temperature rise of the vertical gear shaft shall not exceed 40 degrees after

operating at the maximum speed for one hour. Mill

General User

Requirement

Data and Security

22 Full compliance with the 21CFR part 11, audit trails as well as data integrity

requirements. All

Process User

Requirement

23 Full parameters batch reporting with the ability for printing remotely. All Process User

Requirement

24 Ability to perform a backup for all batch data, over a local drive &/or a

network drive. All

Process User

Requirement

20


25 Product recipes and batch number to save, store and print or archive all the

process parameters and results. All

Process User

Requirement

26 The HSM shall be able to measure, report and display the torque and current

readings for the impeller motor, while for the chopper motor only current. HSM

Process User

Requirement

27

Control over drying cycles, filter shocking cycle, all critical process

parameters shall be detailed, documented, reported and printed for each

batch.

FBD Process User

Requirement

Safety

28

The whole line explosion methodology should be through explosion

containment, with a 12 Bars construction, the explosion relieve shall be

through a relief valve.

All General User

Requirement

29

All electrical cabinets, access doors to the mechanical areas, protections to

Human Main Interface shall be resistant to Ingress Pressure not less than 65

(IP65 rating).

All General User

Requirement

30 Alarm system for exceeding the set point tolerance. All Process User

Requirement

31 Any alarm function for critical process parameters &/or malfunction. All Process User

Requirement

32 Reasonably distributed emergency buttons at several locations. All Process User

Requirement

33 Alarm system for positive pressure build up within the High Shear Mixer. HSM Process User

Requirement

34 Alarm for fluid bed dryer filter damage &/or powder leakage. FBD Process User

Requirement

Environment

35

The high shear mixer shall be physically separated from the FBD by a clean

wall panel, with an internal access door to the FBD to be used when needed.

So, as the other equipment can be kept clean without any cross

contamination, neither through the product transfer tube (through the wall)

nor from the drain system.

All Process User

Requirement

36

The whole line shall be of wall mounted design. All technical accesses

(mechanical, as well as the electrical control panels) shall be from the

technical area behind the wall. That shall allow full maintenance (preventive,

calibration, and parts replacement) to be done from outside the clean area

All General User

Requirement

21


37 Pressure relief system for filtering the air that goes within the room, in case

milling is done into containers / poly bags. Mill

General User

Requirement

Utilities

38

Working (consumption) and facility requirements are to be specified over

the final drawing (e.g. compressed air, electrical connections, etc), in

addition to the documentation package to receive.

All General User

Requirement

Construction

39 The granulation line shall be composed from a HSM coupled with a fluid bed

dryer, along with different auxiliary functional equipment. All

Process User

Requirement

40

All seals and connections, should be unstainable (unable to retain colours),

resistant to organic solvents, easy to clean, and material of construction to

be properly identified in writing.

All Process User

Requirement

41 All product contact surfaces to be constructed with stainless steel 316L with

material of construction certificates. All

Process User

Requirement

42

All product contact surfaces, including, but not limited to, welding areas,

shall be of a mirror finish with roughness factor (Ra) not more than 0,2,

supported with testing certificates.

All Process User

Requirement

43

All exterior surfaces, including, but not limited to, welding areas &/or

product none contact surfaces, shall be of a mirror finish with roughness

factor (Ra) not more than 0,5, supported with testing certificates.

All Process User

Requirement

44

Bottom Drive HSM with a chopper on the side of the bowl, the chopper to

be of knife-blade design construction with 6 to 8 blades. Easy to be removed

for cleaning &/or replacement if required;

HSM Process User

Requirement

45 All axes (chopper and impeller) have to be protected with air seal purge

system from the utility compressed air supply. HSM

General User

Requirement

46 The impeller shall be able to be lifted 15-20 cm from the bowl bottom,

through an air piston, to access the bottom and inspection can be achieved. HSM

General User

Requirement

47 The gap distance between the bowl bottom and the main impeller shall be

of 1,0 mm with a tolerance of +1,0 mm. HSM

Process User

Requirement

48 The impeller diameter shall be within the range of 1050mm till 1100mm. HSM Process User

Requirement

49

Impeller motor shall be not less than 55kW, the motor specifications and

details shall be included within the technical documentation. It has to be

able to operate/tolerate a total load of 440 Kg from a static position during

the factory acceptance test.

HSM Process User

Requirement

22


50 Impeller motor fully variable speed range between 5 rpm and 150 rpm. The

minor unit shall be of 1 rpm. HSM

Process User

Requirement

51 Chopper motor of not less than 15 kW. Motor specifications and details to

be included within the technical documentation. HSM

Process User

Requirement

52 Chopper motor fully variable speed range of minimum 200 rpm. Maximum

shall be 3500 rpm. The variable speed of the minor unit shall be of 1 rpm. HSM

Process User

Requirement

53

Product Sampling port on the bowl side at the level of the chopper, but not

below the level of the impeller to be present, can be opened and closed,

easy to clean, not to trap product &/or fluids so as product carry over to the

next batch/product can be avoided. The sampling port is to be used for

sampling the wet powder, so that a representative sample can be obtained

without opening the bowl cover. The sample receiver shall be removable,

and the size shall be of not less than 25 ml.

HSM Process User

Requirement

54

Granulation solution/fluid loading system shall be composed from a

peristaltic pump and an atomized spray nozzle/gun, with a controlled air

pressure, air pressure range from 0,5 Bar till 5 Bars, which is easily capable

to provide a droplet size of 0,1 mm on average.

HSM Process User

Requirement

55 A watch window, as well as a none heat generating lighting source within

the mixer bowl shall be present. HSM

General User

Requirement

56 Existence of an arm for safe removal of the impeller out from the HSM. HSM General User

Requirement

57

The filters to relieve the internal bowl pressure due the presence of air seals

and/or to create the negative pressure for product loading to the HSM bowl

shall be of stainless-steel cartridge filter system with 5 µm. Filter protection

with a filter bag is optional.

HSM Process User

Requirement

58

Product Sampling port on the bowl side, at a reasonable level to be present,

can be opened and closed, easy to clean, not to trap product &/or fluids so

as product carry over to the next batch/product can be avoided. The

sampling port is to be used for sampling the product as a representative

sample, without opening the FBD. The sample receiver shall be removable,

and the size shall be of not less than 50 ml.

FBD Process User

Requirement

59

The filters are to be of cartridge design, safe handling, easy to handle, and

of stainless-steel design. Other types are acceptable once offered,

documented and preapproved.

FBD Process User

Requirement

23


60 The inlet air dehumidification shall be of high efficiency and reasonable

power consumption, regardless of the external environmental conditions. FBD

General User

Requirement

61 The heating method shall be utilizing steam heat exchangers coils. FBD Process User

Requirement

62 Dry gear system (lubricant and oil free), bottom driven is preferred. Mill General User

Requirement

63

Milling unit is mounted on articulated arm to swing.

• For wet milling it shall be just under the HSM discharge gate.

• For dry milling, articulated arm it shall be installed over a lift in between

the HSM and the FBD, so as it can receive the final product from the HSM

&/or FBD, through a vacuum conveyor system. The final powder

destination can be In-Process blending container, and/or Polybags, and

/or Polyline plastic/stainless steel containers.

Mill Process User

Requirement

64 Impeller to screen gab to be not more than 1,0 mm, the same standard to

be achieved for both, normal perforated screens as well as rasping screens. Mill

Process User

Requirement

65

Speed range including not less than 300 – 1800 rpm, motor with not less

than 3,7 kW, with integrated frequency converter for speed adjustment of

rotor speed.

Mill Process User

Requirement

66

Three screens to be provided with the line:

• One for wet milling application;

• One for dry milling applications of 1,0 mm squared pore screen, plate

thickness of 0,6mm and open area of not less than 50%;

• One for dry milling/sifting applications of 0,8mm round pore screen,

plate thickness of 0,8mm, and open area of not less than 29%.

Mill Process User

Requirement

67 The vacuum conveyor, as well as its holding construction, shall be as

compact as possible in size to avoid space limitation. VC

Process User

Requirement

68 The vacuum conveyor to be flexible to use and light weight equipment for

utilization within the room. VC

Process User

Requirement

69 The vacuum conveyor to be offered with adapters &/or connections to

above mentioned machines. VC

Process User

Requirement

24


Life Cycle and Business Requirements

70

The following documentation is required, both as hard copies, as well as soft

copies, properly classified within electronic folders, in both languages

English & Portuguese:

• Installation Qualification,

• Operation Qualification,

• User manual, for all components manufactured, installed &/or fitted.

• Preventive maintenance and its frequency.

• All different parts demanding calibration &/or verification along with its

frequencies.

• Declarations and Certificates, for all materials of construction, joints and

tubes, CE, GMP,

• Calibration certificates, Roughness factor Testing certificates…

• Factory settings and / or default inputs for all gauges, instruments, PLCs.

• Product contact surface area calculations, in proper drawing formats:

surface area for each part &/or area, plus the total to be documented

over the general drawing.

All General User

Requirement

25

3.4 Functional Risk Assessment

Following the URS definition, it is essential to perform a FRA. The aim of a FRA is to identify critical risks of

the equipment and define measures to eliminate or reduce their impact on product quality. It also helps to

identify the critical and non-critical parts or functions and to identify the tests where those parts or functions will

be tested across the qualification process.

Although the contract with the equipment supplier includes the provision of IQ and OQ protocols, it is

necessary to verify that these documents include all important parameters. In this regard, the FRA provides the

basis for this verification as the FRA results in tests to be performed in the next qualification phases.

3.4.1 FMEA Methodology

The risk management tool chosen for FRA was FMEA. The steps to perform this risk analysis are described

below.

Risk Identification

All actions or operations that might have negative effect on a determined process should be considered as

risks. Independently of having a higher or minor impact, all identified risks should be recorded.

To identify the risks, the following questions should be used:

• What can fail?

• What is the impact of the fail?

• What external fails may occur?

• What control systems may fail?

Risk Analysis

In order to analyse the risks, they have to be compared with measurable criteria. Therefore, it is necessary to

make it possible to quantify risks according to the parameters that should be evaluated: probability, severity and

detectability.

The first parameter is probability. It consists on the occurrence probability of a risk scenario or event. It can

be classified as:

1 - Low Probability: the event is rare, happening once at 100 000 cycles;

2 - Average Probability: the event may happen at each 1 000 cycles;

3 - High Probability: the event may happen at each 100 cycles.

The second parameter to be evaluated is severity. Severity is the potential impact that the occurrence of a

failure can have on the quality of the product or the applicable good practices. Severity can be classified as

follows:

26

1 - Low severity: the severity of the fault has a low impact on quality; the impact of the fault does not

extend in time;

2 - Medium severity: failure has moderate severity in quality and may have an effect in the medium term;

3 - High severity: failure has a high impact on the quality of the product. It has catastrophic consequences

that may extend in time.

The last parameter to evaluate is detectability. Detectability is the evaluation of how a failure can be detected

and eliminated by detection systems and control processes in the systems. Detectability can be classified as

follows:

1 - High Detection: the process has 100% automatic control or monitoring systems to 100%, with high

reliability, that can detect the failure;

2 - Average detection: the process has control systems whose reliability is intermediate; the control is done

by sampling and can depend on human factors;

3 - Low Detection: the process has no automatic control systems and there is no specific check for failure.

Detection happens by chance.

After the quantification of the last three parameters, the final classification of a risk (risk priority number

(RPN)) can be obtained by multiplying probability, severity and detectability. The final value can vary between 1

(if it was chosen 1 to all parameters) and 27 (if was chosen 3 to all parameters).

Based on RPN it is possible to compare different risk scenarios and to set priorities on risk, according to:

• High values imply that serious steps must be taken to reduce the risk;

• Mean values imply that actions must be made, and that failure is potentially heavy;

• Low values imply that the risk is low and do not require special actions not being necessary any

action.

Risk Control

Based on RPN, qualification actions can be taken to demonstrate the control of that failure (table 6).

Table 6: Categorization of Risk Level

Risk Priority Number (RPN) Designation

RPN < 4 Low Risk

4 < RPN < 12 Intermediate Risk

RPN > 12 High Risk

For the definition of actions to take, the following criteria are considered:

• High Risk represents a level of risk that recommends taking actions to mitigate the risk, as well as

actions to demonstrate their control;

27

• Intermediate Risk is a risk that implies actions to demonstrate that risk is controlled;

• Low Risk is an acceptable level of risk. Action may be taken to mitigate or control the risk but it’s not

mandatory.

Risk identification and analysis for the Granulation Line is performed in the following risk matrix (table 7).

The actions to prevent/control the risks are divided in four groups: actions to take place in DQ, in IQ or in OQ

and also actions that should just follow Good Engineering Practices (GEP).

28

Table 7: Risk Assessment Matrix for Granulation Line

No Parameter

Risk Identification Risk Analysis Risk Control

Possible Failure Impact Classification

Actions to prevent/control S P D RL

1

Equipment

Technical

Documentation

• Documentation not available or

missing

• Equipment instructions not

adequate

• Documentation does not comply

with the equipment

• Lack of evidence required

• Improper equipment installation

• Improper or inadequate operation

and maintenance

Medium severity (work can be

affected but it has indirect impact on

the product)

Average probability (sometimes

documents are not updated)

Average detectability (fault can be

detected in normal operation)

2 2 2 8 IQ – Check the availability of all drawings,

datasheets and manuals in approved state

2 Technical

Drawings

• Technical drawings not available

• Technical drawings not updated

• Improper equipment installation

• Difficulty in corrective and

preventive maintenance

• Inadequate maintenance plans

Low severity (work cannot be done

without documentation)

Average probability (sometimes

documents are not updated)

Likely detectable

1 2 2 4 GEP – Check the availability and update of

the installation technical drawings

29

No Parameter




3 Installation Layout

• Equipment layout not in

accordance to diagrams

• Lack of some components

• Layout is not GMP compliant

• Inadequate layout

• Product contamination

It can have impact on the product

Average probability

Easy to detect

3 2 1 6

IQ – Check the correct correlation between

granulation line installation diagram and

the installed equipment

4

Standard

Operational

Procedures (SOP)

• Lack of procedures

• Procedures not updated

• Operation, cleaning, calibration

and maintenance inadequate for

the equipment

High impact on the product

It can happen

Likely detectable

3 2 2 12

IQ – Check if calibration procedures are

available, where applicable

OQ – Check if all other procedures are

available and adequate (maintenance,

operation and cleaning); Check the

availability of calibration and preventive

maintenance plans for the equipment and

instruments

30

No Parameter




5

Identification of

equipment

components

• Components not properly

identified or not correctly

labelled

• Difficult identification of the

equipment (main components and

instruments)

• Increase of maintenance errors,

time and cost


It can happen

Likely detectable

2 2 2 8 IQ – Verify that all components installed are

properly identified and labelled

6 UTILITIES

Electricity

• Connections not properly

performed

• Electric parameters out of

specification (OOS)

• Utility not present

• Inability to perform operations


It can happen

Easy to detect

2 2 1 4 IQ – Check all electrical connections and

parameters

Purified Water


performed

• Purified water OOS

• Operations compromised

High severity on product quality

It can happen

Likely detectable

3 2 2 12 IQ – Check all water connections and

parameters

31

No Parameter




Compressed Air


performed

• Compressed air OOS

• Operations compromised

High severity on product quality

It can happen

Likely detectable

3 2 2 12 IQ – Check compressed air connections and

parameters

7 SPECIFICATIONS AND INSTALLATION OF GRANULATION LINE EQUIPMENT COMPONENTS

High Shear Mixer

• Equipment specifications do not

match the URS

• Equipment does not comply with

the technical specifications

• Equipment is incorrectly installed

• HSM is not operating properly

according to technical

specifications

• Equipment does not work properly

• Operation of granulation line is

compromised

Direct impact on product

It can happen

Likely detectable

3 2 2 12

DQ – Check if all the URS are taken in

consideration in the equipment

specifications

IQ – Verify the HSM main characteristics;

Verify that the HSM is properly installed

OQ – Verify the functionalities and

operation of the HSM

32

No Parameter




Fluid Bed Dryer


match the URS




• FBD is not operating properly


specifications



compromised


It can happen

Likely detectable

3 2 2 12



specifications

IQ – Verify the FBD main characteristics;

Verify that the FBD is properly installed


operation of the FBD

Wet/Dry Mill


match the URS




• Mill is not operating properly


specifications



compromised


It can happen

Likely detectable

3 2 2 12



specifications

IQ – Verify the mill main characteristics;

Verify that the mill is properly installed


operation of the mill

33

No Parameter




Vacuum Conveyor


match the URS




• VC is not operating properly


specifications



compromised


It can happen

Likely detectable

3 2 2 12



specifications

IQ – Verify the VC main characteristics;

Verify that the VC is properly installed


operation of the VC

Valves

• Valves specifications do not

match the URS

• Valves do not comply with

technical specifications

• Valves incorrectly installed


Indirect impact on product

It can happen

Likely detectable

2 2 2 8



specifications

IQ – Verify valves main characteristics;

Verify that all valves are properly installed

Filters

• Filters specifications do not

match the URS

• Filters are clogged, damage or it is

the wrong filter


• Leaks in filters

High impact

It can happen

Likely detectable

3 2 2 12



specifications

IQ – Verify the use of the correct filters and

that none of them are damage; Verify that

all filters are properly installed; verify if

none of the filters are damaged; Verify the

differential pressure in each filter

34

No Parameter




Product transfer

tube between

HSM and FBD

• The tube does not comply with

the specifications

• The tube is not properly installed

• Equipment cannot work in a closed

system

• Contamination of the product

• Inability to develop process


It can happen

Likely detectable

3 2 2 12 IQ – Check if the tube is installed according

to the diagrams

Seals and

Connections

• Seals and connections do not

comply with the specifications

• Seals and connections between

equipment components, not

properly performed


• Inability to develop process

High impact on product quality

Low probability

Likely detectable

3 2 2 12

IQ – Check certificates for seals and

connections; Check if all seals and

connections are installed according to the

diagrams and instructions

Control System

Hardware

• Equipment does not match the

requested

• Equipment incorrectly installed

• Use of inadequate equipment

• Inability to develop the process

Moderate impact on product quality

Average probability

Likely detectable

2 2 2 8

IQ – check the Control System hardware

components installation and

characteristics; Check/record the

equipment configuration and/or version

35

No Parameter




Control System

Software

• Software / components do not

match the requested

• Software incorrectly installed

• Use of inadequate equipment

• Inability to develop the process


Average probability

Likely detectable

2 2 2 8

IQ – check the Control System software

installation and characteristics;

Check/record the equipment configuration

and/or version

8 MEASURING INSTRUMENTS

Product

temperature

sensor

(HSM & FBD)

• Instrumentation not appropriate

for their function

• Lack of calibration/verification

• Impossible measuring /monitoring

of the required parameters

• The measured / monitored values

aren’t trustworthy


It can happen

Likely detectable

3 2 2 12

IQ – Verify that the temperature sensor is

properly installed; Check the availability of

the calibration procedure; Verify that the

temperature sensor is properly calibrated

and the availability of respective

certificates

OQ – Verify that the temperature sensor is

included on the calibration plan

36

No Parameter




Inlet air

temperature and

humidity sensor


for their function







It can happen

Likely detectable

3 2 2 12

IQ – Verify that the temperature and

humidity sensors are properly installed;

Check the availability of the calibration

procedure; Verify that the temperature and

humidity sensors are properly calibrated


certificates

OQ – Verify that the temperature and

humidity sensors are included on the

calibration plan

Outlet air

temperature and

humidity sensor


for their function






Moderate impact on the product

It can happen

Likely detectable

2 2 2 8

IQ – Verify that the temperature and

humidity sensors are properly installed;

Check the availability of the calibration

procedure; Verify that the temperature and

humidity sensors are properly calibrated


certificates

OQ – Verify that the temperature and

humidity sensors are included on the

calibration plan

37

No Parameter




Pressure Sensor

(FBD)


for their function







It can happen

Likely detectable

3 2 2 12

IQ – Verify that the pressure sensor is

properly installed; Check the availability of

the calibration procedure(s), where

applicable; Verify that the pressure sensor

is properly calibrated and the availability of

respective certificates

OQ – Verify that the pressure sensor is

included on a Calibration Plan

9 MAIN OPERATIONAL FUNCITONS

Production of

Granules

• Mixer motor does not work

according to specifications

• Granules OOS


It can happen

Easily detectable

3 2 1 6

OQ – Check the mixer motor speed

- At minimum speed

- At normal speed

- At maximum speed

Production of

Granules

• Chopper does not work according

to specifications

• Granules OOS


It can happen

Easily detectable

3 2 1 6

OQ – Check the chopper motor speed

- At minimum speed

- At normal speed

- At maximum speed

38

No Parameter




Production of

Granules

• Granulation solution spray rate

not according specifications

• Granules OOS


It can happen

Easily detectable

3 2 1 6

OQ – Check the spray rate

- At minimum rate

- At normal rate

- At maximum rate

Dry sieving mill

• Sieving mill mixer not according

specifications

• Screen not according to

specifications

• Granules OOS


It can happen

Easily detectable

3 2 1 6

IQ – Check screen certificate

OQ – Check the speed sieving mill mixer

- At minimum speed

- At normal speed

- At maximum speed

Wet sieving mill

• Sieving mill mixer not according

specifications

• Screen not according to

specifications

• Granules OOS


It can happen

Easily detectable

3 2 1 6

IQ – Check screen certificate

OQ – Check the speed sieving mill mixer

- At minimum speed

- At normal speed

- At maximum speed

Wet powder

drying

• Air flow not according to

specifications

• Dry granules OOS


It can happen

Easily detectable

3 2 1 6

OQ – Check the air flow rate

- At minimum rate

- At normal rate

- At maximum rate

39

No Parameter




10

Materials in

contact with the

product

• Inadequate construction

materials

• Risk to the product

• Product contamination


It can happen

Likely detectable

2 2 2 8 IQ – Verify the relevant material certificates

11 Granulation Line

operation

• Granulation Line components not

properly operating

• Workers not able to operate the

equipment

• Equipment not operating according

to specifications

Direct impact on product quality

It can happen

Likely detectable

3 2 2 12

OQ – Verify the proper operation of the

granulation line; Verify that training has

been performed and documented; Verify

the availability of an updated operation

SOP

12 Alarms and

Malfunctions

• The equipment does not act as

expected in case of alarms and

malfunctions

• Incorrect alarms

• Inability to detect a malfunction in

the equipment

• High risk to the product and

operator

It can have impact on product quality

It can happen

Likely detectable

2 2 2 8 OQ – Check the alarms and faulty operation

conditions of the equipment

40

No Parameter




13 Password access

level

• Incorrect levels of access

• No security against unauthorised

persons

• Risk to the product

• Risk to the equipment


It can happen

Likely detectable

3 2 2 12

OQ – Check the user ID and password

access levels in the applicable control

equipment

14 Data report

management

• Incorrect or inexistent data

reports

• Impossible to consult/print the

data and events report

• Reports do not reflect what

occurred during production


It can happen

Likely detectable

2 2 2 8 OQ – Check the data report management

functionalities, where applicable

15 Audit trail

management

• Incorrect or inexistent audit trail

• Lack of data integrity

• Impossible to consult/print the

data safe storage

• Data safe storage does not reflect

what occurred during production


It can happen

Likely detectable

2 2 2 8 OQ – Check the process data safe storage

41

No Parameter




16 Cleaning • Cleaning is not performed

properly



It can happen

Likely detectable

3 2 2 12

OQ – Check the availability of a cleaning

SOP; Check if the training in cleaning

procedures is performed effectively

Validation of the cleaning process

17 Calibration

• Calibration of the components,

where applicable, is not

performed

• Measuring/ monitoring required

parameters is not possible

• Measured/ monitored values are

not trustworthy

• Product OOS


It can happen

Likely detectable

3 2 2 12

IQ – Perform calibration to all critical

instruments and verify that the results

comply to their acceptance criteria;

OQ – Verify the availability of an updated

SOP for calibration; Verify that all

applicable components are included on the

annual calibration plan; Verify the

availability of a logbook

18 Maintenance • Maintenance of the equipment is

not performed

• Operation of the equipment is

compromised

• Damage of the equipment


It can happen

Likely detectable

3 2 2 12

OQ – Verify the availability of an updated

SOP for maintenance; Verify that all

equipment components are included on

the preventive maintenance plan; Verify

the availability of a logbook

42

No Parameter




19 Operators

Training • Lack of training

• Inadequate equipment operation


Low probability

Likely detectable

3 1 2 6

OQ – Check the training of the operators

who work with the equipment; Check the

availability of an updated SOP for

equipment operation

43

3.4.2 iRisk Tool

The iRisk tool allows to schematize ideas during the process of qualification of an equipment and validation

of manufacturing processes. The use of this tool has permitted a better perception of how qualification activities

are oriented in the pharmaceutical industry.

The program allows the possibility of schematizing the URS and using them as an input for the FRA. Once the

FRA is completed, it is possible to graphically observe the risks that have been identified and compare their

severity, probability, detectability and their RPN, with visual tools that facilitate the interpretation of data. It is

also possible to build reports directly from iRisk.

This tool has several advantages, already described, in the context of integrating teams into risk management

processes. Within the scope of this thesis the huge added value of this tool is the fact that it allows the

visual/graphical demonstration of the risks obtained in the FMEA.

In order to understand the usefulness of the tool, the first 5 items of the FRA were used to build a FRA in

iRisk. Figure 14 shows the graphics obtained using the iRisk tool for the first 5 items of the FRA.

The first graph (figure 14-a) summarizes the RPN values per risk. Since each column is a different risk, visually

it is possible to realise immediately which are the risks with the highest RPN, and, therefore, the uppermost

priorities. In figure 14-b each risk appears with three columns: one for severity (pink), one for probability (green)

and one for detectability (orange). In this last graph the risks can be distinguished by each of the parameters

ranked. It shows which risks have the highest and lowest rank for S, P and D.

It is also possible to place the risks in a risk matrix (figure 15) that allows the visual perception of which risks

are the highest priority. The risks in the green zone are low risks, the ones in the yellow zone are medium risks,

and in the red zone there are the high-level risks. The report built with the iRisk tool can be accessed in annex 2.

Figure 14: Summary of the risks based on (a)RPN; (b) Severity, Detectability and Ocorrence

(a) (b)

44

3.5 Design Qualification

Following URS and FRA the next step of qualification is DQ. In some cases, the DQ can be performed before

or at the same time as the FRA, since these are two independent phases of the qualification process.

DQ was performed based on different documents from the supplier Diosna. The objective was to assure that

all URS were taken into consideration in the equipment specifications.

The documents consulted are the following:

A. Specification SP 2774757;

B. Operating Manual 0-406-293-021-BL_pt;

C. Control Description 0-406-293-021-BA-PT;

D. Completeness of the delivery range/ technical specification FAT_0-406-293-021_3.1;

E. Listing and certificates of product contacting materials;

The results obtained in DQ are represented in table 8, including the document which is source of the

information and its compliance with the predefined URS.

Table 8: Design Qualification for Diosna Granulation Line

URS Equipment Specification Document Comply?

1 All

“DIOSNA Mixer-Dryer-Granulation Lines CCS are used for the

manufacture of pharmaceutical granules in a closed system”

(pg. 9)

A Yes

2 All “Granulation liquid: various water-based binders” (pg. 12) A Yes

3 HSM “Total bowl volume 615L” (pg. 15) A Yes

Figure 15: Risk matrix

45


4 FBD

“Depending on the design of the systems products can be

granulated/agglomerated or coated” (pg. 10)

“In the filter housing one opening with blind flange is located

at suitable position to allow for a later retrofitting top spray

device” (pg.28)

“For positioning of the nozzles below the air distribution

plate the cylindrical piece of the material bowl at the lower

safety collar is extended, so that blind flanges for the nozzles

can be installed” (pg.28)

A Yes

5 FBD “Material bowl size (usable volume): 680L” (pg.23) A Yes

6 Mill “Sieving mill ConiWitt 200 for dry sieving” (pg. 36)

“Sieving mill for wet milling: FreWitt ConiWitt 200W” (pg.52)

A

B Yes

7 VC

“A dust-free feeding from containers or barrels via a

pneumatic conveyance system can be realised” (pg. 17)

“For dust-free discharge of the bowl pneumatic conveying

system is used” (pg. 25)

A Yes

8 VC There is no reference to this URS in the documentation. ---

No Information

9 All

“The operation of the mixer and the dryer is done via two

identical operator interface terminals. Both machines are

visualized and operated via either one of the two operator

interface terminals. However, at any time there is the

possibility to operate each plant separately as both machines

dispose of an independent PLC” (pg. 43)

A Yes

10 All “The control of the plant is based on a standard PLC Siemens

SPS S7-300” (pg. 42) A Yes

11 All “The operation of the mixer and the dryer is done via two

identical operator interface terminals.” (pg. 43) A Yes

12 HSM List of measuring circles: Parameters – spray rate, spray

pressure, pressure container, process time mixer A Yes

13 HSM “The temperature is measured by a PT100 probe which is

insert through the container wall into the product” (pg. 15) A Yes

14 FBD

“Inlet air temperature measurement: a temperature probe

in the air pipe directly in front of the inlet into the fluid bed

apparatus is used for regulation of the process air heater”

(pg. 35)

A Yes

46


“Inlet air humidity measurement including regulation of the

dehumidifier installed in flow direction upstream the process

air heater” (pg. 35)

“Exhaust air temperature measurement: measurement of

the exhaust air temperature can be used as additional

criterion for assessment of the fluid bed process” (pg. 35)

“Exhaust air humidity measurement: the probe is installed in

the air outlet socket of the fluid bed apparatus” (pg. 36)

15 HSM

“The conveying system allows dustless feeding of the mixing

bowl. The powdery components are sucked into the mixer

from barrels or bags by means of a suction lance” (pg. 18)

A Yes

16 HSM

FBD

“WIP cleaning system for the mixer granulator: the

automatic WIP cleaning is made by detachable spray balls in

the mixer lid and in the outlet housing. Delivery contains

spray balls, hoses and valves for triggering” (pg. 39)

“WIP cleaning system for the fluid bed processor” (pg. 39)

A Yes

17 FBD

“The intake air is cooled down by an air cooler operated with

cold water. As soon as the dew point temperature is fallen

below, the air is dehumidified by condensation” (pg.30)

A Yes

18 FBD

“Mixer and dryer are connected by a pipe or hose line. The

product is sucked out of the mixer by the under pressure of

the fluid bed apparatus” (pg. 10)

“The granulated material is sucked into the fluid bed dryer

by vacuum through the connection line” (pg. 21)

“An automated filling of the closed apparatus from

containers is possible by suction via a feeding valve” (pg. 24)

A Yes

19 Mill

“The sieving mill can be used for dry milling ate the discharge

from the fluid bed dryer and for raw material sifting. In both

cases a ConiWitt milling head will be used” (pg. 55)

“Suction shoe and conveying hose for the discharge of the

ConiWitt for raw materials sifting inline during charging of

the P600” (pg. 55)

A Yes

20 VC There is no reference to this URS in the documentation. ---

No Information

21 Mill There is no reference to this URS in the documentation. ---

No Information

22 All “The operator PC runs on the basis of windows. The

visualisation of the plant is made on basis of software A Yes

47


platform Intouch of Wonderware. Intouch fulfils the

requirements of GAMP 5 and it is 21 CFR Part 11 suited” (pg.

43)

23 All

“Certain process parameters can be displayed graphically as

coloured curves or tables. Furthermore, all actions and

alarms occurred during the process are logged” (pg. 44)

A Yes

24 All

“Historical data of preceding batches can be indicated

graphically with recipe number, operator code, date, time

and the most important system data” (pg. 43)

A Yes

25 All

“Individual batch reports can be issued, which include all

important batch data with date, time, batch recipe number

and operator number. Certain process parameters can be

displayed graphically as coloured curves or tables.

Furthermore, all actions and alarms occurred during the

process are logged” (pg. 44)

A Yes

26 HSM

“During the process the current consumption of the mixer

chopper motor is measured and indicated at the control; The

value comes out of the frequency converter” (pg. 19)

“During the process the power consumption of the main

mixing tool is measured and indicated at the control panel;

The power is measured by a dedicated load cell” (pg. 20)

A Yes

27 FBD

All controls in the control panel are described in section 10

“Service mode of FBD” (pg. 56 to 71) and 11 “Automatic

mode of FBD” (pg.72 to 90)

C Yes

28 All

“12 bar shock-proof design of the mixing bowl: The shock-

resistant design of the mixer ensures that explosions, which

develop in the mixer, and also explosions, which strike back

from the fluid bed dryer into the mixer during the product

transfer, keep safely within the mixer” (pg. 46)

“The basic design of the fluid bed processor assumes that

exclusively interior explosion protection has to be fulfilled”

(pg. 47)

“Because of the 12 bar shock-resistant design a decoupling

of the air technique on the inlet and exhaust area is

necessary. For this purpose self-closing quick acting valves

A Yes

48


are installed directly upstream and downstream the fluid bed

apparatus” (pg.47)

29 All

“The cabinets are made of painted steel, protection IP54 and

intended for installation in a non-explosion-proof area” (pg.

42)

A No

30 All

“In some parts of the device (filter, temperature

announcements), an input mask appears by choosing the

green field on the piece. Here you can enter limit values for

an alarm or warning. If the current value reaches the

opposite value, an alarm announcement or warning is

generated.” (pg. 9)

C Yes

31 All

“The active elements appear in green. Active tubular ducts

are shown in yellow. In the event of a problem, flow meters,

pressure measuring devices or pressure switches change

from green to red. Fault signals are displayed in the title of

the current window” (pg. 35)

C Yes

32 All

“Emergency Buttons in HSM – technical area and HSM

screen” (pg. 152)

“Emergency Buttons FBD – technical area, screen and

elevation column” (pg.157)

C Yes

33 HSM “M0226002 HSM alarm – high pressure inside the bowl”

(pg.153) C Yes

34 FBD “D0215007 FBD alarm – filter pressure difference” (pg. 158) C Yes

35 All

“Since the P 600 and CAP 600 are situated in two separate

rooms, a wall lead through element with TC connections is

supplied by DIOSNA” (pg. 21)

A Yes

36 All “The plant concept allows for strict separation of production

and technical area” (pg. 9) A Yes

37 Mill There is no reference to this URS in the documentation. ---

No Information

38 All Throughout the document, the consumption of each

equipment for each utility is specified. A Yes

39 All

“The basic design of the CCS Granulation Line works duly as

granulator/dryer combination and consists of a

mixer/granulator P series, a CAP fluid bed dryer and the

common shared control of the plant”

A Yes

49


40 All “Any product contacting sealings are made of silicone and

FTFE” (pg. 14) A Yes

41 All “Product-contacting stainless-steel parts are made of

stainless steel AISI 316L” (pg. 14) A Yes

42 All “Enhanced surface finish on product contact surfaces Ra <

0,2 m instead of Ra < 0,4 m” (pg. 14) A Yes

43 All “Other stainless steel surfaces are ground at Ra < 0,8” (pg.

44) B No

44 HSM “A special design for the chopper tool with 6-8 cross blades

will be provided” (pg. 16) A Yes

45 HSM

“Shaft seals of main mixing tool and chopper are designed as

air purged seals, during cleaning the seals and the container

are rinsed automatically with water” (pg. 17)

A Yes

46 HSM

“For cleaning and inspection of the mixing material under the

mixing tool this lifting system offers a considerable

facilitation especially for big mixers. The mixing tool is lifted

with help of a pneumatic cylinder under the hollow shaft

drive” (pg. 16)

A Yes

47 HSM There is no reference to this URS in the documentation. --- No Information

48 HSM There is no reference to this URS in the documentation. --- No Information

49 HSM “The drive will be reinforced from the standard 37kW to

55kW” (pg. 16) A Yes

50 HSM “Speed range of 5 – 150 rpm” (pg. 16) A Yes

51 HSM “The chopper motor will be reinforced from the standard

12kW to 15kW” (pg. 16) A Yes

52 HSM “Frequency converter operation of chopper motor 200 -

3500 rpm” (pg. 16) A Yes

53 HSM

“A manual sampling valve will be integrated in the wall of the

mixing bowl. The valve works according to the trumpet valve

principle” (pg. 15)

A Yes

54 HSM

“Controlled addition of liquid via nozzles” (pg. 18)

“Peristaltic pump for low viscous spray media for addition of

granulation liquids, in pharmaceutical design, easily

cleanable, easy hose exchange, with temperature and

pressure resistant hose” (pg. 19)

A Yes

50


55 HSM “The inspection glass is equipped with an illumination for

better observation of the process” (pg. 17) A Yes

56 HSM

“A manually pivoting hoist with manually operated cable

winch allows for a secure and ergonomic dismantling of the

mixing tool” (pg. 16)

A Yes

57 HSM “Filter cartridge stainless steel” (pg.2) E Yes

58 FBD

“The sampler is operated via hand level which releases an

opening in the material bowl. The product sample flows into

a connected cup until the lever is closed again” (pg. 23)

A Yes

59 FBD

“Product filter material: Polyamid 6.6” (pg.3)

“PA 6.6 is in compliance with the regulations 21 CFR “Nylon

Resins” of FDA” (annex 22 of document)

E Yes

60 FBD

“The intake air is cooled down by an air cooler operated with

cold water. As soon as the dew point temperature is fallen

below, the air is dehumidified by condensation” (pg.30)

A Yes

61 FBD “The process air is heated by a steam heat exchanger to the

necessary process air temperature” (pg. 31) A Yes

62 Mill There is no reference to this URS in the documentation. --- No Information

63 Mill

“After completion of the granulation the discharge of the

granules via an optional inline sieving mill into the connected

dryer is done automatically” (pg. 10)

“Below the mixer outlet installed (swivelling design) sieving

mill with regulable drive to homogenise the wet granule” (pg.

20)

“The sieving mill can be used for dry milling ate the discharge

from the fluid bed dryer and for raw material sifting. In both

cases a ConiWitt milling head will be used” (pg. 55)

“Suction shoe and conveying hose for the discharge of the

ConiWitt for raw materials sifting inline during charging of

the P600” (pg. 55)

A Yes

64 Mill

“A round-hole screen 1,0 mm with round impeller is used a

standard sieve; In case of very hard granules rasp sieves are

advantageous” (pg. 37)

A Yes

65 Mill

“Nominal speed (regulated by frequency convertor): 300-

1800 rpm

Motor: 4kW” (pg. 52)

B Yes

51


66 Mill

“The sieve inset depends on the product (standard sieve:

square hole 10.0 mm with round impeller)” (pg.20) A

Yes “An additional sieve insert of 0,8mm round hole is provided

for raw material sieving” (pg. 13) D

67 VC

There is no reference to this URS in the documentation. --- No

Information 68 VC

69 VC

“The delivery scope comprises all components being

necessary for pneumatic feeding: vacuum tight mixer

including shaft seals, filter on the mixer lid with stainless

steel housing, filter cleaning by backwashing, socket in the

mixer lid, suction lance with regulating valve and conductive

plastic hose, support/holder for the lance, pneumatic

vacuum pump (multi stage ejector)” (pg. 18)

A Yes

70 All

“A complete 2-fold technical documentations as well a CD is

delivered along with the machine. The documentation

comprises of following papers: operator manual; controls

description; maintenance instructions; safety instructions;

layout drawings; installation, current flow, clamp and cable

plans; P&I diagram; selected subassembly drawings (e.g.

drives, sealings, pneumatic); spare parts list” (pg. 49/50)

“Qualification documents DIOSNA – blank forms: master

plan; documents of the DQ; documents for performing IQ

with I/O-checks, material certificates for the product

contacting metal parts, material certificates for the product

contacting non-metal”; documents for performing OQ; FAT

protocol; SAT protocol” (pg. 50)

A Yes

As shown in table 8, there is little information about the vacuum conveyor and the mill (URS 8, 20, 21, 37, 62,

67 and 68). This is due to the fact that these two components are of a different brand (they are not Diosna) and,

consequently, the supplier does not have the same level of detailed specifications for this equipment. However,

most of these URS can be assessed at other stages of the qualification, afterwards.

There are also two URS related to HSM that are not specified on the documentation: URS 47 and URS 48.

Although the machine drawings were available for consulting, the measures relating to these URS were not

specified. These URS can be confirmed later, during the installation phase of the equipment.

52

Furthermore, information related to URS 29 and URS 43 does not comply with the equipment specifications.

Whenever the obtained result from an item does not comply with the expected, a deviation is opened.

According to the criticality of the requirement, the deviation is classified as minor, major or critical. Every single

deviation must be closed before the next qualification stage. However, in some cases it is necessary to perform

the following qualification stage to conclude the investigation or the corrective action of the deviation. In these

cases, a conditional approval might be requested to the Quality Assurance Department and the deviation closure

can be done upon the conclusion of the qualification report.

In the cases of the URS for which no information was found the deviation is classified as minor, since these

specifications can be assessed as existing or not in the next qualification phases, so that conditional approval can

be applied in this situation.

For information that is not URS compliant, the deviation can be classified as major or critical, depending on

the risk assessment for the product/process. Before moving on to the next qualification stages, the deviation for

these two URS must be closed. This implies an investigation and acceptance of the new requirements, if it is

concluded that this change does not involve risks to the product/process.

53

4. Conclusion and Further Work

The objective of this work was to qualify a Granulation Line. With this objective in mind, the first step was to

assess the risk that the equipment would have on the pharmaceutical product. Through a questionnaire with 16

questions, it was assessed whether the machine would have a direct, indirect or no impact on the finished

product. As the equipment was in direct contact with the raw material, it was expected that the result of the

GRA would imply the complete qualification of the granulation line, given the direct impact on the quality of the

product.

The qualification process was then started. The first step was to write the URS for the granulation line in order

to define which specifications the company wanted for the equipment. After defining the URS, a risk analysis of

the equipment functions was performed. Through the FRA it was possible to define which tests would have to

be necessarily included in the IQ and OQ protocols in order to minimize/mitigate the risks associated with the

equipment.

The last step that was possible to perform in the qualification phase was the qualification of the design. This

step was especially important, because often, in the industry, it is assumed that the equipment is already known

and the DQ is not performed. Nonetheless, as it was possible to detect, the equipment does not always fully

meet the specifications defined in the URS and it is therefore necessary to open deviations to rectify the non-

conformities and follow the qualification process.

The use of the iRisk tool was an added value for this project, since it allowed to understand how the risk

management process can be integrated with several members of a team in the same company. This tool is an

added value to the qualification process, in order to clearly visualise which risks are a priority and which

qualification tests should be performed.

During the development of this project there were some constraints, namely the lack of documentation from

suppliers available for consultation and the restructuring in the planning of the activities of the new facility. These

occurrences prevented the following steps of qualification (IQ, OQ and PQ) from being part of the scope of this

thesis. However, it was still possible to plan the IQ and OQ activities for the granulation line.

The future steps of this project will involve crossing the tests planned in this thesis for IQ and OQ through

FRA with the qualification protocols provided by DIOSNA and the creation of qualification protocols for Labatec

Farmacêutica. It is planned that, by the end of the year, the equipment will be fully qualified and ready for the

validation of the Mydocalm manufacturing process.

54

5. References

1. OECD Statistics. https://stats.oecd.org/. (accessed on 20/10/2019)

2. About us - Labatec. http://www.labatecpharma.com/about-us/. (accessed on 15/09/2019)

3. 3644-61-9・Tolperisone Hydrochloride・205-10821・203-10822[Detail Information]. Laboratory

Chemicals |Laboratory Chemicals-FUJIFILM Wako Chemicals U.S.A. Corporation https://labchem-

wako.fujifilm.com/us/product/detail/W01W0120-1082.html. (accessed on 06/12/2019)

دواء هو { ميدوكالم } .4 albadia.pharmacy. Pictame - ...مادة من يتكون للعضلات باسط و مرخ

https://www.pictame.biz/media/BhV4uqCFV92. (accessed on 20/10/2019)

5. European Commission. Eudralex, volume 4. EU guidelines for good manufacturing products for human

and veterinary use. Annex 15: Qualification and Validation.

6. Rodrigues, T. Qualificação de Sistemas Aplicada à Indústria Farmacêutica.

7. Guideline on process validation for finished products - information and data to be provided in regulatory

submissions. 15.

8. Abraham, J. International Conference On Harmonisation Of Technical Requirements For Registration Of

Pharmaceuticals For Human Use – Quality Risk Management Q9. In Handbook of Transnational

Economic Governance Regimes; (eds. Tietje, C. & Brouder, A.), January 2006

9. iRISK TM - Risk Management Platform. https://www.irisk.com/. (accessed on 22/09/2019)

10. Augsburger, L. L. & Hoag, S. W. Pharmaceutical dosage forms: tablets. Volume 1: Unit Operations and

Mechanical Properties. (Informa Healthcare, 2010).

11. Faure, A., York, P. & Rowe, R. C. Process control and scale-up of pharmaceutical wet granulation

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on 24/09/2019)

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Annex 1 – General Risk Assessment Form filled for Granulation Line

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Annex 2 – iRisk Report

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