**5. Project life cycle**

A life cycle approach is an important element for ensuring the global quality of a process. As mentioned before, quality has to be designed in order to be controlled. The term "designed quality," applied to a pharmaceutical project, means that objectives are well defined and that critical variables have been identified and quantified. This allows for a monitoring and evaluation of the project: if the critical variables are kept under control, then objectives will be met. Thus, the life cycle has to be considered as a chain of events that progressively increase the amount of information and build quality gradually.

As it can be seen (**Figure 2**), the life cycle of a project is composed of four phases, although only the first two (design and realization) concern what we have been calling pharmaceutical project and are managed by the two partners. The latter two phases (manufacture and discontinuation) are just the consequence of the former two and they belong exclusively to the laboratory. In fact, instead of

**153**

**Figure 3.**

*Pharmaceutical Projects: Walking along the Risk Management Line*

recycling or disposing of materials in an ecological way, etc.).

"manufacture," we can talk of "routine production," where quality is the result of the quality of the project plus all the measures applied to build quality into the products and to monitor that this is correctly realized. The last phase, discontinuation, is simply mentioned to remind us that when facilities have to stop production to be closed, this has to be done in an organized way (i.e., market cannot be left undersupplied by a unilateral decision; the environment has to be protected by

**Figure 3** summarizes the basic definitions related with risk management, as described in guideline ICH Q9 [3]. In any activity, there are hazards, which are significant because they can turn into harms. It is evident that hazards matter because there is a chance that they materialize into harms, and it is obvious that the importance of the harm determines how much attention they deserve. Thus, it is

There is no human activity free from hazards (and, unfortunately, from harms)

**Figure 4** summarizes the different levels of risk or of hazard assessment (to express it in a different way). As we can see, the objective is always reducing the level of risk as much as possible. This reduction, however, should be consistent with the efforts, which we apply for attaining this effect. Sometimes, a high risk might be

and, consequently, risk is always extant. This is why we came to speak of risk management. As we always face risk, it is meaningful to understand it and try to diminish it. When we remove a dish from an (hot) oven, there is a hazard: we can burn our fingers. To diminish the risk, we use an oven glove. By donning a glove, we diminish the probability of the harm and, thus, the risk. And what about the severity of the harm? In general, it is considered that we cannot act against it, as the severity of a harm is an attribute of it. Anyway, we might also think that the simple fact of wearing a glove would diminish the severity of the burn. Yes, in the interpretation of risk, there is always some amount of personal understanding, but this is not very relevant if we come to appreciate the situation well and we apply the same criteria over time. Just to finish with these considerations, we should keep in mind that the exact assessment of risk is second to the accurate understanding of the hazard. This is why in many cases we need not determine risk but just assess the hazards (Which hazards exist? Which are their causes? Are they likely? After all,

*DOI: http://dx.doi.org/10.5772/intechopen.82601*

easy to understand the definition of the risk.

should we worry? Should we take any measure? etc.).

accepted if there is no better alternative.

*Main definitions concerning risk management.*

**6. Risk management**

*Pharmaceutical Projects: Walking along the Risk Management Line DOI: http://dx.doi.org/10.5772/intechopen.82601*

"manufacture," we can talk of "routine production," where quality is the result of the quality of the project plus all the measures applied to build quality into the products and to monitor that this is correctly realized. The last phase, discontinuation, is simply mentioned to remind us that when facilities have to stop production to be closed, this has to be done in an organized way (i.e., market cannot be left undersupplied by a unilateral decision; the environment has to be protected by recycling or disposing of materials in an ecological way, etc.).

### **6. Risk management**

*Perspectives on Risk, Assessment and Management Paradigms*

there is a continual loss of information.

form, are very important in a project.

**5. Project life cycle**

tion and build quality gradually.

or processes do not inform the others, but keep it for them and, consequently,

4.The PQS contains four elements (**Figure 1**). All of them, albeit not in this

A life cycle approach is an important element for ensuring the global quality of a process. As mentioned before, quality has to be designed in order to be controlled. The term "designed quality," applied to a pharmaceutical project, means that objectives are well defined and that critical variables have been identified and quantified. This allows for a monitoring and evaluation of the project: if the critical variables are kept under control, then objectives will be met. Thus, the life cycle has to be considered as a chain of events that progressively increase the amount of informa-

As it can be seen (**Figure 2**), the life cycle of a project is composed of four phases, although only the first two (design and realization) concern what we have been calling pharmaceutical project and are managed by the two partners. The latter two phases (manufacture and discontinuation) are just the consequence of the former two and they belong exclusively to the laboratory. In fact, instead of

**152**

**Figure 2.**

*The pharmaceutical project within the project life cycle.*

**Figure 3** summarizes the basic definitions related with risk management, as described in guideline ICH Q9 [3]. In any activity, there are hazards, which are significant because they can turn into harms. It is evident that hazards matter because there is a chance that they materialize into harms, and it is obvious that the importance of the harm determines how much attention they deserve. Thus, it is easy to understand the definition of the risk.

There is no human activity free from hazards (and, unfortunately, from harms) and, consequently, risk is always extant. This is why we came to speak of risk management. As we always face risk, it is meaningful to understand it and try to diminish it. When we remove a dish from an (hot) oven, there is a hazard: we can burn our fingers. To diminish the risk, we use an oven glove. By donning a glove, we diminish the probability of the harm and, thus, the risk. And what about the severity of the harm? In general, it is considered that we cannot act against it, as the severity of a harm is an attribute of it. Anyway, we might also think that the simple fact of wearing a glove would diminish the severity of the burn. Yes, in the interpretation of risk, there is always some amount of personal understanding, but this is not very relevant if we come to appreciate the situation well and we apply the same criteria over time. Just to finish with these considerations, we should keep in mind that the exact assessment of risk is second to the accurate understanding of the hazard. This is why in many cases we need not determine risk but just assess the hazards (Which hazards exist? Which are their causes? Are they likely? After all, should we worry? Should we take any measure? etc.).

**Figure 4** summarizes the different levels of risk or of hazard assessment (to express it in a different way). As we can see, the objective is always reducing the level of risk as much as possible. This reduction, however, should be consistent with the efforts, which we apply for attaining this effect. Sometimes, a high risk might be accepted if there is no better alternative.

**Figure 3.** *Main definitions concerning risk management.*

**Figure 4.** *Risk.*

There are several tools, which we can use for risk analysis [3]. They can be used and combined according to particular needs. In fact, the application of a standard method is necessary when high levels of formality are required (e.g., in comparative studies or in scientific papers), but for the routine risk assessment within a company, it is possible to be less formal and adapt the tools to better fit our needs. Tools just organize information. They do not improve our information (if our raw data are poor or inaccurate, the application of the best of tools will not mend them). Thus, the quality of a risk analysis depends mainly on how worth our information is and on the knowledge and experience of the person who performs the study.

**Figure 5** lists the most common methodologies used in risk analysis. Among the specific ones, the most popular is, without any doubt, FMECA, an excellent tool when the process under study is well known. Then, it is possible to evaluate risk and use its value as an indicator for process improvement. Anyway, in most cases, when the amount of knowledge is more modest, it is better to start with PHA. HACCP is a very good tool for the control of processes; in fact, the WHO recommends it for

**155**

**Figure 6.**

*Flowchart summarizing the steps of pharmaceutical manufacture.*

*Pharmaceutical Projects: Walking along the Risk Management Line*

comparison of items composed of different elements.

the control of pharmaceutical manufacturing processes [6]. It is not necessary to add that HACCP requires a deep knowledge on the process. FTA is useful to identify the root causes of a problem. HAZOP can help to identify possible problems related to equipment and operation involved in a process. RRF is the choice tool for the

Next to the specific methodologies, we can talk of unspecific ones. Properly speaking they are not risk analysis tools but provide information, which is critical to perform an analysis. Here, we should emphasize flowcharts, which are a key

RRF and PHA. This is why, we consider useful to provide some guidance on them. Flowcharts are very useful to get a clear idea of a process and to perform a hazard assessment. In fact, the layout of a pharmaceutical unit is the translation of the flowchart steps into premises. The example of flowchart, which we present here in **Figure 6**, covers in a simplified way the operational stages of a pharmaceutical unit.

RRF (**Figure 7**) is a tool conceived for the comparison of different items, possessing different types of hazards and risk levels, by reducing them to a common denominator. The application of RRF starts by identifying the items to be compared and identifying their components and subcomponents. Then, the risk factors are determined and their integration allows for the establishment of the global risk of the item. As shown in **Figure 7**, all Rf are given the same weight and, thus, the load of each component depends more on the number of Rf considered than on the importance of the component itself. This can be corrected, for example, by giving a higher classification of risk to single Rf or to all the Rf of a given component.

It is evident that in practice there can be different types of processes.

For the risk management of pharmaceutical projects, we select, besides flowcharts,

*DOI: http://dx.doi.org/10.5772/intechopen.82601*

element to start a risk analysis of a process.

**Figure 5.** *Risk analysis tools.*

#### *Pharmaceutical Projects: Walking along the Risk Management Line DOI: http://dx.doi.org/10.5772/intechopen.82601*

*Perspectives on Risk, Assessment and Management Paradigms*

There are several tools, which we can use for risk analysis [3]. They can be used and combined according to particular needs. In fact, the application of a standard method is necessary when high levels of formality are required (e.g., in comparative studies or in scientific papers), but for the routine risk assessment within a company, it is possible to be less formal and adapt the tools to better fit our needs. Tools just organize information. They do not improve our information (if our raw data are poor or inaccurate, the application of the best of tools will not mend them). Thus, the quality of a risk analysis depends mainly on how worth our information is and

**Figure 5** lists the most common methodologies used in risk analysis. Among the specific ones, the most popular is, without any doubt, FMECA, an excellent tool when the process under study is well known. Then, it is possible to evaluate risk and use its value as an indicator for process improvement. Anyway, in most cases, when the amount of knowledge is more modest, it is better to start with PHA. HACCP is a very good tool for the control of processes; in fact, the WHO recommends it for

on the knowledge and experience of the person who performs the study.

**154**

**Figure 5.** *Risk analysis tools.*

**Figure 4.** *Risk.*

the control of pharmaceutical manufacturing processes [6]. It is not necessary to add that HACCP requires a deep knowledge on the process. FTA is useful to identify the root causes of a problem. HAZOP can help to identify possible problems related to equipment and operation involved in a process. RRF is the choice tool for the comparison of items composed of different elements.

Next to the specific methodologies, we can talk of unspecific ones. Properly speaking they are not risk analysis tools but provide information, which is critical to perform an analysis. Here, we should emphasize flowcharts, which are a key element to start a risk analysis of a process.

For the risk management of pharmaceutical projects, we select, besides flowcharts, RRF and PHA. This is why, we consider useful to provide some guidance on them.

Flowcharts are very useful to get a clear idea of a process and to perform a hazard assessment. In fact, the layout of a pharmaceutical unit is the translation of the flowchart steps into premises. The example of flowchart, which we present here in **Figure 6**, covers in a simplified way the operational stages of a pharmaceutical unit. It is evident that in practice there can be different types of processes.

RRF (**Figure 7**) is a tool conceived for the comparison of different items, possessing different types of hazards and risk levels, by reducing them to a common denominator. The application of RRF starts by identifying the items to be compared and identifying their components and subcomponents. Then, the risk factors are determined and their integration allows for the establishment of the global risk of the item. As shown in **Figure 7**, all Rf are given the same weight and, thus, the load of each component depends more on the number of Rf considered than on the importance of the component itself. This can be corrected, for example, by giving a higher classification of risk to single Rf or to all the Rf of a given component.

**Figure 6.** *Flowchart summarizing the steps of pharmaceutical manufacture.*

**Figure 7.** *Summary of steps for the realization of RRF.*

PHA is very practical for the analysis of situations where there is still limited information. PHA uses charts like the one shown in **Table 1** (although, often, the column describing the effect can be omitted, because it does not provide any useful information).


**157**

*Pharmaceutical Projects: Walking along the Risk Management Line*

Practice shows that, while performing risk analysis, one of the points that creates more confusion is the clear distinction among hazard, cause of the hazard, and effect of the hazard (harm). To simplify this matter, we propose the

We establish six types of hazards as the base of our analysis (**Figure 8**), then we apply them to the item that we study and we determine if this hazard might exist. If it really exists, then it is easier to establish possible causes and their derived effects

It is not necessary to insist on the fact that the selection of the partner with whom a laboratory will realize a project is very important. Following, we provide a

Rf 1.1 = quality system; Rf 1.2 = training program; Rf 1.3 = realization of com-

Rf 2.1 = experience in projects; Rf 2.2 = amount and completeness of documen-

Rf 3.1 = number of people in the company; Rf 3.2 = distance of the nearest point of service of the company to the project site; Rf 3.3 = knowledge of the language of

After determining the risk factors for each component, they are used to calculate

Finally, the items are ranked according to their respective risk. Thus, they can be

As shown in **Figure 9**, a pharmaceutical plan is the practical translation of the

The conditions penned in the URS depend on the particular wishes of each laboratory, whereas the plan to be developed and constructed by the engineering is

Rf 4.1 = price; Rf 4.2 = payment conditions; Rf 4.3 = bonuses; etc.

compared. They can also be "filtered," that is, selected (**Figure 6**).

Then, the global risk of each item is evaluated adding the risks of their

*DOI: http://dx.doi.org/10.5772/intechopen.82601*

*Summary of hazards to be considered in PHA charts.*

following approach.

**Figure 8.**

**7.1 Supplier selection**

and to propose control measures.

**7. Pharmaceutical project management**

simplified example of application of RRF.

missioning; Rf 1.4 = support for qualification; etc.

tation; Rf 2.3 = fulfillment of scheduled requirements; etc.

*Component (1) "Quality"*

*Component (2) "Reliability"*

*Component (3) "Accessibility"*

the site; Rf 3.4 = after sale service; etc. *Component (4) "Budget"*

**7.2 Translation of the URS into a plan**

requirements set up in the URS.

its comprehensive risk.

components.

**Table 1.**

*Example of chart used to develop PHA.*

*Pharmaceutical Projects: Walking along the Risk Management Line DOI: http://dx.doi.org/10.5772/intechopen.82601*

#### **Figure 8.**

*Perspectives on Risk, Assessment and Management Paradigms*

**156**

**Table 1.**

**Stage/ subject**

**Figure 7.**

useful information).

**Possible hazard**

*Summary of steps for the realization of RRF.*

*Example of chart used to develop PHA.*

**Hazard cause**

**Possible effect (harm)**

PHA is very practical for the analysis of situations where there is still limited information. PHA uses charts like the one shown in **Table 1** (although, often, the column describing the effect can be omitted, because it does not provide any

> **Is hazard significant?**

□ Yes/□ No □ Yes/□ No **Control measures** *Summary of hazards to be considered in PHA charts.*

Practice shows that, while performing risk analysis, one of the points that creates more confusion is the clear distinction among hazard, cause of the hazard, and effect of the hazard (harm). To simplify this matter, we propose the following approach.

We establish six types of hazards as the base of our analysis (**Figure 8**), then we apply them to the item that we study and we determine if this hazard might exist. If it really exists, then it is easier to establish possible causes and their derived effects and to propose control measures.

#### **7. Pharmaceutical project management**

#### **7.1 Supplier selection**

It is not necessary to insist on the fact that the selection of the partner with whom a laboratory will realize a project is very important. Following, we provide a simplified example of application of RRF.

*Component (1) "Quality"*

Rf 1.1 = quality system; Rf 1.2 = training program; Rf 1.3 = realization of commissioning; Rf 1.4 = support for qualification; etc.

*Component (2) "Reliability"*

Rf 2.1 = experience in projects; Rf 2.2 = amount and completeness of documentation; Rf 2.3 = fulfillment of scheduled requirements; etc.

*Component (3) "Accessibility"*

Rf 3.1 = number of people in the company; Rf 3.2 = distance of the nearest point of service of the company to the project site; Rf 3.3 = knowledge of the language of the site; Rf 3.4 = after sale service; etc.

*Component (4) "Budget"*

Rf 4.1 = price; Rf 4.2 = payment conditions; Rf 4.3 = bonuses; etc.

After determining the risk factors for each component, they are used to calculate its comprehensive risk.

Then, the global risk of each item is evaluated adding the risks of their components.

Finally, the items are ranked according to their respective risk. Thus, they can be compared. They can also be "filtered," that is, selected (**Figure 6**).

#### **7.2 Translation of the URS into a plan**

As shown in **Figure 9**, a pharmaceutical plan is the practical translation of the requirements set up in the URS.

The conditions penned in the URS depend on the particular wishes of each laboratory, whereas the plan to be developed and constructed by the engineering is

#### **Figure 9.**

*The pharmaceutical project: URS and their translation.*

encoded, by GMP [7–10] and good engineering practice (GEP). GEP is not codified as such. It is understood as the generally admitted good approach.

Let us analyze, using a risk management approach, the requirements that should meet a project. We use an adapted form of PHA.

#### *7.2.1 Hazard #1: (external) contamination*

In **Table 2** are described the main causes of (external) contamination and the control measures to keep them at bay.

#### *7.2.2 Hazard #2: cross-contamination*

In **Table 3** are described the main causes of cross-contamination and the control measures to hold them at bay.

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*Pharmaceutical Projects: Walking along the Risk Management Line*

Inadequate siting of the building Pharmaceutical units should not be located in contaminated areas

and windows)

Inadequate separations Rest rooms and refectories should be separated from areas of

production or storage

Dirty incoming materials Receiving and dispatch bays should be designed and prepared to

Defective parts of equipment Parts of equipment coming into contact with materials and product

animals

areas

Inadequate air-handling Ventilation air should be HEPA-filtered

or in lockers

Access through drains Drains should be designed and built to prevent backflow

Ensure isolation of premises from the outside (sealed panels, floors,

Protection of premises from the entrance of insects, birds, and

Toilets should not have direct communication with the areas of

Maintenance workshops should be separated from the production

Parts and tools used for production should be kept in separate rooms

Premises should have overpressure (see the exceptions in Sections 7.3 and 7.4) to prevent the entrance of unfiltered air from outside

Animal houses should be separated from the other areas

Animal houses should have separate air-handling systems

should not affect them, neither be affected by them

allow the cleaning of the incoming containers

Access to premises by airlocks/changing rooms

Anticipate the placement of traps and baits

production and quality control (QC) laboratory

**Cause Control measures**

*DOI: http://dx.doi.org/10.5772/intechopen.82601*

Insufficient tightness of the

premises

*7.2.3 Hazard #3: error/mix-up*

*(External) contamination.*

**Table 2.**

*7.2.4 Hazard #4: degradation*

should always be considered in a project.

**Table 5** summarizes control measures.

*7.2.5 Hazard #5: equipment malfunction*

mounted, as summarized in **Table 6**.

describes actions to control them.

*7.2.6 Hazard #4: health, safety, and environment*

**Table 4** evaluates the main causes of error/mix-up and provides control measures. Although error/mix-up appears because of the inefficiency of personnel (and this means that their prevention is based on training), an improved design of the premises diminishes their probability. Adequate flows and sufficient working space

Materials and products are damaged when exposed to inadequate conditions.

During routine production, equipment is submitted to a maintenance plan to avoid malfunction. During the project, however, equipment has to be well sited and

The denomination health, safety, and environment (HSE) covers all the aspects that can affect the health and security of personnel and the environment. **Table 7**


*Pharmaceutical Projects: Walking along the Risk Management Line DOI: http://dx.doi.org/10.5772/intechopen.82601*

#### **Table 2.**

*Perspectives on Risk, Assessment and Management Paradigms*

encoded, by GMP [7–10] and good engineering practice (GEP). GEP is not codified

In **Table 2** are described the main causes of (external) contamination and the

In **Table 3** are described the main causes of cross-contamination and the control

Let us analyze, using a risk management approach, the requirements that should

as such. It is understood as the generally admitted good approach.

meet a project. We use an adapted form of PHA.

*7.2.1 Hazard #1: (external) contamination*

*The pharmaceutical project: URS and their translation.*

control measures to keep them at bay.

*7.2.2 Hazard #2: cross-contamination*

measures to hold them at bay.

**158**

**Figure 9.**

*(External) contamination.*

#### *7.2.3 Hazard #3: error/mix-up*

**Table 4** evaluates the main causes of error/mix-up and provides control measures. Although error/mix-up appears because of the inefficiency of personnel (and this means that their prevention is based on training), an improved design of the premises diminishes their probability. Adequate flows and sufficient working space should always be considered in a project.

#### *7.2.4 Hazard #4: degradation*

Materials and products are damaged when exposed to inadequate conditions. **Table 5** summarizes control measures.

#### *7.2.5 Hazard #5: equipment malfunction*

During routine production, equipment is submitted to a maintenance plan to avoid malfunction. During the project, however, equipment has to be well sited and mounted, as summarized in **Table 6**.

#### *7.2.6 Hazard #4: health, safety, and environment*

The denomination health, safety, and environment (HSE) covers all the aspects that can affect the health and security of personnel and the environment. **Table 7** describes actions to control them.


**161**

**Table 5.** *Degradation.*

*Pharmaceutical Projects: Walking along the Risk Management Line*

Inadequate facility design Layout and design must aim to minimize the possibility of errors

personnel and materials

equipment and materials

Inadequate separation The storage areas should ensure the segregation for items under

Free access Personnel access to critical areas should be controlled and restricted Inadequate marking Fixed pipework should be labeled to indicate contents and direction of flow (if this is necessary)

access

Inadequate illumination Working areas should be well lit

and monitored

adversely affect the products

humidity) for the materials and products

Inadequate placement of

Inadequate facility

design

Inadequate conditions

**Cause Control measures**

equipment

**Table 4.** *Error/mix-up.* of security ("chaotic warehouse")

Premises should be designed to be able to follow the logical flows of

The storage areas should allow for the orderly and sure storage of the different sorts of materials and products ("traditional warehouse") or possess a computerized management system providing the same level

The layout of the premises should allow the production to take place in areas connected in the logical sequence of the operations The areas should permit the orderly and local positioning of

In the production areas, there should be in-process storage rooms permitting to keep materials and equipment in an orderly way Packaging areas should be designed and laid out to avoid mix-ups

quarantine, returned, rejected, and recalled. This separation can be assured by separated and closed areas or by a computerized management system providing the same level of segregation

Rooms and equipment should be adequately identified

Equipment should be installed to avoid error and mix-up

Receiving and dispatch bays should protect the products from the weather

Temperature and, if necessary, humidity in the production areas should be adequate

Storage areas should provide adequate conditions of temperature (and if necessary

Electrical supply, lighting, temperature, humidity, and ventilation should not

Acquire adequate information on the product requirements

The receiving and dispatch bays of the warehouse should be separated Printed materials should be stored in a separate area with restricted

The QC laboratory should have sufficient space

**Cause Control measures**

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**Table 3.** *Cross-contamination.* *Pharmaceutical Projects: Walking along the Risk Management Line DOI: http://dx.doi.org/10.5772/intechopen.82601*


#### **Table 4.**

*Perspectives on Risk, Assessment and Management Paradigms*

**Cause Control measures**

Inadequate tightness of the

premises

Inadequate facility design Premises should be designed to allow for adequate cleaning and

working areas for ducting, lightning, etc.

cleanliness (e.g., of classification)

cross-contamination

panels, floors, and windows) Inadequate separations Access to classified areas by specific airlocks/changing rooms

Inadequate cleaning There should be an adequate cleaning area with adequate separations

Inadequate air-handling When operations are likely to generate dust (e.g., sampling, weighing,

unidirectional flow and exhausting

Recycled air should be HEPA-filtered

clean equipment

rooms

system

systems Inadequate equipment Equipment should be installed to avoid contamination

contamination

clean rooms possessing sanitary design

Premises should be designed to avoid the build-up of dust and dirt Repair and maintenance operations should not affect the quality of the products (e.g., performed from outside the clean rooms). Thus, there should be technical areas for equipment and a technical space over the

The layout of the premises should allow the production to take place in areas connected in the logical sequence of the required levels of

Materials and products should only be exposed to the environment in

Packaging areas should be designed and laid out to avoid

The QC laboratory should be designed to suit the operations

Clean rooms should be tight to ensure adequate isolation (sealed

There should be an area for the sampling of starting materials There should be an area for the weighing of starting materials Risk of cross-contamination by highly active, toxic substances or

The QC laboratory should be separated from the production areas The QC laboratory areas where microbiological, biological, and radioisotope tests are performed should be separated from each other

for equipment to be cleaned, cleaning area, drying area, and storage of

Starting materials should be weighed in a special area provided with

Materials and products should only be exposed to the environment in

Pressure differentials should control the flows of air among clean

The QC laboratory areas where microbiological, biological, and radioisotope tests are performed should possess separate air-handling

Washing, cleaning, and drying equipment should not be source of

Whenever possible, closed equipment should be preferred

The QC laboratory should possess an adequate separate air-handling

biological agents should be controlled. See Section 7.3

mixing, etc.), there should be measures to control it

clean rooms possessing appropriate air-handling

sanitization

**160**

**Table 3.**

*Cross-contamination.*

*Error/mix-up.*


#### **Table 5.** *Degradation.*


#### **Table 6.**

*Equipment malfunction.*

#### **7.3 Management of toxic substances**

Sometimes commercial/logistic aspects determine from the outset the characteristics of a pharmaceutical plant: typically, multiproduct facilities (when APIs are not particularly active and general GMP precautions suffice for ensuring that significant


**163**

[14, 15].

exclusively discuss the latter.

*Pharmaceutical Projects: Walking along the Risk Management Line*

cross-contamination will be excluded) or, less frequently, dedicated facilities, when logistic reasons recommend limiting the number of products in order to increase output. A quite different situation may arise when APIs can be deemed "toxic." This term is used in a practical way to provide a general denomination for substances that possess high activity or potency (e.g., tiny amounts are needed to produce a pharma-

When designing premises where toxic APIs will be handled, there has always existed a key question: is it correct if they are multiproduct or we should opt for dedicated ones? The response to this question cannot be general, because substances are diverse. The traditional approach was considering, roughly speaking, three cases. Firstly, we had the APIs, which could be deemed nontoxic and which, as we said before, could be produced in multiproduct facilities. Secondly, we had the APIs possessing high activity (e.g., hormones, cytostatics, certain antibiotics, etc.), which required dedicated facilities. And finally, we had two cases, which required strict segregation. This last group included live microorganisms and products possessing sensitizing or toxic effects (their action, properly speaking, cannot be quantified and

In order to better clarify this group, it was proposed a scientific approach, which is summarized in **Figure 10**. The flowchart combines an EMA guideline on this mat-

When it is spoken of single product or multiproduct facilities, their meaning appears evident, but what about dedicated facilities? This implies separation, but what kind of separation. Only risk management can provide an adequate answer to this question. **Figure 11** describes the rationale of this approach. The rectangle represents the risk level (on the left lower part, the lighter color indicates low risk, whereas, on the right upper part, the darker color shows high risk). Thus, multiproduct facilities are adequate when risk is low, and segregated facilities are necessary when risk is high. Then, in the middle, where risk can be deemed medium, it is possible to think of intermediate solutions (e.g., instead of separation of facilities, separation of products) or campaign production (e.g., separation is not physical but temporal). The severity of the hazard depends on the API, whereas the probability of occurrence is related to the way of manufacturing. In other words, once the "toxicity" of the API is known, the practical level of risk will depend on the production techniques used for the manufacture of the products. Dedicated facilities mean more expensive projects, but at the same time lower risk of cross-contamination

cological effect) or harmful effects (e.g., sensitization, genotoxicity, etc.).

should be considered as "on/off"), such as beta-lactam antibiotics [11].

and, for instance, easier and surer cleaning validations [13].

Biotechnology implies the use of biological systems. Under this term, we design both cells and microorganisms. Most of them (in principle, the cells, and many microorganisms) do not pose any particular thread to personnel. In fact, the contrary is true. They are labile and very susceptible to contamination and require strict measures of control to keep them viable. There are, however, microorganisms, which suppose a thread for the personnel if they infect them during operations. These "biological agents" are internationally classified into four groups (**Table 8**) in function of the level of biosecurity (BSL) or protection level (PL) that they require

The project of a laboratory handling biological agents has to take into account its two types of requirements: on the one hand, those regarding in general a pharmaceutical laboratory and on the other, the particular necessities of facilities containing live microorganisms. We have already considered the former; thus, here we will

**7.4 Management of biological systems**

ter [12] (upper part with a darker shade) with logistic criteria (lower part).

*DOI: http://dx.doi.org/10.5772/intechopen.82601*

**Table 7.** *HSE.*

#### *Pharmaceutical Projects: Walking along the Risk Management Line DOI: http://dx.doi.org/10.5772/intechopen.82601*

*Perspectives on Risk, Assessment and Management Paradigms*

**Cause Control measures**

**Cause Control measures**

Inadequate installation Perform commissioning/qualification

**Table 6.**

*Equipment malfunction.*

**7.3 Management of toxic substances**

Inadequate installation Perform commissioning/qualification

Equipment must be located to suit the operations

in accordance with their particular requirements

Equipment must be located to suit the operations

for the maintenance of the biological agents

There should be special storage areas, safe and secure, for: highly active, radioactive, narcotics, abuse, explosive, flammable, etc.

There should be adequate equipment (freezers, refrigerators, etc.)

Changing rooms and toilets should be easily accessible and

Pipework, light fittings, ventilation points, and other services should be designed and placed to avoid the creation of recesses difficult to clean. And, as far as possible, they should be accessible

Open channels should be avoided where possible, but if they are necessary, they should be shallow to facilitate cleaning The QC laboratory should be designed to suit the operations In the QC laboratory, there should be adequate space for the storage of samples, standards, solvents, reagents, and records Current drawings of critical equipment and utilities should be

There should be a place for the classification of solid waste

(decontamination) prior to its release or transportation to a

Dangerous gaseous effluents should be either filtered or

Inadequate separation Consider in the QC laboratory separate rooms for instrumentation,

Sometimes commercial/logistic aspects determine from the outset the characteristics of a pharmaceutical plant: typically, multiproduct facilities (when APIs are not particularly active and general GMP precautions suffice for ensuring that significant

Dangerous products Highly active, toxic substances or biological agents should be controlled (see Section 7.3)

Dangerous biological agents Biological agents should be handled adequately (see Section 7.4)

Inaccessibility/unhandiness Premises should be designed to suit the operations to be carried

from technical areas

maintained Uncontrolled solid waste There should be adequate places for the storage of solid waste

Uncontrolled effluents There should be a place for the treatment of liquid effluents

handling center

incinerated

adapted to the number of users

out

**162**

**Table 7.** *HSE.*

cross-contamination will be excluded) or, less frequently, dedicated facilities, when logistic reasons recommend limiting the number of products in order to increase output. A quite different situation may arise when APIs can be deemed "toxic." This term is used in a practical way to provide a general denomination for substances that possess high activity or potency (e.g., tiny amounts are needed to produce a pharmacological effect) or harmful effects (e.g., sensitization, genotoxicity, etc.).

When designing premises where toxic APIs will be handled, there has always existed a key question: is it correct if they are multiproduct or we should opt for dedicated ones? The response to this question cannot be general, because substances are diverse. The traditional approach was considering, roughly speaking, three cases. Firstly, we had the APIs, which could be deemed nontoxic and which, as we said before, could be produced in multiproduct facilities. Secondly, we had the APIs possessing high activity (e.g., hormones, cytostatics, certain antibiotics, etc.), which required dedicated facilities. And finally, we had two cases, which required strict segregation. This last group included live microorganisms and products possessing sensitizing or toxic effects (their action, properly speaking, cannot be quantified and should be considered as "on/off"), such as beta-lactam antibiotics [11].

In order to better clarify this group, it was proposed a scientific approach, which is summarized in **Figure 10**. The flowchart combines an EMA guideline on this matter [12] (upper part with a darker shade) with logistic criteria (lower part).

When it is spoken of single product or multiproduct facilities, their meaning appears evident, but what about dedicated facilities? This implies separation, but what kind of separation. Only risk management can provide an adequate answer to this question. **Figure 11** describes the rationale of this approach. The rectangle represents the risk level (on the left lower part, the lighter color indicates low risk, whereas, on the right upper part, the darker color shows high risk). Thus, multiproduct facilities are adequate when risk is low, and segregated facilities are necessary when risk is high. Then, in the middle, where risk can be deemed medium, it is possible to think of intermediate solutions (e.g., instead of separation of facilities, separation of products) or campaign production (e.g., separation is not physical but temporal). The severity of the hazard depends on the API, whereas the probability of occurrence is related to the way of manufacturing. In other words, once the "toxicity" of the API is known, the practical level of risk will depend on the production techniques used for the manufacture of the products. Dedicated facilities mean more expensive projects, but at the same time lower risk of cross-contamination and, for instance, easier and surer cleaning validations [13].

#### **7.4 Management of biological systems**

Biotechnology implies the use of biological systems. Under this term, we design both cells and microorganisms. Most of them (in principle, the cells, and many microorganisms) do not pose any particular thread to personnel. In fact, the contrary is true. They are labile and very susceptible to contamination and require strict measures of control to keep them viable. There are, however, microorganisms, which suppose a thread for the personnel if they infect them during operations. These "biological agents" are internationally classified into four groups (**Table 8**) in function of the level of biosecurity (BSL) or protection level (PL) that they require [14, 15].

The project of a laboratory handling biological agents has to take into account its two types of requirements: on the one hand, those regarding in general a pharmaceutical laboratory and on the other, the particular necessities of facilities containing live microorganisms. We have already considered the former; thus, here we will exclusively discuss the latter.

**Figure 10.** *Decision tree for facilities.*

**165**

**Table 9.**

*Pharmaceutical Projects: Walking along the Risk Management Line*

In a laboratory where biological agents are cultured, these microorganisms suppose the "hazard"; the "cause" is the inadequacy of the measures taken to ensure that these agents will remain contained; and the "effect" is the infection of people by released agents. Thus, our risk analysis will focus on the control measures (**Table 9**).

Easy communication with the exterior (e.g., interphone)

Ensure security in case of emergency (e.g., earthquake, flood, fire, etc.)

Ensure operation of critical equipment in case of power supply cut

Vacuum tubes protected with HEPA filters or disinfectant traps

Provide separation between agents and operators

Provide wash basins with hand-free taps

hazard should be affixed at the entrance of the laboratory and at critical rooms and critical equipment (e.g., incubators,

Inactivation of effluents

hood

Personal risk Minimal Low High Very high Epidemic risk No No Low High Therapy/prevention Unnecessary Available Available Unavailable

**1 2 3 4**

Biological safety cabin (BSC)

Isolator or BSC + personal protective equipment

(PPE)

*DOI: http://dx.doi.org/10.5772/intechopen.82601*

Manipulation Workbench Open

**Characteristic BSL/PL**

**Table 8.**

*The four groups of biological agents.*

**Element Control measures** Premises Area segregation

Ingress Restricted access

Waste Inactivation of "biowaste"

*Control measures for biological hazard in the laboratory.*

Labeling The international sign of biological

freezers, etc.).

Equipment/clean

rooms

Ensure contention

Air-handling system HEPA-filtered/sterilized exhausted air

Ensure depression (∆P−) No recycling of air

Airlocks with interlocked doors Pass-boxes with disinfection systems Sterilizers provided with double doors Separated changing rooms for entry and exit

Ensure possibility of disinfection Operations can be seen from the outside

**Figure 11.**

*Risk analysis rationale for defining the type of facilities.*

*Pharmaceutical Projects: Walking along the Risk Management Line DOI: http://dx.doi.org/10.5772/intechopen.82601*


#### **Table 8.**

*Perspectives on Risk, Assessment and Management Paradigms*

**164**

**Figure 11.**

**Figure 10.**

*Decision tree for facilities.*

*Risk analysis rationale for defining the type of facilities.*

*The four groups of biological agents.*

In a laboratory where biological agents are cultured, these microorganisms suppose the "hazard"; the "cause" is the inadequacy of the measures taken to ensure that these agents will remain contained; and the "effect" is the infection of people by released agents. Thus, our risk analysis will focus on the control measures (**Table 9**).


#### **Table 9.** *Control measures for biological hazard in the laboratory.*

In **Table 9**, we mention a series of elements that should be taken into account when designing a laboratory manipulating biological agents. The characteristics of these elements depend on the BSL/PL. This means that they might be unnecessary for level 1, just recommended for an intermediate level and required for a high level. It has to be studied case by case, using a risk management approach, which should analyze the level of risk and the level of protection provided for the systems in place.
