**11.3. Handling of active products**

GMP establishes the need for dedicated facilities in some cases (production of penicillin or live microorganisms) or requires separation for certain products (antibiotics, hormones, cytotoxics, etc.). Most products are however manufactured in multiproduct facilities, where products share utilities and equipment, after performing the required validations. As products and processes can be very varied it is evident that the orientation provided by GMP can't be very detailed. This is why a QRA approach is very useful.

Quality Risk Analysis: Value for Money in the Pharmaceutical Industry 409

isolated Clean-rooms are isolated from the environment Products are isolated Product containment inside closed systems

Pressure differentials Negative pressure impedes the diffusion of particles Effluent treatment Cleaning effluents are treated before being released to the sewer Waste control Wastes are disposed of in an adequate manner

Manufacturing areas are separated Different pharmaceutical forms are completely separated

differentials)

differentials) Use of closed systems Production is performed in closed systems. Temporal separation of products Campaign working allows for a simplification in cleaning.

carried out

changing rooms There is an specific change room for each area Transfers across air-locks All materials and products are transferred across air-locks

Products are physically separated Only one product at a time

Air treatment HEPA-filtered air

"Sanitary" design and construction Clean-rooms follow GMP-design Cleaning / sanitation Validated cleaning procedures

clothing Use of specific clothing Clothing is related to the type of operation, which is

Release of dust is kept under control (closed

HVAC system provides environment cleanliness (classification) and separation (pressure

HVAC system provides environment cleanliness (classification) and separation (pressure

Personal protective equipment (PPE)

systems / dust extraction)

The appraisal of the hazard can be performed by using primary hazard analysis (PHA) as it was previously described. In this case from the five categories of hazards mentioned only two have to be taken into account: environmental contamination and cross-contamination.

Air handling HEPA-filtered air

**Hazard Cause Preventive measure Comments**

Manufacturing areas are

Control of dust

**Table 16.** Handling of active products – QRA – Environmental contamination

Note: The contents of this table are just given as an example; they don't intend to represent any real situation.

**Hazard Cause Preventive measure Comments** 

Environments are separated

Access of personnel across specific

Differential pressure / Airflows

Note: The contents of this table are just given as an example; they don't intend to represent any real situation.

**Table 17.** Handling of active products – QRA – Cross-contamination

Although in both cases the causes are similar, the array of control measures is very varied

Environmental contamination

Crosscontamination Release of dust, particles, droplets, aerosols, effluents and waste

and concerns different systems.

Release of dust, droplets, particles, aerosols, during operations

Residues on equipment

Dust / particles on

Among both extremes, a dedicated building (with separated equipment and utilities) and a multiproduct facility, there are less radical solutions, such as, for instance, separated areas (rooms or set of rooms with their own air-locks and changing rooms), provided with separate equipment and utilities, within a multiproduct unit. Also, when this is feasible, a simpler way of preventing cross-contamination might be the use of specific parts of equipment (e.g., filters, sieves), instead of dedicated equipment.

Another approach would be segregating the process from its environment by using isolation technology (i.e. production equipment within isolators or closed equipment instead of separating the rooms).

Campaign manufacturing, which certainly requires appropriate validation, is also a way to prevent cross-contamination.

The application of quality risk assessment to the products and to the processes to be performed within a pharmaceutical unit, allows for their rational design.

(Characteristics of starting materials and of the product)

**Figure 16.** Handling of active products: QRA approach

The appraisal of the hazard can be performed by using primary hazard analysis (PHA) as it was previously described. In this case from the five categories of hazards mentioned only two have to be taken into account: environmental contamination and cross-contamination.


Note: The contents of this table are just given as an example; they don't intend to represent any real situation.

**Table 16.** Handling of active products – QRA – Environmental contamination

408 Risk Management – Current Issues and Challenges

**11.3. Handling of active products** 

separating the rooms).

**QRA** 

prevent cross-contamination.

**Product**: Toxicity, physical properties, etc.

**Utilities**: Design, dedicated (separate), etc.

**Probability of occurrence** 

(Characteristics of the process)

**Process**: Flows, batch size, changeover frequency, sequences, etc.

**Equipment**: Dedicated/non dedicated, open/closed, product contact materials.

**Complementary activities**: Cleaning, maintenance, sewage/refuse handling, etc.

**LOW RISK**

**Normal, multi-product facility, equipment, and utilities.**

**Figure 16.** Handling of active products: QRA approach

GMP establishes the need for dedicated facilities in some cases (production of penicillin or live microorganisms) or requires separation for certain products (antibiotics, hormones, cytotoxics, etc.). Most products are however manufactured in multiproduct facilities, where products share utilities and equipment, after performing the required validations. As products and processes can be very varied it is evident that the orientation provided by

Among both extremes, a dedicated building (with separated equipment and utilities) and a multiproduct facility, there are less radical solutions, such as, for instance, separated areas (rooms or set of rooms with their own air-locks and changing rooms), provided with separate equipment and utilities, within a multiproduct unit. Also, when this is feasible, a simpler way of preventing cross-contamination might be the use of specific parts of

Another approach would be segregating the process from its environment by using isolation technology (i.e. production equipment within isolators or closed equipment instead of

Campaign manufacturing, which certainly requires appropriate validation, is also a way to

The application of quality risk assessment to the products and to the processes to be

**Intrinsic severity of substances**  (Characteristics of starting materials and of the product)

**Isolators**

**MIDDLE RISK** 

**Working by**

> **Dedicated rooms or suites of rooms, equipment, and utilities.**

**Dedicated facility, equipment and utilities.** 

**HIGH RISK** 

**Premises**: Flows of materials/personnel, isolator technology, dedicated (separated) buildings/areas/rooms, etc.

**Containment design of facilities, equipment, and utilities.**

GMP can't be very detailed. This is why a QRA approach is very useful.

equipment (e.g., filters, sieves), instead of dedicated equipment.

performed within a pharmaceutical unit, allows for their rational design.

Although in both cases the causes are similar, the array of control measures is very varied and concerns different systems.


Note: The contents of this table are just given as an example; they don't intend to represent any real situation.

**Table 17.** Handling of active products – QRA – Cross-contamination
