1 GENERAL DESCRIPTION.

1.1 – MANUFACTURING SECTOR IDENTIFICATION

This research deals with activities defined as “Manufacturing of drugs and pharmaceutical preparations and manufacturing of basic pharmaceutical products” by the ’91 ISTAT-ATECO economic activity classification. This manufacturing sector is part of the “Manufacturing of pharmaceutical products and of chemical and botanical products for medicinal purposes” (code 24) production sector.

Chart 1 – ’91 ISTAT-ATECO Production sector classification

ISTAT–aTECO ’91 activity code	DESCRIPTION OF ACTIVITY
ISTAT–aTECO ’91 activity code	DESCRIPTION OF ACTIVITY
24410	Basic pharmaceutical product manufacturing.
24420	Manufacturing of drugs and pharmaceutical preparations.

Class 24410 described above is part of the "Manufacturing of pharmaceutical products and of chemical and botanical products for medicinal purposes” production sector that includes:

- test, enhancement and production of active medicinal substances which, due to their therapeutic properties, are used in the manufacture of pharmaceutical products;

- production of blood derivates for pharmaceutical uses;

- production of chemically pure sugars;

- gland processing and production of glandular extracts.

Class 24420, belonging to the same sector, includes:

- production of drugs recorded as such in a national register displaying specific component formulation and quantities and possessing a concrete pharmaceutical form which allows them to be assembled; immune serum and other blood components; vaccines, varied packaged/unpackaged medicinal products for retail sale, including homeopathic preparations, dental cavity fillers and cements for bone reconstruction and chemical birth control preparations;

- Production of drug impregnated or coated cotton wool, gauze, dressings, adhesive plasters, etc. production of sterile surgical sutures.

The companies affected by this research display a production cycle which includes the preparation of packaged/unpackaged medicines for retail sale; chemical birth control preparations; test, enhancement and production of active medicinal substances which, due to their therapeutic properties, are used in the manufacture of pharmaceutical products; production of chemically pure sugars.

Research reference area includes the Florence, Pisa and Siena provinces.

The following results originate from a study of C.C.I.A.A-Unioncamere (Union of Industry and Trades Chambers of Commerce ) data.

1.2 – GEOGRAPHIC SITING of DRUG COMPANIES

Chart 2 reports the provincial breakdown of the 69 drug companies operating in the Toscana Region in 1999.

Chart 2- Number of Local Units in Toscana (year 1999).

Activity Code

ACTIVITY Description

Toscana Region Total Local Units

Provincial breakdown of Local Units

Arezzo

Firenze

Grosseto

Livorno

Lucca

Massa

Pisa

Prato

Pistoia

Siena

24420

Manufacturing of drugs and medicinal preparations

Source: A.R.P.A.T. – S.I.R.A. technical sector processing of C.C.I.A.A.-Unioncamere data.

1.3 – EMPLOYMENT LEVELS

Chart 3 - Employees in Toscana (year 1999).

Activity Code

Activity Description

Toscana Region Total Employees

EMPLOYEES: BREAKDOWN BY PROVINCE

Arezzo

Firenze

Grosseto

Livorno

Lucca

Massa

Pisa

Prato

Pistoia

Siena

24420

Manufacturing of drugs and medicinal preparations

4072

2822

258

208

357

398

Source: A.R.P.A.T. – S.I.R.A. technical sector processing of C.C.I.A.A.-Unioncamere data.

1.4- SAFETY RECORD

Chart 4 – Pharmaceutical industry accidents (Manufacturing of drugs and medicinal preparations) in Toscana (1996-2000)

Year	Accidents (Total)	Fatal accidents
1996	92	1
1997	99	0
1998	81	0
1999	106	0
2000	116	1
Total:	494	2

Source: INAIL

1.5 – OCCUPATIONAL DISEASES

Chart 5 – Pharmaceutical industry occupational diseases (Manufacturing of drugs and medicinal preparations) in Toscana (1996-2000)

Year	Outcome	Occupational disease identification code	Type	Total Cases
1998	Permanent	34	Aliphatic ammines	1

Source: INAIL

1.6 – PHARMACEUTICAL INDUSTRY MANUFACTURING PROCESSES: GENERAL CONSIDERATIONS

Within the pharmaceutical industry, all basic procedures for drug production are performed according to so called Norme di Buona Fabbricazione-NBF (good manufacturing procedures) as already envisaged by Farmacopea Ufficiale (official national pharmacopoeia- edition VII). The above procedures are an integral part of the broader Quality Assurance verification system, which brings together all specifications, procedures and structures aimed at assuring that products meet required quality standards. All production facility organizational functions contribute to the verification system’s implementation. The national official pharmacopoeia includes a chapter listing certain useful definitions for the interpretation of the NBF (good manufacturing procedures). Listed hereunder are the definitions relating to the terms “Medicament, Manufacture, Batch, Validation, Quality Control”.

Medicament.

Any substance or chemical composition displaying curative, prophylactic, diagnostic properties or which allows restoration, modification or correction of organic functions in humans and animals.

Manufacture.

All operations relating to the production of medicaments especially those operations relating to the handling of raw materials, mixture preparation, realization of pharmaceutical forms as well as the filling, packaging and labelling of containers.

Batch.

The bulk of a specific medicament manufactured during a single production cycle. The essential feature of a batch is its homogeneity.

Validation.

The documented implementation of a specific verification programme aimed at systematically obtaining a product meeting predetermined specifications. The validation process affects manufacturing processes, quality control, plant efficiency and environmental considerations.

Quality Control.

The activities and interventions aimed at ensuring the production of uniform medicament batches to meet predetermined specifications.

The application of quality control rules is targeted to obtaining a product for human or animal administration for curative and/or diagnostic purposes.

Consequently the drug must display low contamination and/or sterility characteristics not required of other products. As a result, employee working conditions are quite unique and aimed at preserving the finished product. A drug production work environment includes areas maintained at various levels of decontamination thanks to ambient air filtering systems, operator protection devices and measures, particularly stringent hygiene standards.

These measures, while ensuring that the drug is free from contaminants, also avoid direct worker contact with pharmacologically active and thus hazardous substances. Daily exposure threshold values (TLV) have been set to ensure worker protection. Threshold values have been arbitrarily set at 1:100 of the lowest pharmacologically active dose (minimum effective dose) bearing in mind that the minimum effective dose was calculated on the basis of conventional drug administration and not resulting from worker exposure.

3.1 - WAREHOUSING

WORK PHASE DESCRIPTION

Incoming goods store (raw materials, excipients, labels, printed information materials)

The raw materials and excipient store is generally located close to the production areas. Products are stored on multi-level racks and shelves. Manually operated trolleys and electrical pallet handlers are used to move boxes/containers. Operators may occasionally be called upon to manually handle boxes/containers. Typically the weight of label packs varies between 3 and 19 kg. The handling involves transferring the packs from shelves/racks to the trolleys and may be performed once or twice weekly. For practicality the operator may remove the external protective plastic film in order to grasp the individual packs. The plastic film is removed by cutting away using knives or scissors.

Raw materials and excipients are delivered from the incoming goods store to an outside storage where diesel or electric powered forklift trucks pick-up the items and transport them to the production access areas.

Photo 1. Incoming goods store.

Outgoing finished products

Pre-packaged and palletised finished products are delivered to the outgoing goods store to a wrapping machine (also referred to as film wrapper). The machine includes a rotating turntable and vertical guidance rail and may be accessed frontally for pallet loading/unloading operations. The machine’s control panel is located to one side. When in operation, the turntable rotates and the film dispenser moves up and down so as to completely wrap the items placed on the pallet. Electric forklift trucks are used to move the sealed pallets to shelf and rack storage.

Photo 2. Outgoing goods store

EQUIPMENT AND MACHINERY

Shelving

Vertical metal-frame shelving structures are generally used. Their load capacity depends on the goods to be stored and varying company requirements, such as:

- heavy duty high load shelving structures for pallet storage;

- light load shelving structures for storage of assorted general goods (capsules, labels, etc.) generally packed in cardboard boxes.

Portable ladders are used to access lightweight materials placed on the higher shelves.

Automatic Wrapping Machine

The machine includes a rotating turntable and a vertical guidance rail located to one side. A film dispenser runs along the vertical guide rail. The film dispenser moves up and down while the turntable rotates so that the film completely and uniformly seals the pallet. Upon completion of the cycle the turntable comes to rest, the sealed pallet is removed and stored.

Photo 3. Automatic wrapping machine

Lift Trucks

Electric forklift trucks are generally used.

Risk factors

The principal occupational hazards in this work cycle phase are due to the following factors.

Vertical metal-frame Shelving

DESCRIPTION

If the metal-frame structures are not suitably fixed to the building’s walls and/or their load bearing capacity is not adequate, they may accidentally tip over as a result of:

- impact caused by workers or by the lift trucks;

- uneven load distribution;

- a portable ladder bearing a worker propped against the shelving structure;

- a worker grasping at the structure while falling from the portable ladder.

Shelving may also tip over due to structural failure caused by overloading or because the weight-bearing structure is deteriorated as a result of the corrosive action of rust or because of loose fixing bolts.

A fatality recently occurred in a Tuscan company, operating in a different manufacturing sector, as a result of the worker being crushed under the weight of a shelving structure, which had suffered structural failure.

A further hazard is represented by goods falling off the shelves, possibly on the side opposite the one where the lift truck is operating.

An accident recently occurred in a Tuscan company operating in a different manufacturing sector. Goods fell off the back of the shelves onto the roof of an office inside the warehouse. The goods broke through the roof structure and came to rest on the office floor luckily without causing harm as no employees were in the office at the time of the accident.

EXPECTED INJURIES

Traumatic lesions due to collision and crushing impact.

PREVENTIVE MEASURES

Shelving structures must have a suitable load bearing rating. The load rating shall be signposted (in case of multiple shelves with varying load ratings, each shelf shall be signposted so as to indicate its respective load limit). Shelving shall be firmly fixed to the building’s roof, walls or it shall be fabricated so at exclude any possibility of tipping over. Metal frame structure conditions shall be checked regularly.

As an example, goods falling off shelves on the side opposite to where lift trucks are operating may be inhibited by using sturdy metal grills.

Portable ladders shall be fitted with hook-shaped stays so as to firmly engage the metal structure, hinged non-slip floor rests and non-slip rungs.

Loads shall be evenly distributed along the load bearing structure and handling crew shall be adequately informed and trained.

REFERENCE LEGISLATION

D.P.R.n°547/1955 and subsequent amendments/integrations

D.Lgs.n°626/1994 and subsequent amendments/integrations

Work performed in proximity to moving machinery

DESCRIPTION

The moving parts of the wrapping machine (film spool dispenser moving up/down along the vertical guide rail, rotating turntable and pallet carrying packaged goods) may produce impact, snatch and drag hazards for machine operators.

Normally wrapping machines are fitted with protective side fences that only allow frontal access for pallet loading/unloading operations: this situation may be hazardous for the operator due to turntable and pallet motion.

EXPECTED INJURIES

Lesions or bruising of the limbs due to impact against parts jutting out from the rotating pallet.

PREVENTIVE MEASURES

Moving machinery parts shall be protected by means of fixed protection devices (metal grille, rigid transparent plastic panels) or by suitably placed safety bars apt to inhibit contact between operator’s limbs and the moving parts or by photoelectric cells electrically connected so as to block the machine if an operator is within its operating radius.

An alternative safety system could be a manually operated push button control panel (also allowing the machine to be pulse operated) suitably located so as to allow visual control of the machine’s working area.

REFERENCE LEGISLATION

- Article 6 “Worker duties” D.P.R.n°547 dated 27/04/1955.

- Article 41 “Machinery: “Protection and Safety” D.P.R.n°547 dated 27/04/1955

- Chap.III, Para.III “Power transmission and gears D.P.R.n°547 dated 27/04/1955

- Article 68 “Protection of moving parts and operational radius of machinery” D.P.R.n°547 dated 27/04/1955

- Article 72 “Protection device lockout” D.P.R.n°547 dated 27/04/1955

- Article 73 “Machinery load/unload openings” D.P.R.n°547 dated 27/04/1955

- Articles 76 and 77 “Machinery start-up control devices” D.P.R.n°547 dated 27/04/1955

- Article 81 “Multiple lockout control devices” D.P.R.n°547 dated 27/04/1955

- Article 82 “Machine stop lockout” D.P.R.n°547 dated 27/04/1955

- Article 233 “Control and command devices” D.P.R.n°547 dated 27/04/1955

- Chapter IX “Maintenance and repairs” D.P.R.n°547 dated 27/04/1955

- Article 4 “Duties of the employer, manager and other person in charge” D.Lgs.n°626 dated 19/09/1994

- Chapter III “Use of work equipment” D.Lgs.N°626 dated 19/09/1994

- D.P.R.n°459 dated 24/07/1996 (Machine Directive)

- UNI Regulations EN 291/2, 291/2, 614/1, 294, 349, 811, 418, 1037, 1088, 574, 982, 983, 1012/1, 1012/2.

Vehicle Movements

DESCRIPTION

Goods vehicles delivering raw materials, excipients or other ancillary materials (glassware containers, labels/tags/printed matter in general) moving within the plant perimeter (front gate to warehouse area and vice versa) and electric lift trucks moving within the warehouse area may entail the risk of employees being run over.

EXPECTED INJURIES

Traumatic lesions due to employees being run over or resulting from collisions between moving vehicles.

PREVENTIVE MEASURES

Separate pedestrian and vehicle lanes should be marked out and signposted using horizontal and vertical markings. Establish and signpost a 5 km/hr speed limit. Depending upon the size of the plant apron, assess the possibility of establishing, signposting and enforcing one-way traffic systems.

REFERENCE LEGISLATION

- Article 8 “Traffic routing, hazardous areas, flooring and passages” D.P.R.n°547 dated 27/04/1955

- D.Lgs.n°626/1994 and subsequent amendments/integrations

Manual Load Handling

DESCRIPTION

Manual load handling may occasionally be required within the goods storage areas. The approximate weight of loads handled in this manner may vary from 3 to 20 kgs.

EXPECTED INJURIES

Muscular-skeletal complaints.

PREVENTIVE MEASURES

Where possible manual load handling should be performed using appropriate mechanical aids such as lifting devices, etc. The most appropriate means are automated material transfer systems. Operators must use Personal Protection Equipment(PPE) such as steel-capped footwear and shall have been adequately informed and trained.

REFERENCE LEGISLATION

- Chapter V and Enclosure 6 of D.Lgs.n°626 dated 10/09/1994

- Regulation UNI ISO 938

Use of Sharp Hand Tools

Sharp hand tools such as knives and scissors may be used in removing the plastic sealing film wrapping goods delivered to the storage area. Use of such hand tools may cause cutting injuries.

EXPECTED INJURIES

Cutting injuries.

PREVENTIVE MEASURES

Use tools equipped with safety devices (knives fitted with sliding protective sheaths covering the part of the cutting blade not affected by the operation being performed), cut-resistant gloves, operator information and training.

REFERENCE LEGISLATION

- Article 383 “Hand protection” D.P.R.n°547 dated 27/04/1955.

- D.Lgs.n°626/94 and subsequent amendments/integrations

OUTSOURCING

Warehousing operations strictly speaking are generally not contracted out.

Handling of diverse materials from/to the storage areas may be contracted out if the company’s own employees and means are not used to perform such operations.

EXTERNAL IMPACT

Waste Production

This work cycle phase generates solid wastes, i.e. cardboard or plastic packaging wastes.

3.2 – RAW MATERIAL WEIGHING

WORK PHASE DESCRIPTION

Casella di testo: Active principle weighing station

The obvious purpose of the first work phase performed by pharmaceutical companies, the weighing of the raw materials, is that of establishing the bulk quantities to be delivered to the production shops. The weighing procedure is performed in a specific station equipped with washable floors and walls, air conditioning and filtration systems, located away from other working environments.

Operators employ electronic or manual weighing scales to draw fixed quantities of active principles and excipients from the storage bags and bins, defined “primary containers”. Container weight may vary from 100 grams to 50 kgs. Transfer of raw materials and excipients from storage containers to weighing scales involves the use of spatula and spoons made of various materials for the materials in powder form. Plastic or glass pipettes, cylinders and funnels are used for handling of liquids.

Weighing operations are carefully performed under laminar flow extraction hoods in order to reduce product contamination and/or operator contact.

After having completed the weighing operations, products may be placed in polyethylene bags, bottles or flasks.

EQUIPMENT AND MACHINERY

Electronic and/or mechanical weighing scales

The pharmaceutical industry uses the classic single/twin platter mechanical scales. The more modern electronic scales are characterised by a metal box enclosing the apparatus and by a weighing system generally including a platter. Electronic scales are fitted with local powder/dust exhaust devices or laminar flow exhaust hoods.

A pharmaceutical company reported the use of hood filters capable of trapping up to 85% of dust particles (particle size up to 0.1µm).

Photo

4. Weighing station.

Risk factors

The principal occupational hazards in this work cycle phase are due to the following factors.

Exposure to dust

DESCRIPTION

During this phase operators may be exposed for varying lengths of time to dust. Solid chemicals handled in the weighing station fall within two groups: excipients and active principles.

The industry’s most commonly used powder-form excipients are: glucose, mannitol, saccharose, spray-dried lactose, starch, micro crystal cellulose, bibasic phosphate calcium, talc, polyvinyl pyrrolidone (PVP), natural and synthetic colouring agents.

The pharmaceutical industry considers these substances inert as they are generally lacking pharmacological effects and their particle size falls within the 0.1/1000+ µm range.

Active principles behave quite differently. After having been administered in conformity with the Pharmacopoeia, active principles determine specific pharmacological effects.

Operators may suffer contact with and inhalation of particles dispersed in the working environment.

ESTIMATE

Drug companies have established a 10 mg/m³threshold for exposure to dust in general. More stringent limits have been set for active principle dust content (100µg/m³, in cases involving particularly active substances).

Our data show that active principle dust levels, in certain cases, exceeded up to 57 times the set threshold levels (100 µg/m³).

EXPECTED INJURIES

Allergic asthma, contact dermatitis.

Operators are exposed to the specific pharmacological effects produced by each substance. Assuming the impossibility of completely eliminating all suspended particles, air samples are taken in the vicinity of the weighing station and analysed for contaminants. General and active principle dust content in weighing station samples have been found to be among the highest for closed environments.

Specific pharmacological effects due to active principles.

PREVENTIVE MEASURES

Measures needed to reduce weighing station dust emission are: fitting of local dust/powder exhaust devices to all scales and positioned as close as feasible to the emission source; adequate working environment ambient air circulation. A suitable filter replacement programme must be implemented in order to avoid any reduction of the exhaust capacity.

The feasibility of introducing automated weighing and compressed air transfer systems should be investigated.

Protective facemasks and gloves should be worn as well as, where applicable, the use of protective helmets fitted with automatic breathing equipment. The weighing station should be equipped with a suspended particle-sampling device in order to monitor dust levels.

Three dust protection devices are currently used: “Cobra” type hood (filter trapping capacity up to 2000µg/m³; M3 facemask (5000 µg/m³), “Cresta” type hood (10000 µg/m³).

REFERENCE LEGISLATION

- D.P.R.n°303/1956 and subsequent amendments/integrations

- D.P.R.n°626/1994 and subsequent amendments/integrations

Handling of fragile materials

DESCRIPTION

Weighing station operators may be called upon to handle fragile glassware (cylinders, flasks, graduated pipettes, etc.)

EXPECTED INJURIES

Lesions and cuts resulting from the handling of broken glassware.

PREVENTIVE MEASURES

Use of plastic ware or unbreakable glassware; use of protective plastic film for glassware to reduce multiple fragment hazards; use of cut-resistant gloves; operator information and training.

REFERENCE LEGISLATION

- Article 383 “Hand protection” D.P.R.n°547 dated 27/04/1955

- D.Lgs.n°626/94 and subsequent amendments/integrations

Manual load handling

DESCRIPTION

As indicated previously the operator may be called upon to manually handle loads at the weighing station. At times this task may prove to be particularly taxing.

EXPECTED INJURIES

Muscular-skeletal complaints.

Bruises and lesions to the lower limbs if heavy objects are dropped.

PREVENTIVE MEASURES

Where possible manual load handling should be performed using appropriate mechanical lifting devices. The most appropriate solution would be the use of automated raw materials transfer and/or weighing systems. Operators tasked with handling heavy loads manually must wear metal-capped safety footwear.

Information and training.

REFERENCE LEGISLATION

- Chapter V and Enclosure 6 of D.Lgs.n°626 dated 10/09/1994

- Regulation UNI ISO 938

OUTSOURCING

Disposal of spent laminar flow exhaust hood filters is generally outsourced.

EXTERNAL IMPACT

Atmospheric emissions

Atmospheric emissions are limited to the particles not trapped by the laminar flow hood filters. None of the companies affected by the study have collected emission-sampling data.

3.3 – washing and sterilization

WORK PHASE DESCRIPTION

Production line washing and sterilization is performed on a routine basis as part of all production cycles of the various pharmaceutical forms. The pharmaceutical industry’s primary priority is that of avoiding any form of drug contamination and thus the washing and sterilization processes are essential and call for a series of operations each of which must be performed in accordance with the following specific principles.

1) The lowest feasible bacteria contamination threshold limit shall be set for raw materials and equipment. Regular monitoring shall ensure that said threshold shall not be exceed;

2) Operators shall be specifically trained and working conditions shall be adequately controlled so as to inhibit contamination and the proliferation of micro organisms;

3) the drafting of a protocol suited to the materials to be subjected to sterilization. The protocol shall assess the maximum acceptable risk of not achieving sterilization. Protocol suitability shall be certified prior to the operative process and shall be checked regularly;

4) packaging materials must be compatible with the sterilization method employed while avoiding external micro biotic pollution hazards.

Materials, working environment and equipment washing /sterilization may be performed using physical (e.g.: steam, Beta Gamma or U.V. radiation), mechanical (filtration) and chemical methods (ethylene oxide, formaldehyde, sodium hypochlorite, phenol, oxygen peroxide, organic solvents). Field data lists, among the chemical methods, the use of water, isopropyl alcohol and detergent soap for the routine washing of granulating, powder mixing and capsule filling equipment. Water, methylated spirits and detergent soaps (90% biodegradable) are employed in the granulate packaging areas. Furthermore, production and filling areas of injectables (sterile area of the production line) are washed and sterilized employing 5% concentration hydrogen peroxide solution, 5% concentration sodium hypochlorite solution, 5% concentration phenol solution (twice-yearly) and formaldehyde (twice-yearly).

All heat-resistant materials are sterilized by heating. Direct heating employing a naked flame is rarely used. Much more frequent is the use of “dry heating” methods involving exposure of glassware and metalware to particularly high temperatures for specific lengths of time using ovens or autoclaves described in the following paragraph.

“Moist heat” sterilization offers the same results as dry heating but at noticeably lower temperatures.

Sterilization involves boiling, steam flow (100°C), pressurised saturated steam and tindalization procedures. Moist heat sterilization offers straightforward yet noteworthy advantages: condensed water delivers 527Kcal/Kg at 121°C, is odourless, tasteless, non-toxic and does not contaminate materials.

The Farmacopea Ufficiale della Repubblica Italiana-Official Pharmacopoeia of the Italian Republic (edition X, 1998) envisages the use of U.V., beta and gamma radiation but limits their use to those materials that may not be submitted to other types of sterilization. Radiation sterilization, not employed by any of the companies affected by this study, is generally employed on dressing materials or on sealed containers. On the whole U.V. radiation does not penetrate in depth and in general is not used to sterilise materials but rather the working environments. In areas requiring high sterility levels (e.g.: sterile rooms) U.V. lamps and normal lamps are fitted as part of the lighting system.

All microbiology laboratory equipment must be biologically decontaminated prior to performing maintenance, servicing or repair operations. The purpose of decontamination is the elimination of all pathogens and hazardous chemical products from equipment surfaces in order to protect the health of operators involved in their handling, maintenance or repair.

The most common microbiology laboratory equipment decontamination measures are listed below:

Laminar flow safety booth	Formaldehyde gas recirculation
Incubator	Formaldehyde gas treatment. Surfaces are treated with disinfectants.
Homogeniser	Surfaces and blades treated using disinfectants
Autoclave	Draining of boiler and wiping down of internal and external surfaces using disinfectants
Bunsen burner	Decontamination using disinfectants.
Bain-marie	Voiding of tank and wiping down of tank surfaces with disinfectants.
Colony counter	Decontamination using disinfectants.

EQUIPMENT AND MACHINERY

Autoclaves

Autoclaves are vertical, thick-walled, AISI-316 stainless steel containers with an airtight lid equipped with pressure-sensitive safety valve and steam, air or gas bleed valves.

There are various capacity autoclaves; often they feature a twin-wall structure and are employed to wash and sterilise containers, culture beds and materials. Their operating principle involves loading the materials to be sterilised into the chamber. Steam or a gas at a specified temperature are then pumped in for a set time and subsequently dumped.

This principle is valid for all autoclaves types (laboratory or industrial, both heat-based and chemical-based sterilization systems). In general autoclaves are fitted with two safety devices: a mechanical one locks the lid if the chamber is still pressurised and an electric one that inhibits sterilization procedure initiation if the lid is not properly secured.

All autoclaves are fitted with vacuum pumps and dump valves to pump out air, gas or steam from the chamber. Atmospheric pressure within the chamber is re-established by allowing in filtered air (filter porosity 0,45 µm).

Industrial-type autoclaves may perform numerous programmes including the following:

- sterilization of solutions in test tubes, pressure testing of test tubes by fast vacuum cycle followed by cooling/washing cycle using de-ionised water spray;

- sterilization of packaged syringes and hypodermic needles;

- pressure testing of test tubes using colouring agents (e.g.: methylene blue);

- integral stopper treatment involving washing, rinsing, siliconing, sterilization and fast drying.

U.V. Radiation Systems

These systems include U.V. mains powered lamps as part of the lighting systems of the sterile area, generally alternate U.V. and standard lamps being fitted.

Risk factors

The principal occupational hazards in this work cycle phase are due to the following factors.

Handling of hazardous chemical substances

DESCRIPTION

Cleaning and sterilization operations may cause operators to come into contact with contaminated plant systems, containers and instruments and thus with pharmaceutical and chemical residues. Certain antiseptic action solutions like aldehyde, quaternary bases, alcohol may be used in these phases. Field data reports that the employees of a company use 5% phenol solutions, formaldehyde, 5% sodium hypochlorite solutions and 5% hydrogen peroxide in their sterilization processes.

EXPECTED INJURIES

Sodium hypochlorite is classified as follows:

- 10% or higher concentrations: C (corrosive), R31 (upon contact with acids gives off toxic gasses), R34 (causes burns);

- in concentrations ranging from 5% to 10%: Xi (irritant), R31 (upon contact with acids gives off toxic gasses), R36/38 (eye and skin irritant);

Contact with sodium hypochlorite may cause severe skin and eye irritation; Inhalation may cause intense respiratory tract irritation, chemical bronchopneumonia and pulmonary oedema;

Ingestion may cause severe, potentially fatal lesions (corrosion of mucous membranes, perforation of the oesophagus and stomach wall tissues). The product’s pungent odour substantially reduces the accidental ingestion hazard.

Phenol is classified as follows:

- 5% or higher concentrations: T(toxic), R24/25 (toxic in case of contact with skin or if swallowed, C(corrosive), R34 (causes burns); inhaling organic vapours may cause eye and throat irritation;

- in concentrations ranging from 1% to 5%: Xn (noxious), R21/22 (noxious in case of contact with skin or if swallowed), R36/38 (eye and skin irritant).

I.A.R.C. classifies formaldehyde (formic aldehyde) as a Group 2A carcinogen (probable carcinogen in humans) and by the EC as a Cat.3 carcinogen (suspected possible carcinogenic effects in humans; availability of a sufficient number of studies conducted on animals).

Furthermore formaldehyde is classified as follows:

- in concentrations higher than 25%: T(toxic), C(corrosive), labelling bears hazard warning phrases R23/24/25 (toxic if inhaled/ingested/upon contact with skin), R34 (causes burns), R40 (may cause possible irreversible effects), R43 (may cause skin sensitisation);

- in concentrations ranging from 5% to 25%: Xn (noxious), R20/21/22 (noxious if inhaled/ingested/upon contact with skin), R36/37/38 (Eye, respiratory tract and skin irritant), R40 (may cause possible irreversible effects), R43 (may cause skin sensitisation);

- in concentrations ranging from 1% to 5%: Xn (noxious), R40 (may cause possible irreversible effects), R43 (may cause skin sensitisation);

- in concentrations ranging from 0.2% to 1%: Xi (irritant), R43 (may cause skin sensitisation).

PREVENTIVE MEASURES

The principal preventive measures are as follows:

- assess the feasibility of employing the cleaning in place approach (automatic closed-cycle washing and/or sterilization systems incorporated in machinery);

- examine the product safety cards that the supplier, by law, has furnished and consider the feasibility of replacing them with less hazardous ones;

- sterilization processes that call for the use of hazardous products must be performed on the sealed items of equipment in premises where no employees are present. After the completion of the sterilization process, the premises must be ventilated so as to eliminate any residual hazardous substances from the working environment;

- check that sodium hypochlorite cannot be used in the presence of acids or other incompatible chemical products. Muriatic acid (industrial grade hydrochloric acid solution) and sodium hypochlorite may give off toxic chlorine gas;

- use appropriate metering pumps for safe solution preparation;

- all containers, including those used for solution transfer, must be labelled as required by regulations; all piping must be colour-coded as required by regulations;

- use safety tanks (e.g.: twin wall structure) and/or separate catch tanks to contain possible spills thus allowing recycling or neutralization of spilt products; employ all feasible measures to avoid spills and seepages of concentrated products. Transfer of hazardous products to smaller containers must be performed safely excluding all possible seepages. Safety-type containers must be employed (leakproof, spring-loaded stopper, suitably labelled);

- operators must use appropriate PPEs such as face visors, gloves, non-slip footwear suited to the product being handled, aprons (aprons must cover top edge of work boots so as to stop liquids from trickling into footwear);

- consider the feasibility of automating preparation/dilution/use of closed cycle cleaning solutions;

- the head of plant safety must refer to the product safety cards furnished by the supplier as required by law. The user company must inform and suitable train operators;

- establish and implement written safe work procedures (e.g.: refer to equipment manufacturer suggestions when establishing procedures for the biologic decontamination of microbiology laboratory equipment. If the equipment item being considered has come into contact with hazardous chemicals and/or biologic agents or if such contact is suspected, decontamination must be performed prior to allowing any technical personnel interventions. If total or partial decontamination of the equipment is not possible, the head of the laboratory must formally inform maintenance staff. The signed document shall clearly indicate all safety measures to be implemented in order to avoid possible infections. The laboratory head shall ensure that technical staff be issued with coveralls, gloves, safety eyeglasses or face visor, safety face guard. He shall also ensure access to disinfecting agents, wash basins and safety shower if required;

- operator information and training.

REFERENCE LEGISLATION

- Chap.II, Para.II, Article 18 “Protection from noxious substances” D.P.R.n°303 dated 19.03.1956 “General rules for workplace health and safety”.

- Chap.VIII "Hazardous and noxious materials and products", D.P.R. n°547 dated 27.04.1955.

- D.Lgs.n°52 dated 03/02/1997 “Implementation of Directive 92/32/CEE concerning classification, packaging and labelling of hazardous substances”.

- D.M.S. dated 04/04/1997 “Implementation of Article 25, paragraphs 1 and 2, of D.Lgs.n°52 dated 03/02/1997, concerning classification, packaging and labelling of hazardous substances, with regard to the information file on safety”.

- D.M.S. dated 28/04/1997 “Implementation of Article 37, paragraphs 1 and 2, of D.Lgs.n°52 dated 03/02/1997, concerning classification, packaging and labelling of hazardous substances”.

- D.Lgs.n°90 dated 25/02/1998 “Amendments to D.Lgs.n°52/1997”

- D.Lgs.n°285 dated 16/07/1998 "Implementation of EC Directives on classification, packaging and labelling of hazardous preparations, as per Article 38, Law n°128 dated 24/04/1998”.

- D.M.S. dated 01/09/1998 “Provisions regarding the classification, packaging and labelling of hazardous substances in assimilation of Directive 97/69/CE”.

- D.M.S. dated 07/07/1999 “Provisions regarding the classification, packaging and labelling of hazardous substances in assimilation of Directive 98/73/CE”.

- D.M.S. dated 10/04/2000 “Assimilation of Directives 98/73/CE and 98/98/CE representing respectively the twenty-fourth and twenty-fifth adjustment to Directive 67/548/CEE”.

- D.M.S. dated 30/10/2000 “Amendment to D.M.S. dated 10/04/2000 assimilating Council Directive 98/98/CE dated 15/12/1998 and of amendments to Council Directives which represent the twenty-fourth and twenty-fifth adjustment to the technical progress of Council Directive 67/548/CEE on the adjustment of legal, regulatory and administrative provisions for the classification, packaging and labelling of hazardous substances”.

- D.M.S. dated 26/01/2001 “Provisions regarding classification, packaging and labelling of hazardous substances in assimilation to Directive 2000/32/CE”.

Photo 5. Accidental spill containment system.

Work performed in the presence of steam, hot water and heated surfaces

DESCRIPTION

The external surfaces of autoclaves may reach temperatures ranging from 40° to 50°C.; high risk levels are achieved during container lid opening operations.

Operators may come into contact with hot water and/or steam during cleaning and/or sterilization of equipment and plant systems and with the heated external surfaces of the latter.

EXPECTED INJURIES

Scalding due to contact with heated machinery components or due to contact with hot water or steam.

REPORTED INJURIES

A company reported a severe accident resulting in burns, which occurred during a modification to the hot water cleaning procedure. The modification involved achieving higher temperatures than boiling point at atmospheric pressure.

PREVENTIVE MEASURES

There are interspaces between the inner and outer walls of certain autoclaves. The space acts as a barrier inhibiting heat propagation to the surrounding environment.

Consider the feasibility of employing automated closed-cycle washing and/or sterilization systems.

Consider performing sterilization processes overnight so that autoclaves may cool and be opened the following morning at ambient temperature.

Use of suitable PPEs (insulated gloves, aprons, etc.) will ensure that operators are protected from steam and hot water splashes.

Appropriate operator information and training especially when habitual work procedures are being modified.

REFERENCE LEGISLATION

- Article 9 “Air Circulation”, Article 11 “Temperature” and Article 13 “Humidity” D.P.R.n.303 dated 19/03/1956.

- Article 240 “Protection of high temperature external surfaces” D.P.R.n°547 dated 27/04/1955.

- Article 378 “Clothing” and Article 379 “Protective garments” D.P.R.n°547 dated 27/04/1955.

- D.Lgs.n°626/1994 and subsequent amendments/integrations.

- Regulation UNI EN 563 dated 30/06/1995. Machine Safety. Contact surface temperature. Ergonomic data to establish the temperature threshold values for hot surfaces. The regulation presents ergonomic data and their use to establish temperature thresholds for hot surfaces and to assess the risk of burns.

Work performed in the presence of moving machinery parts

DESCRIPTION

Manual cleaning of certain machine may entail the operator being snagged, dragged or crushed by the machine’s parts in motion. By way of an example, an operator may clean a mixer/blender by pouring the cleaning fluid in the vat and starting the machine in order to better clean the internal surfaces.

Other operators may accidentally start the machine while staff is cleaning the machine’s internal parts.

EXPECTED INJURIES

Lesions and bruises.

PREVENTIVE MEASURES

Hazardous zones must be shielded by fixed guards or fitted with interlocking safety devices to reduce the risk of operators being snagged and dragged. Machinery must be fitted with emergency shut down and accidental start-up lockout devices such as safety devices blocking machine start up when power is restored after a temporary blackout.

The control panel should be fitted with a turnkey operated lockout device so that staff may remove the key prior to starting cleaning operations. Other cleaning, adjustment or maintenance operations involving the removal of guards and shields shall be performed using a hand-held, push button, pulse operation remote control unit connected so as to override the main control panel. The operator may thus monitor operations while standing at a safe distance.

Adopt formal standardized cleaning procedures.

Operator information and training.

REFERENCE LEGISLATION

- D.P.R.n°547/1955 and subsequent amendments/integrations

- D.Lgs.n°626/1994 and subsequent amendments/integrations

- D.P.R.n°459 dated 24/07/1996 (Machine Directive)

Fatiguing tasks and work postures

DESCRIPTION

Careful cleaning of plant systems especially where processing of semi-solid pharmaceutical forms particularly rich in lubricating agents such as suppositories, ovules and ointments takes place, require manual operations involving fatiguing tasks and anomalous work postures.

EXPECTED INJURIES

Muscular-skeletal complaints.

PREVENTIVE MEASURES

- Consider the feasibility of employing built-in, closed-cycle automatic washing and/or sterilization systems (cleaning in place).

- Accurate task organization and operator information and training.

REFERENCE LEGISLATION

- D.Lgs.n°626/1994 and subsequent amendments/integrations

Exposure to ultraviolet radiation (UV).

DESCRIPTION

Workers are exposed to UV radiation when operating in sterile premises where ultraviolet lamps are fitted to the lighting systems. Low frequency UV radiation leads to the formation of ozone resulting from the photochemical reaction with ambient air oxygen.

EXPECTED INJURIES

Prolonged exposure to UV radiation may cause several skin (e.g.: erythema, aging, tumours) and eye complaints (conjunctivitis, cataracts).

Working environment ozone concentrations exceeding 0,1 ppm may cause eye and respiratory tract irritations.

PREVENTIVE MEASURES

Operators must wear appropriate UV-shielding protective eyewear.

Ensure adequate working environment air circulation.

REFERENCE LEGISLATION

- Article 377 of D.P.R.n°547/1995 and subsequent amendments/integrations

- D.Lgs.n°626/1994 and subsequent amendments integrations

OUTSOURCING

In general washing and sterilization processes are not contracted out.

EXTERNAL IMPACT

Liquid wastes production

Waste fluids generated as a result of equipment cleaning operations contain drug production residues mixed with detergents and disinfectants. Fluids may prove to be a water pollution hazard and as such they must be collected and be suitably disposed of after neutralization and decontamination.

Accidental spillage of chemical products

Accidental spillage of chemicals employed during cleaning/sterilization may cause environmental pollution. All feasible measures apt to contain such spills shall be implemented so as to cut down working hazards.

Paved outside areas should allow rainwater to be collected. Should a spillage of chemical products occur on such areas, rainwater should be neutralized and decontaminated prior to discharge to sewage collection systems.

3.4 – granulate preparation

WORK PHASE DESCRIPTION

The initial production step, the processing of powders into granulate, is common to all pharmaceutical forms.

Powders are ground by specific milling machines. Milling is necessary because the particle size of the powders, as delivered by suppliers, does not meet the technical requisites of the drug production industry.

The granulation process is initiated only after the milled powders have been passed through appropriately sized screens/sieves, typically ranging from 0,1 to 1000 µm.

The purpose of granulation is to enhance individual powder, or more frequently, mixture fluidity and cohesion.

Wet or dry granulation procedures are employed.

Dry granulation is employed where permitted by the physical characteristics of the products. After having blended the active principles and excipients, compactors or vibrating granulators are employed to form slugs, which are subsequently crushed and screened.

Wet granulation involves the use of a solvent (water, water/alcohol) or a solvent/binder solution (5% soluble starch, 5-10% gum arabic). The binder solution is gradually fed to a blender where the product mixture is turned into a dough that will be subsequently dried and screened.

Subjected to continuous mixing, the dough is forced through screens or perforated metal sheets.

Drying is achieved by means of static, continuous or discontinuous systems or by directing a powerful jet of compressed air into the blender.

Grinding and screening operations complete the work cycle.

EQUIPMENT AND MACHINERY

Miller/grinders

There are various types of milling/grinding machines (e.g. blade mill, hammer mill, ball grinder). They are fitted with a hopper, for the products to be milled, and a collection/dump system for the milled products.

Compactor

Compactors are fitted with a steel funnel connected to a load hopper. The hopper is fitted with a screw feed for product pre-compression. The funnel feeds into a degassing chamber that includes two rollers. Materials to be compacted are gravity fed and forced by the screw feed into the gap between the two counter-rotating, variable speed, adjustable rollers. Roller surfaces are either smooth or coarse, depending on the desired finished result, i.e. uniform slugs or specific sized pieces.

Twin Whisk Blender

The blender is fitted with a convex bottomed tub. The configuration of the tub’s bottom is such as to form twin depressions within which sturdy, Z-shaped whisker blades turn at a preset velocity. The tub is tip able to facilitate dough discharge and is fitted with safety devices that inhibit whisker blade operation when lifted. A binder solution feed port is also fitted.

Planetary or crown wheel Blender

This blender is fitted with a flat or convex bottomed cylinder-shaped bin. An independent-motion, set velocity paddle moves within the bin. The paddle may be raised either manually or automatically. Certain blenders are fitted with twin blades while others are fitted with scraper blades so as to remove traces of product from bin surfaces.

In addition to its inherent versatility, this blender type offers the obvious advantage of allowing the bin to be removed from the machine and transported elsewhere after completion of blending operations.

Rotating Tub Blender

This blender is fitted with multiple-shaped steel bins (cylinder, cube, V-shaped, etc.), which rotate about an axis. Different shaped bins and movements are employed to accentuate particle displacement and forces that facilitate mixture homogeneity. This blender type is best suited to blend different density powders.

Fluid Bed Granulator-Dryer

The granulator-dryer is fitted with a cylindrical steel chamber. The chamber may be divided into three essential parts. The lower part includes a perforated drum containing the material granules; the central part allows the expansion of the fluidified materials; the upper part is fitted with filters and hoses to trap dust.

By means of another adjacent chamber, air is blown into a duct connected to the perforated drum and thus up into the granulator. The air jet, aimed towards the overhead exhaust flue, fluidifies and mixes the powders in the chamber’s central section.

Single or multiple nozzles, located in the chamber’s central section, spray the granulator mixture onto the moving powder particles. As the granulate is formed, it is immediately dried by the constant airflow. Overhead filters trap small powder particles that would otherwise be dispersed in the flue. These fine particles are periodically shaken free from the filters by a timed device, which then feeds them back into the granulator cycle.

The cycle requires approximately two hours for completion.

Dynamic Tunnel Dryer System

The dynamic tunnel drying system includes a series of warm airflow cabinets enclosing conveyor belts. The moist granulate is fed through hoppers onto trays carried by the belts. Belt velocity may be adjusted. The belts pass the granulate trays under successive outlets which deliver decreasing temperature air jets (typically from 100° down to 35°C), thus drying the granulate in steps.

Dynamic Revolving Drum Dryer System

The moist material is fed into a revolving drum. A constant flow of warm air is blown into the drum in the opposite direction. This method offers the additional advantage of continuously mixing the granulate as it dries.

Vacuum Dryers

Vacuum dryers are fixed or revolving heater/cabinets containing trays carrying moist granulate. Vacuum pumps, capable of achieving residual pressures in the order of 10^-2-10^-3 torr, are fitted above the heater/cabinets. Refrigerated trays generally containing moisture absorbing chemical compounds such as sodium chloride salts or concentrated sulphuric acid collect moisture.

RISK FACTORS

The principal occupational hazards potentially present in this work phase are due to the following factors.

Exposure to dust

DESCRIPTION

Operators may be exposed to dust during miller/grinder loading/unloading, compacting, blending and granulation operations.

ESTIMATE

Field assays have yielded ambient air dust concentration levels ranging from 342 to 3.462 µg/m³ in the blender shop, from 307 to 1.884 µg/m³in the granulator shop.

EXPECTED INJURIES

Allergic asthma, contact dermatitis.

Specific pharmacological effects due to active principles.

PREVENTIVE MEASURES

Use of completely automated load/unload systems.

Use of protective hoods fitted with absolute filters.

During this work phase, industry operators employ protective respirators capable of trapping dust up to 2.000µg/m³.

REFERENCE LEGISLATION

- D.P.R.n°303/1956 and subsequent amendments/integrations

- D.P.R.n°626/1994 and subsequent amendments/integrations

Work performed in proximity of moving machinery parts

DESCRIPTION

Compactors are fitted with mechanical drive screw feed and roller systems. Operators must act manually in order to remove any blockages in the production flow.

EXPECTED INJURIES

Lesions or contusions.

PREVENTIVE MEASURES

All machinery must be fenced off or fitted with safety mechanical interlocking or photoelectric cells inhibiting operator access to hazardous areas while machines are in operation. Where visual monitoring is called for grilles or appropriately located distance bars should be fitted in order to stop operator limbs from coming into contact with moving machinery parts.

Machinery must be fitted with emergency shut down and accidental start-up lockout devices such as safety devices blocking machine start up when power is restored after a temporary blackout.

The control panel should be fitted with a turnkey operated lockout device so that staff may remove the key prior to starting cleaning operations. Other cleaning, adjustment or maintenance operations involving the removal of guards and shields while machine is operating shall be performed using a hand-held, push button, pulse operation remote control unit connected so as to override the main control panel. The operator may thus monitor operations while standing at a safe distance.

Adopt formal standardized cleaning procedures.

Operator information and training.

REFERENCE LEGISLATION

- D.P.R.n°547/1955 and subsequent amendments/integrations

- D.Lgs.n°626/1994 and subsequent amendments/integrations

- D.P.R.n°459 dated 24/07/1996 (Machine Directive)

Exposure to noise

DESCRIPTION

The sources of noise in this work phase are: miller/grinders, compactors, blenders and granulators. Notwithstanding the use of sound dampening devices, noise levels may be quite high.

EXPECTED INJURIES

Continuous exposure to medium-high noise levels may cause hearing injuries (noise-induced hypoacusia) and extra-hearing complaints. Injuries and complaints may result also from exposure to noise levels lower than the thresholds for which legislation prescribes the use of specific preventive measures.

In addition to communication and work performance-related complaints, the following disorders may also arise: cardiovascular effects (high blood pressure, etc.); psychic disorders (asthenia, irritability, depression, insomnia); digestive tract disorders.

PREVENTIVE MEASURES

Preventive measures established by D.Lgs.n°277/91 are applicable in cases of employee noise exposure exceeding 80 dB(A). The provisions established by D.Lgs.n°277/91 are summarised in the “Noise exposure threshold levels” chart reported in this study’s “General Reference Legislation” chapter.

REFERENCE LEGISLATION

- Article 24 “Noise and Motion” D.P.R.n°303 dated 19/03/1956.

- Paragraph IV “Protection of workers against the risks of exposure to noise” D.Lgs.n°277 dated 15/08/1991.

- D.P.R.n°459 dated 24/07/1996 “Regulations for the implementation of Directives 89/392 EEC, 91/368/EEC, 93/44/EEC and 93/68/EEC regarding the rapprochement of member states’ regulations on machines (Machine Directive)

Manual load handling

DESCRIPTION

Machine hopper loading operations in this phase may be performed manually.

EXPECTED INJURIES

Muscular-skeletal complaints

PREVENTIVE MEASURES

Use of mechanical/electrical handling devices or automated loading systems.

Two operator handling of heavy loads.

Manual load handling is permitted for loads up to 30 kgs.(males) and 25kgs.(females). Handling of loads exceeding these limits shall be performed using appropriate devices and/or shall be performed by two operators.

Operator information and training.

REFERENCE LEGISLATION

- Chapter V and Enclosure 6 of D.Lgs.n°626 dated 10/09/1994

- Regulation UNI ISO 938

Explosion – Fire Hazard

DESCRIPTION

Certain solid substances or their mixtures may take on explosion hazard properties during milling/grinding operations.

EXPECTED INJURIES

Traumatic lesions, burns, intoxication.

PREVENTIVE MEASURES

- Explosion hazard assessment;

- Fire hazard depending on the product being handled;

- Electrical grounding of machinery to disperse static electricity capable of sparking fire hazard;

- Operator information and training.

REFERENCE LEGISLATION

- Chapter II, Article 13 "Exits and emergency exits”, Article 14 "Doors and main entrances” D.P.R.n°547 dated 27/04/1955.

- Chapter II, Paragraph VI “Protection from fire and atmospheric electrical discharges” D.P.R.n°547 dated 27/04/1955.

- Chapter VII, Paragraph X “electrical power systems in fire-explosion hazard areas” D.P.R.n°547 dated 27/04/1955.

- Chapter VIII "Hazardous or noxious materials and products" D.P.R.n°547 dated 27/04/1955.

- D.M. dated 16/02/1982 “Amendments to D.M. dated 27/09/1965, concerning the determination of activities subject to fire prevention inspections”.

- D.P.R.n°577 dated 29.07.1982 “Approval of regulations concerning performance of fire prevention services”.

- D.M.I. dated 08/03/1985 "Directives on top priority and essential fire prevention measures for the issue of provisional authorisation as per law dated 7 December 1984, n°818".

- Article 4 “Duties of the employer, manager and other persons in charge”, paragraph 5 letter a) and letter q) of D.Lgs.n°626 dated 19/09/1994 (with subsequent amendments and integrations) “Implementation of Directives 89/391/CEE, 89/654/CEE, 89/655/CEE, 89/656/CEE, 90/269/CEE, 90/270/CEE, 90/394/CEE, 90/679/CEE, 93/88/CEE, 97/42/CE and 99/38/CE concerning worker safety and health enhancement”.

- Articles 12 and 13 “Fire prevention and evacuation of workers” D.Lgs.n°626/1994.

- D.M. dated 10/03/1998 “General safety criteria for fire prevention and emergency management in work areas”.

- UNI-VV.FF Regulations on fire fighting systems, fire detection systems, smoke and heat evacuation systems, etc..

- D.M. dated 3/9/2001 “Amendments and integrations to D.M. 26/6/1984 concerning classification and homologation of materials’ reaction to fire for fire prevention purposes”.

OUTSOURCING

The granulate formation phase may be contracted out.

EXTERNAL IMPACT

Noise propagation

The machinery described above may cause noise to propagate from the production plant possibly disturbing adjacent residential areas. Viable solutions may involve the following: noise reduction at the source, use of sound proofing/dampening panels, positioning of high noise producing operations in the parts of the plant furthest away from residential areas.

3.5 – tablet production

WORK PHASE DESCRIPTION

Tablets are produced by pressing appropriate quantities of homogeneous grain size powder and/or granulate employing suitable machines. Quantitatively tablets are the industry’s principal product, due to this pharmaceutical form’s considerable advantages.

Tablet production involves adding suitable excipients to the active substances. Excipients are pharmacologically inert substances with specific properties that give tablets the required mechanical resilience, good separation after administration, non-adherence to the surfaces of the compressing machines, good fluidity and compressibility.

Typically the mixing of powders takes places inside stainless steel containers using a mobile blender.

Alternatively specific containers called bins are employed in association with suitable machines called bin revolvers.

Suitable proportions of inert substances are automatically added according to the following sequence:

1) Diluents: glucose, lactose, starch, micro crystal cellulose, saccharose. Diluents give body to the tablets;

2) Absorbents: talcum and silica. Absorbents allow liquid active principles to powders;

3) Binders: starch, hydrolyzed gelatine, polyvinyl pyrrolidone (PVP), methylhydroxicellulose. Binders keep the powder particles within the tablets together;

4) Break down agents: starch. Break down agents facilitate release of active substances after administration by assisting tablet breakdown;

5) Glidants and lubricants: colloidal silica, talc, calcium and magnesium stearates. Quantities not exceeding 0.5% in absolute terms are added to facilitate powder fluidity into the compression dies and to facilitate subsequent tablet expulsion;

6) Colouring and flavouring agents: aluminium lakes, iron oxides, natural colouring agents.

After mixing employing the mobile blender, containers are manually transferred to the compressing machines using trolleys.

After mixing employing the bin revolvers, bins are transferred to the compressing machines using pallet-lifting trolleys.

Typically compressing machines are fed by coupling an airtight flexible hose to the bin or by manually tipping bin content into the machines’ loading hopper.

EQUIPMENT AND MACHINES

Mobile blender

A mobile blender is an electric powered mechanical blending device that is inserted into a stainless steel mixing container.

Bin revolver blender

A bin revolver blender is an electric powered machine with a revolving platform supporting the bin employed to blend the powder mixture. The machine is enclosed in a safety cabinet.

Compressing Machines

There are various types of compressing machines. Compressing machines produce tablets by compressing a suitable quantity of powder or granulate into a chamber or die employing two steel rollers. The die is filled automatically by an extension to the load hopper. After the die has been filled the two rollers, acting in a complementary manner, compress the granulate to form the tablet which is subsequently mechanically pushed out by a piston from the die into a collection container.

Production output employing these machines ranges from 500/5,000 items/hour to 180,000/600,000 items/hour depending on the machine type (reciprocating or rotary).

Reciprocating compressing machines have a discontinuous output. All tablet formation operations must be completed prior to beginning a new compression cycle.

A fundamental component of this machine type, in addition to the die and rollers, is the load hopper extension that also acts as an extractor for the completed tablets.

Dies are perforated tempered steel disks. The upper and lower surfaces of the perforated disks perfectly match the surfaces of the tempered steel compression rollers that come in various shapes and sizes.

The hopper extension feeds the powder to the die. The top roller moves downwards and compresses the powder in the die against the bottom roller that acts as the die’s lower surface. Rollers exert pressures ranging from 3-35 metric tons (rotary type machines exert pressures ranging from 5-10 metric tons).

After compression, the top roller moves upward. Subsequently the bottom roller also moves upward thus expelling the tablet from the die. The hopper extension pushes the tablet into a collection container and returns to begin the next die filling sequence, thus initiating a new compression cycle.

Rotary compressing machines differ from the previously described type in that they are fitted with a larger number of continuously operating rollers and because the compression cycle involves the combined and gradual action of the rollers on the die.

The system’s principal component is a circular device on which the dies move. The overhead load hopper and extension system is stationary. In certain cases there may be multiple powder distribution systems and as many as 65-70 dies.

Twin rollers act on each single die. Rollers move toward each other along guide rails.

Rotary compressing machines offer a number of advantages with respect to the reciprocating type: they are fully automated, more versatile, easier to clean and suited to large scale production.

Deduster

All modern compressing machines are fitted with dust removal systems to counter dust produced during the compression cycle and any residual dust coating the surface of the finished tablets.

Compression cycle dust removal systems include large exhaust fans, long flexible hoses and dust intakes fitted to the hopper loading ports and/or close to the die support trays. Dust is collected in appropriate containers.

Finished tablet dust removal systems include two independent elements: a removal system similar to the one described previously positioned at the end of the chute which conveys the tablets into the collection container; a second system which allows the finished tablets to pass through prior to falling into the collection container. The extractor system includes a tablet transfer conduit, a central mesh conduit enclosing a screw feed (which shakes the tablets), a partial vacuum exhaust and a tablet chute.

High output systems are fitted with a metal collection bin enclosing a canvas muff (or frame) dust trap.

Muffs are periodically shaken to free dust particles that are subsequently collected and recycled.

Risk factors

The principal occupational hazards in this work cycle phase are due to the following factors.

Manual load handling

DESCRIPTION

In this phase the hopper may be loaded manually.

EXPECTED INJURIES

Muscular-skeletal complaints.

PREVENTIVE MEASURES

- Use of automated loading systems or handling performed by two operators;

- Manual load handling is permitted for loads up to 30 kgs.(males) and 25kgs.(females). Handling of loads exceeding these limits shall be performed using appropriate devices and/or shall be performed by two operators.

- Operator information and training.

REFERENCE LEGISLATION

- Chapter V and Enclosure 6 of D.Lgs.n°626/1994 and subsequent amendments/integrations

- Regulation UNI ISO 938

Work performed in proximity of moving machinery parts

DESCRIPTION

Operators may be exposed to snagging, snatching, dragging and crushing hazards essentially due to moving parts of compressing machines, conveyor belt or roller systems. Operators must act manually in order to remove any blockages in the production flow.

EXPECTED INJURIES

Lesions or contusions.

PREVENTIVE MEASURES

Machinery must be fitted with emergency shut down and accidental start-up lockout devices such as safety devices blocking machine start up when power is restored after a temporary blackout.

The control panel should be fitted with a turnkey operated lockout device so that staff may remove the key prior to starting cleaning operations. Other cleaning, adjustment or maintenance operations involving the removal of guards and shields while machine is operating shall be performed using a hand-held, push button, pulse operation remote control unit connected so as to override the main control panel. The operator may thus monitor operations while standing at a safe distance.

Adopt formal standardized cleaning procedures.

Operator information and training.

REFERENCE LEGISLATION

- D.P.R.n°547/1955 and subsequent amendments/integrations

- D.Lgs.n°626/1994 and subsequent amendments/integrations

- D.P.R.n°459 dated 24/07/1996 (Machine Directive)

Photo 6. Roller conveyor.

Exposure to dust

DESCRIPTION

Operators may be exposed to potentially hazardous dust during hopper loading and compressing operations.

ESTIMATE

Field assays of tablet compressing shops have yielded ambient air dust concentration levels of 1073µg/m^3.

Firms have reported exposure threshold levels of 100 µg/m³ for active principles and 10 mg/m³ for general dust.

EXPECTED INJURIES

Allergic asthma, contact dermatitis.

Specific pharmacological effects due to active principles.

PREVENTIVE MEASURES

Use of completely automated loading systems.

Use of protective hoods fitted with absolute filters.

During this work phase, industry operators employ protective respirators capable of trapping dust up to 2.000µg/m³.

REFERENCE LEGISLATION

- D.P.R.n°303/1956 and subsequent amendments/integrations

- D.P.R.n°626/1994 and subsequent amendments/integrations

Exposure to noise

DESCRIPTION

Compressing machines are the principal source of noise in this work phase.

ESTIMATE

Overall operator noise exposure periods lacking adequate machinery soundproofing measures may cause hearing injuries.

EXPECTED INJURIES

PREVENTIVE MEASURES

REFERENCE LEGISLATION

- Article 24 “Noise and Motion” D.P.R.n°303 dated 19/03/1956.

- Paragraph IV “Protection of workers against the risks of exposure to noise” D.Lgs.n°277 dated 15/08/1991.

OUTSOURCING

Typically tablet production, if performed, is not subject to outside contracting.

EXTERNAL IMPACT

Noise propagation

Atmospheric Emissions

Filters generally trap dust carried by compressing machinery exhaust fan air.

However dust emissions to the surrounding environment cannot be totally ruled out due to the presence of very fine particles which cannot be trapped by the filters or to a filter system malfunction.

3.8 – ointment, paste, cream and gel production: batch preparation

WORK PHASE DESCRIPTION

This semi-solid pharmaceutical form type is produced by adding solid or liquid active principles to specific lipophilic or hydrophilic excipients. The former include fatty agents, vaseline, silicone, lanoline: the latter include glycol (PEG), gelatine,

methylcellulose and carboxymethylcellulose.

In all cases the batch is produced by dispersing a powder in a liquid excipient or mixture of excipients.

Operators may manually add active principles and excipient powders in the blending machine.

Gel production may at times require the operator to perform manual load operations involving the insertion of metal suction nozzles into 25kgs. capacity bins containing active principles. An automated system pipes bin contents to two turbo-emulsifiers containing a hydroalcohol solution.

Liquid excipients, ethyl alcohol and water are piped by an automated system to the turbo-emulsifiers. Ethyl alcohol is stored in 4,000/5,000 litre capacity underground tanks.

After loading has been completed, the operator monitors blending operations from a control console located in a separate room. The shop is equipped with a small room in which the operator washes small work implements such as suction nozzles, paddles, spatulas, bins and the like, using deionized water.

The emulsion is automatically piped (no operators) to large capacity bulk storage steel containers. Occasionally smaller, transportable steel containers are employed to transfer the preparation from the emulsifiers to the bulk containers.

Operators employ electric powered lift trucks to handle the smaller containers.

EQUIPMENT AND MACHINES

Turbo-emulsifier (blender-homogeniser).

Turbo-emulsifiers are large capacity, steel containers equipped with electrically or magnetically operated mixing paddles. Paddle movement brings about and maintains the consistency of the ointment or gel emulsion.

Photo 7. Turbo-emulsifier.

Manually operated trolleys

Standard type, metal transport trolleys fitted with braking system and rounded corners to avoid causing injuries to operators in case of impact.

Bulk storage tanks

Varying capacity, steel containers used for bulk storage of gel and ointment emulsions, typically as semi-finished products.

Photo 8. Emulsion storage tank.

Risk factors

The principal occupational hazards in this work cycle phase are due to the following factors.

Exposure to dust

DESCRIPTION

Loading active principles into the emulsifiers is typically performed manually. Operators insert a suction nozzle connected to the emulsifier into the bins containing the active principles or excipients.

ESTIMATE

Field data typically reports that an operator performs approximately two active principle and excipient emulsifier loading cycles per 8 hour working shift. Loading operations total 90 minutes resulting in 0,76 mg/m³. mean operator dust exposure levels.

TLV-TWA threshold values reported by firms are 0.5 mg/m³for active principles and 10 mg/m³ for gelling excipients.

EXPECTED INJURIES

Active principle-specific induced injuries.

PREVENTIVE MEASURES

- Use of automated loading systems;

- Use of PPEs (safety helmets fitted with absolute filters, protective clothing, gloves, etc.);

- Operator information and training.

REFERENCE LEGISLATION

- D.P.R. n° 303/1956 and subsequent amendments/integrations

- D.P.R. n° 626/1994 and subsequent amendments/integrations

Handling of hazardous chemical substances

DESCRIPTION

Chemical solvents for the production of the emulsion are handled during this work phase.

EXPECTED INJURIES

Irritation of the upper respiratory tract.

Impairment of vision and central nervous system toxicity.

PREVENTIVE MEASURES

- examine the product safety cards and consider the feasibility of replacing the more hazardous products with less hazardous ones;

- fit local extractor systems;

- implement procedures and means apt to avoid drips and spills;

- Use safety containers bearing prescribed labelling;

- Wear PPEs (protective gloves, hoods/masks, etc.);

- Operator information and training.

REFERENCE LEGISLATION

- Chap. II, Para. II, Article 18 “Protection from noxious substances”, D.P.R.n°303 dated 19.03.1956 “General rules for workplace health and safety ”.

- Chap. VIII "Hazardous and noxious materials and products", D.P.R.n°547 dated 27.04.1955.

- D.Lgs.n°52 dated 03/02/1997 “Implementation of Directive 92/32/CEE concerning classification, packaging and labelling of hazardous substances”.

- D.M.S. dated 28/04/1997 “Implementation of Article 37, paragraphs 1 and 2, of D.Lgs.n°52 dated 03/02/1997, concerning classification, packaging and labelling of hazardous substances”.

- D.Lgs.n°90 dated 25/02/1998 “Amendments to D.Lgs.n°52/1997”

- D.Lgs.n°285 dated 16/07/1998 "Implementation of EC Directives on classification, packaging and labelling of hazardous preparations, as per Article 38, Law n°128 dated 24/04/1998”.

- D.M.S. dated 01/09/1998 “Provisions regarding the classification, packaging and labelling of hazardous substances in assimilation of the Directive 97/69/CE”.

- D.M.S. dated 07/07/1999 “Provisions regarding the classification, packaging and labelling of hazardous substances in assimilation of Directive 98/73/CE”.

- D.M.S. dated 10/04/2000 “Assimilation of Directives 98/73/CE and 98/98/CE representing respectively the twenty-fourth and twenty-fifth adjustment to Directive 67/548/CEE”.

- D.M.S. dated 30/10/2000 “Amendment to D.M.S. dated 10/04/2000 in assimilation of Council Directive 98/98/CE dated 15/12/1998 and of amendments to Council Directives which represent the twenty-fourth and twenty-fifth adjustment to the technical progress of Council Directive 67/548/CEE on the adjustment of legal, regulatory and administrative provisions for the classification, packaging and labelling of hazardous substances”.

- D.M.S. dated 26/01/2001 “Provisions regarding classification, packaging and labelling of hazardous substances in assimilation of Directive 2000/32/CE”.

Work performed in Fire/Explosion hazard-prone environments

DESCRIPTION

Hazardous explosion-prone solvents or mixtures may be employed in this work phase. Certain companies employ a hydroalcohol mix comprising 600 litres of water and 170 litres of ethyl alcohol. Ethyl alcohol renders the working environment liable to fires and explosions.

EXPECTED INJURIES

Traumatic lesions, burns, intoxication.

PREVENTIVE MEASURES

- Store the absolute minimum quantity of inflammable products on site;

- Proper storage of inflammable products in a separate, adequately ventilated storage area or in suitable safety cabinets.

- Installed electrical systems and equipment fit to the hazard class of the premises;

- Establish and police a non smoking policy and ban on unprotected flames;

- Fire hazard assessment; establish evacuation plan, train emergency reaction teams;

- Sizing of exhaust system components to match air flow velocity characteristics in order to avoid build-up of explosive mixtures within the ventilation system;

- Minimum fire fighting measures must include homologated fire extinguishers. An appropriate automatic fire fighting system should be installed in higher risk areas.

- Operator information and training

REFERENCE LEGISLATION

- Article 19 “Separation of noxious areas” D.P.R.n°303 dated 19/03/1956.

- Art. 20 “Protection of air from pollution created by noxious products” D.P.R.n°303/56.

- Chapter II, Article 13 "Exits and emergency exits”, Article 14 "Doors and main entrances” D.P.R.n°547 dated 27/04/1955.

- Chapter II, Paragraph VI “Protection from fire and atmospheric electrical discharges” D.P.R.n°547 dated 27/04/1955.

- Chapter VII, Paragraph X “electrical power systems in fire-explosion hazard areas” D.P.R.n°547 dated 27/04/1955.

- Chapter VIII "Hazardous or noxious materials and products" D.P.R.n°547 dated 27/04/1955.

- D.M. dated 16/02/1982 “Amendments to D.M. dated 27/09/1965, concerning the determination of activities subject to fire prevention inspections”.

- D.P.R.n°577 dated 29.07.1982 “Approval of regulations concerning performance of fire prevention services”.

- D.M.I. dated 08/03/1985 "Directives on top priority and essential fire prevention measures for the issue of provisional authorisation as per Law dated 7 December 1984, n°818".

- D.M.Ind. dated 01/03/1989 "Assimilation of Directive EEC/88/571, “Technical progress update of electrical equipment explosion protection."

- Article 4 “Duties of the employer, manager and other persons in charge”, paragraph 5 letter a) and letter q) of D.Lgs.n°626 dated 19/09/1994 (with subsequent amendments and integrations) “Implementation of Directives 89/391/EEC, 89/654/EEC, 89/655/EEC, 89/656/EEC, 90/269/EEC, 90/270/EEC, 90/394/EEC, 90/679/EEC, 93/88/EEC, 97/42/EC and 99/38/EC concerning worker safety and health enhancement”.

- Articles 12 and 13 “Fire prevention and evacuation of workers” D.Lgs.n°626/1994.

- D.M. dated 10/03/1998 “General safety criteria for fire prevention and emergency management in work areas”.

- UNI-VV.FF Regulations on fire fighting systems, fire detection systems, smoke and heat evacuation systems, etc..

- D.M. dated 3/9/2001 “Amendments and integrations to D.M. 26/6/1984 concerning classification and homologation of materials’ reaction to fire for fire prevention purposes”.

Manual load handling

DESCRIPTION

This work phase envisages the use of 25Kg. containers (bags, bins, etc.). Manual push trolleys are employed to handle powder containers.

EXPECTED INJURIES

Muscular-skeletal complaints.

PREVENTIVE MEASURES

Handling of active principle containers should be performed employing electric powered trolleys fit to limit operator exertion.

REFERENCE LEGISLATION

- Chapter V and Enclosure 6 of D.Lgs.n°626/1994 and subsequent amendments/integrations

- Regulation UNI ISO 938

OUTSOURCING

Daily cleaning of working premises may be subject to outside contracting.

EXTERNAL IMPACT

Liquid wastes

The external impact of this work phase is essentially due to machinery washing operations (see also “Washing and Sterilization” paragraph hereunder).

3.9 – container filling and packaging

WORK PHASE DESCRIPTION

The gel is fed by a closed circuit piping system to the tube fillers. Empty aluminium or plastic tubes are transferred from storage to the filling room using manually operated trolleys.

In this phase the operator is tasked with feeding the empty tubes into a stainless steel collection tray or tub and the plastic caps into a vibrating machine.

A mechanical lifting device raises the empty tubes to a mechanical dusting station. Subsequently a roller conveyor transfers them to the tube filler dispensers.

After filling, tubes are pressure sealed with aluminium bottoms. Tube filling, sealing and transfer operations are fully automated.

The packaging lines control console is fitted to a steel panel located within the shop area.

A conveyor belt transfers the tubes from the filling station to an automatic packaging machine and then to an electronic balance to verify package weight.

Items meeting weight specifications are sent to the labelling station. An automatic boxing machine fills cartons with the labelled items.

Alternatively boxing may be performed manually.

A roller conveyor delivers packaged items to a collection station. Operator transfers a suitable number of items to batch-specific packaging cartons.

Cartons are stacked on wood pallets typically located close to the carton filling stations.

The procedure may be either automated or manual. In the latter case the operator, after sealing the carton, transfers it to the pallet.

Complete pallets are positioned on a loading platform. Electric lift trucks are employed to transfer pallets to the final packaging stations.

EQUIPMENT AND MACHINES

Manually operated trolleys

Standard type, metal transport trolleys fitted with braking system and rounded corners to avoid causing injuries to operators in case of impact.

Plastic stopper vibrator

A vibrating bin/tray continuously feeds the plastic caps to the automatic tube filler.

Photo 9. Vibrating Bin Cap Dispenser

Tube Filler

Tube fillers meter an exact quantity of product to each tube and perform a series of other operations such as tube sealing and final packaging. Fillers may be either fully automated or semi-automated depending on whether empty tubes are fed manually or otherwise.

Typically tube filling is performed by a nozzle connected to an automatic piston-action metering unit. Filled aluminium tubes are sealed by spring-loaded clamps that secure the bottom by crimping, twisting and folding open tube ends in alternate directions.

The spring-loaded clamps retain filled tubes after closing the tube ends.

Plastic tube ends are heat sealed with a bottom.

Photo 10. Tube Filler.

Packaging machine

Packaging machines insert the primary packaging tube, containing the medicament into cardboard packages. Packaging machines, either fully automated or semi-automated, have highly variable outputs thus rendering them adaptable to varying production requirements. Date of packaging, batch/lot number, expiry date and the like are ink printed or embossed onto the cardboard packages.

Labelling machines

Labelling machines place non-adhesive pre-printed labels or blank/pre-printed adhesive labels onto the tubes. Positioning rollers hold label spools as they press labels onto passing items. A labelling verification station is also included.

Boxing machines

Packaged items, either singly or in lots must be packaged in suitable containers ready for shipment.

The operation may be performed manually though for high production outputs (>10,000 items/shift) automated boxing machines are more convenient.

Automated boxers gather 100-200 packaged items, place them in corrugated cardboard boxes or cartons and seal them. Typically the batch production number, expiry date and/or other useful information for warehousing purposes are printed onto the cartons.

Photo 11. Boxing machine.

Risk factors

The principal occupational hazards in this work cycle phase are due to the following factors.

Manual load handling

DESCRIPTION

Manual load handling is performed constantly during this work phase to replenish empty tube, tube bottoms and plastic cap feed hoppers. Container packs are handled manually when transferred from the trolleys to shelf storage.

Final packaging may also be performed manually. The operator transfers the packaged items from the roller conveyor to the packaging cartons. Cartons are stacked on wood pallets positioned close to the working station.

ESTIMATE

Load handling data furnished by a drug company may be broken down as follows:

- empty tube feed: package weight 5 kgs, feed frequency 3/min.;

- filled tube transfer: weight 10.8 kgs, frequency 2/min.;

- labeller feed: weight 7 kgs, frequency 1/min.

Work pace may vary significantly according to production output requirements.

EXPECTED INJURIES

Muscular-skeletal complaints.

PREVENTIVE MEASURES

Use of electric powered or mechanical devices or automated systems.

Manual load handling operations are limited to loads up to 30kgs for men and 25 kgs for women.

Heavier loads shall be handled employing appropriate means and/or shall be performed by two operators.

REFERENCE LEGISLATION

- Chapter V and Enclosure 6 of D.Lgs.n°626/1994 and subsequent amendments/integrations

- Regulation UNI ISO 938

Exposure to noise

DESCRIPTION

Noise sources during this phase are: plastic cap vibrating bin, dispenser, tube filler, packager, labeller and boxing machines.

These types of machines generate considerable noise levels.

ESTIMATE

Field data record noise output levels ranging from 85.5 to 90.4 dB(A) for tube feed dispenser and plastic cap vibrator.

Tube bottom feed station recorded noise levels range from 84.2 to 84.5 dB(A).

Cabinet encased tube filler noise outputs range from 87.9 to88.6 dB(A).

Packaging machine noise outputs range from 83.5 to 84.7 dB(A).

Labeller noise outputs range from 80,8 to 86,4 dB(A).

Automatic boxing noise outputs range from 79,1 to 82,2 dB(A).

EXPECTED INJURIES

Lacking adequate safety measures, continuous operator exposure to work place noise levels may cause hearing injuries (noise-induced hypoacusia) and extra-hearing complaints.

PREVENTIVE MEASURES

REFERENCE LEGISLATION

- Article 24 “Noise and Motion” D.P.R.n°303 dated 19/03/1956.

- Paragraph IV “Protection of workers against the risks of exposure to noise” D.Lgs.n°277 dated 15/08/1991.

Use of sharp hand tools

Prior to beginning tube filling operations, operators transfer empty tubes from cartons delivered from warehouse storage.

Cartons may be opened employing sharp hand tools such as knives and scissors.

Use of such tools may cause cutting injuries.

EXPECTED INJURIES

Cutting injuries due to the use of sharp hand tools in opening of cartons.

PREVENTIVE MEASURES

Use of safety sheath knives exposing only the required portion of the blade;

Use of safety gloves.

REFERENCE LEGISLATION

- Article 383 “Hand protection” D.P.R.n°547 dated 27/04/1955

- D.Lgs.n°626/94 and subsequent amendments/integrations

Work performed in proximity of moving machinery parts

DESCRIPTION

Operators may be exposed to snagging, snatching, dragging and crushing hazards essentially due to moving parts of machines described above (tube fillers, packers, labellers, boxers, conveyor belts or roller systems).

EXPECTED INJURIES

Lesions or contusions.

PREVENTIVE MEASURES

Machinery must be fitted with emergency shut down and accidental start-up lockout devices such as safety devices blocking machine start up when power is restored after a temporary blackout.

The control panel should be fitted with a turnkey operated lockout device so that staff may remove the key prior to starting cleaning operations. Other cleaning, adjustment or maintenance operations involving the removal of guards and shields while machine is operating shall be performed using a hand-held, push button, pulse operation remote control unit connected so as to override the main control panel. The operator may thus monitor operations while standing at a safe distance.

Adopt formal standardized cleaning procedures.

Operator information and training.

REFERENCE LEGISLATION

- D.P.R.n°547/1955 and subsequent amendments/integrations

- D.Lgs.n°626/1994 and subsequent amendments/integrations

- D.P.R.n°459 dated 24/07/1996 (Machine Directive)

Mechanical load handling

DESCRIPTION

Upon completion of packaging operations, cartons containing packaged drugs are stacked on wood pallets and placed on a raised loading platform. Load handling personnel transfer complete pallets to warehouse storage employing electric powered load lifting devices (see also “Warehousing” phase description).

EXPECTED INJURIES

Operators risk crushing injuries caused by pallets being dropped by handling equipment or by impact against moving load lifting devices.

Lesions or contusions.

PREVENTIVE MEASURES AND REFERENCE LEGISLATION

Refer to “Mechanical Load Handling” work phase.

OUTSOURCING

This work phase is not contracted out as it is pivotal to the overall production process.

EXTERNAL IMPACT

Solid waste products such as damaged packets and boxes and packaging scraps are produced during this work phase.

3.10 – solution preparation

WORK PHASE DESCRIPTION

The initial step of liquid form drug production involves mixing solid or liquid active principles and excipients with solvents in suitable stainless steel or glass containers (dissolvers). Operations are performed in asepsis according to good manufacturing procedures.

The most commonly used solvents in liquid form preparations are water and ethyl alcohol though the latter may not always be required.

Preparation of injectables employs de-ionised, sterile and

non-pyrogenic water (i.e. without trace or with tolerable levels of micro organisms or pyrogenic agents [substances apt to raise body temperature]).

Ethyl alcohol is stored in above/below ground tanks and, like water, may be pumped to the dissolver by totally automated systems.

Accidental liquid discharges are prevented by employing spillproof metal sealing clamps to secure pipe/hose dissolver couplings.

EQUIPMENT AND MACHINES

Dissolvers

Dissolvers are raised stainless steel tanks located on tripods or other supporting structure fitted with a suitably located liquid content release cock.

The removable or hinged lid is fitted with sealing gaskets and several ports for securing the stirrer, thermometer, gas fittings for pressurized tank voiding using nitrogen/CO₂)gas and vacuum pump hose coupling.

An active principle load hopper may be connected to the dissolver by suitable piping.

Production dissolvers may be fitted with external heating/cooling muffs. Muffs heat/cool tank content by circulating different temperature coolants.

Large volume dissolvers may be fitted with external metal structures such as ladders and gangways for inspection purposes.

Glass dissolvers may be employed for certain preparation types not requiring heated solvents.

They are fitted with spillproof inlet ports for active principles and cocks for solution tapping. As substances are added manually, glass dissolvers are placed under laminar flow exhaust hoods.

Dissolver capacity may vary but typically reaches several hundred litres.

Photo 12. Glass dissolver.

Photo 13. Steel dissolver.

Dedusters

Dedusters are essentially large capacity vacuum cleaners fitted with a motor, flexible hoses, vacuum nozzles, dust filters and collection containers.

Larger volume systems are fitted with metal collection containers including dust trap canvas or metalframe filtering devices. Filtering devices are shaken regularly and collected dust may be recycled or rejected as production waste.

Solution Containers

One of the companies reported employing amber-coloured glassware containers to transfer solutions from the dissolvers to the sterile chamber for phial filling. Containers are horizontal, cylinder-shaped, dome-ended glassware items fitted with leakproof stoppers and fittings on the lid for phial filler hose coupling.

Easy to handle, glassware containers may be sterilised prior to entering the sterile chamber thus avoiding contamination of products and sterile areas.

Photo 14. Amber-coloured glassware container.

Risk factors

The principal occupational hazards in this work cycle phase are due to the following factors.

Work performed in Fire/Explosion hazard-prone environments

DESCRIPTION

This work phase may involve the use of large quantities of ethyl alcohol. It is classified as easily inflammable (F,R11). Ethyl alcohol renders the working environment liable to fires and explosions.