Risk assessment approach to potent compound control

by John P. Farris, CIH

An overview of risk issues and options to consider when determining room locations and controls in packaging pharmaceutical products

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Operations and safety managers are constantly looking for better ways to make appropriate risk-management decisions for finished pharmaceutical packaging operations involving potent compounds.

These managers can choose from several assessment techniques that can be employed in driving case-by-case risk-based decisions. For example, the Zurich methodology of risk assessment and management is effective at gathering relevant information and assigning probability and consequences to industrial hazards from which informed business decisions are made regarding risk acceptance.

This article will not provide that level of detail; however, the following overview of the risk issues will offer practical options for consideration when determining room locations and controls in packaging pharmaceutical products.

Assessing the risks
The first step is to review all available toxicity and potency data on the product and determine a compound categorization within a chemical compound categorization scheme. If a scientifically defensible occupational exposure limit (OEL) has been set and a method for performing air monitoring has been established, then recommended generic controls from the categorization scheme should be quantitatively evaluated for effectiveness through air monitoring. Once air-monitoring data has been gathered and interpreted by a qualified individual, then the appropriateness of existing exposure controls can be determined and further controls can be recommended, if necessary.

If no OEL exists, then a meaningful air-monitoring survey cannot be completed. In this situation, a qualitative risk assessment should be performed based on many factors including experience from previous valid air-monitoring studies. Several of the recommendations made in this article are based on air monitoring done on similar operations.

Physical form and concentration
The physical form of the product and the percentage of active ingredients in the finished dosage form are critical to the degree of airborne exposure potential. The higher the concentration of active ingredients in the formulation, the greater potential risk. Each physical form has variability based on other factors. In order of highest to lowest risk, with their influencing factors, finished pharmaceutical forms include:

Powders: The most difficult powders to control are light, fluffy electrostatic powders that have been lyophilized or spray dried.

Tablets (uncoated): Tablet hardness and friability will influence airborne emission potentials, as softer and more friable tablets will be subject to tablet breakage or chipping with the resultant release of micro-particles. The process of tablet charging into a packaging line hopper and any other steps that cause the tablets to impact each other will generate additional micro-particles. Tablet de-dusting is another critical factor. If de-dusting has not been done, as in the case of some animal products, tablets will carry more micro-particles on the surfaces and more potential for airborne emissions will exist. If de-dusting is less efficient due to equipment limitations from one process to another, the lower efficiency will lead to higher airborne emissions in packaging.

Coated tablets: Coated tablets are generally less dusty than uncoated tablets, but not dramatically. The same factors apply for coated and uncoated tablets, including hardness, friability, tablet impact and de-dusting.

Liquids: By their nature, liquids must be filled in a closed transfer system; however, leaks can and do occur and must be cleaned up promptly to avoid evaporation and resultant solid powder residue that can become airborne. The filling process can aerosolize liquids where micro-aerosols are generated from the filling heads of the line.

Semi-solids: Semi-solids present little potential for aerosolization and are primarily a skin contact hazard in packaging if volatile materials are not used in the formulation. Semi-solid spills and leaks also should be cleaned promptly.

Capsules: Hard gelatin capsules, particularly banded capsules, present low potential for airborne micro-particle emissions unless the capsules break or unless process upsets in capsule filling deposit dust on the outside of capsule. Soft gelatin capsules are filled only with specialized equipment and present little risk in packaging unless broken.

Consider the variables
Two primary process points must be evaluated on a packaging line; the hopper and the packaging filler head. Air-monitoring surveys performed on tablet packaging operations consistently show that the highest exposure potentials exist for the operator or mechanic that fills the hopper in a manual transfer operation and the operator that sits in front of the filler head.

A risk assessment should look critically at the following variables that affect packaging line airborne emissions.

How and how often the hopper is filled ? Must the hopper must be emptied at the end of a shift? SOPs commonly require that tablets not be left in the hopper when the line is down over night, on weekends or during extended maintenance activities. Open and manual transfers of tablets always result in airborne particle emissions. If hopper charging can be done by vacuum, gravity (through the use of an intermediate bulk container), auger or other mechanical device that eliminates manual handling, then airborne particle emissions will be less. Enclosed hoppers fitted with local exhaust ventilation also will reduce the potential for emissions. Isolating the hopper through barrier controls is another option.

The type of filler and its spatial relationship to the hopper. Open filler channels that must be viewed by the operator have a greater potential to generate airborne particles as the tablets move down the channel than filler channels that are covered. Frequently the hopper is directly over the filler head and the filler operator also is exposed to emissions from the hopper filling operation unless it is well controlled.

Enclosures around the fill head. Enclosures around a liquid fill head will reduce the potential for micro-aerosols to be emitted into the filler operator's breathing zone.

The general room conditions. If the packaging room is dedicated to the potent compound packaging line, proper air pressure relationships, buffer zones, change rooms, showers, administrative controls such as gowning/degowning procedures and proper use of personal protective equipment (PPE) may prevent exposures to operators in surrounding areas. If the packaging operation is contemplated for a large room with other lines, then further controls on emission points may be required to prevent migration of micro-particles to other operators and other product lines.

QA, inspection and refilling
Other tasks that are common to packaging operations include quality assurance and inspection activities and, occasionally, container refilling. These tasks should be reviewed for exposure controls when direct contact with the product is possible.

Several options exist for controlling occupational exposures on a potent finished pharmaceutical packaging line. Four basic approaches, as well as variations of this list, exist for exposure controls on a packaging line. These include:

  • Controlling or eliminating emissions at the source
  • Isolating the line in a dedicated room and relying on PPE
  • Using a combination of engineering controls and PPE and isolating the line in a large room with air pressure relationships and barriers
  • Isolating the hopper loading and filling parts of the line in a small room with wall penetrations for a conveying system to the other parts of the line where the product is enclosed.

The most effective controls are those that control or eliminate the process emission points previously mentioned. An effective method of control is an enclosed hopper charging system, as in the case of an intermediate bulk container (IBC) with dust-tight valves and an enclosed fill head such as one where the tablet channels are behind a Plexiglas cover. This approach presents little risk to operators during routine operations. Packaging lines with open manual charging of the tablet hopper and open-faced tablet channels on the filler present the greatest risk to operators on the line, as well as the general room.

If potent compound packaging must take place in a large room and full enclosure of emissions points is not possible, then segregation of the line with barriers, such as freezer curtain, and establishment of proper air-pressure relationships should be considered.

Maintenance operations
Controlling exposure during non-routine tasks is essential to potent compound safety on a packaging line. Spills and surface powders must be cleaned up promptly using good techniques such as HEPA-rated vacuums and wet cleaning methods. Compressed air and brooms should never be used on a potent compound packaging line. Tablets that hit the floor should be vacuumed up as soon as possible to prevent stepping on tablets, releasing particles into the air and tracking material around and out of the area.

Often, packaging-line operations must be suspended for adjustments or minor maintenance. In addition to lockout and tag-out procedures, mechanics must take appropriate precautions through preliminary cleaning, donning proper PPE before entering parts of the machinery that may have been in contact with the product.

Use the tools available
Potent compound safety can be achieved on a packaging line by quantitatively assessing the risks through valid air monitoring and surface monitoring studies and implementing controls based on the study data. If tools to do a quantitative risk assessment don't exist, a qualitative risk assessment based on experience and understanding the factors that lead to occupational exposure can provide guidance in making business judgements.

Questions about potential exposures in a given situation can be resolved by implementing proven exposure controls in a manner that is appropriately conservative and protective of worker health.

John Farris is the leader of SafeBridge Consultants, a professional technical firm of scientific and engineering consultants providing environmental health and safety services.


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