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This article first appeared in May 2010 Tablets & Capsules

www.tabletscapsules.com

packaging
Assessing risk and controlling exposure to potent compounds during pharmaceutical packaging
John P. Farris

SafeBridge Consultants

Certain pharmaceutical compounds and many finished products are considered occupationally potent, meaning they pose the risk of harming workers who handle them at low levels of exposure. This article helps managers make risk-management decisions in situations where packaging operations potentially expose workers to potent compounds. It also summarizes risk factors and practical aspects to consider when selecting controls and room design.

he literature on occupational health discusses potent pharmaceutical compoundsincluding steroid hormones, opiates, antibiotics, and oncology therapiesthat have a history of causing disease in workers via inhalation and dermal exposure in the workplace [1]. Unfortunately, potent compounds dont have good warning properties: Operators cant see, feel, or smell them or sense them in any other way at hazardous levels of concentration. Thus, operators cant independently determine whether the compound or the surrounding area is safe. Whats more,

containing potent compounds is difficult: Often, a safe level of containment requires controlling particles down to nanogram levels. Even if containment is achieved, finished products comprising these compounds remain occupationally potent and exposure must be controlled throughout packaging operations. This article helps operations and safety managers make appropriate risk-management decisions for pharmaceutical packaging operations that expose workers to potent compounds.

Assessing risk
Several assessment techniques can be used to make case-by-case, risk-based decisions. For example, the Zurich hazard analysis technique and the failure modes and effects analysis technique are effective for gathering relevant information, assessing risk, and predicting the consequences of industrial hazards and failures. The techniques help managers make informed decisions regarding risk acceptance and control. This article does not provide that level of detail; instead, it provides an overview of how to assess risk and determine controls. To assess a products risk, review the products toxicity and potency data and decide on an occupational health category within a chemical-compound categorization scheme (also called control banding) [1-3]. To decide on an occupational health category, look at the health hazards associated with product exposure and select a category where appropriate controls can be determined based on experience with similar compounds. One criterion to examine is the products occupational exposure limit (OEL), which is the concentration of particles in the air to which a healthy worker may be repeatedly exposed to without suffering a health effect. OELs are generally expressed as 8-hour time-weighted averages. After scientifically valid OELs have been set and airmonitoring methods have been established, then airmonitoring surveys should be conducted to quantitatively evaluate the effectiveness of the schemes recommended generic controls. A qualified individual should gather and interpret the data, then determine the appropriateness of the existing controls and recommend additional controls, if necessary. If OELs do not exist, then meaningful surveys cannot be completed. In this situation, a qualitative risk assessment would be performed based on previous surveys, among other factors. Several of the recommendations in this article are based on surveys conducted on similar operations. Use the worksheet in Table 1 to qualitatively assess risk for pharmaceutical packaging. Drug concentration and product form. Of course, the higher the concentration of potent compounds in a product, the higher the potential risk of airborne exposure. The products physical form also influences the risk. The forms, in order from highest to lowest risk, are: Powders. Light, fluffy, electrostatic powders that have been lyophilized or spray dried can fly off weighing equipment due to the air movement in a hood or ventilated balance enclosure.

Uncoated tablets. Soft or friable uncoated tablets are likely to chip or break, releasing particles. Charging tablets into a hopper (or any other action that causes tablet impact) also releases particles. Insufficient dedusting, or skipping dedusting altogether, allows tablets to carry particles on their surfaces. Coated tablets. Coated tablets are generally less dusty than uncoated tablets; however, soft or friable ones may still release particles when they chip or break. Any action that causes tablet impact also releases particles. Liquids. Liquids that leak during filling evaporate and leave behind a powder residue that can become air borne. Filling heads can generate aerosols during processing. Semi-solids. Semi-solid formulations aerosolize little, and if they do not include volatile materials, they are primarily considered a skin-contact hazard during packaging. Semi-solid leaks can also cause the same problems as liquid leaks. Capsules. Two-piece gelatin capsules, particularly those with bands, release few particles, unless they break or capsule fillers deposit dust on them during processing. Softgels also release few aerosolized particles, unless they break. Product-transfer point emissions. Two primary producttransfer points must be evaluated to protect operators from potent products: the hopper and the filler head. Surveys performed on tablet packaging operations consistently showed that the operator who manually filled the hopper and the operator who sat in front of the filler head were most at risk of exposure to airborne particles. Therefore, risk assessment of a packaging line must look critically at the following variables: Hopper. How and how often is the hopper filled? Is the hopper emptied at the end of a shift? It is common for SOPs to require that products be removed from the hopper when the packaging line is stopped during nights or weekends or for extended maintenance. However, open and manual product transfers always release particles. To reduce emissions, use enclosed hoppers with local exhaust ventilation or perform gravity-induced hopper charging via an intermediate bulk container (IBC), vacuum, auger, or other mechanism that eliminates manual handling. Isolating the hopper via barrier or isolation controls is another, albeit elaborate, option. Filler. What type of filler is it? What is its spatial relationship to the hopper? A filler with open channels releases more particles than one with closed channels. Likewise, a filler with open vibratory chutes that feed products from the hopper to the filler head also releases particles. Frequently, the hopper is positioned directly over the filler head, potentially exposing the operator to emissions. Filler heads. Using enclosed filler heads for liquids reduces aerosol emissions in the filler operators breathing zone.

Determining controls
Several controls exist for minimizing occupational exposure on a packaging line. They include: Managing or eliminating emissions at the source, Isolating the line in a dedicated room and relying on personal protective equipment (PPE),

Isolating the line in a large room with differential pressures and barriers and using a combination of engineering controls, and Isolating the hopper loading and filling parts of the line in a small room with wall penetrations for transferring enclosed products to the other parts of the line.

TABLE 1
Pharmaceutical packaging risk assessment and room design worksheet
Product X Risk factors
Potency/toxicity occupational health category Percentage of active ingredients Physical characteristics Hopper filling and enclosure Category 4 Category 3 w/ irreversible effects Category 3 w/ irreversible effects Category 2 Category 1

Very high 5

High 4

Moderate 3

Low 2

Very low 1

Score

75-100

50-74

20-49

5-19

<5

Soft, uncoated Manual, open top Open channel/face, under hopper

Hard, uncoated Manual, closed top Open channel/face, offset from hopper

Hard, coated Manual, closed top w/ LEV* Closed channel/face under hopper

Liquid Mechanical, closed top w/ LEV Closed channel/face w/ LEV, under hopper Isolated room neutral to surrounding rooms/corridor w/out buffer zone or change rooms

Capsule IBC, charging or w/ isolator Closed channel/face w/ LEV, offset from hopper Isolated room negative to surrounding rooms/ corridor w/ buffer zone or change rooms Done in isolators or gloveboxes

Filler head and location

Room design

Large, open room w/ multiple lines

Large room w/ lines separated by barriers and differential pressures

Large room w/ hopper and filler isolated in small room w/ wall penetrations

QA/inspection/ manual refilling

Done in the open

Done in some combination of open and enclosed hoods

Done in laboratory bench hoods or bio-safety cabinets Dedicated, portable HEPA-filtered vacuum

Done in ventilated enclosures for powders

Standard equipment

Common cleaning Portable HEPA-filtered materials vacuum used commonly between lines GMP only GMP and disposable dust/mist respirator SOPs in place for cleaning w/ no dedicated parts of cleaning area

HEPA-filtered vacuum drops built into line

Dedicated, portable HEPA-filtered vacuum and built-in system

PPE

GMP and half-mask/ full-face respirator SOPs in place for cleaning, maintenance w/ dedicated parts of cleaning area

Chemical protective Chemical protective clothing and PAPR** clothing and airline respirator SOPs in place for cleaning, maintenance w/ dedicated parts of cleaning area w/ LEV SOPs in place for cleaning, maintenance w/ CIP system on critical equipment and dedicated parts of cleaning area w/ LEV Total

Cleaning and maintenance

No special SOPs

Minimum room requirements by risk assessment score


<20 Large, open room w/ no PPE beyond line 20-24 Large, open room w/ multiple lines w/ PPE for all in room 25-29 Large room w/ lines separated by barriers and differential pressures 30-34 Isolated room neutral to surrounding rooms/ corridor w/out contiguous buffer zone or change rooms 35-39 Large room w/ hopper and filler isolated in small room w/ wall penetrations 40+ Isolated room negative to surrounding rooms/ corridor w/ contiguous buffer zone or change rooms

* LEV = local exhaust ventilation ** PAPR = powered air-purifying respirator

Controls that manage or eliminate product-transfer points are the most effective. An example is an enclosed hopper charging system, such as an IBC with dust-tight valves and a closed filler head with plastic-covered product channels. The system reduces the risk to operators better than open, manual hopper charging and open channels. Room design. The room is the containment is a misconception within the pharmaceutical industry. In fact, if potent compounds are present, simply using a contained room isnt enough [4]. Operators working in the room should wear PPEtypically powered air-purifying respirators or airline respiratorsrated according to assigned protection factors (APF) set by the National Institute for Occupational Health or other internationally recognized bodies and adopted by the Occupational Safety and Health Administration and international regulatory agencies. Particle levels mandated by APF should not be exceeded; however, during open operations, such as manual filling, this may happen, exposing operators to unsafe amounts of potent compounds. If the room is dedicated to a packaging line for potent compounds, its important to protect operators by establishing proper use of PPE, administrative controls (e.g., gowning and de-gowning procedures), proper differential pressures (in which the pressure of the packaging room is lower than the surrounding rooms and corridors), buffer zones, change rooms, and showers. If the room is large and houses other lines, then additional controls should be put into place to prevent the migration of particles to other operators and lines. If packaging operations take place in a large room where full enclosure of the product-transfer points is not possible, then consider separating the line with physical barriers and establishing proper differential pressures. Another option is to build a wall around the producttransfer points that generate dust and to transfer enclosed products to the general room through penetrations. However, dont rely exclusively on barriers to achieve minimal exposure; operators, equipment, and packaging may carry particles from the room [4]. Establish the guidelines and areas described earlier to protect operators from exposure. QA, inspection, and container refilling or reworking. These tasks are common in packaging operations and must be evaluated for exposure if direct contact with the product is possible. More and more manufacturers are adapting ventilated enclosure controls to fit pharmaceutical equipment. Another option is to isolate equipment in gloveboxes. Conduct performance verification on the containment equipment to ensure operator exposure to particles is minimal. Cleaning and maintenance. Controlling exposure during non-routine tasks is essential to safety on a packaging line. Spills and powder deposits must be cleaned promptly using HEPA-filtered vacuums or wet methods. Compressed air and brooms should never be used since they stir particles into the air. Products that fall on the

floor must be vacuumed up as soon as possible to prevent operators and mechanics from stepping on them and tracking material around and out of the area. Frequently, packaging lines must be stopped for adjustments or minor maintenance. In addition to lockout and tag-out procedures, mechanics must perform preliminary cleaning and don proper PPE before entering the room or contacting parts of the line that could have contacted the product. Final cleaning must be done according to SOPs written to prevent operator or mechanic exposure. If organic solventssuch as alcoholsare used during cleaning, then PPE must provide a barrier to them as well.

Conclusion
More potent compounds are used in finished products than ever before, making it harder to consistently contain particles to a safe level. Potent compound safety is achieved on a packaging line by quantitatively assessing risk via air-monitoring surveys and by implementing controls based on the study data. In cases where risk cannot be quantitatively assessed, then rely on your experience and understanding of the factors that lead to occupational exposure. Implementing proven controls in a manner that is appropriately conservative and protects worker health will help determine potential exposures in a specific situation. But dont rely on GMPs for worker protection guidance! Very few aspects of GMPs are designed to protect operatorsits up to the manufacturers to ensure their safety. T&C

References
1. Naumann, B.D., et al., Performance-based exposure control limits for pharmaceutical active ingredients, American Industrial Hygiene Journal, 57(1):33-42, 1996. 2. Occupational health toxicity/potency categorization and handling practices, fifth revision, SafeBridge Consultants, January 2002. 3. Farris, J.P., Ader, A.W., and Ku, R.H., History, implementation and evolution of the pharmaceutical hazard categorization and control system, Chemistry Today, 24(2):5-10, 2006. 4. Ader, A.W., Farris, J.P., and Sussman, R.G., Assessing potent compound safety capabilities at CMOs, Contract Pharma, 9(9):38-46, 2007.

John P. Farris is chief executive officer, president, and certified industrial hygienist at SafeBridge Consultants, 1924 Old Middlefield Way, Mountain View, CA 94043-2503. Tel. 650 961 4820, fax 650 623 0096. E-mail: john.farris@safebridge.com.