Performing OEL Gap Analysis In A Solid Dosage Facility -- Part 1

By Nicholas Phillips, Terrence Fay and Ashok Krishnamurthy of Lockwood Greene Engineers Inc., and Donna S. Heidel of Johnson & Johnson

What is the PBOEL?
What Are Typical Levels of Containment?
What Are Engineering Controls?
What Is a "GAP" Analysis?
What Is the Mission of the "GAP" Analysis Team?
What Is the "GAP" Analysis Tool?
Who Are the Team Members?
What Takes Place During the On-Site Inspection?
What Are the Primary Areas of Exposure?
What Took Place During the First Audit of a Facility?
What Were Some of the Criteria to be Analyzed?

What is the PBOEL? (Back to Top)
Occupational Exposure Limits (OELs) refer to airborne concentrations of substances that will not result in adverse effects to most healthy workers, exposed for 8 hours per day, 40 hours per week. Most OELs are established as an 8-hour, time-weighted average; however short-term exposure limits (STELs) or ceiling concentrations may also be established for compounds that may result in adverse effects from acute exposures.

For the operations manager, the scientist, and the process engineer, achieving airborne concentrations below the OEL is essential to protect employees from occupational injury or illness. In the past, containment strategies to achieve the OEL were not included during project design or process development; therefore, employee protection from exposure often required reliance on personal protective equipment when the containment offered by the process controls were inadequate. In addition, uncontained processes have resulted in facility contamination outside of the processing area. The performance-based occupational exposure limit (PBOEL) approach provides managers, scientists, and engineers with specific guidance to reach the desired level of containment or control.

A second use of the performance-based occupational exposure limit approach is to provide containment strategies for compounds that are highly potent, carcinogenic or allergenic. Often, numerical OELs cannot be established reliably for these compounds; however, containment strategies, based on our experience handling similar compounds, can be specified.

Finally, performance based occupational exposure limits will offer guidance to research and development scientists in controlling their exposure to compounds for which little or no toxicological information is available, and, therefore, no numerical OEL has been established (reference 1).

What Are Typical Levels of Containment? (Back to Top)
Containment Categories are determined internally and are company and product specific. OSHA does not develop these categories for the pharmaceutical manufacturer. Companies we have worked with have had three, four or up to five categories. These categories should be based on two criteria the potency of a compounds being handled and the capabilities of the technologies available.

Typical Containment Categories are as follows:

• Category I >100 µg/m³
  At this level following normal cGMP is usually enough protection for an operator. This should include hair and shoe covers and the requirement to change into a uniform which is laundered when in the manufacturing operations.
  
• Category II <100 µg/m³ - >20 µg/m³
  This is the first category that requires the use of special equipment to create an additional separation between the operator and the materials being handled. At the category II level, containment can usually be accomplished using laminar flow booths.
  
• Category III <20 µg/m³ - >5 #181;g/m³
  At this point we have reached the lower level of the capabilities of laminar flow technology and another level of control must be used to separate the operator from the material being handled. The use of split butterfly valves (SBV) is usually used to meet these requirements.
  
• Category IV <5 µg/m³
  Below the 5 µg level we have reached the guaranteed limits of SBVs and we must now look to Isolation Technology which is used for the preparation of sterile products to meet this containment requirement. This includes the use of glove boxes with Rapid Transfer Ports (RTP).

What Are Engineering Controls? (Back to Top)
Any operation which requires an operator to use a protective device such as a respirator or a full bunny suit should be a signal that Engineering Controls are necessary. Most globally recognized regulatory and advisory authorities have established engineering controls as the preferred method of controlling occupational exposure. For example, in the United Kingdom, the Substances Hazardous to Health regulations enacted in 1988 require that "so far as reasonably practicable, the prevention or adequate control of exposure of employees to a substance hazardous to health shall be secured by measures other than the provision of personal protective equipment." OSHA states "Consistent with OSHA regulations and policy, engineering controls and work practices are preferred over personal protective equipment to control employee exposures to airborne contaminants." (see reference 2). These indicate that it is the requirement of the manufacturer to install devices, which will allow an operator to basically work in a shirtsleeve environment. There is a basic caveat here in that it is understood, that there needs to be an economic feasibility included in any justification.

What Is a "GAP" Analysis? (Back to Top)
With the dramatic increase in high potency compounds being developed by the pharmaceutical industry, operator exposure has to be constantly reviewed both in the R&D laboratories and the manufacturing environments. Lockwood Greene Engineers (LGE) developed the "GAP" analysis program, at the request of the Johnson & Johnson Corporate Health & Safety Department. LGE and Donna Heidel, J&J Corporate Staff Industrial Hygienist, teamed up to assess both the manufacturing and laboratory environments with specific regard to issue of containment. The primary objective was to determine the "GAP," that is, what engineering controls would be necessary to bring the current operating systems up to a level which would eliminate Personal Protective Equipment (PPE). The "GAP" analysis includes a description of deficiencies and the resulting recommended solutions.

What Is the Mission of the "GAP" Analysis Team? (Back to Top)
The primary mission of the Team is to determine through visual inspection and documentation review how well each pharmaceutical operating facility meets the Internal Guidelines for Performance Based Occupational Exposure Limits (PBOEL).

Under the direction of Heidel, Johnson & Johnson began a program to create a Global Standard for the containment and control of toxic compounds in pharmaceutical manufacturing areas. Focus of the program was the creation and meeting of Performance Based Occupational Exposure Limits (PBOEL)

LG was requested to create a team capable of assessing how well existing facilities meet the criteria set forth in the Global Guide and suggest corrective actions to be instituted if necessary. The project was designed to incorporate two phases:

Phase I:

• Develop a "GAP" Analysis Tool to be the basis for documentation.
  
• Visit each of the facilities to complete an On Site Inspection and Documentation Review.
  
• Generate a Summary Report and Cost Estimate to meet the Engineering Controls requirements.

Phase II:

• Develop a Strategic Plan to institute the changes suggested.

What Is the "GAP" Analysis Tool? (Back to Top)
To assure that each of the sites visited were viewed with a uniform standard for an objective assessment a Tool was developed, which would assist the inspectors in their assessments. This tool is a product focused, matrix-based questionnaire in decision tree format. The Excel spreadsheet was specifically developed for analyzing pharmaceutical operations. It is comprised of a series of questions designed to give yes or no responses and go to statements, which direct the inspector to the next appropriate question. Examples of the question include:

• Is there an airlock?
  
• Are the airlock doors interlocked?
  
• Is there positive pressure to the main corridor?

The tool is designed to be focused on each Category Level so that inspections can be accomplished based on the worst case scenarios. A process train may be used to manufacture Category 3 and Category 2 compounds, therefore the area would only be inspected for the manufacture of the Category 3 materials, since it is implied that if the system meets Category 3 requirements it will also meet Category 2.

Who Are the Team Members? (Back to Top)
The teams have been made up of experts in three focused areas. The first is for the laboratory areas, operator work practices, and the industrial hygiene and the health surveillance programs. This person will inspect to see if the necessary equipment and procedures are in place to insure a safe working environment during the handling of potent compounds whether they are being used in an R&D or QA/QC laboratory. The second team member focuses on the manufacturing areas; this includes warehousing, central weigh, processing areas, packaging, and finished goods storage. Finally the last member of the team is responsible for facility related issues, these include the HVAC, the dust collection, the water systems including waste disposal and any other support utilities that may be effected by potent compounds.

Teams should be comprised of:

• Corporate Representative
  
• Local Representatives
  
• LG Representatives

Team Members:

• Industrial Hygienist
  
• Validation Engineer
  
• Process or Manufacturing Technology Engineer
  
• Mechanical Engineer / Piping and HVAC

What Takes Place During the On-Site Inspection? (Back to Top)
Before to making an on-site inspection the facility is notified, so that certain documents can be collected to be reviewed by the team. The site selects personnel to be part of the inspection team and to act as liaisons between the corporate team and the on site management personnel. Focus for the team is not to complete an "audit" of the facility but to work in concert with the plant staff to clearly understand the operations and needs of the operation.

This is key to performing the assessment since this is an excellent opportunity for the operations groups to be heard concerning the needs they have identified internally. A kickoff meeting starts the program and the team members break down into sub groups to focus on particular areas.

Pre-work for the Laboratory Practices, Work Practices, and Industrial Hygiene/Work Practices Group includes a list of APIs and their respective OELs (including short-term limits, if appropriate), the potential routes of occupational exposure for each API, the ratio of active to inert ingredients in each formulation, the industrial hygiene sampling data for each step of the process(es), the incidence of occupational illness due to exposure to each API, and appropriate operating procedures to evaluate employee work practices.

For the Facility Group documentation is a key requirement since many of the systems cannot be visually inspected. Also, maintenance of these systems is another key aspect of there successful operation. The Laboratory Team relies on visual inspection of the laboratory facilities and a review of the Standard Laboratory procedures. Finally the Process Team needs to see documentation which delineates the product manufacture procedures. This information can be ascertained from Process Flow Diagrams or Batch Records. The team will then follow materials through the entire operation from raw material storage through the process and packaging areas to finished goods.

What Are the Primary Areas of Exposure? (Back to Top)
In order for the team to complete a thorough inspection they must have a clear understanding of which areas tend to result in the most risk for personnel. We must remember that manufacturing operators directly handling the product are not the only ones who are at risk of exposure:

• Laboratories—R&D, QA/QC
  
• Warehousing—Raw Material & Finished Goods
  
• Sampling
  
• Pharmacy, Dispensary, Central Weigh
  
• Processing—Any areas of material transfer, blending, granulation, mixing, compression and encapsulation suites, tablet coating, printing and inspection
  
• Cleaning—Bin Cleaning, Equipment Cleaning, Tool Rooms, CIP Systems
  
• Packaging—Blister and Bottle Filling
  
• Mechanical Support Spaces—HVAC systems, Dust Collection, Waste Water Processing
  
• Employee work practices

What Took Place During the First Audit of a Facility? (Back to Top)
During the first phase of the project, the first inspection was used as a prototype to test the tool and adjust it if necessary, train the core team of analysts, and create a baseline of data for the remaining inspections. Modifications to the tool were based on improving ease of use, applicability to existing conditions, and generating effective data.

What Were Some of the Criteria to be Analyzed? (Back to Top)
There are a number of key elements which were investigated during the assessments, the following represents a list of criteria.

• Product Characteristics—the focus of our surveys was toward airborne contaminants. In the case of powder handling of particular importance is whether the material is easily aerosolized and how will the material flows.
  
• Product Sampling—an area usually overlooked is the sampling room where containers of active are opened to draw samples for identification and micro testing.
  
• Product Containerization/Container Selection—the means for transfer of raw materials and blended batches can readily determine the ease with which particulate can become airborne. The pharmaceutical industry is moving in the direction of Intermediate Bulk Containers (IBC), which allow transfer o ingredients through a close coupled valve. The areas where there is still concern are those operations which require small additions such as in the central weigh where actives are received in plastic bags which are usually shaken to remove the last of the powders.
  
• Product Charging/Discharging—"makes and breaks" for material transfer is a primary area for operator exposure. Elimination by automation or reduction of exposure through the use of high containment transfer couplings are elements that should be examined. Product charging can occur in the central weigh area, transfers to main processing equipment such as blenders, dryers, and granulators and transfers to final form equipment such as encapsulation and compression machines. Discharge occurs from main processing equipment such as granulators, dryers, and mixers.
  
• Ergonomics—if a piece of equipment is designed in such a way as to make its use more difficult for an operator they will tend to figure out a way to defeat the system.
  
• Equipment Cleaning/Clean In Place (CIP)—this can be done on line or off line, CIP is generally a preferable means of eliminating operator exposure but care must be taken in its design to insure that maintenance personnel are not unknowingly exposed.
  
• HVAC, Dust Collection, and Support Utilities—this area is usually over looked in both design and retrofit of facilities. Maintenance personnel risk exposure during removal of HVAC filters, dust collection bags, and ductwork repair.
  
• Results of industrial hygiene personal sampling surveys and incidence of occupational illness. Results of area sampling surveys, including measurements made in hallways and gown-down facilities, to evaluate dust migration from processing areas.
  
• Employee work practices through a review of standard operating procedures and actual observation of work activities transferring and solubilizing of APIs, LOD, friability, hardness, weight and thickness testing, sieve analysis, and HPLC autosamplers.

End of Part 1

This paper was first presented at Interphex in New York City on April 20, 1999.

For more information: Nicholas Phillips, Senior Consultant, Manufacturing Technology, Lockwood Greene Engineers, Inc., The Tower, 270 Davidson Ave., Somerset, NJ 08873-4140. Tel: 732-560-5700. Fax: 732-560-2300.