Performing OEL Gap Analysis In A Solid Dosage Facility - Part 2

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

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. This two-part paper defines the issues, analytical techniques, and engineering methods for achieving essentially "shirtsleeve" working conditions at a solid dosage facility.

How Were Existing Conditions Documented?
How Is the Remediation Strategy Developed?
What Are Some of the Common Process Area Problems?
Common Problem Areas (Facility)
Non-Manufacturing Areas
References

How Were Existing Conditions Documented? (Back to Top)
The first draft reports were a breakdown of conditions by site with a compilation by region. This information was supplied initially to the plant team members for comment and editing, prior to any generally distribution. Data was analyzed as it impacted each of the elements of the guidelines as outlined by J&J. The documents included:

• An outline of existing conditions indicating deficiencies.
  
• Recommended changes to correct the deficiencies.
  
• A cost estimate to apply engineering controls, to meet compliance guidelines. This cost estimate was for a worst case scenario, and did not take into account and "Strategic Changes" in the operations.

After these reports were reviewed by the plant personnel and a compilation by region was created with an executive summary. This report was submitted to the corporate level and the process of developing a strategy for implementation was begun.

How Is the Remediation Strategy Developed? (Back to Top)
Phase II of the program takes into account outside economic influences such as: product profitability and life cycle, is it a new product or are sales in decline, is this the only facility capable of producing the product or are there other plants with the same capability. Primary focus of this program is capital expenditures therefore, the first item to ascertain is to distinguish process containment from facility issues, since facility reconstruction will normally incur a higher potential cost. Another area to determine is the weighting by potential exposure, the more potent compounds will normally require a higher outlay of funding to bring them into compliance with the guidelines.

If we look at the strategic plan based on a regional rather than on a local plant basis; serious compliance issues will take a higher overall priority and interplant product relocation may be a viable solution

What Are Some of the Common Process Area Problems? (Back to Top)
Over the course of many years Lockwood Greene Engineers have visited a great many pharmaceutical manufacturing facilities. The following represents some of the issues, which we have encountered:

• Employee Gowning/De-Gowning Facilities. The areas for employee gowning/de-gowning vary from fair to poor with respect to containment. In existing facilities the focus for gowning and de-gowning has primarily been for GMP issues, therefore little thought to removal of contaminated garments or cleaning and storage of Powered Air-Purifying Respirators (PAPR), has been given. Also personnel flow through common corridors has not been taken in to account. An additional point should be made here, if proper engineering controls are put in place, gowning and de-gowning suites should not be necessary, except for Category 3 and 4 compounds with acute effects.
  
• Receiving and Storage of Raw Materials and Interim Materials. The storage of active raw materials and interim's on upper shelves increasing the hazard of container breakage. The receipt and/or storage of active ingredients with poor containers increases the risk of spillage. The storage of actives and interim's in uncontrolled areas or with inadequate separation from manufacturing areas can allow contamination of the unprotected areas.

• Sampling Areas. In our assessments, this is one of the most overlooked operations. Sampling can take place in a corner of the warehouse, a small improperly ventilated ante room, or in a portable laminar flow hood with side curtains. These may be sufficient for some excipients but not for potent compounds. During sampling the operator is exposed to the potent compound in an undiluted state, therefore properly designed laminar flow sampling booths or fully enclosed glove boxes should be used.

• Weighing Areas. Probably the area of most exposure to potent actives comes during weighing, since ingredients are usually being manually scooped our dumped into other containers. Most operations rely on inadequately designed elephant trunks with capture ducts for point of use dust collection. This may be adequate for excipients but not potent compounds. Many dispensaries are rooms with walls separating the weighing areas into stalls and the reliance upon the dust collection system to avoid cross contamination. This setup requires the use of properly designed laminar flow booths, for potent compounds below 20 µg/m³ glove boxes should be considered.

• Movement and Cleaning of Equipment. Walk through most pharmaceutical operations, even parentaral facilities and you will find equipment such as: mills, tanks, pumps, and change parts in the corridors waiting to be transferred to a cleaning area. The obvious solution to this problem is to install a clean in place system, where this is not feasible, the units should be bagged or covered in plastic during transfer.

  The cleaning areas seldom take into account operator exposure, no separate gowning areas are supplied and operators are not seen wearing respirators. Compression machines, which require a high level of maintenance, should be disassembled in an area accessed through gowning de-gowning airlocks. Maintenance personnel should be protected with respirators and Tyvek jumpsuits.

• Liquids, Cream and Lotions Manufacture. Most liquid additions to mixing vessels can be done through piping and valves, these are not the usually the primary contamination culprits. It is the addition of dry powders through charge ports and manways that creates a hazardous condition. First the operator can be exposed to vapors when the vessel is opened, second operators are seen manually dumping bags or containers of active ingredients into the tanks, protected only by respirators.

  Poor cleaning procedures can also create problems, with operators manually cleaning the inside of vessels. Liquid processes should always make use CIP systems for cleaning

• Powder Blending, Grinding Sieving and Tray Drying Areas. These areas are all situations in which the equipment was chosen primarily for its function rather than with containment in mind. We see many operations using the best technology for the time the product was developed, but do which do not meet today's containment requirements. Open sieves and mills, v-blenders, and tray dryers create environments requiring operator gowning. Under SUPAC much of this equipment can be replaced with closed mills and sieves, bin blenders, and cone dryers which can all be CIP.

  Any operation requiring personnel to gown up and wear a respirator also creates a situation, which requires additional space for airlocks and PPE cleaning.

• Tableting and Encapsulating. Tablet presses and encapsulation machines don't contain dust well. Difficulty stems from poor sealing between the upper portion where the products are formed and the lower portion where the mechanical equipment is located. Also, a great deal of operator intervention is required to maintain punches and make adjustments. Cleaning of the machine for changeover requires a great deal of manual disassembly. The process is inherently dusty requiring de-dusting equipment with poor dust control.

  As mentioned earlier any operation requiring personnel to gown up and wear a respirator also creates a situation, which requires additional space for airlocks and PPE cleaning.

  Additional areas which were observed include open weighing, tablet testing and waste disposal, system charging using dust socks, and open discharge of tablets.

• Tablet Coating. Although coaters are charged with compressed tablet cores dust is still generated. We seldom see precautions taken in this area with regard to airborne contaminants. Open charging and discharging of the coater can be eliminated using tablet bins with discharge chutes.

  Coaters though available with CIP systems are seldom seen with this feature requiring operators to manually clean the internal surfaces.

• Packaging Areas. Although tablets and capsules are relatively dust free when they are brought into the packaging halls some dust can still be generated by wear of uncoated tablets and tablet and capsule breakage. Most dusting occurs at the tablet filler where we have found insufficient pickup around bottle fillers and blister machines. Also inadequate containment between the filler and foiler and around the sealer on blister machines.

  Most operations are set up with the bottle fillers and cappers and blister machines in the same room as operators hand packing finished goods on line. Not only does this present an exposure hazard, it is also not good GMP since exposed product can be contaminated with packaging particulate.

• Work Practices. Some additional issues that have been noted during assessments:
  • Contaminated batch records circulated throughout administrative areas.
    
  • Processing room doors left open.
    
  • Airlocks not interlocked.
    
  • Use of compressed air to clean equipment.
    
  • Dry sweeping.
    
  • Manual transfers of APIs.
    
  • Inadequate spill procedures.
    
  • APIs and formulation spills not immediately cleaned up.
    
  • Wearing work uniforms out of processing areas.
    
  • Contaminated tools and equipment moved out of processing rooms.

• General Areas and Equipment. Some additional observations include:
  • Shop vacs with no clean-out and filter change procedures.
    
  • Corridors with shared access and no interlocking doors in airlocks.
    
  • Spill containment procedures—spills left with no operator in attendance.
    
  • Operators gowning and de-gowning in process room or corridor.
    
  • No misting or air showers for operators to exit process areas.
    
  • PAPR's not stored in reasonable areas.
    
  • Inadequate choices of protective garments and equipment.
    
  • Acoustical hung tiled ceilings in process areas where wash down is necessary.

Common Problem Areas (Facility) (Back to Top)

• Documentation. During our inspections of facilities and in the course of doing validations of new and existing operations we have found the following items to be lacking with regard to documentation.
  • No basis of design on any of the systems reviewed.
    
  • Incomplete current as-builts for facility and systems.
    
  • Lack of 'sequence of operations.'
    
  • Lack of or inadequate air flow direction drawings.
    
  • Incomplete or lack of testing, adjusting, and balancing data.
    
  • Validation data incomplete.
    
  • Lack of certification of HEPA's in some assessments.
    
  • Inadequate SOP's for proper filter handling, disposal, and shutdown of critical equipment.

• Utility Equipment and Support Areas. During our inspections of support operations and non cGMP manufacturing areas which include mechanical space for systems such as Clean In Place mixing and holding tanks, USP water systems, dust collectors, and HVAC systems we have encountered some of the following deficiencies:
  • Deficient air flows with outdoor air observed in manufacturing areas and less than 20 AC/HR.
    
  • Commercial grade air handling units and accessories, in pharmaceutical areas.
    
  • HVAC systems which have extensive corrosion damage for units located outdoors (includes housings and air handling units).
    
  • Many registers were observed to have corroded and dust settlement.
    
  • Different systems serving the same area. System isolation is absent.
    
  • Absence of critical interlocks for system equipment.
    
  • Dust collectors are not up to current pharmaceutical requirements. Cannot contain explosion. Some systems do not have HEPA on discharge.
    
  • No bag in/bag out systems for HVAC filters or dust collector discharge.
    
  • Absence of HEPA's in key processing areas (supply and return/exhausts), compression blending and granulation
    
  • Improper dust collection system distribution. Ducts terminate just below the ceiling not at the source. Dust settlement noted on floors, walls, flexducts and ceilings.
    
  • Duct cleaning—totally absent for systems that have been in operation for many years.

Non-Manufacturing Areas (Back to Top)

• Laboratory Practices. During walk-throughs of laboratory areas the following were some of the problems noted:
  • Incompatible chemical storage.
    
  • Visibly contaminated workbenches.
    
  • No vented balance safety enclosures for weighing small quantities of APIs.
    
  • When present, vented balance safety enclosures located near standard room diffusers or doorways.
    
  • When present, vented balance safety enclosures not equipped with HEPA filters.
    
  • Use of respirators for bench work.
    
  • Auxiliary air fume hoods and no face velocity monitors.
    
  • Grinding, sieve testing, LOD, hardness testing routinely conducted on benches.

• Industrial Hygiene/Health Surveillance. While reviewing documentation and procedures the following items were evident:
  • No or inadequate qualitative risk assessments.
    
  • No routine industrial hygiene sampling surveys.
    
  • Inconsistent or inappropriate respirator use.
    
  • Inadequate PPE doffing procedures.
    
  • Respirators removed after implementation of engineering controls without sampling verification.
    
  • No programs to evaluate for drug interactions.

References (Back to Top)

1. Johnson & Johnson Guidelines for Controlling Occupational Exposure to Pharmaceutically Active Compounds
   
2. OSHA – Air Contaminants Section 7 – VII Feasibility and Regulatory Analyses

End of Part 2. To read Part 1, click here.

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.