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«PDHonline Course K112 (4 PDH) Fundamentals of Aseptic Pharmaceutical Engineering Instructor: Timothy D. Blackburn, MBA, PE PDH Online | PDH Center ...»

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The Fill Environment and Operational Requirements As discussed previously, the manufacturing operation classification depends on whether the product will be sterilized prior to fill, or must be maintained in an Aseptic environment (to be avoided if possible.) The focus on this section of the course will be to understand the fill environment and associated operations specifically. The common approach to ensure the environment remains appropriate is to “cascade” cleanrooms from cleanest to unclassified. For example, in the fill room the environment in the immediate vicinity of the exposed product must be class 100. Air must be unidirectional (verified by smoke tests) to ensure air is not being pulled from the lower grade background environment. This background environment consists of the remainder parts of the room in which the Class 100 area resides. Usually, the entire room is not class 100, but has a class 10,000 environment away from the vicinity of the exposed product.

People and product/component flow is crucial. Workers and materials enter the fill suite through distinct airlocks. Employee entry gowning areas cascade up to the environment of the fill suite and the final “gowning” entry airlock should match the classification of the entering room (for example, the final airlock is class 10,000). The employees go through more restrictive gowning layers until the airlock just prior to the fill suite, where they also add sterile garments. A typical gowning exercise could be as follows. Workers initially prepare by changing into dedicated shoes and non-sterile garments, apply head cover, wash hands/sanitize, and put on 1st sterile gloves. Then, they move into the higher class gowning room and apply sterile attire, starting at the top and working down, consisting of a sterilized hood, body garment, facemasks, goggles, and final sterile gloves.

Materials and product entering the fill suite must be sterilized prior to entering. Generally, particulate is reduced by filtration; sterilization and autoclaving reduce microbes; elevated temperatures or chemicals remove endotoxins. A Sterility Assurance Level (SAL) of 10-6 or better can be achieved with heat sterilization. (SAL is the probability of sterility. 10-6 means that there is a probability of one in one million that a single viable microorganism will be present after sterilization. Another way of saying this is that there is a 6-log reduction. A 1-log reduction means to decrease by a factor of 10 the micro population.) Vials are washed (the final rinse with WFI), and then depyrogenized (destroy or remove pyrogens) via dry heat. Heat is the preferred method of sterilization. Rubber materials are also washed, and sterilized with moist heat. Plastic Page 8of 15 www.PDHcenter.com PDH Course K112 www.PDHonline.org containers can be sterilized with gas (such as Ethylene Oxide, or EtO), which should be the last resort, or irradiation (ultraviolet irradiation is not normally acceptable). Once sterilized, care must be taken that the components remain in a sterile state, and introduction into the Aseptic area does not promote contamination. Items should be introduced unidirectionally (such as a double door autoclave, oven, etc.).

Air pressure in the various rooms is important to prevent airborne migration of contamination. The Cleanrooms have positive pressures in relation to lower rated areas and into airlocks, typically 0.04” to 0.06” water gauge (10-15 Pascals). This is to keep objectionable particulate from migrating into the space.

Barrier Isolators are also a good application in some cases in lieu of open Class 100 areas.

Barrier Isolators totally contain the product in a protective state consistent with Class 100 requirements. It should be obvious by now that the goal is to protect the product from contamination (Level I Isolators provide this protection). But what about protection from workers when the product is potent/toxic? Not only must the product be protected in this case, but the worker must be protected when there are hazards of cancer, mutation, or developmental/reproductive problems resulting from product exposure. Barrier isolators(Level II) are especially helpful in this application, and avoid the use of pressurized suits. Barrier isolators also can simplify/minimize the requirement for cleanrooms, which avoids first-cost as well as the complexity and expense of operating and working in more restrictive cleanroom environments.

Background environment requirement are relaxed. In addition, Barrier Isolators can address an OSHA preference to rely less on PPE (Personal Protective Equipment). However, there are many challenges with this technology, both to initially design and install, as well as on-going operations. Some of the challenges that you need to consider when designing and developing

operational requirements for Barrier Isolators are as follows:

1. Issues associated with transfer methods

2. Leak integrity design and testing

3. Maintain Aseptic (Class 100) environment

4. Cleaning and sterilizing (Hydrogen Peroxide Vapor or Chlorine gas are common methods, but the workers must be protected.)

5. Run speeds are often lower in Barrier Isolators, such as 100 vials/minute or lower.

6. How to handle potent products while simultaneously protecting the product Page 9of 15 www.PDHcenter.com PDH Course K112 www.PDHonline.org

7. High first-costs

8. Ergonomic problems/access

9. Difficulty of maintenance access Another method of having better control in the Aseptic environment is to provide a Restricted Access Barrier System (RABS). This simply separates the operator from the Aseptic environment to minimize the risk of introducing operator contamination. However, this is not a self-contained barrier isolation system, and Aseptic conditions must be maintained by other means.

Practical Design Considerations This section will focus on some practical design considerations for various elements of the facility. Obviously, these are not all-inclusive, but represent many of the typical considerations.

First, lets look at the essential utility, HVAC. It is essential that HVAC systems be designed to produce the required air quality, as well as “flush out” particulate from the space.

Rooms need to recover, including after fumigation. The cleanroom designations are usually in a dynamic mode (i.e. people there and production underway). The air is filtered via HEPA (High Efficiency Particulate Air) filters, which filter out particles down to the 0.3 micron size at 99.97% or better efficiency. The better the cleanroom rating, the higher the air change rate, or ACPH (Air Changes Per Hour). Cleanrooms typically start at about 20 ACPH for class 100,000, for example.

Careful attention should be given during design to enable pressures to be maintained, and effective air currents (remember unidirectional for class 100 zones.) Terminal HEPA filters are necessary for higher-level cleanrooms, although remote filters have been effective for class 100,000. Remember to consider the dewpoint to avoid condensation on the vials. Also remember to design to significantly cooler ambient conditions at the fill area since the workers will have layers of gowning. The monitoring system must be Validated, and report/record/trend critical parameters such as Humidity, Temperature, and Differential Pressure.

Architectural considerations are also essential. A few Architectural considerations may

include the following (see Figure 4 for an example of an Aseptic Fill/Finish concept layout):

1. With any project, the process drives the layout. Be sure you fully understand the process, material, and people flow. These should flow in a logical order. Consider flow of components as well as the completed product.

Page 10of 15 www.PDHcenter.com PDH Course K112 www.PDHonline.org

2. Design the layout to ensure there will not be mix-ups in product, components, or raw materials.

3. Aseptic area finishes should be nonshedding, nonabsorptive, cleanable, and nonreactive to sterilizing agents. Finishes should be smooth with coved corners at floors, walls, and ceilings. The room must be periodically sterilized, and specified finishes must be robust against sterilant attack. Room sterilization is accomplished using liquid sterilants or other agents. Fumigation may be useful, especially in hard-to-reach places.

4. Ledges/horizontal surfaces should be minimized, and surface mounted items should be avoided.

5. Keep layouts simple with minimal equipment in Aseptic areas especially.

6. Except where building codes preclude, swing doors in the direction of the pressure flow otherwise, you will have a hard time keeping them closed.

7. Do not have sinks and drains in the Aseptic areas (avoid sinks or drains in classifications more stringent than Class 100,000).

8. If robotics are used, you may be required to construct super-flat floors.

9. Remember to keep material and personnel access separate to Aseptic areas, as well as have separate gowning and degowning areas (preferred).

10. As much as possible, locate utility support outside rooms. Enable replacement of lights, etc., outside Aseptic areas. Consider walkable ceilings to aid in accessing items above the Aseptic area.

11. Make certain the space is well lit. Place switches outside Aseptic areas.

12. Consider telecommunications equipment to avoid requiring personnel from moving in and out of fill rooms excessively. Video monitoring is also helpful.

13. Investigate whether the facility should be dedicated/self-contained. This is required for some sensitizing materials, possibly in the case of certain antibiotics, hormones, cytotoxics, or highly active drugs. Facilities that handle Bacillus anthracis, Clostridium botulinum, and Clostridium should be dedicated until the organisms are inactivated.

14. Plan for staging outside the Aseptic area. Cardboard, wood, and other materials that could shed fibers should not be introduced to open product areas.

15. Airlocks need to have their doors interlocked to prevent both doors from being opened concurrently. Remember to include override in the event of an emergency.

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Critical utilities (those essential to preserving Aseptic conditions) may include the following:

1. Clean steam

2. Walter for Injection. This must be produced and distributed such that microbial growth is prevented. This often includes circulating above 70oC.

3. Filtered gasses, such as Nitrogen and even Compressed Air Commissioning and Validation The requirements for Commissioning and Validation are extensive, and are beyond the

–  –  –

scope of this course. However, all Direct Impact elements must be Validated/Qualified.

Obviously, for an operation this critical the Commissioning exercise must be thorough and robust.

In addition, the effectiveness of the process to produce sterile product must be verified. This is done via a process simulation utilizing media fill, or a nutrient medium that encourages microbial growth. These are repeated during the year, and must be done for each shift. Properly performed, this will result in an upper 95% confidence limit (Poisson variable), which will verify the ability of the facility/process to produce sterile product. There are two common media, Fluid Thioglycollate (for anaerobic simulations or for microorganisms that thrive best/only when deprived of oxygen) and Soybean-Casein Digest (for aerobic simulations or for microorganisms that require oxygen.) The Regulatory Environment and Resources Obviously, drug regulatory agencies are especially interested in products required to be sterile. Clearly, Aseptic filling is one of the most critical activities in the biopharmaceutical industry. As noted previously, this course intentionally avoids specific references (for the most part) due to the ever-changing regulatory environment. In addition, there are efforts underway at the moment to harmonize various countries’ regulations – there are some differences. Some of the most quoted and discussed regulations are from the FDA6 and the EU7. Know where your product will be sold. If the product is to be distributed in multiple countries, you must ensure the most restrictive requirements of the various regulations govern. Also, refer to the excellent publication by ISPE (International Society of Pharmaceutical Engineers), “Volume 3 - Sterile Manufacturing Facilities." Other important resources can be found from the PDA (Parenteral Drug Association) and USP (United States Pharmacopoeia).

Remember to consider environmental, health, and safety issues as well. OSHA publishes PEL’s (Permissible Exposure Limits) that must be considered. Dusts and flammable liquids can cause explosions and fires. There are limits to concentration levels permitted in the air and waste streams. There are ergonomic considerations, and many safety aspects that require attention.

Conclusion This course provides an introduction to Aseptic Pharmaceutical Engineering. It is now up to you to carefully study the regulations of the countries in which you plan to sell your product.

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As well, other industry publications are available and helpful. Equally importantly is to understand your process requirements and product sensitivities. I hope you agree, this is pretty cool stuff (at least to an engineer.) Specific Key References “Volume 3 - Sterile Manufacturing Facilities,” ISPE, Pharmaceutical Engineering Guides for New and Renovated Facilities Ibid FDA’s “Guidance for Industry – Sterile Drug Products Produced by Aseptic Processing – Current Good Manufacturing Practice,” dated September, 2004 “Volume 3 - Sterile Manufacturing Facilities,” ISPE, Pharmaceutical Engineering Guides for New and Renovated Facilities Ibid At the time of the writing of this course, see FDA’s “Guidance for Industry – Sterile Drug Products Produced by Aseptic Processing – Current Good Manufacturing Practice,” dated September, 2004 At the time of the writing of this course, see the European Commission’s “EC Guide to Good Manufacturing Practice – Revision to Annex 1,” dated May 30, 2003.

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