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The implementation of USP 797, which is an FDA enforceable directive, will have a major impact on any facility involved in the preparation, storing and dispensing of sterile preparations, as Harry Kirk of Nitritex explains in a summary of the facilities requirements
Harry Kirk
Sales and Marketing Director
Nitritex Ltd
Newmarket
UK
Before assessing the implications of this section of USP 797 it is important to understand exactly the requirements of the directive and to which facilities it applies.
Facilities impacted by USP 797 include health care institutions, pharmacies, physicians practice facilities and other facilities:
- Where sterile products are prepared and where manipulations are performed during the compounding of sterile products which increase the potential for microbial contamination of the end product.
- Where products are compounded using devices or ingredients which are not sterile to prepare products that must be sterilised prior to use.
The products impacted include diagnostics, drugs, biologics, nutrients or radiopharmaceuticals which include, but are not limited to, baths and soaks for live organs and tissues, implants, inhalations, injections, irrigations, metered sprays, ophthalmic and OTC preparations.
Contamination risk levels
There are three microbial contamination risk levels identified:
- Low risk – these are sterile facilities with air quality at ISO Class 5 (EU GMP Grade A/B) or better using only sterile ingredients, products, components and devices. In the absence of passing a sterility test, the storage period cannot exceed the following times:
❍ 48 hours at room temperature.
❍ 14 days at cold temperature.
❍ 45 days in a solid frozen state at –20ºC to –10ºC.
- Medium risk – where compounding may require a long duration for sterile products that will be administrated to multiple patients or to one patient on multiple occasions. In the absence of passing a sterility test, the storage period cannot exceed the following times:
❍ 30 hours at room temperature.
❍ Nine days at cold temperature.
❍ 45 days in a solid frozen state at –20ºC to –10ºC.
- High risk – where non-sterile ingredients are incorporated or a non-sterile device is employed before terminal sterilisation. Sterile ingredients, components, devices and mixtures exposed to air quality inferior to ISO Class 5 including storage in such conditions and when non-sterile products are exposed to such conditions for at least six hours before sterilisation. For high risk preparations in the absence of passing a sterility test the storage periods cannot exceed the following periods:
❍ 24 hours at controlled room conditions.
❍ Three days at cold temperature.
❍ 45 days in a solid frozen state at –20ºC to –10ºC.
Cleanroom classification
To meet the challenges presented, cleanrooms are classified according to two levels – low/medium risk and high risk. Each level is required to have the following characteristics and operating conditions:
Low and medium risk cleanrooms
- Air quality must be ISO Class 8 (Fed. Std. 100,000) or better.
- Positive pressure as per ISO 14644-4.
- Have an ante area, not necessarily separated by a physical wall.
- Standard cleanroom construction is sufficient with no requirement for a raised floor. The ante area must not contain any sinks or floor drains. Gowning in low and medium risk environments should be in line with the protocol detailed below.
- Before entering the ante area personnel should remove outer lab coats, make-up, jewellery and thoroughly scrub hands and arms to the elbow.
- After drying hands and arms and having entered the ante area, personnel should don clean non-shedding uniforms consisting of:
❍ Hair covers.
❍ Shoe covers.
❍ Coveralls or knee length coats (if coats they must fit snugly at the wrists and be zipped or snapped in the front).
❍ Appropriate cleanroom gloves.
❍ Facemasks should be put on after entering the clean room.
- Upon leaving the clean room the coveralls or coat should be removed and hung outside the entry in the ante area. Coveralls and coats must only be used for one shift. All other coverings (gloves, shoe covers, hair covers, facemasks) must be discarded and new ones donned prior to re-entry. Re-entry must follow the original gowning procedure outlined above.
High risk cleanrooms
- Air quality must be ISO Class 8 (Fed. Std. 100,000) or better.
- Positive pressure as per ISO 14644-4.
- Have an ante area, but must be a separate room.Standard cleanroom construction is sufficient with no requirement for a raised floor. The anteroom must not contain any sinks or floor drains.Gowning procedures must follow the same procedures as shown for low and medium risk environments.
Barrier isolator
USP 797 guidelines suggest the use of a well designed barrier isolator as an alternative to an ISO Class 5 (Fed. Std. Class 100) laminar flow work station within an ISO Class 8 (Fed. Std. Class 100,000) cleanroom.
If a barrier isolator is used, it must be supported by full operating, maintenance, monitoring and control procedures.
It is, however, not necessary to physically locate the barrier isolator in an ISO Class 8 area. In fact USP 797 does not specify where a barrier isolator should be located. If a barrier isolator is used, gowning should include the following:
- Hair covers.
- Shoe covers.
- Lab coats.
- Facemasks.
Quality assurance programme
A key element of USP 797 is the quality assurance programme, which should be subject to a formal audit schedule. The QA programme must:
- Be formalised in writing.
- Consider all aspects of product preparation and dispensing.
- Describe all monitoring and evaluation activities.
- Have specifications for reporting and evaluating results.
- Identify correct follow-up mechanisms when actions result in limits or thresholds being exceeded.
- Clearly name the individuals who are responsible for each element of the QA programme.
Validation: minimum requirements
Low to medium risk
Personnel validation: three consecutive media fill runs are required without contamination.
Revalidation: one media fill run quarterly without contamination. Should there be contamination of the quarterly media fill, the requirement for revalidation is three consecutive media fill runs without contamination.
High risk
Personnel validation: three consecutive media fill runs without contamination.
Revalidation: one media fill run quarterly without contamination. Should there be contamination of the quarterly media fill the requirement for revalidation is three consecutive media fill runs without contamination.
Process validation: three consecutive media fill runs without contamination.
Revalidation: one media fill run annually without contamination. Should there be failure of revalidation the requirement for revalidation is three consecutive media fill runs without contamination.
Cleaning and sanitising: there is also a requirement for all cleaning and sanitising in the workspaces to be covered by written procedures. All cleaning procedures must be undertaken at the beginning of each shift.
Environmental monitoring
All sterile compounding equipment is subject to verification and a written plan and schedule for monitoring airborne organisms is a requirement. Should viable airborne micro-organisms be detected they are subject to verification. Airborne particulates and automated compounding devices for nutrition compounding are also subject to verification.
Sterility testing
All high risk compounded sterile products that are prepared in groups of more than 25 identical or single dose packages or in multi-dose vials for administration in multiple patients, are subject to sterility testing.
Personnel: training and evaluation
There is major emphasis placed upon training and evaluation of staff skills. The area of most concern is aseptic manipulative skills which should be tested initially and annually for low and medium risk areas and semi-annually for high risk areas.
The use of training from expert personnel, AV instruction and professional advice are all encouraged, supported by practical and written testing.
Conclusion
USP 797 is a multi-faceted directive. In this article I have concentrated on one aspect of the directive only – that of sterile compounding of pharmaceutical and related products.
However, this is a key part of the directive because it affects all facilities that are involved in the preparation of a wide range of drugs and medicinal preparations.
Although many of the requirements of the directive will be contained in standard operating procedures, there are a number of areas that will require attention. In particular there are formal training and evaluation programmes, defined environmental conditions and validation requirements. ■
For more information on USP 797 please contact Harry Kirk at info@nitritex.com
Educated at Durham University, Harry Kirk has held senior management positions in a number of multi-national life science companies. He lived in the Far East for 10 years, managing a cleanroom glove manufacturing facility before returning to the UK in 1990 as Sales and Marketing Director of a UK-based healthcare supplies company. In 1996 he co-founded Nitritex Ltd, a company also based in the UK, specialising in the supply of cleanroom consumables. He is currently Business Development Director of the company with responsibility for new product and market development.
