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Monday, July 14, 2008

Personnel Training Qualification Sterile Pharmaceutical Drug Aseptic Processing

PERSONNEL TRAINING, QUALIFICATION, MONITORING

21 CFR 211.22(a) states that “There shall be a quality control unit that shall have the responsibility and authority to approve or reject all components, pharmaceutical drug product containers, closures, in-process materials, packaging material, labeling, and pharmaceutical drug products, and the authority to reviee pharmaceutical production records to assure that no errors have occurred or, if errors have occurred, that they have been fully investigated. The quality control unit shall be responsible for approving or rejecting drug products manufactured, processed, packed, or held under contract by another company.”

21 CFR 211.22(c) states that “The quality control unit shall have the responsibility for approving or rejecting all procedures or specifications impacting on the identity, strength, quality, and purity of the pharmaceutical drug product.”

21 CFR 211.25(a) states that “Each person engaged in the pharmaceutical manufacturing, processing, packing, or holding of a pharmaceutical drug product shall have education, training, and experience, or any combination thereof, to enable that person to perform the assigned functions. Training shall be in the particular operations that the employee performs and in current good manufacturing practice (including the current good manufacturing practice regulations in this chapter and written procedures required by these regulations) as they relate to the employee's functions. Training in pharmaceutical current good manufacturing practice   practice shall be conducted by qualified individuals on a continuing basis and with sufficient frequency to assure that employees remain familiar with CGMP requirements applicable to them.”

21 CFR 211.25(b) states that “Each person responsible for supervising the pharmaceutical manufacturing, processing, packing, or holding of a drug product shall have the education, training, and experience, or any combination thereof, to perform assigned functions in such a manner as to provide assurance that the drug product has the safety, identity, strength, quality, and purity that it purports or is represented to possess.”

21 CFR 211.25(c) states that “There shall be an adequate number of qualified personnel to perform and supervise the manufacture, processing, packing, or holding of each pharmaceutical drug product.”

21 CFR 211.28(a) states that “Personnel engaged in the manufacture, processing, packing, or holding of a drug product shall wear clean clothing appropriate for the duties they perform. Protective apparel, such as head, face, hand, and arm coverings, shall be worn as necessary to protect drug products from contamination.”

21 CFR 211.28(b) states that “Personnel shall practice good sanitation and health habits.”

21 CFR 211.28(c) states that “Only personnel authorized by supervisory personnel shall enter those areas of the buildings and facilities designated as limited access areas.”

21 CFR 211.28(d) states that “Any person shown at any time (either by medical examination or supervisory observation) to have an apparent illness or open lesions that may adversely affect the safety or quality of drug products shall be excluded from direct contact with components, pharmaceutical drug product containers, closures, in-process materials, and pharmaceutical drug products until the condition is corrected or determined by competent medical personnel not to jeopardize the safety or quality of drug products. All personnel shall be instructed to report to supervisory personnel any health conditions that may have an adverse effect on drug products.”

21 CFR 211.42(c) states, in part, that “Operations shall be performed within specifically defined areas of adequate size. There shall be separate or defined areas or such other control systems for the firm’s operations as are necessary to prevent contamination or mixups during the course of the following procedures: * * * (10) Aseptic processing, which includes as appropriate: * * * (iv) A system for monitoring environmental conditions * * *.”

21 CFR 211.113(b) states that “Appropriate written procedures, designed to prevent microbiological contamination of pharmaceutical drug products purporting to be sterile, shall be established and followed. Such procedures shall include validation of any sterilization process.”
A. Personnel
A well-designed, maintained, and operated aseptic process minimizes personnel intervention. As operator activities increase in an aseptic processing operation, the risk to finished product sterility also increases. To ensure maintenance of product sterility, it is critical for operators involved in aseptic activities to use aseptic technique at all times.
Appropriate training should be conducted before an individual is permitted to enter the aseptic manufacturing area. Fundamental training topics should include aseptic technique, cleanroom behavior, microbiology, hygiene, gowning, patient safety hazards posed by a nonsterile drug product, and the specific written procedures covering aseptic manufacturing area operations. After initial training, personnel should participate regularly in an ongoing training program. Supervisory personnel should routinely evaluate each operator’s conformance to written procedures during actual operations. Similarly, the quality control unit should provide regular oversight of adherence to established, written procedures and aseptic technique during manufacturing operations.
Some of the techniques aimed at maintaining sterility of sterile pharmaceutical items and surfaces include:
•Contact sterile materials only with sterile instruments
Sterile instruments should always be used in the handling of sterilized materials. Between uses, sterile instruments should be held under Class 100 (ISO 5 see clean room classification) conditions and maintained in a manner that prevents contamination (e.g., placed in sterilized containers). Instruments should be replaced as necessary throughout an operation.
After initial gowning, sterile gloves should be regularly sanitized or changed, as appropriate, to minimize the risk of contamination. Personnel should not directly contact sterile products, containers, closures, or critical surfaces with any part of their gown or gloves.
•Move slowly and deliberately
Rapid movements can create unacceptable turbulence in a critical area. Such movements disrupt the unidirectional airflow, presenting a challenge beyond intended cleanroom design and control parameters. The principle of slow, careful movement should be followed throughout the cleanroom.
•Keep the entire body out of the path of unidirectional airflow
Unidirectional airflow design is used to protect sterile equipment surfaces, container-closures, and product. Disruption of the path of unidirectional flow air in the critical area can pose a risk to product sterility.
•Approach a necessary manipulation in a manner that does not compromise sterility of the product
To maintain sterility of nearby sterile materials, a proper aseptic manipulation should be approached from the side and not above the product (in vertical unidirectional flow operations). Also, operators should refrain from speaking when in direct proximity to the critical area.
•Maintain Proper Gown Control
Prior to and throughout aseptic operations, an operator should not engage in any activity that poses an unreasonable contamination risk to the gown.
Only personnel who are qualified and appropriately gowned should be permitted access to the aseptic manufacturing area. The gown should provide a barrier between the body and exposed sterilized materials and prevent contamination from particles generated by, and microorganisms shed from, the body. The US fda  recommends gowns that are sterilized and nonshedding, and cover the skin and hair (face-masks, hoods, beard/moustache covers, protective goggles, and elastic gloves are examples of common elements of gowns). Written procedures should detail the methods used to don each gown component in an aseptic manner. An adequate barrier should be created by the overlapping of gown components (e.g., gloves overlapping sleeves). If an element of a gown is found to be torn or defective, it should be changed immediately. Gloves should be sanitized frequently.
There should be an established program to regularly assess or audit conformance of personnel to relevant aseptic manufacturing requirements. An aseptic gowning qualification program should assess the ability of a cleanroom operator to maintain the quality of the gown after performance of gowning procedures. US FDA recommend that this assessment include microbiological surface sampling of several locations on a gown (e.g., glove fingers, facemask, forearm, chest). Sampling sites should be justified. Following an initial assessment of gowning, periodic requalification will provide for the monitoring of various gowning locations over a suitable period to ensure consistent acceptability of aseptic gowning techniques. Annual requalification is normally sufficient for those automated operations where personnel involvement is minimized and monitoring data indicate environmental control. For any aseptic processing operation, if adverse conditions occur, additional or more frequent requalification could be indicated.
To protect exposed sterilized pharmaceutical product, personnel should to maintain gown quality and strictly adhere to appropriate aseptic techniques. Written procedures should adequately address circumstances under which personnel should be retrained, requalified, or reassigned to other areas.

B. Laboratory Personnel
The basic principles of training, aseptic technique, and personnel qualification in aseptic manufacturing also are applicable to those performing aseptic sampling and microbiological laboratory analyses. Processes and systems cannot be considered to be in control and reproducible if the validity of data produced by the laboratory is in question.
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C. Monitoring Program
Personnel can significantly affect the quality of the environment in which the sterile product is processed. A vigilant and responsive personnel monitoring program should be established. Monitoring should be accomplished by obtaining surface samples of each operator's gloves on a daily basis, or in association with each lot. This sampling should be accompanied by an appropriate sampling frequency for other strategically selected locations of the gown . The quality control unit should establish a more comprehensive monitoring program for operators involved in operations which are especially labor intensive (i.e., those requiring repeated or complex aseptic manipulations).
Asepsis is fundamental to an aseptic processing operation. An ongoing goal for manufacturing personnel in the aseptic processing room is to maintain contamination-free gloves and gowns throughout operations. Sanitizing gloves just prior to sampling is inappropriate because it can prevent recovery of microorganisms that were present during an aseptic manipulation. When operators exceed established levels or show an adverse trend, an investigation should be conducted promptly. Follow-up actions can include increased sampling, increased observation, retraining, gowning requalification, and in certain instances, reassignment of the individual to operations outside of the aseptic manufacturing area. Microbiological trending systems, and assessment of the impact of atypical trends, are discussed in more detail under Section X. Laboratory Controls.
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This Guidance is published by US FDA on September 2004
We also recommend our readers to visit US FDA'S website for undated guidances on sterile drug products

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