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cGMP's for sterile products

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This presentation is compiled by “ Drug Regulations” from freely available resources like the FDA on the World wide web. …

This presentation is compiled by “ Drug Regulations” from freely available resources like the FDA on the World wide web.
“Drug Regulations” is a non profit organization which provides free online resource to the Pharmaceutical Professional.
Visit http://www.drugregulations.org for latest information from the world of Pharmaceuticals.

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  • 1. This presentation is compiled by “ Drug Regulations” a non profit organization which provides free online resource to the Pharmaceutical Professional. Visit http://www.drugregulations.org for latest information from the world of Pharmaceuticals. 12/9/2013 1
  • 2. This presentation is compiled by “ Drug Regulations” from freely available resources like the FDA on the World wide web.  “Drug Regulations” is a non profit organization which provides free online resource to the Pharmaceutical Professional.  Visit http://www.drugregulations.org for latest information from the world of Pharmaceuticals.  Drug Regulations : Online Resource for Latest Information 12/9/2013 2
  • 3.  Basic differences between production using aseptic processing and terminal sterilization.  Terminal sterilization involves ◦ Filling and sealing product containers under high-quality environmental conditions; ◦ Minimization of the microbial and particulate content of the in-process product ; ◦ Ensuring that the subsequent sterilization process is successful;  In most cases, the product, container, and closure have low bioburden, but they are not sterile.  The product in its final container is then subjected to a sterilization process such as heat or irradiation. Drug Regulations : Online Resource for Latest Information 12/9/2013 3
  • 4.  In an aseptic process, ◦ The drug product, container, and closure are first subjected to sterilization methods separately; ◦ Brought together at the end; ◦ There is no process to sterilize the product in its final container; ◦ Critical that containers be filled and sealed in an extremely high-quality environment. Drug Regulations : Online Resource for Latest Information 12/9/2013 4
  • 5.  Aseptic process ◦ Involves more variables than terminal sterilization. ◦ Individual parts of the final product are generally subjected to various sterilization processes.  Glass containers are subjected to dry heat;  Rubber closures are subjected to moist heat; and  Liquid dosage forms are subjected to filtration. ◦ Each of these manufacturing processes require validation and control. Drug Regulations : Online Resource for Latest Information 12/9/2013 5
  • 6.  Each aseptic process could introduce an error.  Aseptic assembly poses the risk of contamination  Requires careful control of any manual or mechanical manipulation of the sterilized drug, Components, Containers, or Closures  A terminally sterilized drug product, on the other hand, undergoes final sterilization in a sealed container, thus limiting the possibility of error. Drug Regulations : Online Resource for Latest Information 12/9/2013 6
  • 7.  Aseptic processing used only when terminal sterilization is not feasible.  Some final packaging may afford unique advantages not be possible with terminal sterilization.  Add adjunct processing steps to increase the level of sterility assurance. Drug Regulations : Online Resource for Latest Information 12/9/2013 7
  • 8.  21 CFR 211.42(b) states, in part, that “The flow of containers, components, closures, drug labeling, product in-process materials, and drug products through the building or buildings shall be designed to prevent contamination.” Drug Regulations : Online Resource for Latest Information 12/9/2013 8
  • 9.  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 mix ups during the course of the following procedures. …..contd Drug Regulations : Online Resource for Latest Information 12/9/2013 9
  • 10.  Aseptic processing, which includes as appropriate: ◦ (i) Floors, walls, and ceilings of smooth, hard surfaces that are easily cleanable; ◦ (ii) Temperature and humidity controls; ◦ (iii) An air supply filtered through high-efficiency particulate air filters under positive pressure, regardless of whether flow is laminar or nonlaminar; ◦ (iv) A system for monitoring environmental conditions; ◦ (v) A system for cleaning and disinfecting the room and equipment to produce aseptic conditions; ◦ (vi) A system for maintaining any equipment used to control the aseptic conditions.” Drug Regulations : Online Resource for Latest Information 12/9/2013 10
  • 11.  21 CFR 211.46(b) states that “Equipment for adequate control over air pressure, microorganisms, dust, humidity, and temperature shall be provided when appropriate for the manufacture, processing, packing, or holding of a drug product.” Drug Regulations : Online Resource for Latest Information 12/9/2013 11
  • 12.  21 CFR 211.46(c) states, in part, that “Air filtration systems, including prefilters and particulate matter air filters, shall be used when appropriate on air supplies to production areas.” Drug Regulations : Online Resource for Latest Information 12/9/2013 12
  • 13.  21 CFR 211.63 states that “Equipment used in the manufacture, processing, packing, or holding of a drug product shall be of appropriate design, adequate size, and suitably located to facilitate operations for its intended use and for its cleaning and maintenance.” Drug Regulations : Online Resource for Latest Information 12/9/2013 13
  • 14.  21 CFR 211.65(a) states that “Equipment shall be constructed so components, that surfaces in-process that materials, contact or drug products shall not be reactive, additive, or absorptive so as to alter the safety, identity, strength, quality, or purity of the drug product beyond the official or other established requirements.” Drug Regulations : Online Resource for Latest Information 12/9/2013 14
  • 15.  21 CFR 211.67(a) states that “Equipment and utensils shall be cleaned, maintained, and sanitized at appropriate intervals to prevent malfunctions or contamination that would alter the safety, identity, strength, quality, or purity of the drug product beyond the official or other established requirements.” Drug Regulations : Online Resource for Latest Information 12/9/2013 15
  • 16.  21 CFR 211.113(b) states that “Appropriate written procedures, microbiological designed contamination to prevent of drug products purporting to be sterile, shall be established and followed. Such procedures shall include validation of any sterilization process.” Drug Regulations : Online Resource for Latest Information 12/9/2013 16
  • 17.  Control parameters should be supported by microbiological and particle data obtained during qualification studies.  Include an assessment of air quality under as-built, static conditions in initial cleanroom qualification. Drug Regulations : Online Resource for Latest Information 12/9/2013 17
  • 18.  Place most emphasis on data generated under dynamic conditions ◦ i.e. with personnel present, equipment in place, and operations ongoing.  Assess conformance with specified clean area classifications under dynamic conditions on a routine basis. Drug Regulations : Online Resource for Latest Information 12/9/2013 18
  • 19.  Table in the next slide summarizes clean area air classifications and recommended action levels of microbiological quality. Drug Regulations : Online Resource for Latest Information 12/9/2013 19
  • 20. Clean Area Classification (0.5 um particles/ft3) ISO Designationb > 0.5 μm particles/m3 Microbiologica l Active Air Action Levels (cfu/m3 )c Microbiologica l Settling Plates Action Levels (diam. 90mm; cfu/4 hours) cd 100 5 3,520 1e 1e 1,000 6 35,200 7 3 10,000 7 352,000 10 5 100,000 8 3,352,000 100 50 Drug Regulations : Online Resource for Latest Information 12/9/2013 20
  • 21.  Legends for last slide a. All classifications based on data measured in the vicinity of exposed materials/articles during periods of activity. b. ISO 14644-1 designations provide uniform particle concentration values for cleanrooms in multiple industries. An ISO 5 particle concentration is equal to Class 100 and approximately equals EU Grade A. c. Values represent recommended levels of environmental quality. You may find it appropriate to establish alternate microbiological action levels due to the nature of the operation or method of analysis. d. The additional use of settling plates is optional. e. Samples from Class 100 (ISO 5) environments should normally yield no microbiological contaminants. Drug Regulations : Online Resource for Latest Information 12/9/2013 21
  • 22.  Critical area ◦ Area in which the sterilized drug product, containers, and closures are exposed to environmental conditions that must be designed to maintain product sterility  (§ 211.42(c)(10)). ◦ Activities conducted in such areas include manipulations of sterile materials prior to and during filling and closing operations.  e.g., aseptic connections, sterile ingredient additions Drug Regulations : Online Resource for Latest Information 12/9/2013 22
  • 23.  This area is critical because ◦ An exposed product is vulnerable to contamination ◦ Product will not be sterilized in its immediate container.  Control and maintain the environment in which aseptic operations (e.g., equipment setup, filling) are conducted. Drug Regulations : Online Resource for Latest Information 12/9/2013 23
  • 24.  Particle content of the air is an important aspect because:  They can enter a product as an extraneous contaminant.  They can also contaminate the product biologically by acting as a vehicle for microorganisms. Drug Regulations : Online Resource for Latest Information 12/9/2013 24
  • 25.  Minimize the particle content of the critical area by appropriately designed air handling systems.  Air in the immediate proximity of exposed sterilized containers/closures and filling/closing operations would be of appropriate particle quality when ◦ it has a per-cubic-meter particle count of no more than 3520 ◦ in a size range of 0.5 μm and larger ◦ when counted at representative locations Drug Regulations : Online Resource for Latest Information 12/9/2013 25
  • 26. ◦ normally not more than 1 foot away from the work site, ◦ within the airflow, and ◦ during filling/closing operations.  This level of air cleanliness is also known as Class 100 (ISO 5). Drug Regulations : Online Resource for Latest Information 12/9/2013 26
  • 27.  FDA recommends that ◦ Take measurements to confirm air cleanliness in critical areas at sites where there is most potential risk to the exposed sterilized product, containers, and closures. ◦ Place the particle counting probe in an orientation demonstrated to obtain a meaningful sample. Drug Regulations : Online Resource for Latest Information 12/9/2013 27
  • 28.  FDA recommends that ◦ Perform regular monitoring during each production shift. ◦ Conduct nonviable particle monitoring with a remote counting system.  These systems are capable of collecting more comprehensive data and are generally less invasive than portable particle counters. Drug Regulations : Online Resource for Latest Information 12/9/2013 28
  • 29.  Some operations can generate high levels of product (e.g., powder) particles  These by their nature, do not pose a risk of product contamination.  In these cases, it may not be feasible to measure air quality within the one-foot distance and still differentiate background levels of particles from air contaminants. Drug Regulations : Online Resource for Latest Information 12/9/2013 29
  • 30.  Sample air to characterize the true level of extrinsic particle contamination  Use baseline information on the non-product particle generation of the operation from Initial qualification of the area under dynamic conditions without the actual filling function. Drug Regulations : Online Resource for Latest Information 12/9/2013 30
  • 31.  Supply HEPA-filtered air in critical areas at a velocity sufficient to ◦ Sweep particles away from the filling/closing area and ◦ Maintain unidirectional airflow during operations.  Justify and establish the velocity parameters for each processing line ◦ appropriate to maintain unidirectional airflow and ◦ air quality under dynamic conditions within the critical area Drug Regulations : Online Resource for Latest Information 12/9/2013 31
  • 32.  Prevent turbulence and stagnant air in the critical area with proper design and control.  Evaluate airflow patterns for turbulence or eddy currents ◦ These can act as a channel or reservoir for air contaminants (e.g., from an adjoining lower classified area).  Conduct in situ air pattern analysis at the critical area  Demonstrate unidirectional airflow and sweeping action over and away from the product under dynamic conditions. Drug Regulations : Online Resource for Latest Information 12/9/2013 32
  • 33.  Document these studies with written conclusions  Include evaluation of the impact of aseptic manipulations and equipment design (e.g., interventions).  Use Videotape or other recording mechanisms in assessing airflow  Use the recording for evaluation of subsequent equipment configuration changes.  Remember ◦ Successfully qualified systems can be compromised by poor operational, maintenance, or personnel practices. Drug Regulations : Online Resource for Latest Information 12/9/2013 33
  • 34.  Air monitoring samples of critical areas should normally yield no microbiological contaminants.  FDA recommends investigating contamination occurrences in this environment. Drug Regulations : Online Resource for Latest Information 12/9/2013 34
  • 35.  Have various classifications and functions. ◦ zones in which nonsterile components, formulated products, inprocess materials, equipment, and container/closures are prepared, held, or transferred.  Design these environments soundly to ◦ Minimize the level of particle contaminants in the final product and ◦ Control the microbiological content (bioburden) of articles and components that are subsequently sterilized. Drug Regulations : Online Resource for Latest Information 12/9/2013 35
  • 36.  Determine classification by the nature of activities  FDA recommends that the area immediately adjacent to the aseptic processing line meet, at a minimum, Class 10,000 (ISO 7) standards (see earlier Table) under dynamic conditions.  This area can also be classified as Class 1,000 (ISO 6) or  Entire aseptic filling room can be maintained at Class 100 (ISO 5).  An area classified at a Class 100,000 (ISO 8) air cleanliness level is appropriate for less critical activities (e.g., equipment cleaning). Drug Regulations : Online Resource for Latest Information 12/9/2013 36
  • 37.  Maintain adequate separation of areas of operation for contamination prevention.  Maintain proper airflow from areas of higher cleanliness to adjacent less clean areas to maintain air quality.  Maintain rooms of higher air cleanliness at a substantial positive pressure differential relative to adjacent rooms of lower air cleanliness. Drug Regulations : Online Resource for Latest Information 12/9/2013 37
  • 38.  Maintain a positive pressure differential of at least 10-15 Pascals (Pa) between adjacent rooms of differing classification (with doors closed).  Maintain sufficient outward airflow to minimize ingress of contamination, when doors are open  Control the time a door can remain ajar Drug Regulations : Online Resource for Latest Information 12/9/2013 38
  • 39.  In case the aseptic processing room and adjacent cleanrooms have the same classification ◦ Maintain a pressure differential (with doors closed) between the aseptic processing room and these adjacent rooms Drug Regulations : Online Resource for Latest Information 12/9/2013 39
  • 40.  In case an unclassified room is adjacent to the aseptic processing room, ◦ Provide a substantial overpressure (e.g., at least 12.5 Pa) from the aseptic processing room at all times to prevent contamination. ◦ Restore and confirm the quality of aseptic processing room if this pressure differential drops below the minimum limit. Drug Regulations : Online Resource for Latest Information 12/9/2013 40
  • 41.  FDA recommends that ◦ Pressure differentials between cleanrooms be monitored continuously; ◦ Monitored throughout each shift; ◦ Frequently recorded; ◦ Document all alarms and deviations from established limits ◦ Investigate all such incidents. Drug Regulations : Online Resource for Latest Information 12/9/2013 41
  • 42.  Another important factor : Air change rate  For Class 100,000 (ISO 8) supporting rooms ◦ 20 air changes per hour is typically acceptable.  Significantly higher air change rates are normally needed for Class 10,000 and Class 100 areas. Drug Regulations : Online Resource for Latest Information 12/9/2013 42
  • 43.  Use a facility monitoring system to rapidly detect atypical changes.  Restore operating conditions to established, qualified levels before reaching action levels.  Set pressure differential specifications to enable prompt detection  Prevent an emerging low pressure problem to preclude ingress of unclassified air into a classified room. Drug Regulations : Online Resource for Latest Information 12/9/2013 43
  • 44.  A compressed gas should be of appropriate purity ◦ Free from oil ◦ Microbiological and particle quality better than that of the air in the environment  Compressed gases such as air, nitrogen, and carbon dioxide are often used in cleanrooms  Frequently employed in purging or overlaying. Drug Regulations : Online Resource for Latest Information 12/9/2013 44
  • 45.  Use membrane filters to filter a compressed gas to meet an appropriate high-quality standard.  These filters are often used to produce a sterile compressed gas to conduct operations involving sterile materials, such as components and equipment. Drug Regulations : Online Resource for Latest Information 12/9/2013 45
  • 46.  FDA recommends that ◦ Sterile membrane filters be used for  Autoclave air lines,  Lyophilizer vacuum breaks, and  Tanks containing sterilized materials. Drug Regulations : Online Resource for Latest Information 12/9/2013 46
  • 47.  FDA recommends that ◦ Sterilized holding tanks and any contained liquids should be held under positive pressure ◦ Appropriately sealed to prevent microbial contamination. ◦ Place safeguards to prevent a pressure change that can result in contamination due to back flow of nonsterile air or liquid. Drug Regulations : Online Resource for Latest Information 12/9/2013 47
  • 48.  Gas filters (including vent filters) should be dry.  Condensate on a gas filter can cause blockage during use or allow for the growth of microorganisms.  Use hydrophobic filters Use heat appropriately to prevent problematic moisture residues. Drug Regulations : Online Resource for Latest Information 12/9/2013 48
  • 49.  Test the integrity of filters upon installation and periodically thereafter (e.g., end of use).  Perform integrity tests after activities that may damage the filter.  Investigate integrity test failures.  Replace filters at appropriate, defined intervals. Drug Regulations : Online Resource for Latest Information 12/9/2013 49
  • 50.  Maintain HEPA filter integrity to ensure aseptic conditions.  Perform leak testing at installation to detect integrity breaches ◦ around the sealing gaskets, ◦ through the frames, or ◦ through various points on the filter media.  Perform leak tests at suitable time intervals for HEPA filters in the aseptic processing facility. Drug Regulations : Online Resource for Latest Information 12/9/2013 50
  • 51.  FDA recommends to perform testing twice a year for the aseptic processing room.  Additional testing may be appropriate when ◦ Air quality is found to be unacceptable; ◦ Facility renovations cause disturbances to ceiling or wall structures; ◦ Media fill or drug product sterility fail. Drug Regulations : Online Resource for Latest Information 12/9/2013 51
  • 52.  Leak test filters that are ◦ Installed in dry heat depyrogenation tunnels; ◦ Installed in ovens commonly used to depyrogenate glass vials.  Justify the use of alternate methods to test HEPA filters in the hot zones of these tunnels and ovens. Drug Regulations : Online Resource for Latest Information 12/9/2013 52
  • 53.  Aerosol used for challenging a HEPA filter should meet specifications for critical physicochemical attributes such as viscosity.  Dioctylphthalate (DOP) and poly-alpha-olefin (PAO) are examples of appropriate leak testing aerosols.  Some aerosols are problematic because they pose the risk of microbial contamination of the environment being tested.  Ensure that use of any alternative aerosol involves evaluation to ensure that it does not promote microbial growth. Drug Regulations : Online Resource for Latest Information 12/9/2013 53
  • 54.  Major difference between filter leak testing and efficiency testing.  An efficiency test is a general test used to determine the rating of the filter.  An intact HEPA filter should be capable of retaining at least 99.97 percent of particulates greater than 0.3 μm in diameter. Drug Regulations : Online Resource for Latest Information 12/9/2013 54
  • 55.  Detect leaks with scheduled leak tests , from the filter media, filter frame, or seal.  Use polydispersed aerosol with a lightscattering mean droplet diameter in the submicron size range, including a sufficient number of particles at approximately 0.3 μm. Drug Regulations : Online Resource for Latest Information 12/9/2013 55
  • 56.  Performance of leak test without a sufficient upstream challenge is ineffective for detecting leaks.  Introduce an aerosol upstream appropriate for the accuracy of the aerosol photometer probe  Use a sampling rate of at least one cubic foot per minute  Perform the leak test in place Drug Regulations : Online Resource for Latest Information 12/9/2013 56
  • 57.  Calculate leakage as per cent of the upstream challenge.  Conduct an appropriate scan on the entire filter face and frame, at a position about one to two inches from the face of the filter.  Document scanning of HEPA filters Drug Regulations : Online Resource for Latest Information 12/9/2013 57
  • 58.  A single probe reading equivalent to 0.01 percent of the upstream challenge indicates a significant leak  Replace HEPA filter  Repair in a limited area , when appropriate  Perform a subsequent confirmatory retest in the area of any repair. Drug Regulations : Online Resource for Latest Information 12/9/2013 58
  • 59.  HEPA filter leak testing alone is insufficient to monitor filter performance.  Conduct periodic monitoring of filter attributes such as uniformity of velocity across the filter (and relative to adjacent filters). Drug Regulations : Online Resource for Latest Information 12/9/2013 59
  • 60.  Contamination can increase by variations in velocity and resultant turbulence  Measure velocities of unidirectional air ◦ Six inches from the filter face ◦ At a defined distance proximal to the work surface for HEPA filters Drug Regulations : Online Resource for Latest Information 12/9/2013 60
  • 61.  Useful data is provided by velocity monitoring.  Measurements should correlate to the velocity range established at the time of in situ air pattern analysis studies.  Replace HEPA filters when ◦ Non uniformity of air velocity across an area of the filter is detected or ◦ Airflow patterns may be adversely affected. Drug Regulations : Online Resource for Latest Information 12/9/2013 61
  • 62.  Contractors often provide these services  Drug manufacturers should define ◦ Equipment specifications, ◦ Test methods ◦ Acceptance criteria  Drug Manufacturers certification should activities ensure are that conducted satisfactorily. Drug Regulations : Online Resource for Latest Information 12/9/2013 62
  • 63.  Design aseptic processes to minimize exposure of sterile articles to the potential contamination hazards of the manufacturing operation.  For High assurance of sterility ◦ Limit the duration of exposure of sterile product elements, ◦ Provide the highest possible environmental control, ◦ Optimize the process flow, and ◦ Design equipment to prevent entrainment of lower quality air into the Class 100 (ISO 5) clean area Drug Regulations : Online Resource for Latest Information 12/9/2013 63
  • 64.  For High assurance of sterility ◦ Optimize both personnel and material flow ◦ Prevent unnecessary activities that could increase the potential for introducing contaminants to  Exposed product,  Container-closures, or  The surrounding environment. Drug Regulations : Online Resource for Latest Information 12/9/2013 64
  • 65.  For High assurance of sterility ◦ Use ergonomic equipment layout to optimize comfort and movement of operators. ◦ Minimize the number of personnel in an aseptic processing room. ◦ Design flow of personnel to limit movement  Reduce the frequency with which entries and exits are made to and from an  Aseptic processing room and  Critical area. Drug Regulations : Online Resource for Latest Information 12/9/2013 65
  • 66.  For High assurance of sterility ◦ Minimize the number of transfers into the critical area of a traditional cleanroom, or an isolator. ◦ Restrict movement adjacent to the critical area ◦ Prevent changes in air currents that introduce lower quality air. Drug Regulations : Online Resource for Latest Information 12/9/2013 66
  • 67.  For High assurance of sterility ◦ Reduce interventions or stoppage during an aseptic process ◦ Design equipment to limit the number and complexity of aseptic interventions  An on-line weight check device reduces personnel intervention. Drug Regulations : Online Resource for Latest Information 12/9/2013 67
  • 68.  For High assurance of sterility ◦ Eliminate a significant aseptic manipulation by using sterilize-in-place (SIP) technology. ◦ Automate process steps, ◦ Use technologies such as robotics, to reduce risk to the product. Drug Regulations : Online Resource for Latest Information 12/9/2013 68
  • 69.  For High assurance of sterility ◦ Transfer products under appropriate cleanroom conditions.  Lyophilization processes include transfer of aseptically filled product in partially sealed containers. ◦ Transfer a partially closed sterile product only in critical areas. Drug Regulations : Online Resource for Latest Information 12/9/2013 69
  • 70.  For High assurance of sterility ◦ Ensure that the area between a filling line and the lyophilizer is Class 100 (ISO 5) . ◦ Transport and loading procedures should afford the same protection. Drug Regulations : Online Resource for Latest Information 12/9/2013 70
  • 71.  For High assurance of sterility ◦ Protect the sterile drug product and its containerclosures by equipment of suitable design. ◦ Use carefully designed curtains and rigid plastic shields to achieve segregation of the aseptic processing line. ◦ Use an isolator system to enhance product protection. Drug Regulations : Online Resource for Latest Information 12/9/2013 71
  • 72.  For High assurance of sterility ◦ Carefully define and control the dynamic interactions permitted between cleanrooms. ◦ Direct product flow from a lower to a higher classified area with a use of a double-door or integrated sterilizer. Drug Regulations : Online Resource for Latest Information 12/9/2013 72
  • 73.  For High assurance of sterility ◦ Control air balance with airlocks and interlocking doors. ◦ Install airlocks between the aseptic manufacturing area entrance and the adjoining unclassified area. ◦ Install airlocks at other appropriate locations such as personnel transitions or material staging areas. ◦ Control material (e.g., in-process supplies, equipment, utensils) as it transfers from lesser to higher classified clean areas to prevent the influx of contaminants. Drug Regulations : Online Resource for Latest Information 12/9/2013 73
  • 74.  For High assurance of sterility ◦ Maintain written procedures to address how materials are to be introduced into the aseptic processing room to ensure that room conditions remain uncompromised. ◦ FDA recommends that materials should be disinfected according to appropriate procedures or, when used in critical areas, rendered sterile by a suitable method. Drug Regulations : Online Resource for Latest Information 12/9/2013 74
  • 75.  For High assurance of sterility ◦ Place appropriate safeguards in place to protect the product if stoppered vials exit an aseptic processing zone or room prior to capping.  Local protection until completion of the crimping step. ◦ Use on-line detection devices for improperly seated stoppers. Drug Regulations : Online Resource for Latest Information 12/9/2013 75
  • 76.  For High assurance of sterility ◦ Design cleanrooms as functional units with specific purposes. ◦ Ensure ease of cleaning and sanitizing by use of appropriate material of construction.  seamless and rounded floor to wall junctions as well as readily accessible corners. Drug Regulations : Online Resource for Latest Information 12/9/2013 76
  • 77.  For High assurance of sterility ◦ Construct floors, walls, and ceilings of smooth, hard surfaces that can be easily cleaned. ◦ Design ceilings and associated HEPA filter banks to protect sterile materials from contamination. ◦ Remove unnecessary equipment, fixtures, or materials from cleanrooms. Drug Regulations : Online Resource for Latest Information 12/9/2013 77
  • 78.  For High assurance of sterility ◦ Equip processing equipment and systems with sanitary fittings and valves. ◦ Do not use drains in classified areas of the aseptic processing facility  other than Class 100,000 (ISO 8) areas. ◦ Use suitable design for any drain installed in an aseptic processing facility. Drug Regulations : Online Resource for Latest Information 12/9/2013 78
  • 79.  For High assurance of sterility ◦ Design equipment appropriately to facilitate ease of sterilization (§ 211.63) . ◦ Ensure ease of installation to facilitate aseptic setup. ◦ Address the effect of equipment design on the cleanroom environment. Drug Regulations : Online Resource for Latest Information 12/9/2013 79
  • 80.  For High assurance of sterility ◦ Avoid horizontal surfaces or ledges that accumulate particles. ◦ Ensure that equipment does not obstruct airflow in critical areas. ◦ Equipment design should not disturb unidirectional airflow. Drug Regulations : Online Resource for Latest Information 12/9/2013 80
  • 81.  For High assurance of sterility ◦ Deviation or change control systems should address  Atypical conditions posed by shutdown of air handling systems  Other utilities  Impact of construction activities on facility control. ◦ Written procedures should address returning a facility to operating conditions following a shutdown. Drug Regulations : Online Resource for Latest Information 12/9/2013 81
  • 82.  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, drug product containers, closures, inprocess materials, packaging material, labeling, and drug products, and the authority to review 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.” Drug Regulations : Online Resource for Latest Information 12/9/2013 82
  • 83.  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 drug product.” Drug Regulations : Online Resource for Latest Information 12/9/2013 83
  • 84.  21 CFR 211.25(a) states that “Each person engaged in the manufacture, processing, packing, or holding of a 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 current good manufacturing 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.” Drug Regulations : Online Resource for Latest Information 12/9/2013 84
  • 85.  21 CFR 211.25(b) states that “Each person responsible for supervising the manufacture, 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.” Drug Regulations : Online Resource for Latest Information 12/9/2013 85
  • 86.  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 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.” Drug Regulations : Online Resource for Latest Information 12/9/2013 86
  • 87.  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.” Drug Regulations : Online Resource for Latest Information 12/9/2013 87
  • 88.  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, drug product containers, closures, in-process materials, and 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.” Drug Regulations : Online Resource for Latest Information 12/9/2013 88
  • 89.  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. Aseptic processing, which includes as appropriate. (iv) A system for monitoring environmental conditions .” Drug Regulations : Online Resource for Latest Information 12/9/2013 89
  • 90.  21 CFR 211.113(b) states that “Appropriate written procedures, microbiological designed contamination to prevent of drug products purporting to be sterile, shall be established and followed. Such procedures shall include validation of any sterilization process.” Drug Regulations : Online Resource for Latest Information 12/9/2013 90
  • 91.  Reduce personnel intervention by a well-designed, maintained, and operated aseptic process.  Reduce operator activities in an aseptic processing operation, to reduce the risk to finished product sterility.  Use aseptic technique at all times to ensure maintenance of product sterility. Drug Regulations : Online Resource for Latest Information 12/9/2013 91
  • 92.  Conduct appropriate training before an individual is permitted to enter the aseptic manufacturing area.  Include following in training topics ◦ Aseptic technique, ◦ Cleanroom behaviour, ◦ Microbiology, ◦ Hygiene, ◦ Gowning, ◦ Patient safety hazards posed by a nonsterile drug product ◦ Specific written procedures covering aseptic manufacturing area operation Drug Regulations : Online Resource for Latest Information 12/9/2013 92
  • 93.  Maintain an ongoing training program.  Evaluate routinely each operator’s conformance to written procedures during actual operations.  Establish regular oversight by Quality Unit ◦ Adherence to established, written procedures ◦ Aseptic technique during manufacturing operations. Drug Regulations : Online Resource for Latest Information 12/9/2013 93
  • 94.  Some of the techniques aimed at maintaining sterility of sterile items and surfaces include: ◦ Contact sterile materials only with sterile instruments  Use sterile instruments in the handling of sterilized materials.  Hold, sterile instruments under Class 100 (ISO 5) conditions and maintain in a manner that prevents contamination (e.g., placed in sterilized containers) between uses.  Replace instruments as necessary throughout an operation. Drug Regulations : Online Resource for Latest Information 12/9/2013 94
  • 95.  Some of the techniques aimed at maintaining sterility of sterile items and surfaces include: ◦ Contact sterile materials only with sterile instruments  Regularly sanitize or change sterile gloves after initial gowning to minimize the risk of contamination.  Do not directly contact sterile products, containers, closures, or critical surfaces. Drug Regulations : Online Resource for Latest Information 12/9/2013 95
  • 96.  Some of the techniques aimed at maintaining sterility of sterile items and surfaces include: ◦ Move slowly and deliberately  Do not create unacceptable turbulence in a critical area by rapid movements.  Do not disrupt the unidirectional airflow, presenting a challenge beyond intended cleanroom design and control parameters by such movements  Follow the principle of slow, careful movement throughout the cleanroom. Drug Regulations : Online Resource for Latest Information 12/9/2013 96
  • 97.  Some of the techniques aimed at maintaining sterility of sterile items and surfaces include: ◦ Keep the entire body out of the path of unidirectional airflow  Use unidirectional airflow design to protect sterile equipment surfaces, container-closures, and product.  Do not disrupt the path of unidirectional flow air in the critical area to pose a risk to product sterility. Drug Regulations : Online Resource for Latest Information 12/9/2013 97
  • 98.  Some of the techniques aimed at maintaining sterility of sterile items and surfaces include: ◦ Approach a necessary manipulation in a manner that does not compromise sterility of the product  Approach from the side and not above the product (in vertical unidirectional flow operations).  Refrain from speaking when in direct proximity to the critical area. Drug Regulations : Online Resource for Latest Information 12/9/2013 98
  • 99.  Some of the techniques aimed at maintaining sterility of sterile items and surfaces include: ◦ Maintain Proper Gown Control  Do not engage in any activity that poses an unreasonable contamination risk to the gown prior to and throughout aseptic operations. Drug Regulations : Online Resource for Latest Information 12/9/2013 99
  • 100.  Maintain Proper Gown Control  Permit personnel who are qualified and appropriately gowned in the aseptic manufacturing area.  The gown should  Provide a barrier between the body and exposed sterilized materials.  Prevent contamination from particles generated by, and microorganisms shed from, the body. Drug Regulations : Online Resource for Latest Information 12/9/2013 10 0
  • 101.  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). Drug Regulations : Online Resource for Latest Information 12/9/2013 10 1
  • 102.  Written procedures should detail the methods used to don each gown component in an aseptic manner.  Create an adequate barrier by the overlapping of gown components (e.g., gloves overlapping sleeves).  Change a gown immediately if an element of a gown is found to be torn or defective.  Sanitize gloves frequently. Drug Regulations : Online Resource for Latest Information 12/9/2013 10 2
  • 103.  Establish a program to regularly assess conformance of personnel.  Assess the ability of a cleanroom operator to maintain the quality of the gown after performance of gowning procedures.  FDA recommends that this assessment include microbiological surface sampling of several locations on a gown (e.g., glove fingers, facemask, forearm, chest). Drug Regulations : Online Resource for Latest Information 12/9/2013 10 3
  • 104.  Justify sampling sites.  Perform periodic requalification  Ensure consistent acceptability of aseptic gowning techniques. Drug Regulations : Online Resource for Latest Information 12/9/2013 10 4
  • 105.  Perform annual requalification ◦ For automated operations ◦ Where personnel involvement is minimized and ◦ When monitoring data indicate environmental control issues  Perform more frequent requalification for any aseptic processing operation if adverse conditions occur. Drug Regulations : Online Resource for Latest Information 12/9/2013 10 5
  • 106.  Maintain gown quality and strictly adhere to appropriate aseptic techniques.  Write procedures to adequately address circumstances under which personnel should be ◦ Retrained, ◦ Requalified, ◦ Reassigned to other areas. Drug Regulations : Online Resource for Latest Information 12/9/2013 10 6
  • 107.  Implement qualification similar training programme and personnel for laboratory personnel as that for manufacturing personnel.  Processes and systems cannot be considered to be in control and reproducible if the validity of data produced by the laboratory is in question. Drug Regulations : Online Resource for Latest Information 12/9/2013 10 7
  • 108.  Personnel significantly affect the quality of the environment.  Establish a vigilant and responsive personnel monitoring program.  Obtain surface samples of each operator's gloves on a daily basis, or in association with each lot. Drug Regulations : Online Resource for Latest Information 12/9/2013 10 8
  • 109.  Implement appropriate sampling frequency for other strategically selected locations of the gown.  Implement comprehensive monitoring program for operations which are especially labour intensive ◦ (i.e., those requiring repeated or complex aseptic manipulations). Drug Regulations : Online Resource for Latest Information 12/9/2013 10 9
  • 110.  Asepsis is fundamental to an aseptic processing operation.  Maintain contamination-free gloves and gowns throughout operations.  Do not sanitize gloves just prior to sampling ◦ This can prevent recovery of microorganisms that were present during an aseptic manipulation. Drug Regulations : Online Resource for Latest Information 12/9/2013 11 0
  • 111.  Conduct an investigation when operators exceed established levels or show an adverse trend.  Implement follow-up actions ◦ Increased sampling, ◦ Increased observation, ◦ Retraining, ◦ Gowning requalification, and ◦ Reassignment of the individual to operations outside of the aseptic manufacturing area. Drug Regulations : Online Resource for Latest Information 12/9/2013 11 1
  • 112.  21 CFR 210.3(b)(3) states that “Component means any ingredient intended for use in the manufacture of a drug product, including those that may not appear in such drug product.”  21 CFR 211.80(a) states that “There shall be written procedures describing in sufficient detail the receipt, identification, storage, handling, sampling, testing, and approval or rejection of components and drug product containers and closures; such written procedures shall be followed.” Drug Regulations : Online Resource for Latest Information 12/9/2013 11 2
  • 113.  21 CFR 211.80(b) states that “Components and drug product containers and closures shall at all times be handled and stored in a manner to prevent contamination.”  21 CFR 211.84(d) states, in part, that “Samples shall be examined and tested as follows: * * * (6) Each lot of a component, drug product container, or closure that is liable to microbiological contamination that is objectionable in view of its intended use shall be subjected to microbiological tests before use.” Drug Regulations : Online Resource for Latest Information 12/9/2013 11 3
  • 114.  21 CFR 211.94(c) states that “Drug product containers and closures shall be clean and, where indicated by the nature of the drug, sterilized and processed to remove pyrogenic properties to assure that they are suitable for their intended use.”  21 CFR specifications, 211.94(d) methods states that of testing, “Standards and, or where indicated, methods of cleaning, sterilizing, and processing to remove pyrogenic properties shall be written and followed for drug product containers and closures.” Drug Regulations : Online Resource for Latest Information 12/9/2013 11 4
  • 115.  21 CFR 211.113(b) states that “Appropriate written procedures, designed to prevent microbiological contamination of drug products purporting to be sterile, shall be established and followed. Such procedures shall include validation of any sterilization process.” Drug Regulations : Online Resource for Latest Information 12/9/2013 11 5
  • 116.  Do not contaminate a drug product through the use of components that are contaminated with microorganisms or endotoxins.  Examples of components include ◦ Active ingredients, ◦ Water for Injection (WFI), and ◦ Other excipients.  Characterize the microbial content (e.g., bioburden, endotoxin) of each component  Establish appropriate acceptance limits. Drug Regulations : Online Resource for Latest Information 12/9/2013 11 6
  • 117.  Parenteral products are intended to be nonpyrogenic. ◦ Endotoxin load data are significant because  Maintain written procedures and appropriate specifications for each lot of components that might contain endotoxins.  Reject any components failing to meet defined endotoxin limits. Drug Regulations : Online Resource for Latest Information 12/9/2013 11 7
  • 118.  In aseptic processing, each component is individually sterilized or  Several components are combined, with the resulting mixture sterilized.  Knowledge of bioburden is important in assessing whether a sterilization process is adequate.  Several methods can be suitable for sterilizing. Drug Regulations : Online Resource for Latest Information 12/9/2013 11 8
  • 119.  Filtration of a solution formed in Water for Injection is a widely used method.  The solution is passed through a sterilizing membrane or cartridge filter.  Filter sterilization is used where the component is soluble and is likely to be adversely affected by heat. Drug Regulations : Online Resource for Latest Information 12/9/2013 11 9
  • 120.  Crystallization and precipitation (or lyophilisation) of filtered solution as a sterile powder is another method. ◦ Involves more handling and manipulation. ◦ Has a higher potential for contamination. Drug Regulations : Online Resource for Latest Information 12/9/2013 12 0
  • 121.  Dry heat sterilization is a suitable method for components that are heat stable and insoluble.  Conducting carefully designed heat penetration and distribution studies is of particular significance for powder sterilization because of the insulating effects of the powder.  Irradiation can be used to sterilize some components.  Conduct studies to demonstrate that the process is appropriate for the component. Drug Regulations : Online Resource for Latest Information 12/9/2013 12 1
  • 122.  Render containers and closures sterile and, for parenteral drug products, nonpyrogenic.  Use a suitable process based on the nature of the container and/or closure materials.  Demonstrate sterility and non-pyrogenicity by validation study.  Specify the frequency of revalidation  Specify time limits for holding sterile, depyrogenated containers and closures. Drug Regulations : Online Resource for Latest Information 12/9/2013 12 2
  • 123.  Implement wash and rinse cycles for glass containers  These cycles remove foreign matter.  FDA recommends use of rinse water of high purity so as not to contaminate containers.  Use final rinse water of WFI, USP specifications Drug Regulations : Online Resource for Latest Information 12/9/2013 12 3
  • 124.  Assess depyrogenation process by spiking containers and closures with known quantities of endotoxin.  Measure endotoxin content after depyrogenation.  Perform challenge studies by directly applying a reconstituted endotoxin solution onto the surfaces being tested. Drug Regulations : Online Resource for Latest Information 12/9/2013 12 4
  • 125.  Dry the endotoxin solution.  Use positive controls to measure endotoxin recovery by the test method.  Process should reduce endotoxin content by at least 99.9 percent (3 logs). Drug Regulations : Online Resource for Latest Information 12/9/2013 12 5
  • 126.  Subjecting glass containers to dry heat generally accomplishes both sterilization and depyrogenation.  Validation of dry heat sterilization and depyrogenation should include ◦ Appropriate heat distribution and penetration studies ◦ Use of worst-case process cycles, ◦ Container characteristics (e.g., mass), and ◦ Specific loading configurations to represent actual production runs. Drug Regulations : Online Resource for Latest Information 12/9/2013 12 6
  • 127.  Plastic containers used for parenteral products also should be non-pyrogenic.  Where applicable, multiple WFI rinses can be effective in removing pyrogens from these containers. Drug Regulations : Online Resource for Latest Information 12/9/2013 12 7
  • 128.  Sterilize plastic containers with an appropriate gas, irradiation, or other suitable means.  For gases such as Ethylene Oxide (EtO), following issues should receive attention. ◦ The parameters and limits of the EtO sterilization cycle should be specified and monitored closely.  (e.g., temperature, pressure, humidity, gas concentration, exposure time, degassing, aeration, and determination of residuals)  EtO is an effective surface sterilant and is also used to penetrate certain packages with porous overwrapping. Drug Regulations : Online Resource for Latest Information 12/9/2013 12 8
  • 129.  Demonstrate the effectiveness of EtO and other gas sterilization processes with Biological indicators.  FDA recommends to control and validate methods ◦ For consistent penetration of the sterilant and ◦ To minimize residuals.  Residuals from EtO processes typically include ethylene oxide as well as its by products, and  Ensure that residues are within specified limits. Drug Regulations : Online Resource for Latest Information 12/9/2013 12 9
  • 130.  Clean Rubber closures (e.g., stoppers and syringe plungers) by multiple cycles of washing and rinsing.  Employ at least Purified Water, USP, of minimal endotoxin content.  Use WFI for parenteral products for final rinse(s)  Achieve depyrogenation by multiple rinses of hot WFI. Drug Regulations : Online Resource for Latest Information 12/9/2013 13 0
  • 131.  Minimize the time between washing, drying and sterilizing as residual moisture on the stoppers can support microbial growth and the generation of endotoxins.  Evaluate carefully sterilization process for rubber stoppers for heat penetration as it is a poor conductor of heat.  Demonstrate successful endotoxin removal from rubber materials in validation of washing procedure. Drug Regulations : Online Resource for Latest Information 12/9/2013 13 1
  • 132.  A potential source of contamination is the siliconization of rubber stoppers.  Silicone used in the preparation of rubber stoppers should ◦ Meet appropriate quality control criteria and ◦ Not have an adverse effect on the safety, quality, or purity of the drug product. Drug Regulations : Online Resource for Latest Information 12/9/2013 13 2
  • 133.  Apply same CGMP requirements to contractors as those established for in-house processing.  Review and assess the contractor's validation protocol and final validation report for container-closure preparation.  Accept containers or closures based on visual identification and Certificate of Analysis review after establishing supplier’s test results. (211.84(d)(3)) Drug Regulations : Online Resource for Latest Information 12/9/2013 13 3
  • 134.  A container closure system that permits penetration of microorganisms is unsuitable for a sterile product.  Detect & remove damaged or defective units during inspection of the final sealed product.  Ensure that shipment of product that may lack container closure integrity and lead to nonsterility is avoided. Drug Regulations : Online Resource for Latest Information 12/9/2013 13 4
  • 135.  Prevent loss of container closure system integrity by equipment suitability problems or incoming container or closure deficiencies ◦ For example, failure to detect vials fractured by faulty machinery as well as by mishandling of bulk finished stock has led to drug recalls.  Implement improved procedures to prevent and detect defects if damage that is not readily detected leads to loss of container closure integrity, Drug Regulations : Online Resource for Latest Information 12/9/2013 13 5
  • 136.  Monitor functional defects in delivery devices (e.g., syringe device defects, delivery volume).  Investigate any defects or results outside the specifications established for in-process and final inspection (§ 211.192) Drug Regulations : Online Resource for Latest Information 12/9/2013 13 6
  • 137.  21 CFR 211.63 states that “Equipment used in the manufacture, processing, packing, or holding of a drug product shall be of appropriate design, adequate size, and suitably located to facilitate operations for its intended use and for its cleaning and maintenance.”  21 CFR 211.65(a) states that “Equipment shall be constructed so that surfaces that contact components, in-process materials, or drug products shall not be reactive, additive, or absorptive so as to alter the safety, identity, strength, quality, or purity of the drug product beyond the official or other established requirements.” Drug Regulations : Online Resource for Latest Information 12/9/2013 13 7
  • 138.  21 CFR 211.67(a) states that “Equipment and utensils shall be cleaned, maintained, and sanitized at appropriate intervals to prevent malfunctions or contamination that would alter the safety, identify, strength, quality, or purity of the drug product beyond the official or other established requirements.”  21 CFR 211.94(c) states that “Drug product containers and closures shall be clean and, where indicated by the nature of the drug, sterilized and processed to remove pyrogenic properties to assure that they are suitable for their intended use.” Drug Regulations : Online Resource for Latest Information 12/9/2013 13 8
  • 139.  21 CFR 211.167(a) states that “For each batch of drug product purporting to be sterile and/or pyrogen-free, there shall be appropriate laboratory testing to determine conformance to such requirements. The test procedures shall be in writing and shall be followed.” Drug Regulations : Online Resource for Latest Information 12/9/2013 13 9
  • 140.  Avoid poor cGMP to prevent endotoxin contamination of an injectable product  Certain patient populations (e.g., neonates), those receiving other injections concomitantly, or those administered a parenteral in atypically large volumes or doses can be at greater risk for pyrogenic reaction than anticipated by the established limits based on body weight of a normal healthy adult. Drug Regulations : Online Resource for Latest Information 12/9/2013 14 0
  • 141.  Such clinical concerns reinforce the importance of exercising appropriate CGMP controls to prevent generation of endotoxins.  Drug product components, containers, closures, storage time limitations, and manufacturing equipment are among the areas to address in establishing endotoxin control. Drug Regulations : Online Resource for Latest Information 12/9/2013 14 1
  • 142.  Clean, dry, and store equipment appropriately to control bioburden and prevent contribution of endotoxin load.  Design equipment to be easily assembled and disassembled, cleaned, sanitized, and/or sterilized.  Employ adequate procedures to prevent endotoxin contamination by both upstream and downstream processing equipment. Drug Regulations : Online Resource for Latest Information 12/9/2013 14 2
  • 143.  Do not use sterilizing-grade filters and moist heat sterilization in removing endotoxin.  Inactivate endotoxin on equipment surfaces by high-temperature dry heat,  Remove endotoxin from equipment surfaces by cleaning procedures. Drug Regulations : Online Resource for Latest Information 12/9/2013 14 3
  • 144.  Employ initial rinses with appropriate high purity water and/or a cleaning agent (e.g., acid, base, surfactant), followed by final rinses with heated WFI for clean-in-place procedures  Dry equipment following cleaning, unless the equipment proceeds immediately to the sterilization step. Regulations : Online Drug Resource for Latest Information 12/9/2013 14 4
  • 145.  21 CFR 211.111 states that ◦ “When appropriate, time limits for the completion of each phase of production shall be established to assure the quality of the drug product. ◦ Deviation from established time limits may be acceptable if such deviation does not compromise the quality of the drug product. ◦ Such deviation shall be justified and documented.”. Drug Regulations : Online Resource for Latest Information 12/9/2013 14 5
  • 146.  Establish time limits for each phase of aseptic processing (§ 211.111).  Time limits should include ◦ The period between the start of bulk product compounding and its sterilization, ◦ Filtration processes ◦ Product exposure while on the processing line ◦ Storage of sterilized equipment, containers and closures. Drug Regulations : Online Resource for Latest Information 12/9/2013 14 6
  • 147.  Support time limits by data.  Establish Bioburden and endotoxin load for stages such as the formulation processing stage. Drug Regulations : Online Resource for Latest Information 12/9/2013 14 7
  • 148.  Limit the total time for product filtration to prevent microorganisms from penetrating the filter.  Such a time limit should also prevent a significant increase in upstream bioburden and endotoxin load. Drug Regulations : Online Resource for Latest Information 12/9/2013 14 8
  • 149.  Establish and Justify maximum use times for filters used solution clarification or particle removal. Drug Regulations : Online Resource for Latest Information 12/9/2013 14 9
  • 150.  21 CFR 211.63, 211.65, and 211.67 address, respectively, “Equipment design, size, and location,” “Equipment construction,” and “Equipment cleaning and maintenance.”  21 CFR 211.84(c) states, in part, that “Samples shall be collected in accordance with the following procedures: * * * (3) Sterile equipment and aseptic sampling techniques shall be used when necessary.” Drug Regulations : Online Resource for Latest Information 12/9/2013 15 0
  • 151.  21 CFR 211.100(a) states, in part, that “There shall be written procedures for production and process control designed to assure that the drug products have the identity, strength, quality, and purity they possess. purport Such or are procedures represented shall include to all requirements in this subpart * * *.” Drug Regulations : Online Resource for Latest Information 12/9/2013 15 1
  • 152.  21 CFR 211.113(b) states that “Appropriate written procedures, microbiological designed contamination to prevent of drug products purporting to be sterile, shall be established and followed. Such procedures shall include validation of any sterilization process.” Drug Regulations : Online Resource for Latest Information 12/9/2013 15 2
  • 153.  To ensure the sterility of products purporting to be sterile, sterilization, aseptic filling and closing operations must be adequately validated (§ 211.113). Drug Regulations : Online Resource for Latest Information 12/9/2013 15 3
  • 154.  The goal of even the most effective sterilization processes can be defeated if the sterilized elements of a product (the drug formulation, the container, and the closure) are brought together under conditions that contaminate any of those elements. Drug Regulations : Online Resource for Latest Information 12/9/2013 15 4
  • 155.  Validate an aseptic processing operation using a microbiological growth medium in place of the product.  This process simulation is also known as a media fill,  Includes exposing the microbiological growth medium to ◦ Product contact surfaces of equipment, ◦ Container closure systems, ◦ Critical environments, and ◦ Process manipulations to closely simulate the same exposure that the product itself will undergo. Drug Regulations : Online Resource for Latest Information 12/9/2013 15 5
  • 156.  Fill the sealed containers with the medium  Incubate to detect microbial contamination.  Interpret results to assess the potential for a unit of drug product to become contaminated during actual operations ◦ (e.g., start-up, sterile ingredient additions, aseptic connections, filling, closing). Drug Regulations : Online Resource for Latest Information 12/9/2013 15 6
  • 157.  Use environmental monitoring data from the process simulation information for to the provide processing useful line evaluation. Drug Regulations : Online Resource for Latest Information 12/9/2013 15 7
  • 158.  Incorporate the contamination risk factors that occur on a production line  Accurately assesses the state of process control  Closely simulate aseptic manufacturing operations  Incorporate ◦ Worst-case activities and ◦ Conditions that provide a challenge to aseptic operations. Drug Regulations : Online Resource for Latest Information 12/9/2013 15 8
  • 159.  FDA recommends that the media fill program address : ◦ Factors associated with the longest permitted run on the processing line that can pose contamination risk (e.g., operator fatigue) ◦ Representative number, type, and complexity of normal interventions that occur with each run, as well as nonroutine interventions and events (e.g., maintenance, stoppages, equipment adjustments) ◦ Lyophilisation, when applicable Drug Regulations : Online Resource for Latest Information 12/9/2013 15 9
  • 160.  FDA recommends that the media fill program address : ◦ Aseptic assembly of equipment (e.g., at start-up, during processing) ◦ Number of personnel and their activities ◦ Representative number of aseptic additions (e.g., charging containers and closures as well as sterile ingredients) or transfers Drug Regulations : Online Resource for Latest Information 12/9/2013 16 0
  • 161.  FDA recommends that the media fill program address : ◦ Shift changes, breaks, and gown changes (when applicable) ◦ Type of aseptic equipment disconnections/connections ◦ Aseptic sample collections Drug Regulations : Online Resource for Latest Information 12/9/2013 16 1
  • 162.  FDA recommends that the media fill program address : ◦ Line speed and configuration ◦ Weight checks ◦ Container closure systems (e.g., sizes, type, compatibility with equipment) ◦ Specific provisions relating to aseptic processing (e.g., conditions permitted before line clearance is mandated) Drug Regulations : Online Resource for Latest Information 12/9/2013 16 2
  • 163.  Prepare a written batch record, documenting production conditions and simulated activities.  Observe the same vigilance in both media fill and routine production runs. Drug Regulations : Online Resource for Latest Information 12/9/2013 16 3
  • 164.  Define rationale for the conditions and activities simulated during the media fill  Do not use media fills to justify practices that pose unnecessary contamination risks. Drug Regulations : Online Resource for Latest Information 12/9/2013 16 4
  • 165.  Repeat media fills to ensure that results are consistent and meaningful.  Single run can be inconclusive,  Multiple runs with divergent results signal a process that is not in control.  FDA recommends that ◦ At least three consecutive separate successful runs be performed during initial line qualification. Drug Regulations : Online Resource for Latest Information 12/9/2013 16 5
  • 166.  Conduct routine semi-annual qualification for each processing line  This will evaluate the state of control of the aseptic process.  Incorporate activities and interventions representative of each shift, and shift changeover, into the design of the semi-annual qualification program.  Address unique time-related and operational features. Drug Regulations : Online Resource for Latest Information 12/9/2013 16 6
  • 167.  All personnel authorized to enter the aseptic processing room should participate  Include technicians and maintenance personnel, at least once a year.  Participation should be consistent with the nature of each operator’s duties during routine production. Drug Regulations : Online Resource for Latest Information 12/9/2013 16 7
  • 168.  Evaluate each change to a product or line change  Assess through additional media fills changes of the aseptic process. Drug Regulations : Online Resource for Latest Information 12/9/2013 16 8
  • 169.  Perform revalidation for ◦ Facility and equipment modifications, ◦ Line configuration changes, ◦ Significant changes in personnel, ◦ Anomalies in environmental testing results, ◦ Container closure system changes, ◦ Extended shutdowns, or ◦ End product sterility testing showing contaminated products may be cause for revalidation of the system. Drug Regulations : Online Resource for Latest Information 12/9/2013 16 9
  • 170.  Conduct an investigation when data from a media fill indicate the process is not be in control,  Determine the origin of the contamination and the scope of the problem.  Implement corrections  Conduct process simulation run(s) to confirm corrections.  Confirm that the process has returned to a state of control. Drug Regulations : Online Resource for Latest Information 12/9/2013 17 0
  • 171.  Preform three media fill runs if investigation fails to reach cause of the media fill failure. Drug Regulations : Online Resource for Latest Information 12/9/2013 17 1
  • 172.  Duration a major consideration  Most accurate simulation- full batch size and duration  Other appropriate models can be justified. Drug Regulations : Online Resource for Latest Information 12/9/2013 17 2
  • 173.  Determine the duration of the media based on the time it takes to incorporate ◦ Manipulations ◦ Interventions ◦ Appropriate consideration of the duration of the actual aseptic processing operation.  Simulate common Interventions routinely  Simulate rare interventions periodically. Drug Regulations : Online Resource for Latest Information 12/9/2013 17 3
  • 174.  Manufacturing lines are automated  Operated at relatively high speeds  Designed to limit operator intervention  Some processes still include considerable operator involvement Drug Regulations : Online Resource for Latest Information 12/9/2013 17 4
  • 175.  If aseptic processing employs manual filling or closing ◦ Process simulation time should be equal to at least actual manufacturing time. Drug Regulations : Online Resource for Latest Information 12/9/2013 17 5
  • 176.  FDA recommendation for lyophilization ◦ Expose unsealed containers to partial evacuation simulating manufacturing process; ◦ Do not freeze the vials; ◦ Take precautions to ensure that the medium remains in an aerobic state Drug Regulations : Online Resource for Latest Information 12/9/2013 17 6
  • 177.  The simulation run sizes should be adequate ◦ To mimic commercial production conditions and ◦ Accurately assess the potential for commercial batch contamination.  The number of units filled during the process simulation should be based on ◦ Contamination risk for a given process and ◦ Sufficient to accurately simulate activities that are representative of the manufacturing process. Drug Regulations : Online Resource for Latest Information 12/9/2013 17 7
  • 178.  Acceptable run size :5,000 to 10,000 units.  For batch sizes under 5,000 ◦ Media filled units = the maximum batch size made on the processing line Drug Regulations : Online Resource for Latest Information 12/9/2013 17 8
  • 179.  Use full batch size for manually intensive filling line.  Use lower number of units for process conducted in an isolator. Drug Regulations : Online Resource for Latest Information 12/9/2013 17 9
  • 180.  Media fill size is an especially important consideration ◦ Some batches are produced over multiple shifts ◦ Some batches yield an unusually large number of units.  Consider these factors while designing the simulation to adequately encompass conditions and  Consider any risk associated with the larger operation. Drug Regulations : Online Resource for Latest Information 12/9/2013 18 0
  • 181.  Address all line speeds employed during production.  Evaluate a single line in each media fill  Justify the speed chosen.  Appropriate to use high line speed for ◦ A processes having frequent interventions or ◦ A significant degree of manual manipulation. Drug Regulations : Online Resource for Latest Information 12/9/2013 18 1
  • 182.  Use of slow appropriate line for speed evaluating is generally manufacturing processes with prolonged exposure of the sterile drug product and containers/closures in the aseptic area. Drug Regulations : Online Resource for Latest Information 12/9/2013 18 2
  • 183.  Use actual conditions under which manufacturing operations are conducted.  DO not conduct media fill ◦ Under extraordinary air particulate and microbial quality, or ◦ Under production controls and precautions taken in preparation for the media fill  This will make the process appear cleaner than it actually is.  Include analogous challenges to support the validity of these studies  Do not reconfigure HVAC systems to operate at worst-case limits.  Do not create worst case situations artificially. Drug Regulations : Online Resource for Latest Information 12/9/2013 18 3
  • 184.  Use growth medium, such as soybean casein digest.  Consider use of anaerobic growth media (e.g., fluid thioglycollate medium) in special circumstances.  Demonstrate growth of gram-positive and gram- negative bacteria, and yeast and mold (e.g., USP indicator organisms).  Determine if USP indicator organisms sufficiently represent production-related isolates. Drug Regulations : Online Resource for Latest Information 12/9/2013 18 4
  • 185.  Use isolates for Environmental monitoring and sterility challenge testing.  Incubate growth promotion units with @ <100 CFU challenge.  Investigate any failure/ contamination ◦ Repeat the media fill promptly. Drug Regulations : Online Resource for Latest Information 12/9/2013 18 5
  • 186.  Simulate the production process accurately  Use media and conditions that optimize detection of any microbiological contamination. Drug Regulations : Online Resource for Latest Information 12/9/2013 18 6
  • 187.  Fill each unit with an appropriate quantity and type of microbial growth medium  Contact the inner container closure surfaces ◦ when the unit is inverted or thoroughly swirled  Permit visual detection of microbial growth. Drug Regulations : Online Resource for Latest Information 12/9/2013 18 7
  • 188.  Concern expressed over the possible contamination of the facility and equipment  Follow adequate precautions like ◦ Proper handling of the medium ◦ Cleaning and sanitization of the equipment and area promptly ◦ Sterilization of the equipment if required Drug Regulations : Online Resource for Latest Information 12/9/2013 18 8
  • 189.  Incubate media units under conditions to detect difficult to culture microorganisms  General guidelines to establish incubation conditions: ◦ Incubation temperature :  Suitable for recovery of bioburden and environmental isolates;  Should at no time be outside the range of 20-35ºC.  Maintained within +2.5ºC of the target temperature. Drug Regulations : Online Resource for Latest Information 12/9/2013 18 9
  • 190.  General guidelines to establish incubation conditions: ◦ Incubation time  Should not be less than 14 days.  For incubation temperatures, incubate for at least 7 days at each temperature  (starting with the lower temperature). Drug Regulations : Online Resource for Latest Information 12/9/2013 19 0
  • 191.  Examine each media-filled unit  Personnel examining should have ◦ Appropriate education, ◦ Training, and ◦ Experience in inspecting media fill units for microbiological contamination.  Have QC oversight when QC personnel do not perform the inspection Drug Regulations : Online Resource for Latest Information 12/9/2013 19 1
  • 192.  Inform QC microbiologist of all suspect units  FDA recommends substituting clear containers (with otherwise identical physical properties) for amber or other opaque containers.  Consider other methods for visual detection as appropriate. Drug Regulations : Online Resource for Latest Information 12/9/2013 19 2
  • 193.  Incubate all integral units after a final product inspection following the media fill.  Reject units that lack integrity.  Incubate all other units  Incubate defective units where the defect is not related to integrity.  Return erroneously rejected units for incubation. Drug Regulations : Online Resource for Latest Information 12/9/2013 19 3
  • 194.  Any unit found damaged during incubation should be included in the data for the media fill run.  Justify any decision to exclude such incubated units (i.e., non-integral) from the final run tally .  Explain this deviation in the media fill report.  Conduct an investigation if a correlation emerges between difficult to detect damage and microbial contamination. Drug Regulations : Online Resource for Latest Information 12/9/2013 19 4
  • 195.  Have clear & specific written procedures for aseptic interventions ◦ Intervention type; ◦ Quantity of units removed  Have consistent production practices  Assesse these practices during media fills. Drug Regulations : Online Resource for Latest Information 12/9/2013 19 5
  • 196.  Do not procedures incubate and intervention batch units if documentation describe an associated clearance adequately.  No justification for exclusion of these units from incubation if procedures lack specificity. Drug Regulations : Online Resource for Latest Information 12/9/2013 19 6
  • 197.  For example, if a production procedure requires removal of 10 units after an intervention at the stoppering station infeed, batch records (i.e., for production and media fills) should clearly document conformance with this procedure.  In no case should more units be removed during a media fill intervention than would be cleared during a production run. Drug Regulations : Online Resource for Latest Information 12/9/2013 19 7
  • 198.  Large-scale line clearance should not compromise the ability of a media fill to detect potential contamination  FDA recommends to avoid a large line clearance that results in the removal of a unit possibly contaminated during an unrelated event or intervention. Drug Regulations : Online Resource for Latest Information 12/9/2013 19 8
  • 199.  Establish appropriate criteria for yield and reconciliation of filled units.  Include a full accounting and description of units rejected from a batch. Drug Regulations : Online Resource for Latest Information 12/9/2013 19 9
  • 200.  QC should observe the process simulation run  Reconcile contaminated units with the approximate time and the activity  Use Video recording in identifying wrong personnel practices Drug Regulations : Online Resource for Latest Information 12/9/2013 20 0
  • 201.  Investigate any contaminated unit  Identify microorganisms to species level.  Survey the possible causes of contamination.  Assess the impact on commercial drugs in case of any failure. (Since last successful media fill). Drug Regulations : Online Resource for Latest Information 12/9/2013 20 1
  • 202.  Regardless of run size contamination shows a potential sterility assurance problem.  The number of contaminated units do not increase proportionally with the number of media fill vials.  Test results should reliably and reproducibly show that the units produced by an aseptic processing operation are sterile. Drug Regulations : Online Resource for Latest Information 12/9/2013 20 2
  • 203.  Modern facilities have demonstrated contamination levels approaching zero  Normally yield no media fill contamination. Drug Regulations : Online Resource for Latest Information 12/9/2013 20 3
  • 204.  FDA Recommended criteria for assessing state of aseptic line control :  When filling fewer than 5000 units, no contaminated units should be detected. ◦ One (1) contaminated unit is considered cause for revalidation, following an investigation. Drug Regulations : Online Resource for Latest Information 12/9/2013 20 4
  • 205.  FDA Recommended criteria for assessing state of aseptic line control :  When filling from 5,000 to 10,000 units: ◦ One (1) contaminated unit should result in an investigation, including consideration of a repeat media fill. ◦ Two (2) contaminated units are considered cause for revalidation, following investigation. Drug Regulations : Online Resource for Latest Information 12/9/2013 20 5
  • 206.  FDA Recommended criteria for assessing state of aseptic line control :  When filling more than 10,000 units: ◦ One (1) contaminated unit should result in an investigation. ◦ Two (2) contaminated units are considered cause for revalidation, following investigation. Drug Regulations : Online Resource for Latest Information 12/9/2013 20 6
  • 207.  Intermittent incidents of microbial contamination indicate a persistent low-level contamination.  Investigate these problem.  Recurring incidents signal an adverse trend .  Identify problems, implement corrections, and revalidation. Drug Regulations : Online Resource for Latest Information 12/9/2013 20 7
  • 208.  A firm's use of media fill acceptance criteria allowing infrequent contamination does not mean that a distributed lot of drug product purporting to be sterile may contain a nonsterile unit.  The purpose of an aseptic process is to prevent any contamination. Drug Regulations : Online Resource for Latest Information 12/9/2013 20 8
  • 209.  A manufacturer is fully liable for the shipment of any nonsterile unit, an act that is prohibited under the FD&C Act (Section 301(a) 21 U.S.C. 331(a)).  FDA also recognizes that there might be some scientific and technical limitations on how precisely and accurately process simulations can characterize a system of controls intended to exclude contamination. Drug Regulations : Online Resource for Latest Information 12/9/2013 20 9
  • 210.  Invalidation of a media fill run should be a rare occurrence.  Abort media fill only when procedures require commercial lots to be equally handled.  Provide supporting documentation and justification. Drug Regulations : Online Resource for Latest Information 12/9/2013 21 0
  • 211.  Filtration is a common method of sterilizing drug product solutions.  Validate a sterilizing grade filter to reproducibly remove viable microorganisms  Rated pore size of 0.2 μm or smaller. Drug Regulations : Online Resource for Latest Information 12/9/2013 21 1
  • 212.  Consider use of redundant sterilizing filters  Validation should include ◦ Microbiological challenges to simulate worst-case production conditions for the material to be filtered and ◦ Integrity test results of the filters used for the study.  Evaluate product bioburden to assess which microorganism represents the worst-case challenge to the filter. Drug Regulations : Online Resource for Latest Information 12/9/2013 21 2
  • 213.  For 0.2 μm rated filters ◦ The microorganism Brevundimonas diminuta (ATCC 19146) when properly grown, harvested and used, is a common challenge Drug Regulations : Online Resource for Latest Information 12/9/2013 21 3
  • 214.  Design process controls to minimize the bioburden of the unfiltered product.  Determine bioburden of unsterilized bulk solutions.  Trend the characteristics of potentially contaminating organisms. Drug Regulations : Online Resource for Latest Information 12/9/2013 21 4
  • 215.  Use bioburden isolate when equivalent or better  Conduct bacterial retention studies with isolate  The number of microorganisms in the challenge is important.  Filter can contain a number of pores larger than the nominal rating.  This has the potential to allow passage of microorganisms. Drug Regulations : Online Resource for Latest Information 12/9/2013 21 5
  • 216.  Probability increase as the number of bioburden organisms  Use a challenge concentration of at least 107 organisms per cm2 of effective filtration area  This should result in no passage of the challenge microorganism. Drug Regulations : Online Resource for Latest Information 12/9/2013 21 6
  • 217.  The challenge concentration used for validation is intended to provide a margin of safety well beyond what would be expected in production. Drug Regulations : Online Resource for Latest Information 12/9/2013 21 7
  • 218.  Direct inoculation into the drug formulation is the preferred method  Provides an assessment of the effect of drug product on the filter matrix and on the challenge organism.  Erroneous conclusions if product has inherent bactericidal activity, or if oil-based formulation.  Use alternate method to assess effects of the product formulation on the membrane's integrity Drug Regulations : Online Resource for Latest Information 12/9/2013 21 8
  • 219.  For example,  Filter a drug product to simulate worst-case combination of process specifications and conditions  Follow this by filtration of the challenge organism for ◦ A significant period of time, ◦ Under the same conditions, ◦ Using an appropriately modified product (e.g., lacking an antimicrobial preservative or other antimicrobial component) as the vehicle.  Justify divergence from actual product and conditions Drug Regulations : Online Resource for Latest Information 12/9/2013 21 9
  • 220.  Factors that can affect filter performance generally include ◦ Viscosity and surface tension of the material to be filtered, ◦ pH, ◦ Compatibility of the material or formulation components with the filter itself ◦ Pressures ◦ Flow rates Drug Regulations : Online Resource for Latest Information 12/9/2013 22 0
  • 221.  Factors that can affect filter performance generally include ◦ Maximum use time, ◦ Temperature, ◦ Osmolality, ◦ The effects of hydraulic shock. Drug Regulations : Online Resource for Latest Information 12/9/2013 22 1
  • 222.  Validation ◦ Evaluate effect of the extremes of processing factors ◦ Use worst-case conditions, such as maximum filter use time and pressure. ◦ Need not be conducted in the actual manufacturing areas. ◦ Laboratory experiments should simulate actual production conditions. ◦ Use membrane used in commercial production in validation studies. Drug Regulations : Online Resource for Latest Information 12/9/2013 22 2
  • 223.  Validation ◦ Advantageous to use production filters ◦ Complex test can be conducted by outside laboratories or by filter manufacturers. ◦ Filter user should review the validation data . ◦ The data should be applicable to the user's products and conditions of use ◦ Filter performance may differ significantly for various conditions and products Drug Regulations : Online Resource for Latest Information 12/9/2013 22 3
  • 224.  Use identical filters (e.g., of identical polymer construction and pore size rating) in production & validation runs.  Discard sterilizing filters routinely after processing of a single lot.  Sterile filter validation should incorporate the maximum number of lots to be processed Drug Regulations : Online Resource for Latest Information 12/9/2013 22 4
  • 225.  Perform integrity testing of the filter(s) prior to processing  Repeat the testing post-use.  Detect any filter leaks or perforations that might have occurred during the filtration Drug Regulations : Online Resource for Latest Information 12/9/2013 22 5
  • 226.  Integrity Tests ◦ Forward flow ◦ Bubble point tests  A production filter’s integrity test specification should be consistent with data generated during bacterial retention validation studies. Drug Regulations : Online Resource for Latest Information 12/9/2013 22 6
  • 227.  Equipment surfaces that contact sterilized drug product or its sterilized containers or closures must be sterile so as not to alter purity of the drug (211.67 and 211.113).  Render free of viable organisms surfaces that are in the vicinity of the sterile product  Validate the processes used to sterilize critical equipment , containers and closures. Drug Regulations : Online Resource for Latest Information 12/9/2013 22 7
  • 228.  Widely used processes: Moist heat and dry heat sterilization.  Maintain sterility of aseptic processing equipment by sterilization between each batch.  Follow aseptic methods for transportation and assembly of equipment, containers, and closures to protect and sustain the product's sterile state. Drug Regulations : Online Resource for Latest Information 12/9/2013 22 8
  • 229.  Conduct validation studies to demonstrate the efficacy of the sterilization cycle.  Perform requalification studies on a periodic basis.  Document the ◦ Specific load configurations ◦ Biological indicator location ◦ Temperature sensor location  Follow validated load pattern during production Drug Regulations : Online Resource for Latest Information 12/9/2013 22 9
  • 230.  Remove air from the autoclave chamber as part of a steam sterilization cycle.  The insulating properties of air interfere with the ability of steam to transfer its energy to the load.  This achieves lower lethality than associated with saturated steam. Drug Regulations : Online Resource for Latest Information 12/9/2013 23 0
  • 231.  Resistance of microorganisms vary widely depending on the material to be sterilized.  During sterilization validation consider nature of material chosen as the carrier of the biological indicator to ensure an appropriately representative study. Drug Regulations : Online Resource for Latest Information 12/9/2013 23 1
  • 232.  Evaluate potentially difficult to reach locations within the sterilizer load or equipment train.  Filter installations substantial in pressure piping can differential cause across a the filter, resulting in a significant temperature drop on the downstream side.  FDA recommends placing biological indicators at appropriate downstream locations of the filter. Drug Regulations : Online Resource for Latest Information 12/9/2013 23 2
  • 233.  Empty chamber studies ◦ Evaluate numerous locations throughout a sterilizing unit (e.g., steam autoclave, dry heat oven) or ◦ Equipment train (e.g., large tanks, immobile piping) to confirm uniformity of conditions (e.g., temperature, pressure).  Conduct these studies with calibrated measurement devices. Drug Regulations : Online Resource for Latest Information 12/9/2013 23 3
  • 234.  Perform heat penetration studies with established sterilizer loads.  Validation with a loaded chamber demonstrates the effects of loading on thermal input to the items being sterilized and  Identify difficult to heat or penetrate items where there could be insufficient lethality to attain sterility. Drug Regulations : Online Resource for Latest Information 12/9/2013 23 4
  • 235.  Confirm the efficacy of sterilization process by placing biological indicators at numerous positions including the most difficult to sterilize places.  Place biological temperature correlation indicators sensor between so as adjacent to the assess the lethality and to microbial predicted lethality based on thermal input. Drug Regulations : Online Resource for Latest Information 12/9/2013 23 5
  • 236.  Give special attention to the sterilization of filters, filling manifolds, and pumps to determine which articles are difficult to sterilize.  Some other examples include ◦ Certain locations of tightly wrapped or densely packed supplies ◦ Securely fastened load articles, ◦ Lengthy tubing ◦ Sterile filter apparatus, hydrophobic filters, and stopper load. Drug Regulations : Online Resource for Latest Information 12/9/2013 23 6
  • 237.  Base cycle specifications on delivery of adequate lethality to the slowest to heat locations.  Demonstrate a sterility assurance level of 10-6 or better.  Focus on the load areas identified as most difficult to penetrate or heat Drug Regulations : Online Resource for Latest Information 12/9/2013 23 7
  • 238.  Establish suitability of the sterilizer by ◦ Qualification, ◦ Maintenance, ◦ Change control, and ◦ Periodic verification of the cycle, ◦ Including biological challenges.  Address issues such as load configuration change or a modification of a sterilizer in Change Control Programme. Drug Regulations : Online Resource for Latest Information 12/9/2013 23 8
  • 239.  Data from sterilization cycle monitoring devices are critical  Calibrate devices that measure cycle parameters  Have written procedures to maintain devices in a calibrated state.  For example, we recommend that procedures address the following: Drug Regulations : Online Resource for Latest Information 12/9/2013 23 9
  • 240.  FDA recommends that procedures address the following: ◦ Temperature and pressure monitoring devices for heat sterilization should be calibrated at suitable intervals. ◦ The sensing devices used for validation studies should be calibrated before and after validation runs. Drug Regulations : Online Resource for Latest Information 12/9/2013 24 0
  • 241.  FDA recommends that procedures address the following: ◦ Devices used to monitor dwell time in the sterilizer should be periodically calibrated. ◦ Confirm microbial count of a biological indicator ◦ Store Biological indicators under appropriate conditions. ◦ Determine D value of Biological Indicator Drug Regulations : Online Resource for Latest Information 12/9/2013 24 1
  • 242.  FDA recommends that procedures address the following: ◦ Establish reliability of a vendor’s Certificate of Analysis to accept D-value of a biological indicator in lieu of confirmatory testing of each lot. ◦ Determine (D-value) for any biological indicator used in a way that is other than described by the vendor. ◦ D-value determinations can be conducted by an independent laboratory. Drug Regulations : Online Resource for Latest Information 12/9/2013 24 2
  • 243.  FDA recommends that procedures address the following: ◦ Calibrate instruments used to determine the purity of steam. ◦ Calibrate devices used to measure belt speed of dry heat depyrogenation tunnels. ◦ Prepare & measure bacterial endotoxin challenges. Drug Regulations : Online Resource for Latest Information 12/9/2013 24 3
  • 244.  Ensure robust process control by properly designed equipment with ◦ Accessibility to sterilant, ◦ Piping slope, and ◦ Proper condensate removal (as applicable).  Equipment control ◦ Ensure through placement of measuring devices at those control points that are most likely to rapidly detect unexpected process variability. Drug Regulations : Online Resource for Latest Information 12/9/2013 24 4
  • 245.  Document steps where manual manipulations of valves are required for sterilizer or SIP operations.  Maintain sterilizing equipment properly for consistent, satisfactory function.  Evaluate sterilizer performance by equilibrium (come up) time  This will assure that the unit continues to operate as per the validated conditions. Drug Regulations : Online Resource for Latest Information 12/9/2013 24 5
  • 246.  21 CFR 211.22(b) states that “Adequate laboratory facilities for the testing and approval (or rejection) of components, drug product containers, closures, packaging materials, in-process materials, and drug products shall be available to the quality control unit.”  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 drug product.” Drug Regulations : Online Resource for Latest Information 12/9/2013 24 6
  • 247.  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; * * *.” Drug Regulations : Online Resource for Latest Information 12/9/2013 24 7
  • 248.  21 CFR 211.56(b) states that “There shall be written procedures assigning responsibility for sanitation and describing in sufficient detail the cleaning schedules, methods, equipment, and materials to be used in cleaning the buildings and facilities; such written procedures shall be followed.” Drug Regulations : Online Resource for Latest Information 12/9/2013 24 8
  • 249.  21 CFR 211.56(c) states, in part, that “There shall be written procedures rodenticides, for insecticides, use of fungicides, suitable fumigating agents, and cleaning and sanitizing agents. Such written procedures shall be designed to prevent the contamination of equipment, components, drug product containers, closures, packaging, labeling materials, or drug products and shall be followed * * *.” Drug Regulations : Online Resource for Latest Information 12/9/2013 24 9
  • 250.  21 CFR 211.110(a) states, in part, that “To assure batch uniformity and integrity of drug products, written procedures shall be established and followed that describe the in-process controls, and tests, or examinations to be conducted on appropriate samples of in-process materials of each batch. Such control procedures shall be established to monitor the output and to validate the performance of those manufacturing processes that may be responsible for causing variability in the characteristics of in-process material and the drug product * * *.” Drug Regulations : Online Resource for Latest Information 12/9/2013 25 0
  • 251.  21 CFR 211.113(b) states that “Appropriate written procedures, designed to prevent microbiological contamination of drug products purporting to be sterile, shall be established and followed. Such procedures shall include validation of any sterilization process.” Drug Regulations : Online Resource for Latest Information 12/9/2013 25 1
  • 252.  21 CFR 211.160(b) states that “Laboratory controls shall include the establishment of scientifically sound and appropriate specifications, standards, sampling plans, and test procedures designed to assure that components, drug product materials, containers, labeling, and closures, drug products in-process conform to appropriate standards of identity, strength, quality, and purity. Laboratory controls shall include: Drug Regulations : Online Resource for Latest Information 12/9/2013 25 2
  • 253.  (1) Determination of conformance to appropriate written specifications for the acceptance of each lot within each shipment of components, drug product containers, closures, and labeling used in the manufacture, processing, packing, or holding of drug products. The specifications shall include a description of the sampling and testing procedures used. Samples shall be representative and adequately identified. Such procedures shall also require appropriate retesting of any component, drug product container, or closure that is subject to deterioration.  (2) Determination of conformance to written specifications and a description of sampling and testing procedures for in-process materials. Such samples shall be representative and properly identified. Drug Regulations : Online Resource for Latest Information 12/9/2013 25 3
  • 254.  (3) Determination of conformance to written descriptions of sampling procedures and appropriate specifications for drug products. Such samples shall be representative and properly identified. (4) The calibration of instruments, apparatus, gauges, and recording devices at suitable intervals in accordance with an established written program containing specific directions, schedules, limits for accuracy and precision, and provisions for remedial action in the event accuracy and/or precision limits are not met. Instruments, apparatus, gauges, and recording devices not meeting established specifications shall not be used.” Drug Regulations : Online Resource for Latest Information 12/9/2013 25 4
  • 255.  21 CFR 211.165(e) states that “The accuracy, sensitivity, specificity, and reproducibility of test methods employed by the firm shall be established and documented. Such validation and documentation may be accomplished in accordance with § 211.194(a)(2).”  21 CFR 211.192 states, in part, that “All drug product production and control records, including those for packaging and labeling, shall be reviewed and approved by the quality control unit to determine compliance with all established, approved written procedures before a batch is released or distributed * * *.” Drug Regulations : Online Resource for Latest Information 12/9/2013 25 5
  • 256.  Environmental monitoring program : One of the most important laboratory controls.  Provides information on the quality of the aseptic processing environment and environmental trends of ancillary clean areas.  Identifies potential routes of contamination,  Allows for implementation of corrections before product contamination occurs (211.42 and 211.113). Drug Regulations : Online Resource for Latest Information 12/9/2013 25 6
  • 257.  Have a well-defined written program and scientifically sound methods.  Cover all production shifts and ◦ include air, ◦ floors, ◦ walls, and ◦ equipment surfaces, including the critical surfaces that come in contact with the product, container, and closures.  Include list of locations to be sampled in written procedures. Drug Regulations : Online Resource for Latest Information 12/9/2013 25 7
  • 258.  Select sample timing, frequency, and location based upon their relationship to the operation performed.  Take samples throughout the classified areas of the aseptic processing facility.  Use scientifically sound sampling procedures.  Use sufficient sample sizes to optimize detection of environmental contaminants at levels that might be expected in a given clean area. Drug Regulations : Online Resource for Latest Information 12/9/2013 25 8
  • 259.  Use locations posing the most microbiological risk to the product as a key part of the program.  Monitor the microbiological quality of the critical area to determine whether or not aseptic conditions are maintained during filling and closing activities.  Take air and surface samples where significant activity or product exposure occurs during production. Drug Regulations : Online Resource for Latest Information 12/9/2013 25 9
  • 260.  Critical surfaces that come in contact with the sterile product should remain sterile throughout an operation.  Identify critical sites to be sampled based on ◦ Points of contamination risk in a process, ◦ Difficulty of setup, ◦ Length of processing time, and ◦ Impact of interventions. Drug Regulations : Online Resource for Latest Information 12/9/2013 26 0
  • 261.  Perform critical surface sampling at the conclusion of the aseptic processing operation to avoid direct contact with sterile surfaces during processing.  Detection of microbial contamination on a critical site would not necessarily result in batch rejection.  Perform an investigation when contaminated critical site is detected ◦ Operational information and ◦ Data that includes an awareness of the potential for a low incidence of false positives. Drug Regulations : Online Resource for Latest Information 12/9/2013 26 1
  • 262.  Environmental monitoring methods do not always recover microorganisms present in the sampled area.  Low-level contamination can be particularly difficult to detect.  Because false negatives can occur, consecutive growth results are only one type of adverse trend. Drug Regulations : Online Resource for Latest Information 12/9/2013 26 2
  • 263.  Track increased incidence of contamination over a given period.  In the absence of any adverse trend, a single result above an action level should trigger an evaluation and a determination about whether remedial measures may be appropriate.  In all room classes, remedial measures should be taken in response to unfavourable trends. Drug Regulations : Online Resource for Latest Information 12/9/2013 26 3
  • 264.  Describe all environmental monitoring locations to allow for reproducible sampling.  Written SOPs should also address elements such as ◦ Frequency of sampling, ◦ When the samples are taken (i.e., during or at the conclusion of operations), ◦ Duration of sampling, ◦ Sample size (e.g., surface area, air volume), ◦ Specific sampling equipment and techniques, ◦ Alert and action levels, and ◦ Appropriate response to deviations from alert or action levels. Drug Regulations : Online Resource for Latest Information 12/9/2013 26 4
  • 265.  Establish microbiological monitoring levels based on the relationship of the sampled location to the operation.  Base the levels on the need to maintain adequate microbiological control throughout the entire sterile manufacturing facility. Drug Regulations : Online Resource for Latest Information 12/9/2013 26 5
  • 266.  Consider environmental monitoring data from historical databases, qualification, and media fills, sanitization cleanroom studies, in developing monitoring levels.  Use data from similar operations in setting action and alert levels, especially for a new operation. Drug Regulations : Online Resource for Latest Information 12/9/2013 26 6
  • 267.  Environmental information monitoring provides the of on quality the manufacturing environment.  Evaluate each individual sample result by comparison to the alert or action levels.  Averaging of results can mask unacceptable localized conditions. Drug Regulations : Online Resource for Latest Information 12/9/2013 26 7
  • 268.  Alert level : Requires attention to the approaching action conditions.  Action level : Requires a more thorough investigation.  Have procedures for data review frequency and actions to be taken.  Have QC oversight of near-term (e.g., daily, weekly, monthly, quarterly) and long-term trends in ◦ environmental and ◦ personnel monitoring data. Drug Regulations : Online Resource for Latest Information 12/9/2013 26 8
  • 269.  Include location, data shift, room, for operator, or other parameters in trends.  Produce specialized data reports for investigations & actions.  Consider significant changes in microbial flora  Define systems to inform management about Drug Regulations trends and investigations. : Online Resource for Latest Information 12/9/2013 26 9
  • 270.  Asses suitability, efficacy, and limitations of disinfecting agents and procedures  Measure effectiveness of disinfectants and procedures ◦ (potential contaminants are adequately removed from surfaces) Drug Regulations : Online Resource for Latest Information 12/9/2013 27 0
  • 271.  Disinfectants should be ◦ Effective against the normal microbial vegetative flora recovered from the facility. ◦ Sterile, ◦ Appropriately handled in suitable (e.g., sterile) containers and ◦ Used for no longer than the predefined period specified by written procedures. Drug Regulations : Online Resource for Latest Information 12/9/2013 27 1
  • 272.  Many common disinfectants are ineffective against spores. ◦ For example, 70 per cent isopropyl alcohol is ineffective against Bacillus spp. spores.  When spore forming organisms are present use sporicidal agent. Drug Regulations : Online Resource for Latest Information 12/9/2013 27 2
  • 273.  Describe disinfection procedures in sufficient detail for reproducibility.  Evaluate accuracy using a routine environmental monitoring program.  Investigate microorganisms associated with adverse trends as to their sensitivity to the disinfectants Drug Regulations : Online Resource for Latest Information 12/9/2013 27 3
  • 274.  Surface Monitoring ◦ Involves sampling of various surfaces  Product contact surfaces  Floors  Walls  Equipment ◦ Use touch plates, swabs, and contact plates Drug Regulations : Online Resource for Latest Information 12/9/2013 27 4
  • 275.  b. Active Air Monitoring ◦ Active devices include but not limited to impaction, centrifugal, and membrane (or gelatin) samplers. ◦ All allow testing of the number of organisms per volume of air sampled. ◦ FDA recommends that such devices be used during each production shift to evaluate aseptic processing areas at carefully chosen locations. Drug Regulations : Online Resource for Latest Information 12/9/2013 27 5
  • 276.  b. Active Air Monitoring ◦ Evaluate the air sampler for its suitability for use in an aseptic environment based on  Collection efficiency,  Cleanability,  Ability to be sterilized, and  Disruption of unidirectional airflow. Drug Regulations : Online Resource for Latest Information 12/9/2013 27 6
  • 277.  b. Active Air Monitoring ◦ Assess the overall suitability of a monitoring device before it is placed into service. ◦ Calibrate such devices ◦ Use according to appropriate procedures Drug Regulations : Online Resource for Latest Information 12/9/2013 27 7
  • 278.  c. Passive Air Monitoring (Settling Plates) ◦ Petri dishes containing nutrient growth medium exposed to the environment. ◦ Only microorganisms that settle onto the agar surface are detected. ◦ Are used as qualitative, or semi-quantitative, air monitors. ◦ Position plates in critical areas in locations posing the greatest risk of product contamination. Drug Regulations : Online Resource for Latest Information 12/9/2013 27 8
  • 279.  c. Passive Air Monitoring (Settling Plates) ◦ Evaluate media exposure conditions to optimize recovery of low levels of environmental isolates. ◦ Exposure conditions should preclude desiccation which inhibits recovery of microorganisms. ◦ Consider data in combination with results from other types of air samples. Drug Regulations : Online Resource for Latest Information 12/9/2013 27 9
  • 280.  Characterization of recovered microorganisms provides vital information  Environmental isolates often correlate with the contaminants found in a media fill or product sterility testing failure.  Overall environmental picture provides valuable information for an investigation. Drug Regulations : Online Resource for Latest Information 12/9/2013 28 0
  • 281.  Identify organisms to the species level ◦ Critical and immediately surrounding clean ◦ personnel  Micro organisms migrate into the aseptic processing room from either uncontrolled or lesser controlled areas. Drug Regulations : Online Resource for Latest Information 12/9/2013 28 1
  • 282.  Establish an adequate program in the lesser-controlled environments  This can often detect adverse trends.  Identify organism till species/genus level in these ancillary environments at frequent intervals to ◦ Establish a valid, current database of contaminants present in the facility during processing ◦ Demonstrate that cleaning and sanitization procedures continue to be effective Drug Regulations : Online Resource for Latest Information 12/9/2013 28 2
  • 283.  Genotypic methods more accurate and precise than biochemical and phenotypic techniques.  Valuable for investigations into  Use appropriate biochemical and phenotypic methods for routine identification of isolates. Drug Regulations : Online Resource for Latest Information 12/9/2013 28 3
  • 284.  The goal of microbiological monitoring is to reproducibly detect microorganisms for purposes of monitoring the state of environmental control.  Consistent methods will yield a database that allows for sound data comparisons and interpretations. Drug Regulations : Online Resource for Latest Information 12/9/2013 28 4
  • 285.  Validate the culture media for fungi and bacteria  Determine appropriate conditions of time and temperature for incubation.  Total aerobic bacterial count can be obtained by incubating at 30 to 35oC for 48 to 72 hours.  Total combined yeast and mold count can generally be obtained by incubating at 20 to 25oC for 5 to 7 days. Drug Regulations : Online Resource for Latest Information 12/9/2013 28 5
  • 286.  Design manufacturing process controls to minimize the bioburden in the unfiltered product.  Bioburden ◦ Increases the challenge to the sterilizing filter, impurities (e.g., endotoxin) to, and ◦ Lead to degradation of, the drug product.  Establish a prefiltration bioburden limit Drug Regulations : Online Resource for Latest Information 12/9/2013 28 6
  • 287.  Other suitable microbiological test methods (e.g., rapid test methods) can be considered ◦ For environmental monitoring, ◦ In-process control testing, and ◦ Finished product release testing  Demonstrate that the methods are equivalent or better than traditional methods (e.g.,USP). Drug Regulations : Online Resource for Latest Information 12/9/2013 28 7
  • 288.  Use routine particle monitoring to detect deviations from qualified processing norms  Investigate a result outside the established classification level  Investigation should be consistent with the severity of the excursion Drug Regulations : Online Resource for Latest Information 12/9/2013 28 8
  • 289.  Evaluate of trending data.  Implement appropriate corrective action to prevent future deviations. Drug Regulations : Online Resource for Latest Information 12/9/2013 28 9
  • 290.  21 CFR 210.3(b)(21) states that “Representative sample means a sample that consists of a number of units that are drawn based on rational criteria such as random sampling and intended to assure that the sample accurately portrays the material being sampled.” Drug Regulations : Online Resource for Latest Information 12/9/2013 29 0
  • 291.  21 CFR 211.110(a) states, in part, that “To assure batch uniformity and integrity of drug products, written procedures shall be established and followed that describe the in-process controls, and tests, or examinations to be conducted on appropriate samples of in-process materials of each batch. Such control procedures shall be established to monitor the output and to validate the performance of those manufacturing processes that may be responsible for causing variability in the characteristics of in-process material and the drug product.” Drug Regulations : Online Resource for Latest Information 12/9/2013 29 1
  • 292.  21 CFR 211.160(b) states that “Laboratory controls shall include the establishment of scientifically sound and appropriate specifications, standards, sampling plans, and test procedures designed to assure that components, drug product materials, containers, labeling, and closures, drug products in-process conform to appropriate standards of identity, strength, quality, and purity. Laboratory controls shall include: Drug Regulations : Online Resource for Latest Information 12/9/2013 29 2
  • 293.  (1) Determination of conformance to appropriate written specifications for the acceptance of each lot within each shipment of components, drug product containers, closures, and labelling used in the manufacture, processing, packing, or holding of drug products. The specifications shall include a description of the sampling and testing procedures used. Samples shall be representative and adequately identified. Such procedures shall also require appropriate retesting of any component, drug product container, or closure that is subject to deterioration Drug Regulations : Online Resource for Latest Information 12/9/2013 29 3
  • 294.  (2) Determination of conformance to written specifications and a description of sampling and testing procedures for in-process materials. Such samples shall be representative and properly identified.  (3) Determination of conformance to written descriptions of sampling procedures and appropriate specifications for drug products. Such samples shall be representative and properly identified. Drug Regulations : Online Resource for Latest Information 12/9/2013 29 4
  • 295.  (4) The calibration of instruments, apparatus, gauges, and recording devices at suitable intervals in accordance with an established directions, written schedules, program limits containing for specific accuracy and precision, and provisions for remedial action in the event accuracy and/or precision limits are not met. Instruments, apparatus, gauges, and recording devices not meeting established specifications shall not be used.” Drug Regulations : Online Resource for Latest Information 12/9/2013 29 5
  • 296.  21 CFR 211.165(a) states, in part, that “For each batch of drug product, there shall be appropriate laboratory determination of satisfactory conformance to final specifications for the drug product, including the identity and strength of each active ingredient, prior to release * * *.”  21 CFR 211.165(e) states that “The accuracy, sensitivity, specificity, and reproducibility of test methods employed by the firm shall be established and documented. Such validation and documentation may be accomplished in accordance with § 211.194(a)(2).” Drug Regulations : Online Resource for Latest Information 12/9/2013 29 6
  • 297.  21 CFR 211.167(a) states that “For each batch of drug product purporting to be sterile and/or pyrogen-free, there shall be appropriate laboratory testing to determine conformance to such requirements. The test procedures shall be in writing and shall be followed.”  21 CFR 211.180(e) states, in part, that “Written records required by this part shall be maintained so that data therein can be used for evaluating, at least annually, the quality standards of each drug product to determine the need for changes in drug product specifications or manufacturing or control procedures * * *.” Drug Regulations : Online Resource for Latest Information 12/9/2013 29 7
  • 298.  21 CFR 211.192 states that “All drug product production and control records, including those for packaging and labeling, shall be reviewed and approved by the quality control unit to determine established, compliance approved written with all procedures before a batch is released or distributed. Drug Regulations : Online Resource for Latest Information 12/9/2013 29 8
  • 299.  21 CFR 211.192 states that “All drug product production and control records, including those for packaging and labeling, shall be reviewed and approved by the quality control unit to determine established, compliance approved written with all procedures before a batch is released or distributed. Drug Regulations : Online Resource for Latest Information 12/9/2013 29 9
  • 300.  Any unexplained discrepancy (including a percentage of theoretical yield exceeding the maximum or minimum percentages established in master production and control records) or the failure of a batch or any of its components to meet any of its specifications shall be thoroughly investigated, whether or not the batch has already been distributed”. Drug Regulations : Online Resource for Latest Information 12/9/2013 30 0
  • 301.  Certain aspects of sterility testing are of particular importance, ◦ Control of the testing environment, ◦ Understanding the test limitations, and ◦ Investigating manufacturing systems following a positive test. Drug Regulations : Online Resource for Latest Information 12/9/2013 30 1
  • 302.  Employ facilities and controls comparable to those used for aseptic filling operations in the testing lab  Poor or deficient sterility test facilities or controls can result in test failure. Drug Regulations : Online Resource for Latest Information 12/9/2013 30 2
  • 303.  In case of production facilities and controls are better than sterility testing, positive sterility test result may be attributed to a faulty laboratory even when the product tested could have been nonsterile.  Therefore, a manufacturing deficiency may go undetected.  The use of isolators for sterility testing minimizes the chance of a false positive test result. Drug Regulations : Online Resource for Latest Information 12/9/2013 30 3
  • 304.  Sterility testing methods are required to be accurate and reproducible ◦ in accordance with 211.194 and 211.165.  Principal source for sterility testing: ◦ USP <71> “Sterility Tests”  sterility testing methods,  information on test procedures and media Drug Regulations : Online Resource for Latest Information 12/9/2013 30 4
  • 305.  Demonstrate the reproducibility of the method to reliably recover representative microorganisms by validation.  Modify the test media if growth is inhibited ◦ increased dilution, ◦ additional membrane filter washes, ◦ addition of inactivating agents  Method validation should demonstrate that the method does not give false negatives. Drug Regulations : Online Resource for Latest Information 12/9/2013 30 5
  • 306.  Media used to perform sterility testing be rendered sterile  Demonstrate growth promotion properties.  Qualified and trained personnel should perform sterility testing.  Written program should update training of personnel & confirm acceptable sterility testing practices. Drug Regulations : Online Resource for Latest Information 12/9/2013 30 6
  • 307.  Due small sample size sterility tests are limited in their ability to detect contamination ◦ Statistical evaluations indicate that the sterility test sampling plan "only enables the detection of contamination in a lot in which 10% of the units are contaminated about nine times out of ten in making the test" ◦ If a 10,000-unit lot with a 0.1 per cent contamination level was sterility tested using 20 units, there is a 98 per cent chance that the batch would pass the test. Drug Regulations : Online Resource for Latest Information 12/9/2013 30 7
  • 308.  Samples should represent the entire batch and processing conditions.  Take samples : ◦ at the beginning, middle, and end of the aseptic processing operation ◦ in conjunction with processing interventions or excursions  Consider any positive result as a serious CGMP issue  Conduct thorough investigation. Drug Regulations : Online Resource for Latest Information 12/9/2013 30 8
  • 309.  Take care should in the performance of the sterility test  Preclude any activity that allows for possible sample contamination.  Consider the lot to be non sterile when microbial growth is observed.  Invalidate an initial positive test only when it is due to laboratory error. ◦ Requires unequivocal evidence of laboratory error. Drug Regulations : Online Resource for Latest Information 12/9/2013 30 9
  • 310.  Perform retest only if conclusive and documented evidence shows contamination as part of testing.  Inconclusive evidence should lead to batch rejection. Drug Regulations : Online Resource for Latest Information 12/9/2013 31 0
  • 311.  Written investigation should ◦ Consider all relevant factors concerning the manufacture of the product ◦ Consider all relevant factors concerning testing of the samples, ◦ Include specific conclusions ◦ Identify corrective actions. Drug Regulations : Online Resource for Latest Information 12/9/2013 31 1
  • 312.  Evidence of Contamination Should be based on at least the following:  1. Identification (speciation) of the organism in the sterility test  Identify sterility test isolates to the species level.  Review Microbiological monitoring data to locate the source of contamination :  laboratory and production environments, personnel, or product bioburden.  Use advanced identification methods (e.g., nucleic-acid based)  Use same methods identifications when comparing data. Drug Regulations : Online Resource for Latest Information 12/9/2013 31 2
  • 313.  Evidence of Contamination Should be based on at least the following:  2. Record of laboratory tests and deviations ◦ Eliminate or implicate laboratory as source of contamination by review laboratory deviation and investigation findings.  If the organism is not found in the laboratory environment, product contamination is more likely than laboratory error.  If the organism is found in laboratory and production environments, it can still indicate product contamination. Drug Regulations : Online Resource for Latest Information 12/9/2013 31 3
  • 314.  Evidence of Contamination Should be based on at least the following:  2. Record of laboratory tests and deviations  Appropriate handling all deviations is an essential aspect of laboratory control.  Document & investigate all deviations  Implement corrective actions for all deviations.  If any deviation is considered to have compromised the integrity of the sterility test, the test should be invalidated immediately without incubation. Drug Regulations : Online Resource for Latest Information 12/9/2013 31 4
  • 315.  Evidence of Contamination Should be based on at least the following:  2. Record of laboratory tests and deviations  View sterility positive result as indicative of production or laboratory problems,  Investigate the entire manufacturing process since such problems often can extend beyond a single batch.  FDA recommends to keep separate trends for  product, container type, filling line, sampling, and testing personnel. Drug Regulations : Online Resource for Latest Information 12/9/2013 31 5
  • 316.  Evidence of Contamination Should be based on at least the following:  2. Record of laboratory tests and deviations  Where the degree of sterility test sample manipulation is similar for a terminally sterilized product and an aseptically processed product, a higher rate of initial sterility failures for the latter should be taken as indicative of aseptic processing production problems. Drug Regulations : Online Resource for Latest Information 12/9/2013 31 6
  • 317.  Evidence of Contamination Should be based on at least the following:  2. Record of laboratory tests and deviations  Review trends of microbial monitoring of the aseptic area of the laboratory and personnel  Upward trends should be promptly investigated as to cause, and corrected.  In some instances, such trends can appear to be more indicative of laboratory error as a possible source of a sterility test failure. Drug Regulations : Online Resource for Latest Information 12/9/2013 31 7
  • 318.  Evidence of Contamination Should be based on at least the following:  2. Record of laboratory tests and deviations  Where a laboratory has a good track record with respect to errors, this history can lower suspicion of the lab as a source of contamination  Then chances are higher that the contamination arose from production.  However, the converse is not true. Drug Regulations : Online Resource for Latest Information 12/9/2013 31 8
  • 319.  Evidence of Contamination Should be based on at least the following:  2. Record of laboratory tests and deviations  In case of poor laboratory track record, it should not be assumed that the contamination is automatically more attributable to the laboratory and consequently overlook a genuine production problem.  Essential that all sterility positives be thoroughly investigated. Drug Regulations : Online Resource for Latest Information 12/9/2013 31 9
  • 320.  Evidence of Contamination Should be based on at least the following:  3. Monitoring of production area environment  Review the trend analysis of microorganisms in the critical and immediately adjacent areas  Review of environmental microbial data results should not be limited to the lot, day, or shift associated with the suspect lot. Drug Regulations : Online Resource for Latest Information 12/9/2013 32 0
  • 321.  Evidence of Contamination Should be based on at least the following:  3. Monitoring of production area environment  Results showing little or no recovery can be misleading, when preceded or followed by an adverse trend or atypically high microbial counts.  Look at both short- and long-term environmental trend analyses. Drug Regulations : Online Resource for Latest Information 12/9/2013 32 1
  • 322.  Evidence of Contamination Should be based on at least the following:  5. Product Pre-sterilization Bioburden  FDA recommends review of trends in product bioburden  Consider whether adverse bioburden trends have occurred. Drug Regulations : Online Resource for Latest Information 12/9/2013 32 2
  • 323.  Evidence of Contamination Should be based on at least the following:  6. Production record review  Review complete batch and production control records to detect any signs of failures or anomalies.  Investigation should include elements such as:  Events that could have impacted on the critical zone  Batch and trending data that indicate whether utility and/or support systems are functioning properly.  For instance, records of air quality monitoring for filling lines could show a time at which there was improper air balance or an unusually high particle count.  Whether construction or maintenance activities could have had an adverse impact Drug Regulations : Online Resource for Latest Information 12/9/2013 32 3
  • 324.  Evidence of Contamination Should be based on at least the following:  7. Manufacturing history  Review manufacturing history of a product or similar products  Review  Past deviations,  problems, or changes (e.g., process, components, equipment)  These factors can provide an indication of the origin of the problem. Drug Regulations : Online Resource for Latest Information 12/9/2013 32 4
  • 325.  21 CFR 211.100(a) states that “There shall be written procedures for production and process control designed to assure that the drug products have the identity, strength, quality, and purity they purport or are represented to possess. Such procedures shall include all requirements procedures, in this including subpart. any These changes, written shall be drafted, reviewed, and approved by the appropriate organizational units and reviewed and approved by the quality control unit.” Drug Regulations : Online Resource for Latest Information 12/9/2013 32 5
  • 326.  21 CFR 211.100(b) states that “Written production and process control procedures shall be followed in the execution of the various production and process control functions and shall be documented at the time of performance. Any deviation from the written procedures shall be recorded and justified.”  21 CFR 211.186 and 211.188 address, respectively, "Master production and control records" and "Batch production and control records." Drug Regulations : Online Resource for Latest Information 12/9/2013 32 6
  • 327.  21 CFR 211.192 states that “All drug product production and control records, including those for packaging and labeling, shall be reviewed and approved by the quality control unit to determine compliance with all established, approved written procedures before a batch is released or distributed. …….contd Drug Regulations : Online Resource for Latest Information 12/9/2013 32 7
  • 328.  Any unexplained discrepancy (including a percentage of theoretical yield exceeding the maximum or minimum percentages established in master production and control records) or the failure of a batch or any of its components to meet any of its specifications whether or shall not be the thoroughly batch has investigated, already been distributed. …….contd Drug Regulations : Online Resource for Latest Information 12/9/2013 32 8
  • 329.  The investigation shall extend to other batches of the same drug product and other drug products that may have been associated with the specific failure or discrepancy. A written record of the investigation shall be made and shall include the conclusions and follow-up.” Drug Regulations : Online Resource for Latest Information 12/9/2013 32 9
  • 330.  Build process and environmental control into aseptic processing  Maintain & implement these activities and strictly on a daily basis.  Review overall process and system performance for that given cycle of manufacture.  Review all batch records and data for conformance with ◦ Written procedures, ◦ Operating parameters, and ◦ Product specifications Drug Regulations : Online Resource for Latest Information 12/9/2013 33 0
  • 331.  Include all in-process and laboratory control results in the batch record documentation (211.188. )  Essential elements of the batch release decision. ◦ Review of environmental ◦ Personnel monitoring data, ◦ Data relating to acceptability of output from support systems (e.g., HEPA / HVAC, WFI, steam generator) ◦ Proper functioning of equipment (e.g., batch alarms report; integrity of various filters) Drug Regulations : Online Resource for Latest Information 12/9/2013 33 1
  • 332.  Record interventions and/or stoppages in detail.  Include sufficient details of line stoppages and any unplanned interventions .  An extensive intervention can increase contamination risk. Drug Regulations : Online Resource for Latest Information 12/9/2013 33 2
  • 333.  Sterility failures have often been attributed to atypical or extensive interventions.  Establish written line clearance procedures for certain interventions : ◦ Machine adjustments ◦ Repairs  Document such interventions with more detail than minor events. Drug Regulations : Online Resource for Latest Information 12/9/2013 33 3
  • 334.  Implement full line clearance for interventions that result in substantial activity near exposed product or container.  Include disruption in power supply, as a manufacturing deviation (211.100, 211.192). Drug Regulations : Online Resource for Latest Information 12/9/2013 33 4
  • 335. This presentation was compiled by “ Drug Regulations” from freely available resources like the FDA on the World wide web.  “Drug Regulations” is a non profit organization which provides free online resource to the Pharmaceutical Professional.  Visit http://www.drugregulations.org for latest information from the world of Pharmaceuticals.  Drug Regulations : Online Resource for Latest Information 12/9/2013 33 5