Validation of Sterile Filtration PharmTech

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Filtration, Sterilizing grade filters Qualifying pharmaceutical filters. The removal rating of a given mem Safety and purity Before they can be. brane filter type refers to the size or used in a sterilizing filtration. narrower dimension of microor process filters must meet or exceed. ganisms and particles removed by minimum safety standards. the filter rather than the actual size The first step is to qualify the filter. or shape i e morphology of the in several important areas of safety. filter pore structure The industry To qualify as a pharmaceutical filter. accepted rating for a sterilizing the filter must be nontoxic according. grade filter is 0 2 or 0 22 mm de to USP specified tests e g USP 87. pending on the manufacturer which Biological Reactivity Tests in vitro. is validated as capable of removing USP 88 Biological Reactivity Tests. 107 cfu cm2 B diminuta under in vitro USP 88 Biological Reactiv. certain extreme processing condi ity Tests in vivo including the Class. tions Tighter filters such as 0 1 mm VI Plastics Tests and be tested free of. filters that demonstrate the same pyrogen or endotoxin to acceptably. bacterial retention also may be rated low levels, as sterilizing grade Pharmaceutical grade filters also. In validating and performing must have very low extractables levels. sterile filtration it is essential to although neither USP nor the Food. identify the bioburden or endemic and Drug Administration have speci. microorganism s in a given fied minimum or maximum levels It. process to use the grade of filter is the responsibility of pharmaceutical. that quantitatively removes the mi manufacturers to set allowable specifi. croorganism s and to demonstrate cations for extractables. quantitative removal by test before As a further indicator of safety. using the filter in production This and purity filters also should rinse. is the essence of filter validation quickly when exposed to high. For filter manufacturers a critical purity water must be compatible. requirement is to provide users with with pharmaceutical process fluids. a reasonably convenient safe easy and pharmaceutical products and. to perform integrity test which con be both sterilizable and integrity. firms the integrity of the filter the testable, seals and contiguous process equip All this pharmaceutical filter safety. ment Liquid sterilizing filters can qualification information typically is. be integrity tested by the bubble provided in the filter manufacturers. point forward flow or diffusion validation guide and product litera. diffusive flow test or the pressure ture for a specific filter. hold test Hydrophobic filters can be Performance qualification Filters. tested with any of those methods or must be qualified by the user to. by the water intrusion test Filter in demonstrate that their performance. tegrity tests are explained in another in processing will meet or exceed. article in this issue minimum process requirements. s14 Pharmaceutical Technology FILTRATION 2004 www phar mtech com. Filtration,atures of normal process conditions, Performance qualification occasional runaway process condi. requirements tions and the temperature ranges of,flow rates processing minimum to maxi.
throughput mum and steam or autoclave steril, pressure and temperature resistance ization including both temperature. hydrophilic or hydrophobic ranges and duration of the steriliza. membrane composition tion cycle s,compatibility Sterilizing grade filters for aque. membrane support layers core or cage ous pharmaceutical liquids are nor. o rings mally hydrophilic or water,housings wettable membrane filters In the. case of solvent or chemical liquids,to be filter sterilized hydrophobic. The filter must be tested to verify or nonwater wetting filters may be. that it provides the flow rates re used They can be wetted by a low. quired by the pharmaceutical surface tension liquid. process The filter system must be Compatibility The filter system. sized to provide flow rates and vol must be qualified to ensure that all. umes adequate to keep pace with product contact surfaces of the filter. filling machines or other production and its constituent parts mem. equipment requirements with some brane support layers core cage. reserve capacity for use in case of and end caps o rings piping. batch contaminant variability and hoses seals pumps gaskets and any. premature plugging The total liquid other components of the sterilizing. volume passed through the filters filtration system can withstand the. its throughput should be adequate hydraulic thermal and chemical. to process a complete batch without challenges of the sterilization and. interruption production processes None of these, Small scale sizing or filterability should extract into the filtered phar.
tests are used as the basis for extrap maceutical product in any signifi. olating or scaling up filtration sys cant amount, tems Sizing of final sterilizing fil Chemical compatibility questions. ters and any upstream prefilters generally are resolved by reference. used to remove coarse contaminants to compatibility tables generated by. and thereby extend the life of the manufacturers of elastomers or. final filters is based upon antici polymers used in o rings gaskets. pated flow rates and throughput in a and seals Membrane compatibilities. given pharmaceutical liquid generally are well established for the. Sterilizing filters and filter hous commonly used membrane materi. ings stainless steel or disposable als Any specific questions can read. plastic must be rugged enough to ily be resolved by testing during the. withstand the pressures and temper qualification stage. s16 Pharmaceutical Technology FILTRATION 2004 www phar mtech com. Sterilization of sterilizing filters facturer s validation guide Product. Sterilizing grade filters can be steril integrity test values are correlated to. ized in a number of ways Capsule the water or model solvent values. filters can be gamma irradiated or Bacterial retention The bacterial. autoclaved Disk filter holders are challenge test validates the ability of. autoclaved with the wetted filter in a filter to provide sterile effluent in a. place Cartridge filter installations specific pharmaceutical liquid It is. frequently are sterilized by steam also the ultimate compatibility test. in place SIP operations because the bacterial challenge si. Common steaming temperatures multaneously tests the physical. used in the United States are 121 chemical interaction of the liquid. 135 8C sustained for 30 60 min in product and the filter under process. the filter installation Whatever conditions Any filter inadequacy. time temperature parameters are caused by this interaction will be. specified it is critical that these pa detected by the bacterial challenge. rameters be validated by the phar Validation of bacterial retention. maceutical manufacturer under op normally is performed by the filter. erating conditions manufacturer or an independent lab. oratory using 47 mm diameter disks,Validation to minimize the volume of pharma. There are four major elements of ceutical product required Larger sur. the filtration validation process face area filters also can be used. physical chemical compatibility Bacterial challenge tests are usu. usually established during the ally performed with an industry. qualification phase before valida standard concentration of 107 cfu of. tion is confirmed during the val B diminuta per cm2 using pharma. idation process ceutical product whenever possible. binding and adsorption filter for the most realistic validation The. characteristics are measured in high bacterial concentration used in. the qualification phase the challenge test constitutes a. bacteria retention capability of the worst case scenario The manufac. filter which is established by chal turer qualifies the filter using a simi. lenging the filter with B diminuta lar challenge, integrity of the process filtration B diminuta is grown to produce. installation as verified by the fil monodispersed cells capable of pen. ter integrity test etrating a 0 45 mm filter typically in. Concerning integrity testing the accordance with ASTM Standard. user must demonstrate that they F838 Following that standard the. know how to install sterilize and organism is cultured in saline lac. integrity test the filters Filter in tose broth SLB and either used. tegrity test values provided by the freshly cultured or concentrated. filter manufacturer are correlated to into a frozen cell paste that is. the bacterial challenge in the manu thawed immediately prior to use A. Pharmaceutical Technology FILTRATION 2004 s17,Filtration. 0 4 m rated membrane filter is Validation parameters. used as a positive control if the or, ganisms pass through this control product contact time.
filter it proves that they are alive differential pressure. small and nonaggregated thus veri flow rates per unit area. fying that the challenge is a strin temperature,gent test bioburden. Validation parameters for bacterial integrity test correlation. challenge using pharmaceutical prod, uct Key considerations for using sound rationale to support the deci. pharmaceutical product liquid to sion and use it in challenge testing. validate sterile filters are listed in the Temperature If the liquid tempera. following chart ture is outside the viable range of. Product contact time The bacterial the challenge bacteria it may be. challenge using pharmaceutical necessary to recirculate the product. product must be run for at least the at process temperature condition. same duration as a product batch ing the filter first and then chal. will be run in processing If the lenge the filter at a temperature at. batch requires eight hours to filter which the bacteria survive. the challenge must be run for at Bioburden Bioburden levels can in. least eight hours It is good practice fluence process filtration efficacy. to run the challenge for a little The probability of passage increases. longer to anticipate unusual pro when the bioburden is high The. cessing circumstances area specific bioload Ba is the. Differential pressure and flow rates per unit bioburden per unit area of filter. area Maximum process differential cfu cm2 or Ba BV A where B is. pressures and flow rates should be the bioburden in cfu mL V is the. incorporated into the protocol total volume to be filtered mL and. Often it is virtually impossible to A is the surface area of the filter in. match both simultaneously At the cm2 It is therefore best to control. start of the challenge when the filter the bioburden of the raw materials. is clean extremely high flow rates to avoid approaching or exceeding. per unit area are necessary to gener the validated limit. ate process level differential pres Integrity test correlation Filters used in. sures pressure drop across the fil the bacterial challenge must be in. ter But as the test filter disks tegrity tested to form the correlation. accumulate bacteria and pressure to retention Because the user can. builds the flow drops One solution not use a destructive challenge test. is to match flow rates at the start of in processing the filter manufac. the challenge and pressures near the turer must supply a correlated non. end Another solution is to decide destructive integrity test that reli. whether pressure or flow is more rel ably assesses the integrity of a given. evant and then develop a technically filter installation In performing the. s18 Pharmaceutical Technology FILTRATION 2004 www phar mtech com. Select filter, Filter extractable Microbial retentivity Physical parameters. validation validation validation,Determine and document Develop nonbactericidal. viability of B diminuta surrogate with same product. in product under characteristics for toxic,process conditions high abuse potential.
or limited supply drugs,B diminuta viable in B diminuta not viable. product under process in product under process,conditions conditions. Direct inoculation of Precondition filter with product. B diminuta into product followed by microbial challenge. under process conditions One or a combination of the following. methods may possibly be used, Modify process Modify formulation Use product for Change from B diminuta. adjust temperature etc adjust pH remove time period challenge use bacteria isolated from. bactericidal component organism is viable formulation or environment. product surrogate, Figure 1 Establishing a microbial challenge protocol 1. challenge test three lots of filters pharmaceutical product is compared. typically are chosen including a to a control over time If there is less. low bubble point lot one with a than one log difference in the counts. bubble point specification that ap the organism is considered viable. proximates the manufacturer s pro under those conditions Results are. duction limit This is important be documented If a pharmaceutical. cause the end user is limited to product is toxic has high potential. using filters in their process that for abuse or is in limited supply a. match or exceed the lowest bubble nonbactericidal surrogate fluid with. point validated in product very similar properties may be devel. Establishing the challenge protocol oped It is recommended that the. The above chart highlights the steps user consult with local FDA inspec. sterile filtration it is essential to identify the bioburden or endemic microorganism s in a given process to use the grade of filter that quantitatively removes the mi croorganism s and to demonstrate quantitative removal by test before using the filter in production This is the essence of filter validation For filter manufacturers a critical requirement is to provide users with a

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