PaperaboutPDATR49

1、P DA'S technical report for biotech cleaning validationABSTRACT1) Q uality by Design principles such as design space can also be applied to cleaningvalidation. As discussed in the recently p ublished PDA Technical Report No. 49:Po ints to Consider for Biotechnology Cleaning Validation, well-desi

2、gned laboratoryscale studies can be p erformed using design of exp eriments, and the data analyzed tounderstand the cleaning p rocess. With the knowledge of large-scale equip ment, onecan create an app roach that results in a successful cleaning validation.Anurag S. RathoreCleaning validation pl ays

3、 an imp ortant role in reducing the p ossibility of p roductcontamination from biop harmaceutical manufacturing equip ment. It demonstrates that the cleaningp rocess adequately and consistently removes p roduct residue, p rocess residue, and environmentalcontaminants from the cleaned equip ment or s

4、ystem, so that this equip ment or system can besafely used to manufacture subsequent p roducts, which may be the same or a differentp roduct .PDA recently issued the Technical Report No. 49:P oints to Consider for BiotechnologyCleaning Validation (1). This report, more than 70 p ages long, was creat

5、ed by a team of Euro peanand North American p rofessionals from biotechnology manufacturers, cleaning-chemical supp liers.regulatory agencies, and consulting comp anies. The report p rovides a single-source overview forbiotechnology manufacturers and compi ements existing guidance and reference docu

6、ments. Itbuilds on and up dates p revious PDA p ublications, including the 1998 Technical Report No. 29:P oints to Consider for Cleaning Validation(2) and the 1996 Technical Monogra ph. Cleaning and10Cleaning Validation: A Biotechnology Persp ective(3). The report uses a life-cycle app roach tobiote

7、chnology cleaning validation that enco mp asses design and devel op ment, p rocess qualification, and ongoing control of effectiveness. It also considers the risks of the p rocess. In p articular, this technical report addresses unique features of biotechnology cleaning validation, including the way

8、 in which limits are established for bulk biotechnology manufacture. The report also considers the effect of degradation of the active on cleaning-validation p ractices and the wides pread use of nons pecific methods, such as total organic carbon (TOC) and total p rotein, for measuring residues of a

9、ctives. Table I p rovides a list of the major topics covered in Technical Report No. 49.1 r I il : Il4 ZTable 12) This article is the twenty-second in the "Elements of Biopharmaceutical Production" series andwill discuss the various issues to consider when designing a cleaning-validation p

10、 rogram.3) CLEANING PROCESS DESIGN AND DEVELOPMENT able 2Consistent with a life-cycle app roach, a cleaning validation p rogram should include the design of the cleaning p rocess before its impi ementation in a manufacturing facility. A key to cleaning-p rocess design is an understanding of the clea

11、ning p rocess itself, including critical quality attributes (CQAs) related to the outcome of the cleaning p rocess, as well as critical p rocess p arameters (CPPs) of the cleaning p rocess itself. The TechnicalReport discusses in detail the understanding of the various ste ps in a cleaning p rocess.

12、 Table II illustrates considerations relating to CQAs and CPPs for cleaning p rocesses. Table III illustratesconsiderations relating to cleaning-p rocess design.p arameters can vary, but in a controlled cleaning p rocess they are typi cally fixed. The exce ption iswhen p rinc iples of p rocess analy

13、tical technology are used for p rocess control. These p arameters are also interrelated. For exa mple, a cleaning p rocess may be effective at a high temp erature for a short time, and may be equally effective at a low temp erature and a long time. The effect of these p arameters on soil removal sho

14、uld be determined, with acce ptable ranges established as part of the design and devel op ment effort. As the cleaning p rocess is designed and devel op ed, other issues, such as the approp riate residue-acce ptance criteria and how to sample and analyze residue, should be considered.4) I n addition

15、, as part of the design and development effort, personnel should consider the variousmaterials of construction used in biotech manufacturing. Laboratory evaluations of cleaningsolution comp atibility (e.g., concentration, time, and temp erature) and surfaces can bep erformed under simulated cleaning

16、 conditions. Differences between the cleaning of soils onthose same surfaces also can be evaluated in the laboratory under simulated cleaningconditions.5) These experiments enable empioyees to make determinations related to cleanability, such as comp aring the equip ment's materials of construct

17、ion, comp aring various soils for a givensurface, and comp aring various cleaning conditions (e.g., concentration of the cleaning agent,time, and temp erature). Worst-case conditions (e.g., cleaning conditions less stringent thanwhat is exp ected in the manufacturing equip ment) may be empio yed in

18、these laboratoryevaluations. The outcome of these studies can be analyzed to create the design sp ace forcleaning. The p eiformance of the cleaning p rocess in the laboratory is then verified byconducting exp eriments in the p ilot -pl ant or scale-up equip ment. Adjustments to cleaningconditions ma

19、y be made during the scale-up p rocess based on pl ant exp erience and laboratorydevel op ment studies.6) D EGRADATION EFFECTS7) A key consideration in bioprocessing is that the active ingredient is usually degraded by cleaning p rocesses that involve hot, aqueous, alkaline cleaning solutions. Altho

20、ugh this degradation is akey mechanism of the cleaning p rocess, and in many cases is required to remove denaturedp roteins from surfaces, it affects various elements of cleaning validation. For exa mple, after acleaning p rocess, the active ingredient itself should not be p resent on cleaning surfa

21、ces; ifresidues are p resent, they may exist as degradation p roducts of the active ingredient. Also, asp ecific analytical method for the active ingredient is not usually an approp riate analyticaltechnique to determine whether the cleaning p rocess is effective. These effects are discussed inmore

22、detail in Technical Report No. 49.8) ANALYTICAL METHODS9) B ecause of the degradation of the active ingredients in the cleaning processes for biotechmanufacture, the most common p ractice is to use TOC as the analytical p rocedure to indicatethe removal of the active. TOC also measures other sources

23、 of organic carbon, including media,cellular materials, detergents, and organic p rocess materials. If total p rotein is used as anons pecific analytical method for the active, that method may measure various p rotein sp ecies.Other methods, such as conductivity, may be used for the cleaning agent.1

24、0)The approp riate analytical methods must be validated. Typi cally, validation involvesp rinc iples from the International Conference on Harmonization's Q2 (R1) (4). Althoughdegraded fragments of the active ingredient are measured in a cleaning-validation p rotocol,analytical method validation

25、is typi cally p erformed with the bulk active itself because thistypi cally reflects the worst case.11) ACCE PTANCE LIMITS FOR ACTIVES of a cleaning p rocedure by showing that the cleaning p rocess can reduce the amounts of po tentially adverse residues to acce ptable levels. For nonbiotech app lica

26、tions, limits for the active ingredient are typi cally established using a carryover calculation, which is based on the safety or toxicity of the active ingredient. For the manufacture of biotech p roducts, however, that app roach only works for fill -inish manufacture, where it is assumed that all

27、measured organic carbon comes from the active ingredient (a worst-case assumption).1 立丄 _.1 r 'J 1 s 11 11Lri_ - T '*wn 1 h1 ' -亠亠亠 -EX J J Ji* - - 'Ip丨.pr- -L w壬,1*| mb1 1."'J1 1 - - -1 _ - 1 -. > ,*h.1. I". J i_ . "N L q r -sz.F -3-n =4 -Il p k-Table 4P ersonn

28、el demonstrate the effectiveness and consistency12) Table IV provides a list of the methods that can help set limits for the various cleaningapplications (1). Limits for cleaning validation generally contain a measure related to the activeprotein or other major component of interest, a measure relat

29、ed to the cleaning agent, ameasure related to bioburden levels, a measure related to endotoxin levels, and a requirementthat the equipment be visually clean. In addition, if the active protein or other processcomponents raise specific toxicity concerns (e.g., cytotoxicity, allergenicity, or reproduc

30、tivehazards), the manufacturer's toxicology or pharmacology groups may determine whether limitsshould be modified or whether dedicated equipment is needed.13) That approach does not work for limits for the active ingredient in bulk active manufacture. If the carryover limits are calculated using

31、 the entire equipment train's surface area, the limitsare extremely low. If the active ingredient were undegraded after the cleaning process, it mightbe possible to measure the active ingredient using a specific analytical technique, such asenzyme-linked immunosorbent assay (ELISA). When the car

32、ryover limit for the active isconverted to a TOC value, it typically is below a quantifiable TOC value for a swab or rinsevalue. That quantifiable value is close to 100 or 200 ppb carbon because of the backgroundsubtraction (i.e., the correction for the blank values).14) A further complicating facto

33、r is that in the manufacture of the bulk active, residues left afterearlier cleaning steps (e.g., until the first purification-process step) may be removed bysubsequent purification processes, such as chromatographic purification. Therefore, consistentwith ICH Q7, the cleaning of these earlier steps

34、 may not be critical for the carryover of residuesto the final bulk active (5). Only a few literature references document the degradation ofspecific drug active proteins during the cleaning process. However, the literature containsample evidence that proteins generally will degrade in hot, alkaline

35、cleaning solutions. Althoughnot well documented, this effect further mitigates the concern about carryover of residues in15)bulk active manufacture.TO ppm TOC for up streamFor these reasons, limits for the manufacture of bulk actives in biotech are generallyestablished based on industry standard pra

36、ctice of about 5p rocesses and 12 ppm for downstream p rocesses for any analytical sample, whether a swabsample or a rinse sample. The industry needs to provide more scientific rationales and data tosupport that practice, and such improvements in support documentation have started to occur.16)SAMPLI

37、NG METHODSAnother key part of a cleaning-validation program is appropriate sampling methods for the17)equipment surfaces and for the nature of the study, including the analytical methods used. Theprinciples for sampling methods for biotech manufacture are not fundamentally different fromthose for sa

38、mpling in nonbiotech cleaning validation. Sampling methods discussed in TechnicalReport No. 49 include "direct surface" samp ling (e.g., using a fibero ptic p robe), swabbing,rinse-water samp ling, and pl acebo samp ling. In p ractice, samp ling for biotech manufacturemay more likely invol

39、ve rinse samples because much of the equip ment is hard-piped and notreadily accessible for swab samp ling. Furthermore, some biotech comp anies like to use mockruns or blank runs (i.e., a type of pl acebo samp ling) to p rovide an accurate pi cture of totalcarryover throughout the entire p rocess o

40、f bulk active manufacture.Table 5Sam pling recovery studies for biotech cleaning validation are not different in p rinc iple from samp ling recovery studies in nonbiotech cleaning validation.However, residues used for sp iking surfaces for recovery studies in biotech cleaning validation may include

41、not only the bulk active, but also soils rep resentative of early-stage harvesting ste ps.Furthermore, these recovery studies rep resent worst cases, in that residues actually sampled in cleaning-validation qualification p rotocols are actually degraded fragments of the active, which, being smaller

42、in molecular weight and more po lar, should be easier to remove in a samp ling recovery study using water as the solvent. Table V p rovides some of the impo rtant considerations for choosing the samp ling method for cleaning.18) MAINTENANCE OF VALIDATED STATE19) A key part of the validation life cyc

43、le for any system is maintaining the validated state on an ongoing basis. Any change in the validated state of a cleaning p rocess might detract from thequality, safety, and p urity of manufactured p roducts. Tools for validation maintenance coveredin Technical Report No. 49 include change control,

44、risk-based p eriodic monitoring, and datatrending review. Training and retraining for manual cleaning p rocesses are also significantbecause they are the p rimary mechanisms for obtaining consistency in manual cleaningp rocesses.20) For biotech and nonbiotech cleaning validation, actual values for r

45、esidues (e.g., in rinse-water sampi es) are significantly below the acce ptance criterion limit. The reason is that mostmanufacturers design their cleaning p rocesses with a reasonable margin of safety so that anysamples taken during qualification p rotocols or during routine maintenance will p ass

46、theacce ptance criteria with a good margin of safety (e.g., a robust cleaning p rocess is designed).Therefore, the fact that actual residue values are significantly below acce ptance limits shouldnot by itself be a reason for making qualification p rotocol limits more stringent. This situation isoft

47、en addressed by establishing action or alert levels for residues for routine monitoringsampi es. Routine monitoring results above such action or alert levels p rovide an indication of apo ssible change in the cleaning p rocess, thus requiring an investigation into the cause.21) ANALYTICAL METHODS-U

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49、Approp riate analytical methods are essential to the successof cleaning validation. They need to be able to adequately detect the residues of concern. Table VI summarizes the key considerations that apply to some of the most common analytical methods in cleaning validation. Sp ecific analytical meth

50、ods (e.g., high-p erformance liquid chromatogra phy andELISA) measure a certain residue in the p resence of exp ected interferences. Interferences may include degradation p roducts and related substances, exc ipi ents, cleaning agents, and cleaning agent byp roducts. In contrast, nons pecific analyt

51、ical methods (such as TOC, Bradford, conductivity, and visual ins pection) measure a general prop erty, such as conductivity or TOC, which could result from various analytes or sources.22) CLEANING-VALIDATION P ROTOCOLS23) Cleaning-validation p rotocols, like p rocess-validation p rotocols, should i

52、nclude purp ose.scop e, res po nsibilities, app licable p roducts and equip ment, cleaning standard op eratingp rocedures, acce ptance criteria, and a requirement for a final report. Key technical elementsinclude residue limits, samp ling p rocedures and analytical methods.24) MASTER P LANNING FOR C

53、LEANING VALIDATION25) The master plan for cleaning validation should p rovide a descri ption of respo nsibilities andactivities for the pl anning and execution of cleaning validation. It should describe the overallpl an, rationale, and methodology for cleaning validation. The plan should p rovide a

54、high-leveldescri ption of the cleaning-validation p hilos ophy and strategy that will support the validationactivities p erformed at the site. Detailed p rocedures for how cleaning validation is executedshould be included in individual p rotocols. The plan will define the efforts required to ensuret

55、hat the cleaning p rogram comp lies with current good manufacturing p ractices. The validationactivities are documented according to the requirements of the plan to p rovide sufficientscientific rationale to assess the suitability of the cleaning p rogram to consistently cleanequip ment to the required sp ecifications.26) RISK MANAGEMENT AND ASSESSMENT27) Quality risk management (QRM) involves elements