清潔驗證的十大常見錯誤!

2019-06-26 來源:天地恒一 點擊:795

Common Pitfalls During Implementation of a Cleaning Validation Program
清潔驗證計劃實施過程中的常見錯誤
BACKGROUND
背景
Since theinitial discussions on Cleaning Validation in the early 1990’s and even afterthe FDA Guidance was published in 1993, there has been a lot of confusionrelated to the application of the Cleaning Validation (CV) requirements in ourindustry. Some operations apply incorrect or ineffective approaches for theimplementation of a CV program due to misunderstanding the purpose ofvalidating cleaning procedures and/or taking an extremely conservative approachmaking for an impractical demand on resources. This article willcover some of the most common pitfalls/faults of a strategy for implementing aCV program.1, 2
自 20 世紀 90 年代初首次討論清潔驗證以來,即便在 1993 年 FDA 指南發布之后,在清潔驗證 (CV) 要求的應用方面出現了許多混亂。某些操作在實施 CV 計劃時采用不正確或無效的方法,原因是誤解了驗證清潔程序和/或采取了極端保守的方法來對資源進行不切實際的需求。本文將介紹實施 CV 計劃策略的一些最常見的錯誤/缺陷。
1、Starting theCleaning Validation activities without an adequate and pre-approved plan orstrategy
在沒有適當和預先批準的計劃或方案的情況下開始清潔驗證活動
When a sitedecides (or is asked by regulators) to start a cleaning validationactivity/program, their first thought is completing the effort quickly. Attimes that haste can lead to the development of protocols to complete the taskwithout proper planification and strategy development. This causes execution ofactivities which may not be adequate, nor have value added, and, in the end,the company can spend time in totally unnecessary tasks. A helpful initialstrategy is to develop a process flow for implementing the program.
當工廠決定(或監管機構要求)開始清潔驗證活動/計劃時,他們首先想到的是盡快完成工作。太過倉促將導致在沒有適當的計劃和制定策略的情況下地制定方案以完成任務。這會導致活動執行可能不夠充分,也沒有增加價值,最終,公司將時間花在完全不必要的任務上。好的做法是是制定實施該計劃的流程。
Process flowincludes the development of matrices for equipment/cleaning procedurecombinations for those products being manufactured. It is acceptable to useproduct family grouping if applicable. This is a primary step to select thecombinations of equipment/cleaning procedures including a worst-case productfor each of the CV efforts defined by the CV protocols. For example, I workedat a facility with 2,000 drug product codes that were changing rathercontinuously. After developing these matrices, we came up with 16 combinationsto be challenged with a specific CV protocol.
工藝流程包括所有在產產品所涉及的設備/清潔程序組合的矩陣。如適用,可以使用產品系列分組。這是選擇設備/清潔程序組合(包括 CV 方案定義的每個 CV 工作的最壞情況產品)的主要步驟。例如,我在一家有 2,000 個藥品的工廠工作,這些產品在不斷變化。開發這些矩陣后,我們提出了16 種組合,以使用特定的 CV 方案進行挑戰。
In some cases,equipment grouping approaches may also be applied. For example, we can select apiece of equipment (or a bracket composed of several pieces) to bechallenged from a group of similar equipment when there are no differencesbetween them beyond the size.
在某些情況下,也可以采用設備分組方法。例如,我們可以從一組類似的設備中選擇一個設備(或多個部件組合)進行挑戰,當它們之間沒有超出尺寸差異。
The next step isto answer the question of which component of the product will be used as thetarget for quantification of residues. Please note that using the term“product” is incorrect when quantifying finished drug formulations.
下一步是回答產品中的哪個成分將作為作殘留檢測目標的問題。請注意,在量化成品配方時,使用術語"產品"不正確。
Based on thisselection, work can start on finding the analytical methods to be able toquantify residue levels of these target components. To support this effort, theacceptable limits for the residues (also called Maximum Carryover or MACO) mustbe established so that the methods will be accurately quantify residue levelsbelow the limits.
基于此選擇,可以開始尋找分析方法,以便能夠檢測這些目標成分的殘留水平。為此,必須確定殘留物的可接受限值(也稱為最大轉移或 MACO),以便這些方法能夠準確檢出低于限值的殘留水平。
Parallel to thedevelopment/validation/verification of the analytical methods, the equipmentcleaning procedures must be reviewed to determine if they are sufficientlydetailed, include all necessary critical parameters (times, temperatures,contact times, flows/pressures) and that personnel are properly trained ontheir execution. Especially for manual cleaning procedures, the accuracy andcompleteness of details on the documentation are critical for demonstratingconsistency and ensuring that the process can be considered “validated” foreach step. Remember, if a cleaning agent is used, then the cleaning agentresidues must also be considered for the development of an analytical methodfor testing those residues. The cleaning agent supplier can provide support inthis task.
在開發/驗證/確認分析方法的同時,必須審查設備清潔程序,以確定它們是否足夠詳細,包括所有必要的關鍵參數(時間、溫度、接觸時間,流速/壓力),并且人員經過適當的執行培訓。特別是對于人工清潔的程序,文件詳細信息的準確性和完整性對于證明一致性并確保工藝每個步驟被視為"已驗證"至關重要。請記住,如果使用清潔劑,則還必須考慮清潔劑殘留,需要開發用于檢測這種殘留的分析方法。清潔劑供應商可以就此中提供支持。
The trainingprogram/process for the cleaning procedures must be reviewed and revised asnecessary to incorporate adequate levels of challenges and qualifications toproperly conduct the cleaning. In addition, approaches for the testing of dirtyand clean hold times needs to be established.
清潔程序的培訓計劃/流程必須進行審查,并進行修訂以包含適當程度的挑戰和確認,以正確進行清潔。此外,還需要制定測試臟的保持時間和干凈的保持時間的方法。
Once all ofthese steps are well on their way to execution, specific CV protocol(s) can beestablished where each document represents the challenges for anequipment/cleaning procedure combination with a worst-case product(s) alreadyselected.
一旦所有這些步驟都順利執行,就可以建立具體的 CV 方案了,其中每個文件代表設備/清潔程序組合與已選擇的最差產品相結合的挑戰。
2、Pre-requisites must be identified before starting the execution of a specificcleaning validation activity/protocol
在開始執行特定的清潔驗證活動/方案之前,必須確定先決條件
As stated above,the pre-requisites for the CV program must be established early and, inaddition, they must be verified, and such verification must be documentedwithin each CV protocol execution. The pre-requisites that must be verifiedwithin each CV protocol include:
如上所述,必須盡早建立 CV 計劃的先決條件,此外,必須確認這些先決條件,并且必須在每個 CV 方案的執行中記錄此類確認。在每個 CV 方案中必須驗證的先決條件包括:
Equipment design that is     adequate for the applied cleaning procedure. For example, a CIP     application will require certain conditions on the equipment design to be     considered adequate. If a CIP system is installed permanently, was this     system qualified? If a stand-alone CIP skid is used, the same question     applies. The question in terms of the adequate design also applies to the     CIP skid itself.
設備設計適合所用清潔程序。例如,CIP 要求設備設計的某些條件被視為充分。如果永久安裝 CIP 系統,則此系統是否已確認?如果使用獨立的 CIP 模塊,也是一樣的問題。在適當的設計方面的問題也適用于CIP模塊本身。
Analytical methods were     validated/verified for the selected target components and the cleaning     agent formula component (if applicable). The methods     can quantify the target components with a limit of quantification which is     lower than the limit for those residues. The equipment used in the     laboratory are also qualified.
對所選目標成分和清潔劑 (如適用)的分析方法進行了驗證/確認。這些方法可以檢測目標成分,其檢出限低于這些殘留物的限值。實驗室使用的設備也已確認。
The cleaning procedure is     adequate, has all the details and required parameters and the     documentation will provide evidence that the procedure was followed as     written.
清潔程序是充分的,具備所有的細節和必要的參數,文件記錄可以提供證據證實書面程序已得到遵循。
Personnel were trained on     the analytical methods, sample collection and the cleaning procedures as     applicable.
對人員進行了分析方法、取樣和清潔程序(如適用)的培訓。
Calibrations of     instruments used are current.
使用的儀器均已校準。
3、CleaningValidation cannot be executed unless the procedures for cleaning are properlydetailed and/or are being documented
除非清潔程序足夠詳細和/或記錄,否則無法執行清潔驗證
In my extensiveyears of assessing cleaning processes and cleaning validation efforts, I haveseen plenty of company representatives that do not understand the criticalityof assuring an adequate cleaning procedure is implemented before a CV activitycan start. In nearly every case such as this, the cleaning procedures needed tobe revised. It is critical to understand how the cleaning steps,conditions/parameters, documentation were developed. In most cases, companiesjust apply a cleaning process that they are familiar with no program fordevelopment of the cleaning process. In one occasion, a company was usingmineral oil as a “cleaning agent”. When asked to dismantle the recirculationlines from the mixing tanks, various residues came out as the lines had neverbeen dismantled for cleaning. Fortunately, as of late more companies arestarting to understand the importance of such efforts, though likely afterspending lots of time/resources trying to validate a cleaning procedure thatwas not well defined. Some critical decisions in defining the cleaningprocedures are:
在我多年評估清潔過程和清潔驗證工作中,我見過很多公司代表,他們不理解在 CV 活動開始之前確保實施適當的清潔程序的重要性。在幾乎所有情況下,都需要修改清潔程序。了解清潔步驟、條件/參數、文件是如何開發的至關重要。在大多數情況下,公司只是應用他們熟悉的清潔過程,而不需要制定清潔流程的計劃。有一次,一家公司使用礦物油作為"清潔劑"。當被要求拆除混合罐的再循環管路時,各種殘留物出來了,因為這些管路從未被拆除進行清潔。幸運的是,最近越來越多的公司開始了解到這項工作的重要性,雖然是在花費了大量時間/資源試圖驗證未明確定義的清潔過程之后。定義清潔程序的一些關鍵決策是:
Is the cleaning done     manually? If so, the procedure needs to be reviewed with a focus to ensure     people will follow the steps consistently.
清潔是否人工完成?如果是這樣,需要重點審查程序,以確保人員可以一致地遵循這些步驟。
If the cleaning is     executed by an automated system, such as a CIP skid or permanently     installed system? In this case the procedure needs to be reviewed from a     different perspective including the operation of the system and the data     to be collected/reviewed. Sometimes this equipment includes on-line     measurement of TIOC and/or conductivity which can be used to monitor the     cleaning process continuously.
如果清潔由自動化系統執行,例如 CIP 模塊或永久安裝的系統?在這種情況下,需要從不同的角度審查程序,包括系統的操作以及需要收集/審核的數據。有時,這種設備包含     TIOC 和/或電導率的在線檢測,可用于持續監控清潔過程。
4、CleaningValidation is executed as a product-specific challenge
為每一個產品進行清潔驗證挑戰
Many companiesstill conduct a cleaning validation strategy by conducting a CV study/protocolfor each product. This is feasible in cases where there are just a few productsbut, more often it can be rather impractical (and nearly impossible) to conducta CV study for each product. This is one of the main reasons to work on astrategy/plan early (see step 1 above) before starting any activity. Ask thequestion: – do we have to conduct a cleaning validation protocol for eachproduct? The answer is NO. As stated above, the strategy is defined by firstselecting the equipment/cleaning procedure combinations to be challenged. Then,the product(s) can be selected based on a worst-case approach or just to testevery product – those will be the options.
許多公司仍然通過針對每種產品開展CV研究/方案。在只有少數產品的情況下,這是可行的,但更常見的是,對每種產品進行CV研究可能相當不切實際(而且幾乎不可能)。這是在開始任何活動之前盡早制定策略/計劃(參見上面的步驟 1)的主要原因之一。問一個問題:——我們是否必須為每個產品執行清潔驗證方案?答案是否定的。如上所述,策略的定義是首先選擇要挑戰的設備/清潔程序組合。然后,可以根據最差條件的方法選擇產品,否則,需要測試每個產品。
5、Cleaning andSanitization are combined into one process
清潔和消毒合并為一個過程
Combiningcleaning and sanitation into one process is common mistake. Even though we cansay both cleaning and sanitization are combined in one step, the purpose ofboth steps are totally different. Some companies mistakenly believe that bycombining the steps combined but leaving the equipment idle for a prolongedperiod is sufficient. This is not an adequate approach. Cleaning isconcerned with removing the residues from the previous product (and thecleaning agent if applicable) using a worst-case dirty hold time. Sanitizationis concerned with the condition of the equipment before it is used next,particularly from a microbial consideration.
將清潔和消毒結合到一個過程中是常見的錯誤。盡管我們可以說清潔和消毒是結合在一個步驟,這兩個步驟的目的完全不同。一些公司錯誤地認為,通過兩個步驟合并之后,設備可以閑置較長時間。這不是一個恰當的做法。清潔關注的是在最壞情況臟保持時間下,清除前一產品(以及清潔劑)殘留。消毒則與設備在下次使用前的狀況有關,尤其是從微生物考慮。
Once it has beendemonstrated that the cleaning is effective after the CV protocol executionusing a worst-case dirty hold time, the fact that you are keeping the equipmentidle for some time brings a set of totally different questions:
一旦CV方案使用最差條件臟的保持時間證明清潔有效,則保持設備閑置一段時間的事實會帶來一系列完全不同的問題:
How long the equipment is     kept idle?
設備閑置多長時間?
Under which conditions is     the equipment kept?
設備在什么條件下保存?
How does this combination     of idle time and storage conditions affect the microbial bioburden on the     equipment surface?
閑置時間和存放條件的這種組合如何影響設備表面的微生物負荷?
As a goodoption, many companies are establishing a sanitization process/step beforeusing the equipment again and this step is validated separately from thecleaning validation. Or, separately they may test for the microbial bioburdenin the equipment surface after the worst-case clean hold time has elapsed tosee whether a sanitization step is necessary. If test fails, the option will beto apply a sanitization step. Of course, these considerations will be affectedby the type of product/process being manufactured – from a topical drug, oralsolid dosage to the more critical sterile products, specifically thoseaseptically filled.
作為一個不錯的選擇,許多公司在再次使用設備之前都建立了消毒程序/步驟,此步驟與清潔驗證分開驗證。或者,在最差條件潔凈的保持時間過后,他們可以單獨測試設備表面的微生物負荷,以查看是否需要進行消毒步驟。如果測試失敗,在應用消毒步驟。當然,這些考慮將受在產產品/工藝類型(從局部藥物、口服固體制劑到更關鍵的無菌產品,尤其是那些無菌灌裝的產品)的影響。
6、The Onlychemical residues of interest are the API residues
化學殘留只考慮API 殘留
In some cases,the residue of interest within a product formula or in the case of an APIproduction facility will be the API itself, but not always. Other components ofthe formula must also be considered, and those may be more difficult to clean,could represent a more toxic material or may just be present in higherconcentrations when compared to the API. In these cases, it is recommended totest both the API and the worst-case formula component based on those criteria.
在某些情況下,產品配方或 API 生產設施中需要考慮的殘留物將是 API 本身,但并非總是如此。配方的其他成分也需要考慮,這些成分可能更難清潔,可能代表毒性更高的材料,或者與API相比,可能只是以更高的濃度存在。在這些情況下,建議基于這些標準檢測 API 和最壞條件的配方成分。
7、Applicationof LD50 directly into the Toxicity MACO calculation
LD50直接應用于毒性MACO計算
The residuelimit calculation for toxicity is much more complex than most companiesrealize. It is not adequate to just take the LD50 value from a reference sourceor MSDS and insert that value into the formula with an arbitrarily selectedempirical factor. The fact that this formula includes at least one empiricalfactor requires a detailed consideration which may force some high-levelscientific analysis from a qualified expert such as a toxicologist. I suggestinvolving an expert if any of their formula components is considered to berelatively high-risk in terms of their toxicity.
毒性殘留限度計算比大多數公司所了解的要復雜得多。僅僅從參考源或 MSDS 中獲取 LD50 值,并將該值代入到公式中,并且使用任意選擇的經驗因子是不夠的。事實上,這個公式至少包括一個經驗因素,這需要詳細考慮一些高水平的科學分析師,如毒理學家。如果配方的任何成分的毒性被認為相對較高,建議有專家參與。
8、Applicationof a process train concept when calculating surface areas andresidue limits for all drug processes
在計算所有藥物工藝的表面積和殘留限度時,應用工藝鏈概念
Some industryexperts say that you “MUST” apply a process train concept for any CV effort.But that concept may not be applicable in every situation. Particularly whencalculating the total surface area for the entire process equipment train withconsideration for the total residues for the entire train. For example, theprocess train concept will make sense if the cleaning is actually conducted asa “process train” which is not the case in most operations. Because thecleaning of each equipment is different, it is recommended to validate thecleaning of each equipment separately.
一些行業專家說,你"必須"應用工藝鏈概念。但是,這一概念可能并非適用于所有情況。特別是在計算整個工藝設備鏈的總表面積以考慮整個設備鏈的總殘留時。例如,如果清潔實際上作為"工藝鏈"進行,則工藝鏈概念是有意義的,而在大多數操作中并非如此。由于每個設備的清潔不同,建議單獨驗證每個設備的清潔。
9、Rinse samplesare enough to demonstrate cleaning process effectiveness
淋洗水足以證明清潔過程的有效性
The decision ofwhether rinse samples will be enough to demonstrate effectiveness of thecleaning procedure and that the residue levels have been reduced to acceptablelevels depends on several factors such as equipment design/physicalcharacteristics and formula components. Are there difficult locations where arinse sample will not have contact with the area and a swab sample must betaken? Are the selected formula components totally soluble under the rinseconditions and the solvent/water being used for the sample?
淋洗水是否足以證明清洗程序的有效性,以及殘留物水平已降至可接受的水平的決定取決于幾個因素,如設備設計/物理特性和配方成分。是否有難以沖洗的地方,淋洗水無法與該表面接觸,必須棉簽擦拭?所選配方成分在沖洗條件下是否完全可溶?
The finaldecision will consider these questions and the risk implied by the productitself (injectable versus topical drug products)
最終決定將考慮這些問題以及產品本身隱含的風險(注射藥物與局部藥物產品)
10、AnalyticalMethods must be specific for the particular entity being measured as residues
分析方法必須專屬于被檢測的殘留物
This questionhas been addressed extensively in the industry, and the consensus is – itdepends. If you can develop/find a non-specific method that canmeasure/quantify the residue of interest under the sampling conditions applied,you may be able to use this method. This decision will reduce the timenecessary for conducting your CV program by a considerablefactor. Another reason to consider using a non-specific method isjust the practicality for some operations where developing and validating aspecific method for each residue will imply extensive time/resources which theymay not have, and the value added by such efforts is not commensurate to theresources applied.
這個問題在業界得到了廣泛的討論,而共識是——這。如果可以開發/找到一種非專屬的方法,在所使用的取樣條件下檢測/計算目標殘留物,則可以使用此方法。此決定將減少執行CV計劃所需的時間,其影響相當大。考慮使用非專屬方法的另一個原因是,對于某些操作而言,開發和驗證每個殘留物的專屬方法將意味著它們可能沒有的大量時間/資源,而此項工作所增加的價值是與所需要的資源不相稱。

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