CLEANING VALIDATIONNarongrit Chitnayee 20 Apr1il 2018 Production managerGeneral Hospital Product CO.,LTD
2ประวตั วิ ิทยากรภก.ณรงค์ฤทธ์ิ ชิดนายีประวตั กิ ารศกึ ษา• ระดบั ปริญญาตรี สาขาเทคโนโลยีเภสชั กรรม คณะเภสชั ศาสตร์ มหาวทิ ยาลยั เชียงใหม่ประวตั กิ ารทางาน• พ.ศ.2548 ตาแหน่งเภสชั กรหวั หน้างานส่วนผลิต บ.เยเนอรัล ฮอสปิตลั โปรดคั ส์ จากดั มหาชน• พ.ศ.2553 ตาแหนง่ ผจก.ส่วน บริหารและพฒั นาการผลิต บ.เยเนอรัล ฮอสปิตลั โปรดคั ส์ จากดั มหาชน• พ.ศ.2558 ตาแหน่งผจก.ฝ่ ายผลิต บ.เยเนอรัล ฮอสปิตลั โปรดคั ส์ จากดั มหาชน tel : 0859686067 Id line : narongritcmz
CLEANINGDefinition of Cleaning “The process of removing contaminants from process equipment to acontrolled level and maintaining the condition of equipment such that theequipment can be safely used for subsequent product manufacture”Cleaning Validation “Documented evidence that an approved cleaning procedure willconsistently reduce active pharmaceutical ingredients (API), processresidues, cleaning agents and microbial residues from product contactequipment surfaces to acceptable levels for the processing of drug products” •Reference: FDA; Guide to Inspections Validation of Cleaning Processes, 1993 3
CLEANING VALIDATIONWhy cleaning validation ?•To verify the effectiveness of cleaning procedures and to ensure no risks areassociated with cross contamination of active ingredients ordetergent/sanitizer.When cleaning validation ?· Initial qualification of a process/equipment· Critical change in a cleaning procedure· Critical change in formulation· Significant change in equipment· Change in a cleaning process equipment· Change in a cleaning agent. 4
CLEANING VALIDATIONWhat Must Be Validated?• Critical cleaning must be validated – Cleaning between different products – Focus on product contact surfaces – Applies to drug products and APIs• Not required for non-critical cleaning – Floors, walls, outside of vessels – Some intermediate steps (ICH Q7A) 5
CLEANING VALIDATION• REGULATORY REQUIREMENTS• CLEANING BASIC CONCEPTS• CLEANING PROCEDURE• DEVELOPING A CLEANING VALIDATION PROGRAM • Cleaning validation policy • Contamination acceptance limits • Cleaning validation planning and execution 6
CLEANING BASIC CONCEPTS• Cleanliness in the pharmaceutical industry is crucial to avoid safety concerns that may result from contamination.• Ideally, a well –designed cleaning procedure should leave the manufacturing equipment free from residue of previous product and a visual inspection would suffice to verify the equipment cleanliness.• The cleaning operations must ensure avoidance of adulteration of product so as to minimize the risk of cross contamination between products or carryover of degradation products. 9
CLEANING BASIC CONCEPTS• Cleaning mechanisms • Several basic mechanisms exist to remove residues from equipment, including mechanical action, dissolution, detergency, and chemical reaction (LeBlanc et al. 1993).• Level of cleaning • Major cleaning is required between products Cleaning validation is required only for major cleaning. • Minor cleaning between batch of the same product. • API process is different from pharmaceutical production in that final process is largely a purification step (Lazar 1997). 10
CLEANING BASIC CONCEPTS• Time limitations • Time limitation have to be established in relation to cleaning between different step in the manufacturing process, taking into account the manufacturing processes and products. • The cleaning procedure should define time limitations in relation to a. Time between end of manufacturing and start of cleaning. b. Time between final rinse and drying. c. Frequency of major cleaning for manufacturing batch of the same product in campaign. d. Time until additional cleaning is performed for unused clean equipment. 11
CLEANING PROCEDURE• Equipment design The cleaning procedure development should consider the design of the equipment and hard-to-clean locations that will be challenged in the cleaning validation study • Product contact surface shall not be reactive, additive or absorptive. • Product contact surface shall be hard and smooth not shed particles. • Product contact surface shall withstand the repeated use of cleaning and sanitizing agent. • Equipment shall be designed so as to prevent dead ends or spots. • Equipment shall be easily dismantled to permit visual inspection. • Valves shall be of a sanitary type. • All connection to utilities shall be fitted with a back flow prevention valve. 12
CLEANING PROCEDURE• Equipment design • Vessel and containers shall be drainable. • Valves and instrumentation shall be installed flush with product contact surface • Small part, screws, and bearings, if unavoidable, shall be fixed in such a way as to prevent their accidental fall into the product. • Any substance required for operation, such as lubricants and coolants, shall not come into contact with the product. • The engine, the electric and electronic parts, should be hermetically encased to allow for easy cleaning and to prevent safety concerns during cleaning. 13
CLEANING PROCEDURE• Manufacturing process and product • Assessment of active ingredients, excipients and formulated products from the perspectives of solubility, toxicity and “cleanability” • Different types of products or processes will leave different type of residues to be removed E.g. : Creams and ointments, can be difficult to clean due to the fact that they can contain many ingredients with different characteristic (oily, fatty). On the contrary, injectable aqueous solution can be easy to clean due to a limited number of ingredients which are usually water soluble and low concentration. 14
CLEANING PROCEDURE• Operator • Training of the operator and his safety should be of great concern, especially in manual cleaning.• Cleaning tools • Washing and cleaning equipment should be chosen and used as not be a source of contamination• Materials and tools • Solvents : water is the most common solvent. • Cleaning agents : not be corrosive, non toxic, not be harmful, environment friendly, easy to rinsed, Detectability of residues, should not produce foam (in case of CIP). 15
CLEANING PROCEDURECleaning methods• Automate Automated cleaning methods are the preferred method ofcleaning pharmaceutical equipment. • Clean-in-Place (CIP) methods the piece of equipment (e.g. a vessel or filling line) is attached to a cleaning skid or equivalent system which provides cleaning solutions of water and/or other solvent(s) and/or detergents. • Cleanout-of-Place (COP) systems consist of parts washers where equipment and components are placed on racks and the racks are placed into the washing machine. 16
CLEANING PROCEDURECleaning methods•Manual Manual cleaning processes cannot be validated in the conventional meaningof validation, but it is possible to verify manual cleaning processes. Manual cleaning is widespread within the pharmaceutical industry and islikely to remain as an acceptable process for the distant future. In order to “future proof” manual cleaning, adopting concepts fromautomated cleaning system can close the gap form automate and manual cleaningsystem. 17
CLEANING PROCEDURECleaning methods• Manual A state of the art manual cleaning systems would consist of • Pre-defined steps with detailed descriptions of each cleaning step (e.g. temperature of cleaning solutions, duration of soakage, duration and description of manual cleaning steps) • Detailed step by step cleaning instructions including photographs of cleaning steps, start and end time of each step, • Double checks at key steps, and at least at the inspection of dried equipment prior to storage. • Ongoing reassessment 18
CLEANING VALIDATION POLICY• The objective of cleaning validation is to attain documented evidence which provides a high degree of assurance that the cleaning procedure can effectively remove residues of a product and of the cleaning agent from the manufacturing equipment, to a level that does not raise patient safety concerns. 19
CLEANING VALIDATION POLICYThe cleaning validation policy consists of the following steps. • Selecting the worst case related to the equipment. • Selecting the worst case related to the product. • Selecting the scientific basic for the contamination limit. • Selecting the sampling method. • Selecting the analytical method. 20
CLEANING VALIDATION POLICYSelecting the worst case related to the equipment. • The grouping of equipment base on product contact surface, operating principle, size, cleaning procedure, a rationale for grouping pieces of equipment and selecting one representative piece for the cleaning validation study is developed. • Identical, interchangeable pieces of equipment with the same cleaning procedure can be grouped together. • Equipment with the same operating principle and the same cleaning procedure, but with different product surface area, can be grouped, if they can be interchanged. • The worst case for group of equipment is represented by the equipment with the larger product contact surface and the hardest-to-clean location. 21
CLEANING VALIDATION POLICY• Selecting the worst case related to the product. For multiproduct equipment, a cleaning validation policy has been developed to select a product, which can represent all other products manufactured in a piece of equipment. The grouping of active substance base on different characteristics such as structural similarity, similar sorption/desorption isotherm behavior, similar formulation, similar potency, solubility, and degree of difficulty (Mendenhall 1989). Only one product out of a group of products processed in a piece of equipment is selected for the cleaning validation study, based on the highest strength and the lowest solubility of the active ingredient (difficult to clean). 22
CLEANING VALIDATION POLICYSelecting the sampling method• Visual • other methods result in a maximum acceptable residue which would be visibly detectable. • Hand held UV lights sources may be used to enhance visibility. • The visual limit of detection must be established through visual detection studies 24
CLEANING VALIDATION POLICYSelecting the sampling method•Swabbing • Subject to operator training, the method is relatively consistent and recovery can be validated. • The most difficult to clean areas must be sampled and the number and location of swabs taken should be adequate to represent the equipment. • Personnel performing swabbing must be qualified and re-qualified on a periodic basis.•Typical guidelines within the swabbing SOP may include 25 • the type of swab used • the swab surface area • the number and location of swabs to be taken • Justification for the solvent used to saturate the swab • How the swab is desorbed
CLEANING VALIDATION POLICYSelecting the sampling method•Swabbing • Advantage • Direct evaluation of surface contamination. • Insoluble substances may be physically collected. • May allow sampling of a defined area. • Applicable to active, microbial, and cleaning agent residues. • Disadvantage • Difficult to implement in large-scale manufacturing equipment. • Extrapolation of results obtained for a small sample surface area to the whole product contact surface of equipment. • Less accessible or hard to clean area more difficult to sampling. • An Invasive technique that may introduce fibers. • Results may be technique dependent. 26
CLEANING VALIDATION POLICYSelecting the sampling method• Rinse samples • Should be ensured that the rinse volume is sufficient to cover all equipment surfaces. • Volume of solvent used for the last rinse must be known. 27
CLEANING VALIDATION POLICYSelecting the sampling method• Rinse samples • Advantage • Easy to sampling. • Evaluation of the entire product contact surface. • Accessibility of all equipment parts to the rinsing solvent. • Best fitted to sealed or large-scale equipment and equipment which is not easily or routinely disassembled. • Disadvantage • No physical removal of the contaminant. • Inability to detect location of residues. • Use of organic solvents for water insoluble material. 28
CLEANING VALIDATION POLICYSelecting the sampling method• Placebo method • The principle involved in placebo is that it is passed through the same pathway as the product therefore; it will have the possibility to scrub off residual product along those pathways. And it usually employed for measuring system cleanliness. • It majorly depends on; 1. Excipients solubility in placebo. 2. Appropriate contact time of the placebo for collecting representative sample. 3. Quantity of the placebo and residue being matched. 29
CLEANING VALIDATION POLICYSelecting the sampling method•Placebo method • Advantage • Placebo contacts the same surfaces as the product • Applicable for hard-to-reach surfaces • Requires no additional sampling steps • Disadvantage • Difficult to determine recovery (contaminants may not be evenly distributed in the placebo) • Lowers analytical specificity and inhibits detect ability • Takes longer and adds expense since equipment must be cleaned after the placebo run • Placebos must be appropriate for each potential product • Residues may not be homogenously distributed • No direct measurement of residues on product contact surfaces 30
CLEANING VALIDATION POLICYThe preferred sampling method and the one considered asthe most acceptable by regulatory authorities is the swabbingmethod. 31
CLEANING VALIDATION POLICYChoice of Equipment Sampling Locations• Sampling sites for each equipment are selected on most difficult to clean product contact surfaces. • Direct or indirect product contact location • Accessibility to swab • Cleanability (difficult to clean) 32
CLEANING VALIDATION POLICYSelecting the sampling methodSample stability• In the event that samples are to be stored for a period of >24 hours, stability of the samples should be considered and validated. The stability of the samples should account for the potential degradation of actives and excipients that could occur as a result of the cleaning process operating conditions and detergent used. 33
CLEANING VALIDATION POLICYSelecting the analytical method The basic requirement for the analytical method 1. The sensitivity of the method shall be appropriate to the calculated contamination limit. 2. The method shall be practical and rapid, and, as much as possible use instrumentation existing in the company. 3. The method shall be validated in accordance with ICH, USP and EP requirements. 4. The analytical development shall include a recovery study to challenge the sampling and testing methods. 34
CLEANING VALIDATION POLICYSelecting the analytical method • HPLC or UPLC specific methods and are the methods of choice • UV Non- specific methods and is not as accurate as HPLC • Conductivity Non-specific methods • Visual •other methods result in a maximum acceptable residue which would be visibly detectable. •Hand held UV lights sources may be used to enhance visibility. •The visual limit of detection must be established through visual detection studies 35
CLEANING VALIDATION POLICYSelecting the analytical method• TOC • Total Organic Carbon analysis is a non-specific method, looking merely for residual carbon molecules. • That any rinse samples or swabs would have a TOC result which is <500ppb. This means that the samples are within the range of WFI. • That any rinse samples or swabs would have a TOC result of <100ppb above a blank of the WFI in use. 36
CLEANING VALIDATION POLICYAnalytical Methods Considerations • Short / no development Non-Specific Methods • Typically faster • My be sensitive to other considerationsMethodology• Conductivity (excipients, cleaning agents)• Total organic carbon (TOC) • Greater likelihood of false positives• Visual • May require a specific method to• pH investigate OOS 37
CLEANING VALIDATION POLICYAnalytical Methods Specific MethodsMethodology Considerations• Chromatography (LC, GC, IC, TLC) • Time consuming to developSpecific detection modes • Typically longer analysis times (LC-UV, Flour, ELSD, CAD, CLND, MS) • Low likelihood of false positives • Typically insensitive to other considerations• Atomic Spectroscopy(AA, ICP-OES, ICP-MS) • Cost / training• ELISA• Ion-mobility spectrometry (IMS) 38
CLEANING VALIDATION POLICYAnalytical Method Validation•Analytical method validation should follow conventional ICHguidelines for method validation i.e. • Reproducibility • Test Method Linearity • Range • Accuracy • Limit of quantitation (mg/ml) • Limit of detection (mg/ml) • Stability of swab samples • Specificity (where applicable) 39
CLEANING VALIDATION POLICYHold Times• Dirty Equipment Hold Times (DEHT) – Maximum period of time between the end of manufacturing to the start of the cleaning procedure for processing equipment, as specified in the associated cleaning process• Clean Equipment Hold Times (CEHT) – Maximum period of time allowed for processing equipment between the end of a cleaning procedure to its next use in production or its sterilization or sanitization, as specified in the associated cleaning and/or sterilization SOP. 40
CONTAMINATION ACCEPTANCE LIMIT• Visually clean PIC/S:IP006-3:2007• No more than 0.1% of normal therapeutic dose of any product willappear in the maximum daily dose of the following product (SF =0.001)• MACO; Maximum allowable carry over• No more than 10 ppm in subsequent product 41
CONTAMINATION ACCEPTANCE LIMIT• Maximum Acceptable Carry Over (MACO) • It is not possible to completely remove all traces of a product by cleaning. allowable amount of “Product A” (the first product) to be left on non- dedicated manufacturing equipment which will then be incorporated into the next product (“Product B”) produced using the equipment. • As a model, there are some assumptions made being that the residue of Product A is evenly spread throughout the equipment, and that all of Product A will be incorporated into Product B. 42
CONTAMINATION ACCEPTANCE LIMIT• Health Based Exposure Limits (HBELs) • A daily dose of a substance below which no adverse effects are anticipated, by any route, even if exposure occurs for a lifetime. • Required for cleaning validation of hazardous products in shared facilities. • Derived from a structured scientific evaluation of relevant data. EMA/CHMP/CVMP/SWP/169430/2012• No Observable Adverse Effect Level (NOAEL) • NOAEL must be established for all critical effects identified • The NOAEL is the highest tested dose at which no adverse effect is observed • If NOAEL is not calculable, the lowest-observed-effect level (LOEL) may be used • Determined by toxicological expert
CONTAMINATION ACCEPTANCE LIMIT• Permitted Daily Exposure (PDE) represents a substance-specific dose that is unlikely to cause an adverse effect if an individual is exposed at or below this dose every day for a lifetime• Acceptable Daily Exposure (ADE) represents a dose that is unlikely to cause an adverse effect if an individual is exposed, by any route, at or below this dose every PDE and ADE are effectively synonymous
CONTAMINATION ACCEPTANCE LIMITBase on Therapeutic daily dose• Maximum Allowable Carry Over Amount (MACO)LTD = Lowest therapeutic doseBS = Smallest batch size for the next productMDD = Maximum daily dose for the next productSF = Safety factor 45
CONTAMINATION ACCEPTANCE LIMIT• Base on Toxicological data• NOEL(A) = No Observed Effect Level (mg/day)• LD50 = Lethal Dose 50 in mg/kg animal. The identification of the• BW = the weight of an average adult (70 kg)• 2000 = an empirical constant• TDD(B) = Standard Therapeutic Daily Dose for the next product (mg/day)• MBS(B) = Minimum batch size for the next product (s)• SF = Safety factor 46
CONTAMINATION ACCEPTANCE LIMIT• Base on Toxicological data (Health base) PIC/s Annex15,2015• NOEL(A) = No Observed Effect Level (mg/day) 47• PDE = Permitted Daily Exposure (mg)• LD50 = Lethal Dose 50 in mg/kg animal.• F1-5 = Uncertainty Factor• BW = the weight of an average adult• 2000 = an empirical constant• TDD(B) = Standard Therapeutic Daily Dose for the next product (mg/day)• MBS(B) = Minimum batch size for the next product (s)
CONTAMINATION ACCEPTANCE LIMITUncertainty Factor• F1 : ค่าปัจจัยความแตกต่างสายพันธ์ุ= 5 หนู Rat – คน = 2.5 กระต่าย - คน= 12 หนู Mice – คน = 3 ลงิ - คน= 2 สุนัข – คน = 10 สตั ว์อ่นื – คน• F2 : ค่าปัจจัยความแตกต่างของบุคคล =10• F3 : ค่าปัจจัยระยะเวลาในการศกึ ษาความเป็ นพิษ= 1 : การศึกษาเร่ืองการเจริญพันธ์ุครอบคลุมระยะ Organogenesis= 2 : การศึกษา 6 เดือนในหนู หรือ 3.5 ปี ในสตั ว์อ่นื = 5 : การศกึ ษา 3 เดอื นในหนู หรือ 2 ปี ในสัตว์อ่นื= 10 : การศึกษาท่มี รี ะยะเวลาส่นั = 10 : การศึกษาคร่ึงชวี ติ ของสัตว์
CONTAMINATION ACCEPTANCE LIMITUncertainty Factor• F4 : ค่าปัจจยั ความเป็ นพษิ ระดับสงู = 1 : สาหรับความเป็ นพษิ ต่อตัวอ่อนในครรภ์ท่เี ก่ยี วข้องกบั ความเป็ นพษิ ของแม่ = 5 : สาหรับความเป็ นพษิ ต่อตวั อ่อนในครรภ์ท่ไี ม่เก่ยี วข้องกับความเป็ นพิษของแม่ = 5 : สาหรับยาท่มี ีผลต่อการเจริญของตัวอ่อนท่เี ก่ยี วข้องกับความเป็ นพษิ ของแม่ = 10 : สาหรับยาท่มี ีผลต่อการเจริญของตัวอ่อนท่ไี ม่เก่ยี วข้องกบั ความเป็ นพษิ ของแม่• F5 : ปัจจยั ความแตกต่างในการใช้ LOEL ในการคานวณ =10
CONTAMINATION ACCEPTANCE LIMITTarget value base on sampling methodSWABBING RINSINGSs = Swab area V = Volume of rinseSe = Product contact surface area R = Recovery factorR = Recovery factor 50
CONTAMINATION ACCEPTANCE LIMITRecovery Validation•Recovery studies are performed by spiking the target analyze on acoupon of each material of construction (MOC)•The same swabbing/rinsing technique as performed on manufacturingequipment is applied to the coupon and a recovery factor is calculatedbased on the recovered amount of material. The WHO defines thefollowing ranges for the recovery factor. Percent Recovery = Amount detected X 100 Amount spiked 51
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