This action might not be possible to undo. Are you sure you want to continue?
By Kusum Shrestha M Pharm 1st year Kathmandu University Batch 2011
products and active pharmaceutical ingredients (APIs) can be contaminated by other pharmaceutical products or APIs, by cleaning agents, by microorganisms, or by other materials (e.g. air borne particles, dust, raw materials). In many cases, same equipment may be used for processing different products. So adequate cleaning procedures are essential.
Implies to validation of cleaning procedures for removal of contaminants associated with the previous products. . Objective of Cleaning Validation is the confirmation of a reliable cleaning procedure so that analytical monitoring may be omitted or reduced to a minimum in a routine phase. residues of cleaning agents as well as the control of potential microbial contaminants.Cleaning Validation is a documented evidence that an approved cleaning procedure will provide equipment which is suitable for processing of pharmaceutical products or APIs.
. But consideration should be given to non-contact parts into which product may migrate. fan of the oven etc At least three consecutive applications of the cleaning procedure should be performed and shown to be successful in order to prove that the method is validated. A single validation study under consideration of “worst case” can be carried out. For e.Normally only cleaning procedures for product contact surfaces of the equipment need to be validated. seals. Cleaning procedures for products and processes which are very similar do not need to be individually validated.g.
Generally in case of batch to batch production it is not necessary to clean after each batch. Re-validation should be considered under following circumstances: Re-validation in cases of changes in equipment. product or processes. However. Periodic Re-validation at defined intervals . cleaning intervals and methods should be determined.
Analytical methods including the limit of detection and limit of quantitation of those methods. Other product.Cleaning validation protocol must include following: Objective of the validation process Responsibilities for performing and approving the validation study Description of the equipments used Cleaning procedures to be used for each product. including the rationale for setting the specific limits. process and equipment Sampling procedures Clearly defined sampling locations Data on recovery studies where appropriate Acceptance criteria. and equipment for which planned validation is valid according to a “bracketing” concept When Re-validation will be required . processes.
. A final validation report should be prepared stating if the cleaning process has been validated successfully. Quality Assurance should be involved in approval of protocols and reports. The cleaning process should be documented in an SOP. Cleaning validation protocol should be formally approved by the Plant Management.
Records should be kept of cleaning performed in such a way that following information is readily available: The area or piece of equipment cleaned The person who carried out the cleaning When the cleaning was carried out The SOP defining the cleaning process The product which was previously processed on the equipment being cleaned .
2. Direct surface sampling (Swab method) Indirect sampling (Use of Rinse solutions) . Samples should be drawn according to the cleaning validation protocol There are two methods of sampling that are considered to be acceptable 1.
The pharmaceutical company’s rationale for selecting limits for product residues should be logically based on a consideration of the materials involved and their therapeutic dose. achievable and verifiable. The limits should be practical. .
Limit calculation for API residue can be conducted by three ways: DOSE CRITERIA: No more than 0. Spiking studies should determine the concentration at which most active ingredients are visible .1% of the normal therapeutic dose of any product will appear in the maximum daily dose of the following product PPM CRITERIA: No more than 10 ppm of any product will appear in another product VISUAL CRITERIA: No quantity of residue should be visible on the equipment after cleaning procedures are performed.
SELECTION OF THE ACCEPTANCE CRITERIA The most stringent criterion amongst above three criteria will be considered as the acceptance criterion. .
MAR = Maximum Allowable Residue LHTDp = Lowest Human therapeutic dose of the previous product BSS = Batch Size of the Subsequent Product IFS = Intake Frequency of the Subsequent product MDS = Mass of the dosage form of the subsequent product .Calculation of the maximum allowable residue MAR = 0.1% x LHTDp (mg) x BSS (g) IFS x MDS (g) Where.
Calculation of Maximum Allowable Residue MAR = 10 ppm (mg/kg) x BSS (kg) Where. MAR = Maximum Allowable Residue BSS = Batch Size of the Subsequent Product .
Concentration above which majority of the APIs are visible to the naked eye is to be determined first Fourman and Mullen specified the visual limit of detection for most active pharmaceutical ingredients with 100 µg/25 cm2 i.e 4 µg/cm2 Spiking studies should be carried out to determine the visible limit .
. volatile solvent is then allowed to dry Person involved in the cleaning process.g. issuance of line clearance are allowed to check for the cleanliness of the test surface Record the readings of all the observers Identify the concentration above which all the observers identified the test surface as dirty to determine the dividing line between visually clean and visually dirty. 25 cm2).Dilution series of the affected API are made in solvent as volatile as possible and defined volumes applied on the marked test surface which corresponds to the sample surfaces (e.
Solution 1 Applied quantity of API Test area Volume applied Concentration of test solution 200 µg 25 cm2 100 µl 2 mg/ml Solution 2 150 µg 25 cm2 100 µl Solution 3 100 µg 25 cm2 100 µl Solution 4 50 µg 25 cm2 100 µl 1.5 mg/ml .5 mg/ml 1 mg/ml 0.
. The efficiency of the cleaning procedures for the removal of detergent residues should be evaluated. there should be no residues detected. The acceptance criteria can be formulated as: “The largest daily dose of the subsequent product may contain as a maximum the acceptable daily quantity of the cleaning agent used”. Acceptable limit should be defined for levels of detergent after cleaning. Ideally.
Acceptable Daily Intake (ADI) ADI (mg) = 5 x 10-4 x LD50 [mg/kg] x 70 kg SF Maximum Acceptable Carry Over (MAC) MAC (mg) = ADI (mg) x BSs (g) D (g) Where. SF = Safety factor BSs = Batch size of the subsequent product D = Daily dose of the subsequent product .
This practice is termed “Bracketing” . and not each individual product. “Worst case” products refers to the most critical products A single validation study under consideration of the “worst case” can be carried out which drastically reduces the scope of cleaning validation Worst case products can be considered for the validation.
flavours etc .FIRST STEP Products are categorized into several risk groups on the basis of Risk factor “solubility”: product contains a poorly soluble active pharmaceutical ingredient Risk factor “ Pharmacology” : product contains a highly potent active pharmaceutical ingredient Risk factor “Formulation” : product contains formulation components that are difficult to remove such as dyes.
Product Solubility Risk group API is practically insoluble Pharmacolo gy Risk group Therapeutic dose is < 100 mg Formulation Risk group Product contains dye. flavours etc No risk Limiting Criterion None of the Limiting Criteria apply A X - - - B C D E X X X X X - X - .
SECOND STEP The critical or worst case products is each risk groups must be identified. The following selection criteria may be used for this: Active pharmaceutical Ingredient content: product has the highest active pharmaceutical content (%) in the category Solubility: The API contained in this product has the lowest solubility in the category Therapeutic dose: The API contained in this product has the lowest therapeutic dose in the category .
Solubility Product Risk group: Content Solubility of API 50% 20% 5% Therapeutic dose Worst case Content of API. solubility A C E Practically 500 mg insoluble Practically 200 mg insoluble Practically 10 mg insoluble Solubility. therapeutic dose Worst case in this group are: Product A and Product E .
Pharmacology Product Content of API 25% Risk group: Solubility soluble Therapeutic dose 50 mg Worst case B Solubility. therapeutic dose E 5% Practically insoluble 10 mg Worst case in this group is Product E .
Hence the cleaning validation is carried out only for these critical markers. taking into account the relevant criteria. The result of the bracketing shows that Product A and Product E represent the worst case. this validation also applies for all other less critical products to be cleaned using the same procedure. If the cleaning procedure has been validated for the worst case products. .
Criticality of effective cleaning needs to be understood Reliable cleaning procedures need to be developed to ensure that the product which we make to cure the disease of the patient is not creating other health related issues besides from curing the concerned disease. . Cleaning validation is broad topic and is a continuous process.
co m/2010/12/visually-clean-and-visuallimits. Thomas Piether. http://pharmaceuticalvalidation. Barbara Piether. Good Manufacturing PracticesCleaning Validation Guidelines.2000.1 Health products and Food branch inspectorate. November 2006. Version 1. GMP Manual Good Manufacturing Practice and Implementation. Anita Maas.html .blogspot. Health Canada.