4CleaningVal9909[1]（翻译版）APIC清洁验证资料

Cleaning Validation in Active pharmaceutical Ingredient manufacturing plants September 1999 Guide to Cleaning Validation in API plants Table of contents 1. Foreword....................................................................................................….....2 2. Objective....................................................................................................….....3 3. Scope..……................................................................................................….....4 4. Potential residues ……………………………..................................................5 5. Current regulatory guidance………………....................................................6 6. Cleaning validation policy........................................................................….....7 7. Levels of cleaning.………….....................................................................….....8 8. Elements of cleaning validation...............................................................….....10 8.1 Establishment of acceptance criteria…....................................................12 8.1.1 chemical determination........................................................................ 12 8.1.2 physical determination......................................................................... 13 8.1.3 microbiological determination..............................................................13 8.2 Cleaning procedures............................................................................... 13 8.3 Sampling................................................................................................15 8.4 Analytical methods…............................................................................. 16 8.5 Validation protocols............................................................................... 17 8.6 Validation reports...................................................................................18 9. Minimum requirements...........…..............................................................….....20 10. Change control…………..........…..............................................................….....21 11. Summary………………...........…..............................................................….....22 12. References…………..…...........…..............................................................….....23 Guide to Cleaning Validation in API plants 2 1. Foreword This Guideline has been produced by the Active Pharmaceutical Ingredients Committee (APIC) Working group. Different organizations will be influenced by their companies and the markets that they serve in the approaches that they take and the policies that they have with respect to the subject. It is also valuable to bear in mind that this is an area that is changing rapidly and what was considered as being acceptable 2-5 years ago is now not adequate. Therefore, companies should be aware of the need to continuously update themselves on current regulatory requirements. Guide to Cleaning Validation in API plants 3 2. Objective The intention of this document has been to define a comprehensive approach to the Validation of Cleaning procedures in Active Pharmaceutical Ingredient manufacturing facilities. Cleaning Validation in the context of Active Pharmaceutical Ingredient manufacture may be defined as: The process of providing documented evidence that the cleaning methods employed within a facility consistently controls potential carryover of product (including intermediates and impurities), cleaning agents and extraneous material into subsequent product to a level which is below predetermined levels. It is necessary to Validate Cleaning procedures for the following reasons: a. It is a customer requirement - it ensures the safety and purity of the product. b. It is a regulatory requirement in Active Pharmaceutical Ingredient product manufacture. c. It also assures from an internal control and compliance point of view the quality of the process. Guide to Cleaning Validation in API plants 4 3. Scope This Document will serve to: 1. Define the basic concepts and terms associated with Cleaning Validation in the Active Pharmaceutical Ingredient industry. 2. Serve as a guide from which Masterplans, Protocols and Reports may be compiled. Note: General validation principles and a glossary of terms also relevant to cleaning validation are detailed in the CEFIC / EFPIA Guide entitled ‘Good Manufacturing Practices for Active Pharmaceutical Ingredient Manufacturers’. It applies to sterile API’s only up to the point where the API is rendered sterile. Guide to Cleaning Validation in API plants 5 4. Potential residues The Active Pharmaceutical Ingredient Industry involves (in general) the manufacture of Active Pharmaceutical Ingredients by both chemical and physical means through a series of multiple step processes. Plants or individual pieces of equipment, including ancillary equipment, may be used in multi-product manufacture or dedicated to individual products. The result of inadequate cleaning procedures is that any of a number of contaminants may be present in the next batch manufactured on the equipment such as: 1. Precursors to the Active Pharmaceutical Ingredient 2. By-products and/or degradation products of the Active Pharmaceutical Ingredient 3. The previous product 4. Solvents and other materials employed during the manufacturing process. 5. Micro-organisms This is particularly the case where microbial growth may be sustained by the product. 6. Cleaning agents themselves and lubricants Guide to Cleaning Validation in API plants 6 5. Current regulatory guidance Refer to the reference section of this document for details of current Regulatory Guidance. Guide to Cleaning Validation in API plants 7 6. Cleaning validation policy The main focus of this document will be to describe equipment and ancillary equipment / process Cleaning Validation in an Active Pharmaceutical Ingredient manufacturing plant. However, it is appropriate to start by giving a brief introduction as to how the concept of Cleaning Validation should be approached in a facility. It is advisable for Active Pharmaceutical Ingredient manufacturing facilities to hold an official Cleaning Validation Policy. Specific department responsibilities should be outlined in this and it should be approved by senior management. This policy should serve to provide a general guideline and direction for company personnel, regulatory authorities and customers as to how the company deals with areas associated with Cleaning Validation. The policy should incorporate the following types of statements: · Definition of terms employed during validation i.e. rinse vs. flush vs. wash etc. · A statement specifying what company policy is on validation of cleaning procedures related to equipment (including ancillary) and processes. · Company policy re dedication of equipment in certain cases (if products are deemed too dangerous and / or highly active to manufacture on multi-product equipment). · Analytical validation policy. · The policy should also state the rational for the methods by which acceptance criteria is determined. · Revalidation policy. Guide to Cleaning Validation in API plants 8 7. Levels of cleaning The degree or level of cleaning and validation required for processes in Active Pharmaceutical Ingredient manufacturing depends largely on: · The equipment usage (i.e. dedicated equipment or not) · The stage of manufacture (early, intermediate or final step) · The nature of the potential contaminants (toxicity, solubility etc.) Each of the above three bullets must be evaluated based on the next product, not only toxicology etc. The rational for this statement is given below: In general, the higher the potential for finished Active Pharmaceutical Ingredient contamination the greater the requirement to validate cleaning methods to ensure product safety. Active Pharmaceutical Ingredient manufacturers may have different levels of cleaning requirements in facilities based on the stage of the process being cleaned and the subsequent product to be manufactured. Table 1 on page 7 illustrates an example of how a company may decide on the level of cleaning between lots. It is the responsibility of the manufacturer to demonstrate that the level of cleaning and validation performed is adequate based on each individual situation and on a justifiable scientific rational. Cleaning should be carried out as soon as practical after the end of processing and should leave the plant in a suitable condition for next use. Guide to Cleaning Validation in API plants 9 Table 1: levels of cleaning LEVEL USED WHEN CLEANING VALIDATION REQUIRED LEVEL 2 i.e. · Product changeover of equipment used in final step · Intermediates of one batch to final step of another yes – essential LEVEL 1 i.e. · Intermediates or final Step of one product to intermediate of another · Early Step to intermediates in a product sequence progression between level 0 and 2 depending on process and nature of contaminant based on scientific rational LEVEL 0 i.e. in-campaign, batch to batch changeover no validation required NB: ALL PROCESSES MUST BE EVALUATED INDIVIDUALLY Guide to Cleaning Validation in API plants 10 8. Elements of cleaning validation A brief outline of the various elements of a basic cleaning validation study is given below (see also Figure 1 on page 11). This is followed by a more detailed view of the individual elements in this section. I. Establishment of acceptance criteria II. Cleaning procedure · Identification of the equipment · characterization of the products (Previous: activity/toxicity, solubility, subsequent: dosage, lot size) · determination and characterization of the cleaning agents III. Analytical method and its validation IV. Sampling Procedure and necessary validation of same V. Validation protocol VI. Validation report Guide to Cleaning Validation in API plants 11 EVALUATE EQUIPMENT SURFACES AND DETERMINE 1. Worst case locations to sample (swab sampling) 1. Volume and type of rinse solvent to be employed (rinse sampling) 1. Equipment surface area (necessary to calculate carryover into subsequent batches) DETERMINE THE MOST APPROPRIATE CLEANING PROCEDURE FOR THE EQUIPMENT - 1. Generate acceptance criteria data for the contaminant. 2. The cleaning method will be determined by the process, the equipment the cleaning agents and the cleaning techniques available. 3. All aspects of the cleaning procedure should be clearly defined in SOPs be they manual / CIP or COP DEVELOP AND VALIDATE THE SAMPLING AND CHOSEN ANALYTICAL METHODS FOR THE COMPOUND(S) BEING CLEANED 1. Swab 2. Rinse (determine % recovery, limit of detection, limit of quantitation, accuracy of method, reproducibility, stability over time ...etc.) INTERIM REPORT: GENERATE INTERIM CLEANING VALIDATION REPORTS ON A CLEAN BY CLEAN BASIS DETAILING THE ACCEPTABILITY OF THE CLEANING PROCEDURE FOR THE EQUIPMENT AND THE PRODUCT. This is only required where there is a long period of time between manufacture of the validation runs (see stage 4 for reporting requirements). Figure 1: Cleaning Validation Process STAGE 1: STAGE 2: STAGE 3 STAGE 4: DEVELOP A CLEANING VALIDATION PROTOCOL FOR THE PRODUCT AND THE EQUIPMENT BEING CLEANED That should encompass for example: 1. Introduction 2. Scope 3. Equipment 4. Cleaning procedure 5. Sampling procedures 6. Analytical testing procedure 7. Acceptance/Cleaning limits. 8. Acceptance criteria for the validation. GENERATE A CLEANING VALIDATION REPORT DETAILING THE ACCEPTABILITY OF THE CLEANING PROCEDURE FOR THE EQUIPMENT AND THE PRODUCT The report should give a full detailed background and introduction to the cleaning Validation study and should evaluate all data generated with respect to the acceptance criteria employed for the study. The report should also indicate the requirement if any for revalidation (period of time /change control etc.) Guide to Cleaning Validation in API plants 12 8.1 Establishment of acceptance criteria The Cleaning Validation should demonstrate that the procedure consistently removes residues of the substance previously manufactured down to levels that are acceptable and that the cleaning procedure itself does not contribute unacceptable levels of residual materials to the equipment. The limits set should be practical, achievable and justifiable. In Active Pharmaceutical Ingredient manufacture there may be partial reactants and unwanted by-products which may not have been chemically identified. Therefore, it may be necessary to focus on by-products as well as the principle reactant. Companies should decide on which residue(s) to quantify based on sound scientific rational. 8.1.1 Chemical determination It is generally the residual Active Pharmaceutical Ingredient or intermediate, which is of greatest concern rather than reaction side products or residual impurities. There are a number of options available when determining acceptance criteria. Where either toxicological or therapeutic data if available then calculation A or B is preferable. If data is not available for either of these calculations or if the result is more stringent calculation C should be used. A. Limiting the level based on toxicity data. An Acceptable Daily Intake (ADI) is calculated with suitable safety factors applied and this is converted to the maximum allowable carryover to the API. B. Pharmacological Dose Method: The philosophy is to reduce the levels of residual product in each piece of equipment, such that no greater than 1/1000 of the normal therapeutic dose will be present per typical dose of the next product to be run in the equipment. The validation protocol should include a calculation, which ties this philosophy to the acceptance criteria for the samples to be tested. C. Limiting the level of product which could appear in the following products. Limits from 10ppm up to 0.1% (based on the ICH impurity document which indicates that up to 0.1% of an individual unknown or 0.5% total unknowns material may be present in the product being tested ) Note FDA Statement on 0.1% impurities Guide to Cleaning Validation in API plants 13 FDA statement: P. Alcock, in Human Drug cGMP Notes, P. Motise, June 98: „...we have found that some firms have incorrectly applied as their acceptance limit the 0.1% impurity identification threshold as discussed in both the ICH impurity guideline and the U.S.P. General Notices. This application of the 0.1% impurity threshold is inappropriate because the limit is intended for qualifying impurities that are associated with the manufacturing process of related compound and not extraneous impurities caused by cross contamination. ...“ ) may be used depending on the stage of the process. It is also necessary to evaluate the ability of the cleaning procedure to remove any cleaning agents introduced. The acceptance criteria for the residual-cleaning agents should reflect the absence of these materials, within the range of the capabilities of the assay and sampling methods. The individual company must decide on the Acceptance Criteria which are justifiable for their particular situation. 8.1.2 Physical determination There should be provision during routine cleaning for a visual examination of the equipment, verifying that it is free of visible residues. The validation protocol should include this requirement as an acceptance criteria. During validation, special attention should be given to areas that are ‘hard to clean’ (e.g. agitator shafts, thermowells, discharge valves etc.) and areas that would be difficult to verify on a routine basis. 8.1.3 Microbiological determination Appropriate studies should be performed (e.g. swabs and/or rinse sampling) where the possibility of microbial contamination of subsequent product is deemed possible and presents a product quality risk. 8.2 Cleaning procedures Written cleaning procedures for each piece of equipment and process1 must be prepared. It is vital that the equipment design is evaluated in detail in conjunction with the product residues to be removed, the available cleaning agents and cleaning techniques when determining the optimum cleaning procedure for the equipment. 1 If one cleaning procedure has been shown to be adequate for a number of products, then it is only necessary to have one cleaning SOP for those products for each piece of equipment. Guide to Cleaning Validation in API plants 14 Cleaning procedures should be sufficiently detailed to remove the possibility of any inconsistencies during the cleaning process. A. Equipment parameters to be evaluated · Identification of the equipment to be cleaned · Difficult to clean areas · Property of materials · Ease of disassembly · Fixed or not · Etc. B. Residues to be cleaned · Cleaning limits · Solubility's of the residues · Length of campaigns · Etc. C. Cleaning agent parameters to be evaluated · Preferably materials that are normally used in the process · Detergents available (as a general guide, minimize use of detergents unless absolutely required) · Solubility properties · Environmental considerations. · Health and safety considerations · Etc. D. Cleaning techniques to be evaluated · Manual cleaning · CIP (Clean-in place) · COP (clean-out-of-place) · Semi automatic · Automatic · Time considerations · Number of cleaning cycles · Etc. E. Other requirements Guide to Cleaning Validation in API plants 15 Procedures must be determined to be operator independent i.e. rugged and reproducible, during the validation studies. The Cleaning documentation should include the following items in order to ensure that it can be followed reproducibly and maintained subsequent to Validation. · Detailed definition of levels of cleaning to be performed. · Detailed description of cleaning methods. · The necessity to inspect and verify equipment cleanliness prior to manufacture of next batch should be stated in the SOP and recorded on the batch record. · The SOP should detail where verification of cycle parameters (if automated) and checklists (for complex manual procedures) is necessary. · Where microbial contamination may be an issue, consideration should be given to the integrity of the vessel prior to manufacture. Written cleaning procedures may also include additional items not specified above, these would include, as an example, the steps needed to protect the equipment from contamination after cleaning. 8.3 Sampling In developing the sampling plan for a validation study, it makes scientific sense to incorporate an understanding of the acceptance criteria and the limitations of the sampling method relative to the surface to be sampled. The two methods of sampling generally employed are swab and / or rinse sampling. (If neither or these methods is shown be a scientifically sound method for testing in a specific instance then an alternative is to consider testing the next product.) The selection of either of these techniques must be consistent with sound scientific judgment and must support the objective of the study, which is to demonstrate that the amount of residual material in the equipment has been reduced to acceptable levels. Each method is described in brief below. 1. SWAB: · Swab sampling does not cover the entire equipment surface area therefore sites must be chosen with care. It is important that, as a minimum, the Guide to Cleaning Validation in API plants 16 swab sites represent worst case locations on the equipment and that the result is then extrapolated to account for the total product contact surface area. This calculation makes it possible to make a worst case determination of potential carryover into subsequent product. ·