Cleaning Validation
inActive pharmaceuticalIngredient 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
...............................................................….....108.1 Establishment of acceptance criteria….................................................... 128.1.1 chemical determination ........................................................................ 128.1.2 physical determination ......................................................................... 138.1.3 microbiological determination.............................................................. 138.2 Cleaning procedures ............................................................................... 138.3 Sampling ................................................................................................ 158.4 Analytical methods…. ............................................................................ 168.5 Validation protocols ............................................................................... 178.6 Validation reports................................................................................... 18
9. Minimum requirements
...........…..............................................................….....20
10. Change control
…………..........…..............................................................…..... 21
11. Summary
………………...........…..............................................................….....22
12. References
…………..…...........…..............................................................…..... 23
Guide to Cleaning Validation in API plants
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1. Foreword
This Guideline has been produced by the Active Pharmaceutical IngredientsCommittee(APIC) Working group.Different organizations will be influenced by their companies and the markets thattheyserve in the approaches that they take and the policies that they have withrespect tothe subject.It is also valuable to bear in mind that this is an area that is changing rapidly andwhatwas considered as being acceptable 2-5 years ago is now not adequate.Therefore,companies should be aware of the need to continuously update themselves oncurrentregulatory requirements.
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2. Objective
The intention of this document has been to define a comprehensive approach totheValidation of Cleaning procedures in Active Pharmaceutical Ingredientmanufacturingfacilities.Cleaning Validation in the context of Active Pharmaceutical Ingredientmanufacturemay be defined as:The process of providing documented evidence that the cleaning methodsemployed within a facility consistently controls potential carryover of product(including intermediates and impurities), cleaning agents and extraneousmaterial 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 productmanufacture.c. It also assures from an internal control and compliance point of view the qualityof the process.
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3. Scope
This Document will serve to:1. Define the basic concepts and terms associated with Cleaning Validation intheActive Pharmaceutical Ingredient industry.2. Serve as a guide from which Masterplans, Protocols and Reports may becompiled.
Note: General validation principles and a glossary of terms also relevant tocleaningvalidation are detailed in the CEFIC / EFPIA Guide entitled ‘Good ManufacturingPractices for Active Pharmaceutical Ingredient Manufacturers’.It applies to sterile API’s only up to the point where the API is rendered sterile.
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4. Potential residues
The Active Pharmaceutical Ingredient Industry involves (in general) themanufacture of Active Pharmaceutical Ingredients by both chemical and physical means throughaseries of multiple step processes. Plants or individual pieces of equipment,includingancillary equipment, may be used in multi-product manufacture or dedicated toindividual products.The result of inadequate cleaning procedures is that any of a number of contaminantsmay be present in the next batch manufactured on the equipment such as:1. Precursors to the Active Pharmaceutical Ingredient2. By-products and/or degradation products of the Active PharmaceuticalIngredient3. The previous product4. Solvents and other materials employed during the manufacturing process.5. Micro-organismsThis is particularly the case where microbial growth may be sustained by theproduct.6. Cleaning agents themselves and lubricants
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5. Current regulatory guidance
Refer to the reference section of this document for details of current RegulatoryGuidance.
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6. Cleaning validation policy
The main focus of this document will be to describe equipment and ancillaryequipment / process Cleaning Validation in an Active Pharmaceutical Ingredientmanufacturing plant. However, it is appropriate to start by giving a brief introduction as to how the concept of Cleaning Validation should be approachedin a facility. It is advisable for Active Pharmaceutical Ingredient manufacturingfacilities to hold an official Cleaning Validation Policy. Specific departmentresponsibilities should be outlined in this and it should be approved by senior management. This policy should serve to provide a general guideline anddirection for company personnel, regulatory authorities and customers as to howthe company deals with areas associated with
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Cleaning Validation API Plant
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