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PHARMACEUTICAL INSPECTION CONVENTION PHARMACEUTICAL INSPECTION CO-OPERATION SCHEME

PI 007-1 31 July 2001

RECOMMENDATION on the

VALIDATION OF ASEPTIC PROCESSES

PIC/S July 2001 Reproduction prohibited for commercial purposes. Reproduction for internal use is authorised, provided that the source is acknowledged.

Editor:

E-mail: Web site:

PIC/S Secretariat 9 11 rue de Varemb CH-1211 Geneva 20 Tel. + 41 22 749 13 24 Fax + 41 22 740 14 37 pics@efta.int http://www.picscheme.org

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PI 007-1

TABLE OF CONTENTS Page 1. 2. 2.1 2.2 2.3 3. 4. 4.1 4.2 4.3 4.4 4.5 4.6 4.7 4.8 4.9 5. 5.1 5.2 5.3 5.4 5.5 6. 7. 7.1 7.2 7.3 7.4 8. DOCUMENT HISTORY ...........................................................1 INTRODUCTION ....................................................................1 Purpose .................................................................................1 Scope ....................................................................................1 General information................................................................1 DEFINITIONS ........................................................................3 PROCESS SIMULATION TEST PROCEDURES ......................4 General Comments ................................................................4 Liquid Products ......................................................................5 Injectable Powder Products ....................................................6 Suspension Products..............................................................6 Freeze Dried (Lyophilised) Products .......................................6 Semi-Solid Products (e.g. sterile ointments) ............................6 Clinical Trials Materials and Small Batch Size Products...........7 Biological and Biotechnology Products....................................7 Sterile Bulk Pharmaceuticals ..................................................7 PROCESS SIMULATION TEST CONDITIONS ........................7 Test Performance...................................................................7 Selection of Growth Medium ...................................................8 Incubation Conditions .............................................................9 Reading of the Test ................................................................9 Test Frequency ......................................................................9 INTERPRETATION OF DATA ...............................................10 ENVIRONMENTAL AND PERSONNEL MONITORING...........12 Air Borne Microbial and Non-Viable Particle Monitoring .........12 Non-viable monitoring...........................................................13 Microbial Monitoring .............................................................13 Intervention Monitoring .........................................................13 STAFF TRAINING ................................................................14

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Page 9. 9.1 9.2 9.3 9.4 9.5 9.6 9.7 9.8 9.9 10. IMPORTANT FACTORS IN VALIDATION OF ASEPTIC MANUFACTURING ..............................................................15 Container/Closure Integrity Testing .......................................15 Container/Closure Sterilisation .............................................15 Equipment Cleaning and Sterilisation....................................15 Disinfection ..........................................................................16 Filter Validation ....................................................................17 Vent Filters ..........................................................................17 Equipment Maintenance and Testing ....................................17 Blow Fill Seal/Form Fill Seal .................................................18 Sterility Test.........................................................................18 REVISION HISTORY ............................................................19

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1.

DOCUMENT HISTORY7 September 1999 1 January 2000 1 September 2001

Adoption by the PIC/S Committee Entry into force of version PR 1/99 Entry into force of version PI 007-1

2. 2.1

INTRODUCTION Purpose

2.1.1 The aim of this document is to provide guidance to the current practice in this field by giving recommendations for the validation of aseptic processes. In particular, the document should provide guidance for GMP inspectors both for training purposes and in preparation for inspections of company premises. 2.2 Scope

2.2.1 This document applies to all manufacturers involved in aseptic processing of finished dosage forms (human and veterinary) as well as manufacturers of sterile labelled bulk drug substances (active pharmaceutical ingredients). 2.2.2 At the time of issue this document reflected the current state of the art. It is not intended to be a barrier to technical innovation or the pursuit of excellence. The advice in this recommendation is not mandatory for industry. However, industry should consider this recommendation as appropriate. 2.3 General information

2.3.1 The basic principles and application of process validation are described in Annex 15 to the EU/PIC/S Guide to GMP and are further elaborated in PIC/S Document PI 006-1 (Recommendations on Validation Master Plan, Installation and Operational Qualification, Non-Sterile Process Validation, Cleaning Validation) and apply also to aseptic processing. Annex I to the EU/ PIC/S Guide to GMP provides the basic requirements for the manufacture of sterile products including those aseptically processed. The Annex includes requirements, standards and recommendations, for example, for monitoring of the environment and of personnel. 2.3.2 Validation of aseptic processes relies upon prospective, concurrent and retrospective validation as well as re-validation.

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2.3.3 Prospective studies would include installation and operational qualification for a new or renovated facility as well as product simulation studies and a prospective process validation with the original product according to PIC/S Document PI 006-2. 2.3.4 Concurrent validation includes a process validation with the same requirements as for prospective studies, but performed during routine production on qualified equipment. 2.3.5 Retrospective validation uses the data of earlier manufactures, but is not a recommended technique for aseptic processes. 2.3.6 Re-validation includes: Regular performance of process simulation studies Monitoring of environment, disinfection procedures, equipment cleaning and sterilisation (including containers and closures) Routine maintenance and re-qualification of equipment, e.g. autoclaves, ovens, HVAC (heating, ventilation and air conditioning) systems, water systems, etc. Regular integrity testing of product filters, containers, closures and vent filters Re-validation after changes 2.3.7 It is the sum total of all validation data that provides the necessary level of assurance for aseptically produced products. 2.3.8 Process simulation studies (media fills) are simulating the whole process in order to evaluate the sterility confidence of the process. Process simulation studies include formulation (compounding), filtration and filling with suitable media. Simulations are made to ensure that the regular process for commercial batches repeatedly and reliably produces the finished product of the required quality. However, each process simulation trial is unique and so it is not possible to extrapolate these results directly to actual production contamination rates. 2.3.9 The methods for simulating an aseptic process vary according to the process used for the various types of products, i.e. liquid, semi-liquid and solid dosage forms. 2.3.10 In these Recommendations the term should indicates requirements that are expected to apply unless shown to be inapplicable or replaced by an alternative demonstrated to provide at least an equivalent level of quality assurance.

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3.

DEFINITIONS Action level: Established criteria, e.g. microbial or particulate levels, requiring immediate follow-up and corrective action if exceeded. Alert limits (environmental monitoring): Established microbial or particulate levels giving early warning of potential drift from normal operating conditions which are not necessarily grounds for definitive corrective action but which require follow-up investigation. Alert limits (media fill): Established levels or numbers of positive media filled units, the cause of which should be investigated, but which are not necessarily grounds for definitive corrective action. Aseptic filling: Operation whereby the product is sterilised separately, then filled and packaged using sterilised containers and closures in critical processing zones. Bioburden: Total number of viable microorganisms pharmaceutical product prior to sterilisation. on or in

Compounding: A process wherein bulk drug substance is combined with another bulk drug substance and/or one or more excipients to produce a drug product. Environmental monitoring programme: Defined documented programme which describes the routine particulate and microbiological monitoring of processing and manufacturing areas, and includes a corrective action plan when action levels are exceeded. Growth promotion test: Test performed to demonstrate that media will support microbial growth. High efficiency particulate air (HEPA) filter: Retentive matrix designed to remove a defined percentage of particulate matter of a defined size. HVAC: Heating, ventilation and air conditioning Integrity test: Test to determine the functional performance of a filter system. Media fills: Method o

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