Dosage Form Validation Guidelines

Table of Contents

1.0 Scope
2.0 Introduction
3.0 Purpose
4.0 Definitions
5.0 Phases of Validation
6.0 Interpretation
7.0 References
GMP Committee Members

1.0 Scope

This Guidance document has been prepared to provide guidance to the pharmaceutical industry in dealing with validation issues for sterile and non-sterile dosage forms, biologicals, and radiopharmaceuticals. It should be noted that additional guidance related to sterile products and not contained in this document should also be considered. These requirements may be found in the five supplemental process validation guidelines available on the Inspectorate's website. The five documents pertain to the following specific processes:

• Moist Heat Sterilization for Pharmaceuticals
• Aseptic Processes for Pharmaceuticals
• Form-Fill-Seal for Pharmaceuticals
• Irradiation Sterilization for Pharmaceuticals
• Gaseous Sterilization for Pharmaceuticals

It is expected that importers and distributors of drug products have documented evidence that their vendors meet validation requirements.

2.0 Introduction

This document provides guidance on issues and topics related to systems, equipment qualification, product and process validation for sterile and non-sterile dosage forms. These topics reflect an area in pharmaceutical, biological, and, radiopharmaceuticals manufacture that is noted as being important by both the Inspectorate and the pharmaceutical industry. These guidelines have been prepared to provide guidance to inspectors, evaluators and the industry in dealing with issues related to validation. Utilization of this information should facilitate compliance with Division 2, Part C of the Regulations to the Food and Drugs Act.
It is not intended that the recommendations made in these guidelines become requirements under all circumstances. Information provided in the Interpretation section for limits to be applied in defined circumstances, as well as the number of batches to be utilized for validation studies are for guidance purposes only. Inspectors, evaluators and the industry may consider other alternate means if proposed and documented with appropriate scientific justification.

3.0 Purpose

These guidelines outline the general principles that the Inspectorate considers to be acceptable elements of validation which may be used by fabricators, packagers/labellers for drug products. The Guidelines on Good Manufacturing Practices (GMP), Division 2, Part C of the Food and Drug Regulations require that:

• all critical production processes be validated
• validation studies are conducted in accordance with pre-defined protocols. Written reports summarizing recorded results and conclusions are prepared, evaluated, approved and maintained
• changes to production processes, operating parameters, equipment or materials that may affect product quality and/or the reproducibility of the process are also to be validated prior to implementation.

These guidelines are not intended to specify how validation is to be conducted, but are indicators of what is expected to be covered by fabricators, packagers/labellers.
The elements of validation presented in these guidelines are not intended to be all-encompassing. The particular requirements of validation may vary according to factors such as the nature of drug products eg. sterile, non-sterile, biologicals, and the complexity of the process. The concepts provided in these guidelines have general applicability and provide an acceptable framework for establishing a comprehensive approach to validation.

4.0 Definitions

Change Control (contrôle des changements): A written procedure that describes the action to be taken if a change is proposed (a) to facilities, materials, equipment, and/or processes used in the fabrication, packaging, and testing of drugs, or (b) that may affect the operation of the quality or support system.
Cleaning Validation (validation des procédés de nettoyage): The documented act of demonstrating that cleaning procedures for the equipment used in fabricating/packaging will reduce to an acceptable level all residues (products/cleaning agents) and to demonstrate that routine cleaning and storage of equipment does not allow microbial proliferation.
Concurrent Validation (validation concomitante): A process where current production batches are used to monitor processing parameters. It gives assurance of the present batch being studied, and offers limited assurance regarding consistency of quality from batch to batch.
Critical Process Parameter (paramètre critique du procédé): A parameter which if not controlled will contribute to the variability of the end product.
Equipment Qualification (qualification de l'équipement): Studies which establish with confidence that the process equipment and ancillary systems are capable of consistently operating within established limits and tolerances. The studies must include equipment specifications, installation qualification, and operational qualification of all major equipment to be used in the manufacture of commercial scale batches. Equipment Qualification should simulate actual production conditions, including "worst case"/ stressed conditions.
Installation Qualification (qualification d'installation): The documented act of demonstrating that process equipment and ancillary systems are appropriately selected and correctly installed.
Major Equipment (équipement principal): A piece of equipment which performs significant processing steps in the sequence of operations required for fabrication/packaging of drug products. Some examples of major equipment include tablet compression machines, mills, blenders, fluid bed dryers, heaters, drying ovens, tablet coaters, encapsulators, fermentors, centrifuges, etc.
Master Production Document (document-type de production): A document that includes specifications for raw material, for packaging material and for packaged dosage form, master formula, sampling procedures, and critical processing related SOPs, whether or not these SOPs are specifically referenced in the master formula.
Measuring Devices (instruments de mesure): A device used in monitoring or measuring process parameters.
Operational Qualification (qualification opérationelle): The documented action of demonstrating that process equipment and ancillary systems work correctly and operate consistently in accordance with established specifications.
Process Capability (capacité du procédé): Studies conducted to identify the critical process parameters that yield a resultant quality, and their acceptable specification ranges, based on the established +/- 3 sigma deviations of the process, under stressed conditions but when free of any assignable causes.
Process Qualification (qualification du procédé): The phase of validation dealing with sampling and testing at various stages of the manufacturing process to ensure that product specifications are met.
Process Re-validation (revalidation du procédé): Required when there is a change in any of the critical process parameters, formulation, primary packaging components, raw material fabricators, major equipment or premises. Failure to meet product and process specifications in sequential batches would also require process re-validation.
Process Validation (validation du procédé): Establishing documented evidence with a high degree of assurance, that a specific process will consistently produce a product meeting its predetermined specifications and quality characteristics. Process validation may take the form of Prospective, Concurrent or Retrospective Validation and Process Qualification or Re-validation.
Prospective Validation (validation prospective): Conducted prior to the distribution of either a new product or a product made under a modified production process, where the modifications are significant and may affect the product's characteristics. It is a pre-planned scientific approach and includes the initial stages of formulation development, process development, setting of process specifications, developing in-process tests, sampling plans, designing of batch records, defining raw material specifications, completion of pilot runs, transfer of technology from scale-up batches to commercial size batches, listing major process equipment and environmental controls.
Retrospective Validation (validation rétrospective): Conducted for a product already being marketed, and is based on extensive data accumulated over several lots and over time. Retrospective Validation may be used for older products which were not validated by the fabricator at the time that they were first marketed, and which are now to be validated to conform to the requirements of Division 2, Part C of the Regulations to the Food and Drugs Act.
Validation (validation): The documented act of demonstrating that any procedure, process, and activity will consistently lead to the expected results. Includes the qualification of systems and equipment.
Validation Master Plan (plan maître de validation): An approved written plan of objectives and actions stating how and when a company will achieve compliance with the GMP requirements regarding validation.
Validation Protocol (protocole de validation): A written plan of actions stating how process validation will be conducted; it will specify who will conduct the various tasks and define testing parameters; sampling plans, testing methods and specifications; will specify product characteristics, and equipment to be used. It must specify the minimum number of batches to be used for validation studies; it must specify the acceptance criteria and who will sign/approve/ disapprove the conclusions derived from such a scientific study.
Validation Team (équipe de validation): A multi-disciplinary team of personnel primarily responsible for conducting and/or supervising validation studies. Such studies may be conducted by person(s) qualified by training and experience in a relevant discipline.
Worst Case Condition (condition de la pire éventualité): The highest and /or lowest value of a given parameter actually evaluated in the validation exercise.

5.0 Phases of Validation

The activities relating to validation studies may be classified into three phases:
Phase 1:
Pre-Validation Phase or the Qualification Phase, which covers all activities relating to product research and development, formulation, pilot batch studies, scale-up studies, transfer of technology to commercial scale batches, establishing stability conditions, storage and handling of in-process and finished dosage forms, Equipment Qualification, Installation Qualification, master production documents, Operational Qualification, Process Capability.
Phase 2:
Process Validation Phase (Process Qualification phase) designed to verify that all established limits of the Critical Process Parameters are valid and that satisfactory products can be produced even under the "worst case" conditions.
Phase 3:
Validation Maintenance Phase requiring frequent review of all process related documents, including validation audit reports to assure that there have been no changes, deviations, failures, modifications to the production process, and that all SOPs have been followed, including Change Control procedures.
At this stage the Validation Team also assures that there have been no changes/ deviations that should have resulted in Requalification and Revalidation.

6.0 Interpretation

General Concepts:
Quality, safety and effectiveness must be built into the product. This requires careful attention to a number of factors such as the selection of quality materials/components, product and process design, control of processes, in-process control, and end-product testing.
Due to the complexity of the drug products, routine end-product testing alone is not sufficient due to several reasons. Furthermore, quality cannot be tested into the finished drug product but rather be built in the manufacturing processes and these processes should be controlled in order that the finished product meets all quality specifications. A careful design and validation of systems and process controls can establish a high degree of confidence that all lots or batches produced will meet their intended specifications.

Validation protocol

A written plan stating how validation will be conducted, including test parameters, product characteristics, production and packaging equipment, and decision points on what constitutes acceptable test results. This document should give details of critical steps of the manufacturing process that should be measured, the allowable range of variability and the manner in which the system will be tested.
The validation protocol provides a synopsis of what is hoped to be accomplished. The protocol should list the selected process and control parameters, state the number of batches to be included in the study, and specify how the data, once assembled, will be treated for relevance. The date of approval by the validation team should also be noted.
In the case where a protocol is altered or modified after its approval, appropriate reasoning for such a change must be documented.
The validation protocol should be numbered, signed and dated, and should contain as a minimum the following information:

• objectives, scope of coverage of the validation study
• validation team membership, their qualifications and responsibilities
• type of validation: prospective, concurrent, retrospective, re-validation
• number and selection of batches to be on the validation study
• a list of all equipment to be used; their normal and worst case operating parameters
• outcome of IQ, OQ for critical equipment
• requirements for calibration of all measuring devices
• critical process parameters and their respective tolerances
• description of the processing steps: copy of the master documents for the product
• sampling points, stages of sampling, methods of sampling, sampling plans
• statistical tools to be used in the analysis of data
• training requirements for the processing operators
• validated test methods to be used in in-process testing and for the finished product
• specifications for raw and packaging materials and test methods
• forms and charts to be used for documenting results
• format for presentation of results, documenting conclusions and for approval of study results.

Validation Master Plan

A validation master plan is a document that summarises the company's overall philosophy, intentions and approaches to be used for establishing performance adequacy. The Validation Master Plan should be agreed upon by management.
Validation in general requires meticulous preparation and careful planning of the various steps in the process. In addition, all work should be carried out in a structured way according to formally authorised standard operating procedures. All observations must be documented and where possible must be recorded as actual numerical results.
The validation master plan should provide an overview of the entire validation operation, its organizational structure, its content and planning. The main elements of it being the list/inventory of the items to be validated and the planning schedule. All validation activities relating to critical technical operations, relevant to product and process controls within a firm should be included in the validation master plan. It should comprise all prospective, concurrent and retrospective validations as well as re-validation.
The Validation Master Plan should be a summary document and should therefore be brief, concise and clear. It should not repeat information documented elsewhere but should refer to existing documents such as policy documents, SOP's and validation protocols and reports.
The format and content should include:

• introduction: validation policy, scope, location and schedule
• organizational structure: personnel responsibilities
• plant/ process /product description: rational for inclusions or exclusions and extent of validation
• specific process considerations that are critical and those requiring extra attention
• list of products/ processes/ systems to be validated, summarized in a matrix format, validation approach
• re-validation activities, actual status and future planning
• key acceptance criteria
• documentation format
• reference to the required SOP's
• time plans of each validation project and sub-project.

Installation and Operational Qualification

The detail and scope of a qualification exercise is in many respects related to the complexity of the equipment involved and the critical nature of that equipment with respect to the quality of the final product. Installation and Operational Qualification exercises assure through appropriate performance tests and related documentation that equipment, ancillary systems and sub-systems have been commissioned correctly. The end results are that all future operations will be reliable and within prescribed operating limits.
The basic principles are:

• equipment be correctly installed in accordance with an installation plan
• requirements for calibration, maintenance and cleaning be covered in approved SOP's
• tests be conducted to assure that equipment is operating correctly, under normal and "worst case" conditions
• operator training requirements pertaining to new equipment be conducted and documented.

At various stages in a validation exercise there is need for protocols, documentation, procedures, equipment, specifications and acceptance criteria for test results. All these need to be reviewed, checked and authorised. It would be expected that representatives from the appropriate professional disciplines, eg. Engineering , Research and Development, Manufacturing, Quality Control and Quality Assurance be actively involved in these undertakings with the final authorisation given by a validation team or the Quality Assurance representative.
Installation Qualification (IQ):
I.Q. is the method of establishing with confidence that all major processing, packaging equipment and ancillary systems are in conformance with installation specifications, equipment manuals, schematics and engineering drawings. This stage of validation includes examination of equipment design, determination of calibration, maintenance and adjustment requirements.
For complicated or large pieces of equipment, a pharmaceutical manufacturer may elect to undertake a pre-delivery check of the equipment at the supplier's assembly facility. This pre-delivery check cannot substitute for the Installation Qualification. However, it is acknowledged that the checks conducted and documented at this stage may duplicate a number of the checks conducted at the I.Q. stage, thus leading to a reduction in the scope of the I.Q. checks.
All equipment, gauges and services should be adequately identified and should be given a serial number or other reference number. This number should appear in the reports for the equipment validation studies conducted.
Installation qualification requires a formal and systematic check of all installed equipment against the equipment supplier's specifications and additional criteria identified by the user as part of the purchase specifications. These checks, tests and challenges should be repeated a significant number of times to assure reliable and meaningful results.
At the I.Q. stage the company should document preventive maintenance requirements for installed equipment. The preventive maintenance schedule should be incorporated into the routine maintenance schedule.
Note:
There will be cases where installation of the equipment had not been qualified at the time of installation, and the engineering drawings and manuals for the equipment are no longer available at the manufacturing site. However, the equipment in place operates for a lengthy period of time without any problem or modifications of its design since it was first installed. In such situations, the Inspectorate considers that it may be appropriate for those specific cases to verify a limited number of the most critical parameters demonstrating that the equipment had been adequately installed. Thereafter, the company could pass directly to the operational qualification (O.Q.) stage if there is sufficient documented evidence that these units have always been well maintained and calibrated according to an adequate pre-established schedule.
Operational Qualification (OQ):
The conduct of an Operational Qualification should follow an authorised protocol. The critical operating parameters for the equipment and systems should be identified at the O.Q. stage. The plans for the O.Q. should identify the studies to be undertaken on the critical variables, the sequence of those studies and the measuring equipment to be used and the acceptance criteria to be met.
Studies on the critical variables should include a condition or a set of conditions encompassing upper and lower processing and operating limits referred to as "worst-case" conditions. The completion of a successful O.Q. should allow the finalisation of operating procedures and operator instructions documentation for the equipment. This information should be used as the basis for training of operators in the requirements for satisfactory operation of the equipment.
The completion of satisfactory I.Q. and O.Q. exercises should permit a formal "release" of the equipment for the next stage in the process validation exercise as long as calibration, cleaning, preventive maintenance and operator training requirements have been finalised and documented.
Re-Qualification:
Modifications to, or relocation of equipment should follow satisfactory review and authorization of the documented change proposal through the change control procedure. This formal review should include consideration of re-qualification of the equipment. Minor changes or changes having no direct impact on final or in-process product quality should be handled through the documentation system of the preventative maintenance program.
Process Validation:
It would normally be expected that process validation be completed prior to the distribution of a finished product that is intended for sale (Prospective Validation). Where this is not possible, it may be necessary to validate processes during routine production (Concurrent Validation). Processes which have been in use for some time without any significant changes may also be validated according to an approved protocol (Retrospective Validation).
a) Prospective Validation:
In Prospective Validation, the validation protocol is executed before the process is put into commercial use. During the product development phase the production process should be broken down into individual steps. Each step should be evaluated on the basis of experience or theoretical considerations to determine the critical parameters that may affect the quality of the finished product. A series of experiments should be designed to determine the criticality of these factors. Each experiment should be planned and documented fully in an authorised protocol.
All equipment, production environment and the analytical testing methods to be used should have been fully validated. Master batch documents can be prepared only after the critical parameters of the process have been identified and machine settings, component specifications and environmental conditions have been determined.
Using this defined process a series of batches should be produced. In theory, the number of process runs carried out and observations made should be sufficient to allow the normal extent of variation and trends to be established to provide sufficient data for evaluation. It is generally considered acceptable that three consecutive batches/runs within the finally agreed parameters, giving product of the desired quality would constitute a proper validation of the process. In practice, it may take some considerable time to accumulate these data.
Some considerations should be exercised when selecting the process validation strategy. Amongst these should be the use of different lots of active raw materials and major excipients, batches produced on different shifts, the use of different equipment and facilities dedicated for commercial production, operating range of the critical processes, and a thorough analysis of the process data in case of Requalification and Revalidation.
During the processing of the validation batches, extensive sampling and testing should be performed on the product at various stages, and should be documented comprehensively. Detailed testing should also be done on the final product in its package.
Upon completion of the review, recommendations should be made on the extent of monitoring and the in-process controls necessary for routine production. These should be incorporated into the Batch manufacturing and packaging record or into appropriate standard operating procedures. Limits, frequencies and actions to be taken in the event of the limits being exceeded should be specified.
Matrix or "Family" approaches to prospective process validation:
It may be possible and acceptable in particular circumstances for a manufacturer that uses the same process for several related products to develop a scientifically sound validation plan for that process rather than different plans for each product manufactured by that process.
The matrix approach generally means a plan to conduct process validation on different strengths of the same product, whereas the "family" approach means a plan to conduct process validation on different products manufactured with the same processes using the same equipment.
The validation process using these approaches must include batches of different strengths or products which should be selected to represent the worst case conditions or scenarios to demonstrate that the process is consistent for all strengths or products involved.
b) Concurrent Validation:
Unconditional use of this approach is not encouraged by the Inspectorate and is not acceptable as being the "norm". In using this approach there is always the risk of having to modify process parameters or specifications over a period of time. This situation often leads to questions regarding disposition of the batches that had already been released for sale, subsequently known to have undesired quality characteristics.
Concurrent validation may be the practical approach under certain circumstances. Examples of these may be:

• when a previously validated process is being transferred to a third party contract manufacturer or to another manufacturing site
• where the product is a different strength of a previously validated product with the same ratio of active / inactive ingredients
• when the number of lots evaluated under the Retrospective Validation were not sufficient to obtain a high degree of assurance demonstrating that the process is fully under control
• when the number of batches produced are limited (e.g. orphan drugs).

It is important in these cases however, that the systems and equipment to be used have been fully validated previously. The justification for conducting concurrent validation must be documented and the protocol must be approved by the Validation Team. A report should be prepared and approved prior to the sale of each batch and a final report should be prepared and approved after the completion of all concurrent batches. It is generally considered acceptable that a minimum of three consecutive batches within the finally agreed parameters, giving the product the desired quality would constitute a proper validation of the process.
c) Retrospective Validation:
In many establishments, processes that are stable and in routine use have not undergone a formally documented validation process. Historical data may be utilized to provide necessary documentary evidence that the processes are validated.
The steps involved in this type of validation still require the preparation of a protocol, the reporting of the results of the data review, leading to a conclusion and recommendation.
Retrospective validation is only acceptable for well established detailed processes that include operational limits for each critical step of the process and will be inappropriate where there have been recent changes in the formulation of the product, operating procedures, equipment and facility.
The source of data for retrospective validation should include amongst others, batch documents, process control charts, maintenance log books, process capability studies, finished product test results, including trend analyses, and stability results.
For the purpose of retrospective validation studies, it is considered acceptable that data from a minimum of ten consecutive batches produced be utilized. When less than ten batches are available, it is considered that the data are not sufficient to demonstrate retrospectively that the process is fully under control. In such cases the study should be supplemented with data generated with concurrent or prospective validation.
Some of the essential elements for Retrospective Validation are:

• Batches manufactured for a defined period (minimum of 10 last consecutive batches)
• Number of lots released per year
• Batch size/strength/manufacturer/year/period
• Master manufacturing/packaging documents
• Current specifications for active materials/finished products
• List of process deviations, corrective actions and changes to manufacturing documents
• Data for stability testing for several batches
• Trend analyses including those for quality related complaints

Process Re-Validation:
Re-validation provides the evidence that changes in a process and /or the process environment that are introduced do not adversely affect process characteristics and product quality. Documentation requirements will be the same as for the initial validation of the process.

Periodic review and trend analysis should be carried out at scheduled intervals. Re-validation becomes necessary in certain situations. The following are examples of some of the planned or unplanned changes that may require re-validation:

• Changes in raw materials (physical properties such as density, viscosity, particle size distribution, and moisture, etc., that may affect the process or product).
• Changes in the source of active raw material manufacturer
• Changes in packaging material (primary container/closure system).
• Changes in the process (e.g., mixing time, drying temperatures and batch size)
• Changes in the equipment (e.g. addition of automatic detection system). Changes of equipment which involve the replacement of equipment on a "like for like" basis would not normally require a re-validation except that this new equipment must be qualified.
• Changes in the plant/facility.
• Variations revealed by trend analysis (e.g. process drifts)

A decision not to perform re-validation studies must be fully justified and documented.
Change Control:
Written procedures should be in place to describe the actions to be taken if a change is proposed to a product component, process equipment, process environment, processing site, method of production or testing or any other change that may affect product quality or support system operations.
All changes must be formally requested, documented and accepted by the Validation Team. The likely impact / risk of the change on the product must be assessed and the need for the extent of re-validation should be determined.
Commitment of the company to control all changes to premises, supporting utilities, systems, materials, equipment and processes used in the fabrication/packaging of pharmaceutical dosage forms is essential to ensure a continued validation status of the systems concerned.
The change control system should ensure that all notified or requested changes are satisfactorily investigated, documented and authorised. Products made by processes subjected to changes should not be released for sale without full awareness and consideration of the change by the Validation Team. The Team should decide if a re-validation must be conducted prior to implementing the proposed change.

7.0 References

1. Guidelines on General Principles of Process Validation, CDER, US-FDA 1987
2. Pharmaceutical Process Validation; 2^nd edition, Editors: I. R. Berry and R.A. Nash, 1993
3. Recommendations on Validation Master Plan, Installation and Operational Qualification, Non-Sterile Process Validation, Cleaning Validation, PIC/S, August 2001

GMP Committee Members

Name	Title / Office / Bureau	Location
France Dansereau	Manager, Drug GMP Inspection Unit, Compliance and Enforcement Coordination Division (CECD), HPFBI*	Ottawa, ON
Kim Dayman-Rutkus	Director, Policy and Regulations Division, HPFBI	Ottawa, ON
Richard Ferland	MRA** Officer	Longueuil, QC
Francisco Fernandes	Compliance Specialist, Ontario & Nunavut Operational Centre, HPFBI	Toronto, ON
Taras Gedz	Bureau of Pharmaceutical Sciences, TPD***	Ottawa, ON
Denis Girard	Scientific Assessment Advisor, VDD****	Ottawa, ON
Raymond Giroux	Drug Specialist, Quebec Operational Centre, HPFBI	Longueuil, QC
Alicja Kasina	Drug Specialist, Atlantic Operational Centre	Halifax, NS
Stephen McCaul	MRA Officer	Toronto, ON
Johanne St-Denis, Secretary	Compliance Officer (CECD), HPFBI	Ottawa, ON
Paul Gustafson	Compliance Officer, Manitoba and Saskatchewan Operational Centre, HPFBI	Winnipeg, MB
Willem Stevens	Senior Biologist/Evaluator, BGTD*****	Ottawa, ON
Stéphane Taillefer	Compliance Specialist, CECD, HPFBI	Longueuil, QC
Sheila Welock	Drug Specialist, Western Operational Centre, HPFBI	Burnaby, BC

* Health Products and Food Branch Inspectorate.
** Mutual Recognition Agreement.
*** Therapeutic Products Directorate.
**** Veterinary Drugs Directorate.
***** Biologics and Genetic Therapies Directorate (BGTD).

Aseptic Process Validatin

This document is intended to provide pharmaceutical dosage form manufacturers with guidance on the validation of aseptic manufacturing processes, as required in Division 2, Part C (Good Manufacturing Practices) of the Food and Drug Regulations, and in a manner which is acceptable to the Health Products and Food Branch Inspectorate.

Sterile Products may be broadly classified into two main categories, according to the manner in which they are produced: those which are sterilized after the product has been filled and sealed in the final container(s) ("terminally sterilized" products) and those where the sterilization stage (or stages) takes place before the bulk product is filled. In this latter instance, all subsequent processing (typically, the filling and sealing operations) must be conducted aseptically in order to prevent recontamination of the sterilized product.

It is recognized that aseptic processes play an important role in rendering sterile formulations which cannot be terminally sterilized. However, terminal sterilization, in particular using moist heat processes, is considered to be the method of choice in the manufacture of sterile products due to the enhanced sterility assurance which it affords. Manufacturers who choose to manufacture a sterile product without terminal sterilization must be prepared to justify this decision by demonstrating that the product cannot be terminally sterilized, even under less severe autoclave cycles tailored to the bioburden of the batch (Probability of Survival approach).

The two most common pharmaceutical applications of aseptic processing methods are (a) the filling of liquid products following sterilization by filtration and (b) the filling of previously sterilized bulk powder products. Both are covered in this guide. The final section of this guide outlines documentation required to provide acceptable evidence that a given process has been thoroughly evaluated and is adequately controlled.

It is assumed that, throughout, manufacturing and control operations are conducted in accordance with the principles of Good Manufacturing Practice, both in general and in specific reference to Sterile Products manufacture.

The steps recommended in this guideline may be summarized as follows:

* As a pre-requisite, all studies should be conducted in accordance with a detailed, pre-established PROTOCOL, or series of protocols, which in turn is subject to formal change-control procedures. (See Section 3).
* Both the personnel conducting the studies, and those running the process being studied should be appropriately TRAINED and QUALIFIED and be suitable and competent to perform the tasks assigned to them (See Section 4).
* All data generated during the course of the studies should be formally REVIEWED and CERTIFIED, as evaluated against pre-determined criteria (See Section 5).
* Suitable TESTING FACILITIES, EQUIPMENT, INSTRUMENTS and METHODOLOGY should be available (See Section 6).
* Suitable CLEAN ROOM FACILITIES should be available, in terms both of the "local" and "background" environments. Assurance that the Clean Room environment is as specified should be secured through initial commissioning ("Qualification") and subsequently through the implementation of a program of re-testing, in-process control and monitoring (See Section 7).
* All processing equipment should be properly INSTALLED, QUALIFIED and MAINTAINED (See Section 8).
* When appropriate attention has been paid to the above, the aseptic process may be validated by means of "MEDIA FILL", (or "PROCESS SIMULATION") studies (See Sections 9 and 10).
* The process should be REVALIDATED at intervals (See Section 11).
* Comprehensive DOCUMENTATION should be available to define, support and record the overall validation process (See Section 12).

Whilst this Guide is concerned only with the validation of ASEPTIC PROCESSES, it is crucial to the success of any such process that the product, materials, components etc. that are being handled/processed aseptically (e.g. bulk solution or powder; containers and closures) plus any equipment, vessels or surfaces (e.g. holding tanks, pipework, filling machines) which will or can come into contact with sterilized products/materials have themselves been previously sterilized by appropriate and validated sterilization processes. In any aseptic filling process, assurance of container/closure integrity is, of course, vital. Evidence that all this is so should be provided as part of the overall Validation Documentation (see Section 12).

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2. VALIDATION - GENERAL/TERMINOLOGY

2.1 In the context of this guide, Process Validation is defined as:

The action taken to demonstrate, and to provide documented evidence that a process will, with a high degree of assurance, consistently achieve the desired and intended results.

2.2 Before Process Validation can commence there must be what may be termed an essential Prevalidation phase. This phase, in addition to such considerations as equipment specification, equipment design and equipment purchase, requires attention to Equipment Qualification.

2.3 Equipment Qualification in turn has two main phases :

2.3.1 Installation Qualification, that is demonstrating and certifying that a piece of equipment is properly installed, is provided with all necessary services, subsidiary equipment and instruments, and is capable of performing in accordance with its basic design parameters.

2.3.2 Operational Qualification, consists of demonstrating that the equipment will perform consistently, and within pre-defined limits, as specified and installed.

2.4 None of these various phases need to be considered as entirely "water-tight" compartments. The divisions have been defined as a matter of convenience in discussion. In practice there is likely to be some overlap, or merging, between the various components of Validation/Qualification. In addition, there are quite wide-spread variations in terminology and conception. Some consider "Qualification" and "Validation" as two separate, yet related activities. Others use the term "Validation" to embrace the overall activity of Prevalidation/Qualification PLUS Process Validation.

The relationships between these various phases may be summarized as follows:

Summerized relationship between these various phases

2.5 Validation has also been considered to have three aspects, or possible strategies - Prospective Validation, Concurrent Validation, and Retrospective Validation.

2.5.1 Prospective Validation applies to new processes and new equipment,where studies are conducted and evaluated, and the overall process/equipment system is confirmed as validated before the commencement of routine production.

2.5.2 Concurrent Validation applies to existing processes and equipment. It consists of studies conducted during normal routine production and can only be considered acceptable for processes which have a manufacturing and test history indicating consistent quality production.

2.5.3 Retrospective Validation applies to existing processes and equipment, and is based solely on historical information. Unless sufficiently detailed past processing and control records are available, retrospective validation studies are unlikely to be either possible or acceptable. For example, it would be necessary to establish that the process had not been modified and that the equipment was still operating under the same conditions of construction and performance as documented in the historical records. Maintenance records and process change control documentation would be necessary to support any such claim. Furthermore, the incidence of process failures, and records of rejects and/or reworking would need to be carefully evaluated for evidence of inconsistency in the process. Manufacturing, maintenance, testing and calibration data would all need to demonstrate process uniformity, consistency and continuity.

2.5.4 Concluding Note on Validation Terminology. While there is considerable variation in the understanding and use of the various terms discussed above, there is general agreement that the critical validation concepts are the following:

* the overall process is understood
* equipment is appropriately specified and designed
* equipment is properly installed and maintained and is demonstrably operating as specified and designed
* the process is validated to ensure that it does achieve the desired and intended result.

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3. PROTOCOL DEVELOPMENT AND CONTROL

3.1 Each stage in the validation of the overall process should proceed in accordance with a pre-established and formally approved, detailed, written protocol, or series of related protocols.

3.2 Prior to the commencement of the studies, written change control procedures should be established, which will prevent unauthorized changes to either the process itself, or to the study protocol, and restrict change during any stage of the study until all relevant data are evaluated.

3.3 Protocols should have a Title, Date and a unique Identification or Reference Number. They should be formally authorized/approved by person(s) with the competence and authority to do so.

3.4 Protocols should specify the following in detail:

3.4.1 The objectives and scope of the study. That is, there should be a clear Definition of Purpose.

3.4.2 A clear and precise definition of the process, equipment, system or sub-system which is to be the subject of the study, with details of performance characteristics.

3.4.3 Installation and qualification requirements for new equipment.

3.4.4 Any up-grading requirements for existing equipment, with justification for the change(s) and a statement of qualification requirements.

3.4.5 Detailed, step-wise statement of actions to be taken in performing the study (or studies).

3.4.6 Assignment of responsibility for performing the study.

3.4.7 Statements on all test methodology to be employed, with a precise statement of the test equipment and/or materials to be used.

3.4.8 Test equipment calibration requirements.

3.4.9 References to any relevant Standard Operating Procedures (SOPs).

3.4.10 Requirements for the content and format of the report on the study.

3.4.11 Acceptance criteria against which the success (or otherwise) of the study is to be evaluated.

3.4.12 The personnel responsible for evaluating and certifying as acceptable each stage in the study, and for the final evaluation and certification of the process as a whole, all as measured against the pre-defined acceptance criteria.

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4. PERSONNEL

As with all Process Validation studies, documented evidence of the relevant experience and training of the personnel involved in conducting the studies should be maintained. However, because the personnel actually performing the aseptic processing (both during the course of any validation studies, and in routine operation) can, and do, have so crucial an effect on the quality of the end-product, it is appropriate and necessary to consider both these aspects of personnel involvement.

4.1 Appropriately qualified personnel should ensure that the protocol and the testing methodology are based on sound scientific principles and that all studies are properly evaluated and certified.

4.2 All personnel conducting tests should be trained and experienced in the use of the instruments, measuring devices and materials used.

4.3 Engineering/maintenance personnel should be fully trained and competent in the operation and maintenance of the machines, equipment, and air control systems involved.

4.4 Although modern automated and barrier techniques may reduce contamination risk, the significance of the "human factor" in all aseptic processing operations cannot be over-stressed. For the results of any validation studies themselves to be valid, it is essential that the risk represented by so potentially random a variable as a human operator is kept as much under control as is possible. That is, steps must be taken to reduce the risk and to minimize the variability.

4.5 This in turn means that any operators involved in performing an aseptic processing operation which is the subject of a validation study should adopt the same techniques, disciplines, and standards of hygiene, clothing and behaviour as in normal routine manufacture. The converse also applies: if operators conduct themselves, during routine production, in manner which is different from their behaviour etc. during the validation studies, then conclusions drawn from the validation will be invalid.

4.6 It is therefore vital that all personnel involved in aseptic processing operations are trained in, and fully understand, the concepts and principles of GMP, and the relevant elements of microbiology. They must understand the importance of personal hygiene and cleanliness, and be made fully aware of the possible hazardous consequences of product contamination.

4.7 Operators should be provided with suitable Clean Room clothing and trained in appropriate gowning technique. The type of clothing to be worn, and the "scrub-up" and gowning process should be defined in written procedures, available to the operators, and preferably displayed in the changing room. The same clothing/gowning standards should be observed during validation studies as in routine production, and vice versa.

4.8 The maximum number of personnel permitted in the Clean Room during normal routine production should also be present in the Clean Room during any validation test runs.

4.9 At all times, operators should be encouraged to report any infections, open lesions or any other conditions which could result in the shedding of abnormal numbers of particles or microorganisms. As with routine manufacture, no person thus affected should be present in the Clean Room during validation test runs.

4.10 As in routine production, Clean Room operators involved in validation studies should be microbiologically monitored by taking test samples from gloves, gowns and facemasks.

4.11 Normal routine process documentation should specify and record the numbers and types of operator interventions that are permitted during processing, and in what circumstances. A similar series of interventions should occur during any validation
test runs. Details should be provided as part of the overall validation documentation (See Section 12).

Note: As stated in the Introduction it is assumed that all routine manufacturing and control operations are conducted in accordance with Good Manufacturing Practice, and this includes a requirement that all personnel are trained and competent to carry-out the tasks assigned to them.

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5. DATA REVIEW AND STUDY CERTIFICATION

5.1 All information or data generated as a result of the study protocol should be evaluated by qualified individuals against protocol criteria and judged as meeting or failing the requirements. Written evidence supporting the evaluation and conclusions should be available.

5.1.1 These evaluations should be made as the information becomes available.

5.1.2 If such an evaluation shows that protocol criteria have not been met, the study should be considered as having failed to demonstrate acceptability, and the reasons should be investigated and documented.

5.1.3 Any failure to follow the procedure as laid down in the protocol must be considered as potentially compromising the validity of the study itself, and requires critical evaluation of the impact on the study.

5.1.4 The final certification of the validation study should specify the pre-determined acceptance criteria, against which success or failure was evaluated.

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6. LABORATORY

6.1 All laboratory tests (including physical, chemical and microbiological determinations) should be performed by a competent laboratory, suitably equipped, and staffed with personnel properly trained and qualified to carry-out the test procedures assigned to them.

6.2 Detailed authorized, written procedures defining the relevant, validated methodology should be available for all laboratory tests which are to be carried out during the course of the study. These procedures should be referenced in the study protocol.

6.3 If any external laboratory facilities are used, a system should be in place for determining the competence of these laboratories to carry out the tests required. This requirement should be referenced in the study protocol.

6.4 All measuring/recording/indicating instruments employed in the studies should be adequate for the purpose, in terms of range, accuracy, reproducibility etc.. They must be calibrated in accordance with pre-defined written procedures before any validation studies are commenced.

6.5 Records of each calibration should be maintained, and should form part of the overall validation documentation.

6.6 For the conclusions drawn from any qualification/validation studies themselves to remain valid during routine production, all controlling and recording instruments must be subjected to a written maintenance and calibration program.

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7. ENVIRONMENTAL CONSIDERATIONS: CLEAN ROOM STANDARDS, QUALIFICATION AND MONITORING

7.1 Although prior to their being sterilized, products, materials, containers, components, closures etc. may be handled/processed in a lower (for example, Grade C) Clean Room environment, subsequent to the sterilization stage(s) all aseptic processing operations should be conducted under local Grade A ("work station") protection, within a general (or "background") Grade B Clean Room environment. However, if certain specialized automated or barrier techniques are employed to provide the localized protection, a lower background environmental standard may be acceptable, provided that process validation studies demonstrate the attainment of an acceptable level of sterility assurance. (Grades A, B and C are as defined in the table for the "Basic Environmental Standards for the Manufacture of Sterile Products" in the Sterile Products section of the current version of the "Good Manufacturing Practices". ).

7.2 For the results of any validation studies to have valid relevance to routine production, they must be conducted under precisely the same environmental conditions as used, or intended to be used, during normal routine production.

7.3 Confirmation and Certification that the room and the work station(s) do, in fact conform to the specified Environmental Standard may be considered as forming part of the Installation Qualification phase. To this end, the following basic work should be carried-out on the initial commissioning (or "Qualification") of a new Clean Room installation:

* Room air filter integrity tests.
* Determination of air velocity at the face of each air inlet filter.
* Room air change rate.
* Room air particle counts.
* Room air pressure differentials and air flow patterns.
* Lighting, heating, humidity.
* Work station(s) air filter efficiency tests.
* Determination of air velocity at face of work station air filters.
* Particle counts within work station areas.

7.4 Following the initial commissioning, a regular re-test program should be adopted, e.g.:

7.4.1 Room and Work Station Air Filter Tests: Repeat at least annually, unless results of normal in-process monitoring indicates a need for more frequent, or additional testing.

7.4.2 Air Velocity and Room Air Changes: Repeat at least twice a year.

7.4.3 Air Particle Counts: Determine as part of regular in-process monitoring, with formal certification by a competent specialist agency 3 times per year.

7.5 Room pressure differentials should be monitored on a continuous, on-going, basis.

7.6 Walls, floors, work stations and surfaces generally should be subject to a pre-determined program of cleaning and disinfection.

7.7 In order to ensure that, during routine manufacture, products remain within the quality parameters established during the overall validation process, it is necessary to design and implement a program of in-process control and monitoring. Similarly, as part of the over-all assurance that process validation studies are conducted under comparably normal processing conditions, a similar in-process control and monitoring program should be operated during the process validation runs.

7.8 In-process monitoring and control may be considered under three headings:

* Environmental Particulate
* Microbiological
* Filter Integrity Testing

7.9 As appropriate to the type of manufacturing process, consideration needs to be given to the following Microbiological Monitoring and Control Procedures:

* Bioburden check on bulk solution, prior to sterile filtration.
* Exposure of "Settle Plates" (Petri dishes of nutrient agar) at critical positions within the general Clean Room environment and at the controlled work station(s).
* Use of Air Sampling devices to determine the number of viable organisms per cubic metre (or cubic foot) of air in the room, and within the work station(s).
* Use of Contact Plates, or Swabs, to check the microbiological quality of surfaces.

7.10 Environmental Particulate monitoring should be carried out using appropriate air Particle Counting devices to check that the general environmental and work station air remain in conformity with specification.

7.11 Filter integrity testing of the filter(s) used to sterilize the product is critical in sterile product manufacturing. If the product cannot be sterilized in the final container, solutions or liquids can be filtered through a sterile filter of normal pore size of 0.22 micron (or less), into a previously sterilized container. The integrity of the sterilized filter should be verified before use and should be confirmed immediately after use by an appropriate method, such as a bubble point, diffusion, or pressure hold tests.

7.12 This in-process monitoring and control should be conducted in accordance with a written, pre-determined program, which includes specified test limits and standards, and with all results formally reported and evaluated against those limits. This requirement applies as much to validation studies as routine manufacture.

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8. EQUIPMENT QUALIFICATION AND MAINTENANCE

8.1 A wide range of different types of mechanized equipment may be used in various aseptic processing operations. Before any process validation studies may be commenced, it is necessary that all such equipment be properly qualified, in both Installation and Operational terms (see 2.2 and seq.), and that this qualification be certified. It is clearly outside the scope of these guidelines to detail Installation and Operational requirements for every possible item of equipment. The essential requirements are that the equipment be:

* Confirmed as having been constructed as specified.
* Properly installed and provided with all necessary functioning services, ancillary equipment and instruments.
* Confirmed as capable of operating consistently, within pre-determined limits, over its defined operating range.

8.2 Processing equipment must be confirmed as Qualified before any subsequent studies can be considered valid.

8.3 For the results of any validation studies themselves to remain valid in routine manufacture, a comprehensive routine maintenance program should be developed, setting out each activity in detail along with the frequency in terms of real time, machine time or other time base. The time base should be clearly defined for each procedure.

8.4 Unless such a program is developed and implemented, and the manufacturing equipment and attendant instruments remain in the same state as during the validation studies, then any assurance derived from those studies could be considered to be negated.

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9. MEDIA FILL STUDIES (SOLUTION PRODUCTS)

9.1 The "Media Fill", or "Broth Fill", technique, is one in which a liquid microbiological nutrient growth medium is prepared and filled in a simulation of a normal manufacturing operation. The nutrient medium processed and handled in a manner which simulates the "normal" manufacturing process as closely as possible with the same exposure to possible contamination (from operators, environment, equipment, and surfaces) as would occur during routine manufacture. The sealed containers of medium thus produced are then incubated under prescribed conditions and examined for evidence of microbial growth, and thus of an indication of the level of contaminated units produced. The process is summarized in Figure 1.

Figure 1: Process Flow Diagram of Liquid Media Filling of Vials.

Process Flow Diagram of Liquid Media Filling of Vials

NOTES:

* Different types of container will require different methods of sterilization. For example glass vials are likely to be dry heat sterilized, plastic vials may be sterilized by irradiation or ethylene oxide.
* Any other components, e.g. teats/droppers will also need to be pre-sterilized by some suitable validated method.
* The process flow for liquid media filling of ampoules will be analogous to the above, without the operations involving stoppers, overseals etc...

9.2 It is important to recognize that, in many instances, media fills are, amongst other things, a test of the human operators' aseptic techniques. In this test situation these operators can hardly remain unaware that nutrient medium is being filled, and that they themselves are, to an extent,"under test". There is, therefore the possibility that they will take more than their usual care, and thus the normal process will not be precisely simulated. Every effort should be made to ensure that the operators do behave normally during the media fills, and conversely (and perhaps importantly) that during routine production they do not deviate in any way from the high standards adopted during those simulation studies.

9.3 A further difficulty which needs to be noted is the possibility of contamination of the facility and equipment by the nutrient medium. If the process is well controlled and the media-fill is promptly followed by cleaning and disinfection, and (as necessary) sterilization of equipment, contamination should not occur. Nevertheless, it is important to recognize the potential hazard, and to respond accordingly.

9.4 It must also be emphasized that the filling of a nutrient medium solution alone does not constitute an acceptable aseptic process validation. The whole manufacturing cycle must be simulated, from the dispensing and reconstitution of the powdered medium under normal manufacturing conditions, to the filling and sealing process itself. Operators (and numbers of operators), numbers and types of filtrations etc. should all be "as normal", as should holding times in any mixing vessels, interim holding tanks etc. General activity should be at a normal level, and no attempt should be made to take any "special" precautions to ensure that the test run is successful. If any deviation from the normal is permitted, it should only be in the direction of presenting a greater, rather than a lesser, microbiological challenge to the process.

9.5 Before any meaningful aseptic process validating media-fills can be carried-out, all necessary Equipment Qualification and Instrument Calibration must be completed, together with the appropriate certification (see e.g. Sections 6 and 8). The Clean Rooms used for all processing stages should also have been confirmed and certified as complying with the required environmental standards. (See Section 8).

9.6 Normal routine in-process control and monitoring procedures (see Section 8) should be operated during the media-fills.

9.7 The liquid Nutrient Medium used should meet the following criteria:

Selectivity:
The medium should have low selectivity, that is, it should be capable of supporting growth of the widest range of micro-organisms that might reasonably be encountered.

Clarity:
As "made-up", it should be clear, so as to allow for the observation of any evidence of growth following incubation.

Filterability:
Where the process being simulated includes a filtration stage, the liquid medium should be capable of being filtered through the same grade and type of microbial retentive filter as that through which the actual product is, or will be, filtered. Liquid Soybean Casein Digest (SCD), also termed "Tryptic Soy Broth" (TSB) is perhaps the liquid medium most frequently employed. However, other formulations (for example, liquid Tryptone Glucose Yeast Extract, Brain Heart Infusion etc.) may be used, provided they meet the criteria set out above.

9.8 The liquid medium should be either sterilized by filtration (if such a stage is part of the normal operation being simulated) or pre-sterilized by heat and cooled to ambient temperature before proceeding.

9.9 The Number of Units to be filled per run should be sufficient to provide a high probability of detecting a low incidence of microbial contamination. For example, in order to give 95% confidence of detecting a contamination rate of 1 in a thousand units filled (i..e. 0.1%) with sterile nutrient media, 3000 units need to be filled and no contaminated unit should be found after the incubation period. (However, see 9.19).

9.10 For the initial validation of a new process or facility, sufficient consecutive media fill runs should be performed to provide assurance that the results obtained are consistent, meaningful and provide an acceptable level of sterility assurance. At least 3 separate, consecutive, successful runs per operator team, or shift, should be performed to acceptable initial validation of a given process line (For Revalidation, see Section 11).

9.11 The Volume to be Filled per unit should be the normal production fill-volume where possible. In the case of high volume containers, a lesser quantity may be used, provided steps are taken to ensure wetting of all the inner surface of the container, and any closure, by the medium, e.g. by shaking or inversion, and/or by inverting the containers part-way through the incubation period. It is good practice to take similar steps to ensure complete inner surface wetting when normal full volumes are filled as well.

9.12 Immediately following filling, all units filled should be examined for leakers and/or damage. In this context, any leak-test method in which heat is employed should obviously not be used. Any leakers or damaged units should be rejected.

9.13 Incubation of the filled units should follow immediately after filling and leak-testing, and should be for a period of 14 days.

9.14 The Incubation Temperature should be 30oC to 35oC. Incubation temperatures should be carefully monitored and maintained throughout the incubation period.

9.15 Test Controls: Media used in the evaluation must pass a growth promotion test where a challenge with between 10 - 100 organisms per container is suitable to show the growth characteristics of the organism.

9.16 Reading of Results: All units filled and incubated should be visually examined for microbial growth after 14 days incubation. Any contaminated units will be identifiable by the turbidity of the medium. Any contaminated units that are found should be examined in the laboratory, and the contaminating organisms identified, to the species level where possible, so that appropriate preventative action may be taken. For the results of the media fill run to be considered valid, all the inoculated control units should display growth.

9.17 The contamination rate found in a media fill run should be calculated as follows:

Arrow Arrow View Contamination Rate Table
(This will open in a new window with a file size of 4 K )
(You may have to use the scroll bar to see the entire table)

Contamination Rate = Upper 95% contamination limit / Number of filled units * 100

9.18 Acceptance Criteria: A currently accepted limit is 0.1% at a 95% confidence level.

9.19 It is however important to recognize that, for example, a media fill run of 3000 units will usually represent only a simulated sample of a normal production run. Actual production runs are likely to be much larger. The contamination level determined from a media fill will therefore be subject to sampling error, such that (for example) 3 contaminated units in a media fill of 3000 may be indicative of a potential contamination rate in actual production significantly greater than 0.1%.

9.20 The following table indicates the maximum permitted number of contaminated units per various Media-Fill "run sizes" to indicate a 0.1% contamination limit with a 95% Confidence Level.

Arrow Arrow View Media Fill Units / Contaminated Units Permitted Table
(This will open in a new window with a file size of 4 K )
(You may have to use the scroll bar to see the entire table)

Thus for example, to provide confidence (95%) of complying with the 0.1% limit, 4750 media-filled units would be required with no more than one unit found contaminated, or 6,300 units with no more than 2, and so on.

9.21 If batches smaller than 3,000 units are produced, the minimum number of containers used for process simulation with sterile nutrient media should be equal to the commercial batch size and no contaminated unit should be found after the incubation period.

9.22 To demonstrate compliance with a contamination limit of one in 10,000 (0.01%) notably larger numbers of units would need to be filled with "broth". For example, in relation to a normal production run of 50,000 units, over 46,000 units would need to be filled with medium, with no more than one unit found contaminated.

9.23 These statistical considerations reveal a distinct practical problem with regard to the number of units which may need to be filled with medium and incubated, particularly in any attempt to demonstrate a probability of a low (for example, less than 0.1%) level of contamination in "standard" production batch sizes. Manufacturers should determine (according to their particular circumstances and production batch sizes) media-fill run sizes, with permitted contamination levels, which will provide adequate confidence in sterility of actual production batches. Purely on the basis of the practical limitations of the test procedure itself, a contamination level in a media fill of 0.1%, detected infrequently, may be considered to be acceptable. Regular, or common, contamination levels (in media fills) of 0.1% or above should be regarded as unsatisfactory.

9.24 Whilst it may be statistically unsound to sum in a simple fashion data from a series of discrete events, and then treat these data as if they had been derived from a single event, a series of "good" media fill results over a period of time (assuming reasonable comparability of conditions etc.) may be regarded as confidence-strengthening, if not in any precisely quantifiable fashion.

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10. MEDIA FILL STUDIES (NON-SOLUTION PRODUCTS)

The same general principles, conditions and statistical considerations as set-out in Section 9 apply, but the various types of non-solution Sterile Products require various adaptations to the approaches already described. In all procedures involving the use of growth media it is vital to control any contamination by the media of equipment, surfaces etc. All media fill studies should be promptly followed by application of thorough cleaning, disinfecting and sterilization procedures.

10.1 Sterile Powders

The use of the media fill technique in the validation of the filling of sterile powder products presents certain special problems, arising from the probable necessity to employ additional equipment, techniques or manipulations which are different (or additional) to those used in routine production. In such circumstances the media-fill cannot unequivocally be said to be a precise process simulation. This inevitable shortcoming may, however, have to be accepted. A number of different approaches have been proposed and used, as follows:

10.1.1 The normal process is simulated as closely as possible, but instead of filling a powder, a sterile liquid medium is filled. This approach is virtually the same as that described for a solution product (Section 9 above) and fails to simulate the actual powder fill.

10.1.2 The normal process is simulated as closely as possible, with a sterile, dry inert powder filled in place of the normal product or material. Lactose, mannitol and polyethylene glycol 8000 are examples of "simulation" powders which have been used. There are two possible variations on this approach:

1. Fill the chosen inert powder into the containers (e.g.
ampoules/vials) which are already filled with sterile liquid medium.
2. Fill the inert powder first, and then add the sterile liquid medium. In both these variations, a powder fill is simulated, but an additional, non-routine step (i.e. the filling of the liquid growth medium) is involved.

10.1.3 Fill sterile dry powdered medium into the containers, in simulation of the normal powder filling operation, aseptically adding sterile aqueous diluent on-line, to form liquid medium solution. As in 9.1.2, a powder fill is simulated, but an additional operation is involved.

10.2 Whichever approach is adopted, it is important to ensure that any powder/medium/diluent combination used does not cause growth inhibition through hyperosmolar or other antimicrobial effects.

10.3 Suspension Products: Simulate the entire normal process as closely as possible, using a sterile inert powder in place of the normal powder product. Micronize etc. (if this is part of the normal process) and form suspension, using sterile liquid growth medium in place of the normal liquid phase of the suspension product. Fill as normal and incubate. (Comments as in 10.2 above similarly apply.)

10.4 Freeze-dried Product: Simulate the entire normal process (i.e. preparation of bulk solution, filling of solution, loading of freeze-dryer, running of freeze-drying cycle, sealing/closing of containers, inspection) but using a liquid growth medium (dispensed as a powder, dissolved and sterilized) in place of normal product. Actual freeze-drying of the medium solution is not practicable, but exposure, holding times in the freeze dryer should be as normal.

10.5 Semi-solid Products (e.g. Sterile Ointments and Creams): Simulate the normal process cycle as closely as possible, filling a sterile liquid growth medium made to similar consistency as the normal product by the addition, for example, of agar (approximately 4 g. per litre) or carboxymethylcellulose.

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11. REVALIDATION

11.1 Following initial aseptic process validation, media-fills and process simulations should be repeated to an extent, and at a frequency, which will depend on the occurrence of events or changes which may bear upon the potential microbial hazard to the process and product. Significant modifications to equipment or facilities, changes in personnel, undesirable trends in environmental monitoring results, and sterility test failures may all indicate an immediate need to implement a full process validation protocol (i.e. minimum of 3 consecutive successful media-fill runs) with the facility in question taken out of service until any problems have been resolved, and the results of the three media-fills have been evaluated and found acceptable.

11.2 In the absence of any significant changes, or of any other events giving cause for concern, then a minimum re-test frequency should be twice per year per operator shift or team, for each process line. For single shift operations, the minimum frequency should be 3 times for each process line per year.

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12. DOCUMENTATION

The following information should be prepared in summary form for the purposes of inspection and evaluation by the appropriate authorities.

12.1 Overview

A comprehensive outline of the protocol followed in the validation of the process should be prepared. The overview should indicate the steps performed, in proper sequence, and should encompass:

1. the approach taken;
2. justification of the approach based on the product factors;
3. summation of any modifications to the equipment required; and
4. any modifications to the protocol resulting from the study.

12.2 Prevalidation

12.2.1 A full description of the aseptic fill equipment and ancillary systems and report(s) confirming successful installation in accordance with the Installation Qualification Procedures and certifying that the equipment and systems, as installed, will perform consistently within defined limits.

12.2.2 Statement of the Environmental Standards designated for each stage of the manufacturing process and certification of the conformity of any controlled environment with the designated standard(s) during the studies (see Section 7).

12.3 Process Qualification

12.3.1 A summary of the procedures and controls for the following, as applied routinely and during the validation studies:

* dispensing ingredients
* water quality and supply
* cleaning/disinfection/sterilization (as appropriate) of all equipment,
* surfaces and services
* sterilization of equipment, vessels and pipelines
* filter integrity testing
* equipment set-up, start-up and adjustment
* clothing and gowning of personnel

12.3.2 Full Process Qualification Report, including:

* medium used
* volume filled
* number of units filled
* number of leakers rejected
* number of units incubated
* incubation temperature
* incubation time
* control organisms used
* filter integrity test results
* record of all in-process monitoring and control results
* summary of number and qualifications of personnel involved in the studies
* policy and records relating to permitted operator interventions (see 4.11)
* written procedures for all laboratory tests and formally recorded results of all laboratory tests, with an evaluation of those results against criteria established in the study protocol(s).

12.3.3 If retrospective validation was conducted, the details of the lot analysis and process condition evaluation, including results of in-process controls, should be compiled for the time period being assessed. Evidence of the equivalence of the manufacturing conditions used for these lots to the current process conditions, including calibration and maintenance history, is required. Evidence that process/product failures and discrepancies were included in the evaluation should be available.

12.4 Expert Evaluation

An evaluation of the entire study against the protocol requirements as outlined above should be prepared and the conclusions drawn at each stage stated. The final conclusions should reflect whether the protocol requirements were met.

The evaluation should include an assessment of the ability of the planned calibration and maintenance programs for the equipment and instrumentation to maintain the validated conditions (see Sections 6, 7 and 8). In addition, all process monitoring and control procedures required to routinely ensure that the validated conditions are maintained should be reported.

The evaluation should be signed by duly authorized officers of the organization who were members of the team establishing the protocol, and who have appropriate expertise in the area assigned to. Overall approval of the study should be authorized by the head of the validation team and the head of the Quality Control Department.

Cleaning Validation Guidelines

This document on Cleaning Validation is intended to address special considerations and issues pertaining to validation of cleaning procedures for equipment used in the manufacture of pharmaceutical products, radiopharmaceuticals, and biological drugs. The document is also intended to establish inspection consistency and uniformity with respect to equipment cleaning procedures.
Principles incorporated in international guidance have been taken into account in the preparation of this document.
The document is intended to cover validation of equipment cleaning for the removal of contaminants associated with previous products, residues of cleaning agents as well as the control of potential microbial contaminants.

2.0 Introduction

This document provides some guidance on issues and topics related to cleaning validation. This topic reflects an area in pharmaceutical, biological and radiopharmaceutical manufacturing that is noted as being important by both the Inspectorate and the pharmaceutical industry. This guideline has been prepared to provide guidance to inspectors, evaluators and industry in reviewing the issues covered. Utilization of this information should facilitate compliance with Division 2 Part C of the Regulations to the Food and Drugs Act.
It is not intended that the recommendations made in these guidelines become requirements under all circumstances. Information provided in the document for limits to be applied in defined circumstances as well as the number of batches to be utilized for cleaning validation studies is for guidance purposes only. Inspectors, evaluators and industry may consider other limits if proposed and documented in accordance with appropriate scientific justification.

3.0 Principles

3.1 The objective of the cleaning validation is to verify the effectiveness of the cleaning procedure for removal of product residues, degradation products, preservatives, excipients and/or cleaning agents so that the analytical monitoring may be reduced to a minimum in the routine phase. In addition one needs to ensure there is no risk associated with cross-contamination of active ingredients.
3.2 Cleaning procedures must strictly follow carefully established and validated methods.
3.3 Appropriate cleaning procedures must be developed for all product-contact equipment used in the production process. Consideration should also be given to non-contact parts into which product may migrate, e.g., seals, flanges, mixing shaft, fans of ovens, heating elements etc.
3.4 Relevant process equipment cleaning validation methods are required for biological drugs because of their inherent characteristics (proteins are sticky by nature), parenteral product purity requirements, the complexity of equipment and the broad spectrum of materials which need to be cleaned.
3.5 Cleaning procedures for products and processes which are very similar do not need to be individually validated. This could be dependent on what is common, equipment and surface area, or an environment involving all product-contact equipment.
It is considered acceptable to select a representative range of similar products and processes. The physical similarities of the products, the formulation, the manner and quantity of use by the consumer, the nature of other product previously manufactured, the size of batch in comparison to previously manufactured product are critical issues that justify a validation program.
A single validation study under consideration of the worst case can then be carried out which takes account of the relevant criteria.
For biological drugs, including vaccines, bracketing may be considered acceptable for similar products and/or equipment provided appropriate justification, based on sound, scientific rationale is given. Some examples are cleaning of fermenters of the same design but with different vessel capacity used for the same type of recombinant proteins expressed in the same rodent cell line and cultivated in closely related growth media; a multi-antigen vaccine used to represent the individual antigen or other combinations of them when validating the same or similar equipment that is used at stages of formulation (adsorption) and/or holding. Validation of cleaning of fermenters should be done upon individual pathogen basis.

4.0 Validation of cleaning processes

4.1 As a general concept, until the validation of the cleaning procedure has been completed, the product contact equipment should be dedicated.
4.2 In a multi-product facility, the effort of validating the cleaning of a specific piece of equipment which has been exposed to a product and the cost of permanently dedicating the equipment to a single product should be considered.
4.3 Equipment cleaning validation may be performed concurrently with actual production steps during process development and clinical manufacturing. Validation programs should be continued through full scale commercial production.
4.4 It is usually not considered acceptable to test-until-clean. This concept involves cleaning, sampling and testing with repetition of this sequence until an acceptable residue limit is attained. For the system or equipment with a validated cleaning procedure, this practice of resampling should not be utilized.
4.5 Products which simulate the physicochemical properties of the substance to be removed may be considered for use instead of the substances themselves, when such substances are either toxic or hazardous.
4.6 Raw materials sourced from different suppliers may have different physical properties and impurity profiles. When applicable such differences should be considered when designing cleaning procedures, as the materials may behave differently.
4.7 All pertinent parameters should be checked to ensure the process as it will ultimately be run is validated. Therefore, if critical temperatures are needed to effect cleaning, then these should be verified. Any chemical agents added should be verified for type as well as quantity. Volumes of wash and rinse fluids, and velocity measurements for cleaning fluids should be measured as appropriate.
4.8 If automated procedures are utilized (Clean-In-Place: CIP), consideration should be given to monitoring the critical control points and the parameters with appropriate sensors and alarm points to ensure the process is highly controlled.
4.9 Validation of cleaning processes should be based on a worst-case scenario including:

1. challenge of the cleaning process to show that the challenge soil can be recovered in sufficient quantity or demonstrate log removal to ensure that the cleaning process is indeed removing the soil to the required level, and
   
2. the use of reduced cleaning parameters such as overloading of contaminants, over drying of equipment surfaces, minimal concentration of cleaning agents and/or minimum contact time of detergents.
   

4.10 At least three (3) consecutive applications of the cleaning procedure should be performed and shown to be successful in order to prove that the method is validated.

5.0 Equipment and Personnel

5.1 All processing equipment should be specifically designed to facilitate cleanability and permit visual inspection and whenever possible, the equipment should be made of smooth surfaces of non-reactive materials.
5.2 Critical areas i.e. those hardest to clean should be identified, particularly in large systems that employ semi-automatic or fully automatic CIP systems.
5.3 Dedicated product-contact equipment should be used for products which are difficult to remove (e.g. tarry or gummy residues in the bulk manufacturing), for equipment which is difficult to clean (e.g. bags for fluid bed dryers), or for products with a high safety risk (e.g. biologicals or products of high potency which may be difficult to detect below an acceptable limit).
5.4 In a bulk process, particularly for very potent chemicals such as some steroids, the issue of by-products needs to be considered if equipment is not dedicated.
5.5 It is difficult to validate a manual cleaning procedure, i.e. an inherently variable/cleaning procedure. Therefore, operators carrying out manual cleaning procedures should be adequately trained, monitored, and periodically assessed.

6.0 Microbiological considerations

6.1 Whether or not CIP systems are used for cleaning of processing equipment, microbiological aspects of equipment cleaning should be considered. This consists largely of preventive measures rather than removal of contamination once it has occurred.
6.2 There should be some documented evidence that routine cleaning and storage of equipment do not allow microbial proliferation. For example, equipment should be dried before storage, and under no circumstances should stagnant water be allowed to remain in equipment subsequent to cleaning operations. Time-frames for the storage of unclean equipment, prior to commencement of cleaning, as well as time frames and conditions for the storage of cleaned equipment should be established.
6.3 The control of the bio-burden through adequate cleaning and storage of equipment is important to ensure that subsequent sterilization or sanitization procedures achieve the necessary assurance of sterility. This is also particularly important from the standpoint of the control of pyrogens in sterile processing since equipment sterilization processes may not be adequate to achieve significant inactivation or removal of pyrogens.

7.0 Documentation

7.1 Detailed cleaning procedure(s) are to be documented in SOPs

7.2 A cleaning validation protocol should describe the procedure used to validate the cleaning process. It should include in addition to other information: description of the equipment used; interval between the end of production and the beginning of the cleaning procedures; cleaning procedures to be used for each product, each manufacturing system or each piece of equipment; sampling procedures with rationales; analytical methods including limit of detection and limit of quantitation; acceptance criteria with rationales and conditions for re-validation.
7.3 Depending upon the complexity of the system and cleaning processes, the amount of documentation necessary for executing various cleaning steps or procedures may vary.
7.4 When more complex cleaning procedures are required, it is important to document the critical cleaning steps. In this regard, specific documentation on the equipment itself which includes information about who cleaned it, when the cleaning was carried out, the product which was previously processed on the equipment being cleaned should be available. However, for relatively simple cleaning operations, the mere documentation that the overall cleaning process was performed might be sufficient.
7.5 Other factors such as history of cleaning, residue levels found after cleaning, and variability of test results may also dictate the amount of documentation required. For example, when variable residue levels are detected following cleaning, particularly for a process that is believed to be acceptable, one must establish the effectiveness of the process and of the operator performance. Appropriate evaluations must be made and when operator performance is deemed a problem, more extensive documentation (guidance) and training may be required.

8.0 Analytical methods

8.1 The analytical methods used to detect residuals or contaminants should be specific for the substance or the class of substances to be assayed (e.g., product residue, detergent residue and/or endotoxin) and be validated before the cleaning validation study is carried out.
8.2 The specificity and sensitivity of the analytical methods should be determined. If levels of contamination or residual are not detected, it does not mean that there is no residual contaminant present after cleaning,. It only means that the levels of contaminant greater than the sensitivity or detection limit of the analytical method are not present in the sample.
8.3 In the case of biological drugs, the use of product-specific assay(s) such as immunoassay(s) to monitor the presence of biological carry-over may not be adequate, a negative test may be the result of denaturation of protein epitope(s). Product-specific assay(s) can be used in addition to total organic carbon (TOC) for the detection of protein residue.
8.4 The analytical method and the percent recovery of contaminants should be challenged in combination with the sampling method(s) used (see below). This is to show that contaminants can be recovered from the equipment surface and to show the level of recovery as well as the consistency of recovery. This is necessary before any conclusions can be made based on the sample results. A negative test may also be the result of poor sampling technique.

9.0 Sampling, rinsing, rinse samples and detergents

9.1 There are two general types of sampling that are considered to be acceptable, direct surface sampling (swab method) and indirect sampling (use of rinse solutions). A combination of the two methods is generally the most desirable, particularly in circumstances where accessibility of equipment parts can mitigate against direct surface sampling.
9.2 Direct Surface Sampling

1. Areas hardest to clean and which are reasonably accessible can be evaluated by direct sampling method, leading to establishing a level of contamination or residue per given surface area. Additionally, residues that are "dried out" or are insoluble can be sampled by physical removal.
   
2. The suitability of the material to be used for sampling and of the sampling medium should be determined. The ability to recover a sample accurately may be affected by the choice of sampling material. It is important to assure that the sampling medium and solvent (used for extraction from the medium) are satisfactory and can be readily used.
   

9.3 Rinse Samples

1. Rinse samples allow sampling of a large surface area and of inaccessible systems or ones that cannot be routinely disassembled. However consideration should be given to the fact that the residue or contaminant may be insoluble or may be physically occluded in the equipment.
   
2. A direct measurement of the residue or contaminant in the relevant solvent should be made when rinse samples are used to validate the cleaning process.
   

9.4 Indirect testing such as conductivity testing may be of some value for routine monitoring once a cleaning process has been validated. This could be applicable to reactors or centrifuge and piping between such large equipment can be sampled only using rinse solution samples.
9.5 If the placebo method is used to validate the cleaning process then it should be used in conjunction with rinse and/or swab samples. It is difficult to provide assurance that the contaminate will be uniformly dispersed throughout the system or that it would be worn off the equipment surface uniformly. Additionally, if the contaminant or residue is of large enough particle size, it may not be uniformly dispersed in the placebo. Finally, the analytical power of the assay may be greatly reduced by dilution of the contaminant.
9.6 It is important to use visual inspection in addition to analytical methodology to ensure the process is acceptable.
9.7 When detergents are used in the cleaning process, their composition should be known to the user and their removal should be demonstrated.
9.8 Detergents should be easily removable, being used to facilitate the cleaning during the cleaning process. Acceptable limits should be defined for detergent residues after cleaning. The possibility of detergent breakdown should also be considered when validating cleaning procedures.
9.9 Water for injection should be used in the last rinse for product-contact equipment to be utilized in the fabrication of sterile products.
9.10 Purified water is considered acceptable for product-contact equipment used in the fabrication of non-sterile products.
NOTE:
Because of the presence of varying levels of organic and inorganic residues as well as of chlorine, tap water should not be used in the last rinse of any cleaning procedure for product-contact equipment.

10.0 Establishment of limits

10.1 The fabricator's rationale for selecting limits for product residues should be logical and based on the materials involved and their therapeutic dose. The limits should be practical, achievable, and verifiable.
10.2 In establishing product residual limits, it may not be adequate to focus only on the main reactant since by-products/chemical variations (active decomposition material) may be more difficult to remove. In addition to chemical testing, Thin Layer chromatography screening may be needed in certain circumstances.
10.3 The approach for setting limits can be (1) product specific cleaning validation for all products; (2) grouping into product families and choosing a worst case product; (3) grouping
into groups of risk (e.g., very soluble products, similar potency, highly toxic products or difficult to detect); (4) setting limits on not allowing more then a certain fraction of carryover; (5) different safety factors for different dosage forms.
10.4 Carry-over of product residues should meet defined criteria for example the most stringent of the following criteria (i, ii, iii):

1. NMT 0.1% of the normal therapeutic dose of any product to appear in the maximum daily dose of the following product;
   
2. NMT 10 ppm of any product to appear in another product;
   
3. No quantity of residue to be visible on the equipment after cleaning procedures are performed. Spiking studies should determine the concentration at which most active ingredients are visible.
   
4. For certain allergenic ingredients, penicillins, cephalosporins or potent steroids and cytotoxics, the limits should be below the limit of detection by best available analytical methods. In practice this may mean that dedicated plants are used for these products.
   

NOTE:
Some limits that have been mentioned by industry representatives in the literature or in presentations include analytical detection levels such as 10 ppm, biological activity levels such as 1/1000 of the normal therapeutic dose, and organoleptic levels such as no visible residue.
Environmental Protection Agency and toxicologists suggest that an acceptable level of a toxic material may be that which is no more than 1/1000 of a toxic dose or 1/100 - 1/1000 of an amount which is not known to show any harmful biological effect in the most sensitive animal system known, e.g., no effect.

11.0 Conclusion

The cleaning validation programme should be based on detailed cleaning procedures, a good training programme, a validation protocol, validated chemical and microbiological methods, a change control programme, a final report and any auditing required to ensure compliance.

12.0 References

1. FDA, Guide to Inspections of Validation of Cleaning Processes, 1993.
   
2. Pharmaceutical Inspection Convention Draft Document, Recommendations on Validation Master Plan, Installation and Operational Qualification, Non-Sterile Process Validation and Cleaning Validation, 1998.
   

The Sterilization Future

Over the past 25 years, sterilization has evolved to keep pace with the medical device industry. Although sterilization technologies themselves have remained unchanged in their physics and chemistry, some significant developments have advanced the methods and processes. The future promises to offer even more substantial developments. Key developments in the sterilization market as a whole should include:• Changes in the sterility assurance level (SAL) requirements for various device groups. Internationally, the requirement for a device to be labeled with a “sterile” statement requires a SAL of 10–6. In the future, this requirement may be revisited to allow products with alternate SALs (i.e., 10–3, 10–4, etc.), based on the need for such elevated SALs and on product use. • Alternative gaseous-sterilization modalities, such as vapor-phase hydrogen peroxide and plasma vapor-phase hydrogen peroxide, offered on a contract basis.• An overseas exodus of sterilization similar to that of device manufacturing.• Modalities that are less energy dependent (i.e., more cost-effective) to combat spiraling energy costs.• Improved manufacturing controls that reduce bioburden spike issues.• Documents from the standards-writing groups covering how to deal with bioburden spikes.• Rapid environmental monitoring techniques for manufacturing. • Further harmonization of international methods. Major advances affecting EtO sterilization and processing include:• BIs that offer essentially instantaneous response times.• Further developments in parametric release for EtO sterilization.• Evolution of the industry guidelines for validation. Developments in gamma sterilization will likely include:• Final development and implementation of VDmax guidelines at doses other than 25 kGy with validation using this technique from 15 to 35 kGy.• Evolution of the industry guidelines for validation. In 2004, the next revision of the AAMI 11137 standards should be released: AAMI 11137-1 draft standard, “Process Requirements for Radiation Sterilization;” AAMI 11137-2 draft standard, “Validation Methods for Radiation Sterilization;” and AAMI 11137-3 draft standard, “Dosimetry for Radiation Sterilization.”• No sterilization dose validation requirement for devices with proven very low bioburdens.• Predictive dosimetry using mathematical modeling that is based on the application of knowledge and computer power currently available.• Parametric release for irradiation processing. Cost-competitive pressures and improved science (based on enhanced computer control and real-time dose-measurement systems) may drive this feasible methodology forward.• Alternative dose-setting strategies, further increasing the options available to the sterilization microbiologist.Laboratory advancements should include:• Rapid microbiological methods that reduce the time needed for bioburden assessment from about a week to a day. The technologies already exist, but they will come into common use as regulatory acceptance, awareness, and their utility become better known.• Genetic-based microbial identification methods as the standard for identification of environmental isolates, bioburden tracking, and failure investigations. • Technology improvements such as isolators, cleanroom HEPA-filtered respirators and improved barrier gowns and gown materials that increase the reliability of existing sterility test methods.• New rapid microbiological methods that replace the existing sterility test procedure.With these developments, sterilization will continue to be an integral part of the medical device industry. As it has in the last 25 years, we are sure that MD&DI will bring you updates and developments as they happen in the next 25 years.

The Sterilization Future

Over the past 25 years, sterilization has evolved to keep pace with the medical device industry. Although sterilization technologies themselves have remained unchanged in their physics and chemistry, some significant developments have advanced the methods and processes. The future promises to offer even more substantial developments. Key developments in the sterilization market as a whole should include:• Changes in the sterility assurance level (SAL) requirements for various device groups. Internationally, the requirement for a device to be labeled with a “sterile” statement requires a SAL of 10–6. In the future, this requirement may be revisited to allow products with alternate SALs (i.e., 10–3, 10–4, etc.), based on the need for such elevated SALs and on product use. • Alternative gaseous-sterilization modalities, such as vapor-phase hydrogen peroxide and plasma vapor-phase hydrogen peroxide, offered on a contract basis.• An overseas exodus of sterilization similar to that of device manufacturing.• Modalities that are less energy dependent (i.e., more cost-effective) to combat spiraling energy costs.• Improved manufacturing controls that reduce bioburden spike issues.• Documents from the standards-writing groups covering how to deal with bioburden spikes.• Rapid environmental monitoring techniques for manufacturing. • Further harmonization of international methods. Major advances affecting EtO sterilization and processing include:• BIs that offer essentially instantaneous response times.• Further developments in parametric release for EtO sterilization.• Evolution of the industry guidelines for validation. Developments in gamma sterilization will likely include:• Final development and implementation of VDmax guidelines at doses other than 25 kGy with validation using this technique from 15 to 35 kGy.• Evolution of the industry guidelines for validation. In 2004, the next revision of the AAMI 11137 standards should be released: AAMI 11137-1 draft standard, “Process Requirements for Radiation Sterilization;” AAMI 11137-2 draft standard, “Validation Methods for Radiation Sterilization;” and AAMI 11137-3 draft standard, “Dosimetry for Radiation Sterilization.”• No sterilization dose validation requirement for devices with proven very low bioburdens.• Predictive dosimetry using mathematical modeling that is based on the application of knowledge and computer power currently available.• Parametric release for irradiation processing. Cost-competitive pressures and improved science (based on enhanced computer control and real-time dose-measurement systems) may drive this feasible methodology forward.• Alternative dose-setting strategies, further increasing the options available to the sterilization microbiologist.Laboratory advancements should include:• Rapid microbiological methods that reduce the time needed for bioburden assessment from about a week to a day. The technologies already exist, but they will come into common use as regulatory acceptance, awareness, and their utility become better known.• Genetic-based microbial identification methods as the standard for identification of environmental isolates, bioburden tracking, and failure investigations. • Technology improvements such as isolators, cleanroom HEPA-filtered respirators and improved barrier gowns and gown materials that increase the reliability of existing sterility test methods.• New rapid microbiological methods that replace the existing sterility test procedure.With these developments, sterilization will continue to be an integral part of the medical device industry. As it has in the last 25 years, we are sure that MD&DI will bring you updates and developments as they happen in the next 25 years.