Ispe Baseline Pharmaceutical Engineering Guide

VOLUME 1: BULK PHARMACEUTICAL CHEMICAL FACILITIES EXECUTIVE SUMMARY November 1997 VOLUME 2: ORAL SOLID DOSAGE FORMS

EXECUTIVE SUMMARY OF FIRST DRAFT

VOLUME 3: STERILE MANUFACTURING FACILITIES EXECUTIVE SUMMARY VOLUME 4: WATER AND STEAM GUIDE EXECUTIVE SUMMARY VOLUME 5: COMMISSIONING AND QUALIFICATION EXECUTIVE SUMMARY VOLUME 6: BIOPHARMACEUTICALS JANUARY 2003

EXECUTIVE SUMMARY OF DRAFT FOR REVIEW

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A GUIDE FOR NEW FACILITIES

VOLUME 1: BULK PHARMACEUTICAL CHEMICAL FACILITIES

EXECUTIVE SUMMARY

November 1 1997

A DOCUMENT DEVELOPED IN PARTNERSHIP BY:

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MSInternational Society for Pharmaceutical Engineering

ISPE Baseline Guide - Bulk Pharmaceutical Chemical Facilities Executive Summary

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ISPE PHARMACEUTICAL ENGINEERING GUIDE

BULK PHARMACEUTICAL CHEMICAL FACILITIES

FOREWORD

The pharmaceutical industry has experienced a ratcheting effect in the cost of new facilities. This increase in cost has been driven in part by uncertainty about the requirements for regulatory compliance. Some significant areas of concern are validation, particularly related to automation systems, the trend to validate back to source utilities, architectural features, and HVAC requirements. The absence of a consistent and widely accepted interpretation of most regulatory requirements has led to one-upmanship between manufacturers. This practice of building increasingly technically advanced facilities has led to increased cost, longer lead times and, in some cases, delays in bringing new products to market.

In May 1994, engineering representatives from the pharmaceutical industry engaged in a discussion with the International Society for Pharmaceutical Engineering (ISPE) and the Food and Drug Administration (FDA). That first discussion allowed for the creation of twelve facility engineering guides, now known as the Baseline Pharmaceutical Engineering Guides. These Guides are intended to assist pharmaceutical manufacturers in the design, construction and commissioning of facilities that comply with the requirements of the FDA. Volume 1, covering Bulk Pharmaceutical Chemicals (BPC), was published in June of 1996.

The BPC Guide has been sponsored by ISPEs Pharmaceutical Advisory Council, made up of senior pharmaceutical engineering executives from owner companies, the FDA and ISPE senior management. Overall planning, direction and technical guidance in the preparation of the Guide was provided by a Steering Committee, many of whom were involved in the BPC Guide.

Editors Disclaimer:

This guide is meant to assist pharmaceutical manufacturers in the design and construction of new facilities that comply with the requirements of the Food and Drug Administration (FDA). The International Society for Pharmaceutical Engineering (ISPE) cannot ensure, and does not warrant, that a facility built in accordance with this guide will be acceptable to FDA.

Copyright International Society for Pharmaceutical Engineering (ISPE) 1996.

Copyright in the whole and every part of this document is owned by ISPE. No reproduction of the whole or any part of this document is to be made without the written authority of ISPE.

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1. INTRODUCTION

1.1 BACKGROUND

The design, construction, commissioning and validation of pharmaceutical facilities are significant challenges for manufacturers, engineering professionals and equipment suppliers. In most cases, these facilities are required to meet cGMP regulations while remaining in compliance with all other governing codes, laws and regulations.

The cost of bringing these facilities on line has been rising, in many cases due to inconsistent interpretation of regulatory requirements. ISPE and engineering representatives from the pharmaceutical industry have entered into a partnership with the Food and Drug Administration (FDA) to develop jointly a common understanding and interpretation of cGMP requirements for facilities. This guide is intended to offer a consistent interpretation, while still allowing a flexible and innovative approach to facility design, construction, commissioning and validation.

This guide was prepared by pharmaceutical engineers, in partnership with FDA, with feedback from industry representatives from all areas and disciplines.

1.2 SCOPE OF THIS GUIDE

This is a guide to be used by industry for the design, construction, commissioning and validation of new bulk pharmaceutical chemical (BPC) facilities. It is neither a standard nor a detailed design guide. It is not intended to replace governing laws or regulations which apply to facilities of this type. It also is not intended to apply to existing facilities which may fall short of the baseline described. The use of this document for new or existing facilities is at the discretion of the facility owner or operator.

The guide covers bulk active, bulk intermediate and bulk excipient facilities, and can be applied to sterile and aseptic bulk manufacturing. It also can be applied to bulk pilot plants and scale-up facilities, but it may not be appropriate for laboratory settings where compounds are synthesized for early development studies. It does not apply to bulk biological facilities. Bulk biological, secondary manufacturing, and sterile and aseptic processing will be the subject of future BASELINE Pharmaceutical Engineering Guides.

The guide is intended primarily for US built facilities, following mainly US standards and references. Further European and other standards and references may be incorporated in future revisions.

The concepts proposed constitute a good baseline from which to proceed. ISPE and FDA have agreed that this document is an acceptable guide to achieving regulatory compliance. All other codes, standards and governing laws still apply, and are mentioned in this document only for completeness.

1.3 KEY FEATURES OF THIS GUIDE

a) The following key concepts are defined and used as a basis for guidance:

Critical process step

Product exposure

Level of protection

Critical parameters

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Critical instruments and systems

Good Engineering Practice

Enhanced documentation

b) The Critical Process Step is used as the basis of a uniform interpretation of regulatory requirements. This allows the determination of the extent of Product Exposure, and the appropriate Level of Protection. These concepts are described in Chapter 2.

Basing the environmental requirements upon the specific processes employed will allow the use of new containment and barrier technologies or specially designed standard operating procedures (SOPs). This will allow engineers the flexibility to design for appropriate levels of protection or containment, avoiding costly designs that go beyond what is required to achieve regulatory compliance.

c) The Critical Parameters for the critical process steps affect product quality, and should be identified and controlled All other parameters are adequately covered through routine documentation and commissioning, defined in Chapter 10 as Good Engineering Practice (see below).

Manufacturers should identify the critical parameters based upon their knowledge of the processes, and document the rationale for later examination. Critical parameters lead to the identification of critical instruments and systems, which require enhanced levels of documentation.

d) Good Engineering Practice recognizes that all systems in a facility, whether they are elevators, process reactors, safety valves or restrooms, routinely undergo some form of commissioning. Nearly all engineering specifications require levels of documentation, inspection and field testing which are appropriate and acceptable to regulators. Good Engineering Practice capitalizes upon this by suggesting that manufacturers engage all stakeholders (engineers, managers, operators, Quality Assurance experts and others) earlier in the planning, design, construction and commissioning phases to ensure that systems are documented only once.

e) Enhanced documentation is required for critical systems and instruments. This adds two dimensions to Good Engineering Practice: document change control and validation. This guide acknowledges that most design and commissioning documents are not routinely updated after facilities are put into service. Regulations require change control for certain documents as described in Chapter 10. Validation is also required for critical systems, to demonstrate consistent, correct operation. This guide suggests that tests and inspection documents produced during routine commissioning need not be repeated in validation protocols. These may refer to existing engineering documentation. The guide also reinforces the need for validation master planning and validation summary reports.

1.4 SUMMARY

This document provides engineers and other professionals in the pharmaceutical industry with consistent guidance on the design, construction and commissioning of BPC facilities, equipment and systems. This approach will allow manufacturers to better serve their customers by helping to reduce the product cost, maintain product quality and thus make more funds available for the discovery of new and innovative medicines. Although considered an industry baseline, the guide is intended to be flexible enough to permit individual companies to develop creative solutions to minimize construction and operating costs.

This guide attempts to facilitate qualification and validation. All other codes, standards and policies should also be considered. The reader should consider this guide a tool to use in conjunction with those already available in the industry.

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2. CONCEPTS AND REGULATORY PHILOSOPHY

2.1 INTRODUCTION

Historically the design of many facilities for BPC plants has mirrored chemical manufacturing plants rather than dosage-form pharmaceuticals. During industrial chemical manufacture, traces of foreign contaminants generally are acceptable. Pharmaceutical facility and process design, however, requires provision for minimizing cross-contamination and trace contamination.

In discussing current facility design considerations for a BPC plant, this guide uses concepts from the pharmaceutical dosage-form industry. For example, physical barrier separation between reactors, centrifuges, dryers and blenders which are used for the manufacture of the drug substance is discussed. It includes a definition of levels of protection based upon the exposure of the substance to the environment, the stage of synthesis, the risk of contamination and the impact of trace levels of contamination at that particular stage.

Because the GMP regulations were originally written specifically for finishing operations and not for bulk manufacturing processes, and because bulk synthesis has very different operating parameters and requirements from those of finishing, there is often confusion as to how the GMPs apply to bulk pharmaceutical production1. Common sense should be used when choosing the appropriate design. The primary consideration is that the facility should not contribute to actual or potential contamination of the BPC drug substance.

This guideline is intended to help the project team establish consistent and minimum parameters for facility design to meet cGMP requirements. Once these minimum requirements have been met, any additional protection desired may be included by the individual manufacturer based upon special requirements or added value to the facility or the product.

2.2 PROJECT APPROACH

a) The control and validation of BPC processes are among the most controversial issues facing regulatory agencies and BPC manufacturers today. Previous FDA publications have stated:

Validate the synthesis and purification steps in the later stages of the BPC process that result in the formation of the bulk drug substance or removal of impurities.

Currently FDA suggests that manufacturers:

...control all manufacturing steps, and validate critical process steps.

1 See Appendix 3: The Nature and Manufacture of Bulk Pharmaceutical Chemicals

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b) This chapter provides guidance to BPC manufacturers in deciding upon:

a recommended level of protection

the extent of validation (but well address QUALIFICATION in detail)

the appropriate use of this guide

c) Each manufacturer should define the level of control, protection, and validation which is appropriate to each process, based upon sound process understanding. They should determine the specific drug substances characterization, and the critical steps and critical parameters which will affect that characterization chemically, physically or biologically.

It is not feasible to require absolute GMP compliance during the pre-critical processing steps of a process. Manufacturers should increase the level of GMP controls as described in Section 2.4 as the processing proceeds from pre-critical through the critical production stages. The step-wise approach shown in Figure 2-1 should be followed when designing a new facility. (We need to extend the definition of non-critical steps to more than PRE-critical)

C H A R A C T E R I Z A T I O N

O F F I N A L D R U G

S U B S T A N C E

I D E N T I F Y C R I T I C A L S T E P S

a n d C R I T I C A L P A R A M E T E R S

D E T E R M I N E D E G R E E

O F P R O T E C T I O N R E Q U I R E D

U S E

A P P R O P R I A T E

D E S I G N G U I D E S

S E E S E C T I O N 2 . 3



S E E R E M A I N D E R O F

T H I S G U I D E

FIGURE 2-1

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2.3 DRUG SUBSTANCE CHARACTERIZATION

a) Before defining the critical steps in a BPC process, the manufacturer should characterize the final drug substance, including its impurity profile. This includes all of the characteristics of the final drug substance which affect its efficacy and purity. These characteristics may be chemical, physical or biological. Chemical properties include the minimum percentage of product or a maximum percentage of impurities (e.g. moisture or solvent content). Physical properties include specific particle size range, specific bulk density range or homogeneity. Biological properties include endotoxin and microbial levels.

The drug substance characterization and the critical processing steps which affect this characterization should be determined by the manufacturer based upon a scientific rationale and the data obtained during product and process development. Scale-up and technology transfer data and documentation should be considered.

b) If manufacturers are buying key ingredients from upstream suppliers, they should examine those ingredients product characterizations and impurity profiles and ensure that they are within specification, and consistent from lot to lot.

2.4 CRITICAL STEPS AND CRITICAL PARAMETERS

a) A critical step is a step after which a drug substance which meets its intended characterization and impurity profile cannot be made if there is process malfunction or contamination. It is a step after which recovery from process malfunction or contamination is not possible.

b) As stated in The Gold Sheet2:

Critical steps are not limited to final stages of BPC processes and may include intermediate steps that:

introduce an essential molecular structural element or result in a major chemical transformation

introduce significant impurities into the product

remove significant impurities from the product

A step may therefore be critical due to its chemistry or with regard to contamination.

c) Figure 2-2 is typical of many BPC processes. Some, however, are more complex and may follow branched rather than straight paths. In these cases the critical steps do not necessarily follow a straightforward path (see Figure 2-3). Note that all steps after a critical step are not necessarily critical.

d) Although there are many exceptions, the critical step or critical operation usually occurs at or after the last reaction in a series of production steps, and before the end drying of the final drug substance. This step usually would be a final filtration, a final crystallization, or a final centrifugation. Figure 2-2 illustrates several processing steps which might be determined by the manufacturer as critical.

2 Gold Sheet, April 1995, Page 3

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e) A pre-critical step is defined as any step before a critical step or critical operation. Although there are exceptions, pre-critical steps generally are points in the process where foreign materials will be removed from the final drug substance by subsequent processing.

f) A critical parameter is a processing parameter that directly influences the drug substance characterization or impurity profile at or after a critical step. Critical parameters may be different for each unit operation of the process.

These critical parameters affect product quality, and should be identified and controlled. Manufacturers should identify the critical parameters based upon their knowledge of the process and document the rationale for later examination. Critical instruments and systems which measure or control critical parameters require enhanced levels of documentation. All other parameters are adequately covered by routine documentation and commissioning (see Chapter 10)

Critical instruments and control devices should be calibrated, and should follow protocols for installation and operational qualification. If the process is under manual control the operators should follow a standard operating procedure and undergo documented and verified training.

A step may be critical due to the chemistry or may be critical with regard to physical contamination. They require different kinds of protection. A critical chemical step requires control of the critical parameters, while a step critical with respect to contamination requires control of the contamination sources such as the environment and operator procedures.

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F I G U R E 2 - 2

R E A C T O R R E A C T O R R E A C T O R

F I L T E R F I L T E R F I L T E R

C R Y S T A L L I Z E R

C E N T R I F U G E

D R Y E R


C E N T R I F U G E

D R Y E R


C E N T R I F U G E

D R Y E R

I N T E R M E D I A T E

D R U G S U B S T A N C E

I N T E R M E D I A T E

D R U G S U B S T A N C E

F I N A L D R U G

S U B S T A N C E

*

*

*

*

*

*

Figure 2-2 illustrates a three stage process. * indicates potential points in the process which may be considered critical.

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F I G U R E 2 - 3

S T E P 1 S T E P 6 S T E P 1 1

S T E P 2 S T E P 7 S T E P 1 2

S T E P 3

S T E P 4

S T E P 5

S T E P 8

S T E P 9

S T E P 1 0

S T E P 1 3

S T E P 1 4

S T E P 1 5

I N T E R M E D I A T ED R U G S U B S T A N C E


F A C I L T Y A F A C I L I T Y B F A C I L I T Y C


* * *

S T E P 1 6

S T E P 1 7

*

** d e n o t e s c r i t i c a l s t e p s : 3 , 5 , 1 0 , 1 5 1 6 , 1 7

*

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2.5 LEVELS OF PROTECTION

a) The required level of protection is based upon the level of product exposure and the point in the manufacturing process during which the exposure occurs. Following an evaluation of the degree of exposure and of whether the exposure occurs at a pre-critical or critical point in the process, with respect to physical impurities, Table 2-1 can be used to determine the level of protection. The identified level of protection may then be used as the basis for defining specific process condition requirements such as room air quality, room finish, cleanability, procedures, control and isolation.

b) Three levels of protection are defined:

Level I - General. An area with normal housekeeping and maintenance

Level II - Protected. An area in which steps are taken to protect exposed drug substances from contamination

Level III - Controlled. An area for which specific environmental conditions are defined, controlled and monitored to prevent contamination of exposed drug substances.

Note that Level III may be further sub-divided into non-aseptic (Level IIIa) and aseptic (Level IIIb) areas depending upon the requirement for microbial contamination control. In certain later sections where no distinction is made, the information given is equally applicable to both cases. (There are different levels of protection for final bulk products which will be sterile filtered or terminally sterilized, as opposed to sterile bulk products. This must be addressed in future revisions to this guide.)

c) An operation is exposed (open) if the drug substance is exposed to the environment during a processing step, or not exposed (closed) if the drug substance is not exposed to the environment.

If a system is exposed only for a period during processing it may be possible to implement a temporary protective measure so that the operation may be regarded as closed.

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E

XP

OS

UR

E

N o t

E x p o s e d

( C l o s e d )

E x p o s e d

( O p e n )

CRITICALITY

Pre -Cr i t i ca l Cr i t ica l

L e v e l I

L e v e l I I

Level I I I

T A B L E 2 - 1

R e c o m m e n d e d L e v e l o f P r o t e c t i o n

2.5.1 Examples

Level I (General)

a) A well-maintained chemical plant. The area is organized, neat and clean. The equipment, piping and instrumentation are maintained in good operating condition.

b) A reactor operation where all materials are charged without exposure to the environment. All sampling occurs without exposing the reactor contents to the environment. The reactor is emptied and its contents are sent to the next operation without being exposed to the environment - this is a Closed operation.

Level II (Protected)

c) Several reactors are in a north-south line, separated by east-west walls. This results in a configuration which is closed on three sides but open on the other (see Figure 2-4). Air is moved from the open side to the rear of each reactor module. This precaution reduces the likelihood of cross-contamination from reactor to reactor, even if they are opened simultaneously.

d) Closed filtration is carried out in a general area. The filter is moved to a clean and enclosed area where it is opened and the drug substance removed. This precaution reduces the likelihood of contamination or cross-contamination of the drug substance compared to opening the filter in a general area.

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e) A crystallizer handhole is opened for only a few seconds to charge an incidental ingredient during a crystallization. This operation is at a pre-critical point in the process. The crystallizer is in a general area. This is an exposed pre-critical operation. Level II Protection is required when the process is exposed, even if only for a short time, so a simple charging booth is used.

Level III (Controlled)

f) Process material is charged to a dryer in a room where the environmental conditions of temperature, room pressurization and humidity are controlled and monitored as determined by the specific process requirements. The room is readily cleanable. Only one material at a time is dried in the room The room and the equipment are thoroughly cleaned after each drug substance is handled. The cleaning procedures are validated.

g) Process material is charged to a filter in a general area. However, the material is not exposed to the environment because it is charged to, and later unloaded from the filter using a glove box. The temperature, pressurization and humidity of the glove box are either controlled and monitored, or equalized with the filter thereby becoming part of the process enclosure. The glove box is thoroughly cleaned after each drug substance is handled. The cleaning procedures are validated. The glove box has become the Level III area.

FIGURE 2-4

See Example 2.5.1 (c) above

AIR

AIR

AIR

AIR

R E A C T O R

N O . 1

R E A C T O R

N O . 2

R E A C T O R

N O . 3

R E A C T O R

N O . 4

No r th

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2.6 CGMP INTERPRETATION FOR SYSTEMS

a) Systems are considered critical. and should be validated (future guide will use the term QUALIFY when referring to equipment, facility, or systems) when they are either in direct physical contact with the drug substance at or after the critical step, or used to measure, monitor, control, or record a critical parameter. Support systems such as heat transfer systems, electric power and non-process contact water for cooling, are not critical and need not be validated. The control of the critical parameters which these support systems affect, however, should be validated.

For example, a heat transfer system would not be considered critical, but if the temperature parameters on the reactor which it affects are critical, their control would be validated, and they would be monitored continuously. If agitator speed, for example, is a critical parameter, the electric power to the agitator would not be critical, but the agitator speed would be validated and monitored.

(For the application levels of protection to process support systems and utility systems, see Chapter 5).

b) Any equipment, piping, instrumentation, rooms, environment, control settings, SOPs, or other factors affecting critical parameters should be under strict change control.

c) Process validation efforts should be focused on the critical processing steps to achieve quality, purity and stability of the drug substances. Although all production steps should be controlled appropriately, not all steps need be validated. Parameters which are not critical need not be included in the process validation.

Currently, FDA recommends that a minimum of three batches of final drug substance be made in order to validate a new process. For very complex processes, additional batches may be necessary.

2.6.1 Example

a) A reaction is at a critical point in the process. One of the critical parameters is the ability to operate the reaction under vacuum at 300 mm Hg. The vessel is maintained under vacuum by a vacuum system that pulls vapors off the reactors vent condenser. The vacuum system is set up so that vapors or liquids in the vacuum system cannot flow backwards to the process condenser. The reactor vacuum is continuously monitored and controlled by a pressure controller modulating a control valve prior to the vacuum system. Nitrogen is added to the reactor to break the vacuum.

The vacuum system does not need to be validated since nothing in the vacuum system touches the contents of the reactor. The vacuum controller and the field instruments that read and control the reactor vacuum should be validated. They are continuously monitored, since they are controlling a critical parameter. The nitrogen quality should be validated since it will directly contact the reactor contents.

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3. PRODUCT AND PROCESS CONSIDERATIONS

To achieve cGMP compliance, the manufacturer must demonstrate that the product is produced consistently to specification. As described in Chapter 2, this requires evidence of control of the critical process parameters which affect the drug substance characterization.

This Chapter covers other key product and process considerations including the control of contamination, product containment, cleaning and process water. The concept of level of protection of product as defined in Chapter 2 is applied. This Chapter shows how the appropriate level of protection can be determined by considering the extent of product exposure, the hazard of the contaminant, and whether the step is critical or non-critical. Causes of contamination are discussed, as are appropriate preventative measures.

During early scope development of a new facility, determining what mix of products will be produced and controlling cross-contamination of products is essential. Decisions on the drug substances to be produced in the facilities and strategies to minimize and prevent cross-contamination are assessed to determine their impact on facility flexibility, capacity and overall cost. Design considerations for producing products of different drug classes and the impact on strategies for controlling cross-contamination are also reviewed.

4. ARCHITECTURAL

This Chapter covers architectural considerations, based upon product exposure, and therefore the level of protection required by the product, as defined in Chapter 2. It gives guidance on the selection of architectural materials of construction and finishes, based upon:

The level of protection

The function of the room or area

Cleanability and durability considerations

Examples of typical, acceptable, materials are also provided.

Guidance is also given on product, material, equipment and personnel flow patterns, and acceptable material storage methods. Also discussed is the use of special enclosures, such as barrier or isolation technologies, as a cost-effective measure to prevent contamination.

5. PROCESS, PROCESS SUPPORT AND UTILITY SYSTEMS

This Chapter gives guidance on the GMP requirements for Process, Process Support and Utility Systems, based on the concepts of product exposure, level of protection, and critical parameters and systems as defined in Chapter 2.

This provides the basis for defining the documentation and commissioning requirements for such systems in terms of Good Engineering Practice or Enhanced Documentation as described in Chapter 10.

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6. HVAC

This Chapter addresses GMP requirements for Heating, Ventilation and Air Conditioning (HVAC) systems. It applies the concepts of critical parameters and level of protection as defined in Chapter 2. Detailed design guidance is given, based on the appropriate level of protection.

This Chapter concentrates on the control and monitoring of GMP critical parameters and differentiates them from design requirements for other reasons. There are other very strong economic and operating factors to be considered. Additional detail on aseptic/sterile processing will be provided in a future ISPE Baseline guide.

The designer should ensure compliance with all applicable building, safety, hygiene and environmental regulations3. The scope, costs and benefits of options for future process flexibility should be discussed with the facility user. Isolation/barrier technologies may be considered to reduce HVAC requirements for GMP.

This Chapter assumes that the designer is familiar with industrial HVAC, as defined in various documents by American Society of Heating, Refrigerating and Air-Conditioning Engineers (ASHRAE) and American Conference of Governmental Industrial Hygienists (ACGIH). A knowledge of local construction codes and National Fire Protection Association (NFPA) standards is also assumed.

(With work proceeding on the sterile guide, air classes for some products may be revised depending on whether the product is sterile final bulk, sterile filtered downstream, or terminally sterilized after filling.)

7. NON-GMP REGULATIONS

This Chapter discusses all US non-GMP regulatory compliance issues covering the environment, safety and buildings. It identifies the regulations that should be considered during facility design4. It does not attempt to interpret the regulations or to assess their pertinence.

This Chapter refers specifically to US built facilities. It is not intended to be a comprehensive source of references to international codes and standards.

8. ELECTRICAL

This Chapter addresses GMP requirements for electrical systems. It applies the concepts of critical parameters, systems, and instruments, and the appropriate level of protection as defined in Chapter 2.

This provides the basis for defining the documentation and commissioning requirements for such systems in terms of Good Engineering Practice as described in Chapter 10. See Table 8-1 for the application of the level of protection approach.

3 See Section 12.2 Non-GMP References, Codes and Standards

4 See also Section 12.2 Non-GMP References, Codes and Standards

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The designer should also ensure compliance with all applicable building, safety, hygiene and environmental regulations5.

9. INSTRUMENTATION AND CONTROLS

This Chapter gives guidance on the GMP requirements for instrumentation and control systems based on the concepts of product exposure, level of protection, and critical parameters and systems as defined in Chapter 2.

This provides the basis for defining the documentation and commissioning requirements for such systems in terms of Good Engineering Practice or Enhanced Documentation as described in Chapter 10.

The designer also should ensure compliance with all applicable building, safety, hygiene and environmental regulations6.

10. COMMISSIONING AND QUALIFICATION

This Chapter gives guidance on commissioning, qualification and documentation, based on the application of the concept of critical systems and equipment as defined in Chapter 2.

Commissioning is a systematic method of challenging and documenting systems and equipment prior to operation, at the conclusion of project construction. Project engineers and managers should deliver the complete facility, fully commissioned and fully documented.

Each component of a facility should be built in accordance with plans and specifications and should be inspected, tested and documented by competent individuals. These activities, and the production of supporting documentation which describe the facility build and operation, are known as Good Engineering Practice. This recommends a minimum level of documentation for all systems and equipment, typically including design documents, test procedures, inspection records, and test evidence. If these documents are appropriately planned, organized and authorized they should satisfy most regulatory requirements.

There are certain circumstances, however, where additional tests and documentation may be required. Enhanced documentation is recommended for critical systems or equipment, as defined in Chapter 2. These typically including the following:

Reactors & agitators

Hold tanks

Centrifuges and filters

Evaporators and distillation systems

Dryers and filter-dryers

Process water

CIP/SIP systems

Solvent storage and recovery

Raw material bulk storage and distribution

Packaging systems

Dispensing systems

Process automation systems related to critical processing



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Nitrogen systems

Mills and blenders

processing Environmental and Control Systems

Enhanced documentation requires documentation maintenance (change control) and validation documents. Section 10.3 lists documents which typically require change control, but the final decision rests with the owner company. Validation demonstrates that critical equipment, systems and utilities are operating within acceptable parameters. This guide recommends that it is acceptable for validation documents to be reduced to brief summaries of existing engineering information, and to refer to commissioning inspection forms, test forms, engineering walkdowns and red lined documentation. These do not have to be repeated, leading to significant savings and reduced paperwork.

11. DEFINITIONS

12. REFERENCES

13. APPENDIX 1: CIP SYSTEM DESIGN

14. APPENDIX 2: THE NATURE AND MANUFACTURE OF BULK PHARMACEUTICAL CHEMICALS

15. APPENDIX 3: COMMISSIONING AND QUALIFICATION PROGRAM

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A GUIDE FOR NEW FACILITIES

VOLUME 2: ORAL SOLID DOSAGE FORMS

EXECUTIVE SUMMARY OF FIRST DRAFT

November 1 1996

A DOCUMENT DEVELOPED IN PARTNERSHIP BY:

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ISPE Baseline Guide - Oral Solid Dosage Facilities Executive Summary. Revision A

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ORAL SOLID DOSAGE FORM FACILITIES

FOREWORD

As noted in the Baseline Guides, Volume 1, the pharmaceutical industry has experienced a ratcheting effect in the cost of new facilities. This increase in cost has been driven in part by uncertainty about the requirements for regulatory compliance. Some significant areas of concern are validation, particularly related to automation systems, the trend to validate back to source utilities, architectural and HVAC requirements. The absence of a consistent and widely accepted interpretation of regulatory requirements has led to one-upmanship. This practice of building increasingly technically advanced facilities has led to increased cost, longer lead times and, in some cases, delays in bringing new products to market.

In May 1994, engineering representatives from the pharmaceutical industry engaged in a discussion with the International Society for Pharmaceutical Engineering (ISPE) and the Food and Drug Administration (FDA). That first discussion allowed for the creation of twelve facility engineering guides, now known as the Baseline Pharmaceutical Engineering Guides. These Guides are intended to assist pharmaceutical manufacturers in the design, construction and commissioning of facilities that comply with the requirements of the FDA. Volume 1, covering Bulk Pharmaceutical Chemicals (BPC), was published in June of 1996. This Guide, for Oral Solid Dosage (OSD) facilities, is the second volume in the series.

As with the BPC Guide, the OSD Guide has been sponsored by ISPEs Pharmaceutical Advisory Council, made up of senior pharmaceutical engineering executives from owner companies, the FDA and ISPE senior management. Overall planning, direction and technical guidance in the preparation of the OSD Guide was provided by a Steering Committee most of whom were involved in the BPC Guide. The OSD Guide itself was produced by a task force of around 50 individuals who expended a great deal of their own time in its preparation and development.

Editors Disclaimer:

This guide is meant to assist pharmaceutical manufacturers in the design and construction of new facilities that comply with the requirements of the Food and Drug Administration (FDA). The International Society for Pharmaceutical Engineering (ISPE) cannot ensure, and does not warrant, that a facility built in accordance with this guide will be acceptable to FDA.

Copyright International Society for Pharmaceutical Engineering (ISPE) 1996.

Copyright in the whole and every part of this document is owned by ISPE. No reproduction of the whole or any part of this document is to be made without the written authority of ISPE.

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ORAL SOLID DOSAGE FACILITIES

ACKNOWLEDGMENTS

ISPE wishes to acknowledge the following for this outstanding effort:

Timothy C. Tyson and Robert P. Best, who were responsible for establishing early discussions with FDA and assembling the most senior engineering executives in the industry.

From FDA, Sharon Smith Holston (Deputy Commissioner for External Affairs), Jeanne Devers White (Director, Industry Affairs, Office of the Commissioner), Joseph Phillips (Deputy Regional Food and Drug Director, Mid-Atlantic Region) and Paul DEramo (Regional Drug Specialist, Mid-Atlantic Region) have been instrumental in establishing a close working relationship with industry during the entire process.

The Steering Committee for their input an guidance in the creation of this Oral Solid Dosage (OSD) Guide, the previously published Bulk Pharmaceutical Chemical (BPC) Guide, and the Guides which are currently being developed or still in the planning phase.

The Membership of the ISPE which provided the critical mass of pharmaceutical industry professionals. Their desire to make a lasting contribution to the industry and to work with the FDA in a unique partnership is the driving force behind these Guides.

The Task Team for the many hours they spent in preparing this document. This effort required innovative thinking, a team approach and a desire to meet deadlines.

The following individuals took lead roles in the preparation of this document:

Wesley Wheeler (Steering Committee Chair) Gregory S. Cierpial (OSD Guide Team Leader) Joseph Phillips (FDA) Paul DEramo (FDA) Jack Chu Bob Hsu Norman Koller John Linder Bryan Mann Stanley Newberger Max Van Vessem David Yoakum

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The following other members of the steering committee and task team worked on one or more of the chapters, and volunteered countless hours to attend meetings and review the many drafts which were prepared over a six month period:

David Altenau Carl Alves Dennis Barrall James Belsky

Douglas Bradley Janit Buccella Mel Crichton * Dave Erumenok

Bernard Friel Tim Fry William Glaser Marck Houghton

Mike Joseph Paul Lang Art Lowe * Dennis Malinger

Rich Mussick Robert Ogera Nick Phillips Jay Porikh

Bill Randolph Adam Shahide Brian Shuntz Paul Skinner

Kelly Summers E. Mitchell Swann Jason Treese Susan Wolfinger

Steven Yu Jose Zulueta

* Steering Committee Member

The steering committee and task team would like to acknowledge Sion Wyn from Activa Systems Ltd. for his outstanding contribution as technical writer and information coordinator of this guide.

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PROVISIONAL TABLE OF CONTENTS 1. INTRODUCTION.............................................................................................

1.1 BACKGROUND............................................................................................................................ 1.2 SCOPE OF THIS GUIDE............................................................................................................... 1.3 KEY FEATURES OF THIS GUIDE.................................................................................................. 1.4 FACILITY COST........................................................................................................................... 1.5 HOW TO USE THIS GUIDE...........................................................................................................

2. CONCEPTS AND REGULATORY PHILOSOPHY............................................................... 2.1 INTRODUCTION........................................................................................................................... 2.2 LEVEL OF PRODUCT PROTECTION............................................................................................. 2.3 PRODUCT PROTECTION FACTORS ............................................................................................. 2.4 EXTENT OF VALIDATION ............................................................................................................ 2.5 DESIGN CONDITIONS VERSUS OPERATING RANGE...................................................................

3. PRODUCT AND PROCESSING CONSIDERATIONS......................................................... 3.1 INTRODUCTION........................................................................................................................... 3.2 PRODUCT CHARACTERISTICS .................................................................................................... 3.3 PROCESS CONSIDERATIONS .....................................................................................................

4. ARCHITECTURAL ..................................................................................................................... 4.1 INTRODUCTION........................................................................................................................... 4.2 PRODUCT AND MATERIAL FLOW ............................................................................................... 4.3 WASTE FLOWS .......................................................................................................................... 4.4 PRODUCT/PERSONNEL PROTECTION......................................................................................... 4.5 MATERIALS FINISHES ................................................................................................................ 4.6 FUNCTIONAL AREAS ..................................................................................................................

5. PROCESS, SUPPORT AND UTILITY SYSTEMS ................................................................ 5.1 INTRODUCTION........................................................................................................................... 5.2 SYSTEM DEFINITIONS ................................................................................................................ 5.3 PROCESS SYSTEMS................................................................................................................... 5.4 PROCESS SUPPORT SYSTEMS .................................................................................................. 5.5 UTILITY SYSTEMS ...................................................................................................................... 5.6 PROCESS WATER....................................................................................................................... 5.7 CLEANING WATER...................................................................................................................... 5.8 PROCESS STEAM .......................................................................................................................

6. HVAC............................................................................................................................................. 6.1 INTRODUCTION........................................................................................................................... 6.2 PROCESS DEFINITION ................................................................................................................ 6.3 CRITICAL PARAMETERS ............................................................................................................. 6.4 NON-GMP DESIGN CONDITION CONSIDERATIONS ..................................................................... 6.5 AIR SYSTEMS ............................................................................................................................. 6.6 HVAC CONTROLS AND MONITORS ............................................................................................. 6.7 COST CONSIDERATIONS ............................................................................................................ 6.8 CLEANING AND MAINTENANCE OF HVAC................................................................................... 6.9 COMMISSIONING CONSIDERATIONS ..........................................................................................

7. ELECTRICAL ..............................................................................................................................

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7.1 INTRODUCTION.......................................................................................................................... 7.2 GENERAL REQUIREMENTS ......................................................................................................... 7.3 POWER DISTRIBUTION............................................................................................................... 7.4 ELECTRICAL CLASSIFICATION................................................................................................... 7.5 LIGHTING.................................................................................................................................... 7.6 GROUNDING ............................................................................................................................... 7.7 TELEPHONES, PAGING AND RADIO SYSTEMS ........................................................................... 7.8 WIRING METHODS ......................................................................................................................

8. INSTRUMENTATION AND CONTROLS............................................................................... 8.1 INTRODUCTION.......................................................................................................................... 8.2 PRINCIPLES ............................................................................................................................... 8.3 FIELD INSTRUMENTATION ......................................................................................................... 8.4 CALIBRATION ............................................................................................................................ 8.5 INSTALLATION METHODS.......................................................................................................... 8.6 CONTROL SYSTEM SOFTWARE................................................................................................. 8.7 CONTROL HARDWARE............................................................................................................... 8.8 OPERATOR INTERFACE .............................................................................................................

9. OTHER CONSIDERATIONS.................................................................................................... 9.1 INTRODUCTION.......................................................................................................................... 9.2 HAZARDOUS OPERATIONS ........................................................................................................ 9.3 OSHA REGULATIONS (29 CFR 1910)........................................................................................... 9.4 ENVIRONMENTAL.......................................................................................................................

10. COMMISSIONING AND QUALIFICATION .......................................................................... 10.1 INTRODUCTION ........................................................................................................................ 10.2 GOOD ENGINEERING PRACTICE............................................................................................... 10.3 COMMISSIONING ..................................................................................................................... 10.4 VALIDATION.............................................................................................................................

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1. INTRODUCTION

1.1 BACKGROUND

The design, construction, commissioning and validation of pharmaceutical facilities are significant challenges for manufacturers, engineering professionals and equipment suppliers. These facilities must meet Current Good Manufacturing Practices (cGMP) regulations while complying with all other governing codes, laws and regulations.

The cost of bringing these facilities on line has been rising, in many cases due to inconsistent interpretation of regulatory requirements. ISPE and engineering representatives from the pharmaceutical industry have entered into a partnership with the Food and Drug Administration (FDA) to jointly develop a common understanding and interpretation of cGMP requirements for facilities. This Guide is intended to offer a consistent interpretation, while still allowing a flexible and innovative approach to facility design, construction, commissioning and validation.

This document provides engineers and other professionals in the pharmaceutical industry with consistent guidance on the design, construction and commissioning of OSD facilities, equipment and systems. This approach will allow manufacturers to better serve their customers by helping to reduce product cost, maintain product quality and thus make more funds available for the discovery of new and innovative medicines. Although considered an industry baseline, the Guide is intended to be flexible enough to permit individual companies to develop creative solutions to minimize construction and operating costs. The reader should consider this Guide a tool to use in conjunction with those already available in the industry.

1.2 SCOPE OF THIS GUIDE

This Guide may be used by industry for the design, construction, commissioning and validation of new oral solid dosage (OSD) facilities. It is neither a standard nor a detailed design guide. It is not intended to replace governing laws or regulations which apply to facilities of this type. It also is not intended to apply to existing facilities which may fall short of the baseline described. The use of this document for new or existing facilities is at the discretion of the facility manufacturer or operator.

The Guide covers facilities for the manufacture of oral solid dosage forms including tablets, capsules, and powder. It may also be applied to clinical supply facilities. It is not intended to address the manufacture of vitamins, excipients, sterile products, topicals, oral liquids or aerosols. Guidance on facility requirements for the manufacture of excipients can be found in the Baseline Guides, Volume 1 - Bulk Pharmaceutical Chemicals, while sterile products, topicals, and oral liquids and aerosols will be the subject of future Baseline Pharmaceutical Engineering Guides.

The Guide is intended primarily for facilities meeting the regulatory requirements to supply the United States (US), market, and follows US standards and references. European and other non-US standards and references may be incorporated in future revisions.

The concepts proposed constitute a baseline from which to proceed. ISPE and FDA have agreed that this document is an acceptable guide to achieving regulatory compliance. Other codes, standards and governing laws still apply, and are mentioned in this document only for completeness and where their impact affects facility design relative to cGMPs.

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1.3 KEY FEATURES OF THIS GUIDE

a) The following key concepts are a basis for this Guide:

Proper application of facility design and procedures to provide GMP compliance

Impact of non-GMP technology selections upon facility design and costs

Manufacturer assessment of contamination risk

Design Conditions versus Operating Range

Good Engineering Practice

Enhanced documentation

b) Although facility GMP compliance can be achieved through the proper application of facility design and procedures, it is not necessary that each GMP issue be addressed by several design mechanisms, or solely by design. Planning and implementation of Standard Operating Procedures (SOPs), facility layout, or containment and barrier technologies may be applied. This will allow the flexibility to design for appropriate levels of protection or containment, while avoiding costly designs that exceed requirements.

For example, it is generally not necessary for a tableting room to have an airlock, multiple pressurization levels, one way personnel flow, special gowning and cleaning procedures to prevent contamination. The manufacturer should apply one, or more, or all of these based upon an assessment of contamination risk.

c) Non-GMP technologies. Some facility design requirements arise from decisions made to address non-GMP issues or preferences of the manufacturer such as operator safety or strategic operating decisions. These non-GMP technologies often affect facility design features aimed at achieving GMP compliance. Section 1.4 provides further discussion, as well as examples, of this concept and its impact upon facility cost.

d) Risk of contamination and the level of protection from contamination provided by the facility and operating procedures, are based upon an assessment by the manufacturer of:

the duration of product exposure

the product mix and and changeover1

the characteristics of those products

Special consideration should be given to substances, such as penicillin and cytotoxic agents, that pose a serious risk because their presence in even trace amounts may render unsafe an otherwise safe product. This is discussed further in Chapters 2 and 3.

1 Changeover is the frequency at which the product being processed in a room ,or in a piece of equipment, changes.

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e) Operating Ranges are based upon specific product needs (acceptance criteria), rather than Design Conditions which are target values for the engineering designer to achieve. For example, a blending room may have a design range of 30 to 50% RH, but the product in that room may be unaffected by humidity in the range of 20 to 70% (validated product acceptance criteria). Therefore, the acceptable operating range within which qualification of the room is acceptable, is 20% to 70%, not 30% to 50%. This is discussed further in Chapter 2.

f) Good Engineering Practice recognizes that all systems in a facility, whether they are elevators, process reactors, safety valves or rest rooms, routinely undergo some form of commissioning. Nearly all engineering specifications require levels of documentation, inspection and field testing which are appropriate and acceptable to regulators. Good Engineering Practice capitalizes upon this by suggesting that manufacturers engage all stakeholders (engineers, managers, operators, Quality Assurance experts and others) very early in the planning, design, construction and commissioning phases to ensure that systems are documented only once. This is discussed further in Chapter 10.

g) Enhanced documentation is required for critical systems and instruments. This adds two dimensions to Good Engineering Practice: document change control and validation. Most design and commissioning documents are not routinely updated after facilities are put into service. Regulations, however, require change control for certain cGMP documentation as described in Chapter 10. Qualification or validation is required for critical systems, to demonstrate consistent, correct operation. This Guide suggests that tests and inspection documents produced during routine commissioning need not be repeated in validation protocols. It is essential, however, that all testing follows approved protocols, and that the results are recorded in a clear and consistent manner.

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1.4 FACILITY COST

This Guide provides a basis for assessing the GMP related design requirements for a new OSD facility. This baseline, however, is not a single point but a curve which defines the lowest cost for a given facility as a function of the non-GMP technologies incorporated into that facility.

Figure 1-1 shows examples of potential impact on facility costs. For example, consider a decision to use closed processing due to operator or environmental safety concerns with a particular material. This leads to reduced risk of contamination of the product from the room environment, and therefore the HVAC system and architectural finish requirements are lower. Utility and electrical system costs may therefore also be lower. There are, however, increased equipment and equipment maintenance costs.

Each manufacturer through the application of this Guide, and appropriate consultations with the FDA, can develop designs which will meet GMP requirements at the lowest possible lifecycle cost, and can also assess the costs and benefits of constructing a facility exceeding these baseline requirements.

Figure 1-2 shows cost versus technological complexity, and illustrative examples. Note that lower levels of technological complexity, generally associated with lower capital cost, may actually increase the overall life cycle costs for the facility.

Figure 1-1 -- Example of Non-GMP Technology Selection Vs. Facility Cost

Cost Impact

Non-GMP Technology

Non-GMP Reason For Selection

Equip. Arch. HVAC Utility Elect. Inst &

Ctrls

Commi-

ssion

Maint.

Closed Processing Industrial Hygiene, Safety

Lights Out Manufacturing: no personnel in the

manufacturing area

Manufacturing Strategy

Automated Transfer Vehicles for Material

Transport

Personnel Cost, Operating Cost

Automating Production Operations

Manufacturing Strategy, Operator

Availability, Safety

Note that Figure 1-1 shows an example only. For each specific facility and operations, the cost impact of these, and other non-GMP technology selections, should be examined separately.

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Figure 1-2 -- Optimal Cost versus Technology

TECHNOLOGICAL COMPLEXITY

Baseline CostTo Meet

GMP Requirements

Optimal Balanceof

Technology and Cost

Company A

Company B

Company C

Company D

Company X

LIFECYCLE

COST

Figure 1-2 shows different approaches taken by different companies for a facility which requires processing of toxic materials, the inhalation of which could be harmful to operators.

To protect operators, Company A elects to use a contained air breathing system and open processing operations. This approach, with its low level of technological complexity, is less costly than contained processing systems. The resultant GMP design requirements, however, result in additional costs for HVAC and architectural systems, leading to increased lifecycle cost as shown in Figure 1-2

Company B selected closed processing to protect the operator. This technology was more expensive than Company As approach, but per this Guide the requirements and associated costs for HVAC and architectural systems were lower. This resulted in lower lifecycle cost than Company A

Company C selected the same closed processing approach as Company B, but elected for a higher level of more expensive architectural finishes than required by this Guide

Company D selected the level of closed and open processing and baseline facility requirements which achieves the lowest lifecycle cost

Company X is at risk of GMP non-compliance

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1.5 HOW TO USE THIS GUIDE

Figure 1-3 shows a methodology for selecting a design philosophy, determining baseline GMP facility design requirements, and developing a cost basis or model. The cost model can be modified by the selection of alternate technologies to:

optimize facility costs

understand the cost tradeoffs associated with technology selection

identify the costs for exceeding baseline facility requirements

Following non-GMP technology decisions, Chapters 2 and 3 of this Guide provide a basis for assessment of the potential risk of product contamination in order to develop a philosophy of design. Chapters 4 through 9 provides guidance on engineering systems such as HVAC, material and equipment selection and installation. Chapter 10 describes facility commissioning requirements.

Figure 1- 3 -- Developing Conceptual Design and Cost Model

BusinessNeed

Non-GMP Driven

TechnologySelection

DesignPhilosophy

ArchChapter 4

ProcesUtilities

Chapter 5

HVACChapter 6

Electrical Chapter 7

OtherConsiderChapter 9

CommissionChapter 10

DesignConcept(Basis)

CostBasis/Model

FacilityDesign

Indicates iteration as necessary to develop and understand alternative technologies and impact on cost basis/model

Concepts &Product RqmtsChapters 2 & 3

CorporatePolicy Safety/IH

Env Regulations

Other

Inst. &ControlsChapter 8

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2. CONCEPTS AND REGULATORY PHILOSOPHY

2.1 INTRODUCTION

Many OSD facilities have similar processing operations, and use similar manufacturing equipment. Many plants run multiple products in processing areas suited for quick turnaround without unacceptable risk of product exposure and cross contamination.

Dust containment often poses a design challenge, while microbial concerns are less than in sterile product manufacturing. Potent or toxic active ingredients are becoming increasingly common and present their own design challenges. This Guide is intended to assist in establishing consistent and minimum parameters for facility design which address these concerns and meet cGMP requirements. Once these minimum standards have been met, additional protection or design enhancements may be included by manufacturers based upon special facility, worker, or product needs.

This chapter provides guidance on the following concepts, which are applied in the design and commissioning guidance provided in Chapters 3 through 10:

Critical Parameter

Level of Product Protection

Product Protection Factors that affect the risk of product contamination and the level of product protection required

Required Extent of Validation

Design Conditions versus Operating Ranges

Each manufacturer should define the level of control, protection and validation which is appropriate to each manufacturing operation, based upon a sound understanding of the process, drug product, and critical parameters. They should determine the risk of product contamination created by exposure to the surrounding environment and the impact of the product mix within an area on the environment.

A critical parameter is a processing parameter (e.g. drying temperature) which affects product quality, efficacy, or stability. Manufacturers should identify the critical parameters based upon their knowledge of the process and document the rationale for later examination. Critical instruments and systems which measure or control critical parameters require enhanced levels of documentation. All other parameters are adequately covered by routine documentation and commissioning (see Chapter 10)

Critical instruments and control devices should be calibrated, and should follow protocols for installation and operational qualification. If the process is under manual control the operators should follow a standard operating procedure and undergo documented and verified training.

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2.2 LEVEL OF PRODUCT PROTECTION

a) Protecting the product from both foreign and cross-contamination is critical. It is important to identify the risks to drug product, and then to identify and evaluate preventative methods. No solution is likely to fit all facilities, but evaluation of the risk of contamination and subsequent design aimed at reducing the risk to an acceptably low level should lead to cost effective solutions.

b) All areas of an OSD facility often do not require the same level of protection. Each area should be evaluated based upon its function, which may vary at different times and with different products. The protection requirement for a product may decrease as it progresses through the manufacturing processes to a finished dosage form.

c) The degree of contamination risk is based primarily upon the duration of exposure to the environment and the number of product changeovers and mix within the facility. In general, the greater these factors, the greater the need for product protection by architecture or engineering systems. Certain products, such as penicillin pose a significant risk, and their inclusion should be very carefully considered or avoided completely.

d) For OSD facilities three Levels of Protection are defined :

Level 1 - General. An area with normal housekeeping and maintenance.

Level 2 - Protected. An area in which steps are taken to protect the exposed product, and materials which will become part of the product, from contamination. These steps may be procedural.

Level 3 - Controlled. An area in which specific environmental conditions are defined, controlled and monitored to prevent contamination of the product, or materials which will become part of the product.

e) Determining an appropriate Level of Protection for each area of the facility, requires consideration of the following:

Product characteristics (briefly described in Section 2.3.1 and in detail in Chapter 3)

Process or manufacturing operation considerations (briefly described in Section 2.3.2 and in detail in Chapter 3)

Degree of product exposure (described in Section 2.3.3)

Facility flexibility (described in Section 2.3.4)

As shown in Figure 2-1, an initial assessment of the Degree of Risk, and therefore appropriate Level of Protection, may be made by considering the degree of exposure and the facility flexibility. The manufacturer should then refine this assessment based on a detailed consideration of product and process characteristics.

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Figure 2-1

Figure 2-1 - Levels of Product Protection

Degree of Risk

3

2

1

Deg

ree

of E

xpos

ure

Facility Flexibility

Single

Product

Multi-Product

Dedicated

Equipment

Multi-Product

Multi-Use

Equipment

Clo

sed

Inte

rmitt

ent

Exp

osur

eE

xpos

ed

Note:

This figure is is intended to illustrate the relationship between the parameters, not the quantitative measure of the parameters.

Levels ofprotection

2.2.1 Example - Applying Figure 2-1

A product is milled in an OSD Milling Room. The following factors are relevant to the assessment of the required Level of Protection:

The facility is multi-product, but each product uses dedicated equipment.

The mill is closed for processing, except that a sample is drawn, exposing the material for a few minutes every hour.

The product itself is very hygroscopic and moisture will damage it.

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The equipment and room will be set up to be easy to clean.

The first two factors suggest a Degree of Risk requiring Level 2 Protection. The nature of the product, however, results in an assessment by the manufacturer of a higher Degree of Risk, and therefore Level 3 Protection, regardless of the easy-to-clean nature of the room.

2.3 PRODUCT PROTECTION FACTORS

This section outlines some of the factors to be considered when determining the appropriate Level of Protection.

2.3.1 Product Characteristics

Each products characteristic should be reviewed and evaluated for impact upon facility requirements. Product characteristics such as toxicity or potency, physical properties such as density and physical state, hygroscopicity, cleanability, light sensitivity, and others, are discussed in detail in Chapter 3.

2.3.2 Process Considerations

Process considerations include:

Materials receipt, storage, and protection methods

Specific unit operations (e.g. weighing, dispensing, blending, granulation, drying, milling, finished dosage) and their arrangement

Material transport and handling

Methods for packaging and storage

Chapter 3 describes various unit operations, equipment types and trade-offs with regard to GMP, along with economic, process and facility factors which should be considered when evaluating Levels of Protection.

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2.3.3 Degree of Product Exposure

Product Exposure is classified as follows:

Closed. Product or material is not exposed to the environment and risk of contamination is minimal. For example, transferring of the product in a closed system (e.g. pneumatic transfer, vacuum transfer, or bin transport). Facility requirements, such as architectural or HVAC needs may be reduced.

Open. Product or material is exposed to the environment and there is potential for contamination by, or of the environment. This often requires enhanced facility requirements such as airlocks or increased ventilation and filtering of air, or a heavy reliance on SOPs (to reduce, for example, cross contamination by operator tracking from one area to another).

Intermittent Exposure. Product or material is only exposed for a brief period during processing. It may be possible to implement a temporary protective measure so that the operation may in effect be regarded as closed. This may be achieved by SOPs or local air flow control.

Note that increasing product/material potency or toxicity often requires increased levels of protection for a given processing technique, primarily to protect the environment from the product.

2.3.4 Facility Flexibility

Facility flexibility refers to the number of different products processed within the facility, or a particular area of the facility. The facility may process:

A single product. No flexibility. Foreign contamination is the primary concern.

Multiple products in dedicated equipment. Moderate flexibility. Contamination between areas of the facility is an additional, major, concern.

Multiple products in multi-use equipment. High flexibility. Contamination within a process (equipment) and/or the individual processing area is possible. In these areas the number and frequency of product changeovers, anf the type of cleaning procedures, directly affects the degree of contamination risk.

2.4 EXTENT OF VALIDATION

Systems are considered critical and should be validated when they are either in direct physical contact with the drug product or used to measure, monitor, or record a critical parameter. Support systems such as heat transfer systems, electric power, non-process water are non-critical and need not be validated. However, the monitoring and control of critical parameters which these support systems affect should be validated.

For example: a heat transfer system is used to control the temperature of a fluid bed dryer in which the product is highly temperature sensitive. In this case the temperature monitoring function (i.e. sensors and alarms) would be validated. However it is not necessary to validate the heat transfer system (pumps, fluid pressure, fluid temperature, control valves, etc.).

Any engineering system, equipment, piping, instrumentation, room environment, control settings, or SOPs affecting critical parameters should be under strict change control.

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2.5 DESIGN CONDITIONS VERSUS OPERATING RANGE

This Guide recognizes the distinction between design conditions and operating ranges, and the impact this distinction has upon validation and facility operation. These criteria are defined as:

Design Condition - the specified range or accuracy of a controlled variable used by the designer as a basis to determine the performance requirements for an engineered system.

Operating Range - the range of validated critical parameters within which acceptable product can be manufactured.

Normal Operating Range - a range which may be selected by the manufacturer as the desired acceptable values for a parameter during normal operations. This range must be within the Operating Range.

a) While it is desirable that a facility should meet all stated Design Conditions, the acceptability of the facility for operation depends on meeting the Operating Ranges.

For example, if the validated acceptance criteria for a product are such that it must remain in a temperature range of 50 to 100 F, this sets the Operating Range for a room in which the product would be for any significant time. Design Conditions may be set at 72 +/- 2 F to establish performance criteria for the HVAC engineer to use in specifying control devices. The Normal Operating Range may be set by the manufacturer at 60 - 90 F to provide a comfortable environment for the operators.

b) Design Conditions and Normal Operating Ranges may be set as wide as possible, as long as they do not exceed the Operating Range (validated acceptance criteria) for the product. This allows flexibility in recognizing the critical parameters and their impact on the product. Design condition selection should consider and reflect Good Engineering Practice.

c) Manufacturers may also wish to apply the concept of Alert and Action points along with Normal Operating Range. Alert Points are based on normal operating experience and are used to initiate corrective measures before reaching an Action Point, which is defined as the allowable limit of process conditions established by acceptance criteria. While Alert Point deviations are not necessarily included as part of batch records, Action Point deviations must be kept as a part of the batch record as it represents a deviation from validated parameters.

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Figure 2-2 illustrates these concepts for a critical parameter.

Action Point Action Point

Alert Point Alert Point

Design Condition

Normal Operating Range

Operating Range - Validated Acceptance Criteria

Figure 2-2 - Values of Critical Parameters for a Product

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3. PRODUCT AND PROCESSING CONSIDERATIONS

This Chapter discusses the product characteristics, and process considerations for typical manufacturing operations. Product characteristics and process consideration may impact Level of Protection and facility design requirements.

The following product characteristics are discussed and evaluated as to their effect on overall facility design:

Toxicity and potency

Physical properties such as state at operating temperature and density

Hygroscopicity

Cleanability and solubility

Sensitivity to light

For each manufacturing operation stage, the GMP, economic, process, and facility implications of design options are discussed. The advantages and disadvantages of various approaches are discussed, and tables are provided which indicate general areas of concern, and areas offering opportunities for cost savings. Each product and process., however, should be reviewed to determine the specific affect on facility design for any given situation.

Processing considerations are also reviewed in the order in which they normally occur in a manufacturing operation. Matrices that pinpoint those areas that should receive special consideration in facility design have been provided.

4. ARCHITECTURAL

This Chapter provides a methodology for selecting materials and finishes which may be applicable to achieving the required Level of Protection (determined as described in Chapters 2 and 3).

Strategies for applying flow, arrangement, and material handling techniques to achieve a lower required Level of Protection in particular areas are also discussed. Guidance is given on the flow of product and material, personnel and waste.

The guidance on appropriate selection of materials and finishes is based on establishing performance criteria (durability, cleanablity, functionality, and maintainability) and selecting finish and substrate materials which meet these and applicable cost requirements. Detailed guidance is given on acceptable materials for various architectural elements, based on the required Level of Protection.

5. PROCESS, SUPPORT AND UTILITY SYSTEMS

This Chapter discusses the Level of Protection required by process, process support, and utility systems and gives guidance on the design, construction and commissioning requirements for these systems.

Process systems are defined as those which contact the product or contact materials which ultimately will become part of the product. Process Support systems are those which directly support the process operation, but do not have contact with the product or materials which ultimately will become part of the product. Utility systems are those which do not contact the product or materials which ultimately will become part of the product and are generally site or building systems which are not tailored to OSD manufacturing or deal with a side effect of the manufacturing process, such as waste disposal.

Specific guidance is given regarding process water, cleaning water, and process steam systems.

6. HVAC This Chapter applies the concepts of Critical Parameters and Level of Protection, as discussed in Chapters 2 and 3, to Heating, Ventilation and Air Conditioning (HVAC) systems. GMP requirements and economic and operating factors influencing system design are discussed.

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Methods such as isolation/barrier technologies or closed processing systems, are discussed as ways to reduce HVAC costs while achieving GMP compliance. Non-GMP design considerations such as worker comfort, and ventilation for hazardous environments are also covered.

Guidance is given on:

Temperature

Relative Humidity

Airborne Particulates

Room Pressurization

Air Change Rate

Air Systems

Controls and Monitors

Cleaning and Maintenance

Commissioning

7. ELECTRICAL This Chapter applies the concepts of critical parameters and Levels of Protection as defined in Chapter 2 to electrical systems, and provides the basis for defining the documentation and commissioning requirements for such systems in terms of Good Engineering Practice as described in Chapter 10.

The design issues covered are:

Power distribution

Electrical classification

Lighting

Grounding

Telephones, paging and radio systems

Wiring methods

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8. INSTRUMENTATION AND CONTROLS This Chapter applies the concepts of critical parameters and Levels of Protection as defined in Chapter 2 to electrical systems. It also provides the basis for defining the documentation and commissioning requirements for such systems in terms of Good Engineering Practice or Enhanced Documentation as described in Chapter 10.

The design issues covered are:

Field instrumentation

Process conditions

Ambient conditions

Installation

Maintenance

Calibration

Control systems

Standard application software

User configurable software

Custom built software

Hardware

Operator interface

9. OTHER CONSIDERATIONS This chapter addresses issues outside of the scope of FDA regulations, but which may ultimately impact GMP design requirements in OSD facilities. It is not intended to be a comprehensive source of reference to non-GMP possible regulatory requirement. Codes, standards and regulations cited refer to facilities built in the United States. Facilities in other locations should comply with the requirement of applicable codes and standards.

10. COMMISSIONING AND QUALIFICATION Commissioning i

Documents

Ispe Baseline Pharmaceutical Engineering Guide