[Emuch.net]01 Bulk Pharmaceutical Chemicals

A GUIDE FOR NEW FA CILITIES

VOLUME 1: BULK PHARMACEUTICAL PHARMACEUTICAL CHEMICAL FACILITIES

EXECUTIVE SUMMARY

November 1 1997

A DOCUMENT DEVELOPED IN PARTNERSHIP PARTNERSHIP BY:

ISPE Baseline Guide - Bulk Pharmaceutical Chemical Facilities 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 ISPE’s 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 b e 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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b)

•

Critical instruments and systems

•

Good Engineering Practice

•

Enhanced documentation

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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 . These concepts are described in Chapter 2. Protection 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 and system s , which require enhanced levels of documentation. critical instrum ents

d)

recognizes that all systems in a facility, whether they are elevators, Good Engineering Practice 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)

d o c u m e n t a t i o n is required for critical systems and instruments. This adds two dimensions to Good Engineering Practice: document change control and validation. This guide Enhanced

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.

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

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ISPE Baseline Guide - Bulk Pharmaceutical Chemical Facilities Summary b)

c)

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This chapter provides guidance to BPC manufacturers in deciding upon: •

a recommended level of protection

•

the extent of validation (but we’ll address QUALIFICATION in detail)

•

the appropriate use of this guide

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 substance’s 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) FIGURE 2-1 CHARACTERIZATION OF FINAL DRUG SUBSTANCE SEE SECTION 2.3

IDENTIFY CRITICAL STEPS a n d C R I T I C A L P A R A M E T E R S SEE SECTION 2.4

DETERMINE DEGREE OF PROTECTION REQUIRED SEE SECTION 2.5

USE APPROPRIATE DESIGN GUIDES SEE REMAINDER OF THIS GUIDE

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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 Sheet 2: 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.

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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 chemica l 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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FIGURE 2-2

REACTOR

REACTOR

REACTOR

*

* FILTER

FILTER

FILTER

* CRYSTALLIZER

CRYSTALLIZER

CRYSTALLIZER

* CENTRIFUGE

CENTRIFUGE

CENTRIFUGE

* DRYER

DRYER

DRYER

* INTERMEDIATE

INTERMEDIATE

FINAL DRUG

DRUG SUBSTANCE

DRUG SUBSTANCE

SUBSTANCE

Figure 2-2 illustrates a three stage process. considered critical.

* indicates

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potential points in the process which may be


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FIGURE 2-3

FACILTY A

*

*

FACILITY B

FACILITY C

STEP 1

STEP 6

STEP 11

STEP 2

STEP 7

STEP 12

STEP 3

STEP 8

STEP 13

STEP 4

STEP 9

STEP 14

*

STEP 5 INTERMEDIATE DRUG SUBSTANCE

*

*

STEP 10

INTERMEDIATE DRUG SUBSTANCE

INTERMEDIATE DRUG SUBSTANCE

STEP 16

* *

STEP 15

STEP 17

denotes critical steps: 3, 5, 10, 15 16, 17

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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 e xposed (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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TABLE 2-1 Recommended Level of Protection

Exposed

Level I

(Open) Level II

E R U S O P X E

Level III Not Exposed (Closed)

Pre-C riti cal

Cr itical

CRITICALITY

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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ISPE Baseline Guide - Bulk Pharmaceutical Chemical Facilities Summary e)

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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

A IR

REACTOR NO. 1

A IR

REACTOR NO. 2

A IR

REACTOR NO. 3

A IR

REACTOR NO. 4

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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 reactor’s 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 regulations 3. 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

•

CIP/SIP systems

•

Hold tanks

•

Solvent storage and recovery

•

Centrifuges and filters

•

Raw material bulk storage and distribution

•

Evaporators and distillation systems

•

Packaging systems

•

Dryers and filter-dryers

•

Dispensing systems

•

Process water

•

Process automation systems related to critical

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ISPE Baseline Guide - Bulk Pharmaceutical Chemical Facilities Summary •

Nitrogen systems

•

Mills and blenders

•

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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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