Designation: X XXXX-XX

4
Work Item Number: WK9864
Date: 04/10/2006
1
2 Standard Guide for a Science-and Risk-Based Approach to
3 Qualification of Biopharmaceutical and Pharmaceutical Manufacturing
4 Systems1
5 This standard is issued under the fixed designation X XXXX; the number immediately following the designation
6 indicates the year of original adoption or, in the case of revision, the year of last revision. A number in parentheses
7 indicates the year of last reapproval. A superscript epsilon (ε) indicates an editorial change since the last revision or
8 reapproval.

9 1. Scope
10 1.1 This guide provides a science and risk based approach to qualification to assure

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11 pharmaceutical and biopharmaceutical systems are fit for use, perform satisfactorily, and
12 may be used in the manufacturing, processing, packaging, and holding of a drug.
13 1.2 Throughout this standard the term drug is used in its broad sense and the standard may be
14 applied to drug products, intermediates, active pharmaceutical ingredients (API) or drug
15 substances.
16 1.3 This guide is applicable to manufacturing facilities, process equipment, support equipment,
17 utilities, and associated process control and automation systems. Note that the qualification
18 of process control and automation systems is synonymous with computer validation of
19 those systems. This guide may also be adapted for other types of systems such as
20 laboratory and information systems.
21 1.4 This standard is applicable to new manufacturing facilities that are to produce either new or
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22 mature products. It may also be applied to modifications of legacy facilities and systems.
23 It is applicable to both traditional approaches to manufacturing control, as well as PAT
24 approaches to manufacturing quality verification and control.
25 1.5 This standard does not purport to address safety, environmental, or other regulatory areas
26 of concern. It is the responsibility of the user of this standard to establish appropriate safety
27 and health practices and determine the applicability of such regulations prior to use.
28 2. Referenced Documents
29 2.1 US Federal Standard 2
30 21CFR 210, 211,600
31 2.2 European Union Standard 3
32 EU Guidelines to Good Manufacturing Practice Medicinal Products for Human and
33 Veterinary Use, Volume 4, Chapter 3 Premises and Equipment
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34 Annex 11 to the EU Guide of Good Manufacturing Practice: Computerised Systems

35 Annex 15 to the EU Guide to Good Manufacturing Practice: Qualification and validation

1This guide is under the jurisdiction of ASTM Committee E55 on Pharmaceutical Application of Process Analytical

Technology and is the direct responsibility of Subcommittee E55.03 on General Pharmaceutical Standards.
Current edition approved XXX. XX, XXXX. Published XX XXXX.
2 Available from the U.S. Government Printing Office, Superintendent of Documents, 732 N. Capitol St., N.W., Mail Stop

SDE, Washington, DC 20401.

3 Available from Eudralex, The European Commission, Entreprise and Industry Directorate-Generale

THIS DOCUMENT IS NOT AN ASTM STANDARD; IT IS UNDER CONSIDERATION WITHIN AN ASTM TECHNICAL COMMITTEE BUT HAS NOT RECEIVED ALL APPROVALS
REQUIRED TO BECOME AN ASTM STANDARD. IT SHALLSHOULD NOT BE REPRODUCED OR CIRCULATED OR QUOTED, IN WHOLE OR IN PART, OUTSIDE OF ASTM
COMMITTEE ACTIVITIES EXCEPT WITH THE APPROVAL OF THE CHAIRMAN OF THE COMMITTEE HAVING JURISDICTION AND THE PRESIDENT OF THE SOCIETY.
COPYRIGHT ASTM, 100 BARR HARBOR DRIVE, WEST CONSHOHOCKEN, PA 19428. ALL RIGHTS RESERVED.
 X XXXX

36 2.3 ISO Standard 4

37 ISO 9001 Quality Management Systems Requirements
38 2.4 International Guideline 5
39 ASTM
40 E55 Standards
41 Continuous Quality Verification
42 Risk Assessment for PAT processes
43 International Conference on Harmonisation of Technical Requirements for Registration
44 of Pharmaceuticals for Human Use (ICH):
45 ICH Q7a -
46 ICH Q8 Pharmaceutical Development

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47 ICH Q9 Quality Risk Management
48 2.5 Technical Reference Guides
49 2.5.1 ISPE Baseline® Guides for New and Renovated Facilities
50 2.5.1.1 Volume 5 – Commissioning and Qualification.
51 2.5.1.2 Volume X – Good Engineering Practices (Draft)
52 2.5.1.3 Volume X – GAMP Guide for Validation of Automated Systems
53
54 3. Terminology
55 3.1 (Note: The terminology in this draft standard will be transferred to the E55 terminology
56 subcommittee)
57
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58 4. Significance and Use
59
60 4.1 Careful design and risk management of the manufacturing process – including its
61 equipment, systems, and controls - can establish a high degree of confidence in the quality
62 of products. Quality of this aspect is managed in order to assure that the systems are
63 performing as expected prior to use and throughout the clinical and commercial product
64 manufacturing lifecycle.
65 4.2 The Qualification process is a structured and documented means by which the system is
66 proven to be fit for its intended use and capable of supporting Process Validation;
67 Qualification sets the stage for and is a precursor to successful process validation.
68 4.3 A science and risk based qualification process, as defined by this standard, consists of
69 identifying process requirements and process risks that are based on the science of the
70 product and process, control of those risks, use of good engineering practices to check the
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71 installation and operation of equipment and systems, and verification that equipment and
72 systems perform to meet the process requirements. This process provides a high degree of
73 assurance that product and process user requirements have been met..
74 4.4 As general technology and scientific knowledge of a specific process evolve, so does
75 understanding of the critical material, equipment, and process variables that must be

4 Available from ISO copyright office, Case postale 56 • CH-1211 Geneva 20, Switzerland
5 Available from ICH Secretariat, c/o IFPMA, 15 ch. Louis-Dunant, P.O. Box 195, 1211 Geneva 20, Switzerland

THIS DOCUMENT IS NOT AN ASTM STANDARD; IT IS UNDER CONSIDERATION WITHIN AN ASTM TECHNICAL COMMITTEE BUT HAS NOT RECEIVED ALL APPROVALS
REQUIRED TO BECOME AN ASTM STANDARD. IT SHALL NOT BE REPRODUCED OR CIRCULATED OR QUOTED, IN WHOLE OR IN PART, OUTSIDE OF ASTM
COMMITTEE ACTIVITIES EXCEPT WITH THE APPROVAL OF THE CHAIRMAN OF THE COMMITTEE HAVING JURISDICTION AND THE PRESIDENT OF THE SOCIETY.
COPYRIGHT ASTM, 100 BARR HARBOR DRIVE, WEST CONSHOHOCKEN, PA 19428. ALL RIGHTS RESERVED.
 X XXXX

76 defined and controlled to ensure product quality and conformity with appropriate
77 specifications through continuous improvements. This standard recognizes the difference
78 between process performance requirements and engineering solutions, and the frequent
79 need to adjust and adapt or change those engineering solutions as knowledge is gained
80 from process pilot studies, equipment start-up, initial operations, and long-term process
81 monitoring and data analysis.
82 4.5 This guide defines the role of the Quality Unit as a quality assurance role where the Quality
83 Unit is involved in risk management throughout the system design, development, and
84 implementation.
85 4.6 This guide delegates quality control of installation and operation verification to appropriate
86 technical experts – persons with appropriate education, training, and experience. The

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87 technical experts will evaluate engineering specifications, test plans and conformance of
88 results to engineering specifications.
89
90 5. Summary of Practice
91 5.1 The risk management approach to qualification is based on scientific and engineering
92 principles and a good understanding of the chemistry, physics, biology, and
93 thermodynamics of the raw materials, manufacturing processes, and final product. This
94 comprehensive understanding yields product and process user requirements necessary to
95 accomplish the manufacture of a quality product.
96 5.2 The baseline process knowledge is typically defined during the development and scale up.
97 Therefore the qualification approach should build on the scientific process understanding,
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98 starting in the development phase and continuing throughout the product life cycle.
99 5.3 Based on this scientific understanding, risks to the manufacturing process can be identified,
100 assessed, and controlled (see appendix II). This is done through an iterative process during
101 design development, whereby the design is continually evaluated and adjusted in terms of
102 its ability to adequately control the manufacturing process risks to an acceptable level.
103 5.4 Meeting product and process user requirements is fundamental to a successful qualification
104 program. In addition, any design implementation will contain various features, functions,
105 and components that singly or in groups act to control risks to the manufacturing process.
106 These features, functions, and components, along with their respective acceptance criteria,
107 comprise the other set of items that must be confirmed as part of the qualification program.
108 These are known as “critical elements.” The critical elements and associated acceptance
109 criteria are a key element of a risk-based qualification program.
110 5.5 A project quality plan (or equivalent document, SOP, etc.) is developed by the project team
to specify and govern the use of good engineering practices and an overall project quality
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111
112 system. Good engineering practices provide a high degree of assurance that equipment and
113 systems have been properly engineered, fabricated, installed, inspected, started, adjusted,
114 and functionally tested.
115 5.6 Performance qualification is the formal testing by which product and process user
116 requirements are confirmed to meet specifications. Performance qualification is thus the
117 fundamental proof that the equipment, systems, and associated automation controls are fit
118 for purpose.

THIS DOCUMENT IS NOT AN ASTM STANDARD; IT IS UNDER CONSIDERATION WITHIN AN ASTM TECHNICAL COMMITTEE BUT HAS NOT RECEIVED ALL APPROVALS
REQUIRED TO BECOME AN ASTM STANDARD. IT SHALL NOT BE REPRODUCED OR CIRCULATED OR QUOTED, IN WHOLE OR IN PART, OUTSIDE OF ASTM
COMMITTEE ACTIVITIES EXCEPT WITH THE APPROVAL OF THE CHAIRMAN OF THE COMMITTEE HAVING JURISDICTION AND THE PRESIDENT OF THE SOCIETY.
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 X XXXX

119 5.7 The responsibilities of the quality unit are three-fold: (i) focus on the important product
120 and process user requirements, risk assessments, and ensure critical elements are defined;
121 (ii) ensure the project team has an adequate quality plan and implementation of good
122 engineering practices; (iii) verify, through performance qualification, that the product and
123 process user requirements have been met. More specifically, the quality unit is involved in
124 the approval of product and process user requirements, approves the project quality plan or
125 similar document, participates in risk assessments and approves the final risk assessment
126 and associated list of critical elements/ acceptance criteria, is involved in the resolution and
127 approval of alternative courses of action when critical elements cannot conform to
128 acceptance criteria, verifies the completion of prequalification tasks, and pre- and post-
129 approves the performance qualification protocol and any non-conformances that may

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130 result. The quality unit also approves changes to any of the above items that had
131 previously been approved by the quality unit.
132 5.8 Figure 1 provides a flow chart of the science and risk based approach to qualification of
133 systems.
134
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THIS DOCUMENT IS NOT AN ASTM STANDARD; IT IS UNDER CONSIDERATION WITHIN AN ASTM TECHNICAL COMMITTEE BUT HAS NOT RECEIVED ALL APPROVALS
REQUIRED TO BECOME AN ASTM STANDARD. IT SHALL NOT BE REPRODUCED OR CIRCULATED OR QUOTED, IN WHOLE OR IN PART, OUTSIDE OF ASTM
COMMITTEE ACTIVITIES EXCEPT WITH THE APPROVAL OF THE CHAIRMAN OF THE COMMITTEE HAVING JURISDICTION AND THE PRESIDENT OF THE SOCIETY.
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 X XXXX

135
136 FIG 1 - Commissioning and Qualification Science- and Risk-Based Approach
137
Product Development: Preliminary Business
138 risk assessment and initial definition
139 of process controls
140 FIG 1 - Commissioning and Qualification Science- Safety/
and Risk-Based Approach
Scale-up and Commercialization:
Further process characterization and Operational
risk assessment of critical to quality
parameters and attributes

Product and Product

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General User Requirements
User Requirements Including business-related, safety
and environmental and operational
requirements
Manufacturing System Risk
Assessment - based on Science

Project-specific activities
related to design, design
Mitigate Risks by Design etc. review, and good engineering
Identify critical elements practices

Finalized System Design Review and

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Finalized Manufacturing System Design Risk Assessment

GEP/ Commissioning

Qualification

Continuous Improvement
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THIS DOCUMENT IS NOT AN ASTM STANDARD; IT IS UNDER CONSIDERATION WITHIN AN ASTM TECHNICAL COMMITTEE BUT HAS NOT RECEIVED ALL APPROVALS
REQUIRED TO BECOME AN ASTM STANDARD. IT SHALL NOT BE REPRODUCED OR CIRCULATED OR QUOTED, IN WHOLE OR IN PART, OUTSIDE OF ASTM
COMMITTEE ACTIVITIES EXCEPT WITH THE APPROVAL OF THE CHAIRMAN OF THE COMMITTEE HAVING JURISDICTION AND THE PRESIDENT OF THE SOCIETY.
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 X XXXX

141
142
143 6. A Science and Risk based Approach to Qualification of Pharmaceutical and
144 Biopharmaceutical Manufacturing Systems
145
146 6.1 Process Knowledge and Product and Process user Requirements
147 6.1.1 This ASTM standard does not cover product development activities for new products,
148 nor process improvement studies of legacy products. However, it does leverage
149 scientific knowledge acquired by these activities and captured in a report (e.g. process
150 knowledge report, development report, or other) as the scientific and engineering basis
151 of the risk assessments performed to support the design, development and verification

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152 to assure pharmaceutical systems and clinical trial systems are fit for use.
153 6.1.2 The process knowledge report includes identification of the critical process parameters
154 (CPPs) and critical product quality attributes (CQAs) with appropriate operating limits
155 or acceptance criteria defined. For the purposes of quality by design, the CQAs and
156 CPPs identified in the product knowledge report represent the initial Product and
157 Process User Requirements that serve as the primary basis for the design and
158 ultimate acceptance criteria for performance qualification. In addition, the process
159 knowledge report will identify the points in the process where it is appropriate to
160 monitor and control the process to control variability that may affect product quality.
161 Further information on product and product and process user requirements are
162 described in Appendix I.
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163 6.1.3 A multi-disciplinary team should develop the list of product and process user
164 requirements, based on the process knowledge report. This list is approved by the
165 Quality Unit and subject to Quality Change Management procedures.
166
167 6.2 Science and Engineering Based Methods of Risk Assessment of the Manufacturing
168 Process. A series of risk assessments are performed throughout the design development to
169 assure the collection of systems and other facets of the design and operating philosophy are
170 capable of monitoring and controlling risks to the manufacturing process, including control
171 of process variability, control of contamination, etc., in order to produce product which
172 meets its predetermined quality attributes.
173 6.2.1 The initial step of system design is a risk assessment on the chosen process against
174 a set of product and process user requirements. The risk management requirements
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175 identified in this risk assessment are designated as critical elements and include all
176 components, functions and features of the design that serve, collectively or singly, to control
177 risks. This information is provided to design engineers to drive the development of the
178 preliminary design.
179 6.2.2 Risks identified should be evaluated as to their probability and criticality to
180 determine the impact to process variation and effect on product quality and safety.
181 6.2.3 Unacceptable risks (e.g., those with an unacceptable combination of probability
182 and severity of impact) should be mitigated following the preferred hierarchy of elimination

THIS DOCUMENT IS NOT AN ASTM STANDARD; IT IS UNDER CONSIDERATION WITHIN AN ASTM TECHNICAL COMMITTEE BUT HAS NOT RECEIVED ALL APPROVALS
REQUIRED TO BECOME AN ASTM STANDARD. IT SHALL NOT BE REPRODUCED OR CIRCULATED OR QUOTED, IN WHOLE OR IN PART, OUTSIDE OF ASTM
COMMITTEE ACTIVITIES EXCEPT WITH THE APPROVAL OF THE CHAIRMAN OF THE COMMITTEE HAVING JURISDICTION AND THE PRESIDENT OF THE SOCIETY.
COPYRIGHT ASTM, 100 BARR HARBOR DRIVE, WEST CONSHOHOCKEN, PA 19428. ALL RIGHTS RESERVED.
 X XXXX

183 by design, elimination by automated control, or elimination by procedural controls. This is

184 done during the course of design development as a key aspect of a series of engineering
185 design reviews. The list of critical elements may be updated based on design changes.
186 Furthermore, changes to product and process user requirements must also be factored into
187 the design as it develops.
188 6.2.4 More specific details on risk management can be found in the ASTM E55.01 on
189 Risk Mitigation, and ICH Q9.
190 6.2.5 At the completion of the system design, a science and engineering based risk
191 assessment on the final system design will be performed to assure that the design is suitable
192 for its intended purpose with a focus on product-quality-impacting aspects of the design.
193 The review will assure the product user requirements have been incorporated into the

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194 design. This exercise also confirms that general cGMP aspects of any manufacturing
195 facility have been adequately addressed by the design. The final set of Critical Elements
196 and their acceptance criteria are identified and documented. The quality unit should
197 approve this final list of critical elements and their acceptance criteria
198
199 6.3 Good Engineering Practices and Commissioning
200 6.3.1 The project team should develop a project quality plan (or similar document; for
201 small projects, an SOP may be appropriate) to specify the quality system, good engineering
202 practices, and general commissioning methods to be used to ensure quality is built into the
203 project. The Quality Unit should approve this document.
204 6.3.2 In the case of vendor-supplied systems, appropriate persons may evaluate the quality
systems of the vendor to determine the ability and extent they may leverage vendor
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205
206 documentation, inspections and tests to eliminate duplication of tasks.. See Appendix
207 II for further information.
208 6.3.3 Commissioning is performed and documented to assure the proper installation and
209 operation of the systems including, but not limited to, the verification and thorough
210 testing of all critical elements. Technical experts will use their engineering knowledge
211 and to determine the appropriate verification tests to assure systems are installed and
212 operate correctly. Technical experts will assure all critical elements meet their pre
213 approved acceptance criteria in this task. If, however a critical element cannot meet
214 the pre-established acceptance criteria, the Quality Unit should be notified, the impact
215 assessed, and appropriate alternative solutions approved.
216 6.3.4 The list of Critical Elements and their acceptance requirements, previously
217 approved by the quality unit, are provided to the commissioning team where they use
218 good engineering practices to develop a commissioning document (e.g. Plan,
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219 protocol, etc). The commissioning document identifies activities to verify the proper
220 system installation, start-up, and operational testing to be performed. This document
221 defines the inspection or test methods, data collection requirements, acceptance
222 criteria, and provisions for recording observations. All critical elements must be
223 inspected or tested, as appropriate.
224 6.3.5 Documentation should include sufficient procedural steps such that a person
225 technically familiar with the equipment could perform the inspection or test in the
226 desired manner.
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 X XXXX

227 6.3.6 Acceptable documentation of observed results is such that a technically competent
228 person can ascertain that the inspection or test was properly performed and the
229 acceptance criteria were met.
230 6.3.7 A person familiar with the technical aspects of the equipment or system should review
231 all completed inspection or test documentation; the technical reviewer should have
232 appropriate responsibility to assure the appropriate results met their acceptance criteria
233 and all tests have been completed and appropriately documented. The technical
234 reviewer is responsible for assessing and resolving departures from specification,
235 subject to the limitation in §6.3.3 regarding critical elements.
236 6.3.8 A Commissioning Report should be issued that confirms the system was
237 commissioned following good engineering practices. The report should reference any

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238 critical element acceptance criteria that were not met and the appropriate plan of
239 action. Principles of Good Engineering Practice (GEP) are described further in
240 appendix III.
241
242 6.4 Qualification.. Systems should be qualified for their intended use to assure they may be used
243 for the manufacturing, processing, packaging, and holding of drug products. Product and
244 process user Requirements are the basis for acceptance of systems as qualified. See appendix
245 IV.
246 6.4.1 A Qualification document (e.g. plan, protocol, etc.) will be written by the
247 appropriate technical experts and approved by the Quality Unit. Approvals may also
248 include other technical experts based on business preferences.
6.4.2 The Qualification document will begin with the verification activity to confirm good
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249
250 engineering practices and commissioning activities have been completed. These
251 requirements include the following:
252 6.4.2.1 The commissioning report including any nonconformance of critical elements and
253 corrective actions, are reviewed and approved by the Quality Unit. This review and approval
254 signifies that any corrective actions to critical elements are adequate such that these actions will
255 not affect the integrity of the performance qualification nor impact product quality and safety to
256 the patient.
257 6.4.2.2 Confirmation of GMP readiness activities have been completed such as the
258 appropriate SOPs have been written and approved and individuals are trained to perform their
259 intended functions. This also includes confirmation that appropriate calibration and maintenance
260 and procedures are in place.
261 6.4.2.3 An integrated Performance Qualification will be performed following standard
262 operating procedures to assure the system(s), acting singly or in combination as appropriate,
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263 perform satisfactorily, are fit for use, and may be used in the manufacturing, processing,
264 packaging, and holding of a drug product. This performance qualification may be performed as
265 a dry run, with placebo or actual product and should demonstrate the system(s) are capable of
266 meeting the product and process user requirements.
267 6.4.3 The results of the performance qualification/ completion of the qualification plan will
268 be documented in a Qualification Report that will include a discussion of the results
269 of the Qualification tasks and discussion of any nonconformance to acceptance
270 criteria, and a statement to identify whether or not the system was found fit for its
8

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 X XXXX

271 intended use. This report will be approved by the Quality Unit. The business may
272 also include technical expert(s) in the approval of the report
273
274 6.5 Continuous Improvement Process.
275 6.5.1 Once the commissioning and qualification process is completed, the system will be
276 subject to the appropriate quality system(s) for ongoing support and continuous
277 improvement.
278 6.5.2 In the case where system improvements are recommended, this standard may be followed
279 to assist with the appropriate design and implementation.
280
281

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282 6.6 Change Management
283 During the life cycle of the manufacturing system, it is important to have well defined principles of
284 change management.
285 6.6.1 Change Control is required to be implemented before commencement of commercial
286 product manufacturing. Change control involves the pre-approval of changes by the
287 quality unit.
288 6.6.2 Quality control change management should be applied to all changes to a document
289 approved by the Quality Unit (e.g. Product and Process Uuser Requirements, Critical
290 Element and Acceptance critthat occur during execution of the Qualification. Any change
291 affected to systems that includes product intended for distribution must be preapproved
292 prior to the implementation of change (see Change Control, above). Else, systems in use
for qualification purposes may be approved post implementation without risk to product.
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293
294 6.6.3 Project Change Management should be applied to all engineering changes. This process is
295 managed and approved by the technical and project authorities. Project change
296 management – which is a Good Engineering Practice control - is to control all other
297 changes up to the point of commercial product manufacture.
298
299
300
301
302 7. Keywords
303
304 7.1 Biopharmaceutical manufacturing system; pharmaceutical manufacturing system;
305 qualification; risk-based life cycle; science-based life cycle
306
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 X XXXX

307
308 APPENDICES
309

310 I. USER REQUIREMENTS

311 1. User Requirements

312 The proper identification of user requirements is the starting point for a science and risk based
313 approach to qualification. A clear definition of user requirements should categorize
314 requirements as outlined below, so that qualification can focus on those elements that
315 potentially may directly impact the quality of the product and are thereby critical to quality –

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316 the Product and process user Requirements.
317
318 1.1 Product and Process User Requirements (PURS) - Qualification efforts focus on the
319 critical to product quality elements that make the product fit for use, as defined in the
320 design space and as outlined in the regulatory common technical documents. ICH Q8 on
321 Pharmaceutical Development provides additional information on the definition of the
322 product design space developed using product knowledge and process understanding
323 determined through development, scientific understanding and manufacturing experience.
324 Manufacturing systems leverage the defined product design space of specific product and
325 process characteristics to define the product and process user requirement which includes
326 all elements that are critical to quality. This includes e.g. the critical quality attributes and
critical process parameters.
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327
328
329 1.2 General User Requirements - In addition to product and process user requirements, end
330 users may have other requirements related to process capacity, equipment availability,
331 environmental discharges, safety, and so forth that are non-GMP requirements. These are
332 collectively referred to as “general user requirements” to distinguish them from those that
333 may impact product quality--the product and process user requirements. General user
334 requirements are managed using good engineering practices; the quality unit does not need
335 to be involved in providing quality oversight of this aspect of the project. In some cases,
336 project teams may wish to dictate design solutions, such as the use of a particular
337 automation solution and so forth before the start of engineering design efforts.
338
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 X XXXX

339 APPENDIXES
340 II VENDOR QUALITY SYSTEMS

341 1. For the science and risk based qualification approach, the quality of vendor supplied equipment,
342 systems and facilities has a clear impact on the amount and depth of the activities subsequently
343 planned and performed by the firm. This section focuses on the vendor quality systems
344 assessments and potential use of vendor inspection and test records.
345 1.1 Assessment of vendor quality systems should be performed for all new custom systems that
346 contain critical elements. Consideration should also be given to performing assessments
347 for critical and complex standard systems. The assessment method chosen should be based
348 on the criticality of the system, the complexity of the system, the degree to which the

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349 vendor quality system will be relied upon within the project and subsequent use of vendor-
350 supplied systems, and previous experience with the vendor as may be applicable.
351 1.2 On this basis, vendor inspection and test documentation may be leveraged to avoid
352 repeating testing, provided that vendor documentation clearly shows that items of interest
353 have been verified or tested in an appropriate manner. This is subject to the vendor being
354 of adequate quality as determined by appropriate assessment of their quality systems by the
355 pharmaceutical manufacturer.
356 1.2.1 Vendors who are to provide engineered systems or software that may contain critical
357 elements or provide high value direct impact equipment should be assessed for the adequacy
358 of their quality system(s). Such assessments may include, but are not limited to:
359 1.2.1.1 Market survey for evidence of past quality performance;
1.2.1.2 Review of certification such as ISO 9000 or other relevant quality-based assessments;
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360
361 Conformance to any applicable standards for fabrication, testing, and delivery of equipment for
362 use in manufacturing processes
363 1.2.2 Based on the results of this assessment(s), plans should be developed using one or more of
364 the following strategies: (1) leveraging of vendor documents, inspections and tests, (2)
365 conducting appropriate oversight of the fabrication and testing process, and (3) conducting
366 independent inspections and testing. The final approach should be designed to provide an
367 adequate level of assurance – based upon risks - that the delivered equipment or software
368 meets engineering specifications and customer quality systems expectations. This approach
369 may, if warranted by the assessment, rely solely on vendor-provided inspections and tests of
370 installation and operational items provided they are representative of actual conditions. Such
371 an approach does not relieve the end user firm of responsibility for the fitness for use of any
372 system, equipment, or component, nor does it relieve the end user firm of the need to verify,
373 through performance qualification, that all product and process user requirements have been
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374 met.

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 X XXXX

375 III. GOOD ENGINEERING PRACTICES AND COMMISSIONING

376 1. Good Engineering Practice (GEP) during the project, including during the commissioning activities,
377 is most important to the science and risk based commissioning and qualification. For facility
378 projects it is critical to follow such practices and for the cooperation with suppliers, engineering
379 and construction companies as well as in companies’ cross-functional teams for the project,
380 commissioning and qualification efforts, these principles are key to taking full advantage of the
381 science and risk based qualification method in this standard.
382 1.1 GEP consists of proven and accepted, cost-effective, engineering methods and practices that
383 ensure the effective satisfaction of stakeholder requirements. As such, GEP ensures that an
384 engineering project meets the requirements of the user while being cost effective, compliant

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385 with regulations and well documented. Guidance and standards are available that have been
386 defined by engineering institutes and other learned bodies supporting GEP
387 1.2 Good Engineering Practice, related to regulated facilities, utilities and equipment systems
388 encompasses the following:
389 1.2.1.1 Design and installation that takes full account of CGMP, safety, health, environmental,
390 ergonomic, operational, maintenance, recognized industry guidance and statutory
391 requirements
392 1.2.1.2 Professional and competent project management, engineering design, procurement,
393 construction, installation, and commissioning
394 1.2.1.3 Appropriate documentation including design concepts, design schematics drawings, as
395 installed drawings, test records, maintenance and operation manuals, statutory inspection
certificates, etc.
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396
397 1.3 Good engineering practices should be applied throughout the project design and delivery
398 process. Good engineering practices can be grouped into three categories: design,
399 fabrication/installation, and change management. The design category includes design
400 development, design review, and the incorporation of appropriate quality assurance provisions
401 into procurement specifications and other contract documents. The fabrication/installation
402 category includes an appropriate degree of oversight or control of the fabrication process and
403 appropriate inspections and tests throughout the fabrication, delivery, installation, and
404 commissioning process. The change management category includes the use of commissioning
405 documents to plan, define, control and record inspections and tests, analysis of departures from
406 specification, implementation of an effective project change management process, and other
407 controls to provide a high degree of assurance that the delivered facility, equipment, and
408 systems meet user requirements.
409 1.4 Automation software and related data/ information technology (IT) systems should be
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410 developed incorporating good automated manufacturing practices and good software
411 development practices
412 1.5 Commissioning is an engineering activity, wherein the as-delivered, as-built, and as-tested items
413 are compared to engineering specifications. It is expected that there will be many instances in
414 which the item does not precisely match the design specifications and drawings. It is an
415 engineering function to determine whether such departures from specification are acceptable or
416 not, provided there are no uncontrolled changes to product and process user requirements or
417 other preapproved quality documents.
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 X XXXX

418 1.6 The manufacturing and maintenance departments have requirements for adequate
419 documentation to support life-cycle operation and maintenance. Such documentation typically
420 includes information on the as-built condition of the equipment and systems; information
421 regarding recommended maintenance, calibration, and spare parts; information regarding the
422 installation, operation, and maintenance of the item; component data sheets; and so forth. It is
423 up to the respective operations and maintenance departments to determine whether adequate
424 information has been provided (typically in the form of a turnover package).
425 1.7 Design Specifications
426 1.7.1 Design drawings and specifications (to include automated systems) should be developed to
427 provide sufficient assurance that the as-installed and as-functioning equipment and systems
428 can meet user requirements.

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429 1.7.2 Design drawings and specifications, once reviewed and approved by the project team,
430 should be subject to project change management procedures.
431 1.7.3 Engineering Design Review
432 1.8 As a good engineering practice, the engineering unit, with representation from end users as
433 appropriate, conduct engineering design reviews (EDRs) to ensure the system design
434 satisfactorily meets the user requirements
435 1.8.1 EDRs should verify that user and design requirements have been included as part of the
436 design. This exercise demonstrates traceability of the requirements to particular systems or
437 other facets of the design.
438 1.8.2 EDRs should verify that risk control mechanisms identified in the risk assessment process
439 are included in the design.
1.8.3 The completion of each EDR is typically documented following good engineering
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440
441 practices.
442 1.9 Planning
443 1.9.1 The project team is responsible for developing an appropriate set of plans that define a
444 complete, comprehensive set of requirements to build in quality and verify that engineering
445 specifications have been met.
446 1.9.2 Planning should occur at the project and system/equipment level. Project level plans should
447 address the overall strategy for ensuring quality of the fabrication, installation, and
448 commissioning of the equipment and facility. System/equipment level plans should
449 address engineered systems and any high-value off-the-shelf items that may have direct
450 impact on product quality.
451 1.10 Field Inspections and Testing Performance
452 1.10.1 Field inspections and tests should be planned and performed such that the results of tests
453 remain valid during subsequent phases of the project. If this is not possible, such situations
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454 should be identified and appropriate reinspections or retesting performed at a later stage of
455 the project.
456 1.10.2 The person performing the inspection or test at the time should complete documentation at
457 the time and location the inspection or test was performed.
458 1.11 Departures from Specification
459 1.11.1 The person performing the inspection or test should note any departures from specification
460 that cannot be corrected for evaluation and disposition by the technical reviewer.
461 1.12 Life-Cycle Support Documentation
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 X XXXX

462 1.12.1 Sufficient component data should be collected during the commissioning process to
463 support life-cycle operation and maintenance.
464 1.12.2 Sufficient as-built drawings should be verified and maintained to support life-cycle
465 operation, maintenance, and changes.
466 1.12.3 Sufficient Vendor and contractor data should be collected and provided to the operations
467 and maintenance departments to support life-cycle information needs by these
468 departments.
469

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470 IV. QUALIFICATION AND CHANGE CONTROL

471 1. The qualification is focused on those aspects of equipment, utilities, process controls, and facilities
472 that can affect product quality and demonstrates that product and process user requirements have
473 been met. Science- and risk-based qualification is predicated on the appropriate and thorough
474 application of good engineering practices.
475
476 1.1 Qualification
477 Qualification consists of confirming the commissioning activities have been completed, GMP
478 readiness activities completed, followed by integrated performance qualification.
479

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480 1.1.1 Prerequisites to executing the Qualification protocol include:
481 1.1.1.1 The Qualification Document (Plan, Protocol, etc.) should be pre approved by the Quality Unit.
482 1.1.1.2 Approved equipment operating procedures
483 1.1.1.3 Personnel , or trainer, trained on those procedures
484 1.1.1.4 The operations and maintenance groups have accepted life-cycle support documentation,
485 1.1.1.5 Commissioning report provided to the quality unit and open nonconformance’s to critical
486 elements acceptance criteria confirmed to not have an impact on the outcome of the PQ.
487 1.1.1.6 The acceptance criteria are that the system can consistently meet product and process user
488 requirements when operated under normal operating conditions and ranges using
489 appropriately trained personnel. Testing should demonstrate repeatable performance and
490 should be performed on the fully integrated system. For some automation systems, there may
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491 be some functions or features that are not associated with a specific piece of equipment or
492 system; such functions and features may be separately qualified.
493 1.1.2 Qualification Summary Reports
494 1.1.2.1 Upon completion of all qualification activities for a given system or piece of equipment, a final
495 qualification summary report should be developed.
496 1.1.2.1.1 The qualification summary report should discuss any commissioning or qualification
497 nonconformance, impacting any critical elements.
498 1.1.2.1.2 The qualification summary report should contain summary PQ data analysis as appropriate
499 and significant observations.
500 1.1.2.1.3 The qualification summary report should summarize system capability and suitability
501 confirming that all product and process user requirements were adequately demonstrated to
502 have been met, with a conclusion as to whether the systems are found to be qualified as fit
503 for use.
504 1.1.2.2 In certain situations, an interim report may be necessary to support use of the system for
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505 product manufacturing purposes. This is likely to occur for water systems in which an
506 extended PQ is performed to check for seasonal variations in water quality or other similar
507 situations.
508 1.1.2.3 The quality unit should approve qualification reports.
509
510 1.2 Change Management and Change Control
511 1.2.1 Project change management is a good engineering practice.

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512 1.2.2 Quality control change management is the same as change management, but includes the
513 approval (but not preapproval) by the quality unit.
514 1.2.3 Quality control change management is in effect only during the course of a project and
515 before manufacturing of products for human use. Change control requires the preapproval
516 of the quality unit.
517 1.2.3.1 Project change management should be used to establish sufficient control over approved
518 designs and specifications (for example, issued for construction documents), field changes,
519 inspected systems and equipment, approved documents, and other configuration items once a
520 baseline has been established. Project change management should require approval by the
521 appropriate technical expert assigned to manage the system design, development and
522 installation.

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523 1.2.3.2 Quality control change management should be applied to changes to product and process
524 user requirements, changes to the final impact assessment (for example, the list of risk control
525 mechanisms), and changes to qualification documents. Quality control change management
526 should also be applied to all changes that occur during execution of the Qualification. Project
527 change management is sufficient to control all other changes up to the point of commercial
528 product manufacture.
529 1.2.3.3 Change control, also known as Formal QA Change Control or Regulatory Change
530 Control, is required to be implemented before commencement of clinical or commercial
531 product manufacture.
532 1.2.3.4 A change management procedure should be established that defines the items to be subject
533 to change management, the establishment point of a baseline for each of those items, change
initiation, review and approval procedures, and identification of those situations requiring
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534
535 change control, for example, notification of the Quality Unit.
536
537 1.2.4 Nonconformance--Nonconformance occurs when a product and process user requirement
538 cannot be met or a critical element cannot be adjusted to meet acceptance criteria.
539 Nonconformance must be documented and approved by the Quality Unit. In addition;
540 other groups may participate as needed to assess the impact of a given nonconformance.
541 Corrective actions should be defined, documented, and implemented and appropriate
542 testing performed to confirm the corrective action worked. Nonconformances that cannot
543 be corrected must be resolved through design, installation, operational changes, or other
544 provisions such as standard operating procedures (SOP) changes to compensate for the
545 non-conformance to ensure risks are adequately controlled.
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 X XXXX

546 V. TERMINOLOGY

547 (NOTE: THESE TERMS WILL BE FIRMED UP ONCE THE CONCEPTS OF THIS
548 DRAFT STANDARD ARE AGREED UPON)

549 1. change control, n--formal system by which qualified representatives of appropriate

550 disciplines review proposed or actual changes that might affect a validated status and

551 must be implemented before initial manufacture of regulated products for human use.

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552 2. change management (project), n--process by which appropriate representatives review

553 proposed or actual changes so that the impact of the change is determined and the change

554 is then tracked and managed where other groups are notified as appropriate and the

555 actions identified are carried out to effect the change.

556 Discussion--Change management is a good engineering practice.

557 3. Clean utilities, n--utilities that supply a raw material, ingredient, or solvent or provide
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558 environmental controls such that the system would be classified as “direct impact” as a

559 result of an assessed risk posed to product quality.

560 4. commissioning, n—well-planned, documented, and managed engineering approach to the

561 startup and turnover of facilities, systems, and equipment to the end user that results in a

562 safe and functional environment that meets established design requirements and

563 stakeholder expectations.

564 5. critical elements, n-components, features, or functions of facilities, equipment, or

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565 systems that serve as a product-quality risk control mechanism, that is, whose operation,

566 contact, data, control, alarm, or failure may pose an unacceptable risk to the quality,

567 purity, strength, effectiveness, or identity of the product.

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568 Discussion--These elements will undergo both commissioning and qualification to assure that

569 they were properly installed and operate as required.

570 6. departure from specification, n--any feature, component, function, and so forth that does

571 not meet a predefined engineering specification.

572 7. design qualification (DQ), n--documented verification, with quality unit review, that the

573 proposed design of the facilities, equipment, and systems has undergone an engineering

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574 review to verify the design incorporates all product and process user requirements,

575 identifies critical elements, and is suitable for the intended purpose.

576 8. design user requirements/design requirements, n--requirements set out in the user

577 requirements specification that dictate a particular design solution as opposed to product

578 and process user or general user requirements that are design independent.

9. design specification, n--specification that defines, in detail, the design of a system or

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580 system element from an engineering perspective.

581 10. direct impact system, n--system that contains one or more critical elements.

582 11. engineering design review, n--documented review of the design, at appropriate stage(s) in

583 the project, for conformance to requirements, operational expectations, and regulatory

584 expectations.

585 12. facility (manufacturing facility), n--defined building structure or area within a building
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586 that contains manufacturing equipment or operations or both subject to good

587 manufacturing practices.

588 13. general user requirements, n--statements of need that describe any requirements of the

589 facility, equipment, or system not related to product/process quality.

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590 14. good engineering practices (GEP), n--established engineering methods and standards that

591 are applied throughout the project life cycle to deliver appropriate, cost-effective

592 solutions.

593 Discussion--GEPs take industry practices, constructability, economics, regulatory

594 requirements, and safety into account.

595 15. good manufacturing practices (GMPs), n--requirements for quality systems and other

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596 facets of manufacturing that meet the expectations of one or more regulatory bodies.

597 16. hazard, n--potential source of harm.

598 17. impact assessment, n--process of evaluating the risk impact of the operating, controlling,

599 alarming, and failure conditions of a system or element on the quality of a product.

600 18. indirect impact system, n--system that does not include any critical elements, that is, a

system that is not expected to pose a risk to product quality but may support a direct
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601

602 impact system.

603 19. installation qualification, n--documented verification of adherence to installation or

604 fabrication specifications for those aspects of a facility, equipment, or system that have

605 been assessed to pose an unacceptable risk to product quality.

606 20. no impact system, n--system that will not have any impact, either directly or indirectly, on

607 the risk to product quality.

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608 21. nonconformance, n--failure to meet the acceptance criteria for a product and process user

609 requirement.

610 22. noncritical elements, n--components, features, or functions that, if not per engineering

611 specification, would nonetheless not pose an unacceptable risk to product quality.

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612 23. operational qualification (OQ), n--documented verification of adherence to functional or

613 operational specifications for those aspects of a facility, equipment, or system that have

614 been assessed to pose an unacceptable risk to product quality.

615 24. performance qualification (PQ), n--documented verification of adherence to performance

616 specifications for those aspects of a facility, equipment, or system that have been

617 assessed to pose an unacceptable risk to product quality.

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618 25. product and process user requirements, n--requirements relating to the product or

619 associated manufacturing process or both that should be achieved to manufacture reliably

620 a product meeting quality specifications.

621 26. process validation, n--establishing documented evidence that provides a high degree of

622 assurance that a specific process will consistently produce a product meeting its

predetermined specifications and quality attributes.

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623

624 27. qualification (DQ/IQ/OQ/PQ), n--action of proving and documenting that those aspects

625 of facilities, equipment, or systems that affect product or process quality or both are

626 properly designed, fabricated, installed, work, and perform as specified.

627 28. quality control change management, n--similar to change management (project), but

628 includes the notification and approval (but not preapproval) of the quality unit.

629 Discussion--Quality control change management is only applicable before the initial
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630 manufacture of regulated products for human use.

631 29. risk, n--combination of the probability of an event and the severity of its consequences

632 where there is at least the possibility of negative consequences.

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 X XXXX

633 Discussion--Risk may also arise from the possibility of deviation from the expected outcome

634 or event.

635 30. risk assessment , n--process whereby the hazards inherent in the process are identified in terms

636 of the risk they pose to product quality.

637 31. risk control mechanism, n--in cases in which an unacceptable risk to the product is

638 assessed, risk control mechanisms are identified to mitigate the risk and risk control

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639 mechanisms may be an engineered system, a piece of equipment, a particular component

640 in a system, an automated function, a feature of a piece of equipment, an SOP, and so

641 forth.

642 Discussion--These risk control mechanisms are then built into the design and become the

643 focus of qualification efforts.

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