Guidance for Industry 

Process Validation: General 

Principles and Practices 

DRAFT GUIDANCE
 

This guidance document is being distributed for comment purposes only. 

Comments and suggestions regarding this draft document should be submitted within 60 days of 

publication in the Federal Register of the notice announcing the availability of the draft 

guidance. Submit comments to the Division of Dockets Management (HFA-305), Food and 

Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. All comments 

should be identified with the docket number listed in the notice of availability that publishes in 

the Federal Register. 

For questions regarding this draft document contact Brian Hasselbalch or Grace McNally 

(CDER) 301-796-3286 or 301-796-3279, Christopher Joneckis (CBER) 301-827-0373, or 

Dennis Bensley (CVM) 301-827-6956. 

U.S. Department of Health and Human Services 

Food and Drug Administration 

Center for Drug Evaluation and Research (CDER) 

Center for Biologics Evaluation and Research (CBER) 

Center for Veterinary Medicine (CVM) 

November 2008 

Current Good Manufacturing Practices (CGMP)
 
 

 

 

 

 

Guidance for Industry 

Process Validation: General 

Principles and Practices 

Additional copies are available from: 

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Division of Drug Information, HFD-240 

Center for Drug Evaluation and Research 

Food and Drug Administration 

10903 New Hampshire Avenue 

Building 51, Room 2201 

Silver Spring, MD 20993-0002 

(Tel) 301-796-3400 

http://www.fda.gov/cder/guidance/index.htm 

and/or

 Office of Communication, Training and 

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Center for Biologics Evaluation and Research 

Food and Drug Administration 

1401 Rockville Pike 

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 (Tel) 800-835-4709 or 301-827-1800 

http://www.fda.gov/cber/guidelines.htm 

and/or 

Communications Staff, HFV-12 

Center for Veterinary Medicine 

Food and Drug Administration 

7519 Standish Place, 

Rockville, MD 20855 

(Tel) 240-276-9300 

http://www.fda.gov/cvm/guidance/published.htm 

U.S. Department of Health and Human Services 

Food and Drug Administration 

Center for Drug Evaluation and Research (CDER) 

Center for Biologics Evaluation and Research (CBER) 

Center for Veterinary Medicine (CVM) 

November 2008 

Current Good Manufacturing Practices (CGMP) 
Contains Nonbinding Recommendations 

Draft — Not for Implementation 

TABLE OF CONTENTS 

I.	 INTRODUCTION............................................................................................................. 1
 

II.	 BACKGROUND ............................................................................................................... 2
 

III.	 STATUTORY AND REGULATORY REQUIREMENTS FOR PROCESS 

VALIDATION................................................................................................................... 4
 

IV.	 RECOMMENDATIONS.................................................................................................. 6
 

A. General Considerations for Process Validation ..........................................................................6
 

B. Specific Stages and Activities of Process Validation in the Product Lifecycle .........................6
 

1. Stage 1 – Process Design.................................................................................................................7
 

2. Stage 2 – Process Qualification.......................................................................................................9
 

3. Stage 3 – Continued Process Verification .....................................................................................13
 

V.	 CONCURRENT RELEASE OF PERFORMANCE QUALIFICATION BATCHES
 

........................................................................................................................................... 14
 

VI.	 DOCUMENTATION...................................................................................................... 15
 

VII.	 ANALYTICAL METHODOLOGY.............................................................................. 16
 
 

 

 

 

 

 

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1 Guidance for Industry1
 

2 

3 Process Validation: General Principles and Practices 

4 

5 

6 This draft guidance, when finalized, will represent the Food and Drug Administration's (FDA's) current 

7 thinking on this topic. It does not create or confer any rights for or on any person and does not operate to 

8 bind FDA or the public. You can use an alternative approach if the approach satisfies the requirements of 

9 the applicable statutes and regulations. If you want to discuss an alternative approach, contact the FDA 

10 staff responsible for implementing this guidance. If you cannot identify the appropriate FDA staff, call 

11 the appropriate number listed on the title page of this guidance. 

12 

13 

14 

15 

16 

17 

18 I. INTRODUCTION 

19 

20 This guidance outlines the general principles and approaches that FDA considers to be 

21 appropriate elements of process validation for the manufacture of human and animal drug and 

22 biological products, including active pharmaceutical ingredients (API or drug substance), 

23 collectively referred to in this guidance as drugs or products. This guidance incorporates 

24 principles and approaches that all manufacturers can use in validating a manufacturing process. 

25 

26 This guidance aligns process validation activities with the product lifecycle concept and with 

27 existing FDA guidance.2

 The lifecycle concept links product and process development, 

28 qualification of the commercial manufacturing process, and maintenance of the process in a state 

29 of control during routine commercial production. This guidance promotes modern 

30 manufacturing principles, process improvement, innovation, and sound science. 

31 

1 This guidance has been prepared by the Division of Manufacturing and Product Quality, Center for Drug 

Evaluation and Research (CDER), in cooperation with the Center for Biologics Evaluation and Research (CBER) 

and the Center for Veterinary Medicine (CVM) at the Food and Drug Administration. FDA’s Office of Regulatory 

Affairs (ORA) also contributed significantly to the development of this guidance. 

2 See the FDA/International Conference on Harmonisation (ICH) guidances for industry: Q8 Pharmaceutical 

Development, Q9 Quality Risk Management, and when finalized, Q10 Pharmaceutical Quality System (a notice of 

availability for the May 2007 ICH draft guidance, Q10 Pharmaceutical Quality System, published in the Federal 

Register on July 13, 2007 (72 FR 38604)). We update guidance documents periodically. To make sure you have the 

most recent version of a guidance, check the CDER guidance page at http://www.fda.gov/cder/guidance/index.htm, 

the CBER guidance page at http://www.fda.gov/cber/guidelines.htm, or the CVM guidance page at 

http://www.fda.gov/cvm/Guidance/published.htm. 
 

 

 

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32 The following categories of drugs are within the scope of this guidance: 

33 

34 • Human drugs 

35 • Veterinary drugs 

36 • Biological and biotechnology products 

37 • Finished products and active pharmaceutical ingredients (API or drug substance)3 

38 • The drug constituent of a combination (drug and medical device) product 

39 

40 The following categories of products are not covered by this guidance: 

41 

42 • Type A medicated articles and medicated feed 

43 • Medical devices 

44 • Dietary supplements 

45 • Human tissues intended for transplantation regulated under section 361 of the Public Health 

46 Service Act4 

47 

48 This guidance does not specify what information should be included as part of a regulatory submission. 

49 Interested persons can refer to the appropriate guidance or contact the appropriate Center in determining 

50 what information should be included in a submission. 

51 

52 This guidance also does not specifically discuss the validation of automated process control systems 

53 (i.e., computer hardware and software interfaces), which are commonly integrated into modern drug 

54 manufacturing equipment. This guidance is relevant, however, to the validation of processes that 

55 include automated equipment in processing. 

56 

57 FDA's guidance documents, including this guidance, do not establish legally enforceable 

58 responsibilities. Instead, guidances describe the Agency's current thinking on a topic and should 

59 be viewed only as recommendations, unless specific regulatory or statutory requirements are 

60 cited. The use of the word should in Agency guidances means that something is suggested or 

61 recommended, but not required. 

62 

63 II. BACKGROUND 

64 

65 In the Federal Register of May 11, 1987 (52 FR 17638), FDA issued a notice announcing the 

66 availability of a guidance entitled Guideline on General Principles of Process Validation (the 

3

 Separate current good manufacturing practice (CGMP) regulations for drug components such as APIs (drug 

substances) and intermediates have not published as of the date of this guidance, but these components are subject to 

the statutory CGMP requirements of section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (the Act) 

(21 U.S.C. 351(a)(2)(B)). Process validation for APIs is discussed in the FDA/ICH guidance for industry, Q7A 

Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients (ICH Q7A), available on the 

Internet at http://www.fda.gov/cder/guidance/index.htm. Section XII of ICH Q7A describes in detail the principles 

to be followed in validating API processes. 

4

 See the FDA guidance for industry, Validation of Procedures for Processing of Human Tissues Intended for 

Transplantation, available on the Internet at http://www.fda.gov/cber/guidelines.htm. 
 

 

 

 

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67 1987 guidance).5 Since then, we have obtained additional experience through our regulatory 

68 oversight that allows us to update our recommendations to industry on this topic. This revised 

69 guidance conveys FDA’s current thinking on process validation and is consistent with basic 

70 principles first introduced in the 1987 guidance. This guidance also provides recommendations 

71 that reflect some of the goals of FDA’s initiative entitled “Pharmaceutical CGMPs for the 21st 

72 Century – A Risk-Based Approach,” particularly with regard to the use of technological 

73 advances in pharmaceutical manufacturing, as well as implementation of modern risk 

74 management and quality system tools and concepts. When finalized, this guidance will replace 

75 the 1987 guidance. 

76 

77 FDA has the authority and responsibility to inspect and evaluate process validation performed by 

78 manufacturers. The CGMP regulations for validating pharmaceutical (drug) manufacturing 

79 require that drug products be produced with a high degree of assurance of meeting all the 

80 attributes they are intended to possess (21 CFR 211.100(a) and 211.110(a)). Effective process 

81 validation contributes significantly to assuring drug quality. The basic principle of quality 

82 assurance is that a drug should be produced that is fit for its intended use; this principle 

83 incorporates the understanding that the following conditions exist: 

84 

85 • Quality, safety, and efficacy are designed or built into the product. 

86 

87 • Quality cannot be adequately assured merely by in-process and finished-product 

88 inspection or testing. 

89 

90 • Each step of a manufacturing process is controlled to assure that the finished product 

91 meets all design characteristics and quality attributes including specifications. 

92 

93 For purposes of this guidance, process validation is defined as the collection and evaluation of 

94 data, from the process design stage throughout production, which establishes scientific 

95 evidence that a process is capable of consistently delivering quality products. Process 

96 validation involves a series of activities taking place over the lifecycle of the product and 

97 process. This guidance describes the process validation activities in three stages. 

98 

99 • Stage 1 – Process Design: The commercial process is defined during this stage based on 

100 knowledge gained through development and scale-up activities. 

101 

102 • Stage 2 – Process Qualification: During this stage, the process design is confirmed as 

103 being capable of reproducible commercial manufacturing. 

104 

105 • Stage 3 – Continued Process Verification: Ongoing assurance is gained during routine 

106 production that the process remains in a state of control. 

5 The 1987 guidance was prepared by a working group that included representation from the Center for Devices and 

Radiological Health (CDRH). Since that time, CDRH elected to publish its own process validation guidance 

through the Global Harmonization Task Force. The principles and recommendations in that document, Quality 

Management Systems – Process Validation, edition 2 (available on the Internet at http://www.ghtf.org/sg3/sg3-

final.html), are also useful to consider for drug manufacturing processes. 
 

 

 

 

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107 

108 This guidance describes activities typical in each stage, but in practice, some activities in 

109 different stages might overlap. 

110 

111 Before any batch from the process is commercially distributed for use by consumers, a 

112 manufacturer should have gained a high degree of assurance in the performance of the 

113 manufacturing process such that it will consistently produce APIs and drug products meeting 

114 those attributes relating to identity, strength, quality, purity, and potency. The assurance should 

115 be obtained from objective information and data from laboratory-, pilot-, and/or commercial116 scale studies. Information and data should demonstrate that the commercial manufacturing 

117 process is capable of consistently producing acceptable quality products within commercial 

118 manufacturing conditions, including those conditions that pose a high risk of process failure. 

119 

120 A successful validation program depends upon information and knowledge from product and 

121 process development. This knowledge and understanding is the basis for establishing an 

122 approach to control that is appropriate for the manufacturing process. Manufacturers should: 

123 

124 • understand the sources of variation 

125 • detect the presence and degree of variation 

126 • understand the impact of variation on the process and ultimately on product attributes 

127 • control the variation in a manner commensurate with the risk it represents to the process 

128 and product 

129 

130 Each manufacturer should judge whether it has gained sufficient understanding to provide a high 

131 degree of assurance in its manufacturing process to justify commercial distribution of the 

132 product. Focusing on qualification efforts without understanding the manufacturing process may 

133 not lead to adequate assurance of quality. After establishing and confirming the process, 

134 manufacturers must maintain the process in a state of control over the life of the process, even as 

135 materials, equipment, production environment, personnel, and manufacturing procedures 

136 change.6 

137 

138 III. STATUTORY AND REGULATORY REQUIREMENTS FOR PROCESS 

139 VALIDATION 

140 

141 Process validation for drugs (finished pharmaceuticals and components) is a legally enforceable 

142 requirement under section 501(a)(2)(B) of the Act, which states the following: 

143 

144 A drug . . . shall be deemed to be adulterated . . . if . . . the methods used in, or the 

145 facilities or controls used for, its manufacture, processing, packing, or holding do not 

146 conform to or are not operated or administered in conformity with current good 

147 manufacturing practice to assure that such drug meets the requirements of this Act as to 

6

 The statute and regulations described in section III of this guidance explain the requirement that the methods and 

facilities used for the manufacturing of drugs be operated and maintained under control sufficient to assure that the 

identity, strength, purity, and quality of a drug are as they purport or are represented to possess. 
 

Contains Nonbinding Recommendations 

Draft — Not for Implementation 

148 safety and has the identity and strength, and meets the quality and purity characteristics, 

149 which it purports or is represented to possess. 

150 

151 FDA regulations describing current good manufacturing practice (CGMP) are provided in 21 

152 CFR parts 210 and 211. 

153 

154 Process validation is required, in both general and specific terms, by the CGMP regulations in 

155 parts 210 and 211. The foundation for process validation is provided in § 211.100(a), which 

156 states that "[t]here shall be written procedures for production and process control designed to 

157 assure that the drug products have the identity, strength, quality, and purity they purport or are 

158 represented to possess" (emphasis added). This regulation requires that manufacturers design a 

159 process including operations and controls that will result in a product meeting these attributes. 

160 Product quality in the context of process validation means that product performance is consistent 

161 from batch-to-batch and unit-to-unit. Many products are single-source or involve complicated 

162 processes to manufacture. Validation also offers assurance that a process is reasonably 

163 safeguarded from sources of variability affecting production output, the loss of which can cause 

164 supply problems, thereby negatively affecting public health. 

165 

166 Other CGMP regulations define the various aspects of validation. Section 211.110(a), Sampling 

167 and testing of in-process materials and drug products, requires that control procedures “. . . be 

168 established to monitor the output and to validate the performance of those manufacturing 

169 processes that may be responsible for causing variability in the characteristics of in-process 

170 material and the drug product" (emphasis added). This regulation establishes the requirement 

171 that even well-designed processes must include in-process control procedures to assure final 

172 product quality. 

173 

174 CGMP regulations require that batch samples represent the batch under analysis (see, e.g., § 

175 211.160(b)(3)) and that the sampling plan result in statistical confidence (§ 211.165(c) and (d)) 

176 that the batch meets its predetermined specifications (§ 211.165(a)). Section 211.110(b) 

177 provides two principles to follow when establishing in-process specifications. The first principle 

178 is that “. . . in-process specifications for such characteristics [of in-process material and the drug 

179 product] shall be consistent with drug product final specifications . . . .” Accordingly, in-process 

180 material should be controlled to assure that the final drug product will meet its quality 

181 requirements. The second principle in this regulation further requires that in-process 

182 specifications “. . . shall be derived from previous acceptable process average and process 

183 variability estimates where possible and determined by the application of suitable statistical 

184 procedures where appropriate.” This requirement, in part, establishes the need for manufacturers 

185 to analyze process performance and control batch-to-batch variability.7 

186 

7

 In the Federal Register of September 29, 1978 (43 FR 45013 at 45052), FDA published a final rule on “Current 

Good Manufacturing Practice in Manufacture, Processing, Packing, or Holding” (available on the Internet at 

http://www.fda.gov/cder/dmpq/preamble.txt). In the preamble of the final rule, the Agency further explains this 

principle. 
 

 

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187 The CGMP regulations also describe and define activities connected with process design, 

188 development, and maintenance. Section 211.180(e) requires that information and data about 

189 product performance and manufacturing experience be periodically reviewed to determine 

190 whether any changes to the established process are warranted. Ongoing feedback about product 

191 performance is an essential feature of process maintenance. 

192 

193 In addition, the CGMP regulations require that facilities in which drugs are manufactured be of 

194 suitable size, construction, and location to facilitate proper operations (21 CFR 211.42). 

195 Equipment must be of appropriate design, adequate size, and suitably located to facilitate 

196 operations for its intended use (21 CFR 211.63). Automated, mechanical, and electronic 

197 equipment must be calibrated, inspected, or checked according to a written program designed to 

198 assure proper performance (21 CFR 211.68). 

199 

200 In summary, the CGMP regulations require that manufacturing processes be designed and 

201 controlled to assure that in-process materials and the finished product meet predetermined 

202 quality requirements and do so consistently and reliably. 

203 

204 IV. RECOMMENDATIONS 

205 

206 A. General Considerations for Process Validation 

207 

208 In all stages of the product lifecycle, good project management and good archiving that capture 

209 scientific knowledge will make the process validation program more effective and efficient. 

210 These practices should ensure uniform collection and assessment of information about the 

211 process, reduce the chance for redundant information gathering and analysis, and enhance the 

212 accessibility of such information later in the product lifecycle. 

213 

214 We recommend an integrated8

 team approach to process validation that includes expertise from a 

215 variety of disciplines, including process engineering, industrial pharmacy, analytical chemistry, 

216 microbiology, statistics, manufacturing, and quality assurance. Project plans, along with the full 

217 support of senior management, are essential elements for success. 

218 

219 Throughout the product lifecycle, various studies can be initiated to discover, observe, correlate, 

220 or confirm information about the product and process. All studies should be planned and 

221 conducted according to sound scientific principles, appropriately documented, and should be 

222 approved in accordance with the established procedure appropriate for the stage of the lifecycle. 

223 

224 B. Specific Stages and Activities of Process Validation in the Product Lifecycle 

225 

226 The following subsections describe the recommended stages and specific activities. 

227 

8

 This concept is discussed in more detail in FDA’s guidance for industry, Quality Systems Approach to 

Pharmaceutical Current Good Manufacturing Practice Regulations, available on the Internet at 

http://www.fda.gov/cder/guidance/index.htm. 
 

 

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228 1. Stage 1 – Process Design 

229 

230 a. Building and Capturing Process Knowledge and Understanding 

231 

232 Process design is the activity of defining the commercial manufacturing process that will 

233 be reflected in the master production and control records. The goal of this stage is to 

234 design a process suitable for routine commercial manufacturing that can consistently 

235 deliver a product that meets its critical quality attributes. 

236 

237 Generally, early process design experiments do not need to be performed under CGMP 

238 conditions. They should, however, be conducted in accordance with sound scientific 

239 methods and principles, including good documentation practices. This recommendation 

240 is consistent with ICH guidance for industry, Q10 Pharmaceutical Quality System.

9 

241 Decisions and justification of the controls should be sufficiently documented and 

242 internally reviewed to verify and preserve their value for use later in the lifecycle of the 

243 process and product. 

244 

245 There are exceptions, however. For example, viral and impurity clearance studies have a 

246 direct impact on drug safety and should be performed under CGMP conditions, even 

247 when performed at small scale. The quality unit should be involved with these studies as 

248 is typical during commercial production. 

249 

250 Product-development activities provide key inputs to the design stage, such as the 

251 intended dosage form, the quality attributes, and a general manufacturing pathway. 

252 Process information available from the product-development stage can be leveraged in 

253 the process-design stage. However, the full spectrum of input variability typical of 

254 commercial production is not generally known at this stage. The functionality and 

255 limitations of commercial manufacturing equipment should be considered, as well as the 

256 contributions of variability by different component lots, production operators, 

257 environmental conditions, and measurement systems in the production setting. 

258 Laboratory or pilot-scale models designed to be representative of the commercial process 

259 can be used to estimate variability. However, it is not a regulatory expectation that the 

260 process be developed and tested until it fails, but rather that a process be controlled 

261 within commercial manufacturing conditions, including those combinations of conditions 

262 posing a high risk of process failure. 

263 

264 Designing an efficient process with an effective process control approach is dependent on 

265 the process knowledge and understanding obtained. Design of Experiment (DOE) 

266 studies can help develop process knowledge by revealing relationships, including 

267 multifactorial interactions, between the variable inputs (e.g., component10 characteristics 

9

 A notice of availability for this draft ICH guidance published in the Federal Register on July 13, 2007 (72 FR 

38604). When finalized, this guidance will represent FDA’s current thinking on this topic. 

10 “Component means any ingredient [raw material] intended for use in the manufacture of a drug product, including 

those that may not appear in such drug product” (21 CFR 210.3(b)(3)). 
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268 or processing parameters) and the resulting outputs (e.g., in-process material, 

269 intermediates, or the final product). Risk analysis tools can be used to screen potential 

270 variables for DOE studies to minimize the total number of experiments conducted while 

271 maximizing knowledge gained. The results of DOE studies can provide justification for 

272 establishing ranges of incoming component quality, equipment parameters, and in273 process material quality attributes. 

274 

275 Other activities, such as experiments or demonstrations at laboratory or pilot scale, allow 

276 evaluation of certain conditions and prediction of performance of the commercial 

277 process. These activities also provide information that can be used to model or simulate 

278 the commercial process. Computer-based or virtual simulations of certain unit operations 

279 or dynamics can provide process understanding and avoid problems at commercial scale. 

280 It is important to understand the degree to which models represent the commercial 

281 process, including any differences that might exist, as this may have an impact on the 

282 relevance of information derived from the studies. 

283 

284 It is essential that activities and studies resulting in product understanding be 

285 documented. Documentation should reflect the basis for decisions made about the 

286 process. For example, manufacturers should document the variables studied for a unit 

287 operation and the rationale for those variables identified as significant. This information 

288 is useful during the process qualification and continued process verification stages, 

289 including when the design is revised or the strategy for control is refined or changed. 

290 

291 b. Establishing a Strategy for Process Control 

292 

293 Process knowledge and understanding is the basis for establishing an approach to process 

294 control for each unit operation and the process overall. Strategies for process control can 

295 be designed to reduce input variation, adjust for input variation during manufacturing 

296 (and so reduce its impact on the output), or combine both approaches. 

297 

298 Process controls address variability to assure quality of the product. Controls can consist 

299 of material analysis and equipment monitoring at significant processing points designed 

300 to assure that the operation remains on target and in control with respect to output quality. 

301 Special attention to control of the process through operational limits and in-process 

302 monitoring is essential (1) where the product attribute is not readily measurable due to 

303 limitations of sampling or detectability (e.g., viral clearance or microbial contamination), 

304 or (2) when intermediates and products cannot be highly characterized and well-defined 

305 quality attributes cannot be identified. These controls are included in the master 

306 production and control records (see 21 CFR 211.186(a) and (b)(9)). 

307 

308 More advanced strategies, such as process analytical technology (PAT), use timely 

309 analysis and control loops to adjust the processing conditions so that the output remains 

310 constant. Manufacturing systems of this type can provide a higher degree of process 

311 control. In the case of PAT strategy, the approach to process qualification will be 

312 different from that for other process designs. Further information on PAT processes can 
 

 

 

 

 

 

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313 be found in FDA’s guidance for industry on PAT – A Framework for Innovative 

314 Pharmaceutical Development, Manufacturing, and Quality Assurance (available on the 

315 Internet at http://www.fda.gov/cder/guidance/index.htm). 

316 

317 The planned commercial production and control records, which contain the operational 

318 limits and overall strategy for process control, should be carried forward to the next stage 

319 for confirmation. 

320 

321 2. Stage 2 – Process Qualification 

322 

323 During the process qualification stage of process validation, the process design is 

324 confirmed as being capable of reproducible commercial manufacture. This stage has two 

325 elements: (1) design of the facility and qualification of the equipment and utilities, and 

326 (2) performance qualification (PQ). During this stage, CGMP-compliant procedures 

327 must be followed and successful completion of this stage is necessary before commercial 

328 distribution.11 Products manufactured during this stage, if acceptable, can be released. 

329 

330 a. Design of a Facility and Qualification of Utilities and Equipment 

331 

332 Proper design of a manufacturing facility is required under 21 CFR part 211, subpart C, 

333 of the CGMP regulations on Buildings and Facilities. It is essential that activities 

334 performed to assure proper facility design and commissioning precede PQ. Activities 

335 undertaken to demonstrate that utilities and pieces of equipment are suitable for their 

336 intended use and perform properly is referred to in this guidance as qualification. These 

337 activities necessarily precede manufacturing products at the commercial scale. 

338 

339 Qualification of utilities and equipment generally includes the following activities: 

340 

341 • Selecting utilities and equipment construction materials, operating principles, and 

342 performance characteristics based on whether they are appropriate for their specific 

343 use. 

344 

345 • Verifying that utility systems and equipment are built and installed in compliance 

346 with the design specifications (e.g., built as designed with proper materials, capacity, 

347 and functions, and properly connected and calibrated). 

348 

349 • Verifying that the utility system and equipment operate in accordance with the 

350 process requirements in all anticipated operating ranges. This should include 

351 challenging the equipment or system functions while under load comparable to that 

352 expected during routine production. It should also include the performance of 

353 interventions, stoppage, and start-up as is expected during routine production. 

11 As discussed in section III of this guidance, process validation (including process qualification) is legally 

enforceable under section 501(a)(2)(B) of the Act. FDA regulations require that process validation procedures be 

established and followed (21 CFR 211.100) before a batch can be distributed (21 CFR 211.22 and 211.165). 
 

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354 Operating ranges should be shown capable of being held as long as would be 

355 necessary during routine production. 

356 

357 Qualification of utilities and equipment can be covered under individual plans or as part 

358 of an overall project plan. The plan should consider the requirements of use and can 

359 incorporate risk management to prioritize certain activities and to identify a level of effort 

360 in both the performance and documentation of qualification activities. The plan should 

361 identify (1) the studies or tests to use, (2) the criteria appropriate to assess outcomes, (3) 

362 the timing of qualification activities, (4) responsibilities, and (5) the procedures for 

363 documenting and approving the qualification. It should also include the firm’s 

364 requirements for the evaluation of changes. Qualification activities should be 

365 documented and summarized in a report with conclusions that address criteria in the plan. 

366 The quality control unit must review and approve the qualification plan and report (21 

367 CFR 211.22). 

368 

369 b. Performance Qualification Approach 

370 

371 The PQ is the second element of stage 2, process qualification. The PQ combines the 

372 actual facility, utilities, equipment (each now qualified), and the trained personnel with 

373 the commercial manufacturing process, control procedures, and components to produce 

374 commercial batches. A successful PQ will confirm the process design and demonstrate 

375 that the commercial manufacturing process performs as expected. 

376 

377 Success at this stage signals an important milestone in the product lifecycle and needs to 

378 be completed before a manufacturer commences commercial distribution of the drug 

379 product.12 The decision to begin commercial distribution should be supported by data 

380 from commercial batches. Data from laboratory and pilot studies can provide additional 

381 assurance. 

382 

383 The approach to PQ should be based on sound science and the manufacturer’s overall 

384 level of product and process understanding. The cumulative data from all relevant 

385 studies (e.g., designed experiments; laboratory, pilot, and commercial batches) should be 

386 used to establish the manufacturing conditions in the PQ. For example, to have sufficient 

387 understanding of the commercial process, the manufacturer will need to consider the 

388 effects of scale; however, it is not typically necessary to explore the entire operating 

389 range at commercial scale if assurance can be provided by other data. Previous credible 

390 experience with sufficiently similar products and processes can also be considered. In 

391 addition, we strongly recommend firms employ objective measures (e.g., statistical 

392 metrics), wherever feasible and meaningful to achieve adequate assurance. 

393 

394 In most cases, PQ will have a higher level of sampling, additional testing, and greater 

395 scrutiny of process performance. The level of monitoring and testing should be sufficient 

396 to confirm uniform product quality throughout the batch during processing. This greater 

12 See section III of this guidance, Statutory and Regulatory Requirements for Process Validation. 
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397 scrutiny accompanied by a higher level of sampling should continue through the process 

398 verification stage, as appropriate. 

399 

400 The extent to which some materials, such as column resins or molecular filtration media, 

401 can be re-used without adversely affecting product quality can be assessed in relevant 

402 laboratory studies, and their usable lifetime should be confirmed by an ongoing PQ 

403 protocol during commercial manufacture. 

404 

405 A manufacturing process that uses PAT may warrant a different PQ approach. Such a 

406 process is one that is designed to measure in real time the attributes of an in-process 

407 material and then adjust the process in a timely control loop so the process maintains the 

408 desired quality of the output material. The process design stage and the process 

409 qualification stage should have as a focus the measurement system and control loop. 

410 Regardless, the goal remains the same: establishing scientific evidence that the process is 

411 reproducible and will consistently deliver quality products. 

412 

413 c. Performance Qualification Protocol 

414 

415 A written protocol that specifies the manufacturing conditions, controls, testing, and 

416 expected outcomes is essential for this stage of process validation. We recommend that 

417 the protocol discuss: 

418 

419 • The manufacturing conditions including operating parameters, processing limits, and 

420 component (raw material) inputs. 

421 

422 • The data to be collected and when and how it will be evaluated. 

423 

424 • Tests to be performed (in-process, release, characterization) and acceptance criteria 

425 for each significant processing step. 

426 

427 • The sampling plan including sampling points, number of samples, and the frequency 

428 of sampling for each unit operation and attribute. The number of samples should be 

429 adequate to provide sufficient statistical confidence of quality both within a batch and 

430 between batches. The confidence level selected can be based on risk analysis as it 

431 relates to the particular attribute under examination. Sampling during this stage 

432 should be more extensive than is typical during routine production. 

433 

434 • Criteria that provide for a rational conclusion of whether the process consistently 

435 produces quality products. The criteria should include: 

436 

437 o A description of the statistical methods to be used in analyzing all collected 

438 data (e.g., statistical metrics defining both intra-batch and inter-batch 

439 variability). 

440 
 

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441 o Provision for addressing deviations from expected conditions and handling of 

442 nonconforming data. Data should not be excluded from further consideration 

443 in terms of PQ without a documented, science-based justification. 

444 

445 • Design of facilities and the qualification of utilities and equipment, personnel training 

446 and qualification, and verification of material sources (components and 

447 container/closures), if not previously accomplished. 

448 

449 • Status of the validation of analytical methods used in measuring the process, in450 process materials, and the product. 

451 

452 • Review and approval by appropriate departments and the quality unit. 

453 

454 d. Protocol Execution and Report 

455 

456 Protocol execution should not begin until the protocol has been reviewed and approved 

457 by all appropriate departments, including the quality unit. Departure from the established 

458 protocol must be made according to established procedure or provisions in the protocol. 

459 Such departures must be justified and approved by all appropriate departments and the 

460 quality unit before implementation (§ 211.100). 

461 

462 The commercial manufacturing process and routine procedures must be followed (§§ 

463 211.100(b) and 211.110(a)). The PQ lots should be manufactured under normal 

464 conditions by personnel expected to routinely perform each step of each unit operation in 

465 the process. Normal operating conditions should cover the utility systems (e.g., air 

466 handling and water purification), material, personnel, environment, and manufacturing 

467 procedures. 

468 

469 A report documenting and assessing adherence to the written protocol should be prepared 

470 in a timely manner after the completion of the protocol. This report should: 

471 

472 • Discuss and cross-reference all aspects of the protocol. 

473 

474 • Summarize data collected and analyze the data, as specified by the protocol. 

475 

476 • Evaluate any unexpected observations and additional data not specified in the 

477 protocol. 

478 

479 • Summarize and discuss all manufacturing nonconformances such as deviations, 

480 aberrant test results, or other information that has bearing on the validity of process. 

481 

482 • Describe in sufficient detail any corrective actions or changes that should be made to 

483 existing procedures and controls. 

484 
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485 • State a clear conclusion as to whether the data indicates the process met the 

486 conditions established in the protocol and whether the process is considered to be in a 

487 sufficient state of control. If not, the report should state what should be accomplished 

488 before such a conclusion can be reached. This conclusion should be based on a 

489 documented justification for the approval of the process, and release of lots produced 

490 by it to the market in consideration of the entire compilation of knowledge and 

491 information gained from the design stage through the process qualification stage. 

492 

493 • Include all appropriate department and quality unit review and approvals. 

494 

495 3. Stage 3 – Continued Process Verification 

496 

497 The goal of the third validation stage is to continually assure that the process remains in a 

498 state of control (the validated state) during commercial manufacture. A system or 

499 systems for detecting unplanned departures from the process as designed is essential to 

500 accomplish this goal. Adherence to the CGMP requirements, specifically including the 

501 collection and evaluation of information and data about the performance of the process 

502 (see below), will allow detection of process drift. The evaluation should determine 

503 whether action must be taken to prevent the process from drifting out of control (§ 

504 211.180(e)). 

505 

506 An ongoing program to collect and analyze product and process data that relate to 

507 product quality must be established (§ 211.180(e)). The data collected should include 

508 relevant process trends and quality of incoming materials or components, in-process 

509 material, and finished products. The data should be statistically trended and reviewed by 

510 trained personnel. The information collected should verify that the critical quality 

511 attributes are being controlled throughout the process. 

512 

513 We recommend that a statistician or person with adequate training in statistical process 

514 control techniques develop the data collection plan and statistical methods and 

515 procedures used in measuring and evaluating process stability and process capability. 

516 Procedures should describe how trending and calculations are to be performed. 

517 Procedures should guard against overreaction to individual events as well as against 

518 failure to detect process drift. Production data should be collected to evaluate process 

519 stability and capability. The quality unit should review this information. If done 

520 properly, these efforts can identify variability in the process and/or product; this 

521 information can be used to alert the manufacturer that the process should be improved. 

522 

523 Good process design and development should anticipate significant sources of variability 

524 and establish appropriate detection, control, and/or mitigation strategies, as well as 

525 appropriate alert and action limits. However, a process is likely to encounter sources of 

526 variation that were not previously detected or to which the process was not previously 

527 exposed. Many tools and techniques, some statistical and others more qualitative, can be 

528 used to detect variation, characterize it, and determine the root cause. We recommend 

529 that the manufacturer use quantitative, statistical methods whenever feasible. We also 
 

 

 

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530 recommend that it scrutinize intra-batch as well as inter-batch variation as part of a 

531 comprehensive continued process verification program. 

532 

533 We recommend continued monitoring and/or sampling at the level established during the 

534 process qualification stage until sufficient data is available to generate significant 

535 variability estimates. Once the variability is known, sampling and/or monitoring should 

536 be adjusted to a statistically appropriate and representative level. Process variability 

537 should be periodically assessed and sampling and/or monitoring adjusted accordingly. 

538 

539 Variation can also be detected by the timely assessment of defect complaints, out-of540 specification findings, process deviation reports, process yield variations, batch records, 

541 incoming raw material records, and adverse event reports. Production line operators and 

542 quality unit staff should be encouraged to provide feedback on process performance. 

543 Operator errors should also be tracked to measure the quality of the training program; to 

544 identify operator performance issues; and to look for potential batch record, procedural, 

545 and/or process improvements that could help to reduce operator error. We recommend 

546 that the quality unit meet periodically with production staff to evaluate data, discuss 

547 possible trends or drifts in the process, and coordinate any correction or follow-up actions 

548 by production. 

549 

550 Data gathered during this stage might suggest ways to improve and/or optimize the 

551 process by altering some aspect of the process or product such as the operating conditions 

552 (ranges and set-points), process controls, component, or in-process material 

553 characteristics. A description of the planned change, a well-justified rationale for the 

554 change, an implementation plan, and quality unit approval before implementation must 

555 be documented (21 CFR 211.100). Depending on the significance to product quality, 

556 modifications may warrant performing additional process design and process 

557 qualification activities.13 

558 

559 Maintenance of the facility, utilities, and equipment is another important aspect of 

560 ensuring that a process remains in control. Once established, qualification status must be 

561 maintained through routine monitoring, maintenance, and calibration procedures and 

562 schedules (21 CFR part 211, subparts C and D). The data should be assessed periodically 

563 to determine whether re-qualification should be performed and the extent of that re564 qualification. Maintenance and calibration frequency should be adjusted based on 

565 feedback from these activities. 

566 

567 V. CONCURRENT RELEASE OF PERFORMANCE QUALIFICATION BATCHES 

568 

569 In most cases, the PQ protocol needs to be completed before the commercial distribution of a 

570 product. In special situations, the PQ protocol can be designed to release a PQ batch for 

13 Certain manufacturing changes may call for a formal notification to the Agency before implementation, as 

directed by existing regulations and filing guidance (i.e., documents that describe procedures for filing information 

to an application). 
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571 distribution before completion of the protocol. The conclusions about the manufacturing 

572 process should be made when the protocol is completed and the data is fully evaluated. 

573 

574 FDA expects that concurrent release will be used rarely. Concurrent release might be 

575 appropriate for processes used infrequently because of limited demand for the product (e.g., 

576 orphan drugs), processes with necessarily low production volume per batch (e.g., 

577 radiopharmaceuticals, including positron emission tomography drugs), and processes 

578 manufacturing medically necessary drugs to alleviate a short supply, which should be 

579 coordinated with the Agency. 

580 

581 When warranted and used, concurrent release should be accompanied by a system for careful 

582 oversight of the distributed batch to facilitate rapid customer feedback. For example, customer 

583 complaints and defect reports should be rapidly assessed to determine root cause and whether the 

584 process should be improved or changed. We recommend that each batch in a concurrent release 

585 program also undergo stability testing and that this test data be promptly evaluated to ensure 

586 rapid detection and correction of any problems. 

587 

588 VI. DOCUMENTATION 

589 

590 Documentation at each stage of the process validation lifecycle is essential for effective 

591 communication in complex, lengthy, and multidisciplinary projects. Documentation is important 

592 so that knowledge gained about a product and process is accessible and comprehensible to others 

593 involved in each stage of the lifecycle. In addition to being a fundamental tenet of following the 

594 scientific method, information transparency and accessibility are essential so that organizational 

595 units responsible and accountable for the process can make informed, science-based decisions 

596 that ultimately support the release of a product to commerce. 

597 

598 The degree and type of documentation required by CGMP is greatest during stage 2, process 

599 qualification, and stage 3, continued process verification. Studies during these stages must 

600 conform to CGMPs and must be approved by the quality unit in accordance with the regulations 

601 (see 21 CFR 211.22 and 211.100). Viral and impurity clearance studies, even when performed at 

602 small scale, also require full quality unit oversight as is necessary during routine commercial 

603 production. 

604 

605 CGMP documents for commercial manufacturing (i.e., the initial commercial master batch 

606 production and control record (21 CFR 211.186) and supporting procedures) are key outputs of 

607 stage 1, process design. We recommend that firms diagram the process flow for the full-scale 

608 process. Process flow diagrams should describe each unit operation, its placement in the overall 

609 process, monitoring and control points, and the component, as well as other processing material 

610 inputs (e.g., processing aids) and expected outputs (i.e., in-process materials and finished 

611 product). It is also useful to generate and preserve process flow diagrams of the various scales as 

612 the process design progresses to facilitate comparison and decision making about their 

613 comparability. 

614 
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615 VII. ANALYTICAL METHODOLOGY 

616 

617 Process knowledge is dependent on accurate and precise measuring techniques that are used to 

618 test and examine the quality of drug components, in-process materials, and finished products. 

619 For data to have value in predicting process outcomes, it is essential that the analytical tests be 

620 scientifically sound (as required under 21 CFR 211.160). While validated analytical methods are 

621 not required during product- and process-development activities, methods should be 

622 scientifically sound (e.g., specific, sensitive, and accurate), suitable, and reliable for the specified 

623 purpose. There should be assurance of proper equipment function for laboratory experiments. 

624 Procedures for analytical method and equipment maintenance, documentation practices, and 

625 calibration practices supporting process-development efforts should be documented or described. 

626 Analytical methods supporting clinical supply production, particularly stage 2 and 3 studies, 

627 must follow appropriate CGMPs in parts 210 and 211. 
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628 REFERENCES 

629 

630 FDA, 1987 (CDER, CBER, and Center for Devices and Radiological Health (CDRH)), 

631 Guideline on General Principles of Process Validation, guidance for industry, May 1987. 

632 

633 FDA, 2002 (CBER), Validation of Procedures for Processing of Human Tissues Intended for 

634 Transplantation, guidance for industry, May 2002. 

635 

636 FDA, 2004 (CDER, CVM, and ORA), PAT — A Framework for Innovative Pharmaceutical 

637 Development, Manufacturing, and Quality Assurance, guidance for industry, September 

638 2004. 

639 

640 FDA, 2006 (CDER, CBER, CVM, and ORA), Quality Systems Approach to Pharmaceutical 

641 Current Good Manufacturing Practice Regulations, guidance for industry, September 

642 2006. 

643 

644 FDA/Global Harmonization Task Force (GHTF; medical devices), 2004, Quality Management 

645 Systems – Process Validation, edition 2, guidance, January 2004. 

646 

647 FDA/ICH, 2001 (CDER and CBER), Q7A Good Manufacturing Practice, Guidance for Active 

648 Pharmaceutical Ingredients, ICH guidance for industry, August 2001. 

649 

650 FDA/ICH, 2006 (CDER and CBER), Q8A Pharmaceutical Development, ICH guidance for 

651 industry, May 2006. 

652 

653 FDA/ICH, 2006 (CDER and CBER), Q9A Quality Risk Management, ICH guidance for industry, 

654 June 2006. 

655 

656 FDA/ICH (CDER and CBER) Q10 Quality Systems, ICH draft guidance for industry, May 2007 

657 (when finalized, this guidance will convey FDA’s current thinking on this topic).