Inspection of Injectable 
Products for Visible Particulates 
Guidance for Industry 
 
 
 
 
 
 
DRAFT GUIDANCE
 
 
  This guidance document is being distributed for comment purposes only.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publication in the Federal Register of the notice announcing the availability of the draft 
guidance.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 electronic comments to https://www.regulations.gov. Submit written 
comments to the Dockets Management Staff (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 (CDER) Eric Dong 240-402-4172; (CBER) 
Office of Communication, Outreach and Development, 800-835-4709 or 240-402-8010; or 
(CVM) AskCVM@fda.hhs.gov. 
 
 
 
 
 
 
 
 
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) 
 
December 2021 
Pharmaceutical Quality/CMC
  Inspection of Injectable 
Products for Visible Particulates 
Guidance for Industry 
 
Additional copies are available from: 
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Center for Drug Evaluation and Research 
Food and Drug Administration 
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and/or 
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 Food and Drug Administration 
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Email: ocod@fda.hhs.gov 
https://www.fda.gov/vaccines-blood-biologics/guidance-compliance-regulatory-information-biologics/biologics-guidances 
and/or 
Policy and Regulations Staff, HFV-6 
Center for Veterinary Medicine 
Food and Drug Administration 
7500 Standish Place, Rockville, MD 20855 
 https://www.fda.gov/animal-veterinary/guidance-regulations/guidance-industry 
 
 
 
 
 
 
 
 
 
 
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) 
 
December 2021 
Pharmaceutical Quality/CMC Contains Nonbinding Recommendations 
Draft  Not for Implementation 
TABLE OF CONTENTS 
 
 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  STATUTORY AND REGULATORY FRAMEWORK ............................................... 2 
III.  CLINICAL RISK OF VISIBLE PARTICULATES ...................................................... 4 
IV.  QUALITY RISK ASSESSMENT .................................................................................... 5 
V.  VISUAL INSPECTION PROGRAM CONSIDERATIONS ........................................ 7 
A.  100% Inspection ............................................................................................................................. 8 
1. Components and Container Closure Systems .................................................................................. 8 
2. Facility and Equipment .................................................................................................................... 8 
3. Process ............................................................................................................................................. 9 
4. Special Injectable Product Considerations .................................................................................... 10 
B.  Statistical Sampling ..................................................................................................................... 11 
C.  Training and Qualification .......................................................................................................... 12 
D.  Quality Assurance Through a Life Cycle Approach ................................................................ 13 
E.  Actions To Address Nonconformance ........................................................................................ 13 
VI.  REFERENCES ................................................................................................................ 15 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1  Inspection of Injectable Products for Visible Particulates 
2  Guidance for Industry1 
3   
4   
5  This draft guidance, when finalized, will represent the current thinking of the Food and Drug 
6  Administration (FDA or Agency) on this topic. It does not establish any rights for any person and is not 
7  binding on FDA or the public. You can use an alternative approach if it satisfies the requirements of the 
8  applicable statutes and regulations. To discuss an alternative approach, contact the FDA staff responsible 
9  for this guidance as listed on the title page.  
10   
11   
12   
13  I.  INTRODUCTION  
14   
15  Visible particulates in injectable products can jeopardize patient safety. This guidance addresses 
16  the development and implementation of a holistic, risk-based approach to visible particulate 
17  control that incorporates product development, manufacturing controls, visual inspection 
18  techniques, particulate identification, investigation, and corrective actions designed to assess, 
19  correct, and prevent the risk of visible particulate contamination.2 The guidance also clarifies that 
20  meeting an applicable United States Pharmacopeia (USP)3 compendial standard alone is not 
21  generally sufficient for meeting the current good manufacturing practice (CGMP) requirements 
22  for the manufacture of injectable products. The guidance does not cover subvisible particulates4 
23  or physical defects that products are typically inspected for along with inspection for visible 
24  particulates (e.g., container integrity flaws, fill volume, appearance of lyophilized 
25  cake/suspension solids). 
26   
27  For the purpose of this guidance: 
28   
29    Particulates refer to mobile, undissolved particles other than gas bubbles that are 
30  unintentionally present in an injectable product.5 They vary in nature (e.g., metal, glass, 
 
1 This guidance has been prepared by the Office of Pharmaceutical Quality in the Center for Drug Evaluation and 
Research in cooperation with the Center for Biologics Evaluation and Research, Center for Veterinary Medicine, 
Office of Regulatory Affairs, and Office of Combination Products in the Office of the Commissioner and in 
consultation with the Center for Devices and Radiological Health at the Food and Drug Administration.  
2 Visual detection of a particulate is a probabilistic process that depends on, among other things, the product and the 
size and shape of the particulate (see United States Pharmacopeia General Chapter <1790> Visual Inspection of 
Injections). Therefore, threshold studies should be conducted to determine the size of visible particulates that can be 
reproducibly detected by trained personnel with near normal visual acuity. For more information about threshold 
studies, see section IV in this guidance.  
3 USP references in this guidance refer to USP 42NF 37. 
4 In general, subvisible particulates are those that cannot be seen with the naked eye. See USP General Chapters 
<788> Particulate Matter in Injections and  787  Subvisible Particulate Matter in Therapeutic Protein Injections 
for information about subvisible particulates control. 
< >
5 See, e.g., USP General Chapter <788>. 
  1  Contains Nonbinding Recommendations 
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31  dust, fiber, rubber, polymer, mold, degradant precipitate) and can be divided into three 
32  categories6:  
33   
34    Inherent particulates are particulates that are an innate product characteristic. 
o
35   
36    Intrinsic particulates are particulates that are derived from the manufacturing 
o
37  equipment, product formulation, or container system. 
38   
39    Extrinsic particulates are particulates that originate from the manufacturing 
o
40  environment and are foreign to the manufacturing process. 
41   
42    Injectable products generally refer to injectable human drugs approved under section 505 
43  of the Federal Food, Drug, and Cosmetic Act (FD&C Act), injectable animal drugs 
44  approved under section 512 or conditionally approved under section 571 of the FD&C 
45  Act, and injectable biological products licensed under section 351 of the Public Health 
46  Service Act. In some cases, the injectable product may be a drug or biological product 
47  constituent part of a combination product, such as a drug or biological product prefilled 
48  into a syringe (see 21 CFR part 3).7  
49   
50  The contents of this document do not have the force and effect of law and are not meant 
51  to bind the public in any way, unless specifically incorporated into a contract. This 
52  document is intended only to provide clarity to the public regarding existing requirements 
53  under the law. FDA guidance documents, including this guidance, should be viewed only 
54  as recommendations, unless specific regulatory or statutory requirements are cited. The 
55  use of the word should in Agency guidance means that something is suggested or 
56  recommended, but not required. 
57   
58   
59  II.  STATUTORY AND REGULATORY FRAMEWORK  
60   
61  Under section 501 of the FD&C Act, a drug product, including an injectable product, is deemed 
62  adulterated if: 
63   
 
6 See USP General Chapter <790> Visible Particulates in Injections, which describes inspection procedures used to 
demonstrate that injectable products are essentially free from particulates, and USP General Chapter  790
informational chapter that provides recommendations on inspection programs for visible particulates covering the 
injectable product life cycle.   <1 >, an 
7 This guidance generally cites regulatory requirements for drugs and biological products, but where appropriate, 
also cites relevant requirements for combination products. The regulatory requirements for combination products 
derive from the statutory and regulatory requirements applicable to their constituent parts, which do not lose their 
distinct regulatory identity when they become part of a combination product. See, e.g., draft guidance for industry 
and FDA staff Principles of Premarket Pathways for Combination Products (February 2019), which, when final, 
will represent FDAs current thinking on this topic. For the most recent version of a guidance, check the FDA 
guidance web page at https://www.fda.gov/regulatory-information/search-fda-guidance-documents. See also FDAs 
Combination Products Guidance Documents web page at https://www.fda.gov/regulatory-information/search-fda-
guidance-documents/combination-products-guidance-documents.  
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64    It has been prepared, packed, or held under insanitary conditions whereby it may have 
65  been contaminated with filth, or whereby it may have been rendered injurious to health 
66  (section 501(a)(2)(A)). 
67   
68    It is a drug and the methods used in, or the facilities or controls used for, its 
69  manufacture, processing, packing, or holding do not conform to or are not operated or 
70  administered in conformity with current good manufacturing practice to assure that such 
71  drug meets the requirements of this Act as to safety and has the identity and strength, and 
72  meets the quality and purity characteristics, which it purports or is represented to 
73  possess (section 501(a)(2)(B)). 
74    
75    It purports to be or is represented as a drug the name of which is recognized in an 
76  official compendium, and its strength differs from, or its quality or purity falls below, the 
77  standards set forth in such compendium (section 501(b)).8 
78   
79    It is a new animal drug that is unsafe within the meaning of section 512 (section 
80  501(a)(5)). 
81   
82  Adherence to FDAs CGMP requirements as set forth in section 501 of the FD&C Act and 21 
83  CFR parts 210 and 211 for drug, animal drug, and biological products;  600.10 through 600.15 
84  for biological products; and part 4 for combination products9 is essential for the control of visible 
85  particulates in injectable products.  
86   
87  Adherence to compendial standards can also assist manufacturers in complying with CGMP 
88  requirements (see, e.g.,  211.194(a)(2) and 211.165(e)). 
89   
90  USP General Chapter <1> Injections and Implanted Drug Products (Parenterals)Product 
91  Quality Tests states that [t]he inspection process should be designed and qualified to ensure that 
92  every lot of all parenteral preparations is essentially free from visible particulates as defined in 
93  USP General Chapter <790> Visible Particulates in Injections. Injectable products with a USP 
94  monograph are required to meet the applicable criteria from these USP General Chapters (see 
95  section 501(b) of the FD&C Act). Noncompendial products should also be essentially free from 
96  visible particulates as defined in USP General Chapter <790>. 
97   
98  Applying acceptance criteria, such as the criterion outlined in USP General Chapter <790>, is an 
99  important component of the overall visible particulate control program, but meeting these 
100  acceptance criteria is not alone sufficient to ensure compliance with the applicable CGMP 
101  requirements identified above, which cover a broader array of manufacturing practices than 
102  product inspection. Full compliance with CGMP requirements is needed to ensure the continued 
103  supply of pure, safe, and effective injectable products. 
 
8 Official compendium is defined in section 201(j) of the FD&C Act as the official United States Pharmacopeia, 
official Homoeopathic Pharmacopeia of the United States, official National Formulary, or any supplement to any of 
them. 
9 21 CFR part 4 establishes the CGMP requirements and postmarketing safety reporting requirements for 
combination products. See also guidance for industry and FDA staff Current Good Manufacturing Practice 
Requirements for Combination Products (January 2017).  
  3  Contains Nonbinding Recommendations 
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104   
105  In accordance with USP General Chapter <1>, injectable products should be prepared in a 
106  manner designed to exclude visible particulates, and the inspection process should be designed 
107  and qualified to ensure that the products are essentially free of visible particulates. Each final 
108  container must be inspected (100% inspection) using a qualified method to detect particles 
109  within the visible size range, and all units that are found to contain visible particulates must be 
110  rejected ( 211.160(b) and 211.110(c) and (d); see also USP General Chapter <1>).  
111   
112  Depending on the clinical risk profile associated with a specific product, FDA may expect that 
113  product to comply with stricter standards than those set forth in the compendia in order for those 
114  products to meet CGMP requirements.10 Applicants implementing postapproval changes to their 
115  manufacturing processes that are intended to ensure a product is essentially free from visible 
116  particulates must follow existing FDA regulations and should follow existing FDA guidance.11 
117   
118   
119  III.  CLINICAL RISK OF VISIBLE PARTICULATES  
120   
121  The clinical manifestations of adverse events caused by particulate contamination vary and may 
122  depend on the route of administration (e.g., intravascular, intravisceral, intramuscular), patient 
123  population, and nature or class of the particulates themselves (e.g., physical size or shape, 
124  quantity, chemical reactivity to certain cells or tissues, immunogenicity, infectivity, 
125  carcinogenicity). Particulates in intravascular or intravisceral injections generally can cause more 
126  adverse events than those in subcutaneous or intramuscular injections. According to published 
127  case reports (Langille 2014; Doessegger et al. 2012), serious adverse events involving injectable 
128  products contaminated with visible particulates have included: 
129   
130    At the systemic level, infection and venous and arterial emboli (thrombotic or 
131  nonthrombotic). 
132    
133    Microscopic emboli, abscesses, and granulomas in visceral organs.  
134   
135    Phlebitis, inflammatory reactions, granulomas, and infections at injection sites.  
136   
137  Furthermore, different patient populations may have different risks for developing adverse events 
138  after exposure to injectable products contaminated with particulates. Risk factors include age 
 
10 There are statutory CGMP requirements applicable to products addressed in this guidance. For human drug 
products, see sections 505(d)(3), 505(j)(4)(A), 505(b)(1)(D), and 505(j)(2)A)(vi) of the FD&C Act. For animal drug 
products, see sections 512(d)(1)(C), 512(c)(2)(A)(i), 512(b)(1)(D), and 512(n)(1)(G) of the FD&C Act. For 
biological products, see section 351(a) of the Public Health Service Act (42 U.S.C. 262(a)(2)(C)). See also 21 CFR 
parts 210 and 211,  600.10 through 600.15, and part 4. 
11 For approved new drug applications, see 21 CFR 314.70 and guidance for industry Changes to an Approved NDA 
or ANDA (April 2004). For approved biologics license applications, see 21 CFR 601.12 and guidances for industry 
Changes to an Approved Application: Biological Products (July 1997), Changes to an Approved Application for 
Specified Biotechnology and Specified Synthetic Biological Products (July 1997), and Chemistry, Manufacturing, 
and Controls Changes to an Approved Application: Certain Biological Products (June 2021). For approved new 
animal drug applications, see 21 CFR 514.8 and guidance for industry Chemistry, Manufacturing, and Controls 
Changes to an Approved NADA or ANADA (May 2007).  
  4  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
139  (e.g., pediatric and elderly patients), personal or family history of thrombophilia, major surgery, 
140  cancer, trauma, underlying infection, autoimmune disease, diabetes-associated late-stage 
141  vasculitis, obesity, and smoking.12  
142   
143  Applicants should consider these clinical risk factors when developing their quality target 
144  product profile and in establishing an appropriate control strategy and acceptance criteria for 
145  visible particulates.13 
146   
147   
148  IV.  QUALITY RISK ASSESSMENT  
149   
150  Visible particulates can have a negative effect on overall product quality. To ensure product 
151  quality and to limit clinical risk, manufacturers should conduct a risk assessment during product 
152  development.14 During this risk assessment, manufacturers should identify the typical visible 
153  particulates that could contaminate the injectable product and characterize their size ranges, 
154  quantity, and composition; determine risks for each type; and provide a visual description (e.g., 
155  photographs or drawings of typical defects) to be used for training purposes.15 Manufacturers 
156  should also consider the potential sources of particulates, appropriate analytical methods to 
157  monitor them, and mitigation strategies to prevent their presence in the final product.  
158   
159  Different considerations are relevant depending on the category of particulates found during the 
160  risk assessment: 
161   
162    Inherent particulates are associated with specific products or their formulationssuch 
163  as proteinaceous particulates, liposomes, or agglomeratesand are considered part of the 
164  quality target product profile. Their presence should not be cause for rejection of 
165  individual units or product batches if they are a property of the approved product and 
166  product release specifications are met. For hard-to-inspect products containing inherent 
167  particulates, such as suspensions or emulsions, manufacturers should develop 
168  supplemental testing methods to ensure adequate detection of visible particulates (see 
169  section V, Visual Inspection Program Considerations). In addition, manufacturers should 
170  monitor time-dependent changes during stability testing that may lead to increases in size 
171  or number beyond the approved acceptance criteria.  
172   
173    Intrinsic particulates can be related to the manufacturing process. Such particulates 
174  could come from components, containers and closures (e.g., glass vials, rubber stoppers), 
175  and product contact processing equipment (e.g., tubing, filters, gaskets). Manufacturers 
176  should control such particulates before the actual manufacturing process through careful 
 
12 The potential clinical risk is further supported by animal studies from the literature (Pesko 1996; Barber 2000; 
Langille 2014). In animals massively infused with particulates, histopathology findings include endothelial cell 
injury in pulmonary capillaries, pulmonary capillary microscopic thrombi, pulmonary microscopic granulomata, and 
inflammatory hepatitis (Liu et al. 1992; Jones and Warren 1992; Bautista et al. 1992). 
13 See International Council for Harmonisation (ICH) guidance for industry Q8(R2) Pharmaceutical Development 
(November 2009). 
14 See section II.3 of Annex II in ICH guidance for industry Q9 Quality Risk Management (June 2006). 
15 See section V.C in this guidance for information about training. 
  5  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
177  selection and quality control of components, containers and closures, packaging 
178  materials, and manufacturing equipment. Additionally, manufacturers should conduct 
179  studies to determine whether their manufacturing processes generate particulates. 
180  Similarly, manufacturers should study and understand the impact of handling, washing, 
181  and sterilization processes on manufacturing equipment (i.e., wear and tear) that could 
182  lead to particulate generation over time. Such process development studies can minimize 
183  intrinsic particulates by informing selection of the appropriate handling, washing, and 
184  sterilization procedures and establishing equipment life spans. Manufacturers should also 
185  evaluate trends in reject data at designated manufacturing facilities and use a life cycle 
186  management approach to monitor and control process-related intrinsic particulates in 
187  their final products. 
188   
189  Intrinsic particulates can also be related to the formulation or stability of the product or 
190  its container closure (e.g., particulates formed because of precipitation of active 
191  pharmaceutical ingredients, glass delamination, or protein-silicone oil interaction). These 
192  types of particulates can form after product release and can change in size or number 
193  when the product is stored. Manufacturers should study the risk of this type of intrinsic 
194  particulate forming under accelerated or stressed conditions in the product development 
195  phase to determine particulate characteristics and any time-dependent particulate 
196  formation or growth that can occur. In addition, an analytical method suitable for 
197  characterizing and monitoring product-specific particulates should be developed. A 
198  robust product design achieved through formulation optimization and container closure 
199  screening during development is critical to reduce the formation of product-related 
200  intrinsic particulates. Information obtained from these studies can be used to support 
201  product-specific inspection processes (e.g., particulate seeding for test kits with known 
202  product-specific intrinsic particulates, particulate identification, and rejection 
203  classification). 
204   
205    Extrinsic particulates arise from sources other than the formulations components, the 
206  containers and closures, or the manufacturing equipments product contact surfaces. 
207  These particulates, derived from materials not intended to be in contact with the 
208  injectable product, can negatively affect product quality and could indicate possible 
209  microbial contamination or another CGMP issue. Their presence in the final product can 
210  occur because of poor conditions in the manufacturing facility (e.g., poor environmental 
211  control; equipment design, age, and maintenance; facility location, construction, and 
212  maintenance; material and personnel flows). Manufacturing facilities must be CGMP 
213  compliant and of appropriate design to support the manufacture of injectable products 
214  (see 21 CFR part 211, subpart C;  211.63; and part 4). 
215   
216  Manufacturers should not rely on downstream adjustments during manufacturing to justify a 
217  poorly designed product or process. Instead, quality should be built into the manufacturing 
218  process, starting with the development phase and continuing during scale-up, process 
219  qualification studies, and commercial manufacturing.16 Successful management of visible 
 
16 See guidance for industry Process Validation: General Principles and Practices (January 2011). 
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220  particulates also includes vigilant assessment of the state of control, early detection of poor 
221  process performance, and effective process improvement throughout the products life cycle. 
222   
223  Proactively addressing risk is an important part of a life cycle approach to visible particulate 
224  control. Formal risk assessments conducted during product development contribute to process 
225  understanding and form a foundation for knowledge management. Their results should be used to 
226  establish adequate product-specific production controls and clearly defined in-process alert and 
227  action limits for particulates. Threshold studies should be conducted to determine the 
228  characteristics (e.g., size, shape, color) of visible particulates that can be reproducibly detected 
229  by trained personnel. These threshold studies can also be the basis for establishing particulate 
230  standards that will be used to establish inspection procedures, help avoid inspection bias, and 
231  allow manufacturers to verify their manufacturing processes are in a state of control.  
232   
233   
234  V.  VISUAL INSPECTION PROGRAM CONSIDERATIONS 
235   
236  Visual inspection can be viewed as part of a larger program to ensure that injectable products are 
237  essentially free of visible particulates.17 During injectable product development, manufacturers 
238  should establish procedures for inspecting the product, statistical sampling plan(s), 
239  acceptance/rejection criteria, and procedures for evaluating inspection results. Inspection 
240  procedures carried over from another site or another product may not always be suitable for a 
241  new product. 
242   
243  During process scale-up or transfer to contract manufacturers, the visual inspection methods 
244  should be assessed to confirm they are still appropriate and valid at the new scale or 
245  manufacturing site. The visual inspection program should allow for appropriate adaptations 
246  based on knowledge gained throughout the products life cycle. For example, the inspection 
247  procedures and/or analytical and statistical methods may need revision if the batch size, 
248  manufacturing process, or conditions change. 
249   
250  In addition to inspection, a visible particulate control program should include the training and 
251  qualification of operators and investigation of discrepancies, including root cause analysis, 
252  corrective actions, and preventive actions. 
253   
254  Trained and qualified personnel, automated inspection technology, or a combination of both 
255  should be used to inspect each unit of injectable product for visible particulates (hereinafter 
256  100% inspection). In addition, the quality unit should sample each batch for acceptance quality 
257  limit (AQL) testing.18 A visual inspection program should ensure that any visible particulates 
258  present in the batch at the time of release are only those that have a low probability of detection 
259  because they are of a size approaching the visible detection limit. This section covers 100% 
260  inspection, statistical sampling, training and qualification, quality assurance through a life cycle 
261  approach, and actions to address nonconformance. 
 
17 See, e.g., USP General Chapter <1790>. 
18 Acceptance quality limit refers to the quality limit that is the worst tolerable process average when a continuing 
series of lots is submitted for acceptance sampling (see ASTM E456, Standard Terminology Relating to Quality 
and Statistics). 
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262   
263  A.  100% Inspection 
264   
265  Manufacturers should conduct 100% inspection during the stage at which there is the greatest 
266  likelihood that visible particulates will be detected in the final container (e.g., before labeling to 
267  maximize container clarity). Manufacturers should ensure that the equipment used and the 
268  physical environment where visual inspection will be performed are designed to minimize 
269  variability and maximize detectability in the inspection process. 
270   
271  Important factors to consider follow. 
272   
273  1.  Components and Container Closure Systems 
274   
275  Visible particulate contamination could be traced to components or container closure systems. 
276  To ensure visible particulate control, manufacturers must have written procedures for the receipt, 
277  identification, storage, handling, sampling, testing, and approval or rejection of components and 
278  product containers (including devices and device components that contact injectable products) 
279  ( 211.80; see also part 4). Such procedures must ensure that components and containers and 
280  closures are tested or examined and approved, as appropriate, before use in manufacturing 
281  ( 211.84). Containers and closures must not alter the products safety, identity, strength, quality, 
282  or purity ( 211.94(a) and 600.11(h); see also part 4). 
283   
284  2.  Facility and Equipment 
285   
286  To comply with CGMP requirements, manufacturing facilities must be designed, constructed, 
287  and outfitted with equipment to prevent injectable products from being contaminated with 
288  particulates. Applicable CGMP regulations include: 
289    
290    Buildings and facilities ( 211.42 through 211.58 and 600.11). 
291    Equipment design, size, and location ( 211.63). 
292    Equipment construction ( 211.65 and 600.11). 
293    Equipment cleaning and maintenance ( 211.67 and 600.11). 
294   
295  Inspections can be conducted manually and/or using a range of automated inspection techniques: 
296   
297    For manual inspections, the inspection station should have a backdrop of one or more 
298  solid colors (e.g., black and white) to provide adequate contrast and to allow maximum 
299  visibility of product contents. The light intensity of the inspection station is also critical 
300  to achieving maximum visibility. Manufacturers should consider container color, size, 
301  and shape as well as product characteristics when determining the ideal intensity.  
302   
303    During semi-automated inspections, a machine rotates the product at a constant rate 
304  past a trained inspectors field of vision. Rejected products are removed mechanically or 
305  by hand.  
306   
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307    Automated inspection technology can be used as part of an investigation in the 
308  inspection process for injectable products, as a replacement for manual inspection, or as 
309  an additional quality assurance step. Automated inspection technology can use different 
310  wavelengths and sensors to detect hard-to-see particulates in sterile powder, suspensions, 
311  or light-protected injection products for which visual inspection is not completely 
312  effective.  
313   
314  Regardless of the techniquemanual, semi-automated, or automatedthe inspection 
315  environment should be free from distractions and extraneous light, and the inspection rate should 
316  be qualified and should allow for thorough visual inspection. Manufacturers can operate 
317  independent inspection stations as separate units or units that are connected in a series. Some 
318  inspection equipment does not require controlled separate facilities for visible particulate 
319  inspection.  
320   
321  For manual and semi-automated inspections, the inspection environment should be 
322  ergonomically designed for inspector comfort.  
323   
324  For semi-automated and automated inspections, equipment must be routinely calibrated, 
325  inspected, or checked in accordance with a written program designed to ensure proper 
326  performance, and records of those calibration checks and inspections must be maintained 
327  ( 211.68). Equipment should also be properly qualified. See section V.C, Training and 
328  Qualification, for more information. 
329   
330  When compared with manual inspection, automated inspection technology may improve 
331  detectability of visible particulates because machine variability is generally easier to control than 
332  the variability individual personnel can bring to tasks performed repetitively over time. In some 
333  cases, the technology can detect higher levels of specific visible particulates. In others, it can 
334  detect particulates at the lower end of the visual inspection range with greater statistical 
335  reliability when compared with manual and semi-automated inspection of the same product 
336  (Melchore 2010).  
337   
338  Automated inspection technology may allow manufacturers to better control product quality. 
339  Manufacturers may need to adjust in-process action and alert limits if they change from manual 
340  to automated inspection. Adjustments should be based on statistical process and batch data 
341  analysis obtained during evaluation and validation of automated inspection equipment.  
342   
343  Among the automated inspection technologies currently in use (e.g., high-speed industrial 
344  camera, visible diode array, X-ray, near-field radar, ultraviolet and near infrared spectroscopy), 
345  each has its advantages and disadvantages but, if properly implemented, all can substantially 
346  improve the accuracy of visual inspection.  
347   
348  3.  Process 
349   
350  Manufacturers should conduct inspection feasibility studies for visible particulate detectability, 
351  unit inspection duration, illumination, and fatigue time frame. These studies should be 
352  scientifically based and analyzed using appropriate statistical methodology. Depending on the 
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353  study results, manufacturers may need to adjust particulate standards or inspection processes or, 
354  in some cases, change equipment to improve accuracy and reduce patient risk. 
355   
356  Manufacturers must implement written procedures for production and process controls ( 
357  211.100), which should cover each aspect of the visual inspection process. Such procedures 
358  should cover handling of the units (e.g., swirling, inversion, distance from light), maximum 
359  length of the inspection period without a rest break, and disposition and documentation of 
360  products that were rejected based on the results of the visual inspection.  
361   
362  A complete program19 for the control and monitoring of particulate matter must include written 
363  procedures for production and process control, sampling and testing of in-process materials, and 
364  control of microbiological contamination that are designed to minimize the occurrence of visible 
365  particulates, identify affected batches of injectable product, and facilitate investigation to 
366  determine the sources of visible particulates ( 211.100, 211.110, and 211.113). 
367   
368  Written procedures should also cover how to conduct 100% inspections to ensure batches are 
369  essentially free of visible particulates. All records must be documented in accordance with 
370  applicable regulatory requirements ( 211.188(b)(5); see also  600.12). Adequate written 
371  procedures can contribute to a more thorough understanding of the potential sources and quantity 
372  of visible particulates, leading to improvements in process design. The increased level of 
373  understanding would also promote a more robust particulate control program and higher quality 
374  investigations (see  211.192).  
375   
376  4.  Special Injectable Product Considerations 
377   
378  Large volume parenterals should undergo the same level of inspection as small volume 
379  injectable products. In many cases, patient risk from particulate contamination is higher for large 
380  volume parenterals than for small volume injectable products because of the volume of product 
381  administered and the potential for a patient to receive a continuous administration over many 
382  days. Packaging and labeling of large volume parenterals (e.g., overwraps and printing on the 
383  flexible bags) can interfere with visual inspection. Large volume intravenous bags that have an 
384  outer bag can be particularly challenging to inspect. Manufacturers should take appropriate 
385  measures to ensure adequate 100% inspection of these products. Supplemental destructive testing 
386  may also be warranted to ensure these products are essentially free of visible particulates if the 
387  packaging does not allow for the identification of particulates within the accepted visible size 
388  range.  
389   
390  Opaque products and containers (e.g., lyophilized powders, suspension products, tinted vials) 
391  present obvious challenges to visual inspection. Using advanced technologies such as those 
392  described in section V.A.2 in this guidance (e.g., X-ray spectroscopy) can help, as can 
393  supplemental destructive testing after the 100% inspection, which provides additional assurance 
394  of product quality. Supplemental destructive testing may not be warranted, however, if the 
395  technology used in the 100% inspection is validated to meet or surpass human inspection 
 
19 USP General Chapter <790> notes that a complete program for the control and monitoring of particulate matter 
remains an essential prerequisite, but it does not describe such a complete program. 
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396  capabilities. Manufacturers should conduct a feasibility study to demonstrate the suitability of 
397  the technology selected for the specific product. 
398   
399  B.  Statistical Sampling  
400   
401  Following 100% inspection, manufacturers should employ statistically sound sampling plans, 
402  validated inspection methods, and appropriate acceptance criteria to ensure that each product 
403  batch meets a pre-established AQL for visible particulate contamination. This is consistent with 
404  USP General Chapters <1> and <790>; however, a more stringent sampling plan and acceptance 
405  criteria may be appropriate for higher risk products.  
406   
407  A sampling plan allows the user to make a specific statistical quality statement20 about the 
408  attribute of interest (e.g., a defect) in a batch based on the sample size and sampling locations. 
409  Manufacturers should select their sampling plans in accordance with the risk for a particular type 
410  of product defect. CGMP regulations require manufacturers to ensure that batches of injectable 
411  products meet appropriate specifications and statistical quality control criteria as a condition for 
412  their approval and release ( 211.165). 
413   
414  Manufacturers should quantify the following parameters with respect to design and use of 
415  sampling plans21: 
416   
417    Operating characteristic curves developed for each defect classification or quality 
418  attribute that is being tested. 
419   
420    Accept/reject criteria, AQL, and unacceptable quality limit (also referred to as rejectable 
421  quality limit, limiting quality, or lot tolerance percent defective). 
422   
423  The methodology and acceptance criteria for the statistical sampling plan should consider patient 
424  risk, particulate type, and product and container characteristics that may interfere with particulate 
425  visibility. For example, an adequate sampling plan with an acceptable AQL for 
426  nondestructive/destructive testing could follow ASTM E2234.22 Firms that wish to propose an 
427  alternative minimum standard for their specific product should ensure that there is a risk-based 
428  justification for the proposed standard. 
429   
430  Extrinsic particulates identified during 100% inspection or AQL of the batchwhich suggests 
431  the presence of filth, sterility assurance issues, or other CGMP violationsmay result in product 
432  that could be considered adulterated, even if the statistical sampling acceptance criteria are met. 
433  Likewise, multiple visible particulates (extrinsic or intrinsic) within a single container may be 
434  indicative of manufacturing problems and should trigger increased scrutiny of the batch.  
435   
 
20 A statistical quality statement could be, for example, There is 95% confidence that there are no more than X% 
defects in the batch. 
21 See ASTM E2234, Standard Practice for Sampling a Stream of Product by Attributes Indexed by AQL; ASTM 
E456, Standard Terminology Relating to Quality and Statistics. 
22 ASTM E2234 is equivalent to the ANSI/ASQ Z1.4 standards referenced in USP General Chapters <790> and 
<1790>. 
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436  If retained samples are used to evaluate the suitability of product in distribution (such as in the 
437  case of product complaints), manufacturers should consider additional factors such as historical 
438  data for the facility and/or product when evaluating the suitability of a given product batch. 
439   
440  According to  211.194(a)(2), the suitability of all testing methods used shall be verified under 
441  actual conditions of use. Manufacturers also must validate and document tests used to ensure 
442  that each batch of the product conforms to final specifications for release and distribution 
443  ( 211.165(e)).  
444   
445  C.  Training and Qualification 
446   
447  Only certified inspectors and qualified equipment should be used to inspect injectable products 
448  for visible particulates. Personnel conducting inspections (100% inspection and AQL inspection) 
449  must be adequately trained (including, as appropriate, periodic retraining or requalification) ( 
450  211.25 and 600.10(b)). 
451   
452  Formalized training and qualification programs promote consistent performance by individual 
453  inspectors or automated inspection machines and help minimize variability among different 
454  inspectors or machines (Melchore 2011). The program can include a combination of training 
455  materials, standard operating procedures (SOPs), on-the-job training, and testing. Inspector 
456  candidates should be trained in the relevant CGMP requirements and should have normal near 
457  visual acuity (with or without the use of corrective lenses) and no impairment of color vision 
458  (Ricci et al. 1998).  
459   
460  Regarding inspection equipment: 
461   
462    The specific backdrop and light intensity selected for manual inspection stations should 
463  be qualified.  
464   
465    Semi-automated inspection equipment should be properly calibrated and qualified at a 
466  specific vial-spin and belt speed. Lighting should also be qualified to allow for accurate 
467  human detection of defective products. 
468   
469    Automated inspection machines should be validated to meet or surpass human inspection 
470  capabilities and can be qualified using training standards or artificial intelligence 
471  technology. 
472   
473  For personnel qualification and automated inspection systems validation, a mixture of good 
474  injectable product units and defective units containing visible particulates should be used 
475  (Melchore 2011). This test set should be prepared and approved by quality assurance staff. 
476  Manufacturers should develop libraries of defective units from samples collected throughout the 
477  product life cycle, samples created to simulate production defects, or samples purchased to be 
478  representative of the types of particulates likely to occur for the drug product and its 
479  manufacturing process. Quality assurance staff should review the library of defective samples 
480  and compare the samples to established standards for proper classification. The library should 
481  contain examples from the lower limits of visual detection determined in the threshold studies. If 
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482  a new particulate matter defect is identified, it should be analyzed to determine its source and 
483  added to the training library. 
484   
485  Typically, the percentage of defective units in a test set should not exceed 1020 percent, and the 
486  test set quantities should be sufficient to provide an adequate degree of confidence in the test 
487  results. Trained inspectors should review defective units before they are included in the test set to 
488  determine if the visible particulates in them can be detected under normal conditions, and the 
489  identity of defective units should be masked to test subjects. The quality unit should control the 
490  test sets to ensure that qualification tests are not manipulated or biased. 
491   
492  The quality unit should also establish and approve qualification protocols that identify the 
493  sample test sets, test duration, grading method for test results, documentation of test results, 
494  acceptance criteria for certification, and actions to be taken for test failures. The protocols should 
495  also specify requalification testing methods and frequency. 
496   
497  D.  Quality Assurance Through a Life Cycle Approach 
498   
499  Process performance and product quality monitoring systems should provide information to 
500  ensure process control throughout a products life cycle. Process performance measurements 
501  (e.g., deviations, in-process defect results, statistical process control reports, equipment and 
502  facility breakdowns) provide information on the state of control during manufacturing. Product 
503  quality indicators (e.g., stability test results, complaints, returned product) can help determine 
504  whether particulate matter in the product caused an event. Similarly, field alert reports and 
505  adverse event reports could reveal possible particulates-related quality issues. This information 
506  should be used to evaluate the effectiveness of visible particulate control strategies. 
507   
508  Trends of increased particulate contamination, identification of new types of particulates, or 
509  particulates that exceed alert or action limits may indicate a flaw in product or process design. 
510  For example, inconsistent product quality could be caused by any one or a combination of these 
511  factors: 
512   
513    Inadequate controls of components, containers, or closures.  
514    A product formulation that is not stable. 
515    Uncontrolled changes to the manufacturing process. 
516    Equipment and facilities that are not suitable for their intended use.  
517    Personnel practices that generate particles. 
518   
519  If an investigation reveals a flaw in product or process design, it is important to redesign the 
520  product or process to ensure reproducible product quality and reduction of particulate matter. 
521   
522  E.  Actions To Address Nonconformance  
523   
524  Manufacturers must investigate quality discrepancies identified through the inspection process, 
525  quality control testing, complaints, or as a result of a batch failure and extend their investigation 
526  to other batches that may be affected ( 211.192 and 211.198). Such investigations should seek 
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527  to identify the particulates and categorize them (intrinsic or extrinsic) because the presence of 
528  certain categories of particulates could indicate CGMP issues or sterility failures.  
529   
530  Investigations can include tightened sampling plans, examination of particles to understand their 
531  origin, and evaluation of batch release impact. The investigation should determine the sources of 
532  the variation and identify appropriate corrective actions and preventive actions. The 
533  investigations may also reveal opportunities to enhance the robustness of particle detection (e.g., 
534  improvements to the 100% inspection or AQL inspection program). 
535   
536  Investigations of manufacturing inspection outcomes should be conducted in situations such as 
537  the following: 
538   
539    Individual or total defect limits are exceeded. 
540    A batch fails to meet AQL limits. 
541   
542  Atypical trends should also be investigated. This includes examining defective units removed 
543  from a batch that are within in-process specifications but outside of statistical (historical) trend 
544  limits for the manufacturing process or defective units with visible particulates that have not 
545  been commonly observed.  
546   
547  Reinspection of product batches may be permissible with appropriate scientific justification and 
548  should be conducted according to approved SOPs with tightened acceptance criteria. FDA does 
549  not recommend more than one reinspection in an attempt to release a batch with atypical defect 
550  levels. Samples failing the AQL reinspection should be counted along with rejects from any 
551  other inspection of the product (e.g., such as 100% inspection and the original AQL visual 
552  inspection) in calculations to account for and reconcile all units of final product in the batch. 
553   
554  Corrective actions, such as reinspection, should be justified based on risk and have quality unit 
555  oversight and must be documented consistent with applicable written procedures ( 211.100(b)).  
556   
557  Customer complaints must be handled according to applicable CGMP regulations ( 211.198) 
558  and should result in particulate identification whenever possible, an investigation into the 
559  potential source of the particulate, corrective actions (if necessary), and analysis of the batchs 
560  retain samples for evidence of visible particulate contamination.  
561   
562  Ensuring the effectiveness, safety, and quality of injectable products is of utmost importance. 
563  Therefore, FDA recommends the use of a holistic, risk-based approach to visible particulate 
564  control. This approach includes the use of a robust visual inspection program along with the 
565  implementation of other relevant CGMP measures to help ensure that injectable products are not 
566  adulterated and are essentially free of visible particulates.   
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567  VI.  REFERENCES 
568   
569  Barber, TA, 2000, Introduction and Overview. In: TA Barber, editor, Control of Particulate 
570  Matter Contamination in Healthcare Manufacturing, Denver, CO: Interpharm Press, 126. 
571   
572  Bautista, AP, A Schuler, Z Spolarics, and JJ Spitzer, 1992, In Vivo Latex Phagocytosis Primes 
573  the Kupffer Cells and Hepatic Neutrophils To Generate Superoxide Anion, J Leukoc Biol, 
574  51(1):3945. 
575   
576  Doessegger, L, HC Mahler, P Szczesny, H Rockstroh, G Kallmeyer, A Langenkamp, J 
577  Herrmann, and J Famulare, 2012, The Potential Clinical Relevance of Visible Particles in 
578  Parenteral Drugs, J Pharm Sci, 101(8):26352644. 
579   
580  Jones, ML and JS Warren, 1992, Monocyte Chemoattractant Protein 1 in a Rat Model of 
581  Pulmonary Granulomatosis, Lab Invest, 66(4):498503. 
582   
583  Langille, SE, 2014, Particulate Matter in Injectable Drug Products. In: RE Madsen and J 
584  Moldenhauer, editors, Contamination Control in Healthcare Product Manufacturing, vol. 2, River 
585  Grove, IL: Davis Healthcare International Publishing, LLC, 139173. 
586   
587  Liu, JF, ZK Su, and WX Ding, 1992, Quantitation of Particulate Microemboli During 
588  Cardiopulmonary Bypass: Experimental and Clinical Studies, Ann Thorac Surg, 54(6):1196
589  1202. 
590   
591  Melchore, JA, 2010, Prerequisites for Optimized Performance of the Eisai 1088W Automated 
592  Inspection System, PDA J Pharm Sci Technol, 64(6):574580. 
593   
594  Melchore, JA, 2011, Sound Practices for Consistent Human Visual Inspection, AAPS 
595  PharmSciTech, 12(1):215221. 
596   
597  Pesko, LJ, 1996, Physiological Consequences of Injected Particulates. In: JZ Knapp, TA Barber, 
598  A Lieberman, editors, Liquid- and Surface-Borne Particle Measurement Handbook, New York, 
599  NY: Marcel Dekker, Inc., 661686. 
600   
601  Ricci, F, C Cedrone, and L Cerulli, 1998, Standardized Measurement of Visual Acuity, 
602  Ophthalmic Epidemiol, 5(1):4153. 
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