ZA Validation 2.0 (Full) ZA 2.0 en Full ZA Validation Criteria v2.0 with additional recommended criteria. The ICH DTD is named correctly. 6.17.57 The ICH DTD is placed in the correct folder. 6.17.38 6.17.57 A currently acceptable version of the ICH DTD is used (checksum matches the published value). 6.17.46 The version number of the ICH DTD/specification used in the sequence being tested is higher than or equal to the version of the DTD used in the sequence numerically preceding the incoming sequence in the eCTD lifecycle. 6.17.65 The version number of the ICH DTD/specification used in the sequence being tested is lower than or equal to the version of the DTD used in the sequence numerically succeeding the incoming sequence in the eCTD lifecycle. 6.17.80 The specified filename is used. 6.17.58 The file is placed in the correct folder. 6.17.38 6.17.58 The checksum for the stylesheet used must match the published checksum for the stylesheet associated with the DTD used for the sequence. 6.17.55 The index.xml is placed in the folder xxxx. 6.17.39 There is a backbone file named index.xml. 6.17.39 The index.xml file is well formed. 6.17.48 The index.xml file is valid. 6.17.48 The reference to the DTD in index.xml is directed to the DTD provided in the util folder. 6.17.48 The reference to the stylesheet in index.xml is directed to the stylesheet provided in the util folder. 6.17.51 The file is placed in the correct folder. 6.17.53 The file is named correctly. 6.17.54 The checksum of the index.xml, when calculated by the validation tool, should match the checksum provided in the index-md5.txt 6.17.5 The checksum-type attribute must have the value md5 or MD5. 6.17.2 The sequence number is 4 digits (i.e. numbers between 0000 and 9999) 6.17.30 The sequence number has not already been used* 6.17.32 The sequence folder name matches the sequence number in the za- envelope in za-regional.xml 6.17.31 The ZA M1 DTD is named correctly. 6.17.57 The ZA M1 DTD is placed in the correct folder. 6.17.57 A currently acceptable version of the ZA M1 DTD is used (checksum matches the published value). 6.17.47 The version number of the ZA M1 DTD/specification used in the sequence being tested is higher than or equal to the version of the ZA M1 DTD used in the sequence numerically preceding the incoming sequence in the eCTD lifecycle. 6.17.66 The version number of the ZA M1 DTD/specification used in the sequence being tested is lower than or equal to the version of the ZA M1 DTD used in the sequence numerically succeeding the incoming sequence in the eCTD lifecycle. 6.17.81 The za-regional.xml is placed in the folder xxxx/m1/za. 6.17.39 There is a ZA M1 backbone file named za-regional.xml. 6.17.39 The za-regional.xml is well formed. 6.17.48 The za-regional.xml is valid. 6.17.48 The reference to the DTD in za-regional.xml is directed to the DTD provided in the util folder. 6.17.52 The reference to the stylesheet in za-regional.xml is directed to the stylesheet provided in the util folder. 6.17.51 A Letter of application must exist in section 1.0. 6.17.267 The operation attribute of the Letter of application must be new. 6.17.181 An Application Form must exist in section 1.2.1. 6.17.268 An Electronic copy declaration must exist in section 1.2.2.4. 6.17.269 A Validation Template has to exist in section 1.8. 6.17.270 The operation attribute of the Application form should be new. 6.17.181 The operation attribute of the Proof of payment should be new. 6.17.280 The operation attribute of the Electronic copy declaration should be new. 6.17.280 The operation attribute of the Tabulated Schedule of Amendments should be new. 6.17.280 The cross-references in the Patient Information Leaflet in section 1.3.2 should be hyperlinked to the package insert in section 1.3.1.1. 6.17.271 The cross-references in the package insert in section 1.3.1.1 should be hyperlinked to the actual references. 6.17.272 The references in Sections B to D of the Validation template in section 1.8 should be hyperlinked to the respective documents in the eCTD. 6.17.273 The references in the “Tabulated Schedule of Amendments” should be hyperlinked to the relevant documents dealing with the recommendations and responses. 6.17.274 A Tabulated Schedule of Amendments must exist in section 1.5.2.1. 6.17.275 The ZA M1 envelope MOD file is named correctly. 6.17.57 The ZA M1 envelope MOD file is placed in the correct folder. 6.17.57 The checksum for the za-envelope.mod file used must match the published checksum for the za-envelope.mod file associated with the DTD used for the sequence. 6.17.47 The ZA M1 leaf MOD file is named correctly. 6.17.57 The ZA M1 leaf MOD file is placed in the correct folder. 6.17.57 The checksum for the za-leaf.mod file used must match the published checksum for the za-leaf.mod file associated with the DTD used for the sequence. 6.17.47 The ZA M1 leaf MOD file is named correctly. 6.17.58 The ZA M1 leaf MOD file is placed in the correct folder. 6.17.58 The checksum for the za-leaf.mod file used must match the published checksum for the za-leaf.mod file associated with the DTD used for the sequence. 6.17.55 For every node-extension the "title" attribute is not empty. 6.17.25 The files provided in the folders for Module 1 are in acceptable formats. 6.17.44 The files provided in the folders for Module 2-5 are in acceptable formats. 6.17.44 Total folder/file path does not exceed 180 characters. 6.17.35 File names do not exceed 64 characters. 6.17.33 Folder names must not exceed 64 characters. 6.17.33 All characters used in referenced file names are valid (according to the name requirements of the ICH eCTD Specification). 6.17.34 All characters used in folder names are valid (according to the name requirements of the ICH eCTD Specification). 6.17.34 There are no empty folders 6.17.62 There are no unreferenced files in M1, M2, M3, M4 and M5 folders (including sub-folders but excluding 'util' subfolders). 6.17.37 The only files in the root folder are the index.xml and index-md5.txt. 6.17.37 Individual files do not exceed 200 MB in size. 6.17.21 The recommended folder structure and folder names from the ICH and ZA specifications are used. 6.17.49 The recommended file names from the ICH and ZA specifications are used for all files. 6.17.49 All files should have one and only one file extension. The file extension should be used to indicate the format of the file. 6.17.9 If documents are placed in section 3.2.R (including subfolders), the structure must follow the structure given in the ZA M1 specification. 6.17.276 The ID attribute value starts with a letter or underscore character. 6.17.20 Checks for elements not having any leaf child nodes - all the lowest level heading elements included in the submission contain at least one leaf. 6.17.19 The regenerated checksum for every referenced file is the same as each associated checksum provided in the backbone file (e.g. za- regional.xml). 6.17.7 For every leaf the "title" attribute is not empty. 6.17.277 All leaves with an operation attribute value of replace, delete or append must have a value for modified-file. 6.17.13 All leaves with an operation attribute value of new must have no value for modified-file. 6.17.42 The syntax of the modified file entry is in accordance with ICH 3.0 or 3.2: If the operation is append, replace or delete, then the modified file attribute must use the correct syntax (i.e. modified- file="../0001/index.xml#a1234567") 6.17.41 No modified file references an invalid document: If the operation is append, replace or delete, then the modified file attribute should point to a valid document. 6.17.14 xlink:href conforms to the eCTD standard (using the relative path to the file and file name) 6.17.29 If the operation is new, append or replace, then xlink:href should point to a document 6.17.27 If the operation is delete, then xlink:href should not exist. 6.17.26 No references in index files (xlink:href) should target files outside the eCTD life cycle. 6.17.24 For all leaves except leaves within node extensions within the same CTD section with an operation attribute value of replace, delete or append, the modified file must be present in the same CTD section of the dossier. 6.17.82 For all leaves within node extensions within the same CTD section with an operation attribute value of replace, delete or append, the modified file should be present in the same node extension. 6.17.265 No PDF has been created and saved as version 1.3 or earlier 6.17.18 There is no security setting or password protection to open any individual file. 6.17.40 There are no further security settings applied to any individual file. 6.17.40 The submission does not contain corrupted files. 6.17.91 PDF Format is PDF 1.4, 1.5 , 1.6, or 1.7 6.17.18 Hyperlinks and bookmarks within documents, or between documents within the same sequence, have a valid target. 6.17.17 Hyperlinks and bookmarks to destinations in a different sequence in the same eCTD have a valid target. 6.17.17 All hyperlinks and bookmarks are set to 'inherit zoom'. 6.17.12 6.17.63 PDFs must have "Fast Web View" active. 6.17.16 PDF Document Properties for the Initial View are set for 'Page Layout = Default' and 'Magnification = Default' 6.17.12 All PDF links and Hyperlinks are relative (are not absolute or rooted). 6.17.15 Bookmarks pane should be visible if bookmarks are included with a PDF document. 6.17.10 The bookmarks panel should not be visible if there are no bookmarks included within a PDF document. 6.17.11 All hyperlinks and bookmarks between two PDFs must be configured as specified in ISO 32000-1:2008 6.17.67 If the submission type is a Response to a pre-registration recommendation or post-registration, then the related sequence attribute is a four digit number. 6.17.278 If the submission type is not a Response to a pre-registration recommendation or post-registration, then the related sequence attribute must be "none". 6.17.279 Ensure that 'checksum' attribute is present and value for the attribute is provided (i.e. not empty string) when 'operation' attribute for the leaf(s) is 'new', 'append' or 'replace' 6.17.3 Ensure that 'checksum' attribute value is not provided when 'operation' attribute for the leaf(s) is 'delete' 6.17.4 Ensure that invalid formatting is not provided for 'checksum' in index-md5.txt (32 characters are not specified for the MD5 checksum, or included trailing spaces or carriage returns) 6.17.6 Ensure that the checksum of the DTD for STFs provided in the util folder must match the checksum value provided by the agency 6.17.8 Allow users to configure file size limit for special file types (i.e. xpt). For all other file types (where configuration is not specified), default max file size value in the 'Check for File Size' field shall be used for validation 6.17.23 Ensure that the xlink:href attribute of the leaf points to a document (current sequence, previous sequence if allowed by the region, across application if allowed by the region) and it is exists in the referenced location 6.17.28 Ensure that there are no corrupted/unreadable files in the submission (meaning PDF files can be opened by ISO 32000-1 compliant software. Content is not invalid or the page count is not 0 or the encryption is not too strong) 6.17.43 Ensure that ICH and regional xml backbone files are named correctly 6.17.56 Ensure that all files and folders in the submission are accessible to the user 6.17.64 Ensure that the hyperlinks and/or bookmarks in the submission documents does not target document outside current eCTD application 6.17.69 Provide list of all documents in the submission containing annotation (other than links and bookmarks) 6.17.83 Ensure that all pdf documents in the submission must not have any attachments 6.17.84 Ensure that all hyperlinks and bookmarks in the submission documents must not have multiple actions (e.g. opening two different pages) 6.17.85 Ensure that all hyperlinks and bookmarks (internal, external, same sequence, across sequences and across applications) in the submission documents are not inactive (without any action). 6.17.86 Ensure that all hyperlinks and bookmarks in the submission documents must not have unknown action (links that could not be identified or contain JavaScript code) and print total count 6.17.87 Ensure that all hyperlinks and bookmarks in the submission documents must not point to external destinations (other than web or email) 6.17.88 Ensure that all hyperlinks and bookmarks in the submission documents must not point to web address or email 6.17.89 Print the count of all of the hyperlinks and the bookmarks with following criteria: - Non-Relative Hyperlinks - Non-Relative Bookmarks - Web link and email hyperlinks - Web links and email bookmarks - External Hyperlinks (excluding web links and emails) - External Bookmarks (excluding web links and emails) - Unknown Action Hyperlinks - Unknown Action Bookmarks - Inactive Hyperlinks - Inactive Bookmarks - Broken Hyperlinks (separate count for inter-application, intra-application and intra-sequence) - Broken Bookmarks (separate count for inter-application, intra-application and intra-sequence) - Number of bookmarks per document - Total number of bookmarks in the submission - Number of hyperlinks per document - Total number of hyperlinks in the submission 6.17.90 Ensure that the links and/or bookmark in the submission documents point to an existing page and/or named destinations 6.17.92 Ensure that 'property' element (if present) is listed before its sibling 'file-tag' element in all of the stf files of the submission 6.17.107 Ensure that 'property' element is present in all of the stf files in the submission created with STF DTD v2.0 only 6.17.108 Ensure that child element 'title' is not provided in the doc-content of the STF files in the submission 6.17.109 Ensure that an STF xml file is referenced in a submission only once 6.17.129 Ensure that 'title' element (within 'study-identifier') is present and value for title is provided in the STF xml file 6.17.130 Ensure that STF files are not missing in the submission (i.e. xlink:href contains ‘stf-xxxxxxxx.xml’ but system is not able to locate the file) 6.17.131 Ensure that STFs (files named as ‘stf-xxxxxxxxx.xml’) in the submission contain study-id information (element and the value is not empty) and reference leafs 6.17.132 Ensure that STF title (within study-identifier element) in the stf xml file matches with the leaf title for the stf in the index.xml file 6.17.133 Ensure that one and only one doc-content file-tag is specified for each file referenced in the STFs. 6.17.134 Ensure that STF is only referenced in the sections of M4 and M5 allowed as per the STF specification 6.17.135 Ensure that STF’s in the submission are named correctly based on the naming convention i.e. ‘STF-<study-id>.xml’ 6.17.136 Ensure that STFs in the submission have valid file extension (file extension is not missing and it is .xml) 6.17.137 Ensure that lifecycle stf must have the same study-id as the original stf (referenced by the modified-file) 6.17.138 Ensure that files referenced by an STF exist in the submission/application (referenced by index.xml) 6.17.139 Ensure that STF file must reference at least one leaf element 6.17.140 Ensure that an STF file does not reference another STF file 6.17.141 Ensure that files in study sections are referenced by an STF 6.17.142 Ensure that valid STF DTD version (e.g. dtd-version = "2.2") is referenced in the STF XML file 6.17.143 Ensure that 'title' element of the 'leaf' and/or 'node-extension' does not begins or ends with a space 6.17.167 Ensure that valid/supported 'dtd-version' is referenced in the ICH and regional backbone xml files 6.17.170 Ensure that 'dtd-version' is referenced in the ICH and regional backbone xml files 6.17.173 Ensure that required attributes (e.g. 'indication' in the section 5.3.5 element or 'type of control' in the STF XML file for a study in section 5.3.5.1) are present in the back bone xmls (index and regional) and in the heading element of STF XML file(s) 6.17.176 Ensure that attribute (i.e. substance, company-name, species) values in ICH, regional and/or STF backbone files does not begins or ends with a space 6.17.177 Ensure that non-required files are not present in the util folder (i.e. submission does not have an stf or leaf but the stylesheet and dtd files are present in the util folder) 6.17.178 Ensure that operation attribute is present and valid value ('new', 'append', 'replace' or 'delete') for the attribute is provided 6.17.180 Ensure that 'category' information must be provided for STFs in following sections: • 4.2.3.1 Single dose toxicity section contains 'species' and 'route-of-admin'. • 4.2.3.2 Repeat dose toxicity section contains 'species', 'route-of-admin', and 'duration' (if applicable). • 4.2.3.4.1 Long term [carcinogenicity] studies contain 'species'. • 5.3.5.1 Study reports of controlled clinical studies pertinent to the claimed indication contain 'type-of-control’. 6.17.182 Ensure that 'modified-file' of lifecycle stf must point to a stf (e.g. not a pdf document) 6.17.183 Ensure that 'file-tag' values and 'category' values are valid as per the 'valid-values.xml' file referenced by the submission 6.17.184 Ensure that value for study-identifier/category element must not be empty 6.17.185 Ensure that 'xlink:href' attribute of a leaf referenced in an STF must exists and must not contain backslashes 6.17.186 Ensure that the titles from the doc-content elements (if present) must match the corresponding leaf title values in the ICH backbone 6.17.187 Ensure that 'append' operation is not applied on an existing lifecycle 'append' leaf (E.g. Detect invalid life cycle pattern: sequence 0001 appends a document in sequence 0000, sequence 0002 append operation leads to the append in 0001.) 6.17.199 Ensure that leaf lifecycle operation ('append', 'replace' or 'delete') is not applied to a lifecycle 'delete' leaf (E.g. sequence 0001 deletes a document in sequence 0000, sequence 0002 any life cycle operation leads to the already deleted leaf in 0001.) 6.17.200 Ensure that a leaf is not lifecycled ('append', 'replace' or 'delete') by more than one leaf to cause branching (i.e. scenario where a append/replace/delete operation is being applied on a leaf, which has already been replaced by another leaf. E.g. sequence 0001 replaces a document in sequence 0000, sequence 0002 append operation leads to the already replaced leaf in 0000.) 6.17.201 Ensure same xlink:href is not referenced more than once in the backbone xml files 6.17.202 Ensure that all element in the submission backbone xml files must have leaf child nodes 6.17.204 Ensure that xlink:href attribute in backbone xml files does not point to leaf outside current sequence 6.17.205 Ensure that 'xlink:href' attribute in backbone xml files does not point to leaf outside application. 6.17.206 Ensure that only operation 'new' is used for all leafs in the initial sequence of the application 6.17.207 Ensure multiple lifecycle operations on same document in same sequence are not allowed (E.g. sequence 0001 includes two lifecylce operations referencing the same leaf in sequence 0000.) 6.17.209 Ensure that most recent stf (stf that was lifecycled last instead of previous or original stf) is lifecycled 6.17.210 Ensure attribute (if present i.e. indication, excipient, dosage-form, manufacturer, product-name, substance etc.) value must not be empty string 6.17.212 Ensure that the initial sequence of the application must be '0000' 6.17.213 Identify and report all invalid STF files. STF files with an incorrect name will be also reported 6.17.214 Ensure that the sequence being validated is the highest sequence in the application 6.17.217 Ensure that the reference for the regional xml backbone file in index.xml must have operation attribute value 'new' 6.17.219 Ensure that 'm1' folder must exist in the submission 6.17.220 Ensure that there is a stylesheet declaration in backbone xml files (index, regional and STF) 6.17.229 Ensure that the sequence numbers in an application are increased incrementally (The sequence number related to the life cycle should increase incrementally with each subsequent submission, for example 0000, 0001, 0002 etc. (the increase should occur in chronological order). 6.17.238 Ensure that TS.xpt is present in STF for module 4, sections 4.2.3.1, 4.2.3.2, 4.2.3.4 and in module 5, sections 5.3.1.1, 5.3.1.2, 5.3.3.1, 5.3.3.2, 5.3.3.3, 5.3.3.4, 5.3.4, 5.3.5.1, 5.3.5.2 6.17.255 Ensure that only one dataset of each type (filename configured) referenced in an STF is marked as 'new' operation Note: This is applicable for : Module 4 : section 4.2.3.1, 4.2.3.2, 4.2.3.4 Module 5: section 5.3.1.1, 5.3.1.2, 5.3.3.1, 5.3.3.2, 5.3.3.3, 5.3.3.4, 5.3.4, 5.3.5.1, 5.3.5.2 6.17.259 Ensure PDF documents with more than 10 pages must have bookmarks 6.17.281