DATA INTEGRITY (ALCOA ++)

 INTRODUCTION 

The purpose of this guidance is to clarify the role of data integrity in current good manufacturing  practice (CGMP) for drugs, as required in 21 CFR parts 210, 211, and 212. Part 210 covers  Current Good Manufacturing Practice in Manufacturing, Processing, Packing, or Holding of  Drugs; General; part 211 covers Current Good Manufacturing Practice for Finished  Pharmaceuticals; and part 212 covers Current Good Manufacturing Practice for Positron  Emission Tomography Drugs. This guidance provides the Agency’s current thinking on the creation and handling of data in accordance with CGMP requirements.

FDA expects that data be reliable and accurate (see the “Background” section). CGMP  regulations and guidance allow for flexible and risk-based strategies to prevent and detect data  integrity issues. Firms should implement meaningful and effective strategies to manage their data  integrity risks based upon their process understanding and knowledge management of technologies and business models.

Please clarify the following terms as they relate to CGMP records: 

a. What is “data integrity”? 

For the purposes of this guidance, data integrity refers to the completeness,  consistency, and accuracy of data. Complete, consistent, and accurate data should  be attributable, legible, contemporaneously recorded, original or a true copy, and accurate (ALCOA).

b. What is “metadata”? 

Metadata is the contextual information required to understand data. A data value  is by itself meaningless without additional information about the data. Metadata is  often described as data about data. Metadata is structured information that describes, explains, or otherwise makes it easier to retrieve, use, or manage data. For example, the number “23” is meaningless without metadata, such as an indication of the unit “mg.” Among other things, metadata for a particular piece of data could include a date/time stamp for when the data were acquired, a user ID of the person who conducted the test or analysis that generated the data, the instrument ID used to acquire the data, audit trails, etc.

Data should be maintained throughout the record’s retention period with all associated metadata required to reconstruct the CGMP activity (e.g., §§ 211.188   and 211.194). The relationships between data and their metadata should be preserved in a secure and traceable manner.

c. What is an “audit trail”?

For purposes of this guidance, audit trail means a secure, computer-generated,  time-stamped electronic record that allows for reconstruction of the course of  events relating to the creation, modification, or deletion of an electronic record. An audit trail is a chronology of the “who, what, when, and why” of a record. For example, the audit trail for a high performance liquid chromatography (HPLC) run could include the user name, date/time of the run, the integration parameters used, and details of a reprocessing, if any, including change justification for the  reprocessing. 

Electronic audit trails include those that track creation, modification, or deletion  of data (such as processing parameters and results) and those that track actions at the record or system level (such as attempts to access the system or rename or delete a file).

CGMP-compliant record-keeping practices prevent data from being lost or obscured (see §§ 211.160(a), 211.194, and 212.110(b)). Electronic record-keeping systems, which include audit trails, can fulfill these CGMP requirements.

d. How does FDA use the terms “static” and “dynamic” as they relate to record formats? 

For the purposes of this guidance, static is used to indicate a fixed-data document  such as a paper record or an electronic image, and dynamic means that the record format allows interaction between the user and the record content. For example, a dynamic chromatographic record may allow the user to change the baseline and reprocess chromatographic data so that the resulting peaks may appear smaller or larger. It also may allow the user to modify formulas or entries in a spreadsheet used to compute test results or other information such as calculated yield.

e. How does FDA use the term “backup” in § 211.68(b)? 

FDA uses the term backup in § 211.68(b) to refer to a true copy of the original data that is maintained securely throughout the records retention period (for example, § 211.180). The backup file should contain the data (which includes associated metadata) and should be in the original format or in a format compatible with the original format. 

This should not be confused with backup copies that may be created during normal computer use and temporarily maintained for disaster recovery (e.g., incase of a computer crash or other interruption). Such temporary backup copies would not satisfy the requirement in § 211.68(b) to maintain a backup file of data.

f. What are the “systems” in “computer or related systems” in § 211.68? 

The American National Standards Institute (ANSI) defines systems as people, machines, and methods organized to accomplish a set of specific functions. Computer or related systems can refer to computer hardware, software, peripheral devices, networks, cloud infrastructure, operators, and associated documents (e.g., user manuals and standard operating procedures).

Basic DI principles applicable to both paper and electronic systems (ALCOA + +):

Data Integrity Attribute	Requirement
Attributable	It should be possible to identify the individual who performed the recorded task. The need to document who performed the task / function, is in part to demonstrate that the function was performed by trained and qualified personnel.  This applies to changes made to records as well: corrections, deletions, changes, etc.
Legible	All records must be legible – the information must be readable in order for it to be of any use.  This applies to all information that would be required to be considered Complete, including all Original records or  entries.   Where the  ‘dynamic’ nature of electronic data (the ability to search, query, trend, etc) is important to the content and meaning of the record, the ability to interact with the data using a suitable application is important to the ‘availability’ of the record.
Contemporaneous	The  evidence  of  actions,  events  or  decisions  should  be recorded as they take place.  This documentation should serve as an accurate attestation of  what was done, or  what was decided and why, i.e. what influenced the decision at that time.
Original	The original record can be described as the first-capture of information, whether recorded on paper (static) or electronically (usually dynamic, depending on the complexity of the system). Information that is originally captured in a dynamic state should remain available in that state.
Accurate	Ensuring results and records are accurate is achieved through many    elements    of    a    robust    Pharmaceutical    Quality Management System. This can be comprised of:          equipment-related factors such as qualification, calibration, maintenance and computer validation.          policies and procedures to control actions and behaviours, including data review procedures to verify adherence to procedural requirements          deviation  management  including   root   cause   analysis, impact assessments and CAPA          trained   and   qualified   personnel   who   understand   the importance   of   following   established   procedures   and documenting their actions and decisions. Together, these elements aim to ensure the accuracy of information,  including  scientific  data,  that  is  used  to  make critical decisions about the quality of products.
Complete	All information that would be critical to recreating an event is important when trying to understand the event.   The level of detail required for an information set to be considered complete would depend on the criticality of the information. (see section 5.4 Data criticality). A complete record of data generated electronically includes relevant metadata.

Consistent	Good Documentation Practices should be applied throughout any process, without exception, including deviations that may occur during the process.  This includes capturing all changes made to data.
Enduring	Part of ensuring records are available is making sure they exist for the entire period during which they might be needed.   This means they need to remain intact and accessible as an indelible/durable record.
Available	Records must be available for review at any time during the required retention period, accessible in a readable format to all applicable personnel who are responsible for their review whether for routine release decisions, investigations, trending, annual reports, audits or inspections.

For more Information contact to tradharaman86@gmail.com