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Understanding USFDA Guidance on Data Integrity – ALCOA Plus-An Overview
Article in Pharma Times · March 2022
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Article
Understanding USFDA Guidance on Data Integrity – AL-
COA Plus - An Overview
B. S. Rao and B. S. Reddy
Abstract
Data is a collection of numerical or non-numerical information that includes pre-clinical, clinical, raw material, manufacturing, analytical,
regulatory, marketing, distribution, sale, environmental activities etc. Data is either static or dynamic in nature. Every drug regulatory
authority ensures quality, safety, efficacy and reliability of a drug product and approves it’s release into the market. The most authentic
way of ensuring this is by documentation because it includes logical link documentation that ensures an activity has been done. 21
CFR parts 211, 212 speaks about documentation, it’s controls, providing complete information, retaining, storing, saving as backup
and retrieving. The current review article is to enlighten the integrity of data collected and documentation.
Keywords: Data, integrity, ALCOA, ALCOA plus, USFDA, guidance
Introduction Contemporaneous indicates that a person has to immediately
As per the Drugs and Cosmetics Act, 1940 one comes across document the conducted event after completion and not the vice
the definitions- drug, manufacture, cosmetic, quality, misbranded versa. This means the individual must complete the activity and
drug, adulterated drug and spurious drug. The latter three immediately document it and definitely not document and later
definitions clearly indicate Good Manufacturing Practices (Schedule conduct the activity.
M) violations and their consequences illustrating how the un- Original indicates that the data is true information that has
intentional becomes intentional errors and vice versa. Similarly, been collected or generated through experimentation or during
other countries have their terminology accordingly. The new an activity.
generation terminology are the counterfeits, falsified medicines,
suspect products, illegitimate product, diverted, stolen, fraudulent Accurate indicates that correct and exact information that was
transactions, unfit for distribution at the Indian, United States and collected or generated.
international perspectives. The guidance is as per 21 CFR part The appended version of ALCOA is called the ALCOA plus,
210, 211, 212 for current Good Manufacturing Practices (cGMP) which additionally includes Complete, Consistent, Enduring and
with respect to manufacturing, processing, packing or holding; Available.
finished; positron emission tomography drugs respectively. As
per the United States FD & C Act, current Good Manufacturing Complete indicates the whole information that also includes
Practices (cGMP) are the minimum guidelines of drug standard with the metadata from which presentable data has been made.
respect to safety, identity, strength, quality and purity. Industry’s Consistency indicates that data generated by several researchers/
responsibility is to ensure safety, efficacy and quality through data individuals should be uniform in presentation. This means that if
integrity. The present review is at the educational, academic and the organization has decided, for instance, a ‘dd-mm-yyyy’ format of
industrial levels. date, every researcher/individual has to follow the same. Enduring
indicates that the data collected or generated has to be maintained
Understanding Data Integrity-ALCOA Plus for the stipulated period of time decided i.e., the life cycle. If an
As per USFDA, data integrity refers to completeness, consistency authority asks for the data, entire metadata has to be produced
and accuracy. In order to achieve these, it is necessary to follow as well to the authority, if asked. Available indicates that at any
ALCOA, which means Attributable, Legible, Contemporaneous, point of time the data and the metadata should be available and
Original and Accurate. easily accessible.
Attributable indicates who has, when was, where was data Other Aspects
generated or collected and whether the person clearly indicated In a pharmaceutical company, an audit indicates who, when,
his/her signature, date and time with countersign by the higher what and why a data is generated, modified, deleted with the
authority. exact time when the data is accessed either it is manual or
Legible indicates that any written and computer generated data computer generated. When a chromatogram is generated, the
should be easily read. Several times, errors occur and especially original dynamic data has to be modified to static to the required
human hand written should be single line stricken off so that any presentable form. In either case, proper procedures are established
person understands what the error was. The person who made the in generating, converting and saving as both dynamic and static
error has to have an asterisk at the error place and as noted with the forms. It is necessary that every data generated has to be saved
same asterisk at free space in the page has to indicate the reason as backup immediately directly in the main server and not in any
for striking, for which an error is made. Where free space in the temporary computer drives and later transferred into the server.
table where no information is written has to be stricken with ‘NA- The data should be saved carefully indicating backup in original
Not Applicable’ and to be signed by the person who has collected format and not the regular saving done by an individual saving in
or generated data. Printed documents that are not legible or not temporary saving folders and retrieving when data is lost. USFDA
properly printed have to be carefully monitored and if necessary suggests planned audit trails to be conducted so that systems are
documented after having proper print documents. well set so as to overcome cGMP violations.
Pharma Times - Vol. 54 - No. 03, March 2022 5
As part of cGMP, every data generated and computer Financial Disclosure Statement
saved should be saved by the person generated and counter The author/s did not receive any specific funding for this
scrutinized, protected by the immediate higher authority so that work.
the data is restricted for access through appropriate logins thus
minimizing shared logins. At the manufacturing level, machinery Conflict of Interest
with common logins and separate logins for machine recipe and
The author/s declare that there is no conflict of interest
operations are usually maintained. Where two persons are not
regarding the publication of this review article. The legal status
available, the same person has to double check and make the
of the document has to be ensured with the corresponding drug
signatures where necessary. Digital signatures are the unique
regulatory authority.
sequence of numbering allotted for an individual. List of authorized
personnel having access has to be established and maintained. References
Documentation, traceability and appropriate electronic signature 1. USA. FDA, Guidance for Industry. Data Integrity and Compliance with
linking has to be established. cGMP [Internet]. December 2018 [cited 2022 Jan 26]. Available from:
https://www.fda.gov/media/119267/download
Blank documents may be issued in a controlled manner with
2. USA. FDA, Draft Guidance. Guidance for Industry. Data Integrity and
appropriate numbering system and an authority has to ensure all
Compliance with cGMP [Internet]. April 2016 [cited on 2022 Jan 26].
the pages issued whether received back. The blank leftover should Available from: https://www.fda.gov/files/drugs/published/Data-
be stricken off with appropriate person’s signature, time, date as Integrity-and-Compliance-With-Current-Good-Manufacturing-Practice-
‘Not Applicable’ and should be placed with the original document Guidance-for-Industry.pdf
in complete format.
USFDA indicates, usage of notebooks with page numbers Advertisement Index
officially leads to a scrutiny of unofficial, blank space left notebooks.
Hence, it is a best practice not to use any notepads, rough notes or
Sr. No. Company Name Pg. No.
loose papers for temporary storage and retrieval of information.
1. Elmach Packages (India) Pvt. Ltd.....................20, 21, 40
For regular day to day administration, execution of activities,
education and training, USFDA permits physical, electronic copies 2. ACE..................................................................................... 6
of original physical or electronic documents provided the intended 3. Ami Polymer. ................................................................... 31
use, content and meaning are preserved. Proper controls have to
be developed, documented to be executed.
Conclusion
As per American National Standard Institute (ANSI), a system is
defined as people, machines and methods organized to accomplish
a set of specific functions. In day to day work, several errors are
documented as data integrity issues or cGMP issues. Such errors
documented within the company can be retrieved from data
bases established in the company throughout the company’s life
span whether the employee exists in the company or not. Such
issues impact delays in the approvals of new products. To avoid
these, USFDA suggests appropriate systems, scrutiny procedures
to be established, documented and executed. Quality personnel,
experienced personnel have to ensure that the activities are
as per established documentation and, scrutiny and rectifying
errors as per established and validated procedures. In analytical
perspective, USFDA indicates violations to cGMP for disguising
tests for achieving compliance, sampling and testing to overcome
unacceptable results. Proper education, training and experience
is expected for effective implementation of cGMP. Suspected,
falsified, altered records should be investigated with the problem’s
scope, root cause, risk assessment and necessary corrective
actions should be initiated and documented. FDA authority has
all the rights to scrutinize any document in the industry since the
industry plans drug products approved to be released in the US
market. Pharmaceutical industries establish pre-planned schedules
of internal (inter/intra departmental), external (third party) audits
so as to fulfill customer and regulatory authority audits.
Pharma Times - Vol. 54 - No. 03, March 2022 6
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