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24 BioPharm International eBook October 2020 www.biopharminternational.com Regulatory Sourcebook Data Integrity ensure consistency of results? Qualifying analysts should be the basis for objective testing of color tests. • Do we need objec t ive ev i- dence such as photographic records for some tests, and is color cor rec ted sof t wa re r e q u i r e d ? S o m e m e l t i n g point instruments can record a video of each test so that there is objective rather than subjective evidence of testing that ensure the integrit y of the result. • Classical methods that do not generate elec t ronic records (e.g., LOD) rely on printouts, which requires that the analyt- ical balance is controlled. • Classical methods that gener- ate hybrid records are primar- ily paper based but may have electronic records (e.g., auto-ti- trator procedures linked to a network with manual weigh- ing and sample preparation). • Uncontrolled blank forms used for recording analytical results a nd have t he p otent ia l to allow testing into compliance must be controlled and recon- ciled. This practice is a require- ment in several data integrity guidance documents (4, 5) and has been discussed in publica- tions by the authors (19, 20). Data are required to be attrib- utable, legible, contemporaneous, original, and accurate (ALCOA) a s w e l l a s c o m p l e t e , c o n s i s - te nt , e ndu r i n g , a nd av a i l a ble (A L COA+). T hese requ i rements need to be considered through- out any analytical procedure to ensure the integrity of the data generated and retained. ALCOA re qu i re me nt s a re d i sc u sse d i n FDA, Medicines and Healthcare p r o d u c t s R e g u l a t o r y A g e n c y, and Phar maceutical Inspec tion Co-operation Scheme data integ- r it y g uidance doc uments (2, 4, 5), and a partial attempt at dis- cussing ALCOA+ is presented in the World Health Organization (WHO) guidance (3). This WHO Guide has the best explanation of the ALCOA principles but the + criteria are inferred. The ALCOA+ criteria are defined as follows. T he c o mple te d at a a n a l y t i - ca l record shou ld comply w it h the nine ALCOA+ data integrity r e q u i r e m e nt s a p p l i c a b l e o v e r the data lifecycle outlined in a E u r o p e a n M e d i c i n e s A g e n c y (EMA) ref lection paper on elec- tronic source data (21) and are defined as: • Attributable: Identification of the individual who performed an activity. • L eg ible: Ca n you read a nd understand the electronic data together with any associated metadata or all written entries on paper? Legible should also extend to any original data t hat ha s b e e n c ha nge d or mod if ied by an aut hor ized individual so that the original entry is not obscured. • Contemporaneous: Documented (on paper or electronically) at the time of an activity. • Original: A written observa- tion or printout or a certified copy thereof or an electronic record including all metadata of an activity. • Acc u rate: No er rors i n t he or ig ina l obser vat ion(s) a nd no e d it i n g w it hout do c u - me nte d a me nd me nt s/aud it trail entries by authorized per- sonnel. Accuracy is ensured and verified by documented rev iew includ ing rev iew of audit trails. • Complete: All data from an analysis including any data generated including original data, data before and af ter r e p e at te st i n g , r e a n a ly si s, modification, re-calculation, re-integration, and deletion. For hybrid systems, the paper output must be linked to the underlying electronic records used to produce it. • C o n s i s t e n t : A l l e l e m e n t s of t he pr i m a r y a n a ly t ic a l record, such as the sequence of events, are in sequence and do not contradict each other (i.e., documented chronolog- ically). Data files are date- (all processes) and time- (when using paper, a hybrid, or elec- tronic systems) stamped in the expected order. • Enduring: Recorded on autho- r i z e d me d i a (e.g., l a b or a - tor y notebook s, nu mb ered worksheets for which there is accountability, or electronic media that can last throughout the record retention period). • Available: The complete collec- tion of records can be accessed or retrieved for rev iew and audit or inspection over the lifetime of the record. T hese f irst f ive cr iter ia were developed initially by Stan Wollen, an FDA inspector (ALCOA) (22) and the additional criteria by the EMA when discussing integrity cri- teria for electronic source data from clinical studies (ALCOA+) (21). The complete data analytical record should comply with the nine ALCOA+ data integrity requrements applicable over the data lifecycle.